bluuebunny/crossref_metadata_2025 huggingface dataset:
Utilisation of Blood Components in Trauma Surgery: A Single-Centre, Retrospective Analysis before and after the Implementation of an Educative PBM Initiative
Authors: Geissler Raoul Georg , Kösters Clemens , Franz Dominik , Buddendick Hubert , Borowski Matthias , Juhra Christian , Lange Matthias , Bunzemeier Holger , Roeder Norbert , Sibrowski Walter , Raschke Michael J. , Schlenke Peter
Published: March 2015

Background: The aim of our single-centre retrospective study presented here is to further analyse the utilisation of allogeneic blood components within a 5-year observation period (2009-2013) in trauma surgery (15,457 patients) under the measures of an educational patient blood management (PBM) initiative. Methods: After the implementation of the PBM initiative in January 2012, the Institute of Transfusion Medicine und Transplantation Immunology educates surgeons and nurses at the Department of Trauma Surgery to avoid unnecessary blood transfusions. A standardised reporting system was used to document the utilisation of blood components carefully for the most frequent diagnoses and surgical interventions in trauma surgery. These measures served as basis for the implementation of an interdisciplinary systematic exchange of information to foster decision-making processes in favour of patient blood management. Results: Since January 2012, the proportion of patients who received a transfusion as well as the number of transfused red blood cell (RBC) (7.3%/6.4%; p = 0.02), fresh frozen plasma (FFP) (1.7%/1.3%; p < 0.05) and platelet (PLT) (1.0%/0.5%; p < 0.001) units were reduced as a result of our PBM initiative. However, among the transfused patients, the number of administered RBC, FFP and PLT units did not decrease significantly. Overall, patients who did not receive transfusions were younger than transfused patients (p = 0.001). The subgroup with the highest probability of blood transfusion administered included patients with intensive care and long-term ventilation (before/after implementation of PBM: RBC 81.5%/75.9%; FFP 33.3%/20.4%; PLT 24.1%/13.0%). Only a total of 60 patients of 531 patients suffering multiple traumas were massively transfused (before/after implementation of PBM: RBC 55.6%/49.8%; FFP 28.4%/20.4%; PLT 17.6%/8.9%). Conclusion: According to our educational PBM initiative, at least the proportion of trauma patients who received allogeneic blood transfusions could be reduced significantly. However, in case of blood transfusions, the total consumption of RBC, FFP and PLT units remained stable in both time periods. This phenomenon might indicate that the actual need of blood transfusions rather depends on the severity of trauma-related blood loss, the coagulopathy rates or the complexity of the surgical intervention which mainly determines the intra-operative blood loss. Taken together, educational training sessions and systematic reporting systems are suitable measures to avoid unnecessary allogeneic blood transfusions and to continuously improve their restrictive application.
EGFR-Mutated Breast Metastasis of Lung Adenocarcinoma: A Case Report
Authors: Dansin Eric , Carnot Aurélien , Servent Véronique , Daussay Dorothée , Robin Yves-Marie , Surmei-Pintilie Ecaterina , Lauridant Géraldine , Descarpentries Clothilde , Révillion Françoise , Delattre Claire
Published: March 2015

Breast metastasis from other primary carcinoma is very rare and could be difficult to identify despite immunohistochemistry analysis. Breast metastasis from lung adenocarcinoma can mimic triple-negative breast cancer. Given the prognosis and therapeutic challenges, a correct diagnosis appears essential, and molecular biomarkers could be useful. We report the case of a 52-year-old woman with a breast mass initially diagnosed as primary breast cancer and secondarily attached to breast metastasis from an EGFR-mutated lung adenocarcinoma. The same activating EGFR mutations were identified in both the primary lung carcinoma and the breast metastasis.
Repolarization Reserve Evolves Dynamically During the Cardiac Action Potential
Authors: Nguyen Thao P. , Singh Neha , Xie Yuanfang , Qu Zhilin , Weiss James N.
Published: March 2015

Background—

Transient outward K currents (I
to
) have been reported both to suppress and to facilitate early afterdepolarizations (EADs) when repolarization reserve is reduced. Here, we used the dynamic clamp technique to analyze how I
to
accounts for these paradoxical effects on EADs by influencing the dynamic evolution of repolarization reserve during the action potential.

Methods and Results—

Isolated patch-clamped rabbit ventricular myocytes were exposed to either oxidative stress (H
2
O
2
) or hypokalemia to induce bradycardia-dependent EADs at a long pacing cycle length of 6 s, when native rabbit I
to
is substantial. EADs disappeared when the pacing cycle length was shortened to 1 s, when I
to
becomes negligible because of incomplete recovery from inactivation. During 6-s pacing cycle length, EADs were blocked by the I
to
blocker 4-aminopyridine, but reappeared when a virtual current with appropriate I
to
-like properties was reintroduced using the dynamic clamp (n=141 trials). During 1-s pacing cycle length in the absence of 4-aminopyridine, adding a virtual I
to
-like current (n=1113 trials) caused EADs to reappear over a wide range of I
to
conductance (0.005–0.15 nS/pF), particularly when inactivation kinetics were slow (τ
inact
≥20 ms) and the pedestal (noninactivating component) was small (<25% of peak I
to
). Faster inactivation or larger pedestals tended to suppress EADs.

Conclusions—

Repolarization reserve evolves dynamically during the cardiac action potential. Whereas sufficiently large I
to
can suppress EADs, a wide range of intermediate I
to
properties can promote EADs by influencing the temporal evolution of other currents affecting late repolarization reserve. These findings raise caution in targeting I
to
as an antiarrhythmic strategy.
Effect of Atrial Fibrillation Ablation on Gastric Motility
Authors: Lakkireddy Dhanunjaya , Reddy Yeruva Madhu , Atkins Donita , Rajasingh Johnson , Kanmanthareddy Arun , Olyaee Mojtaba , Dusing Reginald , Pimentel Rhea , Bommana Sudharani , Dawn Buddhadeb
Published: March 2015

Background—

Collateral damage to the vagal nerve and the upper gastrointestinal (UGI) system during atrial fibrillation ablation has not been systematically evaluated.

