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.

Inoculation of mother's own milk could personalize pasteurized donor human milk used for feeding preterm infants.

BACKGROUND: Human milk is a vehicle for bioactive compounds and beneficial bacteria which promote the establishment of a healthy gut microbiome of newborns, especially of preterm infants. Pasteurized donor human milk (PDHM) is the second-best option when preterm mother's own milk is unavailable. Since pasteurization affect the microbiological quality of donor milk, PDHM was inoculated with different preterm milk samples and then incubated, in order to evaluate the effect in terms of bacterial growth, human milk microbiome and proteolytic phenomena. METHODS: In an in-vitro study PDHM was inoculated at 10% v/v using ten preterm milk samples. Microbiological, metataxonomic and peptidomic analyses, on preterm milk samples at the baseline (T0), on PDHM and on inoculated milk (IM) samples at T0, after 2 h (T1) and 4 h (T2) of incubation at 37 °C, were conducted. RESULTS: IM samples at T2 showed a Total Bacterial Count not significantly different (p > 0.01) compared to preterm milk samples. At T2 lactic acid bacteria level was restored in all IM. After inoculation, metataxonomic analysis in IM samples showed that Proteobacteria remained the predominant phylum while Firmicutes moved from 3% at T1 to 9.4% at T2. Peptidomic profile of IM resembled that of PDHM, incubated for the same time, in terms of number and type of peptides. CONCLUSION: The study demonstrated that inoculation of PDHM with mother's own milk could restore bacterial growth and personalize human milk microbiome in PDHM. This effect could be beneficial because of the presence of maternal probiotic bacteria which make PDHM more similar to mother's own milk.

Boys who are born preterm show a relative lack of fat-free mass at 5 years of age compared to their peers.

AIM: Prematurity is associated with features of metabolic syndrome in young adulthood. We investigated the body composition and blood pressure of children born preterm. METHODS: A longitudinal, observational study was conducted with preterm infants who had a birth weight of <1500 g and a gestational age of <32 weeks. Growth and body composition were assessed by air displacement plethysmography at term equivalent age and at school age and were compared to those of 61 healthy, term breastfed subjects. RESULTS: A total of 63 preterm infants were enrolled. At term equivalent age, growth and fat-free mass were lower in preterm infants than in term newborns, but fat mass was higher. At 5 years of age, children born preterm were still lighter and shorter than children born at term. When the results were analysed by gender, the fat-free mass index was lower in boys born preterm than in their peers (12.1 ± 1.1 versus 13.0 ± 1.0 kg/h(2) p < 0.005), whereas no difference was detected among girls. Diastolic blood pressure was higher in children born preterm than in children born at term (61.14 ± 7.8 vs 56.69 ± 8.2 mmHg, p = 0.009). CONCLUSION: Boys born preterm showed a relative lack of fat-free mass at school age compared to their peers.

Consequences of prematurity on adult morbidities.

Early life events play a key role in the development of adult diseases. Survival is promoted by the developmental adaptation to environment although advantage in the short term implies a long-term cost with regard to the development of adult morbidities. This is particularly true for the infant born prematurely as preterm birth is accompanied by a disruption of the normal organogenesis of multiple organ systems. This review will examine the effect of prematurity on the development of cardiovascular, kidney, respiratory and metabolic diseases in later life in addition to the neurodevelopment disabilities associated with preterm birth.

[Prevalence and duration of breastfeeding during the first six months of life: factors affecting an early cessation]. / Prevalenza e durata dell'allattamento al seno nei primi sei mesi di vita e fattori che influenzano.

