Real-world evidence of ocrelizumab-treated relapsing multiple sclerosis cohort shows changes in progression independent of relapse activity mirroring phase 3 trials.

Ocrelizumab is a B cell-depleting drug widely used in relapsing-remitting multiple sclerosis (RRMS) and primary-progressive MS. In RRMS, it is becoming increasingly apparent that accumulation of disability not only manifests as relapse-associated worsening (RAW) but also as progression independent of relapse activity (PIRA) throughout the disease course. This study's objective was to investigate the role of PIRA in RRMS patients treated with ocrelizumab. We performed a single-center, retrospective, cross-sectional study of clinical data acquired at a German tertiary multiple sclerosis referral center from 2018 to 2022. All patients with RRMS treated with ocrelizumab for at least six months and complete datasets were analyzed. Confirmed disability accumulation (CDA) was defined as a ≥ 12-week confirmed increase from the previous expanded disability status scale (EDSS) score of ≥ 1.0 if the previous EDSS was ≤ 5.5 or a ≥ 0.5-point increase if the previous EDSS was > 5.5. PIRA was defined as CDA without relapse since the last EDSS measurement and at least for the preceding 12 weeks. RAW was defined as CDA in an interval of EDSS measurements with ≥ 1 relapses. Cox proportional hazard models were used to analyze the probability of developing PIRA depending on various factors, including disease duration, previous disease-modifying treatments (DMTs), and optical coherence tomography-assessed retinal degeneration parameters. 97 patients were included in the analysis. Mean follow-up time was 29 months (range 6 to 51 months). 23.5% developed CDA under ocrelizumab therapy (n = 23). Of those, the majority developed PIRA (87.0% of CDA, n = 20) rather than RAW (13.0% of CDA, n = 3). An exploratory investigation using Cox proportional hazards ratios revealed two possible factors associated with an increased probability of developing PIRA: a shorter disease duration prior to ocrelizumab (p = 0.02) and a lower number of previous DMTs prior to ocrelizumab (p = 0.04). Our data show that in ocrelizumab-treated RRMS patients, the main driver of disability accumulation is PIRA rather than RAW. Furthermore, these real-world data show remarkable consistency with data from phase 3 randomized controlled trials of ocrelizumab in RRMS, which may increase confidence in translating results from tightly controlled RCTs into the real-world clinical setting.

Dual roles of the adenosine A2a receptor in autoimmune neuroinflammation.

BACKGROUND: Conditions of inflammatory tissue distress are associated with high extracellular levels of adenosine, due to increased adenosine triphosphate (ATP) degradation upon cellular stress or the release of extracellular ATP upon cell death, which can be degraded to adenosine by membrane-bound ecto-enzymes like CD39 and CD73. Adenosine is recognised to mediate anti-inflammatory effects via the adenosine A2a receptor (A2aR), as shown in experimental models of arthritis. Here, using pharmacological interventions and genetic inactivation, we investigated the roles of A2aR in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). METHODS: We used two independent mouse EAE variants, i.e. active immunization in C57BL/6 with myelin oligodendrocyte glycoprotein (MOG)35-55 or transfer-EAE by proteolipid protein (PLP)139-155-stimulated T lymphocytes and EAE in mice treated with A2aR-agonist CGS21680 at different stages of disease course and in mice lacking A2aR (A2aR(-/-)) compared to direct wild-type littermates. In EAE, we analysed myelin-specific proliferation and cytokine synthesis ex vivo, as well as inflammation and demyelination by immunohistochemistry. In vitro, we investigated the effect of A2aR on migration of CD4(+) T cells, macrophages and microglia, as well as the impact of A2aR on phagocytosis of macrophages and microglia. Statistical tests were Mann-Whitney U and Student's t test. RESULTS: We found an upregulation of A2aR in the central nervous system (CNS) in EAE, predominantly detected on T cells and macrophages/microglia within the inflamed tissue. Preventive EAE treatment with A2aR-specific agonist inhibited myelin-specific T cell proliferation ex vivo and ameliorated disease, while application of the same agonist after disease onset exacerbated non-remitting EAE progression and resulted in more severe tissue destruction. Accordingly, A2aR-deficient mice showed accelerated and exacerbated disease manifestation with increased frequencies of IFN-γ-, IL-17- and GM-CSF-producing CD4(+) T helper cells and higher numbers of inflammatory lesions in the early stage. However, EAE quickly ameliorated and myelin debris accumulation was lower in A2aR(-/-) mice. In vitro, activation of A2aR inhibited phagocytosis of myelin by macrophages and primary microglia as well as migration of CD4(+) T cells, macrophages and primary microglia. CONCLUSIONS: A2aR activation exerts a complex pattern in chronic autoimmune neurodegeneration: while providing anti-inflammatory effects on T cells and thus protection at early stages, A2aR seems to play a detrimental role during later stages of disease and may thus contribute to sustained tissue damage within the inflamed CNS.

