Who Places Feeding Tubes and in What Scenario?

PURPOSE OF REVIEW: Enteral feeding is commonly used to provide patients with nutrition. Access via feeding tubes can be attained by multiple medical specialties through a variety of methods. RECENT FINDINGS: There are limited data available on direct comparisons amongst gastroenterologist, interventional radiologists and surgeons, although there appears to be similar rates of complications. Fluroscopically and surgically placed feeding tubes may have a higher technical success rate than endoscopically placed tubes. The preferred specialty for feeding tube placement varies per institution, often due to logistical matters over technique or concern for complications. Ideally, a multidisciplinary team should exist to determine which approach is best in a patient-specific manner.

The good, the bad, and the ugly: Operative staff perspectives of surgeon coping with intraoperative errors.

BACKGROUND: Intraoperative errors are inevitable, and how surgeons respond impacts patient outcomes. Although previous research has queried surgeons on their responses to errors, no research to our knowledge has considered how surgeons respond to operative errors from a contemporary first-hand source: the operating room staff. This study evaluated how surgeons react to intraoperative errors and the effectiveness of employed strategies as witnessed by operating room staff. METHODS: A survey was distributed to operating room staff at 4 academic hospitals. Items included multiple-choice and open-ended questions assessing surgeon behaviors observed after intraoperative error. Participants reported the perceived effectiveness of the surgeon's actions. RESULTS: Of 294 respondents, 234 (79.6%) reported being in the operating room when an error or adverse event occurred. Strategies positively associated with effective surgeon coping included the surgeon telling the team about the event and announcing a plan. Themes emerged regarding the importance of the surgeon remaining calm, communicating, and not blaming others for the error. Evidence of poor coping also emerged: "Yelling, feet stomping and throwing objects onto the field. [The surgeon] cannot articulate needs well because of anger." CONCLUSION: These data from operating room staff corroborates previous research presenting a framework for effective coping while shedding light on new, often poor, behaviors that have not emerged in prior research. Surgical trainees will benefit from the now-enhanced empirical foundation on which coping curricula and interventions can be built.

A tale of two analyses: Administrative vs primary review of nutrition support team performance.

BACKGROUND: Our pharmacy department performed a medication-use evaluation using administrative data to assess prescription of parenteral nutrition (PN). They found that 31.6% (185 of 586) of nutrition support team (NST) patients received ≤5 days of PN, whereas 120 received ≤3 days. These results raised the question of NST prescribing practices given the incidence of short-duration PN. Since our NST evaluates all PN requests, the study prompted further review to identify reasons for short duration PN. METHODS: Charts of patients receiving PN for ≤3 days in the initial study underwent an in-depth review focusing on indications, reasons for discontinuation, and protein-calorie malnutrition (PCM) at time of NST consultation. RESULTS: A total 120 of 586 patients had PN ≤3 days. PN was clearly indicated in 94 cases: 27 patients received home PN but resolved the need for admission, 11 were admitted to later discharge on PN, 18 chose alternative/palliative care soon after starting PN, and 38 were nil per os for ≥6 days because of ileus, bowel obstruction, or contraindication to enteral feeding. Of the remaining 26 patients, 15 had PCM with poor intake for ≥ 3 days, warranting PN; only nine cases had unclear indications for PN and 11 could have potentially been avoided. CONCLUSION: Administrative data implied inappropriate PN use, whereas in-depth review confirmed appropriate prescription in most patients. Reducing short-duration PN in the management of ileus or obstruction remains difficult because of variable time to symptom resolution. In-depth chart review remains the best method to assess appropriateness of PN use.

When Can we Feed after a Gastrointestinal Bleed?

PURPOSE OF REVIEW: Gastrointestinal (GI) bleeding can carry minimal or significant risk for recurrent hemorrhage. Timing of feeding after GI bleeding remains an area of debate, and here we review the evidence supporting recommendations. RECENT FINDINGS: Improved understanding of the pathophysiology of GI bleeding and the evolution of treatment strategies has significantly altered the management of GI bleeding and the associated propensity for rebleeding. Early feeding following peptic ulcer bleeding remains ill-advised for high risk lesions while early initiation of liquid diets following cessation of esophageal variceal bleeding is appropriate and shortens hospital stays. Time to feeding following GI bleeding is inherently based on the disease etiology, severity, and risk of recurrent hemorrhage. With evolving standards of care, rates of rebleeding following endoscopic hemostasis are decreasing. Some evidence exists for early feeding however, larger multi-center trials are needed to help optimize timing of feeding in higher risk lesions.

