Teduglutide in pediatric intestinal failure: A position statement of the Italian society of pediatric gastroenterology, hepatology and nutrition (SIGENP).

In recent years, the spectrum of possible treatments for Intestinal Failure (IF)-Short Bowel Syndrome (SBS) has been enriched by the implementation of GLP-2 analogues. In Italy, teduglutide (Ted), an analogue of GLP-2, was approved in January 2021 by the Italian Regulatory Agency for Drugs (AIFA) for IF-SBS patients ≥1 year old. According to the Agency indications, Ted can now be prescribed by regional reference centers, with costs fully charged to the National Health Service. Following pediatric-use approval in our country and in light of scarce evidence in childhood, the pediatric network for IF of the Italian Society for Pediatric Gastroenterology, Hepatology and Nutrition (SIGENP) planned to share management methods of Ted in pediatric IF. The main purpose was to identify the best candidates from a cost-effective perspective. Thus, focusing on available literature and on expert opinions, the present position statement provides consensus-based recommendations on the use of Ted for pediatric gastroenterologists and nutritionists treating children with SBS.

Rank-based biomarker index to assess cadmium ecotoxicity on the earthworm Eisenia andrei.

A proper soil risk assessment needs to estimate the processes that affect the fate and the behaviour of a contaminant, which are influenced by soil biotic and abiotic components. For this reason, the measurement of biomarkers in soil bioindicator organisms, such as earthworms, has recently received increasing attention. In this study, the earthworm Eisenia andrei was used to assess the pollutant-induced stress syndrome after exposure to sublethal concentrations of Cd (10 or 100 µg g(-1)) in OECD soil, after 14 d of exposure. Cadmium bioaccumulation and potential biomarkers such as catalase (CAT), hydrogen peroxide (H2O2), glutathione-S-transferase (GST), malondialdehyde (MDA), phenoloxidase (PO), metallothioneins (MTs) and genotoxic damage were determined. Results suggested that the exposure to 10 and 100 µg g(-1) Cd significantly increased Cd bioaccumulation, MTs and MDA; 100 µg g(-1) Cd contamination evidenced significantly higher values of H2O2 content and PO activity; CAT activity was inhibited at the higher concentration while GST and Comet assay did not show any significant differences from the control. Rank-based biomarker index showed that both different contaminated soils had an effect on the earthworms and allowed to validate the ecotoxicological relevance of this battery of biomarkers for a promising integrated multi-marker approach in soil monitoring and assessment.

Understanding the role of haptoglobin in psoriasis: effects of ultraviolet B.

BACKGROUND: Haptoglobin (Hp) is one of the acute phase proteins, whose main function is to bind free haemoglobin (Hb) and transport it to the liver for degradation and iron recycling. In addition to its role as an Hb scavenger, Hp has been shown to behave as an anti-inflammatory, antioxidant and angiogenic factor. We previously investigated the role of Hp in the pathogenesis of psoriasis, and found that it displays some structural modifications that might be associated with protein function in the disease. Phototherapy is an efficacious treatment for psoriasis, although the biological mechanisms by which phototherapy improves psoriasis are still unclear. AIM: To investigate the effects of ultraviolet (UV)B on Hp to clarify the role of Hp in psoriasis. METHODS: Expression of the genes encoding Hp, interleukin (IL)-6 and IL-10 was assessed in UVB-irradiated and unirradiated HaCaT cells. The biological significance of Hp modulation of UVB treatment was confirmed by ELISA and Western blotting. The Hp gene and protein expression in the skin of patients with psoriasis was also investigated. RESULTS: In vitro results showed that UVB modulated IL-6 and IL-10 gene expression and Hp gene and protein expression in HaCaT cells. The in vivo data also showed that Hp levels were increased in the skin of patients with psoriasis compared with healthy controls. CONCLUSIONS: UVB irradiation was able to modulate Hp production in immortalized keratinocytes. The higher levels of Hp in vivo in both lesional and nonlesional skin suggest that it might have a role in the pathogenesis of the disease.

Ultrasound scanning in infants with biliary atresia: the different implications of biliary tract features and liver echostructure.

