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Biomedical subjects

B Goldstein

Publications and source records attributed to B Goldstein.

At least 19 recordsLinked to original sources
PubMed2001

Calculations show substantial serial engagement of T cell receptors.

The serial engagement model provides an attractive and plausible explanation for how a typical antigen presenting cell, exhibiting a low density of peptides recognized by a T cell, can initiate T cell responses. If a single peptide displayed by a major histocompatibility complex (MHC) can bind, sequentially, to different T cell receptors (TCR), then a few peptides can activate many receptors. To date, arguments supporting and questioning the prevalence of serial engagement have centered on the down-regulation of TCR after contact of T cells with antigen presenting cells. Recently, the existence of serial engagement has been challenged by the demonstration that engagement of TCR can down-regulate nonengaged bystander TCR. Here we show that for binding and dissociation rates that characterize interactions between T cell receptors and peptide-MHC, substantial serial engagement occurs. The result is independent of mechanisms and measurements of receptor down-regulation. The conclusion that single peptide-MHC engage many TCR, before diffusing out of the contact region between the antigen-presenting cell and the T cell, is based on a general first passage time calculation for a particle alternating between states in which different diffusion coefficients govern its transport.

Antigen-Presenting Cells↗
PubMed2000

Embryonic polarity: a role for microtubules.

Researchers have suspected that initial polarization of the Caenorhabditis elegans embryo might be directed by microtubules, but demonstrating this has faced obstacles. A new study has cleverly bypassed these obstacles.

Animals↗
PubMed2000

Recombinant bactericidal/permeability-increasing protein (rBPI21) as adjunctive treatment for children with severe meningococcal sepsis: a randomised trial. rBPI21 Meningococcal Sepsis Study Group.

BACKGROUND: Endotoxin is a primary trigger of the inflammatory processes that lead to shock, multiorgan failure, and purpura fulminans in meningococcal sepsis. Bactericidal/permeability-increasing protein (BPI) is a natural protein, stored within the neutrophil granules, that binds to and neutralises the effects of endotoxin in vitro, in laboratory animals, and in humans. To establish whether a recombinant 21-kDa modified fragment of human BPI (rBPI21), containing the active antimicrobial and endotoxin-neutralising moiety, would decrease death and long-term disability from meningococcal sepsis, we did a randomised, double-blind, placebo-controlled trial of rBPI21 in children with severe meningococcal sepsis. METHODS: We enrolled children (2 weeks to 18 years of age) presenting to 22 centres in the UK and the USA with a clinical picture suggestive of meningococcal sepsis, and with evidence of severe disease. Children were randomly assigned rBPI21 (2 mg/kg over 30 min followed by 2 mg/kg over 24 h) or placebo (0.2 mg/mL human albumin solution) in addition to conventional medical therapy. Primary outcome variables were mortality, amputations, and change in paediatric overall performance category (POPC) from before illness to day 60. Analysis was by intention to treat. FINDINGS: Of 1287 patients screened, 892 were excluded, including 57 patients who died or who met criteria for imminent death before receiving the study drug. 190 patients received rBPI21, and 203 placebo. 34 (8.7%) of 393 patients died during the study: 14 (7.4%) in the rBPI21 group and 20 (9.9%) in the placebo group (odds ratio 1.31 [95% CI 0.62-2.74], p=0.48). Compared with patients randomised to placebo, fewer patients treated with rBPI21 had multiple severe amputations (six of 190 [3.2%] vs 15 of 203 [7.4%], odds ratio 2.47 [0.94-6.51], p=0.067), and more had a functional outcome similar to that before illness (as measured by the POPC scale) at day 60 (136 of 176 [77.3%] vs 126 of 190 [66.3%], p=0.019). INTERPRETATION: Because most deaths occurred in the interval between identification of patients and study drug administration, the mortality rate in the placebo group was substantially lower than predicted. The trial was therefore underpowered to detect significant differences in mortality. However, patients receiving rBPI21 had a trend towards improved outcome in all primary outcome variables. Given the excellent severity match between placebo and rBPI21 groups at study entry, the results overall indicate that rBPI21 is beneficial in decreasing complications of meningococcal disease.

