Dramatic Increase in Incidence of Ulcerative Colitis and Crohn's Disease (1988-2011): A Population-Based Study of French Adolescents.

OBJECTIVES: Few data are available to describe the changes in incidence of pediatric-onset inflammatory bowel disease (IBD). The aim of this study was to describe changes in incidence and phenotypic presentation of pediatric-onset IBD in northern France during a 24-year period. METHODS: Pediatric-onset IBD (<17 years) was issued from a population-based IBD study in France between 1988 and 2011. Age groups and digestive location were defined according to the Paris classification. RESULTS: 1,350 incident cases were recorded (8.3% of all IBD) including 990 Crohn's disease (CD), 326 ulcerative colitis (UC) and 34 IBD unclassified (IBDU). Median age at diagnosis was similar in CD (14.4 years (Q1=11.8-Q3=16.0)) and UC (14.0 years (11.0-16.0)) and did not change over time. There were significantly more males with CD (females/males=0.82) than UC (females/males=1.25) (P=0.0042). Median time between onset of symptoms and IBD diagnosis was consistently 3 months (1-6). Mean incidence was 4.4/105 for IBD overall (3.2 for CD, 1.1 for UC and 0.1 for IBDU). From 1988-1990 to 2009-2011, a dramatic increase in incidences of both CD and UC were observed in adolescents (10-16 years): for CD from 4.2 to 9.5/105 (+126%; P<0.001) and for UC, from 1.6 to 4.1/105 (+156%; P<0.001). No modification in age or location at diagnosis was observed in either CD or UC. CONCLUSIONS: In this population-based study, CD and UC incidences increased dramatically in adolescents across a 24-year span, suggesting that one or more strong environmental factors may predispose this population to IBD.

[Ovarian remnant syndrome: diagnostic difficulties and management]. / Syndrome de l'ovaire rémanent: difficultés diagnostiques et stratégies thérapeutiques.

OBJECTIVES: The ovarian remnant syndrome is a rare condition after unilateral or bilateral oophorectomy, with or without a hysterectomy. This syndrome occurs when a fragment of ovarian tissue is left behind and becomes functional and cystic. The purpose of this study is to report the cases of patients treated surgically for an ovarian remnant syndrome during the last 10 years and to recall the diagnostic and therapeutic difficulties. PATIENTS AND METHODS: A retrospective, observational study was carried out between 1997 and 2006. Seven patients were treated surgically for an ovarian remnant syndrome. Perioperative data analysis (history, surgical techniques, and postoperative follow-up) was carried out. RESULTS: The mean age of the patients was 46 years (36-55). The number of previous abdominal surgical procedures ranged from 2 to 5. The syndrome appeared after a mean period of 4 years and 4 months (range 5 months-12 years) after oophorectomy. Among the 7 patients, 3 had had a previous hysterectomy. Pelvic pain was found in all cases. Gonadotropin-releasing hormones agonists were used in 1 patient without success. Aspiration was performed in 2 cases before surgical treatment. Two patients underwent a laparotomy in the first place. Laparoscopy was performed in 5 cases and laparoconversion was necessary in 1 case. Intraoperative difficulties and anatomic variations were found in all cases. Ureteral catheters were placed in 2 cases. Radiotherapy was performed in 1 patient who had a recurrent ovarian remnant. DISCUSSION AND CONCLUSION: The ovarian remnant syndrome is a rare complication. Surgery, either by laparoscopy or by laparotomy, is the recommended treatment. These operations are often difficult and associated with a high risk of complications. Histologically, remnant ovarian tissue associated with hemorragic corpus luteum cysts is the most common finding. The prevention of the ovarian remnant syndrome is based on rigorous surgical treatment during the oophorectomy so as not to leave behind ovarian tissue.

Severe acute pancreatitis in a child with phenylketonuria.