OBJECTIVE: To evaluate ultrasonographic features of the liver and biliary tree, including the presence of the triangular cord, in infants with biliary atresia and to analyze the correspondence between hepatic echostructure and histological aspects of the liver. MATERIALS AND METHODS: 35 consecutive infants (19 males) with documented diagnosis of biliary atresia were included. Ultrasonography evaluation, performed at a mean age of 63.1 ± 34.9 days, was focused on the extrahepatic bile ducts, characteristics of the gallbladder and liver, and the presence of the triangular cord. Liver biopsies were examined with particular regard to the presence and severity of fibrosis. RESULTS: On ultrasound, the gallbladder was not seen in 11 (31 %) cases, while in the remaining 24 patients the gallbladder was regular in 6 patients and irregular in 18 cases. The triangular cord was identified in 9 (26 %) of 35 patients. In 21 patients the liver echostructure appeared normal, while in 14 infants the liver parenchyma was more echogenic and coarse than normal. Liver biopsy showed signs of cirrhosis or fibrosis in all cases, including patients with a normal hepatic echostructure. CONCLUSION: Although the triangular cord was visualized in one-fourth of the infants with biliary atresia, abnormalities of the gallbladder on ultrasound (absence or abnormalities of length/shape) were detected in 83 % of the patients. Therefore, ultrasound evaluation of the liver and biliary tree plays an important role in suspecting biliary atresia. On the other hand, a low correspondence between liver echostructure aspects and the presence and severity of fibrosis at liver biopsy was identified. Therefore, severe liver disease in infants with biliary atresia cannot be excluded only on the basis of ultrasound findings.

Novel missense mutations and unexpected multiple changes of RYR1 gene in 75 malignant hyperthermia families.

Malignant hyperthermia (MH) is an autosomal dominant pharmacogenetic disorder of skeletal muscle characterized by disturbance of intracellular calcium homeostasis in the sarcoplasmic reticulum. Mutations of the ryanodine receptor 1 (RYR1) gene account for most cases, with some studies claiming up to 86% of mutations in this locus. However, RYR1 gene is large and variants are common even in the normal population. We examined 54 families with MH susceptibility and 21 diagnosed with equivocal MH. Thirty-five were selected for an anesthetic reaction, whereas the remainder for hyperCKemia. In these, we studied all 106 exons of the RYR1 gene. When no mutation was found, we also screened: sodium channel voltage-gated, type IV alpha subunit (SCN4A), calcium channel voltage-dependent, L type, alpha 1S subunit (CACNA1S), and L-type voltage-gated calcium channel alpha 2/delta-subunit (CACNL2A). Twenty-nine different RYR1 mutations were discovered in 40 families. Three other MH genes were tested in negative cases. Fourteen RYR1 amino acid changes were novel, of which 12 were located outside the mutational 'hot spots'. In two families, the known mutation p.R3903Q was also observed in malignant hyperthermia-nonsusceptible (MHN) individuals. Unexpectedly, four changes were also found in the same family and two in another. Our study confirms that MH is genetically heterogeneous and that a consistent number of cases are not due to RYR1 mutations. The discordance between in vitro contracture test status and the presence of a proven causative RYR1 mutation suggests that the penetrance may vary due to as yet unknown factors.

Is resistin a link between highly active antiretroviral therapy and fat redistribution in HIV-infected children?

OBJECTIVES: To assess the features of fat redistribution, detected by clinical and ultrasound (US) methods, and the presence of metabolic disorders in HIV-infected children undergoing antiretroviral therapy. To evaluate if serum levels of resistin, a hormone produced only by visceral adipose tissue, are a marker of fat redistribution in these patients. DESIGN AND METHODS: Forty-five consecutive symptomatic HIV-infected children were considered for inclusion in the study. Patients were enrolled if treated for at least 6 months with antiretroviral therapy with or without protease inhibitor (PI) and if compliant to the study protocol. Patients were evaluated for: anthropometric measures, fat redistribution by clinical and US methods, serum lipids, parameters of insulin resistance by homeostasis model assessment for insulin resistance, serum resistin levels by an enzyme-linked immunosorbent assay. RESULTS: Eighteen children fulfilled the inclusion criteria and were enrolled in the study. Twelve (66%) children had clinical and/or US evidence of fat redistribution; 9 (75%) of them were on PI therapy; only 3 of 6 children without fat redistribution were on PI therapy (p<0.05). Serum lipids and insulin resistance parameters did not differ between children with or without fat redistribution. There was a highly significant linear correlation between visceral fat detected by US and circulating resistin levels (r=0.87; p<0.0001). CONCLUSIONS: Fat redistribution occurred in most HIV-infected children undergoing PI therapy. Because serum resistin levels reflect the amount of visceral fat, they could be considered a sensitive marker of fat redistribution in HIV-infected children.

