Background: Elevated concentration of C-reactive protein(CRP) in the maternal blood is associated... more Background: Elevated concentration of C-reactive protein(CRP) in the maternal blood is associated with the presence of intrauterine infection. Newborns born of mothers with perinatal infection, whether indicated as chorioamnionitis or positive CRP, have been associated with probable sepsis in early neonatal period. We purport this study to evaluate the diagnostic performance of maternal inflammatory markers, CRP and chorioamnionitis for prediction of neonatal sepsis.
mtDNAs from 37 Italian subjects affected by Leber hereditary optic neuropathy (LHON) (28 were 117... more mtDNAs from 37 Italian subjects affected by Leber hereditary optic neuropathy (LHON) (28 were 11778 positive, 7 were 3460 positive, and 2 were 14484 positive) and from 99 Italian controls were screened for most of the mutations that currently are associated with LHON. Highresolution restriction-endonuclease analysis also was performed on all subjects, in order to define the phylogenetic relationships between the mtDNA haplotypes and the LHON mutations observed in patients and in controls. This analysis shows that the putative secondary/intermediate LHON mutations 4216, 4917, 13708, 15257, and 15812 are ancient polymorphisms, are associated in specific combinations, and define two common Caucasoidspecific haplotype groupings (haplogroups J and T). On the contrary, the same analysis shows that the primary mutations 11778, 3460, and 14484 are recent and are due to multiple mutational events. However, phylogenetic analysis also reveals a different evolutionary pattern for the three primary mutations. The 3460 mutations are distributed randomly along the phylogenetic trees, without any preferential association with the nine haplogroups (H, I, J, K, T, U, V, W, and X) that characterize European populations, whereas the 11778 and 14484 mutations show a strong preferential association with haplogroup J. This finding suggests that one ancient combination of haplogroup J-specific mutations increases both the penetrance of the two primary mutations 11778 and 14484 and the risk of disease expression.
mtDNAs from 37 Italian subjects affected by Leber hereditary optic neuropathy (LHON) (28 were 117... more mtDNAs from 37 Italian subjects affected by Leber hereditary optic neuropathy (LHON) (28 were 11778 positive, 7 were 3460 positive, and 2 were 14484 positive) and from 99 Italian controls were screened for most of the mutations that currently are associated with LHON. High-resolution restriction-endonuclease analysis also was performed on all subjects, in order to define the phylogenetic relationships between the mtDNA haplotypes and the LHON mutations observed in patients and in controls. This analysis shows that the putative secondary/intermediate LHON mutations 4216, 4917, 13708, 15257, and 15812 are ancient polymorphisms, are associated in specific combinations, and define two common Caucasoid-specific haplotype groupings (haplogroups J and T). On the contrary, the same analysis shows that the primary mutations 11778, 3460, and 14484 are recent and are due to multiple mutational events. However, phylogenetic analysis also reveals a different evolutionary pattern for the three pr...
Haemoglobin C (HbC; beta6Glu --> Lys) is common in malarious areas of West Africa, especially ... more Haemoglobin C (HbC; beta6Glu --> Lys) is common in malarious areas of West Africa, especially in Burkina Faso. Conclusive evidence exists on the protective role against severe malaria of haemoglobin S (HbS; beta6Glu --> Val) heterozygosity, whereas conflicting results for the HbC trait have been reported and no epidemiological data exist on the possible role of the HbCC genotype. In vitro studies suggested that HbCC erythrocytes fail to support the growth of P. falciparum but HbC homozygotes with high P. falciparum parasitaemias have been observed. Here we show, in a large case-control study performed in Burkina Faso on 4,348 Mossi subjects, that HbC is associated with a 29% reduction in risk of clinical malaria in HbAC heterozygotes (P = 0.0008) and of 93% in HbCC homozygotes (P = 0.0011). These findings, together with the limited pathology of HbAC and HbCC compared to the severely disadvantaged HbSS and HbSC genotypes and the low betaS gene frequency in the geographic epicen...
