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D C Whitcomb

Publications and source records attributed to D C Whitcomb.

At least 73 records · Page 4Linked to original sources
PubMed1997

Distribution of pancreatic polypeptide receptors in the rat brain.

Pancreatic polypeptide (PP) is a regulatory peptide that modulates gastrointestinal function. Previously we demonstrated PP receptors in the brainstem and interpeduncular nucleus, and the PP receptors in the brainstem appear to modulate gastric motility and pancreatic exocrine secretion. The purpose of this study is to extend our understanding of the distribution of PP receptors in the rat brain in order to determine the systems that are potentially modulated by PP. Rat brains were studied using 125I-PP receptor autoradiography on cryostat sections of the entire brain cut in three planes (horizontal, sagittal, and coronal). Brain regions exhibiting PP binding sites were confirmed when identified in all three planes of section. Saturable PP binding was identified in the hypothalamus (arcuate and paraventricular n), the rostral forebrain (medial preoptic area, anterior olfactory nucleus, islands of Calleja, the dorsal endopiriform n, piriform cortex, and the bed n of the stria terminalis), medial amygdaloid n; the thalamus (anteromedial thal. n; reuniens thal. n; and paraventricular thal n), the interpeduncular red nucleus, substantia nigra, parabrachial n; locus coeruleus, mesencephalic trigeminal n, dorsal motor n of the vagus, the n solitary tract, and the area postrema. We conclude that PP receptors are distributed widely throughout the rat brain. The distribution of many of these PP binding sites corresponds to brain regions regulating digestion and autonomic function. We speculate, based on the patterns of binding in the olfactory and limbic systems, that PP receptors might be involved in positive reinforcement of ingestion behavioral as well as modulation of gastrointestinal function.

Animals↗
PubMed1997

Hereditary pancreatitis and the risk of pancreatic cancer. International Hereditary Pancreatitis Study Group.

BACKGROUND: Hereditary pancreatitis is an autosomal-dominant disease, with a variable expression and an estimated penetrance of 80%. The gene for this disease has recently been mapped to chromosome 7q35, and the defect is believed to be caused by a mutation in the cationic trypsinogen gene. Acute attacks of abdominal pain begin early in life and the disease often progresses to chronic pancreatitis. Although the risk of pancreatic cancer is thought to be increased in more common types of chronic pancreatitis, the frequency of pancreatic cancer in the inherited type of pancreatitis is uncertain. PURPOSE: The aim of this study was to assess the frequency of pancreatic cancer and other tumors in patients with hereditary form of pancreatitis. METHODS: To determine the natural history of hereditary pancreatitis, we invited all members of the American Pancreatic Association and the International Association of Pancreatology to participate in a longitudinal study of this rare form of pancreatitis. The initial criteria for patient eligibility were as follows: early age (< or = 30 years) at onset of symptoms, positive family history, and absence of other causes. From April 1995 through February 1996, 37 physicians from 10 countries contributed medical records of 246 (125 males and 121 females) patients thought to have hereditary pancreatitis as the most likely diagnosis. This group included 218 patients where the diagnosis appeared to be highly probable and 28 additional patients where the diagnosis of hereditary pancreatitis was less certain: 25 patients who had relatively late onset of disease and a positive family history and three patients with onset of disease before age 30 years but with an uncertain family history. We reviewed all causes of death and compared the observed to the expected frequency of cancer in this historical cohort of patients with hereditary pancreatitis. The strength of the association between pancreatitis and pancreatic cancer was estimated by the standardized incidence ratio (SIR), which is the ratio of observed pancreatic cancer cases in the cohort to the expected pancreatic cancers in the background population, adjusted for age, sex, and country. RESULTS: The mean age (+/- standard deviation [SD]) at onset of symptoms of pancreatitis was 13.9 +/- 12.2 years. Compared with an expected number of 0.150, eight pancreatic adenocarcinomas developed (mean age +/- SD at diagnosis of pancreatic cancer: 56.9 +/- 11.2 years) during 8531 person-years of follow-up, yielding an SIR of 53 (95% confidence interval [CI] = 23-105). The frequency of other tumors was not increased: SIR = 0.7 (95% CI = 0.3-1.6). Eight of 20 reported deaths in the cohort were from pancreatic cancer. Thirty members of the cohort have already been tested for the defective hereditary pancreatitis gene: all 30 carry a mutated copy of the trypsinogen gene. The transmission pattern of hereditary pancreatitis was known for 168 of 238 patients without pancreatic cancer and six of eight with pancreatic cancer. Ninety-nine of the 238 patients without pancreatic cancer and six of the patients with pancreatic cancer inherited the disease through the paternal side of the family. The estimated cumulative risk of pancreatic cancer to age 70 years in patients with hereditary pancreatitis approaches 40%. For patients with a paternal inheritance pattern, the cumulative risk of pancreatic cancer is approximately 75%. CONCLUSIONS: Patients with hereditary pancreatitis have a high risk of pancreatic cancer several decades after the initial onset of pancreatitis. A paternal inheritance pattern increases the probability of developing pancreatic cancer.

