Ca2+-independent phospholipase A2ß-derived PGE2 contributes to osteogenesis.

Bone modeling can be modulated by lipid signals such as arachidonic acid (AA) and its cyclooxygenase 2 (COX2) metabolite, prostaglandin E2 (PGE2), which are recognized mediators of optimal bone formation. Hydrolysis of AA from membrane glycerophospholipids is catalyzed by phospholipases A2 (PLA2s). We reported that mice deficient in the Ca2+- independent PLA2beta (iPLA2ß), encoded by Pla2g6, exhibit a low bone phenotype, but the cause for this remains to be identified. Here, we examined the mechanistic and molecular roles of iPLA2ß in bone formation using bone marrow stromal cells and calvarial osteoblasts from WT and iPLA2ß-deficient mice, and the MC3T3-E1 osteoblast precursor cell line. Our data reveal that transcription of osteogenic factors (Bmp2, Alpl, and Runx2) and osteogenesis are decreased with iPLA2ß-deficiency. These outcomes are corroborated and recapitulated in WT cells treated with a selective inhibitor of iPLA2 ß (10 µM S-BEL), and rescued in iPLA2ß-deficient cells by additions of 10 µM PGE2. Further, under osteogenic conditions we find that PGE2 production is through iPLA2ß activity and that this leads to induction of Runx2 and iPLA2ß transcription. These findings reveal a strong link between osteogenesis and iPLA2ß-derived lipids and raise the intriguing possibility that iPLA2ß-derived PGE2 participates in osteogenesis and in the regulation of Runx2 and also iPLA2ß.

Emission of volatile organic compounds during aerobic decomposition of banana peel.

Emissions of volatile organic compounds (VOCs) were continuously measured during the aerobic decomposition of banana peel in a laboratory-scale landfill simulator over 25 d. Using direct membrane inlet single-photon ionisation time-of-flight mass spectrometry (MI-SPI-ToF-MS), 18 VOCs belonging to 10 functional groups were detected in the air samples, and their VOC emission profiles were established using cluster analysis on time-resolved data. Three emission stages were clearly identified, with the major release for most VOC compounds occurring during the first 14 d. The emission patterns of the individual compounds were quite similar despite the different release mechanisms. In addition, no apparent increase in temperature was observed inside the simulator during the entire experimental period. We suggest that the volatilisation of the constituents in the waste pile contributed equally to VOC emissions as did the degradation of banana peel via microbial activity. The average emission rate of total VOCs reached 44.3 × 10-3 mg VOC kg-1 of dry banana peel, with more than half belonging to malodourous substances. The malodourous emissions of the decaying banana peel in an aerobic environment mainly originated from styrene, dimethyl sulphide, and diethyl sulphide, the most common contributors to offensive odourants during food waste biodegradation.

Efficacy and Safety of Dulaglutide 3.0 mg and 4.5 mg Versus Dulaglutide 1.5 mg in Metformin-Treated Patients With Type 2 Diabetes in a Randomized Controlled Trial (AWARD-11).

