Sense development through non verbal signs: early infancy and clinical psychoterapy

This thesis will describe the development of a relationship which is not necessarily verbal, but which generates communication, creates sense and meaning between human beings and produces “becomings” in the body that feels, perceives and physically transforms itself. This leads to a biosemiotic understanding of both the seen and unseen figure.

Early onset of primary hypogonadism revealed by serum anti-Mullerian hormone determination during infancy and childhood in trisomy 21

Male patients with an extra sex chromosome or autosome are expected to present primary hypogonadism at puberty owing to meiotic germ-cell failure. Scarce information is available on trisomy 21, a frequent autosomal aneuploidy. Our objective was to assess whether trisomy 21 presents with pubertal-onset, germ-cell specific, primary hypogonadism in males, or whether the hypogonadism is established earlier and affects other testicular cell populations. We assessed the functional status of the pituitary-testicular axis, especially Sertoli cell function, in 117 boys with trisomy 21 (ages: 2 months-20 year). To compare with an adequate control population, we established reference levels for serum anti-Mullerian hormone (AMH) in 421 normal males, from birth to adulthood, using a recently developed ultrasensitive assay. In trisomy 21, AMH was lower than normal, indicating Sertoli cell dysfunction, from early infancy, independently of the existence of cryptorchidism. The overall prevalence rate of AMH below the 3rd percentile was 64.3% in infants with trisomy 21. Follicle-stimulating hormone was elevated in patients <6 months and after pubertal onset. Testosterone was within the normal range, but luteinizing hormone was elevated in most patients <6 months and after pubertal onset, indicating a mild Leydig cell dysfunction. We conclude that in trisomy 21, primary hypogonadism involves a combined dysfunction of Sertoli and Leydig cells, which can be observed independently of cryptorchidism soon after birth, thus prompting the search for new hypotheses to explain the pathophysiology of gonadal dysfunction in autosomal trisomy.

Immunomodulation by conjugated linoleic acid (CLA) in early life

Conjugated linoleic acid (CLA) has been reported to exert beneficial physiological effects on body composition and the immune system. However, little information is available on the influence of CLA on immune function during early life periods. The present study evaluates the effect of feeding an 80:20 mixture of cis-9,trans-11- and trans-10,cis-12-CLA isomers duringgestation, suckling and early infancy on the systemic and mucosal immune responses of Wistar rats at three different time points: at the end of the suckling period (21-day-old rats), in early infancy (28-day-old rats), and later in life (adulthood). Cis-9,trans-11- and trans-10,cis-12-CLA isomers were detected in the milk of CLA-fed dams and in the plasma of all CLA-supplemented pups, and the highest content was achieved in those rats supplemented over the longest period. Dietary supplementation with that CLA mix enhances the systemic production of the main in vivo and ex vivo immunoglobulin (Ig) isotypes in 21- and 28-day-old rats. Moreover, CLA supplementation during suckling and early infancy also enhances the humoral immune defenses at intestinal level, by means of mucosal IgA increase, whereas down-regulates thesystemic lymphoproliferative response. Finally, we described herein how feeding a diet enriched with the same isomer mix of cis9,trans11- and trans10,cis12-CLA from gestation to adulthood improves the capacity of adult rats to achieve a specific systemic and mucosal immune responses. All these data support the immunomodulatory effects of dietary supplementation of CLA, particularly of the cis9,trans11-CLA isomer, during early stages of life on immune system development, as well as the long-term effects on the specific immune response in adult age.

Early life host-microbe interactions : implications for the development of asthma