We report for the first time severe acute pancreatitis in a child treated for phenylketonuria (PKU) discovered on neonatal screening. This 2-year-old boy was first hospitalized for bilious vomiting and moderate back pain. Laboratory values included a lipase level of 1.142 U/L, a phenylalanine level of 10mg/dL, and computed tomography revealed Balthazar grade E pancreatitis. Continuous enteral feeding was started on the 3rd day after admission. We observed clinical and biological improvement. Etiologic investigations for pancreatitis returned negative. Despite the severity of the pancreatitis, we did not observe decompensation of the metabolic disease. Specific nutritional management was necessary.

Multifocal pelvic osteomyelitis in a child associated with cat-scratch disease: a case report and review of the literature.

Bone infections in cat-scratch disease (CSD) are uncommon and the diagnosis can be missed. A 3-year-old boy with multifocal pelvic osteomyelitis caused by Bartonella henselae is reported. Serological tests were negative but DNA was detected by polymerase chain reaction assay of a lymph node. A swift recovery followed antibiotic treatment and there was completeresolution within a few months. The literature on 64 cases of osteomyelitis owing to CSD in children and adults since 1954 is reviewed.

Pelvic floor disorders 4 years after first delivery: a comparative study of restrictive versus systematic episiotomy.

OBJECTIVE: To compare two policies for episiotomy: restrictive and systematic. DESIGN: Quasi-randomised comparative study. SETTING: Two French university hospitals with contrasting policies for episiotomy: one using episiotomy restrictively and the second routinely. POPULATION: Seven hundred and seventy-four nulliparous women delivered during 1996 of a singleton in cephalic presentation at a term of 37-41 weeks. METHODS: A questionnaire was mailed 4 years after delivery. Sample size was calculated to allow us to show a 10% difference in the prevalence of urinary incontinence with 80% power. MAIN OUTCOME MEASURES: Urinary incontinence, anal incontinence, perineal pain, and pain during intercourse. RESULTS: We received 627 responses (81%), 320 from women delivered under the restrictive policy, 307 from women delivered under the routine policy. In the restrictive group, 186 (49%) deliveries included mediolateral episiotomies and in the routine group, 348 (88%). Four years after the first delivery, there was no difference in the prevalence of urinary incontinence (26 versus 32%), perineal pain (6 versus 8%), or pain during intercourse (18 versus 21%) between the two groups. Anal incontinence was less prevalent in the restrictive group (11 versus 16%). The difference was significant for flatus (8 versus 13%) but not for faecal incontinence (3% for both groups). Logistic regression confirmed that a policy of routine episiotomy was associated with a risk of anal incontinence nearly twice as high as the risk associated with a restrictive policy (OR = 1.84, 95% CI: 1.05-3.22). CONCLUSIONS: A policy of routine episiotomy does not protect against urinary or anal incontinence 4 years after first delivery.

[Pelvic floor disorders four years after first delivery: a comparative study of restrictive versus systematic episiotomy]. / Troubles périnéaux quatre ans après le premier accouchement: comparaison entre épisiotomie restrictive et systématique.

OBJECTIVE: To compare two policies for episiotomy: restrictive and systematic. PATIENTS AND METHODS: It is a quasi-randomised comparative study between two French university hospitals with contrasting episiotomy policies: one using it restrictively and the second routinely. Population included 774 nulliparous women delivered during 1996 of a singleton in cephalic presentation at a term of 37-41 weeks. A questionnaire was mailed four years after delivery. Sample size was calculated to allow showing a 10% difference in the prevalence of urinary incontinence with 80% power. Main outcome measures were urinary incontinence, anal incontinence, perineal pain and pain during intercourse. RESULTS: We received 627 responses (81%), 320 from women delivered under the restrictive policy, 307 from women delivered under the routine policy. In the restrictive group, 186 (49%) deliveries included mediolateral episiotomies and in the routine group, 348 (88%). Four years after the first delivery, the groups did not differ in the prevalence of urinary incontinence (26% versus 32%), perineal pain (6% versus 8%), or pain during intercourse (18% versus 21%). Anal incontinence was less prevalent in the restrictive group (11% versus 16%). The difference was significant for flatus (8% versus 13%) but not for faecal incontinence (3% for both groups). Logistic regression confirmed that a policy of routine episiotomy was associated with a risk of anal incontinence nearly twice as high as the risk associated with a restrictive policy (OR=1.84, 95 % CI :1.05-3.22). DISCUSSION AND CONCLUSION: A policy of routine episiotomy does not protect against urinary or anal incontinence four years after first delivery.