Adolescent↗
PubMed2000

When cells tell their neighbors which direction to divide.

Many cells must divide in specific orientations, yet for only a handful of cases do we have some understanding of how cells choose division orientations. We know of only a few cases where division orientations are controlled by specific cell-cell interactions. These cases are of interest, because they tell us something new and seemingly fundamental about how cells can function during development. Here, the evidence that interactions control division orientation in some cells of the early C. elegans embryo is presented, and what is known about how contact can regulate division orientation is discussed. Whether contact-mediated division orientation is a peculiarity of C. elegans or whether it may be more widespread is addressed.

Animals↗
PubMed2000

Continuous propofol anaesthesia for patients with myotonic dystrophy.

Myotonic dystrophy, a rare genetic disorder, may pose a serious problem to the anaesthesiologist due to muscular and extramuscular involvement. Thirteen patients, median age 21 yr were anaesthetized by continuous propofol infusion, fentanyl, atracurium and N2O to evaluate this combination in myotonic dystrophy. Intraoperatively, neither exaggerated reactions nor haemodynamic instability was observed. Recovery was smooth and quick. Although there was a significant decrease in mean postoperative vital capacity (965 (349) ml) from the preoperative value (1664 (566) ml, P = 0.0028), there was no change in mean postoperative SpO2 and there were no perioperative respiratory complications. Only two patients complained of nausea and vomiting. Similarly, muscular hypertonia and shivering were not observed. We conclude that the combination of continuous propofol infusion and fentanyl was a successful anaesthetic technique in these young myotonic dystrophy patients undergoing peripheral surgery.

Adolescent↗
PubMed2000

Linear and nonlinear analysis of hemodynamic signals during sepsis and septic shock.

OBJECTIVE: Neuroautonomic modulation of heart rate (HR) and blood pressure were assessed in sepsis or septic shock. We hypothesized that these metrics would be diminished in pediatric patients with sepsis and septic shock, indicating uncoupling of the autonomic and cardiovascular systems. DESIGN: Prospective case series. SETTING: Pediatric intensive care unit in a tertiary care children's hospital. PATIENTS: Thirty pediatric patients with sepsis or septic shock. INTERVENTIONS: None. MEASURES AND MAIN RESULTS: Metrics used included power spectral analysis, a linear frequency domain measure, and detrended fluctuation analysis, a nonlinear technique that assesses the degree of long-range correlation in HR or blood pressure. We found decreased low-frequency (2.68 +/- 0.24 vs. 3.37 +/- 0.17 [SEM] bpm2; p = .03) and high-frequency HR power (2.18 +/- 0.14 vs. 2.79 +/- 0.23 bpm2; p = .04) and increased detrended fluctuation analysis scaling exponent (1.22 +/- 0.06 vs. 1.00 +/- 0.07 bpm2; p = .02) in sepsis vs. shock patients, respectively. Compared with sepsis or shock, recovery was associated with increases in low-frequency (3.61 +/- 0.15 vs. 3.05 +/- 0.19 bpm2; p < .0001) and high-frequency HR power (3.11 +/- 0.15 vs. 2.50 +/- 0.22 bpm2; p < .0001). CONCLUSIONS: We conclude that uncoupling of the autonomic and cardiovascular systems occurs over both short- and long-range time scales during sepsis, and the degree of uncoupling may help differentiate between sepsis, septic shock, and recovery states.

Adolescent↗
PubMed2000

Musculoskeletal conditions after spinal cord injury.

The impact of musculoskeletal diseases on the overall function and well-being of a person with spinal cord injury (SCI) cannot be overstated. Even relatively minor musculoskeletal problems can lead to significant secondary disabilities and new societal limitations. This article reviews common musculoskeletal problems and related secondary disabilities associated with SCI. Following an overview on the epidemiology and pathophysiology of each condition, a typical case is presented with a discussion about diagnostic challenges and therapeutic options.

