Enteral administration of bacteria fermented formula in newborn piglets: A high fidelity model for necrotizing enterocolitis (NEC).

OBJECTIVE: To develop an animal model which replicates neonatal NEC and characterizes the importance of bacterial fermentation of formula and short chain fatty acids (SCFAs) in its pathogenesis. BACKGROUND: NEC is a severe form of intestinal inflammation in preterm neonates and current models do not reproduce the human condition. METHODS: Three groups of newborn piglets: Formula alone (FO), Bacteria alone (E.coli: BO) and E.coli-fermented formula (FF) were anesthetized, instrumented and underwent post-pyloric injection of formula, bacteria or fermented-formula. SCFA levels were measured by gas chromatography-mass spectrometry. At 6 h bowel appearance was assessed, histologic and molecular analysis of intestine were performed. Gut inflammation (p65 NF-κB, TLR4, TNF-α, IL-1ß), apoptosis (cleaved caspase-3, BAX, apoptosis) and tight junction proteins (claudin-2, occludin) were measured. RESULTS: SCFAs were increased in FF. Small bowel from FF piglet's demonstrated inflammation, coagulative necrosis and pneumatosis resembling human NEC. Histologic gut injury (injury score, mast cell activation) were increased by Bacteria, but more severe in FF piglets. Intestinal expression of p65 NF-κB, NF-κB activation, TNF-α and IL-1ß were increased in BO and markedly increased in the FF group (P<0.05 vs. FO). Intestine from Bacteria piglets demonstrated increased apoptotic index, pro-apoptotic protein expression and decreased tight junction proteins. These changes were more severe in FF piglets. CONCLUSIONS: Our piglet model demonstrates the findings of NEC in human neonates: systemic acidosis, intestinal inflammation, pneumatosis and portal venous gas. Bacteria alone can initiate intestinal inflammation, injury and apoptosis, but bacterial fermentation of formula generates SCFAs which contribute to the pathogenesis of NEC.

Has survival improved following resection for pancreatic adenocarcinoma?

INTRODUCTION: This study was undertaken to determine if survival after resection of pancreatic adenocarcinoma has improved over the past two decades. METHODS: The SEER database was queried for patients who underwent pancreatectomy for pancreatic adenocarcinoma from 1992 to 2010. AJCC Stage and survival were determined for patients. Data were analyzed using Mantel-Cox test and linear regression. RESULTS: 15,604 patients underwent pancreatectomy from 1992 to 2010. Survival improved from 1992 to 2010 (p < 0.0001); specifically, median survival increased 1992-2010 (p < 0.0001). However, 5-year survival rates did not change 1992-2010. More patients (p = 0.007) underwent resections of Stage I and relatively more patients (p = 0.004) underwent resections of Stage II cancers 2004-2010 with commensurately smaller tumors (p = 0.01). CONCLUSIONS: From 1992 to 2010, progressively more patients underwent pancreatectomy for pancreatic adenocarcinoma with progressively smaller tumors and earlier stages. These patients lived more years (e.g., improved survival curves and median survival) but without improved 5-year survival, denoting better early and intermediate survival. Early detection, better perioperative care, more efficacious noncurative chemotherapy undoubtedly play a role, but better solutions for long-term survival must be sought.

The 30-year evolution of airway pressure release ventilation (APRV).

Airway pressure release ventilation (APRV) was first described in 1987 and defined as continuous positive airway pressure (CPAP) with a brief release while allowing the patient to spontaneously breathe throughout the respiratory cycle. The current understanding of the optimal strategy to minimize ventilator-induced lung injury is to "open the lung and keep it open". APRV should be ideal for this strategy with the prolonged CPAP duration recruiting the lung and the minimal release duration preventing lung collapse. However, APRV is inconsistently defined with significant variation in the settings used in experimental studies and in clinical practice. The goal of this review was to analyze the published literature and determine APRV efficacy as a lung-protective strategy. We reviewed all original articles in which the authors stated that APRV was used. The primary analysis was to correlate APRV settings with physiologic and clinical outcomes. Results showed that there was tremendous variation in settings that were all defined as APRV, particularly CPAP and release phase duration and the parameters used to guide these settings. Thus, it was impossible to assess efficacy of a single strategy since almost none of the APRV settings were identical. Therefore, we divided all APRV studies divided into two basic categories: (1) fixed-setting APRV (F-APRV) in which the release phase is set and left constant; and (2) personalized-APRV (P-APRV) in which the release phase is set based on changes in lung mechanics using the slope of the expiratory flow curve. Results showed that in no study was there a statistically significant worse outcome with APRV, regardless of the settings (F-ARPV or P-APRV). Multiple studies demonstrated that P-APRV stabilizes alveoli and reduces the incidence of acute respiratory distress syndrome (ARDS) in clinically relevant animal models and in trauma patients. In conclusion, over the 30 years since the mode's inception there have been no strict criteria in defining a mechanical breath as being APRV. P-APRV has shown great promise as a highly lung-protective ventilation strategy.

