PubMed Health⌕ Search

Biomedical subjects

Fernando D Martinez

Publications and source records attributed to Fernando D Martinez.

At least 37 records · Page 2Linked to original sources
PubMed2005

Prenatal factors associated with the development of eczema in the first year of life.

Prenatal factors have been implicated in childhood eczema, but the relationship between maternal cytokine production during pregnancy and infant eczema is unknown. Non-selected women in their third trimester were enrolled in the Tucson Infant Immune Study. Data from three sources were used to define MD-eczema: parent-completed illness questionnaires at age 2, 3, 4, 6 and 9 months regarding physician-seen eczema, parent-completed questionnaires at 12 months regarding physician-diagnosed eczema, and medical record reviews. Blood samples were taken from mothers during their third trimester and from the umbilical cord at birth. Maternal peripheral blood mononuclear cells and cord blood mononuclear cells were stimulated with ConA/PMA, and supernatants were assayed for IFN-gamma and IL-4, -5, -10, and -13. Of 364 children, 28% were seen by a physician for eczema by 1 yr of age. After adjustment for potential confounders using logistic regression, the odds for development of eczema in infancy were significantly higher when mothers had active eczema in pregnancy (OR, 2.46, CI 1.0-5.8, p <0.042) and when mothers were in the highest tertile of serum IgE production (OR 2.28, CI 1.2-4.4, p <0.013). Colds in the third trimester were associated with lower odds of eczema (OR 0.32, CI 0.16-0.63, p <0.001). Our findings from this cohort study suggest that in utero factors, including maternal IgE, colds, and eczema, may influence the risk of infant eczema.

Arizona↗
PubMed2005

Relation of beta2-adrenoceptor polymorphisms at codons 16 and 27 to persistence of asthma symptoms after the onset of puberty.

BACKGROUND: It has long been recognized that many children with asthma outgrow the disease after the onset of puberty, but little is known about genetic factors influencing this outcome. OBJECTIVES: The aim of the present study was to determine whether the polymorphisms at codons 16 and 27 of the beta2-adrenoceptor are significant predictors of the persistence of asthma during adolescence. DESIGN AND PARTICIPANTS: We used data from the prospective Tucson Children's Respiratory Study. Children were genotyped for the polymorphisms at codons 16 and 27. The presence of wheezing/asthma was assessed by questionnaire from age 6 years up to the reported onset of puberty (prepubertal period) and after the onset of puberty up to age 16 years (adolescence). RESULTS: Among children who wheezed in the prepubertal period (n = 168), subjects homozygous for Gly at codon 16 were at significantly increased risk for persistent wheezing after puberty, as compared with carriers of the other genotypes (relative risk [RR], 1.43; 95% confidence interval [CI], 1.06 to 1.92; p = 0.019). This relation was present among boys (RR, 2.17; 95% CI, 1.41 to 3.36) but not girls (RR, 0.85; 95% CI, 0.55 to 1.30), and increased linearly according to the frequency of wheezing episodes after the onset of puberty. These findings persisted after adjusting for ethnicity and other potential confounders and after selecting only white children. The polymorphism at codon 27 showed no relation with risk for persistent wheezing. CONCLUSIONS: This study provides evidence for a strong gender-specific effect of the Gly16 polymorphism on the persistence of asthma after the onset of puberty.

Adolescent↗
PubMed2005

Heterogeneity of the association between lower respiratory illness in infancy and subsequent asthma.

Viral lower respiratory tract illnesses occurring during the first years of life are associated with increased risk of subsequent asthma, but the mechanisms involved have not been completely elucidated. The available evidence suggests that the factors that explain this connection are heterogeneous. Children who start life with lower levels of airway function appear to be more prone to transient forms of wheezing in the first years of life. "Intrinsic" bronchial hyperresponsiveness, that is, that measured shortly after birth and unrelated to markers of atopy, has been reported to predict both early life wheezing and wheezing occurring during the early school years, independent of atopy. It has also been suggested that both decreased interferon-gamma responses measured before any viral lower respiratory illness and increased interferon-gamma responses measured at the time of the illness may predispose to such illnesses. Children in whom the former mechanism is involved should be expected to be more atopic later in life, whereas those with the latter mechanism should be less likely to be atopic. This may explain why early viral respiratory illnesses have been found to be both protective against and a risk factor for subsequent atopy in different studies. Current evidence thus suggests that different and often apparently contradictory mechanisms related to airway function, structure, and immune responsiveness may explain the association between viral lower airway illness in early life and subsequent asthma. Future preventive and therapeutic strategies will need to address the specific mechanisms that explain this association in different groups of subjects.