Plus de 300 millions de personnes dans le monde souffrent de l'asthme. L'asthme est une maladie inflammatoire chronique des voies respiratoires caractérisée par des symptômes variables et récurrents, une obstruction bronchique réversible et des bronchospasmes. Les symptômes communs incluent une respiration sifflante, de la toux, une oppression thoracique et de la dyspnée. Normalement, la maladie commence à se manifester pendant l'enfance. Pourtant, facteurs génétiques héréditaires et événements environnementaux survenant au cours de la petite enfance sont responsables de sa manifestation, indiquant que le développement de la maladie est lié à des événements qui se produisent bien avant son déclenchement. L'infection respiratoire virale aiguë constitue un de ces facteurs environnementaux jouant un rôle prépondérant. Un des virus les plus communs est le virus respiratoire syncytial (VRS), qui infecte presque tous les enfants avant l'âge de 2 ans. Ce virus, s'il infecte des tout-petits, peut en effet provoquer une bronchiolite aiguë, un phénomène qui a été épidémiologiquement lié à l'apparition d'asthme plus tard dans la vie. Dans le premier chapitre de cette thèse, nous avons étudié, chez la souris, comment une infection avec le VRS influe sur l'asthme allergique. Nous avons constaté que seule l'infection des souris à l'état de nouveau-né prédispose à un asthme allergique plus sévère chez l'adulte. En effet, si des souris adultes étaient infectées, elles étaient protégées contre l'apparition des symptômes asthmatiques. Cela nous a mené à investiguer les mécanismes immunitaires spécifiques durant cette courte période du début de la vie. Deux événements se produisent en parallèle au cours de la petite enfance: (1) Le système immunitaire, qui est encore immature immédiatement après la naissance, commence à se développer pour être en mesure de jouer son rôle protecteur contre les agents infectieux. (2) Le corps, y compris les poumons, est colonisé par des bactéries commensales, qui vivent en symbiose avec leur hôte humain. Chez l'adulte, ces bactéries sont connues pour influencer notre système immunitaire, l'éduquant à générer des réponses immunitaires adéquates et efficaces. Dans la deuxième partie de cette thèse, nous avons voulu déterminer si ces bactéries symbiotiques étaient impliquées dans l'éducation du système immunitaire du nouveau-né et quelles conséquences cela pourrait avoir sur les réponses immunitaires engendrées par ce dernier. Pour étudier l'effet de ces bactéries symbiotiques, nous avons utilisé des souris stériles, en d'autres termes des souris qui n'hébergent pas ces bactéries symbiotiques. En comparant ces souris stériles à des souris qui abritent une flore microbienne normale, nous avons constaté que les bactéries symbiotiques sont vitales pour la bonne éducation du système immunitaire du nouveau-né. Nous avons démontré que le contact direct des cellules immunitaires avec la flore microbienne dans les poumons modifie le phénotype de ces cellules immunitaires, ce qui change probablement leur réaction au cours de réponses immunitaires. Nous avons donc vérifié si l'éducation immunitaire induite par cette microflore est importante pour prévenir les maladies pulmonaires telles que l'asthme allergique, affections qui sont causées par une réaction excessive du système immunitaire envers des agents inoffensifs. En effet, nous avons observé que le processus de maturation du système immunitaire néonatal, lequel a été déclenché et façonné par la flore microbienne, est important pour éviter une réaction asthmatique exagérée chez la souris adulte. Ce phénomène est dû aux lymphocytes T régulateurs. Ces cellules, dont la présence est induite dans les poumons, ont des capacités immunosuppressives et atténuent donc les réponses immunitaires pour prévenir une inflammation excessive. En conclusion, nous avons montré dans cette thèse que la colonisation par des bactéries symbiotiques tôt dans la vie est un événement décisif pour la maturation du système immunitaire et pour prévenir le développement de l'asthme. Dans l'avenir, il serait intéressant de découvrir quelles bactéries sont présentes dans les poumons du nouveau-né et lesquelles sont directement impliquées dans ce processus de maturation immunitaire. Une prochaine étape serait alors de favoriser la présence de ces bactéries au début de la vie au moyen d'un traitement avec des agents pré- ou probiotiques, ce qui pourrait éventuellement contribuer à une prévention précoce du développement de l'asthme. -- L'asthme est une maladie chronique inflammatoire des voies respiratoires affectant près de 300 millions d'individus dans le monde. Bien que les traits caractéristiques du phénotype asthmatique s'établissent généralement pendant l'enfance, la prédisposition au développement de la maladie est intimement liée à des événements survenant durant la petite enfance, comme le sont par exemple les infections virales respiratoires aiguës. Les mécanismes par lesquels ces événements provoquent un dysfonctionnement immunitaire et, par conséquent, conduisent au développement de l'asthme n'ont pas encore été entièrement décelés. La dysbiose du microbiote des voies respiratoires a été récemment associes au phénotype asthmatique, touisTcis, la cuûoboiatioî! d un lien cause à effet entre la dysbiose microbienne et l'apparition des symptômes asthmatiques reste à être démontrée. Dans cette thèse, nous avons étudié le rôle que joue la colonisation microbienne des voies respiratoires au cours de la petite enfance dans la maturation du système immunitaire ainsi que dans la protection contre l'inflammation