Progressive multifocal leukoencephalopathy (PML) is a rare but frequently fatal disease caused by the uncontrolled replication of JC virus (JCV), a polyomavirus, in the brains of some immunocompromised individuals. Currently, no effective antiviral treatment for this disease has been identified. As a first step in the identification of such therapy, we screened the Spectrum collection of 2,000 approved drugs and biologically active molecules for their anti-JCV activities in an in vitro infection assay. We identified a number of different drugs and compounds that had significant anti-JCV activities at micromolar concentrations and lacked cellular toxicity. Of the compounds with anti-JCV activities, only mefloquine, an antimalarial agent, has been reported to show sufficiently high penetration into the central nervous system such that it would be predicted to achieve

BackgroundThe human polyomavirus, JC virus (JCV) produces five tumor proteins encoded by transcripts alternatively spliced from one precursor messenger RNA. Significant attention has been given to replication and transforming activities of JCV's large tumor antigen (TAg) and three T′ proteins, but little is known about small tumor antigen (tAg) functions. Amino-terminal sequences of tAg overlap with those of the other tumor proteins, but the carboxy half of tAg is unique. These latter sequences are the least conserved among the early coding regions of primate polyomaviruses.Methodology and FindingsWe investigated the ability of wild type and mutant forms of JCV tAg to interact with cellular proteins involved in regulating cell proliferation and survival. The JCV P99A tAg is mutated at a conserved proline, which in the SV40 tAg is required for efficient interaction with protein phosphatase 2A (PP2A), and the C157A mutant tAg is altered at one of two newly recognized LxCxE motifs. Relative to wild type and C157A tAgs, P99A tAg interacts inefficiently with PP2A in vivo. Unlike SV40 tAg, JCV tAg binds to the Rb family of tumor suppressor proteins. Viral DNAs expressing mutant t proteins replicated less efficiently than did the intact JCV genome. A JCV construct incapable of expressing tAg was replication-incompetent, a defect not complemented in trans using a tAg-expressing vector.ConclusionsJCV tAg possesses unique properties among the polyomavirus small t proteins. It contributes significantly to viral DNA replication in vivo; a tAg null mutant failed to display detectable DNA replication activity, and a tAg substitution mutant, reduced in PP2A binding, was replication-defective. Our observation that JCV tAg binds Rb proteins, indicates all five JCV tumor proteins have the potential to influence cell cycle progression in infected and transformed cells. It remains unclear how these proteins coordinate their unique and overlapping functions.

Background An integrated kidney disease healthcare company implemented a peritoneal dialysis (PD) remote treatment monitoring (RTM) application in 2016. We assessed if RTM utilization associates with hospitalization and technique failure rates.Methods We used data from adult (age $18 years) patients on PD treated from October 2016 through May 2019 who registered online for the RTM. Patients were classified by RTM use during a 30-day baseline after registration. Groups were: nonusers (never entered data), moderate users (entered one to 15 treatments), and frequent users (entered .15 treatments). We compared hospital admission/day and sustained technique failure (required .6 consecutive weeks of hemodialysis) rates over 3, 6, 9, and 12 months of follow-up using Poisson and Cox models adjusted for patient/clinical characteristics.Results Among 6343 patients, 65% were nonusers, 11% were moderate users, and 25% were frequent users. Incidence rate of hospital admission was 22% (incidence rate ratio [IRR]50.78; P50.002), 24% (IRR50.76; P,0.001), 23% (IRR50.77; P#0.001), and 26% (IRR50.74; P#0.001) lower in frequent users after 3, 6, 9, and 12 months, respectively, versus nonusers. Incidence rate of hospital days was 38% (IRR50.62; P50.013), 35% (IRR50.65; P50.001), 34% (IRR50.66; P#0.001), and 32% (IRR50.68; P,0.001) lower in frequent users after 3, 6, 9, and 12 months, respectively, versus nonusers. Sustained technique failure risk at 3, 6, 9, and 12 months was 33% (hazard ratio [HR]50.67; P50.020), 31% (HR50.69; P50.003), 31% (HR50.69; P50.001), and 27% (HR50.73; P50.001) lower, respectively, in frequent users versus nonusers. Among a subgroup of survivors of the 12-month follow-up, sustained technique failure risk was 26% (HR50.74; P50.023) and 21% (HR50.79; P50.054) lower after 9 and 12 months, respectively, in frequent users versus nonusers.Conclusions Our findings suggest frequent use of an RTM application associates with less hospital admissions, shorter hospital length of stay, and lower technique failure rates. Adoption of RTM applications may have the potential to improve timely identification/intervention of complications.

Abnormal decreases in blood pressure during hemodialysis are frequent in end stage renal disease (ESRD) patients treated with hemodialysis, and thought to be largely due to an inadequate cardiovascular response to the rapid blood volume decline. Intradialytic hypotension (IDH) and cardiac instability during dialysis can increase risks for negative health consequences and is possibly preventable though several types of interventions. One intervention that holds promise for prevention of IDH in hemodialysis patients is to reduce the temperature of the dialysate to or below the patient's core temperature. A considerable number of randomized studies have demonstrated a short term benefit of using a cooler dialysate temperature for the prevention of IDH and improved cardiac stability. Despite this, a key observational study was not able to show long term improvements with lower dialysate temperatures utilized in routine clinical practice, albeit possibly confounded by indication. It appears that cooling the dialysate may be reasonable to consider on an individual basis for patients who suffer from persistent IDH if they can tolerate the adjustment and it is effective. However, careful assessment of the etiology of IDH should be performed when considering treatment options. In this review, we detail the current body of evidence on the effectiveness of using low dialysate temperatures for prevention of IDH in ESRD patients, and suggest areas where further research is needed.

The lack of current treatment and preventable measures for acute kidney injury (AKI) in hospitalized patients results in an increased mortality rate of up to 80% and elevated health costs. Additionally, if not properly repaired, those who survive AKI may develop fibrosis and long-term kidney damage. The molecular aspects of kidney injury and repair are still uncertain. Hepatocyte growth factor (HGF) promotes recovery of the injured kidney by inducing survival and migration of tubular epithelial cells to repopulate bare tubule areas. HGF-stimulated kidney epithelial cell migration requires the activation of ADP-ribosylation factor 6 (Arf6) and Rac1 via the cytohesin family of Arf-guanine-nucleotide exchange factors (GEFs), in vitro. We used an ischemia and reperfusion injury (IRI) mouse model to analyze the effects of modulating this signaling pathway on kidney recovery. We treated IRI mice with either HGF, the cytohesin inhibitor SecinH3, or a combination of both. As previously reported, HGF treatment promoted rapid improvement of kidney function as evidenced by creatinine (Cre) and blood urea nitrogen (BUN) levels. In contrast, simultaneous treatment with SecinH3 and HGF blocks the ability of HGF to promote kidney recovery. Immunohistochemistry showed that HGF treatment promoted recovery of tubule structure, and had enhanced levels of active, GTP-bound Arf6 and GTP-Rac1. SecinH3 treatment, however, caused a dramatic decrease in GTP-Arf6 and GTP-Rac1 levels when compared to kidney sections from HGF-treated IRI mice. Additionally, SecinH3 counteracted the renal reparative effects of HGF. Our results support the conclusion that cytohesin function is required for HGF-stimulated renal IRI repair.