Significance of the biodurability of man-made vitreous fibers to risk assessment.

It is generally agreed that the biodurability of man-made vitreous fibers is a major factor for the characterization of potential health effects. As there is currently no standardization of experimental protocols to determine biodurabilty, the results of the clearance assays have not been used up to now for regulatory purposes. Methods used to analyze biodurability in animal models are short-term inhalational exposure and intratracheal instillation of rat respirable fibers. Both test methods have strengths and limitations for regulatory purposes. We outline recommended procedures for standardized biodurability assays that can be used to compare different fiber types. In animal experiments, biodurability is difficult to separate from biopersistence, as mucociliary and macrophage-mediated clearance occur simultaneously with dissolution and disintegration. For intratracheal instillation, a sized rat respirable sample must be used. Precautions should be taken to prevent aggregation of fibers in the lungs. Although from a scientific point of view questions remain about quantifying the influence of fiber length, diameter, dose, and exposure route, consistent data on the biodurability of vitreous glass fibers are available which may be used for regulatory purposes

Investigation of the biodurability of wollastonite and xonotlite.

The in vivo durability of wollastonite materials, coated and uncoated, and of xonotlite was tested. Wollastonite is an anhydrous natural silicate and xonotlite is a hydrated synthetic calcium silicate. UICC crocidolite was used as a positive control with high durability. Using a dry-sizing technique, fractions from the stock materials were prepared according to the definition of "thoracic particulate mass" and "respirable particulate mass" of the American Conference of Governmental Industrial Hygienists. Fibers were instilled intratracheally into female Wistar rats, and the evenness of their distribution in the lung was checked by scanning electron microscopy (SEM). After serial sacrifices at 2 and 14 days, 1, 3, and 6 months, and low temperature ashing of the lung, the fibers were analyzed by SEM. The number and size distribution of fibers were investigated. The total number of crocidolite fibers decreased with a half-time of 240 days, but the number of fibers > 5 microns in length was unchanged after 6 months. The elimination kinetics of wollastonite fibers from the lung were relatively fast, with half-times of 15 to 21 days. The coating of wollastonite in Wollastocoat had no effect on this elimination process. For the thoracic fraction of wollastonite, the elimination from the lung was as fast as for the respirable particulate fraction. The elimination kinetics of xonotlite from the lung was very fast. This material consisted of single crystals of acicular morphology with a median length of 1.3 micron and of agglomerates of these crystals. More than 99% of single crystals and about 85 to 89% of the agglomerates were already eliminated 2 days after instillation

Investigations on health-related properties of two sepiolite samples.

Published i.p. injection studies have shown different biological behavior of different sepiolite samples. There was no evidence for carcinogenic potential of sepiolite from Vicalvaro, Spain, whereas a high tumor incidence was reported for sepiolite from Finland. The low biological activity of the sepiolite from Vicalvaro, compared to the Finnish sample, could be caused by low in vivo persistence or by the short length of the fibers, or both. In this study a further sepiolite sample, obtained as a commercial sample originating from China, was investigated. This sample contained a higher fraction of fibers longer than 5 microns, comparable to the Finnish sepiolite sample. The fraction of fibers with a length > 5 microns was 0.12 and 2.2% for the Vicalvaro and Chinese sepiolite, respectively. For the fiber fraction longer than 8 microns, the corresponding values were 0.0045 and 0.82%. The in vivo persistence of the sepiolite samples from China and Vicalvaro was analyzed after intratracheal instillation of 2 mg in female Wistar rats. Fiber retention in the lungs was analyzed by transmission electron microscopy at different sacrifice dates up to 12 months after application. For the Vicalvaro sepiolite, a splitting of fiber bundles was found during retention time in the lung. Therefore, no half-time of the fiber clearance could be calculated from the number of fibers. The decrease of the calculated retained fiber mass was faster for the Vicalvaro sepiolite (T1/2 = 89 days) compared to the Chinese sepiolite (T1/2 = 129 days). For 2 or 3 rats per group, at sacrifice date 12 months after i.p. injection, the lung was investigated by histopathology. The main difference between both treatment groups was a more pronounced fibrotic response in the Chinese sepiolite-treated rats compared to those treated with Vicalvaro sepiolite. It is concluded that both the higher fraction of long sepiolite fibers and the slower elimination rate of the fiber mass in the Chinese sample were important factors for the different biological reaction in comparison with Vicalvaro sepiolite

Cancer therapeutic potential of combinatorial immuno- and vaso-modulatory interventions

Currently, most of the basic mechanisms governing tumor-immune system interactions, in combination with modulations of tumor-associated vasculature, are far from being completely understood. Here, we propose a mathematical model of vascularized tumor growth, where the main novelty is the modeling of the interplay between functional tumor vasculature and effector cell recruitment dynamics. Parameters are calibrated on the basis of different in vivo immunocompromised Rag1-/- and wild-type (WT) BALB/c murine tumor growth experiments. The model analysis supports that tumor vasculature normalization can be a plausible and effective strategy to treat cancer when combined with appropriate immuno-stimulations. We find that improved levels of functional tumor vasculature, potentially mediated by normalization or stress alleviation strategies, can provide beneficial outcomes in terms of tumor burden reduction and growth control. Normalization of tumor blood vessels opens a therapeutic window of opportunity to augment the antitumor immune responses, as well as to reduce the intratumoral immunosuppression and induced-hypoxia due to vascular abnormalities. The potential success of normalizing tumor-associated vasculature closely depends on the effector cell recruitment dynamics and tumor sizes. Furthermore, an arbitrary increase of initial effector cell concentration does not necessarily imply a better tumor control. We evidence the existence of an optimal concentration range of effector cells for tumor shrinkage. Based on these findings, we suggest a theory-driven therapeutic proposal that optimally combines immuno- and vaso-modulatory interventions

Irreversible pulmonary changes induced in rat lung by dust overload.

