Some considerations in the design and interpretation of antimalarial drug trials in uncomplicated falciparum malaria

BACKGROUND: Treatments for uncomplicated falciparum malaria should have high cure rates. The World Health Organization has recently set a target cure rate of 95% assessed at 28 days. The use of more effective drugs, with longer periods of patient follow-up, and parasite genotyping to distinguish recrudescence from reinfection raise issues related to the design and interpretation of antimalarial treatment trials in uncomplicated falciparum malaria which are discussed here. METHODS: The importance of adequate follow-up is presented and the advantages and disadvantages of non-inferiority trials are discussed. The different methods of interpreting trial results are described, and the difficulties created by loss to follow-up and missing or indeterminate genotyping results are reviewed. CONCLUSION: To characterize cure rates adequately assessment of antimalarial drug efficacy in uncomplicated malaria requires a minimum of 28 days and as much as 63 days follow-up after starting treatment. The longer the duration of follow-up in community-based assessments, the greater is the risk that this will be incomplete, and in endemic areas, the greater is the probability of reinfection. Recrudescence can be distinguished from reinfection using PCR genotyping but there are commonly missing or indeterminate results. There is no consensus on how these data should be analysed, and so a variety of approaches have been employed. It is argued that the correct approach to analysing antimalarial drug efficacy assessments is survival analysis, and patients with missing or indeterminate PCR results should either be censored from the analysis, or if there are sufficient data, results should be adjusted based on the identified ratio of new infections to recrudescences at the time of recurrent parasitaemia. Where the estimated cure rates with currently recommended treatments exceed 95%, individual comparisons with new regimens should generally be designed as non-inferiority trials with sample sizes sufficient to determine adequate precision of cure rate estimates (such that the lower 95% confidence interval bound exceeds 90%)

Current debates in urban theory: a critical assessment

Urban studies today is marked by many active debates. In an earlier paper, we addressed some of these debates by proposing a foundational concept of urbanization and urban form as a way of identifying a common language for urban research. In the present paper we provide a brief recapitulation of that framework. We then use this preliminary material as background to a critique of three currently influential versions of urban analysis, namely, postcolonial urban theory, assemblage theoretic approaches, and planetary urbanism. We evaluate each of these versions in turn and find them seriously wanting as statements about urban realities. We criticize (a) postcolonial urban theory for its particularism and its insistence on the provincialization of knowledge, (b) assemblage theoretic approaches for their indeterminacy and eclecticism, and (c) planetary urbanism for its radical devaluation of the forces of agglomeration and nodality in urban-economic geography

Endogenous Urotensin II Selectively Modulates Erectile Function through eNOS

Urotensin II (U-II) is a cyclic peptide originally isolated from the neurosecretory system of the teleost fish and subsequently found in other species, including man. U-II was identified as the natural ligand of a G-protein coupled receptor, namely UT receptor. U-II and UT receptor are expressed in a variety of peripheral organs and especially in cardiovascular tissue. Recent evidence indicates the involvement of U-II/UT pathway in penile function in human, but the molecular mechanism is still unclear. On these bases the aim of this study is to investigate the mechanism(s) of U-II-induced relaxation in human corpus cavernosum and its relationship with L-arginine/Nitric oxide (NO) pathway.Human corpus cavernosum tissue was obtained following in male-to-female transsexuals undergoing surgical procedure for sex reassignment. Quantitative RT-PCR clearly demonstrated the U-II expression in human corpus cavernosum. U-II (0.1 nM-10 µM) challenge in human corpus cavernosum induced a significant increase in NO production as revealed by fluorometric analysis. NO generation was coupled to a marked increase in the ratio eNOS phosphorilated/eNOS as determined by western blot analysis. A functional study in human corpus cavernosum strips was performed to asses eNOS involvement in U-II-induced relaxation by using a pharmacological modulation. Pre-treatment with both wortmannin or geldanamycinin (inhibitors of eNOS phosphorylation and heath shock protein 90 recruitment, respectively) significantly reduced U-II-induced relaxation (0.1 nM-10 µM) in human corpus cavernosum strips. Finally, a co-immunoprecipitation study demonstrated that UT receptor and eNOS co-immunoprecipitate following U-II challenge of human corpus cavernosum tissue.U-II is endogenously synthesized and locally released in human corpus cavernosum. U-II elicited penile erection through eNOS activation. Thus, U-II/UT pathway may represent a novel therapeutical target in erectile dysfunction

