Study protocol of the GRoningen early-PD Ambroxol treatment (GREAT) trial: a randomized, double-blind, placebo-controlled, single center trial with ambroxol in Parkinson patients with a GBA mutation.

BACKGROUND: To date, no disease modifying therapies are available for Parkinson's disease (PD). Since PD is the second most prevalent neurodegenerative disorder, there is a high demand for such therapies. Both environmental and genetic risk factors play an important role in the etiology and progression of PD. The most common genetic risk factor for PD is a mutation in the GBA1(GBA)-gene, encoding the lysosomal enzyme glucocerebrosidase (GCase). The mucolytic ambroxol is a repurposed drug, which has shown the property to upregulate GCase activity in-vitro and in-vivo. Ambroxol therefore has the potency to become a disease modifying therapy in PD, which was the reason to design this randomized controlled trial with ambroxol in PD patients. METHODS: This trial is a single-center, double-blind, randomized, placebo-controlled study, including 80 PD patients with a GBA mutation, receiving either ambroxol 1800 mg/day or placebo for 48 weeks. The primary outcome measure is the Unified Parkinson's Disease Rating Scale motor subscore (part III) of the Movement Disorder Society (MDS-UPDRSIII) in the practically defined off-state at 60 weeks (after a 12-week washout period). Secondary outcomes include a 3,4-dihydroxy-6-18F-fluoro-I-phenylalanine ([18F]FDOPA) PET-scan of the brain, Magnetic Resonance Imaging (with resting state f-MRI and Diffusion Tensor Imaging), GCase activity, both intra- and extracellularly, sphingolipid profiles in plasma, Montreal Cognitive Assessment (MoCA), quality of life (QoL) measured by the Parkinson's Disease Questionnaire (PDQ-39) and the Non-Motor Symptom Scale (NMSS) questionnaire. DISCUSSION: Ambroxol up to 1200 mg/day has shown effects on human cerebrospinal fluid endpoints, which supports at least passage of the blood-brain-barrier. The dose titration in this trial up to 1800 mg/day will reveal if this dose level is safe and also effective in modifying the course of the disease. TRIAL REGISTRATION: NCT05830396. Registration date: March 20, 2023.

The impact of particle filtration on indoor air quality in a classroom near a highway.

A pilot study was performed to investigate whether the application of a new mechanical ventilation system with a fine F8 (MERV14) filter could improve indoor air quality in a high school near the Amsterdam ring road. PM10, PM2.5, and black carbon (BC) concentrations were measured continuously inside an occupied intervention classroom and outside the school during three sampling periods in the winter of 2013/2014. Initially, 3 weeks of baseline measurements were performed, with the existing ventilation system and normal ventilation habits. Next, an intervention study was performed. A new ventilation system was installed in the classroom, and measurements were performed during 8 school weeks, in alternating 2-week periods with and without the filter in the ventilation system under otherwise identical ventilation conditions. Indoor/outdoor ratios measured during the weeks with filter were compared with those measured without filter to evaluate the ability of the F8 filter to improve indoor air quality. During teaching hours, the filter reduced BC exposure by, on average, 36%. For PM10 and PM2.5, a reduction of 34% and 30% was found, respectively. This implies that application of a fine filter can reduce the exposure of schoolchildren to traffic exhaust at hot spot locations by about one-third.

Transcription-dependent redistribution of the large subunit of RNA polymerase II to discrete nuclear domains.

