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Hobart W Harris

Publications and source records attributed to Hobart W Harris.

At least 19 recordsLinked to original sources
PubMed2006

Inappropriate antibiotic use in soft tissue infections.

HYPOTHESIS: Many soft tissue infections treated with surgical drainage resolve even when treated with antibiotics not active against the organism isolated from the infection. DESIGN: Retrospective. SETTING: Integrated Soft Tissue Infection Services clinic. PATIENTS: All patients treated from July 19, 2000, to August 1, 2001, who underwent surgical drainage of a soft tissue infection and had microbiological culture results. MAIN OUTCOME MEASURES: Documented resolution of the infection with drainage of the abscess and antibiotic therapy alone was deemed a cure. An infection resulting in death or other surgical therapy was deemed a failure. Therapy was appropriate when the organism was sensitive to prescribed antibiotics and was inappropriate when the organism was insensitive. RESULTS: The study included 376 patients with 450 infections. Staphylococcus aureus as the primary organism was isolated from 441 of the cultures. Methicillin sodium-sensitive S aureus and methicillin-resistant S aureus were found in 157 and 284 of these isolates, respectively. Appropriate antibiotics were prescribed in 153 infections with methicillin-sensitive S aureus and in 25 with methicillin-resistant S aureus. Of 441 episodes, 408 were clinically evaluated for cure. Three patients failed treatment, 2 in the appropriately treated group (resulting in death and amputation) and 1 patient with osteomyelitis in the inappropriately treated group. The cure rate for infections treated appropriately or inappropriately was the same. CONCLUSIONS: Treatment of soft tissue infections after surgical drainage, even with inappropriate antibiotics, has a high cure rate. Further studies to evaluate the efficacy of treating these infections without antibiotics are needed.

Adult↗
PubMed2006

Statins attenuate sepsis.

HYPOTHESIS: If (1) 3-hydroxy-3-methylglutaryl-coenzyme reductase inhibitors (statins) block the rate-limiting step in cholesterol synthesis and promote the expression of low-density lipoprotein receptors, (2) "Gram-negative sepsis" results from an abundant systemic response to bacterial lipopolysaccharide (endotoxin), (3) triglyceride-rich lipoproteins can bind endotoxin and low-density lipoprotein receptors enhance the uptake of both of these molecules, and (4) low-density lipoprotein receptor internalization of lipoproteins and endotoxin co-opts a common transcriptional regulatory system (NF-kappaB) that results in reduced cell vulnerability to inflammation, then statins, in addition to their lipid-lowering capacity, enhance endotoxin clearance from the circulation and attenuate the septic response.

Cholesterol↗
PubMed2006

Applying Ockham's razor to pancreatitis prognostication: a four-variable predictive model.

OBJECTIVE: We sought to develop a simple yet accurate prognostic scoring system to determine the severity of acute pancreatitis at admission. SUMMARY BACKGROUND DATA: Because acute pancreatitis has a variable and frequently unpredictable course, identifying individuals at greatest risk for significant, life-threatening complications and stratifying their care appropriately remain a concern. Previous prognostic scoring systems predict severity reasonably well but are limited by time constraints, are unwieldy to use, or both. METHODS: Data from the international phase III trial of the platelet-activating factor receptor-antagonist Lexipafant were used to develop a 4-variable prognostic model. We then compared the model's ability to predict the severity of acute pancreatitis with the Ranson, Glasgow, and APACHE II systems. RESULTS: The model (BALI), which included BUN >or=25 mg/dL, Age >or=65 years, LDH >or=300 IU/L, and IL-6 >or=300 pg/mL, measured at admission, was similar to the Ranson, Glasgow, and APACHE II systems in its ability to identify increased mortality from acute pancreatitis. The receiver operating characteristic curve area for the BALI model was >or=0.82 +/- 0.03 (mean +/- SD) versus 0.75 +/- 0.04 (Ranson), 0.80 +/- 0.03 (Glasgow), and 0.79 +/- 0.03 (APACHE II). Furthermore, at a prevalence of 15%, the positive and negative predictive values for increased mortality were similar for all systems. CONCLUSION: The prognostic ability of the BALI 4-variable model was similar to the Ranson, Glasgow, and APACHE II systems but is unique in its simplicity and ability to accurately predict disease severity when used at admission or anytime during the first 48 hours of hospitalization.

