The global pipeline of new medicines for the control and elimination of malaria

ABSTRACT: Over the past decade, there has been a transformation in the portfolio of medicines to combat malaria. New fixed-dose artemisinin combination therapy is available, with four different types having received approval from Stringent Regulatory Authorities or the World Health Organization (WHO). However, there is still scope for improvement. The Malaria Eradication Research agenda identified several gaps in the current portfolio. Simpler regimens, such as a single-dose cure are needed, compared with the current three-day treatment. In addition, new medicines that prevent transmission and also relapse are needed, but with better safety profiles than current medicines. There is also a big opportunity for new medicines to prevent reinfection and to provide chemoprotection. This study reviews the global portfolio of new medicines in development against malaria, as of the summer of 2012. Cell-based phenotypic screening, and 'fast followers' of clinically validated classes, mean that there are now many new classes of molecules starting in clinical development, especially for the blood stages of malaria. There remain significant gaps for medicines blocking transmission, preventing relapse, and long-duration molecules for chemoprotection. The nascent pipeline of new medicines is significantly stronger than five years ago. However, there are still risks ahead in clinical development and sustainable funding of clinical studies is vital if this early promise is going to be delivered.     

A Dutch guideline for the treatment of scoliosis in neuromuscular disorders

Background

Children with neuromuscular disorders with a progressive muscle weakness such as Duchenne Muscular Dystrophy and Spinal Muscular Atrophy frequently develop a progressive scoliosis. A severe scoliosis compromises respiratory function and makes sitting more difficult. Spinal surgery is considered the primary treatment option for correcting severe scoliosis in neuromuscular disorders. Surgery in this population requires a multidisciplinary approach, careful planning, dedicated surgical procedures, and specialized after care.

Methods

The guideline is based on scientific evidence and expert opinions. A multidisciplinary working group representing experts from all relevant specialties performed the research. A literature search was conducted to collect scientific evidence in answer to specific questions posed by the working group. Literature was classified according to the level of evidence.

Results

For most aspects of the treatment scientific evidence is scarce and only low level cohort studies were found. Nevertheless, a high degree of consensus was reached about the management of patients with scoliosis in neuromuscular disorders. This was translated into a set of recommendations, which are now officially accepted as a general guideline in the Netherlands.

Conclusion

In order to optimize the treatment for scoliosis in neuromuscular disorders a Dutch guideline has been composed. This evidence-based, multidisciplinary guideline addresses conservative treatment, the preoperative, perioperative, and postoperative care of scoliosis in neuromuscular disorders.     

Detection of microspheres in vivo using multispectral optoacoustic tomography

We introduce a new approach to detect individual microparticles that contain NIR fluorescent dye by multispectral optoacoustic tomography in the context of the hemoglobin-rich environment within murine liver. We encapsulated a near infrared (NIR) fluorescent dye within polystyrene microspheres, then injected them into the ileocolic vein, which drains to the liver. NIR absorption was determined using multispectral optoacoustic tomography. To quantitate the minimum diameter of microspheres, we used both colorimetric and spatial information to segment the regions in which the microspheres appear. Regional diameter was estimated by doubling the maximum regional distance. We found that the minimum microsphere size threshold for detection by multispectral optoacoustic tomography images is 78.9 µm.     

Effect of some analgesics on Paraoxonase-1 purified from human serum

The in vitro effects of the analgesic drugs, lornoxicam, indomethacin, tenoxicam, diclofenac sodium, ketoprofen and lincomycine, on the activity of purified human serum paraoxonase (hPON1) (EC 3.1.8.1.) were evaluated. hPON1 was purified from human serum with a final specific activity of 3840 U mg^?1 and a purity of 25.3 % using simple chromatographic methods, including DEAE-Sephadex anion exchange and Sepharose 4B-L-tyrozine-1-napthylamine hydrophobic interaction chromatography. SDS-polyacrylamide gel electrophoresis indicated a single protein band corresponding to hPON1. The six analgesics dose-dependently decreased in vitro hPON1 activity, with IC₅₀ values for lornoxicam, indomethacin, tenoxicam, diclofenac sodium, ketoprofen and lincomycine of 0.136, 0.195, 0.340, 1.639, 6.23 and 9.638 mM, respectively. K_i constants were 0.009, 0.097, 0.306, 0.805, 13.010 and 11.116 mM, respectively. Analgesics showed different inhibition mechanisms: lornoxicam, diclofenac sodium and lincomycine were uncompetitive, indomethacin and tenoxicam were competitive, ketoprofen was noncompetitive. According to the results, inhibition potency was lornoxicam>indomethacin>tenoxicam> diclofenac sodium>ketoprofen> lincomycine.     

Agrobacterium-mediated transformation and assessment of factors influ-encing transgene expression in loblolly pine (Pinus taeda L.)

