Terpenes as Potential Antimalarial Drugs

A fact which favors the increase in morbidity and mortality of malaria cases in the world is the resistance to chemotherapeutic agents that the parasite presents. Therefore, it is necessary to identify new potential targets specific to the parasite in order to be able to perform a rational planning. One target for the evaluation of potential antimalarial compounds is isoprenoid synthesis, which occurs via the 2-C-methyl-d -erythritol-4-phosphate pathway in Plasmodium falciparum. Several intermediaries and final products of this pathway were identified in the parasite and lead us to the conclusion that it is different from the vertebrate host. In this chapter, we describe the effect of some monoterpenes and sesquiterpenes on Plasmodium falciparum and Plasmodium berghei as potential antimalarial drugs

Lobar pneumonia caused by Ralstonia pickettii in a sixty-five-year-old Han Chinese man: a case report

<p>Abstract</p> <p>Introduction</p> <p><it>Ralstonia pickettii </it>is a gram-negative, oxidase-positive bacillus and is an emerging pathogen found in infections described in hospital settings. The cases reported in the literature mostly are nosocomial infections due to contaminated blood products, sterile water, saline, treatment fluids and venous catheters. Human infection unrelated to contaminated solutions is rare. We report a case of lobar pneumonia and pulmonary abscess caused by <it>Ralstonia pickettii </it>in an older patient.</p> <p>Case presentation</p> <p>A sixty-five-year old Han Chinese man presented having had cough, expectoration, chest pain and fever lasting for twenty days. His medical history was notable for hypertension over the previous ten years, and the habit of smoking for forty years. A thoracic computed tomography scan supported the diagnosis of right-sided lobar pneumonia. A lung biopsy was done and pathological analysis confirmed lobar pneumonia. Two lung biopsy specimens from separate sites grew <it>Ralstonia pickettii</it>. After six days, a repeat thoracic scan revealed a right-sided abscess. A thoracentesis was performed and the purulent fluid grew <it>Ralstonia pickettii</it>. The chest tube remained inserted to rinse the cavity with sterile sodium chloride. He received an antibiotic course of intravenous cefoperazone sodium-sulbactam sodium for eighteen days and imipenem-cilastatin for twelve days. A repeat chest X-ray revealed resolution of the pulmonary abscess and improvement of pneumonia. He remained afebrile and free of respiratory symptoms after treatments.</p> <p>Conclusion</p> <p>This case demonstrates a <it>Ralstonia pickettii </it>infection in the absence of an obvious nosocomial source. It is possible that such cases will become common in the future. Therefore, further studies are needed to evaluate its sensitivity to common antibiotics.</p

Malaria prevalence in Nias District, North Sumatra Province, Indonesia

BACKGROUND: The Nias district of the North Sumatra Province of Indonesia has long been known to be endemic for malaria. Following the economic crisis at the end of 1998 and the subsequent tsunami and earthquake, in December 2004 and March 2005, respectively, the malaria control programme in the area deteriorated. The present study aims to provide baseline data for the establishment of a suitable malaria control programme in the area and to analyse the frequency distribution of drug resistance alleles associated with resistance to chloroquine and sulphadoxine-pyrimethamine.\ud METHODS: Malariometric and entomology surveys were performed in three subdistricts. Thin and thick blood smears were stained with Giemsa and examined under binocular light microscopy. Blood blots on filter paper were also prepared for isolation of parasite and host DNA to be used for molecular analysis of band 3 (SAO), pfcrt, pfmdr1, dhfr, and dhps. In addition, haemoglobin measurement was performed in the second and third surveys for the subjects less than 10 years old.\ud RESULTS: Results of the three surveys revealed an average slide positivity rate of 8.13%, with a relatively higher rate in certain foci. Host genetic analysis, to identify the Band 3 deletion associated with Southeast Asian Ovalocytosis (SAO), revealed an overall frequency of 1.0% among the 1,484 samples examined. One hundred six Plasmodium falciparum isolates from three sub-districts were successfully analysed. Alleles of the dhfr and dhps genes associated with resistance to sulphadoxine-pyrimethamine, dhfr C59R and S108N, and dhps A437G and K540E, were present at frequencies of 52.2%, 82.5%, 1.18% and 1.18%, respectively. The pfmdr1 alleles N86Y and N1042D, putatively associated with mefloquine resistance, were present at 31.4% and 2%, respectively. All but one sample carried the pfcrt 76T allele associated with chloroquine resistance. Entomologic surveys identified three potential anopheline vectors in the area, Anopheles barbirostris, Anopheles kochi and Anopheles sundaicus.\ud CONCLUSION: The cross sectional surveys in three different sub-districts of Nias District clearly demonstrated the presence of relatively stable endemic foci of malaria in Nias District, North Sumatra Province, Indonesia. Molecular analysis of the malaria parasite isolates collected from this area strongly indicates resistance to chloroquine and a growing threat of resistance to sulphadoxine-pyrimethamine. This situation highlights the need to develop sustainable malaria control measures through regular surveillance and proper antimalarial drug deployment

Why Is the Correlation between Gene Importance and Gene Evolutionary Rate So Weak?

