bluuebunny/crossref_metadata_2025 huggingface dataset:
4-[(4-Hydroxymethyl-2H-1,2,3-triazol-2-yl)methyl]-6-isopropyl-2H-chromen-2-one
Authors: El-Khatatneh Nasseem , Chandra  , Shamala D. , Shivashankar K. , Mahendra M.
Published: December 2016

In the title compound, C16H17N3O3, the chromene ring is planar, with a maximum deviation of 0.017 (4) Å for the ring O atom. The triazole and the chromene rings, bridged by a methylene C atom, are inclined to one another by 78.3 (2)°. In the crystal, methylene–triazole C—H...N hydrogen bonds lead to the formation of helical supramolecular chains along thebaxis. The sample was refined as an inversion twin. The terminal methylhydroxy group is disordered over two sets of sites [site occupancy = 0.610 (13) for the major component].
Ethyl 2-(6-bromo-2-phenyl-3H-imidazo[4,5-b]pyridin-3-yl)acetate
Authors: Hjouji Mohammed Yassin , Mague Joel T. , Kandri Rodi Youssef , Ouzidan Younes , Essassi El Mokhtar
Published: December 2016

The title imidazo [4,5-b] pyridine derivative, C16H14BrN3O2, crystallizes with two independent molecules (1 and 2) in the asymmetric unit. In molecule 1, the pendant phenyl ring is inclined to the imidazo[4,5-b]pyridine core by 43.10 (4)° while in molecule 2 the corresponding angle is 49.43 (4)°. The two molecules differ primarily in the conformations of the ester substituents. In the crystal, molecules are linkedviaC—H...N and C—H...O hydrogen bonds, forming sheets parallel to theabplane.
Pravastatin attenuates the action of the ETS domain‐containing protein ELK1 to prevent atherosclerosis in apolipoprotein E‐knockout mice via modulation of extracellular signal‐regulated kinase 1/2 signal pathway
Authors: Yan Wei , Li Dan , Zhou Xiaoxu
Published: December 2016

Oxidative stress plays an important role in atherosclerosis, a vascular disease with high morbidity and mortality. The ETS domain‐containing protein ELK1 is an oxidative stress‐sensitive factor modulated by the extracellular signal‐regulated kinase (ERK) 1/2 pathway. However, the role of ELK1 in the prevention of atherosclerosis by pravastatin remains unclear. In the present study, male apolipoprotein E‐knockout (apoE−/−) mice fed a diet containing 1.25% cholesterol (w/w) were divided into two groups, one treated with pravastatin (80 mg/kg, 2‐2.4 mg/mouse per day) for 8 weeks and the other not. Male C57BL/6J mice fed with a normal diet were used as a control group. Human umbilical vein endothelial cells (HUVEC) were cultured and treated with pravastatin (10 μmol/L) for 18 hours before testing for the presence or absence of 100 μmol/L H2O2 (24 hours). Examination of pathological sections from mice aortas revealed that pravastatin treatment almost prevented atherosclerotic plaque formation. Pravastatin also inhibited increases in serum and aortic levels of oxidized low‐density lipoprotein and aortic malondialdehyde levels and decreases in aortic reduced glutathione, and the activities of superoxide dismutase, catalase and glutathione peroxidase. H2O2‐induced increases in reactive oxygen species in HUVECs were reversed by pravastatin by 48%. Pravastatin blocked the phosphorylation of ELK1 and ERK1/2 proteins and reduced mRNA levels of early growth response 1, a known atherogenic transcription factor upregulated by the ROS/ERK/ELK1 pathway, in mice. In conclusion, pravastatin attenuates the action of ELK1 induced by oxidative stress to prevent atherosclerosis, which is dependent partly on modulation of ERK1/2 signalling.
Sex differences in ischaemia/reperfusion‐induced acute kidney injury depends on the degradation of noradrenaline by monoamine oxidase
Authors: Tanaka Ryosuke , Yazawa Maki , Morikawa Yuri , Tsutsui Hidenobu , Ohkita Mamoru , Yukimura Tokihito , Matsumura Yasuo
Published: December 2016

Ischaemic acute kidney injury (AKI) is a leading killer of both sexes; however, resistance to this injury is higher among women than men. We found that renal venous noradrenaline (NAd) overflow after reperfusion played important roles in the development of ischaemic AKI, and that the attenuation of AKI observed in female rats may be dependent on depressing the renal sympathetic nervous system with endogenous oestrogen. In the present study, we used male and female Sprague‐Dawley rats to investigate whether sex differences in the pathogenesis of ischaemic AKI are related to the degradation of NAd by monoamine oxidase (MAO) in the kidney. Ischaemic AKI was achieved by clamping the left renal artery and vein for 45 minutes followed by reperfusion 2 weeks after contralateral nephrectomy. Renal injury was more severe in male rats than in female rats and renal venous plasma NAd levels after reperfusion were markedly elevated in males, but not in females. These sex differences were eliminated by a treatment with isatin, a non‐selective MAO inhibitor, and moclobemide, a selective MAOA inhibitor, but not by selegiline, a selective MAOB inhibitor. Ischaemia decreased the mRNA expression levels of both MAOs in the kidney 1 day after reperfusion; however, MAOA mRNA expression levels were higher in female rats than in male rats. These results suggest that the degradation of NAd by MAOA in the kidney contributes to sex differences in the pathogenesis of ischaemia/reperfusion‐induced AKI.
Effects of unilatral‐ and bilateral inhibition of rostral ventral tegmental area and central nucleus of amygdala on morphine‐induced place conditioning in male Wistar rat
Authors: Mohammadian Zahra , Sahraei Hedayat , Meftahi Gholam Hossein , Ali‐Beik Hengameh
Published: December 2016

