Cirrhosis, spontaneous venous thromboses, and splenic gas gangrene.
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Abdominal Pain↗
Biomedical subjects
Matthew J DiMagno
Publications and source records attributed to Matthew J DiMagno.
Does endoscopic therapy favorably affect the outcome of patients who have recurrent acute pancreatitis and pancreas divisum?
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Acute Disease↗
Chronic pancreatitis.
PURPOSE OF REVIEW: As in our previous reviews, we endeavor to review important new observations in chronic pancreatitis made in the past year. Topics recently reviewed were truncated to accommodate a surge in publications on clinical aspects of chronic pancreatitis, which contained new observations or insights into new or old concepts. RECENT FINDINGS: Cystic fibrosis carriers have been found to be at increased risk of pancreatitis. Autoimmune pancreatitis may belong to a multiorgan immunoglobulin G4-related autoimmune disease, and the natural history of chronic pancreatitis differs among the etiologies. Diffusion-weighted magnetic resonance imaging improves upon previous methodologies for diagnosing reduced pancreatic exocrine secretion, and fecal elastase-1 has been found to be a poor test for diagnosing pancreatic malabsorption. Visceral hyperalgesia or heightened central pain perception may contribute to pain in chronic pancreatitis. Instruments are evolving to assess quality of life in chronic pancreatitis, and fibrolytic agents have been found to have therapeutic promise. SUMMARY: Researchers this past year have further characterized genetic, molecular and clinical aspects of chronic pancreatitis. Advancing the understanding of fibrogenesis, mechanisms of exocrine insufficiency, calcification, and pain and continuing development/modification of diagnostic tests should lead to improved prevention, detection and treatment of the condition. More accurate quantification of outcomes is critical for translating potential therapies from bench to bedside.
Alcoholism↗
Massive lower gastrointestinal bleeding after rejection of pancreatic transplants.
BACKGROUND: This article highlights two cases of massive lower gastrointestinal bleeding in patients on dialysis after rejection of kidney-pancreas transplants. Patient 1 was a 34-year-old female with 27 years of type I diabetes, who had a kidney-pancreas transplant in 1996, which was complicated by rejection of the kidney and pancreas in 2000 and 2002, respectively. Later in 2002, she presented in shock after experiencing cramping abdominal pain and passage of large bloody stools. Patient 2 was a 38-year-old male with 26 years of type I diabetes, who had a pancreas-kidney transplant in 1998, which was complicated by rejection of the kidney and pancreas in early 2003. He presented in late 2003 with a single episode of coffee-ground emesis and two episodes of brisk hematochezia. INVESTIGATION: Arterial angiography. DIAGNOSIS: Pseudoaneurysm and small-bowel fistula from the arterial supply to the transplanted pancreas. MANAGEMENT: Angiographic embolization of the aneurysmal vessel and fistula achieved hemostasis. Patient 1 did not have her transplanted organ surgically removed and suffered a recurrent massive lower gastrointestinal bleed that proved fatal. In Patient 2, subsequent surgery and removal of the rejected pancreas was performed and the patient continues to do well.
Adult↗
Chronic pancreatitis.
PURPOSE OF REVIEW: As in our previous reviews, we endeavor to review important new observations in chronic pancreatitis made in the past year. We included articles, including review articles, only if they contained new observations or readdressed old questions and provided new insights into old and new concepts. RECENT FINDINGS: Important observations include the following: (1) Strong association between cystic fibrosis transmembrane regulator dysfunction/mutations and 'recurrent acute pancreatitis', particularly in patients with pancreas divisum (2) Pancreas divisum may be incidental finding in recurrent acute pancreatitis (3) Smoking increases risk of chronic pancreatitis (4) Coxsackie B virus may increase severity of alcoholic chronic pancreatitis (5) CD4+ T cells and an immune reaction against amylase may play a role in pathogenesis of autoimmune pancreatitis (6) 2-(18F)-Fluro-2-deoxy-D-glucose positron emission tomography might be useful to detect pancreatic cancer in chronic pancreatitis patients at risk for developing pancreatic cancer, but contrast-enhanced Doppler ultrasound or endosonography may be as sensitive and better than contrast enhanced computed tomography (7) Superiority of surgery vs endotherapy for long term pain relief and weight gain in painful chronic pancreatitis (8) Early treatment of pain and malabsorption may improve life quality (9) Antifibrogenesis and fibrolytic agents as potential therapies. SUMMARY: Ongoing basic and clinical research this past year has further characterized genetic, molecular and clinical aspects of chronic pancreatitis. The advent of predictable and lasting treatments of chronic pancreatitis is most likely to appear on the wings of carefully conducted studies targeting genetic and molecular mechanisms of chronic pancreatitis, particularly pancreatic fibrogenesis.
