Biomedical subjects

T J Nevalainen

Publications and source records attributed to T J Nevalainen.

At least 37 records · Page 2Linked to original sources

PubMed2000

Level of circulating phospholipase A2 in prediction of the prognosis of patients with suspected myocardial infarction.

OBJECTIVES: Atherosclerotic lesions result from inflammatory-proliferative responses of the endothelium and smooth muscle of the arterial wall. Poor prognosis of acute myocardial infarction (AMI) patients has been associated with elevated levels of acute phase proteins including C-reactive protein. We investigated the significance of circulating phospholipase A2 in the long-term prognosis of suspected AMI patients. METHODS: The concentration of phospholipase A2 was measured by an immunoassay in sera of 100 suspected AMI patients. Admission phospholipase A2 95 % fractile outliers were excluded to eliminate the effect of acute infectious diseases. The total and atherosclerotic mortalities were followed for a 4-year period. RESULTS: The most powerful prognostic limit for both admission (p = 0.02, RR = 2.6 and 95% CI = 1.2 to 5.6) and maximal (p = 0.06, RR = 2.4 and 95% CI = 0.96 to 5.9) phospholipase A2 groups was > or =8 microg/l. The admission phospholipase A2 level had an independent prognostic significance for atherosclerotic mortality (p = 0.04, RR = 2.4 and CI = 1.02 to 5.8) in multivariate analysis with CK-MB and age. CONCLUSIONS: The elevated serum phospholipase A2 level at admission is an independent predictor of long-term atherosclerotic mortality in patients with suspected AMI. The prognostic significance of phospholipase A2 weakens during hospitalisation concomitant to the onset of the acute inflammatory response to myocardial injury.

Aged↗

PubMed2000

Neutrophil response of transgenic mice expressing human group IIA phospholipase A2 in bacterial infections.

Group IIA phospholipase A2 (PLA2) is a newly recognized acute phase protein with marked antibacterial properties. We have shown previously that transgenic C57BL/6 J mice expressing human group IIA PLA2 (PLA2+ mice) are more resistant to bacterial infections than nontransgenic C57BL/6 J mice that, among mice, are unusual in that they lack the mouse analogue of group IIA PLA2 (PLA2- mice). To elucidate the possible mechanisms involved in the host response of these mice in bacterial infection, peripheral inflammatory cell responses of PLA2+ and PLA2- mice were studied after i.p. administration of Escherichia coli, E. coli lipopolysaccharide or Staphylococcus aureus. Uninfected PLA2+ mice had higher numbers of lymphocytes and polymorphonuclear neutrophil leukocytes (PMNs) in their blood than PLA2- mice. In PLA2+ mice, the number of PMNs increased in peripheral blood in parallel with the concentration of group IIA PLA2 after the administration of bacteria, whereas these responses were not seen in PLA2- mice. High concentrations of group IIA PLA2 in PLA2+ mice may increase the synthesis of bioactive molecules, such as prostaglandins, which in turn may mobilize PMNs into circulation. Our results support the hypothesis that group IIA PLA2 is an important inflammatory mediator in bacterial infections.

Acute-Phase Proteins↗

PubMed2000

Single doses of FK506 and OKT3 reduce severity in early experimental acute pancreatitis.

OBJECTIVE: To find out if two immunomodulatory drugs used in organ transplantation (FK506 (tacrolimus) and OKT3 (Orthoclone) would reduce early inflammatory complications in experimental acute pancreatitis. DESIGN: Laboratory study. SETTING: University hospital, Germany. ANIMALS: 36 Balb/c mice. INTERVENTIONS: Pancreatitis induced by 7 intraperitoneal injections of cerulein 50 microg/kg at hourly intervals followed by FK506 0.32 mg/kg, OKT3 0.6 mg/kg, or 0.9% sodium chloride (controls) (n = 12 in each group). 12 hours after induction of pancreatitis the animals were killed. MAIN OUTCOME MEASURES: Serum amylase activity and interleukin-6 (IL-6) concentrations; histological damage to pancreas and lungs, apoptotic cells in pancreas; and myeloperoxidase activity in lungs. RESULTS: No animal died during the experiment. At 12h serum amylase activity and IL-6 concentrations were increased in all 3 groups, but highest in the OKT3 group. The pancreatic histological score, apoptosis, and inflammatory infiltration were lower in the two experimental groups than controls, but the degree of vacuolisation of acinar cells was similar. Packed cell volume was higher in the control than the experimental groups, and pulmonary damage and myeloperoxidase activity were less in the experimental groups than the controls. CONCLUSION: Single therapeutic doses of FK506 and OKT3 reduced the early severity of pancreatitis, pulmonary damage, and haemoconcentration in mice. Single doses of FK506 or OKT3 may therefore be effective in preventing the early complications of pancreatitis.

