Trial of short-course antimicrobial therapy for intraabdominal infection.

BACKGROUND: The successful treatment of intraabdominal infection requires a combination of anatomical source control and antibiotics. The appropriate duration of antimicrobial therapy remains unclear. METHODS: We randomly assigned 518 patients with complicated intraabdominal infection and adequate source control to receive antibiotics until 2 days after the resolution of fever, leukocytosis, and ileus, with a maximum of 10 days of therapy (control group), or to receive a fixed course of antibiotics (experimental group) for 4±1 calendar days. The primary outcome was a composite of surgical-site infection, recurrent intraabdominal infection, or death within 30 days after the index source-control procedure, according to treatment group. Secondary outcomes included the duration of therapy and rates of subsequent infections. RESULTS: Surgical-site infection, recurrent intraabdominal infection, or death occurred in 56 of 257 patients in the experimental group (21.8%), as compared with 58 of 260 patients in the control group (22.3%) (absolute difference, -0.5 percentage point; 95% confidence interval [CI], -7.0 to 8.0; P=0.92). The median duration of antibiotic therapy was 4.0 days (interquartile range, 4.0 to 5.0) in the experimental group, as compared with 8.0 days (interquartile range, 5.0 to 10.0) in the control group (absolute difference, -4.0 days; 95% CI, -4.7 to -3.3; P<0.001). No significant between-group differences were found in the individual rates of the components of the primary outcome or in other secondary outcomes. CONCLUSIONS: In patients with intraabdominal infections who had undergone an adequate source-control procedure, the outcomes after fixed-duration antibiotic therapy (approximately 4 days) were similar to those after a longer course of antibiotics (approximately 8 days) that extended until after the resolution of physiological abnormalities. (Funded by the National Institutes of Health; STOP-IT ClinicalTrials.gov number, NCT00657566.).

Cost-effectiveness Analysis of Contralateral Prophylactic Mastectomy Compared to Unilateral Mastectomy with Routine Surveillance for Unilateral, Sporadic Breast Cancer.

BACKGROUND: Contralateral prophylactic mastectomy (CPM) rates in younger women with unilateral breast cancer have more than doubled. Studies of cost and quality of life of the procedure remain inconclusive. METHODS: A cost-effectiveness analysis using a decision-tree model in TreeAge Pro 2015 was used to compare long-term costs and quality of life following unilateral mastectomy (UM) with routine surveillance versus CPM for sporadic breast cancer in women aged 45 years. A 10-year risk period for contralateral breast cancer (CBC), reconstruction, wound complications, cost of routine surveillance, and treatment for CBC were used to estimate accrued costs. In addition, a societal perspective was used to estimate quality-adjusted life years (QALYs) following either treatment for a period of 30 years. Medical costs were obtained from the 2014 Medicare physician fee schedule and event probabilities were taken from recent literature. RESULTS: The mean cost of UM with surveillance was $14,141 and CPM was $20,319. Treatment with CPM resulted in $6178 more in costs but equivalent QALYs (17.93) compared with UM over 30 years of follow-up. Even with worst-case scenario and varying assumptions, CPM is dominated by UM in terms of cost and quality. CONCLUSIONS: From this refined model, UM with routine surveillance costs less and provides an equivalent quality of life. Patients undergoing CPM may eliminate the anxiety of routine surveillance, but they face the burden of higher lifetime medical costs.

Large-bowel disease presenting as small-bowel obstruction is associated with a poor prognosis.

INTRODUCTION: Small-bowel obstruction (SBO) is a common cause of admission to the surgical service. On rare occasions, a diagnosed SBO is actually due to large-bowel pathology combined with an incompetent ileocecal valve. The purpose of this study was to investigate this phenomenon. METHODS: We performed a retrospective medical record review of patients that were admitted with a diagnosis of SBO at University of Louisville hospital and the Veterans Affairs hospitals in Louisville, KY, from 2006 until 2014. RESULTS: A total of 498 patients were admitted with SBO during this time period. Forty-one patients were found to have an underlying large-bowel disease. The most common large-bowel pathologies included malignancy (51%), inflammation (15%), and infection (15%). Fifteen (43%) of these patients died during admission; 93% of these were due to either their bowel obstruction or the underlying disease state. This was significantly higher than the general population (9.4% mortality, 6% due to underlying disease). CONCLUSIONS: Patients that present with SBO due to a large-bowel source have a much higher mortality rate than those that present with other causes. Rapid identification of these patients will allow for more timely and appropriate treatment.