APACHE↗
PubMed2005

Triglyceride-rich lipoproteins as agents of innate immunity.

Bacterial endotoxin (i.e., lipopolysaccharide [LPS]) elicits dramatic responses in the host, including elevated plasma lipid levels due to increased synthesis and secretion of triglyceride-rich lipoproteins by the liver and inhibition of lipoprotein lipase. This cytokine-induced hyperlipoproteinemia, clinically termed the "lipemia of sepsis," was customarily thought to involve the mobilization of lipid stores to fuel the host response to infection. However, because lipoproteins can also bind and neutralize LPS, we have long postulated that triglyceride-rich lipoproteins (very-low-density lipoproteins and chylomicrons) are also components of an innate, nonadaptive host immune response to infection. Recent research demonstrates the capacity of lipoproteins to bind LPS, protect against LPS-induced toxicity, and modulate the overall host response to this bacterial toxin.

Acute-Phase Proteins↗
PubMed2005

Heat shock inhibits NF-kB activation in a dose- and time-dependent manner.

BACKGROUND: The heat shock response (HSR) attenuates NF-kappaB mediated activation of the acute inflammatory response by inhibiting IkB degradation. The HSR also confers a protective phenotype upon cells through production of heat shock proteins (HSP). However, the exact conditions that induce the HSR and stimulate the production of protective HSP are poorly defined. Consequently, we hypothesized that the inhibition of NF-kappaB activation through the HSR is dependent both on the degree of cellular injury and the length of the recovery period from the heat shock. METHODS: RAW 264.7 murine macrophages were heated to 43 degrees C for 15 (mild heat shock), 45 (moderate heat shock), or 90 min (severe heat shock), allowed to recover at 37 degrees C for 0 to 24 h, and then exposed to 100 ng/ml of Escherichia coli (055:B5) lipopolysaccharide (LPS). Cellular viability, HSP expression, and the activation of NF-kappaB after LPS exposure were determined by alamarBlue assay, immunoblot, and electrophoretic mobility shift assay, respectively. RESULTS: Transient attenuation of NF-kappaB activation and IkappaB preservation was observed only with moderate heat shock and 1 h of recovery. Mild heat shock had no effect on LPS-induced NF-kappaB activation or IkappaB degradation. Severe heat shock completely inhibited NF-kappaB activation and preserved IkappaB protein levels. Heat shock proteins were detectable 30 min after moderate heat shock, with maximal and sustained levels 2 to 24 h after heat shock. CONCLUSION: The attenuation of NF-kappaB activation after heat shock is both dose- and time-dependent.

Animals↗
PubMed2005

Cholecystectomy after endoscopic sphincterotomy for common bile duct stones: is surgery necessary?

It has been more than 30 years since the introduction of endoscopic sphincterotomy for the management of choledocholithiasis. Once introduced, this endoscopic intervention subsequently enabled clinicians to witness the natural history of leaving the gallbladder in situ once the common duct calculi were removed. Because many people were free of symptoms once the common bile duct was cleared of stones, patients and physicians alike soon questioned whether it was necessary to remove the gallbladder at all. Despite more than two decades of clinical research and numerous published reports, the answer to this question remains elusive. Similarly, the management algorithm for choledocholithiasis in patients with an intact gallbladder remains controversial. We review the available key data regarding this question. Importantly, there are only three prospective, randomized trials that have examined the need for cholecystectomy after endoscopic sphincterotomy, with case studies constituting most of the published reports. Consequently, the literature on this topic remains inconclusive, weakened by its retrospective approach, considerable variability between the patients studied, inconsistent inclusion and exclusion criteria, and frequently poor patient follow-up. Nonetheless, the preponderance of data favor removing the gallbladder after endoscopically clearing the common bile duct of gallstones because an estimated 25% of patients will experience recurrent symptoms within a 2-year follow up period. Recognizing the existence of various mitigating clinical factors, we advocate adopting a selective wait-and-see approach for high-risk patients, especially those with a life expectancy of less than 2 years or severely debilitating comorbidities.