Fiber in the ICU: Should it Be a Regular Part of Feeding?

PURPOSE OF REVIEW: To highlight the controversy of fiber use in the current critical care nutrition guidelines; review the effect of fiber on the gut microbiota in the critically ill; and examine the data on fiber and outcomes in the intensive care setting. RECENT FINDINGS: Fiber is increasingly recognized as a necessary component of colonic health and nutrition support. In critical illness there is a shift toward gut dysbiosis and immune dysregulation. Through fermentation and the generation of short-chain fatty acids, fiber has a role in maintaining intestinal homeostasis, immune function, and supporting commensal bacteria. In contrast to fermentable fiber, recent animal models suggest that non-fermentable fiber can also favorably alter intestinal homeostasis in a mechanism distinct from short chain fatty acids. In the critically ill, RCTs and meta-analyses suggest that soluble and mixed fiber supplemented enteral nutrition can reduce diarrhea and is well tolerated. Based on limited data, there may be benefits in reducing length of hospital stay, certain infections, and glucose metabolism. Nonetheless, the role of fiber enriched nutrition in critically ill patients is controversial as evident in the conflicting guidelines. Despite shortcomings in the literature, soluble and mixed fiber supplemented enteral nutrition is safe and beneficial in most hemodynamically stable intensive care patients. More research is necessary to determine optimal fiber composition.

Coping with errors in the operating room: Intraoperative strategies, postoperative strategies, and sex differences.

BACKGROUND: Prior work has identified intraoperative and postoperative coping strategies among surgeons and has demonstrated surgical errors to have a significant impact on patient outcomes and physicians. Little research has considered which coping strategies are most common among surgeons and if there exist coping strategy differences among sex or training level. METHODS: An electronic survey was distributed to surgical faculty and trainees at 3 institutions. Variables included coping techniques after making an error in the operating room. Participants were asked to report the effectiveness of their overall coping strategy. RESULTS: A total of 168 participants (56% male, 45% faculty) experienced an operative error and answered questions regarding coping strategies. The only coping strategy significantly associated with positive ratings of coping effectiveness was, upon error, taking a step back and taking time to think and act (r = 0.17; P = .024). There were differences between men and women in both intra and postoperative coping strategies. Men (mean = 3.69/5, standard error = .09) viewed their overall coping strategy as more effective than women (mean = 3.38/5, standard error = .09), t(158.86) = 2.47; P = .015. CONCLUSION: Although both male and female surgeons reported making errors in the operating room, differences exist in the strategies surgeons use to cope with these mistakes, and strategies differ in their ratings of effectiveness.

Variation in the Types of Providers Participating in Breast Cancer Follow-Up Care: A SEER-Medicare Analysis.

BACKGROUND: The current guidelines do not delineate the types of providers that should participate in early breast cancer follow-up care (within 3 years after completion of treatment). This study aimed to describe the types of providers participating in early follow-up care of older breast cancer survivors and to identify factors associated with receipt of follow-up care from different types of providers. METHODS: Stages 1-3 breast cancer survivors treated from 2000 to 2007 were identified in the Surveillance, Epidemiology and End results Medicare database (n = 44,306). Oncologist (including medical, radiation, and surgical) follow-up and primary care visits were defined using Medicare specialty provider codes and linked American Medical Association (AMA) Masterfile. The types of providers involved in follow-up care were summarized. Stepped regression models identified factors associated with receipt of medical oncology follow-up care and factors associated with receipt of medical oncology care alone versus combination oncology follow-up care. RESULTS: Oncology follow-up care was provided for 80 % of the patients: 80 % with a medical oncologist, 46 % with a surgeon, and 39 % with a radiation oncologist after radiation treatment. The patients with larger tumor size, positive axillary nodes, estrogen receptor (ER)-positive status, and chemotherapy treatment were more likely to have medical oncology follow-up care than older patients with higher Charlson comorbidity scores who were not receiving axillary care. The only factor associated with increased likelihood of follow-up care with a combination of oncology providers was regular primary care visits (>2 visits/year). CONCLUSIONS: Substantial variation exists in the types of providers that participate in breast cancer follow-up care. Improved guidance for the types of providers involved and delineation of providers' responsibilities during follow-up care could lead to improved efficiency and quality of care.