Non-hazardous pesticide concentrations in surface waters: An integrated approach simulating application thresholds and resulting farm income effects.

Pesticide application rates are high and increasing in upland agricultural systems in Thailand producing vegetables, fruits and ornamental crops, leading to the pollution of stream water with pesticide residues. The objective of this study was to determine the maximum per hectare application rates of two widely used pesticides that would achieve non-hazardous pesticide concentrations in the stream water and to evaluate how farm household incomes would be affected if farmers complied with these restricted application rates. For this purpose we perform an integrated modeling approach of a hydrological solute transport model (the Soil and Water Assessment Tool, SWAT) and an agent-based farm decision model (Mathematical Programming-based Multi-Agent Systems, MPMAS). SWAT was used to simulate the pesticide fate and behavior. The model was calibrated to a 77 km(2) watershed in northern Thailand. The results show that to stay under a pre-defined eco-toxicological threshold, the current average application of chlorothalonil (0.80 kg/ha) and cypermethrin (0.53 kg/ha) would have to be reduced by 80% and 99%, respectively. The income effect of such reductions was simulated using MPMAS. The results suggest that if farm households complied with the application thresholds then their income would reduce by 17.3% in the case of chlorothalonil and by 38.3% in the case of cypermethrin. Less drastic income effects can be expected if methods of integrated pest management were more widely available. The novelty of this study is to combine two models from distinctive disciplines to evaluate pesticide reduction scenarios based on real-world data from a single study site.

Pesticide transport simulation in a tropical catchment by SWAT.

The application of agrochemicals in Southeast Asia is increasing in rate, variety and toxicity with alarming speed. Understanding the behavior of these different contaminants within the environment require comprehensive monitoring programs as well as accurate simulations with hydrological models. We used the SWAT hydrological model to simulate the fate of three different pesticides, one of each usage type (herbicide, fungicide and insecticide) in a mountainous catchment in Northern Thailand. Three key parameters were identified: the sorption coefficient, the decay coefficient and the coefficient controlling pesticide percolation. We yielded satisfactory results simulating pesticide load dynamics during the calibration period (NSE: 0.92-0.67); the results during the validation period were also acceptable (NSE: 0.61-0.28). The results of this study are an important step in understanding the modeling behavior of these pesticides in SWAT and will help to identify thresholds of worst-case scenarios in order to assess the risk for the environment.

Monitoring and risk assessment of pesticides in a tropical river of an agricultural watershed in northern Thailand.

The increasing application of pesticides in the uplands of northern Thailand has increased the transfer of pesticides to surface water. To assess the risk of pesticide use for stream water quality, we monitored the concentrations of seven pesticides (atrazine, dichlorvos, chlorpyrifos, dimethoate, chlorothalonil, (α-, ß-) endosulfan, cypermethrin) frequently used in the Mae Sa watershed (77 km(2)) in water and sediment samples over a period of one and a half years (2007-2008). All investigated pesticides were recorded in the river. Chlorpyrifos was detected most often in water samples (75% at the headwater station), while cypermethrin was most often found in riverbed (86%) and in all suspended sediment samples. The highest concentrations of the pesticides were detected during the rainy season. About 0.002 to 4.1% by mass of the applied pesticides was lost to surface water. The risk assessment was based on the risk characterization ratio (RCR). The RCRs of dichlorvos in water, (α-, ß-) endosulfan, and cypermethrin in water and sediments were higher than unity indicating that they are likely to pose a threat to aquatic ecosystem. Finally, we discuss the role of sampling design on ecotoxicological risk assessment. Our study shows that pesticide contamination of surface waters is an environmental issue in the Mae Sa watershed and that measures need to be undertaken to reduce the loss of pesticides from soil to surface waters.

Contribution of spinal cord biopsy to diagnosis of aquaporin-4 antibody positive neuromyelitis optica spectrum disorder.

