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Biomedical subjects

W M Scheld

Publications and source records attributed to W M Scheld.

At least 37 records · Page 2Linked to original sources
PubMed1996

Fever in neurologic diseases.

In the sense that the brain houses the central mechanism for the regulation of body temperature, almost all illnesses that cause fever must interact with the central nervous system. There are far fewer diseases, however, in which the nervous system symptomatology is of prime diagnostic importance. A helpful way to view fever in association with neurologic disease is to roughly divide these disease entities into four broad categories: (1) neurologic impairment resulting from fever itself, (2) fever as the sole manifestation of a central nervous system infection, (3) systemic febrile disorders with central nervous system signs and symptoms, and (4) primary neurologic diseases, either central or peripheral in origin, with fever as a presenting sign. This article discusses the clinical presentation of disorders in each of these categories as an aid to the clinician in diagnosing and differentiating between these syndromes.

Brain Abscess↗
PubMed1996

Infectious etiologies of rhabdomyolysis: three case reports and review.

Rhabdomyolysis can be precipitated by trauma, ischemia, metabolic defects, electrolyte abnormalities, drugs, and a wide variety of infectious diseases. At our institution, recent cases of rhabdomyolysis induced by influenza prompted us to review the infectious etiologies of this entity. In addition, a thorough literature search revealed numerous case reports but no general review on this subject. This study describes representative recent cases from our institution and details the wide variety of infections that can cause muscle damage. The pathophysiological mechanisms, muscle histology, and correlation with renal dysfunction are also discussed.

Adolescent↗
PubMed1996

The use of corticosteroids in the management of bacterial meningitis in adults.

Despite the introduction of newer antimicrobial agents, bacterial meningitis continues to be associated with significant morbidity and mortality. Evidence from in-vitro studies, experimental animal models, and clinical studies indicate that the host inflammatory response is responsible for much of the deleterious consequences of this disease. Thus, there is much interest in the adjunctive use of antiinflammatory agents in the therapy of bacterial meningitis. Although there is considerable evidence from animal models and from clinical trials in children that adjunctive antiinflammatory therapy with corticosteroids is effective in reducing inflammation and in improving long-term outcomes, similar data involving adults are largely lacking. The rationale for the use of corticosteroids in the management of bacterial meningitis, and the applicability to disease in adults, are discussed, and some recommendations for their use in this setting are made.

Adrenal Cortex Hormones↗
PubMed1995

In vitro models of the blood-brain barrier to study bacterial meningitis.

In vitro models of the blood-brain barrier involving culturing cerebral microvascular endothelial cells may provide information critical to understanding diseases of the central nervous system, such as bacterial meningitis, that would be difficult to obtain from clinical studies or from in vivo models. These models may also identify targets for therapeutic intervention.

Animals↗
PubMed1995

Potential role of nitric oxide in the pathophysiology of experimental bacterial meningitis in rats.

We have investigated the possible role of nitric oxide (NO) in the pathophysiology of bacterial meningitis (BM) by using the rat model of experimental BM. The nitrite concentration in cerebrospinal fluid (CSF) was used as a measure of NO production in vivo since NO rapidly degrades to nitrite and nitrate. Rats were inoculated intracisternally with live bacteria (5 x 10(6) CFU of Haemophilus influenzae type b strain DL42 or Rd-/b+/O2), with bacterial endotoxin (20 ng of DL42 lipooligosaccharide [LOS] or 200 ng of Escherichia coli lipopolysaccharide), or with a saline control vehicle. CSF samples were collected preinoculation and at the time of maximal alteration in blood-brain barrier permeability (BBBP). CSF [nitrite] was quantified by measuring A550 after addition of the Greiss reagent and comparison to a standard curve of sodium nitrite. Rats inoculated with either DL42, Rd-/b+/O2, LOS, or lipopolysaccharide demonstrated a significantly elevated mean peak CSF [nitrite] (8.34, 15.62, 10.75, and 10.44 mM, respectively) versus the concentration prior to treatment and/or those in saline-treated animals (5.29 and 5.33 mM, respectively; P < 0.05 for each comparison). We then determined if there was a correlation between CSF [nitrite] and percent BBBP (%BBBP) at various time points postinoculation with Rd-/b+/O2. %BBBP was defined as the concentration of systemically administered 125I-labeled bovine serum albumin in the CSF divided by the level of 125I-labeled bovine serum albumin in serum multiplied by 100. The mean %BBBP increased in tandem with the mean CSF [nitrite] (R = 0.84, P = 0.018), which peaked at 18 h in the absence of a change in the serum [nitrite]. Systemic administration of the NO synthase inhibitor N-nitro-L-arginine methyl ester demonstrated a significant reduction of mean CSF nitrite production (0.95 versus 6.0 mM in controls; P = 0.02) when administered intravenously to animals which had been inoculated intracisternally with 20 ng of LOS. Suppression of mean leukocyte pleocytosis (3,117 versus 11,590 leukocytes per mm3 in control LOS-challenged rats; P = 0.03) and mean alterations of BBBP (2.11 versus 6.49% in control LOS-challenged rats; P = 0.009) was observed concomitantly with decreased CSF [nitrite]. These results support the hypothesis that NO contributes to increased %BBBP in experimental BM.

