The influence of Hox genes and three intercellular signalling pathways on enteric neuromuscular development.

Normal intestinal motility requires orderly development of the complex nerve plexuses and smooth muscular layers in the gut wall. Organization of these structures results, in part, from cell autonomous programmes directed by transcription factors, which orchestrate appropriate temporal and spatial expression of specific target genes. Hox proteins appear to function in combination to dictate regional codes that establish major structural landmarks in the gut such as sphincters and muscle layers.

Loss of the nf1 tumor suppressor gene decreases fas antigen expression in myeloid cells.

Genetic loss of surface Fas antigen expression leads to reduced apoptosis of myeloid and lymphoid progenitor cells, and a propensity to develop autoimmunity and myeloid leukemia in mouse models. Oncogenic p21(ras) decreases surface Fas antigen expression and renders fibroblasts resistant to Fas mediated apoptosis. Neurofibromin, which is encoded by NF1, is a GTPase activating protein that negatively regulates p21(ras) activity.

Quercetin, an over-the-counter supplement, causes neuroblastoma-like elevation of plasma homovanillic acid.

A 22-month-old boy, who regularly consumed the oral dietary supplement, quercetin, was suspected erroneously of having a catecholamine-producing tumor, based on elevated serum and urine levels of the dopamine metabolite, homovanillic acid (HVA). Subsequent studies of healthy adult volunteers showed that significant elevations in plasma HVA are a consequence of quercetin ingestion.

Clinicopathological significance of Borderline Nuclear Change - High Grade Dyskaryosis Not Excluded.

During a recent discussion on classification of cervical cytology, the introduction of a 'Borderline Nuclear Change - High Grade Dyskaryosis Not Excluded' (BNCH) category was proposed. BNCH cases diagnosed prospectively were retrieved from laboratory records. Questionnaires were sent to referring practitioners regarding clinicopathological outcome.

Immunohistologic evidence supports apoptosis, IgG deposition, and novel macrophage/fibroblast crosstalk in the pathologic cascade leading to congenital heart block.

Objective: To assess in vivo the pathologic cascade leading to fibrosis in congenital heart block (CHB). In vitro studies suggest that CHB is initiated via apoptosis, resulting in translocation of SSA/Ro and SSB/La antigens and surface binding by maternal autoantibodies. These opsonized cardiocytes are phagocytosed by macrophages, which secrete factors inducing fibrosis.

c-Kit-mediated overlapping and unique functional and biochemical outcomes via diverse signaling pathways.

A critical issue in understanding receptor tyrosine kinase signaling is the individual contribution of diverse signaling pathways in regulating cellular growth, survival, and migration. We generated a functionally and biochemically inert c-Kit receptor that lacked the binding sites for seven early signaling pathways. Restoring the Src family kinase (SFK) binding sites in the mutated c-Kit receptor restored cellular survival and migration but only partially rescued proliferation and was associated with the rescue of the Ras/mitogen-activated protein kinase, Rac/JNK kinase, and phosphatidylinositol 3-kinase (PI-3 kinase)/Akt pathways.

Neurofibromin-deficient Schwann cells secrete a potent migratory stimulus for Nf1+/- mast cells.

The NF1 tumor suppressor gene encodes a GTPase-activating protein called neurofibromin that negatively regulates Ras signaling. Mutations in NF1 cause neurofibromatosis type 1 (NF1). The development of neurofibromas, which are complex tumors composed of multiple cell types, is a hallmark of NF1.

Genetic background modifies intestinal pseudo-obstruction and the expression of a reporter gene in Hox11L1-/- mice.

Background & Aims: The transcription factor Hox11L1 is expressed by enteric neurons. Two groups mutated murine Hox11L1, and reported lethal intestinal pseudo-obstruction and colonic hyperganglionosis in many, but not all, homozygous null mutants. We investigated the regulation of Hox11L1 and factors that influence the penetrance of pseudo-obstruction in Hox11L1-null mice.

Neuronal dysplasia: a controversial pathological correlate of intestinal pseudo-obstruction.

The infant or child with intestinal pseudo-obstruction poses many challenges for geneticists and other specialists. Although a well-defined anatomic diagnosis (e.g.

Cleft-palate lateral synechia syndrome: insight into the phenotypic spectrum of Fryns syndrome?

Background: In 1972, Fuhrmann et al. (Humangenetik 1972;14:196-203) described a novel syndrome consisting of cleft palate (CP) and lateral synechiae (LS) between the palate and the floor of the mouth. This constellation of malformations, since denoted as cleft-palate lateral synechiae syndrome (CPLS), is a rare syndrome; only five cases have been reported since the original description.

Cytokine polymorphisms and histologic expression in autopsy studies: contribution of TNF-alpha and TGF-beta 1 to the pathogenesis of autoimmune-associated congenital heart block.

