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Habitual responses towards addiction-related cues play a relevant role in the development and maintenance of addictions. Such automatic responses may be more likely under stress, as stress has been shown to induce a shift from goal-directed to habitual behavior. The current study investigated these mechanisms in risky gaming behavior. Individuals with risky gaming behavior (n = 68), as established by a structured clinical interview, and a matched control group (n = 67) completed a Pavlovian-to-Instrumental Transfer (PIT) paradigm with gaming-related cues and rewards. After the Pavlovian training, participants underwent a stress (Trier Social Stress Test) or control condition before performing the instrumental training and the transfer phase of the PIT paradigm. To assess habitual behavior, the gaming-related rewards were devalued after half of the transfer phase. In both groups, gaming-related cues enhanced the choice of the gaming-related reward and this gaming PIT effect was reduced, however, not eliminated by the devaluation. Unexpectedly, stress did not significantly increase responding for the gaming-related reward in participants aware of the stimulus-outcome associations, however seemed to enhance habitual responding in unaware participants. Our findings underline the relevance of gaming-related cues in triggering habitual responses, which may undermine attempts to change a problematic gaming behavior., (© 2024. The Author(s).)

Background: The activation of permissive beliefs is a cognitive mechanism through which individuals permit themselves to engage in pleasurable, yet potentially unregulated activities. Existing measures are heterogenous, focusing either on specific behaviors or on particular licensing mechanisms. The new Permissive Beliefs Questionnaire (PBQ) seeks to integrate self-licensing mechanisms from various research domains and to be applicable to different behaviors., Methods: Study 1 aimed at exploring the factor structure and reduce the number of items. In study 2, we used confirmatory factor analysis and tested convergent and discriminant validity in three subsamples of individuals playing videogames (n = 489), shopping online (n = 506), and drinking alcohol (n = 511). We tested the hypothesis whether individuals who experience a self-regulatory conflict show a greater expression of permissive beliefs., Results: The final version of the PBQ consists of 12 items which represent two factors: Deserving Reward and Defensive Optimism. The PBQ exhibited robust model fit indices and internal consistencies in the three samples. Permissive beliefs were heightened among individuals intending to downregulate their gaming, shopping, or drinking behaviors as compared to individuals without this intention., Conclusion: The PBQ is a valid measure of permissive beliefs for gaming, online shopping, and drinking alcohol. It serves an ecologic and psychometrically valid tool to address empirical research questions regarding the functioning of permissive beliefs. Additionally, it may be used in clinical settings to measure and raise an understanding for permissive beliefs in clients., Competing Interests: Declaration of competing interest This article is the authors' original work, has not received prior publication, is not under consideration for publication elsewhere, and if accepted, will not be published elsewhere in the same form, in English or in any other language, including electronically without the written consent of the copyright-holder., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Introduction: With the inclusion of gaming disorder in the ICD-11, diagnostic criteria were introduced for this relatively new disorder. These criteria may be applied to other potential specific Internet-use disorders. The 11-item Assessment of Criteria for Specific Internet-use Disorders (ACSID-11) was developed for consistent screening of gaming disorder, online buying-shopping disorder, online pornography-use disorder, social networks-use disorder, and online gambling disorder. This study tested the construct validity of the ACSID-11, including convergent and divergent measures., Methods: The ACSID-11 measures five behavioral addictions with the same set of items by following the principles of the Alcohol, Smoking and Substance Involvement Screening Test (ASSIST). The ACSID-11 was administered to a convenience sample of active Internet users (N = 1597) together with validated and established measures of each specific Internet-use disorder along with screeners for mental health. Included are the Ten-Item Internet Gaming Disorder Test (IGDT-10), the Bergen Shopping Addiction Scale (BSAS), the Problematic Pornography Consumption Scale (PPCS), the Bergen Social Media Addiction Scale (BSMAS) and the Berlin Inventory of Gambling behavior - Screening (BIG-S). The ACSID-11 was compared convergently and divergently through a multitrait-multimethod approach along with contingency tables with the other Internet-use disorder screeners., Results: The multitrait-multimethod results shows that each behavior assessed with the ACSID-11 has moderate to strong correlations (r's from 0.462 to 0.609) with the scores of the corresponding established measures and, furthermore, positive correlations (r's from 0.122 to 0.434) with measures of psychological distress and further shows that the ACSID-11 can be used for a comprehensive assessment of different behaviors. The contingency tables reveal large divergences between the ACSID-11 and other screening instruments concerning the classification of problematic specific Internet use based on the given cut-off values., Conclusion: The current work provides additional validation for the ACSID-11. Accordingly, this tool can be considered as reliable and valid for the simultaneous assessment of different Internet-use disorders: gaming disorder, online buying-shopping disorder, online pornography use disorder, social networks use disorder, and online gambling disorder. With a subsequent clinical validation of the scale and the proposed cut-off score, the ACSID-11 will be a thoroughly validated useful screening tool for clinical practice., Competing Interests: Declaration of competing interest None., (Copyright © 2024. Published by Elsevier Inc.)

The src homology 2 domain-containing inositol 5-phosphatases SHIP1 and SHIP2 are two proteins involved in intracellular signaling pathways and have been linked to the pathogenesis of several diseases. Both protein paralogs are well known for their involvement in the formation of various kinds of cancer. SHIP1, which is expressed predominantly in hematopoietic cells, has been implicated as a tumor suppressor in leukemogenesis especially in myeloid leukemia, whereas SHIP2, which is expressed ubiquitously, has been implicated as an oncogene in a wider variety of cancer types and is suggested to be involved in the process of metastasis of carcinoma cells. However, there are numerous other diseases, such as inflammatory diseases as well as allergic responses, Alzheimer's disease, and stroke, in which SHIP1 can play a role. Moreover, SHIP2 overexpression was shown to correlate with opsismodysplasia and Alzheimer's disease, as well as metabolic diseases. The SHIP1-inhibitor 3-α-aminocholestane (3AC), and SHIP1-activators, such as AQX-435 and AQX-1125, and SHIP2-inhibitors, such as K161 and AS1949490, have been developed and partly tested in clinical trials, which indicates the importance of the SHIP-paralogs as possible targets in the therapy of those diseases. The aim of this article is to provide an overview of the current knowledge about the involvement of SHIP proteins in the pathogenesis of cancer and other human diseases and to create awareness that SHIP1 and SHIP2 are more than just tumor suppressors and oncogenes.

