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Aging is a complex process influenced by mechanisms operating at numerous levels of functioning. Multiple biomarkers of age have been identified, yet we know little about how the different alternative age indicators are intertwined. In the Berlin Aging Study II (nmin= 328; nmax= 1,517, women = 51%; 14.27 years of education), we examined how levels and seven-year changes in indicators derived from blood assays, MRI brain scans, other-ratings, and self-reports converge among older adults. We included eight epigenetic biomarkers (incl. five epigenetic "clocks"), a BioAge composite from clinical laboratory parameters, brain age, skin age, subjective age, subjective life expectancy, and future health horizon. We found moderate associations within aging domains, both cross-sectionally and longitudinally over seven years. However, associations across different domains were infrequent and modest. Notably, participants with older BioAge had correspondingly older epigenetic ages. Our results suggest that different aging clocks are only loosely interconnected and that more specific measures are needed to differentiate healthy from unhealthy aging., (© The Author(s) 2024. Published by Oxford University Press on behalf of The Gerontological Society of America.)

Introduction: The established link between DNA methylation and pathophysiology of dementia, along with its potential role as a molecular mediator of lifestyle and environmental influences, positions blood-derived DNA methylation as a promising tool for early dementia risk detection., Methods: In conjunction with an extensive array of machine learning techniques, we employed whole blood genome-wide DNA methylation data as a surrogate for 14 modifiable and non-modifiable factors in the assessment of dementia risk in independent dementia cohorts., Results: We established a multivariate methylation risk score (MMRS) for identifying mild cognitive impairment cross-sectionally, independent of age and sex (P = 2.0 × 10 -3 ). This score significantly predicted the prospective development of cognitive impairments in independent studies of Alzheimer's disease (hazard ratio for Rey's Auditory Verbal Learning Test (RAVLT)-Learning = 2.47) and Parkinson's disease (hazard ratio for MCI/dementia   = 2.59)., Discussion: Our work shows the potential of employing blood-derived DNA methylation data in the assessment of dementia risk., Highlights: We used whole blood DNA methylation as a surrogate for 14 dementia risk factors. Created a multivariate methylation risk score for predicting cognitive impairment. Emphasized the role of machine learning and omics data in predicting dementia. The score predicts cognitive impairment development at the population level., (© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Structured clinical risk assessments represent a preferred means of assessing levels of aggression risk at different times and in different individuals. Increasing attention has been given to capturing protective factors, with sound risk assessment critical to high-secure forensic mental health care. The aim was to assess the predictive value of the HCR-20 v3 for aggression risk and the long-term care pilot version of the SAPROF (the SAPROF-LC-pilot) in a high-secure forensic mental health inpatient population and to determine the incremental value of protective over risk factors. Participants were adult males detained in a high secure forensic mental health service, with a primary diagnosis of schizophrenia and/or personality disorder. The focus was on examining hospital based aggression (self- and other-directed) at two time points; up to 6 months (T1) and between 7 and 12 months (T2). The HCR-20 V3 and SAPROF-LC-pilot demonstrated good predictive validity but with variability across subscales and aggression types/periods. Historical factors of the HCR-20 V3 and External factors of the SAPROF-LC-pilot failed to predict, aside from a medium effect at T1 for verbal aggression and self-harm, for Historical factors. There was evidence for protective factors adding to prediction over risk factors alone, with the integration of protective and risk factors into a risk judgement particularly helpful in improving prediction accuracy. Protective factors contributed to risk estimates and particularly if integrated with risk factors. Combining risk and protective factors has clear predictive advantages, ensuring that protective factors are not supplementary but important to the aggression assessment process., (© 2024 The Authors. Aggressive Behavior published by Wiley Periodicals LLC.)

Objectives: Change in body weight during the COVID-19 pandemic as an unintended side effect of lockdown measures has been predominantly reported for younger and middle-aged adults. However, information on older adults for which weight loss is known to result in adverse outcomes, is scarce. In this study we describe the body weight change in older adults before, during, and after the COVID-19 lockdown measures and explore putative associated factors with a focus on the period that includes the first six months of the COVID-19 containment measures., Design: Prospective cohort study with three follow-up examinations over the course of 10 years., Setting and Participants: In this study, we analyzed the longitudinal weight change of 472 participants of the Berlin Aging Study II (mean age of 67.5 years at baseline)., Measurements: Body weight was assessed at four time points. Additionally, differences between subgroups characterized by socio-economic, cognitive, and psychosocial variables as well as morbidity burden, biological age markers (epigenetic clocks, telomere length), and frailty were compared., Results: On average, women and men lost 0.87% (n = 227) and 0.5% (n = 245) of their body weight per year in the study period covering the first six months of the COVID-19 pandemic. Weight loss among men was particularly pronounced among groups characterized by change in physical activity due to COVID-19 lockdown, low positive affect, premature epigenetic age (7-CpG clock), diagnosed metabolic syndrome, and a more masculine gender score (all variables: p < 0.05, n = 245)., Conclusion: During the COVID-19 pandemic, older participants lost weight with a 2.5-times (women) and 2-times (men) higher rate than what is expected in this age., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Introduction: This study employed an integrative system and causal inference approach to explore molecular signatures in blood and CSF, the amyloid/tau/neurodegeneration [AT(N)] framework, mild cognitive impairment (MCI) conversion to Alzheimer's disease (AD), and genetic risk for AD., Methods: Using the European Medical Information Framework (EMIF)-AD cohort, we measured 696 proteins in cerebrospinal fluid (n = 371), 4001 proteins in plasma (n = 972), 611 metabolites in plasma (n = 696), and genotyped whole-blood (7,778,465 autosomal single nucleotide epolymorphisms, n = 936). We investigated associations: molecular modules to AT(N), module hubs with AD Polygenic Risk scores and APOE4 genotypes, molecular hubs to MCI conversion and probed for causality with AD using Mendelian randomization (MR)., Results: AT(N) framework associated with protein and lipid hubs. In plasma, Proprotein Convertase Subtilisin/Kexin Type 7 showed evidence for causal associations with AD. AD was causally associated with Reticulocalbin 2 and sphingomyelins, an association driven by the APOE isoform., Discussion: This study reveals multi-omics networks associated with AT(N) and causal AD molecular candidates., (© 2023 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Background: Laboratory evidence supporting diagnosis of the prevalent condition of mast cell activation syndrome (MCAS) currently includes elevated levels in blood or urine of mediators relatively specific to mast cells (MCs) and/or increased numbers of MCs in luminal gastrointestinal (GI) tract tissues. However, identification of elevated mediators is technically challenging and expensive, and controversy persists regarding the normal ranges of numbers/counts of MCs in various GI tract segments, let alone challenges in determining how many of the visualized MCs are activated. To aid diagnosis of MCAS, we developed a potential new approach for the pathologist to identify the extent of GI tract MC activation easily and inexpensively., Participants and Methods: Visualization of MCs in gastrointestinal biopsies from 251 patients vs. 95 controls using antibodies against CD117 and tryptase; MC counting per mm 2 ; calculation of the difference between the CD117-positive MCs (identifying all MCs) vs. tryptase-positive MCs (identifying non-activated tryptase-containing MCs), which we define as the tryptase depletion index (TDI)., Results: Mean total MC counts did not differ significantly between patients and controls, but mean TDIs differed significantly. Non-overlapping confidence intervals at the 99.9% level identified cut-offs of TDIs between patients vs. controls of 26, 45 and 32 MCs/mm 2 in gastric antrum, duodenum, and colon, respectively., Conclusions: The TDI may discriminate between MCAS patients vs. controls. If this preliminary work can be independently confirmed, the TDI may become a useful additional minor diagnostic criterion for MCAS., Competing Interests: Dr. Molderings is the chief medical officer of the start-up company MC Sciences, Ltd. Dr. Afrin and Dr. Weinstock are uncompensated volunteer medical advisors to the start-up company MC Sciences, Ltd. The other authors declare no conflict of interest., (Thieme. All rights reserved.)

