bluuebunny/crossref_metadata_2025 huggingface dataset:
Hydrodynamics selects the pathway for displacive transformations in DNA-linked colloidal crystallites
Authors: Jenkins Ian C. , Casey Marie T. , McGinley James T. , Crocker John C. , Sinno Talid
Published: March 2014

Significance

The use of single-stranded DNA oligomers grafted onto submicron particles to drive interparticle interactions is a versatile technique for assembly. Although progress has been made in the attainable structural complexity, whether these assemblies are kinetically arrested or dynamically reconfigurable materials is not well understood. Here, we study the mechanism responsible for recently observed diffusionless transformations in DNA-assembled colloidal crystallites. We discover that hydrodynamic forces act to establish diffusional anisotropy that selects for specific child structures, consistent with experimental observations. The notion that hydrodynamic correlations play a significant role in such transformations provides evidence that DNA-linked particle assemblies are not simple thermodynamic constructs but, like many other materials of technological interest, require the simultaneous consideration of process and properties.
Disentangling neural representations of value and salience in the human brain
Authors: Kahnt Thorsten , Park Soyoung Q , Haynes John-Dylan , Tobler Philippe N.
Published: March 2014

Significance

The value and salience of predictive cues are important signals for regulating approach–avoidance behavior and attentional processing, respectively. However, the two signals often are confounded in studies of decision-making. Indeed, recent results suggest that neural signals in the primate posterior parietal cortex (PPC) which previously were thought to encode value actually reflect salience. This finding has created considerable uncertainty about previously identified value signals. Here we experimentally dissociate value and salience and use pattern-based functional MRI to demonstrate distinct encoding of both signals in the PPC, thereby reinforcing the earlier reports of value in the PPC. Moreover, we show that the orbitofrontal cortex encodes the predicted value of appetitive and aversive outcomes on a common neural scale.
On the mechanism of photoinduced dimer dissociation in the plant UVR8 photoreceptor
Authors: Voityuk Alexander A. , Marcus Rudolph A. , Michel-Beyerle Maria-Elisabeth
Published: March 2014

Significance

In contrast to other chromophore/protein systems in photobiology, the UV-B photoreceptor UV resistance locus 8 (UVR8) utilizes tryptophan residues as light absorbers. The initial step of a signaling pathway that ultimately leads to UV-B protection and damage repair in plants is the breaking of salt bridges that stabilize the UVR8 protein consisting of two identical subunits. On the basis of the known X-ray structure and high-level quantum-chemical computations, we propose a mechanism that implies excitation energy transfer to the “special tryptophan” W233 near the monomer interface, followed by the formation of a charge-transfer state involving W233 and W285. In the calculations, the large dipole moment of W233(−)-W285(+) facilitates the breaking of arginine–aspartate salt bridges between the two subunits.
Quantitative theory of entropic forces acting on constrained nucleotide sequences applied to viruses
Authors: Greenbaum Benjamin D. , Cocco Simona , Levine Arnold J. , Monasson Rémi
Published: March 2014

Significance

This paper proposes a simple theory, inspired by statistical mechanics, of the interplay of entropic forces and selective forces on dinucleotide frequencies in viral genomes that occur when a virus migrates to a new host. The theory is quantitatively developed, and leads to many predictions about statistical features of viral evolution. The approach is general, and could be easily extended to other genomic data and have wider applications. For example, an analysis of avian influenza entering the human genome has identified selection against CpG dinucleotides, which have been shown to trigger a response of the innate immune system and interferon production.
Structures of the
Toxoplasma
gliding motility adhesin
Authors: Song Gaojie , Springer Timothy A.
Published: March 2014

Significance

Structures of the major adhesin in
Toxoplasma
show how its ligand-binding domain is displayed above the cell surface at the tip of a stalk with six elongated domains. A prodomain inhibits conformational change from closed to open. An associating protein binds to the most membrane-proximal domain. Comparison with orthologues in
Plasmodium
reveals remarkable specializations as well as similarities between diverse apicomplexans.
The changing nature of European equality regimes: explaining convergence and variation
Authors: Krizsan Andrea , Skjeie Hege , Squires Judith
Published: March 2014

This paper maps the changing nature of European equality regimes in order to establish the extent of variation or convergence across Europe and to evaluate the role of transnational policy paradigms and state-level institutions in shaping the emerging European equality regimes. We identify two significant tendencies in respect to European equality institutional regimes. First, a growing complexity in the institutional arrangements designed to address inequalities, with pre-2000 institutional arrangements increasingly augmented by newer equality institutions that adopt a judicialized approach to dealing with inequalities. Second, a Europe-wide tendency to widen the scope of equality policy thinking from a very small number of privileged inequality grounds (most frequently gender and ethnicity) to a much wider range of inequalities to be addressed by state policies. The overall impact of these two changes has been to create equality regimes characterized by a wide variety of forms and levels of protection for the different inequalities. This suggests that while a transnational policy paradigm has framed the evolving nature of equality regimes across Europe, the implementation of this paradigm is moulded by the power dynamics embedded in national and local equality institutions, creating a fragmented and complex patchwork of equality regimes that defy easy regional classification and complicate overly generalized narratives about the influence of global policy paradigms.
Safety of Cardiac Catheterization at a Center Specializing in the Care of Patients with Pulmonary Arterial Hypertension
Authors: Zuckerman Warren A. , Turner Mariel E. , Kerstein Jason , Torres Alejandro , Vincent Julie A. , Krishnan Usha , Kerstein Diane , Rosenzweig Erika B.
Published: March 2014

