Background
Current diagnostic algorithms for systemic mastocytosis (SM) rely on the detection of KITD816V in blood to trigger subsequent bone marrow (BM) investigations.
Methods
Here, we correlated ...the KITD816V mutational status of paired blood and BM samples from 368 adults diagnosed with mast cell activation syndrome (MCAS) and mastocytosis and determined the potential utility of investigating KITD816V in genomic DNA from blood‐purified myeloid cell populations to increase diagnostic sensitivity. In a subset of 69 patients, we further evaluated the kinetics of the KITD816V cell burden during follow‐up and its association with disease outcome.
Results
Our results showed a high correlation (P < .0001) between the KITD816V mutation burden in blood and BM (74% concordant samples), but with a lower mean of KITD816V‐mutated cells in blood (P = .0004) and a high rate of discordant BM+/blood− samples particularly among clonal MCAS (73%) and BM mastocytosis (51%), but also in cutaneous mastocytosis (9%), indolent SM (15%), and well‐differentiated variants of indolent SM (7%). Purification of different compartments of blood‐derived myeloid cells was done in 28 patients who were BM mast cell (MC)+/blood− for KITD816V, revealing KITD816V‐mutated eosinophils (56%), basophils (25%), neutrophils (29%), and/or monocytes (31%) in most (61%) patients. Prognostically, the presence of ≥3.5% KITD816V‐mutated cells (P < .0001) and an unstable KITD816V mutation cell burden (P < .0001) in blood and/or BM were both associated with a significantly shortened progression‐free survival (PFS).
Conclusions
These results confirm the high specificity but limited sensitivity of KITD816V analysis in whole blood for the diagnostic screening of SM and other primary MCAS, which might be overcome by assessing the mutation in blood‐purified myeloid cell populations.
This study evaluates the utility of KITD816V mutational status in blood (vs. bone marrow) for the diagnostic screening of SM and MCAS patients, having a high specificity but a limited sensitivity in patients presenting with clonal MCAS without skin lesions. Assessment of KITD816V in blood‐purified myeloid cell populations increases the diagnostic sensitivity of this mutation in 61% of patients. Further, an unstable (decrease or increase) KIT mutation cell burden during follow‐up is a strong predictor of shortened progression‐free survival in SM.Abbreviations: BM, bone marrow; KITD816V, somatic mutation in codon 816 of the stem cell growth factor receptor gene; MC, mast cell; MCAS, mast cell activation syndromes; No., number; PFS, progression‐free survival; SM, systemic mastocytosis
Background
A close association between hereditary alpha‐tryptasemia (HAT) and mast cell (MC) disorders has been previously reported. However, the relationship between HAT and the diagnostic subtypes ...and clinical features of MC disorders still remains to be established.
Objective
To determine the prevalence of HAT in healthy donors (HD) vs patients with different diagnostic subtypes of MC activation syndromes (MCAS) and mastocytosis, and its relationship with the clinical behavior of the disease.
Methods
A total of 959 subjects were studied including 346 healthy donors (HD), 464 mastocytosis, and 149 non‐clonal MCAS patients. Molecular studies to assess the TPSAB1 genotype were performed, and data on serum baseline tryptase (sBT) and basal MC‐mediator release episodes and triggers of anaphylaxis were collected.
Results
HAT was detected in 15/346 (4%) HD versus 43/149 (29%) non‐clonal MCAS and 84/464 (18%) mastocytosis cases. Among mastocytosis, HAT was more frequently found in patients with MC‐restricted KITD816V (21% vs. 10% among multilineage KITD816V patients; p = .008). Overall, median sBT was higher in cases presenting with HAT (28.9 vs. 24.5 ng/mL; p = .008), while no significant differences in sBT were observed among HAT+ mastocytosis patients depending on the presence of 1 vs. ≥2 extra copies of the α‐tryptase gene (44.1 vs. 35.2 ng/mL, p > .05). In turn, anaphylaxis was more frequently observed in HAT+ versus HAT− mastocytosis patients (76% vs. 65%; p = .018), while HAT+ and HAT− patients who did not refer anaphylaxis as the presenting symptom (n = 308) showed a similar prevalence of subsequent anaphylaxis (35% vs. 36%, respectively).
