ABSTRACT
OBJECTIVE: Fetoscopic laser photocoagulation (FLP) is a well-established treatment for twin-twin transfusion syndrome (TTTS) between 16 and 26 weeks' gestation. High-quality evidence and guidelines regarding the optimal clinical management of very early (prior to 16 weeks), early (between 16 and 18 weeks) and late (after 26 weeks) TTTS are lacking. The aim of this study was to construct a structured expert-based clinical consensus for the management of early and late TTTS. METHODS: A Delphi procedure was conducted among an international panel of experts. Participants were chosen based on their clinical expertise, affiliation and relevant publications. A four-round Delphi survey was conducted using an online platform and responses were collected anonymously. In the first round, a core group of experts was asked to answer open-ended questions regarding the indications, timing and modes of treatment for early and late TTTS. In the second and third rounds, participants were asked to grade each statement on a Likert scale (1, completely disagree; 5, completely agree) and to add any suggestions or modifications. At the end of each round, the median score for each statement was calculated. Statements with a median grade of 5 without suggestions for change were accepted as the consensus. Statements with a median grade of 3 or less were excluded from the Delphi process. Statements with a median grade of 4 were modified according to suggestions and reconsidered in the next round. In the last round, participants were asked to agree or disagree with the statements, and those with more than 70% agreement without suggestions for change were considered the consensus. RESULTS: A total of 122 experts met the inclusion criteria and were invited to participate, of whom 53 (43.4%) agreed to take part in the study. Of those, 75.5% completed all four rounds. A consensus on the optimal management of early and late TTTS was obtained. FLP can be offered as early as 15 weeks' gestation for selected cases, and can be considered up to 28 weeks. Between 16 and 18 weeks, management should be tailored according to Doppler findings. CONCLUSIONS: A consensus-based treatment protocol for early and late TTTS was agreed upon by a panel of experts. This protocol should be modified at the discretion of the operator, according to their experience and the specific demands of each case. This should advance the quality of future studies, guide clinical practice and improve patient care. © 2023 International Society of Ultrasound in Obstetrics and Gynecology.
Subject(s)
Fetofetal Transfusion , Gynecology , Female , Pregnancy , Humans , Consensus , Delphi Technique , Fetofetal Transfusion/diagnostic imaging , Fetofetal Transfusion/surgery , FetoscopyABSTRACT
Population stratification (PS) is a confounding factor in genome-wide association studies (GWASs) and also an interesting process itself. Latin American populations have mixed genetic ancestry, which may account for PS. We have analyzed the relatedness, by means of the identity-by-descent (IBD) estimations, in a sample of 1805 individuals and 1.006.703 autosomal mutations from a case-control study of colorectal cancer in Mexico. When using the recommended protocol for quality control assessment, 402 should have been removed due to relatedness. Our purpose was to analyze this value in the context of an admixed population. For that aim, we reanalyzed the sample using two software designed for admixed populations, obtaining estimates of 110 and 70 related individuals to remove. The results showed that the first estimation of relatedness was an effect of the higher Native American contribution in part of the data samples, being a confounding factor for IBD estimations. We conclude in the importance of considering PS and genetic ancestry in order to avoid spurious results, not only in GWAS but also in relatedness analysis.
Subject(s)
Colorectal Neoplasms/genetics , Genetics, Population , Genome-Wide Association Study , Case-Control Studies , Hispanic or Latino/genetics , Humans , Mexico , Software , American Indian or Alaska Native/geneticsABSTRACT
Surname distribution can be a useful tool for studying the genetic structure of a human population. In South America, the Uruguay population has traditionally been considered to be of European ancestry, despite its trihybrid origin, as proved through genetics. The aim of this study was to investigate the structure of the Uruguayan population, resulting from population movements and surname drift in the country. The distribution of the surnames of 2,501,774 people on the electoral register was studied in the nineteen departments of Uruguay. Multivariate approaches were used to estimate isonymic parameters. Isolation by Distance was measured by correlating isonymic and geographic distances. In the study sample, the most frequent surnames were consistently Spanish, reflecting the fact that the first immigration waves occurred before Uruguayan independence. Only a few surnames of Native origin were recorded. The effective surname number (α) for the entire country was 302, and the average for departments was 235.8 ± 19. Inbreeding estimates were lower in the south-west of the country and in the densely populated Montevideo area. Isonymic distances between departments were significantly correlated with linear geographic distance (p < 0.001) indicating continuously increasing surname distances up to 400 km. Surnames form clusters related to geographic regions affected by different historical processes. The isonymic structure of Uruguay shows a radiation towards the east and north, with short-range migration playing a major role, while the contribution of drift, considering the small variance of α, appears to be minor.