One of the few commonly believed principles of molecular evolution is that functionally more important genes (or DNA sequences) evolve more slowly than less important ones. This principle is widely used by molecular biologists in daily practice. However, recent genomic analysis of a diverse array of organisms found only weak, negative correlations between the evolutionary rate of a gene and its functional importance, typically measured under a single benign lab condition. A frequently suggested cause of the above finding is that gene importance determined in the lab differs from that in an organism's natural environment. Here, we test this hypothesis in yeast using gene importance values experimentally determined in 418 lab conditions or computationally predicted for 10,000 nutritional conditions. In no single condition or combination of conditions did we find a much stronger negative correlation, which is explainable by our subsequent finding that always-essential (enzyme) genes do not evolve significantly more slowly than sometimes-essential or always-nonessential ones. Furthermore, we verified that functional density, approximated by the fraction of amino acid sites within protein domains, is uncorrelated with gene importance. Thus, neither the lab-nature mismatch nor a potentially biased among-gene distribution of functional density explains the observed weakness of the correlation between gene importance and evolutionary rate. We conclude that the weakness is factual, rather than artifactual. In addition to being weakened by population genetic reasons, the correlation is likely to have been further weakened by the presence of multiple nontrivial rate determinants that are independent from gene importance. These findings notwithstanding, we show that the principle of slower evolution of more important genes does have some predictive power when genes with vastly different evolutionary rates are compared, explaining why the principle can be practically useful despite the weakness of the correlation

Hb H disease resulting from the association of an α0-thalassemia allele [-(α)20.5] with an unstable α-globin variant [Hb Icaria]: First report on the occurrence in Brazil

Hb H Disease is caused by the loss or inactivation of three of the four functional α-globin genes. Patients present chronic hemolytic anemia and splenomegaly. In some cases, occasional blood transfusions are required. Deletions are the main cause of this type of thalassemia ( α-thalassemia). We describe here an unusual case of Hb H disease caused by the combination of a common α0 deletion [-( α) 20.5 ] with a rare point mutation (c.427T > A), thus resulting in an elongated and unstable α-globin variant, Hb Icaria, (X142K), with 31 additional amino-acid residues. Very high levels of Hb H and Hb Bart's were detected in the patient's red blood cells (14.7 and 19.0%, respectively). This is the first description of this infrequent association in the Brazilian population

Genetic characterization and phylogeography of the wild boar Sus scrofa introduced into Uruguay

The European wild boar Sus scrofa was first introduced into Uruguay, in southern South America during the early decades of the last century. Subsequently, and starting from founder populations, its range spread throughout the country and into the neighbouring Brazilian state Rio Grande do Sul. Due to the subsequent negative impact, it was officially declared a national pest. The main aim in the present study was to provide a more comprehensive scenario of wild boar differentiation in Uruguay, by using mtDNA markers to access the genetic characterization of populations at present undergoing rapid expansion. A high level of haplotype diversity, intermediate levels of nucleotide diversity and considerable population differentiation, were detected among sampled localities throughout major watercourses and catchment dams countrywide. Phylogenetic analysis revealed the existence of two different phylogroups, thereby reflecting two deliberate introduction events forming distantly genetic lineages in local wild boar populations. Our analysis lends support to the hypothesis that the invasive potential of populations emerge from introgressive hybridization with domestic pigs. On taking into account the appreciable differentiation and reduced migration between locales in wild boar populations, management strategies could be effective if each population were to be considered as a single management unit

WNT signalling in prostate cancer

Genome sequencing and gene expression analyses of prostate tumours have highlighted the potential importance of genetic and epigenetic changes observed in WNT signalling pathway components in prostate tumours-particularly in the development of castration-resistant prostate cancer. WNT signalling is also important in the prostate tumour microenvironment, in which WNT proteins secreted by the tumour stroma promote resistance to therapy, and in prostate cancer stem or progenitor cells, in which WNT-β-catenin signals promote self-renewal or expansion. Preclinical studies have demonstrated the potential of inhibitors that target WNT receptor complexes at the cell membrane or that block the interaction of β-catenin with lymphoid enhancer-binding factor 1 and the androgen receptor, in preventing prostate cancer progression. Some WNT signalling inhibitors are in phase I trials, but they have yet to be tested in patients with prostate cancer

Inhibition of PIKfyve by YM-201636 Dysregulates Autophagy and Leads to Apoptosis-Independent Neuronal Cell Death

The lipid phosphatidylinositol 3,5-bisphosphate (PtdIns(3,5)P-2), synthesised by PIKfyve, regulates a number of intracellular membrane trafficking pathways. Genetic alteration of the PIKfyve complex, leading to even a mild reduction in PtdIns(3,5)P-2 results in marked neurodegeneration via an uncharacterised mechanism. In the present study we have shown that selectively inhibiting PIKfyve activity, using YM-201636, significantly reduces the survival of primary mouse hippocampal neurons in culture. YM-201636 treatment promoted vacuolation of endolysosomal membranes followed by apoptosis-independent cell death. Many vacuoles contained intravacuolar membranes and inclusions reminiscent of autolysosomes. Accordingly, YM-201636 treatment increased the level of the autophagosomal marker protein LC3-II, an effect that was potentiated by inhibition of lysosomal proteases, suggesting that alterations in autophagy could be a contributing factor to neuronal cell death