Quantifying the economic burden of malaria in Nigeria using the willingness to pay approach

Background

Osteoporosis creates brittle bones susceptible to fracture, with resulting high levels of morbidity and mortality. Poor access to bone densitometry services for the residents of North Wales led to the Welsh Assembly Government offering capital to purchase a dual-energy X-ray absorptiometry (DXA) scanner, used to diagnose osteoporosis, for the region. The commissioning question for the six Local Health Boards across North Wales was where to site the new scanner. This decision needed to reflect current inequalities in access to services and concerns over inappropriate prescribing relative to Welsh norms.

Methods

Epidemiological, corporate and comparative healthcare needs assessments were performed. In addition, two cross-sectional surveys were conducted to determine the views of general practices and users of bone densitometry services resident in North Wales. An option appraisal and sensitivity analysis of 13 costed options for DXA scanning was conducted.

Results

We estimated that only 31% of the people in North Wales who met national guidelines were receiving DXA scans. There was definite inequity of access to the current service provided by area of residence. There was also evidence of inequity of access by age and sex. The most suitable option identified in the option appraisal was a bone densitometry service based in the central location of Llandudno.

Conclusion

The assessment identified significant unmet need for DXA scanning. A recommendation was made to improve access through the introduction of a new bone densitometry service based at Llandudno. This would double scanning provision provided and reduce travel costs and time for many North Wales residents. This recommendation was adopted by a joint commissioning group established by the six Local Health Boards in North Wales at the end of 2004 – evidence based commissioning in practice.     

Activation of signaling pathways following localized delivery of systemically administered neurotrophic factors across the blood-brain barrier using focused ultrasound and microbubbles

The brain-derived neurotrophic factor (BDNF) has been shown to have broad neuroprotective effects in addition to its therapeutic role in neurodegenerative disease. In this study, the efficacy of delivering exogenous BDNF to the left hippocampus is demonstrated in wild-type mice (n = 7) through the noninvasively disrupted blood-brain barrier (BBB) using focused ultrasound (FUS). The BDNF bioactivity was found to be preserved following delivery as assessed quantitatively by immunohistochemical detection of the pTrkB receptor and activated pAkt, pMAPK, and pCREB in the hippocampal neurons. It was therefore shown for the first time that systemically administered neurotrophic factors can cross the noninvasively disrupted BBB and trigger neuronal downstream signaling effects in a highly localized region in the brain. This is the first time that the administered molecule is tracked through the BBB and localized in the neuron triggering molecular effects. Additional preliminary findings are shown in wild-type mice with two additional neurotrophic factors such as the glia-derived neurotrophic factor (n = 12) and neurturin (n = 2). This further demonstrates the impact of FUS for the early treatment of CNS diseases at the cellular and molecular level and strengthens its premise for FUS-assisted drug delivery and efficacy.     

Perception of personal dental appearance in Nigerian adolescents

BACKGROUND: The purpose of this study was to investigate the relationship among Nigerian adolescents' awareness of malocclusion, their satisfaction with personal dental appearance, and the severity of their occlusal irregularities. MATERIAL: The sample consisted of 577 randomly selected secondary school adolescents-306 (53%) boys and 271 (47%) girls aged 12 to 17 years (mean age, 14.73 +/- 1.12). A pretested questionnaire was used to assess the subjects' awareness of malocclusion and satisfaction with personal dental appearance; the actual severity of malocclusion was determined by using the dental aesthetic index (DAI), performed by an orthodontist in a school environment under natural illumination. RESULTS: Statistically significant, negative, weak correlations were found between awareness of malocclusion and satisfaction at the various DAI scores as follows: < or =25 (r = -0.3774, P < .001), 26 to 30 (r = -0.4305, P < .001), 31 to 35 (r = -0.5137, P < .001), and > or =36 (r = -0.5104, P < .001). Analysis of variance (ANOVA) did not show a significant value of any of the 3 factors. Multivariate analysis with age as the covariate did not show a significant effect. Also, the association between socioeconomic status and the variables was not significant ( P > .05). Generally, no statistically significant sex differences were found in relation to the DAI scores, awareness, or satisfaction ( P > .05). CONCLUSIONS: Significant, negative, weak correlations were found between Nigerian adolescents' awareness of malocclusion and satisfaction with personal dental appearance at the various severity levels of malocclusion. It would be worthwhile to assess such a relationship with the index of orthodontic treatment need in the Nigerian population.     

Microbubble Type and Distribution Dependence of Focused Ultrasound-Induced Blood–Brain Barrier Opening

Focused ultrasound, in the presence of microbubbles, has been used non-invasively to induce reversible blood–brain barrier (BBB) opening in both rodents and non-human primates. This study was aimed at identifying the dependence of BBB opening properties on polydisperse microbubble (all clinically approved microbubbles are polydisperse) type and distribution by using a clinically approved ultrasound contrast agent (Definity microbubbles) and in-house prepared polydisperse (IHP) microbubbles in mice. A total of 18 C57 BL/6 mice (n = 3) were used in this study, and each mouse was injected with either Definity or IHP microbubbles via the tail vein. The concentration and size distribution of activated Definity and IHP microbubbles were measured, and the microbubbles were diluted to 6 × 10⁸/mL before injection. Immediately after microbubble administration, mice were subjected to focused ultrasound with the following parameters: frequency = 1.5 MHz, pulse repetition frequency = 10 Hz, 1000 cycles, in situ peak rarefactional acoustic pressures = 0.3, 0.45 and 0.6 MPa for a sonication duration of 60 s. Contrast-enhanced magnetic resonance imaging was used to confirm BBB opening and allowed for image-based analysis. Permeability of the treated region and volume of BBB opening did not significantly differ between the two types of microbubbles (p > 0.05) at peak rarefractional acoustic pressures of 0.45 and 0.6 MPa, whereas IHP microbubbles had significantly higher permeability and opening volume (p < 0.05) at the relatively lower pressure of 0.3 MPa. The results from this study indicate that microbubble type and distribution could have significant effects on focused ultrasound-induced BBB opening at lower pressures, but less important effects at higher pressures, possibly because of the stable cavitation that governs the former. This difference may have become less significant at higher pressures, where inertial cavitation typically occurs.     