Asthma↗
PubMed2004

Polymorphisms in the CD14 gene associated with pulmonary function in farmers.

RATIONALE AND OBJECTIVES: Farmers experience airway obstruction, which may be attributable in part to endotoxin inhalation. CD14 is a receptor for endotoxin. MATERIALS AND METHODS: Based on our findings of increased circulating CD14 associated with the CD14/-159 T allele, we hypothesized that carriers of this allele would have decreased lung function among endotoxin-exposed individuals. CD14/-159TT farmers (n = 19) had significantly lower lung function as measured by FEV1 (p = 0.028) and mean forced expiratory flow during the middle half of the FVC (FEF25-75) (p = 0.05) compared with farmers with the C allele (n = 78). Also, farmers with the CD14/-1619GG genotype (n =11) were associated with lower lung function (FEV1, p = 0.008; FEF25-75, p = 0.009) compared with farmers with the A allele (n = 86). RESULTS: No association between CD14/-550 and lung function was observed (FEV1, p = 0.32; FEF25-75, p = 0.11). Increased prevalence of wheezing was reported in farmers homozygous for CD14/-159T (p = 0.013) or CD14/-1619G (p = 0.019) compared with farmers with the CC or AA genotype, respectively. No association was found between TLR4/Asp299Gly and lung function or wheeze. CONCLUSION: We conclude that the CD14/-159 or CD14/-1619 loci may play a role in modulating lung function and wheeze among agricultural workers.

Adult↗
PubMed2004

TOLL-like receptor 10 genetic variation is associated with asthma in two independent samples.

TOLL-like receptor 10 (TLR10) is the most recently identified human homolog of the Drosophila TOLL protein. In humans, the TOLL-like receptors recognize pathogen-associated molecular patterns (PAMPs) as part of innate immune host defenses. Localized to chromosome 4p14, the specific ligands and functions of TLR10 are currently unknown, although it is expressed in lung and in B-lymphocytes. TLR10 is a potential asthma candidate gene because early life innate immune responses to ubiquitous inhaled allergens and PAMPs may influence asthma susceptibility. Resequencing in 47 subjects revealed a total of 78 single nucleotide polymorphisms (SNPS) (1 SNP per 106 bp) of which only 11 had been previously published. A significant association (p < or = 0.02) between two SNPs (c.+1031G>A, c.+2322A>G) and physician-diagnosed asthma was observed in a case control study (517 cases, 519 control subjects) of European American subjects nested within the Nurses' Health Study cohort. The association for these same two SNPs (p < or = 0.015) replicated in an independent family based cohort, where a measure of airway hyperresponsiveness (PC20) was also associated (p = 0.026 for c.+1031G>A). Consistent association in two independent samples and association with an intermediate phenotype provides strong support for TLR10 genetic variation contributing to asthma risk.

Black or African American↗
PubMed2004

Persistence of asthma symptoms during adolescence: role of obesity and age at the onset of puberty.

Little is known about rates and predictors of remission of childhood asthma after the onset of puberty. We used data collected at ages 6, 8, 11, 13, and 16 years from the Tucson Children's Respiratory Study, a population-based birth cohort. The onset of puberty was defined as the age of appearance of the first pubertal signs as reported by parents. Information on wheezing both before and after onset of puberty (mean +/- SD follow-up from onset of puberty, 4.2 +/- 1 year) was available for 781 children. Of these, 166 had asthma (either frequent wheezing or a physician-confirmed diagnosis plus any wheezing) in at least one survey before puberty. In this group, 58% of the children (97 of 166) reported the presence of wheezing after the onset of puberty (unremitting asthma). In contrast, only 30% (39 of 131) of the children with infrequent wheezing before puberty experienced wheezing episodes after the onset of puberty (unremitting wheezing). In addition to frequent wheezing before puberty, obesity, early onset of puberty, active sinusitis, and skin test sensitization were significant and independent predictors of unremitting asthma after the onset of puberty. Our findings from a population-based longitudinal cohort challenge the commonly held view that asthma usually remits during adolescence.

Adolescent↗
PubMed2004

The Prevention of Early Asthma in Kids study: design, rationale and methods for the Childhood Asthma Research and Education network.