Acute Disease↗

PubMed2000

Resistance of transgenic mice expressing human group II phospholipase A2 to Escherichia coli infection.

Group II phospholipase A2 (PLA2) is a newly recognized antibacterial acute-phase protein. Recently we observed that transgenic mice expressing group II PLA2 (PLA2(+) mice) were able to resist experimental Staphylococcus aureus infection by killing the bacteria, as indicated by improved survival and by the small numbers of live bacteria in their tissues (V. J. O. Laine, D. S. Grass, and T. J. Nevalainen, J. Immunol. 162:7402-7408, 1999). To establish the role of group II PLA2 in Escherichia coli infection, the host responses of PLA2(+) mice and their PLA2-deficient C57BL/6J littermates (PLA2(-) mice) were studied after intraperitoneal administration of E. coli. The levels of group II PLA2 in sera of PLA2(+) mice increased after the administration of E. coli, and the concentration of group II PLA2 correlated significantly with the catalytic activity of PLA2 in serum. PLA2(+) mice showed lower rates of mortality and less bacterial growth in peritoneal lavage fluid, blood, and spleen and liver tissues than PLA2(-) mice. Unlike the observations with staphylococcal infection, serum and peritoneal lavage fluid did not inhibit the growth of E. coli in vitro. The results indicate that expression of the group II PLA2 transgene improves the host defense of mice against E. coli infection.

Animals↗

PubMed2000

Distribution of group II phospholipase A2 protein and mRNA in rat tissues.

Group II phospholipase A2 (PLA2) is an acute-phase protein and an important component of the host defense against bacteria. In this study we investigated the distribution of PLA2 protein by immunohistochemistry and the distribution of mRNA of PLA2 by Northern blotting and in situ hybridization in rat tissues. PLA2 protein was localized in the Paneth cells of the intestinal mucosa, chondrocytes and the matrix of cartilage, and megakaryocytes in the spleen. By Northern blotting, mRNA of PLA2 was found in the gastrointestinal tract, lung, heart, and spleen. By in situ hybridization, PLA2 mRNA was localized in the Paneth cells of the small intestinal mucosa but in no other cell types. Our results show specific distribution of PLA2 in a limited number of cell types in rat tissues. The reagents developed in this study (the anti-rat PLA2 antibody and probes for Northern blotting and in situ hybridization of mRNA of rat PLA2) will provide useful tools for future studies concerning the role of PLA2 in various experimental disease models.

Amino Acid Sequence↗

PubMed1999

Protection by group II phospholipase A2 against Staphylococcus aureus.

Group II phospholipase A2 (PLA2) is an enzyme that has marked antibacterial properties in vitro. To define the role of group II PLA2 in the defense against Staphylococcus aureus, we studied host responses in transgenic mice expressing human group II PLA2 and group II PLA2-deficient C57BL/6J mice in experimental S. aureus infection. After the administration of S. aureus, the transgenic mice showed increased expression of group II PLA2 mRNA in the liver and increased concentration of group II PLA2 in serum, whereas the PLA2-deficient mice completely lacked the PLA2 response. Expression of human group II PLA2 resulted in reduced mortality and improved the resistance of the mice by killing the bacteria as indicated by low numbers of live bacteria in their tissues. Human group II PLA2 was responsible for the bactericidal activity of transgenic mouse serum. These results suggest a possible role for group II PLA2 in the innate immunity against S. aureus infection.

Animals↗

PubMed1999

Immunohistochemical labelling for prostate-specific antigen in breast carcinomas.

