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David C Whitcomb

Publications and source records attributed to David C Whitcomb.

69 records · Page 4Linked to original sources
PubMed2002

Pancreatitis as a risk for pancreatic cancer.

Chronic pancreatitis clearly predisposes to pancreatic cancer, with early onset-long duration chronic pancreatitis from cystic fibrosis, TP, and HP conferring the highest risk. Chronic pancreatitis is not a critical step, however, but rather one of several conditions that accelerate the accumulation of critical genetic mutations and chromosomal losses necessary for carcinogenesis. Indeed, other germline mutations, environmental factors such as tobacco smoking and alcohol consumption, or dietary factors may also accelerate the pathway to carcinogenesis, and may be synergistic with the conditions created by chronic pancreatitis. Because patients with chronic pancreatitis are at high risk of pancreatic cancer, the physician is faced with decisions on how to manage this risk. Discontinuing smoking and alcohol consumption, and perhaps dietary modification are obvious recommendations for risk reduction. If, however, the patient is older and already in a very high-risk category (e.g., long-standing HP), then screening for cancers must be considered. Inclusion in multicenter trials is recommended, and information on ongoing studies can be obtained through the office of Dr. Whitcomb, or as posted on www.pancreas.org.

Cell Transformation, Neoplastic↗
PubMed2002

Hereditary pancreatitis: a model for inflammatory diseases of the pancreas.

Acute and chronic pancreatitis remain among the most recalcitrant of all diseases to investigation and intervention. In the majority of patients, excessive alcohol consumption is associated with development of the disease. Therefore, several theories have been proposed seeking to explain the relationship between alcohol and the development of acute and chronic pancreatitis. However, recent investigations in hereditary pancreatitis provided important insights into chronic pancreatitis pathogenesis and offer an important model for understanding pancreatic inflammation. This article highlights several advances gained from investigating hereditary pancreatitis kindreds, and reviews the TIGAR-O risk/aetiology classification system. Finally, the major independent theories on development of chronic pancreatitis are reviewed with respect to the SAPE hypothesis of chronic pancreatitis pathogenesis.

Acute Disease↗
PubMed2002

SPINK1/PSTI mutations are associated with tropical pancreatitis and type II diabetes mellitus in Bangladesh.

BACKGROUND & AIMS: Tropical pancreatitis, including tropical calcific pancreatitis and fibrocalculous pancreatic diabetes, is endemic in parts of Asia and Africa. In a preliminary study, we found serine protease inhibitor, Kazal type 1 (SPINK1) mutations in 6 of 8 patients with fibrocalculous pancreatic diabetes in Bangladesh. A more extensive investigation of patients with pancreatic diseases in Bangladesh, including non-insulin-dependent diabetes mellitus, was undertaken. METHODS: Patients with fibrocalculous pancreatic diabetes (n = 22), tropical calcific pancreatitis (n = 15), and non-insulin-dependent diabetes mellitus (n = 43) and controls (n = 76) from Bangladesh were studied. DNA was extracted, and the SPINK1 gene was sequenced in all patients and 50 controls. Exon 3 was sequenced in an additional 26 controls. RESULTS: SPINK1 N34S mutations appeared in 1 of 76 controls (1.3%), 12 of 22 patients with fibrocalculous pancreatic diabetes (55%; odds ratio, 83; P < 0.00001), 3 of 15 with tropical calcific pancreatitis (20%; odds ratio, 11.2; P = 0.04), and 6 of 43 with non-insulin-dependent diabetes mellitus (14%; odds ratio, 11.9; P = 0.009). P55S was present in 2 of 76 controls (3%) and in 1 of 22 patients with fibrocalculous pancreatic diabetes (5%; P = not significant). A novel Y54H (160T>C) mutation was identified in 1 of 15 tropical calcific pancreatitis patients. CONCLUSIONS: In Bangladesh, the SPINK1 N34S mutation increases the risk of several forms of pancreatic disease, including fibrocalculous pancreatic diabetes, tropical calcific pancreatitis, and non-insulin-dependent diabetes mellitus.

