ALERGIA A LA PROTEíNA DE LA LECHE DE VACA. EVALUACIóN DE SU RESOLUCIóN ESPONTáNEA POR MEDIO DE DESAFíOS DOBLE CIEGO PLACEBO CONTROLADOS / cows milk allergy. an assesment of its spontaneous resolution through double blind placebo controlled challenges.

Introducción. la alergia a la leche de vaca (aplv) es un problema sanitario global. Su diagnóstico adecuado y su seguimiento son esenciales ya que la leche de vaca es un alimento importante en la dieta de muchos lactantes. los desafíos orales doble ciego controlados por placebo (ddcpc) son la herramienta ideal para el diagnóstico y seguimiento de las alergias alimentarias. este estudio describe las características evolutivas de pacientes con aplv y las posibles variables que la pudieran modificar. material y métodos. Se estudiaron pacientes con diagnóstico de aplv previo con desafíos abiertos. Se catalogaron las reacciones de acuerdo a la normativa dracma. positivas fueron las pruebas en las que se presentaron alteraciones clínicas o variaciones hemodinámicas. negativas fueron aquellas en las que el paciente toleró la leche. Se consideraron edades de inicio y de realización del ddcpc, sexo y patología de aplv. resultados. Se estudiaron 106 pacientes (50 masculinos, 56 femeninos), promedio edad de inicio de síntomas 5,31 m (rango: 1-48 meses) y al procedimiento 23,14 m (5 meses - 5 años), y 13 pruebas positivas. un conjunto se refirió al mecanismo fisiopatológico y se dividió en ige mediadas (n=55) con 8 pruebas positivas y mixtas/celulares (n=51) con 5 pruebas positivas. otro conjunto fueron no gastrointestinales (n=61) con 7 pruebas positivas y gastrointestinales (n=45) con 6 pruebas positivas. todos los grupos fueron similares en cuanto a las variables demográficas. el sexo masculino y el diagnóstico de anafilaxia fueron factores de riesgo para no resolver su aplv (p=0,0125 y p=0,002 respectivamente). conclusiones. el momento de resolución de la aplv es independiente del mecanismo fisiopatológico subyacente o la edad de inicio de los síntomas. en general resuelven el problema de manera espontánea hacia los dos años de vida en más de un 87% de los casos. el sexo masculino (en ige mediadas) y el antecedente de anafilaxia podrían ser factores de riesgo para tener menos probabilidades de resolver la APLV. (AU)

Introduction: cow´s milk allergy (cma) is a global health issue. a proper diagnosis and follow up become essential. double blind placebo controlled challenges (dbpcc) is the gold standard for this purpose. this paper describes clinical evolution and characteristics of cma, as well as variables that may modify the affection course. methods & material: a group of patients, with a previous diagnosis of cma by open challenges, has been studied and its results cataloged according to dracma guidelines. tests with hemodynamic changes or clinical symptoms were considered as positives, while those with no clinical reaction were considered as negatives. variables involved were: age of symptoms starting, age of dbpcc performing, gender and cma clinical manifestations. results: 106 patients has been studied (50 male, 56 female), with a median age of 5,31 mo (range 5 ­ 48 mo) at the starting symptoms, and a median age of 23,14 mo (range 5 mo ­ 5 y) at the performing of dbpcc. 13 tests were negative. as regards to the different immune mechanisms, 55 were ige dependent (8 negative), and 51 were mediated by mixed/cellular (5 negative). patients were divided into two groups: with gastrointestinal symptoms (n=45) and with no gastrointestinal symptoms (n=61). they showed 6 and 7 negative results, respectively. all groups were similar. male gender, and anaphylaxis diagnosis turned out to be risk factors not to resolve cma (p=0,0125 and p=0,002 respectively). conclusions: cma resolution is independent of the immune mechanisms involved or the age of its symptoms starting. cma is solved spontaneously towards the age of two in 87% of the cases. male gender, and anaphylaxis may become risk factors not to resolve cma.(AU)

Metabolic parameters and adipokine profile in growth hormone deficient (GHD) children before and after 12-month GH treatment.