Fractures, Bone↗
PubMed2000

Mycotic infections. Effective management of conditions involving the skin, hair, and nails.

Superficial mycotic infections of the skin, hair, or nails are recurring presentations in the geriatric primary care setting. The most common infections are those caused by dermatophytes. The genus Trichophyton gives rise to most of the tinea dermatophytoses, including tinea capitis, tinea pedis, and tinea unguium (onychomycosis). Part of the diagnostic challenge lies in distinguishing the mycotic lesions from those caused by cutaneous diseases such as psoriasis, eczema, dyshidrosis, and contact dermatitis. Because environmental conditions play a major role in fungal infection onset, clinical management should include patient education about conditions conducive to fungal propagation. Oral agents are the primary mode of treatment for fungal infections of the scalp and nails, whereas topical treatments are frontline agents for other superficial skin conditions.

Antifungal Agents↗
PubMed1999

One lyn molecule is sufficient to initiate phosphorylation of aggregated high-affinity IgE receptors.

In response to antigenic stimuli, the multisubunit immune recognition receptors become aggregated and then phosphorylated on their cytoplasmic tyrosines. For the clonotypic receptors of B and T cells and for Fc receptors such as the high-affinity receptor for IgE (FcepsilonRI), a Src family kinase initiates this phosphorylation. We ask whether aggregation of the initiating kinase itself is required for signal transduction or whether, alternatively, a single associated kinase molecule can phosphorylate the receptors in an aggregate. We formulate the alternative molecular mechanisms mathematically and compare predictions with experimental findings on FcepsilonRI-bearing cells expressing varying amounts of the transfected Src family kinase Lyn. The data are consistent with the requirement of only a single Lyn molecule per FcepsilonRI aggregate to initiate signaling and are inconsistent with a mechanism requiring more than one Lyn molecule.

Animals↗
PubMed1999

A quantitative approach to signal transduction.

The high affinity receptor for IgE (FcepsilonRI), is one of a family of immunoreceptors whose antigen-induced clustering leads to a variety of cellular responses. The signaling pathways are enormously complex but by focusing on only the most initial steps, it is now possible to sketch plausible molecular models that relate the interaction of multivalent antigens with the receptor-bound IgE to the earliest cellular events. In this paper, we describe how we have combined quantitative experimentation and mathematical modeling to probe this system further. We also discuss some of the formidable challenges that remain before we can claim reasonably complete understanding of even these early events.

Animals↗
PubMed1999

Transport effects on surface-volume biological reactions.

Many cellular reactions involve a reactant in solution binding to or dissociating from a reactant confined to a surface. This is true as well for a BIAcore, an optical biosensor that is widely used to study the interaction of biomolecules. In the flow cell of this instrument, one of the reactants is immobilized on a flat sensor surface while the other reactant flows past the surface. Both diffusion and convection play important roles in bringing the reactants into contact. Usually BIAcore binding data are analyzed using well known expressions that are valid only in the reaction-limited case when the Damköhler number Da is small. Asymptotic and singular perturbation techniques are used to analyze dissociation of the bound state when Da is small and O(1). Linear and nonlinear integral equations result from the analysis; explicit and asymptotic solutions are constructed for physically realizable cases. In addition, effective rate constants are derived that illustrate the effects of transport on the measured rate constants. All these expressions provide a direct way to estimate the rate constants from BIAcore binding data.

Biological Transport, Active↗
PubMed1999

Effective rate models for the analysis of transport-dependent biosensor data.

Optical biosensors, including the BIACORE, provide an increasingly popular method for determining reaction rates of biomolecules. In a flow chamber, with one reactant immobilized on a chip on the sensor surface, a solution containing the other reactant (the analyte) flows through the chamber. The time course of binding of the reactants is monitored. Scientists using the BIACORE to understand biomolecular reactions need to be able to separate intrinsic reaction rates from the effects of transport in the biosensor. For a model to provide a useful basis for such an analysis, it must reflect transport accurately, while remaining simple enough to couple with a routine for estimating reaction rates from BIACORE data. Models have been proposed previously for this purpose, consisting of an ordinary differential equation with 'effective rate coefficients' incorporating reaction and transport parameters. In this paper we investigate both the theoretical basis and numerical accuracy of these and related models.

