Jaimie D. Nathan

Neurogenic inflammation and pancreatitis

Stimulation of primary sensory neurons produces local vasodilation, plasma extravasation, and pain and is due largely to the release of the tachykinins substance P and calcitonin-gene-related peptide. Pathological activation of sensory neurons and the inflammatory sequelae are known as neurogenic inflammation and appear to be important in many organ systems, including the pancreas. Factors that stimulate primary sensory neurons include hydrogen ions, heat, leukotrienes, arachidonic acid metabolites, bradykinin, and proteases such as trypsin, all of which may participate in the generation of acute pancreatitis. The current review examines the cellular and molecular mechanisms involved in sensory nerve activation within the pancreas and the potential contribution of neurogenic inflammation to the pathogenesis of pancreatitis.

Inguinal hernia: An old condition with new solutions

Objective: To review the recent surgical advances in the treatment of inguinal hernias. Summary Background Data: Traditional tissue‐based techniques (eg, Bassini, McVay, Shouldice) characterized the armamentarium of the inguinal hernia surgeon during the 1970s and early 1980s. With the need to reduce the rate of hernia recurrence, as well as postoperative pain and convalescence, the treatment of inguinal hernias underwent a dramatic evolution over the past 15 years. The major advances included the introduction of the concept of tensionfree hernia surgery, the use of prosthetic materials, and the development of laparoscopic techniques. Results: The recognition that excessive suture‐line tension was primarily responsible for high recurrence rates and significant postoperative pain following tissue‐based repairs led to the introduction of the concept of tension‐free hernia surgery. The development of prosthetic materials ushered in the current era of hernia surgery, allowing a tension‐free repair to be performed even for the largest defects and the most difficult procedures. Tension‐free mesh‐based repairs (eg, Lichtenstein, plug and patch) began to increase in number in the late 1980s. More recently, with the advent of laparoscopy for general surgery, various laparoscopic techniques have been developed for inguinal hernia repair, including the transabdominal preperitoneal repair, the intraperitoneal onlay mesh repair, and the totally extraperitoneal repair. Conclusions: Today, open and laparoscopic mesh‐based techniques dominate the inguinal hernia repair marketplace. The Lichtenstein tension‐free mesh onlay repair is the most frequently performed inguinal hernia operation, with a recurrence rate of less than 1%. Although the use of laparoscopic techniques for bilateral or recurrent hernias is now accepted, the application of laparoscopy to unilateral primary inguinal hernias remains controversial. Ongoing studies will address the questions of long‐term recurrence and cost‐effectiveness of laparoscopic hernia repair.

Insulin receptor (IR) and glucose transporter 2 (GLUT2) proteins form a complex on the rat hepatocyte membrane.

The hepatic glucose transporter, GLUT2, facilitates bidirectional glucose transport across the hepatocyte plasma membrane under insulin regulation. We studied the interactions of IR and GLUT2 proteins to determine whether they are physically coupled in a receptor-transporter complex. By comparing endosome and plasma membrane IR and GLUT2 ratios before and after feeding, it was determined that IR and GLUT2 are internalized in a fixed ratio. When solubilized hepatocytes were immunoprecipitated with antibodies against either IR or GLUT2, both proteins co-precipitated. The association of IR and GLUT2 was further assessed by confocal microscopy. Sections of fed liver were incubated with fluorescein-tagged anti-GLUT2 or Texas Red-tagged anti-IR. Colocalization was observed both at the plasma membrane and in the cytosol. Fluorescence-resonance energy transfer studies further confirmed this association. We conclude that IR and GLUT2 form a receptor-transporter complex in hepatocytes, which forms a mechanism of insulin-mediated hepatic glucose regulation.

Neurohormonal control of pancreatic exocrine secretion.

The neurohormonal control of pancreatic exocrine secretion is a complex interaction of multiple pathways involving a large number of gut hormones, neurotransmitters, and neuropeptides. Recent studies have elucidated a role for cholecystokinin in the regulation of bicarbonate and fluid secretion from pancreatic duct cells and suggested that cholecystokinin stimulation of human pancreatic acinar cells is likely regulated by an indirect mechanism of stimulation of afferent neurons. Evidence supports the regulation of potassium channels in rat pancreatic acinar cells by the cyclic AMP–mediated agonist secretin. Mechanisms for the regulation of cholecystokinin and secretin release by releasing factors have also been elucidated. The area postrema has been implicated in the mediation of inhibition of pancreatic secretion by the gut hormones peptide YY and pancreatic polypeptide. The neurotransmitter serotonin has been demonstrated to play a role in acid-induced secretin release and in pancreatic secretion stimulated by luminal factors. The regulation of pancreatic exocrine secretion by purines, nitric oxide, and &ggr;-aminobutyric acid as well as by the neuropeptides pituitary adenylate cyclase–activating peptide, gastrin-releasing peptide, and substance P is reviewed. The role of the central nervous system in modulating pancreatic secretion is also described. This review highlights the recent advances in knowledge of the neurohormonal regulation of pancreatic exocrine secretion.

