bluuebunny/crossref_metadata_2025 huggingface dataset:
Stability-indicating HPLC-DAD/UV-ESI/MS impurity profiling of the anti-malarial drug lumefantrine
Authors: Verbeken Mathieu , Suleman Sultan , Baert Bram , Vangheluwe Elien , Van Dorpe Sylvia , Burvenich Christian , Duchateau Luc , Jansen Frans H , De Spiegeleer Bart
Published: March 2011

Background

Lumefantrine (benflumetol) is a fluorene derivative belonging to the aryl amino alcohol class of anti-malarial drugs and is commercially available in fixed combination products with β-artemether. Impurity characterization of such drugs, which are widely consumed in tropical countries for malaria control programmes, is of paramount importance. However, until now, no exhaustive impurity profile of lumefantrine has been established, encompassing process-related and degradation impurities in active pharmaceutical ingredients (APIs) and finished pharmaceutical products (FPPs).

Methods

Using HPLC-DAD/UV-ESI/ion trap/MS, a comprehensive impurity profile was established based upon analysis of market samples as well as stress, accelerated and long-term stability results. In-silico toxicological predictions for these lumefantrine related impurities were made using Toxtree® and Derek®.

Results

Several new impurities are identified, of which the desbenzylketo derivative (DBK) is proposed as a new specified degradant. DBK and the remaining unspecified lumefantrine related impurities are predicted, using Toxtree® and Derek®, to have a toxicity risk comparable to the toxicity risk of the API lumefantrine itself.

Conclusions

From unstressed, stressed and accelerated stability samples of lumefantrine API and FPPs, nine compounds were detected and characterized to be lumefantrine related impurities. One new lumefantrine related compound, DBK, was identified and characterized as a specified degradation impurity of lumefantrine in real market samples (FPPs). The in-silico toxicological investigation (Toxtree® and Derek®) indicated overall a toxicity risk for lumefantrine related impurities comparable to that of the API lumefantrine itself.
Phase I randomized dose-ascending placebo-controlled trials of ferroquine - a candidate anti-malarial drug - in adults with asymptomatic Plasmodium falciparum infection
Authors: Mombo-Ngoma Ghyslain , Supan Christian , Dal-Bianco Matthias P , Missinou Michel A , Matsiegui Pierre-Blaise , Ospina Salazar Carmen L , Issifou Saadou , Ter-Minassian Daniel , Ramharter Michael , Kombila Maryvonne , Kremsner Peter G , Lell Bertrand
Published: March 2011

Background

The development and spread of drug resistant Plasmodium falciparum strains is a major concern and novel anti-malarial drugs are, therefore, needed. Ferroquine is a ferrocenic derivative of chloroquine with proven anti-malarial activity against chloroquine-resistant and -sensitive P. falciparum laboratory strains.

Methods

Adult young male aged 18 to 45 years, asymptomatic carriers of P. falciparum, were included in two-dose escalation, double-blind, randomized, placebo-controlled Phase I trials, a single dose study and a multiple dose study aiming to evaluate oral doses of ferroquine from 400 to 1,600 mg.

Results

Overall, 54/66 patients (40 and 26 treated in the single and multiple dose studies, respectively) experienced at least one adverse event, 15 were under placebo. Adverse events were mainly gastrointestinal symptoms such as abdominal pain (16), diarrhoea (5), nausea (13), and vomiting (9), but also headache (11), and dizziness (5). A few patients had slightly elevated liver parameters (10/66) including two patients under placebo. Moderate changes in QTc and morphological changes in T waves were observed in the course of the study. However, no adverse cardiac effects with clinical relevance were observed.

Conclusions

These phase I trials showed that clinically, ferroquine was generally well-tolerated up to 1,600 mg as single dose and up to 800 mg as repeated dose in asymptomatic young male with P. falciparum infection. Further clinical development of ferroquine, either alone or in combination with another anti-malarial, is highly warranted and currently underway.
Supplementing alpha-tocopherol (vitamin E) and vitamin D3 in high fat diet decrease IL-6 production in murine epididymal adipose tissue and 3T3-L1 adipocytes following LPS stimulation
Authors: Lira Fábio S , Rosa José C , Cunha Claudio A , Ribeiro Eliane B , Oller do Nascimento Claudia , Oyama Lila M , Mota João F
Published: March 2011

Background

It is well known that high fat diets (HFDs) induce obesity and an increase in proinflammatory adipokines. Interleukin-6 (IL-6) is considered the major inflammatory mediator in obesity. Obesity is associated with a vitamin deficiency, especially of vitamins E and D3. We examined the effects of vitamin D3 and vitamin E supplementation on levels of IL-6 and IL-10 (as a marker of anti-inflammatory cytokines since, a balance between pro- and anti-inflammatory cytokines is maintained) protein expression in adipose tissue of mice provided with an HFD. Additionally, we measured the effects of vitamin E and vitamin D3 treatment on LPS-stimulated 3T3-L1 adipocytes IL-6 and IL-10 secretion.

Results

IL-6 protein levels and the IL-6/IL-10 ratio were decreased in epididymal white adipose tissue in groups receiving vitamins E and D3 supplementation compared to the HFD group. A 24-hour treatment of vitamin D3 and vitamin E significantly reduced the IL-6 levels in the adipocytes culture medium without affecting IL-10 levels.

