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Biomedical subjects

E Brown

Publications and source records attributed to E Brown.

At least 91 records · Page 5Linked to original sources
PubMed1997

Leukemia and/or myeloproliferative syndrome in neonates with Down syndrome.

Approximately 10% of newborn infants with Down Syndrome develop a form of megakaryoblastic leukemia which usually disappears spontaneously during the first months of life. The evidence that this "Transient Leukemia" is truly leukemia includes the following: it is clonal proliferation, it can be fatal and tissue infiltration of leukemic cells occurs. Also in approximately 25% of cases that recover, Acute Megakaryoblastic Leukemia will develop in the first four years of life, which, if not treated, is fatal. Evidence regarding the megakaryoblastic nature of the leukemic cells is presented as well as a description of the lethal forms of the disease. The study of Transient Leukemia is of considerable importance because it can provide insight into both the nature of leukemia and its relation to trisomy 21.

Biopsy↗
PubMed1997

Neurotrophins stimulate chemotaxis of embryonic cortical neurons.

During mammalian cortical development, neuronal precursors proliferate within ventricular regions then migrate to their target destinations in the cortical plate, where they organize into layers. In the rat, most cortical neuronal migration occurs during the final week of gestation (Bayer et al, 1991; Jacobson, 1991). At this time (E15-E21), reverse transcriptase-polymerase chain reaction demonstrated that cortical homogenates contain mRNA encoding brain derived neurotrophic factor (BDNF) and the catalytic form of its high-affinity receptor, TrkB. Immunocytochemistry and in situ hybridization of sections revealed that the catalytic TrkB receptors predominantly localize to regions containing migratory cells. Many TrkB+ cells exhibited the classic morphology of migrating neurons, suggesting that TrkB ligands play a role in cortical neuronal migration. We analysed whether TrkB ligands influence the motility of embryonic cortical cells (from E15-E21) using a quantitative in vitro chemotaxis assay. High-affinity TrkB ligands (BDNF and NT4/5) stimulated chemotaxis (directed migration) of embryonic neurons at concentrations ranging from 1 to 100 ng/ml. NT-3, a low-affinity TrkB ligand, only stimulated significant migration at high concentrations (> or =100 ng/ml). Peak migration to BDNF was observed at gestational day 18 (E18). BDNF-induced chemotaxis was blocked by either tyrosine kinase inhibitor, K252a, or the Ca2+-chelator, BAPTA-AM, suggesting that BDNF-induces motility via autophosphorylation of TrkB receptor proteins and involves Ca2+-dependent mechanisms. BDNF-stimulation of increased cytosolic Ca2+ was confirmed with optical recordings of E18 cortical cells loaded with Ca2+ indicator dye. Thus, signal transduction through the TrkB receptor complex directs neuronal migration, suggesting that, in vivo, BDNF exerts chemotropic effects that are critical to morphogenesis of the cortex.

Animals↗
PubMed1997

The Ca2+-sensing receptor: a target for polyamines.

The Ca2+-sensing receptor (CaR) is activated at physiological levels of external Ca2+ (Ca(o)) but is expressed in a number of tissues that do not have well-established roles in the control of Ca(o), including several regions of the brain and the intestine. Polyamines are endogenous polyvalent cations that can act as agonists for the CaR, as shown by our current studies of human embryonic kidney (HEK-293) cells transfected with the human CaR. Cellular parameters altered by polyamines included cytosolic free Ca2+ (Ca(i)), inositol phosphate production, and the activity of a nonselective cation channel. Spermine stimulated Ca(i) transients in CaR-transfected HEK cells, with a concentration producing a half-maximal response (EC50) of approximately 500 microM in the presence of 0.5 mM Ca2+, whereas sustained increases in Ca(i) had an EC50 of approximately 200 microM. The order of potency was spermine > spermidine >> putrescine. Elevation of Ca(o) shifted the EC50 for spermine sharply to the left, with substantial stimulation below 100 microM. Addition of subthreshold concentrations of spermine increased the sensitivity of CaR-expressing HEK cells to Ca(o). Parathyroid hormone secretion from bovine parathyroid cells was inhibited by 50% in the presence of 200 microM spermine, a response similar to that elicited by 2.0 mM Ca(o). These data suggest that polyamines could be effective agonists for the CaR, and several tissues, including the brain, may use the CaR as a target for the actions of spermine and other endogenous polycationic agonists.

Animals↗
PubMed1997

The chasm: what can be done, and what should be done.

