Estrogen-mediated individual differences in female rat voluntary running behavior.

Regular exercise has numerous health benefits, but the human population displays significant variability in exercise participation. Rodent models, such as voluntary wheel running (VWR) in rats, can provide insight into the underlying mechanisms of exercise behavior and its regulation. In this study, we focused on the role of estrogen on VWR in female rats. Female rats run more than males, and we aimed to determine to what extent running levels in females were regulated by estrogen signaling. The running behavior of rats (duration, speed, and total distance run) was measured under normal physiological conditions, ovariectomy (OVX), and estrogen replacement in an OVX background. Results show cyclic variations in running linked to the estrous cycle. Ovariectomy markedly reduced running and eliminated the cyclic pattern. Estrogen replacement through estradiol benzoate (EB) injections and osmotic minipumps reinstated running activity to pre-OVX levels and restored the cyclic pattern. Importantly, individual differences and ranking are preserved such that high versus low runners before OVX remain high and low runners after treatment. Further analysis revealed that individual variation in running distance was primarily caused by rats running different speeds, but rats also varied in running duration. However, it is noteworthy that this model also displays features distinct from estrogen-driven running behavior under physiological conditions, notably a delayed onset and a broader duration of running activity. Collectively, this estrogen causality VWR model presents a unique opportunity to investigate sex-specific mechanisms that control voluntary physical activity.NEW & NOTEWORTHY This study investigates estrogen's role in voluntary wheel running (VWR) behavior in female rats. Female rats exhibit greater running than males, with estrogen signaling regulating this activity. The estrous cycle influences running, whereas ovariectomy reduces it, and estrogen replacement restores it, maintaining individual differences under all conditions. Both running speed and duration contribute to VWR variations. These findings emphasize individual estrogen regulation in female exercise and provide an estrogen replacement animal model for investigating neurobiological underpinnings that drive voluntary exercise behavior.

Higher level domain specific skills in mathematics; The relationship between algebra, geometry, executive function skills and mathematics achievement.

Algebra and geometry are important components of mathematics that are often considered gatekeepers for future success. However, most studies that have researched the cognitive skills required for success in mathematics have only considered the domain of arithmetic. We extended models of mathematical skills to consider how executive function skills play both a direct role in secondary-school-level mathematical achievement as well as an indirect role via algebra and geometry, alongside arithmetic. We found that verbal and visuospatial working memory were indirectly associated with mathematical achievement via number fact knowledge, calculation skills, algebra and geometry. Inhibition was also indirectly associated with mathematical achievement via number fact knowledge and calculation skills. These findings highlight that there are multiple mechanisms by which executive function skills may be involved in mathematics outcomes. Therefore, using specific measures of mathematical processes as well as context-rich assessments of mathematical achievement is important to understand these mechanisms.

Chronic intermittent hypoxia promotes glomerular hyperfiltration and potentiates hypoxia-evoked decreases in renal perfusion and PO2.

Introduction: Sleep apnea (SA) is highly prevalent in patients with chronic kidney disease and may contribute to the development and/or progression of this condition. Previous studies suggest that dysregulation of renal hemodynamics and oxygen flux may play a key role in this process. The present study sought to determine how chronic intermittent hypoxia (CIH) associated with SA affects regulation of renal artery blood flow (RBF), renal microcirculatory perfusion (RP), glomerular filtration rate (GFR), and cortical and medullary tissue PO2 as well as expression of genes that could contribute to renal injury. We hypothesized that normoxic RBF and tissue PO2 would be reduced after CIH, but that GFR would be increased relative to baseline, and that RBF, RP, and tissue PO2 would be decreased to a greater extent in CIH vs. sham during exposure to intermittent asphyxia (IA, FiO2 0.10/FiCO2 0.03). Additionally, we hypothesized that gene programs promoting oxidative stress and fibrosis would be activated by CIH in renal tissue. Methods: All physiological variables were measured at baseline (FiO2 0.21) and during exposure to 10 episodes of IA (excluding GFR). Results: GFR was higher in CIH-conditioned vs. sham (p < 0.05), whereas normoxic RBF and renal tissue PO2 were significantly lower in CIH vs. sham (p < 0.05). Reductions in RBF, RP, and renal tissue PO2 during IA occurred in both groups but to a greater extent in CIH (p < 0.05). Pro-oxidative and pro-fibrotic gene programs were activated in renal tissue from CIH but not sham. Conclusion: CIH adversely affects renal hemodynamic regulation and oxygen flux during both normoxia and IA and results in changes in renal tissue gene expression.