pulmonaire de type allergique. Nous avons de surcroît développé un modèle expérimental pour comprendre comment les infections virales respiratoires interfèrent avec ce processus. Dans la première partie de cette thèse, nous avons évalué l'effet d'infections causées par le virus respiratoire syncytial (VRS) sur le développement de l'asthme. En accord avec des études épidémiologiques, nous avons constaté qu'une infection au VRS lors de la période néonatale exacerbait les réponses pulmonaires allergiques ultérieures. Par contraste, une infection à l'âge adulte avait un effet protecteur. Nous avons ainsi démontré que l'influence d'une infection à VRS sur l'issue et la sévérité de l'asthme respiratoire était strictement dépendante de l'âge. Ces résultats nous ont conduit à émettre l'hypothèse que des différences dans le phénotype homéostatique des cellules immunitaires pourraient être responsables de ces disparités liées à l'âge. Par conséquent, dans la deuxième partie de cette thèse, nous avons suivi et caractérisé le processus de maturation des cellules immunitaires dans les poumons du nouveau-né en condition d'homéostasie. Nous avons découvert que leur phénotype change de façon dynamique pendant le développement néonatal et que la colonisation par des microbes était déterminante pour la maturation des cellules immunitaires dans les poumons. Dans la dernière partie de cette thèse, nous avons démontré comment le microbiote pulmonaire éduque le développement immunitaire durant la période néonatale l'orientant de manière à induire une tolérance face aux aéroallergènes. Nous avons découvert que la colonisation microbienne des voies respiratoires provoque une expression transitoire de PD-L1 sur les cellules dendritiques (CD) pulmonaires du type CD11b+ dans les deux premières semaines de la vie. Cet événement engendre par la suite la génération de lymphocytes T régulateurs (TREG) dans les poumons, lesquels sont responsables de la protection contre une réponse inflammatoire allergique exagérée chez la souris adulte. Par conséquent, nous proposons un rôle pivot de la maturation immunitaire induite par le microbiote pulmonaire dans l'établissement de la tolérance aux aéroallergènes. En conclusion, les résultats présentés dans cette thèse fournissent de nouveaux indices révélant comment des événements se produisant lors de la petite enfance peuvent façonner les réponses du système immunitaire dirigées contre les allergènes et soulignent le rôle central joué par le microbiote pulmonaire dans l'édification d'une réponse immunitaire équilibrée. En résumé, notre travail met en évidence le microbiote pulmonaire comme étant une cible potentielle pour la prévention de certaines maladies respiratoires. -- Asthma is a chronic inflammatory disorder of the respiratory tract and affects approximately 300 million individuals world-wide. Although the asthmatic phenotype commonly establishes during childhood, predisposition towards disease development has been linked to events in early infancy, such as severe respiratory viral infections. However, the mechanisms by which these events cause immune dysfunction and, therefore, lead to the development of asthma have yet to be fully deciphered. Dysbiosis of the airway microbiota has recently been associated with the asthmatic phenotype; however, conclusive evidence for a causal link between microbial dysbiosis in the ail ways and asthma development is still missing. In this thesis we investigated the role of early-life microbial airway colonization in immune maturation and the protection against allergic airway inflammation and established an experimental model to address how respiratory viral infections interfere in this process. In the first part of this thesis we evaluated the effect of Respiratory syncytial virus (RSV) infections on the development of asthma. In concurrence with epidemiological studies, we found that neonatal infection exacerbated subsequent allergic airway inflammation. In contrast, adult infection was protective in the same context. Thus, we could demonstrate that the influence of RSV infection on subsequent allergic airway responses was strictly age-dependent. These findings led us to the hypothesis that differences in the homeostatic phenotype of immune cells could be responsible for the age-related disparities seen within the context of RSV. Therefore, in a second part of this thesis, we followed the process of homeostatic immune cell maturation in the neonatal lung. Immune cell phenotypes changed dynamically during neonatal development. We discovered that the colonization with microbes was central to the maturation of immune cells in the lung. In the last part of this thesis, we demonstrated how microbiota-driven immune development during the neonatal period induces tolerance against aeroallergens. We discovered that microbial colonization led to a transient programmed death-ligand (PD-L) 1 expression on CD11b+ pulmonary dendritic cells (DCs) during the first two weeks of life. This in turn induced regulatory T (TREG) cells in the lung, which were responsible for the protection against exaggerated allergic airway inflammation in adult mice. Thus, we propose a key role for microbiota-driven immune maturation in the establishment of tolerance towards aeroallergens. In conclusion, the results presented in this thesis provide new insights into how early-life events shape pulmonary immune responses towards allergens and suggest the airway microbiota as a key player in establishing a balanced immune response. Overall, our work highlights the airway microbiota as potential target for disease prevention.