The rostral ventral tegmental area (VTAR) and central nucleus of amygdala (CeA) are considered the main regions for induction of psychological dependence on abused drugs, such as morphine. The main aim of this study was to investigate the transient inhibition of each right and left side as well as both sides of the VTAR and the CeA by lidocaine (2%) on morphine reward properties using the conditioned place preference (CPP) method. Male Wistar rats (250±20 g) 7 days after recovery from surgery and cannulation were conditioned to morphine (7.5 mg/kg) in CPP apparatus. Five minutes before morphine injection in conditioning phase, lidocaine was administered either uni‐ or bilaterally into the VTAR (0.25 μL/site) or CeA (0.5 μL/site). The results revealed that lidocaine administration into the left side, but not the right side of the VTAR and the CeA reduced morphine CPP significantly. The reduction was potentiated when lidocaine was injected into both sides of the VTAR and the CeA. The number of compartment crossings was reduced when lidocaine was injected into both sides of the VTAR and the CeA as well as the left side. Rearing was reduced when lidocaine was injected into the right, but not the left side of the VTAR. Sniffing and rearing increased when animals received lidocaine in the right side and reduced in the group that received lidocaine in the left side of the CeA. It was concluded that the right and the left side of VTAR and the CeA play different roles in morphine‐induced activity and reward.
Pitavastatin suppresses hyperglycaemia‐induced podocyte injury via bone morphogenetic protein‐7 preservation
Authors: Ohigashi Makoto , Kobara Miyuki , Takahashi Tamotsu , Toba Hiroe , Wada Takehiko , Nakata Tetsuo
Published: December 2016

Podocytes form the essential components of the glomerular filtration barrier and play a critical role in diabetic nephropathy. Recent evidence suggests that HMG‐CoA reductase inhibitors (statins) exert renoprotective effects. We investigated whether pitavastatin directly suppresses hyperglycaemia‐induced podocyte injury using cultured podocytes and, if so, the mechanism of the beneficial effects. Cultured podocytes were exposed to media containing normal (NG; 5 mmol/L) or high (HG; 25 mmol/L) glucose for 1 week. HG increased the lethal injury of podocytes and disruption of F‐actin fibers, and reduced the mRNA expression of novel podocyte markers, synaptopodin and Wilms tumor‐1 (WT‐1), in association with decreased bone morphogenetic protein‐7 (BMP‐7) expression. Pitavastatin (100 nmol/L) reduced podocyte injury and restored the mRNA expression of synaptopodin and WT1; however, these protective effects were abolished by BMP‐7 siRNA. Additionally, pitavastatin suppressed HG‐induced Rho kinase activation, as assessed by the phosphorylation level of myosin phosphatase targeting subunit 1 (MYTP1), and C3 exotoxin, a Rho inhibitor, mimicked the effect of pitavastatin on BMP‐7 preservation. Pitavastatin attenuates hyperglycaemia‐induced podocyte injury via Rho‐Rho kinase‐dependent BMP‐7 preservation.
Spanish‐Speaking Immigrants’ Access to Safety Net Providers and Translation Services Across Traditional and Emerging US Destinations
Authors: NATHENSON ROBERT A. , SALONER BRENDAN , RICHARDS MICHAEL R. , RHODES KARIN V.
Published: December 2016

Policy Points:

Latino immigrants have recently spread beyond traditional US enclaves to “emerging destinations.” The arrival of limited English proficiency (LEP) Spanish‐speakers to these areas can challenge the health care system, as translation services may not be readily available for LEP patients.

Trained auditors posed as family members of LEP patients seeking primary care in a safety net setting. We found substantially lower appointment availability for LEP adults in emerging destinations compared to traditional destinations.

Greater bilingual resources are needed within safety net clinics to accommodate LEP Spanish speakers as this population continues to grow and expand throughout the United States.

Context

Recent demographic trends show Latino immigrants moving to “emerging destinations” outside traditional Latino enclaves. Immigrants in emerging destinations with limited English proficiency (LEP) may experience greater challenges finding health care services oriented to their linguistic needs than those in traditional enclaves, especially if the supply of language resources in these areas has not kept pace with new demand.

Methods

This study uses an experimental audit design to directly compare the ability of uninsured Spanish‐speaking LEP adults to access interpreter services and to obtain new patient primary care appointments at federally qualified health centers (FQHCs) across traditional and emerging destinations. We additionally compare the appointment rates of English‐proficient uninsured and English‐proficient Medicaid patients across these destinations that contacted the same FQHCs. English‐proficient patients serve as an access benchmark that is independent of differences in Spanish language services.

Findings

Results indicate that LEP Spanish‐speaking patients within emerging destinations are 40 percentage points less likely to receive an appointment than those in traditional destinations. English‐proficient groups, by contrast, experience similar levels of access across destinations. Disparities in safety net provider access by destination status are consistent with differences in the availability of bilingual services. Ninety‐two percent of FQHCs in traditional destinations offered appointments with either Spanish‐speaking clinicians or translation services with non‐clinical bilingual staff, while only 54% did so in emerging destinations. LEP patients denied care in emerging destinations must also travel greater distances than in traditional destinations to reach the next available safety net provider.