OBJECTIVES: To assess the mean duration, prevalence and reasons that lead to an early cessation of breastfeeding in a group of healthy term infants in the first six months of life. METHODS: Prospective, observational study. One-hundred Caucasian, non smoking mothers, that intended to breastfeed for at least 12 weeks, were enrolled. Information on anthropometric parameters, type of delivery, socio-demographic characteristics, mode of feeding and reasons for stopping breastfeeding have been obtained through three different questionnaires (submitted at enrollment, on the 7th day, at 1, 2, 3 and 6 months). RESULTS: Exclusive breastfeeding gradually decreased from the 7th day to the 6th month of life. Most of the mothers stopped breastfeeding during the first month and a half or after 3 months and a half. Two percent of the mothers stopped on the 7th day whereas at 6 months the percentage of cessation was 14%. The cumulative percentage of interruption at 6th month was 45%. Maternal factors, like sore nipples or delayed onset of lactation, were the most frequent reasons that led to an early cessation, while during the following months inadequate breast milk and latch-on problems were predominant. On the other hand, attending a pre-natal course or having a previous successful breastfeeding experience were significantly associated with a long-lasting breastfeeding. CONCLUSIONS: Promotion of breastfeeding during the prenatal course and a better support for lactation management during the first months seem to be the areas where more efforts are needed to implement breastfeeding rates.

[Growth and body composition in the premature infant]. / Crescita e composizione corporea nel prematuro.

Great interest has focused recently on the relationship between early nutrition, growth and subsequent health. Indeed, several studies have demonstrated that early life growth patterns exert programming effects on disease risk in later life, highlighting the key role played by early nutrition. Body composition, an index of quality of growth, is one of the factors apparently involved into this "programming" process. The American Academy of Pediatrics recommends to supply adequate amounts of nutrients so that growth and body composition of the preterm infant approximates that of the intrauterine fetus at the same gestational age. However, in clinical practice, the achievement of intrauterine growth rate and body composition is difficult Indeed, most preterm infants experience a significant postnatal growth retardation which can be accompanied by an increased and/or altered adiposity. The estimation of the dynamic features of body composition changes, in order to evaluate the quality, in addition to t he amount of weight gain plays a major role in the nutritional follow-up of preterm infants. Certainly, monitoring the somatic growth and the development of body composition in early infancy represents an extremely important clinical tool in the individualization of the nutritional management, the prevention and/or the recovery from the postnatal retardation and the identification of the subjects at high risk for developing the metabolic syndrome in young adulthood.

[Early nutrition: the role of genetics and epigenetics]. / Nutrizione nelle prime epoche della vita: ruolo della genetica e dell' epigenetica.

Many adult diseases seem to be associated with early nutrition and the subsequent growth pattern. Epidemiological studies hypotized that babies with intrauterine and/or neonatal growth retardation may be at greater risk of metabolic syndrome later in life. According to the Barker's "thrifty phenotype hypotesis" early malnutrition, whereas inducing physiological compensation by the promotion of early survival, appears to confer greater susceptibility to adults diseases. Epigenetics, that is the interindividual variation in DNA methylation patterns and chromatin remodelling, provide a potential explanation for how environmental factors can modify the risk for development of many common diseases. Beginning from animal models, many studies concerning early nutrition, epigenetic modifications and genes expression have been carried out. Maternal undernutrition during pregnancy, especially in the peri-implantation period, not only causes a prolonged growth retardation but also modifies the programming of biochemical mechanisms related to endocrine-metabolic control. Human studies have demonstrated the role played by IGF-1 as indicator of nutritional status and fetal/postnatal growth retardation. It has been reported that alterations in IGF axis, which predispose to adults diseases, may be due to an alterated epigenetic regulation that can modify IGF expression. Despite the critical inter-relation between early nutrition, growth, development, and subsequent health, there are few data on the influence of early nutrition on the modifications of the epigenetic gear. Furthermore it is hoped for a bigger attention to the early nutrition to prevent the development of diseases later in life.

Adiposity in small for gestational age preterm infants assessed at term equivalent age.