The case study of growth hormone in short-stature children offers an example of the high cost of bioengineered therapies and the attendant ethical concerns. Despite uncertainties as to its efficacy, it is estimated that the annual U.S. expenditure for growth hormone, which costs about $20,000 per year for a 30 kg child, exceeds $375 million dollars. Ultimately, at this point in its evolution, the use of GH therapy illustrates the dilemma commonly created by new medical technology--the chasm between what can be done and what should be done. Unfortunately, the knowledge of what can be done precedes the understanding of what should be done.

Child↗
PubMed1997

Neutrophil adhesion and the therapy of inflammation.

Cell adhesion has an essential role in neutrophil recognition of sites of inflammation, migration through endothelium and extracellular matrix, and activation to full effector function at these sites. Adhesion molecules on the neutrophil involved in these events include members of the selectin, integrin, and immunoglobulin superfamilies. Inhibition of neutrophil adhesion holds the promise of interrupting idiopathic inflammation in a variety of diseases, but also can increase susceptibility to infection. The therapeutic challenge is to design agents of sufficient specificity to block the deleterious effects of neutrophil influx and activation without interference with host defense. This will require improved understanding of the molecular events regulating, and regulated by, neutrophil adhesion.

Cell Adhesion↗
PubMed1997

Frontal functions in juvenile myoclonic epilepsy.

The authors investigated cognition in juvenile myoclonic epilepsy (JME), focusing on frontal functions as suggested by maximal spatial distribution of epileptiform activity seen over frontocentral regions. Fifteen patients with JME (mean age, 34.3 years; mean estimated IQ 101) were administered a battery of tests sensitive to frontal dysfunction. The number of patients with impaired test performance and the frequency of impairment per test were calculated. Performance on selected tests was compared with that of 15 patients with temporal lobe epilepsy (TLE) who were matched for estimated IQ using paired t-tests. Although the performance of the group with JME was not uniform--some patients showed marked impairment whereas others showed little or no deficit--a high frequency of impairment was found on tests of concept formation-abstract reasoning and mental flexibility, cognitive speed, and planning and organization. Significant differences were found between the group with JME and the group with TLE on tests requiring mental flexibility and concept formation-abstract reasoning. In conjunction with studies demonstrating intractable seizures in approximately 20% of patients, the results from this study suggest that JME is not a uniformly benign condition. Frontal deficits may have maladaptive behavioral consequences suggestive of personality dysfunction, as described anecdotally by previous investigators.

Adolescent↗
PubMed1996

Do splanchnic viscera contribute to liver preservation reperfusion injury?

Preservation-reperfusion injury of hepatic allografts is thought to be associated with Kupffer cell activation and TNF release from the transplanted organ. Confirmation that the allograft is the source of this TNF in an in vivo model is difficult because of rapid equilibration of this cytokine into all compartments. A novel experimental design was devised to aid in accurate localization of the site of TNF release following a orthotopic liver transplant (OLT). In the first group (anhepatic), livers were removed from rats and splanchnic and systemic venous returns were then reestablished using a conduit of donor IVC and portal vein with a portasystemic shunt. In the second group (asplanchnic), the liver, stomach, pancreas, and intestine of the recipient were removed and a donor liver was reimplanted using the recipient IVC as the source of portal blood. The third (OLT-16) and fourth (OLT 8) groups underwent standard OLT with preservation times of 16 and 8 hr in 4 degrees C Euro-Collins solution, respectively. TNF levels were significantly increased in the OLT-16 group compared with the OLT-8 group. There were modest elevations of TNF in the anhepatic model, but the TNF in the asplanchnic model approached baseline. Absence of TNF in the asplanchnic group and a rise in TNF levels in the anhepatic group to that not significantly different from OLT-16 or OLT-8 suggest that a major source of TNF following preservation reperfusion may be the intestine.

Animals↗
PubMed1996

Tumor chemosensitivity and chemoresistance assays.

BACKGROUND: Chemosensitivity and chemoresistance assays have been used to select potentially more effective chemotherapy regimens and to avoid the toxicity of potentially ineffective drugs. METHODS: Literature review was conducted. RESULTS: The relevant outcome measure for chemosensitivity assays is improved patient survival. However, the relevant outcome measure for chemoresistance assays is more controversial. Advocates propose that the avoidance of the toxicity of potentially ineffective drugs is the relevant outcome, whereas others believe that the latter is an intermediate outcome and that improved patient survival is the appropriate outcome for both chemoresistance and chemosensitivity assays. There have been no clinical trials showing that either of these assays is associated with improved patient survival. CONCLUSIONS: In terms of improved patient survival, the clinical role of chemosensitivity and chemoresistance assays is unproven. The use of the assays will vary depending on the type and stage of the tumor involved, the proposed role of chemotherapy, and the role of the empiric judgement of the physician.