Recent wildfire activity in semi-arid regions like western North America exceeds the range of historical records. High-resolution paleoclimate archives such as stalagmites could illuminate the link between hydroclimate, vegetation change, and fire activity in pre-anthropogenic climate states beyond the timescale of existing tree-ring records. Here we present an analysis of levoglucosan, a combustion-sensitive anhydrosugar, and lignin oxidation products (LOPs) in a stalagmite, reconstructing fire activity and vegetation composition in the California Coast Range across the 8.2 kyr event. Elevated levoglucosan concentrations suggest increased fire activity while altered LOP compositions indicate a shift toward more woody vegetation during the event. These changes are concurrent with increased hydroclimate volatility as shown by carbon and calcium isotope proxies. Together, these records suggest that climate whiplash (oscillations between extreme wetness and aridity) and fire activity in California, both projected to increase with anthropogenic climate change, were tightly coupled during the early Holocene., (© 2022. The Author(s).)

Alzheimer's disease (AD) is the most frequent neurodegenerative disease with an increasing prevalence in industrialized, aging populations. AD susceptibility has an established genetic basis which has been the focus of a large number of genome-wide association studies (GWAS) published over the last decade. Most of these GWAS used dichotomized clinical diagnostic status, i.e., case vs. control classification, as outcome phenotypes, without the use of biomarkers. An alternative and potentially more powerful study design is afforded by using quantitative AD-related phenotypes as GWAS outcome traits, an analysis paradigm that we followed in this work. Specifically, we utilized genotype and phenotype data from n = 931 individuals collected under the auspices of the European Medical Information Framework for Alzheimer's Disease Multimodal Biomarker Discovery (EMIF-AD MBD) study to perform a total of 19 separate GWAS analyses. As outcomes we used five magnetic resonance imaging (MRI) traits and seven cognitive performance traits. For the latter, longitudinal data from at least two timepoints were available in addition to cross-sectional assessments at baseline. Our GWAS analyses revealed several genome-wide significant associations for the neuropsychological performance measures, in particular those assayed longitudinally. Among the most noteworthy signals were associations in or near EHBP1 (EH domain binding protein 1; on chromosome 2p15) and CEP112 (centrosomal protein 112; 17q24.1) with delayed recall as well as SMOC2 (SPARC related modular calcium binding 2; 6p27) with immediate recall in a memory performance test. On the X chromosome, which is often excluded in other GWAS, we identified a genome-wide significant signal near IL1RAPL1 (interleukin 1 receptor accessory protein like 1; Xp21.3). While polygenic score (PGS) analyses showed the expected strong associations with SNPs highlighted in relevant previous GWAS on hippocampal volume and cognitive function, they did not show noteworthy associations with recent AD risk GWAS findings. In summary, our study highlights the power of using quantitative endophenotypes as outcome traits in AD-related GWAS analyses and nominates several new loci not previously implicated in cognitive decline., Competing Interests: HZ has served at scientific advisory boards and/or as a consultant for Abbvie, Alector, Annexon, Artery Therapeutics, AZTherapies, CogRx, Denali, Eisai, Nervgen, Pinteon Therapeutics, Red Abbey Labs, Passage Bio, Roche, Samumed, Siemens Healthineers, Triplet Therapeutics, and Wave, has given lectures in symposia sponsored by Cellectricon, Fujirebio, Alzecure, Biogen, and Roche, and was a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which was a part of the GU Ventures Incubator Program. FB is supported by the NIHR biomedical research centre at UCLH. JP received consultation honoraria from Nestle Institute of Health Sciences, Ono Pharma, OM Pharma, and Fujirebio, unrelated to the submitted work. CT has a collaboration contract with ADx Neurosciences, Quanterix and Eli Lilly, performed contract research or received grants from AC-Immune, Axon Neurosciences, Biogen, Brainstorm Therapeutics, Celgene, EIP Pharma, Eisai, PeopleBio, Roche, Toyama, Vivoryon. She serves on editorial boards of Medidact Neurologie/Springer, Alzheimer Research and Therapy, Neurology: Neuroimmunology and Neuroinflammation, and was editor of a Neuromethods book Springer. CT also holds a speaker’s contract with Roche, Inc. KB has served as a consultant, at advisory boards, or at data monitoring committees for Abcam, Axon, BioArctic, Biogen, JOMDD/Shimadzu. Julius Clinical, Lilly, MagQu, Novartis, Pharmatrophix, Prothena, Roche Diagnostics, and Siemens Healthineers, and was a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which was a part of the GU Ventures Incubator Program, outside the work presented in this paper. SL is currently an employee at Janssen Medical UK. JS was an employee of Janssen R&D, LLC., and is currently an employee and chief medical officer of AC Immune SA. JR was an employee of Neurosciences Therapeutic Area, GlaxoSmithKline R&D, Stevenage, UK., (Copyright © 2022 Homann, Osburg, Ohlei, Dobricic, Deecke, Bos, Vandenberghe, Gabel, Scheltens, Teunissen, Engelborghs, Frisoni, Blin, Richardson, Bordet, Lleó, Alcolea, Popp, Clark, Peyratout, Martinez-Lage, Tainta, Dobson, Legido-Quigley, Sleegers, Van Broeckhoven, Wittig, Franke, Lill, Blennow, Zetterberg, Lovestone, Streffer, ten Kate, Vos, Barkhof, Visser and Bertram.)