RATIONALE: The food challenge test (FCT) still represents the diagnostic gold standard for food a... more RATIONALE: The food challenge test (FCT) still represents the diagnostic gold standard for food allergies. The diagnostic specificity of allergen-specific IgE (sIgE) is still discussed, even when applying the internationally proposed cut-off values. The aim of this study was to compare the performance of the measurement of sIgE with a component-based allergen microarray (ISAC CRD89) and that of the standard ImmunoCAP System in children with allergy to cow's milk proteins (CMPs) or hen's egg that underwent FCT. METHODS: We enrolled 75 children with clinical diagnosis of food allergy to CMPs and/or hen's egg based on the development, in the 2 hours following accidental exposure, of anaphylactic reactions. Skin Prick Test (SPT, Lofarma) were performed and sIgE measured with the CAP and ISAC systems. Sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of SPT and of the two methods for sIgE measurement were evaluated as predictors of a positive FCT. RESULTS: The microarray allergen test performed well with better sensitivity, if positivity to only one allergen was considered and better specificity when two allergens were considered, compared with the results of SPT or of the ImmunoCAP. CONCLUSIONS: In patients with severe allergy to CMPs or to hen's egg, the microarray allergen test appears to have a good clinical performance in predicting the outcome of the FCT. Further studies on large number of patients are warranted to define cut-off values for the test and to investigate the values of different patterns of IgE reactivities.
... Marco Sbracia, Claudio Manna, and Chiara Cavazzini Foundation for Advancement in Reproductive... more ... Marco Sbracia, Claudio Manna, and Chiara Cavazzini Foundation for Advancement in Reproductive Medicine, 00100 Rome Daniele Sellitto Centro di Studio sulla Genetica Evoluzionistica, CNR, 00185 Rome, Italy 1To whom correspondence should be addressed 1749
Background The food challenge test (FCT) is the gold standard for the diagnosis of food allergy. ... more Background The food challenge test (FCT) is the gold standard for the diagnosis of food allergy. This procedure is time consuming, costly and can induce potentially severe symptoms. An ideal in vitro test should allow to avoid the FCT. Objective To assess the clinical performance of microarray for specific IgE (sIgE) detection in children with challenge-proven/excluded cow's milk (CM) or hen's egg (HE) allergy. Methods One-hundred and four children with suspected IgE-mediated hypersensitivity to CM or HE were studied. In all patients, skin prick test, ImmunoCAP, microarray and FCT were performed. Results The microarray components Bos d 8 for CM (27/58 patients) and Gal d 1 (20/46 patients) and Gal d 2 (24/46) for HE were the most frequently recognized allergens. Using the FCT results as the reference parameter, sIgE to Bos d 8 and Gal d 1 had the highest area under the curves. These were not significantly different from those obtained using the ImmunoCAP. Use of 95% clinical decision points (CDP) for sIgE to Bos d 8 and Gal d 1 resulted in higher negative predictive values (78% and 79%, respectively) than those obtained with the ImmunoCAP (57% and 59%). Conclusions Our results show that in children with suspected CM or HE allergy, the microarray has a good ability to predict the FCT results. In a clinical application perspective, the microarray could be used as a second-level assay, if the ImmunoCAP sIgE is o95% CDP. This approach would lead to a decrease in the number of the FCT to be performed, as well as of positive FCTs with a subsequent decrease in severe reaction risk.
mtDNA sequence variation was studied in 419 individuals from nine Eurasian populations, by high-r... more mtDNA sequence variation was studied in 419 individuals from nine Eurasian populations, by high-resolution RFLP analysis, and it was followed by sequencing of the control region of a subset of these mtDNAs and a detailed survey of previously published data from numerous other European populations. This analysis revealed that a major Paleolithic population expansion from the "Atlantic zone" (southwestern Europe) occurred 10,000-15,000 years ago, after the Last Glacial Maximum. As an mtDNA marker for this expansion we identified haplogroup V, an autochthonous European haplogroup, which most likely originated in the northern Iberian peninsula or southwestern France at about the time of the Younger Dryas. Its sister haplogroup, H, which is distributed throughout the entire range of Caucasoid populations and which originated in the Near East ∼25,000-30,000 years ago, also took part in this expansion, thus rendering it by far the most frequent (40%-60%) haplogroup in western Europe. Subsequent migrations after the Younger Dryas eventually carried those "Atlantic" mtDNAs into central and northern Europe. This scenario, already implied by archaeological records, is given overwhelming support from both the distribution of the autochthonous European Y chromosome type 15, as detected by the probes 49a/f, and the synthetic maps of nuclear data.