An Institutional Change in Continuous Renal Replacement Therapy.

BACKGROUND: Critically ill patients with acute kidney injury may require parenteral nutrition (PN) and continuous renal replacement therapy (CRRT). Introduction of a phosphate-free premixed renal replacement fluid without system-wide education in May 2011 resulted in increased incidence of hypophosphatemia, necessitating change in practice. Changes included (1) maximizing phosphate in PN, (2) modifying the CRRT order set, and (3) developing a CRRT competency evaluation for nutrition support team members. This study evaluates the effect of these changes on the incidence of hypophosphatemia. METHODS: Phosphate levels and predicated probability of hypophosphatemia were evaluated for patients receiving PN and CRRT over 3 time periods: prior to implementing the changes (preimplementation), during change implementation (intermediate), and following implementation (postimplementation). Hypophosphatemia was defined as a serum phosphate level <2.5 mg/dL. Generalized linear mixed models were applied for statistical analysis. RESULTS: The retrospective study includes 336 measures from 49 patients. Patients in the intermediate and postimplementation periods were not significantly different from each other and had significantly higher mean phosphate levels than patients in the preimplementation period ( P < .0001). They were also less likely to develop hypophosphatemia compared with preimplementation patients (intermediate: odds ratio [OR], 0.07; 95% confidence interval [CI], 0.03-0.18, P < .0001; postimplementation: OR, 0.09; 95% CI, 0.03-0.27, P < .0001). CONCLUSIONS: Modifications in phosphate dosing together with CRRT education reduced the incidence of hypophosphatemia in PN patients receiving CRRT. Communication of significant changes in clinical care should be shared with all services prior to implementation. Communication and planning between services caring for complex patients are necessary to prevent systems-based problems.

Stratification of Fat-Free Mass Index Percentiles for Body Composition Based on National Health and Nutrition Examination Survey III Bioelectric Impedance Data.

BACKGROUND: Loss of protein mass and lower fat-free mass index (FFMI) are associated with longer length of stay, postsurgical complications, and other poor outcomes in hospitalized patients. Normative data for FFMI of U.S. populations do not exist. This work aims to create a stratified FFMI percentile table for the U.S. population using the large bioelectric impedance analysis data obtained from National Health and Nutrition Examination Surveys (NHANES). METHODS: Fat-free mass (FFM) was calculated from the NHANES III bioelectric impedance analysis and anthropometric data for males and females ages 12 to >90 years for 3 race/ethnicities (non-Hispanic white, non-Hispanic black, and Mexican American). FFM was normalized by subject height to create an FFMI distribution table for the U.S. POPULATION: Selected percentiles were obtained by age, sex, and race/ethnicity. Data were collapsed by race/ethnicity before and after removing obese and underweight participants to create an FFMI decile table for males and females 12 years and older for the healthy-weight U.S. RESULTS: FFMI increased during adolescent growth but stabilized in the early 20s. The FFMI deciles were similar by race/ethnicity, with age group remaining relatively stable between ages 25 and 80 years. The FFMI deciles for males and females were significantly different. CONCLUSIONS: After eliminating the obese and extremely thin, FFMI percentiles remain stable during adult years allowing creation of age- and race/ethnicity-independent decile tables for males and females. These tables allow stratification of individuals for nutrition intervention trials to depict changing nutrition status during medical, surgical, and nutrition interventions.

An Institutional Change in Continuous Renal Replacement Therapy: Nutrition Support Team Resolves Resultant Severe Hypophosphatemia.