Attendance Improves Student Electrocardiography Interpretation Skills Using the Flipped Classroom Format.

The implementation of classroom capture and casting technologies has changed how content can be accessed. Students can access live, streaming, and/or recorded formats of material. Broadening this accessibility has, in turn, introduced flexibility for both the learner and the instructor. This flexibility has impacted the necessity of attendance to access classroom-delivered content. There are many reports that investigate the changing attendance climate as well as the potential impact of attendance on student outcomes. Here we investigated the impact of attending classroom activities on student performance with two common content delivery methods in an undergraduate, pre-clinical cardiology course. Electrocardiography (ECG) interpretation was taught using a flipped classroom format which allowed for the practice of interpretive skills with faculty guidance. Other components of the course related to the diagnosis, treatment, and management of cardiovascular disease were delivered using a lecture-based format. The results demonstrate that attendees outperform their classmates in the ability to interpret ECGs and related content. However, the attending student does not appear to have a performance advantage when content is delivered by lecture. The results provide evidence for students to prioritize their time when making decisions about attendance, based on teaching modality, when given a choice. Further, the information can guide curricular change and help colleges and programs identify curricular activities that have a clear attendance benefit for students. Supplementary Information: The online version contains supplementary material available at 10.1007/s40670-022-01689-5.

Etiology of persistent mathematics difficulties from childhood to adolescence following very preterm birth.

Children born very preterm (VP; <32 weeks' gestation) have poorer mathematics achievement than term-born peers. This study aimed to determine whether VP children's mathematics difficulties persist from primary to secondary school and to explore the nature of mathematics difficulties in adolescence. For this study, 127 VP and 95 term-born adolescents were assessed at age 11-15 years. Mathematics achievement was assessed using the Wechsler Individual Achievement Test-II. Specific mathematics skills and general cognitive skills were assessed using standardized and experimental tests. VP adolescents had poorer mathematics achievement than term-born adolescents (-10.95 points; 95% CI -16.18, -5.73) and poorer number fact knowledge, understanding of arithmetic concepts, written arithmetic, counting, reading and writing large numbers, and algebra. Between-group differences in mathematics skills were no longer significant when working memory and visuospatial skills were controlled for (p's >0.05), with the exception of writing large numbers and conceptual understanding of arithmetic. In a previous study, 83 of the VP adolescents and 49 of the term-born adolescents were assessed at age 8-10 years using measures of the same skills. Amongst these, the between-group difference in mathematics achievement remained stable over time. This study extends findings of a persistent deficit in mathematics achievement among VP children over the primary and secondary school years, and provides evidence of a deficit in factual, procedural and conceptual mathematics skills and in higher order mathematical operations among VP adolescents. We provide further evidence that VP children's mathematics difficulties are driven by deficits in domain-general rather than domain-specific cognitive skills.

A novel assay to assess the effects of estrogen on the cardiac calmodulin binding equilibrium.