Immunohistochemical detection of prostate-specific antigen (PSA) is an aid in determining the prostatic origin of metastatic cells. However, small amounts of PSA have also been found in non-prostatic tissues and tumors, for example in some breast carcinomas, by highly sensitive immunofluorometric methods, but also by immunohistochemistry. Our aim was to evaluate the prevalence and prognostic value of histologically confirmed PSA immunoreactivity in breast carcinoma. Sections of formalin-fixed, paraffin-embedded samples from 171 breast carcinomas were immunostained for PSA. The staining results were compared with the mitotic activity, tumor size, histological grade, steroid receptors and follow-up data. For analysis the material was divided into subgroups according to the patients' age (pre- and postmenopausal). PSA was found by immunohistochemistry in 54 (32%) breast carcinomas. In survival analysis of the whole patient material PSA positivity did not show prognostic value. Among premenopausal patients concomitant estrogen receptor and PSA-negativity proved to be associated with high risk of breast cancer death (RR 6.2), also after adjustment for tumor size, histological grade, and axillary lymph node status. Among postmenopausal patients PSA positivity was associated with progesterone receptor positivity and high differentiation but not with age, nodal status, or mitotic activity. PSA can be detected by immunohistochemistry in a considerable number of breast carcinomas. PSA immunoreactivity alone does not seem to have any value as general prognosticator of breast carcinoma patients. However, concomitant absence of PSA and estrogen receptors was an indicator of unfavourable prognosis among premenopausal patients.

Adult↗

PubMed1999

Phospholipase A2 in serum and colonic mucosa in ulcerative colitis.

Group II phospholipase A2 is involved in the pathogenesis of various inflammatory diseases and in the host defence against bacteria. The enzyme is expressed in the epithelial cells of colonic mucosa in ulcerative colitis. In this study, we measured the concentration of group II phospholipase A2 in serum and colonic mucosa of patients with ulcerative colitis of different severity and of control patients without any inflammatory disease. The activity of ulcerative colitis was assessed by endoscopy. The concentration of group II phospholipase A2 was measured with an immunoassay. The concentrations of group II phospholipase A2 in serum and colonic mucosa were significantly higher in patients with active and inactive ulcerative colitis than in controls. However, the group II phospholipase A2 levels did not separate patients with different disease activity. The concentration of group II phospholipase A2 in colonic mucosa corresponded with the mucosal inflammatory activity (higher in active colonic areas) intra-individually, but not between different patients with ulcerative colitis. Serum group II phospholipase A2 values were above the normal reference range more often than the values of 11 standard laboratory blood tests widely used for the follow-up of inflammatory activity in ulcerative colitis. These results indicate that the concentration of group II phospholipase A2 is increased in serum and colonic mucosa of patients with ulcerative colitis. The clinical value of the measurement of group II phospholipase A2 in the follow-up of ulcerative colitis remains to be clarified.

Adult↗

PubMed1999

Central haemodynamics in experimental acute pancreatitis.

OBJECTIVE: To investigate central haemodynamics in severe and mild acute pancreatitis in pigs. DESIGN: Randomised controlled experiment. SETTING: Animal laboratory, Finland. SUBJECTS: 24 domestic pigs weighing 21-27 kg. INTERVENTIONS: In 8 anaesthetised and mechanically ventilated pigs the pancreatic duct was cannulated and taurocholic acid was infused to induce severe acute pancreatitis. Eight animals received intraductal saline infusion and developed mild acute pancreatitis. Eight pigs were cannulated alone and served as controls. MAIN OUTCOME MEASURES: Cardiac index, heart rate, mean arterial pressure, central venous pressure, mean pulmonary arterial pressure, pulmonary arterial occlusion pressure, haemoglobin, arterial blood gases and acid base balance. RESULTS: Intraductally infused taurocholic acid rapidly induced severe necrotising acute pancreatitis as assessed both macroscopically and histologically. Histological changes of mild acute pancreatitis were seen in animals after intraductal saline infusion. Central haemodynamics, arterial blood gases, and acid base balances were stable throughout the study period in all groups. The main finding was haemoconcentration as indicated by the increase in arterial haemoglobin concentration in pigs with mild and severe acute pancreatitis. CONCLUSION: Haemoconcentration precedes central haemodynamic alterations in experimental acute pancreatitis.

Acute Disease↗

PubMed1999

Systemic lymphocyte activation modulates the severity of diet-induced acute pancreatitis in mice.