Background: Gaming disorder (GD) is a disorder due to addictive behaviors (ICD-11). Cue-reactivity and craving are relevant mechanisms in the development and maintenance of addictive behaviors. When confronted with cues showing in-game content (proximal cues) individuals with higher symptom severity show increased cue-reactivity. Based on conditioning and addiction theories on incentive sensitization, cue-reactivity responses may generalize to more distal cues, e.g. when individuals at risk of developing a GD are confronted with a starting page of an online game. In cue-reactivity paradigms so far, only proximal gaming cues have been used., Methods: We investigated the effect of distal gaming cues compared to gaming-unrelated control cues on cue-reactivity and craving in 88 individuals with non-problematic use of online games (nPGU) and 69 individuals at risk for GD (rGD). The distal cues showed the use of an electronic device (e.g., desktop PC or smartphone) whose screen showed starting pages of either games (target cues), shopping- or pornography sites (control cues) from a first-person perspective., Findings: We found significantly higher urge and arousal ratings as well as longer viewing times for gaming-related compared to gaming-unrelated control cues in rGD compared to nPGU. Valence ratings did not differ between groups., Interpretation: The results demonstrate that already distal gaming-specific cues lead to cue-reactivity and craving in rGD. This finding indicates that based on conditioning processes, cue-reactivity and craving develop during the course of GD and generalize to cues that are only moderately related to the specific gaming activity., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Introduction: Previous research on cognitive functions in Compulsive Sexual Behavior Disorder (CSBD) and problematic pornography use (PPU) reported inconsistent findings and mostly included sexual pictures in the used tasks. The role of general executive functions and cognitive competences (without the presence of appetitive stimuli) in the context of PPU is largely unexplored., Methods: This study investigated differences between individuals with high versus low problem severity of PPU regarding decision making and executive functions. The sample of the laboratory study consisted of N = 102 male adults. Besides measures of trait impulsivity, we used standard neuropsychological tests (Trail Making Test and three-back working memory task) and an intertemporal risky choice paradigm, the Cards & Lottery Task (CLT)., Results: The results show heightened impulsivity (urgency and deficits in perseverance) in individuals with high PPU, but no differences regarding performance in the CLT and executive function tasks., Discussion: The findings indicate that PPU might be associated with impulsive behavior when experiencing strong emotions (urgency) and deficient cognitive performance especially in the presence of sexual stimuli but not in general., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher., (Copyright © 2023 Müller and Antons.)

Background: Studies in convenience, non-clinical samples of young adults suggest overlap between online compulsive buying-shopping disorder (OCBSD) and social-networks-use disorder (SNUD). Considering the dearth of research, this study investigated OCBSD and SNUD in clinical samples., Methods: Women with either OCBSD (n = 37) or SNUD (n = 41) were compared regarding sociodemographic variables, use time of the first-choice application, OCBSD/SNUD severity, general internet use, impulsivity, materialism, perceived chronic stress and the frequency of viewing posts of influencers and the urge to visit shopping websites or social networks after viewing influencer posts., Results: Women in the OCBSD group were older, more often employed, had less often a qualification for university entrance, indicated a lower daily use time of the first-choice application and higher materialistic values as compared to those in the SNUD group. No group differences emerged regarding general internet use, impulsivity and chronic stress. Regression models indicate that chronic stress predicted the symptom severity in the SNUD but not in the OCBSD group. The SNUD group reported a higher frequency of viewing influencer posts as compared to the OCBSD group. The urge for online shopping or using social networks after viewing influencer posts did not significantly differ between both groups., Conclusion: The findings suggest commonalities and distinct features of OCBSD and SNUD which require further investigation., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Aim: To determine the relationship between medical staff's response time (RT) to oxygen saturation (SpO 2 ) below 80% and the associated time from tactile intervention until SpO 2 normalisation (CT)., Methods: Time-lapse video and continuous SpO 2 were recorded for six consecutive 24 h periods. Regression analyses of RT and SpO 2 in association with postmenstrual age (PMA), weight, infant sex and frequency of intermittent hypoxemia (IH)., Results: Five hundred and twelve hypoxemia episodes received tactile intervention in 20 extremely preterm infants (gestational age ≤28 weeks, birthweight <1500 g). Median RT was 20.5 s (IQR 16.63-25.50). RT increased with increased IH frequency (p = 0.023) independently of PMA and weight. SpO 2 decreased by 3.7% with every 10 s RT (p = 0.039). Time until SpO 2 normalisation was strongly associated with RT (β = 0.58, p = 0.042). The association was amplified by lower PMA (p = 0.043). Female preterm infants experienced longer RT than males (p = 0.027). Because the total length of an IH is the sum of RT and CT, preterm infants with low PMA can reach a critical hypoxemia duration of >60 s, even with short RT., Conclusion: The RT is a critical factor that affects the overall time of IH treatments and the depth of desaturation. The consequences of a prolonged RT are worse for more immature preterm infants., (© 2023 The Authors. Acta Paediatrica published by John Wiley & Sons Ltd on behalf of Foundation Acta Paediatrica.)

Microalgae have enormous potential for human nutrition, yet the European Commission has authorized the consumption of only eleven species. Strains of fifteen rarely researched microalgae from two kingdoms were screened regarding their nutritional profile and value for human health in two cultivation phases. Contents of protein, fiber, lipids, fatty acids, minerals, trace elements and heavy metals were determined. In the growth phase, microalgae accumulated more arginine, histidine, ornithine, pure and crude protein, Mg, Mn, Fe and Zn and less Ni, Mo and I 2 compared to the stationary phase. Higher contents of total fat, C14:0, C14:1 n5 , C16:1 n7 , C20:4 n6 , C20:5 n3 and also As were observed in microalgae from the chromista kingdom in comparison to microalgae from the plantae kingdom ( p < 0.05). Conversely, the latter had higher contents of C20:0, C20:1 n9 and C18:3 n3 as well as Ca and Pb ( p < 0.05). More precisely, Chrysotila carterae appeared to have great potential for human nutrition because of its high nutrient contents such as fibers, carotenoids, C20:6 n3 , Mg, Ca, Mn, Fe, Se, Zn, Ni, Mo and I 2 . In summary, microalgae may contribute to a large variety of nutrients, yet the contents differ between kingdoms, cultivation phases and also species.

The increase in adult height for 150 years is linked to overall improvements in nutrition, hygiene, and living standards. Height is positively associated with general health and success on various levels (e.g. quality of life, earnings or happiness). The aim of this study was to investigate whether different subgroups show different trends across birth cohorts. We wanted to know whether taller individuals considered themselves as healthier and their quality of life as better than shorter individuals. We included 19,435 participants from the Swiss population-based Health Survey 2017. GAM were used to assess nonlinear associations between height and birth year. Multinomial logistic regression was used to predict probabilities of self-rated health in relation to height. The increase in average height slows down from the 1970s birth cohorts. Participants with parents from Central/Northern/Western Europe (men 177.9 cm, women: 165.1 cm) or Eastern Europe (men 178.7 cm, women: 165.7 cm) were taller than participants with parents from South America (men 174.3 cm, women: 161. cm) and Asia (men 173.2 cm, women: 160.1 cm). Participants with tertiary education were taller than participants from education levels (mean difference men: 4.5 cm, women: 5.0 cm). Height was positively associated with self-declared aspects of health and life satisfaction. These results support the conclusion that body height as a co-factor of health aspects should be considered in public health research. Although adult body height can no longer be influenced, nutritional status and thus also healthy growth can be influenced in childhood by public health programs, by eliminating social inequalities, and by strengthen healthy living conditions., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Author(s).)

