Self-regulatory practices of drivers with Parkinson's disease: Accuracy of patient reports

BackgroundStudies suggest that drivers with Parkinson's disease (PD) are more likely than controls to restrict their exposure and avoid challenging situations possibly to compensate for declining abilities; however it is questionable whether patient reports should be taken at face value. To address this issue, this study examined agreement between self-reported and actual driving practices in drivers with and without PD.MethodsTwo electronic devices (one with GPS) were installed in the vehicles of 26 drivers with PD (mean age 71.5 ± 6.8, 77% men) and 20 controls (mean age 70.6 ± 7.9, 80% men) for two weeks. Participants completed a questionnaire on usual driving patterns, scales on Situational Driving Frequency (SDF) and Avoidance (SDA), the MoCA and an interview.ResultsSelf-estimates of distance driven (km) over the two weeks were inaccurate in both groups; however the tendency to under-estimate was more pronounced in PD drivers. Drivers with PD reported more self-restrictions (higher SDA scores, p < .01; lower SDF scores, p < .05), yet drove more at night, in bad weather, in rush hour and on highways than they reported. Drivers with PD had significantly lower MoCA scores overall (p < .01) and on the memory subtest (p < .05), however, MoCA scores were not correlated with self-reported restrictions, or actual driving distance in either group.ConclusionsThese findings indicate that patient reports of driving behavior should not be taken at face value by researchers or clinicians. Patients with PD may be more likely than drivers in general to have problems with recall and possibly less awareness of their driving practices.     

Characterization of Lung Injury following Abrin Pulmonary Intoxication in Mice: Comparison to Ricin Poisoning

Abrin is a highly toxic protein obtained from the seeds of the rosary pea plant Abrus precatorius, and it is closely related to ricin in terms of its structure and chemical properties. Both toxins inhibit ribosomal function, halt protein synthesis and lead to cellular death. The major clinical manifestations following pulmonary exposure to these toxins consist of severe lung inflammation and consequent respiratory insufficiency. Despite the high similarity between abrin and ricin in terms of disease progression, the ability to protect mice against these toxins by postexposure antibody-mediated treatment differs significantly, with a markedly higher level of protection achieved against abrin intoxication. In this study, we conducted an in-depth comparison between the kinetics of in vivo abrin and ricin intoxication in a murine model. The data demonstrated differential binding of abrin and ricin to the parenchymal cells of the lungs. Accordingly, toxin-mediated injury to the nonhematopoietic compartment was shown to be markedly lower in the case of abrin intoxication. Thus, profiling of alveolar epithelial cells demonstrated that although toxin-induced damage was restricted to alveolar epithelial type II cells following abrin intoxication, as previously reported for ricin, it was less pronounced. Furthermore, unlike following ricin intoxication, no direct damage was detected in the lung endothelial cell population following abrin exposure. Reduced impairment of intercellular junction molecules following abrin intoxication was detected as well. In contrast, similar damage to the endothelial surface glycocalyx layer was observed for the two toxins. We assume that the reduced damage to the lung stroma, which maintains a higher level of tissue integrity following pulmonary exposure to abrin compared to ricin, contributes to the high efficiency of the anti-abrin antibody treatment at late time points after exposure.     

Lipidomic Profiling of Bronchoalveolar Lavage Fluid Extracellular Vesicles Indicates Their Involvement in Lipopolysaccharide-Induced Acute Lung Injury

Emerging data support the pivotal role of extracellular vesicles (EVs) in normal cellular physiology and disease conditions. However, despite their abundance, there is much less information about the lipid mediators carried in EVs, especially in the context of acute lung injury (ALI). Our data demonstrate that C57BL/6 mice subjected to intranasal Escherichia coli lipopolysaccharide (LPS)-induced ALI release, a higher number of EVs into the alveolar space, compared to saline-treated controls. EVs released during ALI originated from alveolar epithelial cells, macrophages, and neutrophils and carry a diverse array of lipid mediators derived from ω-3 and ω-6 polyunsaturated fatty acids (PUFA). The eicosanoids in EVs correlated with cellular levels of arachidonic acid, expression of cytosolic phospholipase A2, cyclooxygenase (COX), lipoxygenase (LOX), and cytochrome epoxygenase p450 proteins in pulmonary macrophages. Furthermore, EVs from LPS-toll-like receptor 4 knockout (TLR4^-/-) mice contained significantly lower amounts of COX and LOX catalyzed eicosanoids and ω-3 PUFA metabolites. More importantly, EVs from LPS-treated wild-type mice increased TNF-α release by macrophages and reduced alveolar epithelial monolayer barrier integrity compared to EVs from LPS-treated TLR4^−/− mice. In summary, our study demonstrates for the first time that the EV carried PUFA metabolite profile in part depends on the inflammatory status of the lung macrophages and modulates pulmonary macrophage and alveolar epithelial cell function during LPS-induced ALI.     

