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During sepsis the normal induction of circulating insulin-like growth factor-I (IGF-I) by growth hormone (GH) action on liver is attenuated, a phenomenon called hepatic GH resistance. Hepatic GH resistance can be caused by cytokine-mediated activation of the NF-κB pathway which interferes with normal GH-signaling. The afferent and efferent fibers of the vagus nerve are integral to the cholinergic anti-inflammatory pathway (CAP) which attenuates hepatic TNFα production by activating the α7 nicotinic acetylcholine receptor (α7nAChR). We examined the effects of selective afferent vagotomy (SAV) and α7nAChR activation on sepsis-induced mortality, hepatic and systemic inflammation, the GH/IGF system and hepatic GH resistance using Sprague Dawley (SD) rats, C57BL/6 wild type (WT) mice, and α7nAChR knockout (KO) mice. Capsaicin was used to perform SAV and GTS-21 (α7nAChR agonist) was used to activate the α7nAChR. Sepsis-induced mortality, hepatic NF-κB activation, and plasma cytokine levels were increased in SAV rats and reduced in GTS-21-treated mice. The effects of sepsis on the GH/IGF-I system plasma IGF-I, IGF binding protein-1 (IGFBP-1), hepatic IGF-I, IGFBP-1, and GH receptor (GHR) mRNA and rhGH-responsiveness in mice were improved by GTS-21. Collectively these results confirm the protective effects of the anti-inflammatory CAP and α7nAChR activation in sepsis. They also provide evidence the CAP and α7nAChR activation could be used to attenuate hepatic GH resistance and anabolic failure in sepsis.

Targeting single mediators has failed to reduce the mortality of sepsis. We developed a telodendrimer (TD) nanotrap (NT) to capture various biomolecules via multivalent, hybrid and synergistic interactions. Here, we report that the immobilization of TD-NTs in size-exclusive hydrogel resins simultaneously adsorbs septic molecules, e.g. lipopolysaccharides (LPS), cytokines and damage- or pathogen-associated molecular patterns (DAMPs/PAMPs) from blood with high efficiency (92–99%). Distinct surface charges displayed on the majority of pro-inflammatory cytokines (negative) and anti-inflammatory cytokines (positive) allow for the selective capture via TD NTs with different charge moieties. The efficacy of NT therapies in murine sepsis is both time-dependent and charge-dependent. The combination of the optimized NT therapy with a moderate antibiotic treatment results in a 100% survival in severe septic mice by controlling both infection and hyperinflammation, whereas survival are only 50–60% with the individual therapies. Cytokine analysis, inflammatory gene activation and tissue histopathology strongly support the survival benefits of treatments., Sepsis is a difficult to treat condition. Here, the authors present a telodendrimer nanotrap that captures inflammator mediators to improve survival in combination with antibiotic treatment.

Background The recurrence rates and predictors of recurrence in patients with Solid Pseudopapillary tumors (SPT) are unclear, which makes it challenging to determine the duration of follow-up. The aim of the current study was to perform a systematic review and meta-analysis to determine the recurrence rates and pathologic factors associated with recurrence in patients with SPT. Methods A PubMed, Scopus, and Web of Science search was conducted to identify studies of SPT published during the last 15 years: (09/2002–09/2017). Studies reporting on patients with SPT and follow-up of >5 years were included. The search strategy was conducted per 2009 PRISMA guidelines. Results A total of 103 studies reporting on 2599 non-metastatic SPT patients were identified. Sixty-nine patients (2.6%) developed recurrence during follow-up. Pooled estimates from studies with a sample size >20 (N = 33) noted an overall recurrence rate of 2% (95% CI 1–2%). Male gender (OR 1.960), positive lymph nodes (OR 11.9), R1 margins (OR 11.1), and LVI (OR 5.5), were associated with a significantly (all p Conclusion Current meta-analysis suggests that only 2% of patients with SPT experience recurrence after resection. These data will guide the treating physicians and patients regarding recurrence rates and help identify patients at increased risk of recurrence during follow-up.

Background The ASA physical classification score has a major impact on the observed/expected (O/E) mortality ratio in the NSQIP General Vascular Mortality Model. The difference in predicted mortality is greatest between ASAs 3 and 4. We hypothesized under-classified ASA scores significantly affect the O/E mortality. Methods We conducted a retrospective review of NSQIP essential surgery cases from January 2014 to December 2014 (n = 1264) with mortality sub-analysis (n = 33) at our institution. We recorded transfer and emergency status and independently calculated the ASA score for mortalities using published definitions. A random sample of 50 survivors and 10 emergency survivors were reviewed and ASA recalculated. We performed statistical modeling to simulate the effects of ASA misclassifications. Statistical analysis was performed using JMP 10 and SAS 9.4. Results ASA was under-classified in 18.2% of mortalities, most commonly ASAs 3 and 4. Sixteen percent of ASA 3 survivors were misclassified, including 60% in the emergency subgroup (p

Background Hospital readmissions remain a major medical and financial concern to the healthcare system and have become an area of interest in health outcomes performance metrics. There is a pressing need to identify process measures that may help reduce readmissions. Objective Our aim was to assess the patient characteristics and surgical factors associated with 30-day readmissions for colorectal surgery in Upstate New York. Design This was a retrospective cohort study. Settings The study included colectomy cases abstracted for the National Surgical Quality Improvement Program in the Upstate New York Surgical Quality Initiative from June 2013 to June 2014. Patients The study consists of 630 colectomies. Patients with a length of stay >30 days or who died during the index admission were excluded. Main outcome measures Readmission within 30 days of surgery was the main outcome measure. Results Of 630 colectomy patients, 76 patients (12%) were readmitted within 30 days of surgery. Major and minor complications were associated with 30-day postoperative readmission (OR = 2.99 (95% CI, 1.70-5.28) and OR = 2.19 (95% CI, 1.09-4.43)) but excluded from final analysis because they included both predischarge and postdischarge complications. Risk factors independently associated with 30-day postoperative readmission included diabetes mellitus (OR = 1.94 (95% CI, 1.02-3.67)), smoker within the past year (OR = 2.01 (95% CI, 1.12-3.60)), no scheduled follow-up (OR = 2.20 (95% CI, 1.25-3.86)), and ileostomy formation (OR = 1.97 (95% CI, 1.03-3.77)). Limitations Limitations include the retrospective design and only 30 days of postoperative follow-up. Conclusions Consistent with national trends, 1 in 8 patients in the Upstate New York Surgical Quality Initiative program was readmitted within 30 days after colorectal surgery. This study identified several risk factors that may act as tangible targets for intervention, including preoperative smoking cessation programs, optimization of diabetic management, mandatory scheduled follow-up appointments on discharge, and ostomy care pathways.

Osteoclast-like giant cell tumor of the pancreas is very rare. We report a 78-year-old male who was previously treated for large mantle cell lymphoma, was found to have an increased uptake in a peri-pancreatic node from his restaging PET scan. Endoscopic ultrasound-directed fine-needle aspiration of the mass and lymph node revealed an undifferentiated carcinoma with osteoclast-like giant cells. Osteoclast-like giant cell tumors of the pancreas are frequently found to be unresectable at diagnosis due to their large size (>5 cm). In our patient, due to its small size (

Pneumonia and sepsis are major risk factors for acute kidney injury (AKI). Patients with pneumonia and AKI are at increased risk for morbidity and mortality. Surfactant protein D (SP-D) expressed in lung and kidney plays important roles in innate immunity. However, little is known about the role of organ-specific SP-D in the sepsis. The current study uses wild type (WT), SP-D knockout (KO), and humanized SP-D transgenic (hTG, lung-specific SP-D expression) mice to study organ-specific role of SP-D in pneumonia-induced sepsis. Analyses demonstrated differential lung and kidney injury among three-type mice infected with Pseudomonas aeruginosa. After infection, KO mice showed higher injurious scores in both lung and kidney, and decreased renal function than WT and hTG mice. hTG mice exhibited comparable lung injury but more severe kidney injury compared to WT mice. Increased renal tubular apoptosis, NF-κB activation and proinflammatory cytokines in the kidney of KO mice were found when compared with WT and hTG mice. Furthermore, in vitro primary proximal tubular epithelial cells from KO mice showed more apoptosis with higher level of activated caspase-3 than those from WT mice after LPS treatment. Collectively, SP-D attenuates AKI in the sepsis by modulating renal apoptosis, inflammation and NF-κB signaling.