Cholangiopancreatography, Endoscopic Retrograde↗
PubMed2005

Lipoprotein-bound endotoxin exerts an immunomodulatory effect on hepatocytes through the lipid A domain of LPS.

BACKGROUND: We have previously shown that chylomicron (CM)-bound lipopolysaccharide (LPS) inhibits the host innate immune response by rendering hepatocytes tolerant to pro-inflammatory cytokine stimulation. However, LPS is a complex macromolecule containing both lipid and carbohydrate domains. We hypothesized that just as lipid A confers the toxicity of LPS, it is also responsible for the immunoregulatory effect on hepatocytes. METHODS: We pretreated primary rat hepatocytes for 2 h with a series of CM-LPS complexes in which the endotoxin moiety varied in its structure and/or toxicity. Subsequently, the cells were stimulated with a mixture of pro-inflammatory cytokines. Nitric oxide production was measured as an indicator of hepatocellular activation. RESULTS: All pretreatments wherein the CM-bound complex contained the lipid A moiety readily inhibited the hepatocellular cytokine response, including CM bound to lipid A alone. In contrast, CM-LPS complexes containing detoxified LPS, which lacks the lipid A domain, had no effect on the hepatocellular response to cytokines. CONCLUSIONS: The lipid A domain of the LPS macromolecule is both sufficient and essential for the CM-mediated induction of cytokine tolerance in hepatocytes. However, this process is independent of the specific endotoxic activity of the lipid A moiety.

Animals↗
PubMed2004

An epidemic of methicillin-resistant Staphylococcus aureus soft tissue infections among medically underserved patients.

HYPOTHESIS: A high prevalence of methicillin-resistant Staphylococcus aureus (MRSA) in soft tissue infections presents a treatment challenge. DESIGN: Retrospective analysis. SETTING: The San Francisco General Hospital Integrated Soft Tissue Infection (ISIS) Clinic. PATIENTS: Patients treated at the ISIS Clinic from July 1, 2000, to June 30, 2003. MAIN OUTCOME MEASURES: Information on patient demographics, surgical procedures, microbiologic studies, and antibiotic treatments was obtained for all patients treated in the ISIS Clinic. Microbial data and antibiotic susceptibility pattern of S aureus, treatment outcome, and antibiotic prescribed were analyzed for all evaluable patients. RESULTS: The ISIS Clinic treated 6156 unique patients for 12,012 episodes of infection. In this cohort, 5164 (84%) were either homeless or had no health insurance. More than half of the patients (58%) were injection drug users, but most had only 1 prior visit to the clinic (62%). Patients underwent a surgical procedure 7707 times (64%). Of the 837 positive cultures obtained, S aureus was recovered 695 times (83%), and 525 (63%) of the cultures contained MRSA. Therefore, a full 76% of all S aureus isolated was MRSA. In a subset analysis of 622 cultures collected prospectively from consecutive patients, 282 (45%) grew organisms, of which 256 (91%) were S aureus. MRSA represented 59% of all S aureus isolated. Homelessness and injection drug use were risk factors for infection by S aureus and MRSA. In another subgroup of patients with soft tissue infections that required admission to the hospital, MRSA was recovered from the cultures in 149 patients. In these patients with MRSA, 44 (30%) only received a beta-lactam antibiotic, inactive against MRSA, and had full resolution of their infection. CONCLUSIONS: The prevalence of MRSA soft tissue infections in the medically underserved ISIS Clinic cohort is extremely high. The transmission of the MRSA seems to be in the community. Antibiotic therapy directed at MRSA may not be needed in a large number of patients with these soft tissue infections. Studies to identify the source and cause of this MRSA outbreak are urgently needed. Clinical trials to examine the need for antibiotic therapy in soft tissue infections should be conducted.