Global Health↗
Endothelial nitric oxide synthase is protective in the initiation of caerulein-induced acute pancreatitis in mice.
The effect of inhibiting nitric oxide (NO) synthase (NOS) or enhancing NO on the course of acute pancreatitis (AP) is controversial, in part because three NOS isoforms exist: neuronal (nNOS), endothelial (eNOS), and inducible (iNOS). We investigated whether inhibition or selective gene deletion of NOS isoforms modified the initiation phase of caerulein-induced AP in mice and explored whether this affected pancreatic microvascular blood flow (PMBF). We investigated the effects of nonspecific NOS inhibition with N(omega)-nitro-l-arginine (l-NNA; 10 mg/kg ip) or targeted deletion of eNOS, nNOS, or iNOS genes on the initiation phase of caerulein-induced AP in mice using in vivo and in vitro models. Western blot analysis was performed to assess eNOS phosphorylation status, an indicator of enzyme activity, and microsphere studies were used to measure PMBF. l-NNA and eNOS deletion, but not nNOS or iNOS deletion, increased pancreatic trypsin activity and serum lipase during the initiation phase of in vivo caerulein-induced AP. l-NNA and eNOS did not affect trypsin activity in caerulein-hyperstimulated isolated acini, suggesting that nonacinar events mediate the effect of NOS blockade in vivo. The initiation phase of AP in wild-type mice was associated with eNOS Thr(495) residue dephosphorylation, which accompanies eNOS activation, and a 178% increase in PMBF; these effects were absent in eNOS-deleted mice. Thus eNOS is the main isoform influencing the initiation of caerulein-induced AP. eNOS-derived NO exerts a protective effect through actions on nonacinar cell types, most likely endothelial cells, to produce greater PMBF.
Acute Disease↗
Chronic pancreatitis.
PURPOSE OF REVIEW: Clinicians are learning more about chronic pancreatitis but are entering an era of some confusion, primarily driven by uncovering new etiologies of chronic pancreatitis. Ideally, this knowledge will lead to better diagnosis and treatment, and abandonment of ill-conceived treatments. In contrast with previous reviews, this review highlights select contributions this year that may develop into true advances in chronic pancreatitis. RECENT FINDINGS: Small steps have been made to understand better the molecular basis of chronic pancreatitis. Diagnosis of early chronic pancreatitis remains challenging. Rapid diagnosis by combining endoscopy and a direct stimulatory test of pancreatic function may lead to more widespread use of function testing, but this test is not ready for clinical use. Application of microarray and proteomic technologies may aid future diagnosis of chronic pancreatitis. The failure to account clearly for the phenotype of patients with chronic pancreatitis may confound delineating the etiologies of chronic pancreatitis. Clinical description and studies of autoimmune pancreatitis have led to the realization that steroids are an effective treatment for this form of chronic pancreatitis. Genetic-based studies have provided insight into the pathogenic mechanisms of chronic pancreatitis. Investigation of the role of stellate cells, an essential component fibrogenesis, has led to identification of potential novel treatments for chronic pancreatitis. SUMMARY: Ongoing basic and clinical research this past year has characterized further the histologic, genetic, molecular, and clinical aspects of chronic pancreatitis, efforts that may translate into novel therapies once well-designed, controlled studies have been performed.
Journal Article↗
Secretagogue-stimulated pancreatic secretion is differentially regulated by constitutive NOS isoforms in mice.