Animals↗
PubMed1995

Complement-independent binding of microorganisms to primate erythrocytes in vitro by cross-linked monoclonal antibodies via complement receptor 1.

Under certain circumstances, soluble antigens, particulate antigens, and/or microorganisms have been shown to bind to primate erythrocytes via complement receptor 1 (CR1) in the presence of specific antibodies and complement. This immune adherence reaction, specific for CR1, can lead to neutralization of antigens in the circulation and their subsequent clearance from the blood. The present experiments utilized cross-linked monoclonal antibody complexes (heteropolymers) with specificity for both CR1 and either 35S-labeled herpes simplex virus capsid or Haemophilus influenzae as prototype viral and bacterial particulate antigens, respectively. In each case, the respective specific heteropolymers facilitated binding of the target antigens (> or = 70 to 90%) in vitro to erythrocytes in the absence of complement. Several experimental protocols were employed to demonstrate that heteropolymers mediate specific, rapid (> or = 30 s), and quantitative binding of prototypical particulate pathogens to human and monkey erythrocytes but not to sheep erythrocytes, which lack CR1. These results extend the potential use of the erythrocyte-heteropolymer system to the neutralization and clearance of particulate viral and bacterial pathogens from the blood.

Animals↗
PubMed1994

A randomized trial comparing fluconazole with amphotericin B for the treatment of candidemia in patients without neutropenia. Candidemia Study Group and the National Institute.

BACKGROUND: Amphotericin B has long been the standard treatment for candidemia, but its use is complicated by its toxicity. More recently, fluconazole, a water-soluble triazole with activity against candida species and little toxicity, has become available. We conducted a multicenter randomized trial that compared amphotericin B with fluconazole as treatment for candidemia. METHODS: To be eligible, patients had to have a positive blood culture for candida species, a neutrophil count > or = 500 per cubic millimeter, and no major immunodeficiency. Patients were randomly assigned to receive either amphotericin B (0.5 to 0.6 mg per kilogram of body weight per day) or fluconazole (400 mg per day), each continued for at least 14 days after the last positive blood culture. Outcomes were assessed by a group of investigators blinded to treatment assignment. RESULTS: Of the 237 patients enrolled, 206 met all entry criteria. The most common diagnoses were renal failure, nonhematologic cancer, and gastrointestinal disease. There was no statistically significant difference in outcome: of the 103 patients treated with amphotericin B, 81 (79 percent) were judged to have been treated successfully, as were 72 of the 103 patients treated with fluconazole (70 percent P = 0.22; 95 percent confidence interval for the difference, -5 to 23 percent). The bloodstream infection failed to clear in 12 patients in the amphotericin group and 15 in the fluconazole group; the species most commonly associated with failure was Candida albicans. There were 41 deaths in the amphotericin group and 34 deaths in the fluconazole group (P = 0.20). Intravascular catheters appeared to be the most frequent source of candidemia. There was less toxicity with fluconazole than with amphotericin B. CONCLUSIONS: In patients without neutropenia and without major immunodeficiency, fluconazole and amphotericin B are not significantly different in their effectiveness in treating candidemia.

