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ZusammenfassungSchwere Arzneimittelnebenwirkungen stellen mit 5–7 % einen häufigen Grund für eine Krankenhauseinweisung dar. Die Prävalenz von unerwünschten Arzneimittelwirkungen (UAW) während eines stationären Aufenthaltes liegt sogar bei etwa 11,5 %. Die Ursache sind oftmals Medikamentenwechselwirkungen, bedingt durch die Polypharmazie der multimorbiden älteren Patienten. So nimmt ein 65-jähriger Patient im Durchschnitt 5 Medikamente gleichzeitig ein. Aufgrund des zunehmenden Einsatzes von Systemtherapeutika in der Dermatologie und der gleichzeitig zunehmenden Polypharmazie ist das Wissen um Medikamenteninteraktionen für den Dermatologen zur Vermeidung schwerer Arzneimittelnebenwirkungen wesentlich. Dieser Beitrag soll eine Hilfestellung bieten, Patienten und Medikamente mit einem hohen Risiko für schwerwiegende Interaktionen zu identifizieren und dadurch das Auftreten unerwünschter Wirkungen oder auch die Verminderung des therapeutischen Effektes von Wirkstoffen zu vermeiden. Wir möchten darauf hinweisen, dass die folgende Arbeit einzelne Aspekte behandelt und nicht von der Überprüfung einzelner Arzneimittelinteraktionen mittels Interaktionsprogrammen entbindet. Nicht außer Acht gelassen werden sollte, dass neben verschreibungspflichtigen Medikamenten auch Nahrungsmittel, Nahrungsergänzungsmittel und Kräuter zu Interaktionen mit Medikamenten führen können.

Hidradenitis suppurativa (HS) and psoriasis vulgaris (PSO) are chronic inflammatory dermatoses in which proinflammatory cytokines, such as IL-17, play a central role. The prevalence of keratoconjunctivitis sicca (KCS) is commonly higher in PSO than in healthy individuals. This study was thus set up to investigate the prevalence of KCS among patients with HS.In a cross-sectional study standardized tear film parameters and symptom-oriented questionnaires (OSDI, SPEED) were analyzed in a total of 71 subjects (HS n = 20, PSO n = 20, healthy controls n = 31). Additionally, IL-17 and MMP-9 in the tear film were analyzed. These parameters were correlated to the clinical severity of the skin disease. PSO patients served as inflammatory control group.There were statistically significant differences in OSDI (Data show that subjective complaints of KCS may be associated with HS and correlate with the severity of the respective Hurley stage, but do not involve alterations of tear film MMP-9 and IL-17. Clinicians should remain mindful that ocular complications in HS are often more vague than in psoriatic patients, but dry eye symptoms might be detrimental for the patients' quality of life.

The vagus nerve constitutes a key link between the vegetative and the central nervous system. However, the impact of vagal activity on cognitive processes is largely unknown. Recent studies in animals and humans show that vagus nerve stimulation is associated with enhanced reward-seeking and dopamine-release in the brain. Social interaction recruits similar brain circuits to reward processing. We hypothesize that vagus nerve stimulation (VNS) boosts rewarding aspects of social behavior and compare the impact of transcutaneous VNS (tVNS) and sham stimulation on social interaction in 19 epilepsy patients in a double-blind pseudo-randomized study. Using a well-established paradigm, i.e., the prisoner’s dilemma, we investigate effects of stimulation on cooperative behavior, as well as interactions of stimulation effects with patient characteristics. A repeated-measures ANOVA and a linear mixed-effects model provide converging evidence that tVNS boosts cooperation. Partial correlations reveal that this effect varies as a function of neuroticism, a personality trait linked to the dopaminergic system. Behavioral modeling indicates that tVNS induces a behavioral starting bias towards cooperation, which is independent of the decision process. This study provides evidence for the causal influence of vagus nerve activity on social interaction and may have clinical implications for disorders affecting social behavior.

