Maternal iron status in early pregnancy and DNA methylation in offspring: an epigenome-wide meta-analysis.

BACKGROUND: Unbalanced iron homeostasis in pregnancy is associated with an increased risk of adverse birth and childhood health outcomes. DNA methylation has been suggested as a potential underlying mechanism linking environmental exposures such as micronutrient status during pregnancy with offspring health. We performed a meta-analysis on the association of maternal early-pregnancy serum ferritin concentrations, as a marker of body iron stores, and cord blood DNA methylation. We included 1286 mother-newborn pairs from two population-based prospective cohorts. Serum ferritin concentrations were measured in early pregnancy. DNA methylation was measured with the Infinium HumanMethylation450 BeadChip (Illumina). We examined epigenome-wide associations of maternal early-pregnancy serum ferritin and cord blood DNA methylation using robust linear regression analyses, with adjustment for confounders and performed fixed-effects meta-analyses. We additionally examined whether associations of any CpGs identified in cord blood persisted in the peripheral blood of older children and explored associations with other markers of maternal iron status. We also examined whether similar findings were present in the association of cord blood serum ferritin concentrations with cord blood DNA methylation. RESULTS: Maternal early-pregnancy serum ferritin concentrations were inversely associated with DNA methylation at two CpGs (cg02806645 and cg06322988) in PRR23A and one CpG (cg04468817) in PRSS22. Associations at two of these CpG sites persisted at each of the follow-up time points in childhood. Cord blood serum ferritin concentrations were not associated with cord blood DNA methylation levels at the three identified CpGs. CONCLUSION: Maternal early-pregnancy serum ferritin concentrations were associated with lower cord blood DNA methylation levels at three CpGs and these associations partly persisted in older children. Further studies are needed to uncover the role of these CpGs in the underlying mechanisms of the associations of maternal iron status and offspring health outcomes.

A conceptual framework in the study of neuropsychological development in epidemiological studies.

BACKGROUND: A wide range of neuropsychological development outcomes in children are currently measured in a large number of birth cohort and child cohort studies. METHODS: We summarized neuropsychological development assessment protocols from a number of birth cohort studies, reviews and specific books on child neuropsychology into a unifying conceptual framework. RESULTS: We suggest that neuropsychological development can be differentiated into two levels, i.e. functional and clinical. The functional level includes the skills, abilities, capacities and knowledge acquired during maturation of the brain as a result of the development of neural networks. It can be further divided into cognitive, psychomotor and social-emotional development subdomains. The clinical level includes the assessment of neurodevelopmental disorders or the presence of symptoms (subclinical symptomatology) of these disorders in populations under investigation in environmental epidemiology studies. CONCLUSIONS: Through explicit recognition of these levels of outcomes, and in using this framework, epidemiologists will be better able to design research through the informed selection of individual levels of outcomes. The framework also serves to standardize disparate terminologies across this field and allows for pooling of epidemiological data on neuropsychological endpoints where essentially similar levels of outcomes have been analyzed using different tests.

Attention behavior and hyperactivity and concurrent neurocognitive and social competence functioning in 4-year-olds from two population-based birth cohorts.

OBJECTIVE: We studied the associations between Attention Deficit Hyperactivity Disorder (ADHD) symptoms and the neurobehavioral status in two population-based birth cohorts. METHODS: Children (n=467) were assessed by psychologists and teachers for neuropsychological functioning (McCarthy Scales, MCSA), inattention-hyperactivity symptoms (ADHD-DSM-IV form list) and social behavior (California Preschool Social Competence Scale, CPSCS). Regression models were used with covariate adjustment. RESULTS: Sixteen percent of children had ADHD-DSM-IV symptoms. MCSA scores were linearly associated with ADHD symptom scores (general cognitive Beta=-0.6 [-1.0; -0.3] per symptom), specifically inattention scores (general cognitive Beta=-1.8 [-2.3; -1.2]). CPSCS scores were associated with ADHD symptoms (Beta=-2.19 [-2.5; -1.9]). MCSA scores of executive function, perceptive-performance and quantitative sub-areas had stronger associations with ADHD symptoms. CONCLUSIONS: Preschooler ADHD symptoms are associated with concurrent decrements in neurocognitive and social competence functioning. The association patterns are similar to those found in older children with ADHD symptomology (Marks et al., 2005 [36], Seidman, 2006 [46], Sonuga-Barke et al., 2003 [48], Yochman et al., 2006 [53]).

