Targeting inflammatory monocytes by immune-modifying nanoparticles prevents acute kidney allograft rejection.

Inflammatory monocytes are a major component of the cellular infiltrate in acutely rejecting human kidney allografts. Since immune-modifying nanoparticles (IMPs) bind to circulating inflammatory monocytes via the specific scavenger receptor MARCO, causing diversion to the spleen and subsequent apoptosis, we investigated the therapeutic potential of negatively charged, 500-nm diameter polystyrene IMPs to prevent kidney allograft rejection. Kidney transplants were performed from BALB/c (H2d) to C57BL/6 (H2b) mice in two groups: controls (allo) and allo mice infused with IMPs. Groups were studied for 14 (acute rejection) or 100 (chronic rejection) days. Allo mice receiving IMPs exhibited superior survival and markedly less acute rejection, with better kidney function, less tubulitis, and diminished inflammatory cell density, cytokine and cytotoxic molecule expression in the allograft and lower titers of donor-specific IgG2c antibody in serum at day 14, as compared to allo mice. Cells isolated from kidneys from allo mice receiving IMPs showed reduced Ly6Chi monocytes, CD11b+ cells and NKT+ cells compared to allo mice. IMPs predominantly bound CD11b+ cells in the bloodstream and CD11b+ and CD11c-B220+ marginal zone B cells in the spleen. In the spleen, IMPs were found predominantly in red pulp, colocalized with MARCO and expression of cleaved caspase-3. At day 100, allo mice receiving IMPs exhibited reduced macrophage M1 responses but were not protected from chronic rejection. IMPs afforded significant protection from acute rejection, inhibiting both innate and adaptive alloimmunity. Thus, our current experimental findings, coupled with our earlier demonstration of IMP-induced protection in kidney ischemia-reperfusion injury, identify IMPs as a potential induction agent in kidney transplantation.

Improving Recruitment for a Newborn Screening Pilot Study with Adaptations in Response to the COVID-19 Pandemic.

Seven months after the launch of a pilot study to screen newborns for Duchenne Muscular Dystrophy (DMD) in New York State, New York City became an epicenter of the coronavirus disease 2019 (COVID-19) pandemic. All in-person research activities were suspended at the study enrollment institutions of Northwell Health and NewYork-Presbyterian Hospitals, and study recruitment was transitioned to 100% remote. Pre-pandemic, all recruitment was in-person with research staff visiting the postpartum patients 1-2 days after delivery to obtain consent. With the onset of pandemic, the multilingual research staff shifted to calling new mothers while they were in the hospital or shortly after discharge, and consent was collected via emailed e-consent links. With return of study staff to the hospitals, a hybrid approach was implemented with in-person recruitment for babies delivered during the weekdays and remote recruitment for babies delivered on weekends and holidays, a cohort not recruited pre-pandemic. There was a drop in the proportion of eligible babies enrolled with the transition to fully remote recruitment from 64% to 38%. In addition, the proportion of babies enrolled after being approached dropped from 91% to 55%. With hybrid recruitment, the proportion of eligible babies enrolled (70%) and approached babies enrolled (84%) returned to pre-pandemic levels. Our experience adapting our study during the COVID-19 pandemic led us to develop new recruitment strategies that we continue to utilize. The lessons learned from this pilot study can serve to help other research studies adapt novel and effective recruitment methods.

Real-world multicenter study of the safety and efficacy of netupitant plus palonosetron fixed-dose combination to prevent chemotherapy-induced nausea and vomiting among Malaysian patients receiving moderately or highly emetogenic chemotherapy.

AIM: A large proportion of cancer patients are at high risk for chemotherapy-induced nausea and vomiting (CINV), but the choice of anti-emetics for CINV in Malaysia is limited. METHODS: This was a real-world study of a fixed-dose combination of netupitant and palonosetron (NEPA) to inhibit CINV in adult patients receiving moderately (MEC) or highly emetogenic chemotherapy (HEC) for solid/hematological malignancies at eight Malaysian centers. Each HEC/MEC cycle received one dose of NEPA + dexamethasone for CINV prevention. Complete response (no emesis, no rescue medication) (CR), no more than mild nausea (severity score ≤ 2.5), and complete control (CR) (no more than mild nausea) during the acute (0-24 h), delayed (25-120 h), and overall (0-120 h) phases post-chemotherapy were measured. Treatment-related adverse events (AEs) were recorded. RESULTS: During March 2016-April 2018 (NMRR-17-3286-38282), NEPA + dexamethasone was administered to 54 patients (77.8% solid, 22.2% hematological malignancies). Note that 59.3% received HEC, while 40.7% received MEC regimen. During the overall phase of the first cycle, the majority had CR (77.8%), no more than mild nausea (74.1%), and complete control (61.1%). Seventeen patients received two consecutive cycles at any point of chemotherapy cycles. During the overall phases across two consecutive cycles, all patients achieved CR, and the majority reported no more than mild nausea and complete control. No grades 3-4 AEs were reported. CONCLUSIONS: NEPA had sustained efficacy and tolerability at first administration and across two cycles of MEC/HEC for CINV prevention.