High-Volume Hospitals with High-Volume and Low-Volume Surgeons: Is There a "Field Effect" for Pancreaticoduodenectomy?

Since the Leapfrog Group established hospital volume criteria for pancreaticoduodenectomy (PD), the importance of surgeon volume versus hospital volume in obtaining superior outcomes has been debated. This study was undertaken to determine whether low-volume surgeons attain the same outcomes after PD as high-volume surgeons at high-volume hospitals. PDs undertaken from 2010 to 2012 were obtained from the Florida Agency for Health Care Administration. High-volume hospitals were identified. Surgeon volumes within were determined; postoperative length of stay (LOS), in-hospital mortality, discharge status, and hospital charges were examined relative to surgeon volume. Six high-volume hospitals were identified. Each hospital had at least one surgeon undertaking ≥ 12 PDs per year and at least one surgeon undertaking < 12 PDs per year. Within these six hospitals, there were 10 "high-volume" surgeons undertaking 714 PDs over the three-year period (average of 24 PDs per surgeon per year), and 33 "low-volume" surgeons undertaking 225 PDs over the three-year period (average of two PDs per surgeon per year). For all surgeons, the frequency with which surgeons undertook PD did not predict LOS, in-hospital mortality, discharge status, or hospital charges. At the six high-volume hospitals examined from 2010 to 2012, low-volume surgeons undertaking PD did not have different patient outcomes from their high-volume counterparts with respect to patient LOS, in-hospital mortality, patient discharge status, or hospital charges. Although the discussion of volume for complex operations has shifted toward surgeon volume, hospital volume must remain part of the discussion as there seems to be a hospital "field effect."

Preemptive mechanical ventilation can block progressive acute lung injury.

Mortality from acute respiratory distress syndrome (ARDS) remains unacceptable, approaching 45% in certain high-risk patient populations. Treating fulminant ARDS is currently relegated to supportive care measures only. Thus, the best treatment for ARDS may lie with preventing this syndrome from ever occurring. Clinical studies were examined to determine why ARDS has remained resistant to treatment over the past several decades. In addition, both basic science and clinical studies were examined to determine the impact that early, protective mechanical ventilation may have on preventing the development of ARDS in at-risk patients. Fulminant ARDS is highly resistant to both pharmacologic treatment and methods of mechanical ventilation. However, ARDS is a progressive disease with an early treatment window that can be exploited. In particular, protective mechanical ventilation initiated before the onset of lung injury can prevent the progression to ARDS. Airway pressure release ventilation (APRV) is a novel mechanical ventilation strategy for delivering a protective breath that has been shown to block progressive acute lung injury (ALI) and prevent ALI from progressing to ARDS. ARDS mortality currently remains as high as 45% in some studies. As ARDS is a progressive disease, the key to treatment lies with preventing the disease from ever occurring while it remains subclinical. Early protective mechanical ventilation with APRV appears to offer substantial benefit in this regard and may be the prophylactic treatment of choice for preventing ARDS.

Heller myotomy with esophageal diverticulectomy: an operation in need of improvement.

