Continued Decline of Malaria in The Gambia with Implications for Elimination

Background

A substantial decline in malaria was reported to have occurred over several years until 2007 in the western part of The Gambia, encouraging consideration of future elimination in this previously highly endemic region. Scale up of interventions has since increased with support from the Global Fund and other donors.

Methodology/Principal Findings

We continued to examine laboratory records at four health facilities previously studied and investigated six additional facilities for a 7 year period, adding data from 243,707 slide examinations, to determine trends throughout the country until the end of 2009. We actively detected infections in a community cohort of 800 children living in rural villages throughout the 2008 malaria season, and assayed serological changes in another rural population between 2006 and 2009. Proportions of malaria positive slides declined significantly at all of the 10 health facilities between 2003 (annual mean across all sites, 38.7%) and 2009 (annual mean, 7.9%). Statistical modelling of trends confirmed significant seasonality and decline over time at each facility. Slide positivity was lowest in 2009 at all sites, except two where lowest levels were observed in 2006. Mapping households of cases presenting at the latter sites in 2007–2009 indicated that these were not restricted to a few residual foci. Only 2.8% (22/800) of a rural cohort of children had a malaria episode in the 2008 season, and there was substantial serological decline between 2006 and 2009 in a separate rural area.

Conclusions

Malaria has continued to decline in The Gambia, as indicated by a downward trend in slide positivity at health facilities, and unprecedented low incidence and seroprevalence in community surveys. We recommend intensification of control interventions for several years to further reduce incidence, prior to considering an elimination programme.     

Theoretical Assessment of Public Health Impact of Imperfect Prophylactic HIV-1 Vaccines with Therapeutic Benefits

This paper presents a number of deterministic models for theoretically assessing the potential impact of an imperfect prophylactic HIV-1 vaccine that has five biological modes of action, namely “take,” “degree,” “duration,” “infectiousness,” and “progression,” and can lead to increased risky behavior. The models, which are of the form of systems of nonlinear differential equations, are constructed via a progressive refinement of a basic model to incorporate more realistic features of HIV pathogenesis and epidemiology such as staged progression, differential infectivity, and HIV transmission by AIDS patients. The models are analyzed to gain insights into the qualitative features of the associated equilibria. This allows the determination of important epidemiological thresholds such as the basic reproduction numbers and a measure for vaccine impact or efficacy. The key findings of the study include the following (i) if the vaccinated reproduction number is greater than unity, each of the models considered has a locally unstable disease-free equilibrium and a unique endemic equilibrium; (ii) owing to the vaccine-induced backward bifurcation in these models, the classical epidemiological requirement of vaccinated reproduction number being less than unity does not guarantee disease elimination in these models; (iii) an imperfect vaccine will reduce HIV prevalence and mortality if the reproduction number for a wholly vaccinated population is less than the corresponding reproduction number in the absence of vaccination; (iv) the expressions for the vaccine characteristics of the refined models take the same general structure as those of the basic model.     

Expression of the FOS proto-oncogene protein in brain after ICV administration of Tyr-W-MIF-1 (Tyr-Pro-Trp-Gly-NH2)

Tyr-W-MIF-1 is a tetrapeptide recently isolated from brain that has opiate modulating activity. In this study, we used immunocytochemical (ICC) detection of FOS proto-oncogene protein to map brain areas activated by an ICV injection of Tyr-W-MIF-1 (200 μg). The analgesic effect of the peptide, which lasted 1 h, was confirmed in each rat with the tail flick test. FOS was activated in several limbic structures, including the cingulate and infralimbic cortex, nucleus accumbens, and central nucleus of the amygdala. FOS activation also occurred in several diencephalic nuclei, including the supraoptic, paraventricular, and periventricular nuclei of the hypothalamus, and the paraventricular nucleus of the thalamus. Several activated areas contained mu-opiate receptors. However, despite the known selectivity of Tyr-W-MIF-1 for mu receptors, FOS immunoreactivity was also induced in nuclei of the amygdala, hypothalamus, and thalamus, where concentrations of kappa receptors were high but those of mu and delta receptors were not detected. The results show that Tyr-W-MIF-1 induces FOS activation in several brain areas, including but not limited to, areas associated with nociception and stress-induced analgesia.     