Arthroscopy-assisted Trillat procedure for anterior shoulder instability: Surgical technique and preliminary clinical results.

The Trillat procedure performed as open surgery to treat anterior shoulder instability has been proven effective in preventing recurrences and restoring range of motion. An arthroscopically assisted variant of the Trillat procedure is described here, together with the preliminary clinical results in 18 patients treated between 2011 and 2014. After a mean follow-up of 24.7±9.8 months, the clinical outcomes were very satisfactory, with a Walch-Duplay score of 81.5±18.0, a Rowe score of 83.6±16.0, and 94% of satisfied or very satisfied patients. Mean operative time was 55±13min. No recurrences were recorded. As an easily performed procedure that provides good clinical outcomes, the arthroscopically assisted Trillat procedure is a simple and reproducible alternative to arthroscopic Latarjet procedure, which is still reserved for highly experienced surgical teams.

[Primary immunodeficiencies and Bruton's disease genetic analysis: which prospects offers this genetic diagnosis?]. / Déficits immunitaires primitifs et analyse génétique de la maladie de Bruton: quelles perspectives offre ce diagnostic génétique?

Bruton's disease is the most frequently primary X-linked immunodeficiency. Bruton's tyrosine kinase (Btk) is encoded by the XLA gene that when mutated causes bruton's disease. This protein acts in multiple intracellular signaling pathways where the BCR (B-cell receptor) pathway is the most elucidated. Moreover 400 mutations were found and identified as responsible for B-cells differentiation block; consequences are a lack of B-cells in peripheral blood and hypo/agammaglobulinemia. Thus, patients are more susceptible to early and recurring infections occurring before the age of one year. Laboratory testing allow differential diagnosis among primary immunodeficiencies in which others hypogammaglobulinemia. Genetic analyses help physicians for clinical and biological diagnosis, and allow prenatal diagnosis for patient's family. Patient's management is based upon polyclonal immunoglobulin supplementation, infectious diseases prevention and genetic advice.

[Validation of a Bruton's disease genetic analysis method]. / Validation d'une méthode d'analyse génétique de la maladie de Bruton.

Bruton's disease is the most frequently primary X-linked immunodeficiency. Patients are more susceptible to early and recurring infections associated with hypo/agammaglobulinemia and a severe B-cell deficiency. Moreover, 400 mutations were found in the XLA gene which codes the Btk tyrosine kinase and were identified as responsible for Bruton's disease. Genetic study was carried out with one group of patients named NECKER, composed by five XLA patients and two parents whose XLA gene was sequenced by an Italian crew. Results were obtained by PCR of 19 exons and initial/terminal intron's parts, followed by PCR-sequencing with universal primers and sequencing. The results from this study allowed the validation of the sequencing technique by comparing NECKER group data (equivalent results with Italian data). In addition, the mutation multiplicity (described or not, coding/non coding) need an exact analysis that should be given to clinicians through clear and trustful results. In this way, a strategy to analyse untreated results was created based on the mutation type. The genetic analysis could help physicians for uncertain diagnosis in immune defficiencies, allows proposing a genetic advice to the patient's family and the construction of a data base permits a best understanding of this disease.

[Cost effectiveness of Ligasure Precise versus surgical clips during axillary nodal dissection for breast cancer]. / Coût efficacité du Ligasure Precise versus clips chirurgicaux lors du curage axillaire pour cancer du sein.