Cardiac catheterization is important for the management of patients with pulmonary arterial hypertension (PAH). It is used for diagnosis, assessment, and monitoring of PAH patients, as well as to perform interventions such as balloon atrial septostomy and coil embolization of collateral vessels. Although reports on the risks of catheterization in PAH patients are scarce, many centers hesitate to perform these procedures in such fragile patients. We performed a retrospective chart review of all cardiac catheterizations performed in PAH patients over 10 years at our pulmonary hypertension center. Demographic, hemodynamic, and outcome data were collected. Complication rates were determined, and multivariate proportional hazards modeling was performed to identify predictors of catheterization‐related complications. There were 1,637 catheterizations performed in 607 patients over 10 years. Pediatric patients accounted for 50% of these cases, 48% were performed in patients with idiopathic PAH, and 49% were performed under general anesthesia. While the overall complication rate was 5.7%, the rate of major complications was only 1.2% (n = 20). Although there were 8 deaths during the admission following catheterization, only 4 of these were related to the procedure, yielding a catheterization‐related mortality of 0.2%. In conclusion, when performed at a pulmonary hypertension center with expertise in the care of PAH patients, cardiac catheterization is associated with low complication rates and mortality, and it should remain an important tool in the management of these patients.
Piglet Model of Chronic Pulmonary Hypertension
Authors: Mercier Olaf , Tivane Adriano , Dorfmüller Peter , de Perrot Marc , Raoux François , Decante Benoît , Eddahibi Saadia , Dartevelle Philippe , Fadel Elie
Published: March 2014

None of the animal models have been able to reproduce all aspects of CTEPH because of the rapid resolution of the thrombi in the pulmonary vasculature. The aim of this study was to develop an easily reproducible large‐animal model of chronic pulmonary hypertension (PH) related to the development of a postobstructive and overflow vasculopathy. Chronic PH was induced in 5 piglets by ligation of the left pulmonary artery (PA) through a midline sternotomy followed by weekly transcatheter embolization of the right lower‐lobe arteries. Sham‐operated piglets (n = 5) served as controls. Hemodynamics, RV function, lung morphometry, and endothelin‐1 (ET‐1) pathway gene expression (ET‐1 and its receptors ETA and ETB) were assessed after 5 weeks in the obstructed (left lung and right lower lobe) and unobstructed (right upper lobe) territories. All animals developed chronic PH within 5 weeks. Compared to controls, chronic‐PH animals had higher mean PA pressure (28.5 ± 1.7 vs. 11.6 ± 1.8 mmHg, P = 0.0001) and total pulmonary resistance (784 ± 160 vs. 378 ± 51 dyn s−1 cm−5, P = 0.05). Echocardiography showed RV enlargement, RV wall thickening (56 ± 5 vs. 30 ± 4 mm, P = 0.0003), decreased tricuspid annular plane systolic excursion (11.3 ± 0.9 vs. 14.4 ± 0.4 mm, P = 0.01), and paradoxical septal motion. In obstructed territories, morphometry demonstrated increases in the number of bronchial arteries per bronchus (8.7 ± 0.9 vs. 2 ± 0.17, P < 0.0001) and in distal PA media thickness (60% ± 2.8% vs. 29% ± 0.9%, P < 0.0001), consistent with postobstructive vasculopathy. Distal PA media thickness was increased in unobstructed territories (70% ± 2.4% vs. 29% ± 0.9%, P < 0.0001). ET‐1 was overexpressed in unobstructed territories, compared to controls and obstructed territories. In conclusion, the large‐animal model described here is reproducible and led to the development of PH in a relatively short time frame.
Study Design and Rationale for Investigating Phosphodiesterase type 5 Inhibition for the Treatment of Pulmonary Hypertension Due to Chronic Obstructive Lung Disease: The TADA‐PHiLD (TADAlafil for Pulmonary Hypertension Associated with Chronic Obstructive Lung Disease) Trial
Authors: Maron Bradley A. , Goldstein Ronald H. , Rounds Sharon I. , Shapiro Shelley , Jankowich Matthew , Garshick Eric , Moy Marilyn L. , Gagnon David , Choudhary Gaurav
Published: March 2014

In patients with chronic obstructive pulmonary disease (COPD), moderate or severe pulmonary hypertension (COPD‐PH) is associated with increased rates of morbidity and mortality. Despite this, approaches to treatment and the efficacy of phosphodiesterase type 5 inhibition (PDE‐5i) in COPD‐PH are unresolved. We present the clinical rationale and study design to assess the effect of oral tadalafil on exercise capacity, cardiopulmonary hemodynamics, and clinical outcome measures in COPD‐PH patients. Male and female patients 40–85 years old with GOLD stage 2 COPD or higher and pulmonary hypertension diagnosed on the basis of invasive cardiac hemodynamic assessment (mean pulmonary artery pressure [mPAP] >30 mmHg, pulmonary vascular resistance [PVR] >2.5 Wood units, and pulmonary capillary wedge pressure ≤18 mmHg at rest) will be randomized at a 1:1 ratio to receive placebo or oral PDE‐5i with tadalafil (40 mg daily for 12 months). The primary end point is change from baseline in 6‐minute walk distance at 12 months. The secondary end points are change from baseline in PVR and mPAP at 6 months and change from baseline in peak volume of oxygen consumption (o2) during exercise at 12 months. Changes in systemic blood pressure and/or oxyhemoglobin saturation (SaO2) at rest and during exercise will function as safety outcome measures. TADA‐PHiLD (TADAlafil for Pulmonary Hypertension assocIated with chronic obstructive Lung Disease) is the first sufficiently powered randomized clinical trial testing the effect of PDE‐5i on key clinical and drug safety outcome measures in patients with at least moderate PH due to COPD.
Safety of Epoprostenol and Treprostinil in Children Less than 12 Months of Age
Authors: McIntyre Chelsey M. , Hanna Brian D. , Rintoul Natalie , Ramsey E. Zachary
Published: March 2014