Biomarkers as diagnostic tests for delayed graft function in kidney transplantation.

Delayed graft function (DGF) after kidney transplantation is associated with inferior outcomes and higher healthcare costs. DGF is currently defined as the requirement for dialysis within seven days post-transplant; however, this definition is subjective and nonspecific. Novel biomarkers have potential to improve objectivity and enable earlier diagnosis of DGF. We reviewed the literature to describe the range of novel biomarkers previously studied to predict DGF. We identified marked heterogeneity and low reporting quality of published studies. Among the novel biomarkers, serum NGAL had the greatest potential as a biomarker to predict DGF, but requires further assessment and validation through larger scale studies of diagnostic test performance. Given inadequacies in the dialysis-based definition, coupled with the high incidence and impact of DGF, such studies should be pursued.

Strongyloides hyperinfection in an HIV-positive kidney transplant recipient: a case report.

BACKGROUND: Strongyloidiasis is caused by the helminth Strongyloides stercoralis and is well-recognised amongst transplant recipients. Serious complications, including Strongyloides hyperinfection which is a syndrome of accelerated autoinfection, or disseminated disease, can occur post-transplantation, resulting in significant morbidity and mortality. Here we present the first published case we are aware of, describing post-transplant Strongyloides hyperinfection in an HIV-positive kidney transplant patient. We discuss the diagnostic challenges and the role of pre-transplant screening. CASE PRESENTATION: A 58-year-old African-American male, originally from the Caribbean, received a deceased donor kidney transplant for presumed focal segmental glomerulosclerosis. He was known to be HIV-positive, with a stable CD4 count, and an undetectable viral load. Five months post-transplant, he developed gastrointestinal symptoms and weight loss. He had a normal eosinophil count (0.1-0.2 × 109/L), negative serum cytomegalovirus DNA, and negative blood and stool cultures. His Strongyloides serology remained negative throughout. A diagnosis of Strongyloides hyperinfection was made by the histological examination of his duodenum and lung, which identified the parasites. He completed his course of treatment with Ivermectin but exhibited profound deconditioning and required a period of total parenteral nutrition. He was subsequently discharged after a prolonged hospital admission of 54 days. CONCLUSIONS: This case highlights the challenges in diagnosing Strongyloides infection and the need to maintain a high index of clinical suspicion. Non-invasive techniques for the diagnosis of Strongyloides may be insufficient. Routine pre-transplant serological strongyloidiasis screening is now performed at our centre.

Successful kidney transplantation in a patient with stable multiple myeloma.

Renal failure is a common feature of multiple myeloma affecting 20-55% of patients at the initial presentation and is being associated with a significant increase in morbidity and mortality. Renal transplantation for patients with multiple myeloma is rarely considered given the incurable nature of the disease, the risk of post-transplant disease progression and perceived high risk of infections. Here we report a 57-year-old man with end-stage renal failure attributed to presumed IgA nephropathy, with pre-existing stable multiple myeloma, who received a kidney transplant from a two haplotype-matched sibling. Transplantation has been successful and with excellent kidney function and stable multiple myeloma 6 years post-transplant. This case highlights the potential benefits of renal transplantation in highly selected patients with multiple myeloma.

Rapid reduction of high-level pre-formed donor-specific antibodies after simultaneous liver-kidney transplantation: a report of two cases.

BACKGROUND: Kidney transplantation performed in the presence of high-titre donor-specific antibodies (DSA) may result in hyper-acute or accelerated antibody-mediated rejection and rapid allograft loss. Previous studies have shown that this risk may be mitigated with simultaneous liver-kidney transplantation (SLKT); however, the mechanisms are not well defined. Here we report the evolution of pre-formed, high-level DSAs in two highly sensitised SLKT recipients peri-operatively and describe a profound sustained depletion of all DSAs from the time of liver anastomosis with no extra desensitisation therapy required. CASE PRESENTATION: Two patients underwent SLKT and received our centre's standard renal transplant immunosuppression with basiliximab and methylprednisolone for induction therapy and prednisolone, mycophenolate and tacrolimus for maintenance therapy. HLA antibody samples were collected pre-operatively, and immediately post-liver and post-kidney revascularisation, and then regularly in the post-transplant period. Complement Dependant Cytotoxicity (CDC) crossmatches were also performed. Both patients were highly sensitised with a PRA over 97%. One patient had a positive B- and T-cell crossmatch pre-transplant. These positive CDC crossmatches became negative and the level of pre-formed DSAs reduced profoundly and rapidly, within 3 h post-liver revascularisation. The reduction in pre-formed DSAs, regardless of subclass, was seen immediately post-liver revascularisation, before implantation of the renal allografts. No significant reduction in non-donor specific HLA-antibodies was observed. Both patients maintained good graft function with no rejection on kidney allograft protocol biopsies performed at 10-weeks post-transplant. CONCLUSIONS: These cases support the protective immunoregulatory role of the liver in the setting of SLKT, with no extra desensitisation treatment given pre-operatively for these highly sensitised patients.