Objective: This study was undertaken to identify temporal encephaloceles (TEs) and examine their characteristics in patients with temporal lobe epilepsy (TLE) and ex- tratemporal lobe epilepsy (ETLE), as well as in asymptomatic cases. Methods: Four hundred fifty-eight magnetic resonance imaging scans were exam- ined retrospectively to identify TE in 157 patients with TLE, 150 patients with ETLE, and 151 healthy controls (HCs). Results: At least one TE was identified in 9.6% of the TLE patients (n = 15, 95% confidence interval [CI] = 5.3%–15.3%), in 3.3% of patients with ETLE (n = 5, 95% CI = 1.1%–7.6%), and in 2.0% of the HCs (n = 3, 95% CI = .4%–5.7%), indicating a significantly higher frequency in patients with TLE compared to ETLE and HC sub- jects (p = .027, p = .005). Examining the characteristics of TEs in both asymptomatic and epilepsy patients, we found that TEs with a diameter of less than 6.25 mm were more likely to be asymptomatic, with a sensitivity of 91.7% and a specificity of 73.3% (area under the curve = .867, 95% CI = .723–1.00, p = .001). Significance: Temporal encephaloceles may occur without presenting any clinical symp- toms. Patients with TLE show a higher frequency of TEs compared to the ETLE and HC groups. According to our study, TE size could be used to suggest potential epileptogenicity.

Whereas the effect of vagal nerve stimulation on emotional states is well established, its effect on cognitive functions is still unclear. Recent rodent studies show that vagal activation enhances reinforcement learning and neuronal dopamine release. The influence of vagal nerve stimulation on reinforcement learning in humans is still unknown. Here, we studied the effect of transcutaneous vagal nerve stimulation on reinforcement learning in eight long-standing seizure-free epilepsy patients, using a well-established forced-choice reward-based paradigm in a cross-sectional, within-subject study design. We investigated vagal nerve stimulation effects on overall accuracy using non-parametric cluster-based permutation tests. Furthermore, we modelled sub-components of the decision process using drift-diffusion modelling. We found higher accuracies in the vagal nerve stimulation condition compared to sham stimulation. Modelling suggests a stimulation-dependent increase in reward sensitivity and shift of accuracy-speed trade-offs towards maximizing rewards. Moreover, vagal nerve stimulation was associated with increased non-decision times suggesting enhanced sensory or attentional processes. No differences of starting bias were detected for both conditions. Accuracies in the extinction phase were higher in later trials of the vagal nerve stimulation condition, suggesting a perseverative effect compared to sham. Together, our results provide first evidence of causal vagal influence on human reinforcement learning and might have clinical implications for the usage of vagal stimulation in learning deficiency., Weber et al. demonstrate for the first time that vagal nerve stimulation in humans enhances reinforcement learning and decelerates extinction of learned behaviour. Behavioural modelling indicates that vagal stimulation increases reward sensitivity and shifts accuracy-speed trade-offs towards maximizing rewards., Graphical Abstract Graphical Abstract

Objectives Memory complaints in patients with epilepsy have been well-studied. Although memory complaints are commonly reported by patients with chronic epilepsy, to date, few studies exist on memory complaints at the onset of epilepsy. The present study investigated the presence of memory complaints and their relation to mood and memory performance in patients after their first seizure. Thereby, we examined differences between individuals who received a diagnosis of epilepsy immediately with the occurrence of their first seizure and those who were diagnosed as having the first epileptic seizure, without fulfilling the ILAE criteria for the diagnosis of epilepsy. Methods Sixty-one patients participated in the study and completed, among others, a memory task and questionnaires on memory complaints and depression after their first epileptic seizure. We investigated the level of memory complaints and their correlation and accuracy in classification with a memory measure. We compared patients who received an epilepsy diagnosis after the first seizure with those who did not. Results Memory complaints did not correlate with objective memory performance. Classification into impaired/unimpaired showed low concordance between memory complaints and neuropsychological memory measures. After their first epileptic seizure, patients reported few memory complaints overall (10%), and there were no differences in memory complaints between patients with and without an epilepsy diagnosis. Conclusion At epilepsy onset, in contrast to established epilepsies, memory complaints are rare. Although influences of anticonvulsant drugs and seizures are not present at the beginning of epilepsy, this substantial absence of memory complaints at epilepsy onset emphasizes the need for comprehensive neurological and psychological treatment early with the given diagnosis. Treatment should focus on anticonvulsant drug regimens, patients’ concerns and convey realistic expectations.