There is a paucity of data on infant intravenous prostacyclin use, the gold standard for therapy for severe pulmonary hypertension (PH). This review aimed to evaluate the safety, tolerability, and outcomes of infant prostacyclin use. A retrospective observational study was performed in a large pediatric hospital with a dedicated pediatric PH program. Subject medical records, bedside flow sheets, and progress notes were reviewed to identify use of intravenous epoprostenol or treprostinil within the first year of life. The indication for prostacyclin use was recalcitrant hemodynamic compromise associated with PH, identified as either idiopathic PH, persistent PH of the newborn, PH associated with congenital diaphragmatic hernia, congenital heart disease, bronchiolitis, or chronic lung disease. Prostacyclin‐related adverse events included 7 episodes of hypotension, 6 episodes of perceived pain, 2 episodes of cyanosis, and 1 episode of feeding intolerance. Prostacyclin was stopped only for cyanotic episodes associated with use in severe chronic lung disease. Two hemorrhagic events occurred during extracorporeal membrane oxygenation, which were unlikely to be prostacyclin related. Outcomes included 21 deaths unrelated to prostacyclin, 1 lung transplant, 6 PH resolutions, 8 transitions to oral PH medications, and 1 continuation of treprostinil. In conclusion, efficacy could not be evaluated in this study because of the loss of equipoise for neonatal prostacyclin use. Prostacyclin use was well tolerated in neonatal diseases associated with PH, but dose titration was limited by hypotension and hypoxemia.
Bone Marrow–Derived Vascular Modulatory Cells in Pulmonary Arterial Hypertension
Authors: Lanzola Emily , Farha Samar , Erzurum Serpil C. , Asosingh Kewal
Published: March 2014

Hematopoiesis and vascular homeostasis are closely linked to each other via subsets of circulating bone marrow–derived cells with potent activity to repair endothelial injury and promote angiogenesis. As a consequence, abnormalities in hematopoiesis will eventually affect vascular health. Pulmonary arterial hypertension (PAH) is a vascular disease characterized by severe remodeling of the pulmonary artery wall. Over the past decade, circulating hematopoietic cells have been assigned an increasing role in the remodeling, such that these cells have been used in new therapeutic strategies. More recently, research has been extended to the bone marrow where these cells originate to identify abnormalities in hematopoiesis that may underlie PAH. Here, we review the current literature and identify gaps in knowledge of the myeloid effects on PAH.
Rivicola pingtungensis gen. nov., sp. nov., a new member of the family Neisseriaceae isolated from a freshwater river
Authors: Sheu Shih-Yi , Chen Jhen-Ci , Young Chiu-Chung , Chen Wen-Ming
Published: March 2014

A bacterial strain, designated Npb-03T, was isolated from a freshwater river in Taiwan and was characterized using a polyphasic taxonomic approach. The cells were Gram-reaction-negative, straight rod-shaped, non-motile, non-spore-forming and facultatively anaerobic. Growth occurred at 10–37 °C (optimum, 30–35 °C), at pH 6.0–8.0 (optimum, pH 6.0–7.0) and with 0–1.0 % NaCl (optimum, 0 %). The predominant fatty acids were summed feature 3 (comprising C16 : 1ω7c and/or C16 : 1ω6c) and C16 : 0. The major isoprenoid quinone was Q-8 and the DNA G+C content was 64.1 mol%. The polar lipid profile consisted of a mixture of phosphatidylethanolamine, phosphatidylglycerol, diphosphatidylglycerol, an uncharacterized aminolipid and three uncharacterized phospholipids. The major polyamines were putrescine, 2-hydroxyputrescine, cadaverine and spermidine. Phylogenetic analyses based on 16S rRNA gene sequences showed that strain Npb-03T forms a distinct lineage with respect to closely related genera within the family

Neisseriaceae

of the class

Betaproteobacteria

, most closely related to the genera

Aquaspirillum

,

Laribacter

,

Leeia

and

Microvirgula

, and the levels of 16S rRNA gene sequence similarity with respect to the type species of related genera are less than 93 %. On the basis of the genotypic and phenotypic data, strain Npb-03T represents a novel genus and species of the family

Neisseriaceae

, for which the name Rivicola pingtungensis gen. nov., sp. nov. is proposed. The type strain is Npb-03T ( = BCRC 80376T = LMG 26668T = KCTC 23712T).
Anomalies in the refinement of isoleucine
Authors: Berntsen Karen R. M. , Vriend Gert
Published: March 2014

A study of isoleucines in protein structures solved using X-ray crystallography revealed a series of systematic trends for the two side-chain torsion angles χ1and χ2dependent on the resolution, secondary structure and refinement software used. The average torsion angles for the nine rotamers were similar in high-resolution structures solved using either theREFMAC,CNSorPHENIXsoftware. However, at low resolution these programs often refine towards somewhat different χ1and χ2values. Small systematic differences can be observed between refinement software that uses molecular dynamics-type energy terms (for exampleCNS) and software that does not use these terms (for exampleREFMAC). Detailing the standard torsion angles used in refinement software can improve the refinement of protein structures. The target values in the molecular dynamics-type energy functions can also be improved.
(Butoxymethylidene)dimethylazanium tetraphenylborate acetonitrile monosolvate
Authors: Tiritiris Ioannis , Saur Stefan , Kantlehner Willi
Published: March 2014