Subject(s)
Emigration and Immigration , Population Dynamics , Humans , Genetics, Population/methods , Names , UruguayABSTRACT
Mice with germline absence of SEC23B die perinatally, exhibiting massive pancreatic degeneration. We generated mice with tamoxifen-inducible, pancreatic acinar cell-specific Sec23b deletion. Inactivation of Sec23b exclusively in the pancreatic acinar cells of adult mice results in decreased overall pancreatic weights from pancreatic cell loss (decreased pancreatic DNA, RNA, and total protein content), as well as degeneration of exocrine cells, decreased zymogen granules, and alterations in the endoplasmic reticulum (ER), ranging from vesicular ER to markedly expanded cisternae with accumulation of moderate-density content or intracisternal granules. Acinar Sec23b deletion results in induction of ER stress and increased apoptosis in the pancreas, potentially explaining the loss of pancreatic cells and decreased pancreatic weight. These findings demonstrate that SEC23B is required for normal function of pancreatic acinar cells in adult mice.
Subject(s)
Acinar Cells/physiology , Pancreas/physiology , Vesicular Transport Proteins/metabolism , Acinar Cells/cytology , Acinar Cells/metabolism , Animals , Apoptosis/physiology , Cell Proliferation/physiology , Endoplasmic Reticulum/metabolism , Endoplasmic Reticulum Stress/physiology , Epithelial Cells/metabolism , Epithelial Cells/physiology , Mice , Mice, Transgenic , Pancreas/cytology , Pancreas/metabolism , Vesicular Transport Proteins/geneticsSubject(s)
Colitis, Ulcerative/diagnosis , Colitis, Ulcerative/therapy , Colitis, Ulcerative/complications , Combined Modality Therapy , Disease Progression , Europe , Gastrointestinal Agents/therapeutic use , Humans , Ileostomy , Immunosuppressive Agents/therapeutic use , Induction Chemotherapy , Maintenance Chemotherapy , Proctocolectomy, Restorative , Severity of Illness IndexABSTRACT
We describe here a new frameshift mutation of ß-thalassemia in a Uruguayan family with Italian ancestry [ß48 (-T); HBB:c.146delT]. This frameshift results in formation of premature stop codon (TGA) 40 bp downstream and in a short unstable product that is degraded in the cell.
Subject(s)
Family Health , Frameshift Mutation , beta-Globins/genetics , beta-Thalassemia/genetics , Adult , Codon, Nonsense , Exons , Female , Gene Deletion , Heterozygote , Humans , Italy , Pedigree , Protein Stability , Uruguay , White People , beta-Globins/analysis , beta-Globins/metabolism , beta-Thalassemia/blood , beta-Thalassemia/metabolismSubject(s)
Barotrauma/etiology , Hernia, Abdominal/epidemiology , Peritoneal Dialysis/adverse effects , Abdomen/surgery , Body Mass Index , Dialysis Solutions/administration & dosage , Dose-Response Relationship, Drug , Female , Hernia, Abdominal/etiology , Hernia, Abdominal/surgery , Humans , Hydrostatic Pressure/adverse effects , Male , Middle Aged , Peritoneal Dialysis, Continuous Ambulatory/adverse effects , Postoperative Complications/epidemiology , Postoperative Complications/etiology , Recurrence , Retrospective Studies , Risk Factors , Surgical MeshABSTRACT
Like other countries in the Americas, during its colonization Uruguay was the recipient of immigrants from several ethnic groups from Europe, as well as of enslaved Africans. After its independence in 1830, Basques were the first group of Europeans to arrive in the country. In this paper, we aim to contribute to the understanding of the process of integration of these migratory waves into the Uruguayan society. For that purpose, individuals of Basque origin from the city of Trinidad, Uruguay, were chosen to participate in this study. Particularly, we wanted to determine if Basque descendants in Uruguay remained relatively isolated or if they mixed with other ethnic groups. Mitochondrial DNA (mtDNA) of 60 self-identified Basque descendants, taken from a larger sample of subjects with Basque ancestors, was analyzed. The origin of mtDNA haplogroups was 77.8% European, 20.4% Amerindian, and 1.8% African, showing similar frequencies to other Uruguayan regions. Very few sequences showed a clear Basque origin, although other sources such as the Canary Islands are likely. Moreover, genetic distances clearly show that Basque descendants are genetically closer to other Uruguayan groups than to European populations, including Basques. It is possible to conclude that Basques and their descendants in the region of Trinidad did not remain isolated and that their marriage behavior was similar to that of other Uruguayan populations. However, to have a more accurate picture of the way Basques intermarried with other populations in Uruguay, new analyses are needed that take into account paternal lineages as well as biparental genetic markers.
