Resolving the fibrotic niche of human liver cirrhosis at single-cell level.

Liver cirrhosis is a major cause of death worldwide and is characterized by extensive fibrosis. There are currently no effective antifibrotic therapies available. To obtain a better understanding of the cellular and molecular mechanisms involved in disease pathogenesis and enable the discovery of therapeutic targets, here we profile the transcriptomes of more than 100,000 single human cells, yielding molecular definitions for non-parenchymal cell types that are found in healthy and cirrhotic human liver. We identify a scar-associated TREM2+CD9+ subpopulation of macrophages, which expands in liver fibrosis, differentiates from circulating monocytes and is pro-fibrogenic. We also define ACKR1+ and PLVAP+ endothelial cells that expand in cirrhosis, are topographically restricted to the fibrotic niche and enhance the transmigration of leucocytes. Multi-lineage modelling of ligand and receptor interactions between the scar-associated macrophages, endothelial cells and PDGFRα+ collagen-producing mesenchymal cells reveals intra-scar activity of several pro-fibrogenic pathways including TNFRSF12A, PDGFR and NOTCH signalling. Our work dissects unanticipated aspects of the cellular and molecular basis of human organ fibrosis at a single-cell level, and provides a conceptual framework for the discovery of rational therapeutic targets in liver cirrhosis.

Novedad en alimentación infantil: fórmulas a base de leche de cabra / Novelty in infant feeding: formulas based on goat’s milk

La Directiva 2013/46/UE, y posteriormente el Reglamento 2016/127/UE, han autorizado la proteína de leche de cabra como fuente para la elaboración de fórmulas para lactantes. Capricare de inicio y continuación es una fórmula a base de leche de cabra disponible actualmente en farmacias. El proceso de elaboración de esta fórmula es diferente del empleado habitualmente para fórmulas a base de leche de vaca, lo cual repercute en su composición. El contenido lipídico mantiene un 55% de la grasa animal, con un 14% de ácido palmítico, un 31% de éste en posición β-monoglicérido. Contiene también un 6,5% de MCT. La cantidad de calcio inorgánico libre es solo del 20%, ya que el resto está unido a la caseína. Todo ello repercutiría en una optimización de la absorción grasa. Debido a los niveles más bajos de α-s1-caseína, el tamaño de las micelas de caseína en la leche de cabra son de 100-200 nm frente a los 60-80 nm en la leche de vaca. La consecuencia práctica es una digestión gástrica más rápida, más similar a la leche materna, favoreciendo el vaciado gástrico. La leche de cabra tiene un proceso de secreción apocrina que libera componentes celulares de forma natural, como nucleótidos, taurina, poliaminas y aminoácidos libres. Contiene oligosacáridos, muchos de los cuales son estructuralmente similares a los oligosacáridos de la leche humana. En vista de las características de esta fórmula de cabra, es indudable que podría tener su posicionamiento en la dieta de los lactantes con el denominado «disconfort intestinal», o bien como alternativa natural de nutrición del lactante sano. Futuros estudios clínicos serán necesarios para corroborar dicho posicionamiento (AU)

Directive 2013/46/EU and subsequently Regulation 2016/127/EU have authorized goat milk protein as a source for the manufacture of infant formulas. Capricare initiation and continuation is a formula based on goat’s milk, currently available in pharmacies. The process of making this formula is different from that usually used for formulas based on cow’s milk, which has an impact on its composition. The lipid content maintains 55% of the animal fat, with 14% of palmitic acid and 31% thereof in the β-monoglyceride position. It also contains 6.5% MCT. The amount of free inorganic calcium is only 20%, since the rest is bound to casein. All this would have an effect on the optimization of fat absorption. Due to the lower levels of α-s1-casein, casein micelles are smaller in goat milk (50 nm) than cow (75 nm), providing a smaller curd in the stomach. The practical consequence is a faster gastric digestion, more similar to breast milk favoring gastric emptying. Goat’s milk has an apocrine secretion process that naturally releases cellular components, such as nucleotides, taurine, polyamines and free amino acids. It contains oligosaccharides, many of which are structurally similar to the oligosaccharides in human milk. Given the analyzed characteristics of this goat formula is undoubtedly could have its positioning in the diet of infants with the so-called "intestinal discomfort" or as a natural alternative nutrition of the healthy infant. Future clinical studies will be needed to corroborate this positioning (AU)

Airborne pollen trends in the Iberian Peninsula.