In the title solvated salt, C7H16NO+·C24H20B−·C2H3N, the C—N bond lengths in the cation are 1.2831 (19), 1.467 (2) and 1.465 (2) Å, indicating double- and single-bond character, respectively. The C—O bond length of 1.2950 (18) Å shows a double-bond character, pointing towards charge delocalization within the NCO plane of the iminium ion. The two C atoms of then-butyl group are disordered over the two sites, with refined occupancy ratios of 0.890 (5):0.110 (5) and 0.888 (4):0.112 (4). In the crystal, C—H...π interactions occur between the methine H atom, H atoms of the –N(CH3)2and –CH2groups of the cation, and two of the phenyl rings of the tetraphenylborate anion. The latter interaction forms an aromatic pocket in which the cation is embedded. Thus, a two-dimensional pattern is created in theacplane.
Metastable adaptive orthorhombic martensite in zirconia nanoparticles
Authors: Liu Shaocun , Hu Wentao , Zhang Yang , Xiang Jianyong , Wen Fusheng , Xu Bo , He Julong , Yu Dongli , Tian Yongjun , Liu Zhongyuan
Published: March 2014

Reported here are observations of isolated orthorhombic (o) ZrO2nanoparticles (NPs) in thePbcaspace group under atmospheric conditions. These NPs are composed of o domains separated by internal semi-coherent boundaries. They are identified to transform from lamellar-twinned tetragonal (t) NPs. The constraining effect of the twin boundaries impedes a direct martensitic transformation to the monoclinic (m) phase but favours a transformation to the o phase. The internal boundaries are considered to evolve from the lamellar-twinning boundaries, playing an important role in the stabilization of the o structure under atmospheric conditions. The observed o structure should be an adaptive martensite transformed from the t phase, different from the general consideration of the o phase as an intermediate stage. A new lattice correspondence (LC) relationship of (011)o||(100)tand [100]o||[001]tis determined for the t-to-o transformation. A possible transformation path is proposed to be t (space groupP42/nmc) to o (PbcmorPbc21, named oA) to o (Pbca, named oB), and the LC relationship is identified to be (100)t||(100)oA||(011)oBand [001]t||[010]oA||[100]oB.
Maternal complications and perinatal mortality: findings of the World Health Organization Multicountry Survey on Maternal and Newborn Health
Authors: Vogel JP , Souza JP , Mori R , Morisaki N , Lumbiganon P , Laopaiboon M , Ortiz‐Panozo E , Hernandez B , Pérez‐Cuevas R , Roy M , Mittal S , Cecatti JG , Tunçalp Ö , Gülmezoglu AM ,   on behalf of the WHO Multicountry Survey on Maternal and Newborn Health Research Network
Published: March 2014

Objective

We aimed to determine the prevalence and risks of late fetal deaths (LFDs) and early neonatal deaths (ENDs) in women with medical and obstetric complications.

Design

Secondary analysis of the WHO Multicountry Survey on Maternal and Newborn Health (WHOMCS).

Setting

A total of 359 participating facilities in 29 countries.

Population

A total of 308 392 singleton deliveries.

Methods

We reported on perinatal indicators and determined risks of perinatal death in the presence of severe maternal complications (haemorrhagic, infectious, and hypertensive disorders, and other medical conditions).

Main outcome measures

Fresh and macerated LFDs (defined as stillbirths ≥ 1000 g and/or ≥28 weeks of gestation) and ENDs.

Results

The LFD rate was 17.7 per 1000 births; 64.8% were fresh stillbirths. The END rate was 8.4 per 1000 liveborns; 67.1% occurred by day 3 of life. Maternal complications were present in 85.6, 86.5, and 88.6% of macerated LFDs, fresh LFDs, and ENDs, respectively. The risks of all three perinatal mortality outcomes were significantly increased with placental abruption, ruptured uterus, systemic infections/sepsis, pre‐eclampsia, eclampsia, and severe anaemia.

Conclusions

Preventing intrapartum‐related perinatal deaths requires a comprehensive approach to quality intrapartum care, beyond the provision of caesarean section. Early identification and management of women with complications could improve maternal and perinatal outcomes.
Development of criteria for identifying neonatal near‐miss cases: analysis of two WHO multicountry cross‐sectional studies
Authors: Pileggi‐Castro C , Camelo Jr JS , Perdoná GC , Mussi‐Pinhata MM , Cecatti JG , Mori R , Morisaki N , Yunis K , Vogel JP , Tunçalp Ö , Souza JP ,   on behalf of the WHO Multicountry Survey on Maternal and Newborn Health Research Network
Published: March 2014

Objective

To develop and test markers of neonatal severe morbidity for the identification of neonatal near‐miss cases.

Design

This is a database analysis of two World Health Organization cross‐sectional studies: the Global Survey on Maternal and Perinatal Health (WHOGS) and the Multicountry Survey on Maternal and Newborn Health (WHOMCS).

Setting

The WHOGS was performed in 373 health facilities in 24 countries (2004–2008). The WHOMCS was conducted in 359 health facilities in 29 countries (2010–2011).

Population

Data were collected from hospital records of all women admitted for delivery and their respective neonates.

Methods

Pragmatic markers (birthweight <1750 g, Apgar score at 5 minutes <7, and gestational age <33 weeks) were developed with WHOGS data and validated with WHOMCS data. The diagnostic accuracy of neonatal characteristics and management markers of severity was determined in the WHOMCS.

