End-of-life in the pediatric intensive care unit: seeking the family's decision of when and how, not if.
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Biomedical subjects
Publications and source records attributed to B Goldstein.
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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.
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.
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Intratympanic drug therapy (ITDT) is a surgical technique of instilling medication into the middle ear to perfuse the inner ear in treating hearing loss, tinnitus, vertigo, and ear blockage, alone or in combination, in patients with a predominantly inner-ear site of lesion. This preliminary report of ITDT focuses on attempts at tinnitus control (TC). Between November 1997 and February 1999, 10 patients with severe tinnitus were treated with steroid medication and were last seen in February 2000. TC was established in 7 of these 10 patients (70%). The clinical diagnosis of a predominantly cochlear-type tinnitus was established in each patient by a correlation of the clinical history with a medical-audiological tinnitus patient protocol that included cochleovestibular testing. An additional single patient with sudden hearing loss experienced no hearing improvement on ITDT steroid therapy. Vertigo as an associated complaint was reported by 6 of 10 patients with subjective idiopathic tinnitus. Significant control of the associated vertigo complaint was reported by 5 of 10 patients. Duration of tinnitus relief in 7 of 10 patients was hours in 1 of the 7; days in another of the 7; and 1 year or more in 5 of the 7. One of the seven patients reported TC 3 months after the procedure. Complications included tympanic membrane perforation that persisted for more than 6 months in two patients and an increase in the complaint of ear blockage and tinnitus intensity in one patient. In our preliminary study, ITDT with steroid has resulted in both short- and long-term tinnitus relief in 7 of 10 patients (70%) identified to have a predominantly cochlear-type tinnitus.
Tinnitus is one of the most important symptoms in neurootology after vertigo, nausea, and hearing loss. In most cases, the origin of the tinnitus remains inexplicable. Well-known, however, is that tinnitus may arise in any part of the hearing pathway (i.e., both within the cochlea receptor and in the temporal lobe and projections). Tinnitus also is associated frequently with vertigo, nausea and hearing loss. An age predominance exists, with tinnitus more common among those older than 40 years. From this starting point, a great demand exists today for new ideas and developments in the diagnosis and treatment of tinnitus.
As regards the symptom of a predominantly central tinnitus of the severe, disabling type, it has been hypothesized that a deficiency in the benzodiazepine receptor exists in the medial temporal lobe system of brain and is directly related to affect impairments including anxiety, stress, depression, and fear. This hypothesis has been investigated with single-photon emission computed tomography using the benzodiazepine radioligand 123I Iomazenil. Visual analysis revealed preliminary results of diminished benzodiazepine-binding sites in the medial temporal cortex of all patients with severe tinnitus (N = 6), a finding that is consistent with the hypothesis implicating GABAergic mechanisms in the pathophysiology of the disorder. An abnormal gamma-aminobutyric acid--A benzodiazepine receptor density may be an objective neurochemical measure of the severity of a central-type tinnitus and a rationale for treatment. Clinical correlation with the history, clinical course of the patient, and stress questionnaire are presented.
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.
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.
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.
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.
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.
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.
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PURPOSE: Penile self-injection therapy, a second line treatment for erectile dysfunction, is the most efficacious means of reestablishing functional erections when first line therapies fail and the patient wants to avoid penile prosthesis implantation. Despite high efficacy rates, injection therapy has high dropout rates. To our knowledge studies to date analyzing patient attrition have reviewed small numbers of patients followed for only short periods. We elucidate the main reasons for patient dropout in a large penile self-injection program with long-term followup. MATERIALS AND METHODS: A questionnaire was mailed to 1,424 patients who completed the office training and home use phases of a penile self-injection program. RESULTS: The overall attrition rate was 31% of the 720 men who completed the questionnaire, with a mean followup of 38 months. The main reasons for dropout were cost of therapy, patient and partner problems with the concept of penile injection, lack of partner availability and spontaneous improvement in erections. Lack of efficacy of therapy was the primary reason for only 1 of 7 dropouts. Furthermore, adverse effects of penile injections (priapism, penile nodules, pain) appeared to be only minor contributors to dropout. CONCLUSIONS: To our knowledge this study is the largest published, single center cohort of patients treated with injection and followed for an analysis of dropout rates. Based on study data a reduction in dropout rates may be achieved by keeping the cost of therapy low, and ensuring patient and partner education as well as continued support throughout treatment.