TAp73 loss favors Smad-independent TGF-ß signaling that drives EMT in pancreatic ductal adenocarcinoma.

Advances made in pancreatic cancer therapy have been far from sufficient and have allowed only a slight improvement in global survival of patients with pancreatic ductal adenocarcinoma (PDA). Recent progresses in chemotherapy have offered some hope for an otherwise gloomy outlook, however, only a limited number of patients are eligible because of important cytotoxicity. In this context, enhancing our knowledge on PDA initiation and evolution is crucial to highlight certain weaknesses on which to specifically target therapy. We found that loss of transcriptionally active p73 (TAp73), a p53 family member, impacted PDA development. In two relevant and specific engineered pancreatic cancer mouse models, we observed that TAp73 deficiency reduced survival and enhanced epithelial-to-mesenchymal transition (EMT). Through proteomic analysis of conditioned media from TAp73 wild-type (WT) and deficient pancreatic tumor cells, we identified a secreted protein, biglycan (BGN), which is necessary and sufficient to mediate this pro-EMT effect. Interestingly, BGN is modulated by and modulates the transforming growth factor-ß (TGF-ß) pathway, a key regulator of the EMT process. We further examined this link and revealed that TAp73 impacts the TGF-ß pathway by direct regulation of BGN expression and Sma and Mad-related proteins (SMADs) expression/activity. Absence of TAp73 leads to activation of TGF-ß signaling through a SMAD-independent pathway, favoring oncogenic TGF-ß effects and EMT. Altogether, our data highlight the implication of TAp73 in the aggressiveness of pancreatic carcinogenesis through modulation of the TGF-ß signaling. By suggesting TAp73 as a predictive marker for response to TGF-ß inhibitors, our study could improve the classification of PDA patients with a view to offering combined therapy involving TGF-ß inhibitors.

Stromal SLIT2 impacts on pancreatic cancer-associated neural remodeling.

Pancreatic ductal adenocarcinoma (PDA) is a critical health issue in the field of cancer, with few therapeutic options. Evidence supports an implication of the intratumoral microenvironment (stroma) on PDA progression. However, its contribution to the role of neuroplastic changes within the pathophysiology and clinical course of PDA, through tumor recurrence and neuropathic pain, remains unknown, neglecting a putative, therapeutic window. Here, we report that the intratumoral microenvironment is a mediator of PDA-associated neural remodeling (PANR), and we highlight factors such as 'SLIT2' (an axon guidance molecule), which is expressed by cancer-associated fibroblasts (CAFs), that impact on neuroplastic changes in human PDA. We showed that 'CAF-secreted SLIT2' increases neurite outgrowth from dorsal root ganglia neurons as well as from Schwann cell migration/proliferation by modulating N-cadherin/ß-catenin signaling. Importantly, SLIT2/ROBO signaling inhibition disrupts this stromal/neural connection. Finally, we revealed that SLIT2 expression and CAFs are correlated with neural remodeling within human and mouse PDA. All together, our data demonstrate the implication of CAFs, through the secretion of axon guidance molecule, in PANR. Furthermore, it provides rationale to investigate the disruption of the stromal/neural compartment connection with SLIT2/ROBO inhibitors for the treatment of pancreatic cancer recurrence and pain.

TAp73 is required for macrophage-mediated innate immunity and the resolution of inflammatory responses.

The multiple isoforms of p73, a member of the p53 family, share the ability to modulate p53 activities but also have unique properties, leading to a complex and poorly understood functional network. In vivo, p73 isoforms have been implicated in tumor suppression (TAp73(-/-) mice), DNA damage (ΔNp73(-/-) mice) and development (p73(-/-) mice). In this study, we investigated whether TAp73 contributes to innate immunity and septic shock. In response to a lethal lipopolysaccharide (LPS) challenge, TAp73(-/-) mice showed higher blood levels of proinflammatory cytokines and greater mortality than their wild-type littermates. In vitro, TAp73(-/-) macrophages exhibited elevated production of tumor necrosis factor alpha , interleukin-6 and macrophage inflammatory protein-2 as well as prolonged survival, decreased phagocytosis and increased major histocompatibility complex class II expression. Mice depleted of endogenous macrophages and reconstituted with TAp73(-/-) macrophages showed increased sensitivity to LPS challenge. These results suggest that macrophage polarization is altered in the absence of TAp73 such that maintenance of the M1 effector phenotype is prolonged at the expense of the M2 phenotype, thus impairing resolution of the inflammatory response. Our data indicate that TAp73 has a role in macrophage polarization and innate immunity, enhancing the action field of this important regulatory molecule.