BACKGROUND: This study was undertaken to evaluate the outcomes after laparoscopic Heller myotomy with anterior fundoplication and diverticulectomy for patients with achalasia and esophageal diverticula. METHODS: 634 patients undergoing laparoscopic Heller myotomy and anterior fundoplication from 1992 to 2015 are prospectively followed up; patients were stratified for those undergoing concomitant diverticulectomy. Patients graded symptom frequency and severity before and after myotomy, using a Likert scale (0 = never/not bothersome to 10 = always/very bothersome). Median data are presented (mean ± SD). RESULTS: Forty-four patients, age 70 years (65 ± 14.2), underwent laparoscopic Heller myotomy, anterior fundoplication, and diverticulectomy. Operative time was 182 min (183 ± 54.6). Fifty percentage of patients had a postoperative complication: Most notable were leaks at the diverticulectomy site (n = 8) and pulmonary complications (n = 11; 10 effusion, 1 empyema). Length of stay (LOS) was 3 days (5 ± 8.3). All leaks occurred after discharge and resolved without sequelae using transthoracic catheter drainage and parenteral nutrition; two patients received endoscopic esophageal stents. Median follow-up is 39 months. Symptoms amelioration was significant postoperatively, including severity of dysphagia [6 (6 ± 3.9) to 2(4 ± 3.6)]. Seventy-six percentage of patients rated their symptoms at last follow-up as satisfying/very satisfying. Seventy-seven percentage of patients had symptoms once per week or less. Eighty-one percentage would have the operation again knowing what they know now. CONCLUSIONS: Laparoscopic Heller myotomy, anterior fundoplication, and diverticulectomy well palliate the symptoms of achalasia with accompanying esophageal diverticulum. The operations are generally longer than those without diverticulectomy and are accompanied by a relatively longer LOS. Complications are relatively frequent and severe (e.g., leaks and pneumonia). In particular, leaks at the diverticulectomy site are unpredictable, occur after discharge, and remain vexing. Nevertheless, for this advanced form of achalasia, long-term symptom relief and patient satisfaction are high after anterior fundoplication with concomitant diverticulectomy. New and innovative techniques are needed to decrease the frequency of leaks at the diverticulectomy site.

A Single Institution's First 100 Patients Undergoing Laparoscopic Anti-Reflux Fundoplications: Where Are They 20 Years Later?

Although anti-reflux surgery has been used liberally over the past decades for the treatment of gastroesophageal reflux disease (GERD), few studies report follow-up after 10 years. This study was undertaken to report follow-up on 100 consecutive GERD patients up to 22 years after utilizing a laparoscopic fundoplication. Hundred consecutive patients undergoing laparoscopic fundoplication for GERD were prospectively followed beginning in 1992. The frequency and severity of symptoms before and after laparoscopic fundoplication were scored on a Likert scale (1 = never/none to 10 = always/very bothersome). Median data are reported. Of the 100 patients who underwent laparoscopic fundoplication for their GERD, nine were reoperations. Twenty-six patients are deceased on average 11 years after their fundoplications. Seventy-four patients are alive, with 27 patients, actively followed for 19 years after their fundoplications. At most recent follow-up, patients experienced long-term amelioration of symptom frequency and severity after fundoplication (e.g., heartburn frequency = 8-2, severity = 8-1; P < 0.01 for each). Eighty-four per cent of patients rated their symptom frequency as less than once per month. Eighty-eight per cent of patients were satisfied with their postoperative results, and 95 per cent of patients confirmed they would have the operation again knowing what they know now. Long-term follow-up documents high patient satisfaction and durable symptomatic relief up to two decades after laparoscopic fundoplication for GERD. Patients should seek this operation not only for symptomatic relief, but to mitigate the deleterious effects of long-term acid exposure and anti-acid therapy.

Alveolar instability (atelectrauma) is not identified by arterial oxygenation predisposing the development of an occult ventilator-induced lung injury.

BACKGROUND: Improperly set mechanical ventilation (MV) with normal lungs can advance lung injury and increase the incidence of acute respiratory distress syndrome (ARDS). A key mechanism of ventilator-induced lung injury (VILI) is an alteration in alveolar mechanics including alveolar instability or recruitment/derecruitment (R/D). We hypothesize that R/D cannot be identified by PaO2 (masking occult VILI), and if protective ventilation is not applied, ARDS incidence will increase. METHODS: Sprague-Dawley rats (n = 8) were anesthetized, surgically instrumented, and placed on MV. A thoracotomy was performed and an in vivo microscope attached to the pleural surface of the lung with baseline dynamic changes in alveolar size during MV recorded. Alveolar instability was induced by intra-tracheal instillation of Tween and alveolar R/D identified as a marked change in alveolar size from inspiration to expiration with increases in positive end-expiratory pressure (PEEP) levels. RESULTS: Despite maintaining a clinically acceptable PaO2 (55-80 mmHg), the alveoli remained unstable with significant R/D at low PEEP levels. Although PaO2 consistently increased with an increase in PEEP, R/D did not plateau until PEEP was >9 cmH2O. CONCLUSIONS: PaO2 remained clinically acceptable while alveolar instability persisted at all levels of PEEP (especially PEEP <9 cmH2O). Therefore, PaO2 levels cannot be used reliably to guide protective MV strategies or infer that VILI is not occurring. Using PaO2 to set a PEEP level necessary to stabilize the alveoli could underestimate the potential for VILI. These findings highlight the need for more accurate marker(s) of alveolar stability to guide protective MV necessary to prevent VILI.