It is a common knowledge that GH exhibits a large number of metabolic effects, involving lipid and glucose homeostasis. The aim of the study was to investigate the effect of one year GH therapy on metabolic parameters and adipokines in GH deficient (GHD) children. Sixteen prepubertal children (11 M and 5 F) with complete GHD (age range: 3.4-14.7 years) and 20 (13 M and 7 F) age and sex-matched healthy children (age range: 4.6-12.3 years) were studied. Blood was collected from patients before starting GH therapy (0.025 mg/kg/day) and one year later, and from healthy children to measure adiponectin, leptin, osteoprotegerin, resistin, interleukin (IL)-6, tumor necrosis factor (TNF)-α levels, and other glucose and lipid metabolism parameters. Adiponectin and resistin levels were significantly higher (49980 ng/ml vs. 14790 ng/ml and 11.0 pg/ml vs. 6.3, respectively) in GHD children before GH therapy than in controls. Serum IGF-I levels (p=0.0001) and height SDS (p<0.0001) significantly increased after 12 months' of GH therapy. There was a loss of body fat reflected by a significant decline in tricep (p=0.0003) and subscapular skinfold thickness SDS (p=0.0023). After 12 months, there was a significant rise in insulin (p=0.0052) and leptin levels (p=0.0048) and a significant decrease in resistin (p=0.0312) and TNF-α (p=0.0137). We observed that lipid and glucose metabolisms are only slightly affected in GHD children. Growth hormone replacement therapy affects some factors, such as leptin, resistin and fat mass, suggesting that also in children, GH treatment has a role in the regulation of factors secreted by adipose tissue.

Diagnosis of growth hormone deficiency is affected by calibrators used in GH immunoassays.

Growth hormone (GH) values vary among immunoassays depending on different factors, such as the assay method used, specificity of antibodies, matrix difference between standards and samples, and interference with endogenous GH binding proteins (GHBPs). We evaluated whether the use of different calibrators for GH measurement may affect GH values and, consequently, the formulation of GH deficiency (GHD) diagnosis in children. Twenty-three short children (5 F, 18 M; age 11.4±3.1 years), with the clinical characteristics of GHD (height: -2.3±0.5 SDS; height velocity -2.3±1.5 SDS; IGF-I -1.2±0.9 SDS), underwent GH stimulation tests to confirm the clinical diagnosis of GHD. Serum GH values were measured with Immulite 2000, using 2 different calibrators, IS 98/574, a recombinant 22 kDa molecule of more than 95% purity, and IS 80/505, of pituitary origin and resembling a variety of GH isoforms. We found blunted GH secretion in 20 subjects with the Immulite assay using the IS 98/574 GH as a calibrator, confirming the diagnosis of GHD. Subsequently, using IS 80/505 GH as a calibrator, in the same samples only 14 children showed reduced GH levels. The total cost for the first year of GH therapy of patients diagnosed with IS 98/574 as a calibrator was higher than that for patients diagnosed with IS 80/505 as a calibrator. These data confirm that GH values may depend on different calibrators used in the GH assay, affecting the formulation of GHD diagnosis and the consequent decision to start GH treatment.

Alergia al huevo en Pediatría. Documento del Comité de Pediatría de la Asociación Argentina de Alergia e Inmunología Clínica / Egg allergy in pediatrics. Pediatric Committee document of the Argentina Association of Allergy and Clinical Immunology

El huevo de gallina es una fuente de proteínas de alto valor biológico de bajo costo y de vitaminas del complejo B, importantes para la alimentación del niño. Culturalmente es uno de los alimentos básicos de nuestra dieta y, debido a esto, la alergia a sus proteínas es una de las más frecuentes en la infancia y tiene su mayor impacto en niños en edad preescolar. Estos niños representan una población vulnerable debido a que se encuentran en una etapa importante de su crecimiento y desarrollo, y el tratamiento de esta patología genera la adopción de dietas restrictivas que pueden impactar en forma negativa en su salud y calidad de vida. Este impacto está dado en parte por la ubicuidad de sus proteínas, que limita ampliamente la dieta y genera riesgos de reacciones alérgicas que se incrementan a medida que el niño crece y alcanza una mayor independencia. Teniendo en cuenta la importancia de esta patología, el Comité de Pediatría realizó una revisión actualizada con el fin de proveer herramientas útiles para el manejo adecuado de la misma. (AU)