OBJECTIVE: To compare efficacy and safety of dulaglutide at doses of 3.0 and 4.5 mg versus 1.5 mg in patients with type 2 diabetes inadequately controlled with metformin. RESEARCH DESIGN AND METHODS: Patients were randomly assigned to once-weekly dulaglutide 1.5 mg, 3.0 mg, or 4.5 mg for 52 weeks. The primary objective was determining superiority of dulaglutide 3.0 mg and/or 4.5 mg over 1.5 mg in HbA1c reduction at 36 weeks. Secondary superiority objectives included change in body weight. Two estimands addressed efficacy objectives: treatment regimen (regardless of treatment discontinuation or rescue medication) and efficacy (on treatment without rescue medication) in all randomly assigned patients. RESULTS: Mean baseline HbA1c and BMI in randomly assigned patients (N = 1,842) was 8.6% (70 mmol/mol) and 34.2 kg/m2, respectively. At 36 weeks, dulaglutide 4.5 mg provided superior HbA1c reductions compared with 1.5 mg (treatment-regimen estimand: -1.77 vs. -1.54% [-19.4 vs. -16.8 mmol/mol], estimated treatment difference [ETD] -0.24% (-2.6 mmol/mol), P < 0.001; efficacy estimand: -1.87 vs. -1.53% [-20.4 vs. -16.7 mmol/mol], ETD -0.34% (-3.7 mmol/mol), P < 0.001). Dulaglutide 3.0 mg was superior to 1.5 mg for reducing HbA1c, using the efficacy estimand (ETD -0.17% [-1.9 mmol/mol]; P = 0.003) but not the treatment-regimen estimand (ETD -0.10% [-1.1 mmol/mol]; P = 0.096). Dulaglutide 4.5 mg was superior to 1.5 mg for weight loss at 36 weeks for both estimands (treatment regimen: -4.6 vs. -3.0 kg, ETD -1.6 kg, P < 0.001; efficacy: -4.7 vs. -3.1 kg, ETD -1.6 kg, P < 0.001). Common adverse events through 36 weeks included nausea (1.5 mg, 13.4%; 3 mg, 15.6%; 4.5 mg, 16.4%) and vomiting (1.5 mg, 5.6%; 3 mg, 8.3%; 4.5 mg, 9.3%). CONCLUSIONS: In patients with type 2 diabetes inadequately controlled by metformin, escalation from dulaglutide 1.5 mg to 3.0 mg or 4.5 mg provided clinically relevant, dose-related reductions in HbA1c and body weight with a similar safety profile.

An open-source handheld extruder loaded with pore-forming bioink for in situ wound dressing.

The increasing demand in rapid wound dressing and healing has promoted the development of intraoperative strategies, such as intraoperative bioprinting, which allows deposition of bioinks directly at the injury sites to conform to their specific shapes and structures. Although successes have been achieved to varying degrees, either the instrumentation remains complex and high-cost or the bioink is insufficient for desired cellular activities. Here, we report the development of a cost-effective, open-source handheld bioprinter featuring an ergonomic design, which was entirely portable powered by a battery pack. We further integrated an aqueous two-phase emulsion bioink based on gelatin methacryloyl with the handheld system, enabling convenient shape-controlled in situ bioprinting. The unique pore-forming property of the emulsion bioink facilitated liquid and oxygen transport as well as cellular proliferation and spreading, with an additional ability of good elasticity to withstand repeated mechanical compressions. These advantages of our pore-forming bioink-loaded handheld bioprinter are believed to pave a new avenue for effective wound dressing potentially in a personalized manner down the future.

Lipid mediators and biomarkers associated with type 1 diabetes development.

Type 1 diabetes (T1D) is a consequence of autoimmune ß cell destruction, but the role of lipids in this process is unknown. We previously reported that activation of Ca2+-independent phospholipase A2ß (iPLA2ß) modulates polarization of macrophages (MΦ). Hydrolysis of the sn-2 substituent of glycerophospholipids by iPLA2ß can lead to the generation of oxidized lipids (eicosanoids), pro- and antiinflammatory, which can initiate and amplify immune responses triggering ß cell death. As MΦ are early triggers of immune responses in islets, we examined the impact of iPLA2ß-derived lipids (iDLs) in spontaneous-T1D prone nonobese diabetic mice (NOD), in the context of MΦ production and plasma abundances of eicosanoids and sphingolipids. We find that (a) MΦNOD exhibit a proinflammatory lipid landscape during the prediabetic phase; (b) early inhibition or genetic reduction of iPLA2ß reduces production of select proinflammatory lipids, promotes antiinflammatory MΦ phenotype, and reduces T1D incidence; (c) such lipid changes are reflected in NOD plasma during the prediabetic phase and at T1D onset; and (d) importantly, similar lipid signatures are evidenced in plasma of human subjects at high risk for developing T1D. These findings suggest that iDLs contribute to T1D onset and identify select lipids that could be targeted for therapeutics and, in conjunction with autoantibodies, serve as early biomarkers of pre-T1D.

Macrophage polarization is linked to Ca2+-independent phospholipase A2ß-derived lipids and cross-cell signaling in mice.