To explore how neural circuits represent novel versus familiar inputs, we presented mice with repeated sets of images with novel images sparsely substituted. Using two-photon calcium imaging to record from layer 2/3 neurons in the mouse primary visual cortex, we found that novel images evoked excess activity in the majority of neurons. This novelty response rapidly emerged, arising with a time constant of 2.6 ± 0.9 s. When a new image set was repeatedly presented, a majority of neurons had similarly elevated activity for the first few presentations, which decayed to steady state with a time constant of 1.4 ± 0.4 s. When we increased the number of images in the set, the novelty response's amplitude decreased, defining a capacity to store ∼15 familiar images under our conditions. These results could be explained quantitatively using an adaptive subunit model in which presynaptic neurons have individual tuning and gain control. This result shows that local neural circuits can create different representations for novel versus familiar inputs using generic, widely available mechanisms., Competing Interests: The authors declare no competing interest., (Copyright © 2022 the Author(s). Published by PNAS.)

Ingestion of lead (Pb) derived from ammunition used in the hunting of game animals is recognised to be a significant potential source of Pb exposure of wild birds, including birds of prey. However, there are only limited data for birds of prey in Europe regarding tissue concentrations and origins of Pb. Eurasian buzzards (Buteo buteo) found dead in the United Kingdom during an 11-year period were collected and the concentrations of Pb in the liver and femur were measured. Concentrations in the liver consistent with acute exposure to Pb were found in 2.7% of birds and concentration in the femur consistent with exposure to lethal levels were found in 4.0% of individuals. Pb concentration in the femur showed no evidence of consistent variation among or within years, but was greater for old than for young birds. The Pb concentration in the liver showed no effect of the birds' age, but varied markedly among years and showed a consistent tendency to increase substantially within years throughout the UK hunting season for gamebirds. The resemblance of the stable isotope composition of Pb from buzzard livers to that of Pb from the types of shotgun ammunition most widely-used in the UK increased markedly with increasing Pb concentration in the liver. Stable isotope results were consistent with 57% of the mass of Pb in livers of all of the buzzards sampled being derived from shotgun pellets, with this proportion being 89% for the birds with concentrations indicating acute exposure to Pb. Hence, most of the Pb acquired by Eurasian buzzards which have liver concentrations likely to be associated with lethal and sublethal effects is probably obtained when they prey upon or scavenge gamebirds and mammals shot using Pb shotgun pellets., 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 © 2020 Elsevier Ltd. All rights reserved.)

Omalizumab is an effective therapeutic humanized murine IgE antibody in many cases of primary systemic mast cell activation disease (MCAD). The present study should enable the clinician to recognize when treatment of MCAD with omalizumab is contraindicated because of the potential risk of severe serum sickness and to report our successful therapeutic strategy for such adverse event (AE). Our clinical observations, a review of the literature including the event reports in the FDA AE Reporting System, the European Medicines Agency Eudra-Vigilance databases (preferred search terms: omalizumab, Xolair®, and serum sickness) and information from the manufacturer's Novartis database were used. Omalizumab therapy may be more likely to cause serum sickness than previously thought. In patients with regular adrenal function, serum sickness can occur after 3 to 10 days which resolves after the antigen and circulating immune complexes are cleared. If the symptoms do not resolve within a week, injection of 20 to 40 mg of prednisolone on two consecutive days could be given. However, in MCAD patients whose adrenal cortical function is completely suppressed by exogenous glucocorticoid therapy, there is a high risk that serum sickness will be masked by the MCAD and evolve in a severe form with pronounced damage of organs and tissues, potentially leading to death. Therefore, before the application of the first omalizumab dose, it is important to ensure that the function of the adrenal cortex is not significantly limited so that any occurring type III allergy can be self-limiting.

Background: Systemic mast cell activation disease (MCAD, prevalence 5-10%) is a multifactorial, polygenic disease with multisystemic symptoms that is characterized by an unregulated increased release of mast cell mediators and an accumulation of activated mast cells potentially in all organs and tissues. Due to the high prevalence of the disease, physicians involved in surgical, anesthesiological and interventional procedures are often unknowingly faced with MCAD patients experiencing unexpected preoperative, intraoperative and postoperative complications, if no mast cell-specific treatment regimens have been applied., Objective: The findings from a literature search, consensus recommendations of the various international expert groups and extensive own experience in the treatment of MCAD patients enable an empirical and evidence-based care of MCAD patients in association with invasive procedures., Results and Conclusion: Due to the high prevalence of MCAD in the population, it can be assumed that patients with MCAD are correspondingly frequently represented in the surgical patient collective. When MCAD-specific peculiarities are preventively considered in the anesthesiological and surgical procedures in patients with proven or suspected mast cell disease, MCAD patients should not be classified as being at risk.