Nitric oxide (NO) and NO synthase (NOS) play controversial roles in pancreatic secretion. NOS inhibition reduces CCK-stimulated in vivo pancreatic secretion, but it is unclear which NOS isoform is responsible, because NOS inhibitors lack specificity and three NOS isoforms exist: neuronal (nNOS), endothelial (eNOS), and inducible (iNOS). Mice having individual NOS gene deletions were used to clarify the NOS species and cellular interactions influencing pancreatic secretion. In vivo secretion was performed in anesthetized mice by collecting extraduodenal pancreatic duct juice and measuring protein output. Nonselective NOS blockade was induced with N(omega)-nitro-L-arginine (L-NNA; 10 mg/kg). In vivo pancreatic secretion was maximal at 160 pmol.kg(-1).h(-1) CCK octapeptide (CCK-8) and was reduced by NOS blockade (45%) and eNOS deletion (44%). Secretion was unaffected by iNOS deletion but was increased by nNOS deletion (91%). To determine whether the influence of NOS on secretion involved nonacinar events, in vitro CCK-8-stimulated secretion of amylase from isolated acini was studied and found to be unaltered by NOS blockade and eNOS deletion. Influence of NOS on in vivo secretion was further examined with carbachol. Protein secretion, which was maximal at 100 nmol.kg(-1).h(-1) carbachol, was reduced by NOS blockade and eNOS deletion but unaffected by nNOS deletion. NOS blockade by L-NNA had no effect on carbachol-stimulated amylase secretion in vitro. Thus constitutive NOS isoforms can exert opposite effects on in vivo pancreatic secretion. eNOS likely plays a dominant role, because eNOS deletion mimics NOS blockade by inhibiting CCK-8 and carbachol-stimulated secretion, whereas nNOS deletion augments CCK-8 but not carbachol-stimulated secretion.
Amylases↗
Caerulein-induced acute pancreatitis inhibits protein synthesis through effects on eIF2B and eIF4F.
Acute pancreatitis (AP) has been shown in some studies to inhibit total protein synthesis in the pancreas, whereas in other studies, protein synthesis was not affected. Previous in vitro work has shown that high concentrations of cholecystokinin both inhibit protein synthesis and inhibit the activity of the guanine nucleotide exchange factor eukaryotic initiation factor (eIF)2B by increasing the phosphorylation of eIF2alpha. We therefore evaluated in C57BL/6 mice the effects of caerulein-induced AP on pancreatic protein synthesis, eIF2B activity and other protein translation regulatory mechanisms. Repetitive hourly injections of caerulein were administered at 50 microg/kg ip. Pancreatic protein synthesis was reduced 10 min after the initial caerulein administration and was further inhibited after three and five hourly injections. Caerulein inhibited the two major regulatory points of translation initiation: the activity of the guanine nucleotide exchange factor eIF2B (with an increase of eIF2alpha phosphorylation) and the formation of the eIF4F complex due, in part, to degradation of eIF4G. This inhibition was not accounted for by changes in the upstream stimulatory pathway, because caerulein activated Akt as well as phosphorylating the downstream effectors of mTOR, 4E-BP1, and ribosomal protein S6. Caerulein also decreased the phosphorylation of the eukaryotic elongation factor 2, implying that this translation factor was not inhibited in AP. Thus the inhibition of pancreatic protein synthesis in this model of AP most likely results from the inhibition of translation initiation as a result of increased eIF2alpha phosphorylation, reduction of eIF2B activity, and the inhibition of eIF4F complex formation.
Acute Disease↗
Chronic pancreatitis.
PURPOSE OF REVIEW: We are beginning to better understand the causes of chronic pancreatitis. This knowledge will hopefully lead to better diagnosis and treatment and abandonment of ill-conceived treatments. This review highlights contributions that moved the field toward these goals in the past year. RECENT FINDINGS: Small steps have been made toward a better understanding of the molecular basis, particularly genetic causes, of the forms of chronic pancreatitis. Investigation of the role of stellate cells, an essential component of the fibrosis of chronic pancreatitis, has led to the finding that lovastatin inhibits stellate cell activation and could surface as a novel treatment of chronic pancreatitis. The clinical description of autoimmune pancreatitis has led to the realization that steroids are effective treatment for this form of chronic pancreatitis. Other treatments such as extracorporeal shock wave lithotripsy and endoscopic treatments have not been proved, because no controlled studies support these treatments over other treatments. The diagnosis of chronic pancreatitis may be enhanced by the new imaging technique of electronic pancreatoscopy whereby a 2.1-mm diameter scope can be advanced into the pancreatic duct through a duodenoscope. However, the data are too preliminary at this time to advocate this imaging procedure. A potential new endoscopic pancreatic function test may lead to more widespread use of function testing, but this test is not perfected and also cannot be advised for use at present. SUMMARY: Ongoing basic and clinical research this past year has further characterized the genetic, molecular, and clinical aspects of chronic pancreatitis: efforts that may translate into novel therapies, once well-designed, controlled studies have been performed.
Journal Article↗