Distal pancreatectomy and splenectomy: a robotic or LESS approach.

INTRODUCTION: The role and application of robotic surgery are debated, particularly given the expansion of laparoscopy, especially laparoendoscopic single-site (LESS) surgery. This cohort study was undertaken to delineate differences in outcomes between LESS and robotic distal pancreatectomy and splenectomy. METHODS: With Institutional Review Board approval, patients undergoing LESS or robotic distal pancreatectomy and splenectomy from September 1, 2012, through December 31, 2014, were prospectively observed, and data were collected. The results are expressed as the median, with the mean ± SD. RESULTS: Thirty-four patients underwent a minimally invasive distal pancreatectomy and splenectomy: 18 with robotic and 16 with LESS surgery. The patients were similar in sex, age, and body mass index. Conversions to open surgery and estimated blood loss were similar. There were two intraoperative complications in the group that underwent the robotic approach. Time spent in the operating room was significantly longer with the robot (297 vs 254 minutes, P = .03), although operative duration (i.e., incision to closure) was not longer (225 vs 190 minutes; P = .15). Of the operations studied, 79% were undertaken for neoplastic processes. Tumor size was 3.5 cm for both approaches; R0 resections were achieved in all patients. Length of stay was similar in the two study groups (5 vs 4 days). There was one 30-day readmission after robotic surgery. CONCLUSIONS: Patient outcomes are similar with LESS or robotic distal pancreatectomy and splenectomy. Robotic operations require more time in the operating room. Both are safe and efficacious minimally invasive operations that follow similar oncologic principles for similar tumors, and both should be in the surgeon's armamentarium for distal pancreatectomy and splenectomy.

Early application of airway pressure release ventilation may reduce mortality in high-risk trauma patients: a systematic review of observational trauma ARDS literature.

BACKGROUND: Adult respiratory distress syndrome is often refractory to treatment and develops after entering the health care system. This suggests an opportunity to prevent this syndrome before it develops. The objective of this study was to demonstrate that early application of airway pressure release ventilation in high-risk trauma patients reduces hospital mortality as compared with similarly injured patients on conventional ventilation. METHODS: Systematic review of observational data in patients who received conventional ventilation in other trauma centers were compared with patients treated with early airway pressure release ventilation in our trauma center. Relevant studies were identified in a PubMed and MEDLINE search from 1995 to 2012 and included prospective and retrospective observational and cohort studies enrolling 100 or more adult trauma patients with reported adult respiratory distress syndrome incidence and mortality data. RESULTS: Early airway pressure release ventilation as compared with the other trauma centers represented lower mean adult respiratory distress syndrome incidence (14.0% vs. 1.3%) and in-hospital mortality (14.1% vs. 3.9%). CONCLUSION: These data suggest that early airway pressure release ventilation may prevent progression of acute lung injury in high-risk trauma patients, reducing trauma-related adult respiratory distress syndrome mortality. LEVEL OF EVIDENCE: Systematic review, level IV.

Preemptive application of airway pressure release ventilation prevents development of acute respiratory distress syndrome in a rat traumatic hemorrhagic shock model.