Adolescent↗
PubMed1997

Mutations in the cationic trypsinogen gene are associated with recurrent acute and chronic pancreatitis.

BACKGROUND & AIMS: We recently identified a single R117H mutation in the cationic trypsinogen gene in several kindreds with an inherited form of acute and chronic pancreatitis (HP1), providing strong evidence that trypsin plays a central role in premature zymogen activation and pancreatitis. However, not all families studied have this mutation. The aim of this study was to determine the disease-causing mutation in kindreds with hereditary pancreatitis that lack the previously identified mutation. METHODS: Clinical features of the HP1 kindreds were compared with those of the new kindreds (HP2), and genetic linkage analysis, screening for mutations through DNA sequencing, and screening an unaffected population were performed. RESULTS: The onset of symptoms was delayed and hospitalizations were fewer in HP2 compared with HP1 (P < 0.05). Linkage of the disease gene to chromosome 7q35 was established (logarithm of the odds, 3.73). Mutational screening identified a single A to T mutation resulting in an asparagine to isoleucine transition mutation at position 21 (N21I) in cationic trypsinogen. The mutation was absent in 94 unrelated individuals, representing 188 unique chromosomes. CONCLUSIONS: The identification of a second mutation in the cationic trypsinogen gene (HP2) suggests a dominant role of trypsin in premature protease activation-mediated forms of acute pancreatitis. The pathogenesis of hereditary pancreatitis also suggests that chronic pancreatitis may result from recurrent acute pancreatitis.

Acute Disease↗
PubMed1997

Clinical characteristics of hereditary pancreatitis in a large family, based on high-risk haplotype. The Midwest Multicenter Pancreatic Study Group (MMPSG)

OBJECTIVES: Because there are no markers for hereditary pancreatitis (HP), diagnosis has relied on clinical features and inferences. Identification of the HP disease gene locus on chromosome 7q35 provides the first genetic marker for HP, allowing an accurate comparison of the clinical diagnosis of HP with the presence of a high-risk HP haplotype. Our objectives were to compare the clinical diagnosis of HP with inheritance of the HP gene and to characterize the common clinical features. METHODS: A detailed questionnaire was administered to 102 study participants of a large HP kindred. Blood samples were taken for DNA extraction and high-risk haplotype determination. Clinical findings were compared with the presence of a high-risk haplotype. RESULTS: A family tree of more than 500 members and eight generations was constructed, and clinical features of the 102 participants were determined. HP occurred before the age of 5 yr in 58% of subjects, who presented with common symptoms of abdominal pain, nausea/vomiting, and frequent attacks. Thirty-five probands, of whom 80% had clinical symptoms, carried the high-risk haplotype, confirming previous estimates of 80% penetrance. Thirty-two of the study participants had been clinically diagnosed with HP, whereas 70 were clinically unaffected. With regard to the presence of the high-risk haplotype, 87.5% of the clinically diagnosed patients were affected by HP (true positive), whereas 12.5% did not carry the high-risk haplotype (false positive). Seven obligate carriers were identified through DNA analysis; three had previously been unrecognized because of lack of affected offspring. CONCLUSIONS: The diagnosis of hereditary pancreatitis on clinical grounds alone may be inaccurate in less severe cases, as is the exclusion of carrier status through family tree analysis. Therefore, a definitive diagnosis of hereditary pancreatitis in equivocal cases or exclusion of a carrier state should include analysis of genetic markers.

Chromosomes, Human, Pair 7↗
PubMed1996

Hereditary pancreatitis is caused by a mutation in the cationic trypsinogen gene.

Hereditary pancreatitis (HP) is a rare, early-onset genetic disorder characterized by epigastric pain and often more serious complications. We now report that an Arg-His substitution at residue 117 of the cationic trypsinogen gene is associated with the HP phenotype. This mutation was observed in all HP affected individuals and obligate carriers from five kindreds, but not in individuals who married into the families nor in 140 unrelated individuals. X-ray crystal structure analysis, molecular modelling, and protein digest data indicate that the Arg 117 residue is a trypsin-sensitive site. Cleavage at this site is probably part of a fail-safe mechanism by which trypsin, which is activated within the pancreas, may be inactivated; loss of this cleavage site would permit autodigestion resulting in pancreatitis.