AIMS: The Ca2+-binding protein calmodulin (CaM) modulates numerous target proteins but is produced insufficiently to bind all of them, generating a limiting CaM equilibrium. Menopause increases cardiac morbidity; however, it is unknown if the cardiac CaM equilibrium is affected by estrogen. We devised an assay to assess the effects of ovariectomy and estrogen treatment on the cardiac CaM equilibrium. MATERIALS AND METHODS: Sprague-Dawley rats received sham surgery or ovariectomy, followed by 2-week treatment with vehicle or 17ß-estradiol. Ca2+-saturated left ventricular (LV) lysates were processed through CaM sepharose columns, which retained CaM-binding proteins unoccupied by endogenous CaM. Eluants therefrom were subjected to a competitive binding assay against purified CaM and a CaM biosensor to assess the amounts of unoccupied CaM-binding sites. LV cellular composition was assessed by immunohistochemistry. KEY FINDINGS: LV eluants processed from sham animals reduce biosensor response by ~32%, indicating baseline presence of unoccupied CaM-binding sites and a limiting CaM equilibrium. Ovariectomy exacerbates the limiting CaM equilibrium, reducing biosensor response by ~65%. 17ß-estradiol treatment equalizes the difference between sham and ovariectomized animals. These changes reflect whole tissue responses and are not mirrored by changes in total surface areas of cardiomyocytes and fibroblasts. Consistently, Ca2+-dependent, but not Ca2+-independent, interaction between CaM and the cardiac inositol trisphosphate receptor (IP3R) is reduced following ovariectomy and is restored by subsequent 17ß-estradiol treatment. SIGNIFICANCE: Our assay provides a new parameter to assess tissue CaM equilibrium. The exacerbated limiting CaM equilibrium following estrogen loss may contribute to cardiac morbidity and is prevented by estrogen treatment.

No Excess of Mathematics Anxiety in Adolescents Born Very Preterm.

OBJECTIVE: To assess whether adolescents born very preterm (VP; <32 weeks' gestation) have an excess of mathematics anxiety compared with their classmates born at term. METHODS: This cohort study included 127 adolescents born VP (51% male, mean age 13.9 years, SD 0.7) and 95 term-born classmates (56% male, mean age 13.7 years, SD 0.7) who completed the Wechsler Individual Achievement Test Second UK Edition and the Mathematics Anxiety Scale-UK at the age of 11 to 15 years. Self-reported trait anxiety was assessed using a composite of 3 items from the Strengths and Difficulties Questionnaire. RESULTS: Adolescents born VP had significantly poorer mathematics attainment than adolescents born at term (difference in means: -0.64 SD; 95% confidence interval -0.95 to -0.34). However, there were no between-group differences in self-reported mathematics anxiety or trait anxiety. There were significant moderate associations between mathematics anxiety and mathematics attainment for adolescents born VP (rho: -0.45) and at term (rho: -0.54), after controlling for trait anxiety. CONCLUSION: Adolescents born VP do not have heightened mathematics anxiety compared with their term-born classmates, despite poorer attainment in mathematics. Improving domain-general cognitive skills and scaffolding learning in the classroom may be more promising avenues for intervention than attempting to reduce mathematics anxiety.

Regulation of beta adrenoceptor-mediated myocardial contraction and calcium dynamics by the G protein-coupled estrogen receptor 1.

The G protein-coupled estrogen receptor 1 (GPER) produces cardioprotective effects. However, the underlying mechanisms are not well understood. We aimed to investigate the role of GPER in ß adrenoceptor-mediated cardiac contraction and myocardial signaling. In anesthetized animals, intrajugular administration of isoproterenol produces a rapid and sustained rise in left ventricular pressure (LVP) and increases ectopic contractions. Administration of the GPER agonist G-1 during the plateau phase of isoproterenol-induced LVP increase rapidly restores LVP to baseline levels and reduces the frequency of ectopic contractions. In freshly isolated cardiomyocytes, isoproterenol potentiates electrically induced peak currents of L-type Ca2+ channels (LTCC) and increases the potential sensitivity of their inactivation. Coadministration of G-1 prevents isoproterenol-induced potentiation of peak LTCC currents and makes channels more sensitive to being inactivated compared to isoproterenol alone. Isoproterenol treatment of cardiomyocytes without electrical stimulation triggers slow-rising Ca2+ signals that are inhibited by the ß1AR antagonist metoprolol but not by ß2AR antagonist ICI-118551. G-1 pretreatment dose-dependently suppresses isoproterenol-induced total Ca2+ signals and the amplitude and frequency of the intrinsic Ca2+ oscillatory deflections. Pretreatment with the GPER antagonist G-36 produces opposite effects, dose-dependently increasing these signals. ISO promotes robust phosphorylation of Cav1.2 channels at Ser1928. G-1 pretreatment inhibits isoproterenol-stimulated phosphorylation of Cav1.2 at Ser1928, while G-36 pretreatment enhances this signal. Our data indicate that GPER functions as an intrinsic component of ß1AR signaling to moderate myocardial Ca2+ dynamics and contraction.