Early life environment, neurodevelopment and the interrelation with atopy.

Both neurological and immunological systems are vulnerable to early life exposures. Neurological disorders and atopy have been related in animals and humans. Our main objective was to assess whether multiple exposures to early life determinants remain associated with neurodevelopment after considering the potential intermediate role of atopy. A second objective was to assess whether genes associated with atopy may inform about the potential neurotoxical mechanisms. Children were members of the AMICS birth cohort in Menorca (n=418, 87% of the recruited). General cognition was measured with the McCarthy Scales at age 4 and atopy through specific IgE at age 4 and prick test at age 6; 85 single nucleotide polymorphisms (SNPs) in 16 atopy and detoxification genes were genotyped. Among the 27 risk factors assessed, lower maternal social class, maternal smoking during pregnancy, being first born, shorter breastfeeding, higher DDT levels in cord blood, and higher indoor levels of NO2 (among the non-detoxifiers by GSTP1 polymorphism) were independently associated with poorer cognition. These associations were apparently not mediated by the relation between atopy and general cognition. Among the candidate atopic genes, variants in NQ01 (a detoxification gene) and NPRS1 (related with affective disorders like anxiety and stress management) had a significant association with general cognition (p-value<0.001). However, adjustment for the corresponding SNPs did not change the association between the early life determinants and general cognition. Multiple environmental pre-natal exposures were associated with neurodevelopment independently of their role in the immunological system. Atopic genes related to neurodevelopment suggest some potential mechanisms.

Neuropsychologic status at the age 4 years and atopy in a population-based birth cohort.

BACKGROUND: Mental health has been reported to be associated with allergy, but only a few cohort studies have assessed if neurodevelopment predicts atopy. OBJECTIVE: To investigate if neurobehavioral status of healthy 4-year-old children was associated with specific immunoglobulin E (IgE) at the same age and skin prick test results 2 years later. METHODS: A population-based birth cohort enrolled 482 children, 422 of them (87%) provided neurobehavioral data, 341 (71%) had specific IgE measured at the age of 4 years; and 395 (82%) had skin prick tests completed at the age of 6 years. Atopy was defined as IgE levels higher than 0.35 kU/l to any of the three tested allergens at the age of 4 or as a positive skin prick test to any of the six tested allergens at the age of 6. McCarthy Scales of Child Abilities and California Preschool Social Competence Scale were the psychometric instruments used. RESULTS: Twelve percent of children at the age of 4 and 17% at the age of 6 were atopic. Neurobehavioral scores were negatively associated with 6-year-old atopy after adjustment for socio-demographic and allergic factors, A relative risk of 3.06 (95% CI: 1.30-7.24) was associated with the lowest tertile (scorings < or =90 points) of the general cognitive scale. Similar results were found for verbal abilities, executive functions, and social competence. Asthma, wheezing, rhinitis, and eczema at the age of 6, but not at the age of 4, were associated with neurodevelopment at the age of 4. CONCLUSIONS: Neuropsychologic functioning and later atopy are negatively associated in preschool age children.

[Risk and risk management connected with xenograft]. / Risques et gestion des risques li¿es aux x¿enogreffes.

Transmission of an animal virus to man is probably a constant reality. Pathogenicity is is not inevitable. Some vaccines were contaminated by cell culture but remain safe. Haemorrhagic fevers, despite limited outbreaks, are often cited in the media. On the other hand, the influenza A virus has been responsible for a large mortality. The cases of human infection with simian viruses (herpes virus B, cytomegalovirus, spumavirus, immunodeficiency virus) were accidental and have always remained asymptomatic. Monkeypox virus emerges in only some outbreaks. No transmission of animal endogenous retrovirus has been described. The precautionary principle, in the face of an unquantifiable risk, supposes that preventive measures should be taken in advance to reduce the risk at each step: isolation of the animal source after hysterotomy, transport in a germ-free environment, procurement and transplantation in rigorous surgical conditions, long-term follow-up surveillance of the patient, his or her family and healthcare workers. All the phases of the xenotransplantation procedure should be taken to limit the number of places and persons coming into contact with the recipient. Surveillance means regular clinical information. Various samples should be taken from the animal source, recipient, his or her family contacts, medical staff and cryogenically preserved as 'biological memory'. A National Xenotransplantation Register should be set up to gather and share all information on incidents.

["Population and xenograft" investigation. Preliminary results]. / Enqu¿ete "population et x¿enogreffe". R¿esultats pr¿eliminaires.