To examine the role of lymphocyte activation in the development of local and systemic complications in acute pancreatitis, we compared disease severity of choline-deficient, 0.5% ethionine supplemented (CDE) diet-induced acute pancreatitis in T- and B-cell deficient SCID mice and immunocompetent C.B-17 mice. Twenty-five female SCID and 17 female C.B-17 mice were fasted for 24 h and fed a CDE diet for 72 h. Twenty SCID and 12 C.B-17 mice were bled and their organs removed for histologic evaluation. Five control animals of both kinds were fed a regular diet for 6 days. Lung, kidney, and pancreas were examined microscopically, and pancreatic damage scored. Apoptosis was detected by DNA nick-end labeling and confirmed by DNA laddering. Trypsinogen-activation peptide was measured by enzyme-linked immunosorbent assay (ELISA), and the catalytic activity of PLA2 was determined by a radiometric assay. Four-day mortality was 10% in SCID and 33% in C.B-17 mice, and 10-day mortality was 0 in SCID and 60% in C.B-17 mice. SCID mice had mild pulmonary damage, whereas pulmonary injury was severe in C.B-17 mice. Pancreatic damage was severe in both groups. Even though in situ staining of apoptotic cells was found in all pancreatitis animals, apoptosis was confirmed by DNA laddering only in C.B-17 mice. In SCID mice, apoptotic cell staining positively correlated with necrosis (r = 0.91; p < 0.001). Plasma TAP and PLA2 catalytic activity did not differ significantly between the groups. In conclusion, the absence of T and B lymphocytes prevents severe pulmonary injury resulting from acute pancreatitis but does not influence pancreatic or renal damage. Our results suggest that systemic lymphocyte activation does not affect the initiating events that trigger pancreatic injury but modulates the systemic response, in particular, pulmonary injury caused by acute pancreatitis.

Acute Disease↗

PubMed1999

Gene expression of group II phospholipase A2 in intestine in Crohn's disease.

OBJECTIVE: Phospholipase A2 (PLA2) has been suggested to play an important role in the pathogenesis of inflammatory bowel diseases. Our aim was to identify cells that express group II phospholipase A2 (PLA2-II) at the mRNA and enzyme protein levels in the intestine in Crohn's disease. METHODS: Tissue samples were obtained from the intestine of 20 patients with Crohn's disease (seven operated and 13 colonoscopied) and from eight control patients without inflammatory diseases. The samples were studied by immunohistochemistry for PLA2-II enzyme protein and in situ hybridization for PLA2-II mRNA. RESULTS: PLA2-II protein and mRNA were detected in the Paneth cells of the small intestinal mucosa in all patients and controls. PLA2-II protein and mRNA were found in the columnar epithelial cells of the small intestinal mucosa in six of eight and eight of eight patients with Crohn's ileitis, respectively. In the eight control patients PLA2-II protein and mRNA were not found in these cells (p = 0.007 and p < 0.001, respectively). Metaplastic Paneth cells, which consistently contained PLA2-II mRNA, were found in the colonic mucosa in five of six patients with Crohn's colitis and of one of eight control patients (p = 0.026). The columnar epithelial cells of the colonic mucosa contained PLA2-II protein in three of six and PLA2-II mRNA in six of six patients with Crohn's colitis, whereas the protein was found in these cells in none of eight of the controls (p = 0.055) and the mRNA in only one of eight (p = 0.005) controls. CONCLUSIONS: In Crohn's disease, Paneth cells and columnar epithelial cells of the small and large intestinal mucosa synthesize PLA2-II at the site of active inflammation.

Adolescent↗

PubMed1999

Phospholipases A2 in gastric juice of Helicobacter pylori--positive and negative individuals.

Gastric juice is known to have phospholipase A2 catalytic activity. Helicobacter pylori (H. pylori) has been reported to produce phospholipase A2, which is believed to hydrolyse the protective layer of gastric mucosal phospholipids and to promote mucosal damage. The current study aimed at identifying secretory phospholipase A2 subtypes (pancreatic group I phospholipase A2 and synovial-type group II phospholipase A2) in gastric juice and their relation to the presence of H. pylori in gastric mucosal biopsies in the same individuals. Gastric juice was collected from 29 individuals during gastroscopy. Biopsies were taken from the antrum and body of the stomach to determine the H. pylori status. We found catalytically active phospholipase A2 and both group I and group II phospholipases A2 in the gastric juice samples. The catalytic activity and the mass concentrations of group I and group II phospholipases A2 correlated significantly with the pH value in gastric juice. The gastric juice of H. pylori positive individuals did not contain higher amounts of phospholipases A2 than the juice of H. pylori negative individuals. Rather, the mass concentration of group II phospholipase A2 in gastric juice seemed to be somewhat lower in individuals with H. pylori infection than in uninfected individuals. The results of the current study show that both group I and group II phospholipases A2 are present in gastric juice. The main sources of phospholipases A2 in gastric juice are probably other than H. pylori.