UNLABELLED: Introduction. The techniques used for axillary node dissection are constantly evolving. The advent of the grip Ligasure Precise raise the question of its cost-effectiveness compared with surgical clips. OBJECTIVE: To compare the effectiveness of Ligasure compared with surgical clips for simple axillary node dissection or Patey procedure in terms of duration of drainage, cost of hospitalization and complications. MATERIAL: and method. Retrospective study extending from January 1, 2003 to December 31, 2004, concerning 187 patients who underwent simple axillary dissection (100) or Patey procedure (87), with use of surgical clips or Ligasure followed by drainage. RESULTS: The use of Ligasure increased the operative cost because its price is higher than that of a clip grip with a refill. Ligasure significantly decreased the duration of drainage in the two groups but there was significantly more abundant fluid loss in the dissection group. The cost of hospitalization related to the choice of the technique of hemostasis (cost of the material + lasted of drainage X price of the day of hospitalization), was not significantly favor of Ligasure. Taking into account the choice of the hemostasis technique and the total duration of hospitalization (material cost + duration of hospitalization X price of the day of hospitalization), there is no significant difference between the two groups. CONCLUSION: This study compares grip Ligasure Precise with surgical clips for axillary dissection. The duration of drainage was significantly shorter with Ligasure Precise but its benefit in terms of fluid loss remains to be shown. The use of Ligasure does not significantly reduce the cost of hospitalization.

[Desmoid tumors in an adolescent girl with familial adenomatous polyposis]. / Tumeurs desmoïdes dans le cadre d'une polypose adénomateuse familiale chez une adolescente.

Desmoid tumors (DT) are rare and nonmetastasizing fibroblastic neoplasms, characterized by local invasiveness. They occur sporadically or arise in the context of familial adenomatous polyposis (FAP; 5-10% of cases). Most cases develop sporadically in young adults, but some cases also occur in children. We report the case of an adolescent girl with FAP and DT, and we discuss the therapeutic strategies. An adolescent girl with FAP underwent surgery at the age of 14 years with total proctocolectomy. She had a neo-mutation in the APC gene at codon 1068, which is not usually associated with DT. Three years later, she had painful defecations. Imaging showed two abdominal DT. After a multidisciplinary team meeting, the patient was refused for surgery, and medical treatment with antihormonal agents and nonsteroidal anti-inflammatory drugs was started. Imaging 18 months later showed DT stabilization, but the patient had difficulties to control chronic pains, which required morphine treatment, hypnotic sessions, and transcutaneous electric nerve stimulation. This case highlights the importance of DT screening in patients with FAP, mainly after surgery, regardless of their age and genetic mutation. Progress remains to be made in determining DT risk factors and in developing treatment. DT are still difficult to cure because of their potential for local invasion and local recurrence, and need to be managed by a multidisciplinary team.

AR4-2J cell line coexpresses dihydropyridine and omega-conotoxin sensitive Ca2+ channels.

For the first time, we have demonstrated in AR4-2J cells, an experimental model of azaserine-induced carcinoma in the rat exocrine pancreas, the co-expression of alpha 1 subunit of dihydropyridine-sensitive Ca2+ channel and the alpha 1 sub-unit of omega-conotoxin-sensitive Ca2+ channel RNA messengers which share homologous sequences with, respectively, rbC II and rbB I sub-types described in the rat brain. These two types of voltage-dependent Ca2+ channels which are functionally expressed, emphasize the acquisition during carcinogenesis of neuroendocrine features of AR4-2J cells. Additionally, using antisense phosphorothioate oligodeoxynucleotide, we demonstrated clearly the involvement of dihydropyridine-sensitive Ca2+ channels in the control of AR4-2J cell proliferation.

Increase in tumor necrosis factor-alpha production linked to the toxicity of indomethacin for the rat small intestine.