Complications of endoscopic sphincterotomy: results from a single tertiary referral center.

BACKGROUND AND STUDY AIMS: Complications of endoscopic sphincterotomy (ES) have been assessed in recent multicenter studies. The aim of this series was to report and identify risk factors for complications of ES at a single tertiary referral center. PATIENTS AND METHODS: Between 1996 and 2000, 1159 consecutive endoscopic retrograde cholangiopancreatographies (ERCP) procedures were performed and their related complications were assessed. A total of 658 patients (57 %) underwent ES. All the clinical, radiological and biological data were carefully recorded within the 30 days following the procedure. Multivariate analysis was performed using a stepwise logistic model. RESULTS: The morbidity rate for ES was 7.7 %, being moderate to severe in 5 %. Morbidity included acute pancreatitis (3.5 %), perforations (1.8 %), sepsis (1.2 %) and bleeding (1.2 %). The 30-day mortality was 0.9 %. In the 1159 ERCP procedures, 231 patients underwent precut papillotomy (20 %) followed by sphincterotomy in 174 cases. Using logistic regression analysis, the risk factors for ES were precut papillotomy (relative risk, RR 2.76), confidence interval, (CI 1.39 - 5.49) and the presence of sphincter of Oddi dysfunction (RR, 7.72, CI 3.2 - 18.4). CONCLUSIONS: In this single-center series, we found a complication rate of ES in about 7 %, comparable to that in multicenter series. Precut papillotomy and sphincter of Oddi dysfunction were the main independent risk factors for ES.

[Risk factors for Crohn's disease relapse after treatment of intestinal stenosis]. / Facteurs de récidive de la maladie de Crohn après traitement des sténoses intestinales.

BACKGROUND: Postoperative recurrences of Crohn's disease (CD) has been widely investigated in previous studies. Nevertheless, the risk factors for CD recurrence in patients presenting with intestinal stenosis are not clearly identified. PATIENTS AND METHOD: Thirty consecutive patients out of a cohort of 134 patients with CD presented with an intestinal stenosis diagnosed between 1995 and 1999. Epidemiological, clinical, and therapeutic data were carefully recorded. A univariate analysis followed by stepwise descending discriminant analysis was performed. RESULTS: Sixteen patients (53%) underwent surgery, six received steroid therapy, eight were given antibiotics, and seven took immunosuppressive drugs. The mean follow-up after medical or surgical management was 2.8 years. Thirteen patients (43%) had CD relapse during the follow-up. Considering the univariate analysis, the existence of a previous appendectomy and the persistence of tobacco consumption were significantly associated with the risk of CD relapse during the follow-up. The stepwise descending discriminant analysis identified three independant factors: tobacco consumption (p = 0.007), previous appendicectomy (p = 0.04) and duration of the follow-up (p = 0.02). CONCLUSION: The CD relapse after the management of small bowel stenosis occurred in 43% of the patients within a mean follow-up of 2.8 years. The significant factors associated with the risk of CD relapse were tobacco consumption, previous appendectomy and duration of the follow-up.

Overexpression of p8 is inversely correlated with apoptosis in pancreatic cancer.

A recently identified gene, p8, has cell growth-promoting activity and is strongly induced in acute pancreatitis. In this study, we detected p8 and single-stranded DNA (ssDNA) for apoptosis by immunohistochemistry in human pancreatic cancer. The p8 was overexpressed (>30% per 1000 cancer cells) in 26 of 44 (59%) pancreatic cancers, and apoptosis (ssDNA-positive cells >10% per 1000 cancer cells) was recognized in 18 of 44 (41%) pancreatic cancers. There was a significant inverse correlation between the p8 overexpression and apoptosis (P < 0.05). Moreover, the expression pattern of high p8 and low ssDNA was seen significantly more often in lower age (<65 years), in moderately or poorly differentiated cancers, and in node-positive cases (P < 0.05). The p8 expression and apoptosis were not significantly correlated with survival. These results suggest that p8 overexpression is involved in antiapoptotic activity and the biological characteristics of pancreatic cancer.

