Blockage of T-cell costimulation inhibits T-cell action in celiac disease.

BACKGROUND & AIMS: Celiac disease is an exemplary model of T cell-mediated pathology. Therefore, therapeutic approaches that target T cells may successfully control this disease. CTLA-4 immunoglobulin (CTLA-4Ig) can inhibit T-cell activation by blocking the engagement of CD28. We took advantage of this tool to define the pathogenic role of gliadin-specific T cells in the induction of celiac disease. METHODS: Duodenal biopsy specimens from 7 treated celiac patients were challenged in vitro with gliadin and CTLA-4Ig or CD40-Ig. After 24 hours, the biopsy specimens were analyzed for the presence of characteristic modifications induced by gliadin challenge. RESULTS: CTLA-4Ig down-regulated the expression of CD25, intercellular adhesion molecule 1, interleukin 2, and interferon gamma (stained lamina propria mononuclear cells/mm2; P < 0.05) induced by gliadin challenge, caused apoptosis of gliadin-specific T cells (apoptotic T cells/mm2; P < 0.05), and inhibited the production of antiendomysial antibody (P < 0.01). However, it did not control intraepithelial T-cell migration (P = NS) and Fas expression by enterocytes. Conversely, CD40-Ig only controlled production of antiendomysial antibody. CONCLUSIONS: In an organ culture model, CTLA-4Ig controls many but not all of the immunologic features of celiac disease.

DNA fragmentation is a feature of cystic fibrosis epithelial cells: a disease with inappropriate apoptosis?

Cystic fibrosis (CF) is a single-gene disease caused by mutations in the CFTR gene, which result in disrupted chloride secretions with inspissated mucous secretions by exocrine glands. Nick-end labelling was used to assess DNA fragmentation in 14 CF and 24 control duodenal samples, and in two CF and two control lung tissues. In CF small intestine median 46% (range: 30-82) villus enterocytes show DNA fragmentation (vs. 3% (range: 1-7) in controls P < 0.001) and median 37.5% (range: 23-79) crypt enterocytes show Ki67 antigen (P < 0.001). In CF airways 57% (range: 54-70) of epithelial cells show DNA fragmentation. Inappropriate high DNA fragmentation is a feature of various CF epithelia. This could have great impact in understanding the mechanisms leading to disease.

Gluten-sensitive disease with mild enteropathy.

BACKGROUND & AIMS: Celiac disease is a permanent gluten intolerance strongly associated with HLA class II antigens and possibly showing milder changes of mucosal architecture. Ten patients with symptoms suggesting celiac disease and serum antiendomysium antibodies with normal mucosal architecture were studied. METHODS: Immunohistochemical detection of mucosal immune activation and HLA typings were performed. RESULTS: Mucosal immune activation, with normal mucosal architecture and normal gamma/delta+ intraepithelial lymphocytes counts, was found on a gluten-containing diet. In 3 of 6 patients, multiple biopsy specimens showed one sample with severe villous atrophy. Clinical and immunomorphologic features were strictly gluten dependent. The mucosal immune activation was elicited in vitro by gliadin. Only 4 patients had the typical HLA typing of celiac disease. CONCLUSIONS: Gluten-sensitive celiac-like symptoms may occur in patients with serum antiendomysium antibodies, apparently normal intestinal mucosa, and HLA typing not commonly associated with celiac disease. These patients should undergo multiple biopsies, and signs of immunologic activation should be sought accurately; in the presence of mucosal immune activation, a trial with a gluten-free diet should be encouraged to detect gluten dependency. In vitro immunologic response of small intestinal mucosa to gliadin may support the diagnosis of gluten-sensitive enteropathy.

Definition of the initial immunologic modifications upon in vitro gliadin challenge in the small intestine of celiac patients.