Subject(s)
Colonialism/history , DNA, Mitochondrial/genetics , Emigration and Immigration/history , Ethnicity/genetics , Genetics, Population/history , Haplotypes/genetics , Emigration and Immigration/statistics & numerical data , Ethnicity/history , Ethnicity/statistics & numerical data , Female , History, 19th Century , History, 20th Century , History, 21st Century , Humans , Spain , UruguayABSTRACT
El síndrome de Poland es una rara anomalía congénita que incluye la ausencia total o parcial de la musculatura pectoral mayor, habitualmente con otras malformaciones asociadas en la extremidad superior homolateral. Su incidencia se estima en 1/30.000 recién nacidos vivos, con una ratio varón: mujer de 3:1; es más frecuente la afectación del lado derecho (60-75%).Se presenta un caso esporádico en una recién nacida con una afectación leve del lado izquierdo y una hipoplasia del tejido mamario y la areola, en la que se detectó una dextrocardia aislada. Destacamos la necesidad de realizar estudios complementarios (radiografía torácica, serie ósea y ecografía abdominal) en todos los casos (AU)
Poland syndrome is a rare congenital anomaly consisting of unilateral partial or total absence of the greater pectoral muscle, associated usually to other malformations in the superioripsi lateral extremities. Its incidence has been estimated to be1/30,000 live births with a male: female ratio of 3:1, and is mostly right-sided (60-75%). We report the case of a female newborn with a mild defect in the left pectoral muscle, a smaller left areola and hypoplasia of subcutaneous tissue, in association with isolated dextrocardia with the apex pointing to the left. We emphasize the need for additional studies (chest x-ray, bone series, and abdominal ultrasound) in each case (AU)
Subject(s)
Humans , Female , Child , Poland Syndrome/diagnosis , Dextrocardia/complications , Thorax/abnormalities , Musculoskeletal Abnormalities/diagnosisABSTRACT
Dietary protein can stimulate pancreatic growth in the absence of CCK release, but there is little data on the regulation of CCK-independent growth. To identify mechanisms whereby protein stimulates pancreatic growth in the absence of CCK release, C57BL/6 control and CCK-null male mice were fed normal-protein (14% casein) or high-protein (75% casein) chow for 7 days. The weight of the pancreas increased by 32% in C57BL/6 mice and 26% in CCK-null mice fed high-protein chow. Changes in pancreatic weight in control mice were due to both cell hypertrophy and hyperplasia since there was an increase in protein-to-DNA ratio, total DNA content, and DNA synthesis. In CCK-null mice pancreatic growth was almost entirely due to hypertrophy with both protein-to-DNA ratio and cell size increasing without significant increases in DNA content or DNA synthesis. ERK, calcineurin, and mammalian target of rapamycin complex 1 (mTORC1) are activated in models of CCK-induced growth, but there were no differences in ERK or calcineurin activation between fasted and fed CCK-null mice. In contrast, mTORC1 activation was increased after feeding and the duration of activation was prolonged in mice fed high-protein chow compared with normal-protein chow. Changes in pancreatic weight and RNA content were completely inhibited, and changes in protein content were partially abated, when the mTORC1 inhibitor rapamycin was administered during high-protein chow feeding. Prolonged mTORC1 activation is thus required for dietary protein-induced pancreatic growth in the absence of CCK.