A subpopulation of the largest subunit of RNA polymerase II (Pol II LS) is located in 20-50 discrete subnuclear domains that are closely linked to speckle domains, which store splicing proteins. The speckle-associated fraction of Pol II LS is hyperphosphorylated on the COOH-terminal domain (CTD), and it is highly resistant to extraction by detergents. A diffuse nucleoplasmic fraction of Pol II LS is relatively hypophosphorylated on the CTD, and it is easily extracted by detergents. In transcriptionally active nuclei, speckle bound hyperphosphorylated Pol II LS molecules are distributed in irregularly shaped speckle domains, which appear to be interconnected via a reticular network. When transcription is inhibited, hyperphosphorylated Pol II LS and splicing protein SC35 accumulate in speckle domains, which are transformed into enlarged, dot-like structures lacking interconnections. When cells are released from transcriptional inhibition, Pol IIO and SC35 redistribute back to the interconnected speckle pattern of transcriptionally active cells. The redistribution of Pol II and SC35 is synchronous, reversible, and temperature dependent. It is concluded that: (a) hyperphosphorylation of Pol II LS's CTD is a better indicator of its tight association to discrete subnuclear domains than its transcriptional activity; (b) during states of transcriptional inhibition, hyperphosphorylated Pol II LS can be stored in enlarged speckle domains, which under the light microscope appear to coincide with the storage sites for splicing proteins; and (c) Pol II and splicing proteins redistribute simultaneously according to the overall transcriptional activity of the nucleus.

[Cardiovascular disease and chronic kidney disease: from treatment to promoting health]. / Enfermedades cardiovasculares y nefropatía crónica: del tratamiento al fomento de la salud.

Chronic kidney disease is associated with poor cardiovascular outcomes and should be screened for in all patients with cardiovascular disease or risk factors such as hypertension and diabetes mellitus using estimate of glomerular filtration rate and a random urine albumin-to creatinine ratio. Strategies to identify and prevent chronic kidney disease must be part of a comprehensive program of disease prevention, that include evaluation of tobacco use, diet and exercise patterns, body mass index, blood pressure, lipid profile, blood glucose and patient-appropriate cancer screening. The global increase in patients with chronic kidney disease is threatening to reach epidemic proportions over the next decade, and few countries will be able to meet the economic challenges posed. A change in global approach from treatment of renal failure to aggressive primary and secondary prevention is essential. We propose that the United Nations Millennium Developments Goals for 2000-2015 should be expanded to include combatting infectious diseases as well as chronic diseases such as cardiovascular disease, diabetes, renal disease and cancer, using an integrated approach.

Climatic controls of ecohydrological responses in the highlands of northern Ethiopia.

Climate variability and recurrent droughts have a strong negative impact on agricultural production and hydrology in the highlands northern Ethiopia. Since the 1980s, numerous mitigation and land rehabilitation measures have been implemented by local and national authorities to reduce these impacts, are often poorly effective. As underlying reason may be that controlling relationships between climate and ecohydrology at medium-sized catchments (10-10,000km2) of semi-arid highlands are not well known. We investigated trends and relationships in precipitation, temperature, streamflow, and net primary productivity (NPP). The results were mixed, with both significant increasing and decreasing trends for temperature and streamflow. Precipitation time series did not show a significant trend for the majority of stations, both over the years and over each season, except for a few stations. A time series indicated a significant abrupt increase of NPP in annual, seasonal and monthly timescale. Cross-correlation and regression analysis indicate precipitation and maximum temperature were the dominant climatic variables in the Geba catchment for streamflow and NPP. In view of these results, also land use and land cover change over the past three decades was analysed as a possible factor of importance, as human intervention, may affect streamflow and NPP. Factors that mainly correlate with streamflow and NPP are precipitation and maximum temperature. Important interventions that appear beneficial for these responses are construction of micro-dams, soil and water conservation and ecological restoration measures. The awareness that interactions can be quite different in semi-arid and semi-humid regions, as well as in upstream and downstream areas, should be reflected in management aimed at sustainable water and land resources use.

Cadmium re-distribution from pod and root zones and accumulation by peanut (Arachis hypogaea L.).