Conclusions

Vitamin D3 and vitamin E supplementation in an HFD had an anti-inflammatory effect by decreasing IL-6 production in epididymal adipose tissue in mice and in 3T3-L1 adipocytes stimulated with LPS. Our results suggest that vitamin E and D3 supplementation can be used as an adjunctive therapy to reduce the proinflammatory cytokines present in obese patients.
Nonbacterial thrombotic endocarditis associated with cancer of unknown origin complicated with thrombus in the left auricular appendage: case report
Authors: Norisada Kazuko , Tanaka Hidekazu , Onishi Tetsuari , Kaneko Akihiro , Tsuji Takayuki , Yamawaki Kohei , Ryo Keiko , Tatsumi Kazuhiro , Matsumoto Kensuke , Miura Natsuko , Saegusa Jun , Morinaga Yukiko , Hara Shigeo , Kawai Hiroya , Hirata Ken-ichi
Published: March 2011

A 63-year-old man was admitted to our hospital with a complaint of right lateroabdominal pain. He was diagnosed with metastatic colon cancer, and then developed multiple brain embolic infarctions 7 days after admission. Transesophageal echocardiography showed that mobile, echo-dense masses were attached to the anterior and posterior mitral valve leaflet. Furthermore, there was a thrombus in the left auricular appendage despite sinus rhythm. These findings led to a diagnosis of suspected infectious endocarditis with subsequent multiple brain infarctions. The patient's general condition worsened and he died 13 days after admission. An autopsy was performed, and, while poorly differentiated cancer was observed in multiple organs, no primary tumor could be identified. Histological analysis showed that the masses of the mitral valve consisted mainly of fibrin without bacteria or oncocytes. This patient was therefore diagnosed with nonbacterial thrombotic endocarditis associated with cancer of unknown origin complicated with thrombus in the left auricular appendage.
Electrical characterisation of deep level defects in Be-doped AlGaAs grown on (100) and (311)A GaAs substrates by MBE
Authors: Mari Riaz H , Shafi Muhammad , Aziz Mohsin , Khatab Almontaser , Taylor David , Henini Mohamed
Published: March 2011

The growth of high mobility two-dimensional hole gases (2DHGs) using GaAs-GaAlAs heterostructures has been the subject of many investigations. However, despite many efforts hole mobilities in Be-doped structures grown on (100) GaAs substrate remained considerably lower than those obtained by growing on (311)A oriented surface using silicon as p-type dopant. In this study we will report on the properties of hole traps in a set of p-type Be-doped Al0.29Ga0.71As samples grown by molecular beam epitaxy on (100) and (311)A GaAs substrates using deep level transient spectroscopy (DLTS) technique. In addition, the effect of the level of Be-doping concentration on the hole deep traps is investigated. It was observed that with increasing the Be-doping concentration from 1 × 1016 to 1 × 1017 cm-3 the number of detected electrically active defects decreases for samples grown on (311)A substrate, whereas, it increases for (100) orientated samples. The DLTS measurements also reveal that the activation energies of traps detected in (311)A are lower than those in (100). From these findings it is expected that mobilities of 2DHGs in Be-doped GaAs-GaAlAs devices grown on (311)A should be higher than those on (100).
Nanofluids for heat transfer: an engineering approach
Authors: Timofeeva Elena V , Yu Wenhua , France David M , Singh Dileep , Routbort Jules L
Published: March 2011

An overview of systematic studies that address the complexity of nanofluid systems and advance the understanding of nanoscale contributions to viscosity, thermal conductivity, and cooling efficiency of nanofluids is presented. A nanoparticle suspension is considered as a three-phase system including the solid phase (nanoparticles), the liquid phase (fluid media), and the interfacial phase, which contributes significantly to the system properties because of its extremely high surface-to-volume ratio in nanofluids. The systems engineering approach was applied to nanofluid design resulting in a detailed assessment of various parameters in the multivariable nanofluid systems. The relative importance of nanofluid parameters for heat transfer evaluated in this article allows engineering nanofluids with desired set of properties.
Numerical study of instability of nanofluids: the coagulation effect and sedimentation effect
Authors: Ni Yu , Fan JianRen , Hu YaCai
Published: March 2011

This study is a numerical study on the coagulation as well as the sedimentation effect of nanofluids using the Brownian dynamics method. Three cases are simulated, focusing on the effects of the sizes, volume fraction, and ζ potentials of nano-particles on the formation of coagulation and sedimentation of nanofluids. The rms fluctuation of the particle number concentration, as well as the flatness factor of it, is employed to study the formation and variation of the coagulation process. The results indicate a superposition of coagulation and sedimentation effect of small nano-particles. Moreover, it is stable of nanofluids with the volume fraction of particles below the limit of "resolution" of the fluids. In addition, the effect of ζ potentials is against the formation of coagulation and positive to the stability of nanofluids.
AFM-assisted fabrication of thiol SAM pattern with alternating quantified surface potential
Authors: Moores Bradley , Simons Janet , Xu Song , Leonenko Zoya
Published: March 2011

Thiol self-assembled monolayers (SAMs) are widely used in many nano- and bio-technology applications. We report a new approach to create and characterize a thiol SAMs micropattern with alternating charges on a flat gold-coated substrate using atomic force microscopy (AFM) and Kelvin probe force microscopy (KPFM). We produced SAMs-patterns made of alternating positively charged, negatively charged, and hydrophobic-terminated thiols by an automated AFM-assisted manipulation, or nanografting. We show that these thiol patterns possess only small topographical differences as revealed by AFM, and distinguished differences in surface potential (20-50 mV), revealed by KPFM. The pattern can be helpful in the development of biosensor technologies, specifically for selective binding of biomolecules based on charge and hydrophobicity, and serve as a model for creating surfaces with quantified alternating surface potential distribution.
Numerical study of a confined slot impinging jet with nanofluids
Authors: Manca Oronzio , Mesolella Paolo , Nardini Sergio , Ricci Daniele
Published: March 2011

Background

Heat transfer enhancement technology concerns with the aim of developing more efficient systems to satisfy the increasing demands of many applications in the fields of automotive, aerospace, electronic and process industry. A solution for obtaining efficient cooling systems is represented by the use of confined or unconfined impinging jets. Moreover, the possibility of increasing the thermal performances of the working fluids can be taken into account, and the introduction of nanoparticles in a base fluid can be considered.