Phospholipases A2 (PLA2s) catalyze hydrolysis of the sn-2 substituent from glycerophospholipids to yield a free fatty acid (i.e., arachidonic acid), which can be metabolized to pro- or anti-inflammatory eicosanoids. Macrophages modulate inflammatory responses and are affected by Ca2+-independent phospholipase A2 (PLA2)ß (iPLA2ß). Here, we assessed the link between iPLA2ß-derived lipids (iDLs) and macrophage polarization. Macrophages from WT and KO (iPLA2ß-/-) mice were classically M1 pro-inflammatory phenotype activated or alternatively M2 anti-inflammatory phenotype activated, and eicosanoid production was determined by ultra-performance LC ESI-MS/MS. As a genotypic control, we performed similar analyses on macrophages from RIP.iPLA2ß.Tg mice with selective iPLA2ß overexpression in ß-cells. Compared with WT, generation of select pro-inflammatory prostaglandins (PGs) was lower in iPLA2ß-/- , and that of a specialized pro-resolving lipid mediator (SPM), resolvin D2, was higher; both changes are consistent with the M2 phenotype. Conversely, macrophages from RIP.iPLA2ß.Tg mice exhibited an opposite landscape, one associated with the M1 phenotype: namely, increased production of pro-inflammatory eicosanoids (6-keto PGF1α, PGE2, leukotriene B4) and decreased ability to generate resolvin D2. These changes were not linked with secretory PLA2 or cytosolic PLA2α or with leakage of the transgene. Thus, we report previously unidentified links between select iPLA2ß-derived eicosanoids, an SPM, and macrophage polarization. Importantly, our findings reveal for the first time that ß-cell iPLA2ß-derived signaling can predispose macrophage responses. These findings suggest that iDLs play critical roles in macrophage polarization, and we posit that they could be targeted therapeutically to counter inflammation-based disorders.

Efficacy and safety of an expanded dulaglutide dose range: A phase 2, placebo-controlled trial in patients with type 2 diabetes using metformin.

AIMS: Dulaglutide, a once weekly GLP-1 receptor agonist, is approved at two doses (1.5 and 0.75 mg) for treatment of type 2 diabetes (T2D). Two higher doses of dulaglutide (3.0 and 4.5 mg) were evaluated for safety and efficacy to determine whether these doses warrant further study for improved control of glucose and body weight. MATERIALS AND METHODS: This 18-week, double-blind, phase 2 trial randomized 318 patients with T2D using ≥1500 mg metformin, to receive subcutaneous injection of placebo (n = 82), dulaglutide 1.5 mg (n = 81), dulaglutide 3.0 mg (n = 79) or dulaglutide 4.5 mg (n = 76). The primary objective was superiority of dulaglutide doses over placebo in reduction of HbA1c at 18 weeks. Secondary objectives included superiority of dulaglutide over placebo in change from baseline in body weight and fasting serum glucose (FSG) at 18 weeks. Investigational doses of dulaglutide were compared to the 1.5 mg dose as an exploratory objective. RESULTS: HbA1c reduction at 18 weeks was significantly greater with dulaglutide vs placebo (placebo, -0.44% ± 0.10% [-4.8 ± 1.1 mmol/mol]; dulaglutide 1.5 mg, -1.23% ± 0.10% [-13.5 ± 1.1 mmol/mol]; dulaglutide 3.0 mg, -1.31% ± 0.10% [-14.3 ± 1.1 mmol/mol]; dulaglutide 4.5 mg, -1.40% ± 0.10% [-15.3 ± 1.1 mmol/mol]; P < 0.001, each dose), as were changes in body weight (placebo, -1.6 ± 0.39 kg; dulaglutide 1.5 mg, -2.8 ± 0.39 kg; dulaglutide 3.0 mg, -3.9 ± 0.39 kg; dulaglutide 4.5 mg, -4.1 ± 0.41 kg; P < 0.001, each dose). All three dulaglutide doses significantly reduced FSG from baseline (1.5 mg, -36.2 ± 4.7 mg/dL [-2.0 ± 0.3 mmol/L]; 3.0 mg, -34.5 ± 4.5 mg/dL [-1.9 ± 0.3 mmol/L]; 4.5 mg, -38.0 ± 4.7 mg/dL [-2.1 ± 0.3 mmol/L]) vs placebo (-12.4 ± 4.5 mg/dL [-0.7 ± 0.3 mmol/L]) (P < 0.001, all). Safety profiles of the higher doses were consistent with the established safety profile for dulaglutide. Gastrointestinal events were mostly mild to moderate, and was dose-related for nausea. CONCLUSION: All three dulaglutide doses were superior to placebo in improving glycaemic control and reducing body weight in participants with T2D using metformin. The potential for doses of dulaglutide of 3.0 and 4.5 mg to provide additional glycaemic benefit and weight reduction with an acceptable safety profile, compared with the 1.5 mg dose, warrants further study in a phase 3 trial.

