Spontaneous subarachnoid hemorrhage in children.
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Age Factors↗
Biomedical subjects
B Goldstein
Publications and source records attributed to B Goldstein.
Central auditory speech test findings in individuals with subjective idiopathic tinnitus.
This study reports central auditory speech test performance of 25 consecutive patients with subjective idiopathic tinnitus of the severe disabling type. A preliminary study of 14 individuals who had subjective idiopathic tinnitus and complained of difficulty in hearing and understanding revealed a high incidence of abnormal central auditory speech test performance (71%), despite satisfactory peripheral hearing. The results (1) identify objectively for the first time that tinnitus affects specific components of the auditory pathway; (2) provide a basis for monitoring methods of tinnitus control; and (3) provide a basis for understanding "the interference effect" and problem of communication difficulties in patients with tinnitus of the severe disabling type.
Adult↗
Kinetics of multivalent antigen DNP-BSA binding to IgE-Fc epsilon RI in relationship to the stimulated tyrosine phosphorylation of Fc epsilon RI.
Multivalent DNP-BSA is commonly used to cross-link anti-DNP IgE bound to Fc epsilon RI to stimulate cellular responses, although key features of the binding process are unknown. Fluorescence quenching can be used to study the kinetics of DNP-BSA binding to FITC-IgE. We observe that DNP-BSA binds more slowly to IgE than does an equimolar amount of a monovalent DNP ligand, suggesting that the average effective number of DNP groups per BSA is less than one. The binding data are well described by a transient hapten exposure model in which most of the DNP groups are unavailable for binding but have some probability of becoming exposed and available for binding during the time of the binding measurement. Additional experiments indicate that, for suboptimal to optimal concentrations of DNP-BSA, most of the FITC fluorescence quenching on the cell surface is due to cross-linking events. With these concentrations at 15 degrees C, the kinetics of FITC fluorescence quenching by DNP-BSA correlates with the kinetics of DNP-BSA-stimulated tyrosine phosphorylation of Fc epsilon RI. At 35 degrees C, the phosphorylation kinetics are biphasic during the time period in which cross-linking continues to increase. Our results establish a quantitative relationship between the time-course for cross-linking by multivalent Ag and Fc epsilon RI-mediated signaling, and they provide the means to predict the kinetics of cross-linking under a wide variety of conditions.
Animals↗
Embryonic axis specification in nematodes: evolution of the first step in development.
In 1828, von Baer proposed that the early stages of development must be the most conserved [1]. Others have since countered that the middle stages of development are the most conserved [2]. To address whether the earliest step in pattern formation can evolve, we have examined how asymmetry along the antero-posterior (AP) axis is generated in various nematode species. AP asymmetry is specified in Caenorhabditis elegans at fertilization by the sperm, which directs a cytoplasmic rearrangement that segregates critical factors such as the P granules to one side of the uncleaved embryo [3,4]. We found that AP asymmetry is generated differently in another nematode species: the sperm is not used to specify AP asymmetry, there are no signs of cytoplasmic movements, and P granules are segregated differently. Despite these differences, development from the two-cell stage is remarkably similar in the two species. We have reconstructed the evolutionary history of these mechanisms by analyzing the development of 30 nematode species and mapping the results onto a molecular phylogeny of the nematodes [5]. The results suggest that a new mechanism for axis specification evolved in an ancestor of some of the relatives of C. elegans. We conclude that this fundamental step in development can evolve without affecting other aspects of development.
Animals↗
Skin response to repetitive mechanical stress: a new experimental model in pig.
OBJECTIVES: To develop a new animal model for investigating the relations between interface stresses at the skin, adaptation, and breakdown. There were two hypotheses. (1) In skin subjected to varying types of repetitive mechanical stress, the tissue response depends on the direction and magnitude of the load. As the shear stress increases, tissue breakdown occurs earlier. (2) In skin subjected to repetitive mechanical stress of longer duration, there will be evidence of tissue adaptation. DESIGN: Multiple case control, single-blind. INTERVENTIONS: Varying combinations of normal and shear mechanical loads are applied to pig's skin for short durations (breakdown studies) or longer durations (adaptation studies). MAIN OUTCOME MEASURES: Gross evidence of breakdown (visual inspection of skin) and microscopic changes (eg, histologic features of breakdown; thickness of epidermis and dermis; the length and shape of the basement membrane; concentration of inflammatory cells, mast cells, and fibroblasts; and quantity of elastin fibers). RESULTS: The instrumentation was reliable and a significant improvement over past models in that shear forces were delivered and measured in a controlled manner. The animal model and tissue methodology provided consistent results, and it was found that skin breakdown occurred earlier as shear forces were increased. Evidence of tissue adaptation occurred in the long-term experiments, although corresponding morphologic changes have been difficult to elucidate. CONCLUSIONS: To address the problem of skin breakdown, new animal models are strongly needed to better understand basic biologic processes related to pressure ulcer development.