1. The toxic effects of nonsteroidal anti-inflammatory drugs for the lower gastrointestinal tract share certain features with inflammatory processes, suggesting that the release of inflammation cytokines such as TNF-alpha may damage the intestine. 2. Rats received a s.c. injection of indomethacin. Then, jejunum-ileum was taken up for the quantification of ulcerations, production of TNF-alpha, nitrites and PGE2 ex vivo and activity of calcium-independent NO synthase and myeloperoxydase. Activation of NO metabolism and myeloperoxydase were measured as potential effectors of TNF-alpha. 3. Jejunum-ileum from rats having received indomethacin (10 mg kg(-1)) produced TNF-alpha ex vivo. Cytokine production was associated with the onset of macroscopic ulcerations of the small intestine, and preceded nitrite production and tissue activity of myeloperoxidase. 4. Similar intestinal ulcerations and upregulation of TNF-alpha were obtained with flurbiprofen (30 mg kg(-1)), chemically unrelated to indomethacin. 5. TNF-alpha production was proportional to the indomethacin dose (from 3-20 mg kg(-1)) and correlated with the surface area of ulcerations and nitrite production, 24 h after indomethacin administration. 6. Pretreatment of rats with RO 20-1724, a type-IV phosphodiesterase inhibitor which inhibits TNF-alpha synthesis, substantially reduced jejunum-ileum ulcerations, TNF-alpha and nitrite production and tissue enzyme activities. 7. These findings provide evidence that TNF-alpha is increased in indomethacin-induced intestinal ulcerations and support suggestions that TNF-alpha is involved at an early stage of nonsteroidal anti-inflammatory drug toxicity for the small intestine.

Pharmacological study of gastrin-mediated amylase release in pancreatic acinar cells (AR4-2J).

In rat pancreatic acinar cells, amylase release and Ca2+ mobilization are related to the occupancy of CCKA receptor. The rat pancreatic acinar cell line (AR4-2J) possesses both CCKA (CCKA R) and CCKB (CCKB R) sub-type receptors. Using this cell line we attempted to determine the relative involvement of each sub-type in both amylase release and Ca2+ mobilization. For this purpose we used L 364718 a selective antagonist for CCKA R and PD 135158 a selective antagonist for CCKB R. We showed on AR4-2J cells that: a minority of CCKA R (Kd = 0.7 nM), a classical CCKB R (Kd = 0.93 nM) and a new high affinity gastrin binding site (Kd = 2.1 pM) coexisted; CCK through CCKA R and CCKB R, was more potent to stimulate amylase secretion (EC50 = 34 pM) and Ca2+ mobilization (EC50 = 30 pM) than to occupy its receptor. Gastrin induced a biphasic stimulation of amylase release. Gastrin through CCKB R was equally potent to stimulate amylase release (EC50 = 1.72 nM) and Ca2+ mobilization (EC50 = 3.1 nM), whereas through the high affinity gastrin binding site, gastrin-induced amylase release (EC50 = 0.73 pM) did not correlate with the Ca2+ mobilization (EC50 = 3.1 nM). These results demonstrated for the first time the existence, on AR4-2J cells, of a high affinity gastrin receptor whose occupation by gastrin induces amylase release.

Distal deletion of 1p in colorectal tumors: an initial event and/or a step in carcinogenesis? Study by fluorescence in situ hybridization interphase cytogenetics.

Cytogenetics studies have suggested that short arm deletion in chromosome 1 is involved in triggering colorectal tumor development. To elucidate the role of 1p under-representation in the tumoral process, we investigated by fluorescence in situ hybridization interphase cytogenetics, using simultaneously centromeric and p36 telomeric probes for chromosome 1, 27 primary adenocarcinomas, 5 metastases, 5 adenomas and as control 4 normal mucous membranes. The 1p under-representation in paradiploid tumoral cells, interpreted as a 1p deletion, was observed in 8/27 adenocarcinomas, 2/5 metastases and 3/5 adenomas. Thus, in diploid cells 1p deletion was observed in some tumors independently of the stage of the process. The 1p under-representation in total number of examined cells, i.e., diploid and aneuploid, was observed in 14/16 grade B1-B2 tumors, in 5/8 grade C1-C2 tumors, and all grade D tumors (3/3) and all metastases (5/5). There were no correlations with location or histological characteristics of cancers, gender or age of patients. These results show high frequency of 1p under-representation in intestinal tumors, and lead to separate the under-representation of 1p in diploid cells, which correspond to a 1p deletion probably implicated in the initiation of the process, from the under-representation in aneuploid cells, which mainly may be the consequence of complex rearrangements in relation to extension of the malignant process.

