Venous thromboembolism and amyotrophic lateral sclerosis: the Venous Thrombo-Embolism and Sclerosis Lateral Amyotrophic study.

Background: Amyotrophic lateral sclerosis (ALS) is a severe neurodegenerative disease. Given the inflammatory nature of ALS and the high number of ALS-related clinical circumstances (eg, prolonged immobilization and infections), patients with ALS may have a high risk of venous thromboembolism (VTE). Objectives: To determine the annual incidence rate of VTE and the predictors of VTE in patients with ALS. Methods: We analyzed a prospective cohort of patients with ALS diagnosed between 2009 and 2019 followed in the Brest University Hospital ALS Centre. Results: Among 227 patients with ALS, VTE occurred in 19 patients during a median follow-up period of 717 days (IQR, 488-1308), yielding an annual incidence rate of 2.93% (95% CI, 1.88%-4.53%). Predictors for VTE were a family history of VTE (hazard ratio [HR], 15.24; 95% CI, 1.72-134.84; P = .01), the presence of noninvasive ventilation at ALS diagnosis (HR, 6.98; 95% CI, 1.09-44.59; P = .04) and a short time (ie, <213 days) between first symptoms and ALS diagnosis (HR, 5.48; 95% CI, 1.57-19.11; P = .01). Recurrent VTE occurred within 3 months after stopping anticoagulation in 5 patients (26.3%). Conclusion: The annual incidence of VTE in patients with ALS is high. Predictive factors of VTE were a VTE history, noninvasive ventilation, and a short time between first symptoms of ALS and ALS diagnosis.

A systematic review and meta-analysis of the incidence of post-thrombotic syndrome, recurrent thromboembolism, and bleeding after upper extremity vein thrombosis.

BACKGROUND: Data on complications after upper extremity vein thrombosis (UEVT) are limited and heterogeneous. METHODS: The aim of the present study was to evaluate the pooled proportions of venous thromboembolism (VTE) recurrence, bleeding, and post-thrombotic syndrome (PTS) in patients with UEVT. A systematic literature review was conducted of PubMed, Embase, and the Cochrane Library databases from January 2000 to April 2023 in accordance with the PRISMA (preferred reporting items for systematic reviews and meta-analyses) guidelines. All studies included patients with UEVT and were published in English. Meta-analyses of VTE recurrence, bleeding, and of PTS after UEVT were performed to compute pooled estimates and associated 95% confidence intervals (CIs). Subgroup analyses of cancer-associated UEVT and catheter-associated venous thrombosis were conducted. Patients with Paget-Schroetter syndrome or effort thrombosis were excluded. RESULTS: A total of 55 studies with 15,694 patients were included. The pooled proportions for VTE recurrence, major bleeding, and PTS were 4.8% (95% CI, 3.8%-6.2%), 3.0% (95% CI, 2.2%-4.0%), and 23.8% (95% CI, 17.0%-32.3%), respectively. The pooled proportion of VTE recurrence was 2.7% (95% CI, 1.6%-4.6%) for patients treated with direct oral anticoagulants (DOACs), 1.7% (95% CI, 0.8%-3.7%) for patients treated with low-molecular-weight heparin (LMWH), and 4.4% (95% CI, 1.5%-11.8%) for vitamin K antagonists (VKAs; P = .36). The pooled proportion was 6.3% (95% CI, 4.3%-9.1%) for cancer patients compared with 3.1% (95% CI, 2.1%-4.6%) for patients without cancer (P = .01). The pooled proportion of major bleeding for patients treated with DOACs, LMWH, and VKAs, was 2.1% (95% CI, 0.9%-5.1%), 3.2% (95% CI, 1.4%-7.2%), and 3.4% (95% CI, 1.4%-8.4%), respectively (P = .72). The pooled proportion of PTS for patients treated with DOACs, LMWH, and VKAs was 11.8% (95% CI, 6.5%-20.6%), 27.9% (95% CI, 20.9%-36.2%), and 24.5% (95% CI, 17.6%-33.1%), respectively (P = .02). CONCLUSIONS: The results from this study suggest that UEVT is associated with significant rates of PTS and VTE recurrence. Treatment with DOACs might be associated with lower PTS rates than treatment with other anticoagulants.

Upper extremity venous thrombosis in hospitalized patients: A prospective epidemiological study.

