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Biomedical subjects

D C Whitcomb

Publications and source records attributed to D C Whitcomb.

At least 55 records · Page 3Linked to original sources
PubMed1999

Hereditary pancreatitis and pancreatic carcinoma.

Few risk factors for pancreatic cancer have emerged except for chronic pancreatitis. Recently, hereditary pancreatitis was estimated to carry a standardized incidence ratio of 53, a risk about 25 times higher than smoking. A review of the ongoing hereditary pancreatitis study of the Midwest Multicenter Pancreatic Study Group suggests that the risk of pancreatic cancer is related to long-standing pancreatitis rather than to the cationic trypsinogen mutations. No recommendations can be made on screening patients with hereditary pancreatitis for pancreatic cancer at this time. However, prospective data, serum, and pancreatic juice should be collected and banked on consenting patients at risk as part of prospective, multicenter trials so that evidence-based recommendations for hereditary pancreatitis and other types of chronic pancreatitis can be made in the future.

Animals↗
PubMed1999

New insights into hereditary pancreatitis.

The recent discovery that mutations in the trypsinogen gene are responsible for acute and chronic pancreatitis, and that patients with hereditary pancreatitis are at great risk for pancreatic cancer, has opened the door to understanding many aspects of pancreatic disease. This review focuses on the clinical presentation of hereditary pancreatitis, the mechanism of disease, and implications of this disease on understanding acute and chronic pancreatitis.

Acute Disease↗
PubMed1999

Endoscopic pancreatic duct stenting to treat pancreatic ascites.

BACKGROUND: Management of pancreatic ascites with conservative medical therapy or surgery has met with limited success. Decompression of the pancreatic ductal system through transpapillary stent placement, an alternative strategy, has been reported in only a handful of cases of pancreatic ascites. METHODS: We reviewed all cases from 1994 to 1997 in which patients with pancreatic ascites underwent an endoscopic retrograde pancreatogram documenting pancreatic duct disruption with subsequent placement of a transpapillary pancreatic duct stent. Clinical end points were resolution of ascites and need for surgery. RESULTS: There were 8 cases of pancreatic ascites in which a 5F or 7F transpapillary pancreatic duct stent was placed as the initial drainage procedure. Pancreatic ascites resolved in 7 of 8 patients (88%) within 6 weeks. Ascites resolved in the eighth patient, a poor candidate for surgery, following placement of a 5 mm expandable metallic pancreatic stent. No infections, alterations in ductal morphology, or other complications related to stent placement were noted. There was no recurrence of pancreatic ascites or duct disruption at a mean follow-up of 14 months. CONCLUSIONS: Our experience doubles the number of reported cases in which transpapillary pancreatic stent placement safely obviated the need for surgical intervention in the setting of pancreatic ascites. This therapeutic endoscopic intervention should be seriously considered in the initial management of patients with pancreatic ascites.

Adult↗
PubMed1999

Hereditary pancreatitis. Gene defects and their implications.

Hereditary pancreatitis is a rare condition characterized by acute and chronic pancreatitis transmitted in an autosomal dominant fashion. There also is an epidemiologic link to pancreatic cancer in some affected families. Failure of a secondary brake mechanism responsible for inactivation of prematurely activated cationic trypsin in acinar cells seems to be the fundamental defect in type I hereditary pancreatitis (R117H cationic trypsin), and also may explain the pathogenesis of type II hereditary pancreatitis (N211 cationic trypsin). The diagnosis is made based on clinical history and, in certain cases, by molecular diagnostic testing for these gene defects. Medical management of acute and chronic hereditary pancreatitis currently does not differ from that of nonhereditary AP. As in nonhereditary pancreatitis, the surgical approach must be tailored to the individual problem, with an understanding that disease restricted to the head of the gland is atypical and that residual acinar tissue continues to drive the disease state. Although diagnosis and management of pancreatic adenocarcinoma are similar in this cohort, the increased age-accumulated risk suggests that thoughtful screening protocols eventually may be clinically and cost-effective.

Adenocarcinoma↗
PubMed1999

The spectrum of complications of hereditary pancreatitis. Is this a model for future gene therapy?

