Journal of Surgical Research - Articles in Press

Does neoadjuvant chemotherapy improve outcomes for patients with gastric cancer? - Uncorrected Proof

2012-05-17

Abstract: Background: The role of neoadjuvant and adjuvant therapy for gastric cancer remains undefined. We compared the outcomes for patients treated with surgery alone or with the addition of adjuvant or neaodjuvant treatment.Methods: A single-institution, retrospective evaluation of a prospective database of gastric cancer patients treated from 2000 to 2008 was performed.Results: Overall, 173 patients with gastric cancer underwent surgical extirpation. Of the 173 patients, 43% had early-stage disease (less than stage 2) and 57% late-stage disease (stage 2 or greater; American Joint Committee on Cancer, 2010). The median survival from the date of diagnosis for those treated with neoadjuvant chemotherapy (NAC) (n = 35), adjuvant chemotherapy (n = 21), adjuvant chemoradiotherapy (n = 18), both NAC and adjuvant chemotherapy (n = 11), or surgery alone (n = 88) was 26.3, 17.3, longer than 60, longer than 60, and 50.3 months, respectively. The addition of NAC to surgery was detrimental to survival those with early-stage disease (P = 0.002) and did not improve survival in those with late-stage disease (P = 0.687). For those with late-stage disease, surgery with adjuvant chemoradiotherapy exhibited the best overall survival compared with surgery alone (P = 0.021) or surgery with adjuvant chemotherapy (P = 0.01). Patients treated with NAC had a greater rate of R0 resection compared with surgery alone (P = 0.049).Conclusions: NAC for patients with gastric cancer does not significantly improve the overall outcomes for those with late-stage disease and could be detrimental to survival for those with early-stage disease. However, treatment with NAC resulted in an improved rate of R0 resection.

Systemic inflammation after aortic cross clamping is influenced by Toll-like receptor 2 preconditioning and deficiency - Uncorrected Proof

2012-05-16

Abstract: Background: The perioperative morbidity and mortality of abdominal aortic aneurysm repair is linked to systemic inflammation. Important triggers of the latter are Toll-like receptors (TLRs), which play a central role in innate immunity. Ischemia/reperfusion (I/R) injury can be influenced by either TLR stimulation before I/R (preconditioning) or TLR dysfunction (deficiency or polymorphism). The influence of TLR2 stimulation or deficiency on systemic cytokine release and organ damage after aortic cross clamping has not been evaluated yet.Methods: Wild type (WT) and TLR2-deficient mice were subjected to 1 h ischemia and 2 or 4 h reperfusion of the infrarenal aorta. One group of WT mice was preconditioned with the synthetic TLR2 agonist Pam3Cys-Ser-Lys4 (Pam3CSK4). Sham-operated animals without I/R served as controls. Plasma levels of interleukin (IL)-1β, IL-2, IL-4, IL-5, IL-6, IL-10, IL-12, granulocyte macrophage–colony stimulating factor, tumor necrosis factor-α, alanine transaminase (ALT), aspartate transaminase (AST), lactate dehydrogenase (LDH), and creatinine were measured.Results: I/R injury caused by transient clamping of the infrarenal aorta led to a time-dependent increase of all measured cytokines except IL-4, IL-5, and granulocyte macrophage–colony stimulating factor. This was accompanied by elevated markers of organ damage (ALT, AST, and LDH) except creatinine. Preconditioning with Pam3CSK4 led to lower plasma concentrations of all cytokines, with the exception of anti-inflammatory IL-10 which was significantly upregulated. Furthermore, ALT, AST, and LDH plasma concentrations were lower in the preconditioning group. TLR2-deficient mice similarly showed reduced signs of systemic inflammation and organ damage, although less distinctive. IL-2, IL-6, IL-12, ALT, and LDH were time dependently lower compared with WT mice. IL-10 concentration was higher in TLR2-deficient mice compared with WT.Conclusions: Both, preconditioning via TLR2 and TLR2 deficiency, ameliorate systemic inflammation and organ damage during I/R injury caused by clamping of the infrarenal aorta. Compared with untreated WT animals, Pam3CSK4 preconditioned and TLR2-deficient mice showed lower concentrations of pro-inflammatory cytokines, whereas anti-inflammatory IL-10 was elevated in both groups. This was accompanied by reduced organ dysfunction parameters.

Hepatic resection for huge (>15 cm) multinodular HCC with macrovascular invasion - Uncorrected Proof

2012-05-16

Abstract: Background: Surgical resection has routinely not been recommended for patients with huge (>15 cm) multinodular lesions and macrovascular invasion (advanced-stage hepatocellular carcinoma [HCC] patients) because of high operative mortality, recurrence rate, and lack of survival benefit.Methods: A retrospective study of 1425 patients was carried out, of which 1245 patients met EASL/AASLD criteria for hepatic resection (HR-EA group), 116 were surgically treated advanced-stage HCC patients (HR-AS group), and 64 were advanced-stage HCC patients receiving nonsurgical treatments (N-AS group).Conclusion: HR may still be suitable for the HCC patients with huge (>15 cm) multinodular lesions and macrovascular invasion in selected cases. Advanced-stage HCC patients without liver cirrhosis and with a tumor-free resection margin could enjoy longer survival and lower recurrence. Preoperative and/or postoperative TACE provides no survival benefits for advanced-stage HCC patients.

Toll-like receptor 4 ablation improves stem cell survival after hypoxic injury - Uncorrected Proof

Benjamin D. Brewster, Joshua D. Rouch, Meijing Wang, Daniel R. Meldrum — 2012-05-14

Abstract: Introduction: Mesenchymal stem cell (MSC) therapy improves cardiac function after ischemia/reperfusion injury, but its effectiveness is limited by MSC survival in hypoxic environments. Toll-like receptor 4 (TLR4) contributes to pro-apoptotic signaling under hypoxic conditions. Activation of intracellular AKT and ERK pathways opposes this signal and improves cell survival. It is unknown whether ablation of TLR4 affects these pathways after hypoxic injury in MSCs. We hypothesized that: 1) TLR4 knockout (TLR4KO) in MSCs improves survival after hypoxic injury; and 2) this survival difference is due to improved signaling in the AKT and ERK pathways.Materials and methods: Murine wild-type (WT) and TLR4KO MSCs were harvested from bone marrow and grown in vitro. A total of 0.1 × 106 cells/well were incubated in hypoxic conditions versus normoxic controls. After 24 h, these groups were examined for cell survival via counting and compared using a t-test with P < 0.05 = statistical significance. AKT and ERK concentrations were measured in lysate using Western blot analysis.Results: The morphology of WT and TLR4KO MSCs was similar. In line with our previous findings, hypoxia did significantly increase cell death in WT cells (1.79 × 105 living cells/mL control versus 0.88 × 105 hypoxia, P < 0.05). Hypoxic injury did not increase cell death in the TLR4KO group (1.68 × 105 control versus 1.82 × 105 hypoxia, P < 0.05). Increased AKT activation was observed in all TLR4KO groups. TLR4 did not affect phosphorylated ERK levels.Conclusion: TLR4-knockout MSCs show improved survival after hypoxic injury because of increased AKT pathway signal. Use of TLR4-knockout MSCs in ischemia/reperfusion studies results in enhanced cardioprotection; improved stem cell survival was likely a contributing factor.

The effects of irrigation on outcomes in cases of perforated appendicitis in children - Uncorrected Proof

2012-05-14

Abstract: Introduction: Appendicitis is the most common indication for urgent abdominal operation in children. Approximately 20%–30% of patients will have a perforation at operation. Intra-abdominal abscess after appendectomy is reported in 3%–20% of patients and adds significantly to hospital stay with increased morbidity and overall cost. Surgical dogma has long advocated for irrigation in the setting of gross pus to prevent abscess formation.Methods: Following IRB approval, data were retrospectively collected for children who had undergone appendectomy for perforated appendicitis at one of two children's hospitals over the course of 5 y. Perforation was determined by review of operative notes. All patients had free fluid in their peritoneal cavity evacuated by suction, whereas some of the patients also had their peritoneal cavity irrigated with normal saline. Postoperative intra-abdominal abscess rates were determined based on clinical symptoms and confirmatory radiologic studies.Results: There were 99 patients in the suction-only group and 139 in the irrigation group. Standard demographics were relatively similar between the two groups. There were significantly lower rates of intra-abdominal abscess formation (4.0% versus 17.2%, P = 0.002) and wound infection (1.0% versus 8.6%, P = 0.003) in the suction-only group compared with the irrigation group. We further analyzed abscess rates by surgical treatment, either laparoscopic or open appendectomy. There were 85 patients in the laparoscopic group and 152 patients in the open appendectomy group. In this subgroup analysis, there were also significantly lower rates of abscess formation in patients treated with suction only compared with irrigation in the laparoscopic (3.5% versus 18.8%, P = 0.012) and open appendectomy groups (4.2% versus 16.3%, P = 0.036).Conclusions: Results of this retrospective review indicate that a suction-only approach significantly decreased rates of abscess formation and wound infections compared to irrigation in cases of perforated appendicitis in children.

Best temperature for static liver graft storage is 1°C - Uncorrected Proof

2012-05-14

Abstract: Background: The best storage temperature in liver transplantation remains an unsolved question.Methods: After storage for 24h in University of Wisconsin solution at +4°C, +1°C, or −0.5°C, rat livers were subjected, or not, to 15min of warm ischemia, rinsed with Ringer lactate, and subsequently reperfused with oxygenated Krebs-Henseleit buffer.Results: In the presence of warm ischemia, for livers stored at +4°C, creatine kinase (CK) peaked at 21±5IUg−1h−1, hepatic resistance at 34,700±1500dynscm−5, bile flow reached 18±4μLg−1h−1 after 10min, and oxygen consumption stabilized at about 25μmolg−1h−1 after 20min. When livers were stored at +1°C, CK and hepatic resistance were lowered, bile production was 33±6μLg−1h−1 (P<0.05 versus +4°C), and oxygen consumption was 105±10μmolg−1h−1 (P<0.001). For livers stored at−0.5°C, results were not statistically different from those of the +1°C group except for bile flow, which was significantly lower. Without warm ischemia, the peak of CK (P=0.015) and the peak hepatic resistance (P<0.001) of the +4°C group were significantly increased compared with the +1°C or −0.5°C groups. However, no difference in bile flow or oxygen consumption was observed. The number of trypan blue-positive nonparenchymal cells (P=0.003) and the gain in liver weight during the reperfusion (P=0.015) were minimal after storage at +1°C.Conclusions: Static storage at +1°C improved liver function compared with +4°C or −0.5°C. Main beneficial effect was observed with parameters reflecting sinusoidal cells injury.