Effects of trypanosome inferction and postpartum liveweight change on resumption of reproduction activity in N'Dama cows

Data on reproduction, liveweight and trypanosome infection of N'Dama cattle raised under traditional husbandry systems in The Gambia were analyzed to quantify the relative effects of postpartum liveweight change and infection with pathogenic trypanosomes on 2 parameters of reproductive efficiency: the ability to calve within 21 months after the initial parturition and the length of the calving interval. Information for the study was obtained from a database on an epidemiological survey begun in 1985 in The Gambia. Calving records (n=294) from 3 locations were classified on the basis of body weight change and prevalence of trypanosome infection between 1 and 4 months postpartum. Least-squares analyses adjusted for effects of location, season of calving, viability of calf, and parity showed that the proportion of cows that calved within 21 months was 50% for cows which maintained or lost less than 5% of the initial postpartum weight and 31% for cows which lost a higher percentage of weight. Corresponding mean calving intervals were 567 and 666 days, respectively (P<0.05). With regard to trypanosome infection, 49% of uninfected cows and 32% of infected cows (P<0.05) calved again within 21 months, with calving intervals of 581 and 651 days, respectively (P<0.05). The interaction between liveweight change and trypanosome infection status was not significant. Furthermore, the findings suggest that while postpartum body weight loss impairs reproductive performance, trypanosome infection does likewise, and these effects may act independently of each other.     

Endomorphin-2 is an endogenous opioid in primary sensory afferent fibers

Evidence is presented that the recently discovered endogenous mu-selective agonist, endomorphin-2, is localized in primary sensory afferents. Endomorphin-2-like immunoreactivity was found to be colocalized in a subset of substance P- and mu opiate receptor-containing fibers in the superficial laminae of the spinal cord and spinal trigeminal nucleus. Disruption of primary sensory afferents by mechanical (deafferentation by dorsal rhizotomy) or chemical (exposure to the primary afferent neurotoxin, capsaicin) methods virtually abolished endomorphin-2-like immunoreactivity in the dorsal horn. These results indicate that endomorphin-2 is present in primary afferent fibers where it can serve as the endogenous ligand for pre- and postsynaptic mu receptors and as a major modulator of pain perception.     

Permeation of blood-borne IL15 across the blood-brain barrier and the effect of LPS

Interleukin15 (IL 15) is a proinflammatory cytokine with elevated concentrations in autoimmune diseases involving the periphery (e.g. rheumatoid arthritis) and CNS (e.g. multiple sclerosis). Its interactions with the blood-brain barrier (BBB) were studied in normal and lipopolysaccharide (LPS)-treated mice. ¹²⁵I-IL15 remained intact for at least 10 min after i.v. injection and reached CNS parenchyma with regional differences between brain and spinal cord. Both in vivo and in situ brain perfusion of ¹²⁵I-IL15 showed that its permeation of the BBB was non-saturable. LPS induced a significant increase of IL15 uptake by the brain and spinal cord, partly related to a higher general permeability of the BBB. The results suggest that the BBB is an interface for blood-borne IL15 to interact with the CNS in the basal state and during inflammation.     