Intra-abdominal infections survival guide: a position statement by the Global Alliance For Infections In Surgery.

Intra-abdominal infections (IAIs) are an important cause of morbidity and mortality in hospital settings worldwide. The cornerstones of IAI management include rapid, accurate diagnostics; timely, adequate source control; appropriate, short-duration antimicrobial therapy administered according to the principles of pharmacokinetics/pharmacodynamics and antimicrobial stewardship; and hemodynamic and organ functional support with intravenous fluid and adjunctive vasopressor agents for critical illness (sepsis/organ dysfunction or septic shock after correction of hypovolemia). In patients with IAIs, a personalized approach is crucial to optimize outcomes and should be based on multiple aspects that require careful clinical assessment. The anatomic extent of infection, the presumed pathogens involved and risk factors for antimicrobial resistance, the origin and extent of the infection, the patient's clinical condition, and the host's immune status should be assessed continuously to optimize the management of patients with complicated IAIs.

Macrophage genetic reprogramming during chronic peritonitis is augmented by LPS pretreatment.

BACKGROUND: Persistent and tertiary chronic peritonitis is a clinically challenging problem especially in those who are critically ill. This could be attributed to a state of immune-paralysis, known as microbial tolerance. Microbial tolerance is the diminished pro-inflammatory protein response following repeated stimulation by numerous pathogen-associated molecular patterns (PAMPs) of varying origins, which we have shown in this novel model of chronic peritonitis. We aimed in this study to investigate the molecular mechanisms behind microbial tolerance and the early innate immune response resolution in this model. METHODS: C57BL/6 mice were pretreated intra-peritoneally (IP) with saline or endotoxin LPS 10 mg/kg (LPS 10). Following pretreatment, peritonitis was induced 24 h later injecting 10(3)Klebsiella pneumonia CFU IP. Gentamicin was administered 4 h prior to infection and BID thereafter. Peritoneal exudate cells (PEC) were obtained through peritoneal lavage and RNA was isolated (n = 3) at 4, 24, and 48 h following infection. SA Biosciences© RT2-Profiler PCR array mouse Toll-like receptor signaling pathway (PAMM_018A) data were further analyzed by Ingenuity Pathway Inc. analysis (IPA). RESULTS: Of the 89 genes studied, 26 were significantly up-regulated (fold change > 1.2 and P value < 0.05) in the saline pretreated group at 4, 24, and 48 h after infection. There were no down-regulated genes. In the LPS-pretreated group, 35 genes were significantly up-regulated; of these genes, 13 were not increased in the saline pretreated infected mice. This left 22 up-regulated genes in both infected groups. At 4 h, 6 of these 22 genes (CHUK, HMGB1, HSPD1, IRAK2, LY96, and TLR4) were further 2-fold increased in the LPS pretreatment group compared with the saline pretreatment group. Only IRAK2 was 2-fold increased at 24 h. By 48 h, no LPS effect was seen. When applying IPA analysis, six main canonical pathways were constantly dysregulated in the same significance order in both the saline and LPS group at 4, 24, and 48 h. These were: Toll-like receptor and NF-κB signaling, hepatic cholestasis, interleukin-6, and LPS-mediated MAPK signaling pathways, and pattern recognition receptors of bacterial pathway. CONCLUSION: Peritonitis increased PEC gene expression associated with sepsis and a pro-inflammatory response, which was further augmented by LPS pretreatment over 24 h only. Prior exposure to LPS did not induce PEC gene tolerance to subsequent infection with Klebsiella at the mRNA level. Post-transcriptional modification as microRNA down-regulation of inflammatory cytokines could possibly explain such phenomena.