Virus Infections in Early Childhood, Cow’s Milk Formula Exposure and Genetic Predisposition in the Development of Diabetes-Associated Autoimmunity

Varhaislapsuuden virusinfektioiden, lehmänmaitopohjaisen äidinmaitovastikeen ja geneettisen alttiuden merkitys diabetekseen liittyvän autoimmuniteetin kehittymisessä Tyypin 1 diabetes on autoimmuunisairaus, joka syntyy haiman insuliinia tuottavien beta-solujen tuhouduttua elimistön oman immuunipuolustusjärjestelmän hyökkäyksen seurauksena. Sekä perimän että ympäristötekijöiden arvellaan vaikuttavan tautiprosessiin, mutta taudin tarkkaa syntymekanismia ei tunneta. Tutkimuksen tarkoituksena oli selvittää varhaislapsuuden ympäristötekijöiden vaikutusta beta-soluautoimmuniteetin syntyyn, erityispaino tutkimuksessa oli ympäristötekijöiden yhteisvaikutuksessa sekä geneettisten riskitekijöiden ja ympäristötekijöiden vuorovaikutuksessa. Varhaislapsuudessa sairastettu sytomegalovirus- tai enterovirusinfektio ei lisännyt beta-soluautoimmuniteetin riskiä lapsilla, joilla on geneettisesti kohonnut riski sairastua tyypin 1 diabetekseen. Ennen puolen vuoden ikää sairastettu rotavirusinfektio lisäsi hieman tyypin 1 diabetekseen liittyvän autoimmuniteetin riskiä. Tarkemmassa analyysissa varhaislapsuuden enterovirusinfektio osoittautui kuitenkin autovasta-aineiden muodostumisen riskitekijäksi niiden lasten joukossa, jotka olivat saaneet lehmänmaitopohjaista äidinmaidon vastiketta ensimmäisten elinkuukausien aikana. Tämä löydös viittaa enterovirusinfektion ja lehmänmaitopohjaisen vastikkeen yhteisvaikutukseen tyypin 1 diabetekseen liittyvän autoimmuniteetin synnyssä. Löydösten mukaan PTPN22 geenin C1858T polymorfismi vaikuttaa CD4+ T solujen aktivaatioon ja proliferaatiovasteeseen, 1858T alleeliin liittyy alentunut T-soluresepto-rivälitteinen aktivaatio. 1858T alleelin kantajuuteen liittyy lisäksi lisääntynyt autovasta-aineiden ja kliinisen diabeteksen ilmaantuvuus. Tämä yhteys rajoittui yksilöihin, jotka olivat altistuneet lehmänmaitopohjaiselle vastikkeelle ennen kuuden kuukauden ikää. Tulosten mukaan sekä ympäristötekijöiden väliset yhteisvaikutukset että perimä vaikuttavat yksittäisen ympäristötekijän merkitykseen tyypin 1 diabetekseen liittyvän autoimmuniteetin synnyssä. Nämä yhteisvaikutukset ympäristötekijöiden kesken ja perimän ja ympäristötekijöiden välillä selittävät aiemmin julkaistujen tulosten ristiriittaisuutta tutkimuksissa, joissa on analysoitu vain yhden ympäristötekijän vaikutusta diabeteksen ilmaantuvuuteen.

Transitions in Contentious Behaviour in Infancy and Later Aggressive Conduct Problems

Background. Individual trajectories toward aggression originate in early infancy, before there is intent to harm. We focused on infants who were contentious, i.e., prone to engage in anger and use of physical force with other people, and examined change in levels of contentiousness between 6 and 12 months of age with reference to later aggressive conduct problems.
Sample. The CCDS is a nationally representative sample of 321 firstborn children whose families were recruited from antenatal clinics in two National Health Service Trusts.
Method. Mothers, fathers, and a third family member or friend who knew infants well completed the Cardiff Infant Contentiousness Scale (CICS) at 6 months, which was stable form 6 to 12 months, and validated by direct observation of infants’ use of force against peers. Primary caregivers again completed the CICS at 12 months, and up to three informants completed the Child Behaviour Check List at mean ages of 36 and 84 months. We used Latent Transition Analysis to identify different groups of infants in respect to their patterns of contentiousness from 6 to 12 months.
Results
Three ordered classes of contentiousness from low to high were found at 6 and 12 months. Infants exposed to greater family adversity were more likely to move into the high-contentious class from 6 to 12 months. Higher contentiousness in infancy predicted more aggressive conduct problems at 33 months and thereafter.
Conclusions
Infants exposed to family adversity are already at disadvantage by 6 months and likely to escalate in their anger and aggressiveness over time.