BACKGROUND: Once established, the acute respiratory distress syndrome (ARDS) is highly resistant to treatment and retains a high mortality. We hypothesized that preemptive application of airway pressure release ventilation (APRV) in a rat model of trauma/hemorrhagic shock (T/HS) would prevent ARDS. METHODS: Rats were anesthetized, instrumented for hemodynamic monitoring, subjected to T/HS, and randomized into two groups: (a) volume cycled ventilation (VC) (n = 5, tidal volume 10 mL/kg; positive end-expiratory pressure 0.5 cmH(2)O) or (b) APRV (n = 4, P(high) = 15-20 cmH(2)O; T(high) = 1.3-1.5 s to achieve 90% of the total cycle time; T(low) = 0.11-0.14 s, which was set to 75% of the peak expiratory flow rate; P(low) = 0 cmH(2)O). Study duration was 6 h. RESULTS: Airway pressure release ventilation prevented lung injury as measured by PaO(2)/FIO(2) (VC 143.3 ± 42.4 vs. APRV 426.8 ± 26.9, P < 0.05), which correlated with a significant decrease in histopathology as compared with the VC group. In addition, APRV resulted in a significant decrease in bronchoalveolar lavage fluid total protein, increased surfactant protein B concentration, and an increase in epithelial cadherin tissue expression. In vivo microscopy demonstrated that APRV significantly improved alveolar patency and stability as compared with the VC group. CONCLUSIONS: Our findings demonstrate that preemptive mechanical ventilation with APRV attenuates the clinical and histologic lung injury associated with T/HS. The mechanism of injury prevention is related to preservation of alveolar epithelial and endothelial integrity. These data support our hypothesis that preemptive APRV, applied using published guidelines, can prevent the development of ARDS.

Early airway pressure release ventilation prevents ARDS-a novel preventive approach to lung injury.

Acute respiratory distress syndrome (ARDS) afflicts 200,000 patients annually with a mortality rate of 30% to 60% despite wide use of low tidal volume (LTV) ventilation, the present standard of care. High-permeability alveolar edema and instability occur early in the development of ARDS, before clinical signs of lung injury, and represent potential targets for therapy. We hypothesize that early application of a protective ventilation strategy (airway pressure release ventilation [APRV]) will stabilize alveoli and reduce alveolar edema, preventing the development of ARDS. Yorkshire pigs (30-40 kg) were anesthetized and subjected to two-hit injury: (a) intestinal ischemia-reperfusion, (b) peritoneal sepsis, or sham surgery. Following surgery, pigs were randomized into APRV (n = 4), according to current published guidelines for APRV; LTV ventilation (n = 3), using the current published ARDS Network guidelines (6 mL/kg); or sham (n = 5). The clinical care of all pigs was administered per the Surviving Sepsis Campaign guidelines. Animals were killed, and necropsy performed at 48 h. Arterial blood gases were measured to assess for the development of clinical lung injury. Lung tissue epithelial cadherin (E-cadherin) was measured to assess alveolar permeability. Bronchoalveolar lavage fluid (BALF) surfactant protein A was measured to assess alveolar stability. Lung edema content and histopathology were analyzed at 48 h. Airway pressure release ventilation pigs did not develop ARDS. In contrast, pigs in the LTV ventilation met ARDS criteria (PaO2/FIO2 ratio) (APRV: baseline = 471 ± 16; 48 h = 392 ± 8; vs. LTV ventilation: baseline = 551 ± 28; 48 h = 138 ± 88; P < 0.001). Airway pressure release ventilation preserved alveolar epithelial integrity demonstrated by higher levels of E-cadherin in lung tissue as compared with LTV ventilation (P < 0.05). Surfactant protein A levels were higher in BALF from the APRV group, suggesting APRV preserved alveolar stability. Quantitative histologic scoring showed improvements in all stigmata of ARDS in the APRV group versus the LTV ventilation (P < 0.05). Airway pressure release ventilation had significantly lower lung edema (wet-dry weight) than LTV ventilation (P < 0.05). Protective ventilation with APRV immediately following injury prevents development of ARDS. Reduction in lung edema, preservation of lung E-cadherin, and surfactant protein A abundance in BALF suggest that APRV attenuates lung permeability, edema, and surfactant degradation. Protective ventilation could change the clinical paradigm from supportive care for ARDS with LTV ventilation to preventing development of ARDS with APRV.

Early stabilizing alveolar ventilation prevents acute respiratory distress syndrome: a novel timing-based ventilatory intervention to avert lung injury.