Background and Aims: With the inclusion of gaming disorder in the ICD-11, diagnostic criteria were introduced for this relatively new disorder. These criteria may also be applied to other potential specific Internet-use disorders, which may be classified in ICD-11 as other disorders due to addictive behaviors, such as online buying-shopping disorder, online pornography-use disorder, social-networks-use disorder, and online gambling disorder. Due to the heterogeneity in existing instruments, we aimed to develop a consistent and economic measure of major types of (potential) specific Internet-use disorders based on ICD-11 criteria for gaming disorder., Methods: The new 11-item Assessment of Criteria for Specific Internet-use Disorders (ACSID-11) measures five behavioral addictions with the same set of items by following the principles of WHO's ASSIST. The ACSID-11 was administered to active Internet users (N = 985) together with an adaptation of the Ten-Item Internet Gaming Disorder Test (IGDT-10) and screeners for mental health. We used Confirmatory Factor Analyses to analyze the factor structure of ACSID-11., Results: The assumed four-factorial structure was confirmed and was superior to the unidimensional solution. This applied to gaming disorder and to the other specific Internet-use disorders. ACSID-11 scores correlated with IGDT-10 as well as with the measures of psychological distress., Discussion and Conclusions: The ACSID-11 seems to be suitable for the consistent assessment of (potential) specific Internet-use disorders based on ICD-11 diagnostic criteria for gaming disorder. The ACSID-11 may be a useful and economic instrument for studying various behavioral addictions with the same items and improving comparability.

The uncontrolled use of specific Internet applications is increasingly recognized as a mental health issue. Gaming disorder, which is one subtype of specific Internet-use disorders (sIUDs), has been included in the ICD-11 as disorder due to addictive behaviors. Addictive disorders are assumed to be accompanied by cognitive deficits as indicated by weaker performance in executive function and risky decision-making tasks. This study investigates risky decision-making in individuals with tendencies towards sIUDs including gaming, online buying-shopping, and social-networks-use disorders. A total of 293 individuals participated in the study. Based on specific screening instruments, the participants were assigned to a group with tendencies towards sIUD or a control group. Participants completed a risky decision-making task and questionnaires assessing risk-taking propensity, impulsivity, psychopathology, and perceived stress. The group with sIUD tendencies showed higher attentional impulsivity and higher levels of depression and anxiety compared to the control group. The groups did not differ in decision making and risk propensity. Decision making did not have significant effects on sIUD symptoms. Risk for developing sIUDs does not appear to be accompanied by altered general decision-making tendencies. Rather, psychological (pre-)load and attentional deficits appear to be relevant features in uncontrolled use of the Internet.

In Wilson disease, excessive copper accumulates in patients' livers and may, upon serum leakage, severely affect the brain according to current viewpoints. Present remedies aim at avoiding copper toxicity by chelation, for example, by D-penicillamine (DPA) or bis-choline tetrathiomolybdate (ALXN1840), the latter with a very high copper affinity. Hence, ALXN1840 may potentially avoid neurological deterioration that frequently occurs upon DPA treatment. As the etiology of such worsening is unclear, we reasoned that copper loosely bound to albumin, that is, mimicking a potential liver copper leakage into blood, may damage cells that constitute the blood-brain barrier, which was found to be the case in an in vitro model using primary porcine brain capillary endothelial cells. Such blood-brain barrier damage was avoided by ALXN1840, plausibly due to firm protein embedding of the chelator bound copper, but not by DPA. Mitochondrial protection was observed, a prerequisite for blood-brain barrier integrity. Thus, high-affinity copper chelators may minimize such deterioration in the treatment of neurologic Wilson disease., (© 2021 Borchard et al.)

Paralytic poliomyelitis is a rare disease manifestation following poliovirus (PV) infection. The disease determinants remain largely unknown. We used whole exome sequencing to uncover possible contributions of host genetics to the development of disease outcome in humans with poliomyelitis. We identified a patient with a variant in ATG7 , an important regulatory gene in the macroautophagy/autophagy pathway. PV infection did not induce a prominent type I interferon response, but rather activated autophagy in neuronal-like cells, and this was essential for viral control. Importantly, virus-induced autophagy was impaired in patient fibroblasts and associated with increased viral burden and enhanced cell death following infection. Lack of ATG7 prevented control of infection in neuronal-like cells, and reconstitution of patient cells with wild-type ATG7 reestablished autophagy-mediated control of infection. Collectively, these data suggest that ATG7 defect contributes to host susceptibility to PV infection and propose autophagy as an unappreciated antiviral effector in viral infection in humans.

Background and Aims: Social-networks-use disorder is discussed as a potential further type of disorders due to addictive behaviors. Theoretical models assume cue-induced craving and disadvantageous decision making to be relevant mechanisms. This study investigates if the presentation of social-networks-related cues interferes with decision making under ambiguity., Methods: Craving was induced with a cue-reactivity paradigm and assessed with a visual analogue scale. Participants (N = 146) played a modified Iowa Gambling Task with social-networks-related cues and neutral cues presented on the advantageous and disadvantageous decks respectively, or vice versa. Symptoms of social-networks-use disorder were measured with a modified version of the short Internet Addiction Test., Results: Overall, participants chose options with neutral cues more often than those with social-networks-related cues, even if it was disadvantageous. There was a significant interaction between decision-making performance and Iowa Gambling Task condition in predicting symptom severity. The results indicate that choosing decks with social-networks-related cues even if it was disadvantageous is associated with higher tendencies towards a social-networks-use disorder. The interaction with cue-induced craving did not explain further variance., Discussion and Conclusions: The results highlight the relevance of cue reactivity, decision making, and their interaction as potential mechanisms explaining tendencies towards a social-networks-use disorder. Decision making was influenced by affective responses, which could result in a higher risk of a potential addictive behavior. This is consistent with the findings from addiction research and with theoretical approaches assuming an imbalance between affective and cognitive processes in addictive behaviors.