Conclusion
The frequency of HAT in MC disorders varies according to the diagnostic subtype of the disease. HAT does not imply a higher risk (and severity) of anaphylaxis in mastocytosis patients in whom anaphylaxis is not part of the presenting symptoms of the disease.
This study aimed to determine the prevalence of hereditary alpha‐tryptasemia (HAT) in healthy controls and patients with different diagnostic subtypes of mast cell activation syndromes and mastocytosis. HAT was detected in 4% healthy controls and in 29% of nc‐MCAS. Among mastocytosis patients, HAT was detected in 23% CM, 22% BMM, 16% ISM, 13% SSM, and 13% AvdSM cases. Median sBT was higher in cases presenting with HAT+ compared to HAT− mastocytosis patients. However, among HAT+ patients, there is no correlation between the number of extra copies of the α‐tryptase gene and sBT levels. Anaphylaxis was more frequently observed in HAT+ patients with mastocytosis. Those who did not refer anaphylaxis as the presenting symptom showed a similar prevalence of subsequent anaphylaxis (35% HAT− and 36% HAT+ patients).Abbreviations: HAT, hereditary alpha‐tryptasemia; MC, mast cell; sBT, serum baseline tryptase; SM, systemic mastocytosis; TPSAB1, tryptase alpha/beta 1 gene.
Children’s life experiences can position their exploration of global cultural communities within early childhood classrooms. Some early childhood educators, however, are concerned that many young ...children do not have direct experience of global cultures and thus believe that differences between cultural practices will be confusing to young children and global knowledge beyond their capacity. This study, conducted in a Reggio Emilia inspired preschool classroom in the Southwest United States, analysed young children’s enquiries and intercultural understanding as they interacted and responded to an enquiry-based global curriculum. As a resource teacher conducting action research, I implemented the global curriculum and collected field notes, videos from children’s play, artefacts that the children created as they engaged with the global curriculum and a teaching journal. I analysed the data, beginning with deductive categories from the professional literature, approaching intercultural understanding as knowledge, perspective and action. These broad categories were adapted and subcategories created to represent young children’s intercultural understanding as evidenced through their play, enquiries and language. The findings of this study provide evidence to suggest that global exploration can enhance the lives of children when it: (1) builds on children’s curiosity about the world and, through play, (2) highlights the development of knowledge, perspectives and action for a more just world.
Background
Systemic mastocytosis (SM) is a heterogeneous disease characterized by an expansion of KIT‐mutated mast cells (MC). KIT‐mutated MC display activated features and release MC mediators that ...might act on the tumour microenvironment and other immune cells. Here, we investigated the distribution of lymphocyte subsets in blood of patients with distinct subtypes of SM and determined its association with other disease features.
Methods
We studied the distribution of TCD4+ and TCD4− cytotoxic cells and their subsets, as well as total NK‐ and B cells, in blood of 115 SM patients—38 bone marrow mastocytosis (BMM), 67 indolent SM (ISM), 10 aggressive SM (ASM)‐ and 83 age‐matched healthy donors (HD), using spectral flow cytometry and the EuroFlow Immunomonitoring panel, and correlated it with multilineage KITD816V, the alpha‐tryptasemia genotype (HαT) and the clinical manifestations of the disease.
Results
SM patients showed decreased counts (vs. HD) of TCD4− cytotoxic cells, NK cells and several functional subsets of TCD4+ cells (total Th1, Th2‐effector memory, Th22‐terminal effector and Th1‐like Tregs), together with increased T‐follicular‐helper and Th1/Th17‐like Treg counts, associated with different immune profiles per diagnostic subtype of SM, in multilineal versus MC‐restricted KITD816V and in cases with a HαT+ versus HαT− genotype. Unique immune profiles were found among BMM and ISM patients with MC‐restricted KITD816V who displayed HαT, anaphylaxis, hymenoptera venom allergy, bone disease, pruritus, flushing and GI symptoms.
Conclusion
Our results reveal altered T‐ and NK‐cell immune profiles in blood of SM, which vary per disease subtype, the pattern of involvement of haematopoiesis by KITD816V, the HαT genotype and specific clinical manifestations of the disease.