Arginine↗
PubMed1996

A gene for hereditary pancreatitis maps to chromosome 7q35.

BACKGROUND & AIMS: Hereditary pancreatitis (HP) is an autosomal-dominant disorder with incomplete penetrance characterized by recurrent bouts of severe epigastric pain with onset usually at 5-10 years of age. A genetic linkage study was designed to identify the HP gene. METHODS: A 500-member pedigree was constructed from a U.S. kindred centered in eastern Kentucky and western Virginia. A genome-wide search strategy was employed using a 36-member subset of this family to determine the genetic locus for HP. Testing for linkage to microsatellite loci was performed at 20-cM intervals. RESULTS: Linkage was established between the HP phenotype and chromosome 7q in this subset of the family. Modeled as an autosomal dominant disorder with 80% penetrance, a maximal multipoint logarithm of the odds score of 4.3 was obtained using a four-point analysis consisting of markers D7S684, D7S661, D7S505, and the HP locus. Two microsatellite markers, D7S661 and D7S505, that correspond to the 7q35 region of chromosome 7 spanning a 6-cM region did not evidence obligate recombinations with HP. The centromeric and telomeric limits are defined by recombinations at D7S684 and D7S483, respectively, which generates a 19-cM locus for HP. Utilizing family members from the extended pedigree, a break in the high-risk haplotype between D7S684 and D7S661 was observed, which suggests it may be possible to exclude an additional 8 cM from the HP locus. A maximal pairwise logarithm of the odds score of 4.73 at a recombination fraction of theta at D7S684 was obtained with the addition of these extended family members. CONCLUSIONS: Linkage of HP to 7q35 represents a major advancement in our understanding of the genetic basis of this disorder.

Chromosome Mapping↗
PubMed1996

The effects of acute exercise on gallbladder function in an adult female population.

It has been suggested that aerobic exercise influences gallstone disease pathogenesis through its effects on gallbladder motility. The purpose of the present investigation was to examine the effects of acute aerobic exercise on gallbladder emptying. Gallbladder function was evaluated, via cholescintigraphy, in 12 healthy females after undergoing two experimental trials [i.e., postprandial (P) and exercise + postprandial (E + P))]. In the E + P trial, 60 min after injection of 99mTc disofenin, subjects exercised for 30 min at 65.3 +/- 0.9%, (mean +/- SEM) of VO2 peak on a recumbent leg ergometer, and then ingested 8 oz of a liquid meal to promote gallbladder emptying. In the P trial the meal was administered at the same time relative to the E + P trial; however, for the 30 min prior to meal ingestion subjects remained in a resting supine position. Postprandial gallbladder ejection fraction (EF) was nonsignificantly higher in the E + P trial (49.4 +/- 5.1%) than in the P trial (46.6 +/- 6.7%). Results of this study also indicated that during a fasted state the gallbladder undergoes significant periods of spontaneous emptying both at rest EF = 25 +/- 5.6% (P < 0.02) and during exercise EF = 17 +/- 4.3% (P < 0.01). In conclusion, the results of this study indicate that 30 min of aerobic exercise at 65% of VO2 peak does not effect gallbladder motility in a healthy, premenopausal, female population.

Adult↗
PubMed1995

Chronic abdominal pain caused by thoracic disc herniation.

A patient with 7 yr of severe disabling chronic epigastric abdominal pain attributed to chronic pancreatitis was seen in consultation before a 95% pancreatectomy for pain control. Previous attempts to identify and treat the pain lead to extensive radiographic, pharmacological, endoscopic, and surgical interventions, including a Roux-en-Y pancreaticojejunostomy. Pain control was poor despite implantation of a continuous intrathecal morphine infusion pump. A focused physical examination, however, raised the suspicion of thoracic disc disease, which was confirmed after myelogram with computed tomography. Disruption of the T7-T8 disc with protrusion into the vertebral canal and displacement of the spinal cord with an associated bone spur were identified. A microsurgical thoracic discectomy was performed. Immediately, the pain began resolving, and she was pain free and off her medications within several weeks. To our knowledge, this is the first description of a herniated thoracic disc presenting as the pain of chronic pancreatitis. The diagnosis of thoracic disc syndrome requires a high index of suspicion and should be considered in patients with chronic abdominal pain.

Abdominal Pain↗
PubMed1994

Association of acetaminophen hepatotoxicity with fasting and ethanol use.