BACKGROUND & AIMS: Mucosal cell-mediated immune response is considered the central event in the pathogenesis of celiac disease. In cultured intestinal explants from celiacs in remission, we have characterized the early stages of gliadin-induced immune activation. METHODS: Intestinal biopsy specimens (15 treated celiacs and 13 controls) were cultured with gliadin or maize prolamine digests for 24 hours as well as for 1, 2, 4, 6, 8, and 12 hours in some subjects. The expression of immunologic markers was detected by immunocytochemistry. RESULTS: Gliadin challenge may initiate two parallel pathways, one of which leads to T-cell activation and another that precedes it. Epithelial cells overexpress DR molecules after 1 hour, and in a second stage T lymphocytes become fully activated. Moreover, T lymphocytes migrate in the upper mucosal layers. T lymphocytes that migrate in the higher lamina propria compartments are mainly CD4+ and show markers of activation; migrating intraepithelial lymphocytes are CD8+ and do not express these markers. CONCLUSIONS: In vitro gliadin challenge is a suitable model to reproduce various immunologic features of celiac lesions; these may be caused by different pathways. The comprehension of these phenomena is essential to clarify the distinctive pathogenic mechanisms leading to disease and may help in defining novel therapeutic approaches.

In vitro activities of A-gliadin-related synthetic peptides: damaging effect on the atrophic coeliac mucosa and activation of mucosal immune response in the treated coeliac mucosa.

BACKGROUND: Gliadin amino acid sequence(s) responsible for toxicity in susceptible individuals have not been fully elucidated. Previous in vitro studies have suggested the presence of active sequences in the NH(2)-terminal part of the A-gliadin molecule. In this paper the in vitro activity of A-gliadin synthetic peptides 31-55, 31-43, and 44-55 has been investigated. METHODS: Organ culture of jejunal mucosa from untreated and treated coeliac patients was used. In the first system enterocyte height was used as a measure of peptide toxicity; in the second system evidence of activated mucosal cell-mediated immune response was sought. RESULTS: Peptides 31-55 and 31-43 were active on untreated coeliac mucosa at a concentration of 0.5 mg/ml and peptide 44-55 only at a concentration of 3 mg/ml. In in vitro-cultured treated coeliac mucosa peptides 31-55 and 31-43 at 1 mg/ml and peptide 44-55 at 3 mg/ml were able to induce enhanced epithelial expression of HLA-DR and 4F2 molecules and the appearance of CD25 positive cells. CONCLUSIONS: Our results suggest that 31-43 and 44-55 A-gliadin peptides are both active, even if to different extents. In vitro systems remain essential tools to screen material to be subsequently tested in vivo.

[The natural history of allergy to eggs in atopic dermatitis]. / La storia naturale dell'allergia all'uovo nella dermatite atopica.

The outcome of atopic dermatitis and the incidence [correction of prevalence] of asthma was ascertained in a four-year follow-up in 47 children with eczema due to egg allergy. At the end of the study, skin lesions had cleared in 32 (68%) children. Of these, 18 (38.2%) developed tolerance to egg about two years after diagnosis, while 14 (29.7%) continued an elimination diet. Fifteen children (31.9%) are still affected by eczema due to discontinuation of the egg-free diet. At the end of follow-up, 23 children had presented at least three asthma episodes. Therefore, the incidence [correction of prevalence] of asthma in children with atopic dermatitis appears to be significantly higher when egg allergy is present. Egg allergy could be a marker of an atopic condition and therefore be an unfavourable prognostic signal as to the outcome of the disease and the appearance of respiratory allergy.

Morphological method for the diagnosis of human adult type hypolactasia.

The primary adult type hypolactasia is the most common form of genetically determined disaccharidase deficiency. This study examined a large and homogeneous population of the south of Italy: surgical biopsy specimens of proximal jejunum from 178 adult subjects have been assayed for disaccharidase activities; the expression of lactase protein and lactase activity has also been investigated on tissue sections by immunomorphological and enzymohistochemical techniques. Histograms of lactase to sucrase ratio were found to provide a useful distribution of the lactase activity; a lactase to sucrase ratio of 0.17 was found to show discrimination between tissues with persistence of high lactase activity and tissues with adult type hypolactasia. In all 28 subjects with persistent high lactase activity, a uniform distribution of lactase protein and lactase activity in all villus enterocytes was detected, whereas in all 150 subjects with adult type hypolactasia a variable number of villus enterocytes failed to express the lactase. Moreover in hypolactasic samples the lactase activity on tissue sections was constantly detected later than in samples with persistent high lactase activity. The absolute correlation between the immunohistochemical and enzymohistochemical features and the assessment of lactase activity in intestinal homogenates suggests that the morphological criteria are an alternative method for the diagnosis of adult type hypolactasia in human biopsy specimens from proximal small jejunum.