Results

This analysis included 290 610 liveborn neonates from WHOGS and 310 436 liveborn neonates from WHOMCS. The diagnostic accuracy of pragmatic and management markers of severity for identifying early neonatal deaths was very high: sensitivity, 92.8% (95% CI 91.8–93.7%); specificity, 92.7% (95% CI 92.6–92.8%); positive likelihood ratio, 12.7 (95% CI 12.5–12.9); negative likelihood ratio, 0.08 (95% CI 0.07–0.09); diagnostic odds ratio, 163.4 (95% CI 141.6–188.4). A positive association was found between the frequency of neonatal near‐miss cases and Human Development Index.

Conclusion

Newborn infants presenting selected markers of severity and surviving the first neonatal week could be considered as neonatal near‐miss cases. This definition and criteria may be seen as a basis for future applications of the near‐miss concept in neonatal health. These tools can be used to inform policy makers on how best to apply scarce resources for improving the quality of care and reducing neonatal mortality.
Spatial Variation in Prices and Expenditure Inequalities in Australia
Authors: Mishra Ankita , Ray Ranjan
Published: March 2014

This study proposes a method of calculating preference‐based spatial price indices that measure price variation between regions. It shows how the traditional concept of the ‘true cost of living index’, used in temporal price comparisons, can also be used in spatial price comparisons. The usefulness of the proposed procedures is illustrated by applying them to Australian household expenditure data. The results show that during the past two decades spatial price variation has increased steadily, with the most recent period (2005–2009) witnessing a large increase. The results also show that the ranking of the states, on both cost of living and inequality, has altered significantly over the past two decades.
The Debt Maturity Issue in Access Pricing
Authors: Davis Kevin
Published: March 2014

There has been substantial debate and disagreement over the appropriate debt maturity used in determining the cost of debt for use in access pricing decisions in Australia. Some regulators have used a debt maturity corresponding to the length of the regulatory reset period (typically five years). Others have used a longer maturity based on the argument that the assets being financed are long‐lived. In this article it is demonstrated that under the current Australian approach, to meet the objectives of access pricing, the assumed debt maturity should be set equal to the term of the regulatory reset period. Whether practical debt management difficulties for access providers suggest that an alternative approach, placing more emphasis on their actual debt costs (as occurs in some other jurisdictions) should be considered, is also discussed.
Prison Suicides in South Australia: 1996–2010
Authors: Austin Amy E. , van den Heuvel Corinna , Byard Roger W.
Published: March 2014

Forty‐eight deaths occurring in prisons in South Australia were identified between January 1996 and December 2010, including 25 cases of suicide (mean age = 37 years; median age = 34 years; age range = 24–70 years). Most suicides were due to hanging (23/25; 92.0%) with victims using bedding, belts, or shoelaces attached to cell shelves, air vents, doors, or other accessible projections. There were no suicides attributed to drug overdose or sharp force injury. Over a third of all suicides (39.1%) occurred during the first month of confinement, with 26.1% of cases occurring within the first week. There was one suicide reported after 2 years of imprisonment. Given that suicide in state prisons currently occurs at a rate approximately eight times that of the general South Australian community, it appears that the subset of incarcerated individuals represents a group in need of effective preventive strategies to enable more appropriate provisions of existing prisoner resources.
Reliability of solar keratosis clinical diagnosis: A prospective study
Authors: Buinauskaite Evelina , Makstiene Jurgita , Buinauskiene Jurate , Valiukeviciene Skaidra
Published: March 2014

Usually solar keratoses (SK) are diagnosed clinically. However other diseases may clinically present as erythematous macules, papules or patches on sun‐exposed areas; therefore the histopathology remains the gold standard diagnostic tool. Our study, which assessed the efficacy of photodynamic therapy (PDT), showed that one in 20 clinically diagnosed SK lesions grade I–II identified by board‐certified dermatologists were rosacea and only one in 40 were malignant lesions. These findings should be considered by clinicians who treat clinically diagnosed grade I–II SK without response to treatment or diagnose the recurrence of SK after PDT.
Nicotinamide and the skin
Authors: Chen Andrew C , Damian Diona L
Published: March 2014

Nicotinamide, an amide form of vitamin B3, boosts cellular energy and regulates poly‐ADP‐ribose‐polymerase 1, an enzyme with important roles in DNA repair and the expression of inflammatory cytokines. Nicotinamide shows promise for the treatment of a wide range of dermatological conditions, including autoimmune blistering disorders, acne, rosacea, ageing skin and atopic dermatitis. In particular, recent studies have also shown it to be a potential agent for reducing actinic keratoses and preventing skin cancers.
The effects of general anaesthesia on nerve‐motor response characteristics (rheobase and chronaxie) to peripheral nerve stimulation
Authors: Tsui B. C.
Published: March 2014

Using a simple surface nerve stimulation system, I examined the effects of general anaesthesia on rheobase (the minimum current required to stimulate nerve activity) and chronaxie (the minimum time for a stimulus twice the rheobase to elicit nerve activity). Nerve stimulation was used to elicit a motor response from the ulnar nerve at varying pulse widths before and after induction of general anaesthesia. Mean (SD) rheobase before and after general anaesthesia was 0.91 (0.37) mA (95% CI 0.77–1.04 mA) and 1.11 (0.53) mA (95% CI 0.92–1.30 mA), respectively. Mean (SD) chronaxie measured before and after general anaesthesia was 0.32 (0.17) ms (95% CI 0.26–0.38 ms) and 0.29 (0.13) ms (95% CI 0.24–0.33 ms), respectively. Under anaesthesia, rheobase values increased by an average of 20% (p = 0.05), but chronaxie values did not change significantly (p = 0.39). These results suggest that threshold currents used for motor response from nerve stimulation under general anaesthesia might be higher than those used in awake patients.
Comparison of analgesic efficacy of four‐quadrant transversus abdominis plane (TAP) block and continuous posterior TAP analgesia with epidural analgesia in patients undergoing laparoscopic colorectal surgery: an open‐label, randomised, non‐inferiority trial
Authors: Niraj G. , Kelkar A. , Hart E. , Horst C. , Malik D. , Yeow C. , Singh B. , Chaudhri S.
Published: March 2014