Community-Acquired Infections↗
PubMed2003

Induction of cytokine tolerance requires internalization of Chylomicron-Bound LPS into hepatocytes.

BACKGROUND: Chylomicron-bound LPS (CM-LPS) renders hepatocytes unresponsive to stimulation by proinflammatory cytokines, a process termed cytokine tolerance. We have shown that cytokine tolerance is a time- and dose-dependent process requiring functional low-density lipoprotein receptors (LDLR). Thus, we hypothesized that cytokine tolerance directly correlates with the internalization of CM-LPS complexes, and inhibition of lipoprotein binding and/or internalization inhibits the induction of cytokine tolerance in hepatocytes. MATERIALS AND METHODS: We correlated the rate of internalization of radioiodinated CM-LPS complexes with hepatocellular NO production as a measure of cytokine responsiveness. In additional studies, we used four different strategies to inhibit binding/internalization of CM-LPS via LDLR and then determined the effect of each strategy on the induction of cytokine tolerance. RESULTS: There was a strong inverse correlation between the internalization of CM-LPS and the responsiveness of hepatocytes to proinflammatory cytokines (r(2) = -0.997). Furthermore, the greater the degree of LDLR inhibition, the less susceptible hepatocytes were to the induction of cytokine tolerance by CM-bound LPS. Accordingly, cytokine tolerance induction was inhibited in hepatocytes with decreased membrane expression of LDLR as compared to control cells (69 versus 12% control; P = 0.005). Competitive inhibition of CM-LPS binding prevented internalization of CM-LPS and resulted in loss of the cytokine-tolerant phenotype. Whereas CM-LPS successfully induced cytokine tolerance in ldlr(-/-) hepatocytes, it only occurred after a prolonged pretreatment period of 8 h. CM-LPS complexes containing apolipoprotein (apo) E(2) also required a prolonged pretreatment period to induce a level of cytokine tolerance comparable to that induced by CM-LPS complexes containing either apo E(3) or E(4). CONCLUSION: Lipoprotein-bound LPS inhibits the responsiveness of hepatocytes to proinflammatory cytokines in a manner directly correlated with the internalization of LPS. Furthermore, inhibition of lipoprotein binding/internalization prevents this LPS-mediated induction of cytokine tolerance in rodent hepatocytes.

Animals↗
PubMed2003

Induction of cytokine tolerance in rodent hepatocytes by chylomicron-bound LPS is low-density lipoprotein receptor dependent.

We examined the role of lipoprotein receptors in mediating chylomicron-bound lipopolysaccharide (CM-LPS)-induced cytokine tolerance in rodent hepatocytes. We found that 2 h of pretreatment with CM-LPS (5 mg TG/mL) was sufficient to induce cytokine tolerance, as measured by decreased nitric oxide (NO) production by hepatocytes (20% of the Control group, P < 0.03). Tolerance was evident as early as 2 h after pretreatment and disappeared after 40 h. Furthermore, we evaluated the roles of the low-density lipoprotein (LDL) receptor (LDLR) and LDL receptor-related protein (LRP) in the induction of cytokine tolerance in hepatocytes. Biochemical inhibition of the receptors or use of hepatocytes from LDLR-deficient mice revealed that functional LDLR was necessary for the induction of tolerance. However, by increasing the pretreatment time, the LRP compensated for the absence of the LDLR in induction of cytokine tolerance. In conclusion, CM-LPS-mediated induction of cytokine tolerance to proinflammatory cytokines is a time- and dose-dependent process that requires functional lipoprotein receptors. These findings underscore an interrelationship between TG-rich lipoprotein metabolism and innate immunity.