OBJECTIVE: Infants classified as small for gestational age are considered to have developed under adverse intrauterine conditions that lead to lack of fat mass accretion. The aim of this study was to test the null hypothesis that the fat mass in preterm small for gestational age infants assessed at term equivalent age was not different from that of full-term small for gestational age newborns. DESIGN: Observational study. SETTING: Northern Italy. PATIENTS: 67 small for gestational age preterm infants and 132 small for gestational age full-term newborns. MAIN OUTCOME MEASURES: Growth and body composition, assessed by means of a paediatric air displacement plethysmography system, were measured at term equivalent age in the preterm infants and on the third day of life in the full-term newborns. RESULTS: The mean (SD) gestational age of preterm infants was 30.6 (2.3) weeks and their mean (SD) birth weight was 1140 (237) g. At assessment weight was not different between the preterm and full-term infants, whereas the percentage of total body fat mass was higher in the preterm infants (14.3% (SD 4.7%) vs 5.8% (SD 3.5%), p<0.005). CONCLUSIONS: Preterm infants, born small for gestational age, appear to be at risk for increased adiposity, which is a risk factor for the development of the metabolic syndrome.

[Pyoderma gangrenosum: a rare pathology or an omitted diagnosis?]. / Le pyoderma gangrenosum: pathologie rare ou diagnostic omis ?

Pyoderma gangrenosum is a rare pathology of uncertain etiology. It is an inflammatory dermatosis that causes cutaneous necrosis with a characteristically rapid evolution. No precise diagnosis criteria has been established and pyoderma gangrenosum remains an exclusion diagnosis. In 40 to 50% of the cases, the evolution of pyoderma gangrenosum can be worsened by a nonspecific external stimulus such as a trauma or a surgery. This phenomenon, called pathergy, conduces to avoid any surgical excision of the lesion. However, the diagnosis is often omitted and the rapid evolution of the cutaneous necrosis forces the surgeon to perform a surgical debridement of the wound. It causes a worsening of the lesion. It can have disastrous consequences. We present here three different case reports.

Influence of protein and energy intakes on body composition of formula-fed preterm infants after term.

The aim of the present study was to evaluate changes in body composition in 48 preterm infants in relation to protein and energy intakes from term up to 3 months of corrected age, using air displacement plethysmography. Protein intake (grams per kilogram per day) was negatively associated with percentage of fat mass at 1 month of corrected age. The high-protein-intake group showed greater gain in lean body mass gain than did the low-protein-intake group. This finding suggests that during the first month of corrected age, high protein intake results in a significantly different weight gain composition.

Inflammatory bowel disease in children and adolescents in Italy: data from the pediatric national IBD register (1996-2003).

BACKGROUND: The purpose was to assess in Italy the clinical features at diagnosis of inflammatory bowel disease (IBD) in children. METHODS: In 1996 an IBD register of disease onset was established on a national scale. RESULTS: Up to the end of 2003, 1576 cases of pediatric IBD were recorded: 810 (52%) ulcerative colitis (UC), 635 (40%) Crohn's disease (CD), and 131 (8%) indeterminate colitis (IC). In the period 1996-2003 an increase of IBD incidence from 0.89 to 1.39/10(5) inhabitants aged <18 years was observed. IBD was more frequent among children aged between 6 and 12 years (57%) but 20% of patients had onset of the disease under 6 years of age; 28 patients were <1 year of age. Overall, 11% had 1 or more family members with IBD. The mean interval between onset of symptoms and diagnosis was higher in CD (10.1 months) and IC (9 months) versus UC (5.8 months). Extended colitis was the most frequent form in UC and ileocolic involvement the most frequent in CD. Upper intestinal tract involvement was present in 11% of CD patients. IC locations were similar to those of UC. Bloody diarrhea and abdominal pain were the most frequent symptoms in UC and IC, and abdominal pain and diarrhea in CD. Extraintestinal symptoms were more frequent in CD than in UC. CONCLUSIONS: The IBD incidence in children and adolescents in Italy shows an increasing trend for all 3 pathologies. UC diagnoses exceeded CD.

[Body composition in small for gestational age newborns]. / Composizione corporea in neonati piccoli per età gestazionale.

