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Abstract Some smokeless tobacco products, such as Swedish snus, are today considered to be associated with substantially fewer health hazards than cigarettes. This risk differential has contributed to the scientific debate about the possibilities of harm reduction within the tobacco area. Although current manufacturing methods for snus build on those that were introduced more than a century ago, the low levels of unwanted substances in modern Swedish snus are largely due to improvements in production techniques and selection of raw materials in combination with several programs for quality assurance and quality control. These measures have been successively introduced during the past 30-40 years. In the late 1990s they formed the basis for a voluntary quality standard for Swedish snus named GothiaTek®. In recent years the standard has been accepted by the members of the trade organization European Smokeless Tobacco Council (ESTOC) so it has now evolved into an industrial standard for all smokeless tobacco products in Europe. The initial impetus for the mentioned changes of the production was quality problems related to microbial activity and formation of ammonia and nitrite in the finished products. Other contributing factors were that snus came under the jurisdiction of the Swedish Food Act in 1971, and concerns that emerged in the 1960s and 1970s about health effects of tobacco, and the significance of agrochemical residues and other potential toxicants in food stuffs. This paper summarizes the historical development of the manufacture of Swedish snus, describes the chemical composition of modern snus, and gives the background and rationale for the GothiaTek® standard, including the selection of constituents for which the standard sets limits. The paper also discusses the potential future of this voluntary standard in relation to current discussions about tobacco harm reduction and regulatory science in tobacco control.

Neuromyelitis optica is a paradigmatic autoimmune disease of the central nervous system, in which the water-channel protein AQP4 is the target antigen 1 . The immunopathology in neuromyelitis optica is largely driven by autoantibodies to AQP4 2 . However, the T cell response that is required for the generation of these anti-AQP4 antibodies is not well understood. Here we show that B cells endogenously express AQP4 in response to activation with anti-CD40 and IL-21 and are able to present their endogenous AQP4 to T cells with an AQP4-specific T cell receptor (TCR). A population of thymic B cells emulates a CD40-stimulated B cell transcriptome, including AQP4 (in mice and humans), and efficiently purges the thymic TCR repertoire of AQP4-reactive clones. Genetic ablation of Aqp4 in B cells rescues AQP4-specific TCRs despite sufficient expression of AQP4 in medullary thymic epithelial cells, and B-cell-conditional AQP4-deficient mice are fully competent to raise AQP4-specific antibodies in productive germinal-centre responses. Thus, the negative selection of AQP4-specific thymocytes is dependent on the expression and presentation of AQP4 by thymic B cells. As AQP4 is expressed in B cells in a CD40-dependent (but not AIRE-dependent) manner, we propose that thymic B cells might tolerize against a group of germinal-centre-associated antigens, including disease-relevant autoantigens such as AQP4., (© 2024. The Author(s).)

Deletion or T reg cell differentiation are alternative fates of autoreactive MHCII-restricted thymocytes. How these different modes of tolerance determine the size and composition of polyclonal cohorts of autoreactive T cells with shared specificity is poorly understood. We addressed how tolerance to a naturally expressed autoantigen of the central nervous system shapes the CD4 T cell repertoire. Specific cells in the tolerant peripheral repertoire either were Foxp3 + or displayed anergy hallmarks and, surprisingly, were at least as frequent as in the nontolerant repertoire. Despite this apparent lack of deletional tolerance, repertoire inventories uncovered that some T cell receptors (TCRs) were lost from the CD4 T cell pool, whereas others mediated T reg cell differentiation. The antigen responsiveness of these TCRs supported an affinity model of central tolerance. Importantly, the contribution of different diverter TCRs to the nascent thymic T reg cell population reflected their antigen reactivity rather than their frequency among precursors. This reveals a multilayered TCR hierarchy in CD4 T cell tolerance that separates deleted and diverted TCRs and assures that the T reg cell compartment is filled with cells of maximal permissive antigen reactivity., Competing Interests: The authors declare no conflict of interest., (Copyright © 2019 the Author(s). Published by PNAS.)

Background: Relocation from the familiar living environment is a particularly risky transition event for old people with intellectual disability (ID); however, a change of environment has the potential to maintain or improve a person's social participation and self-determination in old age. The research project MUTIG aimed to analyze the frequency and destination of moving home of old persons with ID (≥50 years) in Westphalia for the years 2014 and 2015., Material and Methods: The investigation was based on a secondary analysis of administrative data of all persons over 50 years who received any kind of social aid for integration from the Regional Association of Westphalia-Lippe. For each individual the address and support arrangements at the beginning and the end of the years 2014 and 2015 were compared., Results: Approximately 5% of older people with ID changed address per year. People who moved to nursing homes had previously primarily lived in larger institutions or larger community-based group homes. The number of older persons with ID moving into or out of supported living arrangements was approximately equal., Conclusion: Older persons with ID should also be able to move to smaller supported settings and these settings should provide long-lasting living perspectives (aging in place). The pulling effect that nursing homes exert on residents in residential institutions or larger group homes is critically discussed.

