LUTEINIZING HORMONE RECEPTOR MUTATIONS IN DISORDERS OF SEXUAL DEVELOPMENT AND CANCER

Human male sexual development is regulated by chorionic gonadotropin (CG) and luteinizing hormone (LH). Aberrant sexual development caused by both activating and inactivating mutations of the human luteinizing hormone receptor (LHR) have been described. All known activating mutations of the LHR are missense mutations caused by single base substitution. The most common activating mutation is the replacement of Asp-578 by Gly due to the substitution of A by G at nucleotide position 1733. All activating mutations are present in exon 11 which encodes the transmembrane domain of the receptor. Constitutive activity of the LHR causes LH releasing hormone-independent precocious puberty in boys and the autosomal dominant disorder familial male-limited precocious puberty (FMPP). Both germline and somatic activating mutations of the LHR have been found in patients with testicular tumors. Activating mutations have no effect on females. The molecular genetics of the inactivating mutations of the LHR are more variable and include single base substitution, partial gene deletion, and insertion. These mutations are not localized and are present in both the extracellular and transmembrane domain of the receptor. Inactivation of the LHR gives rise to the autosomal recessive disorder Leydig cell hypoplasia (LCH) and male hypogonadism or male pseudohermaphroditism. Severity of the clinical phenotype in LCH patients correlates with the amount of residual activity of the mutated receptor. Females are less affected by inactivating mutation of the LHR. Symptoms caused by homozygous inactivating mutation of the LHR include polycystic ovaries and primary amenorrhea.     

Overcoming surfactant inhibition with polymers

Inhibition of the function of pulmonary surfactant in the alveolar space is an important element of the pathophysiology of many lung diseases, including meconium aspiration syndrome, pneumonia and acute respiratory distress syndrome. The known mechanisms by which surfactant dysfunction occurs are (a) competitive inhibition of phospholipid entry into the surface monolayer (e.g. by plasma proteins), and (b) infiltration and destabilization of the surface film by extraneous lipids (e.g. meconium-derived free fatty acids). Recent data suggest that addition of non-ionic polymers such as dextran and polyethylene glycol to surfactant mixtures may significantly improve resistance to inhibition. Polymers have been found to neutralize the effects of several different inhibitors, and can produce near-complete restoration of surfactant function. The anti-inhibitory properties of polymers, and their possible role as an adjunct to surfactant therapy, deserve further exploration.     

The Establishment of Some Microflora Associated Biochemical Characteristics in Feces from Children during the First Years of Life

ABSTRACT. This report presents a new approach to the study of the colonization of the digestive tract after birth. We have examined the development of four microflora associated characteristics, MACs, defined as the recording of any anatomical structure, biochemical or physiological function in the macroorganism, which has been influenced by the microflora. These MACs may create a basis for later investigations into the impact of diarrheal diseases and antibiotic therapy. The following biochemical characteristics were studied in feces from children of 0-61 months of age: conversion of cholesterol to coprostanol and bilirubin to urobilins, inactivation of trypsin and degradation of mucin. These results indicate establishment of microbes capable of converting bilirubin to urobilins within the second year of life. The mucin degrading and cholesterol converting microbes are established in most of the children during the same period. Tryptic activity was found to be absent in meconium, present in feces from all children up to 21 months of age, and absent in 6 out of 15 children in the age group 46-61 months. The study indicates that the establishment of the MACs in the digestive tract is a remarkably long drawn out process     

Diet and body composition of preterm infants

There have been few systematic studies of the effects of energy and protein intake on the body composition of preterm infants. Analysis of published studies suggests a roughly inverse relation between energy stored per gram of weight gain (a measure of the fatness of new tissues) and the ratio of protein to energy in the preterm infant's diet. At least within a certain range of energy and protein intakes, a higher protein diet promotes leaner body composition. Studies of the effects of varying the dietary ratio of carbohydrate to fat in preterm infants have shown reduced rates of carbon dioxide production with high-fat diets, fed by either the parenteral or enteral route. The little information available suggests no clear effect of varying the carbohydrate-to-fat ratio on body composition. The mineral content of the body can be influenced by diet. Insufficient intakes of calcium and phosphorus reduce the bone mineral content and thus the whole-body content of these minerals.     