Adenoviridae↗
PubMed2003

Lipoprotein-bound LPS induces cytokine tolerance in hepatocytes.

Bacterial endotoxin (LPS) elicits dramatic responses in the host including elevated plasma lipid levels due to the increased synthesis and secretion of triglyceride (TG)-rich lipoproteins by the liver. We postulate that this cytokine-induced hyperlipoproteinemia, clinically termed the 'lipemia of sepsis', represents an innate, non-adaptive host immune response to infection. Data in support of this hypothesis include the capacity of TG-rich lipoproteins (VLDL and chylomicrons, CM) to bind and neutralize LPS. Herein, we present evidence that CM-bound LPS attenuates the hepatocellular response to pro-inflammatory cytokines. Primary rodent hepatocytes pretreated with CM-LPS complexes for 2 h demonstrated a near 70% reduction in cytokine-induced NO production as compared to non-pretreated control cells (P > or = 0.04). Whereas hepatocytes were maximally tolerant to cytokine stimulation 6 h after CM-LPS pretreatment, the cells spontaneously regained cytokine responsiveness within 40 h. The induction of cytokine tolerance in hepatocytes follows the internalization of CM-LPS complexes and is a process regulated by the LDL receptor. CM-LPS complexes failed to induce cytokine tolerance in hepatocytes wherein lipoprotein receptor activity was inhibited with high dose receptor associated protein (30 microg/ml). Similarly, CM-bound LPS did not induce tolerance in hepatocytes from ldlr(-/-) mice. Thus, the biochemical or genetic inhibition of LDL receptor activity effectively prevented the CM-mediated induction of the cytokine tolerant phenotype. In conclusion, the lipemia of sepsis likely represents a mechanism by which the host combats sporadic, non-life-threatening episodes of endotoxemia. Also, it may indicate a negative regulatory mechanism for the hepatic response to sepsis, serving to effectively down-regulate the acute phase response. A better understanding of how TG-rich lipoproteins modulate the host response to LPS could yield novel biological insights with important clinical implications, including the development of lipid-based therapies for bacterial infections.

Adenoviridae↗
PubMed2002

Care of injection drug users with soft tissue infections in San Francisco, California.

CONTEXT: Illicit injection drug use results in serious soft tissue infections that are the number one nonpsychiatric reason for admission to San Francisco General Hospital (SFGH), San Francisco, Calif. OBJECTIVE: To establish a specialized clinic to provide accessible, high-quality, and cost-effective medical care to patients with soft tissue infections. DESIGN, SETTING, INTERVENTION, AND OUTCOME MEASURES: The Integrated Soft Tissue Infection Services (ISIS) Clinic was established to provide coordinated surgical intervention, substance abuse counseling, and social services for patients with soft tissue infections treated in a public hospital. Demographic information, treatment outcome, and hospital utilization data were analyzed. RESULTS: In the clinic's first year of operation, there were 3365 patient visits and 2255 surgical procedures. A large number of patients reported recent injection of illicit drugs (61%), were homeless (30%), and either had hepatitis C, hepatitis B, or human immunodeficiency virus infection (62%). Patients using heroin were enrolled in either a detoxification or maintenance program (42%). Few patients were designated as treatment failures (2%) or were lost to follow-up (14%). The ISIS Clinic dramatically reduced emergency department visits (-33.9%), surgical service admissions (-47.3%), inpatient acute care bed days (-33.7%), and operating room procedures (-71%), saving approximately $8 765 200 in the first year of operation. CONCLUSIONS: This clinical intervention was notably cost-effective while preserving a high quality of medical services. Owing to limited data, we can only assume that other communities are similarly confronted with this public health problem. The ISIS Clinic could serve as a model intervention and thus have significant impact on the treatment of this prevalent but often overlooked challenge.

Adult↗
PubMed2002

Hepatic endosomal trafficking of lipoprotein-bound endotoxin in rats.