Adrenocortical tumor in a boy: final height is not impaired despite a severe advancement of bone age.

The long-term sequelae on the growth pattern in successfully resected virilizing adrenal tumors (ACT) have not been clearly defined. We report on 10 years follow-up of a boy with virilizing ACT until the attainment of final height. This is the first clinical description in a boy with a marked advancement of bone age, indicating that despite advanced physical and skeletal maturity the prognosis on growth is good, provided that regression of virilization is obtained.

The accumulation of alpha-Tocopherol and Retinol in the milk of water buffalo is correlated with the plasma levels of triiodothyronine.

Milk is the most important source of Retinol and alpha-Tocopherol for calves. These antioxidants save the food quality and prevent lipid oxidation in the mammary gland and the calf growing tissues. In Bubalus bubalis, seasonal changes for the plasma levels of both antioxidants were not found. The levels of Retinol and alpha-Tocopherol in the milk were 2 and 1.7 times higher in winter than in summer, respectively. These levels were correlated with the plasma level of triiodothyronine, and markedly increased in cows injected with triiodothyronine in summer. The cytosol from alveolar epithelial cells of mammary glands was incubated with alpha-Tocopherol and 3H-Retinol and, after gel filtration chromatography, both antioxidants were found associated with proteins migrating as a single peak of 33 kD. The amount of alpha-Tocopherol and Retinol binding proteins was 1.5 and 2.3 times higher in winter than in summer respectively. The Retinol binding proteins migrated as two bands (33 and 16 kD) by electrophoresis in denaturing and reducing conditions. Our data suggest that triiodothyronine enhances the transport of both liposoluble antioxidants through the blood-mammary barrier, and demonstrate that proteins of the mammary epithelial cells are involved in such a transport.

Lecithin-cholesterol acyltransferase activity during maturation of human preovulatory follicles with different concentrations of ascorbate, alpha-tocopherol and nitrotyrosine.

The enzyme lecithin-cholesterol acyltransferase (LCAT) transfers an acyl chain from lecithin to cholesterol or oestradiol, thus playing a crucial role in reverse cholesterol transport and follicular synthesis of potent long-lived oestrogens. The mechanism of catalysis is biphasic, as it is based on a phospholipase and an esterifying activity. Sulfhydryl groups were previously reported to be required for the esterification step. Lecithin-cholesterol acyltransferase has previously been shown to be inhibited by thiol oxidants such as peroxynitrite. Peroxynitrite also converts tyrosine to nitrotyrosines. In the present study, high levels of nitrotyrosine associated with low LCAT activity, and vice versa, were found in human preovulatory follicular fluids. Follicular fluids were also analysed for oestradiol (E) and progesterone (P) concentrations. The E/P ratio, which decreases as ovulation approaches, was used to evaluate the maturation status of each follicle. Enzyme activity was negatively correlated with the E/P ratio. Ascorbate (Asc) and alpha-tocopherol (Toc) were titrated in follicular fluid and plasma to evaluate their accumulation or consumption in the follicle. High LCAT activity was found in follicular fluids where Asc and Toc had accumulated, whereas lower activity was associated with Asc and Toc consumption. The consumption of both antioxidants was positively correlated with the E/P ratio. The results suggest that as follicle maturation progresses, Toc and Asc concentrations increase in follicular fluid, thus protecting LCAT from oxidative damage and loss of activity.

Estradiol esterification in the human preovulatory follicle.