Adult↗

PubMed1998

Group II phospholipase A2 in human male reproductive organs and genital tumors.

BACKGROUND: Group II phospholipase A2 (PLA2) is a lipolytic enzyme suggested to play a role in inflammation and antibacterial defence. In seminal fluid, the concentration of PLA2 is exceedingly high under normal circumstances (about 1,000 times the concentration in blood plasma of healthy humans). To elucidate the origin of the enzyme present in seminal plasma, we investigated the expression of group II PLA2 in male reproductive organs both at protein and mRNA levels. In addition, the presence of the enzyme was studied in common male genital tumors. METHODS: The methods used were immunocytochemistry, in situ hybridization, and Northern blotting. RESULTS: Northern blotting gave positive results for group II PLA2 mRNA in normal prostate, whereas other normal genital tissues gave negative results. Immunohistochemistry and in situ hybridization of group II PLA2 gave identical results. The enzyme was produced exclusively by the secretory epithelial cells of the prostatic gland. Surprisingly, expression was restricted to the posterior lobe and paraurethral glands of the prostate. Cells of prostatic adenocarcinoma expressed group II PLA2, whereas cells of other male genital tumors contained neither the enzyme protein nor the mRNA of group II PLA2. In some cases prostatic cancer cell seemed to express group II PLA2 at a higher rate than normal prostatic gland cells. CONCLUSIONS: The high content of group II PLA2 in seminal plasma is due to the local production and secretion of the enzyme by the epithelial cells of the prostatic glands. Group II PLA2 is expressed focally, suggesting that specialized prostatic glands secrete this enzyme. All prostatic adenocarcinomas tested expressed group II PLA2 in variable amounts.

Epididymis↗

PubMed1998

Experimental study of a novel phospholipase A2 inhibitor in acute pancreatitis.

BACKGROUND: In acute pancreatitis, two different types of secretory phospholipase A2 (PLA2) have been found: pancreatic type I PLA2 and non-pancreatic type II PLA2. In this study a potent new PLA2 inhibitor effective against type II PLA2 was used in an experimental model of acute pancreatitis. METHODS: In 70 rats the efficacy of the compound was analysed in two experimental models of acute pancreatitis: cerulein- and taurocholate-induced acute pancreatitis, imitating mild and severe disease respectively. Serum rat type I PLA2 protein concentration and type I and type II PLA2 catalytic activities were measured while giving the inhibitor therapeutically. In a prophylactic protocol the effect on histology was analysed. RESULTS: In the taurocholate model, type II PLA2 activity was found to be nine-fold higher than in the cerulein model (P < 0.002), whereas the activity of type I PLA2 was not increased. The inhibitor significantly decreased serum type II PLA2 activity in the taurocholate model of acute pancreatitis (P < 0.05) but type I PLA2 protein concentration and type I PLA2 activity were not affected. The inhibitor also reduced histological tissue damage, with significant differences at 3 and 12 h (P < 0.01). CONCLUSION: The PLA2 inhibitor significantly reduced type II PLA2 activity and was able to protect the pancreas against tissue damage. PLA2 inhibition offers the possibility of a treatment for acute pancreatitis.

Acute Disease↗

PubMed1998

Hyperamylasemia after cardiopulmonary bypass: pancreatic cellular injury or impaired renal excretion of amylase?