Subject(s)
Cholecystokinin/metabolism , Dietary Proteins/metabolism , Pancreas, Exocrine/growth & development , Transcription Factors/metabolism , Analysis of Variance , Animals , Blotting, Western , Calcineurin/metabolism , Cholecystokinin/genetics , Male , Mechanistic Target of Rapamycin Complex 1 , Mice , Mice, Knockout , Multiprotein Complexes , Organ Size , Pancreas, Exocrine/metabolism , Phosphorylation , Proteins , Proto-Oncogene Proteins c-akt/metabolism , Signal Transduction , TOR Serine-Threonine KinasesABSTRACT
OBJECTIVE: The incidence of esophageal cancer has increased considerably over recent years, it now being the 6th most frequent cause of cancer-related death. Our study has aimed to compare the clinical value of PET/CT and CT scan in the initial staging of patients with esophageal cancer. MATERIAL AND METHODS: Fifty nine patients (6 women) diagnosed of esophageal cancer were assessed retrospectively. All patients underwent diagnostic CT scan and PET/CT for initial staging within 3 to 15 days following clinical diagnosis. RESULTS: PET/CT showed intracellular (18)F-FDG entrapment having pathological significance in all the tumors (100%), signs of locoregional lymph node infiltration (N1) in 34 and a total of 19 lesions consistent with metastasis (M1) in 14 patients (23.72%). The CT scan detected malignancy in 57 patients (96.6%), abnormal lymph node in 32 patients and 17 N1 in 12 patients (20.33%). In three cases, CT- PET detected synchronous esophageal lesion in staging studies for other neoplastic processes (lung and ear-nose-throat). CONCLUSION: PET/CT showed a higher detection rate of primary malignant lesions, abnormal lymph nodes and distant metastases. A change in stage was only observed in two patients.
Subject(s)
Adenocarcinoma/diagnostic imaging , Carcinoma, Squamous Cell/diagnostic imaging , Esophageal Neoplasms/diagnostic imaging , Fluorine Radioisotopes , Fluorodeoxyglucose F18 , Neoplasm Staging/methods , Positron-Emission Tomography , Radiopharmaceuticals , Tomography, X-Ray Computed , Adenocarcinoma/pathology , Adenocarcinoma/therapy , Carcinoma, Squamous Cell/pathology , Carcinoma, Squamous Cell/therapy , Case Management , Esophageal Neoplasms/pathology , Esophageal Neoplasms/therapy , Female , Humans , Lymphatic Metastasis , Male , Neoplasm Metastasis , Retrospective StudiesABSTRACT
Objetivos: La incidencia del carcinoma de esófago se ha incrementado considerablemente en los últimos años, siendo en la actualidad la sexta causa más frecuente de muerte por cáncer. El objetivo de nuestro estudio es comparar la utilidad de la PET/TAC con 18F-FDG y la TAC en la estadificación inicial en pacientes con carcinoma esofágico. Material y método: Se han valorado de manera retrospectiva 59 pacientes (6 mujeres) diagnosticados de una neoplasia esofágica. A todos los pacientes se les realizó una TAC y una PET/TAC de estadificación inicial entre 3 y 15 días después del diagnóstico. Resultados: La PET/TAC mostró el atrapamiento intracelular de 18F-FDG de significación patológica en todos los tumores (100%), signos de infiltración ganglionar locorregional (N1) en 34 y un total de 19 lesiones compatibles con metástasis (M1) en 14 pacientes (23,72%). La TAC mostró la lesión tumoral en 57 pacientes (96,6%), infiltración ganglionar en 32 pacientes y 17 M1 en 12 pacientes (20,33%). En tres casos la PET/ TAC detectó la lesión esofágica de manera sincrónica en estudios de estadificación de otros procesos neoplásicos (pulmón y área otorrinolaringológica). Conclusión: La PET/TAC mostró una mayor detección de lesiones tumorales primarias, así como adenopatías infiltradas y metástasis a distancia. Sólo se observó un cambio de estadificación en dos pacientes(AU)