Hereditary pancreatitis is an unusual form of acute and chronic pancreatitis that is usually associated with two specific mutations in the cationic trypsinogen gene. The extensive information available on the biochemistry, cell biology, and molecular biology of cationic trypsinogen and its gene provides the groundwork for development of a variety of therapeutic strategies, including gene therapy. Several features of this disease, however, make gene therapy unlikely in the near future. Further research using new models, including transgenic animals, is required before breakthroughs in therapy can be expected.

Amino Acid Sequence↗
PubMed1999

Analysis of the hereditary pancreatitis-associated cationic trypsinogen gene mutations in exons 2 and 3 by enzymatic mutation detection from a single 2.2-kb polymerase chain reaction product.

BACKGROUND: Hereditary pancreatitis is associated with at least 2 mutations in the cationic trypsinogen gene. The purpose of the present study is to test the utility of T4 endonuclease VII for the detection of cationic trypsinogen R117H mutations. In addition, the possibility of screening for R117H, N21I, and A8V mutations in a single 2.2-kb polymerase chain reaction (PCR) product using T4 endonuclease VII was investigated. METHODS: Twenty-nine DNAs from control patients and patients with known cationic trypsinogen R117H, A8V, or N21I mutations were selected from the ongoing hereditary pancreatitis study of the Midwest Multicenter Pancreatic Study Group. The samples were coded and randomized, and a 911-bp sequence containing exon 3 or a 2,212- bp sequence containing exons 2 and 3 were amplified by PCR using fluorescent- labeled primers. The PCR products were digested with T4 endonuclease VII and screened for mutations on an automated DNA sequencer. RESULTS: In all cases with a mutation, a cleavage fragment on the direct and/or complementary DNA strand could easily be visualized, and its approximate size correlated with the predicted location of the known mutations within the PCR product. When the code for affected status was broken, there was 100% correlation between previous DNA sequence or restriction fragment length polymorphism findings and the T4 endonuclease VII digestion results for all 29 DNAs. CONCLUSION: T4 endonuclease VII accurately identified the known cationic trypsinogen gene mutations in exons 2 and 3. Enzymatic mutation detection appears to be an accurate and useful method for screening individuals for known trypsinogen gene mutations and may be useful in identifying previously unidentified mutations within large regions of interest.

Acute Disease↗
PubMed1999

Hereditary pancreatitis: new insights, new directions.

Hereditary pancreatitis is an unusual form of acute and chronic pancreatitis with a familial predisposition. Recently, the gene mutations causing most cases of hereditary pancreatitis have been identified in the cationic trypsinogen gene. The known mutations are trypsinogen R117H and N211. These may predispose to acute pancreatitis by eliminating one of the fail-safe mechanisms used by the pancreas to eliminate prematurely activated trypsin. Accumulation of active trypsin mutants are hypothesized to initiate a digestive enzyme activation cascade in the pancreatic acinar cells leading to autodigestion, an intense inflammatory response, and acute pancreatitis. The observation that these patients also develop typical chronic pancreatitis and may later develop pancreatic cancer provides strong evidence that these conditions are linked. Knowledge of the pathophysiological conditions leading to acute and chronic pancreatitis and the development of a transgenic mouse expressing the mutant human trypsinogen genes will provide directions and tools necessary for the effective treatment or prevention of this human disease.

Animals↗
PubMed1999

Prevalence and predictors of severe acute pancreatitis in patients with acquired immune deficiency syndrome (AIDS).

OBJECTIVE: Recent case control data suggested that a severe course of acute pancreatitis in HIV+ patients was 1) common (50% of cases), 2) poorly predicted by Ranson's criteria (sensitivity 41%), and 3) accurately predicted by a diagnosis of AIDS (positive predictive value 67%). However, the definition of severity included length of stay in hospital and excluded commonly accepted markers (local complications, systemic complications, and need for surgery). The aim of this study was to determine 1) the prevalence of severity and 2) the value of these predictors with regard to severity, as defined by commonly accepted standardized criteria in patients with AIDS and acute pancreatitis. METHODS: A retrospective review identified 50 patients with AIDS exhibiting clinical, laboratory, and/or radiological features of acute pancreatitis. RESULTS: Only five patients followed a severe course as defined by accepted markers. Of these patients, 29 had values available for at least nine of 11 of Ranson's criteria (sensitivity 80%, specificity 54%). Points were awarded most commonly for decreased serum Ca2+ (n = 14) and elevated serum LDH (n = 7). CONCLUSIONS: In patients with AIDS and acute pancreatitis at our institutions, 1) the prevalence of severity and 2) the sensitivity of Ranson's criteria with regard to severity is comparable to that reported in large historical case series of immunocompetent patients. Pseudohypocalcemia and/or elevation in LDH are frequent, likely due to the catabolic infectious disease state.

