The Wadden Sea receives contaminants from various sources and via various transport routes. The contaminants described in this overview are various metals (Cd, Cu, Hg, Pb and Zn) and various organic ...contaminants (polychlorinated biphenyls (PCBs), polycyclic aromatic hydrocarbons (PAHs) and lindane (hexachlorocyclohexane, γ-HCH)). In addition, information is presented about other and emerging contaminants such as antifouling biocides (e.g. TBT and Irgarol), brominated flame retardants (BFRs), poly- and perfluorinated compounds (PFCs) and pharmaceutical and personal care products (PPCPs).
Special attention is given to biogeochemical processes that contribute to the mobilization of contaminants in the surface sediments of the Wadden Sea. Finally, the effects on organisms of contaminants are reviewed and discussed.
The main source of contaminants in the Wadden Sea are the rivers Rhine (via de Dutch coastal zone), Elbe and Weser. The Wadden Sea is not a sink for contaminants and adsorbed contaminants are transported from east to west. The surface sediments of the Wadden Sea are an important source for contaminants to the water above. The input and concentration of most contaminants have significantly decreased in water, sediments, organisms (e.g., mussel, flounder and bird eggs) in various parts of the Wadden Sea in the last three decades. Remarkably, the Cd concentration in mussels is increasing the last decades.
In recent decades, the effects of contaminants on organisms (e.g., flounder, seal) have fallen markedly. Most of the affected populations have recovered, except for TBT induced effects in snails. Little is known about the concentration and effects of most emerging contaminants and the complex environmental mixtures of contaminants.
It is recommended to install an international coordinated monitoring programme for contaminants and their effects in the whole Wadden Sea and to identify the chemical contaminants that really cause the effect.
Felbamate Urolithiasis Sparagana, S. P.; Strand, W. R.; Adams, R. C.
Epilepsia (Copenhagen),
20/May , Letnik:
42, Številka:
5
Journal Article
Recenzirano
Odprti dostop
Purpose: To report a case of felbamate (FBM) urolithiasis.
Methods: Urographic imaging sonography, abdominal computed tomography (CT), intravenous pyelogram, voiding cystourethrogram and urologic ...procedures (cystoscopy with lithotripsy, ureteral stent) to define and capture the stones. Stone identification was by infrared spectroscopy and gas chromatography/mass spectrometry.
Results: A 15‐year‐old boy had painful hematuria, bilateral ureteral obstruction, and urinary retention. Kidney, bladder, and ureteral stones were found, and ureteral stent placement was required to relieve obstruction. The stone material was identified as FBM by chemical analysis. Stone formation ceased with discontinuation of FBM.
Conclusions: FBM urolithiasis can occur, and possible contributory factors include high felbamate dosage, drug polypharmacy, and risk factors for forming stones of other types. FBM urolithiasis may be heralded by crystalluria.
It has been hypothesized that endoscopic decompression of the duplex extravesical ureterocele is necessary to prevent the complications of urinary tract infections and progressive hydronephrosis. ...This study was performed to test this premise.
Infants younger than 2 weeks with an extravesical ureterocele associated with a duplex upper pole moiety were assigned to immediate endoscopic puncture of the ureterocele followed by antibiotic prophylaxis or antibiotic prophylaxis with plans for delayed surgical intervention. Radiographic studies and catheterized urine cultures were obtained at ages 3 and 6 months and for fever greater than 38.5C. All patients included in this study were followed through 6 months of life.
Of the patients 32 underwent endoscopic puncture of the ureterocele. Median patient age at endoscopy was 5 days (range 3 to 13). During the first 6 months of life complications developed in 4 (12%), including febrile urinary tract infections in 3 (9%) and with progressive hydronephrosis due to incomplete puncture of the ureterocele in 1 (3%). The remaining 40 patients were treated with antibiotic prophylaxis and delayed open surgery. Median time to open surgery was 3 months (range 2 to 6). During the first 6 months of life complications developed in 5 (13%), including 3 (8%) febrile urinary tract infections and progressive hydronephrosis in 2 (5%). No statistical difference was noted between the 2 treatment groups.
In patients with extravesical duplex ureteroceles neonatal complications of urinary tract infection and progressive hydronephrosis are not significantly different between those treated with immediate endoscopic decompression versus delayed open surgical intervention.
Intra-articular injection of hyaluronic acid is a common, yet controversial, therapeutic option for patients with knee osteoarthritis (OA). The purpose of this research was to determine the safety ...and efficacy of US-approved viscosupplements for symptomatic knee OA.
We searched MedLine and EMBase for randomized, sham-controlled trials evaluating safety and/or clinical efficacy of US-approved viscosupplements in patients with symptomatic knee OA. Knee pain severity and knee joint function were assessed at 4 to 13 weeks and 14 to 26 weeks. Safety outcomes included serious adverse events, treatment-related serious adverse events, patient withdrawal, and adverse event-related patient withdrawal occurring at any time during follow-up.