Summary Objectives The aim of the present study was to evaluate the safety and efficacy of the add-on treatment of stiripentol (STP) in adult patients with severely pharmacoresistant focal or multifocal epilepsy. Methods Data on adult patients treated with STP from March 2007 to July 2020 and with at least one clinical follow-up (FU) were retrospectively reviewed. Data on tolerability, efficacy and concomitant medication were evaluated at baseline, 6 months (5.5 ± 1.6 months (mean ± SD)) and 12 months (13.1 ± 3.9 months (mean ± SD)). Results Data of 22 patients (54.5% male, mean age 34.4 ± 17.79 years (mean ± SD), including mean duration of epilepsy 17.6 ± 25.5 years (mean ± SD), median seizure frequency 30 ± 20 (median ± MAD) per month, and 63.6% being severely intellectually disabled, with 3 to 18 previous anti-seizure-drugs (ASD), were collected. After 6 months, 72.7% of the patients were still taking STP, and 31% of the patients were responders, including 13% who were seizure-free. The 12-month retention rate was 54.4 %, the response rate was 36.4% and 13.6% of patients were seizure-free at the 12-month FU. Reasons for discontinuation were increased seizure frequency, hyperammonaemia and encephalopathy. Conclusion STP seems to be a useful option in the treatment of patients with severely pharmacoresistant epilepsy. Prospective trials are necessary to examine the efficacy of STP in adult patients with pharmacoresistant focal epilepsy.

Background Transcutaneous auricular vagus nerve stimulation (taVNS) has been investigated regarding its therapeutic properties in several several conditions such as epilepsy, migraine and major depressive disorder and was shown to access similar neural pathways as invasive vagus nerve stimulation. While the vagus nerve's role in gut motility is physiologically established, the effect of taVNS has scarcely been investigated in humans and yielded conflicting results. Real-time gastric magnetic resonance imaging (rtMRI) is an established reproducible method to investigate gastric motility non-invasively. Objective To investigate the influence of taVNS on gastric motility of healthy participants using rtMRI. Methods We conducted a randomized, double-blind study using high-frequency (HF) stimulation at 25Hz or low-frequency (LF) taVNS at 1Hz after ingestions of a standardized meal in 57 healthy participants. The gastric motility index (GMI) was determined by measuring the amplitude and velocity of the peristaltic waves using rtMRI. Results After HF taVNS, GMI was significantly higher than after LF stimulation (p = 0.005), which was mainly attributable to a higher amplitude of the peristaltic waves (p = 0.003). Conclusion We provide evidence that 4-h of taVNS influences gastric motility in healthy human participants for the first time using rtMRI. HF stimulation is associated with higher amplitudes of peristaltic waves in the gastric antrum compared to LF stimulation. Further studies are needed to investigate the effect of different frequencies of taVNS and its therapeutic properties in conditions with impaired gastric motility.