BACKGROUND: Critically ill patients with acute kidney injury may require parenteral nutrition (PN) and continuous renal replacement therapy (CRRT). Introduction of a phosphate-free premixed renal replacement fluid without system-wide education in May 2011 resulted in increased incidence of hypophosphatemia, necessitating change in practice. Changes included (1) maximizing phosphate in PN, (2) modifying the CRRT order set, and (3) developing a CRRT competency evaluation for nutrition support team members. This study evaluates the effect of these changes on the incidence of hypophosphatemia. METHODS: Phosphate levels and predicated probability of hypophosphatemia were evaluated for patients receiving PN and CRRT over 3 time periods: prior to implementing the changes (preimplementation), during change implementation (intermediate), and following implementation (postimplementation). Hypophosphatemia was defined as a serum phosphate level <2.5 mg/dL. Generalized linear mixed models were applied for statistical analysis. RESULTS: The retrospective study includes 336 measures from 49 patients. Patients in the intermediate and postimplementation periods were not significantly different from each other and had significantly higher mean phosphate levels than patients in the preimplementation period (P < .0001). They were also less likely to develop hypophosphatemia compared with preimplementation patients (intermediate: odds ratio [OR], 0.07; 95% confidence interval [CI], 0.03-0.18, P < .0001; postimplementation: OR, 0.09; 95% CI, 0.03-0.27, P < .0001). CONCLUSIONS: Modifications in phosphate dosing together with CRRT education reduced the incidence of hypophosphatemia in PN patients receiving CRRT. Communication of significant changes in clinical care should be shared with all services prior to implementation. Communication and planning between services caring for complex patients are necessary to prevent systems-based problems.

Innate Mucosal Immune System Response of BALB/c vs C57BL/6 Mice to Injury in the Setting of Enteral and Parenteral Feeding.

BACKGROUND: Outbred mice exhibit increased airway and intestinal immunoglobulin A (IgA) following injury when fed normal chow, consistent with humans. Parenteral nutrition (PN) eliminates IgA increases at both sites. Inbred mice are needed for detailed immunological studies; however, specific strains have not been evaluated for this purpose. BALB/c and C57BL/6 are common inbred mouse strains but demonstrate divergent immune responses to analogous stress. This study addressed which inbred mouse strain best replicates the outbred mouse and human immune response to injury. METHODS: Intravenously cannulated mice received chow or PN for 5 days and then underwent sacrifice at 0 or 8 hours following controlled surgical injury (BALB/c: n = 16-21/group; C57BL/6: n = 12-15/group). Bronchoalveolar lavage (BAL) was analyzed by enzyme-linked immunosorbent assay for IgA, tumor necrosis factor-α (TNF-α), interleukin (IL)-1ß, and IL-6, while small intestinal wash fluid (SIWF) was analyzed for IgA. RESULTS: No significant increase in BAL IgA occurred following injury in chow- or PN-fed BALB/c mice (chow: P = .1; PN: P = .7) despite significant increases in BAL TNF-α and SIWF IgA (chow: 264 ± 28 vs 548 ± 37, P < .0001; PN: 150 ± 12 vs 301 ± 17, P < .0001). Injury significantly increased mucosal IgA in chow-fed C57BL/6 mice (BAL: 149 ± 33 vs 342 ± 87, P = .01; SIWF: 236 ± 28 vs 335 ± 32, P = .006) and BAL cytokines. After injury, PN-fed C57BL/6 mice exhibited no difference in BAL IgA (P = .9), BAL cytokines, or SIWF IgA (P = .1). CONCLUSIONS: C57BL/6 mice exhibit similar airway responses to injury as outbred mice and humans, providing an appropriate model for studying mucosal responses to injury. The BALB/c mucosal immune system responds differently to injury and does not replicate the human injury response.

Use of Premixed Parenteral Nutrition During a Phosphate Shortage in a Non-Critically Ill Population.