Posterior transversus abdominis plane blocks have been reported to be an effective method of providing analgesia after lower abdominal surgery. We compared the efficacy of a novel technique of providing continuous transversus abdominis plane analgesia with epidural analgesia in patients on an enhanced recovery programme following laparoscopic colorectal surgery. A non‐inferiority comparison was used. Adult patients undergoing elective laparoscopic colorectal surgery were randomly assigned to receive continuous transversus abdominis plane analgesia (n = 35) vs epidural analgesia (n = 35), in addition to a postoperative analgesic regimen comprising regular paracetamol, regular diclofenac and tramadol as required. Sixty‐one patients completed the study. The transversus group received four‐quadrant transversus abdominis plane blocks and bilateral posterior transversus abdominis plane catheters that were infused with levobupivacaine 0.25% for 48 h. The epidural group received an infusion of bupivacaine and fentanyl. The primary outcome measure was visual analogue scale pain score on coughing at 24 h after surgery. We found no significant difference in median (IQR [range]) visual analogue scores during coughing at 24 h between the transversus group 2.5 (1.0–3.0 [0–5.5]) and the epidural group 2.5 (1.0–5.0 [0–6.0]). The one‐sided 97.5% CI was a 0.0 (∞–1.0) difference in means, establishing non‐inferiority. There were no significant differences between the groups for tramadol consumption. Success rate was 28/30 (93%) in the transversus group vs 27/31 (87%) in the epidural group. Continuous transversus abdominis plane infusion was non‐inferior to epidural infusion in providing analgesia after laparoscopic colorectal surgery.
Ropivacaine plasma levels following local infiltration analgesia for primary total hip arthroplasty
Authors: Gill A. M. , Scott N. B. , Abbas M. , Watson D. G. , Place K. , McDonald D.A.
Published: March 2014

We measured total and free plasma concentrations of ropivacaine following high‐volume, high‐dose local infiltration analgesia in 19 patients aged 65 years or over undergoing unilateral total hip arthroplasty. The patients received 180 ml ropivacaine 0.2% (360 mg), which was injected into the deep and peri‐capsular tissues, the gluteal muscles and fascia lata, and the subcutaneous tissues and skin. Patients were monitored for clinical symptoms and signs of systemic local anaesthetic toxicity. Total levels of plasma ropivacaine varied from 0.081 to 1.707 μg.ml−1 (mean (SD) 0.953 (0.323) μg.ml−1). Free levels of plasma ropivacaine varied from 0.000 to 0.053 μg.ml−1 (mean (SD) 0.024 (0.011) μg.ml−1). No samples reached the toxic threshold for venous ropivacaine concentration, although four patients exhibited mild symptoms consistent with local anaesthetic toxicity. One patient had episodes of complete heart block on ECG monitoring, but plasma ropivacaine levels were below toxic levels. We conclude that plasma levels for ropivacaine associated with toxicity in a volunteer population (total 2.2 μg.ml−1, free 0.15 μg.ml−1) are not reached during local infiltration analgesia for hip arthroplasty in elderly patients.
Therapeutic implications of peptide interactions with G‐protein‐coupled receptors in diabetic vasculopathy
Authors: Carrillo‐Sepulveda M. A. , Matsumoto T. , Nunes K. P. , Webb R. C.
Published: March 2014

The dramatic worldwide increase in the prevalence of diabetes has generated an attempt by the scientific community to identify strategies for its treatment and prevention. Vascular dysfunction is a hallmark of diabetes and frequently leads to the development of atherosclerosis, coronary disease‐derived myocardial infarction, stroke, peripheral arterial disease and diabetic ‘triopathy’ (retinopathy, nephropathy and neuropathy). These vascular complications, developing in an increasingly younger cohort of patients with diabetes, contribute to morbidity and mortality. Despite the development of new anti‐diabetic or anti‐hyperglycaemic drugs, vascular complications remain to be a problem. This warrants a need for new therapeutic strategies to tackle diabetic vasculopathy. There is a growing body of evidence showing that peptide‐binding G‐protein‐coupled receptors (peptide‐binding GPCRs) play an important role in the pathophysiology of vascular dysfunction during diabetes. Thus, in this review, we discuss some of the peptide‐binding GPCRs involved in the regulation of vascular function that have potential to be a therapeutic target in the treatment of diabetic vasculopathy.
The TRPC channel blocker SKF 96365 inhibits glioblastoma cell growth by enhancing reverse mode of the Na+/Ca2+ exchanger and increasing intracellular Ca2+
Authors: Song M , Chen D , Yu S P
Published: March 2014

Background and Purpose

SKF 96365 is well known for its suppressing effect on human glioblastoma growth by inhibiting pre‐activated transient receptor potential canonical (TRPC) channels and Ca2+ influx. The effect of SKF 96363 on glioblastoma cells, however, may be multifaceted and this possibility has been largely ignored.

Experimental Approach

The effects of SKF 96365 on cell cycle and cell viability of cultured human glioblastoma cells were characterized. Western blot, Ca2+ imaging and patch clamp recordings were used to delineate cell death mechanisms. siRNA gene knockdown provided additional evidence.

