Efficacy of combined antiviral therapy with lamivudine and tenofovir in a liver transplanted girl with de novo hepatitis B virus infection.

The management of de novo hepatitis B (HBV) infection in children after liver transplantation is not well defined. Because this infection may induce severe liver disease in the graft liver, an efficient antiviral therapy is desirable. Here, we describe the favorable viral outcome observed in a liver transplanted girl with de novo HBV infection following combination therapy with lamivudine and tenofovir.

Cross-cutting view of current challenges in paediatric solid organ and haematopoietic stem cell transplantation in Europe: the European Reference Network TransplantChild.

The low prevalence of European paediatric transplanted patients and scarcity of resources and expertise led to the need for a multidisciplinary network able to improve the quality of life of paediatric patients and families requiring a solid organ or haematopoietic stem cell transplantation. The European Reference Network (ERN) TransplantChild is one of the 24 ERNs established in a European legal framework to improve the care of patients with rare diseases. ERN TransplantChild is the only ERN focused on both solid organ and haematopoietic stem cell paediatric transplantation, based on the understanding of paediatric transplantation as a complex and highly specialised process where specific complications appear regardless the organ involved, thus linking the skills and knowledge of different organ disciplines. Gathering European centres of expertise in paediatric transplantation will give access to a correct and timely diagnosis, share expertise and knowledge and collect a critical mass of patients and data that increases the speed and value of clinical research outcomes. Therefore, the ERN TransplantChild aims for a paediatric Pan-European, Pan-transplant approach.

Primary Prophylaxis for Gastrointestinal Bleeding in Children With Biliary Atresia and Portal Hypertension Candidates for Liver Transplantation: A Single-Center Experience.

BACKGROUND: Cirrhosis for biliary atresia (BA) is associated with risk of gastrointestinal bleeding (GB) from gastroesophageal varices due to portal hypertension. Primary prophylaxis of GB is controversial in children who are candidates for liver transplantation (LT). The aim of the study was to define the management of gastroesophageal varices and to identify the benefit of primary prophylaxis for GB in BA children waiting for LT. METHODS: A retrospective single-center study including all BA children listed for LT in 2008-2016. Clinical, endoscopical, and biochemical data were analyzed. RESULTS: Of 82 children, 50 (61%) did not receive primary prophylaxis and did not present any episode of bleeding, 16 (19.5%) underwent primary prophylaxis, and 16 (19.5%) presented spontaneous GB and received secondary prophylaxis. Children without primary prophylaxis and GB were younger than patients with primary prophylaxis and those with GB (7.7 years [range, 4.1-37.9 years] vs 11.2 years [range, 5.1-43 years]; P = .03 vs 10.7 years [range, 6.9-39.9 years], respectively; P = .004). Seventy-five percent of GB occurred in children older than 8 months. Fifteen (93.8%) children with GB presented esophageal varices (grade III = 10 [62.5%]) and 10 (62.5%) required endoscopic treatments, consisting mainly of sclerotherapy. Median time to LT was similar for children with or without bleeding (2 months [range, 0-17.7 months] vs 2.2 months [0-17.9 months], respectively; P = .89). After 45.5 months (range, 13.7-105.5 months) of follow-up, the overall patient survival was 97.6%. At the intention-to-treat analysis, the survival rate was 100% for patients without bleeding episode and 87.5% for children with GB (P = .16). CONCLUSIONS: Despite the risk of GB being not clinically predictable in children with BA waiting for LT, our experience suggests that primary prophylaxis of GB might be unnecessary in children younger than 6 months, while it should be considered in older children. Thus, the occurrence of GB does not delay the timing of transplantation.

Prevalence of home artificial nutrition in Italy in 2005: a survey by the Italian Society for Parenteral and Enteral Nutrition (SINPE).