Severe pharmacological side effects have an occurrence of 5-7% and represent a frequent reason for hospital admission. The prevalence of undesired pharmacological side effects during hospitalization is even higher with approximately 11.5%. The causes are often interactions between drugs due to the polypharmacy of multimorbid older patients. On average, a 65-year-old male patient will simultaneously be taking 5 medications. Due to the increasing use of systemic drugs in dermatology and the simultaneously increasing polypharmacy, knowledge of interactions between medications is essential for dermatologists in order to avoid severe side effects of drugs. This article provides assistance in order to identify patients and medications with a high risk for severe interactions and, therefore, to avoid the occurrence of undesired effects or the reduction of the therapeutic effects of active substances. We would like to point out that this article deals with individual aspects and does not mean that the testing of individual drug interactions with interaction programs can be omitted. It should also not be neglected that in addition to prescription-only drugs, foodstuffs, dietary supplements and herbs can also lead to interactions with medications.Schwere Arzneimittelnebenwirkungen stellen mit 5–7 % einen häufigen Grund für eine Krankenhauseinweisung dar. Die Prävalenz von unerwünschten Arzneimittelwirkungen (UAW) während eines stationären Aufenthaltes liegt sogar bei etwa 11,5 %. Die Ursache sind oftmals Medikamentenwechselwirkungen, bedingt durch die Polypharmazie der multimorbiden älteren Patienten. So nimmt ein 65-jähriger Patient im Durchschnitt 5 Medikamente gleichzeitig ein. Aufgrund des zunehmenden Einsatzes von Systemtherapeutika in der Dermatologie und der gleichzeitig zunehmenden Polypharmazie ist das Wissen um Medikamenteninteraktionen für den Dermatologen zur Vermeidung schwerer Arzneimittelnebenwirkungen wesentlich. Dieser Beitrag soll eine Hilfestellung bieten, Patienten und Medikamente mit einem hohen Risiko für schwerwiegende Interaktionen zu identifizieren und dadurch das Auftreten unerwünschter Wirkungen oder auch die Verminderung des therapeutischen Effektes von Wirkstoffen zu vermeiden. Wir möchten darauf hinweisen, dass die folgende Arbeit einzelne Aspekte behandelt und nicht von der Überprüfung einzelner Arzneimittelinteraktionen mittels Interaktionsprogrammen entbindet. Nicht außer Acht gelassen werden sollte, dass neben verschreibungspflichtigen Medikamenten auch Nahrungsmittel, Nahrungsergänzungsmittel und Kräuter zu Interaktionen mit Medikamenten führen können.

Since its introduction, functional transcranial Doppler sonography (fTCD) has been extensively applied in research and clinical settings and has now become part of the routine presurgical work-up of patients with epilepsy. Because of its importance in planning neurosurgical interventions and predicting possible cognitive risks, the reproducibility of fTCD in determining hemispheric language lateralization (HLL) has to be ensured. In the present study, fTCD was performed twice in 33 initially lateralized patients with temporal lobe epilepsy (TLE) as part of their presurgical work-up, using a standard word generation paradigm. Initially, the standard analysis, including only the statistical examination of fTCD data, was applied, and a rather poor retest reliability of r = 0.41 was obtained (p = 0.017). Because of doubts concerning appropriate task performance in some patients, subsequently, a two-step data analysis was introduced, including an additional qualitative evaluation of fTCD data regarding (1) instruction-compliant task performance, (2) sufficient quality of the baseline phase, and (3) adequate increase in cerebral blood flow velocity (CBFV) during the activation phase. Attributable to a more valid interpretation of fTCD data after the application of the qualitative step, the reproducibility of HLL significantly improved (p = 0.007) to a high retest reliability of r = 0.84 (p In clinical settings, psychological and situational factors seem to strongly influence the reproducibility of fTCD determining HLL. Accordingly, we highly recommend the complementation of the standard statistical examination of fTCD data by an additional qualitative evaluation (two-step data analysis), as this extra security is particularly desirable because of its direct implications for the further evaluation of neurosurgical interventions. This article is part of the Special Issue "Individualized Epilepsy Management: Medicines, Surgery and Beyond".