BACKGROUND: Drug shortages pose prescribing problems to clinicians. During fiscal year (FY) 2014, an acute shortage of intravenous potassium phosphate (K-Phos IV), a common supplement in parenteral nutrition (PN), prompted the use of premixed instead of individualized PN to conserve K-Phos IV. Here we quantify the K-Phos IV conserved by using premixed PN and the associated cost differences. MATERIALS AND METHODS: Costs of preparing premixed PN vs individualized PN of equivalent composition were calculated for FY 2014 at a single-center tertiary care facility. Quantity and cost of K-Phos IV saved were calculated based on the number of premixed PN prescriptions. Costs for FY 2015 were projected based on drug costs from July 2014. RESULTS: During FY 2014, prescribing premixed in lieu of individualized PN conserved 16,440 mmol K-Phos IV but increased the cost of PN by $4080.45. However, increases in K-Phos IV cost at the end of FY 2014 resulted in premixed PN as a relatively less expensive therapy than individualized PN for our institution. Cost savings of $7092.20 due to use of premixed PN is projected for FY 2015. CONCLUSIONS: Prescribing premixed PN conserves K-Phos IV during shortages, but it increased direct drug spending in non-critically ill patients at our institution during FY 2014. Persistent shortages can drive market costs of K-Phos IV, however, necessitating frequent reconsideration of resource utilization.

Bombesin Preserves Goblet Cell Resistin-Like Molecule ß During Parenteral Nutrition but Not Other Goblet Cell Products.

INTRODUCTION: Parenteral nutrition (PN) increases the risk of infection in critically ill patients and is associated with defects in gastrointestinal innate immunity. Goblet cells produce mucosal defense compounds, including mucin (principally MUC2), trefoil factor 3 (TFF3), and resistin-like molecule ß (RELMß). Bombesin (BBS), a gastrin-releasing peptide analogue, experimentally reverses PN-induced defects in Paneth cell innate immunity. We hypothesized that PN reduces goblet cell product expression and PN+BBS would reverse these PN-induced defects. METHODS: Two days after intravenous cannulation, male Institute of Cancer Research mice were randomized to chow (n = 15), PN (n = 13), or PN+BBS (15 µg tid) (n = 12) diets for 5 days. Defined segments of ileum and luminal fluid were analyzed for MUC2, TFF3, and RELMß by quantitative reverse transcriptase polymerase chain reaction and Western blot. Th2 cytokines interleukin (IL)-4 and IL-13 were measured by enzyme-linked immunosorbent assay. RESULTS: Compared with chow, PN significantly reduced MUC2 in ileum (P < .01) and luminal fluid (P = .01). BBS supplementation did not improve ileal or luminal MUC2 compared with PN (P > .3). Compared with chow, PN significantly reduced TFF3 in ileum (P < .02) and luminal fluid (P < .01). BBS addition did not improve ileal or luminal TFF3 compared with PN (P > .3). Compared with chow, PN significantly reduced ileal RELMß (P < .01). BBS supplementation significantly increased ileal RELMß to levels similar to chow (P < .03 vs PN; P > .6 vs chow). Th2 cytokines were decreased with PN and returned to chow levels with BBS. CONCLUSION: PN significantly impairs the goblet cell component of innate mucosal immunity. BBS only preserves goblet cell RELMß during PN but not other goblet cell products measured.

The gastrin-releasing peptide analog bombesin preserves exocrine and endocrine pancreas morphology and function during parenteral nutrition.

Stimulation of digestive organs by enteric peptides is lost during total parental nutrition (PN). Here we examine the role of the enteric peptide bombesin (BBS) in stimulation of the exocrine and endocrine pancreas during PN. BBS protects against exocrine pancreas atrophy and dysfunction caused by PN. BBS also augments circulating insulin levels, suggesting an endocrine pancreas phenotype. While no significant changes in gross endocrine pancreas morphology were observed, pancreatic islets isolated from BBS-treated PN mice showed a significantly enhanced insulin secretion response to the glucagon-like peptide-1 (GLP-1) agonist exendin-4, correlating with enhanced GLP-1 receptor expression. BBS itself had no effect on islet function, as reflected in low expression of BBS receptors in islet samples. Intestinal BBS receptor expression was enhanced in PN with BBS, and circulating active GLP-1 levels were significantly enhanced in BBS-treated PN mice. We hypothesized that BBS preserved islet function indirectly, through the enteroendocrine cell-pancreas axis. We confirmed the ability of BBS to directly stimulate intestinal enteroid cells to express the GLP-1 precursor preproglucagon. In conclusion, BBS preserves the exocrine and endocrine pancreas functions during PN; however, the endocrine stimulation is likely indirect, through the enteroendocrine cell-pancreas axis.

