Growth Based Morphogenesis of Vertebrate Limb Bud

Many genes and their regulatory relationships are involved in developmental phenomena. However, by chemical information alone, we cannot fully understand changing organ morphologies through tissue growth because deformation and growth of the organ are essentially mechanical processes. Here, we develop a mathematical model to describe the change of organ morphologies through cell proliferation. Our basic idea is that the proper specification of localized volume source (e.g., cell proliferation) is able to guide organ morphogenesis, and that the specification is given by chemical gradients. We call this idea “growth-based morphogenesis.” We find that this morphogenetic mechanism works if the tissue is elastic for small deformation and plastic for large deformation. To illustrate our concept, we study the development of vertebrate limb buds, in which a limb bud protrudes from a flat lateral plate and extends distally in a self-organized manner. We show how the proportion of limb bud shape depends on different parameters and also show the conditions needed for normal morphogenesis, which can explain abnormal morphology of some mutants. We believe that the ideas shown in the present paper are useful for the morphogenesis of other organs

Comparing Presenting Clinical Features in 48 Children With Microscopic Polyangiitis to 183 Children Who Have Granulomatosis With Polyangiitis (Wegener's) : an ARChiVe Cohort Study

OBJECTIVE: To uniquely classify children with microscopic polyangiitis (MPA), to describe their demographic characteristics, presenting clinical features, and initial treatments in comparison to patients with granulomatosis with polyangiitis (Wegener's) (GPA). METHODS: The European Medicines Agency (EMA) classification algorithm was applied by computation to categorical data from patients recruited to the ARChiVe (A Registry for Childhood Vasculitis: e-entry) cohort, with the data censored to November 2015. The EMA algorithm was used to uniquely distinguish children with MPA from children with GPA, whose diagnoses had been classified according to both adult- and pediatric-specific criteria. Descriptive statistics were used for comparisons. RESULTS: In total, 231 of 440 patients (64% female) fulfilled the classification criteria for either MPA (n\u2009=\u200948) or GPA (n\u2009=\u2009183). The median time to diagnosis was 1.6 months in the MPA group and 2.1 months in the GPA group (ranging to 39 and 73 months, respectively). Patients with MPA were significantly younger than those with GPA (median age 11 years versus 14 years). Constitutional features were equally common between the groups. In patients with MPA compared to those with GPA, pulmonary manifestations were less frequent (44% versus 74%) and less severe (primarily, hemorrhage, requirement for supplemental oxygen, and pulmonary failure). Renal pathologic features were frequently found in both groups (75% of patients with MPA versus 83% of patients with GPA) but tended toward greater severity in those with MPA (primarily, nephrotic-range proteinuria, requirement for dialysis, and end-stage renal disease). Airway/eye involvement was absent among patients with MPA, because these GPA-defining features preclude a diagnosis of MPA within the EMA algorithm. Similar proportions of patients with MPA and those with GPA received combination therapy with corticosteroids plus cyclophosphamide (69% and 78%, respectively) or both drugs in combination with plasmapheresis (19% and 22%, respectively). Other treatments administered, ranging in decreasing frequency from 13% to 3%, were rituximab, methotrexate, azathioprine, and mycophenolate mofetil. CONCLUSION: Younger age at disease onset and, perhaps, both gastrointestinal manifestations and more severe kidney disease seem to characterize the clinical profile in children with MPA compared to those with GPA. Delay in diagnosis suggests that recognition of these systemic vasculitides is suboptimal. Compared with adults, initial treatment regimens in children were comparable, but the complete reversal of female-to-male disease prevalence ratios is a provocative finding

Fibroblast growth factors 2 and 4 stimulate migration of mouse embryonic limb myogenic cells

Fibroblast growth factors (FGFs) are believed to be vital for limb outgrowth and patterning during embryonic development. Although the effect of FGFs on the formation of the skeletal elements has been studied in detail, their effect on the development of the limb musculature is still uncertain. In this study, we used Blindwell chemotactic chambers to examine the effect of FGF-2 and FGF-4 on the motility of myogenic cells obtained from the proximal region of day 11.5 mouse forelimbs. The limb myogenic cells were found to be chemotactically attracted to FGF-2 and FGF-4 at 1-50 ng/ml. Both FGFs increased myogenic cell migration in a dose-dependent manner, with maximal responses attained at 10-50 ng/ml for FGF-2 and at 10 ng/ml for FGF- 4; however, FGF-2 was found to be a more potent chemoattractant than FGF-4. It was possible to inhibit the myogenic cells' response to FGF-2 and FGF-4 by the addition of the appropriate neutralizing antibody. The effects of FGF-2 on cell migration were further investigated by loading this cytokine into Affi-Gel blue beads and transplanting them into day 11.5 forelimb Buds. The results showed that FGF-2 attracted DiI-labelled proximal cells to migrate toward the implanted beads and that the migration was more extensive than that observed in the absence of FGF-2. A checkerboard assay was performed in which various concentrations of FGF-2 and FGF-4 were introduced to both the upper and lower wells of the Blindwell chambers. The results indicated that both FGF isoforms can stimulate chemokinesis as well as chemotaxis in myogenic cells. In addition, the effect of FGF-2 and FGF-4 on other aspects of skeletal muscle development was investigated. FGF-2 at 0.1-10 ng/ml stimulated a significant increase in the number of myocytes expressing sarcomeric myosin on examination after 48 hr in culture, but the effect of FGF-4 was negligible at all concentrations analyzed; however, both FGF-2 and FGF-4 inhibited myocyte fusion compared with the spontaneous fusion observed in control cultures. Finally, we used in situ hybridization and immunohistochemical techniques to determine the distribution of myogenic cells and FGF-2 protein in the day 11.5 mouse forelimbs

Serologic and Cytokine Signatures in Children with Multisystem Inflammatory Syndrome and Coronavirus Disease 2019

Background: The serologic and cytokine responses of children hospitalized with multisystem inflammatory syndrome (MIS-C) vs coronavirus disease 2019 (COVID-19) are poorly understood. Methods: We performed a prospective, multicenter, cross-sectional study of hospitalized children who met the Centers for Disease Control and Prevention case definition for MIS-C (n = 118), acute COVID-19 (n = 88), or contemporaneous healthy controls (n = 24). We measured severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike receptor-binding domain (RBD) immunoglobulin G (IgG) titers and cytokine concentrations in patients and performed multivariable analysis to determine cytokine signatures associated with MIS-C. We also measured nucleocapsid IgG and convalescent RBD IgG in subsets of patients. Results: Children with MIS-C had significantly higher SARS-CoV-2 RBD IgG than children with acute COVID-19 (median, 2783 vs 146; P <.001), and titers correlated with nucleocapsid IgG. For patients with MIS-C, RBD IgG titers declined in convalescence (median, 2783 vs 1135; P =.010) in contrast to patients with COVID-19 (median, 146 vs 4795; P <.001). MIS-C was characterized by transient acute proinflammatory hypercytokinemia, including elevated levels of interleukin (IL) 6, IL-10, IL-17A, and interferon gamma (IFN-γ). Elevation of at least 3 of these cytokines was associated with significantly increased prevalence of prolonged hospitalization ≥8 days (prevalence ratio, 3.29 [95% CI, 1.17-9.23]). Conclusions: MIS-C was associated with high titers of SARS-CoV-2 RBD IgG antibodies and acute hypercytokinemia with IL-6, IL-10, IL-17A, and IFN-γ. © 2022 The Author(s). Published by Oxford University Press on behalf of Infectious Diseases Society of America.Open access journalThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]