[Evaluation of 47,213 infants in neonatal screening for cystic fibrosis, using pancreatitis-associated protein and immunoreactive trypsinogen assays]. / Evaluation sur 47,213 enfants d'une stratégie de dépistage néonatal de la mucoviscidose associant les dosages de pancreatitis-associated protein et de trypsinogène immunoréactive.

OBJECTIVES: The increasing evidence of the benefits of neonatal screening for cystic fibrosis (CF) indicates that this procedure could soon be implemented throughout France. The screening strategy currently used involves the detection of infants with elevated levels of immunoreactive trypsinogen (IRT) (approximately 1% of the population), followed by the detection of CFTR gene mutations. However, genetic analysis has certain drawbacks, the most important of which being the management of heterozygotes, and in France the requirement by law of previous informed consent. In cases of CF, pancreatic alterations are already present in utero. A previous study has demonstrated the value of pancreatitis-associated protein (PAP) as a screening test for CF, and has indicated that a feasible two-stage strategy could involve the following: 1) selection of infants with elevated PAP levels; 2) in this group of infants, subsequent detection of those with elevated IRT levels for direct CF diagnosis by the sweat test thereby avoiding the use of genetic analysis. The study aim was to evaluate this strategy in a large number of neonates. METHODS AND RESULTS: The aforementioned strategy was evaluated in a prospective study involving 47,213 infants in the Provence region of France. In infants with a PAP > 7.5 ng/mL (1.28%), 176 had an elevated IRT level > 700 ng/mL (0.37%). In this limited population sample (0.37% of the total), the sweat test diagnosed five cases of CF. A sixth case involving the monozygous twin of an infant with diagnosed CF remained undetected, probably because of a registration error. Genetic analysis confirmed the diagnosis, and also detected another case in an infant with two CFTR mutations but with a normal phenotype at 20 months of age. As the observed incidence was similar to that which had previously been reported, and as no further case was subsequently detected two years after the end of the study, this indicated that the sensitivity of this screening strategy was satisfactory. Its specificity makes the direct diagnosis of CF cases by the sweat test feasible, without further selection by genetic analysis. CONCLUSION: The PAP/IRT technique for CF detection seems to be suitable for mass screening, without the drawbacks of genetic testing.

Lithostathine and pancreatitis-associated protein are involved in the very early stages of Alzheimer's disease.

According to one of the theories formulated to explain the etiology of Alzheimer's disease (AD), amylosis may reflect a specific inflammatory response. Two inflammatory proteins, lithostathine and PAP, were evidenced by immunohistochemistry in senile plaques and neurofibrillary tangles of patients with AD. In addition, lithostathine and PAP were significantly increased in the cerebrospinal fluid of patients with AD when compared to patients with multiple sclerosis, another inflammatory disease, and to normal control subjects. However, no correlation was observed with age of occurrence. Furthermore, lithostathine and PAP were increased even at the very early stages of AD, and their level remained elevated during the course of the AD unlike TNFalpha whose level, very high at very early stages, regularly decreased. Finally, if part of lithostathine and PAP are synthesized in the brain, a large part comes from serum by passage over the blood-brain barrier. These results indicate (i) the existence of an acute phase response followed by a chronic inflammation in AD, and (ii) that lithostathine and PAP are involved even at the first pre-clinical biochemical events of AD. In addition, because lithostathine undergoes an autolytic cleavage leading to its precipitation and the formation of fibrils, we believe that it may be involved in amyloidosis and tangles by allowing heterogeneous precipitation of other proteins.

[Long-term treatment of Alzheimer's disease: followup of a cohort of 255 patients treated with lacrine for four years]. / Traitement de la maladie d'Alzheimer au long cours: à propos d'une cohorte de 255 patients traités quatre ans par tacrine.