Use of Piggyback Electrolytes for Patients Receiving Individually Prescribed vs Premixed Parenteral Nutrition.

BACKGROUND: Parenteral nutrition (PN) is available as individualized prescriptions frequently prepared with an automated compounding device or as commercially prepared premixed solutions. Our institution exclusively used individualized PN until an amino acid shortage forced a temporary switch to premixed solutions. In general, premixed solutions contain lower electrolyte levels than individualized formulations prescribed for patients with normal organ function. We aimed to quantify supplemental intravenous piggyback (IVPB) electrolyte use in adult patients receiving individualized and premixed PN and to quantify any effect on difference in the cost of therapy. METHODS: We compared use of supplemental IVPB electrolytes administered to patients receiving PN during consecutive periods prior to and during the amino acid shortage. Electrolyte IVPBs tabulated were potassium chloride, 10 and 20 mEq; magnesium sulfate, 2 g and 4 g; potassium phosphate, 7.5 and 15 mmol; and sodium phosphate, 7.5 and 15 mmol IVPB. RESULTS: There was no statistical difference in the number of PN formulations administered per day during each period (14.7 ± 3.9 vs 14.0 ± 2.6, individualized vs premixed, respectively). Total IVPB electrolytes prescribed per day increased significantly from the individualized PN period to the premixed PN period (7.03 ± 3.8 vs 13.8 ± 6.8; P < .0001). The additional IVPB electrolyte supplementation required in patients receiving premixed PN was associated with an additional $11,855.74 cost per 30 days of therapy compared with those who received individualized PN. CONCLUSION: Inpatient use of premixed PN results in a significant increase in IVPB electrolyte supplementation and cost compared with individualized PN use.

Glutamine Improves Innate Immunity and Prevents Bacterial Enteroinvasion During Parenteral Nutrition.

BACKGROUND: Patients receiving parenteral nutrition (PN) are at increased risk of infectious complications compared with enteral feeding, which is in part explained by impaired mucosal immune function during PN. Adding glutamine (GLN) to PN has improved outcome in some clinical patient groups. Although GLN improves acquired mucosal immunity, its effect on innate mucosal immunity (defensins, mucus, lysozymes) has not been investigated. METHODS: Forty-eight hours following venous cannulation, male Institute of Cancer Research mice were randomized to chow (n = 10), PN (n = 12), or PN + GLN (n = 13) for 5 days. Small intestine tissue and luminal fluid were collected for mucin 2 (MUC2), lysozyme, cryptdin 4 analysis, and luminal interleukin (IL)-4, IL-10, and IL-13 level measurement. Tissue was also harvested for ex vivo intestinal segment culture to assess tissue susceptibility to enteroinvasive Escherichia coli. RESULTS: In both luminal and tissue samples, PN reduced MUC2 and lysozyme (P < .0001, respectively) compared with chow, whereas GLN addition increased MUC2 and lysozyme (luminal, P < .05; tissue, P < .0001, respectively) compared with PN alone. PN significantly suppressed cryptdin 4 expression, while GLN supplementation significantly enhanced expression. IL-4, IL-10, and IL-13 decreased significantly with PN compared with chow, whereas GLN significantly increased these cytokines compared with PN. Functionally, bacterial invasion increased with PN compared with chow (P < .05), while GLN significantly decreased enteroinvasion to chow levels (P < .05). CONCLUSIONS: GLN-supplemented PN improves innate immunity and resistance to bacterial mucosal invasion lost with PN alone. This work confirms a clinical rationale for providing glutamine for the protection of the intestinal mucosa.

The enteric nervous system neuropeptide, bombesin, reverses innate immune impairments during parenteral nutrition.

