Preclinical assessment of antiarrhythmic drugs

The morbidity statistics for the United States alone would suggest that there are 400,000 victims each year who succumb to sudden coronary death, which suggests that there is a need for the development of pharmacological interventions capable of preventing ventricular fibrillation (VF) in patients identified as being at high risk. A major deficiency in this area of experimental investigation is the lack of an animal model that would permit preclinical studies to identify potentially useful therapeutic agents. We have developed an experimental canine model of sudden coronary death in which VF occurs in the chronically injured heart that is subjected to a period of transient ischemia in a coronary region remote from the site of a previous myocardial infarction. The experimental model is subject to the induction of ventricular tachyarrhythmias in response to programmed electrical stimulation, thereby permitting the investigator to correlate the effectiveness of a pharmacological agent in preventing electrically induced arrhythmias with its potential to prevent the development of VF in response to ischemia at a site remote from a previous infarct. Thus, acute myocardial ischemia at a site distant from a previous myocardial infarction enhances the likelihood of primary VF in the conscious dog. This model of sudden coronary death may stimulate more closely the clinical state in humans and might serve as an appropriate model for the study of electrophysiological mechanisms associated with the development of VF and for the evaluation of potential antifibrillatory drugs.     

Increased flow precedes remote arteriolar dilations for some microapplied agonists

This study asks which occurs first in time for remote responses: a dilation or a remote change in flow. Arteriolar diameter (approximately 20 microm) and fluorescently labeled red blood cell (RBC) velocity were measured in the cremaster muscle of anesthetized (pentobarbital sodium, 70 mg/kg) hamsters (n = 51). Arterioles were locally stimulated for 60 s with micropipette-applied 10 microg/ml LM-609 (alpha(v)beta(3)-integrin agonist), 10(-3) M adenosine, or 10(-3) M 3-morpholinosydnonimine (SIN-1, nitric oxide donor) as remote response agonists or with 10(-3) M papaverine, which dilates only locally. Observations were made at a remote site 1,200 microm upstream. With LM-609 or adenosine, the RBC velocity increased first (within 5 s), and the remote dilation followed 5-7 s later. N-nitro-L-arginine (100 microM) blocked the LM-609 (100%) and adenosine (60%) remote dilations. SIN-1 induced a concurrent remote dilation and decrease in RBC velocity (approximately 10 s), suggesting the primary signal was to dilate. Papaverine had no remote effects. This study suggests that, although remote responses to some agonists are induced by primary signals to dilate, additionally, network changes in flow can stimulate extensive remote changes in diameter.     

Chemotherapy against human African trypanosomiasis: is there a road to success?

For over fifty years, human African trypanosomiasis (HAT, sleeping sickness) has been treated with suramin, pentamidine and the very toxic organo-arsenical melarsoprol that was the only drug available for effective treatment of the second stage of the disease. Recently there have been significant efforts using molecular and biochemical approaches to drug design, including high-throughput screening, but the number of lead compounds with promising activity against T. brucei spp. and an acceptable toxicity index has remained astonishingly small. Clinical research continues to be difficult due to the economic constraints and the complexity of trials on a low prevalence disease in remote and impoverished African regions. Despite those limitations the situation for the patients is improving thanks to the combination of a number of critical factors. By the late 1990s the disease had reached epidemic levels that triggered political support. WHO would sign a donation agreement with the manufacturers for all drugs to treat HAT. A result of this agreement was that eflornithine which is much safer than melarsoprol became available and widely used by non-governmental organizations. The Impamel I and II programmes demonstrated that against all odds the conduct of clinical trials on HAT was feasible. This allowed the initiation of trials on combination therapies which eventually resulted in the nifurtimox-eflornithine combination treatment (NECT). This combination is currently being introduced as first line treatment, and there is even the prospect of having a new compound, fexinidazole, in the development pipeline. This review summarizes the key information about the existing drugs and gives a comprehensive summary about the recent and currently ongoing efforts towards new drugs.     