OBJECTIVES: To evaluate the association of fasting and alcohol use with hepatotoxicity from acetaminophen ingested for therapeutic reasons. DESIGN: Retrospective case series. SETTING: Hospitals of the University of Pittsburgh (Pa) Medical Center. PATIENTS: A total of 126,779 discharge summaries from January 1987 to July 1993 were reviewed using a comprehensive, whole-text-indexed medical database to identify all patients with acetaminophen ingestion and hepatotoxicity. These patients were categorized according to the intended acetaminophen use and dose of acetaminophen ingested. MAIN OUTCOMES MEASURED: The independent variables of chronic alcohol use, recent alcohol use, and recent fasting were determined for all patients. RESULTS: Forty-nine patients with acetaminophen hepatotoxicity (aspartate aminotransferase > 1000 U/L) were identified. Twenty-one patients (43%) ingested acetaminophen for therapeutic purposes. All patients with hepatotoxicity took more than the recommended limit of 4 g/d. Recent fasting was more common than recent alcohol use among those who suffered hepatotoxicity after a dose of 4 to 10 g of acetaminophen per day (P = .02). Recent alcohol use was more common in the group who took more than 10 g/d than in those who took 4 to 10 g/d (P = .004). CONCLUSION: Acetaminophen hepatotoxicity after a dose of 4 to 10 g/d was associated with fasting and less commonly with alcohol use. Patients who developed hepatoxicity after taking acetaminophen doses of greater than 10 g/d for therapeutic purposes were alcohol users. Acetaminophen hepatotoxicity after an overdose appears to be enhanced by fasting in addition to alcohol ingestion.

Acetaminophen↗
PubMed1994

Saturable binding of circulating peptide YY in the dorsal vagal complex of rats.

The rationale for this study was to test the hypothesis that peripherally released peptide YY (PYY) acts in the vagal nuclear complex of the medulla oblongata to modulate vagal tone centrally. The objective was to determine whether circulating PYY gains access to and binds to the receptors identified in the dorsal vagal complex (DVC) under physiological conditions. Specific brain regions were microdissected after intravenous 125I-labeled PYY and 131I-labeled bovine serum albumin infusions to determine saturable accumulation of PYY in the brain and to determine if there were changes in plasma volume with large PYY infusions. Significant (P < 0.05) saturable binding was observed in the region of the brain stem containing the DVC and the pituitary. There were no significant changes in plasma volume in any region after the infusion of the excess nonradioactive PYY. We conclude that under physiological conditions circulating PYY binds to sites in the pituitary and portions of the DVC that have PYY receptors and an incomplete blood-brain barrier but does not bind to other areas that have an intact blood-brain barrier. Therefore this peripheral hormone may act centrally to modulate the digestive system and is a member of a novel class of gut hormones that function as central neuromodulators.

Animals↗
PubMed1992

Reversible in vitro growth of Alzheimer disease beta-amyloid plaques by deposition of labeled amyloid peptide.

The salient pathological feature of Alzheimer disease (AD) is the presence of a high density of amyloid plaques in the brain tissue of victims. The plaques are predominantly composed of human beta-amyloid peptide (beta A4), a 40-mer whose neurotoxicity is related to its aggregation. Radioiodinated human beta A4 is rapidly deposited in vitro from a dilute (less than 10 pM) solution onto neuritic and diffuse plaques and cerebrovascular amyloid in AD brain tissue, whereas no deposition is detectable in tissue without performed plaques. This growth of plaques by deposition of radiolabeled beta A4 to plaques is reversible, with a dissociation half-time of approximately 1 h. The fraction of grey matter occupied by plaques that bind radiolabeled beta A4 in vitro is dramatically larger in AD cortex (23 +/- 11%) than in age-matched normal controls (less than 2%). In contrast to the human peptide, rat/mouse beta A4 (differing at three positions from human beta A4) does not affect the deposition of radiolabeled human beta A4. beta A4 has no detectable interaction with tachykinin receptors in rat or human brain. The use of radioiodinated beta A4 provides an in vitro system for the quantitative evaluation of agents or conditions that may inhibit or enhance the growth or dissolution of AD plaques. This reagent also provides an extremely sensitive method for visualizing various types of amyloid deposits and a means for characterizing and locating sites of amyloid peptide binding to cells and tissues.

Aged↗
PubMed1992

High affinity binding proteins for pancreatic polypeptide on rat liver membranes.