Differentiating benign from malignant thyroid nodules using micro ribonucleic acid amplification in residual cells obtained by fine needle aspiration biopsy - Uncorrected Proof

2012-05-14

Abstract: Background: Fine needle aspiration biopsy (FNAB) is the most commonly used diagnostic tool to differentiate benign from malignant thyroid nodules. Nevertheless, some FNAB cytology results are not definite. In such cases diagnostic thyroid lobectomy is performed with malignancy rate on final histopathology ranging at 15%–75%. The aim of this study was to improve on the accuracy of FNAB-based cytology by amplification of microRNAs (micro ribonucleic acids [miRs]) from the cells left in the FNAB needle after submission for cytology.Methods: Residual cells were collected from the needle cup after FNAB cytology of 77 consecutive patients with thyroid nodules. miR-enriched RNA was extracted for all patients with cytology showing either follicular lesion or suspicion for malignancy (n=11). The expression of miR-21, -31, -146b, -187, -221, and -222 was determined using real-time polymerase chain reaction. Results were compared with final surgical histopathology.Results: RNA was successfully extracted from all FNAB specimens. Five patients had FNAB cytology suspicious for malignancy. The miR panel was positive in all five (100%). Six patients had follicular lesions on FNAB. The miR panel was positive in three of four patients (75%) with confirmed malignancy and was negative in two of two (0%) patients with benign pathology results. This corresponded to a specificity of 100%, sensitivity of 88%, and accuracy of 90%.Conclusions: RNA extraction from FNAB residual cells is feasible, and a miR panel amplified from the extracted RNA seems like a promising diagnostic tool in this limited number of patients.

Decreased Mrp2 transport in severe macrovesicular fatty liver grafts - Uncorrected Proof

2012-05-14

Abstract: Background: Severe macrosteatotic liver has been regarded as a donor contraindication for liver transplantation. However, it has not yet been determined whether hepatocytes lose function before cold ischemia. This study was designed to elucidate certain pathophysiological alterations and how to ameliorate such hepatic dysfunctions.Materials and methods: Wistar rats were fed with a choline-deficient diet (CD) for up to 6 wk, and their livers were then perfused with Krebs-Henseleit buffer to examine bile output and biliary constituents. Organic anion transport from hepatocellular canalicular membranes through Mrp2 was examined by kinetic analyses for biliary exclusion of 5-carboxyfluorescein (CF), a fluoroprobe excreted through Mrp2.Results: Macrovesicular fatty deposits exceeded 60% and serum aspartate aminotransferase (AST) increased on 6-wk CD (CD6w), but not 3-wk CD (CD3w). Mrp2-deficient rat livers (Eisai hyperbilirubinemia) with 3-wk CD were more vulnerable than CD3w livers. In CD6w rats, bile flow rate and biliary glutathione significantly decreased. These declines coincided with the intracellular localization of Mrp2. Moreover, kinetic analyses for biliary CF revealed significant delay in 6-wk CD-fed rat livers. Pioglitazone, a ligand of PPARγ activating protein kinase A (PKA), significantly attenuated this delay by sorting Mrp2 into bile canalicular membranes. However, a PKA inhibitor blunted the increase in CF exclusion, re-localizing Mrp2 into the hepatocellular cytoplasm. A thromboxane A2 synthase inhibitor also ameliorated the CF exclusion delay.Conclusion: Pioglitazone activated PKA, increasing Mrp2 transports to detoxify xenobiotics. Pioglitazone may allow the donor indications for liver transplantation to be expanded to include severe macrovesicular fatty livers.

Alpha-lipoic acid derivate DHLHZn reduces hepatic ischemia/reperfusion injury by inhibition of pro-inflammatory signaling - Uncorrected Proof

2012-05-14

Abstract: Background and aims: Hepatic ischemia/reperfusion (I/R) injury induces formation of reactive oxygen species and release of pro-inflammatory cytokines, which together cause liver damage and organ dysfunction. The aim of this study was to evaluate the protective effect of alpha-lipoic acid derivate dihydrolipoyl histidinate zinc complex (DHLHZn) against hepatic I/R injury in a rat model.Methods: Thirty male Wistar rats were subjected to 45 min of hepatic ischemia by clamping of the hepatic artery and portal vein, followed by a 6-h reperfusion period. DHLHZn (10 mg/kg) (I/R+DHLHZn group) or saline (I/R group) was administered intraperitoneally twice, 30 min before ischemia and at the beginning of the reperfusion. The rats were killed at the end of the reperfusion period. Serum levels of pro-inflammatory cytokines and liver enzymes, hepatic neutrophil infiltration, and histology were determined. Furthermore, Bio-Plex phosphoprotein assays of the liver extracts were performed to investigate the mechanism of DHLHZn.Results: Serum levels of liver enzymes and pro-inflammatory cytokines and hepatic neutrophil infiltration were increased in the I/R group, but these increases were significantly inhibited in the I/R+DHLHZn group. Levels of phosphorylated mitogen-activated protein kinase family members, such as extracellular signal-regulated kinases, c-JUN N-terminal kinase and p38, and nuclear factor-kappaB in the liver extracts were significantly increased in the I/R group, but the p38 mitogen-activated protein kinase and nuclear factor-kappaB phosphorylation levels were significantly inhibited in the I/R+DHLHZn group.Conclusions: DHLHZn could reduce hepatic I/R injury in a rat model, suggesting that DHLHZn may exert anti-inflammatory effects by inhibition of pro-inflammatory signaling.

Age-related differences in hepatic ischemia/reperfusion: Gene activation, liver injury, and protective effect of melatonin - Uncorrected Proof

2012-05-14

Abstract: Background: Ischemia/reperfusion (I/R) causes functional and structural damage to liver cells, this being more pronounced with increasing age of the tissue. Melatonin is a pineal indole that has been shown to play an important role as a free radical scavenger and anti-inflammatory molecule.Material and methods: The age-dependent responses to I/R were compared in 2-mo-old and 14-mo-old male Wistar rats. After 35 min of hepatic ischemia followed by 36 h of reperfusion, rats were sacrificed. Sham-operated control rats underwent the same protocol without real vascular occlusion. Animals were intraperitoneally injected with 10 mg/kg melatonin 24 h before the operation, at the time of surgery, and 12 and 24 h after it. The tissues were submitted to histopathologic evaluation. The levels of ALT and AST were analyzed in plasma. The expression of TNF-α, IL-1β, IL-10, MCP-1, IFN-γ, iNOS, eNOS, Bad, Bax, Bcl2, AIF, PCNA, and NFKB1 genes were detected by RT-PCR in hepatic tissue.Results: I/R was associated with significant increases in the expression of pro-inflammatory and pro-apoptotic genes in liver. Older rats submitted to I/R were found to respond with increased liver damage as compared with young rats, with serum ALT and AST levels significantly higher than in young animals. Mature rats also showed more evident increases in expression of pro-inflammatory cytokines (IL-1β, MCP-1, and IFN-γ) as well as a decrease in the mRNA expression of IL-10 as compared with young animals. Pro-apoptotic genes (Bax, Bad, and AIF) were significantly enhanced in liver after I/R, without differences between young and mature animals. However, the expression of Bcl2 gene did not show any change. Melatonin treatment was able to lower the expression of pro-inflammatory cytokines and pro-apoptotic genes and to improve liver function, as indicated by normalization of plasma AST and ALT levels and by reduction of necrosis and microsteatosis areas.Conclusions: Melatonin treatment was able to reduce the I/R-stimulated pro-inflammatory and pro-apoptotic genes in the rat liver. Since older animals showed a more marked increase in inflammation and in liver injury, the treatment was more effective in those subjects.

Early protective effect of total hypoxic preconditioning on rats against systemic injury from hemorrhagic shock and resuscitation - Uncorrected Proof

Zeyan Duan, Lei Zhang, Jin Liu, Xujin Xiang, Haixia Lin — 2012-05-14

Abstract: Background: In vivo or in vitro hypoxic preconditioning (HPC) can protect various tissues and cells against subsequent ischemia and/or reperfusion (hypoxia and/or reoxygenation) injury. Total HPC (THPC) in animal models is largely aimed at protecting single organs; however, scant data exist on whole body protection. The present study investigated whether THPC could protect anesthetized rats against the systemic injury induced by hemorrhagic shock and resuscitation (HS/R).Methods: The 4-cycle THPC protocol consisted of 5 min of inhalation hypoxia (fraction of inspired oxygen 10%, N2 90% plus oxygen 10%) followed by 10 min of inhalation air (oxygen 21%). An acute HS/R model of anesthetized rats was used. The rats were divided into severe HS/R or moderate HS/R groups according to a shed blood volume of 60% or 50% (HS/R60% or HS/R50%, respectively) of the total blood volume, respectively. In the severe HS/R group, the heart rate, respiration rate, and mean arterial pressure of the rats were measured, and the survival of the rats was observed. We also examined the pathomorphologic changes in the vital organs of rats and measured the arterial blood gas, heart rate, respiration rate, and mean arterial pressure of the rats in the moderate HS/R group.Results: THPC did not result in irreversible changes or death in the rats. The rats in the THPC + HS60%/R group had a significantly greater survival rate than those in the HS60%/R group (59% versus 33%, log-rank test, chi-square = 4.356, P = 0.037). The histopathologic lung score of the rats in the HS50%/R group (1.7 ± 0.5) was significantly greater than that in the THPC + HS50%/R (1.1 ± 0.6, P = 0.046). The arterial blood gas pH was lower in the HS50%/R group than in the THPC + HS50%/R group. THPC had a greater influence on the arterial partial pressure of oxygen and carbon dioxide than on bicarbonate radical and base excess. The respiration rate in the THPC + HS/R group was faster than that in the HS/R group. No significant differences in heart rate or mean arterial pressure were seen between the THPC + HS/R and HS/R groups.Conclusions: In anesthetized rats, THPC provided early protection against the subsequent systemic injury caused by hemorrhagic shock after resuscitation. THPC might exert systemic protection by improving the function of vital organs (e.g., lungs and, perhaps, the brain).