Estimating evapotranspiration and drought stress with ground-based thermal remote sensing in agriculture: a review

As evaporation of water is an energy-demanding process, increasing evapotranspiration rates decrease the surface temperature (T(s)) of leaves and plants. Based on this principle, ground-based thermal remote sensing has become one of the most important methods for estimating evapotranspiration and drought stress and for irrigation. This paper reviews its application in agriculture. The review consists of four parts. First, the basics of thermal remote sensing are briefly reviewed. Second, the theoretical relation between T(s) and the sensible and latent heat flux is elaborated. A modelling approach was used to evaluate the effect of weather conditions and leaf or vegetation properties on leaf and canopy temperature. T(s) increases with increasing air temperature and incoming radiation and with decreasing wind speed and relative humidity. At the leaf level, the leaf angle and leaf dimension have a large influence on T(s); at the vegetation level, T(s) is strongly impacted by the roughness length; hence, by canopy height and structure. In the third part, an overview of the different ground-based thermal remote sensing techniques and approaches used to estimate drought stress or evapotranspiration in agriculture is provided. Among other methods, stress time, stress degree day, crop water stress index (CWSI), and stomatal conductance index are discussed. The theoretical models are used to evaluate the performance and sensitivity of the most important methods, corroborating the literature data. In the fourth and final part, a critical view on the future and remaining challenges of ground-based thermal remote sensing is presented.     

The missing wetlands: using local ecological knowledge to find cryptic ecosystems

Small, temporally dynamic, biologically diverse isolated wetlands are among the most imperiled ecosystems, yet their conservation is hindered by lack of protective legislation and mapping. As part of an effort to better understand isolated wetland ecology in an area undergoing dramatic land use change, we mapped isolated wetlands in South Carolina’s Piedmont and Blue Ridge regions using remote sensing and local ecological knowledge (LEK). Remote detection of isolated wetlands was limited by digital resource resolution, topography, and wetland size. LEK was the most useful tool for locating small isolated wetlands. We sampled 10% of the study area using LEK and discovered 44 wetlands with “isolated” characteristics, none of which had been identified by remote sensing. Only 8 of 44 wetlands found through LEK could be identified using remote sensing after their discovery. LEK fills a gap in cryptic ecosystem detection when adequate remotely sensed data are not available. Though effective, using LEK is neither as rapid nor as repeatable as remote sensing. We suggest a two-pronged approach for finding cryptic ecosystems: remote sensing coupled with LEK where data resolution is inadequate. For remote detection of isolated wetlands, we suggest a minimum resolution of 0.33 m for Color Infrared, leaf-off, high-water photography. Despite great advances in remote sensing, data are not uniformly available worldwide and LEK may serve as an effective tool for locating cryptic resources for biodiversity conservation. Mapping cryptic resources will allow for more accurate resource and biodiversity conservation planning under current and future climate scenarios.     

Real-Time and Remote MCMC Trace Inspection with Beastiary

Bayesian phylogenetics has gained substantial popularity in the last decade, with most implementations relying on Markov chain Monte Carlo (MCMC). The computational demands of MCMC mean that remote servers are increasingly used. We present Beastiary, a package for real-time and remote inspection of log files generated by MCMC analyses. Beastiary is an easily deployed web-app that can be used to summarize and visualize the output of many popular software packages including BEAST, BEAST2, RevBayes, and MrBayes via a web browser. We describe the design and implementation of Beastiary and some typical use-cases, with a focus on real-time remote monitoring.     

A sticky situation: the unexpected stability of malaria elimination

Malaria eradication involves eliminating malaria from every country where transmission occurs. Current theory suggests that the post-elimination challenges of remaining malaria-free by stopping transmission from imported malaria will have onerous operational and financial requirements. Although resurgent malaria has occurred in a majority of countries that tried but failed to eliminate malaria, a review of resurgence in countries that successfully eliminated finds only four such failures out of 50 successful programmes. Data documenting malaria importation and onwards transmission in these countries suggests malaria transmission potential has declined by more than 50-fold (i.e. more than 98%) since before elimination. These outcomes suggest that elimination is a surprisingly stable state. Elimination''s ‘stickiness’ must be explained either by eliminating countries starting off qualitatively different from non-eliminating countries or becoming different once elimination was achieved. Countries that successfully eliminated were wealthier and had lower baseline endemicity than those that were unsuccessful, but our analysis shows that those same variables were at best incomplete predictors of the patterns of resurgence. Stability is reinforced by the loss of immunity to disease and by the health system''s increasing capacity to control malaria transmission after elimination through routine treatment of cases with antimalarial drugs supplemented by malaria outbreak control. Human travel patterns reinforce these patterns; as malaria recedes, fewer people carry malaria from remote endemic areas to remote areas where transmission potential remains high. Establishment of an international resource with backup capacity to control large outbreaks can make elimination stickier, increase the incentives for countries to eliminate, and ensure steady progress towards global eradication. Although available evidence supports malaria elimination''s stickiness at moderate-to-low transmission in areas with well-developed health systems, it is not yet clear if such patterns will hold in all areas. The sticky endpoint changes the projected costs of maintaining elimination and makes it substantially more attractive for countries acting alone, and it makes spatially progressive elimination a sensible strategy for a malaria eradication endgame.     

