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AIM: α7nAChR agonist GTS-21 is potentially a new treatment for type 2 diabetes (T2D) owing to its ability to stimulate GLP-1 secretion. This study sought to establish if GTS-21 exerts a blood glucose-lowering action in db/db mice, and to test if this action requires coordinate α7nAChR and GLP-1 receptor (GLP-1R) stimulation by GTS-21 and endogenous GLP-1, respectively. MATERIALS AND METHODS: Blood glucose levels were measured during an oral glucose tolerance test (OGTT) using db/db mice administered intraperitoneal GTS-21. Plasma GLP-1, PYY(1–36), GIP, glucagon, and insulin levels were measured by ELISA. A GLP-1R-mediated action of GTS-21 that is secondary to α7nAChR stimulation was evaluated using α7nAChR and GLP-1R knockout (KO) mice, or by co-administration of GTS-21 with DPP-4 inhibitor sitagliptin, or GLP-1R antagonist Exendin(9–39). Insulin sensitivity was assessed in an insulin tolerance test (ITT). RESULTS: Single or multiple dose GTS-21 (0.5–8.0 mg/kg) acted in a dose-dependent manner to lower levels of blood glucose in the OGTT using 10–14 week-old male and female db/db mice. This action of GTS-21 was reproduced by α7nAChR agonist PNU-282987, was enhanced by sitagliptin, was counteracted by Exendin(9–39), and was absent in α7nAChR and GLP-1R KO mice. Plasma GLP-1, PYY(1–36), GIP, glucagon, and insulin levels increased in response to GTS-21, but insulin sensitivity, body weight, and food intake were unchanged. CONCLUSIONS: α7nAChR agonists improve oral glucose tolerance in db/db mice. This action is contingent on coordinate α7nAChR and GLP-1R stimulation. Thus, α7nAChR agonists administered in combination with sitagliptin might serve as a new treatment for T2D.

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.

Intratracheal (IT) lipopolysaccharide (LPS) causes severe acute lung injury (ALI) and systemic inflammation. CMT-3 has pleiotropic anti-inflammatory effects including matrix metalloproteinase (MMP) inhibition, attenuation of neutrophil (PMN) activation, and elastase release. CMT-3's poor water solubility limits its bioavailability when administered orally for treating ALI. We developed a nano-formulation of CMT-3 (nCMT-3) to test the hypothesis that the pleiotropic anti-inflammatory activities of IT nCMT-3 can attenuate LPS-induced ALI.C57BL/6 mice were treated with aerosolized IT nCMT-3 or saline, then had IT LPS or saline administered 2 h later. Tissues were harvested at 24 h. The effects of LPS and nCMT-3 on ALI were assessed by lung histology, MMP level/activity (zymography), NLRP3 protein, and activated caspase-1 levels. Blood and bronchoalveolar lavage fluid (BALF) cell counts, PMN elastase, and soluble triggering receptor expressed on myelocytes-1 (sTREM-1) levels, TNF-α, IL-1β, IL-6, IL-18, and BALF protein levels were also measured.LPS-induced ALI was characterized by histologic lung injury (PMN infiltration, alveolar thickening, edema, and consolidation) elevated proMMP-2, -9 levels and activity, increased NLRP-3 protein and activated caspase-1 levels in lung tissue. LPS-induced increases in plasma and BALF levels of sTREM-1, TNF-α, IL-1β, IL-6, IL-18, PMN elastase and BALF protein levels demonstrate significant lung/systemic inflammation and capillary leak. nCMT-3 significantly ameliorated all of these LPS-induced inflammatory markers to control levels, and decreased the incidence of ALI.Pre-treatment with nCMT3 significantly attenuates LPS-induced lung injury/inflammation by multiple mechanisms including: MMP activation, PMN elastase, sTREM-1 release, and NLRP3 inflammasome/caspase-1 activation.

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.