Numerical Simulations Based on a Meshfree Method for Nickel-Steel Welded Joint Manufactured by Micro-Jet Cooling

The article presents a numerical–experimental approach to the weldability and mechanical resistance of the joint of Alloy 59 (2.4605, nickel-chromium-molybdenum) and S355J2W (1.8965) structural steel manufactured by the MIG process with the use of micro-jet cooling. This research was considered because the standard MIG process does not guarantee the procurement of a mixed hard-rusting structural steel superalloy weld of a repeatable and acceptable quality. Welds made through the classic MIG process express cracks that result from their unfavorable metallographic microstructure, while the joint supported by micro-jet cooling does not reflect any cracks and has a high strength with good flexibility. This was achieved by the application of helium for cooling. The joining technology was also considered in the numerical stage, represented by calculations in situ. For this purpose, the fundamental solution method (FSM) for the simulation of heat transfer during the process of welding with micro-jet cooling was implemented according to the initial boundary value problem (IBVP). The problem was solved employing the method of combining the finite difference method, Picard iterations, approximation by the radial basis function, and the fundamental solution method so as to solve the IVBP. The proposed method was validated by the data and results obtained during in situ experiments. The numerical approach enabled us to obtain variations in the temperature distribution values in HAZ with its different dimensional variants, ranging between 600 °C and 1400 °C.     

Selected Properties of Single and Multi-Layered Particleboards with the Structure Modified by Fibers Implication

One of the ways of potential improvement of the particleboard properties, especially surface quality, can be the incorporation of wood fibers to face layers. This study aimed to evaluate the selected mechanical and physical parameters of single and multi-layered particleboards with the structure modified by the incorporation of various types and amounts of wood fibers. Single, 3- and 5-layers particleboards were produced with two different types of wood fibers added to the face and core layers. The basic mechanical parameters (modulus of rupture, modulus of elasticity, internal bond, surface soundness), as well as density profile and surface roughness, have been investigated. The results have shown that the single-layer panels with fibers did not meet the standard requirements due to unsatisfactory unstable parameters, probably caused by uneven resination. The remaining panels, 3- and 5-layer, met the standard requirements, and, due to fiber incorporation, there is also potential to reduce the panel density, still meeting standard requirements. The addition of fibers from 0% to 75% in face layers leads to an increase in the modulus of rupture from 10.6 N mm⁻² to 15.6 N mm⁻². Depending on the fibers’ type, the surface soundness can vary between 0.7 N mm⁻² and 1.2 N mm⁻². Five-layer panels were of similar or even higher parameters, but due to much-complicated technology, it seems unreasonable to develop this type of composite. The novelty of the conducted research is the attempt to modify the structure of particleboards by adding various amounts of two different types of fibers by mixing them with particles or adding them as separate layers and producing panels of different densities.     

Enzobiotics—A Novel Therapy for the Elimination of Uremic Toxins in Patients with CKD (EETOX Study): A Multicenter Double-Blind Randomized Controlled Trial

Design, participants, setting, and measurements: Predialysis adult participants with chronic kidney disease (CKD) and mean estimated glomerular filtration rate (eGFR) <45 mL/min per 1.73 m²) were recruited in 2019 to a multicentric double-blinded randomized controlled trial of enzobiotic therapy (synbiotics and proteolytic enzymes) conducted over 12 weeks. The primary objective was to evaluate the efficacy and safety of enzobiotics in reducing the generation of p-cresol sulfate (PCS) and indoxyl sulfate (IS), stabilizing renal function, and improving quality of life (QoL), while the secondary objective was to evaluate the feasibility of the diagnostic prediction of IS and PCS from CKD parameters. Results: Of the 85 patients randomized (age 48.76 years, mean eGFR 23.24 mL/min per 1.73 m² in the placebo group; age 54.03 years, eGFR 28.93 mL/min per 1.73 m² in the enzobiotic group), 50 completed the study. The absolute mean value of PCS increased by 12% from 19 µg/mL (Day 0) to 21 µg/mL (Day90) for the placebo group, whereas it decreased by 31% from 23 µg/mL (Day 0) to 16 µg/mL (Day 90) for the enzobiotic group. For IS, the enzobiotic group showed a decrease (6.7%) from 11,668 to 10,888 ng/mL, whereas the placebo group showed an increase (8.8%) from 11,462 to 12,466 ng/mL (Day 90). Each patient improvement ratio for Day 90/Day 0 analysis showed that enzobiotics reduced PCS by 23% (0.77, p = 0.01). IS levels remained unchanged. In the placebo group, PCS increased by 27% (1.27, p = 0.14) and IS increased by 20% (1.20, p = 0.14). The proportion of individuals beyond the risk threshold for PCS (>20 µg/mL) was 53% for the placebo group and 32% for the enzobiotic group. The corresponding levels for IS risk (threshold >20,000 ng/mL) were 35% and 24% for the placebo and enzobiotic groups, respectively. In the placebo group, eGFR decreased by 7% (Day 90) but remained stable (1.00) in the enzobiotic group. QoL as assessed by the adversity ratio decreased significantly (p = 0.00), highlighting an improvement in the enzobiotic group compared to the placebo group. The predictive equations were as follows: PCS (Day 0 = −5.97 + 0.0453 PC + 2.987 UA − 1.310 Creat; IS (Day 0) = 756 + 1143 Creat + 436.0 Creat². Conclusion: Enzobiotics significantly reduced the PCS and IS, as well as improved the QoL.     