Peanut (Arachis hypogaea L.) genotypes may differ greatly with regard to cadmium (Cd) accumulation, but the underlying mechanisms remain unclear. To determine the key factors that may contribute to Cd re-distribution and accumulation in peanut genotypes with different Cd accumulating patterns, a split-pot soil experiment was conducted with three common Chinese peanut cultivars (Fenghua-6, Huayu-20, and Huayu-23). The growth medium was separated into pod and root zones with varied Cd concentrations in each zone to determine the re-distribution of Cd after it is taken up via different routes. The peanut cultivars were divided into two groups based on Cd translocation efficiency as follows: (1) high internal Cd translocation efficiency cultivar (Fenghua-6) and (2) low internal Cd translocation efficiency cultivars (Huayu-20 and Huayu-23). Compared with Fenghua-6, low Cd translocation cultivars Huayu-20 and Huayu-23 showed higher biomass production, especially in stems and leaves, leading to dilution of metal concentrations. Results also showed that Cd concentration in roots increased significantly with increasing Cd concentrations in soils when Cd was applied in the root zone. However, there were no significant differences in the root Cd concentrations between different pod zone Cd treatments and the control, suggesting that root uptake, rather than pod uptake, is responsible for Cd accumulation in the roots of peanuts. Significant differences of Cd distribution were observed between pod and root zone Cd exposure treatments. The three peanut cultivars revealed higher kernel over total Cd fractions for pod than for root zone Cd exposure if only extra applied Cd was considered. This suggests that uptake through peg and pod shell might, at least partially, be responsible for the variation in Cd re-distribution and accumulation among peanut cultivars. Cd uptake by plants via two routes (i.e., via roots and via pegs and pods, respectively) and internal Cd translocation appear to be important mechanisms in determining Cd accumulation in the kernels of peanuts.

Heavy metal concentrations in soil and earthworms in a floodplain grassland.

We determined accumulated heavy metal concentrations (Cd, Pb, Cu, Zn) of earthworms in moderately contaminated floodplain soils. Both soil and mature earthworms were sampled before and after flooding and earthworm species were identified to understand species specific differences in bioconcentration. Accumulated metal concentrations in floodplain earthworms differed before and after flooding. Differences in uptake and elimination mechanisms, in food choice and living habitat of the different earthworm species and changes in speciation of the heavy metals are possible causes for this observation. Regression equations taken from literature, that relate metal accumulation by earthworms in floodplains as a function of metal concentration in soil, performed well when all species specific data were combined in an average accumulation, but did not address differences in accumulation between earthworm species.

Low-Resolution Modeling of Dense Drainage Networks in Confining Layers.

Groundwater-surface water (GW-SW) interaction in numerical groundwater flow models is generally simulated using a Cauchy boundary condition, which relates the flow between the surface water and the groundwater to the product of the head difference between the node and the surface water level, and a coefficient, often referred to as the "conductance." Previous studies have shown that in models with a low grid resolution, the resistance to GW-SW interaction below the surface water bed should often be accounted for in the parameterization of the conductance, in addition to the resistance across the surface water bed. Three conductance expressions that take this resistance into account were investigated: two that were presented by Mehl and Hill (2010) and the one that was presented by De Lange (1999). Their accuracy in low-resolution models regarding salt and water fluxes to a dense drainage network in a confined aquifer system was determined. For a wide range of hydrogeological conditions, the influence of (1) variable groundwater density; (2) vertical grid discretization; and (3) simulation of both ditches and tile drains in a single model cell was investigated. The results indicate that the conductance expression of De Lange (1999) should be used in similar hydrogeological conditions as considered in this paper, as it is better taking into account the resistance to flow below the surface water bed. For the cases that were considered, the influence of variable groundwater density and vertical grid discretization on the accuracy of the conductance expression of De Lange (1999) is small.

Indicators of the sustainability of heavy-metal management in agro-ecosystems.

The aim of sustainable heavy-metal management in agro-ecosystems is to ensure that the soil continues to fulfil its function in agricultural production, in environmental processes such as the cycling of elements, and as a habitat of numerous organisms. Assessment of sustainability has to be carried out in time, since metal accumulation in soil is largely irreversible and may cause problems if certain concentration levels are exceeded. In this study, we provide a concept to assess the sustainability of current metal cycles in agro-ecosystems based on dynamic heavy-metal balances for the plough layer. After presenting some general aspects of dynamic metal balances, we introduce 'sustainability indices'. These characteristic numbers can be used as indicators for potentially adverse effects of current agricultural practices, since they account for (ecotoxicologically founded) soil quality standards and for quality standards for produce, groundwater and surface water. They can also be used to assess the effects of different management options that aim to prevent quality standards from being exceeded as they provide insight in the dynamics governing input-output relationships. This is illustrated with a case study on heavy-metal flows in different arable farming systems.