Airborne pollen monitoring is an effective tool for studying the reproductive phenology of anemophilous plants, an important bioindicator of plant behavior. Recent decades have revealed a trend towards rising airborne pollen concentrations in Europe, attributing these trends to an increase in anthropogenic CO2 emissions and temperature. However, the lack of water availability in southern Europe may prompt a trend towards lower flowering intensity, especially in herbaceous plants. Here we show variations in flowering intensity by analyzing the Annual Pollen Index (API) of 12 anemophilous taxa across 12 locations in the Iberian Peninsula, over the last two decades, and detecting the influence of the North Atlantic Oscillation (NAO). Results revealed differences in the distribution and flowering intensity of anemophilous species. A negative correlation was observed between airborne pollen concentrations and winter averages of the NAO index. This study confirms that changes in rainfall in the Mediterranean region, attributed to climate change, have an important impact on the phenology of plants.

Valoración no invasiva de la administración en recién nacidos y lactantes afetados por cólicos de lactante de una fórmula de inicio y de otra adicionada / Noninvassive assessment of the administration of on initial formula, to be supplemented with another, to newborns and infants with infantile colic

La alimentación de recién nacidos y lactantes con síndrome del cólico lactante, con una leche especial a la que se ha añadido: - Betapol, grasa especial con gran proporción de ácido palmítico en posición beta. del triglicérido, - Componente proteico parcialmente hidrolizado de seroproteína de leche de vaca.- Fructoligosacáridos; mejoran la sintomatología, reducen la esteatorrea y mejoran el estreñimiento, con un aumento significativo del liquido fecal, sin inducir malabsorción de los hidratos de carbono (AU)

Afectación del contenido mineral óseo en patologías digestivas / Involvement of bone mineral content in digestive disease

La mineralización ósea es un proceso dinámico que se inicia intrauterinamente y acaba en la tercera época de la vida. Entre las diferentes circunstancias patológicas que pueden concluir a una alteración de la mineralización se encuentran las patologías digestivas. El objetivo de nuestro trabajo ha sido conocer el CMO en diferentes patologías digestivas, y dar las recomendaciones precisas para el tratamiento y prevención de la desmineralización. Material y método: se efectuaron mediciones de la densidad mineral ósea (DMO) en las vértebras L2-L4, mediante la técnica de absorciometría de doble fotón (modelo DPX-L) en 90 pacientes afectos de las siguientes patologías: enfermedad celíaca (n:18), fibrosis quística (FQ) (n:45), enfermedad inflamatoria intestinal (EII) (n:7), intolerancia a la lactosa/ proteínas vacunas (n:20). Los resultados expresados en forma de Z-Score para las medidas han sido: enfermos celíacos (Z-Score -0,45), FQ (Z-Score - 1,1), EII (Z-Score -1,24) e intolerancia lactosa / proteína vacuna (Z-Score-1,2). En todos lo grupos existían pacientes con valores normales, osteopénicos y osteoporóticos. Podemos concluir que los niños y adolescentes afectos de afecciones gastrointestinales corren el riesgo de padecer osteopenia / osteoporosis. Deben ser controlados mediante la técnica de DMO y adoptar las medidas preventivas o terapéuticas necesarias para evitar una indebida mineralización que repercutirá negativamente en la época adulta (AU)

Methane and hydrogen exhalation in normal children and in lactose malabsorption.