BACKGROUND: Postoperative hyperamylasemia and even acute pancreatitis are associated with coronary artery bypass grafting (CABG). The mechanism of hyperamylasemia and pancreatic acinar cell damage was studied in 20 patients undergoing CABG. METHODS: Serial blood and urine samples at eight time points before, during, and 24 hours after the CABG were collected. Salivary and pancreatic isoamylases, the fractional clearance of isoamylases (i.e., relative to creatinine clearance), pancreatic phospholipase A2 (a specific serum marker of pancreatic acinar cell injury), and cystatin C (a sensitive marker of glomerular filtration rate) were measured. RESULTS: Mild serum hyperamylasemia (300 to 1000 units/L) was found in 11 of 20 (55%) and severe (> 1000 units/L) in 6 of 20 (30%) patients with no signs of clinical acute pancreatitis. Hyperamylasemia occurred from 6 to 24 hours after the CABG and was mainly caused by pancreatic isoamylase. Serum pancreatic phospholipase A2 concentration remained unchanged, which excludes acinar cell damage. Although renal glomerular filtration was normal during CABG as measured by serum cystatin C and creatinine clearance, the fractional clearance of isoamylases decreased. CONCLUSIONS: The decreased rate of excretion into urine, rather than pancreatic cellular damage, is the major source of hyperamylasemia after CABG.

Amylases↗

PubMed1998

Secretory phospholipase A2 in patients with infected pancreatic necroses in acute pancreatitis.

Secretory synovial-type PLA2 (sPLA2-II) in peripheral blood is known to be associated with systemic complications in patients with severe diseases. Being the pacemaking enzyme in eicosanoid synthesis, sPLA2-II is a mediator of the inflammatory response and plays a role in host defense against bacterial infection. We evaluated the clinical role of systemic sPLA2-II in bacterial infection of pancreatic necroses in severe acute pancreatitis. In 58 patients with acute pancreatitis, pancreatic and sPLA2-I and sPLA2-II were measured daily for the first 14 days of hospital treatment by a time-resolved fluoroimmunoassay. All 36 patients with necrotizing pancreatitis underwent regular fine needle aspiration (FNA) to monitor bacterial infection. In 10 patients, infected necroses were found on FNA and postoperative examination. On admission and at most days throughout the observation period, systemic sPLA2-II was significantly higher in patients with infected necroses than in patients with sterile necroses or interstitial pancreatitis. This difference was not found for sPLA2-I, but values were higher in necrotizing pancreatitis than in interstitial pancreatitis at the first 2 days of hospital treatment. If sPLA2-II was >300 ng/ml on 2 successive days within the first 4 days, infected necroses could be predicted with a sensitivity of 89%, a specificity of 88%, and a negative predictive value of 95%. Systemic sPLA2-II has the potential to identify patients at risk of bacterial infection of pancreatic necroses and its routine measurement may therefore, in combination with FNA, offer a valuable tool in monitoring patients with acute necrotizing pancreatitis.

Acute Disease↗

PubMed1998

Expression of group II phospholipase A2 in Paneth cells of an adenoma of the rectum. A case report.

A case of tubulovillous adenoma in the rectum of a 51-year-old man is presented. The tumour contained numerous Paneth cells which formed well-developed glands in the basal areas. Group II phospholipase A2 and lysozyme were found in the tumour cells by immunohistochemistry. mRNA of group II phospholipase A2 was localized in the tumour cells by in situ hybridization. It was concluded that a considerable part of this rare type of tumour consisted of Paneth cells which were capable of synthesizing group II phospholipase A2.

Adenoma, Villous↗

PubMed1998

Elevated group II phospholipase A2 mass concentration in serum and colonic mucosa in Crohn's disease.

Group II phospholipase A2 has been proposed to play an important role in the pathophysiology of inflammatory bowel diseases. This enzyme has also been linked to host defence mechanisms against bacteria. The current study aimed at measuring the mass concentrations of group II phospholipase A2 in serum and colonic mucosa of patients with Crohn's disease of different severity and of appropriate control patients without any inflammatory disease. The activity of the disease was determined by clinical factors (the simple index score) and endoscopic and histological scoring. The mass concentration of group II phospholipase A2 was measured by a time-resolved fluoroimmunoassay. The mass concentrations of group II phospholipase A2 in serum and colonic mucosa were significantly higher both in patients with active and inactive Crohn's disease when compared with controls. There was statistically significant difference in the mass concentration of group II phospholipase A2 in colonic mucosa but not in serum between inactive and active Crohn's disease. The current results indicate that the mass concentration of group II phospholipase A2 is increased in serum and colonic mucosa of patients with Crohn's disease and that the latter is associated with the degree of the inflammatory activity in the intestinal wall. These results support the idea that group II phospholipase A2 is involved in the local and generalised pathological processes of Crohn's disease.

Adolescent↗