Silence et reconnaissance sociale dans le processus de reconstruction d’anciens enfants juifs cachés

Background

During World War II, many hidden Jewish children survived the Nazi occupation by hiding under false identities, in most cases separated from their parents. After the war, these children were not considered as survivors of the Holocaust and their suffering was often not recognized. Consequently, their experiences were ignored in many narratives of the Holocaust, and this until the end of the 1980s.

Objectives

This study aims to explain the long lasting silence of former hidden Jewish children and to understand what later made them communicate about their experiences related to World War II.

Methods

We have collected and analyzed 60 life narratives of former hidden Jewish children in order to understand this phenomenon. These people were between 65 and 78 years old when they were interviewed.

Results

We highlight that cognitive immaturity, psychic sideration, the uncertainty of certain memories, the over-adaptation to the environment and other defensive mechanisms, as well as the absence of social acknowledgment, permit to understand this specific destiny of an early trauma. In the experience of hidden Jewish children trauma is associated with a lack of understanding and a lack of integration of traumatic events. Their young age and the fact of being considered as “lucky” in comparison to other Holocaust survivors reinforced an emotional and representative freezing in the psyche of these children and young adolescents. Psychic freezing is related to their inability to integrate their past and to share it on a collective level. Moreover, their uncertainties in regard to their childhood memories have discouraged them to speak about the past and they lacked backup from the environment to do so; a child though needs the help of an adult in order to understand traumatic events. The over-adaptation to the environment and the fact that often they continued to hide their Jewish identity in adulthood contributed to the maintenance of silence. Furthermore, the lack of social acknowledgement of their trauma and the maintenance of defensive mechanisms impeded the social sharing of their experiences. In the case of hidden children, the narration of a story – that can be told, shared and symbolized – has been impaired by these factors.

Conclusion

The experience of hidden Jewish children highlights the importance of social acknowledgement as a condition for sharing traumatic memories, emotions and the recovery of frozen psychic processes. Social acknowledgement has eventually led to a personal recognition of trauma and to the construction of a collective memory. Social acknowledgment of their trauma, projective identification with their grand-children, the desire to transmit their past, aging and the concept of deferred action can explain the resurgence of childhood memories and the sharing of their experiences after decades of silence. These factors often induced a better understanding and a process of symbolization of what had happened to them. If social sharing led to a revival of trauma, it also provided collective support to elaborate the past.     

EXCITING NEW TREATMENT APPROACHES FOR PATHYPHYSIOLOGIC MECHANISMS OF SICKLE CELL DISEASE

During the past several decades, our understanding of the complex pathophysiology of vasoocclusion associated with sickle cell disease has improved greatly. Interaction of genes, hemoglobin molecules, red cell membrane and metabolic changes, cell-cell interactions and cell-plasma interactions, red cell adhesion to vascular endothelium, activation of coagulation, and vascular reactivity play a role in vaso occlusion. Penicillin prophylaxis of pneumococcal infections and appropriate use of blood transfusions and other supportive measures improved survival of sickle cell patients. Hydroxyurea made a major impact on sickle cell therapy when it was shown to decrease acute painful episodes, acute chest syndrome, and the need for blood transfusion in adults. Significant experience in the use of hydroxyurea has been accumulated in older children. The benefits and risks of hydroxyurea for younger children and long-term risks in all patients will be evaluated in future investigations. Other promising therapies include butyrate compounds, clotrimazole, magnesium supplementation, poloxamer 188, antiadhesion agents, anticoagulant approaches, and nitric oxide. Hemopoietic transplantation remains the only curative therapy. However, several transgenic mouse models are available for studies of gene therapy or other treatment approaches on biochemical, cellular, and pathologic effects of mutant genes.     

DOWN SYNDROME AND LEUKEMIA: WHAT HAVE WE LEARNED?