AIM: To determine the prevalence (cases per million inhabitants) of home artificial nutrition (HAN), enteral (HEN) and parenteral (HPN), in Italy, grouped according to administrative regions, patient age and primary disease, and to analyze the impact both of the presence of an HAN regional regulation and of demographic characteristics. METHODS: In April 2005, the Regional Coordinators of the Italian Society for Parenteral and Enteral Nutrition (SINPE) recorded all the ongoing cases of HAN using a structured questionnaire and were asked to estimate the representativeness of the collected sample with respect to the total expected HAN. RESULTS: A total of 6955 cases of HAN (93.5% adults, 6.5% pediatric patients < or = 18 years) were recorded in 16 of the 20 Italian regions (80% of the Italian population; sample representativeness 78%). HAN prevalence 152.6 (83.9% HEN, 16.1% HPN); the HAN range among the regions was: prevalence 28.1-519.8; oncological disease 13.8-75.7%, neurological disease 15.5-79.9%, intestinal failure 1.3-14.0%. An HAN regulation was present in 11 regions. A positive association (P=0.012) was found between the number of years since the regulation was issued and the HAN prevalence, and also between the % neurological patients and the population density (P=0.130) and the % inhabitants > or = 75 years (P=0.040). CONCLUSIONS: The need for HAN regards a great number of patients throughout the country; there are substantial differences between the regions with respect to both the prevalence and the use of HAN in various disease categories. A specific regulation may favor the development of HAN.

Cyclosporin in steroid-resistant autoimmune hepatitis and HCV-related liver diseases.

Cyclosporin has been used for many years in transplantation, and in this field its role is widely documented. However, other fields of application merit to be investigated, including the role of cyclosporin in treating autoimmune hepatitis and its possible role as an antiviral agent in hepatitis C virus (HCV) infections in both immunocompetent patients and in recipients of orthotopic liver transplants. Cyclosporin A has given promising results in small studies, and experience in transplantation and other immunological disorders indicates that its side-effects can be adequately managed. Cyclosporin certainly deserves further clinical investigation for first-line therapy in autoimmune hepatitis. Cyclosporin A suppresses the HCV genome dose-dependently in vitro at clinically relevant concentrations (150-250 ng/mL). The maximum effect is similar to that obtained with IFN alpha, and the effects of these two agents are certainly additive, and possibly synergistic. The inhibitory action of cyclosporin A appears to be independent upon its immunosuppressive action. Analysis of indirect endpoints in clinical trials on cyclosporin A for immunosuppression in transplant recipients indicates that cyclosporin A treatment can delay recurrence of HCV. Small, open label studies suggest that the observed anti-HCV activity of cyclosporin A can be translated into a real clinical benefit; nevertheless, these findings need to be confirmed in randomized, controlled clinical trials.

Calcium and phosphorus balance in very low birth weight babies on total parenteral nutrition.

A balance study of Ca and P has been performed in 12 Very Low Birth Wt babies receiving prolonged Total Parenteral Nutrition. The mean intake of both minerals was 54.4 mg/kg/day (range 40-70). In order to avoid the formation and precipitation of CaP crystals in the solution, fructose-1,6-diphosphate was used as a source of P. 30 balance studies were performed between the seven and 63 day of life: they were always positive with a mean retention of 47.4 mg/kg/day of Ca and 48.1 mg/kg/day of P. For both minerals, 88% of the amount infused was retained: the correlation between intake and retention was linear and statistically significative (Ca:r = 0.9, p < 0.0001; P:r = 0.68, p < 0.0001). The post-natal and post-conceptional ages of the babies had no influence on Ca and P balance. The blood levels of Ca and P were poorly correlated to both intake and excretion, and were not as indicative of the mineral balance as the retention rates calculated on the basis of the 24 h urinary excretion of the minerals. A very useful test for clinical monitoring of Ca and P balance proved to be the Ca/creatinine and P/creatinine ratios measured on simple urine samples, which were strongly correlated to 24 h excretion. All infants developed radiological signs of mild osteopenia, but there was no case of acute metabolic derangement or rickets. Our data demonstrated that even in sick VLBW infants on TPN it is possible to achieve good retention rates of Ca and P, which are not different from those observed in well VLBW babies fed a 'standard' premature formula.

Effect of fortification on the osmolality of human milk.