A mutation (A1555G) in the mtDNA has been associated with aminoglycoside-induced and nonsyndromic... more A mutation (A1555G) in the mtDNA has been associated with aminoglycoside-induced and nonsyndromic sensorineural deafness. The pathological significance of this mutation in Caucasoid families has not been established, and its relationship with antibiotic treatment is not well understood. We studied 70 Spanish families with sensorineural deafness (36 congenital and 34 late onset) for the mtDNA A1555G mutation. The A1555G mutation was found in 19 families with maternally transmitted deafness but not in the other 51 families or in 200 control subjects. In 12 families all the patients with the A1555G mutation who received aminoglycosides became deaf, representing 30.3% of the deaf patients in these families. None of the deaf patients from seven other families received aminoglycosides. Overall, only 17.7% of the patients with deafness and the A1555G mutation had been treated with aminoglycosides. The age at onset of deafness was lower (median age 5 years, range 1-52 years) in those treated with aminoglycosides than in those who did not receive antibiotics (median age 20 years, range 1-65 years) (P ! ). The mtDNA of these families belongs to haplo-.001 types common in Europeans. These data indicate that the A1555G mutation accounts for a large proportion of the Spanish families with late-onset sensorineural deafness, that the A1555G mutation has an age-dependent penetrance for deafness (enhanced by treatment with aminoglycosides), and that mtDNA backgrounds probably do not play a major role in disease expression.
Objective. Macrophage activation syndrome (MAS) in systemic onset juvenile idiopathic arthritis (... more Objective. Macrophage activation syndrome (MAS) in systemic onset juvenile idiopathic arthritis (SoJIA) is considered to be an acquired form of familial haemophagocytic lymphohistiocytosis (fHLH). FHLH is an autosomal recessive disorder, characterized by diminished NK cell function and caused by mutations in the perforin gene (PRF1) in 20-50% of patients. Interestingly, SoJIA patients display decreased levels of perforin in NK cells and diminished NK cell function as well. Here, we analysed PRF1 and its putative promoter in SoJIA patients with or without a history of MAS.
Background: Elevated concentration of C-reactive protein(CRP) in the maternal blood is associated... more Background: Elevated concentration of C-reactive protein(CRP) in the maternal blood is associated with the presence of intrauterine infection. Newborns born of mothers with perinatal infection, whether indicated as chorioamnionitis or positive CRP, have been associated with probable sepsis in early neonatal period. We purport this study to evaluate the diagnostic performance of maternal inflammatory markers, CRP and chorioamnionitis for prediction of neonatal sepsis.
mtDNAs from 37 Italian subjects affected by Leber hereditary optic neuropathy (LHON) (28 were 117... more mtDNAs from 37 Italian subjects affected by Leber hereditary optic neuropathy (LHON) (28 were 11778 positive, 7 were 3460 positive, and 2 were 14484 positive) and from 99 Italian controls were screened for most of the mutations that currently are associated with LHON. Highresolution restriction-endonuclease analysis also was performed on all subjects, in order to define the phylogenetic relationships between the mtDNA haplotypes and the LHON mutations observed in patients and in controls. This analysis shows that the putative secondary/intermediate LHON mutations 4216, 4917, 13708, 15257, and 15812 are ancient polymorphisms, are associated in specific combinations, and define two common Caucasoidspecific haplotype groupings (haplogroups J and T). On the contrary, the same analysis shows that the primary mutations 11778, 3460, and 14484 are recent and are due to multiple mutational events. However, phylogenetic analysis also reveals a different evolutionary pattern for the three primary mutations. The 3460 mutations are distributed randomly along the phylogenetic trees, without any preferential association with the nine haplogroups (H, I, J, K, T, U, V, W, and X) that characterize European populations, whereas the 11778 and 14484 mutations show a strong preferential association with haplogroup J. This finding suggests that one ancient combination of haplogroup J-specific mutations increases both the penetrance of the two primary mutations 11778 and 14484 and the risk of disease expression.
