Osteocalcin and regulatory cytokine imbalance in children with congenital cleft lip and palate.

The aim of the work was a comprehensive assessment of the cytokine system and peripheral blood osteocalcin with the establishment of features of their interconnections in children with congenital cleft lip and palate (CCLP) in comparison with corresponding controls at different age periods. Levels of IL17, IL4, IL6, IL1ß, IFNγ and osteocalcin were analyzed by enzyme immunoassay in the peripheral blood of 80 children (0-12 months, 1-3 years, 4-9 years, 10-15 years) with CCLP and age-appropriate control of healthy individuals (40 people). An analysis of the obtained data shows that in children with CCLP we revealed significant differences between pro-inflammatory (IL1ß, IL6, IL17), regulatory (IFNγ), anti-inflammatory (IL4) cytokines and osteocalcin compared with controls. Differences were found in the content of IL17, IFNγ, IL4 and osteocalcin in healthy children and in children with CCLP in postnatal ontogenesis. Cytokine deregulation of immunosteogenesis in CCLP, leading to a significant deficit of osteocalcin in the first year of life due to imbalance of the cytokine profile: discordant IL17, IFNγ and IL4 were detected. Obtained data are undoubtedly important in the future for developing new strategies for targeted therapy aimed at normalizing osteocalcin levels at different age periods in children with CCLP.

Innate lymphoid cells: a paradigm for low SSI in cleft lip repair.

BACKGROUND: Cleft lip and palate reconstructions demonstrate significantly lower surgical site infection rates compared with clean-contaminated cases, prompting investigation into the pathophysiology causing this discrepancy. Recent studies have identified a new group of innate lymphocytes called innate lymphoid cells (ILCs), located in barrier surfaces of the skin, airways, and intestine. Our objectives were to explore for the first time the presence of ILCs in the vermillion of neonates and young children undergoing cleft lip reconstruction and characterize their composition by measuring the three classes of ILCs. MATERIALS AND METHODS: Lip tissue samples were collected from 13 subjects undergoing vermillion resection during cleft lip reconstructive surgery. Preparative, transmission electron microscopy, and analytical flow cytometry were performed. The functionality of ILCs was tested in terms of their capacity to produce type 1 (IFN-γ/TNF-α), type 2 (IL-5/IL-13), and type 3 (IL-17/IL-22) cytokines. Data were analyzed using Student t test or the analysis of variance to establish significance (P < 0.05) among groups for all other data. RESULTS: All three classes of ILCs were detected and visualized in the tissue samples. In all samples, the level of ILC2 subset was significantly higher than the other two ILC subsets (P < 0.01), followed by the ILC1 subset, which was present in significantly higher levels than the ILC3 subset (P < 0.05). CONCLUSIONS: Our data place ILCs for the first time in the interface of oral mucosal immunity, tissue microenvironment, and homeostasis during and after tissue development, possibly explaining lower infection rates in cleft lip or palate reconstructions.

Expression analyses of human cleft palate tissue suggest a role for osteopontin and immune related factors in palatal development.

Cleft lip and/or palate (CL/P) is a common congenital malformation with a complex etiology which is not fully elucidated yet. Epidemiological studies point to different etiologies in the cleft lip and palate subgroups, isolated cleft lip (CL), isolated cleft palate (CP) and combined cleft lip and palate (CLP). In order to understand the biological basis in these cleft lip and palate subgroups better we studied the expression profiles in human tissue from patients with CL/P. In each of the CL/P subgroups, samples were obtained from three patients and gene expression analysis was performed. Moreover, selected differentially expressed genes were analyzed by quantitative RT-PCR, and by immunohistochemical staining of craniofacial tissue from human embryos. Osteopontin (SPP1) and other immune related genes were significantly higher expressed in palate tissue from patients with CLP compared to CP and immunostaining in palatal shelves against SPP1, chemokine receptor 4 (CXCR4) and serglycin (PRG1) in human embryonic craniofacial tissue were positive, supporting a role for these genes in palatal development. However, gene expression profiles are subject to variations during growth and therefore we recommend that future gene expression in CL/P studies should use tissue from the correct embryonic time and place if possible, to overcome the biases in the presented study.

[Preoperative bifidum-lactobacterin therapy in children with cleft lip and palate]. / Primenenie bifidum-laktobakterina v dooperatsionnom periode u detei s vrozhdennoi rasshchelinoi verkhnei guby i neba.

Microbiological and immunologic investigations of peripheric blood in 125 children were conducted. They determined a positive role of early correction with eubiotics (bifidum-lactobacterium) in children with congenital cleft lip and congenital cleft palate during 8-9 months before chiloplasty and uraniscoplasty. Using eubiotics results in normalization and restoration of the intestinal microflora, which leads to restoration of cellular and humoral immunity and to decreased rates of accompanying and postoperative complications.