Conclusions

Our findings highlight that current language resources in emerging destinations may be inadequate for keeping up with the transforming needs of the patient population. As the Latino immigrant population continues to expand and diffuse, better accommodation within the health care safety net is likely to increase in importance.
Differential Sensitivity to Ethanol‐Induced Circadian Rhythm Disruption in Adolescent and Adult Mice
Authors: Ruby Christina L. , Palmer Kaitlyn N. , Zhang Jiawen , Risinger Megan O. , Butkowski Melissa A. , Swartzwelder H. Scott
Published: December 2016

Background

Growing evidence supports a central role for the circadian system in alcohol use disorders, but few studies have examined this relationship during adolescence. In mammals, circadian rhythms are regulated by the suprachiasmatic nucleus, a biological clock whose timing is synchronized (reset) to the environment primarily by light (photic) input. Alcohol (ethanol [EtOH]) disrupts circadian timing in part by attenuating photic phase‐resetting responses in adult rodents. However, circadian rhythms change throughout life and it is not yet known whether EtOH has similar effects on circadian regulation during adolescence.

Methods

General circadian locomotor activity was monitored in male C57BL6/J mice beginning in adolescence (P27) or adulthood (P61) in a 12‐hour light, 12‐hour dark photocycle for ~2 weeks to establish baseline circadian activity measures. On the day of the experiment, mice received an acute injection of EtOH (1.5 g/kg, i.p.) or equal volume saline 15 minutes prior to a 30‐minute light pulse at Zeitgeber Time 14 (2 hours into the dark phase) and then were released into constant darkness (DD) for ~2 weeks to assess phase‐resetting responses. Control mice of each age‐group received injections but no light pulse prior to DD.

Results

While adults showed the expected decrease in photic phase‐delays induced by acute EtOH, this effect was absent in adolescent mice. Adolescents also showed baseline differences in circadian rhythmicity compared to adults, including advanced photocycle entrainment, larger photic phase‐delays, a shorter free‐running (endogenous) circadian period, and greater circadian rhythm amplitude.

Conclusions

Collectively, our results indicate that adolescent mice are less sensitive to the effect of EtOH on circadian photic phase‐resetting and that their daily activity rhythms are markedly different than those of adults.
Endometriosis‐associated infertility: aspects of pathophysiological mechanisms and treatment options
Authors: Tanbo Tom , Fedorcsak Peter
Published: December 2016

Endometriosis is a common condition in women of reproductive age. In addition to pain, endometriosis may also reduce fertility. The causes of infertility in women with endometriosis may range from anatomical distortions due to adhesions and fibrosis to endocrine abnormalities and immunological disturbances. In some cases, the various pathophysiological disturbances seem to interact through mechanisms so far not fully understood. Whether surgery should be offered as a treatment option in endometriosis‐associated infertility has become controversial, partly due to its modest or undocumented effect. Medical or hormonal treatment alone has little or no effect and should only be used in conjunction with assisted reproductive technology (ART). Of the various methods of ART, intrauterine insemination, due to its simplicity, can be recommended in women with minimal or mild peritoneal endometriosis, even though insemination may yield a lower success rate than in women without endometriosis. In vitro fertilization (IVF) is an effective treatment option in less‐advanced disease stages, and the success rates are similar to the results in other causes of infertility. However, women with more advanced stages of endometriosis have lower success rates with IVF.
The dysregulated brain: consequences of spatial and temporal brain complexity for bipolar disorder pathophysiology and diagnosis
Authors: Haarman Bartholomeus CM (‘Benno’) , Riemersma‐Van der Lek Rixt F , Burger Huibert , Drexhage Hemmo A , Nolen Willem A
Published: December 2016

Increasingly, evidence has been accumulating emphasizing the importance of looking at bipolar disorder (BD) from a neurodevelopmental and transdimensional perspective to better understand its origins and its course. In this overview article, the problems facing pathophysiological psychiatric research in BD are addressed and interpreted in the light of brain complexity. Brain complexity can be split into spatial complexity, which constitutes the physiological levels of the central nervous system (i.e., the genetic, molecular, cellular, neuronal circuit and phenomenological levels), and temporal complexity, that is, neurodevelopment. The consequences of this consideration are discussed and suggestions for clinical practice and pathophysiological psychiatric research are made.
Distance stability analysis in multidimensional scaling using the jackknife method
Authors: Vera José Fernando
Published: December 2016

Stability or sensitivity analysis is an important topic in data analysis that has received little attention in the application of multidimensional scaling (MDS), for which the only available approaches are given in terms of a coordinate‐based analytical jackknife methodology. Although in MDS the prime interest is in assessing the stability of the points in the configuration, this methodology may be influenced by imprecisions resulting from the inherently necessary Procrustes method. This paper proposes an analytical distance‐based jackknife procedure to study stability and cross‐validation in MDS in terms of the jackknife distances, which is not influenced by the Procrustes method. For each object, the corresponding jackknife estimated points are considered as naturally clustered points, and stability and cross‐validation are analysed in terms of the MDS distances arising from the jackknife procedure, on the basis of a weighted cluster‐MDS algorithm. A jackknife‐relevant configuration is also proposed for cross‐validation in terms of coordinates, in a cluster‐MDS framework.
Mannoside recognition and degradation by bacteria
Authors: Ladevèze Simon , Laville Elisabeth , Despres Jordane , Mosoni Pascale , Potocki‐Véronèse Gabrielle
Published: December 2016