Early allergen exposure and atopic eczema

Background The relationship between exposure to indoor aeroallergens in early life and subsequent eczema is unclear. We have previously failed to show any significant associations between early life exposure to house dust mite and cat fur allergens and either sensitization to these allergens or wheeze. We have also previously reported a lower prevalence of parent-reported, doctor-diagnosed eczema by age 2 years for children exposed to higher concentrations of house dust mite, but no other associations with other definitions of eczema or for exposure to cat allergen. Objectives To extend the exposure–response analysis of allergen exposure and eczema outcomes measured up to age 8 years, and to investigate the role of other genetic and environmental determinants. Methods A total of 593 children (92Æ4% of those eligible) born to all newly pregnant women attending one of three general practitioner surgeries in Ashford, Kent, were followed from birth to age 8 years. Concentrations of house dust mite and cat allergen were measured in dust samples collected from the home at 8 weeks after birth. The risk of subsequent eczema as defined by the U.K. diagnostic criteria was determined according to different levels (quintiles) of allergen exposure at birth. Results By age 8 years, 150 (25Æ3%) children had met the diagnostic criteria for eczema at least once. Visible flexural dermatitis was recorded at least once for 129 (28Æ0%). As in other studies, parental allergic history was positively associated with most eczema outcomes, as were higher maternal education and less crowded homes. No clear linear associations between early exposure to house dust mite or cat allergen were found, regardless of the definition of eczema used. The risk of eczema appeared to increase for the three lowest quintiles of house dust mite allergen exposure (odds ratio, OR 1Æ37 for third quintile compared with first), and then to fall for the two highest quintiles (OR 0Æ66 and 0Æ71) even after controlling for confounding factors. Conclusions The lack of any clear exposure–disease relationship between allergens in early life and subsequent eczema argues against allergen exposure being a major factor causing eczema. If the lower levels of eczema at higher levels of house dust mite are confirmed, then interventions aimed at reducing house dust mite in early infancy could paradoxically increase the risk of subsequent eczema.

Skin microbiome before development of atopic dermatitis: Early colonization with commensal staphylococci at 2 months is associated with a lower risk of atopic dermatitis at 1 year

Background: Disease flares of established atopic dermatitis (AD) are generally associated with a low-diversity skin microbiota and Staphylococcus aureus dominance. The temporal transition of the skin microbiome between early infancy and the dysbiosis of established AD is unknown. Methods: We randomly selected 50 children from the Cork Babies After SCOPE: Evaluating the Longitudinal Impact Using Neurological and Nutritional Endpoints (BASELINE) longitudinal birth cohort for microbiome sampling at 3 points in the first 6 months of life at 4 skin sites relevant to AD: the antecubital and popliteal fossae, nasal tip, and cheek. We identified 10 infants with AD and compared them with 10 randomly selected control infants with no AD. We performed bacterial 16S ribosomal RNA sequencing and analysis directly from clinical samples. Results: Bacterial community structures and diversity shifted over time, suggesting that age strongly affects the skin microbiome in infants. Unlike established AD, these patients with infantile AD did not have noticeably dysbiotic communities before or with disease and were not colonized by S aureus. In comparing patients and control subjects, infants who had affected skin at month 12 had statistically significant differences in bacterial communities on the antecubital fossa at month 2 compared with infants who were unaffected at month 12. In particular, commensal staphylococci were significantly less abundant in infants affected at month 12, suggesting that this genus might protect against the later development of AD. Conclusions: This study suggests that 12-month-old infants with AD were not colonized with S aureus before having AD. Additional studies are needed to confirm whether colonization with commensal staphylococci modulates skin immunity and attenuates development of AD.

Breastfeeding, sleep and wake circadian rhythms show distinct temporal emerging patterns

The emerging patterns of breastfeeding, sleep and wake circadian rhythms in an infant and the breastfeeding emergence pattern of his elder sister are presented. Both children were raised under regular contact with photic and non-photic Zeitgebers. Data are related to the first four months of life of the infants, which correspond to the exclusive and ad libitum breastfeeding stage of their lives. Discrimination is made of fasting-associated-wakefulness (FAW) which is a wake state without feeding. Our data show that while FAW episodes are concentrated in the diurnal phase of the day since the first week of life, breastfeeding rhythm takes longer to show statistically significant circadian periodicity (four weeks) and to become monophasic, concentrated in the diurnal phase of the day (three/four months). This precedence of the consolidation of FAW rhythm indicates tight association between nocturnal sleep fragmentation and the drive to feed, in the first months of life of infants.