Impact of microbial tolerance in persistent secondary Klebsiella pneumoniae peritonitis.

PURPOSE AND METHODS: Microbial tolerance represents a diminished pro-inflammatory response following repeated stimulation by a host of pathogen-associated molecular patterns (PAMPs) of varying origins. Toll-like receptors (TLRs) have been centrally implicated in the development of tolerance. The purpose of this study was to investigate the impact of tolerance in a previously described murine model. C57BL/6 mice were pretreated intraperitoneally with phosphate buffered saline (PBS), heat-killed Klebsiella 2×10(8) CFU (hkKlebsiella), LPS 10mg/kg (LPS 10), or BLP 10mg/kg (BLP 10). Following pretreatment, peritonitis was induced 24h later using 10(3) intraperitoneal Klebsiella CFU. Peritoneal concentrations of TNF-α, IL-10 and nitric oxide (NO), as well as characteristic cell patterns, were determined. Long-term consequences of microbial tolerance were assessed by measuring survival and weight-loss. RESULTS: Following in vitro stimulation with Klebsiella 10(5) and 10(3) CFU, TNF-α and IL-10 secretion were diminished in macrophages harvested from mice pretreated with hkKlebsiella, LPS 10 and BLP 10. Pretreated animals had significantly lower bacterial counts. Conversely, local NO levels were elevated. Survival was not different between the groups. CONCLUSION: Pretreatment with TLR ligands induced microbial tolerance, with reduced peritoneal cytokine concentrations and enhanced early bacterial clearance. However, this did not translate into improved survival.

Liver injury and abscess formation in secondary murine peritonitis.

OBJECTIVE: To investigate liver damage and abscess formation in murine, secondary peritonitis. SUBJECTS: Male C57BL/6 mice. TREATMENT: Intraperitoneal injection with 10(3) CFU Klebsiella pneumoniae and treatment with gentamicin 5 mg/kg/day (BID), subcutaneously. METHODS: Animals were killed at 12, 24, 48 and 72 h after infection. Bacterial burden was determined in the blood and the liver. Liver abscess formation was assessed macroscopically and microscopically. Plasma levels of alkaline phosphatase (ALP) and alanine transaminase (ALT) were measured. Polymorphonuclear leukocyte (PMN) accumulation was assessed via tissue myeloperoxidase (MPO) concentrations. Liver interleukin-10 (IL-10) levels were determined by ELISA. RESULTS: K. pneumoniae was detectable in the blood and the liver at 12 h after infection. Liver abscess formation was visible earliest at 24 h after infection and most pronounced within the right liver lobes. ALP and ALT levels peaked at 12 and 24 h after infection, respectively. MPO was elevated in the right and left liver lobes at 12 h but only in the right lobes at 48 h after infection, compared to tissue levels in naïve mice. Liver IL-10 concentrations were not significantly increased. CONCLUSION: Peritonitis led to liver injury and abscess formation but did not significantly affect tissue concentrations of anti-inflammatory IL-10.

A Review of "Options in Management of Trauma to the Esophagus" (1982) "Submitted for the Literary Festschrift in Honor of J. David Richardson, MD".

This article is an update of a paper which Dave Richardson and I published in 1982, and serves as both an update of management of esophageal injuries and as a lasting tribute to my mentor and hero J. David Richardson.

Microbial tolerance in secondary peritonitis is dose dependent.

Local microbial tolerance was investigated in a murine model of peritonitis. Peritoneal bacterial burden and inflammatory cytokine concentrations were determined at different times, within 48h after infection. Peritoneal macrophages were harvested from naïve mice or from mice 48h after infection and underwent ex vivo stimulation with different concentrations of Klebsiella. Cytokine secretion was determined in the supernatants. Peritoneal bacteria concentrations, remained relatively steady between 24h (median: 5.04 log CFU) and 48h (median: 5.19 log CFU) after infection. Peritoneal cytokine concentrations peaked early but were already diminished at 48h after infection, despite persistent high bacteria levels. Macrophages, harvested from naïve mice responded vigorously to ex vivo stimulation with 10(5) CFU and 2 x 10(8) CFU Klebsiella. Cells harvested from animals 48h after infection, were unresponsive to an ex vivo stimulation with 10(5) CFU Klebsiella, but fully responded to 10(8) CFU. Persistent intraabdominal bacterial infection induced dose dependent microbial tolerance in peritoneal macrophages.