[Experience of 14 cases using hemi-semilaminectomy microsurgery treating by spinal dural arteriovenous fistula].

Objective: To explore the efficacy and feasibility of the hemi-semilaminectomy microsurgical operation treatment of spinal dural arteriovenous fistula (SDAVF). Methods: The clinical data of 32 patients with SDAVF were analyzed retrospectively. Before operation all patients were diagnosed by spinal MRI and spinal angiography, 14 patients were treated by hemi-semilaminectomy approach and other 18 patients were by traditional laminectomy approach. All the data were analyzed by T test and P<0.05 was considered to have significant difference. Results: The nidus of SDAVF located on thoracic segments in 18 cases, lumbar segments in 12 cases, and cervical segment in 2 cases, which was fed by single artery. The hemi-semilaminectomy microsurgical operation showed shorter operation time, less bleeding, less hospitalization time and cost. All the patients followed-up for 6 months-2 years. Symptoms of all the patients were improved compared with those before surgery. Conclusions: On the premise of spinal angiography accurately positioning the location of fistula, the hemi-semi-laminectomy approach microsurgery clipping operation is safe and feasible, and the operation has fewer traumas, also helps to maintain the stability of spine.

Prognostic significance of the T2 substage in patients with esophageal squamous cell carcinoma.

The invasion of the muscularis propria is defined as T2 stage in esophageal squamous cell carcinoma. Evidence is lacking regarding whether the T2 substage based on anatomy may serve as a prognostic indicator. This study aims to confirm the prognostic value of the T2 substage. The clinicopathological characteristics of 120 patients who had pathologically verified T2 tumors between 2006 and 2011 at the Tianjin Medical University Cancer Institute and Hospital were retrospectively studied. Based on the invasion depth, tumors that had penetrated the circular muscle layer were defined as T2a, while T2b disease referred to those that had invaded the longitudinal muscle layer. Factors potentially related to survival were analyzed with univariate and multivariate analyses. The logistic regression model was used to examine the factors associated with lymph node metastasis. To verify the prognostic value of the T2 substage further, patients with T1b and T3 stage disease during the same period were selected for comparisons. The univariate and multivariate analyses demonstrated that the T2 substage and N stage were independent prognostic factors. The T2 substage was highly relevant to lymph node metastasis in the logistic regression model (P = 0.044). When T1b and T3 was considered, the survival of T2a patients was closer to that of T1b patients, while the survival of T2b patients was closer to that of T3 disease (P = 0.000). The T2 substage was an independent prognostic factor. Patients with T2a tumors displayed a favorable survival, while the prognosis of T2b patients was closer to that of T3 patients.

Clinical and experimental role of ring finger protein 180 on lymph node metastasis and survival in gastric cancer.