Background: The number of aged persons with intellectual disability (ID) in Germany is increasing; however, reliable data on the residential settings in which they live are missing. The aim of this study was to estimate how adults with ID of different age groups are distributed over the various residential settings using the example of Westphalia-Lippe., Material and Methods: Administrative data on all adults with ID who received aid for social integration were statistically analyzed. Data on persons with ID in long-term nursing homes were collected via telephone interviews and questionnaires. Finally, the results were merged to obtain a comprehensive overview for Westphalia-Lippe., Results: In Westphalia-Lippe aged persons with ID (≥65 years) rarely live independently but mostly with family members or in supported living arrangements. They are living in larger community-based homes or in residential institutions more frequently than younger persons with ID and one fifth have been living in nursing homes for a comparatively long period of time., Conclusion: Older persons with ID have so far hardly benefited from the increasing residential options for supported living. All forms of services and residential arrangements for persons with ID have to adapt to the changing needs for support in old age. Long-term nursing homes should not mutate into places where people spend the complete phase of old age.

Some smokeless tobacco products, such as Swedish snus, are today considered to be associated with substantially fewer health hazards than cigarettes. This risk differential has contributed to the scientific debate about the possibilities of harm reduction within the tobacco area. Although current manufacturing methods for snus build on those that were introduced more than a century ago, the low levels of unwanted substances in modern Swedish snus are largely due to improvements in production techniques and selection of raw materials in combination with several programs for quality assurance and quality control. These measures have been successively introduced during the past 30-40 years. In the late 1990s they formed the basis for a voluntary quality standard for Swedish snus named GothiaTek®. In recent years the standard has been accepted by the members of the trade organization European Smokeless Tobacco Council (ESTOC) so it has now evolved into an industrial standard for all smokeless tobacco products in Europe.The initial impetus for the mentioned changes of the production was quality problems related to microbial activity and formation of ammonia and nitrite in the finished products. Other contributing factors were that snus came under the jurisdiction of the Swedish Food Act in 1971, and concerns that emerged in the 1960s and 1970s about health effects of tobacco, and the significance of agrochemical residues and other potential toxicants in food stuffs.This paper summarizes the historical development of the manufacture of Swedish snus, describes the chemical composition of modern snus, and gives the background and rationale for the GothiaTek® standard, including the selection of constituents for which the standard sets limits. The paper also discusses the potential future of this voluntary standard in relation to current discussions about tobacco harm reduction and regulatory science in tobacco control.

A number of virtual environments have been developed during the last years. Among them there are some applications for blind people based on different type of audio, from simple sounds to 3-D audio. In this study, we pursued a different approach. We designed AudioMUD by using spoken text to describe the environment, navigation, and interaction. We have also introduced some collaborative features into the interaction between blind users. The core of a multiuser MUD game is a networked textual virtual environment. We developed AudioMUD by adding some collaborative features to the basic idea of a MUD and placed a simulated virtual environment inside the human body. This paper presents the design and usability evaluation of AudioMUD. Blind learners were motivated when interacted with AudioMUD and helped to improve the interaction through audio and interface design elements.

The effects of water quality and exposure to trace elements in irrigation return flows on bluegills (Lepomis macrochirus) were studied in the Merced River and Salt Slough, tributaries to the San Joaquin River, California, during 1988. Our study revealed that conductivity, turbidity, pH, total filterable residue, total hardness, and alkalinity were significantly greater in the Salt Slough, which receives tile drainage, then in the Merced River, which does not receive tile drainage. The concentrations of all trace elements, except aluminum and selenium, were below levels that are expected to have significant chronic toxic effects on bluegills. Selenium body burdens in bluegills from the Salt Slough have increased over fourfold since 1973. Age 1 bluegills from the Salt Slough were significantly shorter than age 1 bluegills from the Merced River. No other significant differences were noted in length by age. The mean length of age 1 bluegills from the Merced River has been increasing since 1983. In contrast, the length of age 1 bluegills from the Salt Slough has been decreasing. Fecundity of bluegills was lower in the Salt Slough than in the Merced River. The concurrent rise in selenium body burdens in bluegills from the Salt Slough and the decreasing total length of age 1 bluegills suggest a causal link between the two. In addition, the apparent depressed fecundity may also be related to the increased body burdens of selenium.

C syndrome is an autosomal recessive craniosynostosis syndrome with characteristic cranial, facial, palate, and joint abnormalities. All but 2 of the reported patients have had severe mental retardation. We report on an 8-month-old girl with C syndrome and apparently normal development except for tasks hindered by her lower body abnormalities. We also offer a possible explanation for the palatal configuration.