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Byline: Cynthia A. Molloy (1,2), Patricia Manning-Courtney (1), Susan Swayne (1), Judy Bean (2), Jennifer M. Brown (4), Donna S. Murray (1,5), Anne M. Kinsman (1), Mark Brasington (4), Charles D. Ulrich (3) Keywords: Autism; human synthetic secretin; clinical trial Abstract: The objective of this study was to determine if an intravenous infusion of synthetic human secretin improves language and behavioral symptoms in children with autism. Forty-two children with the diagnosis of autism were randomized to one of two groups in this double-blind cross-over trial. One group received 2 IU/kg of intravenous synthetic human secretin at the first visit, followed by an equal volume of intravenous saline placebo at week 6. The other group received treatments in the reverse order. All children were evaluated at weeks 1, 3, 6, 9, and 12 with standardized assessments of language, behavior, and autism symptomatology. There were no significant differences in the mean scores on any measure of language, behavior, or autism symptom severity after treatment with secretin compared to treatment with placebo. The results of this study do not support secretin as a treatment for autism. Author Affiliation: (1) Division of Developmental Disabilities, Department of Pediatrics, University of Cincinnati College of Medicine, USA (2) Center for Epidemiology and Biostatistics, Department of Pediatrics, University of Cincinnati College of Medicine, USA (3) Department of Internal Medicine, University of Cincinnati College of Medicine, USA (4) The Kelly O'Leary Center for Pervasive Developmental Disorders, Children's Hospital Medical Center, Cincinnati, Ohio (5) Department of Communication Sciences and Disorders, University of Cincinnati College of Allied Health Sciences, USA Article History: Registration Date: 12/10/2004

A study was conducted to determine the cellular distribution of high-affinity secretin receptors within rat pancreas and to find out the molecular identity of secretin receptors expressed in those cells. Pancreatic plasma membranes prepared from rats were affinity labeled and found to have similar molecular features to those prepared from healthy pancreatic membranes. The identity of the ductular and acinar cell high-affinity secretin-binding proteins was further substantiated by RNase protection assays.

Secretin stimulates ductular bile secretion by binding to the receptors in the bile duct epithelial cells (cholangiocytes) induced by bile duct ligation (BDL). The secretion induced hypercholeresis is regulated by the transcriptional control of secretin receptor (SR) gene expression, resulting in upregulation of SR-mRNA triggered by BDL. The enhanced expression of SR gene in hyperblastic cholangiocytes results in an increase in functional receptors.

The possibility that cholecystokinin (CCK) receptor can be a multiple kinase substrate and a receptor-specific kinase substrate was examined. Permeabilization experiments were conducted on dispersed rat pancreatic acinar cells. The existence of the two kinases that function on the CCK receptor and its analogy to enzymes in the beta-andrenergic receptor family of kinases were established.

Cultured human pancreatic duct cells displaying physiological features prototypical of cystic fibrosis (CF) or normal duct fragments were used to examine the functional role of Na+-HCO3-cotransport (NBC) in pancreatic duct cells. The NBC was found to mediate the HCO3 uptake across the basolateral membranes of pancreatic duct cells. It was also observed that cAMP initiates NBC activity through activation of CF transmembrane conductance regulator (CFTR)-mediated Cl- secretion, suggesting that CFTR drives NBC in pancreatic duct cells.

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. [ABSTRACT FROM AUTHOR]

Vasoactive intestinal peptide (VIP) is a neurotransmitter involved in a number of pathological and physiological processes. VIP is rapidly degraded and simplified stable analogs are needed. VIP's action was extensively studied in rat and guinea pig. However, it is largely unknown whether its pharmacophore in these species resembles human. To address this issue we investigated the VIP pharmacophore for VPAC(1) (the predominant receptor subtype in cancers and widely distributed in normal tissues) by using alanine and D-amino acid scanning. Interaction with rat, guinea pig, and human VPAC(1) was assessed using transfected Chinese hamster ovary (CHO) and PANC1 cells and cells possessing native VPAC(1). Important species differences existed in the VIP pharmacophore. The human VPAC(1) expressed in CHO cells, which were used almost exclusively in previous studies, differed markedly from the native VPAC(1) in T47D cells. The most important amino acids for determining affinity are His(1), Asp(3), Phe(6), Arg(12), Arg(14), and Leu(23). Ser(2), Asp(8), Asn(9), Thr(11), Val(19), Asn(24), Ser(25), Leu(27), and Asn(28) are not essential for high-affinity interaction/activation. [Ala(2,8,9,11,19,24,25,27,28)]VIP, which contained 11 alanines, was synthesized and it was equipotent to VIP at VPAC(1) receptors in all species and was metabolically stable. Our results show in any design of simplified VIP analogs for VPAC(1) it will be important to consider species differences and it is essential to use transfected systems that reflect the native receptor's pharmacophore. Last, with our results a simplified, metabolically stable VIP analog was identified that should be useful as a prototype for design of selective agonists/antagonists that could be useful therapeutically.