Aims: To investigate changes in retinal vessel diameter during acute hyperglycemia in patients with type 1 diabetes., Methods: We conducted a study on 11 subjects with type 1 diabetes. Euglycemia was maintained for 3h followed by induction of hyperglycemia and simultaneous bolus of rapid acting insulin. Two fundus photos were captured during euglycemia and five fundus photos, blood glucose and blood pressure were taken every 30min for 2.5h post-prandial. Central retinal artery equivalent (CRAE) and central retinal vein equivalent (CRVE) were measured over the study visit and examined using generalized linear mixed models., Results: In a multivariate mixed model, mean CRAE and CRVE were reduced at 90min post-prandial in both zones B and C. In repeated measures analysis, arterioles exhibited a significant association with change in vessel caliber per change in blood glucose. Inconsistent effects of blood pressure on vessel diameter were also measured., Conclusions: We document a change in retinal vessel diameter during acute hyperglycemia in persons with type 1 diabetes. Larger controlled studies are required to further investigate this phenomenon and to more accurately assess if hyperglycemia has direct effects on retinal vessel diameter., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Introduction  The common mastocytosis variant systemic mast cell activation syndrome (MCAS) may underlie at least a subset of patients with irritable bowel syndrome (IBS). A critical role of vitamin D (VD) in the stabilization of mast cells (MCs) with deficiency of VD resulting in MC activation has been demonstrated. If so, supplementation of VD would be a potential therapeutic approach in the treatment of those IBS patients. Methods  We investigated in the present study for the first time systematically whether the VD level in 100 MCAS patients differed from that in the German general population (Ggp) and made a first attempt to elucidate potential reasons for possible differences by simultaneously determining the blood levels of heparin and cholesterol. Results  In contrast to the Ggp, the VD level was detected in a sufficient range (> 30 ng/mL) in 53 % of the MCAS patients (Ggp 8 %), and only 34 % had values in the range of deficiency (< 20 ng/mL; GgP 75 %). There was no correlation between VD blood level and heparin and cholesterol blood levels. Conclusions  The demonstration that in the majority of MCAS patients the VD level is not in a deficient range argues against an essential contribution of VD deficiency to the high prevalence of MCAS in Germany. Our findings do not exclude the possibility of smaller effects of VD level on MC activation in vivo. However, if such effects are present, the effect sizes seem to be too small to become identifiable in the multifactorial process of disease development., Competing Interests: Disclosure The authors report no conflicts of interest in this work., (© Georg Thieme Verlag KG Stuttgart · New York.)

Background:  It has been shown repeatedly that mast cells can promote or prevent cancer development and growth. If development and/or progression of a solid cancer is substantially influenced by mast cell activity, the frequencies of occurrence of solid cancers in patients with primary mast cells disorders would be expected to differ from the corresponding prevalence data in the general population. In fact, a recent study demonstrated that patients with systemic mastocytosis (i.e., a rare neoplastic variant of the primary mast cell activation disease) have increased risk for solid cancers, in particular melanoma and non-melanoma skin cancers. The aim of the present study is to examine whether the risk of solid cancer is increased in systemic mast cell activation syndrome (MCAS), the common systemic variant of mast cell activation disease. Methods: In the present descriptive study, we have analysed a large (n=828) patient group with MCAS, consisting of cohorts from Germany and the USA, for occurrence of solid forms of cancer and compared the frequencies of the different cancers with corresponding prevalence data for German and U.S. general populations. Results: Sixty-eight of the 828 MCAS patients (46 female, 22 male) had developed a solid tumor before the diagnosis of MCAS was made. Comparison of the frequencies of the malignancies in the MCAS patients with their prevalence in the general population revealed a significantly increased prevalence for melanoma and cancers of the breast, cervix uteri, ovary, lung, and thyroid in MCAS patients. Conclusions: Our data support the view that mast cells may promote development of certain malignant tumors. These findings indicate a need for increased surveillance of certain types of cancer in MCAS patients irrespective of its individual clinical presentation., Competing Interests: Competing interests: No competing interests were disclosed.

Context: Troponin T upstream open reading frame peptide (TnTuORF) may be useful as a novel biomarker in acute cardiac syndromes., Objective: The study examined the early release kinetics of TnTuORF., Materials and Methods: We analyzed the time course of the release of cardiac troponins I and T and TnTuORF in patients (n = 31) with hypertrophic obstructive cardiomyopathy undergoing transcoronary ablation of septal hypertrophy (TASH)., Results: Fifteen minutes after TASH, the levels of both troponins increased significantly (cTnT median: 18 ng/L versus 27 ng/L; cTnI median: 15 ng/L versus 25 ng/L). TnTuORF showed no variation., Discussion: We observed a significantly greater increase in cTnI compared with cTnT., Conclusion: Our results demonstrate that troponin assays allow early detection of myocardial injury, whereas TnTuORF levels remain unchanged in this setting.

Neurons perform computations by integrating excitatory and inhibitory synaptic inputs. Yet, it is rarely understood what computation is being performed, or how much excitation or inhibition this computation requires. Here we present evidence for a neuronal computation that maximizes the signal-to-noise power ratio (SNR). We recorded from OFF delta retinal ganglion cells in the guinea pig retina and monitored synaptic currents that were evoked by visual stimulation (flashing dark spots). These synaptic currents were mediated by a decrease in an outward current from inhibitory synapses (disinhibition) combined with an increase in an inward current from excitatory synapses. We found that the SNR of combined excitatory and disinhibitory currents was voltage sensitive, peaking at membrane potentials near resting potential. At the membrane potential for maximal SNR, the amplitude of each current, either excitatory or disinhibitory, was proportional to its SNR. Such proportionate scaling is the theoretically best strategy for combining excitatory and disinhibitory currents to maximize the SNR of their combined current. Moreover, as spot size or contrast changed, the amplitudes of excitatory and disinhibitory currents also changed but remained in proportion to their SNRs, indicating a dynamic rebalancing of excitatory and inhibitory currents to maximize SNR. SIGNIFICANCE STATEMENT We present evidence that the balance of excitatory and disinhibitory inputs to a type of retinal ganglion cell maximizes the signal-to-noise ratio power ratio (SNR) of its postsynaptic currents. This is significant because chemical synapses on a retinal ganglion cell require the probabilistic release of transmitter. Consequently, when the same visual stimulus is presented repeatedly, postsynaptic currents vary in amplitude. Thus, maximizing SNR may be a strategy for producing the most reliable signal possible given the inherent unreliability of synaptic transmission., (Copyright © 2017 the authors 0270-6474/17/371468-11$15.00/0.)

Mast cell activation disease (MCAD) is a term referring to a heterogeneous group of disorders characterized by aberrant release of variable subsets of mast cell (MC) mediators together with accumulation of either morphologically altered and immunohistochemically identifiable mutated MCs due to MC proliferation (systemic mastocytosis [SM] and MC leukemia [MCL]) or morphologically ordinary MCs due to decreased apoptosis (MC activation syndrome [MCAS] and well-differentiated SM). Clinical signs and symptoms in MCAD vary depending on disease subtype and result from excessive mediator release by MCs and, in aggressive forms, from organ failure related to MC infiltration. In most cases, treatment of MCAD is directed primarily at controlling the symptoms associated with MC mediator release. In advanced forms, such as aggressive SM and MCL, agents targeting MC proliferation such as kinase inhibitors may be provided. Targeted therapies aimed at blocking mutant protein variants and/or downstream signaling pathways are currently being developed. Other targets, such as specific surface antigens expressed on neoplastic MCs, might be considered for the development of future therapies. Since clinicians are often underprepared to evaluate, diagnose, and effectively treat this clinically heterogeneous disease, we seek to familiarize clinicians with MCAD and review current and future treatment approaches.

