Molar-incisor hypomineralization in a cohort of individuals born with cleft lip and palate.

OBJECTIVE: This study aimed to investigate the frequency of molar-incisor hypomineralization (MIH) in individuals born with cleft lip and or cleft palate. SETTINGS AND SAMPLE: Three hundred eighty-six individuals born with cleft lip and/or palate before orthodontic treatment. METHODS: All the individuals were submitted to a clinical examination and intraoral standardized photos. The registration of MIH was taken by two orthodontists and analysed in association with the cleft type and laterality. The Kruskal-Wallis test and the regression test were used to compare the frequency of molars and incisors affected according to cleft type and laterality, sex and age. RESULTS: We found a frequency of 67.87% of MIH in the studied sample. The frequency varied from 25% (in individuals born with cleft palate) to 77% in individuals born with bilateral cleft lip and palate). The number of affected molars was statistically different depending on cleft type and laterality (P < .001- Kruskal-Wallis test). Differences were found between individuals born with unilateral cleft lip and palate and unilateral cleft lip and alveolus (P = .03), and with isolated cleft palate (P = .03), and between individuals born with bilateral cleft lip and palate and born with unilateral cleft lip and alveolus (P = .01), and cleft palate (P = .01). Sex (P = .21) and age (P = .36) had no influence on the frequency of MIH. A positive correlation was found between the number of molars affected and incisors affected (P < .001). CONCLUSION: Individuals born with cleft lip and palate have a higher frequency of MIH, and the complexity of cleft type was associated with the number of affected molars.

COMT rs4818 less common allele is associated with psychological and psychiatric worse indicators in a cohort of individuals born with cleft lip and palate.

OBJECTIVE: Individuals born with cleft lip and palate may face difficulties in speech function, nutrition, facial aesthetics, and long-term care. These difficulties may increase the risk of psychological and psychiatric diseases. This work aimed to test if the variant allele of COMT was carried more frequently among individuals that have psychological and psychiatric outcomes within a cohort of patients born with cleft lip and palate. METHOD: DNA extraction from saliva of two hundred and fifteen individuals born with cleft lip with and/or palate and genotyping was performed, and the frequency of COMT rs4818 alleles was determined. The domain 'Psychological Function' of Cleft-Q™ was used to generate scores for analysis. The scores were computed, and differences in genotype or allele frequencies between individuals with psychological function scores 60 or above and 59 or below were compared. The history of psychiatric illness (family history of psychiatric disease or self-reported psychiatric illness) was registered. RESULTS: Genotype and allele frequencies were compared between individuals with and without a family history of psychiatric illness. Individuals with lower Psychological Function (Cleft-Q™) scores were more likely to be GG (P = .04) or carriers of allele G (P < .001). The reported psychiatric illness and positive family history of psychiatric illness were compared to COMT rs4818 allele and genotype frequencies of individuals without these indicators, and individuals with psychiatric illness and positive family history of psychiatric illness were more likely to carry allele G (P = .03 and P = .008, respectively). CONCLUSION: The study confirms previously suggested role of COMT rs4818 in psychiatric and psychological outcomes in a distinct cohort of patients born with cleft lip and palate.

CLEFT RR- New app to Calculate Recurrence Risk in Cleft lip and Palate.

OBJECTIVE: To describe the Cleft Recurrence Risk (Cleft RR) App, designed to be used on genetic counseling for cleft lip and/ or palate. DESIGN: A validation study, single cohort. SETTING: Tertiary care children's Hospital. PATIENTS, PARTICIPANTS: The manual obtained the results of 100 cases undergoing genetic counseling at the cleft lip and palate treatment center. INTERVENTIONS: The application for genetic counseling for cleft lip and/ or palate is designed to calculate quickly the recurrence risk considering the ancestry, cleft type, sex, and family history and thus encourage the implementation of genetic counseling in cleft lip and palate centers around the world. MAIN OUTCOME MEASURE(S): The data were submitted to the Bland-Altman statistics. RESULTS: After defining parameters the application development follows the steps: development, prototyping, and documentation. The validation of the calculated data was performed by comparing the results of 100 cases undergoing genetic counseling at the cleft lip and palate treatment center obtained by the manual method with the results obtained by the mobile app method; the data were submitted to the Bland-Altman statistics and a high concordance was found. CONCLUSIONS: The mobile app for use by healthcare professionals proved to be simple to use, easy to apply, and provided accurate results. Cleft Recurrence Risk is an application for smartphones developed for genetic counseling in cleft lip and palate, supplementary use by health professionals, and should not replace professional performance.