Methods and Results—

We performed a prospective, observational study assessing the effect of atrial fibrillation ablation on the function of the vagus nerve/UGI system. All patients underwent esophageal manometry, gastric emptying study, and sham-feeding test (corresponding to esophageal, gastric, and small intestinal function evaluation, respectively) before ablation (baseline) and subsequently at 24 hours, 90 days, and 180 days after the procedure. In addition, UGI symptom assessment using the patient assessment of upper gastrointestinal disorders–symptom severity index (PAGI-SYM) questionnaire was performed at baseline and during each of the subsequent evaluations. Of the 27 patients enrolled in the study, 9 (33%) patients had abnormal UGI function at baseline; defined as at least one of the 3 abnormal tests. At 24 hours after the radiofrequency catheter ablation, 20 (74%) patients had at least 1 new abnormality on the UGI function tests (
P
<0.001). New onset esophageal dysmotility, delayed gastric emptying time, and abnormal sham-feeding tests were observed in 13 (48%), 13 (48%), and 9 (33%) patients, respectively. Mean PAGI-SYM scores increased from 7.78±6.6 at baseline to 15.56±13.4 (
P
=0.002) at 24 hours. New onset abnormalities persisted in 9 (33%) patients at 3 months and normalized in all patients at 6 months.

Conclusions—

Atrial fibrillation ablation results in functional impairment of the UGI system, including the esophagus, stomach, and small intestine. This impairment is transient and is probably mediated by the injury to the components of the vagal nerve.

Clinical Trial Registration—

URL:
http://clinicaltrials.gov
. Unique Identifier: NCT01396356.
Cardiac Response to Low-Energy Field Pacing Challenges the Standard Theory of Defibrillation
Authors: Caldwell Bryan J. , Trew Mark L. , Pertsov Arkady M.
Published: March 2015

Background—

The electric response of myocardial tissue to periodic field stimuli has attracted significant attention as the basis for low-energy antifibrillation pacing, potentially more effective than traditional single high-energy shocks. In conventional models, an electric field produces a highly nonuniform response of the myocardial wall, with discrete excitations, or hot spots (HS), occurring at cathodal tissue surfaces or large coronary vessels. We test this prediction using novel 3-dimensional tomographic optical imaging.

Methods and Results—

Experiments were performed in isolated coronary perfused pig ventricular wall preparations stained with near-infrared voltage-sensitive fluorescent dye DI-4-ANBDQBS. The 3-dimensional coordinates of HS were determined using alternating transillumination. To relate HS formation with myocardial structures, we used ultradeep confocal imaging (interrogation depths, >4 mm). The peak HS distribution is located deep inside the heart wall, and the depth is not significantly affected by field polarity. We did not observe the strong colocalization of HS with major coronary vessels anticipated from theory. Yet, we observed considerable lateral displacement of HS with field polarity reversal. Models that de-emphasized lateral intracellular coupling and accounted for resistive heterogeneity in the extracellular space showed similar HS distributions to the experimental observations.

Conclusions—

The HS distributions within the myocardial wall and the significant lateral displacements with field polarity reversal are inconsistent with standard theories of defibrillation. Extended theories based on enhanced descriptions of cellular scale electric mechanisms may be necessary. The considerable lateral displacement of HS with field polarity reversal supports the hypothesis of biphasic stimuli in low-energy antifibrillation pacing being advantageous.
LKB1 Knockout Mouse Develops Spontaneous Atrial Fibrillation and Provides Mechanistic Insights Into Human Disease Process
Authors: Ozcan Cevher , Battaglia Emily , Young Rebeccah , Suzuki Gen
Published: March 2015

Background

Atrial fibrillation (
AF
) is a complex disease process, and the molecular mechanisms underlying initiation and progression of the disease are unclear. Consequently, AF has been difficult to model. In this study, we have presented a novel transgenic mouse model of
AF
that mimics human disease and characterized the mechanisms of atrial electroanatomical remodeling in the genesis of
AF
.

Methods and Results

Cardiac‐specific liver kinase B1 (
LKB
1) knockout (
KO
) mice were generated, and 47% aged 4 weeks and 95% aged 12 weeks developed spontaneous
AF
from sinus rhythm by demonstrating paroxysmal and persistent stages of the disease. Electrocardiographic characteristics of sinus rhythm were similar in
KO
and wild‐type mice. Atrioventricular block and atrial flutter were common in
KO mice
. Heart rate was slower with persistent AF. In parallel with
AF
,
KO
mice developed progressive biatrial enlargement with inflammation, heterogeneous fibrosis, and loss of cardiomyocyte population with apoptosis and necrosis. Atrial tissue was infiltrated with inflammatory cells. C‐reactive protein, interleukin 6, and tumor necrosis factor α were significantly elevated in serum. KO atria demonstrated elevated reactive oxygen species and decreased
AMP‐activated protein kinase
activity. Cardiomyocyte and myofibrillar ultrastructure were disrupted. Intercellular matrix and gap junction were interrupted. Connexins 40 and 43 were reduced. Persistent AF caused left ventricular dysfunction and heart failure. Survival and exercise capacity were worse in
KO
mice.