Targeted drug delivery with focused ultrasound-induced blood-brain barrier opening using acoustically-activated nanodroplets

Focused ultrasound (FUS) in the presence of systemically administered microbubbles has been shown to locally, transiently and reversibly increase the permeability of the blood–brain barrier (BBB), thus allowing targeted delivery of therapeutic agents in the brain for the treatment of central nervous system diseases. Currently, microbubbles are the only agents that have been used to facilitate the FUS-induced BBB opening. However, they are constrained within the intravascular space due to their micron-size diameters, limiting the delivery effect at or near the microvessels. In the present study, acoustically-activated nanodroplets were used as a new class of contrast agents to mediate FUS-induced BBB opening in order to study the feasibility of utilizing these nanoscale phase-shift particles for targeted drug delivery in the brain. Significant dextran delivery was achieved in the mouse hippocampus using nanodroplets at clinically relevant pressures. Passive cavitation detection was used in the attempt to establish a correlation between the amount of dextran delivered in the brain and the acoustic emission recorded during sonication. Conventional microbubbles with the same lipid shell composition and perfluorobutane core as the nanodroplets were also used to compare the efficiency of an FUS-induced dextran delivery. It was found that nanodroplets had a higher BBB opening pressure threshold but a lower stable cavitation threshold than microbubbles, suggesting that contrast agent-dependent acoustic emission monitoring was needed. A more homogeneous dextran delivery within the targeted hippocampus was achieved using nanodroplets without inducing inertial cavitation or compromising safety. Our results offered a new means of developing the FUS-induced BBB opening technology for potential extravascular targeted drug delivery in the brain, extending the potential drug delivery region beyond the cerebral vasculature.     

Characterization of trace metal leachability from highway construction solid waste using the toxicity characteristic leaching procedure

The potential risk of soil, surface and ground water contamination by trace metals leached from highway construction solid wastes is a major environmental concern. The objectives of this study were to evaluate trace metal leachability, toxicity of the leachate to aquatic organism and environmental impacts of highway construction solid waste (HCSW). Potential leachability, defined as the maximum metal pool that may become available for leaching at a constant pH 4 decreased in the following order: Zn > Ni > As > Pb > Cu. Potential metal leachability was controlled mainly by solid phase distribution of metals in wastes. The kinetics of metal release were determined using the cascade leaching test (CLT) with water at pH 4. With the exception of zinc in the first fraction, metal concentrations in all consecutive leaching fractions remained below the maximum permissible level in water for human consumption. The result of toxicity test showed that the leachates were in concentrations that did not exceed toxic concentrations for aquatic toxicity tests. The results indicate low risk of surface and ground water contamination resulting from highway construction solid wastes.     

Synthesis of halogen-substituted pyridyl and pyrimidyl derivatives of [3,2-c]pyrazolo corticosteroids: strategies for the development of glucocorticoid receptor mediated imaging agents

Ligands for the glucocorticoid receptor labeled with high-energy isotopes are highly desired for their potential applications in nuclear medical studies of the brain where the dysregulation of this receptor system is thought to be involved in various neurodegenerative disorders. Analogues of the glucocorticoid cortivazol have previously been prepared as target compounds for labeling with high-energy isotopes. However, the phenyl rings of arylpyrazoles of this type are not sufficiently activated for nucleophilic substitution reactions that are generally required for the synthesis of radiohalogenated analogues. Since suitably substituted aromatic nitrogen heterocyclic groups are amenable to nucleophilic substitution, the goal of this study was the synthesis of pyridylpyrazolo and pyrimidylpyrazolo analogues similar to cortivazol that could be labeled with radiohalogens in the pyridine or pyrimidine rings. We describe the synthesis of several [3,2-c]pyrazolo steroids containing pyridyl, halopyridyl, and pyrimidyl substituents at the 2' position of the pyrazole ring. These compounds were tested for binding to the glucocorticoid receptor and for biological activity in glucocorticoid responsive HeLa cells grown in tissue culture. Of the pyridyl and pyrimidyl derivatives, 2'-(3-pyridyl)-11 beta,17,21-trihydroxy-16 alpha-methyl-20-oxopregn-4-eno[3,2-c]pyrazole showed superior activity in both assays and it was used as the basis for the synthesis of several analogues that were halogenated in the pyridine ring. These halogenated compounds were all tested for their binding to the glucocorticoid receptor and for their biological activity. One, a fluorinated compound 2'-(2-fluoro-5-pyridyl)-11 beta,17,21-trihydroxy-16 alpha-methyl-20-oxopregn-4-eno[3,2-c]pyrazole had excellent activity, considerably better than the potent glucocorticoid dexamethasone. Most importantly, fluorination was achieved using a nucleophilic exchange reaction, a method that is adaptable to radiolabeling with the positron-emitting isotope fluorine-18. Thus, considering its superior biological activity and adaptability for facile radiosynthesis, this target compound has the potential for imaging of glucocorticoid receptor containing tissues using positron emission tomography.