Malaria control priorities and constraints

Each year, there are still between 300-500 million clinical cases of malaria and over one million deaths due to the disease, 90% of which occur in Africa south of the Sahara. In all continents, malaria risk is highest in remote rural areas where poverty abounds, population densities are low and the quality and coverage of the health services are poor or in existent. A sustained impact on the malaria burden can only be achieved through the cost-effective use of current tools, by including malaria in health sector development and inter-sectorial action, by mobilizing malaria control within communities and by investing in new and more effective tools. This paper highlights some of the constraints faced by countries in controlling malaria and outlines the priority activities that are being carried out to address these constraints within both communities and the health services. It aims to be set the scene for the papers of this Centenary book which address some of these issues in more detail.     

The effect of GnRH analogs on urinary incontinence after ablation of the ovaries in dogs

After removal of the ovaries approximately 20% of dogs develop urinary incontinence. Removal of the gonads results in estrogen deficiency and chronic elevation in the production and secretion of FSH and LH. The gonadotrophins may directly or indirectly, adversely affect the sphincter function of the urethra. Estrogen replacement therapy and treatment with sympathomimetics, such as ephedrine or phenylpropanolamine (PPA), are effective only in some of the affected dogs, and many of these subsequently become nonresponsive. Since the role of the elevated gonadotrophins has not been elucidated, we used depot preparations of GnRH analogues to down-regulate gonadotrophins once or twice in 13 ovariectomized (ovx), incontinent dogs, which were either refractory to alpha-adrenergics (n=11) or in which alpha-adrenergics were contraindicated (n=2). Dogs were treated with leuprolide, deslorelin, buserelin or triptorelin. In 7 dogs treatments with GnRH analogues alone (n=11) resulted in continence for 50-738 days (mean 247). In all dogs except one, where GnRH treatments did not resolve the incontinence completely, additional treatment with phenylpropanolamine was successful. With additional treatment of phenylpropanolamine complete continence was restored for 21-367 days (mean 159). All treatments caused long-term reduction of circulating FSH and LH concentrations to very low or undetectable levels. No adverse effects of treatments were observed.     

Multicoil2: predicting coiled coils and their oligomerization states from sequence in the twilight zone

The alpha-helical coiled coil can adopt a variety of topologies, among the most common of which are parallel and antiparallel dimers and trimers. We present Multicoil2, an algorithm that predicts both the location and oligomerization state (two versus three helices) of coiled coils in protein sequences. Multicoil2 combines the pairwise correlations of the previous Multicoil method with the flexibility of Hidden Markov Models (HMMs) in a Markov Random Field (MRF). The resulting algorithm integrates sequence features, including pairwise interactions, through multinomial logistic regression to devise an optimized scoring function for distinguishing dimer, trimer and non-coiled-coil oligomerization states; this scoring function is used to produce Markov Random Field potentials that incorporate pairwise correlations localized in sequence. Multicoil2 significantly improves both coiled-coil detection and dimer versus trimer state prediction over the original Multicoil algorithm retrained on a newly-constructed database of coiled-coil sequences. The new database, comprised of 2,105 sequences containing 124,088 residues, includes reliable structural annotations based on experimental data in the literature. Notably, the enhanced performance of Multicoil2 is evident when tested in stringent leave-family-out cross-validation on the new database, reflecting expected performance on challenging new prediction targets that have minimal sequence similarity to known coiled-coil families. The Multicoil2 program and training database are available for download from http://multicoil2.csail.mit.edu.     

Use of a gonadotropin releasing hormone agonist implant as an alternative for surgical castration in male ferrets (Mustela putorius furo)

Surgical castration in ferrets has been implicated as an etiological factor in the development of hyperadrenocorticism in this species due to a castration-related increase in plasma gonadotropins. In search for a suitable alternative, the effect of treatment with the depot GnRH-agonist implant, deslorelin, on plasma testosterone concentrations and concurrent testes size, spermatogenesis, and the typical musky odor of intact male ferrets was investigated. Twenty-one male ferrets, equally divided into three groups, were either surgically castrated, received a slow release deslorelin implant or received a placebo implant. Plasma FSH and testosterone concentrations, testis size and spermatogenesis were all suppressed after the use of the deslorelin implant. The musky odor in the ferrets which had received a deslorelin implant was less compared to the ferrets which were either surgically castrated or had received a placebo implant. These results indicate that the deslorelin implant effectively prevents reproduction and the musky odor of intact male ferrets and is therefore considered a suitable alternative for surgical castration in these animals.     

Short-term progestin treatments prevent estrous induction by a GnRH agonist implant in anestrous bitches

The objective of this study was to test the efficacy and safety of a short-term progestin treatment administered at two different times to prevent estrous induction in response to the administration of an implant releasing the GnRH agonist, deslorelin acetate (DA), in anestrous bitches. Interestrous intervals (IEI) observed prior to and post DA were compared. Forty-two anestrous bitches, with previous IEI history, were randomly allocated to one of the following treatments: PL: placebo sc (n = 12); MA: megestrol acetate 2mg/kg po for 8 days (n = 4); DA: 10mg sc (n = 8); MA&DA-1: MA beginning the day before DA (n = 8); and MA&DA-4: MA beginning 4 days before DA (n = 10). The dose of MA was identical for each treatment. All bitches were examined daily for 1 month and then every 3 months until the next spontaneous post-treatment estrous cycle. Post-GnRH estrous response occurred in 0, 0, 100, 50, and 10% of the PL, MA, DA, MA&DA-1, MA&DA-4, groups, respectively (<0.01). There was an interaction between the treatment and period for the duration of the IEI (< 0.01). Changes in IEI were different among treatments (p<0.01); the three DA-treated groups (147.5% +/- 10.3, 161.3% +/- 14.1, 148.6% +/- 19.2) differed from both the MA (12.9% +/- 17.6) and PL (8.1% +/- 7.8), but not among themselves. It is concluded that an 8 days megestrol protocol and DA on Day 4 was better than DA on Day 1 to prevent estrous response in anestrous bitches and that both protocols significantly increased the IEI.     

A review of advances in the use of the GnRH agonist deslorelin in control of reproduction

The prevention of breeding in animals using GnRH analogues has been the object of research over many years. Recently, a new drug delivery formulation was developed which enabled the development of products that could be commercialised for veterinary use. The formulation has now been approved in certain countries for use in male dogs, and applications are being expanded to cover repeat usage, extended duration, use in females, other indications and other animal species. With respect to repeat usage, dogs have been re-implanted for four consecutive doses and monitored until they returned to normal steroidogenesis. All dogs returned to normal steroidogenesis following cessation of treatment. In females, it was previously shown that implanted bitches with progesterone < 5 ng/mL at the time of implantation had an induced estrus. In a new study at Chulalongkorn University, implanting female pups at around 4 mo prevented this occurrence, whereas implantation at 7 mo did not.