HIV-positive kidney transplants for HIV-positive individuals: Attitudes and concerns of South African patients and health care workers

In South Africa, an estimated 30% of the cadaveric donor pool is HIV-infected; in consequence, these organs are discarded. An undersupply of donor organs combined with limited resources, tends to exclude HIV-positive patients from renal replacement programmes. We evaluated the acceptance of using HIV-positive donor kidneys for transplantation into HIV-infected recipients, and found that the vast majority (90% of health care workers and 80% of patients, N=20 and 80, respectively) found this approach acceptable for expanding the organ donor pool, which indicates broad patient and health care worker support for using HIV-infected donor kidneys.Participants: 80 patients were recruited from four different groups: those with HIV on stable antiretroviral (ARV) therapy but with no kidney disease; stable antiretroviral therapy, with kidney disease, including on dialysis; and HIV-uninfected patients, both on dialysis and those with functional kidney transplants. Discussions with 20 health care workers were also conducted. Results: The vast majority (90% of health care workers and 80% of patients, n=20 and 80 respectively) found transplant of HIV-infected organs to HIV-positive recipients an acceptable method for expanding the organ donor pool. This study found no significant difference between the groups of patients regarding whether they approved of using HIV-positive donors; HIV positive patients were willing to accept kidneys from HIV-infected family members, while HIV-negative patients were very unlikely to accept HIV-infected organs. Health care workers expressed concern about initiatives to expand the donor pool and educate patients concerning transplant eligibility. Conclusion: These findings indicate broad patient and health care worker support for the use of HIV-infected donor kidneys for some types of renal patients

VPS29 Is Not an Active Metallo-Phosphatase but Is a Rigid Scaffold Required for Retromer Interaction with Accessory Proteins

VPS29 is a key component of the cargo-binding core complex of retromer, a protein assembly with diverse roles in transport of receptors within the endosomal system. VPS29 has a fold related to metal-binding phosphatases and mediates interactions between retromer and other regulatory proteins. In this study we examine the functional interactions of mammalian VPS29, using X-ray crystallography and NMR spectroscopy. We find that although VPS29 can coordinate metal ions Mn2+ and Zn2+ in both the putative active site and at other locations, the affinity for metals is low, and lack of activity in phosphatase assays using a putative peptide substrate support the conclusion that VPS29 is not a functional metalloenzyme. There is evidence that structural elements of VPS29 critical for binding the retromer subunit VPS35 may undergo both metal-dependent and independent conformational changes regulating complex formation, however studies using ITC and NMR residual dipolar coupling (RDC) measurements show that this is not the case. Finally, NMR chemical shift mapping indicates that VPS29 is able to associate with SNX1 via a conserved hydrophobic surface, but with a low affinity that suggests additional interactions will be required to stabilise the complex in vivo. Our conclusion is that VPS29 is a metal ion-independent, rigid scaffolding domain, which is essential but not sufficient for incorporation of retromer into functional endosomal transport assemblies

Integrated dataset of screening hits against multiple neglected disease pathogens.

New chemical entities are desperately needed that overcome the limitations of existing drugs for neglected diseases. Screening a diverse library of 10,000 drug-like compounds against 7 neglected disease pathogens resulted in an integrated dataset of 744 hits. We discuss the prioritization of these hits for each pathogen and the strong correlation observed between compounds active against more than two pathogens and mammalian cell toxicity. Our work suggests that the efficiency of early drug discovery for neglected diseases can be enhanced through a collaborative, multi-pathogen approach

HIV-positive kidney transplants for HIV-positive individuals: Attitudes and concerns of South African patients and health care workers

In South Africa, an estimated 30% of the cadaveric donor pool is HIV-infected; in consequence, these organs are discarded. An undersupply of donor organs combined with limited resources, tends to exclude HIV-positive patients from renal replacement programmes. We evaluated the acceptance of using HIV-positive donor kidneys for transplantation into HIV-infected recipients, and found that the vast majority (90% of health care workers and 80% of patients, N=20 and 80, respectively) found this approach acceptable for expanding the organ donor pool, which indicates broad patient and health care worker support for using HIV-infected donor kidneys.Participants: 80 patients were recruited from four different groups: those with HIV on stable antiretroviral (ARV) therapy but with no kidney disease; stable antiretroviral therapy, with kidney disease, including on dialysis; and HIV-uninfected patients, both on dialysis and those with functional kidney transplants. Discussions with 20 health care workers were also conducted. Results: The vast majority (90% of health care workers and 80% of patients, n=20 and 80 respectively) found transplant of HIV-infected organs to HIV-positive recipients an acceptable method for expanding the organ donor pool. This study found no significant difference between the groups of patients regarding whether they approved of using HIV-positive donors; HIV positive patients were willing to accept kidneys from HIV-infected family members, while HIV-negative patients were very unlikely to accept HIV-infected organs. Health care workers expressed concern about initiatives to expand the donor pool and educate patients concerning transplant eligibility. Conclusion: These findings indicate broad patient and health care worker support for the use of HIV-infected donor kidneys for some types of renal patients