We describe the follow-up of a cohort of 255 Alzheimer's disease (AD) patients (81 males, 174 females) treated by tacrine during 4 years. We performed the survey of hepatic, cholinergic and general tolérance. Drug efficacy was measured by MMS examination on weeks 0, 18, 30, 52, 104, 156 and 208. A total of 190 patients (74.5 percent) were dropped out of this study, 75 (29 percent) for adverse events. We found 85 hepatic (33 percent), 79 cholinergic (31 percent), 31 (12 percent) neuropsychiatric and 72 general (28 percent) side effects. In term of drug efficacy we observed a global decline of 2.5 MMS points during the first year and 2 MMS points between W52 and W156. Tacrine's symptomatic efficacy, defined as the number of patients improved or stabilized at W30, was present in 50 patients (46 percent) among the 109 patients reaching W30. The intensity of symptomatic efficacy was expressed by a 2.7 MMS points increase in 37 patients improved on W30. The long term effects of Tacrine, measured by the MMS score at one year, showed a positive impact as the MMS was 2.5 points above the expected score in non treated AD patients. This study raises the practical problem of optimal cholinesterase inhibitors use in AD and the theoretical question of long term action of cholinesterase inhibitors on cerebral lesions of AD.

Association of APOE promoter but not A2M polymorphisms with risk of developing Alzheimer's disease.

The APOE4 allele is widely accepted as a major risk factor for late-onset Alzheimer's disease (AD). Recently, it has been reported that polymorphisms in the APOE promoter and in the alpha2-macroglobulin gene (A2M) are associated with AD. We have analyzed the distribution of APOE alleles, -219T/G APOE promoter polymorphism, and A2M/A2Mdel polymorphism in a large case-control study. Our results showed that APOE genotype was the only informative marker of AD risk contrary to -219T/G and A2M/A2Mdel polymorphism. In AD patients however, a strong linkage disequilibrium was observed between the T allele of -219T/G polymorphism and APOE4 allele. This result indicates that -219T/G APOE promoter polymorphism is a risk factor for AD by increasing the APOE4-associated risk.

Effects of low animal protein or high-fiber diets on urine composition in calcium nephrolithiasis.

BACKGROUND: The purpose of this article is to evaluate the impact of low protein and high fiber intakes on risk factors of stone recurrence in idiopathic calcium stone formers (ICSFs). METHODS: Ninety-six ICSFs were randomly assigned a low animal protein diet (< 10% of total energy), a high-fiber diet (> 25 g/day), or a usual diet (control group); all patients were recommended to increase their fluid intake. Their daily urine compositions were analyzed at baseline and at four months. Compliance with dietary recommendations was checked by validated food frequency questionnaires. Compliance with total and animal protein intakes was assessed by 24-hour urea and sulfate outputs, respectively. The nutritional intervention (oral instructions, written leaflet, phoning) and food assessment were carried out by a research dietitian. RESULTS: At baseline, diets and the daily urine composition did not differ between the three groups. At four months, while diets differed significantly, the 24-hour output of calcium and oxalate did not differ significantly within and between groups after adjustment for potential confounders (age, sex, and personal and family history of calcium stones) and baseline values. However, as many as 12 out of 31 ICSFs (95% CI, 22 to 58%) assigned to a low animal protein diet achieved a reduction in the urine urea excretion rate of more than 50 mmol/day and also exhibited a significant decrease in urinary calcium excretion that averaged 1.8 mmol/day. A significant correlation between urea and calcium outputs was observed only among patients with hypercalciuria. CONCLUSIONS: These results show that only ICSFs who markedly decrease their animal protein intake, especially those with hypercalciuria, can expect to benefit from dietary recommendations.

[Inhibition of peritoneal bacterial adhesion using oligosaccharides. An experimental model of peritonitis in rats]. / Inhibition de l'adhésion bactérienne péritonéale par des oligosaccharides. Modèle expérimental de péritonite chez le rat.