Toll-like receptors are transmembrane proteins which sense and transmit infectious and inflammatory responses to the cells expressing them. Therapeutic strategies for the blockade of excessive Toll-like receptor signaling are being actively pursued for several diseases. Recently, Sparstolonin B, isolated from Chinese herb, which suppresses selectively Toll-like receptors has been studied in various inflammatory models. The objective of this review is to summarize the current literature regarding the use of Sparstolonin B in various in vitro and in vivo studies and to provide an overview regarding the potential use of this agent in different inflammatory diseases. Additionally, the current knowledge regarding the role of Toll-like receptors in inflammatory disease and the usage of various Toll-like receptor antagonists will be summarized. Based on our review, we believe Sparstolonin B could serve as a potential therapeutic agent for treatment of Toll-like receptor-mediated inflammatory disorders.

The cholinergic anti-inflammatory reflex (CAIR) represents an important homeostatic regulatory mechanism for sensing and controlling the body's response to inflammatory stimuli. Vagovagal reflexes are an integral component of CAIR whose anti-inflammatory effects are mediated by acetylcholine (ACh) acting at α7 nicotinic acetylcholine receptors (α7nAChR) located on cells of the immune system. Recently, it is appreciated that CAIR and α7nAChR also participate in the control of metabolic homeostasis. This has led to the understanding that defective vagovagal reflex circuitry underlying CAIR might explain the coexistence of obesity, diabetes, and inflammation in the metabolic syndrome. Thus, there is renewed interest in the α7nAChR that mediates CAIR, particularly from the standpoint of therapeutics. Of special note is the recent finding that α7nAChR agonist GTS-21 acts at L-cells of the distal intestine to stimulate the release of two glucoregulatory and anorexigenic hormones: glucagon-like peptide-1 (GLP-1) and peptide YY (PYY). Furthermore, α7nAChR agonist PNU 282987 exerts trophic factor-like actions to support pancreatic β-cell survival under conditions of stress resembling diabetes. This review provides an overview of α7nAChR function as it pertains to CAIR, vagovagal reflexes, and metabolic homeostasis. We also consider the possible usefulness of α7nAChR agonists for treatment of obesity, diabetes, and inflammation.

SP-A/D KO mice with sepsis demonstrate more severe lung, kidney, and gut injury/apoptosis than WT controls. We hypothesize SP-A and SP-D directly regulate lipopolysaccharide (LPS)-induced P38 mitogen-activated protein kinase (MAPK) activation and gut apoptosis during sepsis.Primary IECs were established from SP-A/D KO or C57BL/6 WT mice, stimulated with LPS and harvested at 24 h. IECs from WT mice were treated with SP-A, SP-D, or vehicle for 20 h, then LPS for 24 h. Apoptosis, cleaved caspase-3 levels and the ratio of BAX/Bcl-2 were assayed. The role of P38 MAPK was examined using the P38 MAPK-agonist U46619 and inhibitor SB203580 in LPS-treated cells. p-P38 MAPK/t-P38 MAPK, TLR4, and CD14 were measured by Western Blot.LPS-induced apoptosis, caspase-3 levels, BAX/Bcl-2, and p-P38/t-P38 MAPK were increased in SP-A/D KO IECs. SP-A and SP-D attenuate LPS-induced increase in apoptosis, cleaved caspase-3, BAX/Bcl-2, and p-P38/t-P38 MAPK in WT IECs. U46619 increased apoptosis, caspase-3, and BAX/Bcl-2 in IECs which was attenuated by SP-A/D. SB203580 attenuates the LPS-induced increase in apoptosis, caspase-3, and BAX/Bcl-2 in WT IECs. Addition of SP-A or SP-D to SB203580 completely ameliorates LPS-induced apoptosis. The LPS-induced increase in TLR4 and CD14 expression is greater in IECs from SP-A/D KO mice and treatment of WT IECs with SP-A or SP-D prevents the LPS-induced increase in TLR4 and CD14.SP-A and SP-D attenuate LPS-induced increases in apoptosis, caspase-3, and BAX/Bcl-2 in IECs. Attenuation of LPS-induced activation of TLR4 and P38 MAPK signaling pathways represents potential mechanisms for the protective effects of SP-A/D on apoptosis.