Results

In this article, a numerical investigation on confined impinging slot jet working with a mixture of water and Al2O3 nanoparticles is described. The flow is turbulent and a constant temperature is applied on the impinging. A single-phase model approach has been adopted. Different geometric ratios, particle volume concentrations and Reynolds number have been considered to study the behavior of the system in terms of average and local Nusselt number, convective heat transfer coefficient and required pumping power profiles, temperature fields and stream function contours.

Conclusions

The dimensionless stream function contours show that the intensity and size of the vortex structures depend on the confining effects, given by H/ W ratio, Reynolds number and particle concentrations. Furthermore, for increasing concentrations, nanofluids realize increasing fluid bulk temperature, as a result of the elevated thermal conductivity of mixtures. The local Nusselt number profiles show the highest values at the stagnation point, and the lowest at the end of the heated plate. The average Nusselt number increases for increasing particle concentrations and Reynolds numbers; moreover, the highest values are observed for H/W = 10, and a maximum increase of 18% is detected at a concentration equal to 6%. The required pumping power as well as Reynolds number increases and particle concentrations grow, which is almost 4.8 times greater than the values calculated in the case of base fluid.

List of symbols
Relationship between structural changes, hydrogen content and annealing in stacks of ultrathin Si/Ge amorphous layers
Authors: Frigeri Cesare , Serényi Miklós , Khánh Nguyen Quoc , Csik Attila , Riesz Ferenc , Erdélyi Zoltán , Nasi Lucia , Beke Dezső László , Boyen Hans-Gerd
Published: March 2011

Hydrogenated multilayers (MLs) of a-Si/a-Ge have been analysed to establish the reasons of H release during annealing that has been seen to bring about structural modifications even up to well-detectable surface degradation. Analyses carried out on single layers of a-Si and a-Ge show that H is released from its bond to the host lattice atom and that it escapes from the layer much more efficiently in a-Ge than in a-Si because of the smaller binding energy of the H-Ge bond and probably of a greater weakness of the Ge lattice. This should support the previous hypothesis that the structural degradation of a-Si/a-Ge MLs primary starts with the formation of H bubbles in the Ge layers.
Nonlinear dynamics of non-equilibrium holes in p-type modulation-doped GaInNAs/GaAs quantum wells
Authors: Khalil Hagir Mohammed , Sun Yun , Balkan Naci , Amann Andreas , Sopanen Markku
Published: March 2011

Nonlinear charge transport parallel to the layers of p-modulation-doped GaInNAs/GaAs quantum wells (QWs) is studied both theoretically and experimentally. Experimental results show that at low temperature, T = 13 K, the presence of an applied electric field of about 6 kV/cm leads to the heating of the high mobility holes in the GaInNAs QWs, and their real-space transfer (RST) into the low-mobility GaAs barriers. This results in a negative differential mobility and self-generated oscillatory instabilities in the RST regime. We developed an analytical model based upon the coupled nonlinear dynamics of the real-space hole transfer and of the interface potential barrier controlled by space-charge in the doped GaAs layer. Our simulation results predict dc bias-dependent self-generated current oscillations with frequencies in the high microwave range.
Evc2 is a positive modulator of Hedgehog signalling that interacts with Evc at the cilia membrane and is also found in the nucleus
Authors: Blair Helen J , Tompson Stuart , Liu Yu-Ning , Campbell Jennifer , MacArthur Katie , Ponting Chris P , Ruiz-Perez Victor L , Goodship Judith A
Published: March 2011

Background

Evc is essential for Indian Hedgehog (Hh) signalling in the cartilage growth plate. The gene encoding Evc2 is in close proximity in divergent orientation to Evc and mutations in both human genes lead to the chondrodysplasia Ellis-van Creveld syndrome.

Results

Bioinformatic analysis reveals that the Evc and Evc2 genes arose through a duplication event early in metazoan evolution and were subsequently lost in arthropods and nematodes. Here we demonstrate that Evc2 is essential for Hh pathway activation in response to the Smo agonist purmorphamine. A yeast two-hybrid screen using Evc as bait identified Evc2 as an Evc binding partner and we confirmed the interaction by immunoprecipitation. We developed anti-Evc2 antibodies and show that Evc2 and Evc co-localize at the basal body and also on primary cilia. In transfected cells, basal body and cilia localization is observed when Evc and Evc2 constructs are co-transfected but not when either construct is transfected individually. We show that Evc and Evc2 are cilia transmembrane proteins, the C-terminus for both being intracellular and Evc2, but not Evc, having an extracellular portion. Furthermore, Evc is absent at the basal body in Evc2 null cells. Using Western blots of cytoplasmic and nuclear protein, we also demonstrate that full length Evc2 but not Evc, is located in the nucleus.