Impact of Fruit and Vegetable Protein vs. Milk Protein on Metabolic Control of Children with Phenylketonuria: A Randomized Crossover Controlled Trial

Fruits and vegetables containing phenylalanine ≤ 75 mg/100 g (except potatoes) have little impact on blood phenylalanine in phenylketonuria (PKU). In a randomized, controlled, crossover intervention trial, we examined the effect of increasing phenylalanine intake from fruits and vegetables, containing phenylalanine 76–100 mg /100 g, compared with milk protein sources on blood phenylalanine control. This was a five-phase study (4 weeks each phase). In Phase A, patients remained on their usual diet and then were randomly allocated to start Phase B and C (an additional phenylalanine intake of 50 mg/day, then 100 mg from fruits and vegetables containing phenylalanine 76–100 mg/100 g) or Phase D and E (an additional phenylalanine intake of 50 mg/day then 100 mg/day from milk sources). There was a 7-day washout with the usual phenylalanine-restricted diet between Phase B/C and D/E. Blood phenylalanine was measured on the last 3 days of each week. If four out of six consecutive blood phenylalanine levels were >360 μmol/L in one arm, this intervention was stopped. Sixteen patients (median age 10.5 y; range 6–12 y) were recruited. At baseline, a median of 6 g/day (range: 3–25) natural protein and 60 g/day (range: 60–80) protein equivalent from protein substitute were prescribed. Median phenylalanine levels were: Phase A—240 μmol/L; Phase B—260 μmol/L; Phase C—280 μmol/L; Phase D—270 μmol/L and Phase E—280 μmol/L. All patients tolerated an extra 50 mg/day of phenylalanine from fruit and vegetables, containing phenylalanine 76–100 mg/100 g, but only 11/16 (69%) tolerated an additional 100 mg /day. With milk protein, only 8/16 (50%) tolerated an extra 50 mg/day and only 5/16 (31%) tolerated an additional 100 mg/day of phenylalanine. Tolerance was defined as maintaining consistent blood phenylalanine levels < 360 μmol/L throughout each study arm. There was a trend that vegetable protein had less impact on blood phenylalanine control than milk protein, but overall, the differences were not statistically significant (p = 0.152). This evidence supports the PKU European Guidelines cutoff that fruit and vegetables containing 76–100 mg phenylalanine/100 g should be calculated as part of the phenylalanine exchange system. Tolerance of the ‘free use’ of these fruits and vegetables depends on inter-patient variability but cannot be recommended for all patients with PKU.     

Molecular ontogeny of donor-derived follicular lymphomas occurring after hematopoietic cell transplantation

The relative timing of genetic alterations that contribute to follicular lymphoma remains unknown. We analyzed a donor-recipient pair who both developed grade 2/3A follicular lymphoma 7 years after allogeneic transplantation and donor lymphocyte infusions. Both patients harbored identical BCL2/IGH rearrangements also present in 1 in 2,000 cells in the donor lymphocyte infusion, and the same V(D)J rearrangement, which underwent somatic hypermutation both before and after clonal divergence. Exome sequencing of both follicular lymphomas identified 15 shared mutations, of which 14 (including alterations in EP300 and KLHL6) were recovered from the donor lymphocyte infusion by ultra-deep sequencing (average read coverage, 361,723), indicating acquisition at least 7 years before clinical presentation. Six additional mutations were present in only one follicular lymphoma and not the donor lymphocyte infusion, including an ARID1A premature stop, indicating later acquisition during clonal divergence. Thus, ultrasensitive sequencing can map clonal evolution within rare subpopulations during human lymphomagenesis in vivo. SIGNIFICANCE: For the first time, we define the molecular ontogeny of follicular lymphoma during clonal evolution in vivo. By using ultrasensitive mutation detection, we mapped the time-course of somatic alterations after passage of a malignant ancestor by hematopoietic cell transplantation.