Resolution of acute inflammation is an active process coordinated by proresolving lipid mediators (SPMs) such as lipoxins (LXs) and resolvins (Rvs), which are formed by the concerted action of 2 lipoxygenases (LOs). Because the exact molecular mechanisms of SPM biosynthesis are not completely understood, we aimed to investigate LX and D-type Rv formation in human leukocytes and HEK293T cells overexpressing leukotriene (LT) pathway enzymes. Activity assays in precursor (15-hydroxyeicosatetraenoic acids, 17-HDoHE)-treated granulocytes [polymorphonuclear leukocytes (PMNLs)] showed a strict dependence of LXA4/RvD1 biosynthesis on cell integrity, and incubation with recombinant human 5-LO did not lead to LX or Rv formation. Pharmacologic inhibition of 5-LO activating protein (FLAP) by MK-886 inhibited LXA4/RvD1 biosynthesis in precursor-treated PMNLs (drug concentration causing 50% inhibition ∼ 0.3/0.2 µM), as did knockdown of the enzyme in MM6 cells, and precursor-treated HEK293T overexpressing 5-LO produced high amounts of LXA4 only in the presence of FLAP. In addition, inhibition of cytosolic phospholipase A2α (cPLA2α) interfered with LXA4/RvD1 formation from exogenous precursors in PMNLs. Furthermore, inhibition of the LT synthases LTA4 hydrolase and LTC4 synthase in PMNL/platelet coincubations augmented LXA4 levels. These findings show that several enzymes known to be involved in the biosynthesis of proinflammatory LTs, such as FLAP and cPLA2α, also contribute to LX and Rv formation., (© FASEB.)

The activation and infiltration of polymorphonuclear neutrophils (PMN) are critical key steps in inflammation. PMN-mediated inflammation is limited by anti-inflammatory and pro-resolving mechanisms, including specialized pro-resolving lipid mediators (SPM). We examined the effects of 15-epi-LXA4 on inflammation and the biosynthesis of pro-inflammatory mediators, such as prostaglandins, leukotriene B4 and various hydroxyeicosatetraenoic acids and SPM, in an oxazolone (OXA)-induced hypersensitivity model for dermal inflammation. 15-epi-LXA4 (100 μM, 5 μL subcutaneously injected) significantly (P < 0.05) reduced inflammation in skin, 24 hours after the OXA challenge, as compared to skin treated with vehicle. No significant influence on the biosynthesis of prostaglandins or leukotriene B4 was observed, whereas the level of 15S-hydroxy-eicosatetraenoic acid was significantly (P < 0.05) lower in the skin areas treated with 15-epi-LXA4. In spite of the use of a fully validated analytical procedure, no SPM were detected in the biological samples. To investigate the reason for the lack of analytical signal, we tried to mimic the production of SPM (lipoxins, resolvins, maresin and protectin) by injecting them subcutaneously into the skin of mice and studying the in vivo availability and distribution of the compounds. All analytes showed very little lateral distribution in skin tissue and their levels were markedly decreased (> 95%) 2 hours after injection. However, docosahexaenoic acid derivatives were biologically more stable than SPM derived from arachidonic acid or eicosapentaenoic acid.

Neurologists and psychiatrists frequently encounter patients whose central and/or peripheral neurologic and/or psychiatric symptoms (NPS) are accompanied by other symptoms for which investigation finds no unifying cause and for which empiric therapy often provides little to no benefit. Systemic mast cell activation disease (MCAD) has rarely been considered in the differential diagnosis in such situations. Traditionally, MCAD has been considered as just one rare (neoplastic) disease, mastocytosis, generally focusing on the mast cell (MC) mediators tryptase and histamine and the suggestive, blatant symptoms of flushing and anaphylaxis. Recently another form of MCAD, MC activation syndrome (MC), has been recognized, featuring inappropriate MC activation with little to no neoplasia and likely much more heterogeneously clonal and far more prevalent than mastocytosis. There also has developed greater appreciation for the truly very large menagerie of MC mediators and their complex patterns of release, engendering complex, nebulous presentations of chronic and acute illness best characterized as multisystem polymorbidity of generally inflammatory ± allergic themes--including very wide arrays of central and peripheral NPS. Significantly helpful treatment--including for neuropsychiatric issues--usually can be identified once MCAD is accurately diagnosed. We describe MCAD's pathogenesis, presentation (focusing on NPS), and therapy, especially vis-à-vis neuropsychotropes. Since MCAD patients often present NPS, neurologists and psychiatrists have the opportunity, in recognizing the diagnostic possibility of MCAD, to short-circuit the often decades-long delay in establishing the correct diagnosis required to identify optimal therapy., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Diagnosis of mast cell activation disease (MCAD), i.e. systemic mastocytosis (SM) and idiopathic systemic mast cell activation syndrome (MCAS), usually requires demonstration of increased mast cell (MC) mediator release. Since only a few MC mediators are currently established as biomarkers of MCAD, the sensitivity of plasma heparin level (pHL) as an indicator of increased MC activation was compared with that of serum tryptase, chromogranin A and urinary N-methylhistamine levels in 257 MCAD patients. Basal pHL had a sensitivity of 41% in MCAS patients and 27% in SM patients. Non-pharmacologic stimulation of MC degranulation by obstruction of venous flow for 10 minutes increased the sensitivity of pHL in MCAS patients to 59% and in SM patients to 47%. In MCAS patients tryptase, chromogranin A, and N-methylhistamine levels exhibited low sensitivities (10%, 12%, and 22%, respectively), whereas sensitivities for SM were higher (73%, 63%, and 43%, respectively). Taken together, these data suggest pHL appears more sensitive than the other mediators for detecting systemic MC activity in patients with MCAS. The simple, brief venous occlusion test appears to be a useful indicator of the presence of pathologically irritable MCs, at least in the obstructed compartment of the body.