Since July 2014 General Surgery residency programs have been required to use the Accreditation Council for Graduate Medical Education milestones twice annually to assess the progress of their trainees. We felt this change was a great opportunity to use this new evaluation tool for resident self-assessment and to furthermore engage the faculty in the educational efforts of the program.We piloted the milestones with postgraduate year (PGY) II and IV residents during the 2013/2014 academic year to get faculty and residents acquainted with the instrument. In July 2014, we implemented the same protocol for all residents. Residents meet with their advisers quarterly. Two of these meetings are used for milestones assessment. The residents perform an independent self-evaluation and the adviser grades them independently. They discuss the evaluations focusing mainly on areas of greatest disagreement. The faculty member then presents the resident to the clinical competency committee (CCC) and the committee decides on the final scores and submits them to the Accreditation Council for Graduate Medical Education website. We stored all records anonymously in a MySQL database. We used Anova with Tukey post hoc analysis to evaluate differences between groups. We used intraclass correlation coefficients and Krippendorff's α to assess interrater reliability.We analyzed evaluations for 44 residents. We created scale scores across all Likert items for each evaluation. We compared score differences by PGY level and raters (self, adviser, and CCC). We found highly significant increases of scores between most PGY levels (p0.05). There were no significant score differences per PGY level between the raters. The interrater reliability for the total score and 6 competency domains was very high (ICC: 0.87-0.98 and α: 0.84-0.97). Even though this milestone evaluation process added additional work for residents and faculty we had very good participation (93.9% by residents and 92.9% by faculty) and feedback was generally positive.Even though implementation of the milestones has added additional work for general surgery residency programs, it has also opened opportunities to furthermore engage the residents in reflection and self-evaluation and to create additional venues for faculty to get involved with the educational process within the residency program. Using the adviser as the initial rater seems to correlate closely with the final CCC assessment. Self-evaluation by the resident is a requirement by the RRC and the milestones seem to be a good instrument to use for this purpose. Our early assessment suggests the milestones provide a useful instrument to track trainee progression through their residency.

Staphylococcus aureus pneumonia is an important cause of sepsis which causes gut injury, inflammation, and apoptosis. The surfactant proteins surfactant protein A (SP-A) and surfactant protein D (SP-D) bind bacterial pathogens and facilitate clearance of pathogens, apoptotic bodies, and modulate immune responses. SP-A and SP-D are expressed in both lung and gut epithelia. We hypothesize SP-A and SP-D regulate pneumonia severity and gut injury during pneumonia.Wild-type (WT) and SP-A and SP-D double knockout (SP-A/D KO) mice were subjected to S. aureus or sham pneumonia. Bronchoalveolar lavage and tissue harvest were performed 24 h later. Pneumonia severity, gut mucosal injury, inflammation, and apoptosis were measured using a combination of histology, immunohistochemistry, cytokine assay, TUNEL assay, quantitative real-time polymerase chain reaction, and Western blot analyses.Pneumonia increased gut inflammation, apoptosis, and mucosal injury in both groups. Pneumonia histology and bacterial growth in bronchoalveolar lavage fluid demonstrate more severe infection in SP-A/D KO mice compared with WT controls. SP-A/D KO mice with pneumonia also demonstrate more severe histologic gut mucosal injury, increased gut apoptosis, elevated caspase-3 levels, and Bax/Bcl-2 mRNA expression compared with WT pneumonia mice. Nuclear factor κB (NF-κB) p65 expression and its nuclear translocation, gut levels of tumor necrosis factor α and interleukin-1β were all increased in SP-A/D KO mice with pneumonia compared with WT controls.These data provide evidence SP-A and SP-D attenuate S. aureus pneumonia severity resulting in decreased intestinal mucosal injury, apoptosis, and inflammation. Improved pulmonary clearance of S. aureus decreased caspase-3 and Bax/Bcl-2 expressions and decreased activation of the NF-κB signaling pathway in intestine represent potential mechanisms for the effects of SP-A and SP-D on gut injury during pneumonia.

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.