The nutrient composition of 15 commercially available microalgae powders of Arthrospira platensis , Chlorella pyrenoidosa and vulgaris , Dunaliella salina , Haematococcus pluvialis , Tetraselmis chuii , and Aphanizomenon flos-aquae was analyzed. The Dunaliella salina powders were characterized by a high content of carbohydrates, saturated fatty acids (SFAs), omega-6-polyunsaturated fatty acids (n6-PUFAs), heavy metals, and α-tocopherol, whereas the protein amounts, essential amino acids (EAAs), omega-3-PUFAs (n3-PUFAs), vitamins, and minerals were low. In the powder of Haematococcus pluvialis , ten times higher amounts of carotenoids compared to all other analyzed powders were determined, yet it was low in vitamins D and E, protein, and EAAs, and the n6/n3-PUFAs ratio was comparably high. Vitamin B 12 , quantified as cobalamin, was below 0.02 mg/100 g dry weight (d.w.) in all studied powders. Based on our analysis, microalgae such as Aphanizomenon and Chlorella may contribute to an adequate intake of critical nutrients such as protein with a high content of EAAs, dietary fibers, n3-PUFAs, Ca, Fe, Mg, and Zn, as well as vitamin D and E. Yet, the nutritional value of Aphanizomenon flos-aquae was slightly decreased by high contents of SFAs. The present data show that microalgae are rich in valuable nutrients, but the macro- and micronutrient profiles differ strongly between and within species.

Background: The tendency to strive for immediate gratification by neglecting potential negative long-term outcomes characterizes addictive behaviors, such as substance use or gaming disorder. Problematic social-network use is currently discussed as another potential addictive behavior, which is considered to result from an imbalance between affective and cognitive processes, indicated by traits such as increased impulsivity and/or decreased executive functions and decision-making abilities., Methods: This study investigates the respective functions in social-network users by use of the Cards and Lottery Task (CLT) - a decision-making task under risk conditions in which options contain conflicting immediate and long-term outcomes at the same time. A sample of German and Spanish participants (N = 290) performed the CLT as well as the Modified Card Sorting Test (MCST), Barratt Impulsiveness Scale (BIS), the short Internet Addiction Test specified for social-networking (sIAT-SNS), and screeners on other potentially problematic behaviors., Results: Comparing extreme groups based on sIAT-SNS scores (1SD above/below mean), individuals with problematic social-network use (n = 56), as compared to those with non-problematic social-network use (n = 50), showed increased attentional impulsivity and reduced executive functions. No differences were observed in decision-making performance., Conclusion: The findings indicate that problematic social-network use is related to attentional rather than general decision-making deficits. Furthermore, problematic social-network use is likely to co-occur with other problematic Internet-use behaviors, particularly gaming or shopping., Competing Interests: Declaration of Competing Interest none., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Social media including social-networking sites (SNS) encourage people to disclose personal information via profiles and posts. It is assumed that positive short-term effects and immediate feedback (e.g., getting Likes) have a rewarding nature and may complicate the rational weighing of possible negative long-term consequences related to self-disclosure. Dual-process theories assume risky behaviors to result from more impulsive/short-term oriented compared to reflective/long-term oriented decision making. The current laboratory study investigates whether the extent of online self-disclosure is explained by the general tendency to choose short-term rewards by neglecting long-term risks as well as by tendencies toward a problematic social-networks-use. Participants ( N = 88) were asked to log into their Facebook account to answer questions about their actual self-disclosing behavior. Furthermore, they performed an experimental decision-making task and answered a questionnaire assessing problematic social-networks-use. The quantity of self-disclosure via posts was negatively associated with advantageous decision making and positively with tendencies toward a problematic social-networks-use. The findings indicate that high self-disclosure via posts is associated with a general tendency to neglect long-term risks. Moreover, a problematic social-networks-use can additionally increase individual's self-disclosure via posts., (Copyright © 2020 Ostendorf, Müller and Brand.)

The optimization of the thermal treatment of cationic starch in the paper industry offers the opportunity to reduce the energy consumption of this process . Four different industrially relevant cationic starches, varying in source, cationization method and degree of substitution were treated by a steam-jet cooking procedure, comparable to industrially employed starch cooking processes. The influence of the starch properties and cooking parameters on the adsorption behavior of the starches on cellulosic pulp was investigated. The adsorbed amount was affected by the cooking temperature and the type of starch. For some starch grades, a cooking temperature of 115 °C can be employed to achieve sufficient starch retention on the pulp fibers. The energy consumption could further be reduced by cooking at higher starch concentrations without loss of adsorption efficiency., Competing Interests: The authors declare no conflict of interest.

Background and Aims: In addition to craving responses to salient food cues, the anticipation of short-term rewarding consumption of palatable food may overrun the anticipation of long-term negative consequences of obesity. The present investigation addressed the potential interplay of food cravings and decision-making abilities in individuals with obesity., Method: Study 1 included 107 bariatric surgery candidates with class 2/3 obesity (OB-group) and study 2 included 54 individuals with normal weight/pre-obesity (nonOB-group). In both studies, standardized questionnaires concerning food cravings, food addiction, and psychopathology were administered. A cue-reactivity paradigm was used to measure craving responses toward semi-individualized images of highly palatable, processed food/fruit (appetitive food cues) compared to images of raw vegetables (non-appetitive food cues). Decision-making was measured with a modified computerized version of the Iowa Gambling Task (IGT) with food pictures. Both groups were divided into two subgroups that were randomized to different IGT conditions. In one IGT condition the advantageous IGT card decks were covered by pictures of palatable, processed food or fruit and the disadvantageous decks by images of raw vegetables (= congruent condition), and in the other IGT condition vice versa ., Results: Participants in the OB-group admitted on average higher craving responses toward palatable, processed food or fruit cues compared to pictures of raw vegetables. This was not the case in the nonOB-group. Contrary to our hypothesis, decision-making performance in both groups was worse when pictures of palatable, processed food or fruit were associated with advantageous IGT card decks compared to performance when those pictures were linked to the disadvantageous decks. The interference effect of food pictures processing on advantageous decision-making has been observed particularly in those individuals of the OB-group who exhibited high craving responses toward palatable, processed food cues or high levels of food addiction., Discussion: The results indicate that food pictures processing interferes with decision-making, regardless of weight status. Opposed to the hypothesis, stronger tendencies to avoid than to approach pictures presenting processed, tasty food were observed. Further research should examine how cognitive avoidance tendencies toward processed, high energy food and approach tendencies toward healthy food can be transferred to real life situations., (Copyright © 2020 Lescher, Wegmann, Müller, Laskowski, Wunder, Jiménez-Murcia, Szycik, de Zwaan and Müller.)