Eggs are a source of low cost high biological value protein and complex B vitamins important for the child's nutrition. Culturally it is one of the staples of our diet and because of this, egg allergy is one of the most common food allergies in childhood and has its greatest impact on preschool children. These children represent a vulnerable population because they are at an important stage in their growth and development and the treatment of this condition generates the adoption of restrictive diets that may impact negatively on their health and quality of life. This impact is given in part by the ubiquity of their proteins that largely restrict the diet and generates risks of allergic reactions that increase as the child grows and earns greater independence. Given the importance of this issue the Pediatrics Committee conducted an updated review to provide useful tools to manage this condition.(AU)

Estudio multicéntrico de evaluación del conocimiento de los pediatras acerca de reacciones alérgicas a vacunas para enfermedades infecciosas / A multicenter study assessing pediatrician's knowledge about allergic reactions to infectious disease vaccines

Resumen. Las reacciones alérgicas a las vacunas contra agentes infecciosos han generado preocupación entre los pediatras. Sin embargo, se desconoce el grado de información que tienen estos especialistas de nuestro país sobre este tema. Objetivo. Contar con datos estadísticos acerca de este problema. Población. Trescientos veinte pediatras encuestados. Método. Estudio multicéntrico descriptivo prospectivo de corte transversal realizado con encuestas estandarizadas Resultados. El 12,5% de los encuestados reconoció la presencia de síntomas de aparición rápida como reacción de hipersensibilidad inmediata. (61,6%) consideró a estas reacciones como infrecuentes. El 72,6% reconoció a la neomicina como causa de alergia, el 51,6 % al timerosal, el 73% a los conservantes, un 30,4% a la gelatina y la mitad de los encuestados al componente activo. El 62,3% reconoció a la proteína del huevo como componente de la vacuna MMR. Ante antecedentes de alergia al huevo, el 35% de los médicos contestó que contraindica siempre las vacunas que contienen proteína del huevo, el 14% no las contraindica nunca y el 9% no sabe. Los médicos de menos de 5 años de recibidos reconocieron con mayor frecuencia la presencia de una reacción alérgica a vacunas (p = 0,004). Los médicos de más de 10 años de recibidos solicitan más frecuentemente interconsulta con el especialista ante casos de vacunación de pacientes con alergia a la proteína del huevo (p = 0,01). Conclusiones. Existe un grado importante de desconocimiento acerca de las reacciones alérgicas a vacunas, los componentes de las vacunas involucrados en dichas reacciones y las conductas a tomar frente a pacientes con alergia al huevo.(AU)

Background: Allergic reactions to infectious disease vaccines have generated concern among pediatricians. It is unknown the level of pediatrician's knowledge about this issue. The aim of this study is to obtain statistical data about this issue in our country. Population: 320 pediatricians. Methods: A transversal prospective descriptive multicenter study by means of a survey. Results: 12.5% of participants were capable to identify symptoms of immediate hypersensitivity reactions and 61.6% considered that these reactions are not frequent. The pediatricians pointed out as the most commonly allergen components the following ones: Neomicine (72.6%), thymerosal (51.6 %), preservatives (73%), gelatin (30.4%) and active component (nearly 50%). 62.3% knew that eggs proteins are part of MMR vaccine. In the case of patient with history of egg allergy, 35% answered that they always contraindicate vaccination with egg protein vaccines while14% do not contraindicate and 9% do not know what to do. Physicians less than 5 years of graduation recognized more frequently the presence of allergic reactions (p: 0.004). Physicians with 10 or more years of graduation asked for specialist opinion more frequently in the case of patients with egg allergy (p: 0.01). Conclusions: It was found an important lack of information about allergic vaccine reactions, the involved vaccine constituents and the correct management of situations related to egg allergy.(AU)

Hyperimmunoglobulinaemia in Babinga Pygmies is present from infancy.

Pygmies, a population characterized by short stature, have high immunoglobulin (Ig) concentrations. In this study, we evaluated Ig levels in Cameroons Babinga Pygmies from infancy to adulthood and the effects of a national health program on these Ig levels. We found that IgG and IgM levels were outside the normal range for Italians of the same age and were comparable to those measured in Babinga Pygmies living in the same region by Siccardi in 1975. In conclusion, the hypergammaglobulinaemia of Babinga Pygmies is already present in infants and is not affected by sanitation improvements, suggesting that it could be partly genetically-determined.