Conclusions

We demonstrate for the first time that Evc2 is a positive regulator of the Hh signalling pathway and that it is located at the basal body of primary cilia. We show that the presence of Evc and Evc2 at the basal body and cilia membrane is co-dependent. In addition, Evc2, but not Evc, is present in the cell nucleus suggesting movement of Evc2 between the cilium and nucleus.
Mutation of a diacidic motif in SIV-PBj Nef impairs T-cell activation and enteropathic disease
Authors: Tschulena Ulrich , Sanzenbacher Ralf , Mühlebach Michael D , Berger André , Münch Jan , Schindler Michael , Kirchhoff Frank , Plesker Roland , Coulibaly Cheick , Panitz Sylvia , Prüfer Steffen , Muckenfuss Heide , Hamdorf Matthias , Schweizer Matthias , Cichutek Klaus , Flory Egbert
Published: March 2011

Background

The non-pathogenic course of SIV infection in its natural host is characterized by robust viral replication in the absence of chronic immune activation and T cell proliferation. In contrast, acutely lethal enteropathic SIVsmm strain PBj induces a strong immune activation and causes a severe acute and lethal disease in pig-tailed macaques after cross-species transmission. One important pathogenicity factor of the PBj virus is the PBj-Nef protein, which contains a conserved diacidic motif and, unusually, an immunoreceptor tyrosine-based activation motif (ITAM).

Results

Mutation of the diacidic motif in the Nef protein of the SIVsmmPBj abolishes the acute phenotype of this virus.In vitro, wild-type and mutant PBj (PBj-Nef202/203GG) viruses replicated to similar levels in macaque PBMCs, but PBj-Nef202/203GG no longer triggers ERK mitogen-activated protein (MAP) kinase pathway including an alteration of a Nef-associated Raf-1/ERK-2 multiprotein signaling complex. Moreover, stimulation of IL-2 and down-modulation of CD4 and CD28 were impaired in the mutant virus. Pig-tailed macaques infected with PBj-Nef202/203GG did not show enteropathic complications and lethality as observed with wild-type PBj virus, despite efficient replication of both virusesin vivo. Furthermore, PBj-Nef202/203GG infected animals revealed reduced T-cell activation in periphery lymphoid organs and no detectable induction of IL-2 and IL-6.

Conclusions

In sum, we report here that mutation of the diacidic motif in the PBj-Nef protein abolishes disease progression in pig-tailed macaques despite efficient replication. These data suggest that alterations in the ability of a lentivirus to promote T cell activation and proliferation can have a dramatic impact on its pathogenic potential.
Management of HIV-1 associated hepatitis in patients with acquired immunodeficiency syndrome: role of a successful control of viral replication
Authors: Esposito Antonella , Conti Valentina , Cagliuso Maria , Pastori Daniele , Fantauzzi Alessandra , Mezzaroma Ivano
Published: March 2011

In HIV-1 infected patients, increase of liver enzymes may be mainly due to viral coinfections, alcohol intake, hepatotoxic drugs or autoimmune diseases. Three cases of aminotransferase elevation occurred during a phase of uncontrolled viral replication combined with a severe immunodeficiency and resolved by an effective HAART are described, focusing on the etio-pathogenetic role possibly played by HIV-1 infection.
Complexity of VTA DA neural activities in response to PFC transection in nicotine treated rats
Authors: Chen Ting Y , Zhang Die , Dragomir Andrei , Akay Yasemin M , Akay Metin
Published: March 2011

Background

The dopaminergic (DA) neurons in the ventral tegmental area (VTA) are widely implicated in the addiction and natural reward circuitry of the brain. These neurons project to several areas of the brain, including prefrontal cortex (PFC), nucleus accubens (NAc) and amygdala. The functional coupling between PFC and VTA has been demonstrated, but little is known about how PFC mediates nicotinic modulation in VTA DA neurons. The objectives of this study were to investigate the effect of acute nicotine exposure on the VTA DA neuronal firing and to understand how the disruption of communication from PFC affects the firing patterns of VTA DA neurons.

Methods

Extracellular single-unit recordings were performed on Sprague-Dawley rats and nicotine was administered after stable recording was established as baseline. In order to test how input from PFC affects the VTA DA neuronal firing, bilateral transections were made immediate caudal to PFC to mechanically delete the interaction between VTA and PFC.

Results

The complexity of the recorded neural firing was subsequently assessed using a method based on the Lempel-Ziv estimator. The results were compared with those obtained when computing the entropy of neural firing. Exposure to nicotine triggered a significant increase in VTA DA neurons firing complexity when communication between PFC and VTA was present, while transection obliterated the effect of nicotine. Similar results were obtained when entropy values were estimated.

Conclusions

Our findings suggest that PFC plays a vital role in mediating VTA activity. We speculate that increased firing complexity with acute nicotine administration in PFC intact subjects is due to the close functional coupling between PFC and VTA. This hypothesis is supported by the fact that deletion of PFC results in minor alterations of VTA DA neural firing when nicotine is acutely administered.
Hepatitis Associated Aplastic Anemia: A review
Authors: Rauff Bisma , Idrees Muhammad , Shah Shahida Amjad Riaz , Butt Sadia , Butt Azeem M , Ali Liaqat , Hussain Abrar , Irshad-ur-Rehman  , Ali Muhammad
Published: March 2011