INTRODUCTIONRecombinant DNA technology is a powerful toolfor the introduction of foreign genes into longlivedperennials and fOr fundamelltal studies of gene expression. Using such techniques, we can overcomethe difficulties associated with the breeding of a long-lived perennial. At present, although considerablereseaxch effort has been devoted to the genetic en-gineering of fOrest trees, it has lagged behind ad-vances made in herbaceous crops due both to eco-nomics and the recalcitrant n…     

The effects of operant control over food and light on the behaviour of domestic hens

In intensive farming systems, the animals have little control over important elements in their environments. For instance, food of a pre-set type is delivered at set times, and the lighting schedule is controlled by the farmer. It has been suggested that low levels of environmental control over important events may reduce welfare by increasing passivity and stress. This study aimed to evaluate the effect of providing control over food and lighting additional to a restricted regime on the behaviour of small groups of laying hens (Gallus gallus domesticus). Twelve pens, each containing five birds, were paired to give six controlling and six non-controlling pens. These pairs of pens were yoked, such that birds in the controlling pens were able to make an operant response to gain access to extra food and light, whilst the yoked pens also received these outcomes but were unable to control their occurrence. The birds were kept continuously in the experimental conditions for 9 weeks. Records were made of general behaviour and activity, aggression and plumage damage scores, every 2 weeks. Data on key-pecking and egg production were continuously recorded throughout the experiment. The controlling birds used the operant keys to open the feeder for an average of 92min and to turn on the light for 46min per pen per day. The high number of key-pecks indicates that the birds were motivated to make use of the keys to control access to additional food and light. The non-controlling treatment pens showed significantly higher levels of preening and resting. Contrary to previous studies the use of operant feeders in this experiment did not induce a high level of feather pecking or aggressive interactions, as there was no significant difference between treatments. During the experiment the non-controlling hens laid significantly more eggs than the controlling hens. The results suggest that lack of control over these particular environmental events induced mild stress in the non-controlling pens of birds, and that further investigations into the effect of lack of control on welfare would be warranted.     

A likelihood method for the detection of selection and recombination using nucleotide sequences

Different regions along nucleotide sequences are often subject to different evolutionary forces. Recombination will result in regions having different evolutionary histories, while selection can cause regions to evolve at different rates. This paper presents a statistical method based on likelihood for detecting such processes by identifying the regions which do not fit with a single phylogenetic topology and nucleotide substitution process along the entire sequence. Subsequent reanalysis of these anomalous regions may then be possible. The method is tested using simulations, and its application is demonstrated using the primate psi eta-globin pseudogene, the V3 region of the envelope gene of HIV-1, and argF sequences from Neisseria bacteria. Reanalysis of anomalous regions is shown to reveal possible immune selection in HIV-1 and recombination in Neisseria. A computer program which implements the method is available.      

SNL fibroblast feeder layers support derivation and maintenance of human induced pluripotent stem cells

Induced pluripotent stem(iPS) cells can be derived from human somatic cells by cellular reprogramming.This technology provides a potential source of non-controversial therapeutic cells for tissue repair,drug discovery,and opportunities for studying the molecular basis of human disease.Normally,mouse embryonic fibroblasts(MEFs) are used as feeder layers in the initial derivation of iPS lines.The purpose of this study was to determine whether SNL fibroblasts can be used to support the growth of human iPS cell...     

Plagiarism of the host immune system: lessons about chemokine immunology from viruses

In their attempts to evade the host immune response, mammalian viruses have evolved a wide range of strategies. These include the expression and modification of various host cytokines and receptors. Understanding the mechanism of action of these virally encoded proteins will clearly deepen our insights into immunology. In the past few months several new virally encoded chemokines have been described which can modify both the host immune and antiviral response. Their manipulation of the cytokine structure-function relationship may also be useful in the development of reagents for treating immune and proliferative diseases.     

Incentive Value learning in Domestic Hens

The present experiment investigated whether domestic hens (Gallus domesticus) assign different incentive values to novel food depending on their deprivation state when they encounter this novel food. Firstly, hens were trained to search under wood shavings in a food dish to find a small amount of a novel food. Half of the hens were then presented with the novel food while food deprived, and the other half were presented to it while sated. In the test, all hens were food deprived, and given access to the food dish used in the first stage, filled with shavings but without food. Hens that had experienced the food while deprived spent more time on food‐related behaviours in and at the dish than did hens that had not (pecking at dish, Median 63 vs. 37, p < 0.05). These results indicate that the first group had assigned a higher value to the novel food. The results show for the first time that incentive value learning occurs in domestic hens. This implies that care must be taken when designing choice tests to take into account the animal’s motivational state when it previously encountered the resources being studied.