Variations in biological and immunological activity of growth hormone during the neonatal period.

BACKGROUND/AIMS: It was postulated that a high growth hormone (GH) bioactivity might explain the rapid growth rate of neonates. The aim of this study is to verify changes in serum GH biological potency (Bio-/Immuno-GH ratio) and their effects on serum growth factors during the first month of life in term and preterm babies. METHODS: Blood samples were collected from 10 small-for-gestational-age preterm (SGAPT), 17 appropriate for gestational age preterm (AGAPT) and 26 AGA term (T) neonates on days 4, 15 and 30 of life to evaluate serum GH values measured by IFMA (IFMA-GH) and bioassay (Bio-GH), serum insulin-like growth factor-I (IGF-I) and IGF-binding protein-3 (IGFBP-3). RESULTS: High serum Bio-GH values on the first few days of life correspond to high IFMA-GH values, suggesting full biological potency of circulating GH. Furthermore, IGF-I/IGFBP-3 molar ratio values in preterm babies were higher than in full-term infants. CONCLUSIONS: These data confirmed the hypothesis that the higher growth velocity in the first month of life of preterm neonates is due to an increased bioavailability of IGF-I. A progressive maturation of the hypothalamic-pituitary-IGF-I axis without any alteration in the GH biological potency seems to underpin the increase of the growth factors early in life.

Dose dependency of the serum bio/immuno GH ratio in children during pharmacological secretion tests.

Dissociation between GH bioactivity (bio-GH) and GH immunoactivity (immuno-GH) is due to the heterogeneity of the molecule: the measurements do not always provide reliable information on the bio-GH. We studied the ratio of bio-GH and immuno-GH during pharmacological secretion tests in 211 sera to study the concentration-response curve of the assay (C1), 16 samples of normally growing subjects with idiopathic short stature (C2), 13 samples from patients with GH deficiency (GHD1) and 6 samples of 3 patients with GHD and normal provocative tests (GHD2). GH bioactivity was determined by the Nb2 cell proliferation assay (bio-GH) and immuno-GH by a time-resolved immunofluorometric assay (IFMA) (immuno-GH). A non-linear negative relationship between the serum bio-GH/immuno-GH ratio and serum immuno-GH was observed in C1. In log-log plotting representation, two cut-off lines were drawn: a vertical cut-off line separating above-below cut-off serum peak immuno-GH values in provocative tests, and a diagonal cut-off line separating normal-abnormal serum bio-GH/immunoGH ratio; four areas were defined. GHD1 had normal ratios, but below cut-off peak immuno-GH responses. P2 and P3 of Group GHD2 had abnormal ratios in samples with low serum immuno-GH but only P2 had autosomal dominant mutation. P1 had the same autosomal dominant isolated GHD as P2 but a low normal ratio. Our data underline the importance of relatively low serum GH concentrations in mediating GH biological actions. An abnormal serum bio-GH/immuno-GH ratio might explain certain cases of GHD and might be useful in detecting abnormal circulating isoforms of GH in patients with growth failure.

Can GH induce chromosome breaks or microsatellite instability in GH-deficient children?

The role of GH in carcinogenesis is unclear. We studied the effect of recombinant human GH (rhGH) in vitro on chromosomal and genomic instability. Thirteen children, aged 9.57 +/- 1.08 yr (mean +/- SEM), with complete (no.=5) or partial (no.=8) GH deficiency were evaluated before and during GH treatment. We examined the incidence of chromosome and chromatid breaks, and microsatellite instability after in vitro addition of two different doses of rhGH to peripheral blood lymphocytes obtained from the patients. No differences were observed between the samples of GH-deficient children before and after GH therapy as regards the percentage of chromosome and chromatids breaks, and in microsatellite instability. Our data show that in vitro addition of rhGH does not induce chromosomal and/or genomic instability in cultured lymphocytes.

Hyperparathyroidism.