Background: The COVID 19 pandemic increased publication productivity enormously with numerous new COVID-19-related articles appearing daily, despite the fact that many health care workers in the partially overburdened national health care systems were faced with major challenges., Methods: In a cross-sectional, observational, retrospective study we compared and correlated 17 epidemiologic, health care system-related and health-economic factors from medical databases and intergovernmental organisations potentially influencing the COVID-19 and non-COVID-19 publication productivity between 1 January and 30 April 2020 amongst the 30 countries most severely affected by the pandemic. These factors were additionally correlated with the national pre-COVID-19 publication rate for the same pre-year period to identify potential changes in the general publication behaviour., Findings: COVID-19 and non-COVID-19 publication rates correlated strongest with access to and quality of health care (ρ = 0.80 and 0.87, p < 0.0001), COVID-19 cases per capita (ρ = 0.78 and 0.72, p < 0.0001), GDP per capita (ρ = 0.69 and 0.76, p < 0.0001), health spending per capita (ρ = 0.61 and 0.73, p < 0.0001) and the pre-COVID-19 Hirsch-Index (ρ = 0.61 and 0.62, p = 0.002 and <0.0001). Ratios of publication rates for "Cancer", "Diabetes" and "Stroke" in 2020 versus the pre-year period were 0.88 ± 0.06, 1.02 ± 0.18 and 0.9 ± 0.20, resulting in a pooled ratio of 0.93 ± 0.06 for non-COVID-19 publications., Interpretation: There are marked geographic and national differences in publication productivity during the COVID-19 pandemic. Both COVID-19- and non-COVID-19 publication productivity correlates with epidemiologic, health care system-related and healtheconomic factors, and pre-COVID publication expertise. Countries with a stable scientific infrastructure appear to maintain non-COVID-19 publication productivity nearly at the pre-year level and at the same time use their resilience to produce COVID-19 publications at high rates.

Background: In Germany, public interest in a vegan diet is steadily growing. There are, however, no current data on the macro- and micronutrient status of vegans., Methods: In a cross-sectional study entitled "The Risks and Benefits of a Vegan Diet" (RBVD), we investigated the dietary intake, basic laboratory parameters, vitamin status, and trace-element status of 36 vegans and 36 persons on an omnivorous diet. Each group consisted of 18 men and 18 women aged 30-60., Results: Nearly all the vegans and one-third of the persons on a mixed diet had consumed supplements in the previous 4 weeks. Vegans and nonvegans had similar energy intake but differed in the intake of both macronutrients (e.g., dietary fiber) and micronutrients (e.g., vitamins B12, B2, D, E, and K, as well as folate, iodine, and iron). There were no intergroup differences in the biomarkers of vitamin B12, vitamin D, or iron status. The ferritin values and blood counts indicated iron deficiency in four vegans and three non-vegans. Measurements in 24-hour urine samples revealed lower calcium excretion and markedly lower iodine excretion in vegans compared to non-vegans; in one-third of the vegans, iodine excretion was lower than the WHO threshold value (<20 μg/L) for severe iodine deficiency., Conclusion: Vitamin B12 status was similarly good in vegans and non-vegans, even though the vegans consumed very little dietary B12. This may be due to the high rate of supplementation. The findings imply a need to also assure adequate iodine intake in the population, especially among persons on a vegan diet.

Background: A growing body of research demonstrated impaired executive functions in individuals with severe obesity, including increased sensitivity to reward and impulsive decision making under risk conditions. For the assessment of decision making in patients with severe obesity, studies widely used the Iowa Gambling Task (IGT) or the Delay Discounting Task (DDT), which cover short-term or long-term consequences of decisions only. A further development originating from the field of addiction research is the Cards and Lottery Task (CLT), in which each decision made has conflicting immediate and long-term consequences at the same time. The present study aimed to validate the CLT in individuals with severe obesity., Methods: Patients with severe obesity (N = 78, 67% women, 42.9 ± 10.4 years old, body mass index of 48.1 ± 8.3 kg/m 2 ) were included. Convergent validity was evaluated using the computerized Delay Discounting Task and well-established self-report questionnaires assessing different aspects of impulsivity. For discriminant validity, CLT performance was compared between symptom groups characterized by high versus low impulsivity. The task's clinical validity was evaluated based on associations with general and eating disorder psychopathology, and body mass index. Test-retest reliability was determined by administering the CLT in n = 31 participants without weight-loss treatment one year later. The task's sensitivity to change due to weight loss was evaluated by retesting n = 32 patients one year after receiving obesity surgery., Results: The number of advantageous decisions in the CLT was significantly positively associated with delay discounting and effortful control, and significantly negatively correlated with behavioral impulsivity. CLT performance differed significantly between individuals with and without symptoms of attention-deficit/hyperactivity disorder and between samples with severe obesity and healthy controls. Clinically, CLT performance was significantly associated with general, but not eating disorder psychopathology. The CLT showed moderate test-retest reliability after one year in weight-stable individuals and was sensitive to change in those undergoing obesity surgery., Conclusions: This study identified the CLT to be a highly promising, new complex measure of short- and long-term decision making with good reliability and validity in individuals with severe obesity. Future studies should assess its association with the IGT and predictive value for real-life health behavior., (Copyright © 2020 Schäfer, Schmidt, Müller, Dietrich and Hilbert.)

Whether males and females differ in decision-making remains highly debatable. However, a male advantage in decision making is observed in animal as well as human models of the iowa gambling task (IGT), and, in case of the latter, the difference is observed across a wide range of age groups. It is unclear if these sex differences on the IGT are malleable to environmental influences such as sociocultural factors. We tested sex differences during the uncertainty and risk phases of the IGT in data pooled from three countries that reflected high, moderate, to low gender-equity (Germany, United States, and India: N = 531, female = 269). Comparing the net scores in uncertainty vs. risk blocks (first two vs. last two blocks) confirmed the male-advantage on the IGT across the three countries, specifically in the risk blocks, with the highest male-advantage observed for Germany. Results are discussed in terms of sex differences in reaction to uncertainty vs. risk, and the counter-intuitive effect of gender-equitable environment suggesting that national/environmental factors might influence advantageous decision making, but in ways that accentuate rather than abate sex differences., (Copyright © 2020 Singh, Schiebener, Müller, Liebherr, Brand and Buelow.)

Soils in Germany are commonly low in selenium; consequently, a sufficient dietary supply is not always ensured. The extent of such provision adequacy is estimated by the optimal effect range of biomarkers, which often reflects the physiological requirement. Preceding epidemiological studies indicate that low selenium serum concentrations could be related to cardiovascular diseases. Inter alia, risk factors for cardiovascular diseases are physical inactivity, overweight, as well as disadvantageous eating habits. In order to assess whether these risk factors can be modulated, a cardio-protective diet comprising fixed menu plans combined with physical exercise was applied in the German MoKaRi (modulation of cardiovascular risk factors) intervention study. We analyzed serum samples of the MoKaRi cohort (51 participants) for total selenium, GPx activity, and selenoprotein P at different timepoints of the study (0, 10, 20, 40 weeks) to explore the suitability of these selenium-associated markers as indicators of selenium status. Overall, the time-dependent fluctuations in serum selenium concentration suggest a successful change in nutritional and lifestyle behavior. Compared to baseline, a pronounced increase in GPx activity and selenoprotein P was observed, while serum selenium decreased in participants with initially adequate serum selenium content. SELENOP concentration showed a moderate positive monotonic correlation (r = 0.467, p < 0.0001) to total Se concentration, while only a weak linear relationship was observed for GPx activity versus total Se concentration (r = 0.186, p = 0.021). Evidently, other factors apart from the available Se pool must have an impact on the GPx activity, leading to the conclusion that, without having identified these factors, GPx activity should not be used as a status marker for Se.