Pediatric asthma remains an important public health concern as its prevalence and cost to the health care system is rising. In order to promote innovative research in asthma therapies, the National Heart, Lung and Blood Institute created the Childhood Asthma Research and Education Network in 1999. As its first study, the steering committee of the Childhood Asthma Research and Education Network designed a randomized clinical trial to determine if persistent asthma could be prevented in children at a high risk to develop the disease. This communication presents the design of its first clinical trial, the Prevention of Asthma in Kids (PEAK) trial and the organization of the Childhood Asthma Research and Education Network that developed and implemented this trial. Studies of the natural history of asthma have shown that, in persistent asthma, the initial asthma-like symptoms and loss of lung function occur predominately during the first years of life. Therefore, in the Prevention of Asthma in Kids study, children 2 and 3 years old with a positive asthma predictive index were randomized to twice daily treatment with fluticasone 88 microg or placebo via metered-dose inhaler and Aerochamber for 2 years. The double blind treatment period was followed by a 1-year observational period. Lung function was measured by spirometry and oscillometry technique at 4-month intervals throughout the study. Bronchodilator reversibility and exhaled nitric oxide (ENO) studies were performed at the end of the treatment and observation periods. The primary outcome measure was the number of asthma-free days. Other secondary outcomes included number of exacerbations, use of asthma medications and lung function. These measures were chosen to reflect the progression of the disease from intermittent wheezing to persistent asthma and measurement of the extent of airflow limitation and airway reactivity.

Administration, Inhalation↗
PubMed2004

Parental asthma as a risk factor for the development of early skin test sensitization in children.

BACKGROUND: Recent epidemiologic evidence has challenged the paradigm suggesting a direct causal relationship between allergic sensitization and asthma. OBJECTIVE: We sought to investigate the role of a familial predisposition for asthma in the development of atopy in children. METHODS: Subjects were participants in the Tucson Children's Respiratory Study. Skin tests to aeroallergens were performed in parents and in children at ages 6, 11, and 16 years. Parents were considered asthmatic if they reported physician-confirmed asthma. Parents were divided into 4 phenotypes on the basis of skin sensitization (Skt+ or Skt-) and asthma status (As+ or As-): Skt-/As-, Skt-/As+, Skt+/As-, and Skt+/As+. RESULTS: Children's allergic sensitization differed among parental phenotypes at all ages (P <.0001). Children in the Skt+/As- and Skt+/As+ groups were significantly more likely to be allergic than children in the Skt-/As- group at all ages. Among children with allergic parents, those with at least one parent with asthma were significantly more likely to have positive skin test responses than those with nonasthmatic parents at age 6 years (52.4% vs 37.4%, P <.005) and 11 years (70.1% vs 55.6%, P <.005) but not at age 16 years (82.3% vs 75.1%, P =.180). Results were independent of wheezing in the child and of the characteristics of atopy in parents. The Skt-/As+ group had too few subjects for meaningful comparisons. CONCLUSION: Among children of atopic parents, parental asthma is a risk factor for allergic sensitization in early childhood. The strong association between allergic sensitization and asthma is at least in part explained by an increased susceptibility to allergen sensitization in subjects predisposed to asthma.

Adolescent↗
PubMed2004

Toll-like receptor 2 as a major gene for asthma in children of European farmers.

BACKGROUND: The finding that the prevalence of asthma and allergies is less frequent in children raised on animal farms has led to the conjecture that exposure to microbial products modifies immune responses. The toll-like receptors (TLRs) represent an evolutionarily conserved family of innate immunity receptors with microbial molecules as ligands. OBJECTIVES: We reasoned that polymorphisms in genes encoding TLRs might modulate the protective effects observed in farming populations. METHODS: Farmers' and nonfarmers' children living in rural areas in Austria and Germany and who were enrolled in the cross-sectional ALEX study were genotyped for single nucleotide polymorphisms in the TLR2 and TLR4 genes. The frequencies of asthma, allergic rhinitis, and atopic sensitization were compared between the genotypes in relation to exposure to farming and endotoxin. RESULTS: Among farmers' children, those carrying a T allele in TLR2/-16934 compared with children with genotype AA were significantly less likely to have a diagnosis of asthma (3% vs 13%, P = .012), current asthma symptoms (3% vs 16%, P = .004), atopic sensitization (14% vs 27%, P = .023), and current hay fever symptoms (3% vs 14%, P = .01). The association between TLR2/-16934 and asthma among children of farmers was independent of atopy. No such association was found among children from the same rural communities but not living on farms. CONCLUSION: Our results suggest that genetic variation in TLR2 is a major determinant of the susceptibility to asthma and allergies in children of farmers.

Adult↗
PubMed2004

Atopic characteristics of children with recurrent wheezing at high risk for the development of childhood asthma.