Bile salts increase epithelial cell proliferation through HuR-induced c-Myc expression - Uncorrected Proof

Erin E. Perrone, Lan Liu, Douglas J. Turner, Eric D. Strauch — 2012-05-11

Abstract: Background: Bile salts increase intestinal mucosal proliferation through an increase in c-Myc, a transcription factor that controls the expression of numerous translation regulatory proteins. HuR is an RNA-binding protein that regulates translation of target mRNAs. RNA-binding proteins can control mRNA stability by binding to AU- and U-rich elements located in the 3ʹ-untranslated regions (3ʹ-UTRs) of target mRNAs.Aim: To determine how bile salt–induced c-Myc stimulates enterocyte proliferation.Methods: Enterocyte proliferation was measured both in vivo using C57Bl6 mice and in vitro using IEC-6 cells after taurodeoxycholate (TDCA) supplementation. HuR and c-Myc protein expression was determined by immunoblot. c-Myc mRNA expression was determined by PCR. HuR expression was inhibited using specific small interfering RNA. HuR binding to c-Myc mRNA was determined by immunoprecipitation.Results: TDCA increased enterocyte proliferation in vivo and in vitro. TDCA stimulates translocation of HuR from the nucleus to the cytoplasm. Cytoplasmic HuR regulates c-Myc translation by HuR binding to the 3ʹ-UTR of c-Myc mRNA. Increased TDCA-induced c-Myc increases enterocyte proliferation.Conclusions: Bile salts have beneficial effects on the intestinal epithelial mucosa, which are important in maintaining intestinal mucosal integrity and function. These data further support an important beneficial role of bile salts in regulation of mucosal growth and repair. Decreased enterocyte exposure to luminal bile salts, as occurs during critical illness, liver failure, starvation, and intestinal injury, may have a detrimental effect on mucosal integrity.

Interplay of antibiotics and bacterial inoculum on suture-associated biofilms - Uncorrected Proof

Donavon J. Hess, Michelle J. Henry-Stanley, Carol L. Wells — 2012-05-11

Abstract: Background: Biofilms are often antibiotic resistant, and it is unclear if prophylactic antibiotics can effectively prevent biofilm formation. Experiments were designed to test the ability of high (bactericidal) concentrations of ampicillin (AMP), vancomycin (VAN), and oxacillin (OXA) to prevent formation of suture-associated biofilms initiated with low (104) and high (107) numbers of Staphylococcus aureus.Materials and methods: S. aureus biofilms were cultivated overnight on silk suture incubated in biofilm growth medium supplemented with bactericidal concentrations of AMP, VAN, or OXA. Standard microbiological methods were used to quantify total numbers of viable suture-associated S. aureus. Crystal violet staining followed by spectroscopy was used to quantify biofilm biomass, which includes bacterial cells plus matrix components. To observe the effects of antibiotics on the microscopic appearance of biofilm formation, biofilms were cultivated on glass slides, then stained with fluorescent dyes, and observed by confocal microscopy.Results: In the presence of a relatively low inoculum (104) of S. aureus cells, bactericidal concentrations of AMP, VAN, or OXA were effective in preventing development of suture-associated biofilms. However, similar concentrations of these antibiotics were typically ineffective in preventing biofilm development on sutures inoculated with 107 S. aureus, a concentration relevant to contaminated skin. Confocal microscopy confirmed that bactericidal concentrations of AMP, VAN, or OXA inhibited, but did not prevent, development of S. aureus biofilms.Conclusion: Bactericidal concentrations of AMP, VAN, or OXA inhibited formation of suture-associated biofilms initiated with low numbers (104), but not high numbers (107), of S. aureus cells.

Hemodialysis reliable outflow device, in end-stage dialysis access: A decision analysis model - Uncorrected Proof

Leigh Anne Dageforde Redhage, Peter R. Bream, Derek E. Moore — 2012-05-11

Abstract: Background: The hemodialysis reliable outflow (HeRO) dialysis access device is a permanent tunneled dialysis graft connected to a central venous catheter and is used in patients with end-stage dialysis access (ESDA) issues because of central venous stenosis. The safety and effectiveness of the HeRO device has previously been proven, but no study thus far has compared the cost of its use with tunneled dialysis catheters (TDCs) and thigh grafts in patients with ESDA.Materials and methods: A decision analytic model was developed to simulate outcomes for patients with ESDA undergoing placement of a HeRO dialysis access device, TDC, or thigh graft. Outcomes of interest were infection, thrombosis, and ischemic events. Baseline values, ranges, and costs were determined from a systematic review of the literature. Total costs were based on 1y of post-procedure outcomes. Sensitivity analyses were conducted to test model strength.Results: The HeRO dialysis access device is the least costly dialysis access with an average 1-y cost of $6521. The 1-y cost for a TDC was $8477. A thigh graft accounted for $9567 in a 1-y time period.Conclusions: The HeRO dialysis access device is the least costly method of ESDA. The primary determinants of cost in this model are infection in TDCs and leg ischemia necessitating amputation in thigh grafts. Further study is necessary to incorporate patient preference and quality of life into the model.

Liver transplantation with donation after cardiac death donors: A comprehensive update - Corrected Proof

2012-05-11

Abstract: Background: Use of donation after cardiac death (DCD) donors has been proposed as an effective way to expand the availability of hepatic allografts used in orthotopic liver transplantation (OLT); yet, there remains no consensus in the medical literature as to how to choose optimal recipients and donors based on available information.Methods: We queried the United Network of Organ Sharing/Organ Procurement and Transplantation Network database for hepatic DCD allografts used in OLT. As of March 31, 2011, 85,148 patients received hepatic allografts from donation-after-brain-death (DBD) donors, and 2351 patients received hepatic allografts from DCD donors. We performed survival analysis using log-rank and Kaplan-Meier tests. We performed univariate and multivariate analyses using the Cox proportional hazards model. All statistics were performed with SPSS 15.0.Results: Patients receiving hepatic DCD allografts had significantly worse survival compared with patients receiving hepatic DBD allografts. Pediatric patients who received a hepatic DCD allograft had similar survival to those who received a hepatic DBD allograft. The optimal recipient-related characteristics were age <50 y, International Normalized Ratio <2.0, albumin >3.5 gm/dL, and cold ischemia time <8 h; optimal donor-related characteristics included age <50 y and donor warm ischemia time <20 min.Conclusions: By identifying certain characteristics, the transplant clinician’s decision-making process can be assisted so that similar survival outcomes after OLT can be achieved with the use of hepatic DCD allografts.

Magnesium deficiency promotes secretion of high-mobility group box 1 protein from lipopolysaccharide-activated macrophages in vitro - Uncorrected Proof

2012-05-11

Abstract: Background: High-mobility group box 1 (HMGB1) is a critical mediator of sepsis that is closely related to sepsis lethality. Magnesium deficiency predisposes to worse outcomes from endotoxin challenge by promoting the production of cytokines. However, whether magnesium deficiency affects the expression and release of HMGB1 is not currently known. In the present study, we explored the effect of magnesium deficiency on the expression and secretion of HMGB1 in lipopolysaccharide (LPS)-activated RAW264.7 macrophages.Methods: RAW264.7 cells were incubated with LPS in normal magnesium (1 mmol/L magnesium sulfate) or low magnesium (0.1 mmol/L magnesium sulfate) in Roswell Park Memorial Institute 1640 medium. An enzyme-linked immunosorbent assay was used to detect HMGB1 levels in the culture supernatant. Real-time polymerase chain reaction was used to assess the HMGB1 mRNA levels. A nuclear/cytoplasm extraction kit was used to extract the nuclear and cytoplasmic proteins. Western blotting was used to observe the changes in translocation of HMGB1 from the nucleus to the cytoplasm. A nuclear factor κ-light chain enhancer of activated B cells (NF-κB) p50/p65 transcription factor assay kit was used to analyze the NF-κB activity in nuclear extracts.Results: Magnesium deficiency promoted translocation of HMGB1 from the nucleus to the cytoplasm and its extracellular secretion in LPS-activated macrophages, while enhancing the expression of HMGB1 mRNA. Furthermore, magnesium deficiency promoted the translocation of NF-κB from the cytoplasm to the nucleus in LPS-activated macrophages.Conclusions: Magnesium deficiency promotes the translocation of HMGB1 from the nucleus to the cytoplasm and the expression of HMGB1 mRNA. Magnesium deficiency also activates the NF-κB signaling pathway.

Erythropoietin improves the efficiency of endothelial progenitor cell therapy after myocardial infarction in mice: Effects on transplanted cell survival and autologous endothelial progenitor cell mobilization - Uncorrected Proof

Yan Cheng, Ruoyu Hu, Lei Lv, Lin Ling, Shisen Jiang — 2012-05-11

Abstract: Background: Endothelial progenitor cells (EPCs) participate in vascular repair and angiogenesis. Thus, EPC transplantation into ischemic myocardium might improve cardiac function; however, the vast majority of cells die within a short period. The present study was designed to investigate whether exogenous erythropoietin (EPO) delivery could improve the survival of transplanted EPCs and enhance the efficiency of EPC-based cell therapy.Methods: Myocardial infarction was induced in wild-type mice by ligating the left anterior descending coronary artery. Enhanced green fluorescent protein-EPCs with or without EPO were transplanted into peri-infarct myocardium. Enhanced green fluorescent protein-EPCs were detected 7 and 28 d after surgery. The amount of circulating EPCs was analyzed 3 and 28 d after surgery. The stromal cell-derived factor-1α and vascular endothelial growth factor concentrations, microvessel density, apoptosis, fibrosis in the peri-infarct myocardium, and cardiac function were compared among the groups.Results: More enhanced green fluorescent protein-EPCs were found in the hearts treated with EPC + EPO than in those treated with EPC alone. The circulating EPC level was markedly elevated after EPC + EPO treatment compared with EPC application alone. Stromal cell-derived factor-1α and vascular endothelial growth factor were increased accordingly, along with increased microvessel density, decreased apoptosis, and reduced fibrosis in the peri-infarct myocardium. Left ventricular fractional shortening was greater and the interventricular septum was thicker after EPC + EPO treatment compared with EPC treatment alone.Conclusions: EPO improved the efficiency of EPC therapy in mice with myocardial infarction. This effect was associated with enhanced transplanted EPC survival and autologous EPC mobilization.

Hepatic arterial reconstruction for orthotopic liver transplantation in the rat - Corrected Proof

2012-05-10

Abstract: Background: Orthotopic liver transplantation (OLT) models in rats have been investigated in many studies. The reconstruction of hepatic artery is required for reliable OLT and also requires advanced skills.Methods: The hepatic artery reconstructions by a hand-suture technique and a new method using a micro T-tube were investigated in rats with a whole-liver syngeneic graft. Operative time and postoperative patency were compared between the hand-suture and micro T-tube techniques.Results: Our technique using the micro T-tube shortened the operative time of recipient surgery compared with the hand-suture technique and prolonged the operative time for the donor. The patency ratio was maintained at 24h after OLT with hand suturing but was significantly reduced with the micro T-tube, which had a patency ratio of 0.83 only up to 6h after OLT.Conclusion: The micro T-tube technique may have potential usefulness in the rat OLT model but requires further modification.