Key Results

SKF 96365 repressed glioblastoma cell growth via increasing intracellular Ca2+ ([Ca2+]i) irrespective of whether TRPC channels were blocked or not. The effect of SKF 96365 primarily resulted from enhanced reverse operation of the Na+/Ca2+ exchanger (NCX) with an EC50 of 9.79 μM. SKF 96365 arrested the glioblastoma cells in the S and G2 phases and activated p38‐MAPK and JNK, which were all prevented by the Ca2+ chelator BAPTA‐AM or EGTA. The expression of NCX in glioblastoma cells was significantly higher than in normal human astrocytes. Knockdown of the NCX1 isoforms diminished the effect of SKF 96365 on glioblastoma cells.

Conclusions and Implications

At the same concentration, SKF 96365 blocks TRPC channels and enhances the reverse mode of the NCX causing [Ca2+]i accumulation and cytotoxicity. This finding suggests an alternative pharmacological mechanism of SKF 96365. It also indicates that modulation of the NCX is an effective method to disrupt Ca2+ homeostasis and suppress human glioblastoma cells.
Suppression of cell membrane permeability by suramin: involvement of its inhibitory actions on connexin 43 hemichannels
Authors: Chi Yuan , Gao Kun , Zhang Hui , Takeda Masayuki , Yao Jian
Published: March 2014

Background and Purpose

Suramin is a clinically prescribed drug for treatment of human African trypanosomiasis, cancer and infection. It is also a well‐known pharmacological antagonist of P2 purinoceptors. Despite its clinical use and use in research, the biological actions of this molecule are still incompletely understood. Here, we investigated the effects of suramin on membrane channels, as exemplified by its actions on non‐junctional connexin43 (Cx43) hemichannels, pore‐forming α‐haemolysin and channels involved in ATP release under hypotonic conditions.

Experimental Approach

Hemichannels were activated by removing extracellular Ca2+. The influences of suramin on hemichannel activities were evaluated by its effects on influx of fluorescent dyes and efflux of ATP. The membrane permeability and integrity were assessed through cellular retention of preloaded calcein and LDH release.

Key Results

Suramin blocked Cx43 hemichannel permeability induced by removal of extracellular Ca2+ without much effect on Cx43 expression and gap junctional intercellular communication. This action of suramin was mimicked by its analogue NF023 and NF449 but not by another P2 purinoceptor antagonist PPADS. Besides hemichannels, suramin also significantly blocked intracellular and extracellular exchanges of small molecules caused by α‐haemolysin from Staphylococcus aureus and by exposure of cells to hypotonic solution. Furthermore, it prevented α‐haemolysin‐ and hypotonic stress‐elicited cell injury.

Conclusion and Implications

Suramin blocked membrane channels and protected cells against toxin‐ and hypotonic stress‐elicited injury. Our finding provides novel mechanistic insights into the pharmacological actions of suramin. Suramin might be therapeutically exploited to protect membrane integrity under certain pathological situations.
Intrinsic defence capacity and therapeutic potential of natriuretic peptides in pulmonary hypertension associated with lung fibrosis
Authors: Baliga R S , Scotton C J , Trinder S L , Chambers R C , MacAllister R J , Hobbs A J
Published: March 2014

Background and Purpose

Idiopathic pulmonary fibrosis (IPF) is a progressive fibro‐proliferative disorder refractory to current therapy commonly complicated by the development of pulmonary hypertension (PH); the associated morbidity and mortality are substantial. Natriuretic peptides possess vasodilator and anti‐fibrotic actions, and pharmacological augmentation of their bioactivity ameliorates renal and myocardial fibrosis. Here, we investigated whether natriuretic peptides possess an intrinsic cytoprotective function preventing the development of pulmonary fibrosis and associated PH, and whether therapeutics targeting natriuretic peptide signalling demonstrate efficacy in this life‐threatening disorder.

Experimental Approach

Pulmonary haemodynamics, right ventricular function and markers of lung fibrosis were determined in wild‐type (WT) and natriuretic peptide receptor (NPR)‐A knockout (KO) mice exposed to bleomycin (1 mg·kg−1). Human myofibroblast differentiation was studied in vitro.

Key Results

Exacerbated cardiac, vascular and fibrotic pathology was observed in NPR‐A KO animals, compared with WT mice, exposed to bleomycin. Treatment with a drug combination that raised circulating natriuretic peptide levels (ecadotril) and potentiated natriuretic peptide‐dependent signalling (sildenafil) reduced indices of disease progression, whether administered prophylactically or to animals with established lung disease. This positive pharmacodynamic effect was diminished in NPR‐A KO mice. Atrial natriuretic peptide and sildenafil synergistically reduced TGFβ‐induced human myofibroblast differentiation, a key driver of remodelling in IPF patients.

Conclusions and Implications

These data highlight an endogenous host‐defence capacity of natriuretic peptides in lung fibrosis and PH. A combination of ecadotril and sildenafil reversed the pulmonary haemodynamic aberrations and remodelling that characterize the disease, advocating therapeutic manipulation of natriuretic peptide bioactivity in patients with IPF.
Analgesic synergy between opioid and α2‐adrenoceptors
Authors: Chabot‐Doré A‐J , Schuster D J , Stone L S , Wilcox G L
Published: March 2014