Hepatitis-associated aplastic anemia (HAAA) is an uncommon but distinct variant of aplastic anemia in which pancytopenia appears two to three months after an acute attack of hepatitis. HAAA occurs most frequently in young male children and is lethal if leave untreated. The etiology of this syndrome is proposed to be attributed to various hepatitis and non hepatitis viruses. Several hepatitis viruses such as HAV, HBV, HCV, HDV, HEV and HGV have been associated with this set of symptoms. Viruses other than the hepatitis viruses such as parvovirus B19, Cytomegalovirus, Epstein bar virus, Transfusion Transmitted virus (TTV) and non-A-E hepatitis virus (unknown viruses) has also been documented to develop the syndrome. Considerable evidences including the clinical features, severe imbalance of the T cell immune system and effective response to immunosuppressive therapy strongly present HAAA as an immune mediated mechanism. However, no association of HAAA has been found with blood transfusions, drugs and toxins. Besides hepatitis and non hepatitis viruses and immunopathogenesis phenomenon as causative agents of the disorder, telomerase mutation, a genetic factor has also been predisposed for the development of aplastic anemia. Diagnosis includes clinical manifestations, blood profiling, viral serological markers testing, immune functioning and bone marrow hypocellularity examination. Patients presenting the features of HAAA have been mostly treated with bone marrow or hematopoietic cell transplantation from HLA matched donor, and if not available then by immunosuppressive therapy. New therapeutic approaches involve the administration of steroids especially the glucocorticoids to augment the immunosuppressive therapy response. Pancytopenia following an episode of acute hepatitis response better to hematopoietic cell transplantation than immunosuppressive therapy.
Assessing quality and completeness of human transcriptional regulatory pathways on a genome-wide scale
Authors: Shmelkov Evgeny , Tang Zuojian , Aifantis Iannis , Statnikov Alexander
Published: March 2011

Background

Pathway databases are becoming increasingly important and almost omnipresent in most types of biological and translational research. However, little is known about the quality and completeness of pathways stored in these databases. The present study conducts a comprehensive assessment of transcriptional regulatory pathways in humans for seven well-studied transcription factors: MYC, NOTCH1, BCL6, TP53, AR, STAT1, and RELA. The employed benchmarking methodology first involves integrating genome-wide binding with functional gene expression data to derive direct targets of transcription factors. Then the lists of experimentally obtained direct targets are compared with relevant lists of transcriptional targets from 10 commonly used pathway databases.

Results

The results of this study show that for the majority of pathway databases, the overlap between experimentally obtained target genes and targets reported in transcriptional regulatory pathway databases is surprisingly small and often is not statistically significant. The only exception is MetaCore pathway database which yields statistically significant intersection with experimental results in 84% cases. Additionally, we suggest that the lists of experimentally derived direct targets obtained in this study can be used to reveal new biological insight in transcriptional regulation and suggest novel putative therapeutic targets in cancer.

Conclusions

Our study opens a debate on validity of using many popular pathway databases to obtain transcriptional regulatory targets. We conclude that the choice of pathway databases should be informed by solid scientific evidence and rigorous empirical evaluation.

Reviewers

This article was reviewed by Prof. Wing Hung Wong, Dr. Thiago Motta Venancio (nominated by Dr. L Aravind), and Prof. Geoff J McLachlan.
Effect of a single dose of pregabalin on herpes zoster pain
Authors: Jensen-Dahm Christina , Rowbotham Michael C , Reda Haatem , Petersen Karin Lottrup
Published: March 2011

Background

The effect of pregabalin on acute herpes zoster pain has not been previously evaluated.

Methods

In a randomized, double-blind, placebo-controlled, two-session crossover study the effect of a single oral dose of pregabalin (150 mg) on pain and allodynia was evaluated in 8 subjects with herpes zoster.

Results

Over 6 hours of observation, pain decreased by a mean of 33% with pregabalin and 14% with placebo (p < 0.10). Effects on allodynia and SF-MPQ were not significant.

Conclusions

Compared to an earlier study of gabapentin 900 mg for acute zoster pain and allodynia that followed a nearly identical protocol, pregabalin had a similar effect on pain and was well tolerated, with no difference from placebo on sleepiness. Common side effects of light-headedness, unsteady gait, and slowed thinking were almost identical to that observed in the earlier study of gabapentin. Subject recruitment proved difficult in part due to the widespread off-label use of gabapentin and pregabalin for acute zoster pain in our region of the USA.

Trial Registration

ClinicalTrials.gov Identifier: NCT00352651
Randomized clinical trial comparing percutaneous closure of patent foramen ovale (PFO) using the Amplatzer PFO Occluder with medical treatment in patients with cryptogenic embolism (PC-Trial): rationale and design
Authors: Khattab Ahmed A , Windecker Stephan , Jüni Peter , Hildick-Smith David , Dudek Dariusz , Andersen Henning R , Ibrahim Reda , Schuler Gerhard , Walton Antony S , Wahl Andreas , Mattle Heinrich P , Meier Bernhard
Published: March 2011

Background

Several studies have shown an association of cryptogenic stroke and embolism with patent foramen ovale (PFO), but the question how to prevent further events in such patients is unresolved. Options include antithrombotic treatment with warfarin or antiplatelet agents or surgical or endovascular closure of the PFO. The PC-Trial was set up to compare endovascular closure and best medical treatment for prevention of recurrent events.

Methods

The PC-Trial is a randomized clinical trial comparing the efficacy of percutaneous closure of the PFO using the Amplatzer PFO occluder with best medical treatment in patients with cryptogenic embolism, i.e. mostly cryptogenic stroke. Warfarin for 6 months followed by antiplatelet agents is recommended as medical treatment. Randomization is stratified according to patients age (<45 versus ≥45 years), presence of atrial septal aneurysm (ASA yes or no) and number of embolic events before randomization (one versus more than one event). Primary endpoints are death, nonfatal stroke and peripheral embolism.