mtDNAs from 37 Italian subjects affected by Leber hereditary optic neuropathy (LHON) (28 were 117... more mtDNAs from 37 Italian subjects affected by Leber hereditary optic neuropathy (LHON) (28 were 11778 positive, 7 were 3460 positive, and 2 were 14484 positive) and from 99 Italian controls were screened for most of the mutations that currently are associated with LHON. High-resolution restriction-endonuclease analysis also was performed on all subjects, in order to define the phylogenetic relationships between the mtDNA haplotypes and the LHON mutations observed in patients and in controls. This analysis shows that the putative secondary/intermediate LHON mutations 4216, 4917, 13708, 15257, and 15812 are ancient polymorphisms, are associated in specific combinations, and define two common Caucasoid-specific haplotype groupings (haplogroups J and T). On the contrary, the same analysis shows that the primary mutations 11778, 3460, and 14484 are recent and are due to multiple mutational events. However, phylogenetic analysis also reveals a different evolutionary pattern for the three pr...
Haemoglobin C (HbC; beta6Glu --> Lys) is common in malarious areas of West Africa, especially ... more Haemoglobin C (HbC; beta6Glu --> Lys) is common in malarious areas of West Africa, especially in Burkina Faso. Conclusive evidence exists on the protective role against severe malaria of haemoglobin S (HbS; beta6Glu --> Val) heterozygosity, whereas conflicting results for the HbC trait have been reported and no epidemiological data exist on the possible role of the HbCC genotype. In vitro studies suggested that HbCC erythrocytes fail to support the growth of P. falciparum but HbC homozygotes with high P. falciparum parasitaemias have been observed. Here we show, in a large case-control study performed in Burkina Faso on 4,348 Mossi subjects, that HbC is associated with a 29% reduction in risk of clinical malaria in HbAC heterozygotes (P = 0.0008) and of 93% in HbCC homozygotes (P = 0.0011). These findings, together with the limited pathology of HbAC and HbCC compared to the severely disadvantaged HbSS and HbSC genotypes and the low betaS gene frequency in the geographic epicen...
RATIONALE: The food challenge test (FCT) still represents the diagnostic gold standard for food a... more RATIONALE: The food challenge test (FCT) still represents the diagnostic gold standard for food allergies. The diagnostic specificity of allergen-specific IgE (sIgE) is still discussed, even when applying the internationally proposed cut-off values. The aim of this study was to compare the performance of the measurement of sIgE with a component-based allergen microarray (ISAC CRD89) and that of the standard ImmunoCAP System in children with allergy to cow's milk proteins (CMPs) or hen's egg that underwent FCT. METHODS: We enrolled 75 children with clinical diagnosis of food allergy to CMPs and/or hen's egg based on the development, in the 2 hours following accidental exposure, of anaphylactic reactions. Skin Prick Test (SPT, Lofarma) were performed and sIgE measured with the CAP and ISAC systems. Sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of SPT and of the two methods for sIgE measurement were evaluated as predictors of a positive FCT. RESULTS: The microarray allergen test performed well with better sensitivity, if positivity to only one allergen was considered and better specificity when two allergens were considered, compared with the results of SPT or of the ImmunoCAP. CONCLUSIONS: In patients with severe allergy to CMPs or to hen's egg, the microarray allergen test appears to have a good clinical performance in predicting the outcome of the FCT. Further studies on large number of patients are warranted to define cut-off values for the test and to investigate the values of different patterns of IgE reactivities.
... Marco Sbracia, Claudio Manna, and Chiara Cavazzini Foundation for Advancement in Reproductive... more ... Marco Sbracia, Claudio Manna, and Chiara Cavazzini Foundation for Advancement in Reproductive Medicine, 00100 Rome Daniele Sellitto Centro di Studio sulla Genetica Evoluzionistica, CNR, 00185 Rome, Italy 1To whom correspondence should be addressed 1749
Background The food challenge test (FCT) is the gold standard for the diagnosis of food allergy. ... more Background The food challenge test (FCT) is the gold standard for the diagnosis of food allergy. This procedure is time consuming, costly and can induce potentially severe symptoms. An ideal in vitro test should allow to avoid the FCT. Objective To assess the clinical performance of microarray for specific IgE (sIgE) detection in children with challenge-proven/excluded cow's milk (CM) or hen's egg (HE) allergy. Methods One-hundred and four children with suspected IgE-mediated hypersensitivity to CM or HE were studied. In all patients, skin prick test, ImmunoCAP, microarray and FCT were performed. Results The microarray components Bos d 8 for CM (27/58 patients) and Gal d 1 (20/46 patients) and Gal d 2 (24/46) for HE were the most frequently recognized allergens. Using the FCT results as the reference parameter, sIgE to Bos d 8 and Gal d 1 had the highest area under the curves. These were not significantly different from those obtained using the ImmunoCAP. Use of 95% clinical decision points (CDP) for sIgE to Bos d 8 and Gal d 1 resulted in higher negative predictive values (78% and 79%, respectively) than those obtained with the ImmunoCAP (57% and 59%). Conclusions Our results show that in children with suspected CM or HE allergy, the microarray has a good ability to predict the FCT results. In a clinical application perspective, the microarray could be used as a second-level assay, if the ImmunoCAP sIgE is o95% CDP. This approach would lead to a decrease in the number of the FCT to be performed, as well as of positive FCTs with a subsequent decrease in severe reaction risk.