In the preovulatory follicle, the LH surge stimulates progesterone production, reduces estradiol synthesis, and scales up the permeability of the blood-follicle barrier. The purpose of this study was to investigate whether the extent of these changes is correlated with the levels of estradiol, estradiol esters, and cholesteryl esters in the follicular fluid. The follicular levels of progesterone, estradiol, estradiol linoleate, cholesterol, and cholesteryl linoleate were measured by HPLC. The estradiol linoleate/estradiol ratio, which reflects the efficiency of in vivo estradiol esterification, and the cholesteryl linoleate/cholesterol ratio were calculated and found negatively correlated. The estradiol level was positively correlated with the cholesteryl linoleate/cholesterol ratio while negatively correlated with the estradiol linoleate/estradiol ratio. The in vitro activity of lecithin-cholesterol acyltransferase, the enzyme esterifying both cholesterol and estradiol, was assayed by incubating the fluid with labeled substrates. This activity was not correlated with either the estradiol linoleate/estradiol or the cholesteryl linoleate/cholesterol ratio. The enzyme K(m) and V(max) values were lower with estradiol than with cholesterol. Higher estradiol linoleate/estradiol ratios and lower cholesteryl linoleate/cholesterol ratios were associated with higher level of Haptoglobin penetration into the follicle. This level, which was determined by ELISA, was found increased with increased progesterone concentration and, therefore, used as a marker of the LH-stimulated permeability of the blood-follicle barrier. Our data suggest that early preovulatory follicles contain more cholesteryl esters and less estradiol esters than follicles closer to ovulation.

Storage in the yolk platelets of low MW DNA produced by the regressing follicle cells.

The present work was carried out to clarify the nature and origin of the yolk DNA present in vitellogenic oocytes of the lizard Podarcis sicula. Morphological and biochemical evidences indicate that it has an intrafollicular origin, from the apoptotic bodies resulting from follicle cells regression at the end of previtellogenesis. This conclusion is reinforced by the observation that the oocyte membrane, in in vitro experiments, is unpermeable to exogenous DNA. Biochemical evidences reveal that the yolk DNA has a low (200bp) molecular weight and this suggests that it is produced by the endonucleases typically involved in apoptotic DNA laddering. Indeed, immunocytochemical analyses demonstrate that follicle cells contain significant amounts of DNAse I. In immunoblots, carried out during different periods of the ovarian cycle, the enzyme shows a MW of about 33, 66 or 100 kDa thus indicating that its activity in the follicle of Podarcis is modulated by dimerization and/or binding to regulatory factors. Mol. Reprod. Dev. 59: 422-430, 2001.

Bovine viral diarrhoea virus infection in bone marrow of experimentally infected calves.

Colostrum-deprived calves were inoculated with either a field isolate of bovine viral diarrhoea virus (BVDV) containing cytopathogenic (CP) and noncytopathogenic (NCP) biotypes or with only the NCP biotype. Paraffin wax-embedded sections of bone marrow from these calves, examined by means of an immunoperoxidase method, showed BVDV antigen in megakaryocytes and myeloid cells. Infection of such cells may play a role in the pathogenesis of thrombocytopenia, leucopenia and neutropenia, as reported in cattle infected with BVDV.

Etiology and risk factors of severe and protracted diarrhea.

Severe and protracted diarrhea (SPD) is the most severe form of diarrhea in infancy and has also been defined as intractable diarrhea. Its etiology is poorly defined. We have retrospectively evaluated the etiology, the outcome, and the risk factors of 38 children, admitted with protracted diarrhea and need for total parenteral nutrition (TPN) from 1977 to 1993. Children with anatomic abnormalities and/or primary immunodeficiency were excluded. There was an inverse relationship between the number of patients and the age of diarrheal onset (mean age, 2.9 +/- 3.5 months). Etiology of SPD was an enteric infection in 18 cases (eight Salmonella, three Staphylococcus, five rotavirus, one adenovirus, one Cryptosporidium), multiple alimentary intolerance (eight cases), familial microvillous atrophy (two), autoimmune enteropathy (two), celiac disease, lymphangectasia, eosinophilic enteropathy, intestinal pseudoobstruction, and intestinal neurodysplasia (1 case each). Etiology was not detected in three cases. Overall, 12 children died, five are presently being treated, and 21 had full remission. Comparative evaluation of risk factors between children with SPD and a control population of children with diarrhea but without the need for TPN showed that low birth weight, no breast feeding, history of fatal diarrhea in a relative, and early onset of diarrhea had a significantly higher incidence in the former. Social background was similar in the two populations. We conclude that a specific etiology can be identified in the majority of cases of SPD. The etiologic spectrum of SPD is broad, but an enteric infection is the most common cause of SPD. The severity of this condition is related, at least in part, to established risk factors.