Erratum - Uncorrected Proof

2012-05-10

In the February 2012 issue of the Journal of Surgical Research, we regret that in the Abstract 34.8 on page 284, ‘‘Follow-Up of Pancreatic Cysts: is Yearly Imaging Really Necessary?,’’ by D. Xourafas, W. Jiang, S.R. Lipsitz, A. Tavakkolizadeh, S.W. Ashley; Brigham and Women's Hospital/Harvard Medical School, Boston, MA (J Surg Res 2012;172:187-350), the author names were incorrectly listed. They are now presented correctly above.

Predicting complicated choledocholithiasis - Uncorrected Proof

2012-05-09

Abstract: Introduction: Management of choledocholithiasis and its complications is variable and often requires transfer to a specialty facility. This study links patient-specific characteristics with the outcome measure of complicated choledocholithiasis to identify high-risk patients who may require expedited treatment or transfer to a higher level of care.Materials and methods: Patients with a discharge diagnosis of choledocholithiasis (CDL) were identified from the 2009 Nationwide Inpatient Sample (NIS). Patient characteristics were identified associated with the primary outcome measure of complicated choledocholithiasis (cCDL), defined as acute pancreatitis or cholangitis during the admission for CDL. Predictors of mortality were also evaluated. Analysis was performed using complex-sample univariate and adjusted analyses.Results: We identified 123,990 discharges with a diagnosis of CDL. The overall incidence of CDL was 314 per 100,000 NIS discharges. Forty-one percent of CDL discharges were for cCDL (acute pancreatitis 31%, cholangitis 12%). Risk factors for cCDL included age (risk increased 0.8% per year), male gender (odds ratio [OR] 1.2, 95% confidence interval [CI] 1.1–1.2), alcohol abuse (OR 1.5, CI 1.3–1.8), diabetes (OR 1.1, CI 1.0–1.2), hypertension (OR 1.1, CI 1.0–1.2), obesity (OR 1.2, CI 1.1–1.3), nonelective admission (OR 2.3, CI 2.0–2.6), and Asian/Pacific Islander race/ethnicity (OR 1.2, CI 1.0–1.5). Patients with cCDL had increased odds of mortality (OR 1.5, CI 1.2–2.0).Conclusions: Increased age, nonelective admission, and specific comorbid conditions are associated with cCDL, which has increased mortality. These factors can be used to identify patients needing timely access to treatment or transfer to a higher level of care.

Aortic balloon occlusion is effective in controlling pelvic hemorrhage - Corrected Proof

2012-05-09

Abstract: Background: The objective of this study was to evaluate the efficacy of resuscitative endovascular aortic balloon occlusion (REBOA) of the distal aorta in a porcine model of pelvic hemorrhage.Methods: Swine were entered into three phases of study: injury (iliac artery), hemorrhage (45 s), and intervention (180 min). Three groups were studied: no intervention (NI, n = 7), a kaolin-impregnated gauze (Combat Gauze) (CG, n = 7), or REBOA (n = 7). The protocol was repeated with a dilutional coagulopathy (CG-C, n = 7, and REBOA-C, n = 7). Measures of physiology, rates of hemorrhage, and mortality were recorded.Results: Rate of hemorrhage was greatest in the NI group, followed by the REBOA and CG groups (822 ± 415 mL/min versus 11 ± 13 and 0.2 ± 0.4 mL/min respectively; P < 0.001). MAP following intervention (at 15 min) was the same in the CG and REBOA groups and higher than in the NI group (70 ± 4 and 70 ± 11 mm Hg versus 5 ± 13 mm Hg respectively; P < 0.001). There was 100% mortality in the NI group, with no deaths in the CG or REBOA group. In the setting of coagulopathy, the rate of bleeding was higher in the CG-C versus the REBOA-C group (229 ± 295 mL/min versus 20 ± 7 mL/min, P = 0.085). MAP following intervention (15 min) was higher in the REBOA-C than the CG-C group (71 ± 12 mm Hg versus 28 ± 31 mm Hg; P = 0.005). There were 5 deaths (71.4%) in the CG-C group, but none in the REBOA-C group (P = 0.010).Conclusion: Balloon occlusion of the aorta is an effective method to control pelvic arterial hemorrhage. This technique should be further developed as an adjunct to manage noncompressible pelvic hemorrhage.

Minocycline ameliorates lung and liver dysfunction in a rodent model of hemorrhagic shock/resuscitation plus abdominal compartment syndrome - Corrected Proof

Cay-Huyen Chen, Pei-Shan Tsai, Chun-Jen Huang — 2012-05-09

Abstract: Background: We sought to elucidate whether minocycline, a broad-spectrum tetracycline antibiotic with potent anti-inflammation capacity, could mitigate inflammatory response and organ dysfunction in the lungs and liver induced by hemorrhagic shock/resuscitation (HS) plus abdominal compartment syndrome (ACS).Materials and methods: Adult male rats were randomized to receive HS plus ACS or HS plus ACS plus minocycline (denoted as the HS/A and HS/A-M group, respectively; n = 12). Sham-instrumentation groups were employed to serve as the controls. Hemorrhagic shock/resuscitation was induced by blood drawing (mean arterial pressure: 40–45 mm Hg for 60 min) followed by shed blood/saline mixture reinfusion. Subsequently, intra-abdominal pressure (IAP) was increased to 25 mm Hg by injecting air into the preplaced intraperitoneal latex balloon to induce ACS. Minocycline (20 mg/kg) was intravenously administered immediately after resuscitation. IAP was maintained at 25 mm Hg for 6 h. Then, all rats were euthanized.Results: The levels of polymorphonuclear leukocyte infiltration, the wet/dry weight ratio, and the concentrations of inflammatory molecules (e.g., chemokine, cytokine, and prostaglandin E2) in lung and liver tissues of the HS/A group were significantly higher than those of the HS/A-M groups (all P < 0.05). Moreover, the levels of lung dysfunction (assayed by arterial blood gas) and liver dysfunction (assayed by plasma concentrations of bilirubin, aspartate aminotransferase, and alaninine aminotransferase) of the HS/A group were significantly higher than those of the HS/A-M group (all P < 0.05).Conclusions: Minocycline ameliorates inflammatory response and organ dysfunction in the lungs and liver induced by hemorrhagic shock/resuscitation plus abdominal compartment syndrome.

Neutrophil elastase inhibitor improves survival rate after ischemia reperfusion injury caused by supravisceral aortic clamping in rats - Uncorrected Proof

2012-05-09

Abstract: Background: Sivelestat sodium hydrate is a specific neutrophil elastase inhibitor effective in acute lung injury (ALI) associated with systemic inflammatory response syndrome. Bowel ischemia reperfusion injury (IRI) induced by supravisceral aortic clamping is associated with an excessive systemic inflammatory response, resulting in remote organ damage, including ALI. In this study, we investigated whether sivelestat can attenuate neutrophil sequestration in the lung, alleviate ALI, and improve survival in a rat bowel IRI model.Methods: Adult male Sprague-Dawley rats underwent bowel IRI induced by supravisceral aortic clamping and were randomly assigned to receive sivelestat or saline (control) and monitored for survival. We randomly assigned other rats to undergo laparotomy alone (sham operation), IRI alone, or IRI and sivelestat treatment. We evaluated blood samples for organ function, cytokine levels, and neutrophil elastase activity after reperfusion. Organs were analyzed histologically. We also determined lung injury in another set of rats.Results: Bowel IRI induced a significant increase in serum variables indicative of organ function, cytokine concentrations, neutrophil elastase activity, and lung permeability and edema, which reflected the presence of both systemic inflammatory response syndrome and compensatory anti-inflammatory response syndrome. Treatment with sivelestat significantly improved survival rate, lung permeability, and edema, and significantly decreased levels of creatinine, interleukin 6, interleukin 10, and neutrophil elastase activity. Histological studies showed that sivelestat-treated rats had less bowel IRI-induced damage to lung and liver tissue than controls.Conclusion: In a rat model, administration of sivelestat attenuated the effects of bowel IRI induced by supravisceral aortic clamping, and improved the survival rate.

Gaq G proteins modulate MMP-9 gelatinase during remodeling of the murine femoral artery - Uncorrected Proof

Yiping Zou, Yuyang Fu, Mark G. Davies — 2012-05-09

Abstract: Background: Vessels heal after injury and G protein–coupled receptors are involved in the vascular smooth muscle cell proliferation required to form intimal hyperplasia. We have previously identified the role of Gaq in vascular smooth muscle cell proliferation in vitro. This study now examines the role of Gaq in the developing intimal hyperplasia in a murine model and the impact of disruption of Gaq signaling on intimal hyperplasia development.Methods: We employed a murine femoral wire injury model in which a micro-wire is passed through a branch of the femoral artery and used to denude the common femoral artery. We perfusion-fixed specimens and stained sections with hematoxylin-eosin and Movat's stains such that morphometric analysis could be performed using an Image-Pro system. We also harvested additional specimens of femoral artery and snap-froze them for Western blotting or zymography, to allow for the study of G protein expression and both protease expression and activity. We used contralateral vessels as controls. We immersed additional vessels in pluronic gel containing the chemical Gaq G protein inhibitors GP-2A, siRNA to Gaq or adenovirus containing mutant inactive Gaq.Results: Gαq expression increased in a time-dependent manner after femoral artery injury. Sham-operated vessels did not produce such a response. Inhibition of Gaq reduced cell proliferation without affecting cell migration. Interruption of Gaq signaling also inhibited the development of intimal hyperplasia. Inhibition of Gαq did not alter peak urinary-type plasminogen activator activity and expression, but did increase early plasminogen activator inhibitor-1 activity and expression. Inhibition of Gαq reduced peak metalloproteinase (MMP)-9 activity at Day 3 but did not influence peak MMP-2 activity at Day 7. Protein expression for MMP-9 was also decreased, but that of MMP-2 was not affected. There were no changes in the expression or the activity of the respective inhibitors for MMP-9 and MMP-2, and tissue inhibitor of metalloproteinases-1 and -2.Conclusions: These data demonstrate that femoral wire injury in the mouse is associated with a time-dependent increase in Gαq expression. Inhibition of Gαq alters cell proliferation and is associated with decreased MMP-9 expression and activity.