The chronic shortage of human organs is the argument for xenotransplantation. In emergencies, acceptability is closely linked to the benefit. Little information is available on attitudes towards xenotransplantation. A poll of the attitudes was carried out, based on a questionnaire with targeted questions and background information. The goal of the study was to have a better understanding of people's attitudes towards xenotransplantation and to know the eventual changes in the answers after having been given information. For 75% of the sample, xenotransplantation would be a future biotechnology. The animal sources that would be considered for xenotransplantation were the pig and monkey. A period of ten years or more is necessary for 69% of the respondents before xenografts are performed routinely; for 19%, five years or less are needed. Human organ donation should be continued, according to 90% of the sample. Roughly, 46.4% support xenotransplantation, though in the case of a life-or-death situation acceptance reaches 65.7%. This level is higher (77%) for relatives or unknown people (71%); 74% of respondents were in favour of using normal animals and a large majority (88%) support research on xenotransplantation. A good level of confidence in medical biotechnology research and practice is suggested by this study, contrary to the results of a European survey on biotechnology.

Microbiological hazards of xenotransplantation. 1. Doubts and convictions relating to the risk of xenozoonosis.

The use of a xenogenic organ, tissue or cells for transplantation permits in theory the transmission of microbiological agents from one species to another. The risk of transmission of an unknown animal pathogen to man is assumed to be a public health issue. The genotype homology between human beings and non-human primates, theoretically, should increase the probability of transmission of microbiological agents. It is also assumed that pathogenicity is intensified in closely related species. Historically, most zoonoses come from species that are distant from man. Viruses are more often responsible for human disease than other animal microbial agents. Exposure of humans to animal viruses does not predicate infection. The pathogenicity of an animal virus for man may be immediate or delayed by a possible recombination of adaptive processes. The ultimate risk is the inter-human transmission of a highly pathogenic and fatal animal disease. The retrovirus possesses the enzyme which enables it to become inserted into chromosomal DNA. With an endogenous retrovirus, viral genomes are transmitted through heredity. Some of the retrovirally derived sequences in mammals are fossil viruses. It has been argued that the more closely the species are related, the less likely the retrovirus is to be transmitted, because of xenotropism.

Microbiological hazards of xenotransplantation. 2. Facing the risk.

The high number of xenotransplantations that have been carried out around the world since the beginning of the century, combined with the quantity of animal experiments that have exposed man to animal viruses under similar conditions, should be measured against the low incidence of known pathological consequences. The pathogenic potential of animal viruses for man, then, is unpredictable; and while the risk is acknowledged, it cannot be defined. Unless no benefit can be in xenotransplantation, the application of the precautionary principle to the extent of a moratorium seems to be excessive. The precautionary principle offers possible modes of action in the face of an unquantifiable risk. In the event of xenotransplantation, precautionary measures should be taken in advance, in order to limit risk to the maximum extent. The risk is reduced and the benefit/risk ratio becomes higher, rendering the challenge acceptable. Preventive measures should be taken as the knowledge grows about possible modes of transmission. Guidelines of good practice should be implemented at each step of the xenotransplantation process: birth of animal source by hysterotomy in a 'Specific Pathogen-Free' (SPF) centre rearing in incubator then in isolated conditions (SPF centre) transportation to and rearing in the procurement site (SPF hospital special wing) surgical procurement and xenotransplantation (hospital) post-surgical reanimation (intensive care unit) convalescence (isolated room--hospital) long-term recipient follow-up (home) All these steps should be taken in such a way as to limit the number of persons coming into contact with the recipient.

Summary of principles of good practice for the production of pigs used for xenotransplantation. A report of the expert committee on xenotransplantation. Groupe d'Experts Xénogreffes.

The choice and selection of pigs used as donors of organs or tissues are founded on the concept of quality assurance of the animals included in the original herd. The rearing conditions in this herd have to guarantee a defined health status. All the stages of production, rearing, slaughter and collection of organs or tissues used for xenotransplantation or xenograft have to be fully controlled in regard to health.

[Graft safety and need satisfaction: searching for a crucial balance]. / Sécurité des greffes et satisfaction des besoins: la recherche d'un équilibre indispensable.