BACKGROUND: The frequency of upper extremities vein thrombosis (UEVT) is rising with the increasing use of endovenous devices. These thromboses are particularly common among hospitalized patients. The epidemiology and risk factors for UEVT are poorly understood in a hospitalized population. OBJECTIVE: To assess the prevalence of UEVT in hospitalized patients and study thrombosis risk factors according to their location. METHODS: Prospective evaluation of patients hospitalized in a university hospital with clinical and Doppler ultrasound (DUS) assessment of the upper extremities. RESULTS: Of the 400 patients included, 91(22.8 %) had UEVT including 8 (8.8 %) proximal thrombosis, 32 (35.2 %) arm venous thrombosis and 51 (56.0 %) forearm venous thrombosis; 7 (7.7 %) patients with UEVT had a concomitant symptomatic pulmonary embolism. In this population of hospitalized patients, 40 (10 %) had proximal or arm thrombosis and 51 (12.8 %) forearm thrombosis. All patients with UEVT had a venous catheter and 63 (69.2 %) of UEVT patients had therapeutic or prophylactic anticoagulation at the time of DUS evaluation. In multivariate analysis, peripheral intravenous catheter (PIVC) OR 3.71 [1.90; 7.91] (p < 0.001); MID line OR 3.58 [1.46; 8.91] (p = 0.005) and infection disease OR 2.21 [1.26; 4386] (p = 0.005) were associated with UEVT. Central venous catheter OR 66.24 [12.64; 587.03] was associated with proximal UEVT and MID line OR 12.61 [4.64; 35.77] (p < 0.001) with arm UEVT. Forearm UEVT were associated with PIVCOR 10.71[3.14; 67.37] (p = 0.001); infectious disease OR 2.87 [1.48; 5.60] (p = 0.002), iron infusion OR 3.11 [1.23; 7.47] and hospitalization for postpartum OR 4.37 [0.97; 18.06] (p = 0.04). CONCLUSION: One in 5 hospitalized patients suffers from UEVT. Proximal venous thrombosis is uncommon. The presence of a catheter and hospitalization for infection are the factors most frequently associated with UEVT.

Comparative Persistence of Engineered Nanoparticles in a Complex Aquatic Ecosystem.

During nanoparticle environmental exposure, presence in the water column is expected to dominate long distance transport as well as initial aquatic organism exposure. Much work has been done to understand potential ecological and toxicological effects of these particles. However, little has been done to date to understand the comparative persistence of engineered particles in realistic environmental systems. Presented here is a study of the water column lifetimes of 3 different classes of nanoparticles prepared with a combination of surface chemistries in wetland mesocosms. We find that, when introduced as a single pulse, all tested nanoparticles persist in the water column for periods ranging from 36 h to 10 days. Specifically, we found a range of nanoparticle residence times in the order Ag > TiO2 > SWCNT > CeO2. We further explored the hypothesis that heteroaggregation was the primary driving factor for nanoparticle removal from the water column in all but one case, and that values of surface affinity (α) measured in the laboratory appear to predict relative removal rates when heteroaggregation dominates. Though persistence in the water column was relatively short in all cases, differences in persistence may play a role in determining nanoparticle fate and impacts and were poorly predicted by currently prevailing benchmarks such as particle surface preparation.

An adaptable mesocosm platform for performing integrated assessments of nanomaterial risk in complex environmental systems.

Physical-chemists, (micro)biologists, and ecologists need to conduct meaningful experiments to study the environmental risk of engineered nanomaterials with access to relevant mechanistic data across several spatial and temporal scales. Indoor aquatic mesocosms (60L) that can be tailored to virtually mimic any ecosystem appear as a particularly well-suited device. Here, this concept is illustrated by a pilot study aimed at assessing the distribution of a CeO2-based nanomaterial within our system at low concentration (1.5 mg/L). Physico-chemical as well as microbiological parameters took two weeks to equilibrate. These parameters were found to be reproducible across the 9-mesocosm setup over a 45-day period of time. Recovery mass balances of 115 ± 18% and 60 ± 30% of the Ce were obtained for the pulse dosing and the chronic dosing, respectively. This demonstrated the relevance of our experimental approach that allows for adequately monitoring the fate and impact of a given nanomaterial.

Emerging contaminant or an old toxin in disguise? Silver nanoparticle impacts on ecosystems.