The Flynn effect describes an increase in intelligence quotient (IQ) in the general population of about 3 points per decade. While this effect is well established in healthy individuals, research exploring the link to brain pathologies is scarce. We investigated the Flynn effect in a German sample of 203 patients with epilepsy with left, right, and bilateral lesions. Intelligence quotient values were obtained using the Wechsler Adult Intelligence Scales (WAIS) III and IV. Our results showed a stable Flynn effect with nearly no difference in adjusted full scale IQ (FSIQ) scores (0.02 IQ points) between the WAIS-III and WAIS-IV samples. There were no significant interactions between the side of pathology and corrected IQ values. Our sample showed a tendency towards performing worse in the WAIS-IV in three out of four subscales independently of the Flynn effect, pointing out methodological differences between the newer Wechsler editions. However, although patients with bilateral lesions performed worst across all subscales, they exhibited a similar pattern as patients with lesions in the left or right hemisphere, indicating that also more severe forms of brain pathologies can profit from the mechanisms behind the Flynn effect.

Objectives To assess first clinical experiences with brivaracetam (BRV) in the treatment of epilepsies. Methods Data on patients treated with BRV from February to December 2016 and with at least one clinical follow-up were collected from electronic patient records. Data on safety and efficacy were evaluated retrospectively. Results In total, 93 patients were analyzed; 12 (12.9%) received BRV in monotherapy. The mean duration to follow-up was 4.85 months (MD = 4 months; SD = 3.63). Fifty-seven patients had more than one seizure per month at baseline and had a follow-up of more than 4 weeks; the rate of ≥50% responders was 35.1% (n = 20) in this group, of which five (8.8%) patients were newly seizure-free. In 50.5% (47/93), patients were switched from levetiracetam (LEV) to BRV, of which 43 (46.2%) were switched immediately. Adverse events (AE) occurred in 39.8%, with 22.6% experiencing behavioral and 25.8% experiencing non-behavioral AE. LEV-related AE (LEV-AE) were significantly reduced by switching to BRV. The discontinuation of BRV was reported in 26/93 patients (28%); 10 of those were switched back to LEV with an observed reduction of AE in 70%. For clinical reasons, 12 patients received BRV in monotherapy, 75% were seizure–free, and previous LEV-AE improved in 6/9 patients. BRV-related AE occurred in 5/12 cases, and five patients discontinued BRV. Conclusion BRV seems to be a safe, easy, and effective option in the treatment of patients with epilepsy, especially in the treatment of patients who have psychiatric comorbidities and might not be good candidates for LEV treatment. BRV broadens the therapeutic spectrum and facilitates personalized treatment.

We propose a conceptual model of how time pressure affects emotional well-being associated with mundane routine activities. A selective review of research in several areas affirms the plausibility of the conceptual model, which posits negative effects on emotional well-being of insufficient time allocated to restorative and other activities instrumental for attaining desirable work, family life, and leisure goals. Previous research also affirms that practicing time management can have indirect positive effects by decreasing time pressure, whereas material wealth can have both negative indirect effects and positive indirect effects by increasing and decreasing time pressure, respectively. Several issues remain to be studied empirically. The conceptual model is a ground for additional, preferably cross-cultural, research.

Activation-induced cytidine deaminase (AID) is indispensable for immunoglobulin maturation by somatic hypermutations and class switch recombination and is supposed to deaminate cytidines in DNA, while its homolog APOBEC-1 edits apolipoprotein (apo) B mRNA by cytidine deamination. We studied the editing activity of APOBEC-1 and AID in yeast using the selectable marker Gal4 linked to its specific inhibitor protein Gal80 via an apo B cassette (Gal4-C) or via the variable region of a mouse immunoglobulin heavy chain gene (Gal4-VH). Expression of APOBEC-1 induced C to U editing in up to 15% of the Gal4-C transcripts, while AID was inactive in this reaction even in the presence of the APOBEC-1 complementation factor. After expression of APOBEC-1 as well as AID approximately 10(-3) of yeast cells survived low stringency selection and expressed beta-galactosidase. Neither AID nor APOBEC-1 mutated the VH sequence of Gal4-VH, and consequently the yeast colonies did not escape high stringent selection. AID, however, induced frequent plasmid recombinations that were only rarely observed with APOBEC-1. In conclusion, AID cannot substitute APOBEC-1 to edit the apo B mRNA, and the expression of AID in yeast is not sufficient for the generation of point mutations in a highly transcribed Gal4-VH sequence. Cofactors for AID induced somatic hypermutations of immunoglobulin variable regions, that are present in B cells and a variety of non-B cells, appear to be missing in yeast. In contrast to APOBEC-1, AID alone does not exhibit an intrinsic specificity for its target sequences.