Inhibitory effects of (-)-epigallocatechin-3-gallate and pterostilbene on pancreatic cancer growth in vitro - Corrected Proof

Shannon F. Kostin, Debbie E. McDonald, David W. McFadden — 2012-05-07

Abstract: Background: It has been previously shown that the naturally occurring antioxidant (-)-epigallocatechin-3-gallate (EGCG), found in green tea, and pterostilbene, a stilbenoid derived from blueberries, inhibit pancreatic cancer in vitro when used individually. We hypothesized that the combination of EGCG and pterostilbene would reveal additive effects in vitro.Methods: Using the pancreatic cancer cell lines MIA PaCa-2 and PANC-1, efficacy and synergism were evaluated for cell proliferation and viability (3-(4,5-dimethyltiazol-2-y1)-2,5-diphenltetrazolium bromide assays, cell cycle analysis) and mitochondrial apoptosis (mitochondrial depolarization, cytochrome C release, caspase-3/7 activity, cell death detection using enzyme-linked immunosorbent assay).Results: Cell proliferation assays revealed significant additive antiproliferative effects with pterostilbene and EGCG in both cell lines at the later, 72-h, point (P < 0.05). MIA underwent S-phase arrest with the combination (10–12% increase); however, cell cycle arrest was not observed in PANC. The combination induced mitochondrial depolarization and upregulated cytochrome C (P < 0.05) in MIA, but these effects were not observed in PANC. EGCG increased caspase-3/7 in MIA; however, the combination did not significantly increase the activity in either cell line (P < 0.05). Apoptosis was only observed in PANC (P < 0.05). The reduction in proliferation in MIA in the 3-(4,5-dimethyltiazol-2-y1)-2,5-diphenltetrazolium bromide assays with the combination indicated that cell death occurs, possibly through another mechanism.Conclusions: Our results are encouraging regarding the future use of EGCG and pterostilbene to improve traditional pancreatic cancer therapies. In conclusion, EGCG and pterostilbene have additive, antiproliferative effects in vitro and alter the apoptotic mechanisms in both cell lines by modulation at different points in the mechanism.

Medical malpractice and hernia repair: An analysis of case law - Corrected Proof

2012-05-07

Abstract: Background: Litigation analysis and clinician education are essential to reduce the number and cost of malpractice claims. This study evaluates the clinical characteristics and legal outcomes of medical malpractice litigation initiated by patients having undergone a hernia repair operation.Materials and methods: Published civil suits were obtained from a legal database for state and federal decisions constituting case law. The published material includes information on defendants, plaintiffs, allegations, outcomes, and a variety of legal issues. A retrospective review of 44 published cases from 25 states was performed.Results: Complications were present in 20 of 44 (45%) suits, four (9%) of which were because of infection. Death occurred in five (11%) cases, and failure to obtain informed consent was alleged in seven (16%) of the suits. Retained foreign bodies were present in 7 of the 44 (16%) suits. Other allegations included incorrect surgical technique, insufficient need for surgery, and emotional distress. Most (64%) patients initiating malpractice litigation were male, and inguinal, hiatal, and ventral hernia repairs account for 39%, 27%, and 14% of cases, respectively. Most suits (40%) were initiated in Southern states. Surgical mesh was indicated in 5 of 44 (11%) suits but four of five were unrelated to the suit. One patient initiated litigation because of the fact that the surgeon did not use mesh during surgery, which was discussed preoperatively during the informed consent. The court ruled in favor of the plaintiff in 12 of 44 (27%) suits, with compensation ranging from roughly $19,000 to $8,000,000. Louisiana and New York had six and seven suits each, which appears disproportionate given their respective populations.Conclusion: Complications and death resulting from alleged clinical negligence play a significant role in both the initiation and the outcome of malpractice litigation. Retained foreign bodies and lack of informed consent account for roughly one-third of malpractice litigation associated with hernia repairs. Many of these suits may be avoided with proper patient education and documentation of such along with standard operative preventative measures.

Deconstructing intraoperative communication failures - Corrected Proof

2012-05-07

Abstract: Background: Communication failure is a common contributor to adverse events. We sought to characterize communication failures during complex operations.Methods: We video recorded and transcribed six complex operations, representing 22h of patient care. For each communication event, we determined the participants and the content discussed. Failures were classified into four types: audience (key individuals missing), purpose (issue nonresolution), content (insufficient/inaccurate information), and/or occasion (futile timing). We added a systems category to reflect communication occurring at the organizational level. The impact of each identified failure was described.Results: We observed communication failures in every case (mean 29, median 28, range 13–48), at a rate of one every 8min. Cross-disciplinary exchanges resulted in failure nearly twice as often as intradisciplinary ones. Discussions about or mandated by hospital policy (20%), personnel (18%), or other patient care (17%) were most error prone. Audience and purpose each accounted for >40% of failures. A substantial proportion (26%) reflected flawed systems for communication, particularly those for disseminating policy (29% of system failures), coordinating personnel (27%), and conveying the procedure planned (27%) or the equipment needed (24%). In 81% of failures, inefficiency (extraneous discussion and/or work) resulted. Resource waste (19%) and work-arounds (13%) also were frequently seen.Conclusions: During complex operations, communication failures occur frequently and lead to inefficiency. Prevention may be achieved by improving synchronous, cross-disciplinary communication. The rate of failure during discussions about/mandated by policy highlights the need for carefully designed standardized interventions. System-level support for asynchronous perioperative communication may streamline operating room coordination and preparation efforts.

Comparison of pediatric appendectomy outcomes between pediatric surgeons and general surgery residents - Corrected Proof

2012-05-04

Abstract: Background: Appendectomy is the most common urgent procedure in children, and surgical outcomes may be affected by the surgeon's experience. This study's aim is to compare appendectomy outcomes performed by pediatric surgeons (PSs) and general surgery residents (GSRs).Materials and methods: A retrospective review of all patients younger than 16y treated for appendicitis at two different campuses of the same institution during the years 2008–2009 was performed. Appendectomies were performed by PS in one campus and GSR in the other. Primary end points included postoperative morbidity and hospital length of stay.Results: During the study period, 246 (61%) patients were operated by senior GSR (postgraduate year 5–7) versus 157 (39%) patients by PS. There was no significant difference in patients' characteristics at presentation to the emergency room and the rate of appendeceal perforation (11% versus 15%, P=0.32), and noninfectious appendicitis (5% versus 5% P=0.78) also was similar. Laparoscopic surgery was performed more commonly by GSR (16% versus 9%, P=0.02) with shorter operating time (54±1.5 versus 60±2.1, P=0.01). Interestingly, the emergency room to operating room time was shorter for GSR group (419±14 versus 529±24min, P<0.001). The hospital length of stay was shorter for the GSR group (4.0±0.2 versus 4.5±0.2, P=0.03), and broad-spectrum antibiotics were used less commonly (20% versus 53%, P<0.0001) and so was home antibiotics continuation (13% versus 30%, P<0.0001). Nevertheless, postoperative complication rate was similar (5% versus 7%, P=0.29) and so was the rate of readmissions (2% versus 5%, P=0.52).Conclusions: The results of this study suggest that the presence of a PS does not affect the outcomes of appendectomies.

Gut to artery to ureter—Robbing peter to pay paul - Uncorrected Proof

Ruoya Wang, Luke Brewster — 2012-05-04

Traumatic ureteral injury sustained from surgical operation or disease can require the reconstruction of the ureter to maintain proper urinary track function. In cases of large trauma, the ilium may serve as a suitable conduit to graft the damaged section . However, this procedure is intensive and carries both urinary track and intestinal complications. As a result, numerous studies have investigated the use of synthetic conduits but have been met with limited success. Recently, porcine small intestinal submucosa was used to successfully repair small defects ; however, small intestinal submucosa was found to be suboptimal for replacing long segments . A potential method to circumvent the current challenges is to cellularly seed a scaffold in vitro with stem cells, thus priming the conduit to be more receptive to implantation by allowing a restoration of cellular function when the stem cells differentiate. Adipose-derived stem cells (ADSCs) are being widely investigated for regenerative therapy applications. These adult stem cells can be sourced from readily available human adipose tissue . However, proper differentiation of ADSC into functional cells remains challenging and can depend on many influences, including growth factors, matrix properties, and the local mechanical environment .

Associations between pediatric choledochal cysts, biliary atresia, and congenital cardiac anomalies - Corrected Proof

Andrew J. Murphy, Jason R. Axt, Harold N. Lovvorn — 2012-05-01

Abstract: Background: In our institutional experience treating pediatric choledochal cysts over the past 12 y, we noted that seven of 32 patients (21.9%) had comorbid congenital cardiac anomalies. This association has not been previously described other than in isolated case reports. We aimed to quantify this association on a national level.Materials and methods: We queried the 2009 Healthcare Cost and Utilization Project Kids' Inpatient Database. We identified patients with a diagnosis of choledochal cyst (ICD-9-CM 75169, 75162, and 75160) or biliary atresia (75161). We defined cardiac anomalies using the Clinical Classification Software code (CCS 213). Comorbid choledochal cysts or biliary atresia and congenital cardiac anomalies were quantified in both infant (<12 mo) and child (1–18 y) subpopulations.Results: Of 1646 estimated discharges for patients with choledochal cysts, 506 (30.7%) were for patients who also had congenital cardiac anomalies, compared with 2.6% in the general hospitalized population (χ2; P < 0.001). The frequency of congenital cardiac anomalies was lower in 1973 hospitalizations for biliary atresia (13.8%) than in those for patients with choledochal cysts (χ2; P < 0.001). We detected cardiac anomalies in 44.9% of choledochal cyst hospitalizations for infants <12 mo (versus 3.44% general hospitalized population; χ2; P < 0.001), but in 6.9% of children ages 1–18 y (versus 1.3% general hospitalized population; χ2; P < 0.001).Conclusions: We observed a strong association between pediatric choledochal cysts and congenital cardiac anomalies that commonly manifests in infancy. When choledochal cysts are diagnosed either prenatally or in infancy, we suggest echocardiographic screening for cardiac anomalies, which may affect the timing of surgery and anesthetic planning.

Epithelioid sarcoma: One institution's experience with a rare sarcoma - Corrected Proof

2012-05-01

Abstract: Background: Epithelioid sarcomas (ES) are extremely rare soft tissue sarcomas. As such, their clinical behavior and response to treatment are poorly described in the literature.Methods: We queried the centralized cancer registry and pathology archives at the Johns Hopkins Medical Institution and identified 22 patients with a diagnosis of ES. We excluded two patients because of inadequate data. A pathologist reviewed patient charts and reexamined available histological slides. This study was performed with institutional review board approval.Results: The median age at diagnosis was 27.8 y; most patients (75%) were male. Regional lymph node metastases were present in 10% of patients at presentation. The majority of tumors (57.9%) recurred and 35% recurred more than once, although the number of recurrences did not affect survival (P = 0.48). Patients did not experience a decrease in time to recurrence with increasing number of resections. The median time between resection and recurrence was 1.23 y and the maximum was 18.8 y. Median overall survival was 56.2 mo and 5-y survival was 92%.Conclusions: Our study reveals that ES is an extremely rare tumor with a protracted and recurrent course, but overall survival may be more favorable than in the past. Patients benefit from aggressive and repeated resection. Epithelioid sarcoma is unique because it metastasizes to regional nodal basins. Extended surveillance is indicated, because recurrences can appear after decades of quiescence.