The use of antimicrobial silver nanoparticles (AgNPs) in consumer-products is rising. Much of these AgNPs are expected to enter the wastewater stream, with up to 10% of that eventually released as effluent into aquatic ecosystems with unknown ecological consequences. We examined AgNP impacts on aquatic ecosystems by comparing the effects of two AgNP sizes (12 and 49 nm) to ionic silver (Ag(+); added as AgNO3), a historically problematic contaminant with known impacts. Using 19 wetland mesocosms, we added Ag to the 360 L aquatic compartment to reach 2.5 mg Ag L(-1). Silver treatments and two coating controls were done in triplicate, and compared to four replicate controls. All three silver treatments were toxic to aquatic plants, leading to a significant release of dissolved organic carbon and chloride following exposure. Simultaneously, dissolved methane concentrations increased forty-fold relative to controls in all three Ag treatments. Despite dramatic toxicity differences observed in lab studies for these three forms of Ag, our results show surprising convergence in the direction, magnitude, and duration of ecosystem-scale impacts for all Ag treatments. Our results suggest that all forms of Ag changed solute chemistry driving transformations of Ag which then altered Ag impacts.

Long-term transformation and fate of manufactured ag nanoparticles in a simulated large scale freshwater emergent wetland.

Transformations and long-term fate of engineered nanomaterials must be measured in realistic complex natural systems to accurately assess the risks that they may pose. Here, we determine the long-term behavior of poly(vinylpyrrolidone)-coated silver nanoparticles (AgNPs) in freshwater mesocosms simulating an emergent wetland environment. AgNPs were either applied to the water column or to the terrestrial soils. The distribution of silver among water, solids, and biota, and Ag speciation in soils and sediment was determined 18 months after dosing. Most (70 wt %) of the added Ag resided in the soils and sediments, and largely remained in the compartment in which they were dosed. However, some movement between soil and sediment was observed. Movement of AgNPs from terrestrial soils to sediments was more facile than from sediments to soils, suggesting that erosion and runoff is a potential pathway for AgNPs to enter waterways. The AgNPs in terrestrial soils were transformed to Ag(2)S (~52%), whereas AgNPs in the subaquatic sediment were present as Ag(2)S (55%) and Ag-sulfhydryl compounds (27%). Despite significant sulfidation of the AgNPs, a fraction of the added Ag resided in the terrestrial plant biomass (~3 wt % for the terrestrially dosed mesocosm), and relatively high body burdens of Ag (0.5-3.3 µg Ag/g wet weight) were found in mosquito fish and chironomids in both mesocosms. Thus, Ag from the NPs remained bioavailable even after partial sulfidation and when water column total Ag concentrations are low (<0.002 mg/L).

More than the ions: the effects of silver nanoparticles on Lolium multiflorum.

Silver nanoparticles (AgNPs) are increasingly used as antimicrobial additives in consumer products and may have adverse impacts on organisms when they inadvertently enter ecosystems. This study investigated the uptake and toxicity of AgNPs to the common grass, Lolium multiflorum. We found that root and shoot Ag content increased with increasing AgNP exposures. AgNPs inhibited seedling growth. While exposed to 40 mg L(-1) GA-coated AgNPs, seedlings failed to develop root hairs, had highly vacuolated and collapsed cortical cells and broken epidermis and rootcap. In contrast, seedlings exposed to identical concentrations of AgNO(3) or supernatants of ultracentrifuged AgNP solutions showed no such abnormalities. AgNP toxicity was influenced by total NP surface area with smaller AgNPs (6 nm) more strongly affecting growth than did similar concentrations of larger (25 nm) NPs for a given mass. Cysteine (which binds Ag(+)) mitigated the effects of AgNO(3) but did not reduce the toxicity of AgNP treatments. X-ray spectro-microscopy documented silver speciation within exposed roots and suggested that silver is oxidized within plant tissues. Collectively, this study suggests that growth inhibition and cell damage can be directly attributed either to the nanoparticles themselves or to the ability of AgNPs to deliver dissolved Ag to critical biotic receptors.

Heparin modifies the immunogenicity of positively charged proteins.

The immune response in heparin-induced thrombocytopenia is initiated by and directed to large multimolecular complexes of platelet factor 4 (PF4) and heparin (H). We have previously shown that PF4:H multimolecular complexes assemble through electrostatic interactions and, once formed, are highly immunogenic in vivo. Based on these observations, we hypothesized that other positively charged proteins would exhibit similar biologic interactions with H. To test this hypothesis, we selected 2 unrelated positively charged proteins, protamine (PRT) and lysozyme, and studied H-dependent interactions using in vitro and in vivo techniques. Our studies indicate that PRT/H and lysozyme/H, like PF4/H, show H-dependent binding over a range of H concentrations and that formation of complexes occurs at distinct stoichiometric ratios. We show that protein/H complexes are capable of eliciting high-titer antigen-specific antibodies in a murine immunization model and that PRT/H antibodies occur in patients undergoing cardiopulmonary bypass surgery. Finally, our studies indicate that protein/H complexes, but not uncomplexed protein, directly activate dendritic cells in vitro leading to interleukin-12 release. Taken together, these studies indicate that H significantly alters the biophysical and biologic properties of positively charged compounds through formation of multimolecular complexes that lead to dendritic cell activation and trigger immune responses in vivo.