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-1β), 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-1β were increased in BO and markedly increased in the FF group (P

Enteroendocrine L cells secrete the incretin hormone glucagon-like peptide-1 (GLP-1), and they also express the α7 nicotinic acetylcholine receptor (α7nAChR), which may regulate GLP-1 secretion. Here, GTS-21, a selective α7nAChR agonist, was used to examine the effect of α7nAChR activation in L-cell lines, mouse intestinal primary cell cultures, and C57BL/6 mice. GTS-21 stimulated GLP-1 secretion in vitro, and this effect was attenuated by an α7nAChR antagonist or by α7nAChR-specific small interfering RNA. Under in vitro cell culture conditions of glucotoxicity, GTS-21 restored GLP-1 secretion and improved L-cell viability while also acting in vivo to raise levels of circulating GLP-1 in mice. To assess potential signaling mechanisms underlying these actions of GTS-21, we first monitored Ca(2+), cAMP, and phosphatidylinositol 3-kinase (PI3K) activity. As expected for a GLP-1 secretagogue promoting Ca(2+) influx through α7nAChR cation channels, [Ca(2+)](i) increased in response to GTS-21, but [cAMP](i) was unchanged. Surprisingly, pharmacological inhibition of growth factor signaling pathways revealed that GTS-21 also acts on the PI3K–protein kinase B–mammalian target of rapamycin pathway to promote L-cell viability. Moreover, the Ca(2+) chelator BAPTA-AM counteracted GTS-21‒stimulated PI3K activity, thereby indicating unexpected crosstalk of L-cell Ca(2+) and growth factor signaling pathways. Collectively, these data demonstrate that α7nAChR activation enhances GLP-1 secretion by increasing levels of cytosolic Ca(2+) while also revealing Ca(2+)- and PI3K-dependent processes of α7nAChR activation that promote L-cell survival.

We sought to determine the time-course in androgen and semen parameters in men after weight loss associated with bariatric surgery with a prospective cohort study of 6 male subjects, age 18-40 years, meeting NIH bariatric surgery guidelines, conducted in 2005-2008, with study visits at baseline, then 1, 3, 6 and 12 months after surgery. All men had a Roux-en-y-Gastric-Bypass (RYGB) performed at Penn State Milton S. Hershey Medical Center. We collected at each visit biometric, questionnaire, serum, and urinary specimens as well as a semen analysis. Urinary integrated total testosterone levels increased significantly by 3 months after surgery, and remained elevated throughout the study. Circulating testosterone levels were also higher at 1 and 6 months after surgery, compared to baseline. Serum SHBG levels were significantly elevated at all time points post-operatively. After RYGB surgery, there were no significant changes in urinary estrogen metabolites (estrone 3-glucuronide) or serum estradiol levels, serial semen parameters, or male sexual function by questionnaire. This study supports the idea that a threshold of weight loss is necessary to improve male reproductive function by reversing male hypogonadism, manifested as increased testosterone levels. Further serial semen analysis results showed normal ranges for most parameters despite massive weight loss.

An 81-year-old man collapsed at home after complaining of left upper quadrant (LUQ) abdominal pain and presented to the local hospital. He was hypotensive on arrival, but stabilized with transfusion of 2 units of packed red blood cells. His abdominal examination was significant for LUQ tenderness with no signs of peritonitis. Abdominal CT scan (figure 1) revealed splenomegaly with grade 3 splenic injury and moderate hemoperitoneum. Blood work was significant for anemia and elevated creatinine (Cr 1.9 mg/dL). Spontaneous splenic rupture (SRS) was suspected and the patient was transferred to the nearest level 1 trauma center for management. Figure 1 Abdominal CT depicting splenic rupture. 1. Non-operative management (NOM). 2. Emergency splenectomy. 3. Splenic angioembolization (SAE). 4. Stabilization and laparoscopic total splenectomy. Correct answer D We stabilized the patient and performed a laparoscopic total splenectomy. The patient’s vital signs were normal on arrival, so he was monitored in the intensive care unit with plan for emergency splenectomy if he destabilized. His creatinine and hematocrit normalized, so he underwent laparoscopic hand-assisted splenectomy. Operative findings revealed splenomegaly with hemoperitoneum. The spleen was mobilized from its attachments, the splenic vessels were …

After being shot in the abdomen with a small caliber gun, a 16-year-old boy was transported to the emergency department (ED) in a private vehicle. On arrival to the ED, he was pale, tachycardic, and hypotensive. Intravenous access was obtained, and 1 L of saline and 2 units of packed red blood cells were given to stabilize the patient. Abdominal examination showed a subxiphoid entrance wound with no signs of peritonitis. No exit wound or other significant physical examination findings were noted. Focused Assessment with Sonography for Trauma (FAST) examination was negative for pericardial fluid but positive for minimal intra-abdominal fluid. Chest radiograph was negative for hemothorax and pneumothorax. His vital signs remained stable so he was taken for CT imaging. CT scan (figure 1) showed a linear laceration of the left hepatic lobe with the bullet trajectory passing through the supraceliac aorta. Irregularity of the aortic wall and extensive retroperitoneal hemorrhage surrounding the aorta were concerning for aortic injury, but no contrast extravasation was noted. A L1 vertebral …

A relationship between surgical volume and improved surgical outcomes has been described in gastric bypass patients but the relative importance of surgeon versus hospital volume is unknown. Our objective was to examine whether in-hospital and 30-day mortality are determined more by surgeon volume or hospital volume or whether each has an independent effect. A retrospective cohort study was performed of all hospitals in Pennsylvania providing gastric bypass surgery from 1999 to 2003.Data from the Pennsylvania Health Care Cost Containment Council included 14,714 gastric bypass procedures in patients aged18 years. In-hospital and 30-day mortality were stratified by hospital volume categories (high [≥300], medium [125-299], and low [125]) and surgeon volume categories (high [≥50] and low [50]). Multivariate analyses were performed using logistic regression analysis to control for patient demographics and severity.High-volume surgeons at high-volume hospitals had the lowest in-hospital mortality rates of all categories (.12%) and low-volume surgeons at low-volume hospitals had the poorest outcomes (.57%). The same trend was observed for 30-day mortality (.30% versus .98%). After controlling for other covariates, high-volume surgeons at high-volume hospitals also had significantly lower odds of both in-hospital (odds ratio 20, P = .002) and 30-day mortality (odds ratio .30, P = .001). This relationship held true even after excluding surgeons who only performed procedures within a single year.In Pennsylvania, both higher surgeon and hospital volume were associated with better outcomes for bariatric surgical procedures. Although a high-surgeon volume correlated with lowered mortality, we also found that high-volume hospitals demonstrated improved outcomes, highlighting the importance of factors other than surgical expertise in determining the outcomes.

The review focuses on current methodology for the most accurate way to determine resting metabolic rate in critically ill patients and to evaluate whether application of any particular method improves clinical outcome.Consensus is that indirect calorimetry is the most accurate method for determining resting metabolic rate. Whenever an alternate method of determining energy expenditure is tested (e.g. equations), the criterion method used in the validation is indirect calorimetry. Of the alternates to indirect calorimetry, the Penn State equation has the strongest validation work supporting it. No study has been undertaken to determine whether the drop in accuracy associated with estimation methods translates into deterioration in clinical outcome compared to nutrition support guided by measurements.Indirect calorimetry is the most accurate way to determine calorie needs in critically ill patients. Compared to indirect calorimetry, metabolic rate equations are accurate about 75% of the time. No study has been performed to determine whether the measurement or estimation method improves clinical outcome.

