Search

Malaria, caused by Plasmodium parasites, continues to be a devastating global health issue. Despite a decline in malaria related deaths over the last decade, overall progress has plateaued. Key challenges to malaria prevention and control include the lack of a broadly effective vaccine and parasite drug resistance, including to the current gold standard artemisinin combination therapies (ACTs). New drugs with unique modes of action are therefore a priority for both the treatment and prevention of malaria. Unlike treatment drugs which need to kill parasites quickly to reduce or prevent clinical symptoms, compounds that kill parasites more slowly may be an option for malaria prevention. Natural products and natural product derived compounds have historically been an excellent source of antimalarial drugs, including the artemisinin component of ACTs. In this study, 424 natural product derived compounds were screened for in vitro activity against P. falciparum in assays designed to detect slow action activity, with 46 hit compounds identified as having >50% inhibition at 10 μM. Dose response assays revealed nine compounds with submicromolar activity, with slow action activity confirmed for two compounds, alstonine and himbeline (50% inhibitory concentration (IC 50 ) 0.17 and 0.58 μM, respectively). Both compounds displayed >140-fold better activity against P. falciparum versus two human cell lines (Selectivity Index (SI) >1,111 and > 144, respectively). Importantly, P. falciparum multi-drug resistant lines showed no cross-resistance to alstonine or himbeline, with some resistant lines being more sensitive to these two compounds compared to the drug sensitive line. In addition, alstonine displayed cross-species activity against the zoonotic species, P. knowelsi (IC 50 ~1 μM). Outcomes of this study provide a starting point for further investigations into these compounds as antiplasmodial drug candidates and the investigation of their molecular targets., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

A plethora of studies indicate that iron metabolism is dysregulated in Parkinson's disease (PD). The literature reveals well-documented alterations consistent with established dogma, but also intriguing paradoxical observations requiring mechanistic dissection. An important fact is the iron loading in dopaminergic neurons of the substantia nigra pars compacta (SNpc), which are the cells primarily affected in PD. Assessment of these changes reveal increased expression of proteins critical for iron uptake, namely transferrin receptor 1 and the divalent metal transporter 1 (DMT1), and decreased expression of the iron exporter, ferroportin-1 (FPN1). Consistent with this is the activation of iron regulator protein (IRP) RNA-binding activity, which is an important regulator of iron homeostasis, with its activation indicating cytosolic iron deficiency. In fact, IRPs bind to iron-responsive elements (IREs) in the 3ꞌ untranslated region (UTR) of certain mRNAs to stabilize their half-life, while binding to the 5ꞌ UTR prevents translation. Iron loading of dopaminergic neurons in PD may occur through these mechanisms, leading to increased neuronal iron and iron-mediated reactive oxygen species (ROS) generation. The "gold standard" histological marker of PD, Lewy bodies, are mainly composed of α-synuclein, the expression of which is markedly increased in PD. Of note, an atypical IRE exists in the α-synuclein 5ꞌ UTR that may explain its up-regulation by increased iron. This dysregulation could be impacted by the unique autonomous pacemaking of dopaminergic neurons of the SNpc that engages L-type Ca +2 channels, which imparts a bioenergetic energy deficit and mitochondrial redox stress. This dysfunction could then drive alterations in iron trafficking that attempt to rescue energy deficits such as the increased iron uptake to provide iron for key electron transport proteins. Considering the increased iron-loading in PD brains, therapies utilizing limited iron chelation have shown success. Greater therapeutic advancements should be possible once the exact molecular pathways of iron processing are dissected., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)

A near-shore marine intertidal environment-associated Streptomyces isolate (USC-633) from the Sunshine Coast Region of Queensland, Australia, cultivated under a range of chemically defined and complex media to determine optimal parameters resulting in the secretion of diverse array of secondary metabolites with antimicrobial properties against various antibiotic resistant bacteria. Following extraction, fractioning and re-testing of active metabolites resulted in persistent antibacterial activity against Escherichia coli (Migula) (ATCC 13706) and subsequent Nuclear Magnetic Resonance (NMR) analysis of the active fractions confirmed the induction of metabolites different than the ones in fractions which did not display activity against the same bacterial species. Overall findings again confirmed the value of One Strain-Many Compounds (OSMAC) approach that tests a wide range of growth parameters to trigger bioactive compound secretion increasing the likelihood of finding novel therapeutic agents. The isolate was found to be adaptable to both marine and terrestrial conditions corresponding to its original near-shore marine intertidal environment. Wide variations in its morphology, sporulation and diffusible pigment production were observed when different growth media were used.