UNLABELLED: Methane (CH4) and hydrogen (H2) are gases produced in the colon by the breakdown of carbohydrates, due to the action of anaerobic methanogenic bacteria. No papers have been published in pediatrics concerning these gases production and exhalation. Understanding of the pattern of H2, CH4, carbon dioxide (CO2), butyrates, indolellipsis,etc., production and exhalation, which may differ in gastrointestinal diseases, may be helpful as far as the diagnosis and treatment of some gastrointestinal conditions is concerned. Exhalation of H2, CH4 and CO2 by breath air was studied in basal conditions in 338 normal infants and in 27 lactose malabsorbers. Moreover, stools collected and stored for 10-12 h in anaerobic and aerobic conditions were incubated in anaerobiosis at 38 degrees C. After a 4-h incubation period, H2, CH4 and CO2 were determined. RESULTS: Methane production is independent of hydrogen production; the number of children producing CH4 increases from 0% at 12 months of age to 44% at the age of 9 years. In lactose malabsorption, we found 26 children producing increased quantities of H2 and no methane, and only one producing methane but no hydrogen, which proves that methanogenic bacteria are independent of H2-producing bacteria, and that CH4 determination is compulsory in the study of lactose malabsorption. The incubation of stools in an anaerobic milieu at 38 degrees C for 4 h, in an attempt to imitate the human colon, showed a great production of methane and less of H2 in the stools collected and stored in anaerobic conditions. The same incubation method was applied to the stools collected and stored in aerobic conditions: production of H2 and CH4 was much lower than in the collected and stored anaerobic group. The appearance of CH4 in the stools of the aerobic group proves that methanogenic bacteria are, to a small degree, resistant to oxygen. CONCLUSIONS: The study of gas exhalation in pediatrics merits more study by researchers, with a view to defining a special pattern of gas production in pathological conditions. The anaerobic stool incubation method is a good model for studying gas production under the effect of different diets and the gas production pattern in gastrointestinal diseases.

Analysis of risk factors following pediatric liver transplantation.

Several recipient, donor and operation factors as well as postoperative complications related to patient survival after liver transplantation (LT) in children were studied by univariate and multivariate analyses. In a 13-year period, 103 patients under 15 years of age underwent 120 LT; the mean age was 63 months and 36% were under 2 years of age. Indications for LT were cholestatic disease in 68 (56%), metabolic diseases in 18 (14%), fulminant hepatic failure in 8 (7.5%), cirrhosis in 7 (5.8%), and retransplants in 17 (14%). Whole liver was transplanted in 79% of cases and partial liver in 21%. Actuarial survival at 1, 5, and 10 years was 70%, 61%, and 57%, respectively. United Network of Organ Sharing (UNOS) I recipients (RR = 2.7), primary non-function (PNF) (RR = 13.9), and hepatic artery thrombosis (HAT) (RR = 3.8) were independent factors for lower patient survival in multivariate analysis. Thus, in our experience, postoperative mortality as a consequence of the patient's condition before transplantation, or complications such as PNF or HAT, are the major causes of decreased survival in pediatric LT.

Fungemia with Saccharomyces cerevisiae in two newborns, only one of whom had been treated with ultra-levura.

Ultra-Levura (Upsamedica, Spain) is a yeast (Saccharomyces boulardii) widely used as a biotherapeutic agent. To date, few adverse effects have been reported, although fungemia with Saccharomyces cerevisiae can occur in weak and immunosuppressed patients. Reported here are two cases of fungemia with Saccharomyces cerevisiae. One patient had been treated with Ultra-Levura and the other contracted the infection from the first. This is the first report of infection with Saccharomyces boulardii (Saccharomyces cerevisiae) in a patient who was not being treated with the agent.

Prevalence of hepatitis G virus in healthy children in liver disease, and human immunodeficiency virus-1 infection: response to interferon.

BACKGROUND: A new virus of the Flaviviridae family, the hepatitis G virus (HGV/HGBV-C), has been identified recently. The purpose of this study was to determine the prevalence of HGV infection in healthy children, in patients with liver disease, and in human immunodeficiency virus (HIV)-1-infected patients. The role of HGV in the clinical course of chronic HCV, the response to interferon-alpha2b, and the possible implications of intravenous gamma-globulin in the transmission of the virus were also evaluated. METHODS: Fifty healthy children, 66 patients with a variety of liver diseases, 19 patients with acquired immune deficiency syndrome (AIDS), and various batches of commercial intravenous immunoglobulins were investigated. Viral HGV RNA (5'NCR-NS5) and anti-HGV envelope protein E2 were assayed. RESULTS: The prevalence of HGV infection was 6% in the healthy children and 42% in the liver disease group. Viremia and anti-E2 were found in 11% and 79% of patients with AIDS. Four (27%) of 15 patients with chronic HCV, receiving treatment with interferon, were coinfected by HGV and became HGV-RNA negative during therapy. One year after the end of interferon therapy, three of them were again HGV RNA positive. CONCLUSIONS: The prevalence of HGV infection is high in healthy children higher in children affected with liver disease, but its potential pathologic implication is questionable, and further studies are warranted. Hepatitis G virus is sensitive to interferon therapy, although the infection often recurs after discontinuation of treatment.