Background: Angiographic embolization (AE) has emerged as an important therapy for patients with nonvariceal upper gastrointestinal bleeding (UGIB). We hypothesized that discrete factors predictive of AE failure could be identified. Methods: A retrospective review was performed for patients with nonvariceal UGIB who underwent AE from 1999 to 2009 at Penn State Milton S. Hershey Medical Center. AE clinical failure was defined as requirement for another intervention (surgery, endoscopic therapy, or another AE) for nonvariceal UGIB and/or death from bleeding after AE. Statistical analysis was performed using Fisher's exact test and Student's t test to explore the risk of AE failure. Results: Of 48 total AE cases, 17 patients (35.4%) had clinically failed AE. Mortality rate was significantly higher in patients with AE clinical failure than in patients with AE clinical success (64.7% vs. 12.9%, p = 0.001). Factors associated with AE clinical failure include anticoagulant use before admission (p = 0.001), use of corticosteroids before admission (p = 0.045), pre-AE vasopressor use (p = 0.038), and embolization using either coils alone (p = 0.05) or using coils with or without additional embolic materials (p = 0.018). Conclusions: AE clinical failure portends poor prognosis. Caution should be exercised when considering AE, particularly AE using coils, in patients with a history of anticoagulant, corticosteroid, or vasopressor use.

The present study determined whether the muscle atrophy produced by colitis is associated with altered rates of muscle protein synthesis or degradation, as well as the potential role of the local (eg, muscle) insulin-like growth factor (IGF) system and muscle-specific ubiquitin E3 ligases atrogin-1 and MuRF1 in mediating altered muscle protein balance. Colitis was induced in C57BL/6 mice by intrarectal administration of trinitrobenzene sulfonic acid (TNBS), and blood and tissues were collected on day 10. Mice with inflammatory bowel disease demonstrated reduced skeletal muscle mass and protein content, whereas colonic segment weight and gross damage score were both increased in mice with colitis, compared with time-matched control values. There was no change in muscle protein synthesis in mice with inflammatory bowel disease; but there was an increased protein breakdown (45%), proteasome activity (85%), and messenger RNA (mRNA) expression for atrogin-1 and MuRF1 (200%-300%) in muscle. These changes were associated with a reduction in liver (but not muscle) IGF-I mRNA as well as a reduction in both total and free IGF-I in the blood. Colitis decreased the hepatic content of IGF binding protein (IGFBP)-3 mRNA by 40% and increased IGFBP-1 mRNA by 100%. In contrast, colitis did alter IGFBP mRNAs in muscle. The tumor necrosis factor-α, interleukin-6, and nitric oxide synthase 2 mRNA content of both liver and skeletal muscle was increased in TNBS-treated mice; and plasma tumor necrosis factor-α and interleukin-6 concentrations were also elevated. These data suggest that TNBS-induced colitis is independent of a change in muscle protein synthesis but dependent on stimulation of protein degradation via increased expression of muscle-specific atrogenes, which may be mediated in part by the reduction in circulating concentration of IGF-I and the concomitant increase in inflammatory mediators observed in the blood and muscle per se.

Revisional bariatric surgery (RBS) outcomes have been poorly characterized. We compared the RBS and primary bariatric surgery (PBS) outcomes at the Penn State Milton S. Hershey Medical Center in the United States.A total of 72 RBS cases from 2000 to 2007 were reviewed and grouped by indication: failure of weight loss, gastrojejunal complications, or other. The RBS patients were compared with the 856 PBS patients who underwent Roux-en-Y gastric bypass. The mean follow-up time was 12.6 ± 1.2 months for the RBS group and 16 ± 0.5 months for the PBS group. Weight loss was analyzed as the kilograms lost and patients with ≥ 50% excess body weight loss (EBWL). Outcomes included mortality, leaks, surgical site infections, and length of stay.The weight loss was 23 ± 2.8 kg after RBS and 41.3 ± 0.7 kg after PBS (P.05 versus PBS). The post-RBS weight loss varied by surgical indication: failure of weight loss, 27.1 ± 2 kg; gastrojejunal complications, 8.7 ± 3.4 kg; and other 23.5 ± 10.6 kg. Also, 29% of the RBS patients had ≥ 50% excess body weight loss (versus the prerevision weight) and 61% (versus the initial weight) compared with 52.7% after PBS. Only age ≤ 50 years was associated with ≥ 50% excess body weight loss after RBS for the failure of weight loss group. No RBS patients died. However, leaks, surgical site infections, and length of stay were increased after RBS.The results of our study have shown that weight loss after RBS varies with the surgical indication and is affected by age50 years. Although the RBS patients had decreased weight loss and increased complications compared with the PBS patients, ≥ 50% EBWL was achieved by a significant number of RBS patients.

Roux-en-Y gastric bypass surgery (GBS) is the most effective treatment for morbid obesity. GBS is a restrictive malabsorptive procedure, but many patients also report altered taste preferences. This study investigated the effects of GBS or a sham operation (SH) on body weight, glucose tolerance, and behavioral and neuronal taste functions in the obese Otsuka Long-Evans Tokushima Fatty (OLETF) rats lacking CCK-1 receptors and lean controls (LETO). OLETF-GBS rats lost body weight (−26%) and demonstrated improved glucose tolerance. They also expressed a reduction in 24-h two-bottle preference for sucrose (0.3 and 1.0 M) and decreased 10-s lick responses for sucrose (0.3 through 1.5 M) compared with OLETF-SH or LETO-GBS. A similar effect was noted for other sweet compounds but not for salty, sour, or bitter tastants. In lean rats, GBS did not alter responses to any stimulus tested. Extracellular recordings from 170 taste-responsive neurons of the pontine parabrachial nucleus revealed a rightward shift in concentration responses to oral sucrose in obese compared with lean rats (OLETF-SH vs. LETO-SH): overall increased response magnitudes (above 0.9 M), and maximum responses occurring at higher concentrations (+0.46 M). These effects were reversed by GBS, and neural responses in OLETF-GBS were statistically not different from those in any LETO groups. These findings confirm obesity-related alterations in taste functions and demonstrate the ability of GBS to alleviate these impairments. Furthermore, the beneficial effects of GBS appear to be independent of CCK-1 receptor signaling. An understanding of the underlying mechanisms for reduced preferences for sweet taste could help in developing less invasive treatments for obesity.

The hindgut hypothesis posits improvements in Type 2 diabetes after gastric bypass surgery are due to enhanced delivery of undigested nutrients to the ileum, which increase incretin production and insulin sensitivity. The present study investigates the effect of ileal interposition (IT), surgically relocating a segment of distal ileum to the proximal jejunum, on glucose tolerance, insulin sensitivity, and glucose transport in the obese Zucker rat. Two groups of obese Zucker rats were studied: IT and sham surgery ad libitum fed (controls). Changes in food intake, body weight and composition, glucose tolerance, insulin sensitivity and tissue glucose uptake, and insulin signaling as well as plasma concentrations of glucagon-like peptide-1 and glucose-dependent insulinotropic peptide were measured. The IT procedure did not significantly alter food intake, body weight, or composition. Obese Zucker rats demonstrated improved glucose tolerance 3 wk after IT compared with the control group ( P < 0.05). Euglycemic, hyperinsulinemic clamp and 1-[14C]-2-deoxyglucose tracer studies indicate that IT improves whole body glucose disposal, insulin-stimulated glucose uptake, and the ratio of phospho- to total Akt ( P < 0.01 vs. control) in striated muscle. After oral glucose, the plasma concentration of glucagon-like peptide-1 was increased, whereas GIP was decreased following IT. Enhanced nutrient delivery to the ileum after IT improves glucose tolerance, insulin sensitivity and muscle glucose uptake without altering food intake, body weight, or composition. These findings support the concept that anatomic and endocrine alterations in gut function play a role in the improvements in glucose homeostasis after the IT procedure.