While the use of social media and online-communication applications has become an integral part of everyday life, some individuals suffer from an excessive, uncontrolled use of social media despite experiencing negative consequences. In accordance with neuropsychological models of addiction, we assume the tendency of a social-networks-use disorder to be related to an interplay of predisposing personality traits (e.g., impulsivity), and reductions in cognitive functions (e.g., executive functions, inhibitory control). The current study makes first strides towards examining this interplay. In addition to a newly developed social-networks-specific auditory Go-NoGo paradigm, other neuropsychological paradigms were used. Impulsivity and social-networks-use-disorder symptoms were assessed by standardized questionnaires. The results show that the symptom severity of a social-networks-use disorder is mainly associated with attentional impulsivity. General executive functions and specific inhibitory control of social-networks-related cues have no direct effect on symptom severity. However, moderated regression analyses emphasize that increased symptom severity is associated with higher attentional impulsivity, especially if there are additionally reductions in executive functions or specific inhibitory control. The results complement previous findings and inform future research on social-networks-use disorder. The findings support the applicability of theoretical models of addictive behaviors to the social-networks-use disorder and point to social-networks-related specificities regarding attention-related facets.

Aims of the Study: An extracorporeal membrane oxygenation system (ECMO), as a bridge to either recovery, a ventricular assist device (VAD), or heart or lung transplantation, may be the only lifesaving option for critically ill patients suffering from refractory cardiac, respiratory or combined cardiopulmonary failure. As peripheral hospitals may not offer ECMO treatment, tertiary care centres provide specialised ECMO teams for on-site implantation and subsequent patient transfer on ECMO to the tertiary hospital. This study reports the results of the largest ECMO transportation programme in Switzerland and describes its feasibility and safety., Methods: Patients transported on ECMO by our mobile ECMO team to our tertiary centre between 1 September 2009 and 31 December, 2016 underwent retrospective analysis. Implantation was performed by our specialised ECMO team (primary transport) or by the medical staff of the referring hospital (secondary transport) with subsequent transfer to our institution. Type of ECMO, transport data, patient baseline characteristics, operative variables and postoperative outcomes including complications and mortality were collected from medical records., Results: Fifty-eight patients were included (three patients excluded: one repatriation, two with incomplete medical records). Thirty-five patients (60%) received veno-venous, 22 (38%) veno-arterial and one patient (2%) veno-venoarterial ECMO. Forty-nine (84%) patients underwent primary and nine (16%) secondary transport. Thirty-five (60%) patients were transferred by helicopter and 23 (40%) by ambulance, with median distances of 38.1 (13&ndash;225) km and 21 (3-71) km respectively. No clinical or technical complications occurred during transportation. During hospitalisation, three patients had ECMO-associated complications (two compartment syndrome of lower limb, one haemothorax after central ECMO upgrade). Median days on ECMO was 8 (&lt;1&ndash;49) and median days in hospital was 17 (&lt;1&ndash;122). ECMO weaning was successful in 41 patients (71%), on-transport survival was 100%, 40 patients survived to discharge (69%), and overall survival was 67% (39 patients) at a median follow-up of 58 days (&lt;1&ndash;1441). Cumulative survival was significantly affected by cardiogenic shock vs. ARDS (p = 0.001), veno-arterial and veno-venoarterial vs. veno-venous ECMO (p = 0.001) and after secondary vs. primary transport (p &lt;0.001). The ECMO weaning rate was significantly lower after secondary transfer (22%, two patients, both vaECMO) vs. primary transfer (80%, p = 0.002, 39 patients of which 35 (71%) had vvECMO)., Conclusions: The first results of our ECMO transportation programme show its feasibility, safety and efficacy without on-site implant or on-transport complications or mortality. The favourable early survival may justify the large effort with respect to logistics, costs and manpower. With rising awareness, referring centres may increasingly consider this lifesaving option at an early stage, which may further improve outcomes.

The integration of redox- and reactive oxygen species-dependent signaling and metabolic activities is fundamental to plant acclimation to biotic and abiotic stresses. Previous data suggest the existence of a dynamically interacting module in the chloroplast stroma consisting of cyclophilin 20-3 (Cyp20-3), O-acetylserine(thiol)lyase B (OASTL-B), 2-cysteine peroxiredoxins A/B (2-CysPrx) and serine acetyltransferase 2;1 (SERAT2;1). The functionality of this COPS module is influenced by redox stimuli and oxophytodienoic acid (OPDA), which is the precursor for jasmonic acid. The concept of an integrating function of these proteins in stress signaling was challenged by combining transcriptome and biochemical analyses in Arabidopsis mutants devoid of oastlB, serat2;1, cyp20-3 and 2-cysprxA/B, and wild-type (WT). Leaf transcriptomes were analyzed 6 h after transfer to light intensity 10-fold in excess of growth light or under growth light. The survey of KEGG-based gene ontology groups showed common upregulation of translation- and protein homeostasis-associated transcripts under control conditions in all mutants compared with WT. The results revealed that the interference of the module was accompanied with disturbance of carbohydrate, sulfur and nitrogen metabolism, and also citric acid cycle intermediates. Apart from common regulation, specific responses at the transcriptome and metabolite level linked Cyp20-3 to cell wall-bound carbohydrates and oxylipin signaling, and 2-CysPrx to photosynthesis, sugar and amino acid metabolism. Deletion of either OASTL-B or SERAT2;1 frequently induced antagonistic changes in biochemical or molecular features. Enhanced sensitivity of mutant seedlings to OPDA and leaf discs to NaHS-administration confirmed the presumed functional interference of the COPS module in redox and oxylipin signaling., (© 2017 The Authors The Plant Journal © 2017 John Wiley & Sons Ltd.)

Arsenic-containing fatty acids are a group of fat-soluble arsenic species (arsenolipids) which are present in marine fish and other seafood. Recently, it has been shown that arsenic-containing hydrocarbons, another group of arsenolipids, exert toxicity in similar concentrations comparable to arsenite although the toxic modes of action differ. Hence, a risk assessment of arsenolipids is urgently needed. In this study the cellular toxicity of a saturated (AsFA 362) and an unsaturated (AsFA 388) arsenic-containing fatty acid and three of their proposed metabolites (DMA V , DMAPr and thio-DMAPr) were investigated in human liver cells (HepG2). Even though both arsenic-containing fatty acids were less toxic as compared to arsenic-containing hydrocarbons and arsenite, significant effects were observable at μM concentrations. DMA V causes effects in a similar concentration range and it could be seen that it is metabolised to its highly toxic thio analogue thio-DMA V in HepG2 cells. Nevertheless, DMAPr and thio-DMAPr did not exert any cytotoxicity. In summary, our data indicate that risks to human health related to the presence of arsenic-containing fatty acids in marine food cannot be excluded. This stresses the need for a full in vitro and in vivo toxicological characterisation of these arsenolipids.

