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Taha Toros Arşivi, Dosya No: 220-Kaptanzade Ali Rıza Be

Defining the clinical and cognitive phenotype of child savants with autism spectrum disorder

Objective: Whilst savant syndrome is most commonly observed in individuals with Autism Spectrum Disorder (ASD), it has historically been associated with intellectual impairment, and little is known about the clinical and cognitive characteristics of intellectually able individuals with ASD and savant skills. Methods: Participants with ASD and validated savant skills were compared with age and intelligence matched non-savants with ASD using a range of diagnostic and standardised tests. Results: Although the analysis of the clinical data revealed few differences between the groups, striking differences emerged during cognitive testing. Children with savant skills exhibited highly superior working memory and their scores on tests of analytic skills were also superior to those of non-savants. Conclusion: We propose that obsessionality, focused attention, superior working memory and analytic skills facilitate veridical mapping and pattern perception abilities characteristic in savant syndrome

4‑Aminoquinoline Antimalarials Containing a Benzyl­methyl­pyridyl­methyl­amine Group Are Active against Drug Resistant <i>Plasmodium falciparum</i> and Exhibit Oral Activity in Mice

Emergence of drug resistant <i>Plasmodium falciparum</i> including artemisinin-tolerant parasites highlights the need for new antimalarials. We have previously shown that dibemequines, 4-amino-7-chloroquinolines with dibenzylmethyl­amine (dibemethin) side chains, are efficacious. In this study, analogues in which the terminal phenyl group of the dibemethin was replaced with a 2-pyridyl group and in which the 4-amino-7-chloroquinoline was either maintained or replaced with a 4-aminoquinoline-7-carbonitrile were synthesized in an effort to improve druglikeness. These compounds exhibited significantly improved solubility and decreased lipophilicity and were potent against chloroquine-sensitive (NF54) and -resistant (Dd2 and 7G8) <i>P. falciparum</i> strains with 5/6 having IC₅₀ < 100 nM against the NF54 strain. All inhibited both β-hematin (synthetic hemozoin) formation and hemozoin formation in the parasite. Parasitemia was reduced by over 90% in <i>P. berghei</i> infected mice in 3/6 derivatives following oral dosing at 4 × 30 mg/kg, with microsomal metabolic stability data suggesting that this could be attributed to highly active metabolites

Linezolid population pharmacokinetic model in plasma and cerebrospinal fluid among patients with tuberculosis meningitis.

BACKGROUND: Linezolid is evaluated in novel treatment regimens for tuberculous meningitis (TBM). Linezolid pharmacokinetics have not been characterized in this population, particularly in cerebrospinal fluid (CSF) where exposures may be affected by changes in protein concentration. Linezolid co-administration with high-dose rifampicin, has also not been studied. We aimed to characterize linezolid plasma and CSF pharmacokinetics in adults with TBM. METHODS: In LASER-TBM pharmacokinetic-substudy, the intervention groups received high-dose rifampicin (35mg/kg) plus linezolid 1200mg/day for 28days, then reduced to 600mg/day. Plasma sampling was done on day 3 (intensive) and on day 28 (sparse). A lumbar CSF sample was obtained on both visits. RESULTS: 30-participants, median(min-max) age and weight of 40(27-56)years and 58(30-96)kg, contributed 247 plasma and 28 CSF observations. Plasma pharmacokinetics was described by one-compartment model with first-order absorption and saturable elimination. Maximal clearance was 7.25L/h, and Km was 27.2mg/L. Rifampicin co-treatment duration did not affect linezolid pharmacokinetics. CSF-Plasma partitioning correlated with CSF total-protein upto 1.2g/L where the partition-coefficient reached maximal value of 37%. Plasma-CSF equilibration half-life was ∼3.5hours. CONCLUSION: Linezolid was readily detected in CSF despite high-dose rifampicin co-administration. These findings support continued clinical evaluation of linezolid plus high-dose rifampicin for the treatment of TBM in adults