Improving developmental and educational support for children born preterm: evaluation of an e-learning resource for education professionals.

OBJECTIVES: Children born preterm are at higher risk for special educational needs and poor academic attainment compared with term-born peers, yet education professionals receive limited training and have poor knowledge of preterm birth. We have developed an interactive e-learning resource and evaluated its efficacy in improving teachers' knowledge of preterm birth and their confidence in supporting the learning of children born preterm. SETTING: Eight primary, infant or junior schools in England. PARTICIPANTS: 61 teachers of children aged 4-11 years, of which 55 (90%) were female. INTERVENTION: Interactive e-learning resource designed to improve education professionals' knowledge of long-term outcomes following preterm birth and strategies that can be used to support children's learning (www.pretermbirth.info). In a repeated measures design, participants were given up to 30 days access to the e-learning resource, before and after which they completed the Preterm Birth Knowledge Scale (PB-KS; scores 0-33; higher scores indicate greater knowledge) to assess knowledge of outcomes of prematurity. Four Likert scale items were used to assess confidence in supporting children's learning and 10 items were used to evaluate the utility of the resource. PB-KS scores and responses on confidence item were compared pre-resource and post-resource use. RESULTS: PB-KS scores significantly increased after accessing the e-learning resource (median (95% CI): pre-resource 13 (11 to 14); post-resource 29 (28 to 30)), equating to a 2.6 SD increase in PB-KS scores. Teachers' confidence in supporting children born preterm was also significantly improved after using the resource. The utility of the resource was evaluated positively by participants with 97% reporting that they would recommend its use to others. CONCLUSIONS: The e-learning resource substantially improved teachers' knowledge of preterm birth and their confidence in supporting preterm children in the classroom. Use of this resource may represent a key advance in improving educational outcomes for children born preterm.

Calcium/calmodulin regulates signaling at the α1A adrenoceptor.

Cardiovascular functions are mediated by multiple 7-pass transmembrane receptors whose activation promotes contraction or relaxation of the tissues. The α1 adrenoceptor type 1A plays important roles in the control of vascular tone and myocardial contractility via Ca2+-dependent actions. Here, using novel FRET-based biosensors, we identified a novel Ca2+-dependent interaction between calmodulin (CaM) and the human α1A adrenoceptor at the juxtamembranous region of its 4th submembrane domain (SMD4JM, a.a. 333-361). SMD4JM houses the known nuclear localization signal of α1A adrenoceptor (NLS, a.a. 334-349). We found that NLS itself also interacts with CaM, but with lower affinity and Ca2+ sensitivity, indicating that full interaction between CaM and α1A receptor in this region requires segment a.a. 333-361. Combined K353Q/L356A substitutions in the non-NLS segment of SMD4JM cause a 3.5-fold reduction in the affinity of CaM-SMD4JM interaction. Overexpression of wild-type α1A adrenoceptor in cells enhances phosphorylation of the extracellular signal-regulated kinases 1/2 (ERK1/2) stimulated by A61603, while overexpression of the K353Q/L356A α1A receptor mutant significantly reduces this signal. Norepinephrine stimulates intracellular Ca2+ signals that are higher in cells overexpressing wild-type receptor but lower in cells overexpressing the K353Q/L356A receptor compared to non-transfected cells in the same microscopic environments. These data support a novel and important role for Ca2+-dependent CaM interaction at SMD4JM in α1A adrenoceptor-mediated signaling.