BACKGROUND: Peritoneal colonization is a crucial event in the pathogenesis of peritonitis and its local complications. Adherence to the serosal mesothelium is mediated in a number of microorganisms derived from the digestive tract (especially E. coli) by type-1 fimbriae which have an oligosaccharide specificity. PURPOSE: To evaluate the effect of repeated peritoneal washes with saline solution and oligosaccharides on E. coli peritoneal adherence in a rat peritonitis model. METHODS: Sixty rats were randomized in 3 groups of 20. E. coli was inoculated at a constant concentration of 10(8)/mL per 100 g of weight. Then, peritoneal washes were achieved daily during three consecutive days (D1, D2, D3), with saline solution in Group I (control group), Methyl alpha-D-Mannoside (MADM) in Group II, and p-Nitro-phenyl alpha-D-Mannoside (pNADM) in Group III. Peritoneal samples were obtained before and after lavage at D1, D2, and D3. Microbial recovery was expressed as cfu/mg of tissue, and converted into a percentage of the initial value. A 10% threshold defined efficiency of the wash (inhibition of adherence for 90% of bacteries). RESULTS: Compared with data from Group I, E. coli peritoneal adherence was significantly lower after washes in Group III (D1: p = 0.03; D2: p = 0.009; D3: p = 0.003). Repeated washes were more efficient in Group III than in Group II (D1: p = 0.1; D2: p = 0.5; D3: p = 0.001). CONCLUSION: These results suggest that the addition of oligosaccharides, especially of pNADM, reduces the peritoneal adherence of E. coli when a peritoneal wash is performed for peritonitis.

Blood concentrations of pancreatitis associated protein in neonates: relevance to neonatal screening for cystic fibrosis.

AIM: To determine whether pancreatitis associated protein (PAP) is a marker for cystic fibrosis which could be used in neonatal screening for the disease. METHODS: PAP was assayed on screening cards from 202,807 neonates. Babies with PAP > or = 15 ng/ml, or > or = 11.5 ng/ml and immunoreactive trypsinogen (IRT) > or = 700 ng/ml were recalled for clinical examination, sweat testing, and cystic fibrosis transmembrane regulator (CFTR) gene analysis. RESULTS: Median PAP value was 2.8 ng/ml. Forty four cases of cystic fibrosis were recorded. Recalled neonates (n = 398) included only 11 carriers. A receiver operating characteristic curve analysis showed that PAP above 8.0 ng/ml would select 0.76% of babies, including all those with cystic fibrosis, except for one with meconium ileus and two with mild CFTR mutations. Screening 27,146 babies with both PAP and IRT showed that only 0.12% had PAP > 8.0 ng/ml and IRT > 700 ng/ml, including all cases of cystic fibrosis. CONCLUSION: PAP is increased in most neonates with cystic fibrosis and could be used for CF screening. Its combination with IRT looks promising.

Nucleation of calcium oxalate crystals by albumin: involvement in the prevention of stone formation.

BACKGROUND: Urine is supersaturated in calcium oxalate, which means that it will contain calcium oxalate crystals that form spontaneously. Their size must be controlled to prevent retention in ducts and the eventual development of a lithiasis. This is achieved, in part, by specific inhibitors of crystal growth. We investigated whether promoters of crystal nucleation could also participate in that control, because for the same amount of salt that will precipitate from a supersaturated solution, increasing the number of crystals will decrease their average size and facilitate their elimination. METHODS: Albumin was purified from commercial sources and from the urine of healthy subjects or idiopathic calcium stone formers. Its aggregation properties were characterized by biophysical and biochemical techniques. Albumin was then either attached to several supports or left free in solution and incubated in a metastable solution of calcium oxalate. Kinetics of calcium oxalate crystallization were determined by turbidimetry. The nature and efficiency of nucleation were measured by examining the type and number of neoformed crystals. RESULTS: Albumin, one of the most abundant proteins in urine, was a powerful nucleator of calcium oxalate crystals in vitro, with the polymers being more active than monomers. In addition, nucleation by albumin apparently led exclusively to the formation of calcium oxalate dihydrate crystals, whereas calcium oxalate monohydrate crystals were formed in the absence of albumin. An analysis of calcium oxalate crystals in urine showed that the dihydrate form was present in healthy subjects and stone formers, whereas the monohydrate, which is thermodynamically more stable and constitutes the core of most calcium oxalate stones, was present in stone formers only. Finally, urinary albumin purified from healthy subjects contained significantly more polymers and was a stronger promoter of calcium oxalate nucleation than albumin from idiopathic calcium stone formers. CONCLUSIONS: Promotion by albumin of calcium oxalate crystallization with specific formation of the dihydrate form might be protective, because with rapid nucleation of small crystals, the saturation levels fall; thus, larger crystal formation and aggregation with subsequent stone formation may be prevented. We believe that albumin may be an important factor of urine stability.