OBJECTIVES: Aim of the present study was to test the hypothesis that the body composition of small for gestational age preterm infants, assessed at term equivalent age, was different as compared to that of small for gestational age full-term newborns. METHODS: Growth parameters and body composition, assessed by means of an air displacement pediatric plethysmography system, was measured in 120 newborns (67 preterm and 53 full-term). RESULTS: Similar weight was found in preterm and full-term newborns at term equivalent age and at birth, respectively. On the contrary, percentage of total body fat mass was significantly higher in preterm newborns as compared to full-term newborns (14.3 +/- 4.7% vs. 5.7 +/- 3.8% respectively, P < 0.05). In the preterm group gestational age was negatively associated with total fat mass at term equivalent age. CONCLUSIONS. The preterm newborns, especially if born small for gestational age, appear to be at risk for developing an altered body composition, which is a risk factor for the development of the metabolic syndrome in adult life. Preterm infants, born small for gestational age, appear to develop a quantity of fat mass higher than the adipose tissue they would have accumulated if they had completed their intrauterine gestation. The gestational age and the nutritional management in the early postnatal life could play a key role in affecting the body composition in these vulnerable infants.

Quantitative ultrasound and dual-energy x ray absorptiometry in bone status assessment of ex-preterm infants.

Preterm infants are at increased risk of low bone mass. Quantitative ultrasound (QUS) is a non-invasive method for assessment of bone status. The application of QUS in a cohort of ex-preterm infants was investigated. This study suggests that QUS cannot be used as a surrogate for dual-energy x ray absorptiometry.

Antibodies to recombinant human tissue-transglutaminase in coeliac disease: diagnostic effectiveness and decline pattern after gluten-free diet.

BACKGROUND/AIMS: To assess the sensitivity and specificity of IgA and IgG tissue-transglutaminase antibodies assay, the pattern of antibody decline after gluten withdrawal and their modifications with reference to dietary compliance. SUBJECTS: We studied sera from 143 untreated coeliac children and adolescents (8.8+/-6.1 years), 212 sera from 97 of those patients after gluten withdrawal, and 64 control subjects with non-coeliac intestinal disorders (6.8+/-4.8 years). METHODS: Samples were tested for IgA and IgG class tissue-transglutaminase antibodies by radiobinding assay, using human-derived tissue-transglutaminase, and for IgA anti-endomysium antibodies by indirect immunofluorescence on monkey oesophagus. RESULTS: Untreated coeliac patients had significantly higher titres of IgA and IgG tissue-transglutaminase antibodies than controls (p<0.00001); the diagnostic sensitivity was 95.8% and 99.3%, respectively, and the specificity was 95.3%. Three patients with selective IgA deficiency were positive for IgG tissue-transglutaminase antibodies. The concordance rate between IgA tissue-transglutaminase antibodies and anti-endomysium antibodies was 98.1%. Patients on gluten-free diet showed a significant decrease in IgA and IgG tissue-transglutaminase antibodies with respect to untreated patients (p<0.0001). Tissue-transglutaminase was more sensible than anti-endomysium antibodies to detect small amounts of gluten intake when the compliance was poor. CONCLUSIONS: The recombinant human tissue-transglutaminase antibodies assay is a highly sensitive and specific test for diagnosis of coeliac disease, and it is useful in monitoring the compliance to gluten-free diet.

A history of plant virology. Mendelian genetics and resistance of plants to viruses.

Virology was borne at the end of the nineteenth century, some years before the re-discovery of the so-called "Mendel's Laws". The rapid development of genetics was helpful to horticulturists and plant pathologists to produce hybrids of important cropping species resistant to several virus diseases. The concepts of Mendelian genetics were applied to plant virology by Francis Oliver Holmes, an American scientist who must be considered a pioneer in several fields of modern plant virology. During the Thirties, Holmes studied in particular the hypersensitive response of solanaceous plants to TMV and discovered the N dominant gene of tobacco hypersensitive to this virus. After the Second World War, the theoretic and practical support given by geneticists assisted plant virologists in better understanding the mechanism of inheritance of the character "resistance". The major problems posed by breeding for plant resistance were detected and critically discussed in several reviews published between the Fifties and the Sixties. These results, together with the discovery of the genetic functions of RNA virus raised interest on the possible relations between viral and plant genes. This fundamental subject saw the entry into the virological scene of molecular genetics, and in 1970 the Russian virologist Joseph Atabekov introduced host specificity to viruses as a central point of plant virology. From the mid 1980s, this point attracted the interest of several virologists, and many results led to several theoretic models of genetic interactions between plant and virus products. In the last fifteen years, the introduction of transgenic plants has given a remarkable contribution to the question of host specificity, which, however, still awaits a general explanation.