Risk of inadequate bone mineralization in diseases involving long-term suppression of dairy products.

BACKGROUND: Eighty percent of peak bone mass should be achieved from birth through adolescence. An adequate calcium intake is essential, and it is advisable that 60% of the recommended calcium allowance be dairy calcium. This study was conducted to examine bone mineral content (BMC) in patients with diseases that usually involve long-term suppression of dairy products. METHODS: Thirty patients, aged 2 to 14 years (mean, 7 years), 10 with late-onset, genetically induced lactose intolerance, 7 with cow's milk protein allergy, 3 with short-bowel syndrome, and 10 with hypercholesterolemia were involved in the study. They were receiving various dietary regimens for periods longer than 2 years: 14 patients received special formulas for children (lactose-free cow's milk formula, highly hydrolyzed cow's milk protein formula, soy protein isolate formula), 4 patients received liquid soy beverages, 6 patients received skim milk (1% fat), and 6 patients had exclusion of dairy products. Bone mineral density (BMD) was assessed by dual-energy x-ray absorptiometry. RESULTS: Nine patients had osteoporosis, 6 had osteopenia, and 15 had results within normal ranges. Overall, the group had a standard deviation score of -1.3 (osteopenia). The statistical correlation between the BMD value and the percentage intake of recommended daily allowance (RDA) of dairy (or substitute) calcium (in milligrams per day) was highly significant (P < 0.0001, r = 0.89). CONCLUSIONS: All patients with diseases involving total or partial withdrawal from milk products for a prolonged period are a group at potential risk of defective bone mineralization and should be monitored through BMD assessment.

Changes in growth, growth hormone, and insulin-like growth factor-I (IGF-I) after orthotopic liver transplantation.

Growth failure is an important consequence of chronic liver disease in childhood. Insulin-like growth factor-I (IGF-I), which is synthesized and released by the liver, plays an important role as a growth regulator in humans. We examined the growth hormone (GH)/IGF-I axis before and after orthotopic liver transplantation (LT) in 14 children aged between 2 and 11 years (mean 5.6 +/- 1.1 years). Pre-transplantation serum GH levels (7.5 +/- 1.2 ng/ml) were significantly higher (P < 0.001) compared with controls (5 +/- 0.5 ng/ml). However, post-transplantation levels (1.8 +/- 0.8 ng/ml) did not differ from those in the control group. Serum IGF-I levels showed a statistically significant increase after LT (20.1 +/- 9.4 vs 190 +/- 66.2 ng/ml; P < 0.001) and became indistinguishable from the levels in the control group (180 +/- 96 ng/ml). In comparison with pre-transplantation data (z - 2.70), there was an increase in height 4 years postoperatively (z - 1.68). Catch-up growth was highly significant, in particular during the 1st year after LT (z -1. 58 +/- 1.63 vs 2.59 +/- 5.29; P < 0.01). We conclude that a GH resistance state found in patients with severe chronic liver disease reverted following LT. Given that IGF-1 depends upon liver function, this could be one of the main factors in the significant catch-up growth in pediatric LT recipients.

Protein in infant formulas. Future aspects of development.

Cow's milk protein intolerant infants (CMPI), shifted to a cow's milk protein hydrolysate based formula, often experience an improvement in signs of malabsorption; on the other hand, they also present a pattern of watery stools. In an attempt to find high levels of some gastrointestinal hormones that might induce hypermotility, motilin and neurotensin levels were studied in infants on starting formula and in cow's milk protein intolerant infants, on a cow's milk protein hydrolysate based formula. In 12 infants on unmodified cow's milk based formula (starting formula), motilin levels were: mean 71.66 pmol/L (s: 17); neurotensin 26.53 (s: 10.9). In 19 cow's milk protein intolerant infants on a cow's milk protein hydrolysate based formula, motilin levels were: mean 163.65 pmol/L (s: 70.06) (p<0.05); neurotensin: 31.76 pmol/L (s: 15.03) (p>0.05). Motilin (but not neurotensin) is higher in cow's milk protein intolerant infants on a cow's milk protein hydrolysate based formula. We conclude that high motilin levels can induce a different pattern of motility, and can be a pathogenetic factor in the persistence of loose and watery stools in infants with CMPI on a protein hydrolysate based formula.