BACKGROUND: Established acute respiratory distress syndrome (ARDS) is often refractory to treatment. Clinical trials have demonstrated modest treatment effects, and mortality remains high. Ventilator strategies must be developed to prevent ARDS. HYPOTHESIS: Early ventilatory intervention will block progression to ARDS if the ventilator mode (1) maintains alveolar stability and (2) reduces pulmonary edema formation. METHODS: Yorkshire pigs (38-45 kg) were anesthetized and subjected to a "two-hit" ischemia-reperfusion and peritoneal sepsis. After injury, animals were randomized into two groups: early preventative ventilation (airway pressure release ventilation [APRV]) versus nonpreventative ventilation (NPV) and followed for 48 hours. All animals received anesthesia, antibiotics, and fluid or vasopressor therapy as per the Surviving Sepsis Campaign. Titrated for optimal alveolar stability were the following ventilation parameters: (1) NPV group--tidal volume, 10 mL/kg + positive end-expiratory pressure - 5 cm/H2O volume-cycled mode; (2) APRV group--tidal volume, 10 to 15 mL/kg; high pressure, low pressure, time duration of inspiration (Thigh), and time duration of release phase (Tlow). Physiological data and plasma were collected throughout the 48-hour study period, followed by BAL and necropsy. RESULTS: APRV prevented the development of ARDS (p < 0.001 vs. NPV) by PaO2/FIO2 ratio. Quantitative histological scoring showed that APRV prevented lung tissue injury (p < 0.001 vs. NPV). Bronchoalveolar lavage fluid showed that APRV lowered total protein and interleukin 6 while preserving surfactant proteins A and B (p < 0.05 vs. NPV). APRV significantly lowered lung water (p < 0.001 vs. NPV). Plasma interleukin 6 concentrations were similar between groups. CONCLUSION: Early preventative mechanical ventilation with APRV blocked ARDS development, preserved surfactant proteins, and reduced pulmonary inflammation and edema despite systemic inflammation similar to NPV. These data suggest that early preventative ventilation strategies stabilizing alveoli and reducing pulmonary edema can attenuate ARDS after ischemia-reperfusion and sepsis.

The role of hyaluronic acid in atherosclerosis and intimal hyperplasia.

Atherosclerosis is a chronic inflammatory condition of the blood vessel wall that can lead to arterial narrowing and subsequent vascular compromise. Although there are a variety of open and endovascular procedures used to alleviate the obstructions caused by atherosclerotic plaque, blood vessel instrumentation itself can lead to renarrowing of the vessel lumen through intimal hyperplasia, wound contracture, or a combination of the two. While the cell types involved in both atherosclerosis and vessel renarrowing after surgical intervention are largely characterized, current research has shown that components of the extracellular matrix are also important in the pathogenesis of the aforementioned processes. One such component is hyaluronic acid (HA). The objective of this review, therefore, is to examine the involvement of HA in these pathologic processes. Literature on the structure and function of HA was reviewed, with particular attention given to the role of HA in the processes of atherogenesis, intimal hyperplasia, and wound contracture after blood vessel instrumentation. HA interacts with vascular smooth muscle cells (VSMCs), endothelial cells (ECs), and platelets to promote atherogenesis. In particular, VSMCs manufacture large amounts of HA that form "cable-like" structures important for leukocyte adhesion and rolling. Additionally, transmigration of leukocytes across the EC layer is mediated by HA. Platelets cleave large molecules of HA into fragments that up-regulate leukocyte production of chemokines and cytokines. HA also has a role in both intimal hyperplasia and wound contracture, the two processes most responsible for vessel renarrowing after vascular instrumentation. HA has a complex, and sometimes conflicting, role in the pathologic processes of atherogenesis and vessel wall renarrowing after surgical intervention.

Lung injury induced by sepsis: lessons learned from large animal models and future directions for treatment.

Acute lung injury (ALI) and the acute respiratory distress syndrome (ARDS) remain common complications of sepsis. Unfortunately, development of effective pharmacologic and ventilatory treatment strategies for sepsis-induced ALI/ARDS has not made significant progress over the past several decades. One of the major reasons for this conundrum involves the animal models used as platforms for testing new treatment strategies. High-fidelity, clinically translational, large animal models are essential for developing treatments that will ultimately be successful in human clinical trials. Additionally, treatment strategies purely based on pharmacologic intervention are largely destined for failure as the redundancies in the systemic inflammatory response largely negate the effectiveness of a single-action drug. Conversely, a treatment strategy based on the appropriate use of mechanical ventilation affects lung physiology on a breath-to-breath basis and has the potential to treat, and even prevent, the ALI/ARDS associated with sepsis.