Adaptation, Physiological↗
Magnetic resonance imaging of nonhealing pressure ulcers and myocutaneous flaps.
OBJECTIVE: To evaluate the use of magnetic resonance imaging (MRI) in making clinical decisions when assessing nonhealing pressure ulcers and nonhealing myocutaneous flaps for the presence of an abscess, osteomyelitis, sinus tracts, and fluid collections. DESIGN: Retrospective review of patient charts and radiographic studies. SETTING: Regional spinal cord injury center. SUBJECTS: Twelve patients who had MRI as part of their evaluation for a nonhealing pressure ulcer or myocutaneous flap. RESULTS: Seven patients had MRI for preoperative evaluation, four with a previous flap that had recurrent breakdown and three with a new grade III or IV ulcer. Five patients had MRI for postoperative evaluation of myocutaneous flaps with delayed healing. MRI was useful in identifying osteomyelitis in three patients and sinus tracts that required surgical revision in six patients. MRI was also used in two patients to assess the size of fluid collections postoperatively in determining whether the patients should be mobilized after surgery. These chronic nonhealing wounds resulted in multiple admissions and lengthy hospital stays and required multiple surgical revisions. Patients who did poorly with healing or had repeated breakdown tended to have concurrent issues such as poor self care, increased age, increased time of spinal cord injury, poor nutrition, or other medical problems. CONCLUSION: Chronic nonhealing pressure ulcers and myocutaneous flaps can be difficult to treat and evaluate with conventional methods. There are multiple reasons for failure to heal. MRI can be a useful tool for identifying some of these factors including osteomyelitis, fluid collections, abcesses, and sinus tracts in the perioperative period. Identifying the appropriate patient populations and clinical indications for the optimal use of MRI should be subject of further study.
Abscess↗
Posttraumatic syringomyelia: profound neuronal loss, yet preserved function.
Posttraumatic syrinxes may extend many cord segments rostral to a spinal cord injury (SCI) and significantly dilate the spinal cord, yet few neurologic deficits may be noted. Careful physical examination may reveal ascending loss of pain and temperature without evident functional motor decline. We present a 49-year-old man with T4 paraplegia and a large posttraumatic syrinx who died 3 weeks after syringoperitoneal shunting. Neuropathologic study revealed a large bilateral syrinx cavity from T1 to C6 that tapered to a small unilateral syrinx at C2. Light microscopy of sections from T1 to C2 showed massive loss of intermediate to intermedio-lateral gray neurons and moderate reduction of motoneurons at T1 to C6 levels. Despite these findings, manual muscle testing results remained normal for wrist extensors and elbow extensors, and the patient continued to perform independent sliding board transfers. We conclude that this large progressive syrinx did not merely dissect neural elements apart but caused extensive neuronal damage. Loss of interneurons was evident in spinal segments with preserved strength and function. Possible mechanisms to explain the relatively minimal clinical deficits in view of the neuronal loss are discussed.
Activities of Daily Living↗
Extending the range of rate constants available from BIACORE: interpreting mass transport-influenced binding data.
Surface-based binding assays are often influenced by the transport of analyte to the sensor surface. Using simulated data sets, we test a simple two-compartment model to see if its description of transport and binding is sufficient to accurately analyze BIACORE data. First we present a computer model that can generate realistic BIACORE data. This model calculates the laminar flow of analyte within the flow cell, its diffusion both perpendicular and parallel to the sensor surface, and the reversible chemical reaction between analyte and immobilized reactant. We use this computer model to generate binding data under a variety of conditions. An analysis of these data sets with the two-compartment model demonstrates that good estimates of the intrinsic reaction rate constants are recovered even when mass transport influences the binding reaction. We also discuss the conditions under which the two-compartment model can be used to determine the diffusion coefficient of the analyte. Our results illustrate that this model can significantly extend the range of association rate constants that can be accurately determined from BIACORE.
Binding Sites↗
Decomplexification in critical illness and injury: relationship between heart rate variability, severity of illness, and outcome.