Relation between cytogenetic characteristics of two human colonic adenocarcinoma cell lines and their ability to grow locally or metastasize or both: an experimental study in the nude mouse.

This study was aimed at elucidating the relation between the cytogenetic characteristics and the invasive ability of two human colonic adenocarcinoma cells lines, HT29 and CaCO2. These two cell lines have very different tumorigenic and metastatic capacities after intrasplenic injection into nude mice: high for HT29 and relatively weak for CaCO2. At the time of injection, cytogenetic studies of the two cell lines revealed shared abnormalities: paratriploidy with seven common extra chromosomes or chromosome regions and specific particularities. In HT29 cells, we observed a large marker of unknown origin, an isochromosome i(11)(q10) and 5, 12, 13, 15, 19, and (19q+) supernumerary chromosomes, and, finally, the absence of one chromosome 16. In CaCO2 cells, we observed a chromosome 1-derived marker with q24-31 duplication, 12q and 16 supernumerary chromosomes, and a der(16) marker. The most striking difference between the karyotypes of these two cell lines concerned chromosome 16 (under- and overexpressed in HT29 and CaCO2 cells, respectively), overexpression of chromosomes 13, 15, and 19 in HT29 cells, and the relative loss of 12p in CaCO2 cells. Although some differences may be due to the intrinsic characteristics of the stem line, the establishment of specific cytogenetic abnormalities points out the role of many regions of the genome in tumorigenic and metastatic capacities of malignant cells.

Dihydropyrimidine dehydrogenase activity in normal, inflammatory and tumour tissues of colon and liver in humans.

BACKGROUND/PURPOSE: Dihydropyridmidine dehydrogenase (DPD) is the initial and rate-limiting enzyme in the catabolism of 5-fluorouracil (5FU). Although this catabolism is likely to occur in the liver in humans, there may be a local inactivation in tumours, modifying the efficacy of 5FU. The aim of this study was to examine the DPD activity in normal, inflammatory and malignant tissues from both the colon and the liver to assess the modifications of DPD activity in the process of tumourigenesis. METHODS: DPD activity was evaluated in 107 patients, corresponding to 194 samples (70 colorectal tumour and normal colon, nine metastases secondary to a colon cancer, ten inflammatory colon, 20 samples of normal liver, seven from primary liver cancer, and eight from inflammatory liver). DPD activity was determined using an enzymatic reaction followed by analysis of 5FU and its catabolite dihydro-5FU by high-performance liquid chromatograph. Results were expressed as pmol of 5FU catabolized/min x mg protein. RESULTS: DPD was highly variable in tumour and normal tissues, both from colon and liver. In colon, the correlation between DPD activity in tumour and normal mucosa was weak, even if it was statistically significant due to the higher number of samples. In inflammatory colon tissue (ulcerative colitis or Crohn's disease), DPD activity was significantly higher than in normal tissue (P = 0.006). In liver metastases from colon cancer, DPD activity was not significantly different from that observed in primary colon tumour (P = 0.32). In liver, DPD activity was significantly lower in primary liver tumour than in uninvolved liver specimens (P = 0.001). In inflammatory liver tissue (hepatitis), DPD activity ranged between normal and tumour tissues, and did not differ significantly either from normal tissue or primary liver cancer. CONCLUSIONS: DPD activity was modified in colon and in liver during a pathological process and the dysregulation of DPD increased from a benign to a malignant tissue.

Different implications of Ca2+i and and Ca2+e in CCK/gastrin-induced amylase secretion in AR4-2J cells.

