Pediatric electronic pages: looking back and looking ahead.
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Child↗
Biomedical subjects
K Anderson
Publications and source records attributed to K Anderson.
Anatomy and histological characteristics of the spinoglenoid ligament.
The spinoglenoid (inferior transverse scapular) ligament, when present, is located at the spinoglenoid notch. The ligament originates on the spine of the scapula and inserts on the superior margin of the glenoid neck. Because of discrepancies in the literature, we sought to determine its prevalence and to define its histological characteristics. We dissected 112 shoulders of seventy-six cadavera and classified the ligament as absent or an insubstantial structure, a thin fibrous band (type I), or a distinct ligament (type II). We found no distinct ligamentous structure in twenty-two shoulders (20 percent), a type-I ligament in sixty-eight shoulders (61 percent), and a type-II ligament in twenty-two shoulders (20 percent). Overall, ninety (80 percent) of the shoulders had a fibrous band of tissue that, together with the spine of the scapula, formed a narrow fibro-osseous tunnel through which the suprascapular nerve traveled. The bone-spinoglenoid ligament-bone complexes from three specimens were analyzed histologically. There were two type-I ligaments and one type-II ligament; all three ligaments were composed of collagen fibers. One type-I ligament and the type-II ligament demonstrated Sharpey fibers at their origin on the spine of the scapula. The other type-I ligament attached to the spine of the scapula through the periosteum. All three ligaments inserted into the periosteum of the glenoid neck.
Adolescent↗
Forces required to initiate sliding in second-generation intramedullary nails.
Second-generation intramedullary nails, which allow the fixation screw that is placed in the femoral head to slide distally and thus allow compression of the fracture of the femoral neck, have become a popular option for the treatment of ipsilateral fractures of the femoral neck and shaft. However, the sliding characteristics of the screw within the barrel of the nail or the side-plate have not been assessed biomechanically, to our knowledge. The goal of the current study was to investigate the forces required to initiate sliding of the proximal screw in intramedullary devices and to compare these forces with those required to initiate sliding of hip screws. The loading configuration simulated the typical angle of 135 degrees between the intramedullary nail and the proximal screw. The forces required to initiate sliding of the proximal screw, with the screw extended fifty-one, seventy-six, eighty-six, and 102 millimeters beyond the proximal end of the barrel, were measured for three different types of second-generation intramedullary nails (Recon, ZMS, and Gamma), a sliding compression hip screw, and an intramedullary hip screw, and these forces were then compared. With each amount of extension of the screw, the hip screws required lower forces to initiate sliding than did the second-generation intramedullary devices. Of the second-generation devices, the Gamma nail required the highest forces to initiate sliding; the Recon and ZMS nails required 20 to 40 percent lower forces compared with the Gamma nail. None of the devices jammed in any of the loading configurations that were tested. When the extension of the screw was increased, higher forces were required to initiate sliding.
Biomechanical Phenomena↗
Modulation of Anger and Aggression.
Traumatic brain injury commonly results in anger and aggressive behavior. The hypothalamus, limbic system, and prefrontal cortex mediate aggression, and frequently are injured during trauma. Many neurotransmitters that modulate aggressive behavior, including norepinephrine, serotonin, dopamine, and acetylcholine are affected by brain injury. The pharmacological treatment of aggression is divided into medications used for acute behavioral control, and those used for the prophylaxis of episodes. Specific recommendations are made for the choice of specific medications.
Journal Article↗
Commitment and differentiation of lung cell lineages.