Objective: The incidence of esophageal cancer has increased considerably over recent years, it now being the 6th most frequent cause of cancer-related death. Our study has aimed to compare the clinical value of PET/CT and CT scan in the initial staging of patients with esophageal cancer. Material and methods: Fifty nine patients (6 women) diagnosed of esophageal cancer were assessed retrospectively. All patients underwent diagnostic CT scan and PET/CT for initial staging within 3 to 15 days following clinical diagnosis. Results: PET/CT showed intracellular 18F-FDG entrapment having pathological significance in all the tumors (100%), signs of locoregional lymph node infiltration (N1) in 34 and a total of 19 lesions consistent with metastasis (M1) in 14 patients (23.72%). The CT scan detected malignancy in 57 patients (96.6%), abnormal lymph node in 32 patients and 17 N1 in 12 patients (20.33%). In three cases, CT- PET detected synchronous esophageal lesion in staging studies for other neoplastic processes (lung and ear-nose-throat). Conclusion: PET/CT showed a higher detection rate of primary malignant lesions, abnormal lymph nodes and distant metastases. A change in stage was only observed in two patients(AU)
Subject(s)
Humans , Male , Female , Adult , Middle Aged , Aged , Aged, 80 and over , Adenocarcinoma , Carcinoma, Squamous Cell , Esophageal Neoplasms , Radionuclide Imaging , Fluorine Radioisotopes , Fluorodeoxyglucose F18 , Radiopharmaceuticals , Positron-Emission Tomography , Tomography, X-Ray Computed , Neoplasm Staging/methods , Adenocarcinoma , Carcinoma, Squamous Cell/pathology , Esophageal Neoplasms/pathology , Lymphatic Metastasis , Neoplasm Metastasis , Retrospective StudiesABSTRACT
Apoptosis, necrosis and neovascularization are three processes that occur during ischemic preconditioning in a range of organs. In the stomach, the effect of this preconditioning (the delay phenomenon) has helped to improve gastric vascularization prior to esophagogastric anastomosis after esophagectomy. Here we present a sequential study of the histological recovery of the gastric fundus and the phenomena of apoptosis, necrosis and neovascularization in an experimental model of partial gastric ischemia. Partial gastric devascularization was performed by ligature of the left gastric vessels in Sprague-Dawley rats. Rats were assigned to groups in accordance with their evaluation period: control, 1, 3, 6, 10, 15 and 21 days. Histological analysis, caspase-3 activity, DNA fragmentation and vascular endothelial cell proliferation (Ki-67) were measured in tissue samples after sacrifice. After 24 h of partial gastric ischemia, rates of apoptosis and necrosis were higher in the experimental groups than in controls. Tissue injury was higher 3 and 6 days post-ischemia. From day 10 after partial gastric ischemia, apoptosis and necrosis started to decrease, and on days 15 and 21 showed no differences in relation to controls. Neovascularization began between days 1 and 3, reaching its peak at 15 days after ischemia and coinciding with complete histological recovery. Both necrosis and apoptosis play a role in tissue injury during the first days after partial gastric ischemia. After 15 days, the evolution of both the histology and the neovascularization suggested that this is the optimal time for performing gastric transposition.