Leukotriene B4 Mediates Inflammation via TRPV1 in Duct Obstruction-induced Pancreatitis in Rats

Objectives: We tested the hypothesis that leukotriene B4 (LTB4) mediates pancreatic inflammation in rats via activation of the transient receptor potential vanilloid 1 (TRPV1). Methods: Leukotriene B4 or a vehicle was administered to adult rats via celiac axis injection after pretreatment with the TRPV1 antagonist, capsazepine, or vehicle, and the severity of subsequent pancreatitis was assessed by measuring pancreatic edema, myeloperoxidase (MPO) activity, and histological grading. In a second experiment, acute pancreatitis was induced by common pancreaticobiliary duct ligation. Six hours after surgery, pancreatic tissue levels of LTB4 were determined by enzyme-linked immunosorbent assay. Also, the effects of inhibition of LTB4 biosynthesis by pretreatment with the 5-lipoxygenase-activating peptide inhibitor, MK-886, were determined. Results: Celiac axis administration of LTB4 significantly increased pancreatic edema and MPO activity, and produced histological evidence of pancreatic edema, neutrophil infiltration, and necrosis. Capsazepine pretreatment significantly reduced all inflammatory parameters in LTB4-induced pancreatitis. Pancreatic tissue levels of LTB4 were significantly elevated in rats that underwent common pancreaticobiliary duct ligation compared with control rats. MK-886 pretreatment significantly inhibited pancreatic edema, histological damage, and pancreatic MPO concentrations. Conclusions: Common pancreaticobiliary duct obstruction causes an increase in pancreatic LTB4 concentrations that in turn mediates activation of TRPV1 resulting in acute pancreatitis.

Protection against chronic pancreatitis and pancreatic fibrosis in mice overexpressing pancreatic secretory trypsin inhibitor.

Objectives: Mutations in the gene encoding for pancreatic secretory trypsin inhibitor (PSTI) can contribute to chronic pancreatitis. In the current study, we tested whether overexpression of PSTI-I in mice protects against chronic pancreatitis and pancreatic fibrosis. Methods: Rat PSTI-I expression was targeted to pancreatic acinar cells in transgenic mice. Chronic pancreatitis was achieved by intraperitoneal injection of cerulein for 10 weeks. Pancreatitis severity was assessed by histological grading of inflammatory infiltrate, atrophy, and fibrosis; quantitation of myeloperoxidase (MPO) activity; quantitative morphometric analysis of collagen content; and measurements of type I collagen, fibronectin, and transforming growth factor &bgr; mRNA expression. Results: Cerulein administration to nontransgenic mice produced histological evidence of inflammatory infiltrate, glandular atrophy, and parenchymal fibrosis and increased collagen production, MPO activity, and collagen I and fibronectin mRNA levels. In cerulein-treated PSTI transgenic mice, there were significant reductions in inflammatory infiltrate, MPO activity, fibrosis, and collagen I and fibronectin mRNA levels. Transgenic mice treated with cerulein had significantly less collagen than nontransgenic mice. Conclusions: The severity of chronic pancreatitis and pancreatic fibrosis is significantly reduced in mice expressing rat PSTI-I. We propose that pancreatic trypsin inhibitors play a protective role in the pancreatic response to repeated injurious events.

Outcomes following liver transplantation

As the field of Liver Transplantation has matured, survival alone is no longer an acceptable single metric of success. This chapter explores the impact of the PELD system for donor organ allocation, surgical modification of donor organs, living donation, and long-term transplant-related complications on overall quality of life and outcome. Strategies to improve survival, overall outcome, and health-related quality of life in long-term recipients are outlined.

Impaired hepatocyte glucose transport protein (GLUT2) internalization in chronic pancreatitis.