In 1998, 3,033 organs were transplanted and 3,186 stem cell and 4,053 cornea grafts were performed in France. Organ shortage varies for each organ but is particularly critical for kidneys. Given the physiological and therapeutic efficacy of grafting, an increase in organ procurement is likely to raise safety problems. This paper concerns donor-transmitted infections, mainly viral infections. Regulations on health risks express a social and cultural refusal to accept any hazard. This collective concern is however in opposition with the interests of individual patients who are likely to accept a greater risk for an obvious benefit. Although the assessment of the risk/benefit ratio is clearly different between organ and tissue transplantation, further thought needs to be given to the problem of acceptance of infectious risk in organ transplantation. In France, special exceptions are now legally authorized for specific situations. Infectious agents transmitted by grafting have not been largely reported, mainly because screening tests were not available. The number of transmitted infections is increasing with the expansion of transport facilities and with the various geographical origins of the population. In some cases, search for histocompatibility between relatives living in endemic areas introduces new risks, for example tropical diseases. Diagnosis is often made by serological or molecular biological tests which may be difficult to analyze depending on their specificity. Organ transplantation is often an emergency requiring rapid decision making, for the donor or the recipient. However, with a quality assurance process based on accepted guidelines, the appropriate answers to operational problems can be given rapidly. Patient satisfaction can be achieved only if the public health challenge is met. Increasing organ procurement can clearly be expected to be beneficial, but at the cost of higher risks. Nevertheless, benefit and risk are quite different, benefit is for the time being while risk is delayed and may be uncertain depending on individual survival. Because of the variability of human disease, especially in situations where an ultimate therapy is involved, automatic application of a standard procedure must be avoided as it would inevitable lead to a cut-back in organ procurement in an attempt to achieve a theoretically safe situation which would be contrary to individual patient's self-interest. Health care workers should have good knowledge of the epidemiology of these diseases in order to assess risk. The patient must be able to express informed consent.

[Epidemiological stratification of malaria in the Comoro archipelago]. / Stratification épidémiologique du paludisme dans l'archipel des Comores.

In the Comoros Islands, the level of malarial endemicity varies greatly from one island to the other, even though the total area (4 islands) covers less than 2,300 km2 and has a population of some 600,000 people only. The epidemiological stratification is based on the diversity of human and physical characterisation. They both determine the presence and the behaviour as well as the size of the vector's populations. Vectorial dynamics can explain varying levels of endemicity given parasitological indicators and specific morbidity. Analyzing these criteria shows up different epidemiological features and serves as a basic guideline for malaria control. The efficiency of this control depends on the relationships between the intensity and the length of the transmission, in the framework of protection mechanisms; it is of crucial importance for clinical treatment. Further elements are the age of the patient, the season and the geographic situation of the area. Stratification provides explanations for these relationships and helps to define antimalarial programmes adapting to each situation a range of therapeutic and antivectorial methods. The availability and accessibility of anti-malarial medicine is the minimum requirement for reducing mortality: domestic spray insecticides for reducing transmission are effective for several years and should be followed by the use of mosquito nets or curtains impregnated with pyrethrinoids, and in the particular case of Grande Comore, the use of larvivorous fish. As anywhere else, the economic development, which is dependent on political stability, is the essential basis for malaria control.

[Sale of chloroquine in the street in Niamey (Niger)]. / Les ventes de chloroquine dans la rue à Niamey (Niger).

Self-treatment of malaria with chloroquine is extremely common in West Africa for the febrile attacks self-diagnosed as a presumed malaria case. A survey was conducted for one year in Niamey to assess the importance of the self-treatment practice. Transmission of malaria is permanent along the river banks and seasonal in some suburbs. Chloroquine is made available by local ambulatory sellers. A sample of 199 persons purchase on average four tablets each which is less than the curative dose recommended by WHO. Self-medication is an adequate practice for reaching the primary goal of malaria strategy in sub-Saharan Africa, i.e. to reduce morbidity and mortality through prompt therapy. Developing this practice is a top public health priority. Even if the dose is not appropriate, self-medication protects against serious attacks without preventing immunization and does not seem to induce greater risk of extension of chloroquine-resistance.

[The anopheles of Niger]. / Les anophèles du Niger.

Nineteen species of Anopheles have been observed in the Republic of Niger but only Anopheles gambiae, An. arabiensis and An. funestus are of epidemiological importance as malaria vectors. The two species of the An. gambiae complex have the same breeding sites. But in a large part of the country they disappear all during the dry season because of the lack of adequate pools of water. Their survival is as yet an unexplained phenomenon. The most northern wet season distribution of An. gambiae complex, depending on the latitude of the intertropical front. An. funestus was no longer found after 1970 because its breeding places were destroyed both by dryness and human activity. The Republic of Niger is a border area between the palearctic Mediterranean biogeographical region and the Afrotropical one. Two different vectorial systems of malaria transmission are separated by the Sahara desert. The risk of importation of an African vector such as An. gambiae and a parasite such as Plasmodium falciparum must be considered. For the time being, the low volume of road traffic limits the risk but the construction of a paved Transsaharian highway with new human settlements and developing cultivated areas with irrigation increases the dangers of epidemic outbreaks in these oases.

