Cholestatic liver disease in children.

Inherited syndromes of intrahepatic cholestasis and biliary atresia are the most common causes of chronic liver disease and the prime indication for liver transplantation in children. Our understanding of the pathogenesis of these diseases has increased substantially by the discovery of genetic mutations in children with intrahepatic cholestasis and the findings that inflammatory circuits are operative at the time of diagnosis of biliary atresia. Building on this solid foundation, recent studies provide new insight into genotype-phenotype relationships and how mutations produce altered bile composition and cholestasis. New evidence exists that although liver transplantation is curative for patients with end-stage liver disease owing to cholestasis, some patients may develop recurrence of cholestasis because of the emergence of autoantibodies that disrupt canalicular function in the new graft. Progress is also evident in biliary atresia, with recent studies identifying candidate modifier genes and directly implicating lymphocytes and inflammatory signals in the pathogenesis of bile duct injury and obstruction.

Loss of proteolytically processed filaggrin caused by epidermal deletion of Matriptase/MT-SP1.

Profilaggrin is a large epidermal polyprotein that is proteolytically processed during keratinocyte differentiation to release multiple filaggrin monomer units as well as a calcium-binding regulatory NH2-terminal filaggrin S-100 protein. We show that epidermal deficiency of the transmembrane serine protease Matriptase/MT-SP1 perturbs lipid matrix formation, cornified envelope morphogenesis, and stratum corneum desquamation. Surprisingly, proteomic analysis of Matriptase/MT-SP1-deficient epidermis revealed the selective loss of both proteolytically processed filaggrin monomer units and the NH2-terminal filaggrin S-100 regulatory protein. This was associated with a profound accumulation of profilaggrin and aberrant profilaggrin-processing products in the stratum corneum. The data identify keratinocyte Matriptase/MT-SP1 as an essential component of the profilaggrin-processing pathway and a key regulator of terminal epidermal differentiation.

Matriptase/MT-SP1 is required for postnatal survival, epidermal barrier function, hair follicle development, and thymic homeostasis.

Matriptase/MT-SP1 is a novel tumor-associated type II transmembrane serine protease that is highly expressed in the epidermis, thymic stroma, and other epithelia. A null mutation was introduced into the Matriptase/MT-SP1 gene of mice to determine the role of Matriptase/MT-SP1 in epidermal development and neoplasia. Matriptase/MT-SP1-deficient mice developed to term but uniformly died within 48 h of birth. All epidermal surfaces of newborn mice were grossly abnormal with a dry, red, shiny, and wrinkled appearance. Matriptase/MT-SP1-deficiency caused striking malformations of the stratum corneum, characterized by dysmorphic and pleomorphic corneocytes and the absence of vesicular bodies in transitional layer cells. This aberrant skin development seriously compromised both inward and outward epidermal barrier function, leading to the rapid and fatal dehydration of Matriptase/MT-SP1-deficient pups. Loss of Matriptase/MT-SP1 also seriously affected hair follicle development resulting in generalized follicular hypoplasia, absence of erupted vibrissae, lack of vibrissal hair canal formation, ingrown vibrissae, and wholesale abortion of vibrissal follicles. Furthermore, Matriptase/MT-SP1-deficiency resulted in dramatically increased thymocyte apoptosis, and depletion of thymocytes. This study demonstrates that Matriptase/MT-SP1 has pleiotropic functions in the development of the epidermis, hair follicles, and cellular immune system.

Shwachman-Diamond syndrome in a Mexican family.

Shwachman-Diamond Syndrome (SDS) is an inherited condition with multisystemic abnormalities including pancreatic exocrine dysfunction, neutropenia, short stature, and skeletal abnormalities. In this report, we describe the case of a 14-year-old female with a history of neutropenia, pancreatic exocrine insufficiency and pancreatic endocrine sufficiency, pancreatic lipomatosis (10), and the development of myeloid leukemia. Postmortem examination revealed a high probability of SDS. We also describe the clinical findings in the patient's six siblings, suggesting this as a familial form of SDS. Because the gene(s) responsible for this syndrome have not yet been identified, genetic confirmation is not yet possible. This is the first report in the literature of a Mexican family with probable SDS.

Familial pancreatic enzyme insufficiency.