The expression of a single-chain Fv antibody fragment in different plant hosts and tissues by using Potato virus X as a vector.

Some aspects of the expression of a single-chain Fv antibody fragment (scFv) driven by the plant viral vector Potato virus X (PVX) have been studied by quantitative ELISA. After inoculation of the infectious transcript, the vector was stable only for a few passages of sap transmission in the inoculated leaves of Nicotiana benthamiana and the reversal to wild type was more pronounced in the systemically invaded leaves. The amount of synthesized scFv varied when different solanaceous hosts were tested, being generally higher and less variable in inoculated than in systemically invaded leaves. In tomato and Datura stramonium the scFv was synthesized only in the inoculated leaves. The scFv was also synthesized in the PVX local hosts Chenopodium amaranticolor and C. quinoa. No correlation was found between PVX and scFv concentration in the inoculated and systemically invaded leaves of N. benthamiana and N. clevelandii.

A history of plant virology. Cross protection.

Cross protection is a type of induced resistance developing in plants against viruses. Its basis is that prior infection with one virus affords protection against closely related ones. Its history started about seventy years ago, when the Dutchman Thung and the Englishman Salaman described the phenomenon independently. During the 1930s, several virologists confirmed the discovery, which was considered the first possibility to protect plants against virus infection. Growing interest also led plant virologists to formulate the first hypotheses on its mechanism, with the onset of a still unsolved debate. The hypotheses, that have been succeeded until the 1970s, included (i) antibody formation, (ii) exhaustion of essential metabolites, (iii) limited sites for virus multiplication, and (iv) specific adsorption by new cell compounds. These hypotheses were re-proposed and discussed on several occasions without arriving at a final conclusion. The statement of molecular genetics of viruses produced new interesting "theories", fundamentally based on the interference between virus strains. A model developed by the Americans Palukaitis and Zaitlin in 1984 indicates that excess of progeny positive-sense RNA of the protecting strain would sequester the minus-strand RNA of the challenging strain. Other models involve a function of the coat protein, or gene recombination. However, no model that could unify all the various facets of cross protection has hitherto been proposed. All that has not stopped the phenomenon having practical application. From the first attempts against a severe disease of cocoa in West Africa realized by Posnette in the 1940s, a number of crops (such as tomato, tobacco, citrus, cucurbits, grapevine, soybean, papaya, and so on) have been submitted to this practice. During the 1980s, cross protection came to a standstill because of the development of new resistant or tolerant cultivars. Its story is by no means ended, and much work is needed to understand its limits and possibilities.

The discovery of the chemical nature of tobacco mosaic virus.

The path to arrive at the elucidation of the chemical nature of plant viruses was greatly facilitated by the availability of Tobacco mosaic virus (TMV) as biological tool. The first hypothesis on the chemical nature of TMV was advanced in 1899 by the American Albert Wood, who suggested an enzyme nature. This hypothesis, severely questioned by Harry Hallard in 1915, was re-proposed by several virologists. In 1926, the American Maurice Mulvania concluded that the virus might be a protein with the biological characteristics of an autocatalytic enzyme. Before arriving at the experimental evidence it was necessary to resolve two questions: the estimation of virus infectivity in quantitative terms, performed by Francis Holmes in 1928, and the purification of the virus, performed by Carl George Vinson between 1927 and 1934. Vinson gave a conclusive contribution to solve the question of the chemical nature of TMV by settling the protocol of TMV purification. He put forward the hypothesis of the protein nature in the early 1930s but had not the required firm belief to gave the final experimental evidence of it. Who first arrived at the experimental evidence of the protein nature of the virus was the American Wendell Meredith Stanley, in 1935. His celebrated work, a classic of the fundamental Virology, was followed by several papers in which this result was firmly reaffirmed. The heuristic value of Stanley's discovery held out a year: the decisive evidence of the actual chemical nature of TMV was offered in the late 1936 by an English group under the leadership of Frederick Charles Bawden. In their short paper, Bawden and co-operators demonstrated that TMV had a ribonucleoprotein nature, a result that was confirmed in the following years for several TMV strains and other viruses. Stanley and his group did accept this result only after a year of reticence and contradictions. The conversion to the ribonucleoprotein nature raised a dignified protest by Bawden and the sarcasm of his closest co-operator, Norman Wingate Pirie, because Stanley proved to be very reluctant to recognize the merit of the English group. The world of Virology continues to consider Stanley as the first scientist who elucidated the actual nature of a virus, and this eminent scientist was awarded the Nobel Prize for Chemistry, in 1946. By examining the papers Stanley published from 1937 to 1945, one can however find proof of his ambiguity, a fact that justifies the bitterness of Bawden and the sarcastic comments of Pirie.