[Immunological and biochemical indices during the use of hyperbaric oxygenation for treating patients with jaw deformities]. / Immunologicheskie i biokhimicheskie pokazateli pri ispol'zovanii giperbaricheskoi oksigenatsii dlia lecheniia bol'nykh s deformatsiiami cheliustei.

Analysis of changes in immunological and biochemical parameters in patients operated on for congenital deformations of the jaw bones and improperly grown fractures showed that postoperative therapy including hyperbaric oxygenation sessions was conducive to increase of immunological reactivity in patients with initially reduced immunological reactivity. No changes in urinary excretion of hydroxyproline were observed in the patients with deformations of the jaws.

Evidence in infants with cleft palate that breast milk protects against otitis media.

OBJECTIVE: Most infants with cleft palate suckle unproductively and require feeding by artificial means. Most also have unremitting otitis media accompanied by (usually) nonpurulent middle-ear effusion, a complication generally attributed to impaired eustachian tube ventilatory function. We observed two infants with cleft palate in whom one or both ears appeared effusion-free on more than one occasion, and who also were receiving or previously had received breast milk feedings. This prompted us to analyze the relation between middle-ear status and feeding mode in a large series of infants with cleft palate. Our objective was to determine whether in these infants the receipt of breast milk mitigated the otherwise virtually invariable development and continued presence of otitis media. METHODS: We reviewed and analyzed data concerning both feeding mode and the presence or absence of middle-ear effusion in 315 infants with cleft palate, as recorded systematically in the course of prospective studies at our Cleft Palate-Craniofacial Center. Analysis was limited to periods preceding the infants' receipt of tympanostomy-tube placement or palate repair, or their second birthday, whichever occurred first. RESULTS: Freedom from effusion in one or both ears was found at one or more visits in only seven (2.7%) of 261 infants fed cow's milk or soy formula exclusively, but in 17 (32%) of 54 infants fed breast milk exclusively or in part for varying periods (P < .0001). In virtually all instances, the breast milk had been harvested by the mother and fed to the infant via an artificial feeder. Baseline clinical and sociodemographic characteristics and surveillance in the two groups of infants were comparable. CONCLUSIONS: Artificially fed breast milk provides variable protection against the development of otitis media in infants with cleft palate. This finding supports the likelihood of a similarly protective effect of breast milk in noncleft infants. The finding also suggests strongly that in infants with cleft palate, impaired eustachian tube function is not the only pathogenetic factor in the infants' initial development of middle-ear effusion.

[HLA antigens in cleft lip-palate patients]. / HLA-Antigene bei Lippen-Kiefer-Gaumenspalten.

HLA typing of 50 patients with cleft lip and/or cleft palate (50 HLA-ABC and 35 HLA-DR tests) and, in part, also of their families showed an increased frequency of the antigens HLA-AII, DRw6 and the haplotype HLA-A11, B35 as against the normal population. Disorders of wound healing were observed more frequently in patients with HLA antigens A11 and B15 than in those without these antigens. Based on these hints of an HLA association (p values after correction are not significant), and the frequent coincidence of HLA-DR antigen in the patients' parents, as well as the increased rate of HLA-DR homozygosity of the patients, it is assumed that genetic factors of the HLA complex or an HLA-linked complex play a part in the etiology of clefts of the lip and cleft palate.

Population and family studies of HLA in Japanese with cleft lip and cleft palate.

Population and family studies of HLA were performed in Japanese patients with cleft lip and/or cleft palate (CL/P). Frequency of HLA-Cw 7 was significantly increased in cleft lip (CL) patients (37.5%) and cleft palate (CP) patients (37.8%) but was not increased in cleft lip and palate (CLP) patients (17.5%), compared with control subjects (13.3%). However, the intensities of the associations were not great (relative risk = 4.0). The affected sib pairs method was studied in 13 families with CL- or CLP-affected sib pairs and 10 families with CP-affected sib pairs. However, in both groups of families the distributions of HLA haplotypes in affected sib pairs did not significantly differ from random Mendelian expectation. Thus, HLA-linked major genes (loci) which determine the development of CL/P were not found. These results seem indirectly to support the multifactorial theory of CL/P, but does not exclude other possible genetic mechanisms.

Phenytoin teratogenicity in the primary and secondary mouse embryonic palate is influenced by the H-2 histocompatibility locus.

Inbred and congenic strains of mice have been studied for susceptibility to phenytoin-induced cleft lip with or without cleft palate (CLP) and isolated cleft palate (CP). The role of genes linked to the H-2 complex on chromosome 17 has been confirmed. Congenic strains with the A background have identical levels of spontaneous CLP, whereas those strains having the A background with the H-2a haplotype have significantly higher rates of induced CLP than their congenic partners with the H-2b or H-2s haplotype. No such significant difference in the degree of CLP produced by phenytoin is demonstrable in strains with the B background. Rates of isolated CP produced by phenytoin are significantly higher in strains with H-2a than in their congenic partner strains with either H-2b or H-2s, whether the background is A or B.