A father and son with profound reduction of exocrine pancreatic activity and little visible pancreatic tissue on ultrasound or computed tomography are described. Both have some degree of liver disease, which is more marked in the son. The disorder, apparently familial, does not correspond to any reported previously.

Correlation of haemagglutination activity with trypsin-like protease activity of Porphyromonas gingivalis.

Porphyromonas gingivalis is a Gram-negative anaerobic bacterium associated with various forms of periodontal disease. Several characteristics of P. gingivalis are thought to contribute to its pathogenicity; these include haemagglutination and trypsin-like protease activity. Previous studies suggest an association between haemagglutination and trypsin-like protease activity of P. gingivalis. To investigate this, two complementary quantitative experimental approaches were taken. Five independent mutants of P. gingivalis deficient in trypsin-like protease activity were shown to exhibit reduced haemagglutination activity. In addition, enhancers (cysteine and dithiothreitol) and inhibitors (N-ethylmaleimide, N-p-tosyl-L-lysine-chloromethyl ketone, and phenylmethylsulphonyl fluoride) of trypsin-like protease activity were shown, respectively, to significantly enhance and inhibit haemagglutination activity of washed, wild-type P. gingivalis cells (p less than 0.05, paired t-test). Statistical analysis indicated a strong correlation between haemagglutination and trypsin-like protease activity (r = 0.85, p less than 0.001, Spearman rank correlation). The effect of the protease enhancers and inhibitors on haemagglutination activity was specific for P. gingivalis, as they did not significantly change the haemagglutination activity of Fusobacterium nucleatum. These results suggest that the proteolytic site of the trypsin-like protease participates in haemagglutination activity of P. gingivalis.

[Trypsin and alpha-amylase activity in the pancreas of guinea pigs. V. Effects of administration of vitamin A and B 2 during the larval stage of ascariasis]. / Aktywnosc trypsyny i alfa-amylazy w trzustce swinek morskich. V. Wplyw podawania witamin A i B2 w czasie askarydozy larwalnej.

The infection of guinea pigs with Ascaris suum larvae resulted in decrease of the activities of trypsin and alpha-amylase, and in increase of lipase activity in extracts from their pancreas. The activity of alpha-amylase, lipase and the relative weight of lungs of infected animals which were given vitamin A, did not differ from control animals. The activity of trypsin from pancreas these animals was higher than that measured in only infected guinea pigs but it was lower than in control animals. Application of vitamin B2 and the infection of guinea pigs with A. suum did not lead to the synonymous results.

[Substantiation of the use of pepsidil in secretory insufficiency of the digestive glands caused by antitubercular drugs]. / Obosnovanie ispol'zovaniia pepsidila pri sekretornoi nedostatochnosti pishchevaritel'nykh zhelez, vyzvannoi protivotuberkuleznymi preparatami.

The experiments on rats were undertaken to study the action of pepsidil to make up for the biosynthesis deficiency of digestive enzymes in the stomach and pancreas caused by antituberculous drugs (methazide + PAS, isoniazid + PAS, isoniazid + rifampicin + ethambutol). It was proved that pepsidil reduced an inhibiting action of antituberculous drugs on the activity of gastroenteric tract proteinases. The given condition should be taken into account when antituberculous treatment is conducted.

[Malabsorption and developmental retardation due to secondary trypsin deficiency].

A 1.5-year-old girl was admitted with chronic diarrhea of 10 months duration and retarded physical and psychomotor development. Duodenal tryptic activity was absent on testing with secretin and cholecystokinin. With pancreatic enzyme replacement diarrhea ceased and growth recommenced. Duodenal tryptic activity returned to normal within 6 months. A 10-year follow-up revealed normal physical and mental growth. Secondary deficiency of trypsin is a rare cause of malabsorption in childhood; correct and timely treatment can avoid severe, irreversible developmental defects.

Trophic effects on the pancreas of trypsin and bile salt deficiency in the small-intestinal lumen.