Low-intensity ultrasound accelerates mandibular implant bone integration in dogs with mandibular osteoradionecrosis - Uncorrected Proof

Gaoyi Wu, Lei Chen, Guoxiong Zhu, Yanliang Wang — 2012-04-30

Abstract: Background: To investigate whether low-intensity ultrasound accelerates healing in bone tissues close to dental implants with osteoradionecrosis of the mandible and is suitable for development as a therapy in patients with dental implants receiving radiotherapy.Materials and methods: Dog models of radiative bone injury surrounding dental implants in both sides of mandible were established by undergoing four treats of radiotherapy, each 15Gy. After radiative treatment, antibiotics were administered and the left injury was treated with ultrasound and the right with debridement. Measures for evaluation included spiral computed tomography (CT), Micro-CT, microvessel density, and pull-out experiment, and data were collected and analyzed.Results: After 4mo of radiotherapy, both sides of mandible displayed preclinic symptom of radiative osteonecrosis. Microvessel density of the side treated by ultrasound was 6.2152±0.6508 and that of the debridement side was 3.8490±0.8954 (P<0.05). Micro-CT results showed that bone volume fraction of trabecula, thickness of trabecula, trabecula spacing, and trabecula number of the ultrasound-treated mandible were 0.3605±0.0337, 0.0287±0.0045, 0.0369±0.0073, 71.6124±14.1649, and 7.2915±1.4937, whereas those of the debridement side were 0.1779±0.0178, 0.0151±0.0021, 0.6623±0.1125, 33.2686±5.949, and 5.0689±0.5028, respectively; statistical significance was observed (P<0.05). Pull-out experiment suggested that pull-out strength of the ultrasound-treated side was 0.5793±0.1066 whereas that of the debridement side was 0.2980±0.0243, representing a statistical significance (P<0.05).Conclusions: Low-intensity ultrasound can accelerate the healing of bone tissues surrounding dental implants in osteoradionecrosis of the mandible animals.

Role of inhibition of p38 mitogen-activated protein kinase in liver dysfunction after hemorrhagic shock and resuscitation - Corrected Proof

2012-04-30

Abstract: Background: The liver is one of the organs most frequently affected by trauma and hemorrhagic shock; the exact role of p38 mitogen-activated protein kinase (MAPK) activation in response to hepatic hemorrhagic shock/resuscitation (HS/R) remains unclear.Materials and methods: C57Bl/6 mice were divided into four groups: sham-operated group, SB-only group, control group, and SB + HS/R group. Hepatocellular injury (aspartate aminotransferase [AST] and alanine aminotransferase [ALT]) and tumor necrosis factor (TNF-α) and interleukin (IL-1β) messenger ribonucleic acid (mRNA) expression in the liver were assessed 6 h after resuscitation, p38 MAPK activation in the liver was assessed at 30 min after resuscitation.Results: p38 MAPK activation was higher in the control group than other groups 30 min after resuscitation. p38 MAPK activation level in the SB + HS/R group did not change significantly compared with that of sham and SB-only groups, but was significantly lower than that in the control group. The TNF-α mRNA expression in the control group was significantly higher than that in the sham group. The TNF-α mRNA levels after HS/R in the SB + HS/R group were significantly lower than those in the control group and were roughly the same as those in the sham and SB-only groups. IL-1β mRNA expression showed similar changes in the four groups. Serum ALT and AST levels in the control group were significantly higher than those in the sham group. The increase in serum ALT and AST levels after HS/R in the SB + HS/R group was significantly less pronounced than that in the control group and markedly higher than that in the sham group.Conclusions: p38 MAPK was phosphorylated during the HS/R process. Inhibiting the activation of p38 MAPK may attenuate HS/R injury to the liver.

A new model to analyze metaphyseal bone healing in mice - Corrected Proof

2012-04-30

Abstract: Background: Despite the increasing clinical problems with metaphyseal fractures, most experimental studies investigate the healing of diaphyseal fractures. Although the mouse would be the preferable species to study the molecular and genetic aspects of metaphyseal fracture healing, a murine model does not exist yet. Using a special locking plate system, we herein introduce a new model, which allows the analysis of metaphyseal bone healing in mice.Methods: In 24 CD-1 mice the distal metaphysis of the femur was osteotomized. After stabilization with the locking plate, bone repair was analyzed radiologically, biomechanically, and histologically after 2 (n=12) and 5wk (n=12). Additionally, the stiffness of the bone-implant construct was tested biomechanically ex vivo.Results: The torsional stiffness of the bone-implant construct was low compared with nonfractured control femora (0.23±0.1Nmm/° versus 1.78±0.15Nmm/°, P<0.05). The cause of failure was a pullout of the distal screw. At 2wk after stabilization, radiological analysis showed that most bones were partly bridged. At 5wk, all bones showed radiological union. Accordingly, biomechanical analyses revealed a significantly higher torsional stiffness after 5wk compared with that after 2wk. Successful healing was indicated by a torsional stiffness of 90% of the contralateral control femora. Histological analyses showed new woven bone bridging the osteotomy without external callus formation and in absence of any cartilaginous tissue, indicating intramembranous healing.Conclusion: With the model introduced herein we report, for the first time, successful metaphyseal bone repair in mice. The model may be used to obtain deeper insights into the molecular mechanisms of metaphyseal fracture healing.

All-trans retinoic acid preconditioning protects against liver ischemia/reperfusion injury by inhibiting the nuclear factor kappa B signaling pathway - Corrected Proof

2012-04-30

Abstract: Background: Inflammatory response plays a pathogenic role in liver ischemia/reperfusion (I/R) injury. All-trans retinoic acid (ATRA) is an active metabolite of vitamin A with anti-inflammatory effects. However, there are few reports on the anti-inflammatory effects of ATRA on liver I/R injury. The purpose of this study was to investigate the effects of ATRA on liver I/R injury and related mechanisms.Methods: A total of 54 male Sprague–Dawley rats were randomly divided into three groups (18 rats each), namely, sham, I/R, and I/R+ATRA groups. ATRA was intraperitoneally administered at a dose of 15mg/kg/d 14d before ischemia surgery. The segmental (70%) hepatic ischemia model was used by clamping the portal vein, hepatic artery, and bile duct of the left and median for 1h. The rats were sacrificed 3, 6, and 24h after reperfusion, and blood and liver tissue samples were obtained. Liver injury was evaluated by biochemical and histopathologic examinations. Myeloperoxidase activity was spectrophotometrically measured. The expression of pro-inflammatory cytokines, such as tumor necrosis factor-α and interleukin-6 was measured by enzyme-linked immunosorbent assay and real-time polymerase chain reaction. Liver nuclear factor kappa B (NF-κB) was detected by immunohistochemistry. The expression of NF-κB p65 and inhibitor NF-κB-α (IκBα) was determined by Western blot analysis.Results: The serum alanine aminotransferase level, Suzuki scores of hepatic histology, and hepatic myeloperoxidase activity, as indices of hepatic injury, were increased after reperfusion. The increase was attenuated by preadministration with ATRA. Compared with the I/R group, ATRA treatment increased IκBα expression and suppressed NF-κB p65 expression. Subsequently, the levels of tumor necrosis factor-α and interleukin-6 after liver I/R were effectively downregulated.Conclusions: ATRA administration can significantly attenuate I/R injury in rat liver. The protective mechanism is related to its anti-inflammatory function of inhibiting NF-κB activation.

Effects of fatty acids on endothelial cells: Inflammation and monocyte adhesion - Corrected Proof

2012-04-30

Abstract: Background: Diet is known to have an important impact on cardiovascular health. n-3 Fatty acids (FAs), found in high quantity in fish oil, have demonstrated beneficial effects in patients with coronary artery disease. The role of n-6 FAs remains more controversial. The objective of this study was to examine the effect of arachidonic acid (AA), an n-6 FA, and eicosapentanoic acid (EPA), an n-3 FA, on the interaction between monocytes and endothelial cells (ECs).Design: We used a cellular model of ECs (EA.hy.926) and monocytes (human leukemic myelomonocytic U937). Confluent ECs were treated with AA or EPA, in the presence of tumor necrosis factor-alpha (TNF-α) or vehicle alone for either 4 or 24h. Adhesion of monocytes to the endothelial monolayer was performed. For gene expression, reverse transcription, followed by real-time quantitative polymerase chain reaction, was performed.Results: There was a significant increase in adhesion of monocytes to the endothelial monolayer in the presence of n-6 FAs, both in the presence and in the absence of TNF-α at 4 and 24h. The adhesion of monocytes to the endothelial monolayer was decreased with n-3 FAs at 24h. Intercellular adhesion molecule 1, vascular cell adhesion molecule 1, E-Selectin, Interleukin 6, and TNF-α were significantly increased in ECs treated with n-6 FAs.Conclusions: We conclude that AA increases inflammation and enhances the ability of ECs to bind monocytes in vitro. EPA leads to a decrease in the ability of EA.hy.926 to bind monocytes, although the effect appears more modest. Taken together, these data indicate that the n-6 FA AA could potentiate inflammation and early events of atherosclerosis.

Effects of undifferentiated cultured omental adipose-derived stem cells on peripheral nerve regeneration - Corrected Proof

Rahim Mohammadi, Saeed Azizi, Keyvan Amini — 2012-04-30

Abstract: Background/Aims: Employment of regenerative properties of stem cells at the service of nerve repair has been initiated during recent decades. Effects of transplantation of undifferentiated cultured omental adipose-derived stem cells (uADSCs) on peripheral nerve regeneration were studied using a rat sciatic nerve transection model.Methods: A 10-mm sciatic nerve defect was bridged using a silicone rubber chamber filled with uADSCs. In control group, the silicone conduit was filled with phosphate-buffered saline alone. The regenerated nerve fibers were studied 4, 8, and 12wk after surgery. In sham-operated group, the sciatic nerve was only exposed and manipulated.Results: Functional study confirmed faster recovery of regenerated axons in uADSC-transplanted animals than in control group (P<0.05). Gastrocnemius muscle mass in uADSC-transplanted animals is found to be significantly more than that in control group. Morphometric indices of the regenerated fibers showed that the number and diameter of the myelinated fibers were significantly higher in uADSC-transplanted animals than in control group. In immunohistochemistry, location of reactions to S-100 in uADSC-transplanted animals was clearly more positive than that in control group.Conclusion: uADSC transplantation could be considered as a readily accessible source of stromal cells that improve functional recovery of sciatic nerve.