Studies on the Traditional Uses of Some Medicinal Shrubs of Swat Kohistan, Pakistan

The traditional herbal medicine bequeathed fromgenerationto generationis richin domestic recipes andcommunal practice . Encompassing concepts and meth-ods for the protection and restoration of health, tradi-tional medicine has served as a fount of alternativemedicine , newpharmaceuticals , and healthcare prod-ucts. The best known examples of traditional medi-cine , differing in concept and protocol , are well-de-veloped systems such as acupuncture , Unani systemand ayurvedic medicine that have…     

The cost of antibiotic mass drug administration for trachoma control in a remote area of South Sudan

Background

Mass drug administration (MDA) of antibiotics is a key component of the so-called “SAFE” strategy for trachoma control, while MDA of anthelminthics provides the cornerstone for control of a number of other neglected tropical diseases (NTDs). Simultaneous delivery of two or more of these drugs, renowned as “integrated NTD control,” is being promoted to reduce costs and expand intervention coverage. A cost analysis was conducted alongside an MDA campaign in a remote trachoma endemic area, to inform budgeting for NTD control in South Sudan.

Methods and Findings

A first round of antibiotic MDA was conducted in the highly trachoma endemic county of Mayom, Unity state, from June to August 2010. A core team of seven staff delivered the intervention, including recruitment and training of 44 supervisors and 542 community drug distributors. Using an ingredients approach, financial and economic costs were captured from the provider perspective in a detailed costing database. Overall, 123,760 individuals were treated for trachoma, resulting in an estimated treatment coverage of 94%. The economic cost per person treated was USD 1.53, excluding the cost of the antibiotic azithromycin. Ninety four per cent of the delivery costs were recurrent costs, with personnel and travel/transport costs taking up the largest share.

Conclusions

In a remote setting and for the initial round, MDA of antibiotics was considerably more expensive than USD 0.5 per person treated, an estimate frequently quoted to advocate for integrated NTD control. Drug delivery costs in South Sudan are unlikely to decrease substantially during subsequent MDA rounds, as the major cost drivers were recurrent costs. MDA campaigns for delivery of one or more drugs in South Sudan should thus be budgeted at around USD 1.5 per person treated, at least until further costing data for delivery of other NTD drugs, singly or in combination, are available.     

Drug Promiscuity in PDB: Protein Binding Site Similarity Is Key

Drug repositioning applies established drugs to new disease indications with increasing success. A pre-requisite for drug repurposing is drug promiscuity (polypharmacology) – a drug’s ability to bind to several targets. There is a long standing debate on the reasons for drug promiscuity. Based on large compound screens, hydrophobicity and molecular weight have been suggested as key reasons. However, the results are sometimes contradictory and leave space for further analysis. Protein structures offer a structural dimension to explain promiscuity: Can a drug bind multiple targets because the drug is flexible or because the targets are structurally similar or even share similar binding sites? We present a systematic study of drug promiscuity based on structural data of PDB target proteins with a set of 164 promiscuous drugs. We show that there is no correlation between the degree of promiscuity and ligand properties such as hydrophobicity or molecular weight but a weak correlation to conformational flexibility. However, we do find a correlation between promiscuity and structural similarity as well as binding site similarity of protein targets. In particular, 71% of the drugs have at least two targets with similar binding sites. In order to overcome issues in detection of remotely similar binding sites, we employed a score for binding site similarity: LigandRMSD measures the similarity of the aligned ligands and uncovers remote local similarities in proteins. It can be applied to arbitrary structural binding site alignments. Three representative examples, namely the anti-cancer drug methotrexate, the natural product quercetin and the anti-diabetic drug acarbose are discussed in detail. Our findings suggest that global structural and binding site similarity play a more important role to explain the observed drug promiscuity in the PDB than physicochemical drug properties like hydrophobicity or molecular weight. Additionally, we find ligand flexibility to have a minor influence.     