Amphotericin B↗
PubMed1994

Cross-linked bispecific monoclonal antibody heteropolymers facilitate the clearance of human IgM from the circulation of squirrel monkeys.

We have previously demonstrated that cross-linked bispecific monoclonal antibodies (mAb) heteropolymers (HP), specific for primate erythrocyte (E) complement receptor type 1 (CR1) and target antigen (Ag), facilitate the binding of these target Ag to human and non-human primate E. Once bound in vitro to rhesus monkey E, upon re-infusion these HP/Ag complexes are recognized in vivo by cells of the reticuloendothelial system (RES) and removed from the circulation without loss of the E. We now show, in squirrel monkeys, that an HP specific for E CR1 and human IgM (anti-CR1 x anti-IgM) can be used to facilitate in vivo E binding and clearance from the circulation of a previously injected and circulating model protein pathogen, human IgM. Approximately 70-80% of 125I-labeled human IgM is cleared from the circulation of each of five squirrel monkeys via the HP system. We observe, in experiments analogous to previous studies on immune complex (IC) clearance, that subsequent to HP/Ag clearance there is a decrease in the number of CR1 epitopes per E which is manifested when we use both monoclonal and polyclonal anti-CR1 probes. Our results indicate that the primary organs responsible for uptake of the complexes are the liver and spleen. This work strongly suggests that the HP/Ag complexes, bound to E, function as IC prototypes and are recognized and processed as such in vivo. Thus, the HP-E system may eventually serve as a viable immunotherapy for the clearance of blood-borne pathogens from the circulation.

Animals↗
PubMed1994

Mechanisms of brain injury in bacterial meningitis: workshop summary.

Morbidity and mortality associated with bacterial meningitis remain high, although antibiotic therapy has improved during recent decades. The major intracranial complications of bacterial meningitis are cerebrovascular arterial and venous involvement, brain edema, and hydrocephalus with a subsequent increase of intracranial pressure. Experiments in animal models and cell culture systems have focused on the pathogenesis and pathophysiology of bacterial meningitis in an attempt to identify the bacterial and/or host factors responsible for brain injury during the course of infection. An international workshop entitled "Bacterial Meningitis: Mechanisms of Brain Injury" was organized by the Department of Neurology at the University of Munich and was held in Eibsee, Germany, in June 1993. This conference provided a forum for the exchange of current information on bacterial meningitis, including data on the clinical spectrum of complications, the associated morphological alterations, the role of soluble inflammatory mediators (in particular cytokines) and of leukocyte-endothelial cell interactions in tissue injury, and the molecular mechanisms of neuronal injury, with potential mediators such as reactive oxygen species, reactive nitrogen species, and excitatory amino acids. It is hoped that a better understanding of the pathophysiological events that take place during bacterial meningitis will lead to the development of new therapeutic regimens.

Animals↗
PubMed1994

Platelet-activating factor augments meningeal inflammation elicited by Haemophilus influenzae lipooligosaccharide in an animal model of meningitis.

Research into the pathophysiology of bacterial meningitis has suggested a role for various endogenous inflammatory mediators, such as platelet-activating factor (PAF). In the present study, rats were inoculated intracisternally with various doses of PAF, with Haemophilus influenzae lipooligosaccharide (LOS) in high doses (20 ng) alone, and with a low dose of LOS (200 pg) with or without low doses of PAF (25 ng to 2.5 micrograms). Values for cerebrospinal fluid leukocytosis and percent blood-brain barrier permeability to systemically administered 125I-labeled albumin observed after inoculation of low-dose LOS with PAF were greater (P < 0.05) than those observed after inoculation of low-dose LOS alone and not statistically different from those observed after inoculation of high-dose LOS. PAF alone elicited an inflammatory response only at high doses (25 micrograms). These results support the hypothesis that low cerebrospinal fluid PAF concentrations, such as those observed in children with bacterial meningitis, may augment the inflammatory response to the presence of bacteria in the subarachnoid space.

Animals↗
PubMed1993

Adjunctive therapy for bacterial meningitis: rationale for use, current status, and prospects for the future.