Developmental differences in approaches to nonsymbolic comparison tasks.

Nonsymbolic comparison tasks are widely used to measure children's and adults' approximate number system (ANS) acuity. Recent evidence has demonstrated that task performance can be influenced by changes to the visual characteristics of the stimuli, leading some researchers to suggest it is unlikely that an ANS exists that can extract number information independently of the visual characteristics of the arrays. Here, we analysed 124 children's and 120 adults' dot comparison accuracy scores from three separate studies to investigate individual and developmental differences in how numerical and visual information contribute to nonsymbolic numerosity judgements. We found that, in contrast to adults, the majority of children did not use numerical information over and above visual cue information to compare quantities. This finding was consistent across different studies. The results have implications for research on the relationship between dot comparison performance and formal mathematics achievement. Specifically, if most children's performance on dot comparison tasks can be accounted for without the involvement of numerical information, it seems unlikely that observed correlations with mathematics achievement stem from ANS acuity alone.

The measurement of approximate number system acuity across the lifespan is compromised by congruency effects.

Recent studies have highlighted the influence of visual cues such as dot size and cumulative surface area on the measurement of the approximate number system (ANS). Previous studies assessing ANS acuity in ageing have all applied stimuli generated by the Panamath protocol, which does not control nor measure the influence of convex hull. Crucially, convex hull has recently been identified as an influential visual cue present in dot arrays, with its impact on older adults' ANS acuity yet to be investigated. The current study therefore investigated the manipulation of convex hull by the Panamath protocol, and its effect on the measurement of ANS acuity in younger and older participants. First, analyses of the stimuli generated by Panamath revealed a confound between numerosity ratio and convex hull ratio. Second, although older adults were somewhat less accurate than younger adults on convex hull incongruent trials, ANS acuity was broadly similar between the groups. These findings have implications for the valid measurement of ANS acuity across all ages, and suggest that the Panamath protocol produces stimuli that do not adequately control for the influence of convex hull on numerosity discrimination.

Understanding arithmetic concepts: The role of domain-specific and domain-general skills.

A large body of research has identified cognitive skills associated with overall mathematics achievement, focusing primarily on identifying associates of procedural skills. Conceptual understanding, however, has received less attention, despite its importance for the development of mathematics proficiency. Consequently, we know little about the quantitative and domain-general skills associated with conceptual understanding. Here we investigated 8-10-year-old children's conceptual understanding of arithmetic, as well as a wide range of basic quantitative skills, numerical representations and domain-general skills. We found that conceptual understanding was most strongly associated with performance on a number line task. This relationship was not explained by the use of particular strategies on the number line task, and may instead reflect children's knowledge of the structure of the number system. Understanding the skills involved in conceptual learning is important to support efforts by educators to improve children's conceptual understanding of mathematics.

A distinct biomolecular profile identifies monoclonal mast cell disorders in patients with idiopathic anaphylaxis.

BACKGROUND: Clonal mast cell disorders are known to occur in a subset of patients with systemic reactions to Hymenoptera stings. This observation has prompted the question of whether clonal mast cell disorders also occur in patients with idiopathic anaphylaxis (IA). OBJECTIVE: We sought to determine the prevalence of clonal mast cell disorders among patients with IA, criteria to identify those patients who require a bone marrow biopsy, and whether the pathogenesis of IA involves a hyperresponsive mast cell compartment. METHODS: We prospectively enrolled patients with IA (≥3 episodes/y) who then underwent a medical evaluation that included a serum tryptase determination, allele-specific quantitative PCR (ASqPCR) for the KIT D816V mutation, and a bone marrow examination. Mast cells were cultured from peripheral blood CD34+ cells and examined for releasability after FcεRI aggregation. RESULTS: Clonal mast cell disease was diagnosed in 14% of patients referred with IA. ASqPCR for the KIT D816V mutation was a useful adjunct in helping identify those with systemic mastocytosis but not monoclonal mast cell activation syndrome. A modified overall clonal prediction model was developed by using clinical findings, a serum tryptase determination, and ASqPCR. There was no evidence of a hyperresponsive mast cell phenotype in patients with IA. CONCLUSION: Patients with clonal mast cell disease can present as having IA. Distinct clinical and laboratory features can be used to select those patients more likely to have an underlying clonal mast cell disorder (monoclonal mast cell activation syndrome or systemic mastocytosis) and thus candidates for a bone marrow biopsy.