Discussion

patients were randomized in 29 centers of Europe, Canada, and Australia. Randomization started February 2000. Enrollment of 414 patients was completed in February 2009. All patients will be followed-up longitudinally. Follow-up is maintained until the last enrolled patient is beyond 2.5 years of follow-up (expected in 2011).

Trial Registration

Trial listed in ClinicalTrials.gov as NCT00166257 and sponsored by AGA Medical, Plymouth, MN, USA
Conservative management versus open reduction and internal fixation for mid-shaft clavicle fractures in adults - The Clavicle Trial: study protocol for a multicentre randomized controlled trial
Authors: Longo Umile Giuseppe , Banerjee Sughran , Barber Julie , Chambler Andrew , Cobiella Carlos , Corbett Steven , Crowther Mark , Drew Steven , Francis Andrea , Lee Marcus , Garlick Nicholas , Packham Iain , Pearse Yemi , Richards Andrew , Roberts Chris , Tennent Duncan , Tims Emily , Ahrens Philip Michael
Published: March 2011

Background

Clavicle fractures account for around 4% of all fractures and up to 44% of fractures of the shoulder girdle. Fractures of the middle third (or mid-shaft) account for approximately 80% of all clavicle fractures. Management of this group of fractures is often challenging and the outcome can be unsatisfactory. In particular it is not clear whether surgery produces better outcomes than non-surgical management. Currently there is much variation in the use of surgery and a lack of good quality evidence to inform our decision.

Methods/Design

We aim to undertake a multicentre randomised controlled trial evaluating the effectiveness and safety of conservative management versus open reduction and internal fixation for displaced mid-shaft clavicle fractures in adults. Surgical treatment will be performed using the Acumed clavicle fixation system. Conservative management will consist of immobilisation in a sling at the side in internal rotation for 6 weeks or until clinical or radiological union. We aim to recruit 300 patients. These patients will be followed-up for at least 9 months. The primary endpoint will be the rate of non-union at 3 months following treatment. Secondary endpoints will be limb function measured using the Constant-Murley Score and the Disabilities of the Arm, Shoulder and Hand (DASH) Score at 3 and 9 months post-operatively.

Discussion

This article presents the protocol for a multicentre randomised controlled trial. It gives extensive details of, and the basis for, the chosen methods, and describes the key measures taken to avoid bias and to ensure validity.

Trial Registration

United Kingdom Clinical Research Network ID: 8665. The date of registration of the trial is 07/09/2006. The date the first patient was recruited is 18/12/2007.
A factorial randomized controlled trial to evaluate the effect of micronutrients supplementation and regular aerobic exercise on maternal endothelium-dependent vasodilatation and oxidative stress of the newborn
Authors: Ramírez-Vélez Robinson , Romero Miryam , Echeverri Isabella , Ortega José Guillermo , Mosquera Mildrey , Salazar Blanca , Girón Sandra Lorena , Saldarriaga Wilmar , Aguilar de Plata Ana Cecilia , Mateus Julio Cesar
Published: March 2011

Background

Many studies have suggested a relationship between metabolic abnormalities and impaired fetal growth with the development of non-transmissible chronic diseases in the adulthood. Moreover, it has been proposed that maternal factors such as endothelial function and oxidative stress are key mechanisms of both fetal metabolic alterations and subsequent development of non-transmissible chronic diseases. The objective of this project is to evaluate the effect of micronutrient supplementation and regular aerobic exercise on endothelium-dependent vasodilation maternal and stress oxidative of the newborn.

Methods and design

320 pregnant women attending to usual prenatal care in Cali, Colombia will be included in a factorial randomized controlled trial. Women will be assigned to the following intervention groups: 1. Control group: usual prenatal care (PC) and placebo (maltodextrine). 2. Exercise group: PC, placebo and aerobic physical exercise. 3. Micronutrients group: PC and a micronutrients capsule consisting of zinc (30 mg), selenium (70 μg), vitamin A (400 μg), alphatocopherol (30 mg), vitamin C (200 mg), and niacin (100 mg). 4. Combined interventions Group: PC, supplementation of micronutrients, and aerobic physical exercise. Anthropometric measures will be taken at the start and at the end of the interventions.

Discussion

Since in previous studies has been showed that the maternal endothelial function and oxidative stress are related to oxidative stress of the newborn, this study proposes that complementation with micronutrients during pregnancy and/or regular physical exercise can be an early and innovative alternative to strengthen the prevention of chronic diseases in the population.

Trial registration

NCT00872365.
Revision of a nonunited subtrochanteric femoral fracture around a failed intramedullary nail with the use of RIA products, BMP-7 and hydroxyapatite: a case report
Authors: Tzioupis Christopher , Panteliadis Pavlos , Gamie Zakareya , Tsiridis Eleftherios
Published: March 2011

Introduction

Femoral subtrochanteric fractures are commonly treated using intramedullary devices. Failure of the implant and subsequent nonunion is still an issue, however, and limited evidence exists regarding the most appropriate treatment.

Case presentation

We report the case of an 80-year-old Caucasian woman with a subtrochanteric fracture originally treated using a trochanteric gamma nail which failed, resulting in a nonunion and fracture of its proximal end. The nonunion was revised with the removal of the broken trochanteric gamma nail, application of a condylar blade plate, ipsilateral Reamer/Irrigator/Aspirator autografting, recombinant human bone morphogenetic protein-7 and injectable hydroxyapatite cement. The fracture united fully at ten months following revision surgery, with no signs of femoral head avascular necrosis at 18-month follow-up.