The increased risk of transient myeloproliferative disorder (TMD) and acute myeloid leukemia (AML) during early childhood in Down syndrome (DS) has stimulated research related to the role of trisomy 21 in the development of hematological neoplasm. The unique biological features of TMD including spontaneous resolution in the majority of cases, the increased risk of developing AML (25%) following resolution of TMD and the superior outcome of DS AML patients with cytarabine-based regimens highlight further areas of research interest. Alteration of intracellular redox reaction kinetics secondary to increased expression of chromosome 21-localized genes (e.g. superoxide dismutase) and the associated changes in apoptotic responses in DS tissues, may account for the increased sensitivity of DS myeloblasts to chemotherapy agents. The identification of the pharmacological and molecular basis for the increased sensitivity of DS myeloblasts to cytarabine and daunorubicin based on altered expression of chromosome 21-localized genes may ultimately lead to improvements in the therapy of AML in non-DS individuals.     

Current understanding of egg allergy

Egg is one of the most important allergens in childhood feeding, and egg allergy can pose quality-of-life concerns. A clear clinical history and the detection of egg white-specific immunoglobulin E (IgE) will confirm the diagnosis of IgE-mediated reactions. Non-IgE-mediated symptoms, such as those of eosinophilic diseases of the gut, might also be observed. Egg avoidance and education regarding the treatment of allergic reactions are the cornerstones of management of egg allergy. This article discusses epidemiology, risk factors, diagnosis, treatment, and natural history of egg allergy.     

Streptococcus pneumoniae antibiotic resistance in Northern Territory children in day care

BACKGROUND: There is evidence that the rapid rise in Streptococcus pneumoniae (SP) antimicrobial resistance seen in other countries may have commenced in Australia. Streptococcus pneumoniae carriage and resistance levels are described for urban Northern Territory children in day care. METHODS: A prospective cohort study was conducted of 250 children in nine Darwin day care centres between 24 March and 15 September 1997. Each fortnight nasopharyngeal swabs were collected from children, and parents were interviewed about medications administered. RESULTS: Streptococcus pneumoniae was detected in 52% (1028/1974) of all nasopharyngeal swabs. Streptococcus pneumoniae was isolated from 92% (231/250) of children at some time. Penicillin resistance was found in 30% (312/1028) of isolates using a screening test. Of these, 256 (82%) had resistance confirmed by E-test. Two hundred and one (20% of all isolates) had intermediate penicillin resistance and 55 (5% of all isolates) had high level resistance. Ceftriaxone resistance was found in 19% of children's first isolates. Resistance to other antibiotics was also common: co-trimoxazole 45%, erythromycin 17%, tetracycline 17% and chloramphenicol 13%. A total of 17% (172/1028) of the isolates were multiresistant. The average fortnightly proportion of children given antibiotics was 16% (405/2476). CONCLUSION: Levels of intermediate and high level penicillin resistance in this day care population are consistent with previous data from the Northern Territory, and considerably higher than the rest of Australia. The national trend of increasing pencillin resistance is likely to continue.     

Exposition des enfants de 0 à 3 ans aux écrans : résultats des cohortes de naissance sur les déterminants et les conséquences en termes de développement

ObjectiveAs parents and children have more and more leisure or educational screen activities available, there is curiosity about the impact of exposure to screen content on cognitive, socioemotional, physical and behavioural development of the child. Some recent studies suggest that early exposure may have a negative impact. Studies differ in methods and sample sizes. The aim of this study is to compute results on exposure of infants to screens from recent birth cohort studies, including determinants of exposure and the impact of this exposure on development.MethodsBased on a selection by an algorithm of research applied to PubMed and Google Scholar, birth cohort studies with a focus on determinants or consequences of early exposure of infants were included. Twenty studies from different countries were computed to do this review. Methods and results were discussed and compared.ResultsMain determinants of early exposure to screens were linked to family living conditions and to the characteristics of the parents. Low level of education of parents, low household income, no day-care for the child, no siblings, high use of screens by parents, symptoms of stress or depression by parents, lack of outdoor equipment or few outings were associated to higher early exposure to screens. It seemed that early exposure could have an impact on cognitive development, psychosocial development, emotional development, physical development, behaviour, and on engagement and performance at school. Revised studies differed in terms of measurement of exposure and in terms of difference in control variables computed in multivariate analysis. Exposure to screens could result in decreased attention to parent-child interactions or decreased attention of the infant to his/her own body and to his/her environment which could in turn impact development.ConclusionIn future studies, the way early exposure to screens is measured requires full attention. Also, controlling for socioeconomic conditions and physical and mental availability of caregivers is important to identify the impact of screens alone on the development. Future analysis of cohort analysis, such as ELFE cohort in France, could allow to individualize the effect of exposure to screens between the ages of 0 to 3, controlling for adequate environmental factors.     