ABSTRACT

Mannosides constitute a vast group of glycans widely distributed in nature. Produced by almost all organisms, these carbohydrates are involved in numerous cellular processes, such as cell structuration, protein maturation and signalling, mediation of protein–protein interactions and cell recognition. The ubiquitous presence of mannosides in the environment means they are a reliable source of carbon and energy for bacteria, which have developed complex strategies to harvest them. This review focuses on the various mannosides that can be found in nature and details their structure. It underlines their involvement in cellular interactions and finally describes the latest discoveries regarding the catalytic machinery and metabolic pathways that bacteria have developed to metabolize them.
ENRI: A tool for selecting structure‐based virtual screening target conformations
Authors: Akbar Rahmad , Jusoh Siti Azma , Amaro Rommie E. , Helms Volkhard
Published: December 2016

Finding pharmaceutically relevant target conformations from an arbitrary set of protein conformations remains a challenge in structure‐based virtual screening (SBVS). The growth in the number of available conformations, either experimentally determined or computationally derived, obscures the situation further. While the inflated conformation space potentially contains viable druggable targets, the increase of conformational complexity, as a consequence, poses a selection problem. To address this challenge, we took advantage of machine learning methods, namely an over‐sampling and a binary classification procedure, and present a novel method to select druggable receptor conformations. Specifically, we trained a binary classifier on a set of nuclear receptor conformations, wherein each conformation was labeled with an enrichment measure for a corresponding SBVS. The classifier enabled us to formulate suggestions and identify enriching SBVS targets for six of seven nuclear receptors. Further, the classifier can be extended to other proteins of interest simply by feeding new training data sets to the classifier. Our work, thus, provides a methodology to identify pharmaceutically interesting receptor conformations for nuclear receptors and other drug targets.
Influence of misfit on the occurrence of veneering porcelain fractures (chipping) in implant‐supported metal‐ceramic fixed dental prostheses: an in vitro pilot trial
Authors: Löfgren Nils , Larsson Christel , Mattheos Nikos , Janda Martin
Published: December 2016

Objective

Technical complications such as veneer fractures are more common in implant‐supported than tooth‐supported restorations. The underlying causes have not been fully identified. The aim of this study was to evaluate whether misfit between the restoration and the implant may affect the risk of veneer fractures.

Materials and methods

Twenty standardized five‐unit implant‐supported metal‐ceramic fixed dental prostheses (FDP)s were manufactured and fixed in acrylic blocks. The test group consisted of ten FDPs fixed with a 150‐μm misfit at the distal abutment. The remaining ten FDPs were fixed without misfit and acted as a control group. All FDPS underwent cyclic loading for a total of 100,000 cycles at 30‐300 N. The FDPs were checked for cracks or chip‐off fractures regularly. After cyclic load, the retorque value of all abutment screws was checked.

Results

Cracks within the veneering porcelain were noted in nine FDPs in the test group and one FDP in the control group. This difference was statistically significant (P < 0.001). Fractures of the veneering porcelain occurred in three FDPs in the test group. No fractures occurred in the control group. This difference was not statistically significant. There were no significant differences in retorque values neither between the groups nor between different abutment positions in the FDPs.

Conclusions

Within the limitations of this in vitro pilot trial, it is suggested that misfit between a restoration and the supporting implant may increase the risk of cracking and/or chipping of the veneering porcelain for metal‐ceramic FDPs.
Transformation of Experience: Toward a New Relationship with Nature
Authors: Clayton Susan , Colléony Agathe , Conversy Pauline , Maclouf Etienne , Martin Léo , Torres Ana‐Cristina , Truong Minh‐Xuan , Prévot Anne‐Caroline
Published: December 2016

Despite decades of awareness about the biodiversity crisis, it remains a wicked problem. Besides preservation and restoration strategies, one approach has focused on increasing public concern about biodiversity issues by emphasizing opportunities for people to experience natural environments. In this article, we endeavor to complicate the understanding of these experiences of nature (EoN). Because EoN are embedded in social and cultural contexts, transformative or new EoN are emerging in combination with societal changes in work, home, and technology. Policies that acknowledge and accept a diversity of culturally situated EoN, including negative EoN, could help people reconnect with the complexity and dynamics of biodiversity. A new conceptualization of EoN that encompasses diverse experiences and reflects the sociocultural context could help to stimulate a broader transformation in the relationship between society and nature, one that better integrates the two spheres. Such a transformation is necessary to more effectively address the biodiversity crisis.
Is oxygen saturation variable of simplified pulmonary embolism severity index reliable for identification of patients, suitable for outpatient treatment
Authors: Erol Serhat , Gürün Kaya Aslıhan , Arslan Ciftçi Fatma , Çiledağ Aydın , Şen Elif , Kaya Akın , Çelik Gökhan , Savaş İsmail
Published: December 2016

Introduction

The pulmonary embolism severity index (PESI) or simplified version (sPESI) are widely validated risk scores for the identification of eligible patients for outpatient treatment. Saturation is one of these criteria. For this metric, saturation of 90% or greater is assigned zero points. However, 90% saturation does not always exclude hypoxemic respiratory failure.

Objective

The aims of this study were first was to define corresponding partial arterial oxygen pressure (PaO2) values according to saturation in pulmonary embolism (PE) patients, and the second was to define a target saturation that can exclude hypoxemic respiratory failure and enable secure discharge of PE patients from emergency departments.

Methods

This is a retrospective study. To determine the optimal saturation value by which to detect hypoxemic respiratory failure, we generated receiver operating characteristic (ROC) curves and calculated the negative predictive value.