Glyoxal, methylglyoxal and other physiological α-oxoaldehydes are formed by the lipid peroxidation, glycation and degradation of glycolytic intermediates. They are detoxified enzymically by the glyoxalase system. To investigate the physiological function of glyoxalase I in parasitic organisms, the cDNA for glyoxalase I from the filarial nematode Onchocerca volvulus (designated Ov-GloI) has been cloned and characterized. The isolated cDNA contains an open reading frame of 579bp encoding a protein with a calculated molecular mass of 21930Da. Owing to the high degree of sequence identity (60%) with human glyoxalase I, for which the X-ray structure is available, it has been possible to build a three-dimensional model of Ov-GloI. The modelled core of Ov-GloI is conserved compared with the human glyoxalase I; however, there are critical differences in the residues lining the hydrophobic substrate-binding pocket of Ov-GloI. A 22kDa protein was obtained by heterologous expression in Escherichia coli. A homogeneous enzyme preparation was obtained by affinity purification and functional characterization of the recombinant enzyme included the determination of kinetic constants for methylglyoxal and phenylglyoxal as well as inhibition studies. Gel filtration demonstrated a dimeric structure. To assess the role of Ov-GloI as a potential vaccine candidate or serodiagnostic tool, the serological reactivity of the recombinant Ov-GloI was analysed with sera from microfilaria carriers and specific IgG1 antibodies were detected. The effects of oxidative insult, namely plumbagin and xanthine/xanthine oxidase, on the gene transcript level of Ov-GloI were investigated. By using a semi-quantitative PCR ELISA it was shown that Ov-GloI is expressed at elevated levels under conditions of oxidative stress.

We propose a conceptual model of how time pressure affects emotional well-being associated with mundane routine activities. A selective review of research in several areas affirms the plausibility of the conceptual model, which posits negative effects on emotional well-being of insufficient time allocated to restorative and other activities instrumental for attaining desirable work, family life, and leisure goals. Previous research also affirms that practicing time management can have indirect positive effects by decreasing time pressure, whereas material wealth can have both negative indirect effects and positive indirect effects by increasing and decreasing time pressure, respectively. Several issues remain to be studied empirically. The conceptual model is a ground for additional, preferably cross-cultural, research.

To analyse whether a specific cytokine pattern is elicited in response to the autoantigen proteinase 3 (PR3) in active Wegener's granulomatosis (WG).Six-colour flow cytometry was used to analyse cytokine production and surface markers of the total CD4+ T-cell population ex vivo and in PR3-stimulated T-cell lines of patients with active PR3-ANCA-positive WG, PR3-ANCA-negative Churg-Strauss syndrome (CSS), and healthy controls (HC).The cytokine response of the total PB CD4+ T cell population was skewed towards distinct pro-inflammatory cytokine patterns in WG (Th1-type) and CSS (Th17, Th1-/Th2-type). Th2-type as well as Th17 cell populations including Th17/Th1, Th17/Th2 and Th22 cells were elicited in response to PR3 stimulation in WG. In contrast, CSS patients displayed a Th2-type dominated response following PR3 stimulation.These data suggest that the cytokine response of the total CD4+ T-cell population and PR3-specific cells is influenced by the underlying disorder.