To form a large diffusible interface capable of conducting respiratory gases to and from the circulation, the lung must undergo extensive cell proliferation, branching morphogenesis, and alveolar saccule formation, to generate sufficient surface area. In addition, the cells must differentiate into at least 40 distinct lung cell lineages. Specific transcriptional factors, peptide growth factor receptor-mediated signaling pathways, extracellular matrix components, and integrin-signaling pathways interact to direct lung morphogenesis and lung cell lineage differentiation. Branching mutants of the respiratory tracheae in Drosophila have identified several functionally conserved genes in the fibroblast growth factor signaling pathway that also regulate pulmonary organogenesis in mice and probably also in man. Key transcriptional factors including Nkx2.1, hepatocyte nuclear factor family forkhead homologues, GATA family zinc finger factors, pou and homeodomain proteins, as well as basic helix-loop-helix factors, serve as master genes to integrate the developmental genetic instruction of lung morphogenesis and cell lineage determination. Lung mesenchyme serves as a 'compleat' inducer of lung morphogenesis by secreting soluble peptide growth factors. In general, peptide growth factors signaling through cognate receptors with tyrosine kinase intracellular signaling domains such as epidermal growth factor receptor, fibroblast growth factor receptors, hepatocyte growth factor/scatter factor receptor, c-met, insulin-like growth factor receptor, and platelet-derived growth factor receptor, stimulate lung morphogenesis, while the cognate receptors with serine/threonine kinase intracellular signaling domains, such as the transforming growth factor-beta receptor family are inhibitory. The extracellular matrix also plays a key role in determining branching morphogenesis. Pulmonary neuroendocrine (PNE) cells differentiate earliest in gestation among lung epithelial cells. PNE cells are principally derived from endoderm and not neural crest. PNE cells have been proposed to function as airway chemoreceptors, while PNE cell secretory granules contain many bioactive substances such as GRP which may direct proliferation of adjacent epithelial cells. Mammalian achaete-schute homolog-1 null mutant mice do not develop PNE cells. Candidate molecular switches in the transition from a quiescent to a proliferative alveolar epithelial cell (AEC) phenotype and back again following acute hyperoxia, include autocrine peptide growth factor signaling pathways and cell cycle regulatory elements. AEC type 2 also appear capable of reversible transdifferentiation into AEC type 1 and intermediate phenotypes in response to cues from extracellular matrix and cell shape, as well as soluble factors. Evidence for expression of telomerase by alveolar epithelial stem cells, which correlates with self-renewal potential, is now beginning to emerge. Lung regeneration following lobectomy in juvenile rodents is associated with co-ordinated cell proliferation, re-expression of elastin and formation of alveoli. Retinoic acid has recently shown promise as a stimulator of alveolization in juvenile rats. Our future goal is to devise new rational and gene therapeutic strategies to stimulating lung growth and maturation, ameliorating lung injury, augmenting lung repair, and inducing lung regeneration. The ideal agent or agents would therefore mimic the instructive role of lung mesenchyme, correctly inducing the temporospatial pattern of lung cell lineages necessary to restore pulmonary gas diffusing capacity.
Animals↗
16 tips for reaching agreement.
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Conflict, Psychological↗
Assessment of liver function in primary cultures of hepatocytes using diethoxy (5,6) chloromethylfluorescein and confocal laser scanning microscopy.
A method is presented which can be used to assess the function of hepatocytes in complex culture configurations without disrupting the integrity of the cell environment. It utilises a fluorescent probe for cytochrome P450 dependent mixed function oxidase (MFO) activity diethoxy (5,6) chloromethylfluorescein, and confocal laser scanning microscopy. The MFO activity of individual cells in primary cultures of intact hepatocytes can be detected in situ, and quantified by image analysis. This may be a valuable means of monitoring the effect of culture conditions on the function of bioartificial liver devices, and could be used to assess the need for effective oxygenation of cells, the influence of shear stress and of exposure to patient serum during clinical use.
Animals↗
The growth and expansion of Pediatrics: 1948 to 1998.
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History, 20th Century↗
Metabolism of carvedilol in dogs, rats, and mice.
The excretion and biotransformation of carvedilol [1-[carbazolyl-(4)-oxy]-3-[(2-methoxyphenoxyethyl)amino]-2-p ropanol], a new, multiple-action, neurohormonal antagonist that exhibits the combined pharmacological activities of beta-adrenoreceptor antagonism, vasodilation, and antioxidation, were investigated in dogs, rats, and mice. Carvedilol was absorbed well, and biliary secretion was predominant in each species. Carvedilol was metabolized extensively in each species, and elimination of unchanged compound was minor in bile duct-catheterized rats and dogs. In dogs, glucuronidation of the parent compound and hydroxylation of the carbazolyl ring, with subsequent glucuronidation, were the major metabolic pathways. Rats showed the simplest metabolite profile; the primary metabolites were formed by hydroxylation of the carbazolyl ring, with subsequent glucuronidation. Mice displayed the most complicated metabolite profile; glucuronidation of the parent compound and hydroxylation of either the carbazolyl or phenyl ring, with subsequent glucuronidation, were the major metabolic routes. O-Dealkylation was a minor pathway in all species examined.
Adrenergic beta-Antagonists↗
16 tips for reaching agreement.
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Humans↗
Molecular determinants of selectivity in 5-hydroxytryptamine1B receptor-G protein interactions.