Opioid and α2‐adrenoceptor agonists are potent analgesic drugs and their analgesic effects can synergize when co‐administered. These supra‐additive interactions are potentially beneficial clinically; by increasing efficacy and/or reducing the total drug required to produce sufficient pain relief, undesired side effects can be minimized. However, combination therapies of opioids and α2‐adrenoceptor agonists remain underutilized clinically, in spite of a large body of preclinical evidence describing their synergistic interaction. One possible obstacle to the translation of preclinical findings to clinical applications is a lack of understanding of the mechanisms underlying the synergistic interactions between these two drug classes. In this review, we provide a detailed overview of the interactions between different opioid and α2‐adrenoceptor agonist combinations in preclinical studies. These studies have identified the spinal cord as an important site of action of synergistic interactions, provided insights into which receptors mediate these interactions and explored downstream signalling events enabling synergy. It is now well documented that the activation of both μ and δ opioid receptors can produce synergy with α2‐adrenoceptor agonists and that α2‐adrenoceptor agonists can mediate synergy through either the α2A or the α2C adrenoceptor subtypes. Current hypotheses surrounding the cellular mechanisms mediating opioid–adrenoceptor synergy, including PKC signalling and receptor oligomerization, and the evidence supporting them are presented. Finally, the implications of these findings for clinical applications and drug discovery are discussed.

Linked Articles

This article is part of a themed section on Opioids: New Pathways to Functional Selectivity. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2015.172.issue-2
In vivo profiling of seven common opioids for antinociception, constipation and respiratory depression: no two opioids have the same profile
Authors: Kuo A , Wyse B D , Meutermans W , Smith M T
Published: March 2014

Background and Purpose

For patients experiencing inadequate analgesia and intolerable opioid‐related side effects on one strong opioid analgesic, pain relief with acceptable tolerability is often achieved by rotation to a second strong opioid. These observations suggest subtle pharmacodynamic differences between opioids in vivo. This study in rats was designed to assess differences between opioids in their in vivo profiles.

Experimental Approach

Male Sprague Dawley rats were given single i.c.v. bolus doses of morphine, morphine‐6‐glucuronide (M6G), fentanyl, oxycodone, buprenorphine, DPDPE ([D‐penicillamine2,5]‐enkephalin) or U69,593. Antinociception, constipation and respiratory depression were assessed using the warm water tail‐flick test, the castor oil‐induced diarrhoea test and whole body plethysmography respectively.

Key Results

These opioid agonists produced dose‐dependent antinociception, constipation and respiratory depression. For antinociception, morphine, fentanyl and oxycodone were full agonists, buprenorphine and M6G were partial agonists, whereas DPDPE and U69,593 had low potency. For constipation, M6G, fentanyl and buprenorphine were full agonists, oxycodone was a partial agonist, morphine produced a bell‐shaped dose–response curve, whereas DPDPE and U69,593 were inactive. For respiratory depression, morphine, M6G, fentanyl and buprenorphine were full agonists, oxycodone was a partial agonist, whereas DPDPE and U69,593 were inactive. The respiratory depressant effects of fentanyl and oxycodone were of short duration, whereas morphine, M6G and buprenorphine evoked prolonged respiratory depression.

Conclusion and Implications

For the seven opioids we assessed, no two had the same profile for evoking antinociception, constipation and respiratory depression, suggesting that these effects are differentially regulated. Our findings may explain the clinical success of ‘opioid rotation’.

Linked Articles

This article is part of a themed section on Opioids: New Pathways to Functional Selectivity. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2015.172.issue-2
Discovery and Structure Optimization of a Series of Isatin Derivatives as Mycobacterium tuberculosis Chorismate Mutase Inhibitors
Authors: Jeankumar Variam U. , Alokam Reshma , Sridevi Jonnalagadda P. , Suryadevara Priyanka , Matikonda Siddharth S. , Peddi Santosh , Sahithi Seedarala , Alvala Mallika , Yogeeswari Perumal , Sriram Dharmarajan
Published: March 2014

In this study, the crystal structure of the Mycobacterium tuberculosis (MTB) enzyme chorismate mutase (CM) bound to transition state analogue (PDB: 2FP2) was used as a framework for virtual screening of the BITS‐Pilani in‐house database (2500 compounds) to identify new scaffold. We identified isatin as novel small molecule MTB CM inhibitors; further twenty‐four isatin derivatives were synthesized and evaluated in vitro for their ability to inhibit MTB CM, and activity against M. tuberculosis as steps towards the derivation of structure–activity relationships (SAR) and lead optimization. Compound 3‐(4‐nitrobenzylidene)indolin‐2‐one, 24 emerged as the most promising lead with an IC50 of 1.01 ± 0.22 μm for purified CM and MIC of 23.5 μm for M. tuberculosis, with little or no cytotoxicity.
Invisible Losses and the Logics of Resettlement Compensation
Authors: WITTER REBECCA , SATTERFIELD TERRE
Published: March 2014

The necessity of compensating people negatively affected by conservation and other development projects has been widely acknowledged. It is less widely acknowledged that because conventional compensation assessments focus on material resources and their economic equivalents, many important losses incurred by resettlers are invisible to project authorities. Through ethnographic observations and interviews, we documented losses identified by people facing resettlement from Mozambique's Limpopo National Park. We also examined resettlement planning documents to determine why decision makers’ assessments of natural resource use and value neglect losses residents identified as critical. Identifying, preventing, and mitigating invisible losses in resettlement planning necessitates a better understanding of intangible benefits residents derive from resources, which are often as or more important than their readily apparent material properties. These benefits include but are not limited to decision‐making authority linked to owning land versus having the use of fields; ancestral identity and social belonging linked to gravesites; the importance of tree roots that provide a powerful sense of security because they suppress hunger in periods of scarcity; and the importance of people's location within social networks and hierarchies as they determine the benefits versus risks that will be incurred through resettlement.

Pérdidas Invisibles y la Lógica de la Compensación de Repoblación