Chemotherapy, Adjuvant↗
PubMed1996

Where the outside meets the inside: integrins as activators and targets of signal transduction cascades.

In fibroblasts, signaling through the adhesion receptors known as integrins synergizes with other cellular stimulators such as the growth factors. There is currently great interest in the details of the ensuing 'outside in' signal transduction mechanisms, and the focal adhesion kinase in particular, has been a focus of attention. Less is understood of signalling through integrins on leukocytes which also perform a costimulator role. The activity of these leukocyte integrins is not constitutive but is initiated via signalling through other receptors, termed 'inside out' signalling. These signals cause movement and clustering of integrins in the membrane leading to strengthened adhesion between cells.

Cell Adhesion↗
PubMed1996

Optimally functional fluorescein isothiocyanate-labelled fibrinogen for quantitative studies of binding to activated platelets and platelet aggregation.

Dynamic and quantitative studies of the binding of fibrinogen (Fg) to its receptor, GPIIb-IIIa, on activated platelets, leading to platelet aggregation, are best studied with fluorescently-labelled Fg by flow cytometry. Due to conflicting reports on the functionality of FITC-labelled Fg, we have developed a reproducible and 'mild' labelling of fibrinogen with FITC-celite at pH 7.4-8.5 for direct and dynamic studies of specific Fg binding to activated platelets evaluated for native platelet-rich plasma, for washed platelets, and for activated, fixed platelets. We have demonstrated the equivalence of FITC-labelled and unlabelled Fg for binding to activated GPIIb-IIIa receptors, and in the rate and extent of mediating platelet aggregation. We found that FITC-Fg labelled at pH > or = 9 had reduced to absent specific binding to activated platelets, whether using soluble FITC or FITC-celite. The FITC-labelled Fg must be diluted 3-fold with unlabelled Fg when evaluating maximal Fg binding to activated platelets in order to prevent autoquenching of the FITC-Fg which leads to underestimation of Fg levels. The dissociation constant (KD) of Fg on stable preparations of activated, fixed platelets, determined with FITC-Fg binding to platelets by flow cytometry, was in the range reported for 125I-labelled Fg, 70-255 nm with Bmax = 10000-25000 Fg per platelet (n = 20). The FITC-Fg was used to monitor Fg binding to activated platelets directly by plasma, as well as to evaluate platelet subpopulations which maximally bind Fg according to the concentration of ADP used as activator. It is expected that this 'mildly' labelled FITC-Fg will stimulate further studies of platelet activation directly in native anticoagulated blood/plasma, for both basic and clinical research.

Blood Platelets↗
PubMed1996

Delineation by use of specific monoclonal antibodies of the T-cell receptor and major histocompatibility complex interaction sites on the superantigen toxic shock syndrome toxin 1.

Murine monoclonal antibodies (MAbs) specific for toxic shock syndrome toxin 1 (TSST-1), a bacterial superantigen, showed the ability either to detect TSST-1 bound to histocompatibility locus antigen (HLA)-DR molecules or to inhibit TSST-1 binding to HLA-DR. A MAb capable of detecting DR-bound TSST-1 could also inhibit the toxin-induced activation of a T-cell receptor Vbeta15-expressing murine T-cell hybridoma. Alternatively, MAbs with specificity for the HLA-DR association site could present TSST-1 in vitro, stimulating CD4+ human T cells to proliferate. These functional activities correlated directly with with MAb specificity for HLA-DR versus T-cell receptor Vbeta interaction sites on TSST-1 as determined by reactivity with a panel of recombinant TSST-1 mutant molecules. Therefore, these MAbs discriminate the superantigen functional sites on the TSST-1 molecule and constitute reagents with the property of being potent modulators of the toxic activity of TSST-1.

Animals↗
PubMed1996

Reversible parkinsonism and cognitive impairment with chronic valproate use.

Following our initial report of the insidious development of reversible, valproate-induced hearing, motor, and cognitive dysfunction in two patients, we evaluated 36 patients in an epilepsy clinic who had been taking therapeutic levels of valproate for at least 12 months; 29 of these patients were examined according to a prospective protocol. We observed varying degrees of parkinsonism and cognitive impairment, from none to severe. Discontinuation of valproate in 32 affected patients led to subjective and objective improvement on follow-up testing at least 3 months later. Improvement was greatest in patients who were affected most. We conclude that a syndrome of reversible parkinsonism and cognitive impairment may develop insidiously in patients who have been treated with valproate for more than 12 months. The association with valproate may be overlooked due to the insidious onset.

Adult↗