Contrasting Roles for TLR Ligands in HIV-1 Pathogenesis

The first line of a host's response to various pathogens is triggered by their engagement of cellular pattern recognition receptors (PRRs). Binding of microbial ligands to these receptors leads to the induction of a variety of cellular factors that alter intracellular and extracellular environment and interfere directly or indirectly with the life cycle of the triggering pathogen. Such changes may also affect any coinfecting microbe. Using ligands to Toll-like receptors (TLRs) 5 and 9, we examined their effect on human immunodeficiency virus (HIV)-1 replication in lymphoid tissue ex vivo. We found marked differences in the outcomes of such treatment. While flagellin (TLR5 agonist) treatment enhanced replication of CC chemokine receptor 5 (CCR 5)-tropic and CXC chemokine receptor 4 (CXCR4)-tropic HIV-1, treatment with oligodeoxynucleotide (ODN) M362 (TLR9 agonist) suppressed both viral variants. The differential effects of these TLR ligands on HIV-1 replication correlated with changes in production of CC chemokines CCL3, CCL4, CCL5, and of CXC chemokines CXCL10, and CXCL12 in the ligand-treated HIV-1-infected tissues. The nature and/or magnitude of these changes were dependent on the ligand as well as on the HIV-1 viral strain. Moreover, the tested ligands differed in their ability to induce cellular activation as evaluated by the expression of the cluster of differentiation markers (CD) 25, CD38, CD39, CD69, CD154, and human leukocyte antigen D related (HLA)-DR as well as of a cell proliferation marker, Ki67, and of CCR5. No significant effect of the ligand treatment was observed on apoptosis and cell death/loss in the treated lymphoid tissue ex vivo. Our results suggest that binding of microbial ligands to TLRs is one of the mechanisms that mediate interactions between coinfected microbes and HIV-1 in human tissues. Thus, the engagement of appropriate TLRs by microbial molecules or their mimetic might become a new strategy for HIV therapy or prevention

Impact-toughening mechanisms of calcium carbonate-reinforced polypropylene nanocomposite

The impact fracture mechanisms of polypropylene (PP), containing 9.2 vol \% of calcium carbonate (CaCO3) nanoparticles, were investigated using optical microscopy and transmission electron microscopy. The incorporation of CaCO3 nanoparticles reduces the size of spherulites and induces the formation of P-phase crystallites, which leads to a more ductile PP matrix. Double-notch four-point bending (DN-4PB) Charpy impact specimens and notched Izod impact specimens were utilized to study the fracture mechanism(s) responsible for the observed toughening effect. A detailed investigation reveals that the CaCO3 nanoparticles act as stress concentrators to initiate massive crazes, followed by shear banding in PP matrix. These toughening mechanisms are responsible for the observed, improved impact strength. A comparison of the fracture mechanisms observed between DN-4PB Charpy and Izod impact tests is also made to show the effectiveness of DN4PB for investigation of impact fracture mechanisms of polymeric systems. (c) 2006 Wiley Periodicals, Inc

Neuroprotective Effect of Long-term NDI1 Gene Expression in a Chronic Mouse Model of Parkinson Disorder

Previously, we showed that the internal rotenone-insensitive nicotinamide adenine dinucleotide (NADH)-quinone oxidoreductase (NDI1) gene from Saccharomyces cerevisiae (baker's yeast) can be successfully inserted into the mitochondria of mice and rats and the expressed enzyme was found to be fully functional. In this study, we investigated the ability of the Ndi1 enzyme to protect the dopaminergic neurons in a chronic mouse model of Parkinson disorder. After expression of the NDI1 gene in the unilateral substantia nigra of male C57BL/6 mice for 8 months, a chronic Parkinsonian model was created by administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) with probenecid and evaluated using neurochemical and behavioral responses 1–4 weeks post-MPTP/probenecid injection. We showed that expression of Ndi1 was able to significantly prevent the loss of dopamine and tyrosine hydroxylase as well as the dopaminergic transporters in the striatum of the chronic Parkinsonian mice. Behavioral assessment based on a methamphetamine-induced rotation test and spontaneous swing test further supported neurological preservation in the NDI1-treated Parkinsonian mice. The data presented in this study demonstrate a protective effect of the NDI1 gene in dopaminergic neurons, suggesting its therapeutic potential for Parkinson-like disorders

Effectiveness and underlying mechanisms of a group-based cognitive behavioural therapy-based indicative prevention program for children with elevated anxiety levels

Contains fulltext : 116470.pdf (publisher's version ) (Open Access)Background Anxiety is a problem for many children, particularly because of its negative consequences not only on the wellbeing of the child, but also on society. Adequate prevention and treatment might be the key in tackling this problem. Cognitive behavioural therapy (CBT) has been found effective for treating anxiety disorders. “Coping Cat” is one of the few evidence-based CBT programs designed to treat anxiety symptoms in children. The main aim of this project is to conduct a Randomized Controlled Trial (RCT) to evaluate the effectiveness of a Dutch version of Coping Cat as an indicative group-based prevention program. The second aim is to gain insight into the mechanisms underlying its effectiveness. Methods/design Coping Cat will be tested in Dutch primary school children grades five through eight (ages 7 to 13) with elevated levels of anxiety. This RCT has two conditions: 130 children will be randomly assigned to the experimental (N=65, Coping Cat) and control groups (N=65, no program). All children and their mothers will be asked to complete baseline, post intervention, and 3-month follow-up assessments. In addition, children in both the experimental and control group will be asked to complete 12 weekly questionnaires matched to the treatment sessions. Main outcome measure will be the child’s anxiety symptoms level (SCAS). Four potential mediators will be examined, namely active coping, positive cognitive restructuring, self efficacy and cognitions about ones coping ability (from now on coping cognitions). Discussion It is hypothesized that children in the experimental condition will experience reduced levels of anxiety in comparison with the control group. Further, active coping, positive cognitive restructuring, and coping cognitions are expected to mediate program effectiveness. If Coping Cat proves effective as a prevention program and working mechanisms can be found, this group-based approach might lead to the development of a cost-effective program suitable for prevention purposes that would be easily implemented on a large scale.7 p