Comorbidity Factors and Brain Mechanisms Linking Chronic Stress and Systemic Illness.

Neuropsychiatric symptoms and mental illness are commonly present in patients with chronic systemic diseases. Mood disorders, such as depression, are present in up to 50% of these patients, resulting in impaired physical recovery and more intricate treatment regimen. Stress associated with both physical and emotional aspects of systemic illness is thought to elicit detrimental effects to initiate comorbid mental disorders. However, clinical reports also indicate that the relationship between systemic and psychiatric illnesses is bidirectional, further increasing the complexity of the underlying pathophysiological processes. In this review, we discuss the recent evidence linking chronic stress and systemic illness, such as activation of the immune response system and release of common proinflammatory mediators. Altogether, discovery of new targets is needed for development of better treatments for stress-related psychiatric illnesses as well as improvement of mental health aspects of different systemic diseases.

Explaining the relationship between number line estimation and mathematical achievement: The role of visuomotor integration and visuospatial skills.

Performance on number line tasks, typically used as a measure of numerical representations, are reliably related to children's mathematical achievement. However, recent debate has questioned what precisely performance on the number line estimation task measures. Specifically, there has been a suggestion that this task may measure not only numerical representations but also proportional judgment skills; if this is the case, then individual differences in visuospatial skills, not just the precision of numerical representations, may explain the relationship between number line estimation and mathematical achievement. The current study investigated the relationships among visuospatial skills, visuomotor integration, number line estimation, and mathematical achievement. In total, 77 children were assessed using a number line estimation task, a standardized measure of mathematical achievement, and tests of visuospatial skills and visuomotor integration. The majority of measures were significantly correlated. In addition, the relationship between one metric from the number line estimation task (R(2)LIN) and mathematical achievement was fully explained by visuomotor integration and visuospatial skill competency. These results have important implications for understanding what the number line task measures as well as the choice of number line metric for research purposes.

Dot comparison stimuli are not all alike: the effect of different visual controls on ANS measurement.

The most common method of indexing Approximate Number System (ANS) acuity is to use a nonsymbolic dot comparison task. Currently there is no standard protocol for creating the dot array stimuli and it is unclear whether tasks that control for different visual cues, such as cumulative surface area and convex hull size, measure the same cognitive constructs. Here we investigated how the accuracy and reliability of magnitude judgements is influenced by visual controls through a comparison of performance on dot comparison trials created with two standard methods: the Panamath program and Gebuis & Reynvoet's script. Fifty-one adult participants completed blocks of trials employing images constructed using the two protocols twice to obtain a measure of immediate test-retest reliability. We found no significant correlation between participants' accuracy scores on trials created with the two protocols, suggesting that tasks employing these protocols may measure different cognitive constructs. Additionally, there were significant differences in the test-retest reliabilities for trials created with each protocol. Finally, strong congruency effects for convex hull size were found for both sets of protocol trials, which provides some clarification for conflicting results in the literature.

The roles of sensitization and neuroplasticity in the long-term regulation of blood pressure and hypertension.