Background and Aims. Local and systemic inflammation represent a major feature of atherosclerotic cardiovascular disease (CVD) and are also linked to nonalcoholic fatty liver disease (NAFLD). Studies indicate that NAFLD might be a risk factor for CVD whereas low-to-moderate alcohol consumption is associated with lower cardiovascular morbidity and mortality compared to abstainers and heavy drinkers. We hypothesize that FLD interacts with the effect of alcohol intake on markers of inflammation, and thus potentially on cardiovascular risk. Methods and Results. We evaluated alcohol consumption, markers of inflammation and sonographic criteria of FLD in 515 subjects, representing a subsample of a cross-sectional population based study (Echinococcus multilocularis and Internal Diseases in Leutkirch (EMIL) Study). Presence of FLD was markedly reduced in subjects drinking 0-20 g alcohol/d (19%), compared to nondrinkers (35%) and heavy drinkers (34-44.9%). Serum concentrations of inflammatory markers were substantially higher in subjects with FLD. However, presence of FLD showed no effect on the association between alcohol consumption and inflammatory biomarkers. Conclusions. Based on data from a population-based sample, there is no evidence for a link between FLD, alcohol consumption, and inflammatory cardiovascular risk markers. However, larger prospective studies are needed to confirm this.

Mixed hematopoietic chimerism is a powerful means of generating donor-specific tolerance, allowing long-term graft acceptance without lifelong dependence on immunosuppressive drugs. To avoid the need for whole body irradiation and associated side effects, we utilized a radiation-free minimal conditioning regime to induce long-term tolerance across major histocompatibility barriers. We found that low-dose busulfan, in combination with host T cell depletion and short-term sirolimus-based immunosuppression, facilitated efficient donor engraftment. Tolerance was achieved when mice were transplanted with whole or T cell-depleted bone marrow, or purified progenitor cells. Tolerance induction was associated with an expansion in regulatory T cells and was not abrogated in the absence of a thymus, suggesting a dominant or compensatory peripheral mode of tolerance. Importantly, we were able to generate durable chimerism and tolerance to donor skin grafts in both young and aged mice, despite age-related thymic atrophy and immune senescence. Clinically, this is especially relevant as the majority of transplant recipients are older patients whose immune recovery might be dangerously slow and would benefit from radiation-free minimal conditioning regimes that allow efficient donor engraftment without fully ablating the recipient immune system., (© Copyright 2014 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Pro-resolving lipid mediators are a class of endogenously synthesized molecules derived from different fatty acids, such as arachidonic, docosahexaenoic or eicosapentaenoic acid, which are derived into four different product families: lipoxins, resolvins, maresins and protectins. For quantitation of these compounds, a sensitive, selective and robust liquid chromatography-tandem mass spectrometry method was developed and validated for the simultaneous quantitation of lipoxin A4, 6-epi-lipoxin A4, lipoxin B4 and lipoxin A5, the D-series resolvins D1 and D2 as well as aspirin-triggered lipoxin A4 and resolvin D1, maresin and protectin and the pathway markers 17(S)-hydroxy-docosahexaenoic acid and 17(R)-hydroxy-docosahexaenoic acid in cell culture supernatants. For this purpose, a chiral column was connected in series with a reversed-phase column to achieve efficient analyte separation and high sensitivity. Sample pre-treatment included a fast and simple liquid-liquid extraction procedure. Limits of quantitation in the range of 0.1-0.5ng/mL cell culture media, absolute recoveries between 90 and 115%, intra- and interday precision of less than 13% and an accuracy of less than 11% were obtained. Stability of the samples after 60 days storage at -80°C, three freeze/thaw cycles and 4h at room temperature has been demonstrated for all analytes. Sample extracts can be stored at 7°C for 24h without degradation of the analytes. Deviations of less than 13% in the accuracy, evaluated in terms of relative error, were obtained. The suitability of the method has been demonstrated in cell culture supernatants of human polymorphonuclear leukocytes, stimulated with 15R-hydroxy-eicosatetraenoic acid and in cell culture media of human polymorphonuclear leukocytes co-incubated with human platelets. From all studied analytes, lipoxin A4 and 6-epi-lipoxin A4 were found in cell culture media under both incubation conditions, while 15-epi-lipoxin A4 was additionally detected in cell culture supernatants of polymorphonuclear leukocytes stimulated with 15R-hydroxy-eicosatetraenoic acid., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Lipoxins belong to the family of so-called pro-resolving endogenous lipid mediators which are derived from arachidonic acid and play a key role in the counter-regulation of inflammation. Arachidonic acid is also precursor of multiple pro-inflammatory lipid mediators, such as prostaglandins and leukotrienes, which are simultaneously present in biological compartments. The close structural relationship between several of these lipid mediators and the absence of blank matrix samples enormously complicates the unequivocal identification of these compounds. The determination of lipoxin A4 has been accomplished by chromatographic separation using a C18 reversed phase column and tandem mass spectrometry detection. Samples were liquid-liquid extracted with ethyl acetate before injection. Identification of the analyte was done based on three criteria: retention time, ratio of the m/z transitions and MS/MS spectrum. To avoid false positive results due to endogenous interferences, the extracted samples were re-injected into a chiral Lux Amylose-2 chromatographic column. The authors recommend the use of chiral chromatography in the determination of pro-resolving lipid mediators, together with transition area ratio and fragmentation spectra to improve selectivity for identification and quantitation purposes., (Copyright © 2014 Elsevier B.V. All rights reserved.)

In the present paper clinical phenotypes, pathogenetic relationships, and diagnostic algorithms as well as therapeutic concepts of/for systemic mast cell activation disease are reviewed. The reader should be able to recognize and diagnose a systemic mast cell activation disease, as well as to counsel a personalized drug therapy. In the case of chronic multisystem polymorbidity systemic mast cell activation disease should be considered as a differential diagnosis at an early stage. In most cases, specific, little invasive investigations allow diagnosing the disease and, hence, an appropriate therapy can be initiated., (© Georg Thieme Verlag KG Stuttgart · New York.)

Background: Systemic mast cell activation disease (MCAD) is characterized by an increased and unregulated release of mast cell mediators which can evoke a multifaceted clinical picture often resembling irritable bowel syndrome or fibromyalgia. Because of the considerable prevalence (~ 17 %) of MCAD surgeons are frequently unwittingly confronted with MCAD patients in whom unexpected intraoperative and postoperative complications may occur. Therefore, knowledge of the particular requirements is of relevance for surgical treatment of MCAD patients., Objective: The present paper outlines a concept of surgical treatment of MCAD patients based on the literature which is illustrated by a case report on emergency laparoscopic cholecystectomy., Conclusions: Due to the high prevalence of MCAD in the general population it can be assumed that the frequency in the surgical patient population is similar. If a patient has MCAD, specific characteristics should be taken into account in the surgical procedure to avoid increased operative and complication risks resulting from MCAD.