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 …

Background Reactive oxygen species are increased in multiple gastrointestinal diseases and contribute to their pathogenesis. glutathione (GSH) is an antioxidant that helps to prevent reactive oxygen species–mediated mucosal damage. This study examines the mechanisms by which GSH attenuates hydrogen peroxide (H2O2)–induced injury in intestinal epithelial cells. Methods IEC-6 cells were cultured and treated with H2O2 ± GSH. Inflammation was measured by nuclear factor kappa-B (NF-κB) P65 expression, NF-κB nuclear translocation, iκBα phosphorylation, and interleukin 1 beta secretion. Terminal deoxynucleotidyl transferase–mediated UTP end-labeling staining and cleaved caspase-3 were used to assess apoptosis. The role of P38 mitogen-activated protein kinase (P38 MAPK) signaling was examined using the P38 MAPK agonist U46619 and inhibitor SB203580 in H2O2 and GSH-treated cells. Phosphorylated and total P38 MAPKs and cleaved caspase-3 were measured by Western blot. Data are means ± standard deviation, statistical significance P Results Pretreatment with GSH attenuates the activation of NF-κB and P38 MAPK signaling pathways by H2O2. GSH also decreased H2O2-mediated increases in interleukin 1 beta secretion, cleaved caspase-3 activation, and apoptosis in IEC-6 cells. SB203580 attenuated the increase in apoptosis and cleaved caspase-3 in H2O2-treated cells. The increase in apoptotic index and cleaved caspase-3 observed in U46619-treated cells was also diminished by GSH. Conclusions GSH appears to ameliorate oxidative injury in intestinal epithelial cells by attenuating H2O2-mediated activation of NF-κB and P38 MAPK signaling pathways that regulate intestinal inflammation and apoptosis.

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.

Rational assembly of small molecule libraries for purposes of drug discovery requires an efficient approach in which the synthesis of bioactive compounds is enabled so that numerous structurally related compounds of a similar basic formulation can be derived. Here, we describe (4 + 3) and (3 + 2) indole annulation strategies that quickly generate complex indole heterocycle libraries that contain novel cyclohepta- and cyclopenta[b]indoles, respectively. Screening of one such library comprised of these indoles identifies JWU-A021 to be an especially potent stimulator of glucagon-like peptide-1 (GLP-1) secretion in vitro. Surprisingly, JWU-A021 is also a potent stimulator of Ca2+ influx through TRPA1 cation channels (EC50ca. 200 nM), thereby explaining its ability to stimulate GLP-1 release. Of additional importance, the available evidence indicates that JWU-A021 is one of the most potent non-electrophilic TRPA-1 channel agonists yet to be reported in the literature.

Staphylococcus aureus is a common cause of nosocomial pneumonia frequently resulting in acute respiratory distress syndrome (ARDS). Surfactant protein B (SP-B) gene expresses two proteins involved in lowering surface tension and host defense. Genotyping studies demonstrate a significant association between human SP-B genetic variants and ARDS. Curcumins have been shown to attenuate host inflammation in many sepsis models. Our hypothesis is that functional differences of SP-B variants and treatment with curcumin (CMC2.24) modulate lung injury in bacterial pneumonia. Humanized transgenic mice, expressing either SP-B T or C allele without mouse SP-B gene, were used. Bioluminescent labeled S. aureus Xen 36 (50 μL) was injected intratracheally to cause pneumonia. Infected mice received daily CMC2.24 (40 mg/kg) or vehicle alone by oral gavage. Dynamic changes of bacteria were monitored using in vivo imaging system. Histological, cellular, and molecular indices of lung injury were studied in infected mice 48 h after infection. In vivo imaging analysis revealed total flux (bacterial number) was higher in the lung of infected SP-B-C mice compared with infected SP-B-T mice (P < 0.05). Infected SP-B-C mice demonstrated increased mortality, lung injury, apoptosis, and NF-κB expression compared with infected SP-B-T mice. Compared with controls, CMC2.24 treatment significantly reduced the following: mortality, total bacterial flux and lung tissue apoptosis, inflammatory cells, NF-κB expression (P < 0.05), and MMPs-2, -9, -12 activities (P < 0.05). We conclude that mice with SP-B-C allele are more susceptible to S. aureus pneumonia than mice with SP-B-T allele, and that CMC2.24 attenuates lung injury thus reducing mortality.