Conclusions

LKB
1
KO
mice develop spontaneous
AF
from sinus rhythm and progress into persistent AF by replicating the human
AF
disease process. Progressive inflammatory atrial cardiomyopathy is the genesis of
AF,
through mechanistic electrical and structural remodeling.
Living (on) Dust: Around the Globe with Mineral Particles & Microbial Hitchhikers
Authors: Bakke Monika
Published: March 2015

Moving dust is full of life, but this life is not what makes it move. Since the establishment of the germ theory of disease, dust has mainly been viewed as being invisibly threatening and visibly distressful. In this article, the author emphasizes that there has been another view on dust all along: This view both links the presence of dust in the atmosphere to meteorological events crucial for life and acknowledges its vital impact on the global ecology of land, water and air in a deep-time perspective. Moving dust is a planetary force of inseparable organic and nonorganic matter that shelters, transports, feeds but also kills life. Recently the force of dust, which has yet to be fully comprehended, has been employed in controversial geoengineering practices.
“Dead Eyes Open”: The Role of Experiments in Galvanic Reanimation in Nineteenth-Century Popular Culture
Authors: Stephens Elizabeth
Published: March 2015

During the first decades of the 19th century, a number of prominent scientists conducted experiments in the revival of dead organisms using new galvanic technologies. In several cases, these experiments were conducted on human bodies, using the corpses of executed criminals. Such experiments captured the cultural imaginary of the day, posing new questions about the relationship between emergent technologies, automated movement, and human agency. This article examines the role played by spectacle, aesthetics, and new practices and technologies of visualization in these scientific experiments.
Learning Dynamics of a Single Polar Variable Complex-Valued Neuron
Authors: Nitta Tohru
Published: March 2015

This letter investigates the characteristics of the complex-valued neuron model with parameters represented by polar coordinates (called polar variable complex-valued neuron). The parameters of the polar variable complex-valued neuron are unidentifiable. The plateau phenomenon can occur during learning of the polar variable complex-valued neuron. Furthermore, computer simulations suggest that a single polar variable complex-valued neuron has the following characteristics in the case of using the steepest gradient-descent method with square error: (1) unidentifiable parameters (singular points) degrade the learning speed and (2) a plateau can occur during learning. When the weight is attracted to the singular point, the learning tends to become stuck. However, computer simulations also show that the steepest gradient-descent method with amplitude-phase error and the complex-valued natural gradient method could reduce the effects of the singular points. The learning dynamics near singular points depends on the error functions and the training algorithms used.
Input-Anticipating Critical Reservoirs Show Power Law Forgetting of Unexpected Input Events
Authors: Mayer Norbert Michael
Published: March 2015

Usually reservoir computing shows an exponential memory decay. This letter investigates under which circumstances echo state networks can show a power law forgetting. That means traces of earlier events can be found in the reservoir for very long time spans. Such a setting requires critical connectivity exactly at the limit of what is permissible according to the echo state condition. However, for general matrices, the limit cannot be determined exactly from theory. In addition, the behavior of the network is strongly influenced by the input flow. Results are presented that use certain types of restricted recurrent connectivity and anticipation learning with regard to the input, where power law forgetting can indeed be achieved.
Two new species of dragon millipedes, genus Desmoxytes Chamnerlin, 1923, from Laos (Diplopoda: Polydesmida: Paradoxosomatidae), with redescriptions of all four species of Attems from Vietnam
Authors: LIKHITRAKARN NATDANAI , GOLOVATCH SERGEI I. , PANHA SOMSAK
Published: March 2015

Two new species of Desmoxytes are described and abundantly illustrated: D. rhinoceros sp. n. and D. rhinoparva sp. n., from southern and northern Laos, respectively. Illustrated redescriptions of all four Vietnamese Desmoxytes species proposed by Carl Attems are also provided, based on type material.
Status changes, new synonymies, key and descriptions of seven new species in the subgenus Scarabaeus (Scarabaeolus) Balthasar 1965 (Coleoptera: Scarabaeidae: Scarabaeinae)
Authors: DESCHODT CHRISTIAN M.
Published: March 2015

Distribution of the subgenus Scarabaeus (Scarabaeolus) Balthasar 1965 (tribe Scarabaeini) is centred on southern and south central Africa with only three out of 27 species recorded from West and northeast Africa. After taxonomic corrections and descriptions of seven new southern African species this somewhat controversial subgenus now comprises 33 valid species of which one is flightless. In this paper, Scarabaeus (Scarabaeolus) vansoni Ferreira 1958 syn. nov. is synonymized with Scarabaeus (Scarabaeolus) lucidulus (Boheman 1860) and Scarabaeus (Scarabaeolus) xavieri Ferreira 1968 syn. nov. is synonymized with Scarabaeus (Scarabaeolus) andreaei zur Strassen 1963. Scarabaeus (Scarabaeolus) reichei Waterhouse 1890 stat. rev. is removed from synonymy with Scarabaeus (Scarabaeolus) canaliculatus Fairmaire, 1888 and reinstated as a valid species. Distribution maps for S. (S.) reichei, S. (S.) canaliculatus and a third close relative, Scarabaeus (Scarabaeolus) fritschi Harold 1868 are provided. The seven new species comprise: Scarabaeus (Scarabaeolus) soutpansbergensis Deschodt and Davis spec. nov., Scarabaeus (Scarabaeolus) megaparvulus Davis and Deschodt spec. nov., Scarabaeus (Scarabaeolus) niemandi Deschodt and Davis spec. nov., Scarabaeus (Scarabaeolus) carniphilus Davis and Deschodt spec. nov., Scarabaeus (Scarabaeolus) ermienae Deschodt and Davis spec. nov., Scarabaeus (Scarabaeolus) planipennis Davis and Deschodt spec. nov. and Scarabaeus (Scarabaeolus) nitidus Davis and Deschodt spec. nov. A key is provided for all the known winged species together with notes on some of the previously described species.
A new species in the newly recorded genus Trachyusa (Hymenoptera: Braconidae: Alysiinae) from China
Authors: YAO JUNLI , KULA ROBERT R. , CHEN JIAHUA
Published: March 2015