Acquired Immunodeficiency Syndrome↗
PubMed1998

Overexpression of hepatic pancreatic polypeptide receptors in chronic pancreatitis.

Pancreatic polypeptide (PP) receptors have recently been demonstrated on liver microsomal membranes although the mechanisms of PP action on hepatocytes remain uncertain. The binding characteristics of these high affinity receptors under pathophysiologic conditions were studied in rats with oleic acid-induced chronic pancreatitis (CP), a state associated with diminished pancreatic PP content. Sixteen pancreatitic and 11 sham-operated control animals either were 16-h fasted or were given free access to food prior to organ removal. Competitive binding studies were performed by incubating hepatocyte microsomal preparation with 125I-labeled PP (20-40 pM) and increasing concentrations of nonlabeled PP (1 x 10(-10) to 1 x 10(-6) M). After total and nonspecific binding was quantified by gamma counting, coefficients of dissociation (Kd) and maximal binding sites (Bmax) were determined by Scatchard analysis of specifically bound radioactivity. Binding data were normalized to membrane protein content and expressed as means +/- standard error. Bmax was significantly greater in tissue from fed control animals than from fasted controls (4.46 +/- 0.36 versus 2.83 +/- 0.25, P < 0.05). Bmax was significantly greater under fasted conditions in tissue from CP animals than from controls (5.25 +/- 0.94 versus 2.83 +/- 0.25, P < 0.01). Under fed conditions, this differences was abolished by the increase in maximal binding in the control group. The fasting-associated decrease in maximal binding sites observed in controls did not occur in CP specimens. Increased Bmax in fed versus fasted control, as well as fasted CP versus fasted control, were associated with slight reciprocal decreases in receptor affinity. These data indicate that hepatic PP receptor concentration is upregulated in this model of chronic pancreatitis, most likely due to diminished exposure to ligand. Furthermore, normal PP receptor responses to the fed/fasted state are blunted in this condition. Regulatable PP receptor changes may play a role in altered hepatic metabolism previously observed in chronic pancreatitis.

Animals↗
PubMed1998

Lack of R117H mutation in the cationic trypsinogen gene in patients with tropical pancreatitis from Bangladesh.

The etiology of nonalcoholic chronic pancreatitis, occurring in tropical regions, is unknown. Although environmental factors may play a role in its pathogenesis, a specific genetic predisposition may be necessary. The genetic mutation responsible for hereditary pancreatitis was described recently. Unlike in patients with hereditary pancreatitis, we found a lack of the R117H mutation in the cationic trypsinogen gene in all patients with tropical pancreatitis from Bangladesh.

Adolescent↗
PubMed1998

Cellular distribution of secretin receptor expression in rat pancreas.

Secretin is an important regulator of pancreatic function, but the molecular basis of its actions is not well understood. We have, therefore, used in situ autoradiography, photoaffinity labeling, and RNase protection assays with healthy rat pancreas, dispersed acinar cells, and pancreas depleted of acinar cells to explore the cellular distribution and molecular identity of high-affinity secretin receptors in this complex organ. The autoradiographic examination of 125I-labeled [Tyr10]rat secretin-27 binding to normal pancreas demonstrated saturable and specific high-affinity binding sites on both acinar and duct cells, with a uniform lobular distribution, but with no binding above background over islets or vascular structures. Photoaffinity labeling demonstrated that the ductular binding site in acinar cell-depleted copper-deficient rat pancreas represented the same glycoprotein with a molecular weight of 50,000-62,000 that was present on acinar cells. RNase protection assays confirmed the molecular identity of the secretin receptors expressed on these distinct cells. The apparent absence or extreme low density of similar secretin receptors on islets and pancreatic vascular structures suggests that the pharmacological effects of secretin on those cells may either be indirect or mediated by another secretin family receptor that recognizes this hormone with lower affinity.

Animals↗