Background: Human mesenchymal stem cells (MSC) have been utilized for cardiac regeneration after myocardial damage. Their clinical effects are marginal and only a minority of administered cells could make their way into the myocardium. The chemokine receptor CXCR4 has been identified as crucial for migration and homing of stem cells. In this study we overexpressed CXCR4 on human MSC to improve cell trafficking and tissue repair., Methods: Human MSC were isolated from the spongiosa of tibia and femur as well as from pelvic bone marrow. MSC were characterized by differentiation assays and FACS analysis. CXCR4 was overexpressed by mRNA-nucleofection. Intracellular signaling was analyzed to demonstrate functionality of CXCR4. The modified Boyden chamber, wounding assays and time lapse microscopy were utilized to investigate MSC migration., Results: MSC did not express relevant amounts of CXCR4 spontaneously. CXCR4 could be overexpressed in 93% of MSC with a cell viability of 62%. Functionality of the overexpressed CXCR4 was demonstrated by a significant cytosolic Ca(2+) increase and activation of different MAP kinases followed by SDF-1α stimulation. In contrast no improvement of cell migration could be observed. There was a strong basal MSC chemokinesis independent from CXCR4 expression., Conclusions: CXCR4 could be effectively overexpressed in human MSC by mRNA-nucleofection. Despite functionality of CXCR4 MSC were characterized by a strong basal chemokinesis that could not be further enhanced by CXCR4 overexpression. As isolation, culture and nucleofection of pelvic bone marrow-derived MSC basically fulfill the GMP-requirements our approach seems suited for an in vivo application in patients., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

The generation of induced pluripotent stem cells (iPS cells) has pioneered the field of regenerative medicine and developmental biology. They can be generated by overexpression of a defined set of transcription factors in somatic cells derived from easily accessible tissues such as skin or plucked hair or even human urine. In case of applying this tool to patients who are classified into a disease group, it enables the generation of a disease- and patient-specific research platform. iPS cells have proven a significant tool to elucidate pathophysiological mechanisms in various diseases such as diabetes, blood disorders, defined neurological disorders, and genetic liver disease. One of the first successfully modelled human diseases was long QT syndrome, an inherited cardiac channelopathy which causes potentially fatal cardiac arrhythmia. This review summarizes the efforts of reprogramming various types of long QT syndrome and discusses the potential underlying mechanisms and their application.

Redundancies and correlations in the responses of sensory neurons may seem to waste neural resources, but they can also carry cues about structured stimuli and may help the brain to correct for response errors. To investigate the effect of stimulus structure on redundancy in retina, we measured simultaneous responses from populations of retinal ganglion cells presented with natural and artificial stimuli that varied greatly in correlation structure; these stimuli and recordings are publicly available online. Responding to spatio-temporally structured stimuli such as natural movies, pairs of ganglion cells were modestly more correlated than in response to white noise checkerboards, but they were much less correlated than predicted by a non-adapting functional model of retinal response. Meanwhile, responding to stimuli with purely spatial correlations, pairs of ganglion cells showed increased correlations consistent with a static, non-adapting receptive field and nonlinearity. We found that in response to spatio-temporally correlated stimuli, ganglion cells had faster temporal kernels and tended to have stronger surrounds. These properties of individual cells, along with gain changes that opposed changes in effective contrast at the ganglion cell input, largely explained the pattern of pairwise correlations across stimuli where receptive field measurements were possible.

Mast cell activation disease comprises disorders characterized by accumulation of genetically altered mast cells and/or abnormal release of these cells' mediators, affecting functions in potentially every organ system, often without causing abnormalities in routine laboratory or radiologic testing. In most cases of mast cell activation disease, diagnosis is possible by relatively non-invasive investigation. Effective therapy often consists simply of antihistamines and mast cell membrane-stabilising compounds supplemented with medications targeted at specific symptoms and complications. Mast cell activation disease is now appreciated to likely be considerably prevalent and thus should be considered routinely in the differential diagnosis of patients with chronic multisystem polymorbidity or patients in whom a definitively diagnosed major illness does not well account for the entirety of the patient's presentation.

Previous findings suggested an involvement of mast cells in the pathogenesis of irritable bowel syndrome (IBS). The pathophysiological significance of mast cells is defined both by their number in tissue and by their activity. In the present pilot study activity of mast cells in patients with therapy-resistant IBS was investigated for the first time systematically. Twenty patients with therapy-resistant IBS were investigated for the presence of a pathologically increased mast cell mediator release by means of a validated structured interview suitable to identify mast cell mediator-related symptoms and by determing selected surrogate parameters for mast cell activity. Nineteen of the 20 patients presented mast cell mediator-related symptoms. Pathologically increased mast cell activity-related coagulation and fibrinolysis parameters were detected in 11 of 12 patients investigated in that regard. One patient had an elevated level of methylhistamine in urine. The present data provide evidence that in patients with therapy-resistant IBS a pathologically increased systemic mast cell activity may occur with high prevalence. This finding fits to the idea of an assumed contribution of activated mast cells in the pathophysiology of IBS., (© Georg Thieme Verlag KG Stuttgart · New York.)

We present an algorithm to identify individual neural spikes observed on high-density multi-electrode arrays (MEAs). Our method can distinguish large numbers of distinct neural units, even when spikes overlap, and accounts for intrinsic variability of spikes from each unit. As MEAs grow larger, it is important to find spike-identification methods that are scalable, that is, the computational cost of spike fitting should scale well with the number of units observed. Our algorithm accomplishes this goal, and is fast, because it exploits the spatial locality of each unit and the basic biophysics of extracellular signal propagation. Human interaction plays a key role in our method; but effort is minimized and streamlined via a graphical interface. We illustrate our method on data from guinea pig retinal ganglion cells and document its performance on simulated data consisting of spikes added to experimentally measured background noise. We present several tests demonstrating that the algorithm is highly accurate: it exhibits low error rates on fits to synthetic data, low refractory violation rates, good receptive field coverage, and consistency across users.