Results

Total of 65 patients were included in this study. Mean PaO2 levels from SaO2 89% to SaO2 93% were 52.8, 57.1, 57.3, 61, and 63.8 mmHg, respectively. ROC curve analysis revealed SaO2 level of 91.5% to be optimal target saturation for excluding respiratory failure with 84.6% specificity and 89.7% sensitivity; area under the curve was 0.885 (95% CI 0.796‐0.975). The negative predictive value was 80% for SaO2 level of 92%.

Conclusion

Patients with PE may be in respiratory failure despite an oxyhemoglobin saturation of ≥90%. Although saturation is likely more important than precise PaO2 in tissue oxygenation, clinicians should be aware of the physiological effects of hypoxemia and take this into account before making outpatient treatment decisions.
Reverse Translational Study of Fenofibrate's Observed Effects in Diabetes‐Associated Retinopathy
Authors: Farris RA , Price ET
Published: December 2016

Clinical trials suggest that fenofibrate reduces the progression of retinopathies in patients with type 2 diabetes. Furthermore, patients with retinopathies have elevated levels of inflammatory chemokines and dysfunctional retinal angiogenesis. Therefore, we investigated the effects of fenofibrate on the production of inflammatory chemokines and genes associated with angiogenesis. Retinal pigment epithelial cells (RPECs) were cultured with IL‐1β and fenofibrate ranging from 1–50 μM. ENA‐78, IL‐8, and RANTES were measured in cell culture by ELISA. ENA‐78, ABCA1, and ABCG1 gene expression were tested by RT‐PCR. IL‐1β significantly induced the production of ENA‐78, IL‐8, and RANTES. Fenofibrate at concentrations of 25–50 uM blunted the IL‐1β induced production of ENA‐78 (p < 0.05) with no significant effects on RANTES and IL‐8. Fenofibrate also reduced the expression of the ENA‐78 gene as well as ABCA1 and ABCG1, which are genes involved in angiogenesis. Fenofibrate decreases ENA‐78 production and ABCA1/ABCG1 gene expression in RPECs.
Evolutionary history of the endangered shrub snapdragon (Galvezia leucantha) of the Galápagos Islands
Authors: Guzmán Beatriz , Heleno Ruben , Nogales Manuel , Simbaña Walter , Traveset Anna , Vargas Pablo
Published: December 2016

Aim

The endangered Galápagos shrub snapdragon (Galvezia leucantha, Antirrhineae, Plantaginaceae) is restricted to small populations on four islands. In this study, we appraised results from taxonomy, genetics, phylogenetics, phylogeography and pollination ecology to reconstruct the evolutionary history of the genus Galvezia.

Location

Peru, continental Ecuador and Galápagos.

Methods

We sequenced the nuclear ribosomal ITS and two plastid regions, ndhF and ndhF‐rpL32, to infer the origin of Galvezia and patterns of colonization to and across the Galápagos archipelago, based on Bayesian inference and statistical parsimony analyses. To investigate genetic diversity and differentiation within G. leucantha, we screened the genome of six populations and obtained 194 AFLP fingerprints. Autogamy tests and pollination network analyses were performed to evaluate the colonization potential and to investigate the structure of the pollinators’ assemblage of Galvezia.

Results

Relationships of seven nucleotide‐substitution haplotypes and 11 nucleotide‐substitution ribotypes of Galvezia revealed monophyly for the Galapagos species. Dating estimates indicated divergence of the insular Galvezia lineage in the Middle‐Upper Pleistocene (0.66–0.09 Ma). In addition, distribution of genotypes (seven haplotypes, eight ribotypes) across the three continental species showed geographical differentiation, while low differentiation and distribution of G. leucantha. AFLP genetic diversity is relatively high (HT = 0.109), but a low proportion of the total allelic variance is attributed to variation among subspecies/islands (Hb = 0.035, hierarchical AMOVA: 3.77% of total variance). The endemic bee (Xylocopa darwinii) accounted for 87.30% of the floral visits to G. leucantha.

Main conclusions

We inferred a single origin for an insular lineage that colonized the Galápagos Islands from northern Peru in the Pleistocene. Recent colonization of the archipelago, Pleistocene land bridges between islands and active gene flow promoted by X. darwinii may account for the low‐moderate genetic differentiation of G. leucantha subspecies. An unusual pollination shift from ornithophily (hummingbirds on the continent) to entomophily (Xylocopa in the Galápagos Islands) is supported.
Treatment of prednisolone‐induced hyperglycaemia in hospitalized patients: Insights from a randomized, controlled study
Authors: Radhakutty Anjana , Stranks Jessica L. , Mangelsdorf Brenda L. , Drake Sophie M. , Roberts Gregory W. , Zimmermann Anthony T. , Stranks Stephen N. , Thompson Campbell H. , Burt Morton G.
Published: December 2016

Aim

Prednisolone causes hyperglycaemia predominantly between midday and midnight. Consequently, glargine‐based basal‐bolus insulin regimens may under treat daytime hyperglycaemia and cause nocturnal hypoglycaemia. We investigated whether an isophane‐based insulin regimen is safer and more effective than a glargine‐based regimen in hospitalized patients.

Materials and methods

Fifty inpatients prescribed ≥20 mg/day prednisolone acutely with (1) finger prick blood glucose level (BGL) ≥15 mmol/L or (2) BGLs ≥10 mmol/L within the previous 24 hours were randomized to either insulin isophane or glargine before breakfast and insulin aspart before meals. The initial daily insulin dose was 0.5 U/kg bodyweight or 130% of the current daily insulin dose. Glycaemic control was assessed using a continuous glucose monitoring system.