AIM: To evaluate the effect of fortification on the osmolality of human milk. METHODS: The osmolality of 47 samples of human milk was determined at baseline, just after, and 24 hours after supplementation with five different human milk fortifiers (HMF) at 4 degrees C. RESULTS: Ten minutes after HMF supplementation the osmolality of human milk was significantly higher than the sum of the respective values of HMF dissolved in water and human milk, measured separately at baseline (p<0.0001), with the exception of the HMF containing only proteins. After 24 hours a further increase in osmolality was observed. Linear regression analysis showed that total dextrin content (r=0.84) was the main determinant of the increase. CONCLUSIONS: Human milk and HMF interact to induce a rapid increase in osmolality higher than would be expected from composition alone. This rise could be explained by the amylase activity of human milk, inducing hydrolysis of the dextrin content of HMF, leading to small osmotically active molecules of oligosaccharides. The high osmolality of fortified human milk should be considered in the nutritional management of preterm infants.

Cystic fibrosis in children: HRCT findings and distribution of disease.

To assess the type, severity, and regional lung distribution of cystic fibrosis (CF) lesions as shown using high-resolution CT (HRCT), comparing these findings with chest radiographs and pulmonary function tests (PFTs), we obtained HRCTs in 36 patients with CF (mean age 13), who were clinically stable. We assessed four lung regions (upper and lower, right and left) and assigned each a semiquantitative score for (a) bronchial abnormalities, (b) parenchymal abnormalities, and (c) overinflation, based on the severity and profusion of the corresponding lesions. A similar regional assessment of chest radiographs was also done using the Chrispin-Norman method. PFT results were correlated with the radiological data. On HRCT, bronchial lesions were present in 89% of the patients and in 78% of the regions; bronchiectasis was the predominant abnormality in our population, visible in 100% of the abnormal regions. Less frequent were bronchial wall thickening (48%) and mucous plugs (29%). Parenchymal abnormalities were recognizable in 58% of the patients and 31% of the regions; alveolar consolidation was more frequent (80%) than were destructive changes (36%). Overinflation was found in 81% of the patients and 85% of the regions. We found the severity and profusion of bronchial lesions and parenchymal destructive changes to be unevenly distributed among the different regions, the upper lungs being more heavily involved than the lower, particularly on the right. Alveolar consolidation and overinflation were more uniform in distribution. HRCT patient scores correlated significantly with radiographic scores (r = 0.861) and with PFTs, especially with forced expiratory volume for 1 s (FEV1; r = 0.658). HRCT can be useful in the clinical management of patients with CF, depicting the type and distribution of bronchial and parenchymal lesions, particularly when chest radiographic results are unclear. In the planning and postural drainage, special attention should be given to the apical and posterior parts of the lungs, especially on the right; these are the areas most frequently and most severely involved by the disease.

[Total parenteral nutrition in pregnancy]. / Nutrizione parenterale totale in gravidanza.

The authors report three cases of pregnant women who were incapable or unable to freed themselves enterally and were monitored by the Division of Obstetrics and Gynecology at the "Burlo Garofolo" Institute for Infancy from 1992 to 1996. The series included two patients suffering from severe hyperemesis gravidarum and a third patient with severe atopic eczema secondary to food allergens. Starting at different stages of pregnancy these patients were treated using total parenteral nutrition (TPN) following the placement of a venous catheter using percutaneous access through the subclavian artery and leading into the superior vena cava. This solution not only ensured an appropriate calorie intake but also enabled electrolytic controls to be performed, adapting the intake of these elements to the real needs of the patients assessed by means of regular hematochemical tests. It is also worth pointing out that the calorie intake supplied during TPN was achieved through the use of lipid emulsions whose administration during pregnancy has been regarded as being risky owing to the possible onset of fatty placental infiltrations and the enhanced risk of premature birth. The authors underline the good results obtained in this series using TPN both with regard to the satisfactory level of maternal nutrition and the optimal evolution of pregnancy leading to the birth of healthy neonates with a normal weight.

Serum immunoglobulin and complement levels in prematures with parenteral feeding--preliminary results.

Immunoglobulins IgA, IgG and IgM and complement factors C3 and C4 have been measured in a population of premature infants to evaluate their degree of immunological maturity. All the infants were receiving complete parenteral nutrition. In parallel, the same parameters were measured in twenty two full term, healthy neonates. To explore maturation and liver function, the authors used other proteins as nutritional markers. Differences in the immunoglobulins, but not in the complement fractions were seen between the two groups. Two applications are suggested: incidence of infections and post partum maturation.