After decades of investigation, the causes of essential hypertension remain obscure. The contribution of the nervous system has been excluded by some on the basis that baroreceptor mechanisms maintain blood pressure only over the short term. However, this point of view ignores one of the most powerful contributions of the brain in maintaining biological fitness-specifically, the ability to promote adaptation of behavioral and physiological responses to cope with new challenges and maintain this new capacity through processes involving neuroplasticity. We present a body of recent findings demonstrating that prior, short-term challenges can induce persistent changes in the central nervous system to result in an enhanced blood pressure response to hypertension-eliciting stimuli. This sensitized hypertensinogenic state is maintained in the absence of the inducing stimuli, and it is accompanied by sustained upregulation of components of the brain renin-angiotensin-aldosterone system and other molecular changes recognized to be associated with central nervous system neuroplasticity. Although the heritability of hypertension is high, it is becoming increasingly clear that factors beyond just genes contribute to the etiology of this disease. Life experiences and attendant changes in cellular and molecular components in the neural network controlling sympathetic tone can enhance the hypertensive response to recurrent, sustained, or new stressors. Although the epigenetic mechanisms that allow the brain to be reprogrammed in the face of challenges to cardiovascular homeostasis can be adaptive, this capacity can also be maladaptive under conditions present in different evolutionary eras or ontogenetic periods.

Assessment of clinical findings, tryptase levels, and bone marrow histopathology in the management of pediatric mastocytosis.

BACKGROUND: The management of children with pediatric mastocytosis poses a challenge. This is because there is limited information as to the application of clinical and laboratory findings and bone marrow histopathology as they relate to medical intervention and communication. OBJECTIVE: We sought to examine clinical aspects of pediatric mastocytosis in relationship to serum tryptase levels and bone marrow pathology to provide practical guidance for management. METHODS: Between 1986 and 2012, 105 children were evaluated at the National Institutes of Health. Organomegaly was confirmed by means of ultrasound. Baseline tryptase levels and at least 1 subsequent tryptase measurement was available in 84 and 37 of these children, respectively. Fifty-three children underwent a bone marrow examination. These data were used to examine relationships between clinical findings, tryptase levels, and marrow histopathology. RESULTS: In patients with high tryptase levels and severe mediator symptoms, all with organomegaly had systemic disease, and none without organomegaly had systemic disease. Serum tryptase levels differed significantly between patients with urticaria pigmentosa and those with diffuse cutaneous (P < .0001) and systemic mastocytosis (P < .0001) and in all 3 categories versus control subjects (P < .0001). Tryptase levels and symptoms decreased over time in most patients, and tryptase levels correlated with bone marrow mast cell burden in patients with systemic mastocytosis (P < .0001). There was a significant relationship between clinical resolution and the percentage decrease in tryptase levels (P = .0014). CONCLUSIONS: The majority of children experienced major or complete disease resolution (57%), whereas the remainder exhibited partial improvement. Organomegaly was a strong indicator of systemic disease. Serum tryptase levels furthered classification and reflected clinicopathologic findings, while sequential tryptase measurements were useful in supplementing clinical judgment as to disease course.

Nature and origins of mathematics difficulties in very preterm children: a different etiology than developmental dyscalculia.

BACKGROUND: Children born very preterm (<32 wk) are at high risk for mathematics learning difficulties that are out of proportion to other academic and cognitive deficits. However, the etiology of mathematics difficulties in very preterm children is unknown. We sought to identify the nature and origins of preterm children's mathematics difficulties. METHODS: One hundred and fifteen very preterm children aged 8-10 y were assessed in school with a control group of 77 term-born classmates. Achievement in mathematics, working memory, visuospatial processing, inhibition, and processing speed were assessed using standardized tests. Numerical representations and specific mathematics skills were assessed using experimental tests. RESULTS: Very preterm children had significantly poorer mathematics achievement, working memory, and visuospatial skills than term-born controls. Although preterm children had poorer performance in specific mathematics skills, there was no evidence of imprecise numerical representations. Difficulties in mathematics were associated with deficits in visuospatial processing and working memory. CONCLUSION: Mathematics difficulties in very preterm children are associated with deficits in working memory and visuospatial processing not numerical representations. Thus, very preterm children's mathematics difficulties are different in nature from those of children with developmental dyscalculia. Interventions targeting general cognitive problems, rather than numerical representations, may improve very preterm children's mathematics achievement.