Longitudinally extensive transverse myelitis is characteristic but not pathognomonic for neuromyelitis optica spectrum disorders (NMOSDs) and may mimic local tumors. In this retrospective study based on a cohort of 175 NMOSD patients we identified seven patients who initially presented with a longitudinally extensive spinal cord lesion and underwent spinal cord biopsy due to magnetic resonance imaging (MRI)-suspected malignancies. Remarkably, routine neuropathology was inconclusive and did not guide the diagnostic process to anti-aquaporin-4 (AQP4)-seropositive NMOSD. Serious postoperative complications occurred in 5/7 patients and persisted during follow-up in 2/7 patients (29%). Considering these sequelae, AQP4-antibody testing should be mandatory in patients with inconclusive longitudinally extensive spinal cord lesions prior to biopsy.

Neuromyelitis optica and pregnancy during therapeutic B cell depletion: infant exposure to anti-AQP4 antibody and prevention of rebound relapses with low-dose rituximab postpartum.

Neuromyelitis optica (NMO) predominantly affects women, some in childbearing age, and requires early therapeutic intervention to prevent disabling relapses. We report an anti-AQP4 antibody-seropositive patient who became pregnant seven months after low-dose (100 mg) rituximab application. Pregnancy showed no complications, and low-dose rituximab restarted two days after delivery resulted in neurological stability for 24 months. Remarkably, her otherwise healthy newborn presented with anti-AQP4 antibody and reduced B lymphocyte counts in umbilical cord blood, which normalized three months later. Confirming and extending previous reports, our case suggests that low-dose rituximab might be compatible with pregnancy and prevent rebound NMO disease activity postpartum.

Graveyards - special landfills.

Graveyards have been a matter of controversial debate for many years in terms of the risk they pose to the environment. However, literature data are inconclusive and there are no systematic studies available from modern graveyards with special reference to soil found in the vicinity of the coffin. To our knowledge, the present study is the first to systematically investigate a comprehensive exhumation series (involving 40 graves) in order to determine burial-related changes in matter and element content. Human burials lead to the accumulation of certain elements, with higher than normal levels of N, C, Zn, Ba, Ca and Na being observed in soils below coffins. Decomposition material inside coffins has much higher levels of heavy metals and alkaline elements than the surrounding soil. However, the major problem observed was the large quantity of synthetic bedding material which is more likely to lead to the formation of adipocere under the moist conditions given. Adipocere formation, which is the result of the anaerobic bacterial hydrolysis of fat, is known to interrupt the natural decomposition process and delay the post-mortem release of elements. We assume that once the inhumed matter has completely decomposed, much higher than normal levels of pollutants will be released into and have an ecological effect on the soil and water environment.

[Oral fingolimod in multiple sclerosis: therapeutic modulation of the sphingosine-1-phosphate system]. / Orales Fingolimod bei Multipler Sklerose : Therapeutische Modulation des Sphingosin-1-Phosphat-Systems.

In this article the recent clinical data on novel therapy of relapsing multiple sclerosis with oral fingolimod (FTY720), lead substance of the recently described class of sphingosine-1-phosphate (S1P) receptor modulators are reviewed. Results of the two phase III studies (FREEDOMS; TRANSFORMS) corroborating previous phase II trial observations suggest that fingolimod has a strong anti-inflammatory effect in relapsing multiple sclerosis (MS), most probably by suppression of lymphocyte re-circulation from lymph nodes to inflammatory tissues (lymphocyte egress). Patients treated with fingolimod show a robust reduction of relapse frequency, compared to placebo (FREEDOMS) or an active comparator (interferon-ß1a) (TRANSFORMS) and they show less inflammatory lesions on brain MR imaging. Furthermore, data from experimental research indicate that fingolimod may equally promote neural repair in vivo as well. Thus, the proposed immunological and neurobiological profile of fingolimod as well as the data from the recent clinical trials will be discussed in the context of the expected safety profile.

Simulating pesticide transport from a sloped tropical soil to an adjacent stream.

Preferential flow from stream banks is an important component of pesticide transport in the mountainous areas of northern Thailand. Models can help evaluate and interpret field data and help identify the most important transport processes. We developed a simple model to simulate the loss of pesticides from a sloped litchi (Litchi chinensis Sonn.) orchard to an adjacent stream. The water regime was modeled with a two-domain reservoir model, which accounts for rapid preferential flow simultaneously with slow flow processes in the soil matrix. Preferential flow is triggered when the topsoil matrix is saturated or the infiltration capacity exceeded. In addition, close to matrix saturation, rainfall events induce water release to the fractures and lead to desorption of pesticides from fracture walls and outflow to the stream. Pesticides undergo first order degradation and equilibrium sorption to soil matrix and fracture walls. The model was able to reproduce the dynamics of the discharge reasonably well (model efficiency [EF] = 0.56). The cumulative pesticide mass (EF = 0.91) and the pesticide concentration in the stream were slightly underestimated, but the deviation from measurement data is acceptable. Shape and timing of the simulated concentration peaks occurred in the same pattern as observed data. While the effect of surface runoff and preferential interflow on pesticide mass transport could not be absolutely clarified, according to our simulations, most concentration peaks in the stream are caused by preferential interflow pointing to the important role of this flow path in the hilly areas of northern Thailand.