[Asymptomatic arteriopathy of the lower limbs. Prevalence and risk factors in a population of southern Italy]. / Arteriopatia asintomatica degli arti inferiori. Prevalenza e fattori di rischio in una popolazione del sud Italia.

Peripheral vascular diseases, both symptomatic and asymptomatic, are strong predictors of total and cardiovascular mortality. The commonly used Rose questionnaire, although highly specific, has a low sensitivity to detecting peripheral vascular disease and is not adequate for asymptomatic subjects. Doppler ultrasound measurement of the ankle/brachial systolic blood pressure ratio is a non-invasive, reproducible and accurate method of assessment of peripheral vascular disease and has been validated by angiography. METHODS. Five hundred and ten subjects, corresponding to fifty percent of the people working as civil servants in the Catanzaro city hall, were invited to join the study by a letter. Three hundred and eighty four participated. Exclusion criterion was claudicatio intermittens as detected by Rose questionnaire. All the subjects filled a questionnaire to assess coronary heart disease risk factors and underwent a full clinical examination. Brachial blood pressure was measured on both arms with participants in supine position, just before ECG. The systolic ankle blood pressure was measured with ultrasonic technique. The blood pressure cuff was placed just proximal to the medial malleolus. The ankle-brachial systolic pressure index (Winsor Index) was determined by dividing the highest of the posterior tibial or dorsalis pedis pressures by the highest brachial pressure. A limit of 0.95 was chosen to identify subjects with peripheral arterial disease. Venous blood for serum cholesterol and triglycerides, apolipoprotein AI and B and blood glucose, was collected after an overnight fasting, into Vacutainer Tubes (Becton & Dickinson). RESULTS. No subject had claudicatio intermittens. Sixteen subjects were excluded from the statistical analysis because of missing data. Two hundred and sixty-three were males and 105 females. Twenty-one (5.7%) out of 368 participants had a Winsor Index < 0.95 in at least one leg. These subjects had higher values of systolic and diastolic blood pressure compared to normal subjects whereas no differences were observed with regard to age, BMI, lipid profile and blood glucose. Furthermore the prevalence of hypertension was higher in the group of subjects with asymptomatic peripheral arterial disease. The prevalence of other risk factors for atherosclerosis (cigarette smoking, hyperlipidemia, diabetes mellitus, obesity) was similar in subjects with or without peripheral arterial disease. DISCUSSION. In the present study the prevalence of Winsor Index < 0.95 was 5.7%, similar to that reported by other authors. Hypertension was the only risk factor for atherosclerosis associated with peripheral arterial disease. Other authors also reported a higher prevalence of cigarette smoking among subjects with peripheral disease. In our population this association was not found but the participants were younger and consequently the exposure to this risk factor was shorter. CONCLUSION. The measurement of systolic ankle blood pressure by Doppler ultrasounds is a non-invasive, well accepted, highly specific and sensitive method to detect asymptomatic peripheral arterial disease. It might be of value in better defining the cardiovascular risk profile both in epidemiologic studies and clinical practice, especially in subjects with hypertension.

Annuloplasty in children and young adolescents with severe rheumatic mitral insufficiency.

Eleven patients aged 8 to 15 years underwent measured asymmetrical annuloplasty for severe mitral regurgitation in the years 1961 through 1966. They had had a total of 20 attacks of acute rheumatic fever. The intervals between the last attack of acute rheumatic fever and operation ranged from 2 to 8 years. The criteria for surgery were congestive failure and progressive cardiac enlargement. Using the hydraulic formula of Gorlin, a mitral annuloplasty was tailored to the size of each patient so that insufficiency was eliminated without producing hemodynamically significant stenosis. In this group of 11 children there has been one death. The majority of our 11 patients reacquired murmurs of mitral regurgitation. Satisfactory results, however, are not dependent on complete hemodynamic correction. All patients have improved remarkably and have sustained this improvement up to 7 years. These results suggest that mitral annuloplasty should be the operation of choice in children with severe mitral regurgitation.