Neuroinflammation facilitates LIF entry into brain: role of TNF

Leukemia inhibitory factor (LIF) is a proinflammatory cytokine mediating a variety of central nervous system (CNS) responses to inflammatory stimuli. During lipopolysaccharide (LPS)-induced inflammation, blood concentrations of LIF increase, correlating with lethality of sepsis. Circulating LIF crosses the blood-brain barrier (BBB) by a saturable transport system. Here we determine how this transport system is regulated in neuroinflammation. Using transport assays that quantify the influx rate and volume of distribution of LIF in mice, we show that LPS facilitated the permeation of LIF from the blood to the brain without compromising the paracellular permeability of the BBB as determined by coadministration of fluorescein. Concurrently, gp130 (shared by the interleukin-6 family of cytokines), but not gp190 (the specific receptor for LIF) or cilliary neutrophic factor (CNTF-Ralpha, a unique receptor for cilliary neurotrophic factor that also uses gp130 and gp190), showed increased levels of mRNA and protein expression in cerebral microvessels from the LPS-treated mice. The upregulation of gp130 by LPS was at least partially mediated by vascular tumor necrosis factor receptor (TNFR)1 and TNFR2. This was shown by elevated TNFR1 and TNFR2 mRNA and protein in cerebral microvessels after LPS and by the absence of the LPS effect on gp130 in knockout mice lacking these receptors. The results show that neuroinflammation by LPS induces endothelial signaling and enhances cytokine transport across the BBB.     

A Diffusion Barrier Between the Area Postrema and Nucleus Tractus Solitarius

The blood–brain barrier (BBB) is a structural and functional barrier that prevents free exchange of circulating substances with the brain, where the endothelial cells of microvessels are joined by tight junctions. The circumventricular organs (CVOs), by contrast, lack tight junctions and exhibit more direct communication with the circulating blood and cerebrospinal fluid. Despite many outstanding morphological studies at the electron microscopic level, there remain misconceptions that the CVOs provide direct passage of blood-borne substances to the rest of the brain. This study will show the structure of the anatomical borders of the dorsal vagal complex in the brainstem. A distinct diffusion barrier between the area postrema (AP, a CVO) and the nucleus tractus solitarius (NTS) was illustrated by immunohistochemistry at both the light and electron microscopic levels. The border zone between the AP and NTS was underlined by a continuous monolayer of columnar cells that were immunopositive for both the tight junction protein zona occludin-1 and the astrocyte marker glial fibrillary acidic protein. This observation of a diffusion barrier between the AP and NTS resolves a long-standing dispute about whether the NTS is a structural extension of the AP with a leaky BBB. Special issue article in honor of Dr. Ji-Sheng Han.     

Gene expression of the ericoid mycorrhizal fungus Oidiodendron maius in the presence of high zinc concentrations

A heavy metal tolerant strain of the ericoid mycorrhizal species Oidiodendron maius, isolated from roots of Vaccinium myrtillus growing in soil heavily contaminated with zinc, was previously shown to tolerate high concentrations of zinc and cadmium ions in the growth medium. We have investigated the genetic basis of this fungal strain tolerance to high zinc concentrations by using an untargeted approach. From a cDNA library constructed by using mRNA from Zn-treated O. maius mycelia, 444 clones were randomly selected and 318 were sequenced. Sequence analysis identified 219 unique clones: 117 showed homology to previously identified genes, 26 matched unknown protein coding regions found in other organisms, and 76 were novel. Variation in the gene expression level after a 20-day treatment with high concentrations of Zn was monitored on 130 unigenes by reverse northern blot hybridisation. Sixteen unigenes were shown to be either up- (9) or down- (7) regulated. The putative function of these genes and their involvement in stress tolerance is discussed.     

Multi-point estimation of total energy expenditure: a comparison between zinc-reduction and platinum-equilibration methodologies

Reducing water to hydrogen gas by zinc or uranium metal for determining D/H ratio is both tedious and time consuming. This has forced most energy metabolism investigators to use the "two-point" technique instead of the "Multi-point" technique for estimating total energy expenditure (TEE). Recently, we purchased a new platinum (Pt)-equilibration system that significantly reduces both time and labor required for D/H ratio determination. In this study, we compared TEE obtained from nine overweight but healthy subjects, estimated using the traditional Zn-reduction method to that obtained from the new Pt-equilibration system. Rate constants, pool spaces, and CO2 production rates obtained from use of the two methodologies were not significantly different. Correlation analysis demonstrated that TEEs estimated using the two methods were significantly correlated (r=0.925, p=0.0001). Sample equilibration time was reduced by 66% compared to those of similar methods. The data demonstrated that the Zn-reduction method could be replaced by the Pt-equilibration method when TEE was estimated using the "Multi-Point" technique. Furthermore, D equilibration time was significantly reduced.