Allergic factors associated with the development of asthma and the influence of cetirizine in a double-blind, randomised, placebo-controlled trial: First results of ETA®

There is a common progression known as the allergic march from atopic dermatitis to allergic asthma. Cetirizine has several antiallergic properties that suggest a potential effect on the development of airway inflammation and asthma in infants with atopic dermatitis. Methods. Over a two year period, 817 infants aged one to two years who suffered from atopic dermatitis and with a history of atopic disease in a parent or sibling were included in the ETAC^® (Early Treatment of the Atopic Child) trial, a multi-country, double-blind, randomised, placebo-controlled trial. The infants were treated for 18 months with either cetirizine (0.25mg/ kg b.i.d.) or placebo. The number of infants who developed asthma was compared between the two groups. Clinical and biological assessments including analysis of total and specific IgE antibodies were performed. Results. In the placebo group, the relative risk (RR) for developing asthma was elevated in patients with a raised level of total IgE (≥ 30 kU/I) or specific IgE (≥ 0.35 kUA/I) for grass pollen, house dust mite or cat dander (RR between 1.4 and 1.7). Compared to placebo, cetirizine significantly reduced the incidence of asthma for patients sensitised to grass pollen (RR = 0.5) or to house dust mite (RR = 0.6). However, in the population that included all infants with normal and elevated total or specific IgE (intention-to-treat - ITT), there was no difference between the numbers of infants developing asthma while receiving cetirizine or placebo. The adverse events profile was similar in the two treatment groups. Discussion. Raised total IgE level and raised specific IgE levels to grass pollen, house dust mite or cat dander were predictive of subsequent asthma. Cetirizine halved the number of patients developing asthma in the subgroups sensitised to grass pollen or house dust mite (i.e. 20% of the study population). In view of the proven safety of the drug, we propose this treatment as a primary pharmacological intervention strategy to prevent the development of asthma in specifically sensitised infants with atopic dermatitis.     

GROWTH HORMONE DEFICIENCY FOLLOWING RADIOTHERAPY FOR ORBITAL AND PARAMENINGEAL SARCOMAS

Growth hormone deficiency (GHD) is a recognized late effect of successful treatment of tumors requiring cranial irradiation. Growth after treatment was assessed in 16 patients with sarcomas of the orbital and parameningeal regions. Median age at diagnosis was 6.35 years and median follow-up was 7.2 years. Treatment consisted of combination chemotherapy and radical radiotherapy, conventionally fractionated with a median dose 4500 cGy; the hypothalamic/pituitary region received a median dose of 4163 cGy. Height was measured every 6 months and 13/16 patients underwent tests of GH function. At GH testing median height standard deviation score (SDS) was 0.7, a median decrease of 0.55 since tumor diagnosis. Seven patients were treated with human GH (hGH) at a median of 3.7 years from tumor diagnosis and followed for a median of 2.7 years. Treatment with hGH resulted in a median increase in height SDS of 0.9. Careful surveillance with timely introduction of GH replacement is required for treatment of GHD following treatment of orbital and parameningeal sarcomas.     