The effect of trypsin inhibitor-containing diets was studied in rats, mice, and hamsters for 30 weeks. In rats, pancreatic weight, DNA, RNA, and protein increased in response to a diet of raw soya flour (containing trypsin inhibitor). In mice, pancreatic weight, DNA, RNA and protein content increased with the same diet. Only rats developed micro- and macro-nodules. In rats, longer treatment with raw soya flour resulted in further growth in the pancreas, with ultimate development of adenomas and carcinomas of the acinar pancreas. The pancreatic changes were reversible up to 6 months of feeding the raw soya diet, but thereafter became irreversible. Pancreatic growth, similar to that produced by trypsin inhibitor, was also produced by cholestyramine, perhaps as a result of its bile salt-binding properties. We conclude that removal of proteases and bile salts from the upper small intestine results in pancreatic growth, which may become neoplastic.

[Trypsin deficiency in diabetes mellitus of children and adolescents (author's transl)]. / Trypsinmangel bei Diabetes mellitus im Kindes- und Jugendlichen Alter.

In 111 children and juveniles aged 7--27 years suffering from insulin-dependent diabetes mellitus the immunoreactive plasma human pancreatic trypsin was measured by means of the method RIAGnost-Trypsin-test, Behring. Decreased plasma trypsin was measured at the onset of diabetes already. In patients with diabetes with a period of 8--13 years the trypsin values were found to be significantly lower (79.6 +/- 35.3 ng/ml) than in these suffering from diabetes 0--3 years (100,4 +/- 36.9 ng/ml). None of all these patients had clinical pancreatic disease. Abnormalities in exocrine pancreatic function occur in patients with insulin-dependent diabetes mellitus, which is not confined to pancreatic islets only. Until today clinical consequences not can be drawn.

Hypotrypsinaemia in diabetes mellitus.

Plasma trypsin concentrations were measured in 403 fasting diabetics and 106 healthy controls. Basal trypsin concentrations in the normal subjects were 88 +/- 6 ng/ml (mean +/- S.E.M.). Mean plasma trypsin concentrations in diabetics treated with diet alone (n = 74) were 45 +/- 2 ng/ml, while in a group of young (less than 35 years, n = 88) insulin-dependent diabetics, they were very low at 29 +/- 2 ng/ml and these levels were inversely related to insulin dosage. The findings may help in the understanding of the pathophysiological changes in the exocrine pancreas in the diabetic state and may also shed some light on the physiological interrelationship between the endocrine and exocrine pancreas.

[Determination of the ribonuclease activity of the duodenal contents of children as a test in the differential diagnosis of cystic fibrosis and pancreatic exocrine insufficiency]. / Oznaczanie aktywnosci rybonukleazy w tresci dwunastniczej u dzieci jako test róznicujacy cystic fibrosis od niewydolnosci zewna trzwydzielniczej trzustki.

Ribonuclease activity was determined in the duodenal contents of healthy children, in children with cystic fibrosis and with pancreatic exocrine insufficiency. Assays were made at 7.0, in 0.05 M buffer without and with 0.35 M NaCl. The ratio of activity in 0.35 M NaCl to that in buffer alone was found to be 2.4 +/- 1.3 for children with cystic fibrosis as compared with 12 +/- 5 for the control group and children with pancreatic exocrine insufficiency.

Enterokinase and trypsin activities in pancreatic insufficiency and diseases of the small intestine.

The interrelationship of enterokinase and trypsin activities were investigated in 133 infants and children with a variety of gastrointestinal and pancreatic disorders. Fourteen patients with diarrhea and grade II mucosal injury revealed a significant (P less than 0.01) reduction of enterokinase, trypsin, and disaccharidase activites as compared to 59 children with normal mucosa. Nine patients with cystic fibrosis and pancreatic insufficiency had normal mucosal enterokinase activity and elevated intraluminal enterokinase activity with very low or no trypsin activity. Patients with hypoproteinemia and gastrointestinal protein loss, associated with intestinal lymphangiectasia (4 patients) and intestinal lymphoid nodular hyperplasia (3 patients), had normal or insignificant decrease of enterokinase and trypsin activities. In patients with steatorrhea, a normal sweat test, normal intestinal mucosa, and absent trypsin activity, two entities were defined. One group (3 patients) was diagnosed as Schwachman-Diamond syndrome with pancreatic insufficiency and normal mucosal and intraluminal enterokinase activity. The second group (2 patients) with absent mucosal and intraluminal enterokinase activity and normal lipase and amylase activities was diagnosed as congenital enterokinase deficiency.