Chronic pancreatitis (CP) is associated with impaired glucose tolerance and with reduced hepatic sensitivity to insulin. We have previously shown that in normal and sham-operated rats, insulin suppresses hepatic glucose production, and this suppression is associated with a decrease in the hepatocyte plasma membrane-bound quantity of the facilitative glucose transport protein GLUT2. The insulin-mediated reduction in membrane-bound GLUT2 is impaired in CP, and may play a role in the glucose intolerance associated with CP. To determine whether GLUT2 is actively internalized and whether this mechanism is disordered in CP, livers from fed and fasting rats in whom CP had been induced 2–3 months earlier by pancreatic duct oleic acid infusion, and in sham-operated (sham) rats, were fractionated to yield endosome (E)- and plasma membrane (PM)-enriched fractions. Forty-five minutes after duodenal intubation alone (fasting) or intubation plus duodenal feeding, livers were removed, homogenized and ultracentrifuged, and microsomal pellets were separated by sucrose density gradient ultracentrifugation. GLUT2 content of fractions was determined by Western blotting and scanning densitometry. The E:PM ratio of GLUT2 increased from 0.68 ± 0.11 (mean ± SEM) in fasting sham livers (n = 8) to 1.04 ± 0.09 in fed sham livers (n = 8;p < 0.05). However, there was no change in the E:PM ratio of GLUT2 in CP livers after duodenal feeding (0.90 ± 0.12 vs. 0.86 ± 0.10;n = 8,8;p = NS). To test our findings using confocal laser scanning microscopy, liver specimens from fed and fasting CP and sham rats were minced, fixed in 4% paraformaldehyde, sectioned, and stained with rabbit anti-rat GLUT2 antibody followed by rhodamine-labeled secondary antibody. GLUT2 was quantified by mean pixel intensity in an 8 × 16-pixel area of PM and a 16 × 16-pixel area of cytosol (CYT) in each of 30 random cells/field (400×) in each of three rats per group. As in the fractionation study, duodenal feeding increased the CYT:PM ratio of GLUT2 from 0.75 ± 0.01 in fasting sham liver to 0.86 ± 0.01 in fed sham liver (p < 0.0001), while the CYT:PM ratio in CP remained unchanged. We conclude that feeding induces a shift in GLUT2 from the plasma membrane to the endosomal pool. The feeding-induced internalization of GLUT2 is absent in livers from rats with CP and may play a role in the glucose intolerance associated with CP.

Treatment of Metronidazole-Refractory Clostridium difficile Enteritis with Vancomycin

BACKGROUND Clostridium difficile infection of the colon is a common and well-described clinical entity. Clostridium difficile enteritis of the small bowel is believed to be less common and has been described sparsely in the literature. METHODS Case report and literature review. RESULTS We describe a patient who had undergone total proctocolectomy with ileal pouch-anal anastomosis who was treated with broad-spectrum antibiotics and contracted C. difficile refractory to metronidazole. The enteritis resolved quickly after initiation of combined oral vancomycin and metronidazole. A literature review found that eight of the fifteen previously reported cases of C. difficile-associated small-bowel enteritis resulted in death. CONCLUSIONS It is important for physicians who treat acolonic patients to be aware of C. difficile enteritis of the small bowel so that it can be suspected, diagnosed, and treated.

Management and long‐term consequences of portal vein thrombosis after liver transplantation in children

Portal vein thrombosis (PVT) occurs in ≤12% of pediatric recipients of liver transplantation (LT). Known complications of PVT include portal hypertension, allograft loss, and mortality. The management of PVT is varied. A single‐center, case‐control study of pediatric LT recipients with portal vein (PV) changes after LT was performed. Cases were categorized as early PVT (if PVT was detected within 30 days of transplantation) or late PVT (if PVT was detected more than 30 days after transplantation or if early PVT persisted beyond 30 days). Two non‐PVT control patients were matched on the basis of the recipient weight, transplant indication, and allograft type to each patient with PVT. Thirty‐two of the 415 LT recipients (7.7%) received 37 allografts and developed PVT. In comparison with control patients, a higher proportion of patients with PVT had PVT present before LT (13.3% versus 0%, P = 0.01). Patients with early PVT usually returned to the operating room, and 9 of 15 patients (60%) had PV flow restored. Patients with late PVT had lower white blood cell (4.9 [1000/μL] versus 6.8 [1000/μL], P < 0.01) and platelet counts (140 [1000/μL] versus 259 [1000/μL], P < 0.01), an elevated international normalized ratio (1.2 versus 1.0, P < 0.001), and more gastrointestinal bleeding (25% versus 8.3%, P = 0.03) compared to controls. Patients with PVT were also less frequently at the expected grade level (52% versus 88%, P < 0.001). The patient survival rates were 84%, 78%, and 78% and 91%, 84%, and 79% for cases and controls at 1, 5, and 10 years, respectively. The allograft survival rates were 90%, 80%, and 80% for cases and 94%, 89%, and 87% for controls at 1, 5, and 10 years, respectively. In conclusion, patients with early and late PVT had preserved allograft function, and there was no impact on mortality. Patients diagnosed with early PVT often underwent operative interventions with successful restoration of flow. Patients diagnosed with late PVT experienced variceal bleeding, and some required portosystemic shunting procedures. Academic delays were also more common. In late PVT, the clinical presentation dictates care because the optimal management algorithm has not yet been determined. Multi‐institutional studies are needed to confirm these findings and improve patient outcomes. Liver Transpl 19:315–321, 2013.