The objective of this study was to investigate whether the effects of dust overload are reversible upon cessation of subchronic exposure to test toner. Female rats were exposed 6 hr/day, 5 days/week for 3 months to a test toner at 0, 10, and 40 mg/m3. The retained quantity of test toner in the lungs at the end of exposure was 0.4 and 3.0 mg for the low and high exposure groups, respectively. Fifteen months later, the corresponding values were 0.12 and 2.65 mg in the lungs. Alveolar clearance of tracer aerosols as well as cytologic and enzymatic parameters in the bronchoalveolar fluid was investigated at the end of exposure and subsequently up to 15 months later. The alveolar clearance of 59Fe2O3, 51Cr-polystyrene, and 85Sr-polystyrene tracer aerosols was slightly retarded at the low and substantially impaired at the high exposure level. At the low exposure level, there was some recovery in the clearance behavior up to 6 months after exposure. In contrast, at the high exposure level there was no indication of a reversal of the impaired clearance. For the beta-glucuronidase activity and the number of polymorphonuclear cells, the pattern of the effects was similar to the effects on the half-time tracer particle clearance. In conclusion, the dust overload at a lung burden of 3 mg test toner in rats was persistent for at least 15 months after termination of exposure

Urinary NMR Profiling in Pediatric Acute Kidney Injury—A Pilot Study

Acute kidney injury (AKI) in critically ill children and adults is associated with significant short- and long-term morbidity and mortality. As serum creatinine- and urine output-based definitions of AKI have relevant limitations, there is a persistent need for better diagnostics of AKI. Nuclear magnetic resonance (NMR) spectroscopy allows for analysis of metabolic profiles without extensive sample manipulations. In the study reported here, we examined the diagnostic accuracy of NMR urine metabolite patterns for the diagnosis of neonatal and pediatric AKI according to the Kidney Disease: Improving Global Outcomes (KDIGO) definition. A cohort of 65 neonatal and pediatric patients (0–18 years) with established AKI of heterogeneous etiology was compared to both a group of apparently healthy children (n = 53) and a group of critically ill children without AKI (n = 31). Multivariate analysis identified a panel of four metabolites that allowed diagnosis of AKI with an area under the receiver operating characteristics curve (AUC-ROC) of 0.95 (95% confidence interval 0.86–1.00). Especially urinary citrate levels were significantly reduced whereas leucine and valine levels were elevated. Metabolomic differentiation of AKI causes appeared promising but these results need to be validated in larger studies. In conclusion, this study shows that NMR spectroscopy yields high diagnostic accuracy for AKI in pediatric patients

Expiratory Muscle Strength Training for Therapy of Pharyngeal Dysphagia in Parkinson's Disease

Background Pharyngeal dysphagia in Parkinson's disease (PD) is a common and clinically relevant symptom associated with poor nutrition intake, reduced quality of life, and aspiration pneumonia. Despite this, effective behavioral treatment approaches are rare. Objective The objective of this study was to verify if 4 week of expiratory muscle strength training can improve pharyngeal dysphagia in the short and long term and is able to induce neuroplastic changes in cortical swallowing processing. Methods In this double-blind, randomized, controlled trial, 50 patients with hypokinetic pharyngeal dysphagia, as confirmed by flexible endoscopic evaluation of swallowing, performed a 4-week expiratory muscle strength training. Twenty-five participants used a calibrated (“active”) device, 25 used a sham handheld device. Swallowing function was evaluated directly before and after the training period, as well as after a period of 3 month using flexible endoscopic evaluation of swallowing. Swallowing-related cortical activation was measured in 22 participants (active:sham; 11:11) using whole-head magnetencephalography. Results The active group showed significant improvement in the flexible endoscopic evaluation of swallowing–based dysphagia score after 4 weeks and after 3 months, whereas in the sham group no significant changes from baseline were observed. Especially, clear reduction in pharyngeal residues was found. Regarding the cortical swallowing network before and after training, no statistically significant differences were found by magnetencephalography examination. Conclusions Four-week expiratory muscle strength training significantly reduces overall dysphagia severity in PD patients, with a sustained effect after 3 months compared with sham training. This was mainly achieved by improving swallowing efficiency. The treatment effect is probably caused by peripheral mechanisms, as no changes in the cortical swallowing network were identified. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Societ

Glycolipids produced by Rouxiella sp. DSM 100043 and isolation of the biosurfactants via foam-fractionation

Additional file 1. Table S1, Figure S1–Figure S3: Mass spectrometry data and plots of purified foam extracts of Rouxiella sp. DSM 100043. Figure S4: Full NMR spectra of Rouxiella sp. DMS 100043 glycolipids present in fractions 64-65