Hyperparathyroidism is a disease characterized by hypercalcemia with hypophosphoremia resulting from increased secretion of parathyroid hormone (PTH). The disease may be divided into 3 forms: a) primary, b) secondary, c) tertiary (secondary refractory form). Primary hyperparathyroidism is rare in children; hyperplasia is more frequent during the early years of life (neonates and infants) and is difficult to distinguish from adenoma in children. The disease may be asymptomatic; elevated calcemia levels (>12 <13.5 mg/dl) are accompanied by anorexia, asthenia and persistent stipsis; severely elevated concentrations (>13.5 mg/dl) are accompanied by nausea, vomiting, polyuria due to osmosis, with dehydration and progressive onset of lethargy, stupor and coma. Osteopenia or osteitis fibrosa cystica may be present due to augmented bone resorption. Height and weight increases are altered due to anorexia and dehydration. Differential diagnosis includes iatrogenic causes of hypercalcemia (excessive vitamin D intake, prolonged immobilization, etc.) and idiopathic familial hypercalcemia. Emergency treatment is required in cases of extremely elevated hypercalcemia (Ca >13.5-14 mg/dl), due to risk of injury to the heart, the central nervous system, the gastrointestinal tract and the kidneys. The 4 cardinal points of treatment are: hydration, calciuresis, inhibition of bone calcium resorption, treatment of the cause underlying hyperparathyroidism. Secondary hyperparathyroidism is found in cases where chronic hypocalcemia is present, particularly in chronic renal failure, untreated deficiency rickets, chronic intestinal malabsorption, hepatobiliary disease, types I and II vitamin D-dependent rickets, tubular acidosis or Fanconi's syndrome. The tertiary form is distinguished by the autonomous nature of the parathyroid glands which have become hypertrophic/hyperplastic due to uncontrollable, chronic severe renal failure. It can also be of iatrogenic origin due to excessive intake of inorganic phosphates in familial hypophosphatemic rickets or chronic vitamin D deficiency.

Unresolved problems in optimal therapy of pubertal disorders in oncological and bone marrow transplanted patients.

Specialised clinics for the long-term follow-up of survivors from childhood cancer have developed over recent years. The problems encountered among patients who received multiple chemotherapy and radiotherapy can be challenging and require high expertise and close collaboration among different professionals (e.g. oncologists, endocrinologists, radiotherapists, psychologists). Endocrine disorders are often seen, particularly among those who received cranial radiotherapy or gonadotoxic chemotherapy; puberty can be affected and the spectrum of disorders may range from precocious or accelerated puberty to delayed, arrested or even absent pubertal development. Growth impairment can be multifactorial and growth hormone deficiency is an important but probably not the only factor involved. Many questions remain about the optimal management of this group of young patients. In the consensus guidelines that follow the overview an attempt is made to help optimise patients' growth and puberty by suggesting practical clinical approaches to some of the most challenging issues.

Isochromosome (7)(q10) in Shwachman syndrome without MDS/AML and role of chromosome 7 anomalies in myeloproliferative disorders.

Shwachman syndrome (SS) is an autosomal recessive disorder in which bone marrow dysfunction is observed, with development of myelodysplastic syndromes (MDS) and acute myeloid leukemias (AML) in up to one third of the cases. Inconclusive data are available as to increased chromosome breakage in SS, while chromosome 7 anomalies, and often an isochromosome (7)(q10), are frequent in cases with MDS/AML. We report on the consistent presence of an i(7)(q10) in the bone marrow and blood lymphocytes in one of two sisters affected with SS without any clinical or cytological signs of MDS/AML. Thus, this patient was either a case of constitutional mosaicism for the i(7)(q10), or this had to be acquired in a nondysplastic and non-neoplastic marrow clone. DNA polymorphism analysis demonstrated the paternal origin of the i(7q). We postulate that the SS mutation acts as a mutator gene, and causes karyotype instability; abnormal clones would thus arise in the marrow, and chromosome 7 anomalies, i(7q) in particular, will in turn lead to MDS/AML. If this interpretation is correct, it would be also an indication to consider chromosome 7 anomalies in general, out of SS, as primary changes in MDS/AML pathogenesis.

Long-term follow-up evaluation of magnetic resonance imaging in the prognosis of permanent GH deficiency.