The importance of Ca2+ in the regulation of secretion is well-known. However, recent experiments suggest that a rise in intracellular Ca2+ (Ca2+i) does not necessarily trigger secretion in pancreatic acinar cells. In AR4-2J cells the role of the Ca2+ mobilization induced by cholecystokinin/gastrin (CCK/G), which is dependent of the intracellular calcium store and the calcium influx operating through voltage-dependent calcium channels, has never been directly demonstrated. Therefore, we attempted to determine whether Ca2+i and/or extracellular Ca2+ (Ca2+e) mobilized by CCK/G plays a role in the amylase secretion of these cells. We measured the [Ca2+]i by spectrofluorometry and amylase release in different experimental procedures modulating the two pools of calcium. Ionomycin increased both [Ca2+]i and amylase related. In Ca(2+)-depleted cells or in the presence of thapsigargin the transient rise in Ca2+i and the amylase secretion induced by CCK/G were suppressed. A 50 mM K+ solution or Bay K 8644, which activated the Ca2+ influx, did not induce any variation of the basal amylase secretion. Moreover, amylase secretion induced by CCK/G did not change significantly in Ca(2+)-free medium or in the presence of nifedipine. These results indicate that in AR4-2J cells, amylase secretion is dependent of the large increase in Ca2+i induced by CCK/G and independent of the Ca2+ influx through voltage-dependent calcium channels dihydropyridine sensitive.

Molecular cloning, developmental expression and pharmacological characterization of the CCKB/gastrin receptor in the calf pancreas.

We have cloned the calf predominant pancreatic cholecystokinin B (CCKB)/gastrin receptor cDNA. It encodes a 454 amino acid protein with 90% identity with the CCKB/gastrin receptor cloned in other species and tissues. However, the calf pancreatic CCKB/gastrin receptor contains a pentapeptide cassette within the third intracellular loop which is absent in the cloned human brain and stomach receptor. Quantification of the CCKB/gastrin receptor mRNA levels by reverse transcription polymerase chain reaction demonstrated the same level of transcripts at birth, +7 and +28 days. On the other hand, binding study with pancreatic membranes showing a dramatic increase (600-fold) in the number of CCKB/gastrin receptor sites between at birth and +28 days indicates that the development of the calf pancreatic CCKB/gastrin receptor occurs during the first 4 weeks of post-natal life. COS monkey cells (COS-7 cells) transiently transfected by the cloned cDNA exhibit binding of 125I-Bolton-Hunter-[Thr28,Ahx31]CCK-(25-33) and 125I-Bolton-Hunter-[Leu15]human gastrin-(2-17) to two affinity classes of sites. Kd values of the high affinity binding components indicate a 4-fold higher affinity of the receptor for sulfated gastrin than for CCK. Finally, the recombinant receptor is coupled to G proteins and [Ca2+]i mobilization, and is expressed as a glycoprotein of 82 kDa.

Role of tumour necrosis factor-alpha and inducible nitric oxide synthase in the prevention of nitro-flurbiprofen small intestine toxicity.

The present study compares the intestinal toxicity of nitro-flurbiprofen and flurbiprofen in order to determine their differential properties on tumour necrosis factor-alpha production and inducible nitric oxide synthase induction. Rats received one s.c. injection of flurbiprofen, nitro-flurbiprofen at equimolar dose of solvent. Twenty-four hours later, the rats were sacrificed and small intestine tissue was taken up for macroscopical quantification of ulceration, ex vivo production of tumour necrosis factor-alpha and nitrites, and determination of tissue inducible nitric oxide synthase and myeloperoxidase activities. Anti-inflammatory activity was examined in the carrageenan-induced paw edema model. We demonstrated that flurbiprofen induced dose-dependently small intestine production of tumour necrosis factor-alpha, nitrites, myeloperoxidase and inducible nitric oxide synthase activities. On the other hand, nitro-flurbiprofen did neither induce tumour necrosis factor-alpha nor nitrite production. Concurrently, no small intestine ulceration was observed with nitro-flurbiprofen whereas flurbiprofen induced dose-dependent ulceration. Nitro-flurbiprofen is devoid of intestinal toxicity despite inhibiting cyclooxygenase activity. This is associated with the absence of tumour necrosis factor-alpha and inducible nitric oxide synthase induction in normal rats. Nitro-flurbiprofen is an anti-inflammatory drug with a much more favorable gastro-intestinal toxicity profile than flurbiprofen.