Trachyusa whartoni Yao sp. nov. from Dalian, Liaoning, China is described and illustrated. Trachyusa is a newly recorded genus in China. A key to the species of Trachyusa is provided based on the keys of Belokobylskij (1998), Papp (1967), and van Achterberg and O'Connor (1990). Type specimens of the new species are deposited in the Beneficial Insects Institute, Fujian Agriculture and Forestry University, Fuzhou, China.
Evaluating Radial Current Measurement of Multifrequency HF Radar with Multidepth ADCP Data during a Small Storm
Authors: Zhao Chen , Chen Zezong , Zeng Gengfei , Zhang Longgang , Xie Fei
Published: March 2015

A multifrequency high-frequency (MHF) radar system was designed and developed by Wuhan University in 2007. This system can simultaneously operate at four frequencies mainly in the 7.5–25-MHz band. This paper focuses on discussing the performances of an MHF radar system deployed along the coast of the East China Sea based on comparisons with multidepth ADCP datasets, which were obtained from ADCPs deployed at different locations in August 2010 during a small storm. The comparisons illustrate that radar-derived radial currents are correlated with ADCP data at mainly a 2–4-m depth with correlation coefficients over 0.95 and RMS differences less than 0.12 m s−1for both operating frequencies. Bearing offsets at points A, C, and D are computed for different operating frequencies with magnitudes of 0°–11°.

The capability of MHF radar to measure currents at different depths is explored. The results indicate that the effective depth of current measurements by MHF radar increases with decreasing operating frequency. A linear regression (with a regression coefficient of 0.0576) of the responses in the mean effective depth on the predictors in radio wavelength is obtained. The dominant semidiurnal and diurnal constituents are also analyzed. The radial current amplitudes of the M2and K1constituents are strong in this area during this experiment. The residual currents vary with wind speed, with a correlation coefficient of 0.52. A correlation coefficient of 0.79 between nontidal currents and the radial wind speed after a clockwise rotation of the wind vector by about 50° was obtained.
The Role of Tonal Onglides in German Nuclear Pitch Accents
Authors: Ritter Simon , Grice Martine
Published: March 2015

A perception experiment with native German listeners provided evidence for the relevance of the tonal onglide in nuclear accents – the pitch movement leading towards the target on the accented syllable. Listeners were able to distinguish between two pragmatic meanings of a short phrase (given/non-contrastive and new/contrastive) using the tonal onglide as the sole acoustic cue. On the basis of these findings, we argue that the onglide merits a phonological status in an intonation model of German and should not be regarded as merely phonetic detail.
Role functioning among adults with schizophrenia
Authors: Westcott Cassandra , Waghorn Geoff , McLean Duncan , Statham Dixie , Mowry Bryan
Published: March 2015

Introduction

The extent that adults with schizophrenia and schizoaffective disorders participate in socially valued roles within their community is an important aspect of recovery and rehabilitation. Although previous research has explored functioning in specific roles (for example, education, employment and independent living) less is known about combined participation in different types of socially valued roles. The purpose of this investigation was to describe the role functioning of a community sample of 255 adults with schizophrenia or schizoaffective disorder.

Method

The diagnostic interview for genetics study 2.0 was administered by trained clinicians and provided the background clinical information for this report. A subsample from the genetics study was interviewed by telephone using the socially valued role classification scale. Participants were specifically asked about their participation in employment, education and training, rehabilitation, caring for others, and home duties and self-care.

Results

Overall role participation was high, with 80% participating in socially valued roles other than independent living. Role functioning in each role category was relatively independent of functioning in other role domains.

Conclusion

Occupational therapists can best facilitate the rehabilitation and recovery of community residents with severe mental illness by adopting a role-specific approach based on individual preferences for particular role domains.
Prevention of Murine Influenza a Virus Pneumonitis by Surfactant Nano-Emulsions
Authors: Donovan Brian W , Reuter Jon D , Cao Zhengyi , Myc Andrzej , Johnson Kent J , Baker James R
Published: March 2015

Non-ionic surfactant nano-emulsions have extensive anti-microbial activity and are biocompatible with skin and mucous membranes at effective concentrations. Two nano-emulsion formulations (8N8 and 20N10) made from soybean oil, tributyl phosphate and Triton X-100, were tested for their ability to prevent murine influenza virus pneumonia in vivo. In the initial study, CD-1 mice were administered various dilutions of the nano-emulsions intranasally, and safe dosages and concentrations were determined. Non-toxic concentrations of the nano-emulsions were then mixed with influenza virus and applied to the nares of mice. Animals receiving mixtures of two different emulsions (8N8 or 20N10) and a LD50 of virus survived the challenge without evidence of viral infection. To determine if the nano-emulsions could prevent influenza virus infection in vivo when used as a prophylactic treatment, the nano-emulsions (8N8 at 1.0% and 20N10 at 1.0% or 0.2%) were applied to mouse nares 90 min before exposure to 5×105 p.f.u./ml virus by nebulized aerosol. Animals pretreated with the nano-emulsions had significantly decreased clinical signs of infection. Only 26.0% (8N8 at 1.0%), 31.25% (20N10 at 1.0%) and 37.0% (20N10 at 0.2%) of animals pretreated with nano-emulsion died from pneumonitis, whereas >80.0% of mock pretreated animals succumbed to infection ( P<0.005). These findings suggest that non-ionic surfactant nano-emulsions have therapeutic potential for the prevention of influenza virus infection in vivo.
TSAO-T Analogues Bearing Amino Acids at Position N-3 of Thymine: Synthesis and Anti-Human Immunodeficiency Virus Activity
Authors: Chamorro C , De Clercq E , Balzarini J , Camarasa M-J , San-Félix A
Published: March 2015

Novel analogues of the anti-HIV-1 lead compound [1-[2‘,5’-bis- O-( tert-butyldimethylsilyl)-β-D-ribofuranosyl]thymine]-3‘-spiro-5’-(4“-amino-1”,2“-oxathiole-2‘,2’-dioxide) (TSAO-T) bearing different amino acids at position N-3 of thymine were prepared and evaluated as inhibitors of HIV replication. The synthesis of the target compounds was accomplished by coupling of the appropriate TSAO intermediate with a conveniently protected (L) amino acid in the presence of BOP and triethylamine, followed by depro-tection of the amino acid moiety. Several TSAO derivatives, bearing at N-3 position of the thymine base an L-amino acid retaining the free carboxylic acid, acquired activity against HIV-2, in addition to their inhibitory effect on HIV-1.
Antiviral Effect of Brassinosteroids against Herpes Virus and Arenaviruses
Authors: Wachsman Mónica B , López Elsa MF , Ramirez Javier A , Galagovsky Lydia R , Coto Celia E
Published: March 2015