A total of 29 studies representing 4,866 unique patients (active: 2,673, control: 2,193) were included. All sham-controlled trials used saline injections as a control. Viscosupplementation resulted in very large treatment effects between 4 and 26 weeks for knee pain and function compared to preinjection values, with standardized mean difference values ranging from 1.07 to 1.37 (all P<0.001). Compared to controls, standardized mean difference with viscosupplementation ranged from 0.38 to 0.43 for knee pain and 0.32 to 0.34 for knee function (all P<0.001). There were no statistically significant differences between viscosupplementation and controls for any safety outcome, with absolute risk differences of 0.7% (95% confidence interval CI: -0.2 to 1.5%) for serious adverse events, 0% (95% CI: -0.4 to 0.4%) for treatment-related serious adverse events, 0% (95% CI: -1.6 to 1.6%) for patient withdrawal, and 0.2% (95% CI: -0.4 to 0.8%) for adverse event-related patient withdrawal.
Intra-articular injection of US-approved viscosupplements is safe and efficacious through 26 weeks in patients with symptomatic knee OA.
An intercomparison of nine chemical mechanisms (e.g. ADOM, CBM-IV, EMEP, RADM2) as used by 12 contributing groups was conducted. The results for three scenarios are presented covering remote ...situations with a net O
3 loss of around 2.7 ppb (LAND and FREE) and a moderately polluted situation with O
3 formation of around 100 ppb (PLUMEI) over a 5 day simulation period. The overall tendencies (i.e. the total net production/loss over 5 days) for O
3 show a r.m.s. error of 38, 15 and 16%; for H
2O
2 the errors are 76, 23 and 30% (for LAND, FREE, PLUMEI). In terms of ozone production in PLUME1, the most productive mechanisms are EMEP and IVL, the RADM-type mechanisms lie in the mid-range and the CBM-1V type mechanisms fall at the bottom of the range. The differences in H
2O
2 can partly be explained by an incorrect use of the HO
2 + HO
2 rate constant and by differences in the treatment of the peroxy radical interactions. In the PLUME1 case the r.m.s. error of the PAN tendency was found to be 29%. Differences between mechanisms for the HO radical are 10, 15 and 19% and for the NO
3 radical 35, 16 and 40% (for LAND, FREE, PLUME1) in terms of the r.m.s. error of the results for a 12 h time period centred around the last noon (HO), respectively, a 8 h time period centred around the last midnight (NO
3) of simulation. Especially for NO
3 some differences are due to different numerical treatment of photolytic processes in the models. Large differences between mechanisms are observed for higher organic peroxides and higher aldehydes with a r.m.s. error of around 50% for the final concentration in PLUME1. The protocol of the intercomparison is given in the appendix, so that the comparison could be repeated for the purpose of mechanism development and sensitivity studies.
Abstract
BACKGROUND: Estrogen contribute to the progression of breast cancer via estrogen receptor 1 (ESR1) and current therapies involve either antiestrogens or aromatase inhibitors. However, most ...patients develop resistance to these drugs. Critically, therapy-resistant tumors retain ESR1-signaling. Mechanisms of therapy resistance involve the activation of ESR1 in the absence of ligand or mutations in ESR1 that allow interaction between the ESR1 and coregulators leading to sustained ESR1 signaling and proliferation. For patients with therapy-resistant breast cancers, there is a critical unmet need for novel agents to disrupt ESR1 signaling by blocking ESR1 interactions with its coregulators.
METHODS: Using rational design, we synthesized and evaluated a small organic molecule (ESR1 coregulator binding inhibitor, ECBI) that mimics the ESR1 coregulator nuclear receptor box motif. Using in vitro cell proliferation and apoptosis assays, we tested the effect of ECBI on several breast cancer and therapy-resistant model cells. Mechanistic studies were conducted using established biochemical assays, reporter gene assays, RT-qPCR and RNA-Seq analysis. Differentially expressed genes were analyzed using Ingenuity Pathway Analysis (IPA). ESR1 positive (MCF7 and ZR75) xenografts were used for preclinical evaluation and toxicity. The efficacy of ECBI was tested using ex vivo cultures of freshly extirpated primary human breast tissues.
RESULTS: In estrogen induced proliferation assays using several ESR1 positive model cells, ECBI significantly inhibited growth and promoted apoptosis. Importantly, ECBI showed little or no activity on ESR1 negative cells. Further, ECBI also reduced the proliferation of several ESR1 positive hormonal therapy resistant cells. Mechanistic studies showed that ECBI interacts with ESR1, efficiently blocks ESR1 interactions with coregulators and reduces the ESR1 driven ERE reporter gene activity. Further, ECBI directly interacted with mutant-ESR1 with high affinity and significantly inhibited mutant-ESR1 driven oncogenic activity. RNA sequencing analysis revealed that ECBI blocks multiple ESR1 driven pathways, likely representing the ability of a single ECBI compound to block multiple ESR1-coregulator interactions. Treatment of ESR1-positive xenograft tumors with ECBI (10 mg/kg/day/oral) significantly reduced the tumor volume compared to control. Further, ECBI also significantly reduced the tumor growth of coregulator-overexpressed breast cancer cells in xenograft model. Using human primary breast tissue ex vivo cultures, we have provided evidence that ECBI has potential to dramatically reduce proliferation of human breast tumors.