[Balance sheet of tolerance-efficacy on the use of tacrine in 100 cases of Alzheimer's disease]. / Bilan tolérance-efficacité d'un an d'utilisation de la tacrine dans 100 cas de maladie d'Alzheimer.

We report our first 100 cases of Alzheimer's (AD) patients treated with tacrine (Cognex) for a period of one year. At the beginning of treatment the mean Mini-Mental-Status (MMS) score was 15.1. To date 71 patients are still under treatment (12 for more than 12 months). Forty-three instances of side-effects were observed, of which 31 involved hepatic side-effects with an increase in ALAT > IN (normal value) (6 cases > 3N), the mean date of appearance was 10.4 +/- 6.8 weeks, there were 16 cholinergic side-effects (nausea, vomiting, diarrhoea), plus 4 neurologic and 2 cutaneous side-effects. These side-effects led to the arrest of the treatment in 19 cases (16 for hepatic toxicity). Treatment was reattempted after interruption in 13 cases; successfully in 3 instances only. The measure of tacrine efficacy was based on 52 MMS score re-evaluations in week 18: there was an increase of the MMS score in 22 cases (3.3 points +/- 2.5), a stabilisation in 11 cases and a decrease in 19 cases (3.3 points +/- 2.2.). In week 30, the MMS scores (35 patients) increased in 9 cases (3.6 points +/- 2.4), stabilized in 5 cases and decreased in 21 cases (3.9 points +/- 3.3). At week 52, only 28 per cent of the patients were considered as either improved or stabilized. We conclude that there is a necessity for close follow-up of tacrine-treated patients, and that globally at 8 months there is an improvement or a stabilization in 40 per cent of patients and long term (at one year) a stabilizing effect on AD patients.

Dietary and urinary risk factors for stones in idiopathic calcium stone formers compared with healthy subjects.

BACKGROUND: The high social-economic cost of nephrolithiasis wholly justifies the attempts to understand its mechanism and avoid recurrences. The influence of dietary habits and urinary risk factors has been evaluated, but the results were discrepant, probably because of differences in the methodologies used to compare patients and controls. METHODS: The aim was to assess dietary and urinary risk factors for urinary stones by comparison between 108 calcium stone formers (SF) and 210 healthy subjects (HS). All subjects were recruited during the same 1 year period. Personal characteristics, dietary habits (evaluated through a food frequency questionnaire) and urinary biochemical parameters were collected. The high predominance of men in the SF group led us to focus on the 79 SF and the 96 HS men. RESULTS: A familial history of stones was reported more frequently in SF than in HS, 42.9% vs 17.6%, P<0.005. Body weight was higher in SF, 76.8+/-12.2 kg vs 72.8+/-9.6 kg, P=0.02; and calcium intake was lower in SF, 794.8+/-294.1 mg vs 943.6+/-345.4 mg, P<0.01. For urinary parameters, calcium and oxalate output were significantly higher in SF. Urinary urea, as a reflection of daily protein intake, and uric acid were also higher in SF. Urinary citrate excretion related to body weight was lower in SF. Calciuria was significantly correlated with urinary urea in both SF and HS, but the correlation was stronger for SF. Calciuria correlated significantly with natriuria only in HS. CONCLUSIONS: The main differences between SF and HS were that SF had a family history of stones, a higher body weight, a lower daily intake of calcium, and a higher urinary output of calcium and oxalate. These results underline the combined role of genetic and nutritional factors in the pathogenesis of urinary stone formation.

Prevalence of hepatitis G virus infection in kidney transplant recipients.

BACKGROUND: We investigated the prevalence, risk factors, and consequences of hepatitis G virus (HGV) infection in 87 kidney transplant recipients. METHODS: Infection was diagnosed with reverse transcriptase polymerase chain reaction using primers in the NS3 region of the viral genoma. RESULTS: Twenty-four patients (27.5%) were HGV RNA positive (HGV+ group) and 63 patients (72.5%) were HGV RNA negative (HGV- group). No statistically significant differences were found between the two groups for age, sex, transplantation and hemodialysis duration, number of kidney transplantations, serum creatinine, history of transfusions, hepatitis B and C virus infections, and percentage of patients having suffered from acute rejection. Acute and chronic hepatitis were not more prevalent in the HGV+ group than in the HGV- group. CONCLUSIONS: HGV infection is highly prevalent in kidney transplant recipients but does not alter liver or kidney functions. HGV contamination may be linked to nosocomial transmission during long-term hemodialysis.