Subject(s)
Ischemic Preconditioning , Neovascularization, Pathologic , Stomach/blood supply , Animals , Apoptosis , Disease Models, Animal , Esophagus/blood supply , Esophagus/surgery , Male , Necrosis , Rats , Rats, Sprague-Dawley , Stomach/pathology , Stomach/physiopathology , Stomach/surgeryABSTRACT
Our aim in this study is to evaluate the efficacy of decontamination of the high digestive tract in reducing the incidence of anastomotic dehiscence, pulmonary infection and mortality after resective gastro-esophageal surgery. A prospective randomized and double-blinded study was conducted in patients undergoing total gastrectomy for gastric cancer and esophagectomy for esophageal cancer. Two groups were studied: group A patients were given erythromycin + gentamicine + nistatine sulfate orally; group B patients were given placebo. Mortality, incidence of anastomotic dehiscence and incidence of pulmonary infection were the end points evaluated. One hundred and nine consecutive patients were randomized. Eighteen (16.5%) were excluded. From the 91 patients who were evaluated, 42 (46.2%) received an esophagectomy and 49 (53.8%) had a total gastrectomy. Esophagectomies showed: a 0% rate of anastomotic dehiscence in group A and 12.5% in group B, P = 0.176; a pulmonary infection rate of 22.2% in group A and 29.1% in group B, P = 0.443; and mortality rate was 0% in group A and 12.5% in group B, P = 0.176. After gastrectomy, anastomotic dehiscence rate was 4.5% in group A and 0% in group B, P = 0.449; pulmonary infection rate was 4.5% in group A and 11.1% in group B, P = 0.387 and mortality was 9% in group A and 0% in group B, P = 0.196. Decontamination protocol does not help in decreasing the incidence of anastomotic dehiscence, pulmonary infection and mortality in the present study. Nevertheless, there seems to be a tendency to low pulmonary infection after gastrectomy and esophagectomy and to improve the incidence of anastomotic dehiscence after esophagectomy. Further studies are needed to re-evaluate these findings.
Subject(s)
Anti-Bacterial Agents/therapeutic use , Antibiotic Prophylaxis , Erythromycin/therapeutic use , Esophagectomy , Esophagus/surgery , Gastrectomy , Gentamicins/therapeutic use , Nystatin/therapeutic use , Pneumonia, Bacterial/prevention & control , Preoperative Care , Stomach/surgery , Adult , Aged , Aged, 80 and over , Anastomosis, Surgical , Decontamination , Double-Blind Method , Female , Humans , Male , Middle Aged , Prospective Studies , Surgical Wound Dehiscence/prevention & controlABSTRACT
BACKGROUND: NOD2/CARD15 gene variants have not been universally associated with stricturing behaviour in Crohn's disease. Other behaviour modifying genes could explain these results. AIM: To study the combined influence of NOD2/CARD15 variants and 4G/4G genotype of type-1 plasminogen activator inhibitor (PAI-1) gene on Crohn's disease behaviour. METHODS: One hundred and seventy Crohn's disease patients were studied prospectively, with a mean follow-up of 7+/- 6 years. Disease behaviour was registered by using two criteria: the Vienna classification and a non-hierarchical classification based on the behavioural Vienna categories. RESULTS: In the multivariate analysis for stricturing behaviour according to the Vienna categories, only absence of colonic disease (OR, 4.0; 95% CI: 1.49-11.1; P = 0.006) was an independent predictive factor. However, in the multivariate analysis for stricturing disease applying a non-hierarchical criteria, ileal disease (OR, 4.19; 95% CI: 1.30-13.5; P = 0.01), and carrying both NOD2/CARD15 variants and the 4G/4G PAI-1 genotype (OR, 5.02; 95% CI: 1.44-17.48; P = 0.01) were independent predictive factors. In the multivariate analysis for penetrating behaviour, the 4G/4G PAI-1 (OR, 3.10; 95% CI: 1.54-6.23; P = 0.001) and male sex (OR, 2.44; 95% CI: 1.30-4.60; P = 0.005) were independent predictive factors irrespective of criteria applied. CONCLUSIONS: Combined PAI-1 and NOD2/CARD15 genotyping predict complicated Crohn's disease. Patients with these variants could benefit from early interventions.