OBJECTIVE: In patients with GH deficiency (GHD), magnetic resonance imaging (MRI) has revealed morphological abnormalities such as pituitary hypoplasia, pituitary stalk agenesis (PSA) and ectopia of the posterior pituitary (PPE). The MRI anomalies have been more frequently reported in patients with multiple pituitary hormone deficiency (MPHD) than in subjects with isolated GH deficiency (IGHD). The aim of this work was to define which MRI anatomical abnormalities of the hypothalamo-pituitary area can be considered as a prognostic marker of permanent GHD. DESIGN: To investigate the relationship between the neuroradiological images and endocrine findings, we clinically re-evaluated 93 out of the 121 GHD patients with IGHD and MPHD previously studied. RESULTS: No additional hormone deficiencies were observed in 55 out of 60 patients initially classified as having IGHD with a normal (15 cases) or reduced (40 cases) pituitary gland size, without other MRI abnormalities. The remaining five children, who had initially shown an apparently IGHD in spite of PSA and PPE, developed a MPHD over time. In 33 MPHD patients with (25 cases) or without (8 cases) MRI abnormalities, the associated hormone deficiencies were confirmed during follow-up. CONCLUSIONS: The IGHD patients showing PSA and PPE inevitably develop additional hormone deficiencies, while IGHD subjects having no MRI abnormalities maintain IGHD. Moreover, the anatomical abnormalities of the hypothalamo-pituitary area can be considered as a prognostic marker of permanent GHD.

Relationships between neuroradiological and clinical features in apparently idiopathic hypopituitarism.

In this study, perinatal history, postnatal auxological and clinical evolution and endocrine features were retrospectively evaluated in 49 children, adolescents and young adults with apparently idiopathic hypopituitarism. They were divided into two groups according to magnetic resonance images: 32 patients with isolated pituitary hypoplasia (group A) and 17 with pituitary stalk interruption syndrome (group B). The aim of the study was to assess whether these neuroradiological pictures are associated with specific endocrine and clinical patterns. No significant difference in terms of gestational age, intrauterine growth and rates of adverse perinatal events was found between the two groups. Clinical signs documenting the existence of pituitary dysfunction in utero or shortly after birth were either slightly (micropenis, cryptorchidism, cholestatic jaundice) or significantly (hypoglycemia) more frequent in patients in group B. Although diagnosis of hypopituitarism was made significantly earlier in patients in group B, height deficiency at diagnosis was similar in both groups. Endocrine investigations revealed a more severe and widespread impairment of pituitary function among those in group B. The main conclusion is that the postnatal clinical course is more severe when growth hormone deficiency is associated with pituitary stalk interruption syndrome than when the pituitary is only reduced in height, probably because of the more severe and widespread impairment of pituitary function in the former cases.

Modulating effect of human growth hormone on tumour necrosis factor-alpha and interleukin-1beta.

We measured serum tumour necrosis factor-alpha (TNF-alpha) as well as interleukin-1betta (IL-1beta) and GH concentrations in 15 children with isolated growth hormone deficiency (GHD), age range 5.1-13.9 years, before and 4 and 24h after the first GH injection (0.1 IU/kg s.c.). No differences were found in basal concentrations of serum TNF-alpha and IL-1beta between GHD children (10.01 +/- 1.55 pg/ml and 2.14 +/- .16 ng/ml respectively) and sex- and age-matched controls (11.57 +/- 2.16 pg/ml and 3.78 +/- 1.46 ng/ml respectively). In GHD children, serum TNF-alpha and IL-1beta values had significantly increased (P < 0.002) 4h (26.75 +/- 5.57 pg/ml and 2.99 +/- 0.21 ng/ml respectively) and decreased again 24 h after GH administration. Likewise, serum GH levels had significantly increased 4 h (from 1.29 +/- 0.69 to 48.71 +/- 13.35 ng/ml, P < 0.001) and decreased to basal values 24h after GH administration. A significant correlation was found between basal serum concentrations of GH and those of both TNF-alpha (P < 0.01) and IL-1beta (P < 0.05). However, no correlation was found between serum GH concentration and either TNF-alpha or IL-1beta levels 4 and 24h after GH administration. Our data suggest that GH plays a role in modulating TNF-alpha and IL-1beta release in humans.