Tumor Necrosis Factor–Alpha Gene Expression in Human Whole Blood

Tumor necrosis factor‐alpha (TNF) is recognized as a principal mediator of a variety of pathophysiologic and immunologic events. Lipopolysaccharide (LPS) challenge, either in vitro or in vivo, results in significant TNF production. In this study we present data demonstrating LPS‐induced TNF mRNA expression and bioactivity using an in vitro tissue system of whole blood (WB). The kinetics of LPS‐induced TNF production by WB was significantly accelerated as compared to isolated cultured peripheral blood monocytes (PBM). At post‐LPS challenge, plasma from WB demonstrated a rapid rise in TNF bioactivity, peaking by 4 hr (1,021 units/ml/106 cells), plateauing between 4 and 8 hr, and then decreasing over the next 16 hr. In contrast, the highest measured TNF bioactivity from PBM did not occur until the 24‐hr time‐point (175 units/ml/106 cells). Whole blood buffy‐coat TNF mRNA was assessed by Northern blot analysis, and demonstrated significant TNF mRNA accumulation at 1 hr and a peak 2 hr post‐LPS challenge. By 8 hr TNF mRNA was undetectable. Concomitant administration of LPS with either prostaglandin E2 (10‐6M) or Dexamethasone (10‐6M) resulted in significant suppression of LPS‐induced TNF production. This data supports WB as a useful in vitro medium for the molecular and cellular analyis of TNF. As specialized connective tissue, WB may provide an important environment to study the pharmacologic manipulation of TNF mRNA and bioactivity.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/141678/1/jlb0366.pd

Subtotal Pancreatectomy for Chronic Pancreatitis

Chronic pancreatitis results when pancreatic structure or function is irreversibly damaged by repeated or ongoing inflammation, regardless of the underlying etiology. Most patients present with medically intractable pain and radiological evidence of diffuse gland involvement. Surgical therapy is directed mainly toward palliation of symptoms, and cure is unusual except when the inflammatory process is limited to a specific segment of the pancreas. Surgical strategy should be individualized on the basis of alterations in pancreatic morphology and duct anatomy. In properly selected patients, duct drainage procedures effectively relieve pain and preserve pancreatic function with low perioperative morbidity and mortality. Extensive distal pancreatectomy is effective in relieving pain, but it can be technically challenging and in general should be limited to patients with small-duct disease because of severe metabolic consequences. Intraportal islet cell autotransplantation or segmental pancreatic autotransplantation may ameliorate the long-term effects of insulin-dependent diabetes, but it will have limited applicability until methods for optimizing and purifying islets are developed and the optimal route and site of islet cell implantation have been identified.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/41297/1/268_2003_Article_7242.pd

A Multi-Institutional Phase II Trial of Preoperative Full-Dose Gemcitabine and Concurrent Radiation for Patients With Potentially Resectable Pancreatic Carcinoma

We report the results of a multi-institutional phase II trial that used preoperative full-dose gemcitabine and radiotherapy for patients with potentially resectable pancreatic carcinoma.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/41411/1/10434_2006_Article_9435.pd

Surgical strategies for liver cell adenoma

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/41589/1/534_2006_Article_BF02350918.pd

Mortality and pulmonary complications in patients undergoing surgery with perioperative SARS-CoV-2 infection: an international cohort study

Background: The impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on postoperative recovery needs to be understood to inform clinical decision making during and after the COVID-19 pandemic. This study reports 30-day mortality and pulmonary complication rates in patients with perioperative SARS-CoV-2 infection. Methods: This international, multicentre, cohort study at 235 hospitals in 24 countries included all patients undergoing surgery who had SARS-CoV-2 infection confirmed within 7 days before or 30 days after surgery. The primary outcome measure was 30-day postoperative mortality and was assessed in all enrolled patients. The main secondary outcome measure was pulmonary complications, defined as pneumonia, acute respiratory distress syndrome, or unexpected postoperative ventilation. Findings: This analysis includes 1128 patients who had surgery between Jan 1 and March 31, 2020, of whom 835 (74·0%) had emergency surgery and 280 (24·8%) had elective surgery. SARS-CoV-2 infection was confirmed preoperatively in 294 (26·1%) patients. 30-day mortality was 23·8% (268 of 1128). Pulmonary complications occurred in 577 (51·2%) of 1128 patients; 30-day mortality in these patients was 38·0% (219 of 577), accounting for 81·7% (219 of 268) of all deaths. In adjusted analyses, 30-day mortality was associated with male sex (odds ratio 1·75 [95% CI 1·28–2·40], p\textless0·0001), age 70 years or older versus younger than 70 years (2·30 [1·65–3·22], p\textless0·0001), American Society of Anesthesiologists grades 3–5 versus grades 1–2 (2·35 [1·57–3·53], p\textless0·0001), malignant versus benign or obstetric diagnosis (1·55 [1·01–2·39], p=0·046), emergency versus elective surgery (1·67 [1·06–2·63], p=0·026), and major versus minor surgery (1·52 [1·01–2·31], p=0·047). Interpretation: Postoperative pulmonary complications occur in half of patients with perioperative SARS-CoV-2 infection and are associated with high mortality. Thresholds for surgery during the COVID-19 pandemic should be higher than during normal practice, particularly in men aged 70 years and older. Consideration should be given for postponing non-urgent procedures and promoting non-operative treatment to delay or avoid the need for surgery. Funding: National Institute for Health Research (NIHR), Association of Coloproctology of Great Britain and Ireland, Bowel and Cancer Research, Bowel Disease Research Foundation, Association of Upper Gastrointestinal Surgeons, British Association of Surgical Oncology, British Gynaecological Cancer Society, European Society of Coloproctology, NIHR Academy, Sarcoma UK, Vascular Society for Great Britain and Ireland, and Yorkshire Cancer Research