CONCLUSIONS: The ECBI is a novel agent that targets ESR1 with a unique mechanism of action. ECBI has distinct pharmacologic advantages of oral bioavailability, in vivo stability, and is associated with minimal systemic side effects. Remarkably, ECBI block both native and mutant forms of ESR1 and have activity against therapy resistant breast cancer cell proliferation both in vitro and in vivo and against primary human tumor tissues ex vivo. Thus development of ECBI represents a quantum leap in therapies to target ESR1.
Citation Format: Vadlamudi RK, Sareddy GR, Viswanadhapalli S, Lee T-K, Ma S-H, Lee WR, Mann M, Krishnan SR, Gonugunta V, Strand DW, Tekmal RR, Ahn J-M, Raj GV. ESR1 coregulator binding inhibitor (ECBI) as a novel therapeutic to target hormone therapy resistant metastatic breast cancer. abstract. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr S3-04.
Prunebelly syndrome and posterior urethral valves are conditions of detrusor dysfunction associated with antenatal urethral obstruction. The resultant severe hydroureteronephrosis and renal dysplasia ...initiate a sequence potentially leading to renal failure. This article reviews clinical features and explores neonatal evaluation and treatment for both conditions. A comprehensive approach to initial management aimed at optimal renal preservation and bladder rehabilitation is proposed.
Net-spinning caddisflies commonly inhabit the chronically sedimented waters of midwestern agricultural catchments despite the presumed costs of sedimentation-induced gill-and net-fouling. We ...conducted a laboratory experiment to determine whether larval growth and survival of
Hydropsyche betteni and
Ceratopsyche sparna are affected by daily exposure to moderate levels of sedimentation. Sedimentation did not alter the relative growth rate of either species although slight losses by
H. betteni and gains by
C. sparna produced significant differences between species.
H. betteni had a decreased likelihood of survival in sedimentation treatments relative to controls, but significantly outperformed
C. sparna overall. Larval
C. sparna are reportedly more sensitive than
H. betteni to the instream effects of agricultural land use; however, the results of this experiment suggest that this differential sensitivity is probably not caused by episodic increases in suspended sediment concentration.
We have identified imidazopyridine derivatives as a novel class of NO synthase inhibitors with high selectivity for the inducible
isoform. 2-2-(4-Methoxy-pyridin-2-yl)-ethyl-3 H -imidazo4,5- b ...pyridine (BYK191023) showed half-maximal inhibition of crudely purified human inducible (iNOS), neuronal (nNOS), and endothelial
(eNOS) NO synthases at 86 nM, 17 μM, and 162 μM, respectively. Inhibition of inducible NO synthase was competitive with l -arginine, pointing to an interaction of BYK191023 with the catalytic center of the enzyme. In radioligand and surface plasmon
resonance experiments, BYK191023 exhibited an affinity for iNOS, nNOS, and eNOS of 450 nM, 30 μM, and >500 μM, respectively.
Inhibition of cellular nitrate/nitrite synthesis in RAW, rat mesangium, and human embryonic kidney 293 cells after iNOS induction
showed 40- to 100-fold higher IC 50 values than at the isolated enzyme, in agreement with the much higher l -arginine concentrations in cell culture media and inside intact cells. BYK191023 did not show any toxicity in various rodent
and human cell lines up to high micromolar concentrations. The inhibitory potency of BYK191023 was tested in isolated organ
models of iNOS (lipopolysaccharide-treated and phenylephrine-precontracted rat aorta; IC 50 = 7 μM), eNOS (arecaidine propargyl ester-induced relaxation of phenylephrine-precontracted rat aorta; IC 50 > 100 μM), and nNOS (field-stimulated relaxation of phenylephrine-precontracted rabbit corpus cavernosum; IC 50 > 100 μM). These data confirm the high selectivity of BYK191023 for iNOS over eNOS and nNOS found at isolated enzymes. In
summary, we have identified a new highly selective iNOS inhibitor structurally unrelated to known compounds and l -arginine. BYK191023 is a valuable tool for the investigation of iNOS-mediated effects in vitro and in vivo.
Acute renal failure in Burkitt lymphoma is commonly the result of tumor lysis syndrome. We present a 15-year-old boy who developed hypertension, seizures, and acute renal failure due to extrinsic ...compression of the bladder and ureters by a large retrovesical Burkitt lymphoma. The causes of acute renal failure in Burkitt lymphoma and the incidence of acute urinary obstruction in this disease are reviewed.
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