Common microbial pathogens in surgical practice.

Despite ongoing major advances in antisepsis and in the development of potent antimicrobial agents since the early twentieth century, human beings remain subject to bacterial and fungal infection through mechanisms of virulence that continue to evade the latest advents in the microbiologic field today. Infection persists in surgical patients and only via the procurement of an in-depth knowledge of microorganism evolution and progression and an intricate understanding of human immune defense mechanisms are surgeons able to tackle infection in a fashion synonymous to that which allowed historic legends to transform the mere concept of surgery into reality. This article broadly describes current microbial pathogens and related issues in surgical disease.

Pathogen- and Danger-Associated Molecular Patterns and the Cytokine Response in Sepsis.

The sepsis syndrome is a systemic host inflammatory response accompanied by organ dysfunction in response to invading microbial pathogens. The host recognizes both danger and pathogens through its pattern recognition receptors on immune cells. These receptors bind to pathogen- (PAMP) and danger- (DAMP) associated molecular patterns derived from microbes and host tissues, respectively. These processes set in motion a cascade of events in host cells and tissue, which activate multiple cytokines that serve as activators of the host inflammatory response as well as eventually lead to resolution of the response if the host recovers. The following article describes some of these DAMPs and PAMPs, and how they activate pathways that activate the host cytokine immune response to injury and infection.

Women in surgery: A longer term follow-up.

BACKGROUND: There are an increasing number of women in surgery. Previously, many questions focused upon their ability to complete surgical training and contribute fully to the surgical workforce. More meaningful information lies in identifying the long-term follow-up of where, and in what specialty, women residents eventually practice. METHODS: All residents entering general surgery training at the University of Louisville between 1996 and 2009 were studied. Comparison between men and women was performed for program completion, length of residency training, and eventual specialty practice. RESULTS: One hundred and eight residents entered general surgery residency. Twenty-three (21%) did not complete training. There was no difference in attrition rates between men or women (22% vs. 19%, p = 0.77). Women completing residency were just as likely to practice general surgery (either private or academic practice) as their male counterparts (67% vs. 67% p = 0.96). CONCLUSIONS: Women are a valuable resource in surgery and are able to complete a vigorous residency. Long-term follow-up is crucial and permits us to evaluate this important group of trainees practicing surgery today.

Endogenous IL-10 leads to impaired bacterial clearance and reduced survival in a murine model of chronic peritonitis.

We previously observed insufficient neutrophil accumulation and a lack of TNF-alpha response at the site of infection until bacteria numbers >10(5) colony forming units in our model of chronic murine peritonitis, suggesting a defective host response after bacterial challenge with Klebsiella pneumoniae (Klebsiella). The aim of this study was to determine a potentially immunosuppressive effect of IL-10 in this model of chronic peritonitis. Balb/c animals were injected with 10(3) colony forming units Klebsiella intraperitoneally. Gentamicin (5 mg/kg/day BID) was given subcutaneously (s.c.) for two days and then withdrawn. Animals were treated with anti-IL-10 antibody or IgG isotype control (s.c.) before or after Klebsiella administration. Survival was determined over 14 days. Similarly treated animals were harvested after 48 h to obtain liver tissue, peritoneal fluid and blood. Bacteria and neutrophil counts were determined. TNF-alpha and IL-10 were measured by ELISA. Anti-IL-10 antibody significantly increased survival and bacterial clearance in the observed compartments. Anti-IL-10 administration did not lead to an increase in TNF-alpha concentrations or neutrophil accumulation at the site of infection at lower levels of Klebsiella. We conclude that endogenous IL-10 is detrimental for survival and bacterial clearance in this model of chronic peritonitis.