Background: When trauma patients arrive in the emergency department (ED), coagulopathy frequently is present. The time course, however, in which this coagulopathy develops is poorly understood. No study has fully evaluated the coagulation status, including thromboelastometry on-scene and at hospital arrival. We hypothesized that measured coagulation variables might change when measured at the scene of injury and upon arrival to the ED., Methods: We performed a prospective, single-center, observational study investigating coagulation status in 50 trauma patients on-scene and at arrival in the ED. Measurements included arterial blood gases, ROTEM®, protein S100, protein C activity, protein S, Quick value, international normalized ratio, activated partial thromboplastin time, D-dimer, coagulation factor V (FV), coagulation factor XIII (FXIII), fibrinogen, hemoglobin, hematocrit, platelets, and volume and blood products being administered during the first 24 hours., Results: Significant changes between on-scene and the ED were observed for the following values: partial venous oxygen pressure increased and sodium, glucose, and lactate decreased. For EXTEM, INTEM, and APTEM, clotting time and clot formation time increased significantly, whereas maximal clot firmness and angle α decreased significantly (all P ≤ 0.004). For FIBTEM, clotting time increased significantly and maximal clot firmness decreased significantly. In the laboratory, significant reductions in hemoglobin, hematocrit, platelets, activated partial thromboplastin time, fibrinogen, FV, FXIII, protein C activity, protein S, and protein S100 were observed (all P ≤ 0.001)., Conclusions: Although most all laboratory and rotational thromboelastometry coagulation tests worsened over time when measured on-scene and in the ED, monitoring coagulation at the scene of trauma does not provide clinically important information in a majority of trauma patients. One hour after injury, significant activation and consumption of fibrinogen, FV, FXIII, protein C activity, and protein S were observed.

This work presents the development of a robotic wheelchair that can be commanded by users in a supervised way or by a fully automatic unsupervised navigation system. It provides flexibility to choose different modalities to command the wheelchair, in addition to be suitable for people with different levels of disabilities. Users can command the wheelchair based on their eye blinks, eye movements, head movements, by sip-and-puff and through brain signals. The wheelchair can also operate like an auto-guided vehicle, following metallic tapes, or in an autonomous way. The system is provided with an easy to use and flexible graphical user interface onboard a personal digital assistant, which is used to allow users to choose commands to be sent to the robotic wheelchair. Several experiments were carried out with people with disabilities, and the results validate the developed system as an assistive tool for people with distinct levels of disability.

Background: Germline genetic testing for familial cancer syndromes is usually performed serially for the most likely genetic causes. In recent years the way genetic testing carried out has changed, as next generation sequencing now allows the simultaneous testing of multiple susceptibility genes at low costs., Case Presentation: Here, we present a female with bilateral breast cancer and endometrial adenocarcinoma. After simultaneous sequencing of 150 genes (890 kb) associated with hereditary cancer we identified pathogenic mutations in two high-penetrance genes, i.e. TP53 and CDH1 that would most likely not have been elucidated by serial screening of candidate genes., Conclusion: As the two mutated genes are located on different chromosomes and cause different cancer syndromes these findings had a tremendous impact not only on genetic counseling of the index patient and her family but also on subsequent surveillance strategies.

Förster resonance energy transfer (FRET) describes excitation energy exchange between two adjacent molecules typically in distances ranging from 2 to 10 nm. The process depends on dipole-dipole coupling of the molecules and its probability of occurrence cannot be proven directly. Mostly, fluorescence is employed for quantification as it represents a concurring process of relaxation of the excited singlet state S1 so that the probability of fluorescence decreases as the probability of FRET increases. This reflects closer proximity of the molecules or an orientation of donor and acceptor transition dipoles that facilitates FRET. Monitoring sensitized emission by 3-Filter-FRET allows for fast image acquisition and is suitable for quantifying FRET in dynamic systems such as living cells. In recent years, several calibration protocols were established to overcome to previous difficulties in measuring FRET-efficiencies. Thus, we can now obtain by 3-filter FRET FRET-efficiencies that are comparable to results from sophisticated fluorescence lifetime measurements. With the discovery of fluorescent proteins and their improvement toward spectral variants and usability in plant cells, the tool box for in vivo FRET-analyses in plant cells was provided and FRET became applicable for the in vivo detection of protein-protein interactions and for monitoring conformational dynamics. The latter opened the door toward a multitude of FRET-sensors such as the widely applied Ca(2+)-sensor Cameleon. Recently, FRET-couples of two fluorescent proteins were supplemented by additional fluorescent proteins toward FRET-cascades in order to monitor more complex arrangements. Novel FRET-couples involving switchable fluorescent proteins promise to increase the utility of FRET through combination with photoactivation-based super-resolution microscopy.

Genetically modified antigen-presenting cells (APC) represent an attractive strategy for in vitro immunomodulation. In the human system, APC expressing HLA-A1 and a membrane-bound form of CD95L (m-CD95L) were used for selective depletion of HLA-A1-specific T cells. In short-term assays, m-CD95L-expressing APC-induced apoptosis in activated T cells and the constitutive presence of m-CD95L and HLA-A1 expressing APC in long-term T cell cultures prevented the expansion of CD4(+) and CD8(+) HLA-A1-specific T cells and the development of HLA-A1-specific cytotoxicity. However, immunity towards third party, viral and bacterial antigens was maintained and T cells spared from depletion could be induced to develop cytotoxicity towards unrelated antigens. Interestingly, inhibition of HLA-A1-specific T cell response absolutely requires the coexpression of m-CD95L and HLA-A1 antigen on the same APC. Thus, m-CD95L expressing APC might be used in clinical settings to obtain tolerance induction in allogeneic transplantation systems or autoimmune diseases.

The thymus organ supports the development of T cells and is located in the thorax. Here, we report the existence of a second thymus in the mouse neck, which develops after birth and grows to the size of a small lymph node. The cervical thymus had a typical medulla-cortex structure, was found to support T cell development, and could correct T cell deficiency in athymic nude mice upon transplantation. The identification of a regular second thymus in the mouse may provide evolutionary links to thymus organogenesis in other vertebrates and suggests a need to reconsider the effect of thoracic thymectomy on de novo T cell production.