Micro-trench experiments on interflow and lateral pesticide transport in a sloped soil in northern Thailand.

During recent decades, a change in land use in the mountainous regions of Northern Thailand has been accompanied by an increased input of agrochemicals. We identified lateral water flow and pesticide transport pathways and mechanisms in a Hapludult on a sloped litchi orchard in Northern Thailand. During two rainy seasons, two micro-trench experiments were performed at the plot scale (2 by 3 m). The first experiment was performed at the footslope of the orchard; the second was performed at a midslope position. Two salt tracers (bromide and chloride) and two pesticides {methomyl [S-methyl-N-(methylcarbamoyloxy)thioacetimidate] and chlorothalonil (2,4,5,6-Tetrachlor-1,3-benzdicarbonitril)} were applied in stripes parallel to the slope 150 and 300 cm away from the trench. At the trench, soil water was collected by wick samplers. Tensiometers and time-domain reflectometry probes were installed. At the end of the experiment, soil samples were taken and analyzed for residual concentrations of tracers and pesticides. Lateral subsurface flow of water occurred exclusively along preferential flow paths and was mainly observed at 0- to 30- and 60- to 90-cm depth. Lateral transport of pesticides was negligible, but both pesticides were found beneath the application area at 90 cm depth. Therefore, they may pose a groundwater contamination risk. The amount of wick flow and the location of interflow were mainly a function of rain amount and antecedent soil water suction. During dry periods, water flow was restricted to the topsoil. After heavy rain events and wet periods, interflow was mainly observed in the subsoil. The cumulative rain amount between samplings necessary to induce interflow was 20 mm. At the footslope, the interflow was seven times higher, and the network of water-bearing pores increased compared with the midslope position.

[Inclusion of veterinarians in the structure of swine production]. / Einbeziehung des Tierarztes in die Strukturen der Schweineproduktion.

German pig production is for the most part characterised by very differentiated structures. Features of these structures are, inter alia, herd size (a great number of small farms, especially in piglet production) as well as specialisation on piglet production on the one hand and pig fattening on the other, both with regional concentrations. In addition, contractually certified integrated systems in the form of animal hygienic units are not widely distributed. The particular structures of German pig production require a special animal health management as well as special measures of hygiene. The veterinarian are requested to develop adequate conceptions in co-operation with pig holding farms and breeding/production organizations and to apply them in practice: for an effective animal health provision, for a systematic supervision of the herds by veterinarians, for an effective system of controlling and warning. Special attention must be paid to animal transportation. Effective animal health care ist a component of quality production and must be taken into account as a factor of competitive trade in the future.

Persistence of rabies antibody in free-ranging raccoons.

The immune status of a wildlife population to rabies virus probably influences the occurrences of epizootics among that species in a given geographical area. This is not to say that enzootic transmission of the virus will not occur, but rather that attainment of epizootic levels may be hampered through herd immunity. After an epizootic of rabies in a raccoon population in the Fall of 1970, a serologic surveillance program was initiated from November 1970 through August 1974. The surveillance provided the opportunity to determine the persistence of antibody in individual animals as well as to compare the sensitivity of intracerebral mouse inoculation and the RFFIT. The average point prevalence of neutralizing antibody was 20.9% (range, 15.5% [1970] to 25.0% [1974]). Fifty-one (18%) of the 476 raccoons monitored during the study period were trapped more than once. The testing of sequential serum samples from individual seropositive raccoons indicated that serum neutralizing antibody can persist for at least 37 months. It cannot be stated with certainty that these antibody titers resulted from a single exposure to rabies virus and were not boosted by further experience with the virus. Serial serology tests on three young raccoons (less than 15, 30, and 52 weeks of age) suggest that endemic rabies virus was circulating in or near the study area between June 1972 and February 1974. Thirty-six raccoons trapped in November 1970 were shipped to the Centers for Disease Control, Lawrenceville, Ga, where they were held in captivity for observations and serologic monitoring.(ABSTRACT TRUNCATED AT 250 WORDS)