Vascular smooth muscle cell migration induced by domains of thrombospondin-1 is differentially regulated.

BACKGROUND: Thrombospondin-1 (TSP-1) stimulates vascular smooth muscle cell (VSMC) migration via defined intracellular signaling pathways. The aim of this study was to examine the signaling pathways whereby TSP-1 folded domains (amino-terminal [NH(2)], procollagen homology [PCH], all 3 type 1 repeats [3TSR], and a single recombinant protein containing the 3rd type 2 repeat, the type 3 repeats, and the carboxyl-terminal [E3T3C1]) induce VSMC migration. METHODS: Quiescent VSMCs were pretreated with serum-free media or inhibitors: PP2 (c-Src), LY294002 (phosphatidylinositol 3-kinase), FPT (Ras), Y27632 (Rho kinase), SB202190 (p38 kinase), and PD98059 (extracellular signal-regulated kinase). Migration induced by serum-free media, TSP-1, NH(2), PCH, 3TSR, and E3T3C1 was assessed using a modified Boyden chamber. RESULTS: TSP-1, NH(2), 3TSR, and E3T3C1 induced VSMC chemotaxis (P < .05), but PCH did not (P > .05). PP2, FPT, SB202190, and PD98059 attenuated chemotaxis stimulated by TSP-1, NH(2), 3TSR, and E3T3C1 (P < .05). LY294002 inhibited TSP-1-induced and E3T3C1-induced (P < .05) but not NH(2)-induced or 3TSR-induced (P > .05) chemotaxis. Y27632 inhibited NH(2)-induced, 3TSR-induced, and E3T3C1-induced (P < .05) but not TSP-1-induced (P > .05) induced chemotaxis. CONCLUSIONS: TSP-1 folded domains are differentially dependent on intracellular signaling pathways to induce migration.

Jack of all trades: pleiotropy and the application of chemically modified tetracycline-3 in sepsis and the acute respiratory distress syndrome (ARDS).

Sepsis is a disease process that has humbled the medical profession for centuries with its resistance to therapy, relentless mortality, and pathophysiologic complexity. Despite 30 years of aggressive, concerted, well-resourced efforts the biomedical community has been unable to reduce the mortality of sepsis from 30%, nor the mortality of septic shock from greater than 50%. In the last decade only one new drug for sepsis has been brought to the market, drotrecogin alfa-activated (Xigris™), and the success of this drug has been limited by patient safety issues. Clearly a new agent is desperately needed. The advent of recombinant human immune modulators held promise but the outcomes of clinical trials using biologics that target single immune mediators have been disappointing. The complex pathophysiology of the systemic inflammatory response syndrome (SIRS) is self-amplifying and redundant at multiple levels. In this review we argue that perhaps pharmacologic therapy for sepsis will only be successful if it addresses this pathophysiologic complexity; the drug would have to be pleiotropic, working on many components of the inflammatory cascade at once. In this context, therapy that targets any single inflammatory mediator will not adequately address the complexity of SIRS. We propose that chemically modified tetracycline-3, CMT-3 (or COL-3), a non-antimicrobial modified tetracycline with pleiotropic anti-inflammatory properties, is an excellent agent for the management of sepsis and its associated complication of the acute respiratory distress syndrome (ARDS). The purpose of this review is threefold: (1) to examine the shortcomings of current approaches to treatment of sepsis and ARDS in light of their pathophysiology, (2) to explore the application of COL-3 in ARDS and sepsis, and finally (3) to elucidate the mechanisms of COL-3 that may have potential therapeutic benefit in ARDS and sepsis.

Outcome of lower extremity revascularization for peripheral artery occlusive disease: is there a difference between men and women?

The incidence of peripheral arterial occlusive disease (PAD) increases with age. Women represent a growing percentage of the elderly population who present with PAD. While speculation exists that gender affects outcome after revascularization procedures, the literature is confusing and often conflicting. This review compares outcomes by gender after open surgical and endovascular lower extremity revascularization (LER) procedures including: demographic differences, patency rates, limb salvage rates, long-term survival, perioperative complications and 30-day mortality. This review summarizes the existing data and discusses current influences on outcome after LER.