OBJECTIVES: To determine if decomplexification of heart rate dynamics occurs in critically ill and injured pediatric patients. We hypothesized that heart rate power spectra, a measure of heart rate dynamics, would inversely correlate with measures of severity of illness and outcome. DESIGN: A prospective clinical study. SETTING: A 12-bed pediatric intensive care unit (ICU) in a tertiary care children's hospital. PATIENTS: One hundred thirty-five consecutive pediatric ICU admissions. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We compared heart rate power spectra with the Pediatric Risk of Mortality (PRISM) score, the Pediatric Cerebral Performance Category (PCPC), and the Pediatric Overall Performance Category (POPC). We found significant negative correlations between minimum low-frequency and high-frequency heart rate power spectral values recorded during ICU stay and the maximum PRISM score (log low-frequency heart rate power vs. PRISM, r2 = .293, p < .001; and log high-frequency heart rate power vs. PRISM, r2 = .243, p < .001) and outcome at ICU discharge (log low-frequency heart rate power vs. POPC or PCPC, r2 = .429, p < .001; and log high-frequency heart rate power vs. POPC or PCPC, r2 = .271, p < .001). CONCLUSIONS: Our data support the hypothesis that measures of heart rate power spectra are inversely related and negatively correlated to severity of illness and outcome in critically ill and injured children. The phenomenon of decomplexification of physiologic dynamics may have important clinical implications in critical illness and injury.
Adolescent↗
Tracheobronchography: old is not necessarily outdated--especially for the young.
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Airway Obstruction↗
Uncoupling of the autonomic and cardiovascular systems in acute brain injury.
We hypothesized that acute brain injury results in decreased heart rate (HR) variability and baroreflex sensitivity indicative of uncoupling of the autonomic and cardiovascular systems and that the degree of uncoupling should be proportional to the degree of neurological injury. We used HR and blood pressure (BP) power spectral analysis to measure neuroautonomic regulation of HR and BP and the transfer function magnitude (TF) between BP and HR as a measure of baroreflex modulation of HR. In 24 brain-injured patients [anoxic/ischemic injury (n = 7), multiple trauma (n = 6), head trauma (n = 5), central nervous system infection (n = 4), and intracranial hemorrhage (n = 2)], neurological injury and survival was associated with low-frequency (0.01-0.15 Hz) HR and BP power and TF. Brain-dead patients showed decreased low-frequency HR power [0. 51 +/- 0.36 (SE) vs. 2.54 +/- 0.14 beats/min2, P = 0.03] and TF [0. 61 +/- 0.16 (SE) vs. 1.29 +/- 0.07 beats . min-1 . mmHg-1, P = 0.05] compared with non-brain-dead patients. We conclude that 1) severity of neurological injury and outcome are inversely associated with HR and BP variability and 2) there is direct evidence for cardiovascular and autonomic uncoupling in acute brain injury with complete uncoupling during brain death.
Acute Disease↗
Homage to Prof. Dr. Abraham Shulman: Tinnitus-A Life with Tinnitology.
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Journal Article↗
Short-term administration of selegiline for mild-to-moderate dementia of the Alzheimer's type.
As a follow-up to an earlier study showing short-term benefit in inpatients with more severe dementia, the authors studied the short-term cognitive, functional, and behavioral effects of selegiline in outpatients with mild-to-moderate dementia of the Alzheimer type (DAT) by means of a double-blind, randomized, crossover study of placebo vs. selegiline. Fifty outpatients with mild-to-moderate DAT and no behavioral disturbances were given selegiline in two 8-week treatment periods separated by a 4-week washout. Outcome was assessed with standardized measures of dementia severity, daily functioning, behavior, and cognition. There was no drug-placebo difference in any outcome measure. Selegiline did not show short-term benefit in this study, contrary to the earlier study, perhaps because the patients were studied less intensively and/or lacked behavioral problems that could show response, although the medication was well tolerated.
Aged↗
Linear and nonlinear dynamics and the pathophysiology of shock.
Rapid progress has been made in the use of linear and nonlinear time series analysis of heart rate and blood pressure variability as an indicator of disease severity and prognosis for patients in shock. Clinical and experimental studies have demonstrated the potential for linear and nonlinear measurements as a method for quantifying changes in neuroautonomic cardiovascular regulatory mechanisms. These measures have been demonstrated to correlate with severity of illness and outcome for critically ill and injured patients, including those with shock. These powerful mathematical techniques may allow for new insights into the pathophysiology of shock. In addition, these measures may also enable detection of early changes in neuroautonomic cardiovascular regulatory mechanisms during the development of shock before the onset of overt hypotension and inadequate tissue perfusion or may be used to assess the response to therapy. Further studies are needed to establish the role of these tools in clinical use.
Animals↗
Exploiting the difference between intrinsic and extrinsic kinases: implications for regulation of signaling by immunoreceptors.