The thymus harbors an organ-typical dense network of branching and anastomosing blood vessels. To address the molecular basis for morphogenesis of this thymus-specific vascular pattern, we have inactivated a key vascular growth factor, VEGF-A, in thymus epithelial cells (TECs). Both Vegf-A alleles were deleted in TECs by a complementation strategy termed nude mouse [mutated in the transcription factor Foxn1 (forkhead box N1)] blastocyst complementation. Injection of Foxn1(+/+) ES cells into Foxn1(nu/nu) blastocysts reconstituted a functional thymus. By dissecting thymus stromal cell subsets, we have defined, in addition to medullary TECs (mTECs) and cortical TECs (cTECs), another prominent stromal cell subset designated cortical mesenchymal cells (cMes). In chimeric thymi, mTECs and cTECs but not cMes were exclusively ES cell-derived. According to this distinct origin, the Vegf-A gene was deleted in mTECs and cTECs, whereas cMes still expressed Vegf-A. This genetic mosaic was associated with hypovascularization and disruption of the organ-typical network of vascular arcades. Thus, vascular growth factor production by TECs is required for normal thymus vascular architecture. These experiments provide insights into Foxn1-dependent and Foxn1-independent stromal cell development and demonstrate the value of this chimeric approach to analyzing gene function in thymus epithelium.

We report on the first HLA B13-restricted minimal cytotoxic T lymphocyte (CTL) epitope RQDILDLWI (RI9, amino acids 106-114 in HIV-1 Nef). In most patients the frequency of RI9-specific CTL exceeded the number of CTL against other epitopes, indicating that RI9 is a dominant epitope in HLA B13-positive patients. Targeting this conserved Nef epitope may be an important factor for the published association of HLA B13 with a favourable course of HIV-1 infection.

Primary Immunodeficiencies constitute a group of highly complex congenital disorders most of which are characterized by a very poor prognosis. Allogeneic hematopoietic stem cell transplantation (HSCT) has become an established curative treatment approach in many of these disorders, which may be permanently corrected. In this presentation basic and practical aspects of HSCT are presented, with an emphasis on its application in lymphocyte disorders such as severe combined immunodeficiency (SCID). Optimal results and outcome of HSCT are highly dependant on early and correct diagnosis of these rare disorders, and HSCT should usually be applied early in the course of the disease in order to prevent irreversible complications from infections. Clinical results will be summarized based on recent analysis performed in large patient cohorts, which have shown steady improvements and have led to a marked change in the prognosis of patients with primary immunodeficiencies.

Infantile osteopetrosis (OP) carries an extremely poor prognosis unless treated early by hematopoietic stem cell transplantation. We explored the use of purified blood progenitor cells from HLA-haploidentical parents in 7 patients lacking suitable matched donors. Blood progenitor cells were purified by positive selection and by additional T-cell depletion using rosette formation. For conditioning, patients received busulfan, thiotepa, and either cyclophosphamide (5 patients) or fludarabine (2 patients). Stable donor engraftment developed in 6 of 7 patients. Graft-versus-host disease was not observed. Three of the 7 patients had no major complications and 4 of 7 had both veno-occlusive disease and respiratory failure. Five of 7 patients survive with complete cure of OP at a median of 4 years. Patients with OP lacking HLA-matched donors can be successfully treated by transplantation of purified blood progenitor cells from HLA-haploidentical donors.

A study in 121 infants with severe combined immunodeficiency (SCID) was performed to determine the prevalence of an engraftment by transplacentally acquired maternal T cells and to explore clinical and immunological findings related to this abnormality. Each newly diagnosed patient with SCID presenting with circulating T cells was evaluated for chimerism by performing selective HLA typing of T cells and non-T cells. In patients with engraftment, maternal T cells were characterized phenotypically and functionally, and results were correlated with clinical findings in the patients. Maternal T cells were detected in the circulation in 48 patients; these cells ranged from fewer than 100/microL in 14 cases to more than 2000/microL in 4 cases (median, 415/microL). Clinical signs of graft-versus-host disease (GVHD) were absent in 29 patients. In the other cases, manifestations of GVHD were present, involving the skin and in 14 cases also the liver. Skin GVHD was mild in 8 patients. In these patients, as well as in patients with no signs of GVHD, maternal T cells were predominantly CD8(+) and, with one exception, failed to respond to mitogen stimulation. In 9 patients, manifestations of skin GVHD were prominent. T cells in these cases were predominantly CD4(+) and responded, with one exception, to mitogen stimulation. In 8 of the cases with prominent skin GVHD, the underlying SCID variant was characterized by the absence of B cells. In this study, further understanding is provided of a phenomenon that is responsible for the significant heterogeneity of clinical and immunological findings in SCID.

Donor T cells after stem cell transplantation reconstitute by 2 different pathways: by expansion from grafted, mature T cells and by intrathymic maturation from progenitor cells. This study characterized thymic-dependent reconstitution of CD4(+) T cells following different transplant modalities in patients with severe combined immunodeficiency (SCID). Three groups of patients were studied: one group after transplantation from human leukocyte antigen (HLA)-identical siblings with unmanipulated grafts without conditioning, a second group after transplantation from HLA-nonidentical parents with T-cell-depleted grafts without preconditioning, and a third group with prior conditioning. Reconstitution of the T-cell compartment was monitored by determining the expression of CD45 isoforms by developing CD4(+) cells in the peripheral blood and in discriminating expanded (CD45RO(+)) and newly generated (CD45RA(+)) T cells. Concomitantly, changes in the size of the thymus were evaluated sequentially by ultrasonography. Reconstitution of CD4(+)CD45RA(+) cells was delayed in all patients for several months, including patients after HLA-identical transplantation, and was always paralleled by normalization of the size of the thymus. No engraftment of donor progenitor cells was observed, as studied in one patient transplanted without conditioning. CD4(+)CD45RO(+) cells were detected early after transplantation only in patients given unmanipulated grafts. The study showed that thymic-dependent T-cell maturation in these patients with SCID runs an autonomous course, independent of graft manipulation, of major HLA disparities, and of whether conditioning is used or not. In addition, thymic maturation may not require engraftment of donor-derived CD34(+) cells in the marrow. (Blood. 2000;96:4344-4349)

The potent calciotropic hormone calcitriol (1,25-dihydroxyvitamin D3, 1,25(OH)2D3) has been shown to be very effective and safe in the topical treatment of psoriasis. In vitro, 1,25(OH)2D3 inhibits proliferation and stimulates differentiation of human keratinocytes. Increasing evidence suggests an immunoregulatory function of this potent steroid hormone. To further characterize the biological effects of topical calcitriol treatment in psoriasis, we have analyzed immunohistochemically the expression of markers for epidermal proliferation (proliferating cell nuclear antigen=PCNA) and differentiation (transglutaminase K, involucrin, cytokeratin 16), as well as inflammation (CD1a, 55 kDa TNF-receptor, NAP-1/IL-8) in calcitriol-treated psoriatic skin in situ. Our findings strongly support the hypothesis that calcitriol modulates keratinocyte proliferation/differentiation as well as inflammation in human skin in vivo. The immunoreactivity of markers for epidermal proliferation and differentiation, as well as of CD1a and NAP-1/IL-8, changed after 8 weeks of calcitriol treatment almost completely to the pattern characteristic for non-lesional psoriatic skin, while a large number of 55 kDa TNF-receptor positive cells could be found in the dermal compartment.