BACKGROUND: The hypermethylation of ring finger protein (RNF) 180 DNA promoter is significantly associated with lymph node metastasis of gastric cancer. The present study explored the potential mechanism of RNF180-regulated lymph node metastasis of gastric cancer. METHODS: Associations between clinicopathological and survival data and RNF180 expression in gastric cancer tissues were analysed. The effects of RNF180 re-expression on gastric cancer cells were determined by means of proliferation, invasion, growth and lymphangiogenesis assays. A genome microarray was used to find potential target genes associated with lymphatic metastasis of gastric cancer cells regulated by RNF180. RESULTS: RNF180 was silenced or downregulated in 99 (73·9 per cent) of 134 gastric cancer tissues compared with 41·8 per cent of paired non-tumour tissues from patients. As an independent prognostic indicator of gastric cancer, RNF180 expression in gastric cancer tissues was negatively related to the number of metastatic lymph nodes. RNF180 was also downregulated in all seven gastric cancer cell lines examined. The re-expression of RNF180 in gastric cancer cells inhibited colony formation, proliferation, migration and invasion in vitro; re-expression of RNF180 also suppressed tumour growth and lymphangiogenesis in mice. Furthermore, re-expression of RNF180 downregulated the expression of hepatocyte growth factor, matrix metalloproteinase (MMP) 2, MMP-14, vascular endothelial growth factor C/D and chemokine receptor 7 in gastric cancer cells; it also downregulated the expression of podoplanin in tumour tissue of nude mice. CONCLUSION: RNF180 appears to act as a suppressor gene that inhibits lymph node metastasis in gastric cancer. SURGICAL RELEVANCE: Biological mechanisms that lead to lymph node metastasis in gastric cancer have not been clarified. Ring finger protein (RNF) 180 has been shown to participate in the processes of lymph node metastasis in several human malignancies. In this study, silencing or downregulation of RNF180 expression was significantly associated with lymph node metastasis of gastric cancer. In vitro, RNF180 expression suppressed the common biological characteristics of gastric cancer cells (HGC-27), including proliferation, invasion, lymphangio genesis and chemotaxis. RNF180 expression also inhibited tumour growth and tumour lymphangiogenesis in vivo. These results show that RNF180 is capable of inhibiting lymph node metastasis of gastric cancer by suppressing the intracellular activation of malignant molecular signals. Therefore, RNF180 could be considered as a promising biomarker for evaluation of the tumour aggressiveness and may be a target for future therapeutic intervention.

OPTIMIZED HUMAN REGULAR U-500 INSULIN TREATMENT IMPROVES ß-CELL FUNCTION IN SEVERELY INSULIN-RESISTANT PATIENTS WITH LONG-STANDING TYPE 2 DIABETES AND HIGH INSULIN REQUIREMENTS.

OBJECTIVE: To assess ß-cell function and insulin sensitivity following improvement in glycemic control in severely insulin-resistant patients with poorly controlled type 2 diabetes (T2D). METHODS: A subset of patients in a 24-week, open-label, randomized trial comparing thrice-daily (n = 14/162) versus twice-daily (n = 11/163) human regular U-500 insulin (U-500R) underwent mixed meal tolerance testing at baseline and endpoint. Baseline characteristics were similar between treatment groups (combined means: age, 54.0 years; diabetes duration, 13.6 years; body mass index, 38.8 kg/m(2); glycated hemoglobin [HbA1c], 8.3%; U-100 insulin dose, 287.6 units/day, 2.6 units/kg/day). Primary outcome measure was ratio of area under the curve (AUC) for C-peptide to glucose (AUCC-peptide/AUCglucose) at 24-week endpoint. RESULTS: Change from baseline HbA1c, daily U-500R dose, and weight were -1.17% (P = .0002), +80.8 units (P = .0003), and +5.9 kg (P = .33), respectively. ß-Cell function significantly improved after 24 weeks of U-500R therapy in combined treatment groups. The AUCC-peptide/AUCglucose increased 34.0% (ratio of least-squares geometric mean, 1.34; 95% confidence interval, 1.18 to 1.52; P = .0001). Integral of total insulin secretion rate increased from 27.0 to 33.7 nmol/m(2), and glucose sensitivity improved from 18.3 to 24.0 pmol/min/m(2)/mM (both, P = .02). Matsuda index improved from 0.8 to 1.3 (P = .008). CONCLUSION: Despite long-standing diabetes and poor glycemic control at baseline, functional recovery of ß-cells was observed with improved glycemic control in these severely insulin-resistant patients with T2D, possibly due to alleviation of glucotoxicity.