Results

On Day 1, there were no significant differences in percentage of time outside a target glucose range of 4 to 10 mmol/L (41.3% ± 5.5% vs 50.0% ± 5.7%,
P
 = .28), mean daily glucose (10.2 ± 0.7 vs 10.8 ± 0.8 mmol/L,
P
 = .57) or glucose <4 mmol/L (2.2% ± 1.1% vs 2.0% ± 1.3%,
P
 = .92) in patients randomized to isophane and glargine. In patients treated for 3 days, the prednisolone dose was reduced (
P
 = .02) and the insulin dose was increased over time (
P
 = .02), but the percentage of time outside the 4 to 10 mmol/L glucose range did not differ over time (
P
 = .45) or between groups (
P
 = .24).

Conclusions

There were no differences in the efficacy or safety of the isophane and glargine‐based insulin regimens. We recommend an initial daily insulin dose of 0.5 units/kg bodyweight if not on insulin, a greater than 30% increase in pre‐prednisolone insulin dose and larger insulin dose adjustments in patients with prednisolone‐induced hyperglycaemia.
MasterOnline Periodontology and Implant Therapy—revisited after seven years: A case study of the structures and outcomes in a blended learning CPD
Authors: Ratka‐Krüger P. , Wölber J. P. , Blank J. , Holst K. , Hörmeyer I. , Vögele E.
Published: December 2016

Introduction

There is a great need for postgraduate training and continuing professional development (CPD), specifically in the field of periodontology. Despite the plenty of periodontal CPDs, there is a lack of information about the performance of CPDs in a blended learning setting. This study is a case study of the structures and outcomes in a blended learning CPD programme in periodontology, the MasterOnline Periodontology and Implant Therapy hosted by the University of Freiburg's Dental School.

Material and Methods

The structures of the blended learning CPD were analysed with the aims to (i) make explicit how various innovative educational methods and ICT tools can be successfully applied to a Web‐supported postgraduate periodontology training programme, (ii) identify the programme's impact on learning transfer in students' dental practices and (iii) identify other outcomes, synergies and any changes required during the existence. Using qualitative interviewing, the various types of learning transfer and elements of the study programme that foster transfer could be exemplified.

Results

A period of 7 years was analysed. In this duration, 50 students successfully graduated to a master of science. Qualitative interviews were performed with six students and four teachers affirming the learning transfer in a blended learning setting.

Conclusions

This case study shows that blended learning can be a successful approach for CPD in dentistry.
Do dental undergraduates think that Thiel‐embalmed cadavers are a more realistic model for teaching exodontia?
Authors: Hanson C. , Wilkinson T. , Macluskey M.
Published: December 2016

Introduction

Teaching exodontia to novice undergraduates requires a realistic model. Thiel‐embalmed cadavers retain the flexibility of the soft tissues and could be used to teach exodontia.

Objective

The objective was to determine whether Thiel‐embalmed cadavers were perceived to be a more realistic model by undergraduates in comparison with mannequins.

Materials and Methods

Over a period of 4 years (2011‐2014), students were randomly assigned into two groups: those taught exodontia on mannequins only (NT) and those who also experienced cadaveric teaching (T). This was followed by an assessment.

Results

There were 174 students in the T group and 108 in the NT group. Sixty‐five per cent of the T group and 69% of the NT group provided feedback. Ninety‐eight per cent (98%) felt that they had been advantaged by being included in the group compared with 95% in the NT who felt disadvantaged. The majority (98%) thought that using the cadavers was advantageous and gave a realistic feel for soft tissue management (89%) and that it was similar to managing a patient (81%). Self‐reported confidence in undertaking an extraction was not different between the two groups (P=.078), and performance in the extraction assessment was not significantly different between the two groups over the 4 years (P=.8).

Conclusion

The Thiel‐embalmed cadavers were well received by the students who found it a more realistic model for exodontia than a mannequin, even though this did not impact on their performance in a following assessment. Future work on these cadavers may be expanded to include surgical procedures.
Dental students' perceptions on the contribution and impact role of a clinical teacher
Authors: Shoaib L. A. , Safii S. H. , Naimie Z. , Ahmad N. A. , Sukumaran P. , Yunus R. M.
Published: December 2016

Objectives

This study was conducted in University of Malaya to evaluate student perceptions on the contribution and role of an effective clinical teacher based on the cognitive apprenticeship model in clinical practice.

Methods

Self‐administered questionnaires were distributed to 233 undergraduate dental students involved with clinical teaching. This modified and validated questionnaire focusing on students' learning environment was used in order to gain relevant information related to dental clinical teaching. Six domains with different criteria applicable to clinical teaching in dentistry were selected consisting of modelling (four criteria), coaching (four criteria), scaffolding (four criteria), articulation (four criteria), reflection (two criteria) and general learning environment (six criteria). Data analyses were performed using IBM SPSS Statistics 20.

Results

Majority of the students expressed positive perceptions on their clinical learning experience towards the clinical teachers in the Faculty of Dentistry, University of Malaya, in all criteria of the domains. Few negative feedbacks concerning the general learning environment were reported.