Although Abs to SSA/Ro-SSB/La are necessary for the development of congenital heart block (CHB), the low frequency suggests that fetal factors are contributory. Because CHB involves a cascade from inflammation to scarring, polymorphisms of the TNF-alpha promoter region and codons 10 and 25 of the TGF-beta gene were evaluated in 88 children (40 CHB, 17 rash, 31 unaffected siblings) and 74 mothers from the Research Registry for Neonatal Lupus (NL). Cytokine expression was assessed in autopsy material from two fetuses with CHB.

A rare complex DNA rearrangement in the murine Steel gene results in exon duplication and a lethal phenotype.

Kit ligand (Kitl), encoded by the Steel (Sl) locus, plays an essential role in hematopoiesis, gametogenesis, and melanogenesis during both embryonic and adult life. We have characterized a new spontaneous mutant of the Sl locus in mice designated KitlSl-20J that arose in the breeding colony at Jackson Laboratories. Heterozygous KitlSl-20J mice display a white belly spot and intercrossing results in an embryonic lethal phenotype in the homozygous state.

Relationship of malocclusion severity and treatment fee to consumer's expectation of treatment outcome.

Understanding consumer expectations is important if orthodontists are to be successful in marketing their elective services. The purpose of this study was to examine the relationship between consumer outcome expectations and treatment variables, including cost of treatment and malocclusion severity. The subjects were parents of patients recruited from 9 private orthodontic practices in southwestern Pennsylvania who were entering a single comprehensive phase of orthodontic treatment, characterized by a full fee and complete fixed appliances.

Functional p85alpha gene is required for normal murine fetal erythropoiesis.

In vitro studies suggest that activation of class IA phosphatidylinositol 3 (PI-3) kinase is necessary for normal erythroid cell development. However, when class IA PI-3 kinase-deficient mice were generated by a targeted deletion of the p85alpha regulatory subunit, fetal erythropoiesis was reportedly unaffected. Given the discrepancies between these studies, we performed a more detailed in vivo analysis of class IA PI-3 kinase-deficient embryos.

Genetic evidence for convergence of c-Kit- and alpha4 integrin-mediated signals on class IA PI-3kinase and the Rac pathway in regulating integrin-directed migration in mast cells.

Mast cells play a critical role in host defense against a number of pathogens. Increased mast cell infiltration has been described in allergic asthma, in rheumatoid arthritis, and during helminthes infection. Despite the importance of mast cells in allergic disease and defense against infection, little is known about the mechanisms by which mast cells migrate to various tissues under steady state conditions or during infection or inflammation.

Functional and biochemical consequences of abrogating the activation of multiple diverse early signaling pathways in Kit. Role for Src kinase pathway in Kit-induced cooperation with erythropoietin receptor.

Kit receptor tyrosine kinase and erythropoietin receptor (Epo-R) cooperate in regulating blood cell development. Mice that lack the expression of Kit or Epo-R die in utero of severe anemia. Stimulation of Kit by its ligand, stem cell factor activates several distinct early signaling pathways, including phospholipase C gamma, phosphatidylinositol 3-kinase, Src kinase, Grb2, and Grb7.

Perception of orthodontic treatment need: opinion comparisons of orthodontists, pediatric dentists, and general practitioners.

Aim: To determine the relationship between treatment need assessment scores of orthodontists, general practitioners, and pediatric dentists.

Study Design: Observational.

Sample: Ten general dental practitioners, 18 orthodontists and 15 pediatric dentists reviewed 137 dental casts and recorded their opinion on whether orthodontic treatment was needed.

Lymphoproliferative defects in mice lacking the expression of neurofibromin: functional and biochemical consequences of Nf1 deficiency in T-cell development and function.

Ras plays an essential role in lymphocyte development and function. However, in vivo consequence(s) of regulation of Ras activity by guanosine triphosphatase (GTPase)-activating proteins (GAPs) on lymphocyte development and function are not known. In this study we demonstrate that neurofibromin, the protein encoded by the NF1 tumor suppressor gene functions as a GAP for Ras in T cells.

Thrombopoietin promotes mixed lineage and megakaryocytic colony-forming cell growth but inhibits primitive and definitive erythropoiesis in cells isolated from early murine yolk sacs.

The role of thrombopoietin (Tpo) in promoting hematopoiesis has been extensively studied in late fetal, neonatal, and adult mice. However, the effects of Tpo on early yolk sac hematopoiesis have been largely unexplored. We examined whole embryos or the cells isolated from embryo proper and yolk sacs and identified both Tpo and c-mpl (Tpo receptor) mRNA transcripts in tissues as early as embryonic day 6.

Transdifferentiation of cardiac fibroblasts, a fetal factor in anti-SSA/Ro-SSB/La antibody-mediated congenital heart block.

The signature lesion of autoantibody-associated congenital heart block (CHB) is fibrosis of the conducting tissue. To date, participation of myofibroblasts in the cascade to injury has been unexplored. The importance of myofibroblast/macrophage cross-talk is demonstrated by the novel finding of these cell types in the heart of a neonate dying of CHB.