TWO TREATMENT APPROACHES FOR HUMAN REGULAR U-500 INSULIN IN PATIENTS WITH TYPE 2 DIABETES NOT ACHIEVING ADEQUATE GLYCEMIC CONTROL ON HIGH-DOSE U-100 INSULIN THERAPY WITH OR WITHOUT ORAL AGENTS: A RANDOMIZED, TITRATION-TO-TARGET CLINICAL TRIAL.

OBJECTIVE: To compare the efficacy and safety of 2 dosing regimens for human regular U-500 insulin (U-500R, 500 units/mL) replacing high-dose U-100 insulins with or without oral antihyperglycemic drugs in patients with inadequately controlled type 2 diabetes (T2D). METHODS: We conducted a 24-week, open-label, parallel trial in 325 patients (demographics [means]: age, 55.4 years; diabetes duration, 15.2 years; body mass index, 41.9 kg/m(2); glycated hemoglobin [HbA1c], 8.7%; U-100 insulin dose, 287.5 units administered in 5 injections/day [median; range, 2 to 10]). Patients were randomized to thrice-daily (TID, n = 162) or twice-daily (BID, n = 163) U-500R after a 4-week lead-in period. The primary outcome was HbA1c change from baseline. RESULTS: After 24 weeks, both treatments demonstrated significant HbA1c reductions (TID, -1.12%; BID, -1.22%; both, P<.001) and clinical equivalence (difference, -0.10%; 95% confidence interval, -0.33 to 0.12%; noninferiority margin, 0.4%). Comparable increases in total daily U-500R dose (TID, 242.7 to 343.1 units; BID, 249.0 to 335.0 units) were observed. Incidence and rate of documented symptomatic hypoglycemia (≤70 mg/dL) were lower for TID versus BID (P = .003 and P = .02, respectively); severe hypoglycemia was similar between treatments. Weight gain was similar in both groups (TID, 5.4 kg; BID, 4.9 kg). CONCLUSION: Initiation and titration of U-500R using either algorithm (TID or BID) improves glycemic control effectively and safely with fewer injections in patients with T2D treated with high-dose/high-volume U-100 insulin. These results provide clinicians with a practical framework for using U-500R in severely insulin-resistant patients with suboptimally controlled T2D.

Shed Syndecan-1 is involved in chemotherapy resistance via the EGFR pathway in colorectal cancer.

BACKGROUND: Syndecan-1 (Sdc-1) shedding induced by matrix metalloproteinase-7 (MMP-7) and additional proteases has an important role in cancer development. However, the impact of Sdc-1 shedding on chemotherapeutic resistance has not been reported. METHODS: We examined Sdc-1 shedding in colorectal cancer by enzyme-linked immunosorbent assay (ELISA), Dot blot, reverse transcription-PCR (RT-PCR), immunohistochemistry and so on, its impact on chemotherapeutic sensitivity by collagen gel droplet embedded culture-drug sensitivity test (CD-DST) and MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide), and potential mechanisms of action by Dot blot, western blot and immunofluorescence. RESULTS: Sdc-1 shedding was increased in colorectal cancer patients, Sdc-1 serum levels in postoperative patients were lower than in preoperative patients, but still higher than those observed in healthy adults. Patients with high preoperative Sdc-1 serum levels were less responsive to 5-Fluorouracil, Oxaliplatin, Irintecan, Cisplatin or Paclitaxel chemotherapy. Moreover, the disease-free survival of patients with high preoperative Sdc-1 serum levels was significantly poorer. The possible mechanism of chemotherapy resistance in colorectal cancer can be attributed to Sdc-1 shedding, which enhances EGFR phosphorylation and downstream signalling. CONCLUSIONS: Shed Sdc-1 is involved in chemotherapy resistance via the EGFR pathway in colorectal cancer, and Sdc-1 serum levels could be a new prognostic marker in colorectal cancer.

The pain response to mydriatic eyedrops in preterm infants.