BACKGROUND: Few studies have characterized the atopic profile of toddler-aged children with recurrent wheezing at high risk of the development of persistent asthma. Objective We sought to determine the atopic profile of toddler-aged children with frequent wheeze at high risk for the development of persistent asthma who either had a parental history of asthma, a personal history of atopic dermatitis, or both. METHODS: Participants enrolled in the Prevention of Early Asthma in Kids study (n = 285) on the basis of a modified Asthma Predictive Index were characterized on the basis of allergy and asthma questionnaire responses and allergy skin puncture test results. RESULTS: The majority of the children (60.7%, n = 148) were sensitized to either food or aeroallergens. Male children were significantly more likely to be sensitized to aeroallergens ( P = .03) and to have a blood eosinophil level of 4% or greater ( P = .03) and a total serum IgE level of greater than 100 IU/mL ( P = .0004). Additionally, eosinophilia and total serum IgE level had the strongest correlation with aeroallergen sensitization. CONCLUSION: The high prevalence of aeroallergen sensitization in this high-risk cohort suggests that aeroallergens might have an important role in the early development of asthma. As such, the Prevention of Early Asthma in Kids cohort appears to be an appropriate cohort in which to test whether early intervention with an inhaled corticosteroid can significantly attenuate, or perhaps even prevent, the allergic march from the initial stages of allergic sensitization to the subsequent development of asthma in toddlers with episodic wheezing.

Age Factors↗
PubMed2004

Asthma phenotypes in childhood: lessons from an epidemiological approach.

Asthma is a heterogenous disease with variable signs and symptoms among patients. It also presents significant individual variability over time. Recently, some important population-based studies that followed children from birth or from early childhood into adulthood have shed new light on how we understand this syndrome. Three phenotypes have been identified in children with asthma: transient wheezing, non-atopic wheezing of the toddler and pre-school-aged child and IgE-mediated wheezing. Transient wheezing is associated with symptoms that are limited to the first 3-5 years of life, decreased lung function, maternal smoking during pregnancy and exposure to other siblings or children at daycare centres. There is no association between transient wheezing and family history of asthma or allergic sensitisation. Children wheezing with respiratory syncytial virus in the first years of life are more likely to be wheezing up to 13 years of age; this is independent of atopy (non-atopic wheezers) and is not related to atopic sensitisation. Wheezing associated with evidence of allergic sensitisation has been identified as the 'classic' asthma phenotype. Early allergic sensitisation is a major risk factor for persistent asthma.

Asthma↗
PubMed2004

Drug development strategies for asthma: in search of a new paradigm.

The spiraling costs of asthma treatment seem set to continue rising, given the equivocal performance of the latest generation of specific anti-inflammatory drugs in trials in adult asthmatics. We argue that the continuation of this trend is inevitable unless there is a substantial realignment of entrenched drug development policy in the pharmaceutical industry and a parallel shift in licensing policy by regulatory authorities to encourage the development of drugs capable of halting the progression from acute to chronic asthma when the disease first manifests in childhood. The theoretical framework for such an approach, including proof-of-principle data from studies in children with early-stage disease and a range of candidate drugs, already exists. What is needed is informed debate on the risks versus potential benefits of this approach.

Animals↗
PubMed2004

The differential effect of genetic variation on soluble CD14 levels in human plasma and milk.

PROBLEM: The protein CD14 is a pattern recognition receptor for bacterial lipopolysaccharide (LPS). Whether genetic variation has the same influence on soluble CD14 (sCD14) levels in human plasma and milk remains to be determined. METHOD OF STUDY: We measured sCD14 levels in plasma during pregnancy (n = 196) and in milk in the postpartum (n = 152) for women genotyped for the single nucleotide polymorphisms (SNPs) at positions -1619, -550, and -159 from the transcription start site of the CD14 gene. RESULTS: Plasma- and milk-sCD14 levels differed significantly both by CD14/-1619 and CD14/-550 genotypes and by haplotypes. Most interestingly, sCD14 levels were regulated differentially by the same genetic variants in plasma and milk, with the CD14/-550T allele and the corresponding are ATC haplotype associated with high sCD14 in milk but low sCD14 in plasma. A correlation between sCD14 levels in plasma and milk was absent (r = 0.091, P = NS). CONCLUSIONS: Our findings suggest the existence of cell-specific regulation mechanisms of CD14 gene expression.

Adult↗
PubMed2003

Reduced interferon gamma production and soluble CD14 levels in early life predict recurrent wheezing by 1 year of age.