Enzymatic resolution of racemates with a ‘remote’ stereogenic center as an efficient tool in drug,flavor and vitamin synthesis

The enantioselective recognition of ‘remote’ stereogenic centers represents a scientific task in organic chemistry being also of current interest in the pharmaceutical industry. This is due to a range of pharmaceutically relevant molecules or intermediates thereof bearing a stereogenic center, which is separated from the functional group by a larger non-chiral moiety such as, for example, a longer sequence of bonds of at least three carbon or hetero-atoms or by a planar aromatic moiety. Notably, biocatalysis turned out to provide an excellent solution for a range of challenging syntheses in this field. For example, efficient enzymatic resolution processes of racemates with such a ‘remote’ stereogenic center were developed for the synthesis of pelitrexol, lasofoxifene and (S)-monastrol. In general, good yields accompanied by high enantioselectivities were obtained, thus underlining the tremendous potential of enzymes to recognize and enantioselectively transform enantiomers of racemates with ‘remote’ stereogenic centers. Such or similar types of stereoselective recognitions of ‘remote’ stereogenic centers by means of enzymes have been also reported in the field of flavor and vitamin synthesis. Thus, biocatalysis represents a promising solution for the efficient approach to enantiomerically pure complex chiral molecules with stereogenic centers being located apart from the functional group, and it can be expected that enzymatic resolution will be increasingly applied when searching for an efficient and also technically feasible process for also novel complex chiral molecules bearing a ‘remote’ stereogenic center.     

Performance evaluation of a remote memory system with commodity hardware for large-memory data processing

The explosion of data and transactions demands a creative approach for data processing in a variety of applications. Research on remote memory systems (RMSs), so as to exploit the superior characteristics of dynamic random access memory (DRAM), has been performed for many decades, and today’s information explosion galvanizes researchers into shedding new light on the technology. Prior studies have mainly focused on architectural suggestions for such systems, highlighting different design rationale. These studies have shown that choosing the appropriate applications to run on an RMS is important in fully utilizing the advantages of remote memory. This article provides an extensive performance evaluation for various types of data processing applications so as to address the efficacy of an RMS by means of a prototype RMS with reliability functionality. The prototype RMS used is a practical kernel-level RMS that renders large memory data processing feasible. The abstract concept of remote memory was materialized by borrowing unused local memory in commodity PCs via a high speed network capable of Remote Direct Memory Access (RDMA) operations. The prototype RMS uses remote memory without any part of its computation power coming from remote computers. Our experimental results suggest that an RMS can be practical in supporting the rigorous demands of commercial in memory database systems that have high data access locality. Our evaluation also convinces us of the possibility that a reliable RMS can satisfy both the high degree of reliability and efficiency for large memory data processing applications whose data access pattern has high locality.     

Drug repurposing for chronic myeloid leukemia: in silico and in vitro investigation of DrugBank database for allosteric Bcr-Abl inhibitors

Chronic myeloid leukemia (CML) is caused by chromosomal rearrangement resulting in the expression of Bcr-Abl fusion protein with deregulated Abl tyrosine kinase activity. Approved drugs – imatinib, dasatinib, nilotinib, and ponatinib – target the ATP-binding site of Abl kinase. Even though these drugs are initially effective, long-term usefulness is limited by the development of resistance. To overcome this problem, targeting the allosteric site of Abl kinase, which is remote from the ATP-binding site is found to be a useful strategy. In this study, structure-based and ligand-based virtual screening methods were applied to narrow down possible drugs (from DrugBank database) that could target the allosteric site of Abl kinase. Detailed investigations of the selected drugs in the allosteric site of Abl kinase, using molecular dynamics and steered molecular dynamics simulation shows that gefitinib, an EGFR inhibitor approved for the treatment of lung cancer, could bind effectively to the allosteric site of Bcr-Abl. More interestingly, gefitinib was found to enhance the ability of imatinib to bind at the ATP-binding site of Bcr-Abl kinase. Based on the in silico findings, gefitinib was tested in combination with imatinib in K562 CML cell line using MTT cell proliferation assay and found to have a synergistic antiproliferative activity. Further detailed mechanistic study could help to unravel the full potential of imatinib – gefitinib combination for the treatment of CML.     

Remote monitoring in implantable defibrillator therapy

The major device manufacturers have introduced systems for remote patient monitoring. These remote monitoring systems promise more efficient patient management, especially in today’s clinical setting with the growing number of defibrillator implantations. The aim of this article is to present the role of remote patient monitoring in implantable cardioverter-defibrillator follow-up, its potential benefits and its barriers to widespread diffusion. (Neth Heart J 2008;16:53-6.)     