OBJECTIVE: Evaluate physiological and behavioral pain responses of premature infants following instillation of mydriatic eyedrops for retinopathy of prematurity (ROP) examinations. While burning and stinging occurs in older patients, the infant pain response is not well characterized. STUDY DESIGN: Vital sign and video monitor recorded infant responses before, during and after mydriatic (tropicamide 1%, phenylephrine 2.5%) administration upon first ROP exam. Two masked observers graded Premature Infant Pain Profile (PIPP) scores immediately before and following eyedrop administration. Scores <7 indicate no/minimal pain, 7 to 12 slight/moderate, >12 severe. RESULT: Twenty infants had mean premydriatic PIPP score 3.6 (s.d. 1.6), mean postmydriatic score 5.7 (s.d. 3.4), mean change 2.1 (s.d. 3.4) (P=0.01). One (5%) had premydriatic PIPP score ≥7, seven (35%) post scores ≥7 (P=0.07) with one >12. CONCLUSION: Mydriatic drops cause a clinically significant pain response in one-third of infants. Non-pharmacological supportive measures are recommended for all infants until predictive factors are defined.

Filtration and clogging of permeable pavement loaded by urban drainage.

Permeable pavement, as a sustainable infrastructure material can promote hydrologic restoration, particulate matter (PM) and solute control. However, filtration and commensurate clogging are two aspects of continued interest and discussion. This study quantifies filtration and clogging of cementitious permeable pavement (CPP) for loadings from 50 to 200 mg/L of hetero-disperse sandy-silt PM. The CPP mix design provides a hetero-disperse pore size distribution (PSD)(pore), effective porosity (φ(e)) of 24% and median pore size of 658 µm with a standard deviation of 457 µm. The PM mass separation across the entire particle size distribution (PSD)(PM) exceeds 80%; with complete separation for PM greater than 300 µm and 50% separation for suspended PM. Turbidity is reduced (42-95%), and effluent is below 10 NTU in the first quartile of a loading period. Permeable pavement illustrates reductions in initial (clean-bed) hydraulic conductivity (k(0)) with loading time. For all PM loadings, k(0) (3.1 × 10(-1) mm/s) was reduced to 10(-4) mm/s for runoff loading durations from 100 to 250 h, respectively. Temporal hydraulic conductivity (k) follows exponential profiles. Maintenance by vacuuming and sonication illustrate that 96-99% of k(0) is recovered. Permeable pavement constitutive properties integrated with measured PM loads and a year of continuous rainfall-runoff simulation illustrate k reduction with historical loadings. Study results measure and model filtration and hydraulic conductivity phenomena as well as maintenance requirements of permeable pavement directly loaded by urban drainage.

Relationship between exposure to prasugrel active metabolite and clinical outcomes in the TRITON-TIMI 38 substudy.

In TRITON-TIMI 38, levels of the prasugrel active metabolite (pras-AM) were measured in a population pharmacokinetic substudy that characterized the intrinsic and extrinsic factors influencing exposure. Higher exposure to the pras-AM was observed in low-weight or very elderly patients. The authors hypothesized that this higher exposure might explain the higher risk of non-coronary artery bypass graft (CABG)-related TIMI-related bleeding observed in these 2 patient populations. The relationship between estimated exposure to the pras-AM and clinical outcomes was assessed in 1159 prasugrel-treated patients enrolled in the substudy using multivariable logistic regression analysis. There was no relationship between pras-AM exposure and efficacy through 3 days or after 3 days. Higher estimated pras-AM exposure was associated with a higher incidence of non-CABG-related TIMI major or minor bleeding after 3 days (P < .05) but not through 3 days from start of study drug. Factors associated with increased risk for non-CABG-related TIMI bleeding (≥75 years and <60 kg) also identified subgroups with higher exposure to the pras-AM. Within low body weight and very elderly subgroups, bleeding was largely confined to patients having the highest exposure to the pras-AM, indicating that a prasugrel lower dose in these subgroups may reduce the risk of bleeding while maintaining efficacy.

Increased levels of lead in the blood and frequencies of lymphocytic micronucleated binucleated cells among workers from an electronic-waste recycling site.