Conclusion

The essential requirements for success when revising a nonunited fracture are to provide anatomical reduction, mechanical stability, bone defect augmentation and biological stimulation to achieve healing. Current advances in molecular biology, such as recombinant human bone morphogenetic protein-7, and biotechnology such as the Reamer/Irrigator/Aspirator system and hydroxyapatite injectable cement can improve patient outcomes over the use of our traditional revision techniques.
Two-step synthesis of fatty acid ethyl ester from soybean oil catalyzed by Yarrowia lipolytica lipase
Authors: Meng Yonghong , Wang Guili , Yang Na , Zhou Zhiqi , Li Yuejuan , Liang Xiaomei , Chen Jinnan , Li Ying , Li Jilun
Published: March 2011

Background

Enzymatic biodiesel production by transesterification in solvent media has been investigated intensively, but glycerol, as a by-product, could block the immobilized enzyme and excess n-hexane, as a solution aid, would reduce the productivity of the enzyme. Esterification, a solvent-free and no-glycerol-release system for biodiesel production, has been developed, and two-step catalysis of soybean oil, hydrolysis followed by esterification, with Yarrowia lipolytica lipase is reported in this paper.

Results

First, soybean oil was hydrolyzed at 40°C by 100 U of lipase broth per 1 g of oil with approximately 30% to 60% (vol/vol) water. The free fatty acid (FFA) distilled from this hydrolysis mixture was used for the esterification of FFA to fatty acid ethyl ester by immobilized lipase. A mixture of 2.82 g of FFA and equimolar ethanol (addition in three steps) were shaken at 30°C with 18 U of lipase per 1 gram of FFA. The degree of esterification reached 85% after 3 hours. The lipase membranes were taken out, dehydrated and subjected to fresh esterification so that over 82% of esterification was maintained, even though the esterification was repeated every 3 hours for 25 batches.

Conclusion

The two-step enzymatic process without glycerol released and solvent-free demonstrated higher efficiency and safety than enzymatic transesterification, which seems very promising for lipase-catalyzed, large-scale production of biodiesel, especially from high acid value waste oil.
Time course analysis of gene expression identifies multiple genes with differential expression in patients with in-stent restenosis
Authors: Ganesh Santhi K , Joo Jungnam , Skelding Kimberly , Mehta Laxmi , Zheng Gang , O'Neill Kathleen , Billings Eric M , Helgadottir Anna , Andersen Karl , Thorgeirsson Gudmundur , Gudnason Thorarinn , Geller Nancy L , Simari Robert D , Holmes David R , O'Neill William W , Nabel Elizabeth G
Published: March 2011

Background

The vascular disease in-stent restenosis (ISR) is characterized by formation of neointima and adverse inward remodeling of the artery after injury by coronary stent implantation. We hypothesized that the analysis of gene expression in peripheral blood mononuclear cells (PBMCs) would demonstrate differences in transcript expression between individuals who develop ISR and those who do not.

Methods and Results

We determined and investigated PBMC gene expression of 358 patients undergoing an index procedure to treat in de novo coronary artery lesions with bare metallic stents, using a novel time-varying intercept model to optimally assess the time course of gene expression across a time course of blood samples. Validation analyses were conducted in an independent sample of 97 patients with similar time-course blood sampling and gene expression data. We identified 47 probesets with differential expression, of which 36 were validated upon independent replication testing. The genes identified have varied functions, including some related to cellular growth and metabolism, such as the NAB2 and LAMP genes.

Conclusions

In a study of patients undergoing bare metallic stent implantation, we have identified and replicated differential gene expression in peripheral blood mononuclear cells, studied across a time series of blood samples. The genes identified suggest alterations in cellular growth and metabolism pathways, and these results provide the basis for further specific functional hypothesis generation and testing of the mechanisms of ISR.
Sphingosine-1 phosphate receptor (S1p1), a critical receptor controlling human lymphocyte trafficking, is expressed in hen and human ovaries and ovarian tumors
Authors: Bradaric Michael J , Barua Animesh , Penumatsa Krishna , Yi Yu , Edassery Seby L , Sharma Sameer , Abramowicz Jacques S , Bahr Janice M , Luborsky Judith L
Published: March 2011

Background

Sphingosine-1 receptor 1 (S1P1) plays a major role in regulating lymphocyte egress from peripheral lymph tissue. Lymphocyte trafficking is potentially a critical response to tumors and to tumor vaccines. Also, the receptor has been shown to influence metastasis. However, there is little information on its expression in the aged ovary or ovarian tumors. As a basis for further studies in the laying hen model of spontaneous ovarian cancer, the objective of this study was to determine if S1P1 is expressed in hens, and if the morphological distribution of S1P1 is similar in hen and human ovary and ovarian tumors.

Methods

S1P1 mRNA was ascertained in hen tissue by RT-PCR using hen specific primers. S1P1 protein expression and localization was evaluated in hen and human tissue with a human S1P1 antibody by Western blot and immunohistochemistry.

Results

S1P1 mRNA was expressed in all hen tissues examined. Protein was detected in human and hen ovary and ovarian tumors at 47, 72 and 108 kDa in Western blots. S1P1 was similarly expressed on endothelial cells, lymphocytes and surface epithelial cells in normal ovaries and tumor-containing ovaries of the hen. In addition, S1P1 distribution was heterogeneous in both hen and human ovarian tumors by immunohistochemistry.