A novel mutation in the L12 domain of keratin 5 in the Kobner variant of epidermolysis bullosa simplex

We have identified a novel mutation within the linker L12 region of keratin 5 (K5) in a family with the Kobner variant of epidermolysis bullosa simplex. The pattern of inheritance of the disorder in this family is consistent with an autosomal dominant mode of transmission. Affected individuals develop extensive and generalized blistering at birth or early infancy but in later years clinical manifestations are largely confined to palmo-plantar surfaces. Direct sequencing of polymerase chain reaction products revealed a T to C transition within codon 323 of K5 in affected individuals, resulting in a valine to alanine substitution of the seventh residue within the L12 linker domain. This mutation was not observed in unaffected family members or in 100 K5 alleles of unrelated individuals with normal skin. The other critical regions of K5 and K14 were unremarkable in this family except for common polymorphisms that have been previously described. The valine at position 7 of the L12 domain is absolutely conserved in all type II keratins, and in other intermediate filament subunits as well, which suggests that this residue makes an important contribution to filament integrity. Secondary structure analysis revealed that alanine at this position markedly reduces both the hydrophobicity and the beta-sheet nature of the L12 domain. This is the first report of a mutation at this position in an intermediate filament subunit and reinforces the importance of this region to filament biology.

Novel mutations of the BSCL2 and AGPAT2 genes in 10 families with Berardinelli-Seip congenital generalized lipodystrophy syndrome

P>Context Congenital generalized lipodystrophy, or Berardinelli-Seip syndrome, is a rare autosomal recessive disease caused by mutations in either the BSCL2 or AGPAT2 genes. This syndrome is characterized by an almost complete loss of adipose tissue usually diagnosed at birth or early infancy resulting in apparent muscle hypertrophy. Common clinical features are acanthosis nigricans, hepatomegaly with or without splenomegaly and high stature. Acromegaloid features, cardiomyopathy and mental retardation can also be present. Design We investigated 11 kindreds from different geographical areas of Brazil (northeast and southeast). All coding regions as well as flanking intronic regions of both genes were examined. Polymerase chain reaction (PCR) amplifications were performed using primers described previously and PCR products were sequenced directly. Results Four AGPAT2 and two BSCL2 families harboured the same set of mutations. BSCL2 gene mutations were found in the homozygous form in four kindreds (c.412C > T c.464T > C, c.518-519insA, IVS5-2A > G), and in two kindreds compound mutations were found (c.1363C > T, c.424A > G). In the other four families, one mutation of the AGPAT2 gene was found (IVS3-1G > C and c.299G > A). Conclusions We have demonstrated four novel mutations of the BSCL2 and AGPAT2 genes responsible for Berardinelli-Seip syndrome and Brunzell syndrome (AGPAT2-related syndrome).

Comparison of measured sleeping metabolic rate and predicted basal metabolic rate during the first year of life: evidence of a bias changing with increasing metabolic rate

Objective: To compare measurements of sleeping metabolic rate (SMR) in infancy with predicted basal metabolic rate (BMR) estimated by the equations of Schofield. Methods: Some 104 serial measurements of SMR by indirect calorimetry were performed in 43 healthy infants at 1.5, 3, 6, 9 and 12 months of age. Predicted BMR was calculated using the weight only (BMR-wo) and weight and height (BMR-wh) equations of Schofield for 0-3-y-olds. Measured SMR values were compared with both predictive values by means of the Bland-Altman statistical test. Results: The mean measured SMR was 1.48 MJ/day. The mean predicted BMR values were 1.66 and 1.47 MJ/day for the weight only and weight and height equations, respectively. The Bland-Altman analysis showed that BMR-wo equation on average overestimated SMR by 0.18 MJ/day (11%) and the BMR-wh equation underestimated SMR by 0.01 MJ/day (1%). However the 95% limits of agreement were wide: - 0.64 to - 0.28MJ/day (28%) for the former equation and - 0.39 to +0.41 MJ/day (27%) for the latter equation. Moreover there was a significant correlation between the mean of the measured and predicted metabolic rate and the difference between them. Conclusions: The wide variation seen in the difference between measured and predicted metabolic rate and the bias probably with age indicates there is a need to measure actual metabolic rate for individual clinical care in this age group.