[Our experience in the management of portal cavernoma in children]. / Nuestra experiencia en el manejo de la cavernomatosis portal en el niño.

The authors present 14 patients affected with portal cavernoma, diagnosed and controlled over the last 12 years. The splenomegaly (60%) and the digestive hemorrhages (40%) were the initial study causes. The cavernoma appeared idiopathic in 10 patients or secondary either to a catheterization of umbilical vein (3 cases) or onfalitis (1 case). The first clinical manifestation oscillated between the ages of 3 months to nine years. The diagnosis was performed in the initial cases (4 cases) using splenoportography (3 cases) and superior mesenteric arteriography (SMA) in the other. In the remaining cases the ultrasonography together with the endoscopic evidence of the varies backed up the diagnosis. Before the intervention, a SMA was performed in all cases. The surgical decision was taken with regards to the persistence of the digestive bleeding after the start of medical treatment with propranolol, cimetidine, and sucralfate, along with the existence of dangerous varices. Eight patients were operated on, two by the Warren technique, four by mesocaval jugular graft interposition (MJI) and two by azigo portal disconnection (APD). The shunts initially controlled the bleeding in all cases. There was one rebleeding instance at eleven months in a patient operated on by MJI, and in another by APD. Four patients continue medical treatment without problems, and two are free of treatment. Our experience with varies sclerosis is limited to two cases, although since the beginning of the treatment, one year ago, neither of them has bled.

[Transjugular portosystemic shunt. An alternative in recurrent hemorrhage in portal hypertension in children]. / La derivación porto sistémica transyugular. Una alternativa ante ciertas hemorragias recidivantes por hipertensión portal en el niño.

The transjugular portosystemic bypass is a new technique for treating portal hypertension of an intrahepatic nature by inserting a multipurpose catheter through the jugular vein and vena cava as far as the suprahepatic vein, with the aid of a puncture device it is fed via the hepatic parenchyma into a portal branch. The passageway thus created is distended with a balloon to permit the insertion of an extensible metal mesh prosthesis or "stent" to maintain a permeable connection. Our experiment was conducted on a paediatric patient suffering from mucoviscidosis with severe pulmonary and hepatic involvement and recurrent bleeding in an uncontrollable position. After inserting the bypass, portal pressure dropped sharply and the bleeding stopped, the patient being discharged on the sixth day. Two months after the bypass, the coronary vein of the stomach, the seat of the gastric varicose veins, was selectively occluded through the stent via the femoral vein. Six months after follow-up, the digestive bleeding has not recurred.

Committee report: childhood diet and prevention of coronary heart disease. ESPGAN Committee on Nutrition. European Society of Pediatric Gastroenterology and Nutrition.

Coronary heart disease is a major cause of morbidity and mortality in Europe, particularly northern, central, and eastern Europe. Several strategies have been recommended for children and adolescents to promote a healthy lifestyle and thereby reduce the risk of coronary heart disease in later life. The European Society of Pediatric Gastroenterology and Nutrition (ESPGAN) Committee on Nutrition reviewed some of these strategies, and our conclusions and recommendations are reported herein.

Trans fatty acid content of human milk in Spain.

The C18 fatty acid fraction of 38 samples of mature human milk from Spanish women was analyzed using capillary gas chromatography. The average content of trans fatty acids found in these samples represented 0.95% of total fatty acids. This value is lower than the percentage found in human milk from other developed countries in which the consumption of hydrogenated fat is higher. Trans fatty acid content in human milk has been related to the types of fats and oils present in the diets of the nursing mothers. According to the results obtained in this survey, we can also conclude that the amount of trans forms in breast milk lipids is lower than the trans content found in infant formulas in Spain.