Unlabelled: The current noninvasive methods of deep-venous thrombosis (DVT) detection in the asymptomatic patient are sufficiently inaccurate so as to preclude their routine use. This present study reports the accuracy of scintigraphic scanning with 99mTc-rt-PA in asymptomatic postoperative patients using contrast venography as the gold standard., Methods: Fifty-three consecutive postarthroplasty patients (30 THR, 23 TKR) (16 women, 37 men; mean age 71 yr; range 52-85 yr) underwent scintigraphic scanning with 99mTc-rt-PA and contrast venography, on the operated leg, in order to assess the accuracy of this new technique in these asymptomatic patients., Results: Eighty-four segments were of diagnostic quality on contrast venography. Of the 15 thrombosed segments, 14 had positive scans. In the 69 nonthrombosed segments, 63 had negative scans. Thus, scintigraphic scanning with 99mTc-rt-PA had a sensitivity of 93% and a specificity of 91%., Conclusion: This study demonstrated that scintigraphic scanning with modified 99mTc-rt-PA is accurate in the detection of DVT in patients undergoing total hip or total knee arthroplasty.

Unlabelled: We report a method for deep venous thrombosis (DVT) detection which uses 99mTc-labeled modified recombinant tissue plasminogen activator (rt-PA) scintigraphy. A Phase III clinical trial was performed on 79 patients with suspected DVT., Methods: The plasminogen binding site of rt-PA was permanently inhibited without inactivating the fibrin binding site. The modified molecule was radiolabeled with 99mTc. Scintigraphy was performed and the results were compared to those of contrast venography., Results: Of 14 thrombosed proximal segments, 13 had positive scans; in the 53 nonthrombosed proximal segments, 49 had negative scans. In proximal vein thrombosis, rt-PA scintigraphy had a sensitivity of 93% and a specificity of 92%. Of the 36 thrombosed calf vein segments, 31 had positive scans; in the 30 nonthrombosed calf segments, 28 had negative scans. In calf vein thrombosis, scanning has a sensitivity of 86% and a specificity of 93%., Conclusions: Scintigraphic scanning with this 99mTc modified rt-PA permits accurate detection of thrombus in both proximal and calf veins in patients with clinically suspected DVT. The technique detects both fresh and aged thrombi and is unaffected by heparin administration. Further study in other patient groups is needed to define the overall clinical utility.

Unlabelled: Controversy exists as to whether patients with single segmental mismatch (SSM) on a ventilation/perfusion (VQ) lung scan should be given a low or an intermediate probability of pulmonary embolism (PE)., Methods: Pulmonary angiography was used to evaluate the incidence of PE in SSM at the authors' institution. From January 1991 to January 1993, 1449 VQ scans were performed., Results: With modified Biello criteria, 283 were high probability; 628, low probability; 273, normal; and 273, intermediate probability. Of the intermediate probability scans, 61 had SSM. Forty of these patients underwent pulmonary angiography. Twelve patients had PE in the area of the SSM, giving an incidence of PE of 30%. The risk of PE in SSM in the different lung regions was also analyzed. Twenty-three SSM were in the bases of the lung with a 22% incidence of PE; 17 SSM were either in the midzone or apex with a 41% incidence of PE (p = not significant)., Conclusion: SSM carries a 30% risk of PE. Accordingly, SSM should be given an intermediate probability of PE and not a low probability of PE.

We present a patient with tubulointerstitial renal disease and poor renal 99mTc-DMSA uptake. A 99mTc-DTPA scan was normal and the creatinine clearance only minimally decreased. In this case, 99mTc-DMSA uptake did not correlate with "global renal function," but rather with the functioning tubular mass.

There remains no clear consensus as to the appropriate further investigation and management of the patient suspected of pulmonary embolism (PE) who has an intermediate lung scan. Clinical assessment is documented as unreliable, yet many of these patients are unlikely to be treated or to have further tests despite a 36% chance of having PE. Using Medical Decision Analysis, four management strategies for such patients have been examined in terms of mortality and morbidity up to 6 mo post-presentation. The strategies were: (1) treat all patients; (2) treat no patients; (3) perform pulmonary angiography; and (4) perform contrast venography. In the last two strategies, the patients with positive examinations are treated; those with negative examinations are not treated. An extensive literature review was performed to provide probability estimates of chance events and outcomes. If all patients are treated, there is 96.8% chance of survival, with an 85.8% chance of survival with no major complications. If no patients are treated, survival is 89.3% and complication-free survival is 89.3%. Angiography and venography results were 96.7%, 93.1% and 94.6% and 89.6%, respectively. We conclude that in patients suspected of PE who have intermediate lung scan results, the optimal strategy is pulmonary angiography since this results in the highest survival with the lowest complications.

This report of cerebral tumours in 60 children admitted to the medical wards of King Edward VIII Hospital, Durban, shows that cerebral tumour is the commonest solid neoplasm in both Black and Indian children. There is a significantly lower incidence of cerebral tumour in Black children. No difference was apparent in age, sex ratio, site or histological types in our racial groups compared with studies in White children from other parts of the world.