Conclusion

The results show that S1P1 is expressed in the hen and human ovary as well as in ovarian tumors. These findings support the use of the hen in further studies of the role of S1P1 in metastasis and immune cell trafficking in ovarian tumor development.
Quality of interhospital transport of the critically ill: impact of a Mobile Intensive Care Unit with a specialized retrieval team
Authors: Wiegersma Janke S , Droogh Joep M , Zijlstra Jan G , Fokkema Janneke , Ligtenberg Jack JM
Published: March 2011

Introduction

In order to minimize the additional risk of interhospital transport of critically ill patients, we started a mobile intensive care unit (MICU) with a specialized retrieval team, reaching out from our university hospital-based intensive care unit to our adherence region in March 2009. To evaluate the effects of this implementation, we performed a prospective audit comparing adverse events and patient stability during MICU transfers with our previous data on transfers performed by standard ambulance.

Methods

All transfers performed by MICU from March 2009 until December 2009 were included. Data on 14 vital variables were collected at the moment of departure, arrival and 24 hours after admission. Variables before and after transfer were compared using the paired-sample T-test. Major deterioration was expressed as a variable beyond a predefined critical threshold and was analyzed using the McNemar test and the Wilcoxon Signed Ranks test. Results were compared to the data of our previous prospective study on interhospital transfer performed by ambulance.

Results

A total of 74 interhospital transfers of ICU patients over a 10-month period were evaluated. An increase of total number of variables beyond critical threshold at arrival, indicating a worsening of condition, was found in 38 percent of patients. Thirty-two percent exhibited a decrease of one or more variables beyond critical threshold and 30% showed no difference. There was no correlation between patient status at arrival and the duration of transfer or severity of disease. ICU mortality was 28%. Systolic blood pressure, glucose and haemoglobin were significantly different at arrival compared to departure, although significant values for major deterioration were never reached. Compared to standard ambulance transfers of ICU patients, there were less adverse events: 12.5% vs. 34%, which in the current study were merely caused by technical (and not medical) problems. Although mean Acute Physiology and Chronic Health Evaluation II (APACHE II) score was significantly higher, patients transferred by MICU showed less deterioration in pulmonary parameters during transfer than patients transferred by standard ambulance.

Conclusions

Transfer by MICU imposes less risk to critically ill patients compared to transfer performed by standard ambulance and has, therefore, resulted in an improved quality of interhospital transport of ICU patients in the north-eastern part of the Netherlands.
Cytomegalovirus reactivation and associated outcome of critically ill patients with severe sepsis
Authors: Heininger Alexandra , Haeberle Helene , Fischer Imma , Beck Robert , Riessen Reimer , Rohde Frank , Meisner Christoph , Jahn Gerhard , Koenigsrainer Alfred , Unertl Klaus , Hamprecht Klaus
Published: March 2011

Introduction

Sepsis has been identified as a risk factor for human cytomegalovirus (CMV) reactivation in critically ill patients. However, the contribution of CMV reactivation on morbidity and mortality is still controversial. Therefore, we analyzed the incidence and impact of CMV reactivation on outcome in patients with severe sepsis.

Methods

In a prospective longitudinal double-blinded observational study, 97 adult nonimmunosuppressed CMV-seropositive patients with new onset of severe sepsis were included. Leukocytes, plasma and tracheal secretions were examined weekly for CMV-DNA by PCR. Tracheal secretions were additionally tested for HSV (Herpes Simplex Virus)-DNA. The influence of CMV-reactivation on the endpoints was analysed by Cox proportional-hazard regression analysis. Time-dependency was evaluated by landmark analysis.

Results

Six out 97 died and five were discharged from the hospital within 72 hours and were excluded of the analysis. CMV reactivation occurred in 35 of the 86 (40.69%) analysed patients. HSV infection occurred in 23 of the 35 (65.7%) CMV reactivators. In 10 patients CMV-plasma-DNAemia appeared with a DNA-content below 600 copies/ml in four cases and a peak amount of 2,830 copies/ml on average. In patients with and without CMV reactivation mortality rates were similar (37.1% vs. 35.3%, P = 0.861), respectively. However, in the multivariate COX regression analyses CMV reactivation was independently associated with increased length of stay in the ICU (30.0, interquartile range 14 to 48 vs. 12.0, interquartile range 7 to 19 days; HR (hazard ratio) 3.365; 95% CI (confidence interval) 1.233 to 9.183, P = 0.018) and in the hospital (33.0, interquartile range 24 to 62 vs. 16.0, interquartile range 10 to 24 days, HR 3.3, 95% CI 1.78 to 6.25, P < 0.001) as well as prolonged mechanical ventilation (22.0, interquartile range 6 to 36 vs. 7.5, interquartile range 5 to 15.5 days; HR 2.6,CI 95% 1.39 to 4.94; P < 0.001) and impaired pulmonary gas exchange (six days, interquartile range 1 to 17, vs. three, interquartile range 1 to 7, days in reactivators vs. non-reactivators, P = 0.038). HSV reactivation proved not to be a risk factor for these adverse effects.

Conclusions

These data indicate an independent correlation between CMV reactivation and increased morbidity in the well-defined group of nonimmunosuppressed patients with severe sepsis, but CMV reactivation had no impact on mortality in this group with low CMV-DNA plasma levels. Thus, the potential harms and benefits of antiviral treatment have to be weighed cautiously in patients with severe sepsis or septic shock.