Thalidomide as rescue therapy for acute severe ulcerative colitis.

INTRODUCTION: Acute severe exacerbations of Ulcerative Colitis (UC) represent a medical emergency in children and adults. Intravenous steroids remain the first line therapy for this condition, although the steroid refractoriness is common. Second-line therapy, based on the infliximab or thiopurines should be started if no response to corticosteroids is noted. The use of infliximab in children with acute severe UC, nevertheless, does not avoid the colectomy in all cases. METHODS: We present a case of severe acute UC in a paediatric patient successfully treated with thalidomide following the failed treatment with infliximab and a review of the literature. CONCLUSIONS: This is the first case of a patient presenting with acute severe UC who was treated with thalidomide, with favorable evolution. In our case the use of this drug was able to avoid the colectomy that represent the conventional but very invasive recommended therapeutic option of this condition. Therefore, thalidomide may be considered as rescue therapy in selected and carefully monitored cases of acute severe CU.

Impaired striatum-dependent behavior in GASP-1-knock-out mice.

G protein-coupled receptor (GPCR) associated sorting protein-1 (GASP-1) is suspected to play a key role in recycling and degradation of several GPCRs. In a previous study, we have shown that GASP-1-knock-out (GASP-1-KO) mice displayed deficits in acquiring a cocaine self-administration task, associated with an exacerbated down-regulation of striatal dopaminergic and cholinergic receptors. Among several possibilities, GASP-1 deficiency could have impaired memory processes underlying the acquisition of the operant conditioning task. Therefore, the present study investigated cognitive performances of GASP-1-KO mice and their wild-type littermates (WT) in a broad variety of memory tasks. Consistent with a deficit in procedural memory, GASP-1-KO mice showed delayed acquisition of a food-reinforced bar-press task. During water-maze training in hidden- or visible-platform paradigms, mutant and WT mice acquired the tasks at the same rate. However, GASP-1 mice exhibited persistent thigmotaxic swimming, longer distance to the platform, and reduced swim speed. There was no deficit in several tasks requiring simple behavioral responses (Barnes maze, object recognition and passive avoidance tasks). Thus, the ability to acquire and/or express complex responses seems affected in GASP-1-deficient mice. Hippocampal functions were preserved, as the retention of an acquired memory in spatial tasks remained unaffected. The pattern of behavioral deficits observed in GASP-1-KO mice is coherent with current knowledge on the role of striatal GPCRs in acquisition/expression of skilled behavior and in motivation. Together with the previous findings, the so far established phenotype of GASP-1-KO mice makes them a potentially exciting tool to study striatal functions.

Artificial nutrition and bone marrow transplantation.

Parenteral nutrition has a central role in the supportive therapy of patients submitted to a BMT. A central catheter is mandatory for transfusions, antibiotic therapy and a proper nutrition. A good nutritional support contributes to maintain hydration, reduce lean body mass loss, increase patient comfort and improve survival in patients who can not eat or absorb for a prolonged period of time. After a BMT metabolic complications are frequent and require careful monitoring; in critical care patients, the major risks are electrolyte and glucose disturbances. Liver disease is a main metabolic complication of PN, but it can occur in any cancer patient due to therapy or to graft-versus-host disease. Its best prevention requires the avoidance of prolonged enteral fasting.

Molecular aspects of the endocrine tumours of the pancreas and the gastrointestinal tract.

Neuroendocrine tumours of the gastroenteropancreatic tract are growths originating either from the cells of the diffuse (neuro)endocrine system, such as gastric carcinoids and islet cell tumours, or from nerve structures, such as duodenal paragangliomas. A great deal of cellular and clinical information is available whereas data concerning the genetic and molecular basis of diffuse (neuro)endocrine system tumours of the gastroenteropancreatic tract are very few and fragmentary. The present paper reviews some genetic and molecular investigations of potential interest. As far as concerns the genetic background of diffuse (neuro)endocrine system tumours, the frequent loss of heterozygosity for the locus of Multiple Endocrine Neoplasia type 1 in tumour samples suggests a potential role of the Multiple Endocrine Neoplasia gene. With regard to the molecular background, no mutation of the p53 or retinoblastoma susceptibility (Rb) genes has been demonstrated. Useful data have been generated by in situ analysis of the proliferation activity of tumours.