Biomechanical evaluation of various fixation methods for proximal extra-articular tibial fractures - Corrected Proof

Wei Feng, Li Fu, Jianguo Liu, Xin Qi, Dongsong Li, Chen Yang — 2012-04-30

Abstract: Objective: Proximal tibial fractures are a challenging clinical problem. The treatment protocols for these fractures include a dynamic compression plate (DCP), a locking compression plate (LCP), interlocking intramedullary nailing (IMN), and external fixation (Ex-Fix). However, the optimal fixation method for proximal tibial fractures remains controversial. The purpose of this study was to investigate the biomechanical properties of these four fixation instruments in the treatment of tibial proximal fractures.Methods: Thirty-two tibial specimens were retrieved and randomly divided into four groups. Extra-articular proximal tibial fractures (AO classification 41-A2) were created in each specimen. The fractures were subsequently fixed by DCP, LCP, IMN, and Ex-Fix. The bone density of the proximal tibiae was examined by quantitative computed tomography. Each specimen was subjected to axial compression and three-point bending tests.Results: Bone mineral density did not significantly differ among the groups. In compression testing of the four fixation instruments, the highest degree of axial stiffness was found in the IMN group; there was no significant difference between DCP and LCP groups (P>0.05). The results of the three-point bending test revealed that DCP demonstrated the highest bending stiffness, which differed significantly from the other groups (P<0.05). The Ex-Fix had the lowest level of stiffness during the compression and three-point bending tests.Conclusions: IMN has good mechanical properties, but its clinical application for proximal tibial fractures often leads to malalignment deformities. Compared with DCP, LCP is strong enough to fix the proximal tibial fractures and has the additional benefit of minimally invasive surgery.

Face transplant perfusion assessment using near-infrared fluorescence imaging - Corrected Proof

2012-04-30

Abstract: Background: Composite tissue allografts (CTAs) including partial face transplantation have been achieved clinically. However, risks of complications including tissue ischemia, rejection, and transplant failure are significant. Safe and effective techniques to assess perfusion are needed to decrease complications in composite tissue flaps. Near-infrared (NIR) fluorescence imaging has been previously shown to provide a real-time, intraoperative evaluation of perfusion. This study investigates the use of NIR imaging in partial face CTA harvest.Methods: We created hemifacial CTAs (n = 8) using an established porcine model. This included ear cartilage, nerve, lymphoid tissue, muscle, and skin with perfusion by the carotid artery and external jugular vein. We injected animals systemically with indocyanine green and obtained NIR fluorescence images simultaneously with color video. In addition, we assessed the elevated hemifacial flaps using standard of care (i.e., clinical examination and Doppler).Results: Flap design was facilitated by NIR imaging with localization of perforators to the hemifacial CTA flap. In particular, an arterial and venous phase could be clearly identified. We assessed perfusion of the flap by NIR fluorescence intensity after injection of indocyanine green. Sequential clamping of the artery and vein confirmed correlation of perfusion deficits with NIR imaging as well as with clinical examination and Doppler.Conclusions: Evaluation and assessment of perfusion are important in facial transplantation. The results from our pilot study indicate that NIR imaging has the capability to assess perfusion of partial facial CTAs. This emergent technology shows promise in assessing tissue perfusion in a composite flap.

Inhibitory effects of recombinant IL-4 and recombinant IL-13 on UHMWPE-induced bone destruction in the murine air pouch model - Corrected Proof

Yang Wang, Ning-Ning Wu, Yu-Qin Mou, Liang Chen, Zhong-Liang Deng — 2012-04-30

Abstract: Purpose: We administered recombinant interleukin (IL)-4 and recombinant IL-13 locally into the air pouch of mice to improve bone resorption induced by ultra-high-molecular-weight polyethylene (UHMWPE) particles.Methods: Air pouches were established on the back of BALB/c mice, followed by the surgical introduction of a section of calvaria from a syngeneic mouse donor. We stimulated the bone-implanted pouches with the UHMWPE suspension. We divided UHMWPE-containing mice into four study groups to receive injections of phosphate-buffered saline (control), IL-4 alone, IL-13 alone, or IL-4 and IL-13 into the pouches. We harvested the tissues at 14 d after treatment for molecular and histological analyses.Results: The inhibitory effect of IL-4 was stronger than that of IL-13 toward osteoclast differentiation and osteoblast for the induction of osteoprotegerin production and down-regulation of receptor for activation of nuclear factor-κB ligand production. Furthermore, the combined treatment with both IL-4 and 1L-13 had a more important role in inhibiting bone resorption in these pouches with UHMWPE stimulation, compared with IL-4 or IL-13 treatment alone.Conclusions: Local administration of recombinant IL-4 and IL-13 may be a feasible and effective therapeutic candidate to treat or prevent wear debris-associated osteolysis.

Operative findings in antenatal abdominal masses of unknown etiology in females - Corrected Proof

Vincent E. Mortellaro, Frankie B. Fike, Susan W. Sharp, Shawn D. St. Peter — 2012-04-30

Abstract: Background: Perinatal findings of abdominal masses pose a diagnostic challenge to clinicians. This study presents the operative findings of patients who underwent exploration for perinatally identified abdominal masses of unknown etiology.Methods: Retrospective review of all patients with abdominal masses of unknown etiology identified in the antenatal period was conducted from January 1, 2000 to July 1, 2010. Patient demographics were collected. Preoperative radiographic studies, operative findings, and pathologic evaluation were reviewed.Results: There were 17 patients identified within the study period. The median age was 30d at the time of operation (range 0–287d). The median height was 51cm (range 45–77cm), and the median weight was 4.0kg (range 2.6–10.4kg). All patients were asymptomatic. After birth, ultrasound identified abdominal masses in 14 patients, and computed tomography scan was used in four patients where one patient had both an ultrasound and a computed tomography scan. Mass resection was performed using laparoscopy in 15 patients, whereas two patients underwent open resection. At the time of surgery, 11 patients were diagnosed with ovarian cysts, four patients with ovarian torsion with an associated cyst, and two patients with an enteric duplication cyst. On final pathology, eight patients had benign ovarian cysts, seven patients had hemorrhagic ovarian necrosis, and two patients had duplication cysts.Conclusion: Females with antenatally identified abdominal masses of unknown etiology appear to be benign in nature. In this series, a benign ovarian cyst is the most common diagnosis, and these lesions can be approached laparoscopically.

Computed tomography scanning in pediatric trauma: Opportunities for performance improvement and radiation safety - Corrected Proof

2012-04-30

Abstract: Background: Recently, pediatric CT scanning protocols have reduced radiation exposure in children. Because evaluation with CT scan after trauma contributes to significant radiation exposure, we reviewed the CT scans in children at both initial presentation at a non-pediatric facility and subsequent transfer to a level I pediatric trauma center (PTC) to determine the number of scans, body area scanned, radiation dosage, and proportion of scans at each facility.Methods: The trauma database was retrospectively reviewed for children aged 0 to 17 y initially evaluated for trauma at another facility and then transferred to our PTC for pediatric specialty care between January 2000 and December 2010.Results: A total of 1562 patients with 1335 CT scans were reviewed over an 11-y period. The majority of CT scans occur at the referring facility compared to the PTC in a ratio of 7:3. CT of the head was the most frequent scan obtained (52%), and 17.9% of CT scans were repeated at the PTC. Less than 1% of CT scans performed at the non-pediatric centers contained radiation dosage information, precluding analysis of radiation exposure.Conclusions: The majority of CT scans for trauma occur at non-pediatric facilities, which demonstrates the need for referring facilities to perform optimal CT scans with the least amount of radiation exposure to the child. We believe this provides an opportunity for PTC performance improvement by facilitating the transfer of images and educating referring facilities about indications for CT scans, dosage amounts, and radiation reduction protocols.

Caroli disealse patients have excellent survival after liver transplant - Uncorrected Proof

2012-04-30

Abstract: Background: Caroli disease (CD) is characterized by dilation of the intrahepatic biliary tree, which may result in malignancy. Treatments include management of symptoms and hepatic resection to decrease disease burden. In patients with CD not amenable to these treatments, orthotopic liver transplantation (OLT) has been used. This study examines if OLT is a reasonable treatment for patients with CD.Materials and methods: The United Network of Organ Sharing/Organ Procurement and Transplantation Network database between September 30, 1987 and March 31, 2011 was queried. Cases without patient or allograft survival time or without a diagnosis were excluded from analysis. Patients with CD were compared to patients with primary biliary cirrhosis (PBC), secondary biliary cirrhosis (BC), primary sclerosing cholangitis (PSC), and all indications for OLT. Survival analysis was performed by log-rank test and Kaplan-Meier.Results: One hundred forty patients with CD were compared to 4797 patients with PBC, 489 patients with secondary BC, 6033 patients with PSC, and 92,210 patients post-OLT. Patient and allograft survivals of CD patients at 1, 3, 5, and 10 y are, respectively, 88.5%, 83.4%, 80.9%, and 77.8%; and 81.2%, 74.8%, 70.6%, and 67.9%. CD patients have significantly improved patient and allograft survivals after OLT compared to patients with secondary BC (P = 0.003, P = 0.015) and all other patients undergoing OLT (P = 0.003, P = 0.026). There is a trend towards long-term improved patient and allograft survival in transplanted patients with CD compared to patients with PBC and PSC.Conclusions: These results suggest that OLT should be considered an effective treatment modality for patients with CD resulting in excellent long-term outcomes.

Formation of intestinal atresias in the Fgfr2IIIb−/− mice is not associated with defects in notochord development or alterations in Shh expression - Corrected Proof

2012-04-30

Abstract: Purpose: The etiology of intestinal atresia remains elusive but has been ascribed to a number of possible events including in utero vascular accidents, failure of recanalization of the intestinal lumen, and mechanical compression. Another such event that has been postulated to be a cause in atresia formation is disruption in notochord development. This hypothesis arose from clinical observations of notochord abnormalities in patients with intestinal atresias as well as abnormal notochord development observed in a pharmacologic animal model of intestinal atresia. Atresias in this model result from in utero exposure to Adriamycin, wherein notochord defects were noted in up to 80% of embryos that manifested intestinal atresias. Embryos with notochord abnormalities were observed to have ectopic expression of Sonic Hedgehog (Shh), which in turn was postulated to be causative in atresia formation. We were interested in determining whether disruptions in notochord development or Shh expression occurred in an established genetic model of intestinal atresia and used the fibroblast growth factor receptor 2IIIb homozygous mutant (Fgfr2IIIb−/−) mouse model. These embryos develop colonic atresias (100% penetrance) and duodenal atresias (42% penetrance).Methods: Wild-type and Fgfr2IIIb−/− mouse embryos were harvested at embryonic day (E) 10.5, E11.5, E12.5, and E13.5. Whole-mount in situ hybridization was performed on E10.5 embryos for Shh. Embryos at each time point were harvested and sectioned for hematoxylin-eosin staining. Sections were photographed specifically for the notochord and resulting images reconstructed in 3-D using Amira software. Colons were isolated from wild-type and Fgfr2IIIb−/− embryos at E10.5, then cultured for 48 hours in Matrigel with FGF10 in the presence or absence of exogenous Shh protein. Explants were harvested, fixed in formalin, and photographed.Results: Fgfr2IIIb−/− mouse embryos exhibit no disruptions in Shh expression at E10.5, when the first events in atresia formation are known to occur. Three-dimensional reconstructions failed to demonstrate any anatomical disruptions in the notochord by discontinuity or excessive branching. Culture of wild-type intestines in the presence of Shh failed to induce atresia formation in either the duodenum or colon. Cultured Fgfr2IIIb−/− intestines developed atresias of the colon in either the presence or absence of Shh protein.Conclusions: Although disruptions in notochord development can be associated with intestinal atresia formation, in the Fgfr2IIIb−/− genetic animal model neither disruptions in notochord development nor the presence of exogenous Shh protein are causative in the formation of these defects.