Summary The translocation t(11;14)(q13;q32) is the genetic hallmark of mantle cell lymphoma (MCL) but is not sufficient for inducing lymphomagenesis. Here we performed genome-wide 100K GeneChip Mapping in 26 t(11;14)-positive MCL and six MCL cell lines. Partial uniparental disomy (pUPD) was shown to be a recurrent chromosomal event not only in MCL cell lines but also in primary MCL. Remarkably, pUPD affected recurrent targets of deletion like 11q, 13q and 17p. Moreover, we identified 12 novel regions of recurrent gain and loss as well as 12 high-level amplifications and eight homozygously deleted regions hitherto undescribed in MCL. Interestingly, GeneChip analyses identified different genes, encoding proteins involved in microtubule dynamics, such as MAP2, MAP6 and TP53, as targets for chromosomal aberration in MCL. Further investigation, including mutation analyses, fluorescence in situ hybridisation as well as epigenetic and expression studies, revealed additional aberrations frequently affecting these genes. In total, 19 of 20 MCL cases, which were subjected to genetic and epigenetic analyses, and five of six MCL cell lines harboured at least one aberration in MAP2, MAP6 or TP53. These findings provide evidence that alterations of microtubule dynamics might be one of the critical events in MCL lymphomagenesis contributing to chromosomal instability.

Editing of apolipoprotein (apo) B mRNA is mediated by an enzyme-complex that consists of the catalytic cytidine deaminase APOBEC-1 and the mRNA binding protein APOBEC-1 complementation factor or APOBEC-1 stimulating protein (ACF/ASP). Here we describe the detailed characterization of the structure, expression and splicing pattern of the mouse ACF/ASP gene. ACF/ASP mRNA is mainly expressed in mouse liver, small intestine and kidney. The deduced protein sequences of ACF/ASP from mouse and man share an identity of 93%. The mouse ACF/ASP gene consists of 12 exons and gives rise predominantly to full-length transcripts. To a minor extent (10%) ACF/ASP mRNA with unspliced exon 8 is generated in liver, kidney and small intestine that encodes a truncated protein with a predicted molecular weight of 43 kDa. The promoter of the mouse ACF/ASP gene lacks a canonical TATA-box, but contains a cluster of Sp1 binding sites and uses multiple transcriptional initiation sites. Transfection studies demonstrated a preference of this promoter for cell lines derived from the gastrointestinal tract and proved the location of the promoter core region. The high sequence identity between man and mouse-much higher as observed for APOBEC-1-indicates a strong evolutionary constraint on the structure-function relationship of ACF/ASP, most probably due to a central role in editing and processing of apo B mRNA.

Activation-induced cytidine deaminase (AID) induces somatic hypermutation (SHM), class switch recombination (CSR), and immunoglobulin gene conversion in B-lymphocytes. Here we report for the first time the expression of AID in healthy human B-lymphocytes and in B-cell non-Hodgkin lymphomas (B-NHL). AID mRNA expression in humans is restricted to the CD19(+)CD38(+)IgD(-) germinal center cells, namely the CD19(+)CD38(+)CD44(-) centroblasts. After in vitro stimulation of naive human B cells by CD40-L and IL-4, AID mRNA is strongly induced for only 48 hours. In a survey of human B-NHL AID was found to be constitutively expressed in follicular lymphoma and in diffuse large B-cell lymphoma but to be absent in B-precursor lymphoblastic leukemia, in mantle cell lymphoma, and in plasma cell myeloma. In B-cell chronic lymphatic leukemia, in immunocytoma, and in extranodal marginal zone B-cell lymphoma of MALT, AID mRNA was expressed only in some samples. In follicular lymphoma and diffuse large B-cell lymphoma, the expression of AID mRNA was coincident with the presence of SHM in the variable region exons of the immunoglobulin heavy-chain gene. In human B-NHL, the AID mRNA is spliced into 4 different variants but does not contain point mutations. Thus AID, which is highly regulated during healthy B-cell development, is constitutively expressed in human germinal center B-NHL and in subsets of nongerminal center B-NHL. This constitutive expression of AID may promote illegitimate DNA recombinations and somatic mutations in B-NHL.