A natural brassinosteroid and a series of synthetic derivatives were found to be good inhibitors of herpes simplex virus type 1 (HSV-1) and arenavirus replication in cell culture. The synthetic compounds tested were analogues of the 24(S) ethylbrassinone. Compounds (22R,23R,24S)-2α, 3α,5α,22,23-pentahydroxy-stigmastan-6-one and (22R,23R,24S)-3β-bromo-5α,22,23-trihydroxy stigmastan-6-one were cytotoxic at concentrations of 20–40 µM. (22S,23S,24S)-2α,3α,22,23-tetrahydroxy-5α,stigmastan-6-one, (22R,23R,24S)-3β-acetoxy-22,23-dihydroxy-5α-cholestan-6-one, (22S,23S,24S)-3β-bromo-22,23-dihydroxy-5α-cholestan-6-one and (22S,23S,24S)-3β-bromo-5α,22,23-trihydroxy-stigmastan-6-one were the most active of the series against HSV-1, with selectivity index (SI) values (CC50/EC50) ranging from 10.6 to 16.5. The majority of the compounds were potent inhibitors of arenaviruses, (22S,23S,24S)-3β-bromo-5α,22,23-trihydroxy-stigmastan-6-one being the most active, with SI values of 307.8 and 692.5 for Tacaribe and Junin viruses, respectively. The antiviral activity of brassinosteroid derivatives was not because of direct inactivation; time-of-addition experiments suggested that a late step in HSV-1 multiplication was affected, whereas arenaviruses remained susceptible to the compounds throughout the replicative cycle.
Phosphoramidate Derivatives of Stavudine as Inhibitors of HIV: Unnatural Amino Acids May Substitute for Alanine
Authors: McGuigan Christopher , Bidois Laure , Hiouni Aziz , Ballatore Carlo , De Clercq Erik , Balzarini Jan
Published: March 2015

Some novel phosphoramidate derivatives of the nucleoside analogue stavudine have been prepared as membrane-soluble prodrugs of the bioactive free phosphate forms. Phenyl phosphates linked via nitrogen to methyl esterified amino acid analogues were studied, where the amino acid was an unnatural α-alkyl (or aryl) glycine or an α,α- dialkyl glycine. All compounds were characterized by a range of spectroscopic, spectrometric and analytical methods and were subjected to in vitro evaluation of their anti-human immunodeficiency virus efficacy. It is notable that certain unnatural amino acid derivatives could substitute for alanine with only a relatively small loss of activity and, moreover, that this activity did not fall-off with increasing alkyl chain length for the C2-C4 mono-alkyl series. These data are further probed by the application of our recently reported 31P-NMR-based carboxyl esterase assay, with informative results.
N-[2-(4-Methylphenyl)Ethyl]-N′-[2-(5-Bromopyridyl)]-Thiourea as a Potent Inhibitor of NNRTI-Resistant and Multidrug-Resistant Human Immunodeficiency Virus Type 1
Authors: Uckun Fatih M , Mao Chen , Pendergrass Sharon , Maher Danielle , Zhu Dan , Tuel-Ahlgren Lisa , Venkatachalam TK
Published: March 2015

The composite non-nucleoside reverse transcriptase inhibitor (NNRTI) binding pocket model was used to study a number of thiourea analogues with different substitutions at the 4-phenyl position including N-[2-(4-methylphenyl)ethyl]-N′-[2-(5-bromopyridyl)]-thiourea (compound HI-244), which inhibited recombinant RT better than trovirdine or compound HI-275 with an unsubstituted phenyl ring. HI-244 effectively inhibited the replication of HIV-1 strain HTLVIIIB in human peripheral blood mononuclear cells with an IC50 value of 0.007 μM, which is equal to the IC50 value of trovirdine. Notably, HI-244 was 20 times more effective than trovirdine against the multidrug-resistant HIV-1 strain RT-MDR with a V106A mutation (as well as additional mutations involving the RT residues 74 V, 41L and 215Y) and seven times more potent than trovirdine against the NNRTI- resistant HIV-1 strain A17 with a Y181C mutation.
Non-Nucleoside HIV-1 Reverse Transcriptase Inhibitors: Synthesis and Biological Evaluation of Novel Quinoxalinylethylpyridylthioureas as Potent Antiviral Agents
Authors: Campiani G , Fabbrini M , Morelli E , Nacci V , Greco G , Novellino E , Maga G , Spadari S , Bergamini A , Faggioli E , Uccella I , Bolacchi F , Marini S , Coletta M , Fracasso C , Caccia S
Published: March 2015

New heterocyclic derivatives of ethylpyridylthiourea, quinoxalinylethylpyridylthiourea (QXPT) and analogues, inhibited human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) activity and prevented HIV-1 cytopathogenicity in T4 lymphocytes. Several of these novel non-nucleoside RT inhibitors, with a substituted pyrroloquinoxalinone heteroaromatic skeleton, showed inhibitory activity against wild-type RT as well as against mutant RTs containing the single amino acid substitutions L100I, K103N, V106A, Y181I and Y188L that was much greater than other non-nucleoside inhibitors such as nevirapine. Maximum potency in enzymatic assays was achieved with a fluoropyrroloquinoxaline skeleton linked to the ethylpyridylthiourea moiety (FQXPT). In cell-based assays on different cell lines and on human monocyte-macrophages, 6-FQXPT exhibited EC50 values in the nanomolar range, with a promising selectivity index. Moreover, 6-FQXPT showed synergistic antiviral activity with zidovudine.
Extract of Prunella Vulgaris Spikes Inhibits HIV Replication at Reverse Transcription in vitro and can Be Absorbed from Intestine in vivo
Authors: Kageyama Seiji , Kurokawa Masahiko , Shiraki Kimiyasu
Published: March 2015