Conclusion

Further improvement in the delivery of clinical teaching preferably by using wide variety of teaching–learning activities can be taken into account through students' feedback on their learning experience.
Intrafibrillar mineralization of polyacrylic acid‐bound collagen fibrils using a two‐dimensional collagen model and Portland cement‐based resins
Authors: Wu Shiyu , Gu Lisha , Huang Zihua , Sun Qiurong , Chen Huimin , Ling Junqi , Mai Sui
Published: December 2016

The biomimetic remineralization of apatite‐depleted dentin is a potential method for enhancing the durability of resin–dentin bonding. To advance this strategy from its initial proof‐of‐concept design, we sought to investigate the characteristics of polyacrylic acid (PAA) adsorption to desorption from type I collagen and to test the mineralization ability of PAA‐bound collagen. Portland cement and β‐tricalcium phosphate (β‐TCP) were homogenized with a hydrophilic resin blend to produce experimental resins. The collagen fibrils reconstituted on nickel (Ni) grids were mineralized using different methods: (i) group I consisted of collagen treated with Portland cement‐based resin in simulated body fluid (SBF); (ii) group II consisted of PAA‐bound collagen treated with Portland cement‐based resin in SBF; and (iii) group III consisted of PAA‐bound collagen treated with β‐TCP‐doped Portland cement‐based resin in deionized water. Intrafibrillar mineralization was evaluated using transmission electron microscopy. We found that a carbonyl‐associated peak at pH 3.0 increased as adsorption time increased, whereas a hydrogen bond‐associated peak increased as desorption time increased. The experimental resins maintained an alkaline pH and the continuous release of calcium ions. Apatite was detected within PAA‐bound collagen in groups II and III. Our results suggest that PAA‐bound type I collagen fibrils can be mineralized using Portland cement‐based resins.
Quadrilateral suspensory and straight sesamoidean ligament calcifying desmopathy in an Arabian mare
Authors: Hui S. K. Y. , Turner S. J. , Leaman T. R. , de Brot S. , Barakzai S. Z.
Published: December 2016

A 5‐year‐old Arabian mare was referred for the investigation of recent behavioural change, generalised stiffness, and owner‐reported polyuria and polydipsia. Clinical examination revealed severe pain associated with palpation along the entire length of the suspensory ligament (SL) and palmar soft tissues of the pastern regions of both forelimbs. Radiographs of the distal forelimbs demonstrated marked radiopaque striations within the straight sesamoidean ligaments (SSLs), and less severe but similar changes in the regions of the SL branches. Ultrasonography of both distal forelimbs revealed multifocal, hyperechoic lesions within the SSLs. The SL bodies and branches were enlarged and had mixed echogenicity on ultrasound scan. The horse was subjected to euthanasia at the owner's request and submitted for post‐mortem examination. Relevant gross findings were restricted to the SLs and SSLs of all four limbs, all of which contained severe mineralisation and irregularly arranged fibres. Histological examination revealed severe, multifocal to coalescing, dystrophic mineralisation with cartilaginous and osseous metaplasia, which suggested a primary calcifying desmopathy affecting all four SLs and SSLs. Clinical findings in the case reported here were similar to that of degenerative suspensory ligament desmitis previously reported by many authors, but diagnostic imaging and histopathological findings were significantly different.
Digital imaging biomarkers feed machine learning for melanoma screening
Authors: Gareau Daniel S. , Correa da Rosa Joel , Yagerman Sarah , Carucci John A. , Gulati Nicholas , Hueto Ferran , DeFazio Jennifer L. , Suárez‐Fariñas Mayte , Marghoob Ashfaq , Krueger James G.
Published: December 2016

We developed an automated approach for generating quantitative image analysis metrics (imaging biomarkers) that are then analysed with a set of 13 machine learning algorithms to generate an overall risk score that is called a Q‐score. These methods were applied to a set of 120 “difficult” dermoscopy images of dysplastic nevi and melanomas that were subsequently excised/classified. This approach yielded 98% sensitivity and 36% specificity for melanoma detection, approaching sensitivity/specificity of expert lesion evaluation. Importantly, we found strong spectral dependence of many imaging biomarkers in blue or red colour channels, suggesting the need to optimize spectral evaluation of pigmented lesions.
Severe excessive daytime sleepiness induced by hydroxyurea
Authors: Revol Bruno , Joyeux‐Faure Marie , Albahary Marie‐Victoire , Gressin Remy , Mallaret Michel , Pepin Jean‐Louis , Launois Sandrine H.
Published: December 2016

Excessive daytime sleepiness (EDS) has been reported with many drugs, either as an extension of a hypnotic effect (e.g. central nervous system depressants) or as an idiosyncratic response of the patient. Here, we report unexpected and severe subjective and objective EDS induced by hydroxyurea therapy, with a favorable outcome after withdrawal. Clinical history, sleep log, polysomnography, and multiple sleep latency tests confirming the absence of other EDS causes are presented.
Uncovering the spatial heterogeneity of Ediacaran carbon cycling
Authors: Li C. , Hardisty D. S. , Luo G. , Huang J. , Algeo T. J. , Cheng M. , Shi W. , An Z. , Tong J. , Xie S. , Jiao N. , Lyons T. W.
Published: December 2016