Decreased neutrophil response in a model of chronic intraperitoneal Klebsiella infection.

BACKGROUND: Previously, we developed an infection model by intraperitoneal (IP) injection of Klebsiella pneumoniae. The high early mortality rate prompted a study of the effect of gentamicin on the disease course. METHODS: Infection was induced in Balb/c mice by IP inoculation of 10(3) colony-forming units (cfu) of K. pneumoniae serotype 2. Mice then received either saline or gentamicin twice daily at 5 mg/kg/day. Survival and weight loss were determined daily over 14 days. Leukocyte counts (WBC) were performed on peritoneal lavage fluid (PL) and peripheral blood. Bacterial counts in blood, lung homogenate, and PL were determined by culture. RESULTS: A significant survival benefit was seen in the gentamicin group by 48 h (p < 0.05), which persisted at 14 days. Weight loss of 2 g (p < 0.05) occurred in all mice by day three, with recovery seen only in the gentamicin-treated mice. Mice that did not regain their weight by day seven or lost more than 4 g (20%) died. All animals had peritoneal bacteria recovered at all time points. The gentamicin group showed fewer bacteria at one day in lung, blood, and PL, the difference being significant for the PL. Gentamicin did not clear peritoneal bacteria, and counts remained at inoculum concentration (10(3) cfu), but elicited no significant neutrophil influx. Whereas there was a progressive increase in total lavage WBC over time, the gentamicin group showed no significant neutrophil influx in PL or lung until bacterial counts exceeded 10(5) cfu. CONCLUSIONS: Despite persistent intra-abdominal infection, gentamicin treatment significantly prolonged survival in this uniformly lethal model. Although antibiotic treatment did not suppress bacteremia, it did diminish bacterial spread from the blood to the lung. This procedure produced a clinically relevant, novel model of antibiotic-treated chronic intraperitoneal infection, which will allow future study of specific host defense mechanisms.

Alveolar interleukin-10 regulates neutrophil apoptosis in severely traumatized patients.

BACKGROUND: The lung produces a localized immunologic response to systemic trauma, characterized by an initial proinflammatory period with production of interleukin (IL)-8 and IL-18, followed by an anti-inflammatory phase with elevated levels of IL-10. Recent studies have shown a correlation between alveolar IL-10 and the rate of local neutrophil apoptosis. The aim of the present study was to further characterize the association of alveolar IL-8 and IL-10 after trauma with neutrophil activation, apoptosis, and phagocytic capacity. METHODS: Bronchoalveolar lavage fluid (BALF) was obtained from 17 trauma patients with an Injury Severity Score >/=16 who required mechanical ventilation. Neutrophils from venous blood of healthy volunteers were incubated in either (1) cell culture media (control), (2) culture media + BALF, (3) culture media + BALF + anti-IL-8 neutralizing antibody, or (4) culture media + BALF + anti-IL-10. Surface CD11b expression, ability to phagocytose fluorescent bacteria, and neutrophil apoptosis were determined by flow cytometry. RESULTS: Phagocytosis and CD11b expression were both augmented on postinjury day 1 when compared with controls. Neutralization of IL-10 or IL-8 produced no significant differences in phagocytosis or CD11b expression. However, neutralization of IL-10 significantly decreased the rate of apoptosis in samples from postinjury day 1. CONCLUSION: Phagocytosis and CD11b expression on neutrophils are IL-8 and IL-10 independent. However, our data indicate that alveolar neutrophil apoptosis is dependent on IL-10 at early time points after injury. Elucidation of this pathway may allow novel interventions to prevent posttraumatic pulmonary dysfunction.

Enterocutaneous fistula: are treatments improving?

