Wash-off potential of pyrethroids after use of total release fogger products.

Pyrethroids are frequently detected in urban wastewater. Even though treatment facilities remove most pyrethroids (> 90 %) in wastewater, residual concentrations can exceed thresholds that are acutely toxic to sensitive aquatic species. Total release foggers (also known as "bug bombs") are widely used by the general public for insect control. It was hypothesized that these products serve as a source of pyrethroids entering the urban wastewater through the deposition of the active ingredients on various surfaces and subsequent transfer from the contaminated surfaces to the waste stream through cleaning activities. Based on experiments conducted in an enclosure, we found that substantial amounts of a pyrethroid (i.e., cypermethrin) were deposited on various surfaces after a total release fogger use. A series of experiments simulating scenarios that would be representative of common residential cleaning activities indicated that the pyrethroid could be transferred from the contaminated surfaces to other adsorptive materials via physical contact (with or without water as a solvent). The pyrethroid was readily extracted from the adsorptive materials (cotton fabric and filter paper) when water was used as a solvent. Adding a small amount of detergent to the water significantly increased the extraction efficiency compared to water alone. These results indicate that insecticides used in total release foggers can contribute to insecticide loading into the wastewater treatment system via several possible routes, such as contact with or cleaning of exposed surfaces and washing contaminated clothing after their use within a structure.

Effect of Pelacarsen on Lipoprotein(a) Cholesterol and Corrected Low-Density Lipoprotein Cholesterol.

BACKGROUND: Laboratory methods that report low-density lipoprotein cholesterol (LDL-C) include both LDL-C and lipoprotein(a) cholesterol [Lp(a)-C] content. OBJECTIVES: The purpose of this study was to assess the effect of pelacarsen on directly measured Lp(a)-C and LDL-C corrected for its Lp(a)-C content. METHODS: The authors evaluated subjects with a history of cardiovascular disease and elevated Lp(a) randomized to 5 groups of cumulative monthly doses of 20-80 mg pelacarsen vs placebo. Direct Lp(a)-C was measured on isolated Lp(a) using LPA4-magnetic beads directed to apolipoprotein(a). LDL-C was reported as: 1) LDL-C as reported by the clinical laboratory; 2) LDL-Ccorr = laboratory-reported LDL-C - direct Lp(a)-C; and 3) LDL-CcorrDahlén = laboratory LDL-C - [Lp(a) mass × 0.30] estimated by the Dahlén formula. RESULTS: The baseline median Lp(a)-C values in the groups ranged from 11.9 to 15.6 mg/dL. Compared with placebo, pelacarsen resulted in dose-dependent decreases in Lp(a)-C (2% vs -29% to -67%; P = 0.001-<0.0001). Baseline laboratory-reported mean LDL-C ranged from 68.5 to 89.5 mg/dL, whereas LDL-Ccorr ranged from 55 to 74 mg/dL. Pelacarsen resulted in mean percent/absolute changes of -2% to -19%/-0.7 to -8.0 mg/dL (P = 0.95-0.05) in LDL-Ccorr, -7% to -26%/-5.4 to -9.4 mg/dL (P = 0.44-<0.0001) in laboratory-reported LDL-C, and 3.1% to 28.3%/0.1 to 9.5 mg/dL (P = 0.006-0.50) increases in LDL-CcorrDahlén. Total apoB declined by 3%-16% (P = 0.40-<0.0001), but non-Lp(a) apoB was not significantly changed. CONCLUSIONS: Pelacarsen significantly lowers direct Lp(a)-C and has neutral to mild lowering of LDL-Ccorr. In patients with elevated Lp(a), LDL-Ccorr provides a more accurate reflection of changes in LDL-C than either laboratory-reported LDL-C or the Dahlén formula.

The interplay of oxidative stress and ARMS2-HTRA1 genetic risk in neovascular AMD.

Age-related macular degeneration (AMD) is the leading cause of vision loss in adults over 60 years old globally. There are two forms of advanced AMD: "dry" and "wet". Dry AMD is characterized by geographic atrophy of the retinal pigment epithelium and overlying photoreceptors in the macular region; whereas wet AMD is characterized by vascular penetrance from the choroid into the retina, known as choroidal neovascularization (CNV). Both phenotypes eventually lead to loss of central vision. The pathogenesis of AMD involves the interplay of genetic polymorphisms and environmental risk factors, many of which elevate retinal oxidative stress. Excess reactive oxygen species react with cellular macromolecules, forming oxidation-modified byproducts that elicit chronic inflammation and promote CNV. Additionally, genome-wide association studies have identified several genetic variants in the age-related maculopathy susceptibility 2/high-temperature requirement A serine peptidase 1 (ARMS2-HTRA1) locus associated with the progression of late-stage AMD, especially the wet subtype. In this review, we will focus on the interplay of oxidative stress and HTRA1 in drusen deposition, chronic inflammation, and chronic angiogenesis. We aim to present a multifactorial model of wet AMD progression, supporting HTRA1 as a novel therapeutic target upstream of vascular endothelial growth factor (VEGF), the conventional target in AMD therapeutics. By inhibiting HTRA1's proteolytic activity, we can reduce pro-angiogenic signaling and prevent proteolytic breakdown of the blood-retina barrier. The anti-HTRA1 approach offers a promising alternative treatment option to wet AMD, complementary to anti-VEGF therapy.

Ongoing controversies and recent insights of the ARMS2-HTRA1 locus in age-related macular degeneration.