Constitutively activated tumour MC in SM patients are associated with a broad activation of the innate immune response and an altered distribution of other adaptive immune cells. The altered circulating T‐ and NK‐cell immune profile in SM varies depending on disease subtype, the pattern of involvement of haematopoiesis by KITD816V, the HαT genotype and specific clinical manifestations of the disease. These altered immune profiles contribute to a better understanding of the different patterns of clinical manifestations of the disease, independently of the MC burden. Abbreviations: ASM, aggressive systemic mastocytosis; BMM, bone marrow mastocytosis; CM, central memory; EE, early effector; EM, effector memory; HD, healthy donor; HVA, Hymenoptera venom allergy; ISM, indolent systemic mastocytosis; KIT, receptor tyrosine kinase; MC, mast cell; NK, natural killer; SM, systemic mastocytosis; TE, terminal effector; TFH cell, T‐follicular cell; TM, transitional memory; Tregs, T‐regulatory cells.
Background Systemic mast cell activation disorders (MCADs) are characterized by severe and systemic mast cell (MC) mediators–related symptoms frequently associated with increased serum baseline ...tryptase (sBt). Objective To analyze the clinical, biological, and molecular characteristics of adult patients presenting with systemic MC activation symptoms/anaphylaxis in the absence of skin mastocytosis who showed clonal (c) versus nonclonal (nc) MCs and to provide indication criteria for bone marrow (BM) studies. Methods Eighty-three patients were studied. Patients showing clonal BM MCs were grouped into indolent systemic mastocytosis without skin lesions (ISMs- ; n = 48) and other c-MCADs (n = 3)—both with CD25++ BM MCs and either positive mast/stem cell growth factor receptor gene ( KIT ) mutation or clonal human androgen receptor assay (HUMARA) tests—and nc-MCAD (CD25-negative BM MCs in the absence of KIT mutation; n = 32) and compared for their clinical, biological, and molecular characteristics. Results Most clonal patients (48/51; 94%) met the World Health Organization criteria for systemic mastocytosis and were classified as ISMs- , whereas the other 3 c-MCAD and all nc-MCAD patients did not. In addition, although both patients with ISMs- and patients with nc-MCAD presented with idiopathic and allergen-induced anaphylaxis, the former showed a higher frequency of men, cardiovascular symptoms, and insect bite as a trigger, together with greater sBt. Based on a multivariate analysis, a highly efficient model to predict clonality before BM sampling was built that includes male sex ( P = .01), presyncopal and/or syncopal episodes ( P = .009) in the absence of urticaria and angioedema ( P = .003), and sBt >25 μg/L ( P = .006) as independent predictive factors. Conclusions Patients with c-MCAD and ISMs- display unique clinical and laboratory features different from nc-MCAD patients. A significant percentage of c-MCAD patients can be considered as true ISMs- diagnosed at early phases of the disease.
(1) Background: Pelvic-floor-muscle (PFM) activation acts synergistically with multiple muscles while performing functional actions in humans. The purpose of this study was to characterize the ...activity of the PFMs and gluteus medius (GM) while walking and running in physically active nulliparous females. (2) Methods: The peak and average amplitude of maximal voluntary contractions (MVCs) during 60 s of walking (5 and 7 km/h) and running (9 and 11 km/h) were measured with electromyography of the GM and PFMs in 10 healthy female runners. (3) Results: The activation of both muscles increased (
< 0.001) while walking and running. The MVC of the GM was reached when walking and tripled when running, while the PFMs were activated at half their MVC when running. The global ratio of the GM (75.3%) was predominant over that of the PFMs (24.6%) while static and walking. The ratio reached 9/1 (GM/PFM) while running. (4) Conclusion: The GM and PFMs were active while walking and running. The GM's MVC tripled at high speeds, while the PFMs reached only half of their maximum contraction.
Abstract Caries management at the lesion level is dependent on the lesion activity, the presence of a cavitation (either cleanable or non-cleanable), and lesion depth as evaluated via radiographic ...examination. A variety of non-invasive, micro-invasive, and minimally invasive treatment (with or without restoration) options are available for primary and permanent teeth. Non-invasive strategies include oral hygiene instructions, dietary counseling, and personal as well as professional use of fluoridated products that reduce demineralization and increase re-mineralization. Micro-invasive procedures include the use of occlusal resin sealants and resin infiltrants, while minimally invasive strategies comprise those related to selective removal of caries tissues and placement of restorations. Deep caries management includes indirect pulp capping, while exposed pulp may be treated using direct pulp capping and partial or complete pulpotomy. The aim of the present study was to review available evidence on recommended preventive and restorative strategies for caries lesions in Latin American/Caribbean countries, and subsequently develop evidence-based recommendations for treatment options that take into consideration material availability, emphasize ways to adapt available treatments to the local context, and suggest ways in which dentists and health systems can adopt these treatments.