Gastrogastric fistula (GGF) is a known complication of gastric bypass surgery. Revisional surgery for GGF repair can be technically challenging. We describe our experience with endoscopic repair of small GGFs. A retrospective review was performed to identify patients in whom symptomatic GGF was repaired endoscopically at our institution between September 2004 and September 2008. At endoscopy, the fistulous margins were debrided using cold biopsy forceps or ablated using Argon Plasma Coagulation (APC). The fistula was then repaired with endoclips. Status of GGF repair was assessed intra-operatively, at 2 weeks by upper gastrointestinal (UGI) series, and at regular follow-up thereafter. GGF repair was attempted in eight female patients (mean age = 47 years). The average time interval between gastric bypass surgery and GGF presentation was 81 months. The presenting symptoms included nausea, vomiting, abdominal pain, and weight regain. The average duration of endoscopic procedure was 55 min. All GGFs were small (

The metabolic effects of Roux-en-Y gastric bypass (RYGB) are caused by postsurgical changes in gastrointestinal anatomy affecting gut function. Glutamine is a critical gut nutrient implicated in regulating glucose metabolism as a substrate for intestinal gluconeogenesis. The present study examines the effects of obesity and RYGB on intestinal glutamine transport and metabolism. First, lean and obese Zucker rats (ZRs) were compared. Then the effects of RYGB and sham surgery with pair feeding (PF) in obese ZRs were studied. Segments of small intestine (biliopancreatic limb, Roux limb, and common channel) mucosa were harvested and brush border membrane vesicles (BBMVs) were isolated on postoperative day 28. Glutamine transporter activity and abundance, B0AT1 protein, and mRNA levels were measured. Levels of glutaminase, cytosolic phosphoenolpyruvate carboxykinase (PEPCK-C), and glucose-6-phosphatase (G6Pase) were measured to assess glutamine metabolism and intestinal gluconeogenesis. Obesity increased glutamine transport and B0AT1 expression throughout the intestine. RYGB increased glutamine transport activity in the biliopancreatic (3.8-fold) and Roux limbs (1.4-fold) but had no effect on the common channel. The relative abundance of B0AT1 mRNA and protein were increased in the biliopancreatic (6-fold) and Roux limbs (10-fold) after RYGB ( P < 0.05 vs. PF), but not the common channel. Glutaminase levels were increased, whereas the relative abundance of PEPCK-C and G6Pase were decreased in all segments of intestine after RYGB. RYGB selectively increased glutamine absorption in biliopancreatic and Roux limbs by a mechanism involving increased B0AT1 expression. Post-RYGB glutaminase levels were increased, but the reductions in PEPCK-C and G6Pase suggest that RYGB downregulates intestinal gluconeogenesis.

Roux-en-Y gastric bypass surgery (RYGBP) leads to improvements in satiety and obesity-related comorbidities. The mechanism(s) underlying these improvements are not known but may be revealed in part by discovery proteomics. Therefore, fasting plasma was collected from 12 subjects (mean BMI45) during RYGBP and during a second procedure approximately 17 months later. Body weight, obesity-related comorbidities, and medication use were decreased after RYGBP. Mass spectrometry-based proteomic analysis was performed on a subset of seven samples using isobaric isotope-coded affinity tags (four plex iTRAQ). Initial proteomic analysis (n = 7) quantified and identified hundreds of plasma proteins. Manual inspection of the data revealed a 2.6 +/- 0.5-fold increase in apolipoprotein A-IV (apo A-IV, gene designation: APOA4), a approximately 46-kDa glycoprotein synthesized mainly in the bypassed small bowel and liver after RYGBP. The change in apo A-IV was significantly greater than other apolipoproteins. Immunoblot analysis of the full longitudinal sample set (n = 12) indicated even higher increases (8.3 +/- 0.2 fold) in apo A-IV. Thus iTRAQ may underestimate the changes in protein concentrations compared to western blotting of apo A-IV. Apo A-IV inhibits gastric emptying and serves as a satiety factor whose synthesis and secretion are increased by the ingestion of dietary fat. It also possesses anti-inflammatory and antiatherogenic properties. Based on these functions, we speculate changes in apo A-IV may contribute to weight loss as well as the improvements in inflammation and cardiovascular disease after RYGBP. In addition, the findings provide evidence validating the use of iTRAQ proteomics in discovery-based studies of post-RYGBP improvements in obesity-related medical comorbidities.

Background The regionalization of trauma care, the Emergency Medical Treatment and Active Labor Act of 1986, the advent of Accountable Care Organizations and bundled payments have brought Level 1 trauma centers (TC) to a new crossroads. By protocol, injured patients are preferentially transferred to designated TCs when a higher level of care is indicated. Trauma transfers frequently come during off hours and may not always appear to be related to injury severity. Based on this observation, we hypothesized patients transferred from regional hospitals to Level 1 TCs would have lower injury severity scores (ISS) and unfavorable payor status. Methods We queried our TC registry to identify trauma transfers (TTP) and primary trauma patients (PTP) treated at our level 1 TC between 2004 and 2012. Demographics, payor status, length of stay (LOS), injury severity score (ISS), and discharging service were compared. Results 5699 TTP and 11147 PTP were identified. Uninsured patients comprised 11 % (n = 602) of TTP compared with 15 % (n = 1,721) of PTP (P

Sepsis causes multiple-organ dysfunction including pancreatic injury, thus resulting in high mortality. Innate immune molecule surfactant protein D (SP-D) plays a critical role in host defense and regulating inflammation of infectious diseases. In this study we investigated SP-D functions in the acute pancreatic injury (API) with C57BL/6 Wild-type (WT) and SP-D knockout (KO) mice in cecal ligation and puncture (CLP) model. Our results confirm SP-D expression in pancreatic islets and intercalated ducts and are the first to explore the role of pancreatic SP-D in sepsis. CLP decreased pancreatic SP-D levels and caused severe pancreatic injury with higher serum amylase 24 h after CLP. Apoptosis and neutrophil infiltration were increased in the pancreas of septic KO mice (p in vitro islet cultures stimulated with LPS produced higher TNF-α and IL-6 (p

Background: When angiography is performed in all hemodynamically normal patients with splenic injury, only 30% require embolization. This study examines the use of selective splenic angioembolization (SAE) as part of a management algorithm for adult splenic injury. Methods: Criteria for selective SAE were added to our adult splenic injury protocol in July 1999. SAE was performed in hemodynamically stable patients if computed tomographic (CT) scan revealed injury to the hilum or vascular blush and when nonoperative patients had a gradual decrease in hematocrit. Patients were grouped by management strategy: nonoperative; operative; or SAE. Demographics, injury severity, and outcomes of the different groups were compared. Medical records, CT scans, and registry data were reviewed for all SAE cases, deaths, and treatment failures. Data are means ± SE.p < 0.05 versus nonoperative management by analysis of variance. Results: From July 1999 to August 2003, 194 adults were treated for splenic injury. Nine patients underwent SAE, six for CT findings (1° vascular blush) and three for decreasing hematocrit. Three patients failed SAE (33%), one for bleeding and two for delayed splenic infarction. Eleven patients failed nonoperative therapy (8%); splenorrhaphy was performed in three and splenectomy in eight. Operative patients were more seriously injured and had higher Injury Severity Scores and mortality; splenectomy (39 of 48) was more commonly performed than splenorrhaphy (9 of 48) in this group. Conclusion: Use of a splenic injury algorithm is associated with a high success rate for nonoperative management of splenic trauma. Using selective criteria, only 5% of patients were treated with SAE. SAE salvaged six patients with high-grade splenic injury or decreasing hematocrit but had a 33% failure rate. Failure of nonoperative management was most commonly caused by errors in judgment, primarily recognition of high-risk injury patterns on CT scan or attempting nonoperative management in anticoagulated or coagulopathic patients.

