Liver Function Test Abnormalities in Experimental and Clinical Plasmodium vivax Infection

Liver transaminase elevations after treatment in malaria volunteer infection studies (VISs) have raised safety concerns. We investigated transaminase elevations from two human Plasmodium vivax VISs where subjects were treated with chloroquine (n = 24) or artefenomel (n = 8) and compared them with studies in Thailand (n = 41) and Malaysia (n = 76). In the VISs, alanine transaminase (ALT) increased to ≥ 2.5 × upper limit of normal (ULN) in 11/32 (34%) volunteers, peaking 5–8 days posttreatment. Transaminase elevations were asymptomatic, were not associated with elevated bilirubin, and resolved by day 42. The risk of an ALT ≥ 2.5 × ULN increased more than 4-fold (odds ratio [OR] 4.28; 95% CI: 1.26–14.59; P = 0.02) for every log10 increase in the parasite clearance burden (PCB), defined as the log-fold reduction in parasitemia 24 hours post-treatment. Although an elevated ALT ≥ 2.5 × ULN was more common after artefenomel than after chloroquine (5/8 [63%] versus 6/24 [25%]; OR 5.0; 95% CI: 0.91–27.47; P = 0.06), this risk disappeared when corrected for parasite clearance burden (PCB). Peak ALT also correlated with peak C-reactive protein (R = 0.44; P = 0.012). Elevations in ALT (≥ 2.5 × ULN) were less common in malaria-endemic settings, occurring in 1/41 (2.5%) Thai patients treated with artefenomel, and in none of 76 Malaysians treated with chloroquine or artemisinin combination therapy. Post-treatment transaminase elevations are common in experimental P. vivax infection but do not appear to impact on participant safety. Although the mechanism of these changes remains uncertain, host inflammatory response to parasite clearance may be contributory

Development and evaluation of a new Plasmodium falciparum 3D7 blood stage malaria cell bank for use in malaria volunteer infection studies

Background: New anti-malarial therapeutics are required to counter the threat of increasing drug resistance. Malaria volunteer infection studies (VIS), particularly the induced blood stage malaria (IBSM) model, play a key role in accelerating anti-malarial drug development. Supply of the reference 3D7-V2 Plasmodium falciparum malaria cell bank (MCB) is limited. This study aimed to develop a new MCB, and compare the safety and infectivity of this MCB with the existing 3D7-V2 MCB, in a VIS. A second bank (3D7-V1) developed in 1995 was also evaluated. Methods: The 3D7-V2 MCB was expanded in vitro using a bioreactor to produce a new MCB designated 3D7-MBE-008. This bank and 3D7-V1 were then evaluated using the IBSM model, where healthy participants were intravenously inoculated with blood-stage parasites. Participants were treated with artemether-lumefantrine when parasitaemia or clinical thresholds were reached. Safety, infectivity and parasite growth and clearance were evaluated. Results: The in vitro expansion of 3D7-V2 produced 200 vials of the 3D7-MBE-008 MCB, with a parasitaemia of 4.3%. This compares to 0.1% in the existing 3D7-V2 MCB, and < 0.01% in the 3D7-V1 MCB. All four participants (two per MCB) developed detectable P. falciparum infection after inoculation with approximately 2800 parasites. For the 3D7-MBE-008 MCB, the parasite multiplication rate of 48 h (PMR48) using non-linear mixed effects modelling was 34.6 (95% CI 18.5–64.6), similar to the parental 3D7-V2 line; parasitaemia in both participants exceeded 10,000/mL by day 8. Growth of the 3D7-V1 was slower (PMR48 of 11.5 [95% CI 8.5–15.6]), with parasitaemia exceeding 10,000 parasites/mL on days 10 and 8.5. Rapid parasite clearance followed artemether-lumefantrine treatment in all four participants, with clearance half-lives of 4.01 and 4.06 (weighted mean 4.04 [95% CI 3.61–4.57]) hours for 3D7-MBE-008 and 4.11 and 4.52 (weighted mean 4.31 [95% CI 4.16–4.47]) hours for 3D7-V1. A total of 59 adverse events occurred; most were of mild severity with three being severe in the 3D7-MBE-008 study. Conclusion: The safety, growth and clearance profiles of the expanded 3D7-MBE-008 MCB closely resemble that of its parent, indicating its suitability for future studies. Trial Registration: Australian New Zealand Clinical Trials registry numbers: P3487 (3D7-V1): ACTRN12619001085167. P3491 (3D7-MBE-008): ACTRN1261900107913

The Enhancer of Trithorax and Polycomb Corto Interacts with Cyclin G in Drosophila