Predicting outcomes in the setting of blunt thoracic trauma - Uncorrected Proof

Meade Barlow, Jose M. Prince — 2012-04-30

At times, blunt thoracic trauma represents a particular challenge to the treating clinician. As the current report by Mommsen et al. states, the overwhelming majority of patients suffering from severe thoracic trauma have also sustained additional injuries elsewhere. Given the wide spectrum of outcomes that can result from thoracic trauma in the context of a multiply injured patient, tools that enable clinicians to predict which patients are more likely to suffer from late complications secondary to thoracic trauma would allow us to focus our resources more towards patients who are at greater risk.

Mixing it up: Antibiotic cycling in the SICU - Uncorrected Proof

Michael Kuncewitch, Jose M. Prince — 2012-04-30

As antimicrobial resistance—and gram-negative resistance in particular—has grown as a major health care concern, more attention is being paid to the application of “antibiotic heterogeneity” in the critical care setting. There seems to be no consensus, however, regarding whether antibiotic cycling/rotation or mixing represents the optimal approach to decreasing resistance patterns. It is therefore with particular attention that we read the article by Sarraf-Yazdi et al. on the long-term effect of an antibiotic rotation schedule in a surgical intensive care unit (SICU) , as this study contributes promising data and a new approach to the debate.

Pterostilbene induces mitochondrially derived apoptosis in breast cancer cells in vitro - Corrected Proof

Dora Moon, Denise McCormack, Debbie McDonald, David McFadden — 2012-04-30

Abstract: Background: The ability of a breast cancer cell to evade apoptosis has a key role in tumor progression and sensitivity to treatment. High levels of Bcl-2–associated X protein (Bax) in tumor cells have been found to promote apoptosis and sensitize cells to anti-cancer therapies. Bcl-2–associated X protein redistribution to the mitochondrial membrane results in the release of proapoptotic factors including cytochrome C, second-mitochondrial-derived activator of caspase/direct inhibitor of apoptosis-binding protein with low PI (Smac/DIABLO), and Ca2+. We aimed to explore this pathway in cancerous breast cell lines treated with the naturally occurring antioxidant 3,5-dimethoxy-4-hydroxystilbene (pterostilbene).Methods: We used whole cell lysates +/− Bax SiRNA from the cell lines MCF-7 and MDA-MB-231 in an enzyme-linked immunosorbent assay to quantify Bax, cytochrome C, Smac/DIABLO expression, and manganese superoxide dismutase (MnSOD) activity after treatment with pterostilbene. We quantified cell death using histone-related DNA complexes from cytosolic and mitochondrial fractions and used methylthiazol tetrazolium assay to analyze cell proliferation, in the presence of Bax-silencing or scrambled RNA. We measured changes in cytosolic calcium using the ratiometric calcium-sensitive dye fura-2-AM using an inverted ratiometric monochromator microscope.Results: Treatment of MCF-7 and MDA-MB-231 (MDA) cells with pterostilbene caused concentration-dependent increases in intracellular Bax at all doses tested. RNA silencing of Bax resulted in reduced rates of apoptosis in both cells types and increased cell survival when treated with pterostilbene. We observed an increase in cytochrome C in MDA cells after treatment with pterostilbene. The MCF-7 cells showed a net increase in cytosolic cytochrome C, with a corresponding reduction in mitochondrial cytochrome C after treatment with 50 and 75 μmol/L pterostilbene. We observed this again in Smac/DIABLO expression in both cell types. In MCF-7 cells, pterostilbene treatment caused an increase in cytosolic but a decrease in mitochondrial Smac/DIABLO protein concentrations. Pterostilbene significantly increase MnSOD activity in MDA-MB-231 cells. Finally, pterostilbene resulted in significant increases in cytosolic calcium concentrations.Conclusions: The natural dietary compound pterostilbene has an anti-proliferative effect and induces apoptosis in breast cancer cells in vitro via Bax activation and overexpression, resulting in increased MnSOD, Smac/DIABLO, and cytochrome C activity and cytosolic Ca2+ overload.

The effects of dexmedetomidine on mesenteric arterial occlusion-associated gut ischemia and reperfusion-induced gut and kidney injury in rabbits - Corrected Proof

2012-04-27

Abstract: Objective: We assessed the antioxidant activity of dexmedetomidine (Dex) administered during the ischemic period in a rabbit model of mesenteric ischemia/reperfusion (I/R) injury using biochemical and histopathological methods.Methods: A total of 24 male New Zealand white rabbits weighing between 2.5 and 3.0 kg were randomly divided into three groups: the sham group (Group S, n = 8), the I/R group (Group I/R, n = 8), and the I/R plus Dex treatment group (Group Dex, n = 8). In the I/R group, ischemia was achieved with 60 min of mesenteric occlusion. The sham group provided normal basal values. The rabbits in Group I/R were operated to achieve I/R. Group Dex received intravenous Dex 30 min after the commencement of reperfusion (10 μg/kg Dex was infused within 10 min, and then a maintenance dose of 10 μg/kg/h Dex was infused intravenously). For the measurement of tissue malondialdehyde, total antioxidant status, total oxidant status, lipid hydroperoxide levels, superoxide dismutase, catalase, and myeloperoxidase activity levels in the renal tissue samples of animals, the rabbits in each group were sacrificed 3 h after reperfusion. The histopathological examination scores were determined using the intestinal and renal tissues.Results: The mean malondialdehyde, total oxidant status, myeloperoxidase, and lipid hydroperoxide levels were significantly higher in Group I/R than in Groups S and Dex (P < 0.05). There also were significant decreases in the mean total antioxidant status, catalase, and superoxide dismutase activities in Group I/R compared with Groups S and Dex (P < 0.05). The histopathological examination scores of the intestinal and renal tissues were significantly higher in Group I/R compared with Groups S and Dex (P < 0.05).Conclusion: Dex treatment may have biochemical and histopathological benefits by preventing I/R-related cellular damage of intestinal and renal tissues as shown in an experimental mesenteric ischemia model. The preference to use Dex for anesthesia during the mesenteric ischemia procedure may attenuate I/R injury in intestinal and renal tissues.

Volume-outcome effects for children undergoing resection of renal malignancies - Corrected Proof

Jason R. Axt, Andrew J. Murphy, Patrick G. Arbogast, Harold N. Lovvorn — 2012-04-25

Abstract: Introduction: Adults undergoing oncologic resections at low-volume centers experience increased perioperative morbidity and mortality. The volume-outcome effect has not been extensively studied in pediatric oncologic resections.Methods: To clarify volume-outcome effects in pediatric oncologic resections, we analyzed resection of renal malignancies in children less than 15 y of age. We conducted a cross-sectional analysis of hospital discharges included in the health care utilization project kids' inpatient database from 1997 to 2009, examining in-hospital operative complications, length of stay (LOS), and inflation-adjusted hospital charges. Hospital volume was expressed as low (n = 1–2), medium (n = 3–4), and high (n > 4) annual volume of resections.Results: One thousand five hundred thirty-eight patients underwent renal malignancy resection. Of these, 527 patients had resection in low-, 422 in medium-, and 589 in high-volume hospitals. Relative to low-volume hospitals, those resected in medium-volume hospitals had an odds ratio of 0.62 (95% confidence interval 0.39–0.99, P = 0.046) for operative complication and those in high-volume hospitals had an odds ratio of 1.02 (95% confidence interval 0.63–1.65, P = 0.95). There was no detectable association with LOS (P = 0.113) or inflation-adjusted charges (P = 0.331).Conclusions: The number of complications, total charges, and LOS attributable to resection of a childhood renal malignancy did not differ among high-, medium-, or low-operative volume hospitals, although oncologic outcomes could not be determined because of the limited nature of this administrative database.

Microvascular porcine model for the optimization of vascularized composite tissue transplantation - Uncorrected Proof

2012-04-23

Abstract: Background: Devastating extremity injuries are prevalent but most often survivable on the modern battlefield. The complexity of these injuries requires advanced methods of reconstruction. This study is designed to validate the feasibility of gracilis myocutaneous flap transplantation via microvascular free tissue transfer in a porcine model. This model will facilitate study of autotransplant physiology as well as vascularized composite allotransplantation as an evolving method for reconstructing previously nonreconstructable injuries.Material and methods: A donor gracilis myocutaneous flap is procured from Yorkshire swine. The right external carotid artery and internal jugular vein are prepared as the recipient axis for microvascular anastomoses. Group 1 undergoes immediate microvascular anastomosis with resultant 1-h ischemic period. Group 2 undergoes delayed anastomosis with 3-h ischemic period. Markers of ischemia-reperfusion injury are evaluated after anastomosis and on postoperative days 1, 2, 7, and 14.Results: A novel porcine model for microvascular composite tissue transplantation is demonstrated. Ischemia period-dependent elevations in circulating biomarkers (lactate dehydrogenase [LDH], creatine kinase [CK], and aspartate transaminase [AST]) demonstrate the effects of prolonged ischemia. Both groups showed marked LDH elevation without significant statistical intergroup difference (P=0.250). The difference in CK and AST levels at 24h showed strong significance (P<0.0001).Conclusions: A novel method of vascularized gracilis myocutaneous flap transplantation was validated in the Yorkshire swine. Assays for skeletal muscle tissue injury (LDH, CK, and AST) showed ischemia period-dependent response providing assessment of ischemia-reperfusion injury at the cellular level. Subsequent studies will evaluate agents that mitigate ischemia-reperfusion injury and transition these findings to potentiate vascularized composite allotransplantation.