Triglyceride-rich lipoproteins (chylomicrons (CM), VLDL) can bind and protect against endotoxin (LPS)-induced shock and mortality in rodents. The protective effect of lipoproteins is in part due to the increased plasma clearance and biliary excretion of LPS. Specifically, CM-LPS complexes are principally removed from the circulation by the liver with a rapid plasma half-life approximating that for CM alone. Thus, we hypothesized that hepatocytes clear CM-bound LPS via known lipoprotein receptors and traffic the toxic macromolecule through the same endosomal pathway employed for the catabolism of triglyceride-rich lipoproteins. To examine the endosomal uptake and biliary excretion of LPS, we isolated early and late hepatic endosomal fractions and hepatic bile from rats following the injection of radiolabeled CM-bound LPS. The uptake of (125)I-LPS was compared in animals that overexpressed either the LDL receptor or the LDL receptor-related protein (LRP) versus untreated control with normal lipoprotein levels. Herein we present data indicating that both the LDL receptor and the LRP participate in the rapid internalization of CM-bound LPS by hepatocytes. Upregulation of the LDL receptor increased the accumulation of (125)I-LPS in late endosomes (P < 0.03). In contrast, increased levels of the LRP were associated with negligible movement of LPS into late endosomes but a trend toward the increased biliary excretion of the radiolabeled macromolecule. Taken together these data further elucidate the role of the liver in the host innate immune response to infection and potentially implicate distinct roles for the LDL receptor and LRP in the catabolism of CM-bound LPS.

Animals↗
PubMed2002

Endogenous lipoproteins impact the response to endotoxin in humans.

OBJECTIVE: To determine whether endogenous lipoproteins can abrogate the host response to lipopolysaccharide (LPS) in vivo. DESIGN: Randomized, placebo-controlled study. SETTING: Urban public hospital with academic affiliation. SUBJECTS: Eighteen healthy, normolipidemic, normal weight volunteers, 21-35 yrs of age. INTERVENTIONS: Fasting and postprandial (hypertriglyceridemic) subjects were injected with endotoxin (LPS, Lot EC-5, 4 ng/kg = 20 endotoxin units/kg) as either a bolus or following preincubation of the LPS with autologous whole blood vs. saline. In addition, LPS-induced cytokine production was determined ex vivo to examine the capacity of fasting vs. hypertriglyceridemic whole blood to attenuate the effect of large, potentially lethal concentrations of LPS in humans. MEASUREMENTS: Vital signs were recorded and serial blood samples analyzed for changes in white blood cell count, cytokine, and stress hormone levels over 24 hrs. The distribution of lipoproteins in fasting and postprandial blood after preincubation was determined using 125I-LPS. MAIN RESULTS: Endogenous lipoproteins abrogated the host response to LPS in vivo, but only after preincubation with the LPS. Peak oral temperature (p < .05) and white blood cell count (p < .05), and plasma tumor necrosis factor (TNF)-alpha (p < .01) and adrenocorticotropic hormone levels (p < .03) were significantly reduced in volunteers injected with LPS preincubated with whole blood vs. LPS preincubated with saline. Approximately 80% of the LPS was bound to lipoproteins after preincubation with either fasting or hypertriglyceridemic blood. Thus, protection was associated with lipoprotein binding. In addition, hypertriglyceridemic but not fasting blood inhibited the ex vivo TNF-alpha response to large, highly toxic doses of LPS (p < .05). Without the preincubation of lipoproteins with LPS, there was a trend for an exaggerated clinical and TNF-alpha response in the hypertriglyceridemic subjects. CONCLUSION: Preincubation of LPS with whole blood promotes lipoprotein-LPS binding and is associated with an attenuated response to this toxic macromolecule. Although the clinical relevance of these data requires further elucidation, our results continue to support a lipid-based therapeutic strategy to combat gram-negative sepsis.

Acute-Phase Proteins↗