BACKGROUND: Indirect calorimetry is the criterion method for determining resting metabolic rate for nutrition support in critically ill patients. However, calculation equations are more commonly used. In the current study we tested the validity of 2 such calculation systems. METHODS: Indirect calorimetry was performed with an open-circuit device in mechanically ventilated surgical, trauma, and medical patients at rest. Feedings were not stopped for the measurements. Two predictive equations by Ireton-Jones and 3 versions of a multivariate equation developed at our institution (referred to as Penn State equations) were then used to estimate resting metabolic rate. These estimates were compared on a percentage basis with the measured value of resting metabolic rate. Estimated resting metabolic rate within 10% of measured was considered accurate, whereas estimations >15% different from measured were considered large errors. RESULTS: Forty-seven subjects were measured. A larger percentage of subjects were est...

To evaluate several equations for predicting resting metabolic rate against measured values in obese and nonobese people.Resting metabolic rate was measured with indirect calorimetry. Four calculation standards using various combinations of weight, height, and age were used to predict resting metabolic rate: a) Harris-Benedict equation, b) Harris-Benedict equation using adjusted body weight in obese individuals, c) Owen, and d) Mifflin. Main outcome was percentage of subjects whose calculated metabolic rate was outside a +/-10% limit from measured values. Subjects/Setting 130 nonhospitalized adult volunteers grouped by degree of obesity (range of body mass index, 18.8 to 96.8). Statistical Analysis Performed Analysis of proportions was used to determine differences in the percentage of subjects estimated accurately by each equation; alpha was set at 0.05.Calculated resting metabolic rate was more than 10% different from measured in 22% of subjects using the Mifflin equation, 33% using the Harris-Benedict equation (P=.05 vs Mifflin), and 35% using the Owen equation (P.05 vs Mifflin). The error rate using Harris-Benedict with adjusted weight in obesity was 74% (vs 36% in obese subjects using actual weight in the standard Harris-Benedict equation).Of the calculation standards tested, the Mifflin standard provided an accurate estimate of actual resting metabolic rate in the largest percentage of nonobese and obese individuals and therefore deserves consideration as the standard for calculating resting metabolic rate in obese and nonobese adults. Use of adjusted body weight in the Harris-Benedict equation led to less overestimation by that equation in obese people at the expense of increased incidence of underestimation.

Background Roux-en-Y gastric bypass (RYGB) surgery is a very effective bariatric procedure to achieve significant and sustained weight loss, yet little is known about the procedure’s impact on the brain. This study examined the effects of RYGB on the brain’s response to the anticipation of highly palatable versus regular food. Methods High fat diet-induced obese rats underwent RYGB or sham operation and were then tested for conditioned place preference (CPP) for the bacon-paired chamber, relative to the chow-paired chamber. After CPP, animals were placed in either chamber without the food stimulus, and brain-glucose metabolism (BGluM) was measured using positron emission tomography (μPET). Results Bacon CPP was only observed in RYGB rats that had stable weight loss following surgery. BGluM assessment revealed that RYGB selectively activated regions of the right and midline cerebellum (Lob 8) involved in subjective processes related to reward or expectation. Also, bacon anticipation led to significant activation in the medial parabrachial nuclei (important in gustatory processing) and dorsomedial tegmental area (key to reward, motivation, cognition and addiction) in RYGB rats; and activation in the retrosplenial cortex (default mode network), and the primary visual cortex in control rats. Conclusions RYGB alters brain activity in areas involved in reward expectation and sensory (taste) processing when anticipating a palatable fatty food. Thus, RYGB may lead to changes in brain activity in regions that process reward and taste-related behaviors. Specific cerebellar regions with altered metabolism following RYGB may help identify novel therapeutic targets for treatment of obesity.

Sepsis is a major cause of acute kidney injury (AKI) with high rates of morbidity and mortality. Surfactant proteins A and D (SP-A, SP-D) play a critical role in host defense and regulate inflammation during infection. Recent studies indicate SP-A and SP-D are expressed in the kidney. The current study examines the role of SP-A and SP-D in the pathogenesis of sepsis-induced AKI. Wild-type (WT) and SP-A/SP-D double-knockout (KO) C57BL/6 mice were treated by cecal ligation and puncture (CLP) or sham surgery. Histological, cellular, and molecular indices of kidney injury were investigated in septic mice 6 and 24 h after CLP. Twenty-four hours after CLP, kidney injury was more severe, renal function was decreased, and blood creatinine and blood urea nitrogen were higher in septic SP-A/SP-D KO mice (P < 0.05, versus septic WT mice). Kidney edema and vascular permeability were increased in septic SP-A/SP-D KO mice (P < 0.01, versus septic WT mice). Apoptotic cells increased significantly (P < 0.01) in the kidney of septic SP-A/SP-D KO mice compared with septic WT mice. Molecular analysis revealed levels of Bcl-2 (an inhibitor of apoptosis) were lower and levels of caspase 3 (a biomarker of apoptosis) were higher in the kidney of septic SP-A/SP-D KO mice (P < 0.01, versus septic WT mice). Furthermore, levels of nuclear factor κB and phosphorylated IκB-α increased significantly in the kidney of septic SP-A/SP-D KO mice compared with septic WT mice, suggesting SP-A/SP-D KO mice have a more pronounced inflammatory response to sepsis. We conclude SP-A and SP-D attenuate kidney injury by modulating inflammation and apoptosis in sepsis-induced AKI.

Many preclinical studies in critical care medicine and related disciplines rely on hypothesis-driven research in mice. The underlying premise posits that mice sufficiently emulate numerous pathophysiological alterations produced by trauma/sepsis and can serve as an experimental platform for answering clinically relevant questions. Recently the lay press severely criticized the translational relevance of mouse models in critical care medicine. A series of provocative editorials were elicited by a highly-publicized research report in the Proceedings of the National Academy of Sciences (PNAS; February 2013), which identified an unrecognized gene expression profile mismatch between human and murine leukocytes following burn/trauma/endotoxemia. Based on their data, the authors concluded that mouse models of trauma/inflammation are unsuitable for studying corresponding human conditions. We believe this conclusion was not justified. In conjunction with resulting negative commentary in the popular press, it can seriously jeopardize future basic research in critical care medicine. We will address some limitations of that PNAS report to provide a framework for discussing its conclusions and attempt to present a balanced summary of strengths/weaknesses of use of mouse models. While many investigators agree that animal research is a central component for improved patient outcomes, it is important to acknowledge known limitations in clinical translation from mouse to man. The scientific community is responsible to discuss valid limitations without over-interpretation. Hopefully a balanced view of the strengths/weaknesses of using animals for trauma/endotoxemia/critical care research will not result in hasty discount of the clear need for using animals to advance treatment of critically ill patients.

Background: Computerized human patient simulators (HPSs) have been used to improve diagnostic and therapeutic decision making. The goal of this study was to investigate the impact of HPSs and Advanced Trauma Life Support (ATLS) on the development of trauma management skills and self-confidence in surgical interns. Methods: Three teams of interns completed two ATLS-like trauma scenarios on the HPS (pre-ATLS). They then took the ATLS provider course. After ATLS, the interns were evaluated on two different HPS trauma scenarios (post-ATLS). Two teams of senior residents, experienced in trauma care, completed the same HPS scenarios and were used as controls. Trauma management skills were scored in three areas-critical treatment decisions, potential for adverse outcomes, and team behavior-by staff trauma surgeons. After participating in the HPS trauma scenarios, the interns completed self-confidence questionnaires and a course evaluation survey. Results: Trauma management skill scores increased 23% in critical treatment decisions, 25% in potential for adverse outcomes, and 47% in team behavior after ATLS/HPS (p < 0.002). Senior residents' performance on HPS trauma scenarios was better than the interns (p < 0.05) in all three areas evaluated. The interns' self-confidence scores rose significantly after the course. (p < 0.01) The HPS course evaluation survey averaged 8.3 out of a maximum 10. Conclusion: Use of HPSs in conjunction with ATLS appears to enhance the development of trauma management skills. The surgical interns participating in the study deemed the HPS to be a worthwhile experience and a confidence-building tool. In particular, trauma team behavior improved significantly after ATLS/HPS.