Peptide-derived broad-reacting antisera against tospovirus NSs-protein.

Sequence alignments of tospovirus species of serogroup I to IV revealed a stretch of 24 amino acids at the C terminus of the non-structural protein NSs with a highly conserved sequence. Based on this sequence the 24 amino acids peptide YFLSKTLEVLPKNLQTMSYLDSIQC was synthesized and used to raise antisera in two rabbits. The specificity of the antisera against NSs from infected plants was confirmed with Western blots and by immunogold labelling and electron microscopy. These antisera detected tospovirus isolates of serogroup I to III in antigen-coated plate ELISA and Western blots but failed to detect isolates of serogroup IV. Epitope scanning using overlapping octopeptides composing the peptide suggested that the antisera contained antibodies against two different epitopes. Strongly reacting peptides were found at the C-terminus of the original peptide sequence when probing with one of the antisera. In this part the sequence was homologous to serogroup I, II and III, with all deviations from serogroup IV located here. Additional octopeptides, based on this region, synthesized with sequence modifications back to the serogroup IV sequence in all possible combinations, had low reactivity. However two of the modified peptides with partly restored serogroup IV sequences revealed promising reactivity and could be suitable to raise an antiserum with broader reactivity, including serogroup IV.

An Ophiovirus isolated from lettuce with big-vein symptoms.

Big-vein is a widespread and damaging disease of lettuce, transmitted through soil by the chytrid fungus Olpidium brassicae, and generally supposed to be caused by Lettuce big-vein virus (LBVV; genus Varicosavirus). This virus is reported to have rigid rod-shaped particles, a divided double-stranded RNA genome, and one capsid protein of 48 kD, but has not been isolated or rigorously shown to cause the disease. We provide evidence that a totally different virus, here named Mirafiori lettuce virus (MiLV), is also very frequently associated with lettuce showing big-vein symptoms. MiLV was mechanically transmissible from lettuce to Chenopodium quinoa and to several other herbaceous test plants. The virus was partially purified, and an antiserum prepared, which did not react with LBVV particles in decoration tests. As reported for LBVV, MiLV was labile, soil-transmitted and had a single capsid protein of 48 kD, but the particles morphologically resembled those of ophioviruses, and like these, MiLV had a genome of three RNA segments approximately 8.5, 1.9 and 1.7 kb in size. MiLV preparations reacted strongly in Western blots and in ISEM with antiserum to Tulip mild mottle mosaic virus, an ophiovirus from Japan also apparently Olpidium-transmitted. They reacted weakly but clearly in Western blots with antiserum to Ranunculus white mottle virus, another ophiovirus. When lettuce seedlings were mechanically inoculated with crude or partially purified extracts from MiLV-infected test plants, many became systemically infected with MiLV and some developed big-vein symptoms. Such plants did not react in ELISA using an LBVV antiserum or an antiserum to tobacco stunt virus, and varicosavirus-like particles were never seen in them in the EM after negative staining. We conclude that MiLV is a hitherto undescribed virus assignable to the genus Ophiovirus. The cause or causes of lettuce big-vein disease and the properties of LBVV may need to be re-evaluated in light of our results.