It is unknown whether reduced production of IFNgamma in early life, before any lower respiratory tract illness, is a risk factor for recurrent wheezing in infancy. We followed 238 infants prospectively from birth to 1 year of age. At birth and at 3 months of age, IFNgamma production from polyclonally stimulated peripheral blood mononuclear cells and soluble CD14 (sCD14) levels in plasma were measured. The odds of developing recurrent wheezing (assessed by questionnaire) in the first year of life were up to 4.5 times higher for children in the lowest quartile of IFNgamma production at 3 months (p = 0.0005) and 3.2 times higher for children in the lowest quartile of sCD14 levels at birth (p = 0.004) as compared with children in the other 3 combined quartiles of IFNgamma and sCD14, respectively. Findings were confirmed in the multivariate analysis. IFNgamma production at 3 months and sCD14 levels at birth were correlated (r = 0.188, p = 0.031). Our findings from a longitudinal cohort suggest that impaired IFNgamma production at 3 months and reduced plasma-sCD14 levels at birth significantly increase the risk of developing recurrent wheezing in the first year of life.

Age Factors↗
PubMed2003

Systemic responsiveness to lipopolysaccharide and polymorphisms in the toll-like receptor 4 gene in human beings.

BACKGROUND: The response to lipopolysaccharide exposure is highly variable and might be a result of genetic diversity between individuals. The toll-like receptor 4 (TLR-4) is the principal receptor for lipopolysacharide. OBJECTIVES: We investigated the association between single-nucleotide polymorphisms in the TLR4 locus and levels of systemic inflammatory markers in response to lipopolysaccharide. METHODS: Healthy subjects (n = 116) were genotyped for the most frequent polymorphisms found in the promoter and coding region of the TLR4 gene (-2026A/T, -1607T/C, +896A/G, and +1196C/T relative to the translation start site). Subjects were challenged with 20 microg lipopolysaccharide by inhalation. RESULTS: Polymorphisms at +896 and +1196 were in complete linkage disequilibrium, and no homozygotes for the less common allele, G and T respectively, were found. After lipopolysaccharide inhalation, subjects heterozygous for either TLR-4/+896 or TLR4/+1196 had significantly lower numbers of white blood cell counts and lower levels of C-reactive protein and lipopolysaccharide-binding protein compared with homozygotes with the common allele. None of the heterozygous subjects (n = 18) except 1 were high responders to lipopolysaccharide (defined as a rise in C-reactive protein > 10 mg/L), whereas 36 of 98 homozygous subjects were high responders (P <.02). No association was observed between the TLR-4/-2026 and TLR-4/-1607 polymorphisms and lipopolysaccharide responsiveness. CONCLUSION: The single-nucleotide polymorphisms at position +896 or +1196 in the TLR-4 gene is associated with systemic inflammatory hyporesponsiveness to inhaled lipopolysaccharide.

Acute-Phase Proteins↗
PubMed2003

A complete screening of the IL4 gene: novel polymorphisms and their association with asthma and IgE in childhood.

BACKGROUND: IL-4, a cytokine with immunomodulatory functions, is involved in the upregulation of IgE production characteristic of asthma and allergy. Thus far, 2 single nucleotide polymorphisms (SNPs) in the promoter (C-589T) and 5' untranslated region (C-33T) of the IL4 gene have been identified. Polymorphism C-589T was reported to influence total serum IgE levels and bronchial hyperresponsiveness. However, no study has investigated the putative existence of further SNPs in exons, introns, and flanking regions of the IL4 gene. OBJECTIVE: A complete screening of the IL4 gene and its flanking regions for new polymorphisms was performed. Large-scale association studies in 1120 German schoolchildren were conducted to determine the effect of all polymorphisms present in the IL4 gene on the phenotypic expression of atopic diseases. METHODS: Denaturing HPLC and standard sequencing techniques were performed to detect novel polymorphisms in 33 unrelated subjects unselected for atopic diseases. Linkage disequilibrium was assessed for all polymorphisms in the IL4 gene, and association studies were performed. RESULTS: A total of 16 polymorphisms were identified in the IL4 gene, 14 of which were not reported previously. The pattern of linkage disequilibrium observed in IL4 could not be explained by physical distance. A significant association between a cluster of polymorphisms in strong linkage disequilibrium with each other and a physician's diagnosis of asthma and total serum IgE levels was found. CONCLUSION: These results indicate a possible involvement of SNPs in the IL4 gene in the development of asthma and the regulation of total serum IgE.

Asthma↗