Comparative toxicity of C60 aggregates toward mammalian cells: role of tetrahydrofuran (THF) decomposition.

C60 fullerene is a promising material because of its unique physiochemical properties. However, previous studies have reported that colloidal aggregates of C60 (nC60) produce toxicity in fish and human cell cultures. The preparation method of nC60 raises questions as to whether the observed effects stem from fullerenes or from the organic solvents used during the preparation of the suspensions. In this paper, we set out to elucidate the mechanism by which tetrahydrofuran (THF) treatment to enhance the preparation of nC60 leads to cytotoxicity in a mouse macrophage cell line. Our results demonstrate that THF/nC60 but not fullerol or aqueous nC60 generates cellular toxicity through a pathway that involves increased intracellular flux and mitochondrial perturbation in RAW 264.7 cells. Interestingly, the supernatant of the THF/n60 suspension rather than the colloidal fullerene aggregates mimics the cytotoxic effects due to the presence of gamma-butyrolactone and formic acid. Thus, the role of nC60 in the cellular responses is likely not due to the direct effect of the nC60 material surface on the cells but is related to the conversion of THF into a toxic byproduct during preparation of the suspension.

Filtration method characterizing the reversibility of colloidal fouling layers at a membrane surface: analysis through critical flux and osmotic pressure.

A filtration procedure was developed to measure the reversibility of fouling during cross-flow filtration based on the square wave of applied pressure. The principle of this method, the apparatus required, and the associated mathematical relationships are detailed. This method allows for differentiating the reversible accumulation of matter on, and the irreversible fouling of, a membrane surface. Distinguishing these two forms of attachment to a membrane surface provides a means by which the critical flux may be determined. To validate this method, experiments were performed with a latex suspension at different degrees of destabilization (obtained by the addition of salt to the suspension) and at different cross-flow velocities. The dependence of the critical flux on these conditions is discussed and analysed through the osmotic pressure of the colloidal dispersion.

Transport and retention of colloidal aggregates of C60 in porous media: effects of organic macromolecules, ionic composition, and preparation method.

The physical-chemical behavior of the fullerene C60 in environmental and physiological media is of interest for understanding the potential transport, exposure, and impacts of these materials on organisms and ecosystems. We considerthe role of electrolyte composition and concentration, the effect of organic macromolecules, and the mode of preparation of colloidal aggregates of C60 (nC60) on the deposition of these colloids in a porous medium such as a groundwater aquifer or a water treatment filter. Results for nC60 deposition are qualitatively consistent with trends anticipated by theory. Deposition was found to increase with increasing ionic strength, the presence of polysaccharide-type organic matter, and lower Darcy velocities. Factors that will tend to decrease the retention of these materials in porous media include a low ionic strength and the presence of humic-like substances, while the ionic strengths typical of many natural waters and the presence polysaccharide-based natural organic matter, as may be produced by algae or bacteria, will tend to favor deposition and reduced potential for exposure. Variability in the method of preparing colloidal aggregates of fullerenes was observed to yield significant differences in nC60 properties and transport behavior.

Determinants of PF4/heparin immunogenicity.

Heparin-induced thrombocytopenia (HIT) is an antibody-mediated disorder that occurs with variable frequency in patients exposed to heparin. HIT antibodies preferentially recognize large macromolecular complexes formed between PF4 and heparin over a narrow range of molar ratios, but the biophysical properties of complexes that initiate antibody production are unknown. To identify structural determinants underlying PF4/heparin immunogenicity, we characterized the in vitro interactions of murine PF4 (mPF4) and heparin with respect to light absorption, size, and surface charge (zeta potential). We show that PF4/heparin macromolecular assembly occurs through colloidal interactions, wherein heparin facilitates the growth of complexes through charge neutralization. The size of PF4/heparin macromolecules is governed by the molar ratios of the reactants. Maximal complex size occurs at molar ratios of PF4/heparin at which surface charge is neutral. When mice are immunized with complexes that differ in size and/or zeta potential, antibody formation varies inversely with heparin concentration and is most robust in animals immunized with complexes displaying a net positive zeta-potential. These studies suggest that the clinical heterogeneity in the HIT immune response may be due in part to requirements for specific biophysical parameters of the PF4/heparin complexes that occur in settings of intense platelet activation and PF4 release.