We report on the outcome of 4 patients with therapy-resistant systemic mast cell activation disease (MCAD) treated with the anti-IgE monoclonal antibody omalizumab in compassionate use. Two patients achieved an impressive persistent clinical response to treatment with omalizumab. In the third patient symptoms gradually improved. In the fourth patient omalizumab treatment had to be discontinued due to intolerable mast cell mediator-induced symptoms. In conclusion, omalizumab can lessen the intensity of the symptoms of systemic MCAD. Hence, omalizumab should be considered as a therapeutic option in cases of systemic MCAD that are resistant to evidence-based therapy.

Systemic mast cell activation syndrome is a mast cell disorder characterized by an unregulated increased activation of mast cells leading to a pathologically enhanced release of mediators. Mutations in tyrosine kinase kit which crucially determines mast cell activity have been suggested as a necessary condition for the development of a clinically symptomatic mast cell disease. At the level of mRNA in mast cell progenitor cells of 20 patients with systemic mast cell activation syndrome and of 20 gender- and age-matched healthy volunteers, the tyrosine kinase kit was investigated for genetic alterations by means of RT-PCR and direct sequencing of the amplificates. In mast cells of 13 out of these 20 patients, multiple predominantly novel potential functionally activating point mutations or complex alterations of the mRNA sequence encoding the tyrosine kinase kit were detected. In contrast, in 19 of the 20 healthy subjects, no functionally relevant alterations of c-kit transcripts were detected. The present findings support the idea that the systemic mast cell activation syndrome is a clonal disease most commonly associated with variable activating mutations in the tyrosine kinase kit.

Systemic mastocytosis comprises disorders characterized by an accumulation of genetically altered mast cells in all organs and tissues due to an increased proliferation rate and reduced apoptosis of those pathologic mast cells. Release of their mediators can effectively influence organ function and can lead to systemic effects without inducing traces in routinely used laboratory parameters or imaging methods. In most cases, little invasive investigations allow diagnosing the disease and, hence, an appropriate therapy consisting of a basic medication with antihistamine and mast cell membrane-stabilizing compounds that should be supplemented, if required, by a medication adapted to individual symptoms, can be initiated. Because of the probably high prevalence of the disorder, systemic mastocytosis should be considered as a differential diagnosis in particular in the case of chronic gastrointestinal complaints such as abdominal pain/discomfort possibly associated with diarrhea, at an early stage.

Urolithiasis is expected to cause a considerable complication in patients with systemic mastocytosis. The aim of the present report is to demonstrate that due to pathological activation and irritability of mast cells, special features in the diagnostic investigation and therapy of urolithiasis have to be considered in patients with systemic mastocytosis. The clinical presentation, diagnostic investigation and therapeutic procedure of urolithiasis in a patient with systemic mastocytosis are described. Urolithiasis may be a significant complication of systemic mastocytosis. Non-contrast CT is the main tool for diagnosing urolithiasis after a detailed history and clinical exam. Patients with systemic mastocytosis should receive a premedication composed of a glucocorticoid and H(1)- and H(2)-histamine receptor antagonists. An increased vulnerability of mucosal tissues is expected in patients with systemic mastocytosis that may limit the options of operative and postoperative therapy. Opioids should be used cautiously for analgesia in patients with systemic mastocytosis.

Background/aims: This study was aimed at investigating the form and prevalence of liver involvement in patients with systemic mast cell activation syndrome, a possibly common subvariant of systemic mastocytosis. An attempt was made to shed light on potential mechanisms responsible for mast cell mediator-related liver abnormalities., Methods: The methods used were clinical investigation, biochemical determination of cholesterol, transaminases and bilirubin in blood, determination of chitotriosidase by enzyme-linked immunosorbent assay technique, and quantitative reverse transcribed-polymerase chain reaction to determine chitotriosidase expression., Results: An elevation of plasma cholesterol was detected in 75% of the patients; elevations of transaminases and bilirubin were determined in 40 and 36% of the patients respectively; hepatomegaly or morphological hepatic alterations were observed in 34%. Chitotriosidase level in blood as a surrogate parameter for Kupffer cell activation in the liver was unchanged. However, chitotriosidase expression in isolated mast cells was downregulated at the mRNA level., Conclusions: Hypercholesterolaemia and liver abnormalities are frequently found in patients with the mast cell activation syndrome. Hence, the mast cell activation syndrome should be considered at an early stage as a possible cause of hypercholesterolaemia and of hepatic abnormalities of unknown reason. Mast cell activation may be indicated by a reduced expression of the enzyme chitotriosidase in blood-derived mast cells as well as by an increased plasma cholesterol level.

Objective: Sequencing efforts to discover mutations in the tyrosine kinase Kit related to systemic mast cell disorders have so far been focused mainly on only a few of the 21 exons of the encoding gene c-kit, thus considerably limiting the possibility to quantitatively reveal pathogenetic relationships. The purpose of this study was to analyze and compare the total sequence of Kit tyrosine kinase at the level of the mRNAs obtained from patients with clear systemic signs of a pathologically increased mast cell mediator release and those from healthy volunteers., Material and Methods: Kit encoding mRNA isolated from mast cell progenitors in peripheral blood from 17 patients with a mast cell activation disorder and from 5 healthy volunteers as well as from the human mast cell leukemia cell line HMC1 was analyzed for alterations., Results: Multiple novel point mutations and six isoforms of Kit which are due to alternative mRNA splicing were detected. One isoform, the insertion of a glutamine residue at amino acid position 252, was found to be a new splice variant expressed in all patients but in none of the healthy volunteers., Conclusions: Systemic mast cell activation disorder was pathogenetically characterized by two or more alterations in the Kit tyrosine kinase providing not only a means of confirming the diagnosis, but also of assessing prognosis and of starting adequate therapeutic interventions. The insertion of Q252 appears to be pathognomic for that disease, providing a novel means for the identification of chronic non-specific gastrointestinal symptoms as manifestations of a systemic mast cell activation disorder.

Systemic mast cell disease often becomes clinically manifest as a mast cell mediator activation syndrome with episodic or chronic nonspecific abdominal symptoms. As a result of genetic alterations, pathological mast cells have an increased proliferation rate as well as accumulation within different organs with consequential effect on gastrointestinal secretion, absorption, pain perception and motility caused by release of their mediators. These changes may not be detected in routine laboratory or imaging methods. This report describes how the diagnosis systemic mast cell disease can be established with a diagnostic questionnaire based on a synopsis of clinical findings relevant to a mast cell mediator activation syndrome.