HIV-positive kidney transplants for HIV-positive individuals: Attitudes and concerns of South African patients and health care workers

In South Africa, an estimated 30% of the cadaveric donor pool is HIV-infected; in consequence, these organs are discarded. An under-supply of donor organs combined with limited resources tends to exclude HIV-positive patients from renal replacement programmes. We evaluated the acceptance of using HIV-positive donor kidneys for transplantation into HIV-infected recipients, and found that the vast majority (90% of health care workers and 80% of patients, N = 20 and 80, respectively) found this approach acceptable for expanding the organ donor pool, which indicates broad patient and health care worker support for using HIV-infected donor kidneys

Onchocerciasis Drug Discovery: In Vitro Evaluation of FDA-Approved Drugs against <i>Onchocerca gutturosa</i> in Gambia

Onchocerciasis treatment and control relies mainly on the use of ivermectin which has high activity against the microfilarial stage of Onchocerca volvulus but limited activity against the long-lived, tissue dwelling adult nematodes. As this neglected tropical disease has now been targeted for elimination, there is an urgent need for new drugs to combat these parasites, ideally with macrofilaricidal activity. In this study, we have examined the anti-Onchocerca activity of a range of existing FDA-approved drugs with a view to repurposing, which can lead to rapid and relatively inexpensive development. From the Pharmakon-1600 library, 106 drugs were selected and tested against O. gutturosa adult male parasites using a concentration of 1.25 × 10−5 M in an in vitro 5-day standard assay to assess motility and viability (using MTT/formazan colorimetry). The findings revealed that 44 drugs produced marginal/moderate activity (50–99% motility and/or MTT reductions) including cefuroxime sodium, methenamine, primaquine phosphate and rivastigmine tartrate, while 23 drugs produced good activity (100% motility reductions and significant MTT reductions), including atovaquone, isradipine, losartan, rifaximin, cefaclor and pyrantel pamoate. Although this study represents only a first step, some of the identified hits indicate there are potential anti-Onchocerca drug candidates worthy of further investigation

Oxfendazole mediates macrofilaricidal efficacy against the filarial nematode Litomosoides sigmodontis in vivo and inhibits Onchocerca spec. motility in vitro.

A major impediment to eliminate lymphatic filariasis and onchocerciasis is the lack of effective short-course macrofilaricidal drugs or regimens that are proven to be safe for both infections. In this study we tested oxfendazole, an anthelmintic shown to be well tolerated in phase 1 clinical trials. In vitro, oxfendazole exhibited modest to marginal motility inhibition of adult worms of Onchocerca gutturosa, pre-adult worms of Onchocerca volvulus and Onchocerca lienalis microfilariae. In vivo, five days of oral treatments provided sterile cure with up to 100% macrofilaricidal efficacy in the murine Litomosoides sigmodontis model of filariasis. In addition, 10 days of oral treatments with oxfendazole inhibited filarial embryogenesis in patent L. sigmodontis-infected jirds and subsequently led to a protracted but complete clearance of microfilaremia. The macrofilaricidal effect observed in vivo was selective, as treatment with oxfendazole of microfilariae-injected naïve mice was ineffective. Based on pharmacokinetic analysis, the driver of efficacy is the maintenance of a minimal efficacious concentration of approximately 100 ng/ml (based on subcutaneous treatment at 25 mg/kg in mice). From animal models, the human efficacious dose is predicted to range from 1.5 to 4.1 mg/kg. Such a dose has already been proven to be safe in phase 1 clinical trials. Oxfendazole therefore has potential to be efficacious for treatment of human filariasis without causing adverse reactions due to drug-induced microfilariae killing