[Serologic studies of non-venereal treponematoses in infants in Niamey, Niger]. / Etude sérologique des tréponematoses non vénériennes chez l'enfant à Niamey, Niger.

Though no longer reported by health centers, non-venereal treponematoses is still endemic in both arid (Bejel) and Sahelo-soudanian (Pian) areas of Niger. This study describes randomized TPHA testing carried out among children under 5 years of age living in three different sections of Niamey. Clinical examination was not performed before testing. In the overall sample of 183 children, the percent of positive tests was 12.0% with no difference according to place of residence or age. Only 3 of 37 children under the age of 12 months were seropositive Relative levels were too high to be dismissed as serological artifacts. The most likely explanation for the high antitreponemic antibodies is endemic syphilis, or Bejel, which is increasing in this region. Results in children under the age of 12 months suggest that congenital syphilis is uncommon.

Evolution of malaria in Africa for the past 40 years: impact of climatic and human factors.

Different malarial situations in Africa within the past 40 years are discussed in order to evaluate the impact of climatic and human factors on the disease. North of the equator, more droughts and lower rainfall have been recorded since 1972; and in eastern and southern Africa, there have been alternating dry and wet periods in relation to El Niño. Since 1955, the increase in human population from 125 to 450 million has resulted in both expansion of land cultivation and urbanization. In stable malaria areas of West and Central Africa and on the Madagascar coasts, the endemic situation has not changed since 1955. However, in unstable malaria areas such as the highlands and Sahel significant changes have occurred. In Madagascar, cessation of malaria control programs resulted in the deadly epidemic of 1987-88. The same situation was observed in Swaziland in 1984-85. In Uganda, malaria incidence has increased more than 30 times in the highlands (1,500-1,800 m), but its altitudinal limit has not overcome that of the beginning of the century. Cultivation of valley bottoms and extension of settlements are in large part responsible for this increase, along with abnormally heavy rainfall that favored the severe epidemic of 1994. A similar increase in malaria was observed in neighboring highlands of Rwanda and Burundi, and epidemics have been recorded in Ethiopia since 1958. In contrast, in the Sahel (Niayes region, Senegal), stricken by droughts since 1972, endemic malaria decreased drastically after the disappearance of the main vector, Anopheles funestus, due to the destruction of its larval sites by cultivation. Even during the very wet year of 1995. An funestus did not reinvade the region and malaria did not increase. The same situation was observed in the Sahelian zone of Niger. Therefore, the temperature increase of 0.5 degree C during the last 2 decades cannot be incriminated as a major cause for these malaria changes, which are mainly due to the combination of climatic, human, and operational factors.

[Human diseases transmitted by Culicidae in southwest Indian Ocean islands]. / Maladies humaines transmises par les culicidés dans les îles du sud-ouest de l'Océan Indien.

South-West Indian Ocean islands were inhabited at the beginning and free from all kind of vector. In Madagascar, Mayotte, Moheli and Anjouan, malaria vectors were carried by the first settlements. According to epidemics, the anopheles arrived in 1867 in Mauritius, 1869 in La Reunion and 1920 in Grande Comore. Rodrigues, Saint-Brandon and the Seychelles are still free from malaria vectors in the coastal part of Madagascarcar and in Comores archipelago, malaria is stable with a permanent transmission. Unstable malaria is seasonaly transmitted in the high territories of Madagascar; it was the same in Mauritius and Reunion island before the eradication campaign. Lymphatic filariasis is quoted in Madagascar, but Comores archipelago is an area with high transmission. The incidence of the disease is moderate in La Reunion and Mauritius and very low in Chagos and Seychelles archipelagos. There is no transmission in Rodrigues and St Brandon. Epidemics of dengue were described during the second part of the XIXth century in Mauritius and La Reunion, then in 1943 in Mayotte. But the disease was controlled in the fifties by the antimalaria campaign. A new epidemy appeared in Seychelles by the end of 1976 and then in Reunion and Mauritius next year. An isolated outbreak was described in Grande Comore only in 1994.