Subject(s)
Crohn Disease/genetics , Genetic Predisposition to Disease/genetics , Nod2 Signaling Adaptor Protein/genetics , Plasminogen Activator Inhibitor 1/genetics , Polymorphism, Genetic , Adult , Aged , Female , Genotype , Humans , Male , Middle Aged , Prospective Studies , Risk FactorsABSTRACT
Cholecystokinin (CCK)-induced pancreatic growth in mice involves parallel increases in DNA and protein. The mammalian target of rapamycin (mTOR) signalling pathway regulates mRNA translation and its activation is implicated in growth of various tissues. The aim of this study was to elucidate whether mTOR activation is required for pancreatic growth in a mouse model of increased endogenous CCK release. In mice fed chow containing the synthetic protease inhibitor camostat, protein synthetic rates and phosphorylation of two downstream targets of mTOR, eukaryotic initiation factor 4E binding protein 1 (4E-BP1) and the ribosomal protein S6 (S6), increased in comparison with fasted controls. The camostat-induced increases in protein synthesis and 4E-BP1 and S6 phosphorylation were almost totally abolished by administration of the mTOR inhibitor rapamycin 1 h prior to camostat feeding. In contrast, the phosphorylation of ERK1/2 and JNK and the expression of the early response genes c-jun, c-fos, ATF3 and egr-1 induced by camostat feeding were not affected by rapamycin. In mice fed camostat for 7 days, the ratio of pancreatic to body weight increased by 143%, but when rapamycin was administered daily this was reduced to a 22% increase. Changes in pancreatic mass were paralleled by protein and DNA content following camostat feeding and rapamycin administration. Moreover, while BrdU incorporation, an indicator of DNA synthesis, was increased to 448% of control values after 2 days of camostat feeding, rapamycin administration completely inhibited this increase. We conclude that the mTOR signalling pathway is required for CCK-induced cell division and pancreatic growth.
Subject(s)
Gabexate/analogs & derivatives , Pancreas/drug effects , Protease Inhibitors/pharmacology , Protein Kinases/metabolism , Signal Transduction , Adaptor Proteins, Signal Transducing , Animals , Carrier Proteins/metabolism , Cell Cycle Proteins , DNA/biosynthesis , Diet , Esters , Eukaryotic Initiation Factors , Gabexate/administration & dosage , Gabexate/pharmacology , Guanidines , Male , Mice , Mice, Inbred ICR , Organ Size , Pancreas/enzymology , Pancreas/growth & development , Phosphoproteins/metabolism , Phosphorylation , Protease Inhibitors/administration & dosage , Protein Biosynthesis , Protein Kinase Inhibitors/administration & dosage , Protein Kinase Inhibitors/pharmacology , Ribosomal Protein S6/metabolism , Sirolimus/administration & dosage , Sirolimus/pharmacology , TOR Serine-Threonine KinasesABSTRACT
BACKGROUND AND AIMS: Increased pancreatitis associated protein (PAP) mRNA has been reported in active inflammatory bowel disease (IBD). The aims of the current study were to characterise PAP production in IBD and the effects of PAP on inflammation. PATIENTS AND METHODS: Serum PAP levels were determined in healthy controls (n = 29), inflammatory controls (n = 14), and IBD patients (n = 171). Ex vivo PAP secretion in intestinal tissue was measured in 56 IBD patients and 13 healthy controls. Cellular origin of PAP was determined by immunohistochemistry. The effects of exogenous PAP on nuclear factor kappaB (NFkappaB) activation, proinflammatory cytokine production, and endothelial adhesion molecule expression were also analysed ex vivo. RESULTS: Patients with active IBD had increased serum PAP levels compared with controls, and these levels correlated with clinical and endoscopic disease severity. Ex vivo intestinal PAP synthesis was increased in active IBD and correlated with endoscopic and histological severity of inflammatory lesions. PAP localised to colonic Paneth cells. Incubation of mucosa from active Crohn's disease with PAP dose dependently reduced proinflammatory cytokines secretion. PAP prevented TNF-alpha induced NFkappaB activation in monocytic, epithelial, and endothelial cells and reduced proinflammatory cytokine mRNA levels and adhesion molecule expression. CONCLUSIONS: PAP is synthesised by Paneth cells and is overexpressed in colonic tissue of active IBD. PAP inhibits NFkappaB activation and downregulates cytokine production and adhesion molecule expression in inflamed tissue. It may represent an anti-inflammatory mechanism and new therapeutic strategy in IBD.