Age-related macular degeneration (AMD) is the most common cause of central vision loss among elderly populations in industrialized countries. Genome-wide association studies have consistently associated two genomic loci with progression to late-stage AMD: the complement factor H (CFH) locus on chromosome 1q31 and the age-related maculopathy susceptibility 2-HtrA serine peptidase 1 (ARMS2-HTRA1) locus on chromosome 10q26. While the CFH risk variant has been shown to alter complement activity, the ARMS2-HTRA1 risk haplotype remains enigmatic due to high linkage disequilibrium and inconsistent functional findings spanning two genes that are plausibly causative for AMD risk. In this review, we detail the genetic and functional evidence used to support either ARMS2 or HTRA1 as the causal gene for AMD risk, emphasizing both the historical development and the current understanding of the ARMS2-HTRA1 locus in AMD pathogenesis. We conclude by summarizing the evidence in favor of HTRA1 and present our hypothesis whereby HTRA1-derived ECM fragments mediate AMD pathogenesis.

Durable response for ampullary and duodenal adenocarcinoma with a nab-paclitaxel plus gemcitabine ± cisplatin combination.

BACKGROUND/AIM: There is no standard salvage chemotherapy for metastatic periampullary adenocarcinoma and duodenal adenocarcinoma and the prognosis of those who fail oxaliplatin, irinotecan, and 5FU is dismal. We examined nanoparticle albumin-bound paclitaxel (nab-paclitaxel) as salvage therapy for these two malignancies. METHODS: Patients who failed oxaliplatin, irinotecan, and 5FU and whose archival tumors stained immunohistochemical (IHC) tumor positive for CK7 or MUC1 received nab-paclitaxel and gemcitabine therapy with or without cisplatin. RESULTS: Three patients, 2 with metastatic ampullary adenocarcinoma and 1 with duodenal adenocarcinoma with positive IHC staining for CK7 or MUC1 who failed 2 lines of chemotherapy with oxaliplatin, irinotecan, and 5FU received nab-paclitaxel and gemcitabine with or without cisplatin. All achieved excellent tumor response on CT scans with marked falls in tumor markers CA19-9 and CEA as well as ≥1 year of progression-free survival. All 3 have continued to survive 2-3 years since diagnosed with stage 4 metastatic adenocarcinoma. CONCLUSIONS: Nab-paclitaxel plus gemcitabine with or without cisplatin should be investigated as a standard-of-care chemotherapy regimen for patients with ampullary adenocarcinoma and duodenal adenocarcinoma.

Fixed, low-dose rasburicase for the treatment or prevention of hyperuricemia in adult oncology patients.

PURPOSE: Rasburicase is a recombinant urate oxidase enzyme administered to high risk patients or to those with preexisting hyperuricemia from tumor lysis syndrome (TLS). The objective of this retrospective review is to evaluate and characterize the use of fixed, low-dose rasburicase for the treatment of hyperuricemia in adult patients. PATIENTS/METHODS: A retrospective chart review from 1 October 2005 to 31 December 2011 was conducted in adult oncology patients who received fixed, low-dose rasburicase. Patients who met the inclusion criteria were evaluated for the uric acid level change from baseline and the achievement of uric acid level less than 8 mg/dL. RESULTS: Forty-five patients were included in the analysis in which 26 (58%) patients received 3 mg rasburicase. For the 39 patients with baseline uric acid levels 8 mg/dL or higher, 80% achieved a uric acid level lower than 8 mg/dL with a single rasburicase dose. Six patients (13%) required renal replacement therapy despite rasburicase. The median uric acid level reduction 24 h post rasburicase dose 1.5 mg, 3 mg, 4.5 mg, and 6 mg were 5.5, 5.8, 3.8, and 10.05 mg/dL, respectively. There was no clinical difference between obese and non-obese patients in terms of their median uric acid reduction, 5.5 vs. 7 mg/dL, respectively. CONCLUSION: Fixed, low dose rasburicase produced a consistent lowering of uric acid levels and may be utilized in the management of hyperuricemia in TLS. Further study is necessary to determine if a larger fixed dose would be required in those patients with a higher baseline uric acid level.

Inpatient versus outpatient management of neutropenic fever in gynecologic oncology patients: is risk stratification useful?

OBJECTIVE: This study aimed to evaluate the utility of risk stratification of gynecologic oncology patients with neutropenic fever (NF). METHODS: A retrospective chart review of gynecologic cancer patients admitted with NF from 2007 to 2011 was performed, wherein demographic, oncologic, and NF characteristics (hospitalization length, complications, and death) were collected. The Multinational Association for Supportive Care in Cancer (MASCC) risk index score was calculated; low risk was considered ≥ 21. SAS 9.2 was used for statistical analyses. RESULTS: Eighty-three patients met the study criteria. Most (92%) were Caucasian and had advanced stage disease (71%). Primary tumors were 58% ovary, 35% endometrium, and 6% cervix. All patients were receiving chemotherapy on admission (72% for primary, 28% for recurrent disease). Forty-eight percent had a positive culture, and most (58%) positive cultures were urine. Seventy-six percent of patients were considered low risk. High-risk patients were more likely to have a severe complication (10% versus 50%, p=0.0003), multiple severe complications (3% versus 20%, p=0.0278), ICU admission (2% versus 40%, p<0.0001), overall mortality (2% versus 15%, p=0.0417), and death due to neutropenic fever (0% versus 15%, p=0.0124). MASCC had a positive predictive value of 50% and negative predictive value of 90%. The median MASCC score for all patients was 22 (range, 11-26), but the median MASCC score for those with death or a severe complication was 17 (range, 11-24). CONCLUSION: Based on this pilot data, MASCC score appears promising in determining suitability for outpatient management of NF in gynecologic oncology patients. Prospective study is ongoing to confirm safety and determine impact on cost.