Cu accumulation in the earthworm Dendrobaena veneta in a heavy metal (Cu, Pb, Zn) contaminated site compared to Cu accumulation in laboratory experiments.

Earthworms (Dendrobaena veneta) were exposed to heavy metal contaminated soil from a field site under both laboratory and field conditions. In the laboratory study, D. veneta were analysed for Cu after 2 weeks' exposure. The tissue Cu concentration (Cu(W)) increased proportionally with the total extractable soil Cu content (Cu(T)) in soils that contained less than 150 mg Cu kg(-1). In D. veneta exposed to soils containing more than Cu(T) = 150 mg kg(-1), however, we observed no further increase in Cu(W). In a 64-m(2) field plot at a contaminated site, 81 soil samples were taken and analysed for Cu, Pb, Zn and pH. In June 1994, 1000 D. veneta were homogeneously distributed in the plot and sampled after 1, 2 and 5 weeks to analyse for Cu. Additionally, 2000 D. veneta were introduced in September 1994 and sampled after 1, 2 and 4 weeks. At locations where earthworms were removed, the soil Cu content was estimated by disjunctive kriging. Cu concentration factors (ratio of Cu(W) to Cu(T)) in the field experiment were in excellent agreement with those of the laboratory experiment. This indicates that, with a sufficiently high sampling density, it may be feasible to predict earthworm Cu accumulation in the field using a concentration factor determined in the laboratory.

A stochastic empirical model for regional heavy-metal balances in agroecosystems.

Mass flux balancing provides essential information for preventive strategies against heavy-metal accumulation in agricultural soils that may result from atmospheric deposition and application of fertilizers and pesticides. In this paper we present the empirical stochastic balance model, PROTERRA-S, that estimates heavy-metal and phosphorus accumulation in agricultural soils on the regional level. The basic units of these balances are land use systems defined by livestock production and cultivated crops. The model is designed to use available databases, such as regional agricultural statistics and soil information systems. In a case study, we assessed the phosphorus, cadmium, and zinc balances for the Sundgau region, Switzerland. The regional P requirements of crops were mainly supplied by animal manure (56%) and commercial fertilizers (40%). Net cadmium fluxes of the land use systems ranged from 1.0 g ha(-1) yr(-1) (dairy and mixed farm types) to 17.8 g ha(-1) yr(-1) (animal husbandry systems), whereas the regional net cadmium flux was only 1.4 g ha(-1) yr(-1). The regional net zinc flux was 605 g ha(-1) yr(-1). The smallest net zinc flux of 101 g ha(-1) yr(-1) was found for an arable farm type, whereas for animal husbandry systems fluxes up to 39.8 kg ha(-1) yr(-1) were estimated. Comparison of model results with reported metal balances of experimental farms shows that identification of agricultural land with high risks of heavy-metal accumulation benefits from stratification of heavy-metal balances according to land use systems while accounting for their P fertilization plans. Consequently, the model may support sustainable management of heavy-metal cycles in agricultural soils.

A set of constitutive relationships accounting for residual NAPL in the unsaturated zone.

Although laboratory experiments show that non-aqueous phase liquid (NAPL) is retained in the unsaturated zone, no existing multiphase flow model has been developed to account for residual NAPL after NAPL drainage in the unsaturated zone. We developed a static constitutive set of saturation-capillary pressure relationships for water, NAPL and air that accounts for both this residual NAPL and entrapped NAPL. The set of constitutive relationships is formulated similarly to the set of scaled relationships that is frequently applied in continuum models. The new set consists of three fluid-phase systems: a three-phase system and a two-phase system, that both comply with the original constitutive model, and a newly introduced residual NAPL system. The new system can be added relatively easily to the original two- and three-phase systems. Entrapment is included in the model. The constitutive relationships of the non-drainable residual NAPL system are based on qualitative fluid behavior derived from a pore scale model. The pore scale model reveals that the amount of residual NAPL depends on the spreading coefficient and the water saturation. Furthermore, residual NAPL is history-dependent. At the continuum scale, a critical NAPL pressure head defines the transition from free, mobile NAPL to residual NAPL. Although the Pc-S relationships for water and total liquid are not independent in case of residual NAPL, two two-phase Pc-S relations can represent a three-phase residual system of Pc-S relations. A newly introduced parameter, referred to as the residual oil pressure head, reflects the mutual dependency of water and oil. Example calculations show consistent behavior of the constitutive model. Entrapment and retention in the unsaturated zone cooperate to retain NAPL. Moreover, the results of our constitutive model are in agreement with experimental observations.