We report here the identification on rat liver plasma membranes and microsomes of proteins that bind pancreatic polypeptide (PP) with high affinity and specificity (plasma membranes: KD = 4.6 nM, Bmax = 3.28 pmol/mg protein; microsomes: KD = 3.45 nM, Bmax = 18.7 pmol/mg protein). These binding proteins appeared coupled to a G-protein, since 0.1 mM guanosine 5'-O-(3-thiotriphosphate) decreased the affinity by half. When 125I-labeled PP-binding protein complexes covalently cross-linked with disuccinimido suberate were analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, two radioactive bands with M(r) values of 52,000 and 38,000 were demonstrated. Both bands were inhibited by unlabeled PP with an IC50 of approximately 5 nM (but not by neuropeptide Y or peptide YY). After the cross-linked complexes were solubilized from liver microsomes with 0.2% Triton X-100 and gel-filtered, they did not interact with the lectins wheat germ agglutinin, Ulex europaeus agglutinin, Ricinus communis agglutinin, and soy bean agglutinin. That these binding proteins may not be glycosylated was further supported by the failure of either peptide N-glycosidase F and endo-beta-N-acetylglucosaminidase F to alter the size of the PP-binding protein complexes on gel electrophoresis. These PP-binding proteins may serve as receptors and mediate a hepatic effect of PP.

Animals↗
PubMed1992

A new twist in the brain-gut axis.

Gastrointestinal functions are precisely regulated by hormonal and neural negative feedback loops. In addition to the classic hormonal and vago-vagal reflex mechanisms, these studies indicate that there are direct actions of gut hormones on the dorsal vagal complex. The current data demonstrate that pancreatic polypeptide is released into the circulation by vagal-cholinergic dependent mechanisms. It travels to the brainstem in the circulation, transverses the blood-brain barrier through "leaky" regions of this barrier in the area postrema and nucleus of the tractus solitarius and binds to specific receptors in the dorsal vagal complex. By binding to these sites, pancreatic polypeptide can directly inhibit vagal input to the pancreas and other gastrointestinal organs. These observations provide an anatomic basis to explain why pancreatic polypeptide is a more potent inhibitor of the action of central stimulants of pancreatic secretion than it is of the response to peripheral secretagogues. They also establish a novel mechanism by which gut peptides can influence brain function directly.

Animals↗
PubMed1992

Localization and characterization of pancreatic polypeptide receptors in rat adrenal glands.

Pancreatic polypeptide (PP) is released from pancreatic islets after meals or in response to stress. Although PP exhibits a wide spectrum of biological effects, few, if any, are mediated by a direct action of PP on its ultimate target organ. Recently, PP receptors have been identified in areas of the brain with an incomplete blood-brain barrier suggesting that PP may act indirectly through the central nervous system. In the present study, we sought to identify peripheral PP binding sites using an in vivo radioreceptor assay and in vitro autoradiography. Using these techniques, we have identified saturable binding sites for PP in the zona fasciculata, zona reticularis, and the medulla of the rat adrenal gland. We have characterized these sites using equilibrium analysis of membrane-radioligand binding and by quantitative autoradiography of radioligand binding to frozen tissue sections. Binding of PP to these sites is saturable, of high affinity, and specific as well as time, temperature, and membrane dependent. Moreover, PP binds to these putative receptor sites in vivo at physiological concentrations. Many of the actions of PPs have been demonstrated to be indirect. Because PP receptors have been identified in the brain and now in the adrenal gland, we suggest that some of the effects of PP may be mediated through direct and indirect modulation of the brain and adrenal axis.

Adrenal Glands↗
PubMed1992

'Diaphragmlike' stricture and ulcer of the colon during diclofenac treatment.

Diclofenac sodium is a widely used enteric-coated nonsteroidal anti-inflammatory drug. We describe a woman with Hemoccult-positive stools and iron deficiency anemia who developed both a colonic ulcer and a "diaphragm-like" colonic stricture while taking enteric-coated diclofenac. These lesions were evident on colonoscopy but not on barium studies. Biopsy specimens of the ulcer and stricture revealed particulate matter that was indistinguishable from diclofenac pill fragments by electron microscopy. Discontinuation of diclofenac therapy resulted in resolution of anemia and Hemoccult-positive stools. We conclude that (1) enteric-coated diclofenac is associated with both colonic ulcers and diaphragm-like colonic strictures; (2) the pathophysiologic mechanism for the development of both ulcers and strictures may involve a direct action of diclofenac within these lesions; (3) colonoscopy may be superior to barium studies in evaluating patients receiving diclofenac who have iron deficiency anemia and/or Hemoccult-positive stools.

Anemia, Hypochromic↗