mtDNA sequence variation was studied in 419 individuals from nine Eurasian populations, by high-r... more mtDNA sequence variation was studied in 419 individuals from nine Eurasian populations, by high-resolution RFLP analysis, and it was followed by sequencing of the control region of a subset of these mtDNAs and a detailed survey of previously published data from numerous other European populations. This analysis revealed that a major Paleolithic population expansion from the "Atlantic zone" (southwestern Europe) occurred 10,000-15,000 years ago, after the Last Glacial Maximum. As an mtDNA marker for this expansion we identified haplogroup V, an autochthonous European haplogroup, which most likely originated in the northern Iberian peninsula or southwestern France at about the time of the Younger Dryas. Its sister haplogroup, H, which is distributed throughout the entire range of Caucasoid populations and which originated in the Near East ∼25,000-30,000 years ago, also took part in this expansion, thus rendering it by far the most frequent (40%-60%) haplogroup in western Europe. Subsequent migrations after the Younger Dryas eventually carried those "Atlantic" mtDNAs into central and northern Europe. This scenario, already implied by archaeological records, is given overwhelming support from both the distribution of the autochthonous European Y chromosome type 15, as detected by the probes 49a/f, and the synthetic maps of nuclear data.
A mutation (A1555G) in the mtDNA has been associated with aminoglycoside-induced and nonsyndromic... more A mutation (A1555G) in the mtDNA has been associated with aminoglycoside-induced and nonsyndromic sensorineural deafness. The pathological significance of this mutation in Caucasoid families has not been established, and its relationship with antibiotic treatment is not well understood. We studied 70 Spanish families with sensorineural deafness (36 congenital and 34 late onset) for the mtDNA A1555G mutation. The A1555G mutation was found in 19 families with maternally transmitted deafness but not in the other 51 families or in 200 control subjects. In 12 families all the patients with the A1555G mutation who received aminoglycosides became deaf, representing 30.3% of the deaf patients in these families. None of the deaf patients from seven other families received aminoglycosides. Overall, only 17.7% of the patients with deafness and the A1555G mutation had been treated with aminoglycosides. The age at onset of deafness was lower (median age 5 years, range 1-52 years) in those treated with aminoglycosides than in those who did not receive antibiotics (median age 20 years, range 1-65 years) (P ! ). The mtDNA of these families belongs to haplo-.001 types common in Europeans. These data indicate that the A1555G mutation accounts for a large proportion of the Spanish families with late-onset sensorineural deafness, that the A1555G mutation has an age-dependent penetrance for deafness (enhanced by treatment with aminoglycosides), and that mtDNA backgrounds probably do not play a major role in disease expression.
Objective. Macrophage activation syndrome (MAS) in systemic onset juvenile idiopathic arthritis (... more Objective. Macrophage activation syndrome (MAS) in systemic onset juvenile idiopathic arthritis (SoJIA) is considered to be an acquired form of familial haemophagocytic lymphohistiocytosis (fHLH). FHLH is an autosomal recessive disorder, characterized by diminished NK cell function and caused by mutations in the perforin gene (PRF1) in 20-50% of patients. Interestingly, SoJIA patients display decreased levels of perforin in NK cells and diminished NK cell function as well. Here, we analysed PRF1 and its putative promoter in SoJIA patients with or without a history of MAS.
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