Origin and Genetic Background of Insulinomas.

Insulin-producing B cell tumors (insulinomas) are the most frequent functioning endocrine tumors of the pancreas. Available experimental evidence suggests that the islet B cell is the most likely cell of origin of insulinomas, while the duct endocrine cell should be considered if rearrangement of the pancreatic parenchyma occurs. Data on the genetic background of insulinomas suggest that the B cell tumor development may result from alteration of several genes, including the multiple endocrine neoplasia type 1 (MEN1) gene.

Efficacy of long-term treatment with thalidomide in children and young adults with Crohn disease: preliminary results.

BACKGROUND: Several proinflammatory cytokines are involved in the pathogenesis of inflammatory bowel diseases. A significant role has been given to tumor necrosis factor alpha (TNF-alpha) as a guide proinflammatory cytokine. Thalidomide selectively reduces TNF-alpha production by inflammatory cells. The aim of the study was to assess the efficacy of thalidomide to induce and maintain remission in refractory Crohn disease. METHODS: The decision to administer thalidomide was made on the basis of patient intolerance or resistance to conventional medical treatment or as the last medical resort before surgical intervention. Only 5 of 96 patients with inflammatory bowel disease satisfied these criteria. All five patients had Crohn disease (male: mean age, 17 years). Thalidomide was administered at night at a dose of 1.5-2 mg/kg/day. The Pediatric Crohn Disease Activity Index, modified Harvey-Bradshaw scores, and steroids reduction were used to assess clinical response. RESULTS: Disease activity decreased consistently in four patients with a reduction of mean Pediatric Crohn Disease Activity Index from 36,9 to 2,5 and the mean Harvey-Bradshaw from 8.5 to 0.75 after 3 months of treatment. Steroid treatment (mean dose, 35 mg/day before treatment) was tapered and then discontinued, in four patients, within 1-3 months. Four patients are in remission after 19-24 months of treatment. The fifth patient discontinued thalidomide after 1 week because of distal paresthesia. CONCLUSION: Thalidomide seems to be an effective and safe treatment in patients with refractory Crohn disease. This is the first report of long-term use of thalidomide in refractory Crohn disease in pediatric patients.

Failure to thrive: the earliest feature of cystic fibrosis in infants diagnosed by neonatal screening.

The benefits of early treatment of nutritional and respiratory problems in the CF infant and of genetic counselling for the parents are widely recognized. However, clinical diagnosis of CF is often delayed despite early onset of symptoms and the usefulness of neonatal population screening as a preventive measure is still under debate. This study analyses the clinical history of CF patients diagnosed exclusively on the basis of positive neonatal screening tests with the aim of identifying the earliest markers of the disease. We studied 103 CF infants born in north-east Italy, diagnosed following neonatal screening: assay of immunoreactive trypsin (IRT) from a heel-prick blood sample followed by a measurement of meconium lactase in cases with raised IRT. Diagnosis was confirmed by sweat test at an average age of 39 days. Eighty-one patients (79%) had symptoms strongly suggestive of CF at diagnosis, and signs and/or symptoms of pancreatic insufficiency were present in 16 of the remaining 22 cases. The most frequent symptom was growth failure (69% of infants) and of these, 44% weighed the same as at birth or less. Pancreatic insufficiency was confirmed by the low level of faecal chymotrypsin found in 85% of cases. IRT was elevated in all cases. CF had not been suspected in any symptomatic infant, although most of the infants had been monitored by a paediatrician. In conclusion, most infants with CF diagnosed by neonatal screening are already symptomatic in the first six weeks of life and the most frequent symptom is failure to thrive; pancreatic insufficiency was already present in most cases. In areas without CF neonatal screening programs, the disease should be excluded by differential diagnosis in all cases with growth failure notwithstanding adequate caloric intake in the first months of life. The high sensitivity, low cost and simple execution of IRT and fecal chymotrypsin tests make them an ideal first step in suspect cases before proceeding to the sweat test, often performed late because of limited availability.