Transport and degradation of propyleneglycol and potassium acetate in the unsaturated zone.

De-icing chemicals used during the winter season are potential pollutants for the groundwater underneath the new main airport of Norway. Several field experiments examining the transport and degradation of propyleneglycol (PG), potassium acetate (KAc) and non-reactive tracers were performed in a lysimeter trench under natural snowmelting conditions. Chemicals were applied underneath the snow cover and the transport in a heterogeneous coarse sandy soil was examined by extracting soil water from 30 or 40 suction cups placed at five depths between 0.4 and 2.4 m depth. Transport and degradation was analysed by spatial moment calculations. The de-icing chemicals showed the same basic displacement as chemically inactive tracers, an initial fast transport during the melting period followed by a period of stagnation throughout the summer season. PG seemed to be displaced to greater depths compared to non-reactive tracer after the first application. However, computer simulations of transport and degradation in a heterogeneous unsaturated soil showed that decreasing degradation constants with depth can generate a downward movement of the centre of mass without any flow occurring in the system. Potassium acetate showed some adsorption, with calculated retardation factors of approximately 1.3 and 1.2. The degradation rate constant for PG was calculated to be 0.015 day-1 in 1994 and increased to 0.047 day-1 in the second application made in 1995. The degradation rate constant for acetate was estimated to be 0.02 day-1. Increased manganese concentrations seem to be a good indicator of degradation of PG and Ac.

Infiltration and redistribution of LNAPL into unsaturated layered porous media.

Enhanced understanding of light non-aqueous phase liquid (LNAPL) infiltration into heterogeneous porous media is important for the effective design of remediation strategies. We used a 2-D experimental facility that allows for visual observation of LNAPL contours in order to study LNAPL redistribution in a layered porous medium. The layers are situated in the unsaturated zone near the watertable and they are inclined to be able to observe the effect of discontinuities in capillary forces and relative permeabilities. Two experiments were performed. The first experiment consisted of LNAPL infiltration into a fine sand matrix with a coarse sand layer, and the second experiment consisted of a coarse sand matrix and a fine sand layer. The numerical multi-phase flow model STOMP was validated with regard to the experimental results. This model is able to adequately reproduce the experimental LNAPL contours. Numerical sensitivity analysis was also performed. The capillarity contrast between sands was found to be the main controlling factor determining the final LNAPL distribution.

[Isovaleric acidemia: identical biochemical picture in 3 patients with variable clinical manifestations]. / Isovaleriaanzuur-acidemie: identiek biochemisch beeld bij drie patiënten met uiteenlopende klinische verschijnselen.

Three patients are described with different forms of isovaleric acidemia: a girl with the neonatal form and two brothers with an intermittent form. In all three patients the biochemical aspects are identical: Considerable amounts of metabolites of isovaleric acid, especially isovalerylglycine, are secreted with the urine. In the patients' cultured fibroblasts leucine oxydation is greatly depressed. The clinical presentation of the younger brother prompted to a direct search for a metabolic defect. After diagnosing an isovaleric acidemia in the younger brother, investigations on the presence of the same defect were performed in the elder brother too, though he did not show clinical symptoms. As a result, also isovaleric acidemia was found. It is concluded that sibs of patients with a proven inborn error of metabolism have to be studied too for the presence of the same defect. In all patients, especially in the girl with the neonatal form of isovaleric acidemia diet therapy had a beneficial effect on the further course of the disease.

Transport and degradation of propylene glycol in the vadose zone: model development and sensitivity analysis.