Chronic abdominal sepsis is associated with impaired tissue repair. Treatment of burn patients with growth hormone results in improved healing of skin graft donor sites. The goal of this study was to determine whether administration of growth hormone could attenuate the inhibitory effects of sepsis on cutaneous wound healing. Four groups of male Sprague Dawley rats were studied: control, control + growth hormone, sepsis, and sepsis + growth hormone. Sepsis was caused by implantation of a bacterial focus in the peritoneal cavity. Control animals underwent sham laparotomy, and polyvinyl alcohol sponge implants were placed in subdermal pockets in all animals. Saline or growth hormone (400 μg) was injected subcutaneously every 12 hours. On day 5, the incisional wounds and polyvinyl alcohol sponge implants were harvested. The breaking strength of abdominal incisions was measured. Granulation tissue penetration and quality were determined by scoring polyvinyl alcohol sponge implant histology from 1 to 4 in a blinded fashion. Collagen deposition in polyvinyl alcohol sponge implants was quantitated by hydroxyproline assay. Septic mortality was not altered by growth hormone administration. Septic animals showed a reduction in food consumption for 2 days after surgery (p < 0.05 vs. controls), which was not affected by growth hormone administration. The breaking strength of incisional wounds and hydroxyproline content of polyvinyl alcohol sponge implants was reduced in septic rats (p < 0.001 vs. controls) but administration of growth hormone for 5 days did not improve breaking strength or collagen deposition in either group. We conclude that the administration of growth hormone for 5 days did not improve collagen deposition or breaking strength in cutaneous wounds from control or septic animals. The results suggest that growth hormone treatment is unlikely to improve tissue repair in sepsis-induced catabolic illness.

The present study examined whether administration in vivo of a maximally stimulating dose of growth hormone (GH) was capable of modulating selected aspects of the GH-insulin-like growth factor (IGF) system to the same extent in alcohol-fed and control animals. Rats were maintained on an alcohol-containing diet for 14 weeks, while control animals were fed isocalorically. After surgical implantation of a catheter in the carotid artery, rats were starved overnight. The next morning, rats were injected with recombinant human GH (500 microg/kg, s.c.) or an equal volume of saline at time 0 and 12 h. Blood samples were collected prior to GH and at 6, 12 and 24 h thereafter; tissues were collected at the end of the study. Time-matched control and alcohol-fed rats not receiving GH were also included. Although the plasma concentrations of both total and free IGF-I were decreased 30-40% in alcohol-fed rats, the ability of GH to elevate circulating IGF-I was not diminished. GH was equally effective at increasing IGF-I peptide levels in both liver and skeletal muscle. GH also produced comparable increases in IGF-I mRNA in muscle in both groups. Hepatic GH receptor (GHR) peptide levels were not significantly altered by either alcohol or GH. Alcohol feeding decreased plasma levels of IGF binding protein (IGFBP)-3 and increased IGFBP-1, and GH did not significantly alter this profile. Hepatic expression of suppressor of cytokine signalling (SOCS-3) mRNA was not different between the groups. However, SOCS-3 mRNA was increased by approximately 50% in control animals in response to GH, but remained unchanged in alcohol-fed rats. These data indicate that the decrease in hepatic IGF-I synthesis and plasma IGF-I observed in alcohol-fed rats was independent of a change in GHR levels. In contrast, the ability of a maximally stimulating dose of GH to modulate selected biological responses in vivo was not impaired by chronic alcohol consumption and was associated with a lack of a GH-induced increase in SOCS-3 mRNA.

BACKGROUND Tumor necrosis factor (TNF) is an important mediator of impaired wound healing during sepsis. To determine whether the inhibitory effects of systemic TNF on wound healing are mediated directly by TNF or by means of the induction of interleukin-1 (IL-1), we investigated the effects of TNF and interleukin- receptor antagonist (IL-1ra) on wound healing in healthy rats. METHODS Male Sprague-Dawley rats were anesthetized, and jugular catheters were placed. After recovery of 48 hours, osmotic minipumps were inserted into the peritoneal cavity and polyvinyl alcohol implants were placed subcutaneously. Control rats were infused with saline (24 microL/day, i.p., and 15 mL/day, i.v.). TNF rats received TNF i.p. (100 microg/kg per day) and saline i.v. (15 mL/day). TNF+IL-1ra rats received TNF i.p. (100 microg/kg per day) and IL-1ra i.v. (2 mg/kg per day;15 mL/day). All animals were pair fed to the TNF group. On day 6, the wounds were harvested. The breaking strength of the abdominal incision was measured. Granulation tissue penetration and quality were determined by scoring polyvinyl alcohol implant histology from 1 to 4 in a blinded manner. Collagen deposition in polyvinyl alcohol implants was quantified by hydroxyproline assay. RESULTS TNF decreased the breaking strength of incisional wounds to 40% of control levels (p < 0.001). IL-1ra restored the breaking strength of incisions from TNF-infused animals to 80% of control levels. Similar reductions in granulation tissue penetration, quality, and hydroxyproline content were observed in TNF-treated animals and were partially ameliorated by IL-1ra. CONCLUSION IL-1ra significantly attenuates the inhibitory effects of systemic TNF on wound healing. These results suggest that the inhibitory effects of TNF on cutaneous tissue repair are mediated in part by IL-1.

Chronic interleukin (IL)-1 administration is associated with negative nitrogen balance and the loss of lean body mass. To elucidate the molecular mechanism(s) by which IL-1 modulates protein metabolism in muscle, we investigated the effects of chronic (6 day) IL-1alpha infusion on protein synthesis in Individual muscles (gastrocnemius, soleus, heart) compared with saline-infused control rats. IL-1 significantly decreased muscle weight, protein content, and the rate of protein synthesis in gastrocnemius (fast-twitch muscle). IL-1 had no effect on these parameters in the heart, whereas only the rate of protein synthesis was reduced in soleus (slow-twitch muscle). The reduction in gastrocnemius protein synthesis was not the result of a decrease in total RNA content, but was associated with a diminished translational efficiency. The diminished translational efficiency correlated with a 40% reduction in the epsilon-subunit of eukaryotic initiation factor 2B (elF2Bepsilon) in gastrocnemius from IL-1 -treated animals. However, the content of the alpha-subunit of elF2 (elF2alpha) was unaffected. In contrast, the elF2alpha content in heart was increased by IL-1, although elF2Bepsilon levels were unchanged. Reductions in skeletal muscle protein synthesis were not associated with a concomitant reduction in circulating or tissue content of insulin-like growth factor I. In summary, the IL-1-induced decrease in gastrocnemius protein synthesis appears to be regulated at the level of RNA translation via a reduction in elF2Bepsilon. These findings support a regulatory role for IL-1 as a mediator of muscle protein synthesis and the alterations in body composition observed in catabolic states where this cytokine is overexpressed.