Adult↗
PubMed2002

Genetics and pancreatic disease.

The recognition that variations in the DNA sequence of key genes predispose individuals to acute pancreatitis, chronic pancreatitis, and pancreatic cancer represents one of the greatest breakthroughs in pancreas research. This review highlights recent progress in understanding mutations in the cationic trypsinogen gene, the pancreatic secretory trypsin inhibitor gene, and the cystic fibrosis transmembrane conductance regulator gene with respect to pancreatitis. It also notes progress in the use of microarray technology, classification of chronic pancreatitis, and predisposition to pancreatic cancer.

Journal Article↗
PubMed2002

Pancreatic cholesterol esterase, ES-10, and fatty acid ethyl ester synthase III gene expression are increased in the pancreas and liver but not in the brain or heart with long-term ethanol feeding in rats.

INTRODUCTION: Chronic alcohol consumption predisposes susceptible individuals to both acute and chronic pancreatitis. AIMS: Our hypothesis was that alcohol increases the risk of pancreatitis by disrupting defense mechanisms and/or enhancing injury-associated pathways through altered gene expression. Hence, we studied the expression of pancreatic genes in rats chronically exposed to ethanol. METHODOLOGY: Male Wistar rats were pair-fed liquid diets without and with ethanol for 4 weeks. Total RNA was extracted from rat pancreas and other organs. The mRNA expression patterns among pancreatic samples from ethanol-fed rats and controls were compared with use of mRNA differential display. The differentially expressed cDNA tags were isolated, cloned, and sequenced. RESULTS: One cDNA tag that was overexpressed in the pancreas showed 99% sequence homology to a rat pancreatic cholesterol esterase mRNA (CEL; Enzyme Commission number [EC] 3.1.1.13). The differential expression was confirmed by realtime PCR. Gene expression was also increased in the liver but not in the heart or brain of the alcohol-fed rats. Because CEL has fatty acid ethyl ester (FAEE)-generating activity and FAEEs play a major role in acute alcoholic pancreatitis, we determined the expression of other genes encoding for FAEE-generating enzymes and showed similar organ-specific expression patterns. CONCLUSION: Our results demonstrate that chronic ethanol consumption induced expression of FAEE-related genes in the pancreas and liver. This upregulation may be a central mechanism leading to acinar cell injury.

Acyltransferases↗
PubMed2002

Conservative treatment of chronic pancreatitis.

Chronic pancreatitis has been difficult to treat because the origin, pathophysiologic mechanisms and causes of unrelenting pain are so poorly understood. Furthermore, the pharmacologic agents often employed in other diseases with pain appear to be ineffective in many cases. The conservative management of chronic pancreatitis aims at (1) limiting progression and complications of the disease; (2) replacing lost exocrine and endocrine function; and (3) pain control. Thus, life style changes such as cessation of alcohol consumption and tobacco smoking, trials of pancreatic enzymes, treatment of duct obstruction and pseudocysts, and surgical therapies are currently employed. The good news is that the understanding of the underlying pathophysiological mechanisms is now advancing rapidly, and hopefully patient-specific and highly effective therapies will become available in the near future.

Chronic Disease↗
PubMed2002

Acute pancreatitis in children.