BACKGROUND: We studied the etiology, treatment, and outcome of enterocutaneous fistulas in 106 patients to evaluate our current practice and the impact of newer therapies-octreotide, wound vacuum-assisted closure (VAC), and fibrin glue-on clinical outcomes. Review of the literature and our own 1990 study indicate a mortality rate of 5% to 20% for enterocutaneous fistula, and a healing rate of 75% to 85% after definitive surgery. METHODS: We reviewed all cases of gastrointestinal-cutaneous fistula from 1997 to 2005 at 2 large teaching hospitals. We identified 106 patients with enterocutaneous fistula; patients with irritable bowel disease and anorectal fistulas were excluded. RESULTS: The origin of the fistula was the small bowel in 67 patients, colon in 26, stomach in 8, and duodenum in 5. The etiology of the fistula was previous operation in 81 patients, trauma in 15, hernia mesh erosion in 6, diverticulitis in 2, and radiation in 2. Of the 106 patients in the study, 31 had a high output fistula (greater than 200 mL/day), 44 had a low output fistula, and, in 31 patients, the fistula output was low but there was no record of volume. Initial treatment was nonoperative except for patients with an abscess who needed urgent drainage. In 24 patients, the effect of octreotide was monitored: in 8 patients, fistula output declined; in 16 patients, octreotide was of no benefit. Fibrin glue was used in 8 patients and was of benefit to 1. The wound VAC was used in 13 patients: 12 patients still required operative repair of the fistula, whereas the fistula was healed in 1 patient. The main benefit of the VAC system was improved wound care in all patients before definitive surgery. Total parenteral nutrition was used in most patients to provide nutritional support. Operative repair was performed in 77 patients and was successful in 69 (89%), failing in 6 patients with persistent cancer or infection. Nonoperative treatment was used in 29 patients and resulted in healing in 60%. Of 106 patients, 7 (7%) died of fistula complications. The cause of death was persistence or recurrence of cancer in 4 patients and persistent sepsis in 3. CONCLUSION: Enterocutaneous fistula continues to be a serious surgical problem. The wound VAC and fibrin glue had anecdotal successes (n = 2), and one-third of patients responded to octreotide. We believe that octreotide should be tried in most patients and that the wound VAC has a role in selected patients. Although 7% overall mortality is lower than in previous studies, the number managed without operation (27%) remains the same. In addition to early control of sepsis, nutritional support, and wound care, a well-timed operation was the most effective treatment.

Risk factors for surgical site infection.

BACKGROUND: As many as 5% of patients undergoing surgery develop surgical site infections (SSIs), which may cause much morbidity and may sometimes be fatal. Treating SSIs imposes a substantial strain on the financial resources of the health care system. METHODS: Review of current practice and guidelines. RESULTS: Important patient-related factors for SSI include existing infection, low serum albumin concentration, older age, obesity, smoking, diabetes mellitus, and ischemia secondary to vascular disease or irradiation. Surgical risk factors include prolonged procedures and inadequacies in either the surgical scrub or the antiseptic preparation of the skin. Physiological states that increase the risk of SSI include trauma, shock, blood transfusion, hypothermia, hypoxia, and hyperglycemia. Parameters that may be associated independently with an increased risk of SSI, and that may predict infection, include abdominal surgery, a contaminated or dirty operation, and more than three diagnoses at the time of discharge. The major sources of infection are microorganisms on the patient's skin and, less often, the alimentary tract or female genital tract. The organism most often isolated is Staphylococcus aureus, which often is resistant to methicillin. Antibiotic-resistant bacteria are a continuing and increasing problem. CONCLUSIONS: A wide range of patient-related, surgery-related, and physiological factors heighten the risk of SSI.

Antibiotic modulation in a clinically relevant model of chronic intraabdominal infection.

Continuous and twice-daily cefoxitin dosing was used in a highly lethal model of acute peritonitis in mice using intraperitoneal (IP) Klebsiella pneumoniae (Kpn). The purpose was to use antibiotics to create a model of chronic infection. Male Balb/c mice (averaging 20 g body weight) were inoculated IP with 10(3) colony-forming units (CFU) Kpn serotype 2. Controls received subcutaneous saline either twice daily or continuously. Antibiotic groups received 300 mg/kg per day of cefoxitin either twice daily or continuously. Survival and daily weight losses were determined. Another group was inoculated with 10(3) Kpn given twice daily saline or cefoxitin and harvested at 24 hours. Leukocyte counts were performed on peritoneal exudate cells (PEC) and peripheral blood. Cultures determined Kpn counts in blood, lung, and PEC. By 24 hours, saline-treated animals had lost more weight than cefoxitin mice (1 g vs. 2 g, P < 0.05). Continuous cefoxitin showed significant advantage with 50 per cent mortality at 5 days. Kpn levels were not significantly altered by cefoxitin. Cefoxitin treatment extended chronicity by preventing weight loss and increasing survival in a highly lethal, monomicrobial peritonitis model. This model will allow future study of specific host defense mechanisms over a prolonged time period.