18F-FDG Uptake in Benign Fibrous Histiocytoma of Adrenal Gland: A Potential Pitfall.

A 47-year-old man with newly diagnosed nasopharyngeal carcinoma underwent staging F-FDG PET/CT. Apart from showing increased FDG uptake in the primary site and locoregional nodal and liver metastases, an unusual site of intense FDG focus was demonstrated in the left adrenal gland. He underwent CT-guided biopsy, and the histopathologic diagnosis was benign fibrous histiocytoma.

A [(32)P]NAD(+)-based method to identify and quantitate long residence time enoyl-acyl carrier protein reductase inhibitors.

The classical methods for quantifying drug-target residence time (tR) use loss or regain of enzyme activity in progress curve kinetic assays. However, such methods become imprecise at very long residence times, mitigating the use of alternative strategies. Using the NAD(P)H-dependent FabI enoyl-acyl carrier protein (enoyl-ACP) reductase as a model system, we developed a Penefsky column-based method for direct measurement of tR, where the off-rate of the drug was determined with radiolabeled [adenylate-(32)P]NAD(P(+)) cofactor. In total, 23 FabI inhibitors were analyzed, and a mathematical model was used to estimate limits to the tR values of each inhibitor based on percentage drug-target complex recovery following gel filtration. In general, this method showed good agreement with the classical steady-state kinetic methods for compounds with tR values of 10 to 100 min. In addition, we were able to identify seven long tR inhibitors (100-1500 min) and to accurately determine their tR values. The method was then used to measure tR as a function of temperature, an analysis not previously possible using the standard kinetic approach due to decreased NAD(P)H stability at elevated temperatures. In general, a 4-fold difference in tR was observed when the temperature was increased from 25 to 37 °C.

A phase I study of LY317615 (enzastaurin) and temozolomide in patients with gliomas (EORTC trial 26054).

We report a phase 1 study to examine the safety and recommended dose of the oral protein kinase C-beta inhibitor (anti-angiogenic) enzastaurin in combination with single-agent temozolomide. The study was conducted in patients with recurrent glioblastoma or newly diagnosed disease that was not treatable with standard (chemo)radiotherapy. Patients were treated with standard dose temozolomide (200 mg/m(2) for 5 days every 4 weeks) together with daily oral enzastaurin. Three dose levels of enzastaurin were investigated: 250 mg daily (OD), 500 mg OD, and 250 mg twice daily (BID). Dose-limiting toxicity was determined in the first 2 cycles, but treatment continued until limiting toxicity or disease progression was identified. Twenty-eight patients were enrolled. No dose-limiting toxicity was noted at 250 mg OD or 500 mg OD. However, at 250 mg BID, 2 dose-limiting episodes of thrombocytopenia were noted. The recommended dose for enzastaurin in combination with standard 4-weekly temozolomide is therefore 500 mg OD. The pharmacokinetics of enzastaurin in combination with temozolomide was evaluated. Temozolomide did not appear to effect enzastaurin exposures at the 250 mg or 500 mg OD dose levels.

Cerebrospinal fluid in long-lasting delirium compared with Alzheimer's dementia.

BACKGROUND: Delirium is a common syndrome affecting older people in hospital, whose pathophysiology is poorly understood, but sequelae of increased cognitive and functional impairment suggest neuronal loss. METHODS: Cohort study comparing cerebrospinal fluid, blood, and clinical markers of delirium and neuronal cell death in 20 older hospitalized patients with delirium and 20 outpatients with Alzheimer's dementia. RESULTS: Compared with participants with dementia, patients with delirium demonstrated higher CSF lactate (1.87 vs 1.48 mmol/L, p < .001) and protein levels (0.62 vs 0.44 g/L, p = .036) and lower levels of neuron-specific enolase (4.84 vs 8.98 ng/mL, p < .001) but no difference in S100B. The changes correlated with clinical indices and outcomes. CONCLUSION: Older patients with delirium experience significant metabolic disturbance in the brain, which requires further investigation.