Abstract The Ciclovías comprise worldwide programs in which streets are closed to motor-vehicles and open to individuals for leisure activities. Currently, 93% of the regular programs are in Latin ...American countries (LAC). The aims of this study were to describe the characteristics of regular Ciclovías in 7 LAC and to analyze the factors that influence the sustainability and scaling-up of five case studies. We conducted a survey of 67 Ciclovías in 2014–2015. In addition, we conducted semi-structured interviews with current and former program coordinators and reviewed policy documents from Ciclovías in 5 LAC. The greatest expansion of Ciclovías has occurred since 2000. The number of participants per event ranged from 40 to 1,500,000 (mean 41,399 ± 193,330; median 1600), and the length ranged from 1 to 113.6 km (mean 9.1 ± 16.4; median 3). Ciclovía routes connect low-middle and high income neighborhoods (89.3%), and include the participation of minority populations (61.2%). The main complementary activity offered was physical activity (PA) classes (94.0%), and 80.0% of the programs included strategies to promote biking. All five case studies met definitions for sustainability and scaling-up. All programs shared some level of government support, alliances, community appropriation, champions, compatibility with the mission of the host organization, organizational capacity, flexibility, perceived benefits, and funding stability. However, they differed in operational conditions, political favorability, sources of funding, and number of alliances. The Ciclovías of LAC showed heterogeneity within their design and sustainability factors. Both their heterogeneity and flexibility to adjust to changes make them promising examples of socially inclusive programs to promote PA.
Monoclonal B-cell lymphocytosis (MBL) indicates the presence of less than 5 × 109/L circulating monoclonal B cells in otherwise healthy subjects. Recently, it has been reported that circulating ...chronic lymphocytic leukemia (CLL)–like B cells can be detected using 4- or 5-multicolor flow cytometry in 5% to 7% of adults with normal lymphocyte counts. We investigated the frequency of circulating monoclonal B cells in 608 healthy subjects older than 40 years with normal blood counts, using a highly sensitive 8-color flow cytometry approach and systematic screening for total PB leukocyte count higher than 5 × 106. We show that the frequency of PB monoclonal B cells is markedly higher than previously reported (12% for CLL-like B cells, found at frequencies of 0.17 ± 0.13 × 109 cells/L), the incidence progressively increasing with age. Most cases (62%) showed clonal B-cell levels below the maximum sensitivity of the techniques described by others (< 0.01%), supporting the notion that detection of MBL may largely depend on the sensitivity of the flow cytometry approach used.
and
(
) mutations are the most common mutations in T-cell large granular lymphocytic leukemia (T-LGLL) and chronic lymphoproliferative disorders of NK cells (CLPD-NK), but their clinical impact ...remains unknown. We investigated the frequency and type of
mutations in FACS-sorted populations of expanded T/NK-LGL from 100 (82 clonal; 6 oligoclonal; 12 polyclonal) patients, and its relationship with disease features. Seventeen non-LGL T-CLPD patients and 628 age-matched healthy donors were analyzed as controls.
(
= 30) and
(
= 1) mutations were detected in 28/82 clonal T/NK-LGLL patients (34%), while absent (0/18, 0%) among oligoclonal/polyclonal LGL-lymphocytosis. Mutations were found across all diagnostic subgroups: TCD8
-LGLL, 36%; CLPD-NK, 38%; TCD4
-LGLL, 7%; Tαβ
DP-LGLL, 100%; Tαβ
DN-LGLL, 50%; Tγδ
-LGLL, 44%.
-mutated T-LGLL/CLPD-NK showed overall reduced (
< 0.05) blood counts of most normal leukocyte subsets, with a higher rate (vs. nonmutated LGLL) of neutropenia (
= 0.04), severe neutropenia (
= 0.02), and cases requiring treatment (
= 0.0001), together with a shorter time-to-therapy (
= 0.0001), particularly in non-Y640F
mutated patients. These findings confirm and extend on previous observations about the high prevalence of
mutations across different subtypes of LGLL, and its association with a more marked decrease of all major blood-cell subsets and a shortened time-to-therapy.
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