The recognition between G protein and cognate receptor plays a key role in specific cellular responses to environmental stimuli. Here we explore specificity in receptor-G protein coupling by taking advantage of the ability of the 5-hydroxytryptamine1B (5-HT1B) receptor to discriminate between G protein heterotrimers containing Galphai1 or Galphat. Gi1 can interact with the 5-HT1B receptor and stabilize a high affinity agonist binding state of this receptor, but Gt cannot. A series of Galphat/Galphai1 chimeric proteins have been generated in Escherichia coli, and their functional integrity has been reported previously (Skiba, N. P., Bae, H., and Hamm, H. E. (1996) J. Biol. Chem. 271, 413-424). We have tested the functional coupling abilities of the Galphat/Galphai1 chimeras to 5-HT1B receptors using high affinity agonist binding and receptor-stimulated guanosine 5'-3-O-(thio)triphosphate (GTPgammaS) binding. In the presence of betagamma subunits, amino acid residues 299-318 of Galphai1 increase agonist binding to the 5-HT1B receptor and receptor stimulation of GTPgammaS binding. Moreover, Galphai1 containing only Galphat amino acid sequences from this region does not show any coupling ability to 5-HT1B receptors. Our studies suggest that the alpha4 helix and alpha4-beta6 loop region of Galphas are an important region for specific recognition between receptors and Gi family members.
Amino Acid Sequence↗
Cyclophosphamide, doxorubicin, vincristine, prednisone dose intensification with granulocyte colony-stimulating factor markedly depletes stem cell reserve for autologous bone marrow transplantation.
Hematopoietic growth factors allow dose escalation of chemotherapy. This approach may potentially reduce the quality and quantity of hematopoietic stem cells. The capacity of stem cells recovered after dose intensification to support myeloablative therapy is unknown. In patients with previously untreated advanced follicular lymphoma, trilineage hematopoietic engraftment was compared in two sequential trials of induction therapy (standard dose cyclophosphamide, doxorubicin, vincristine, prednisone [CHOP] without growth factors or dose intensification CHOP supported by granulocyte colony-stimulating factor [G-CSF ]) followed by identical myeloablative therapy and autologous stem cell support. Neutrophil, platelet, and red blood cell (RBC) engraftment were compared on days 100, 180, and 360 after stem cell reinfusion. Despite similar patient characteristics including reinfusion of comparable numbers of marrow mononuclear cells, after stem cell transplantation, a highly significant prolongation of neutrophil and platelet engraftment was seen in patients who received high dose CHOP and G-CSF in comparison to standard dose CHOP. These findings suggest that dose intensified chemotherapy and G-CSF recruited stem cells into a proliferative phase and that G-CSF allowed retreatment at a time when stem cells were susceptible to damage by cytotoxic therapy. Such inadequate hematologic engraftment after myeloablative therapy might be avoided by either shortening the time that growth factor support is administered, lengthening the interval between cycles, or attempting to repetitively harvest additional stem cells either from the marrow or peripheral blood. Therefore, intensification of chemotherapy with growth factor support must be used with caution if stem cells are to be used to support myeloablative therapy.
Adult↗
Cytochrome c-dependent and -independent induction of apoptosis in multiple myeloma cells.
Cytochrome c is a mitochondrial protein that induces apoptosis when accumulated in the cytosol in response to diverse stress inducers. This protein has also been shown to cause apoptosis when added to cell free extracts. In this report, we studied the role of cytochrome c (cyto-c) in dexamethasone (Dex), anti-Fas monoclonal antibody (mAb), and ionizing radiation-induced apoptosis in multiple myeloma cells. The results demonstrate that ionizing radiation-induced apoptosis is associated with an increase in cytosolic cyto-c levels, whereas apoptosis induced by Dex or anti-Fas mAb has no detectable effect on cyto-c release. By contrast, caspase-3 was activated in response to all of these agents. Thus, our findings suggest that Dex or anti-Fas mAb-induced apoptosis is not accompanied by cyto-c release and that there are at least two different pathways leading to activation of caspases and induction of apoptosis in multiple myeloma cells that can be distinguished by accumulation of cytosolic cyto-c.
Apoptosis↗
[Alarmingly inadequate clinical evaluation and marketing of intrauterine devices].
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Advertising↗
Bimolecular exon ligation by the human spliceosome.
Intron excision is an essential step in eukaryotic gene expression, but the molecular mechanisms by which the spliceosome accurately identifies splice sites in nuclear precursors to messenger RNAs (pre-mRNAs) are not well understood. A bimolecular assay for the second step of splicing has now revealed that exon ligation by the human spliceosome does not require covalent attachment of a 3' splice site to the branch site. Furthermore, accurate definition of the 3' splice site in this system is independent of either a covalently attached polypyrimidine tract or specific 3' exon sequences. Rather, in this system 3' splice site selection apparently occurs with a 5' --> 3' directionality.