It has been reported that extracts of the spike of Prunella vulgaris (PS) exhibit anti-HIV activity at the adsorption and reverse transcription stages. In this study, the actual activity of PS in cells, kinetic analysis of the inhibitory activity of PS against HIV reverse transcriptase and the feasibility of oral administration were examined. First, to clarify whether this extract shows anti-HIV activity in cells in vitro, the number of copies of proviral DNA in HIV-exposed cells was calculated. The number of copies was significantly decreased in cells cultured in the presence of PS extract, but not in the presence of dextran sulphate. The activity of PS extract in the cells was also assessed by the drug addition test, during and after HIV adsorption. PS extract and dextran sulphate suppressed HIV production to similar levels when added after HIV adsorption. However, only PS extract suppressed HIV production at the same concentration when the drugs were added during HIV adsorption. Presumably, the penetration of the PS extract into the cells was required for this activity. Secondly, fractionated PS inhibited HIV reverse transcription in a non-competitive manner. This fractionated PS kept anti-HIV activity, but inhibited HIV replication and adsorption to a lesser extent compared to dextran sulphate. Lastly, an active component(s) was detected in plasma in vivo, after injection into the intestine, which demonstrates the feasibility of oral administration dosing.
Synthesis and Enantioselectivity of the Antiviral Effects of (R,Z)-,(S,Z)-methylenecyclopropane Analogues of Purine Nucleosides and Phosphoralaninate Prodrugs: Influence of Heterocyclic Base, Type of Virus and Host Cells
Authors: Qiu Y-L , Geiser F , Kira T , Gullen E , Cheng Y-C , Ptak RG , Breitenbach JM , Drach JC , Hartline CB , Kern ER , Zemlicka J
Published: March 2015

A series of R and S enantiomers of 2-aminopurine methylenecyclopropane analogues of nucleosides was synthesized. Two diastereoisomeric lipophilic phosphate prodrugs derived from R and S enantiomers of 2,6-diaminopurine analogue were also prepared. Enantioselectivity (diastereoselectivity in case of prodrugs) of in vitro antiviral effects was investigated with human and murine cytomegalovirus (HCMV and MCMV, respectively), herpes simplex virus types 1 and 2 (HSV-1 and HSV-2, respectively), human immunodeficiency virus type 1 (HIV-1), hepatitis B virus (HBV), Epstein—Barr virus (EBV) and varicella zoster virus (VZV). Strong differences in enantioselectivity were found between the R and S enantiomers of adenine analogue and enantiomeric 2-aminopurine analogues. Thus, the enantiomers of adenine analogue were equipotent against HCMV but not MCMV, where the S enantiomer is strongly preferred. The same S preference was found throughout the 2-aminopurine series for both HCMV and MCMV. In contrast, R-synadenol in HIV-1 assays was the best agent, whereas the S enantiomers of moderately effective 2-amino-6-cyclo-propylamino and 2-amino-6-methoxypurine analogues were preferred. Little enantiomeric preference was found for R and S enantiomers of synadenol and the corresponding enantiomers of 2,6-diaminopurine analogue against HBV. A mixed pattern of enantioselectivity was observed for EBV depending on the type of host cells and assay. Against VZV, the R and S enantiomers of adenine analogue were equipotent or almost equipotent, but throughout the series of 2-aminopurine analogues a distinct preference for the S enantiomers was found. The stereoselectivity pattern of both diastereoisomeric prodrugs mostly followed enantioselectivity of the parent analogues. The varying enantioselectivities in the series of purine methylenecyclopropane analogues are probably a consequence of differences in the mechanisms of action in different virus/host cell systems.
Piperidinylethyl, Phenoxyethyl and Fluoroethyl Bromopyridyl Thiourea Compounds with Potent Anti-HIV Activity
Authors: Venkatachalam TK , Sudbeck Elise A , Mao Chen , Uckun Fatih M
Published: March 2015

Derivatives of piperidinylethyl, phenoxyethyl and fluoroethyl bromopyridyl thioureas were designed and synthesized as non-nucleoside reverse transcriptase inhibitors (NNRTIs) of HIV-1 reverse transcriptase (RT). The anti-HIV activity of these compounds was examined by determining their ability to inhibit the replication of the HIV-1 strain HTLVIIIB in human peripheral blood mononuclear cells. The unsubstituted parent pyridyl thiourea compound N-[2-(1-piperidine)ethyl]-N′-[2-(pyridyl)] thiourea (1) exhibited no anti-HIV activity, even at 100 μM. However, the thiourea derivatives that contain a bromo- or chloro-substituted pyridyl group, compounds 2 and 5, inhibited HIV-1 replication at nanomolar concentrations. The addition of a methyl group onto the piperidine ring significantly altered the potency of these compounds; while methyl substitution at the 3-position of the piperidine ring reduced the activity, methyl substitution at the 2-position enhanced the anti-HIV activity. The IC50 value of the lead piperidinyl compound, N-[2-(2-methylpiperidinylethyl)]-N′-[2-(5-bromopyridyl)] thiourea (4) was >0.001 μM. All three phenoxyethyl derivatives, including the unsubstituted parent phenoxyethyl pyridyl thiourea compound N-[2-(phenoxy)ethyl]-N-[2-(pyridyl)]thiourea (8) and the bromo-/chloro-substituted phenoxyethyl halopyridyl thiourea compounds N-[2-(phenoxy)ethyl]-N-[2-(5-chloropyridyl)]thiourea (9) and N-[2-(phenoxy)ethyl]-N-[2-(5-bromopyridyl)]thiourea (10) exhibited potent anti-HIV activity with nanomolar IC50 values. The corresponding fluoroethyl halopyridyl thiourea compounds β-fluoro[2-phenethyl]-N′[2-(5-chloropyridyl)]thiourea (11) and β-fluoro[2-phenethyl]-N′[2-(5-bromopyridyl)]thiourea (12) inhibited HIV-1 replication in PBMC with subnanomolar IC50 values and selectivity indices <30000. Compared to the corresponding phenoxyethyl thiourea compounds 9 and 10, these compounds were <4–5–fold more active as anti-HIV agents. Notably, the lead fluorothiourea compounds 11 and 12 were both substantially more active against the NNRTI-resistant HIV strains RT-MDR (V106A) and A17 (Y181C) than nevirapine or delavirdine. Taken together, our results provide additional experimental evidence that the structural features of the ‘linker unit” between the pyridyl and phenyl moieties and changes in the phenyl group of PETT-related thiourea compounds significantly affects their biological activity as NNRTIs of HIV-1 RT.
Selection of Resistance-Conferring Mutations in HIV-1 by the Nucleoside Reverse Transcriptase Inhibitors (+/-)dOTC and (+/-)dOTFC
Authors: Richard Nathalie , Salomon Horacio , Oliveira Maureen , Rando Robert , Mansour Tarek , Gu Zhengxian , Wainberg Mark A
Published: March 2015