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 (

Chronic models of inflammatory bowel disease are lacking in preadult rodents. The primary goal of our study was to develop a chronic model of hapten-induced intestinal inflammation and fibrosis in young rats. Second, we aimed to determine the profiles of key Th-1, Th-2, and Th-17 proinflammatory and profibrotic cytokines, during the progression of colitis in young rats.Chronic hapten-induced colitis was induced by the administration of intracolonic 2,4,6-trinitrobenzene sulfonic acid (TNBS) in young Wistar rats (postnatal days 23, 35, 48, and 59). After 1, 3, or 4 cycles of TNBS, rats were euthanized and the colons were removed for the measurement of macroscopic, histologic, and biochemical parameters of colitis.Young rats developed moderate to severe colitis in the distal colon, without significant morbidity or mortality. Macroscopic severity, histologic pathology, and colonic weights increased progressively with repeated TNBS administration. Cobblestone-like ulceration and fibrosis was evident in the colon, particularly after 4 cycles of TNBS. There was a unique cytokine pattern associated with colitis in young rats. Interleukin (IL)-12 and tumor necrosis factor (TNF)-alpha peaked during the earlier postnatal time points (days 28 and 54) and then declined after repetitive administration of the hapten (day 67). In contrast, IL-13 and IL-17 were consistently elevated after administration of TNBS to the colon of young rats.A new model of colitis was established in young rats, which has a unique pattern of Th-1, Th-2, and Th-17 cytokine induction. This chronic TNBS model may be useful for studying the development of inflammation and fibrosis in preadult animals.

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

Surfactant protein B (SP-B) is essential for lung function. Previous studies have indicated that a SP-B 1580C/T polymorphism (SNP rs1130866) was associated with lung diseases including pneumonia. The SNP causes an altered N-linked glycosylation modification at Asn129 of proSP-B, e.g. the C allele with this glycosylation site but not in the T allele. This study aimed to generate humanized SP-B transgenic mice carrying either SP-B C or T allele without a mouse SP-B background and then examine functional susceptibility to bacterial pneumonia in vivo . A total of 18 transgenic mouse founders were generated by the DNA microinjection method. These founders were back-crossed with SP-B KO mice to eliminate mouse SP-B background. Four founder lines expressing similar SP-B levels to human lung were chosen for further investigation. After intratracheal infection with 50 μl of Pseudomonas aeruginosa solution (1 × 10 6 CFU/mouse) or saline in SP-B-C, SP-B-T mice the mice were sacrificed 24 h post-infection and tissues were harvested. Analysis of surfactant activity revealed differential susceptibility between SP-B-C and SP-B-T mice to bacterial infection, e.g. higher minimum surface tension in infected SP-B-C versus infected SP-B-T mice. These results demonstrate for the first time that human SP-B C allele is more susceptible to bacterial pneumonia than SP-B T allele in vivo .

To investigate the effects of surfactant proteins A and D (SP-A and SP-D, respectively) in urinary tract infection (UTI), SP-A and SP-D double knockout (SP-A/D KO) and wild type (WT) C57BL/6 female mice were infected with uropathogenic Escherichia coli by intravesical inoculation. Compared with WT mice SP-A/D KO mice showed increased susceptibility to UTI, as evidenced by higher bacterial CFU, more infiltrating neutrophils and severe pathological changes. Keratinocyte-derived chemokine increased in the kidney of WT mice but not in SP-A/D KO mice 24 h post-infection. Compared with control, the level of IL-17 was elevated in the kidney of infected WT and SP-A/D KO mice and the level of IL-17 was higher in the infected SP-A/D KO mice than in infected WT mice 24 and 48 h post-infection. The basal level of p38 MAPK phosphorylation in SP-A/D KO mice was higher than in WT mice. The phosphorylated p38 level was elevated in the kidney of WT mice post infection but not in SP-A/D KO mice. Furthermore, in vitro growth of uropathogenic E. coli was inhibited by SP-A and SP-D. We conclude that SP-A and SP-D function as mediators of innate immunity by inhibiting bacterial growth and modulating renal inflammation in part by regulating p38 MAPK-related pathway in murine UTI.