Calcium carbonate crystals promote calcium oxalate crystallization by heterogeneous or epitaxial nucleation: possible involvement in the control of urinary lithogenesis.

A large proportion of urinary stones have calcium oxalate (CaOx) as the major mineral phase. In these stones, CaOx is generally associated with minor amounts of other calcium salts. Several reports showing the presence of calcium carbonate (CaCO3) and calcium phosphate in renal stones suggested that crystals of those salts might be present in the early steps of stone formation. Such crystals might therefore promote CaOx crystallization from supersaturated urine by providing an appropriate substrate for heterogeneous nucleation. That possibility was investigated by seeding a metastable solution of 45Ca oxalate with vaterite or calcite crystallites. Accretion of CaOx was monitored by 45Ca incorporation. We showed that (1) seeds of vaterite (the hexagonal polymorph of CaCO3) and calcite (the rhomboedric form) could initiate calcium oxalate crystal growth; (2) in the presence of lithostathine, an inhibitor of CaCO3 crystal growth, such accretion was not observed. In addition, scanning electron microscopy demonstrated that growth occurred by epitaxy onto calcite seeds whereas no special orientation was observed onto vaterite. It was concluded that calcium carbonate crystals promote crystallization of calcium oxalate and that inhibitors controlling calcium carbonate crystal formation in Henle's loop might play an important role in the prevention of calcium oxalate stone formation.

Developmental, nutritional, and hormonal regulation of the pancreatitis-associated protein I and III gene expression in the rat small intestine.

BACKGROUND: The pancreatitis-associated protein (PAP) I and III, but not PAP II, mRNAs are constitutively expressed in the small intestine of rats. METHODS: We studied expression of both PAP I and PAP III mRNAs during development and on nutritional and hormonal manipulations. RESULTS: Between day 20 of gestation and day 21 of age, PAP mRNAs could barely be detected. Their concentrations increased dramatically from day 21 to day 45 of age and remained constant thereafter. Rats adapted to a diet with low carbohydrate content showed a significant decrease in PAP mRNA concentrations. Finally, whereas thyroidectomy and ovariectomy induced a decrease in both mRNA concentrations, and adrenalectomy a limited decrease in PAP III mRNA only, diabetes and castration did not alter the expression of either gene. CONCLUSION: Gene expression of PAP I and III mRNAs is regulated in a coordinate manner in the rat small intestine during development and on nutritional and hormonal manipulations.

Is biliary lithiasis associated with pancreatographic changes?

The aetiological role of biliary lithiasis for chronic pancreatitis remains controversial. Previous studies based on pancreatographic studies reported changes in the pancreatic duct system caused by biliary lithiasis. This study analysed retrospectively the endoscopic retrograde cholangiopancreatography of 165 patients presenting with biliary lithiasis and of 53 controls. Among the 165 patients, 113 had choledochal stones (53 with gall bladder stones, 50 had had a cholecystectomy, 10 with a normal gall bladder), 35 had gall bladder stones without choledochal stones, 17 had cholecystectomy for gall bladder stones. Pancreatograms were analysed by measuring the diameter of the pancreatic duct in the head, the body, and the tail of the pancreas, and evaluating the regularity of the main pancreatic duct and the presence of stenosis, the regularity or the dilatation of secondary ducts, and the presence of cysts. In addition, we established a score, based on the above parameters, by which pancreatograms were classified as normal or with mild, intermediate, moderate or severe abnormalities. A multivariate analysis (stepwise multiple discriminant analysis) was performed for age, sex, presence of gall stones, presence of choledochal stones. Patients were comparable with controls for sex, alcohol consumption but were younger (55 v 68 years, p < 0.01). In patients and in controls, the frequency of pancreatographic abnormalities increased significantly with age. The pancreatographic features of patients and controls were not significantly different. In the multivariate analysis, age was the only factor with significant predicting value for pancreatographic abnormalities. In conclusion, biliary lithiasis in itself is not an aetiological factor for chronic pancreatitis, older age being responsible for the abnormalities seen by pancreatography of patients with biliary lithiasis.