Biological Transport↗
PubMed1999

Effect of N(G)-nitro-L-arginine methyl ester on autonomic modulation of heart rate variability during hypovolemic shock.

OBJECTIVE: To study the changes in neuroautonomic regulation of heart rate and the effects of N(G)-nitro-L-arginine methyl ester (L-NAME), a competitive inhibitor of nitric oxide synthase, on efferent sympathetic cardiac activity and blood pressure during hypovolemic shock. Hypotension during hypovolemic shock may be attributable, in part, to the failure of neuroautonomic regulation of heart rate and blood pressure. In addition, the release of nitric oxide may contribute to hypotension through vasodilation and inhibition of efferent sympathetic activity. DESIGN: Prospective, controlled trial. SETTING: Experimental laboratory in a university hospital. SUBJECTS: Seventeen anesthetized adult male New Zealand White rabbits. INTERVENTIONS: The rabbits were divided into four groups: control (n = 3), control plus L-NAME (n = 5), hypovolemic (n = 4), and hypovolemic plus L-NAME (n = 5). Hypovolemic rabbits were bled of 10% of their circulating blood volume (85 mL/kg) every 10 mins until 30% cumulative hypovolemia was reached. Rabbits received either three doses of saline 1 mL/kg every 10 mins or L-NAME 10 mg/kg in 1 mL/kg of saline solution administered after each hemorrhage for a total of three doses. Changes in heart rate, respiratory rate, mean arterial pressure, plasma catecholamine levels, and heart rate power spectra were recorded every 10 mins during serial hypovolemia and during a 30-min recovery period. MEASUREMENTS AND MAIN RESULTS: During hypovolemic shock there was a decrease in log low-frequency heart rate power (p = .001) and in systolic (p = .003), diastolic (p < .001), and mean (p < .001) blood pressures compared with control rabbits. Treatment with L-NAME during hypovolemia resulted in increased log low-frequency heart rate power (p = .03) and systolic (p = .01), diastolic (p = .007), and mean (p = .009) blood pressures compared with hypovolemic rabbits who received saline placebo. CONCLUSIONS: We found that treatment with L-NAME increased efferent sympathetic cardiac activity and mean arterial pressure during hypovolemic shock compared with control rabbits. We conclude that L-NAME may blunt hypotension during hypovolemic shock by inhibiting nitric oxide synthase and may act to restore neuroautonomic cardiovascular reactivity. Spectral analysis of heart rate variability may allow for insights into the pathophysiology of shock and provide a means of monitoring the neuroautonomic cardiovascular response to therapy.

Animals↗
PubMed1999

Solution assembly of the pseudo-high affinity and intermediate affinity interleukin-2 receptor complexes.

The high affinity interleukin-2 receptor is composed of three cell surface subunits, IL-2Ralpha, IL-2Rbeta, and IL-2Rgamma. Functional forms of the IL-2 receptor exist, however, that enlist only two of the three subunits. On activated T-cells, the alpha- and beta-subunits combine as a preformed heterodimer (the pseudo-high affinity receptor) that serves to capture IL-2. On a subpopulation of natural killer cells, the beta- and gamma-subunits interact in a ligand-dependent manner to form the intermediate affinity receptor site. Previously, we have demonstrated the feasibility of employing coiled-coil molecular recognition for the solution assembly of a heteromeric IL-2 receptor complex. In that study, although the receptor was functional, the coiled-coil complex was a trimer rather than the desired heterodimer. We have now redesigned the hydrophobic heptad sequences of the coiled-coils to generate soluble forms of both the pseudo-high affinity and the intermediate affinity heterodimeric IL-2 receptors. The properties of these complexes were examined and their relevance to the physiological IL-2 receptor mechanism is discussed.

Amino Acid Sequence↗