When receptors must interact with an extrinsic kinase to initiate signaling, the kinase can play a regulatory role that is not available to intrinsic receptor kinases. Whether control is exercised at this level depends critically on the amount of kinase available to the receptors and on the potential for redistribution of the kinase during signaling. This study demonstrates that the high affinity receptor for IgE (Fc epsilonRI) on rat basophilic leukemia cells is regulated by its initiating kinase. We present a mathematical model that allows for the reversible recruitment of extrinsic kinases to phosphorylated immunoreceptor tyrosine-based activation motifs. By comparing model predictions to experimental time courses of phosphorylation, we infer that Lyn is limiting, that redistribution occurs after receptors are aggregated, and that the redistribution makes the relationship between tyrosine phosphorylation and receptor aggregation nonlinear.
Animals↗
Preliminary evaluation of recombinant amino-terminal fragment of human bactericidal/permeability-increasing protein in children with severe meningococcal sepsis.
BACKGROUND: Meningococcal sepsis remains an important cause of morbidity and mortality. We hypothesised that children with severe meningococcaemia might benefit from inhibition of the inflammatory processes thought responsible for fulminant disease. rBPI21 is a recombinant, N-terminal fragment of human bactericidal/permeability-increasing protein, which kills meningococci and binds to and clears bacterial endotoxin, these being the primary inducers of the systemic inflammation. The aim of this study was to determine the safety and kinetics of rBPI21 in children with severe meningococcaemia and to make a preliminary assessment of clinical outcome. METHODS: In this open-label, dose-escalation, phase I/II trial in severe meningococcaemia (Glasgow meningococcal prognostic septicaemia score [GMSPS] > or = 8), 26 patients aged 1-18 years, who had received their first dose of antibiotics no more than 8 hours earlier were given rBPI21 by infusion at total doses of 1.0, 2.0, and 4.0 mg/kg. FINDINGS: The patients had significantly raised plasma concentrations of bacterial endotoxin and cytokines. Peak and steady state BPI concentrations were comparable with pharmacokinetic data in healthy adults. All complications were compatible with the expected pattern for severe meningococcal sepsis. Only one patient died. This outcome was found to compare favourably with a predicted mortality of > or = 30% by GMSPS, > or = 15% by plasma endotoxin values, > or = 28% by plasma interleukin-6 concentrations, 29-49% by severity of coagulopathy, and 20% (11/54) by comparison with recent historical patients consecutively treated in participating centres before this study. INTERPRETATION: This, the first clinical trial or rBPI21, shows that rBPI21 can be safely administered to children with severe meningococcaemia and that the pharmacokinetics are consistent with patterns seen in healthy adults. Predicted mortality, on the basis of GMSPS, laboratory indices of inflammation and coagulopathy, and historical controls, was for between four and eight deaths. These findings have prompted a phase III randomised trial.
Adult↗
Physical medicine and rehabilitation.
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Brain Injuries↗
Altered patterns of tyrosine phosphorylation and Syk activation for sterically restricted cyclic dimers of IgE-Fc epsilonRI.
Previous studies in our laboratory established that the symmetrical bivalent ligand, N,N'-bis-[[epsilon-(2,4-dinitrophenyl)amino]caproyl]-L-tyrosyl]-L-cystin e ((DCT)2-cys), stably cross-links anti-2,4-dinitrophenyl-immunoglobulin E (IgE) bound to high affinity receptors Fc epsilonRI on the surface of RBL-2H3 cells, forming mostly cyclic dimers containing two IgE-Fc epsilonRI and two (DCT)2-cys (Posner et al. (1995) J. Immunol. 155, 3601-3609). These cyclic dimers do not trigger Ca2+ or degranulation responses under a variety of conditions. However, we find that the linearly cross-linked IgE-Fc epsilonRI formed at higher concentrations of (DCT)2-cys do trigger degranulation in the presence of cytochalasin D, an inhibitor of actin polymerization. We further investigated stimulation by (DCT)2-cys of the earliest known events in the functional response, i.e., tyrosine phosphorylation of the beta and gamma subunits of Fc epsilonRI. At the higher (DCT)2-cys concentrations corresponding to linear dimers and maximal degranulation, tyrosine phosphorylation of both beta and gamma are observed. At lower (DCT)2-cys concentrations where cross-linking is maximal and cyclic dimers are overwhelmingly dominant, only gamma tyrosine phosphorylation is observed. Cytochalasin D does not affect these phosphorylation patterns, but instead appears to enhance coupling to downstream signaling events. Phosphorylation of Syk occurs at the higher (DCT)2-cys concentrations in parallel with beta phosphorylation but does not occur in its absence at the lower (DCT)2-cys concentrations. These results suggest that cyclic dimers of IgE-Fc epsilonRI are sterically restricted such that they stimulate tyrosine phosphorylation of gamma but not beta, and this is not sufficient for Syk binding and/or activation.
Cell Line↗