OBJECTIVES: Currently, there is no scoring system for predicting severity in acute pancreatitis in children. Our intent was to evaluate the performance of existing scoring systems in children, to develop a system for children, and to examine the etiology of acute pancreatitis in children. METHODS: A chart review of children with acute pancreatitis was conducted at six centers, three serving as criterion centers and three as validation centers. Ranson and Glasgow scores were calculated for each admission. Additional clinical data were collected, and parameters correlating with severity were incorporated into a new scoring system. Performance characteristics were calculated for each system. RESULTS: A total of 301 admissions were reviewed, 202 in the criterion group and 99 in the validation group. Eight parameters were included in a new scoring system for children. The parameters were as follows: age (<7 yr), weight (<23 kg), admission WBC (>18,500), admission LDH (>2,000), 48-h trough Ca2+ (<8.3 mg/dl), 48-h trough albumin (<2.6 g/dl), 48-h fluid sequestration (>75 ml/ kg/48 h), and 48-h rise in BUN (>5 mg/dl). When the cut-off for predicting a severe outcome was set at 3 criteria, the new system had better sensitivity versus Ranson and Glasgow scores (70% vs 30% and 35%, respectively) and a better negative predictive value (91% vs 85% and 85%). The specificity (79% vs 94% and 94%) and positive predictive value (45% vs 57% and 61%) fell slightly. CONCLUSION: The new scoring system performs better in this group than do existing systems.

Acute Disease↗
PubMed2002

Autosomal dominant infantile gastroesophageal reflux disease: exclusion of a 13q14 locus in five well characterized families.

OBJECTIVES: A genetic locus for pediatric reflux was proposed on chromosome 13q14, but is unconfirmed in independent kindreds. We sought to test this locus in families with multiple affected infants from our database of well characterized infants with reflux. METHODS: We screened the database for families with multiple affected infants. Affected proband phenotype required histological esophagitis; affected sibling/cousin phenotype required a threshold score on a diagnostic questionnaire. Screened families were reduced to five based on pedigree, consent, and phenotypic clarity. Linkage of the phenotype with the four previously reported markers (D13S218, D13S1288, D13S1253, and D13S263) was tested, using an autosomal dominant, 70% penetrance model. Linkage required logarithm-of-odds score > or = 3. RESULTS: Of 54 individuals in the five probands' generation, 21 (39%) were affected based on questionnaire, of whom nearly one half also had histological confirmation of esophagitis. Linkage to the defined region was excluded for the five families by two-point LOD scores (-1.47 at D13S218, -1.32 at D13S1288, -3.43 at D13S1253, and -3.92 at D13S263) and by multipoint (multipoint LOD scores less than -2 between D13S218 and D13S263) linkage analysis. No family demonstrated even suggestive positive linkage (i.e., LOD score >1). CONCLUSIONS: In five rigorously phenotyped families with autosomal dominant pattern infantile reflux, we excluded genetic linkage to the region of 13ql4 previously identified responsible for an autosomal dominant form of pediatric reflux. These results suggest genetic heterogeneity, possibly related to phenotypic heterogeneity, in familial pediatric gastroesophageal reflux disease.

Child↗
PubMed2002

Sex differences in hepatic gene expression in a rat model of ethanol-induced liver injury.

Sex differences in susceptibility to alcohol-induced liver injury have been observed in both humans and experimental animal models. Using a standard model of alcohol-induced fatty liver injury and microarray analysis, we have identified differential expression of hepatic genes in both sexes. The genes that exhibit differential expression are of three types: those that are changed only in male rats fed alcohol, those that change in only female rats fed alcohol, and those that change in both sexes, although not always in the same manner. Certain of the differentially expressed genes have previously been identified as participants in the induction of alcohol-induced liver injury. However, this analysis has identified a number of genes that heretofore have not been implicated in alcoholic liver injury; such genes may provide new areas of investigation into the pathogenesis of this disease.

Animals↗
PubMed2002

Animal models in alcoholic pancreatitis--what can we learn?

