Her2 Activation Mechanism Reflects Evolutionary Preservation of Asymmetric Ectodomain Dimers in the Human EGFR Family.

Her2 activation mechanism reflects evolutionary preservation of asymmetric ectodomain dimers in the human EGFR family.

Elife. 2013; 2: e00708
Arkhipov A, Shan Y, Kim ET, Dror RO, Shaw DE

The receptor tyrosine kinase Her2, an intensely pursued drug target, differs from other members of the EGFR family in that it does not bind EGF-like ligands, relying instead on heterodimerization with other (ligand-bound) EGFR-family receptors for activation. The structural basis for Her2 heterodimerization, however, remains poorly understood. The unexpected recent finding of asymmetric ectodomain dimer structures of Drosophila EGFR (dEGFR) suggests a possible structural basis for Her2 heterodimerization, but all available structures for dimers of human EGFR family ectodomains are symmetric. Here, we report results from long-timescale molecular dynamics simulations indicating that a single ligand is necessary and sufficient to stabilize the ectodomain interface of Her2 heterodimers, which assume an asymmetric conformation similar to that of dEGFR dimers. This structural parallelism suggests a dimerization mechanism that has been conserved in the evolution of the EGFR family from Drosophila to human. DOI:http://dx.doi.org/10.7554/eLife.00708.001. HubMed – drug

Evidence of long term benefit of morbidity reduction due to praziquantel treatment against schistosoma mansoni in kigungu fishing village in entebbe, Uganda.

Afr J Infect Dis. 2011; 5(2): 33-9
Odongo-Aginya EI, Kironde F, Lyazi M, Sempewo H, Correa Oliveira R

Praziquantel (PZQ) is efficacious against Schistosoma mansoni. This was prospective cohort study. This study was carried out at Kigungu fishing village, Entebbe, Uganda. The goal of the study was to establish cost effective regiment for mass drug administration (MDA) of Praziquentel in the morbidity reduction of S.mansoni infection. In January 2004, nine hundred and forty five (945) participants were registered in this study. Our analysis was based on examining microscopically three slides prepared from each of 945 stool specimens delivered by each of the participant using modified Kato/Katz method. These included male and female, children and adults living in Kigungu fishing village in Entebbe Uganda. In total 901, cohorts were re-examined for infections clearance six months later in July 2004 and 18 months later in June 2005, 625 cohorts were again re-evaluated for S.mansoni infections after the baseline study. At baseline, (448) of 945 (47.5%) cohorts were S. mansoni positive. All these participants were treatment with a single oral dose of praziquantel at 40mg/kg. At the same time, 495 (52.5%) were S. mansoni negative. Of the 625 (66.3%) cohorts who came back for final review, 80 (12.8%) were still positive for S. mansoni while 210 (33.6%) remained negative after the base line treatment with praziquantel. On the other hand 103 (16.3%) of cohorts who were initially negative at the base line became S.mansoni positive after 18 months and 213(34.1%) remained negative for S.mansoni. The force of re-infection after six months was significant {(P=0.0001), (OR 0.47) CI at 95% (0.31-0.71)}. Nevertheless the force of reinfection was not significant after 18 months {(P=0.766), (OR 0.95) CI at 95% (0.68-1.34)}.The geometric mean eggs excretion of the 80 cohorts who were S.mansoni positive at 18 months was 151.967.This did not reach the geometric mean egg excreted by the same cohorts at baseline which was 285.05. The egg excretion was reduced by 46.8%. Similarly there was marked decrease in clinical symptoms amongst the cohorts. Our study suggests evidence of long-term benefit of praziquantel in Kigungu and that a yearly administration of praziquantel to the community could be a regiment for mass drug administration (MAD) for this community to control schistosomiasis morbidity. HubMed – drug

Sensitivity of microscopy compared to molecular diagnosis of p. Falciparum: implications on malaria treatment in epidemic areas in kenya.

Afr J Infect Dis. 2011; 5(1): 1-6
Wangai LN, Karau MG, Njiruh PN, Sabah O, Kimani FT, Magoma G, Kiambo N

Detection of Plasmodium species by microscopy has been the gold standard for diagnosis of malaria for more than a century. Despite the fact that there is a significant decline in the number of positive cases reported from microscopy, antimalarial drugs prescriptions are on continuous increase as patients present with symptoms of malaria. This makes it difficult to establish accuracy, sensitivity and specificity of light microscopy in diagnosis of malaria in epidemic areas. This study was designed to compare microscopy with polymerase chain reaction as diagnostic methods for malaria in three epidemic areas in Kenya. A total of 356 patients presenting with malaria symptoms were diagnosed by microscopy and dried blood filter paper spots were collected from patient in Kisii, West Pokot and Narok districts. Plasmodium falciparum DNA was extracted from the dried blood filter samples. Primers specific for the Plasmodium Species were designed and used in a two step amplification of the Pfmdr gene. The PCR products were analyzed in ethidium bromide stained 1.5% agarose gel. It was found that 72 out of 350 specimens diagnosed as negative were positive for P. falciparum by nested PCR, while 6 which were microscopy positive were confirmed so by nested PCR. This study demonstrates that there is a high level of misdiagnosis which may either lead to denial for deserved treatment or undeserved treatment. Nested PCR detection of malaria parasites is a very useful complement to microscopy although it is expensive and takes long time. Additionally, smear negative patients suspected to have malaria should be subjected to PCR diagnosis to improve rational drug use. The economic burden of misdiagnosis and mistreatment of malaria outweighs that of PCR diagnosis, hence this diagnostic mode could be tenable in the long run even in rural areas. HubMed – drug

Is chloroquine better than artemisinin combination therapy as first line treatment in adult nigerians with uncomplicated malaria?-A cost effectiveness analysis.

Afr J Infect Dis. 2010; 4(2): 29-42
Bello SO, Chika A, Bello AY

The current case management and drug policy of malaria in Nigeria recommended by the Federal ministry of health may not be appropriate for all age categories. This suspicion was tested by running a cost effectiveness analysis of two possible and alternative strategies: Artemisinin Combination Therapy (ACT) or Chloroquine and ACT only if CQ fails (CANACT), in adult non pregnant Nigerians aged 20-45yrs. The result confirms that ACT is indeed more effective but also more costly with an incremental cost effectiveness ratio (ICER) of #2,546,527.00 per QALY that is much higher than the estimated upper limit of #25,000.00 that either patients or provider may be willing to pay. The CANACT strategy may be the most cost effective strategy in this subgroup of Nigerian patients and also provides better value for money. HubMed – drug