[The prevention of allergic diseases with a hypoallergenic formula: a follow-up at 24 months. The preliminary results]. / La prevenzione delle malattie allergiche con formula H.A.: follow-up a 24 mesi. Primi risultati.

One hundred-eight infants from atopic families were admitted to the study. Each had at least one first-degree relative affected by asthma or rhinitis, conjunctivitis, eczema, cow's milk protein intolerance. All infants not breast fed were hypoallergenic formula. 46 infants were breast fed, 39 were bottle fed by the ordinary formula and 23 received the hypoallergenic one. No other food was introduced up to 6 months. Cow's milk proteins, egg, poultry and fish were introduced after 6 months. All infants were followed up to 24 months. Incidence of allergic diseases up to 24 months was not significantly different among the 3 groups.

[Erythrohemophagocytic lymphohistiocytosis. A clinical report of 3 cases]. / Linfoistiocitosi eritroematofagica. Contributo clinico di 3 casi.

Three infants suffering from hepatosplenomegaly, pancytopenia, hyperlipidemia, low fibrinogen levels and fever are reported. Two patients died during the first year of life, the third one received allogenic bone transplantation and survives. Clinical and haematological features are consistent with diagnosis of hemophagocytic lymphohistiocytosis.

[Atrial natriuretic factor in normal newborn infants and its effects on kidney function in anoxic syndrome and respiratory distress]. / Studio sul comportamento del fattore atriale natriuretico nei neonati normali e suoi effetti sulla funzionalità renale in corso di sindrome anossica e di distress respiratorio.

The Authors have studied 26 newborns suffering from anossic syndrome and/or respiratory distress. In them are valued as well as the renal function, also the behaviour of atrial natriuretic factor (F.A.N.). As a group of control 25 healthy and to term newborns were studied. In all subjects studied, but more specifically in the anossic, it became evident a net increase of F.A.N., which however was within the normal ranges about the 15th year of life. The Authors conclude that in normal newborn this behaviour of F.A.N. reflects the important circulation modification which is certified after birth, whereas in pathological newborns, in whom 69% of cases a functional renal failure is present, the increase of F.A.N. is not without significance in the shortening of time of re-establishment of renal function.

Familial erythrophagocytic lymphohistiocytosis: adverse prognostic significance of delayed diagnosis.

Familial erythrophagocytic lymphohistiocytosis (FEL) is a rare disorder of the monocyte-macrophage system, for which an autosomal recessive mode of inheritance has been postulated. It is characterized by a dismal prognosis and is peculiar of early infancy. Three new cases of infants affected by FEL are reported. All three patients were diagnosed about three months after the onset of symptoms, and all three died shortly after diagnosis. The need for early diagnosis and prompt, intensive cytotoxic chemotherapy is emphasized.

[Elevated atrial natriuretic peptide (ANP) levels and normotension in Bartter's syndrome in childhood]. / Elevati livelli di peptide atriale natriuretico (ANP) e normotensione nella sindrome di Bartter dell'infanzia.

The authors describe a case of Bartter's syndrome, a variety of disease in the newborn, and they point out the most specific of the disease symptoms, that is the normal PA in presence of elevated plasma renin activity. So it was necessary to determine the ANP, the values of which, controlled for a period of 18 months, appeared above the normal ones. The authors conclude that this date would better explain the apparently contradictory date of the normotension.

[Juvenile xanthogranuloma. Description of a case with liver involvement]. / Xantogranuloma giovanile. Descrizione di un caso con interessamento epatico.

Juvenile Xanthogranuloma. Report of a case with hepatic involvement. The Authors present a case of Juvenile Xanthogranuloma (JX) in a 3 months female child with cutaneous and hepatic nodules associated to dyspnea attributable to obstructive bronchopneumopathy. Histologically the lesions are xanthomatous with proliferation of fat-laden histiocytes. The hepatic involvement is characterized by hepatomegaly and yellow nodules on liver surface as seen at laparoscopy. On liver biopsy there is remarkable expansion of portal triad caused by aggregates of large foamy mono-polynuclear histiocytes with Touton giant cells. The cutaneous nodule biopsy shows histiocytic infiltrate in inter-adnexal dermal space with many giant cells holding great lipidic vacuoles. The patient's follow-up is characterized by slow and progressive clinical improvement with resolution of cutaneous, hepatic and pulmonary pathology. The Authors emphasize the differential diagnosis between this systemic form of JX and Langerhans cell Histiocytosis (Histiocytosis X) with multiorgan involvement. This diagnosis is necessary in order to establish therapy and prognosis.