We examined the effects of TNF-binding protein (TNFBP) on regulatory mechanisms of muscle protein synthesis during sepsis in four groups of rats: Control; Control+TNFBP; Septic; and Septic+TNFBP. Saline (1.0 ml) or TNFBP (1 mg/kg, 1.0 ml) was injected daily starting 4 h before the induction of sepsis. The effect of TNFBP on gastrocnemius weight, protein content, and the rate of protein synthesis was examined 5 days later. Sepsis reduced the rate of protein synthesis by 35% relative to controls by depressing translational efficiency. Decreases in protein synthesis were accompanied by similar reductions in protein content and muscle weight. Treatment of septic animals with TNFBP for 5 days prevented the sepsis-induced inhibition of protein synthesis and restored translational efficiency to control values. TNFBP treatment of Control rats for 5 days was without effect on muscle protein content or protein synthesis. We also assessed potential mechanisms regulating translational efficiency. The phosphorylation state of p70S6 kinase was not altered by sepsis. Sepsis reduced the gastrocnemius content of eukaryotic initiation factor 2Bε (eIF2Bε), but not eIF2α. The decrease in eIF2Bε content was prevented by treatment of septic rats with TNFBP. TNFBP ameliorates the sepsis-induced changes in protein metabolism in gastrocnemius, indicating a role for TNF in the septic process. The data suggest that TNF may impair muscle protein synthesis by reducing expression of specific initiation factors during sepsis.

Background. Hyperlactatemia is a metabolic complication of hypermetabolic, hyperdynamic sepsis. An important mechanism responsible for elevating plasma lactate concentrations in sepsis is altered regulation of the pyruvate dehydrogenase complex (PDH) in skeletal muscle. We investigated the ability of a specific tumor necrosis factor binding protein, TNFbp, to modulate lactate concentrations and skeletal muscle PDH activity in a rodent model of chronic abdominal sepsis. Materials and methods. We examined the regulation of lactate metabolism in four groups of animals: Control, Control + TNFbp, Septic, and Septic + TNFbp. Chronic (5 days) sepsis was induced by the creation of a stable intraabdominal abscess using a sterile fecal-agar pellet inoculated with E. coli plus B. Fragilis as the foreign body nidus. TNFbp (1 mg/kg/day) was injected subcutaneously daily. Results. Sepsis increased plasma and skeletal muscle lactate concentrations 2-fold compared with control. In septic rats treated with TNFbp, plasma and skeletal muscle lactate concentrations were significantly decreased compared with untreated septic rats. In skeletal muscle, sepsis resulted in a 70% decrease in the proportion of the PDH in the active form compared with controls. The sepsis-induced inhibition in the PDH complex activity was prevented by TNFbp. PDH kinase was enhanced 1.8-fold in sepsis, and the increase in PDH kinase activity was prevented by treatment with TNFbp. TNFbp treatment did not have any effects on plasma lactate or the proportion of active skeletal muscle PDH activity in control animals. Conclusions. TNFbp prevents the sepsis-induced hyperlactatemia and derangements in skeletal muscle lactate concentrations and PDH activity. These observations suggest that TNF is an important mediator responsible for lactate dyshomeostasis during sepsis.

Inflammatory cytokines may mediate the host response to infection via central nervous system, endocrine, and/or paracrine/autocrine signaling mechanisms. Previous studies have shown that intravenous administration of interleukin (IL)-1 beta alters the concentration of the anabolic hormone insulin-like growth factor (IGF)-I in plasma and various tissues. The purpose of the present study was to determine 1) whether the intracerebroventricular injection of IL-1 beta can influence peripheral IGF-I levels in control animals and 2) whether the central administration of a IL-1 receptor antagonist (IL-1ra) can prevent the changes in peripheral IGF-I induced by endotoxin [lipopolysaccharide (LPS)] or sepsis produced by cecal ligation and puncture. In the first experiment, injection of IL-1 beta (100 ng/rat) decreased IGF-I levels in plasma, liver, and gastrocnemius muscle 28-36% by 1.5 h in conscious fasted rats. IGF-I levels remained reduced at 3 h, but returned to baseline by 6 h. IGF-I content was not altered in soleus, kidney, spleen, intestine, or whole brain after IL-1 beta. In the second series of experiments, LPS injected intravenously decreased IGF-I levels in plasma, liver, and gastrocnemius at 1.5 h, and levels were even further reduced at 3 and 6 h in these tissues (59, 57, and 48%, respectively). Moreover, the IGF-I content was also decreased in soleus (30-35%) and increased in kidney (2- to 3-fold) after LPS. In the third experiment, changes in IGF-I levels in plasma and tissues, similar to those seen in LPS-treated rats, were detected 24 h after induction of peritonitis. Intracerebroventricular infusion of IL-1ra did not alter any of the changes in IGF-I produced by either LPS or sepsis, although it did attenuate the concomitant changes in growth hormone levels. These data suggest that, although central IL-1 beta is capable of modulating peripheral IGF-I levels, central administration of IL-1ra was unable to modulate the changes in peripheral IGF-I in blood and tissues produced by either endotoxemia or peritonitis.

Summary Background Despite the availability of potent antibiotics and intensive care, mortality rates from septic shock are 40–70%. We assessed the safety and efficacy of murine monoclonal antibody to human tumour necrosis factor α (TNF α MAb) in the treatment of septic shock. Methods In a randomised, multicentre, double-blind, placebo-controlled clinical trial in 105 hospitals in the USA and Canada, we randomly assigned 1879 patients a single infusion of 7·5 mg/kg TNFα MAb (n=949) or placebo (0·25% human serum albumin n=930). Our main outcome measurement was the rate of all-cause mortality at 28 days. Findings 382 (40·3%) of 948 patients who received TNFα MAb and 398 (42·8%) of 930 who received placebo had died at 28 days (95% CI −0·02 to 0·07, p=0·27). We found no association between therapy with TNFα MAb and increased rapidity in reversal of initial shock or prevention of subsequent shock. Similarly, baseline plasma interleukin-6 concentrations of more than 1000 pg/mL or detectable circulating TNF concentrations were not associated with improvement in survival after TNFα MAb therapy. Coagulopathy but not other organ or system failures, was significantly decreased in the TNFα MAb group compared with placebo (day 7, p Interpretation We did not find an improvement in survival after septic shock with TNFα MAb. Therapy not solely dependent on TNFα blockade may be required to improve survival.

The purpose of this study was to determine the association of injury type (trauma, surgery, medical disease), systemic inflammatory response syndrome (SIRS) and fever with the degree of hypermetabolism in critically ill patients. Medical records of 204 critically ill, mechanically ventilated injured, surgical and medical patients were reviewed for indirect calorimetry and associated data. Analysis of variance and covariance was used to test the effects of injury, fever and SIRS on the degree of hypermetabolism. All injury types were found to be hypermetabolic. Analysis of variance of hypermetabolism with injury type and presence of fever as main effects revealed a significant increase in hypermetabolic response from fever, of similar magnitude across all injury types. Subjects with SIRS were significantly more hypermetabolic than subjects without SIRS. However, analysis of variance indicated no effect for SIRS but a significant effect for fever in increasing the hypermetabolic response. It is concluded that fever portends a magnification of the hypermetabolic response, being similar across injury types. SIRS does not identify hypermetabolic patients independent of fever. The host response to injury, not the injury itself, determines metabolic rate in critically ill patients. Neither SIRS nor injury type should be used to classify hypermetabolic states without stratifying for presence of fever.

Background: The role of systemic tumor necrosis factor (TNF) as a mediator of impaired wound healing in sepsis is unclear. The purpose of this study was to examine the effects of a specific TNF antagonist (TNFbp) on wound healing during chronic abdominal sepsis. Methods: Male Sprague-Dawley rats were divided into four groups: control, control+TNFbp, sepsis, and sepsis+TNFbp. Saline (1.0 mL) or TNFbp (1 mg/kg, 1.0 mL) was injected subcutaneously daily, polyvinylalcohol (PVA) sponge implants were placed in subcutaneous pockets, and sepsis was induced by creation of a chronic, intra-abdominal abscess. Sponge implants were removed on day 5 and examined histologically. Granulation tissue infiltration and quality (connective tissue, cellularity, vascularity) were scored on a scale from 1 to 4 in a blinded fashion. Results: Septic mortality (19 vs. 25%) was not influenced by TNFbp. Granulation tissue penetration and quality were decreased in septic animals. The administration of TNFbp significantly attenuated the effects of sepsis on granulation tissue histology, but not to control levels. Conclusions: These studies provide evidence that TNF contributes to the impaired wound healing observed in this model of chronic abdominal sepsis.