The patterns of resistance-conferring mutations that are selected in HIV-1 reverse transcriptase (RT) by the racemates of 2′-dideoxy-3′-oxa-4′-thiocytidine (+/-)dOTC and its fluorinated derivative (+/-)dOTFC were characterized. Genotypic and phenotypic analyses of HIV-1 clinical isolates and HXB2D variants selected with (+/-)dOTC and (+/-)dOTFC were performed in primary cells and in the MT-2 T cell line. HIV-1 variants selected with (+/-)dOTC or (+/-)dOTFC displayed fivefold decreased susceptibility to the respective compounds. A substitution of methionine to valine was identified at position 184 (M184V) in variants selected with (+/-)dOTC. In contrast, a mutation of lysine to arginine at position 65 (K65R) was found in variants selected with (+/-)dOTFC. These patterns of selected mutations differ from those seen with the individual enantiomers. Studies with mutated recombinant HXB2D-M184V and -K65R confirmed that these mutations are important for phenotypic resistance in MT-2 cells. Clinical isolates that display resistance to (-)2′-deoxy-3′-thiacytidine (3TC) also showed cross-resistance to (+/-)dOTC and (+/-)dOTFC. These studies demonstrate that similar genotypes may be selected by the dOTC and dOTFC compounds to those with the structurally related drug 3TC.
Antiviral Activity of Mixed-Valence Rare Earth Borotungstate Heteropoly Blues against Influenza Virus in Mice
Authors: Liu Jie , Mei Wenjie , Li Yangguang , Wang Enbo , Ji Liangnian , Tao Peizhen
Published: March 2015

The acute and accumulated toxicity of the rare earth borotungstate heteropoly blues, HPB-2, Ce2H3[BW9VIW2VMn(H2O)O39]·.12H2O, which is active against influenza virus in Kunming mice, were investigated in Kunming mice following oral and intraperitoneal administration. The activity of HPB-2 against influenza virus (FM1) in the mice was then investigated. HPB-2, given either orally (p.o.) or intraperitoneally (i.p.), was shown to have activity. HPB-2 was shown to be more effective than the positive control, ribavirin, and it was also found that i.p. administration was more effective than p.o. administration.
Structure—Activity Relationship Studies on New DABOs: Effect of Substitutions at Pyrimidine C-5 and C-6 Positions on Anti-HIV-1 Activity
Authors: Sbardella Gianluca , Mai Antonello , Artico Marino , Chimenti Paola , Massa Silvio , Loddo Roberta , Marongiu M Elena , La Colla Paolo , Pani Alessandra
Published: March 2015

Several 5-alkyl, 5-alkenyl, 5-iso-alkyl, 5-halo, 5-aminomethyl and 5-carboxy derivatives of S-DABOs (dihydro-alkyl (or cyclo-alkyl)thio-benzyloxopyrimidines), DATNOs (dihydro-alkylthionaphthylmethyl-oxopyrimidines) and F2-S-DABOs (dihydro-alkyl (or cyclo-alkyl)thio-2,6-difluorobenzyl-oxopyrimidines) have been prepared and tested as anti-HIV-1 agents. S-DABO derivatives bearing at C-6 position monosubstituted phenylmethyl or heteroarylmethyl units have also been synthesized. 2-Alkylthio-3,4-dihydropyrimidin-4(3 H)-one derivatives of F2- S-DABO series bearing small alkyl groups at C-5 proved to be potent inhibitors of HIV-1 replication in vitro with selectivity indexes ranging from 250 to <2500.
In vitro and in vivo Activity of 1-O-Hexadecylpropane-Diol-3-Phospho-Ganciclovir and 1-O-Hexadecylpropanediol-3-Phospho-Penciclovir in Cytomegalovirus and Herpes Simplex Virus Infections
Authors: Hostetler Karl Y , Rybak Rachel J , Beadle James R , Gardner Michael F , Aldern Kathy A , Wright Kristine N , Kern Earl R
Published: March 2015