Despite the introduction of numerous therapeutic advances, the morbidity and mortality associated with bacterial meningitis remain significant. Research into the pathophysiology of bacterial meningitis has revealed that the inflammatory response resulting from bacterial invasion of the subarachnoid space is due in large part to the activity of host-derived mediators. This inflammatory response is ultimately responsible for the long-term neurological sequelae and death associated with bacterial meningitis. In vitro and in vivo models of bacterial meningitis have identified several points in the inflammatory cascade that may be amenable to therapeutic intervention. Numerous potential therapeutic agents that may limit inflammation of the subarachnoid space have been and are being developed, and trials in animal models and in humans are under way. The judicious use of safe and effective agents with demonstrated efficacy as adjuncts to bactericidal antimicrobial agents in the therapy for bacterial meningitis in humans may improve the prognosis of this disease.

Adrenal Cortex Hormones↗
PubMed1993

Pathogenesis and pathophysiology of bacterial meningitis.

Bacterial meningitis remains a disease with associated unacceptable morbidity and mortality rates despite the availability of effective bactericidal antimicrobial therapy. Through the use of experimental animal models of infection, a great deal of information has been gleaned concerning the pathogenic and pathophysiologic mechanisms operable in bacterial meningitis. Most cases of bacterial meningitis begin with host acquisition of a new organism by nasopharyngeal colonization followed by systemic invasion and development of a high-grade bacteremia. Bacterial encapsulation contributes to this bacteremia by inhibiting neutrophil phagocytosis and resisting classic complement-mediated bactericidal activity. Central nervous system invasion then occurs, although the exact site of bacterial traversal into the central nervous system is unknown. By production and/or release of virulence factors into and stimulation of formation of inflammatory cytokines within the central nervous system, meningeal pathogens increase permeability of the blood-brain barrier, thus allowing protein and neutrophils to move into the subarachnoid space. There is then an intense subarachnoid space inflammatory response, which leads to many of the pathophysiologic consequences of bacterial meningitis, including cerebral edema and increased intracranial pressure. Attenuation of this inflammatory response with adjunctive dexamethasone therapy is associated with reduced concentrations of tumor necrosis factor in the cerebrospinal fluid, with diminished cerebrospinal fluid leukocytosis, and perhaps with improvement of morbidity, as demonstrated in recent clinical trials. Further information on the pathogenesis and pathophysiology of bacterial meningitis should lead to the development of more innovative treatment and/or preventive strategies for this disorder.

Animals↗
PubMed1993

Pathogenesis and pathophysiology of bacterial meningitis.

Despite the availability of bactericidal antibiotics with potent in vitro activity against the major meningeal pathogens, the morbidity and mortality from bacterial meningitis remains unacceptably high. Animal models have proven to be extremely valuable in the study of the pathogenesis and pathophysiology of bacterial meningitis, with the hopes of providing new information that may lead to an improved outcome from this disorder. Bacterial meningitis usually begins with nasopharyngeal colonization by a new organism, followed by invasion and bacteremia. Subsequently there is central nervous system invasion, although the exact site and mechanism of meningeal invasion are unknown. The generation of an intense subarachnoid space inflammatory response, induced by release of bacterial virulence factors and/or inflammatory cytokines, contributes to many of the pathophysiologic consequences of bacterial meningitis, including cerebral edema, increased intracranial pressure, and alterations of cerebral blood flow. Attenuation of this inflammatory response (e.g. by co-administration of antiinflammatory agents) may diminish many of these pathophysiologic consequences of meningitis, and perhaps improve morbidity and mortality from this disorder.

Animals↗
PubMed1993

Fluoroquinolones: how to use (but not overuse) these antibiotics.

The fluoroquinolone antibiotics are relatively new agents with long serum half lives, a high degree of bioavailability, and a broad spectrum of activity against many gram-negative and some gram-positive organisms. They are useful in a range of clinical settings but should not be considered as first-line treatment of many infections. Specific indications include chronic osteomyelitis caused by multiple-resistant gram-negative bacilli, chronic bacterial prostatitis refractory to other oral antibiotics, complicated urinary tract infections, and empiric therapy of suspected bacterial GI infections. Quinolones may also be considered when patients are allergic to a conventional agent, when infections are caused by multiple-resistant gram-negative bacilli, or when the toxicity of an alternate therapy is greater.

Aged↗