Stem cell factor and c-kit are involved in hepatic recovery after acetaminophen-induced liver injury in mice

Stem cell factor (SCF) and its receptor c-kit are important in hematopoiesis and cellular proliferation. c-kit has also been identified as a cell surface marker for progenitor cells. We have previously shown that there is a large reservoir of hepatic SCF, and this molecule plays a significant role in liver regeneration after 70% hepatectomy. In the current study, we further examined the expression of SCF and c-kit in acetaminophen (APAP)-induced liver injury in C57BL/6J mice or SCF-deficient sl-sld mice and their appropriate wild-type controls. Following APAP-induced liver injury, c-kit mRNA expression increased, with peak levels detected 48 h postinjury. Hepatic SCF mRNA levels after APAP injury were also increased, with peak levels seen 16 h post-APAP. The mortality rate in SCF-deficient mice treated with APAP was significantly higher than that of wild-type mice; furthermore, administration of exogenous SCF significantly reduced the mortality of APAP-treated wild-type mice. Bromodeoxyuridine incorporation experiments showed that SCF significantly increased hepatocyte proliferation at 48 and 72 h in APAP-treated mice. SCF inhibited APAP-induced hepatocyte apoptosis and increased Bcl-2 and Bcl-xL expression, suggesting that this decrease in hepatocyte apoptosis is mediated through Bcl-2 and Bcl-xL. In summary, SCF and c-kit expression was increased after APAP-induced liver injury. Administration of exogenous SCF reduces mortality in APAP-treated mice, increases hepatocyte proliferation, and prevents hepatocyte apoptosis induced by APAP, suggesting that these molecules are important in the liver's recovery from these injuries

IL-22 is involved in liver regeneration after hepatectomy

Hepatocyte proliferation following partial hepatectomy is an important component of liver regeneration, and recent in vitro studies have shown that IL-22 is involved in cellular proliferation in a variety of cell types, including hepatocytes. IL-22 functions through IL-10Rβ and IL-22Rα. The goal of this study was to investigate the potential role of IL-22 in liver regeneration after 70% hepatectomy. Following 70% hepatectomy, done under general anesthesia in mice, serum IL-22 and hepatic IL-22Rα mRNA were significantly increased. Although administration of exogenous IL-22 prior to hepatectomy did not increase hepatocyte proliferation, administration of anti-IL-22 antibody before hepatectomy did significantly decrease hepatocyte proliferation. Furthermore, IL-22 treatment prior to 70% hepatectomy induced stat-3 activation; no significant changes were seen in ERK1/2 activation, stat-1 activation, or stat-5 activation. IL-22 pretreatment also significantly increased hepatic and serum IL-6 levels. In addition, animals treated with anti-IL-22 antibody also expressed less TGF-α. In conclusion, these data suggest that IL-22 is involved in liver regeneration and this may be due to interaction with IL-6 and TGF-α cascades

LPS Pretreatment Protects from Hepatic Ischemia/Reperfusion

In vivo administration of nonlethal doses of lipopolysaccharide (LPS) to rodents can result in protection from subsequent lethal doses of endotoxin or LPS. We have previously demonstrated that hepatic ischemia/reperfusion (I/R) results in a TNF-dependent lung and liver injury and we postulated that pretreatment with sublethal concentrations of LPS prior to hepatic I/R could be protective from this injury. To test this hypothesis, five groups of rats were studied. LPS-I/R received 25 [mu]g of LPS iv 24 hr prior to I/R, VEH-I/R received an equivalent volume of vehicle iv 24 hr prior to I/R, LPS-LPS received 25 [mu]g of LPS iv 24 hr prior to sham laparotomy at which time an additional 25 [mu]g of LPS was given iv, VEH-LPS received an equivalent volume of vehicle 24 hr prior to sham laparotomy and 25 [mu]g of LPS iv immediately prior to sham laparotomy, and SHAM consisted of sham-operated control animals. Peak plasma tumor necrosis factor-[alpha] (TNF) levels occurred between 30 and 150 min of reperfusion: LPS-I/R 778 +/- 150 pg/ml (n = 5), VEH-I/R = 145 +/- 46 pg/ml (n = 5), LPS-LPS = 970 +/- 716 pg/ml (n = 4), VEH-LPS = 15,949 +/- 10,937 (n = 5), and SHAM = 3 +/- 1 (n = 5). As previously demonstrated by other investigators, pretreatment with LPS decreases TNF release in response to a second dose of LPS; however, TNF release was increased following hepatic I/R in those animals pretreated with LPS (LPS-I/R vs VEH-I/R, P = 0.014). Pulmonary injury was assessed by total protein and cell counts in bronchoalveolar lavage (BAL) fluid. Total protein concentration in BAL fluid from LPS-I/R 59.48 +/- 14.87 [mu]g/ml (n = 11) and from VEH-I/R = 239.41 +/- 60.12 [mu]g/ml (n = 16) (P n = 7), 81.71 +/- 1 O. 14 [mu]g/m] (n = 7), and 33.02 +/- 12.22 [mu]g/ml (n = 8), respectively, and were not significantly different from each other. BAL fluid cell counts paralleled protein levels in each group. These data suggest that pretreatment with LPS increases TNF release in response to I/R, but protects from the subsequent pulmonary injury. In addition, liver injury in this model was assessed by quantitation of serum AST. There was no evidence of a difference in the liver injury which followed hepatic ischemia/reperfusion in animals which were pretreated with LPS before hepatic I/R.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/31366/1/0000278.pd