BACKGROUND: Lack of enteral stimulation during parenteral nutrition (PN) impairs mucosal immunity. Bombesin (BBS), a gastrin-releasing peptide analogue, reverses PN-induced defects in acquired immunity. Paneth cells produce antimicrobial peptides (AMPs) of innate immunity for release after cholinergic stimulation. OBJECTIVE: Determine if BBS restores AMPs and bactericidal function during PN. METHODS: Intravenously cannulated male ICR mice were randomized to Chow, PN, or PN+BBS (15 µg 3 times daily, n = 7 per group) for 5 days. Ileum was analyzed for AMPs (Protein: sPLA2 by fluorescence, lysozyme and RegIII-γ by western andcryptdin-4 by ELISA; mRNA: all by RT-PCR). Cholinergic stimulated (100 µM bethanechol) ileal specimens assessed Pseudomonas bactericidal activity. Ileum (Chow: n = 7; PN: n = 9; PN+BBS: n = 8) was assessed for Escherichia coli invasion in ex-vivo culture. RESULTS: PN significantly decreased most AMPs versus Chow while BBS maintained Chow levels (sPLA2: Chow: 107 + 14*, PN: 44.6 + 7.2, PN+BBS: 78.7 + 13.4* Fl/min/µL/total protein; Lysozyme: Chow: 63.9 + 11.9*, PN: 26.8 + 6.2; PN+BBS: 64.9 + 13.8* lysozyme/total protein; RegIII-γ: Chow: 51.5 + 10.0*, PN: 20.4 + 4.3, PN+BBS: 31.0 + 8.4 RegIII-γ/total protein; Cryptdin-4: Chow: 18.4 + 1.5*, PN: 12.7 + 1.6, PN+BBS: 26.1 + 2.4*† pg/mg [all *P < 0.05 vs PN and †P < 0.05 vs Chow]). Functionally, BBS prevented PN loss of bactericidal activity after cholinergic stimulation (Chow: 25.3 + 3.6*, PN: 13.0 + 3.2; PN+BBS: 27.0 + 4.7* percent bacterial killing, *P < 0.05 vs PN). BBS reduced bacterial invasion in unstimulated tissue barely missing significance (P = 0.06). CONCLUSIONS: The enteric nervous system (ENS) controls AMP levels in Paneth cells during PN but mucosal protection by innate immunity requires both ENS and parasympathetic stimulation.

Protective role of bortezomib in steatotic liver ischemia/reperfusion injury through abrogation of MMP activation and YKL-40 expression.

Steatotic liver grafts tolerate ischemia-reperfusion (I/R) injury poorly, contributing to poor survival following transplantation. However the molecular mechanisms leading to I/R injury still remain to be defined. We have previously reported that the protective effect of bortezomib towards inhibiting cold induced I/R injury in obese rat liver transplant model is through NF-κB down modulation. In this report using an orthotopic liver transplant (OLT) model in Zucker rats (from obese, leptin deficient donor, to lean recipient) we defined the mechanisms of steatotic liver injury, and characterized the role of bortezomib in inhibiting MMP activation and YKL-40, both of which are involved in extracellular matrix deposition and fibrosis, the key pathological features of liver allograft failure. Obese donor rats were treated with bortezomib (i.v., 0.1mg/kg immediately prior to liver procurement) to assess the role of MMP and YKL-40 in steatotic liver I/R injury. I/R injury in steatotic livers resulted in significant increases in expression of YKL-40 (9 fold), and activation of MMP-2 (15 fold)/MMP-9 (12 fold). Bortezomib treatment reduced the expression of YKL-40 and MMP to basal levels. Bortezomib also inhibited the pro-fibrotic (VEGF, HGF, bFGF, TGF-ß) and pro-inflammatory (IL-1ß, TNF-α and IFN-γ) cytokines significantly in comparison to untreated animals with I/R injury. These results demonstrate that I/R injury in steatotic livers following transplantation are associated with MMP activation and YKL-40 upregulation resulting in pro-fibrotic and pro-inflammatory cytokine release. Administration of the proteosomal inhibitor, bortezomib, effectively attenuated the I/R injury by inhibiting MMP and YKL-40 expression and therefore support the clinical utility of this drug in donor management for preventing I/R injury and its sequelae.