Anti-inflammatory effects of miR-21 in the macrophage response to peritonitis.

We investigated the role of microRNA-21 in the macrophage response to peritonitis; microRNA-21 expression increases in peritoneal macrophages after lipopolysaccharide stimulation but is delayed until 48 hours after cecal ligation and puncture. MicroRNA-21-null mice and bone marrow-derived cell lines were exposed to cecal ligation and puncture or lipopolysaccharide, and survival, microRNA-21 levels, target messenger RNAs and proteins, and cytokines were assayed. Macrophages were also transfected with microRNA-21 mimics and antagomirs, and similar endpoints were measured. Survival in microRNA-21-null mice was significantly decreased after lipopolysaccharide-induced peritonitis but unchanged after cecal ligation and puncture compared with similarly treated wild-type mice. MicroRNA-21 expression, tumor necrosis factor-α, interleukin 6, and programmed cell death protein 4 levels were increased after lipopolysaccharide addition in peritoneal cells. Pelino1 and sprouty (SPRY) messenger RNAs were similarly increased early, whereas programmed cell death protein 4 messenger RNA was decreased after lipopolysaccharide, and all microR-21 target messenger RNAs were subsequently decreased by 24 hours after lipopolysaccharide. Transfection with mimics and antagomirs led to appropriate responses in microRNA-21 and tumor necrosis factor-α. Knockdown of microRNA-21 in bone marrow-derived cells showed increased tumor necrosis factor-α and decreased interleukin 10 in response to lipopolysaccharide. Target proteins were unaffected by knockdown as was extracellular signal-regulated kinase; however, the nuclear factor κB p65 subunit was increased after lipopolysaccharide in the microRNA-21 knockout cells. In contrast, there was little change in these parameters after cecal ligation and puncture induction between null and wild-type mice. MicroRNA-21 is beneficial to survival in mice following lipopolysaccharide peritonitis. Overexpression of microRNA-21 decreased tumor necrosis factor-α secretion, whereas suppression of microRNA-21 expression increased tumor necrosis factor-α and interleukin 6, and decreased interleukin 10 levels after lipopolysaccharide. Protein targets of microRNA-21 were not different following suppression of microRNA-21. Nuclear factor κB was increased by suppression of microRNA-21. These findings demonstrate microRNA-21 is beneficial in modulating the macrophage response to lipopolysaccharide peritonitis and an improved understanding of the anti-inflammatory effects of microRNA-21 may result in novel, targeted therapy against peritonitis and sepsis.

Infection and organ failure in the surgical patient: a tribute to seminal contributions by Hiram C. Polk, Jr, M.D.

Despite intensive research over past decades, infections and organ failure remain the most common severe complications in the critically ill surgical patient. Multiple-organ dysfunction syndrome represents the clinical endpoint of a cascade of mainly immunologic and cardiovascular events, ultimately leading to progressive patient deterioration and high mortality. Few clinicians have contributed as vigorously as Hiram C. Polk, Jr, to improve the treatment and outcome in surgical patients suffering from these disorders. His effort to standardize perioperative antibiotic prophylaxis, to introduce quantitative tracheal cultures for the diagnosis of pneumonia in trauma patients, or to use blood markers such as monocyte HLA-DR expression to identify patients at risk for adverse outcome are but some excerpts of his career as an academic surgeon. This article describes surgical infections and organ failure from a historical perspective, with emphasis on Polk's contributions, and describes our current understanding of the pathophysiology of organ dysfunction in surgical patients.