Transport and degradation of de-icing chemical (containing propylene glycol, PG) in the vadose zone were studied with a lysimeter experiment and a model, in which transient water flow, kinetic degradation of PG and soil chemistry were combined. The lysimeter experiment indicated that aerobic as well as anaerobic degradation occurs in the vadose zone. Therefore, the model included both types of degradation, which was made possible by assuming advection-controlled (mobile) and diffusion-controlled (immobile) zones. In the mobile zone, oxygen can be transported by diffusion in the gas phase. The immobile zone is always water-saturated, and oxygen only diffuses slowly in the water phase. Therefore, the model is designed in a way that the redox potential can decrease when PG is degraded, and thus, anaerobic degradation can occur. In our model, manganese oxide (MnO2, which is present in the soil) and NO3- (applied to enhance biodegradation) can be used as electron acceptors for anaerobic degradation. The application of NO3- does not result in a lower leaching of PG nor in a slower depletion of MnO2. The thickness of the snowcover influences the leached fraction of PG, as with a high infiltration rate, transport is fast, there is less time for degradation and thus more PG will leach. The model showed that, in this soil, the effect of the water flow dominates over the effect of the degradation parameters on the leaching at a 1-m depth.

Comparative performance of gene-based warfarin dosing algorithms in a multiethnic population.

SUMMARY BACKGROUND: Gene-based warfarin dosing algorithms have largely been developed in homogeneous populations, and their generalizability has not been established. OBJECTIVES: We sought to assess the performance of published algorithms in a racially diverse and multiethnic sample, and determine if additional clinical variables or genetic variants associated with dose could enhance algorithm performance. PATIENTS AND METHODS: In 145 compliant patients on warfarin with a goal international normalized ratio (INR) of 2-3, stable, therapeutic doses were compared with predicted doses using 12 reported algorithms that incorporated CYP2C9 and VKORC1 variants. Additional covariates tested with each model included race, concurrent medications, medications known to interact with warfarin and previously described CYP4F2, CALU and GGCX variants. RESULTS: The mean patient age was 67 +/- 14 years; 90 (62%) were male. Eighty-two (57%) were Caucasian, 28 (19%) African-American, 20 (14%) Hispanic and 15 (10%) Asian. The median warfarin dose was 35 mg per week (interquartile range 23-53 mg per week). Gene-based dosing algorithms explained 37-55% of the variation in warfarin dose requirements. Neither the addition of race, number of concurrent medications nor the number of concurrent medications interacting with warfarin enhanced algorithm performance. Similarly, consideration of CYP4F2, CALU or GGCX variant genotypes did not improve algorithms. CONCLUSIONS: Existing gene-based dosing algorithms explained between approximately one-third and one-half of the variability in warfarin dose requirements in this racially and ethnically diverse cohort. Additional clinical and recently described genetic variants associated with warfarin dose did not enhance prediction in our patient population.

Vasopressin administration facilitates fluid removal during hemodialysis.

Inadequate secretion of vasopressin during fluid removal by hemodialysis may contribute to the cardiovascular instability that complicates this therapy and administration of exogenous hormone, by supporting arterial pressure, may facilitate volume removal. To test this, we measured plasma vasopressin in patients with end-stage renal disease (ESRD) during hemodialysis and found that despite significant fluid removal, plasma vasopressin concentration did not increase. We further found that ESRD did not alter the endogenous removal rate of plasma vasopressin and that plasma hormone is not dialyzed. Finally, in a randomized, double-blinded, placebo-controlled trial in 22 hypertensive patients, we examined the effect of a constant infusion of a non-pressor dose of vasopressin on the arterial pressure response during a hemodialysis in which the target fluid loss was increased by 0.5 kg over the baseline prescription. We found that arterial pressure was more stable in the patients receiving vasopressin and that while only one patient (9%) in the vasopressin group had a symptomatic hypotensive episode, 64% of the patients receiving placebo had such an episode (P=0.024). Moreover, increased fluid removal was achieved only in the vasopressin group (520+/-90 ml vs 64+/-130 ml, P=0.01). Thus, administration of non-pressor doses of vasopressin to hypertensive subjects improves cardiovascular stability during hemodialysis and allows increased removal of excess extracellular fluid. Inadequate vasopressin secretion during hemodialysis-induced fluid removal is a likely contributor to the intradialytic hypotension that limits fluid removal.