In recent years, adverse health effects of chemicals from electronic waste (e-waste) have been reported. However, little is known about the genotoxic effects of chemicals in e-waste. In the present study, air concentrations of the toxic metals at e-waste and control sites were analyzed using inductively-coupled plasma mass spectrometry. Levels of toxic metals (lead, copper and cadmium) in blood and urine were detected using atomic absorption spectrophotometry in 48 exposed individuals and 56 age- and sex-matched controls. The frequencies of lymphocytic micronucleated binucleated cells (MNBNCs) were determined using a cytokinesis-block micronucleus assay. Results indicated that blood lead levels were significantly higher in the exposed group (median: 11.449 µg/dL, 1st/3rd quartiles: 9.351-14.410 µg/dL) than in the control group (median: 9.104 µg/dL, 1st/3rd quartiles: 7.275-11.389 µg/dL). The exposed group had higher MNBNCs frequencies (median: 4.0 per thousand, 1st/3rd quartiles: 2.0-7.0 per thousand) compared with the controls (median: 1.0 per thousand, 1st/3rd quartiles: 0.0-2.0 per thousand). Additionally, MNBNCs frequencies and blood lead levels were positively correlated (r = 0.254, p<0.01). Further analysis suggested that a history of working with e-waste was a predictor for increased blood lead levels and MNBNCs frequencies in the subjects. The results suggest that both the living and occupational environments at the e-waste site may be risk factors for increased MNBNCs frequencies among those who are exposed.

Triclosan: its occurrence, fate and effects in the Australian environment.

Triclosan (TCS) is an antimicrobial agent used widely in household products such as soaps, household cleaners, cosmetics, sportswear, mouthwash and toothpaste. It is a bioaccumulative compound known for its high toxicity to algae, daphnids, fish and other aquatic organisms. We investigated its occurrence in effluents, biosolids and surface waters in Australia, as well as its fate in Australian soils and wastewater treatment plants (WWTPs), including the effects on microbial processes in soils. The concentrations of TCS in 19 effluents ranged from 23 to 434 ng/L (median 108 ng/L) and in 17 biosolids from 0.09 to 16.79 mg/kg on dry weight basis (median 2.32 mg/kg). TCS at concentrations of up to 75 ng/L were detected in receiving waters from five creeks affected by effluent discharge from WWTPs. The removal rate of TCS in five selected WWTPs ranged from 72 and 93%, ascribed mainly to sorption onto sludge and biological degradation. Biodegradation in a clay loam soil was noted with a half life of 18 days. However the half-lives under field conditions are expected to be very different. The studies on the effect of TCS on soil microbiological processes showed that triclosan can disrupt the nitrogen cyclein sensitive soils at concentrations ≥5 mg/kg. In view of the recent risk assessment by the Australian regulatory agency NICNAS, there is an urgent need to assess exposure to TCS and its effect on ecosystem health.

The onset of inhibition of platelet aggregation with prasugrel compared with clopidogrel loading doses using gatekeeping analysis of integrated clinical pharmacology data.

The purpose of this analysis was to determine the time by which a prasugrel 60-mg loading dose (LD) achieved significantly greater inhibition of platelet aggregation (IPA) than the peak IPA after a clopidogrel 300-mg LD or 600-mg LD. Data were pooled from nine studies representing 587 individuals: 274 healthy subjects and 313 patients with stable coronary artery disease. The primary pharmacodynamic measure was IPA using 20 [mu]M adenosine-5'-diphosphate as the agonist. Gatekeeping analysis compared the peak IPA at 4, 6, and 24 hours after a clopidogrel 300-mg or 600-mg LD with IPA at various prior time points backwards after a prasugrel LD until a statistically nonsignificant difference was reached. Prasugrel 60-mg LD produced greater IPA by 30 minutes than the peak IPA after a clopidogrel 300-mg LD (P < 0.0001). Significantly greater IPA was achieved at 1 hour after prasugrel 60-mg LD compared with the peak IPA after 600-mg clopidogrel LD (P < 0.0001), regardless of sex, body weight, or age and as early as 30 minutes in the diabetic subgroup. A prasugrel 60-mg LD produces significantly faster onset and greater IPA compared with a clopidogrel 300-mg LD or 600-mg LD.