Although the majority of patients with chronic pancreatitis present a history of excessive alcohol consumption, the pathophysiology underlying chronic alcoholic pancreatitis remains poorly defined. Since experimental animal models represent helpful tools in understanding human disease, numerous laboratory studies have been designed to study the effects of alcohol on the pancreas. In the present article we summarize the existing animal models that have been used to investigate the effects of acute and chronic alcohol application on the development of morphological alterations and pancreatic injury. Despite considerable experimental effort, acute or chronic ethanol feeding alone failed to cause acute or chronic pancreatitis in animals. However, ethanol-feeding and the combination with other procedures has demonstrated several mechanisms that play a role in ethanol-induced pancreatic injury. Among these ethanol-induced alterations and mechanisms are the reduction of pancreatic blood-flow and microcirculation, damaging effects of ethanol metabolites, increased pancreatic acinar cell expression of digestive and lysosomal enzymes, increased glandular enzyme content, additional nutritional factors, pancreatic duct obstruction, and limitations of pancreatic regeneration. Although no satisfactory animal model for alcoholic pancreatitis has been developed, these animal models have provided insights in several factors that predispose the pancreas to development of pancreatic injury and contribute to alcoholic pancreatitis.

Alcohol Drinking↗
PubMed2002

IAP Guidelines for the Surgical Management of Acute Pancreatitis.

During 2002 the International Association of Pancreatology developed evidenced-based guidelines on the surgical management of acute pancreatitis. There were 11 guidelines, 10 of which were recommendations grade B and one (the second) grade A. (1) Mild acute pancreatitis is not an indication for pancreatic surgery. (2) The use of prophylactic broad-spectrum antibiotics reduces infection rates in computed tomography-proven necrotizing pancreatitis but may not improve survival. (3) Fine-needle aspiration for bacteriology should be performed to differentiate between sterile and infected pancreatic necrosis in patients with sepsis syndrome. (4) Infected pancreatic necrosis in patients with clinical signs and symptoms of sepsis is an indication for intervention including surgery and radiological drainage. (5) Patients with sterile pancreatic necrosis (with negative fine-needle aspiration for bacteriology) should be managed conservatively and only undergo intervention in selected cases. (6) Early surgery within 14 days after onset of the disease is not recommended in patients with necrotizing pancreatitis unless there are specific indications. (7) Surgical and other forms of interventional management should favor an organ-preserving approach, which involves debridement or necrosectomy combined with a postoperative management concept that maximizes postoperative evacuation of retroperitoneal debris and exudate. (8) Cholecystectomy should be performed to avoid recurrence of gallstone-associated acute pancreatitis. (9) In mild gallstone-associated acute pancreatitis, cholecystectomy should be performed as soon as the patient has recovered and ideally during the same hospital admission. (10) In severe gallstone-associated acute pancreatitis, cholecystectomy should be delayed until there is sufficient resolution of the inflammatory response and clinical recovery. (11) Endoscopic sphincterotomy is an alternative to cholecystectomy in those who are not fit to undergo surgery in order to lower the risk of recurrence of gallstone-associated acute pancreatitis. There is however a theoretical risk of introducing infection into sterile pancreatic necrosis. These guidelines should now form the basis for audit studies in order to determine the quality of patient care delivery.

Acute Disease↗
PubMedDate not supplied

Hereditary, familial, and idiopathic chronic pancreatitis are not associated with polymorphisms in the tumor necrosis factor alpha (TNF-alpha) promoter region or the TNF receptor 1 (TNFR1) gene.

PURPOSE: Genetic alterations that are associated with acute and chronic pancreatitis remain to be identified. METHODS: The authors investigated two functionally active tumor necrosis factor (TNF) promoter region polymorphisms at positions -238 and -308 and the entire coding region of the corresponding TNF receptor 1 (TNFR1) gene in 54 patients with hereditary, familial, and idiopathic chronic pancreatitis who were previously tested negative for cationic trypsinogen mutations by direct DNA sequencing. RESULTS: In three patients, we detected novel DNA variants in the TNFR1 gene that did not segregate with the disease. The genotype frequencies of the TNF promoter polymorphisms were similar between patients and controls. CONCLUSION: These polymorphisms are not associated with hereditary, familial, or idiopathic chronic pancreatitis.

Antigens, CD↗