Antigliadin antibody, D-xylose, and cellobiose/mannitol permeability tests as indicators of mucosal damage in children with coeliac disease.

A dual sugar (cellobiose/mannitol) permeability test using an iso-osmolar solution was performed, to compare its ability to predict small-bowel mucosal damage in children affected by coeliac disease with the determination of serum levels of D-xylose and antigliadin antibody. Eighty-three children (67 on gluten-containing diet and 16 on gluten-free diet) were investigated. The D-xylose and the serum antigliadin antibody test predicted accurately 70% and 78% of the small-bowel biopsy results, respectively, whereas the cellobiose-mannitol permeability test predicted 93%. These data confirm the superiority of the permeability test over the D-xylose test, although the former cannot be advocated as a substitute for jejunal biopsy. Our results suggest a complementary use of the permeability test and the antigliadin antibody measurement as screening tests for coeliac disease before applying more invasive procedures.

[Endoscopic surgery of the digestive system: state of the art. Opinion of an endoscopic surgeon]. / Chirurgia endoscopica dell'apparato digerente: stato dell'arte. L'opinione di un endoscopista chirurgo.

The Authors review the possible applications of surgical endoscopy in oesophageal, gastric, biliary, pancreatic and colic diseases. This critical assessment, performed under the abdominal endoscopic surgeon's point of view, is based on the overall experience of about 20 years of surgery, with particular regard to the sclerosis of oesophageal varices, neoplastic obstructions of oesophagus, biliary tract, colon and localized Laser treatment of neoplasms. Based on the results achieved, thanks to selective indications and monitoring by conventional surgical experience, the Authors conclude by staging a better reliability of the surgeon who performs surgical endoscopy to obtain good results after an accurate selection of those cases which can really benefit from endoscopic management.

[Prevention of acute hypertensive encephalopathy in the course of acute post-streptococcal glomerulonephritis in children: considerations in 31 cases]. / La prevenzione dell'encefalopatia acuta ipertensiva in corso di glomerulonefrite acuta post streptococcica (GNAPS) nel bambino: considerazioni su 31 casi.

The authors analysed 31 cases of an acute hypertensive glomerulonephritis. The antihypertensive efficacy of two medicines: a vasodilator (dihidralazine) and a diuretic (Furosemide) was underlibed an these patients. Their efficacy was evident not only in the stabilization of P.A. around normal values on three days, but also on the disappearance of signs of on hypertensive encephalopathy whereas these ones were present.

[Does the therapy with indomethacin interfere with growth in Bartter's syndrome in childhood?]. / La terapia con indometacina interferisce con l'accrescimento nella sindrome di Bartter dell'infanzia?

The authors describe a new-born form of Bartter's syndrome treated for about 6 years with Indomethacin in a quantity of 2 mg/Kg/die except short periods, during which it was given triamterene in a quantity of 2 mg/Kg/die. While with the first medicine the growth of height has had an average increase of about 9 cm a year, with the second one there hasn't been any result neither on growth nor on the rest of symptomatology. The A.A. on the base of recent experimental data think that the deficiency of height could be due to a scanty affinity of peripherical receptors and SmC, that could be removed from the provision of Indomethacin.

[Endoscopic sclerotherapy of esophageal varices]. / La sclerosi endoscopica delle varici esofagee.

Magnetic tape recordings of endoscopic images relating to pathologies with it is extremely important to follow morphological changes after treatment offer unquestionable advantages especially in the field of sclerosing endoscopic therapy for esophageal varices. This study--which was carried out using a 3/4 inch U-Matic videotape lasting 10 minutes--confirm the above statement. The criteria of selection for sclerosing techniques are illustrated according to the authors' personal evaluations made on the basis of experience accumulated during more than 10 years' activity; the results of modulated treatment are compared as both emergency and elective treatment, used as the single therapy or following deconnection or portosystemic derivation operations. The choices are confirmed by the number of successful outcomes, with only minimal and almost always easily controlled complications. This has led to the method's inclusion in clinical practice as yet another means of controlling hemorrhages due to portal hypertension, in addition to permitting a marked increase in the percentage of success following deconnecting and derivative operations performed in patients in better conditions of clinical compensation.