SPONGY DEGENERATION OF THE BRAIN, CANAVAN DISEASE: BIOCHEMICAL AND MOLECULAR FINDINGS

Canavan disease is a severe progressive leukodystrophy characterized by swelling and spongy degeneration of the white matter of the brain. It is an autosomal recessive disease found more frequently among Ashkenazi Jews. The clinical features are those of severe mental retardation with inability to gain developmental milestones. Hypotonia, head lag and macrocephaly are characteristic of Canavan disease and become apparent after 5-6 months of age. Massive excretion in the urine of N-acetylaspartic acid is the biochemical marker for Canavan disease, which is caused by deficiency of the enzyme aspartocylase. This discovery allowed for accurate diagnosis of Canavan disease, while prior to that, a brain biopsy was needed. The gene for aspartoacylase has been cloned and two mutations predominate among Ashkenazi Jewish individuals with Canavan disease and account for more than 98% of the Ashkenazi Jewish patients. The mutations among other ethnic groups are more diverse. The carrier frequency for the two common mutations among Ashkenazi Jews was found to be surprisingly high, 1:37. Screening for carriers is now common practice for this population. A knock-out mouse for Canavan disease is being genetically engineered in our laboratory. The mouse model will allow for development of strategies for gene therapy.     

L’évaluation thérapeutique pour enfant : théorie,procédures et illustration

Therapeutic assessment (TA) is a relatively new paradigm in which psychological tests are used as the centerpiece of a brief therapeutic intervention. TA is a semi-structured form of collaborative psychological assessment, and clients are involved as co-investigators in many aspects of the assessment. Although TA was originally elaborated for adult clients, it has since been researched and used in clinical practice with children and families. TA with children (TA-C) is conceived of as a brief family therapy intervention through which parents are helped to develop a more coherent, empathic, accurate, and useful understanding of their child. It is believed that this changed view of the child leads to healthier family interactions, and that these often are sufficient to resolve the presenting problems. The goal of this article is to introduce the reader to TA-C by means of a comprehensive case example. The theoretical underpinnings of TA-C are described and each of the semi-structured steps is explained and illustrated. These steps include the collection of individualized assessment questions from parents, psychological testing of the child, parental observation of certain stages of the assessment, a family session designed to explore systemic hypotheses about the child's difficulties, and the provision of assessment feedback to both parents and the child. The case illustrated involves the O’Hara family and their 7-year-old son, an only child. The parents sought psychological testing of their son at the urging of their pediatrician, who had been treating the boy for several years for persistent nighttime enuresis. Over the course of the assessment sessions, the parents came to realize that their son's difficulties were a reflection of emotions that they had been unable to tolerate regarding the loss of an important family member. With the emotional support of the assessor and their extended family, the parents gradually were able to acknowledge, accept, and integrate these emotions, and their son's enuresis disappeared.     

Prospects for xenotransplantation

The major limitation on the application of transplantation for the treatment of human disease is a severe shortage of human donor organs and tissues. One approach to overcoming this problem is xenotransplantation, that is the transplantation of animal organs into humans. The major hurdle to xenotransplantation is the immune response of the recipient against the graft. Recent years have brought new information concerning this hurdle and insights of strategies for overcoming it. Other hurdles include the physiological function of the graft in the foreign environment including the possibility of molecular incompatibilities between the donor and recipient and the possibility of transferring infectious diseases from the graft to the recipient. The current perspective on these issues will be presented in the review that follows.     

Transmission des émotions entre mère et bébé : du normal au pathologique

There are a multitude of emotional expressions that play across a baby's face. The adult in front of him recognizes these expressions, identifies them and transfers the sense to the baby, which the author calls “trans-subjectivity”. The emotional freedom of the parent and the baby allows both to run the gamut of emotions and for the child to little by little understand them. On the other hand when the privileged relational partner of the baby is herself caught up in the freedom of her emotions, constantly fixed on a particular emotion, there is a risk of taking from this rich and varied gamut of emotions only those which more or less fit with her own problems. This privileged attention given to a specific expression risks giving it an overly important role. This in turn leads to the unconscious transmission of this type of emotion to the child, which is always fascinated by that, which interests the adult. Some clinical examples show how this pathological transmission of emotions could occur without either of the partners being aware of it.