Optimization of Drug Loading Procedures and Characterization of Liposomal Formulations of Two Novel Agents Intended for Boron Neutron Capture Therapy (BNCT)

Abstract

The characterization of two liposomal formulations of boronated DNA-interacting agents has been performed. It is shown that the two boronated drugs, WSA-Water Soluble Acridine and WSP-Water Soluble Phenantridine, can be encapsulated within unilamellar sterically stabilized liposomes with high drug-to-lipid ratios (up to 0.50:1 (mol:mol)), using transmembrane pH gradients. The steric stabilization of the liposomes was accomplished by the addition of DSPE-PEG(2000) (PEG-lipid) to DSPC/Cho lipid mixtures and the composition used was DSPC: Cho: DSPE-PEG 55:40:5 (moI%). The loading of the drugs resulted in drug precipitation in the liposomal aqueous core as observed by cryo-transmission electron microscopy (c-TEM). Moreover, it is shown that when pH gradients across the bilayer were used for remote loading of WSP or when ammonium sulfate gradients were used for remote loading of WSA, the formation of small bilayer fragments (discs) was induced. We present compelling evidence that the formation of discs is a consequence of precipitate growth in the liposomal interior. The precipitate growth causes some of the liposomes to rupture resulting in the above mentioned disc-formation and a substantial decrease in trapping efficiency. The in vitro stability of the drug loaded liposomes was excellent, both in buffer and in 25% human serum. For most of the formulations, the release of the drugs was below or around 10% after 24 hours at 37^oC. Furthermore, the influence of initial internal pH and internal buffering capacity on release properties of WSA and WSP were investigated. It is shown that the release profiles of the drugs can be controlled, to a large extent, by varying the composition of the internal liposomal aqueous phase.     

Predicting the cover and richness of intertidal macroalgae in remote areas: a case study in the Antarctic Peninsula

Antarctica is an iconic region for scientific explorations as it is remote and a critical component of the global climate system. Recent climate change causes a dramatic retreat of ice in Antarctica with associated impacts to its coastal ecosystem. These anthropogenic impacts have a potential to increase habitat availability for Antarctic intertidal assemblages. Assessing the extent and ecological consequences of these changes requires us to develop accurate biotic baselines and quantitative predictive tools. In this study, we demonstrated that satellite‐based remote sensing, when used jointly with in situ ground‐truthing and machine learning algorithms, provides a powerful tool to predict the cover and richness of intertidal macroalgae. The salient finding was that the Sentinel‐based remote sensing described a significant proportion of variability in the cover and richness of Antarctic macroalgae. The highest performing models were for macroalgal richness and the cover of green algae as opposed to the model of brown and red algal cover. When expanding the geographical range of the ground‐truthing, even involving only a few sample points, it becomes possible to potentially map other Antarctic intertidal macroalgal habitats and monitor their dynamics. This is a significant milestone as logistical constraints are an integral part of the Antarctic expeditions. The method has also a potential in other remote coastal areas where extensive in situ mapping is not feasible.     

Remote homology detection: a motif based approach

MOTIVATION: Remote homology detection is the problem of detecting homology in cases of low sequence similarity. It is a hard computational problem with no approach that works well in all cases. RESULTS: We present a method for detecting remote homology that is based on the presence of discrete sequence motifs. The motif content of a pair of sequences is used to define a similarity that is used as a kernel for a Support Vector Machine (SVM) classifier. We test the method on two remote homology detection tasks: prediction of a previously unseen SCOP family and prediction of an enzyme class given other enzymes that have a similar function on other substrates. We find that it performs significantly better than an SVM method that uses BLAST or Smith-Waterman similarity scores as features.     

Grampian Health Board's joint drug formulary.

OBJECTIVE--To develop a model for creating a joint general practice-hospital formulary, using the example of ulcer healing drugs. DESIGN--A joint formulary development group produced draft guidelines based on an earlier hospital formulary, which were sent to interested local general practitioners for consultation. Revised guidelines were then drawn up and forwarded to the health board''s medicines committee for approval and distribution. SETTING--Grampian Health Board. SUBJECTS--Nine members of joint formulary development group plus local general practitioners who were invited to comment on a list of 11 ulcer healing drugs. MAIN OUTCOME MEASURE--Degree of coincidence of drugs selected by hospital doctors and general practitioners. RESULTS--The ulcer healing drugs selected by the panel of general practitioners and by hospital doctors were highly coincident. The cost of one day''s treatment with drugs varied considerably between hospital and general practice--for example, one drug cost 46p in hospital and 1 pounds in general practice and another cost 1.26 pounds in hospital and 1.01 pounds in general practice. Overall, six drugs cost more in hospital and five cost more in general practice. CONCLUSIONS--A joint formulary for use in hospitals and general practice in a health board can be devised fairly simply by consultation as virtually the same drugs are used in both types of practice. It should influence the health board''s expenditure on drugs and affect the choice of drugs when a patient is discharged from hospital or is referred to any hospital in the region.