Additional file 2: of Progress towards the UNAIDS 90–90-90 goals by age and gender in a rural area of KwaZulu-Natal, South Africa: a household-based community cross-sectional survey

Mbongolwane survey Women questionnaire: questions to the individual female participants. (PDF 63 kb

Additional file 1: of Progress towards the UNAIDS 90–90-90 goals by age and gender in a rural area of KwaZulu-Natal, South Africa: a household-based community cross-sectional survey

Mbongolwane survey Household questionnaire: questions to the head of the household. (PDF 32 kb

Additional file 3: of Progress towards the UNAIDS 90–90-90 goals by age and gender in a rural area of KwaZulu-Natal, South Africa: a household-based community cross-sectional survey

Mbongolwane survey Men questionnaire: questions to the individual male participants. (PDF 54 kb

Syntheses and in Vitro Antiplasmodial Activity of Aminoalkylated Chalcones and Analogues

A series of readily synthesized and inexpensive aminoalkylated chalcones and diarylpropane analogues (<b>1</b>–<b>55</b>) were synthesized and tested against chloroquinone-sensitive (D10 and NF54) and -resistant (Dd2 and K1) strains of <i>Plasmodium falciparum</i>. Hydrogenation of the enone to a diarylpropane moiety increased antiplasmodial bioactivity significantly. The influence of the structure of the amine moiety, A-ring substituents, propyl vs ethyl linker, and chloride salt formation on further enhancing antiplasmodial activity was investigated. Several compounds have IC₅₀ values similar to or better than chloroquine (CQ). The most active compound (<b>26</b>) had an IC₅₀ value of 0.01 μM. No signs of resistance were detected, as can be expected from compounds with structures unrelated to CQ and other currently used antimalarial drugs. Toxicity tests (in vitro CHO cell assay) gave high SI indices

Khayelitsha Hospital TB study pharmacokinetic variables: Non compartmental analysis

Human immunodeficiency virus associated tuberculosis (HIV-TB) comprise 10% of global tuberculosis cases but contribute a disproportionate 22% of global tuberculosis mortality. HIV-infected patients hospitalized with HIV-TB have high high case fatality rates despite treatment and often present with a clinical picture compatible with sepsis. There is paucity of data in critically ill HIV-infected patients admitted to hospital at the time of tuberculosis diagnosis. Improved, evidence-based treatment interventions in this patient group are urgently needed to improve survival.We performed intensive pharmacokinetic studies (from 0-8 hours) in a high burden setting (Khayelitsha Hospital, Cape Town), within the routine service. We assessed rifampicin, isoniazid and pyrazinamide exposure in a group of hospitalized HIV-TB patients and a group of outpatients on the third day of standard antituberculosis therapy using non-compartmental analysis. We followed hospitalized patients for 12 weeks to asses survival. We compared pharmacokinetic exposures in hospitalized patients and outpatients; hospitalized patients who survived twelve weeks and those who died; and hospitalized patients presenting with high lactate (more than 2.2 mmol/L) and patient presenting with normal lactate. </div

Medicinal Chemistry Optimization of Antiplasmodial Imidazopyridazine Hits from High Throughput Screening of a SoftFocus Kinase Library: Part 2

On the basis of our recent results on a novel series of imidazopyridazine-based antimalarials, we focused on identifying compounds with improved aqueous solubility and hERG profile while maintaining metabolic stability and in vitro potency. Toward this objective, 41 compounds were synthesized and evaluated for antiplasmodial activity against NF54 (sensitive) and K1 (multidrug resistant) strains of the malaria parasite <i>Plasmodium falciparum</i> and evaluated for both aqueous solubility and metabolic stability. Selected compounds were tested for in vitro hERG activity and in vivo efficacy in the <i>P. berghei</i> mouse model. Several compounds were identified with significantly improved aqueous solubility, good metabolic stability, and a clean hERG profile relative to a previous frontrunner lead compound. A sulfoxide-based imidazopyridazine analog <b>45</b>, arising from a prodrug-like strategy, was completely curative in the <i>Plasmodium berghei</i> mouse model at 4 × 50 mg/kg po