Autophagy is a protective cellular mechanism in response to various stresses, including sepsis. Sepsis is defined as systemic inflammation by infection. Surfactant protein A and D (SP-A and SP-D) are involved in host defense, regulation of inflammation, and homeostasis, but their roles in the autophagic activity and relevant gene expression in sepsis are unclear. In this study, mice lacking SP-A and SP-D (SP-A/D KO mice) and background-matched wild-type (WT) C57BL/6 mice underwent either cecal ligation and puncture (CLP) or sham surgery. The results showed that SP-A/D KO mice had lower mortality than WT mice in CLP sepsis. Liver tissues showed marked pathological changes in both septic SP-A/D KO and WT mice 24 hrs after CLP treatment; and quantitative analysis of liver histopathology revealed significant difference between septic SP-A/D and septic WT mice. SP-A/D KO mice had higher basal and sepsis-induced level of autophagy than WT mice (p < 0.05), as judged by Western blot and electron microscopic analyses. The expression of 84 autophagy-related genes revealed differential basal and sepsis-induced gene expression between SP-A/D KO and WT mice. The expression increased in three genes and decreased in four genes in septic WT mice, as compared to septic SP-A/D KO mice (p < 0.05). Furthermore, differential responses to sepsis between SP-A/D KO and WT mice were found in six signaling pathways related to autophagy and apoptosis. Therefore, enhanced autophagic activity improves the survival of septic SP-A/D KO mice through the regulation of liver autophagy/apoptosis-related gene expression and signaling pathway activation.

Background. Our goal was to revalidate this institution's original criteria for safe nonoperative management of splenic injury. Methods. This was a prospective series between October 1991 and December 1995 entering all patients with splenic injury to a modified algorithm. Patients were taken to the operating room if hemodynamically unstable (systolic blood pressure less than 90 mm Hg; pulse greater than 110 beats per minute) after 2 liters of fluid resuscitation, positive abdominal examination findings, American Association for the Surgery of Trauma Organ Injury Scale Grade IV or V injuries by computed tomographic scan (unless younger than 15 years old), or associated severe head injuries (unless younger than 15 years old), or age greater than 55. The remainder of the patients were closely observed. Results. One hundred seventy-three patients were entered—six were excluded by death before operating room salvage, and one was excluded because of operation for a ruptured thoracic aorta. Therefore 166 patients were reviewed. Seventy splenectomies and 18 splenorrhaphies were performed, and 78 patients were treated nonoperatively (58% splenic salvage). Two failures occurred in the nonoperative group: a 16-year-old with a grade IV hilar injury was operated on on the eighth day after injury because of a continually falling hematocrit, and a 25-year-old with unresolved tachycardia was operated on at 6 hours (97% success rate). The patients in the operative group had a greater severity of injury as determined by mean Injury Severity Score of 32, 18 deaths, a mean transfusion requirement of 14 units of blood compared with mean injury severity score of 21, two deaths from brain injury, and no transfusions given in 58 of the 78 nonoperative cases. Conclusions. Prospectively applied, these guidelines allow the safe nonoperative management of patients with blunt splenic injury.

The breakdown of myofibrillar and sarcoplasmic (nonmyofibrillar) proteins are regulated independently in sepsis, however, the factors regulating their synthesis are unknown. In this study, we assessed the effects of sepsis and interleukin-1 receptor antagonist on sarcoplasmic and myofibrillar protein synthesis in gastrocnemius. The rate of sarcoplasmic protein synthesis was 3.5 times that of myofibrillar proteins in control and septic rats. The synthesis of both sarcoplasmic and myofibrillar proteins was diminished proportionately during sepsis (p < .05). Infusion of interleukin-1 receptor antagonist (2 mg.kg.-1.h.-1) prevented the sepsis-induced inhibition of total, sarcoplasmic, and myofibrillar protein synthesis. Changes in the abundance of messenger RNA could not account for the inhibition of protein synthesis observed in sepsis. Furthermore, in vitro translation of messenger RNA isolated from control and septic muscle revealed no major differences. These results suggest the following: 1) the inhibition of total mixed proteins during sepsis is a consequence of reduced synthesis of both myofibrillar and sarcoplasmic proteins; 2) IL-1ra maintains control values of protein synthesis by sparing the reduction in synthesis of both myofibrillar and sarcoplasmic proteins during sepsis; and 3) the abundance of messenger RNA is not a rate-limiting determinant of protein synthesis in muscle from septic rats. An alteration in the translational efficiency of existing mRNA appears to be the major mechanism responsible for the inhibition of protein synthesis during sepsis.

Background Expert panels of colorectal surgeons consistently rank anastomotic leak as among the most important quality metrics for colectomies. Nonetheless, most administrative and clinical databases do not collect data on anastomotic leaks and rely on reported organ space surgical site infections (OSI) as a proxy for identifying anastomotic leaks. This study questions the validity of using OSI as a surrogate for anastomotic leak. Methods The Upstate New York Surgical Quality Initiative (UNYSQI) is a collaboration of 12 hospitals that prospectively collects colectomy-specific metrics, including anastomotic leak, in addition to standard National Surgical Quality Improvement Program (NSQIP) data, including OSIs. Cases with an organ space infection and/or anastomotic leak were selected from the 2010–2011 UNYSQI database. Patient characteristics and outcomes were compared for cases with organ space infections and anastomotic leaks. Results Overall, 3% of colectomies had a reported organ space infection and 4% had an anastomotic leak. Among cases having anastomotic leaks, only 25% were also coded as having an organ space infection, leaving 75% of anastomotic leaks not captured by the NSQIP database (κ = 0.272; P ≤ .001). Conclusion Organ space infection is a poor surrogate for anastomotic leak, resulting in grossly underestimated leak rates and seemingly represents different postoperative courses. Procedure-specific quality measures for colorectal surgery should include data collection on anastomotic leaks to provide accurate data for use in improving patient care.

Reproductive function may improve after bariatric surgery, although the mechanisms and time-related changes are unclear.The objective of the study was to determine whether ovulation frequency/quality as well as associated reproductive parameters improve after Roux en Y gastric bypass surgery.This was a prospective cohort study that enrolled female subjects from 2005 to 2008 with study visits at baseline and then 1, 3, 6, 12, and up to 24 months after surgery.The study was conducted at an academic health center.Twenty-nine obese, reproductive-aged women not using confounding medications participated in the study.The primary outcome was integrated levels of urinary progestin (pregnanediol 3-glururonide) from daily urinary collections at 12 months postoperatively. Secondary outcomes were changes in vaginal bleeding, other biometric, hormonal, ultrasound, dual-energy x-ray absorptiometry measures, and Female Sexual Function Index.Ninety percent of patients with morbid obesity had ovulatory cycles at baseline, and the ovulatory frequency and luteal phase quality (based on integrated pregnanediol 3-glururonide levels) were not modified by bariatric surgery. The follicular phase was shorter postoperatively [6.5 d shorter at 3 months and 7.9-8.9 d shorter at 6-24 months (P0.01)]. Biochemical hyperandrogenism improved, largely due to an immediate postoperative increase in serum SHBG levels (P0.01), with no change in clinical hyperandrogenism (sebum production, acne, hirsutism). Bone density was preserved, contrasting with a significant loss of lean muscle mass and fat (P0.001), reflecting preferential abdominal fat loss (P0.001). Female sexual function improved 28% (P = 0.02) by 12 months.Ovulation persists despite morbid obesity and the changes from bypass surgery. Reproductive function after surgery is characterized by a shortened follicular phase and improved female sexual function.