Records of the Ediacaran carbon cycle (635–541 million years ago) include the Shuram excursion (SE), the largest negative carbonate carbon isotope excursion in Earth history (down to −12‰). The nature of this excursion remains enigmatic given the difficulties of interpreting a perceived extreme global decrease in the δ13C of seawater dissolved inorganic carbon. Here, we present carbonate and organic carbon isotope (δ13Ccarb and δ13Corg) records from the Ediacaran Doushantuo Formation along a proximal‐to‐distal transect across the Yangtze Platform of South China as a test of the spatial variation of the SE. Contrary to expectations, our results show that the magnitude and morphology of this excursion and its relationship with coexisting δ13Corg are highly heterogeneous across the platform. Integrated geochemical, mineralogical, petrographic, and stratigraphic evidence indicates that the SE is a primary marine signature. Data compilations demonstrate that the SE was also accompanied globally by parallel negative shifts of δ34S of carbonate‐associated sulfate (CAS) and increased 87Sr/86Sr ratio and coastal CAS concentration, suggesting elevated continental weathering and coastal marine sulfate concentration during the SE. In light of these observations, we propose a heterogeneous oxidation model to explain the high spatial heterogeneity of the SE and coexisting δ13Corg records of the Doushantuo, with likely relevance to the SE in other regions. In this model, we infer continued marine redox stratification through the SE but with increased availability of oxidants (e.g., O2 and sulfate) limited to marginal near‐surface marine environments. Oxidation of limited spatiotemporal extent provides a mechanism to drive heterogeneous oxidation of subsurface reduced carbon mostly in shelf areas. Regardless of the mechanism driving the SE, future models must consider the evidence for spatial heterogeneity in δ13C presented in this study.
River Seepage Conductance in Large‐Scale Regional Studies
Authors: Morel‐Seytoux Hubert J. , Miller Calvin D. , Miracapillo Cinzia , Mehl Steffen
Published: December 2016

Flow exchange between surface and groundwater is of great importance be it for beneficial allocation and use of water resources or for the proper exercise of water rights. In large‐scale regional studies, most numerical models use coarse grid sizes, which make it difficult to provide an accurate depiction of the phenomenon. In particular, a somewhat arbitrary leakance coefficient in a third type (i.e., Cauchy, General Head) boundary condition is used to calculate the seepage discharge as a function of the difference of head in the river and in the aquifer, whose value is often found by calibration. A different approach is presented to analytically estimate that leakance coefficient. It is shown that a simple equivalence can be deduced from the analytical solution for the empirical coefficient, so that it provides the accuracy of the analytical solution while the model maintains a very coarse grid, treating the water‐table aquifer as a single calculation layer. Relating the empirical leakance coefficient to the exact conductance, derived from physical principles, provides a physical basis for the leakance coefficient. Factors such as normalized wetted perimeter, degree of penetration of the river, presence of a clogging layer, and anisotropy can be included with little computational demand. In addition the river coefficient in models such as MODFLOW, for example, can be easily modified when grid size is changed without need for recalibration.
Kinetic analysis and binding studies of a new recombinant human factor VIIa for treatment of haemophilia
Authors: Grandoni J. , Perret G. , Forier C.
Published: December 2016

Introduction/Aim

LR769 is a new second‐generation recombinant human Factor VIIa (rhFVIIa) developed for haemophilia treatment. We determined enzymatic properties of LR769 and its interaction with antithrombin, tissue factor, platelets and endothelial protein C receptor (EPCR), compared with NovoSevenRT.

Methods

Kinetic enzyme assays and active site titration were used for enzymatic studies. Surface Plasmon Resonance (SPR) was used for determination of binding constants. Cellular binding was determined for platelets and cultured human umbilical vein endothelial cells (HUVEC).

Results

The dissociation constant (Kd) for activated platelet binding was in the 1 μm range for both products. At saturation, more LR769 than NovoSevenRT was bound to the platelets. Binding to HUVEC was 25–50% higher for LR769 than for NovoSevenRT. Protein C, soluble EPCR, and anti‐EPCR antibody all reduced the binding, indicating specificity for EPCR. LR769 was similar to NovoSevenRT in all kinetic assays. Active site titration demonstrated 0.7 mole of active site/mole of protein. The kcat/Km values for activation of FX and FIX with purified recombinant tissue factor and phospholipids were 10.5 s−1/0.32 μm and 3.3 s−1/0.44 μm respectively. The apparent second‐order rate constant for inactivation by human plasma AT was 5.9 ± 0.4 × 103 m−1 s−1. The Kd values for binding of LR769 to soluble tissue factor and full‐length tissue factor were 8.1 nm and 0.9 nm, respectively, and the Kd for binding to soluble EPCR was 41 nm.

Conclusion

Overall, LR769 exhibited characteristics similar to NovoSevenRT, but bound EPCR on HUVEC with somewhat higher affinity than NovoSevenRT.
BAY 81‐8973, a full‐length recombinant factor VIII: manufacturing processes and product characteristics
Authors: Garger S. , Severs J. , Regan L. , Hesslein A. , Ignowski J. , Wu P. , Long E. , Gupta S. , Liu S. , Wang W.
Published: December 2016

BAY 81‐8973 (Kovaltry®, Bayer, Berkeley, CA, USA) is an unmodified, full‐length recombinant human factor VIII (FVIII) approved for prophylaxis and on‐demand treatment of bleeding episodes in patients with haemophilia A. The BAY 81‐8973 manufacturing process is based on the process used for sucrose‐formulated recombinant FVIII (rFVIII‐FS), with changes and enhancements made to improve production efficiency, further augment pathogen safety, and eliminate animal‐ and human‐derived raw materials from the production processes. The baby hamster kidney cell line used for BAY 81‐8973 was developed by introducing the gene for human heat shock protein 70 into the rFVIII‐FS cell line, a change that improved cell line robustness and productivity. Pathogen safety was enhanced by including a 20‐nm filtration step, which can remove viruses, transmissible spongiform encephalopathy agents and potential protein aggregates. No human‐ or animal‐derived proteins are added to the cell culture process, purification or final formulation. The BAY 81‐8973 manufacturing process results in a product of enhanced purity with a consistently high degree of sialylation of N‐linked glycans on the molecular surface. The innovative manufacturing techniques used for BAY 81‐8973 yield an effective rFVIII product with a favourable safety profile for treatment of haemophilia A.