Human cytomegalovirus (HCMV) and herpes simplex virus (HSV) can cause a wide variety of clinical manifestations in man. Ganciclovir (GCV) is effective against HCMV infection when administered by the intravenous route and may be used orally in large doses for prophylaxis of HCMV infections in organ transplantation patients and in AIDS patients. In previous studies with acyclovir (ACV), we found that covalent attachment of an alkyl glycerol phosphate moiety greatly increased oral bioavailability and increased antiviral activity against hepatitis B virus. Adducts of ACV with alkyl propanediol phosphate were more active than the alkyl glycerol phosphate analogue in vitro in 2.2.15 cells, which constitutively produce hepatitis B virus. To see if this strategy would work for two other poorly absorbed nucleoside analogues, we synthesized 1-O-hexadecylpropanediol-3-phospho-GCV (HDP-P-GCV) and 1-O-hexadecyl-propanediol-3-phospho-penciclovir (HDP-P-PCV), and evaluated the in vitro antiviral activity, selectivity and oral antiviral activity of both compounds versus GCV or PCV in mice infected with HSV-1 or HDP-P-GCV versus murine cytomegalovirus (MCMV). HDP-P-GCV is orally active in both MCMV and HSV-1 infection in mice with antiviral activity equivalent to (HSV-1) or greater than oral GCV (MCMV). Oral HDP-P-PCV was more active than PCV orally versus intranasal HSV-1 infection in mice.
Treatment of Lethal Vaccinia Virus Respiratory Infections in Mice with Cidofovir
Authors: Smee Donald F , Bailey Kevin W , Sidwell Robert W
Published: March 2015

Intranasal infection of BALB/c mice with the WR strain of vaccinia virus leads to pneumonia, profound weight loss and death. Five days after intranasal inoculation, virus from untreated mice was recovered from 11 organs, tissues and whole blood. The highest titres [<108 plaque forming units (pfu)/g] were in lungs and nose/sinus tissue, with about 107 pfu/g in spleen and blood. Seven other organs contained 30- to ≤50-fold lower amounts of virus. Mice infected with the related cowpox virus (for comparative purposes) had the majority of virus located in the respiratory tract. The vaccinia mouse model was used to study the efficacy of cidofovir treatments on the infection. Subcutaneous injections of 30 or 100 mg/kg/day, given on days 1 and 4 after virus challenge, reduced mortality by 60–100%. However, lung virus titres on days 2–5 were educed no more than 10-fold by these treatments. A moderate improvement in drug efficacy occurred with daily treatments for 5 days. The efficacy of cidofovir also increased as the virus challenge dose decreased, where subcutaneous or intraperitoneal treatment routes showed similar degrees of protection. Although it has been known for many years that the WR strain of vaccinia virus can cause lethal infections by intranasal route, its application to antiviral therapy represents a new model for studying anti-orthopoxvirus agents.
Furano Pyrimidines as Novel Potent and Selective Anti-VZV Agents
Authors: McGuigan C , Brancale A , Barucki H , Srinivasan S , Jones G , Pathirana R , Carangio A , Blewett S , Luoni G , Bidet O , Jukes A , Jarvis C , Andrei G , Snoeck R , De Clercq E , Balzarini J
Published: March 2015

Bicyclic furano pyrimidine nucleosides have been found to be highly potent and selective inhibitors of varicella zoster virus (VZV). They are inactive against herpes simplex virus and have been known for several decades as (unwanted) synthetic by-products in the Pd-catalysed coupling of acetylenes to 5-iodo nucleosides. These fluorescent bicyclic nucleosides are now established as a new family of potent antivirals. They are unusual in that they exhibit complete specificity for VZV and require an alkyl (or alkylaryl) side-chain for biological activity. The latter requirement confers extremely high lipophilicities on these compounds, unknown amongst chemotherapeutic nucleosides, which may be of considerable importance in formulation, dosing and tissue distribution. The most potent compounds reported are p-alkylaryl compounds, with EC50 values below 1nM versus VZV and selectivity index values of around 1000000. Here, we review the discovery, synthesis, characterization, antiviral profile, SAR, mechanism of action and development prospects for this new family of antivirals.
Antiviral Activity and Intracellular Metabolism of Bis(tButylSATE) Phosphotriester of β-L-2′,3'Dideoxyadenosine, a Potent Inhibitor of HIV and HBV Replication
Authors: Placidi L , Faraj A , Loi AG , Pierra C , Egron D , Cretton-Scott E , Gosselin G , Périgaud C , Martin LT , Schinazi RF , Imbach JL , el Kouni MH , Bryant ML , Sommadossi JP
Published: March 2015

The β-L-nucleoside analogue β-L-2′,3′-dideoxy adenosine (β-L-ddA) has been shown to exhibit limited antiviral activities. This was attributed to its rapid catabolism through cleavage of the glycosidic bond and poor phosphorylation to the nucleotide β-L-2′,3′-dideoxyadenosine-5′-monophosphate (β-L-ddAMP) (Placidi et al., 2000). However, the nucleotide β-L-2′,3′-dideoxyadenosine-5′-triphosphate (β-L-ddATP) inhibited the activity of both HIV-1 reverse transcriptase (RT) and viral DNA polymerase isolated from woodchuck hepatitis virus-infected serum (a model of hepatitis B) with an inhibitory concentration (IC50) of 2.0 μM without inhibiting human DNA polymerases α, β, or γ up to a concentration of 100 μM. These results suggested that prodrugs of β-L-ddAMP may bypass the poor metabolic activation of β-L-ddA and lead to more potent and selective antiviral activity. Therefore, the mononucleoside phosphotriester derivative of β-L-ddAMP incorporating the S-pivaloyl-2-thioethyl (tButylSATE) groups, β-L-ddAMP-bis(tButylSATE) was synthesized. β-L-ddAMP-bis(tButylSATE) inhibited HIV replication in human peripheral blood mononuclear cells (PBMCs) and HBV replication in 2.2.15 cells with effective concentrations (EC50s) of 2 and 80 nM, respectively. Intracellular metabolism of β-L-ddAMP-bis(tButylSATE) demonstrated that β-L-ddATP was the predominant intracellular metabolite in PBMC and liver cells. The intracellular half-life of β-L-ddATP was 5.4 and 9.2 h in HepG2 and PBMCS, respectively. The intracellular concentrations of β-L-ddATP were maintained above the EC50 for the inhibition of HIV RT and hepatitis B virus (HBV) for as long as 24 h after removal of the drug.