BACKGROUND: Polycomb (PcG) and trithorax (trxG) genes encode proteins involved in the maintenance of gene expression patterns, notably Hox genes, throughout development. PcG proteins are required for long-term gene repression whereas TrxG proteins are positive regulators that counteract PcG action. PcG and TrxG proteins form large complexes that bind chromatin at overlapping sites called Polycomb and Trithorax Response Elements (PRE/TRE). A third class of proteins, so-called "Enhancers of Trithorax and Polycomb" (ETP), interacts with either complexes, behaving sometimes as repressors and sometimes as activators. The role of ETP proteins is largely unknown. METHODOLOGY/PRINCIPAL FINDINGS: In a two-hybrid screen, we identified Cyclin G (CycG) as a partner of the Drosophila ETP Corto. Inactivation of CycG by RNA interference highlights its essential role during development. We show here that Corto and CycG directly interact and bind to each other in embryos and S2 cells. Moreover, CycG is targeted to polytene chromosomes where it co-localizes at multiple sites with Corto and with the PcG factor Polyhomeotic (PH). We observed that corto is involved in maintaining Abd-B repression outside its normal expression domain in embryos. This could be achieved by association between Corto and CycG since both proteins bind the regulatory element iab-7 PRE and the promoter of the Abd-B gene. CONCLUSIONS/SIGNIFICANCE: Our results suggest that CycG could regulate the activity of Corto at chromatin and thus be involved in changing Corto from an Enhancer of TrxG into an Enhancer of PcG

The Activities of Current Antimalarial Drugs on the Life Cycle Stages of Plasmodium: A Comparative Study with Human and Rodent Parasites

Michael Delves and colleagues compare the activity of 50 current and experimental antimalarials against liver, sexual blood, and mosquito stages of selected human and nonhuman parasite species, including Plasmodium falciparum, Plasmodium berghei, and Plasmodium yoelii

Nodular malignant melanoma and multiple cutaneous neoplasms under immunosuppression with azathioprine.

Immunosuppressed patients are at increased risk of skin cancer. A 67-year-old renal transplant recipient developed a nodular malignant melanoma after 30 years of immunosuppression with azathioprine and prednisolone. The patient died of metastatic disease 3 months after the diagnosis was made. The function of the renal graft was not affected at all. Renal transplant recipients are at high risk of developing nonmelanocytic skin tumors when on immunosuppressive therapy with cyclosporine A. Less common is the development of skin cancer during immunosuppression with azathioprine. Latest reports show the increased incidence of malignant melanoma in immunosuppressed patients. Our case illustrates the necessity of close dermatological surveillance of allograft recipients, to assure an early recognition of any malignant skin tumor and to reduce the risk of systemic metastatic disease

Transmitter PIC for THz applications based on generic integration technology

A generic InP based monolithic photonic integration platform is introduced that is capable of simultaneously incorporating transmitter, receiver and passive-optical functionalities. On this basis, an integrated transmitter component for THz applications has been implemented

Closing the species gap: Translational approaches to studying sensory processing differences relevant for autism spectrum disorder

Lay Summary: It has always been difficult to relate results from animal research to humans. We try to close this gap by studying changes in sensory processing using careful protocol design and collaboration between clinicians and researchers. Sensory pathways are comparable between animals and humans, and are affected in the same way as the rest of the brain in ASD. Using changes in hearing as a template, we point the field in an innovative direction by providing a framework for collecting cohesive data in rodents and humans. _______________________________________ study of sensory phenotypes has great potential for increasing research translation between species, a necessity to decipher the neural mechanisms that contribute to higher-order differences in neurological conditions such as autism spectrum disorder (ASD). Over the past decade, despite separate advances in our understanding of the structural and functional differences within the brain of autistic and non-autistic individuals and in rodent models for ASD, researchers have had difficulty translating the findings in murine species to humans, mostly due to incompatibility in experimental methodologies used to screen for ASD phenotypes. Focusing on sensory phenotypes offers an avenue to close the species gap because sensory pathways are highly conserved across species and are affected by the same risk-factors as the higher-order brain areas mostly responsible for the diagnostic criteria for ASD. By first reviewing how sensory processing has been studied to date, we direct our focus to electrophysiological and behavioral techniques that can be used to study sensory phenotypes consistently across species. Using auditory sensory phenotypes as a template, we seek to improve the accessibility of translational methods by providing a framework for collecting cohesive data in both rodents and humans. Specifically, evoked-potentials, acoustic startle paradigms, and psychophysical detection/discrimination paradigms can be created and implemented in a coordinated and systematic fashion across species. Through careful protocol design and collaboration, sensory processing phenotypes can be harnessed to bridge the gap that exists between preclinical animal studies and human testing, so that mutually held questions in autism research can be answered