Adenoviridae↗
CD6-depleted allogeneic bone marrow transplantation for acute leukemia in first complete remission.
The appropriate timing of bone marrow transplantation (BMT) for adults with acute myelogenous leukemia (AML) and acute lymphoblastic leukemia (ALL) is controversial. Although allogeneic transplantation results in a lower risk of disease recurrence than intensive chemotherapy alone, overall outcome following BMT may not be improved due to the higher incidence of therapy-related fatal complications, frequently as a result of the development of graft-versus-host disease (GVHD). Selective T-cell depletion of donor marrow can reduce the incidence of GVHD and thereby limit transplant-related toxicity. Herein we report the risk of GVHD, incidence of transplant related mortality (TRM), likelihood of disease relapse, and overall survival in adult patients undergoing BMT with CD6 depleted allogeneic marrow for acute leukemia in first remission. Forty-one consecutive allogeneic transplants were performed on patients with acute leukemia and high-risk features (28 AML, 13 ALL) using T12 monoclonal antibody and complement to remove CD6+ T cells from donor marrow. No pre- or posttransplant immune suppressive medications for GVHD prophylaxis were administered. The actuarial estimated risk of grade 2 to 4 acute GVHD was 15% in patients receiving HLA identical grafts. Chronic GVHD developed in five patients. The estimated risk of TRM for patients in first complete remission was 5% at Day +100 and 16% at 2 years. Fatalities attributable to infection with cytomegalovirus or Epstein-Barr virus occurred in only three patients. Estimated probabilities of relapse, overall survival, and event-free survival at 4 years were 25%, 71%, and 63%, respectively. No significant differences in GVHD, TRM, relapse rate, or survival was observed for patients with AML compared with those with ALL. Allogeneic transplantation with CD6 depleted bone marrow is effective in consolidating remissions of high-risk patients with acute leukemia in first remission without excessive toxicity.
Acute Disease↗
Osteopetrosis in mice lacking haematopoietic transcription factor PU.1.
Osteoclasts are multinucleated cells and the principal resorptive cells of bone. Although osteoclasts are of myeloid origin, the role of haematopoietic transcription factors in osteoclastogenesis has not been explored. Here we show that messenger RNA for the myeloid- and B-cell-specific transcription factor PU.1 progressively increases as marrow macrophages assume the osteoclast phenotype in vitro. The association between PU.1 and osteoclast differentiation was confirmed by demonstrating that PU.1 expression increased with the induction of osteoclastogenesis by either 1,25-dihydroxyvitamin D3 or dexamethasone. Consistent with the participation of PU.1 in osteoclastogenesis, we found that the development of both osteoclasts and macrophages is arrested in PU.1-deficient mice. Reflecting the absence of osteoclasts, PU.1-/- mice exhibit the classic hallmarks of osteopetrosis, a family of sclerotic bone diseases. These animals were rescued by marrow transplantation, with complete restoration of osteoclast and macrophage differentiation, verifying that the PU.1 lesion is intrinsic to haematopoietic cells. The absence of both osteoclasts and macrophages in PU.1-mutant animals suggests that the transcription factor regulates the initial stages of myeloid differentiation, and that its absence represents the earliest developmental osteopetrotic mutant yet described.
Animals↗
Differential T cell signaling induced by antagonist peptide-MHC complexes and the associated phenotypic responses.
Certain changes in TCR contact residues have been shown to have profound effects on the capacity of a peptide Ag to stimulate a T cell response. Although some of these changes apparently lead to a complete loss of the ability to interact with the TCR, others result in partial agonist activity (e.g., cytokine production without proliferation) or antagonist activity (i.e., the capacity to inhibit the engagement to the TCR by Ag). We show MHC class II-restricted antagonist activity was associated with a differential pattern of early tyrosine phosphorylation events that was characterized by a preponderance of phosphorylation of low molecular mass TCRzeta and the failure to phosphorylate Zap-70. These early tyrosine phosphorylation patterns are the same as those previously described for partial agonists. Thus, a partial agonist phenotype such as anergy induction cannot be ascribed in a causal manner to this pattern of tyrosine phosphorylation. We further extend the studies of signal transduction elicited by agonist and antagonist peptides by characterizing differential recruitment of Zap-70 associated with TCRzeta isoforms and differential phosphorylation of p120 proto-oncogene c-Cbl. Another early event following TCR engagement by Ag, down-modulation of the TCR, was studied with antagonist peptides. We show that antagonist peptides do not cause TCR down-modulation. This failure may represent a mechanism by which antagonists inhibit antigen-mediated stimulation of T cells.
Amino Acid Sequence↗