Multiple Structural Microform Defects Suggest Role of Modifier Genes.

ABSTRACT: One of the biggest challenges in clinical genetics is establishing associations between specific germline mutations and the resulting spectrum of phenotypes. The careful characterization of clinical presentations continues to be a tool for establishing these genotype phenotype correlations. The authors intend, by presenting a case study, proposing that the concomitant occurrence of a combinations of mild structural anomalies in the same individual may be due to changes in genes that can be linked by related pathways. A new born with cleft lip and palate was referred at the Cleft Lip and Palate Center. The anamnese was performed and collected data of familiar history, parental consanguinity, and information about pregnancy period. The careful characterization of clinical presentations and the genetic pathways was studied. It is possible that there is no single mutation that can be clearly identified as the etiology of the combination of the defects displayed in the present case.

IRE1 Less Common Homozygous Genotype in Families With Positive History of Cancer and Individuals Born With Cleft Lip/Palate.

ABSTRACT: The aim of this study was to test if the marker rs196929 in IRE1 associated with cleft lip and palate depending on the family history for cancer. A consecutive sample of 836 individuals were recruited between April and October of 2019 (303 born with cleft lip and palate, 256 relatives mostly of the maternal side of individuals born with cleft lip and palate, and 277 unaffected unrelated individuals). Parents or guardians of the children answered a questionnaire with basic demographic information about their children and their family history of cleft lip and palate and cancer. DNA was obtained from whole saliva and IRE1 rs196929 was genotyped using TaqMan chemistry and end-point analysis. Over-representation of alleles was determined using chi-square as implemented in PLINK using an alpha of 0.05. There was an excess of less common homozygotes of IRE1 rs196929 among relatives of individuals born with cleft lip and palate when they had positive family history of cancer in comparison with individuals born with cleft lip and palate or with unrelated unaffected individuals (P = 0.0006 and P < 0.001, respectively). This pattern was similar when families reported one type of cancer or multiple ones, or when cancer affecting females (breast or reproductive tract) or the structures of the gastro-intestinal tract were considered. These results provide support for a role of the ER stress IRE1-XPB1 pathway in the higher frequency of cancer in families of individuals born with cleft lip and palate.

Talon Cusp Associates With MMP2 in a Cohort of Individuals Born With Oral Clefts.

OBJECTIVE: The aim of this study was to use dental development as a tool to subphenotype oral clefts and investigate the association of MMP2 with dentin-pulp complex anomalies, in order to identify dental anomalies that are a part of a "cleft syndrome." DESIGN: Two hundred and ninety individuals born with cleft lip and palate were evaluated and several clinical features, such as cleft completeness or incompleteness, laterality, and presence of dental anomalies were used to assess each individual's cleft status. We tested for overrepresentation of MMP2 single nucleotide polymorphism rs9923304 alleles depending on individuals having certain dental anomalies. Chi-square and Fisher exact tests were used in all comparisons (α = .05). RESULTS: All individuals studied had at least one dental anomaly outside the cleft area. Significant differences between individuals born with clefts with and without talon cusp (P = .04) were observed for the frequency of the MMP2 less common allele. CONCLUSION: All individuals born with cleft lip and palate had alterations of the dentition, and a quarter to half of the individuals had alterations of the internal anatomy of their teeth, which further indicates that dental anomalies can be considered as an extended phenotype for clefts. MMP2 was associated with talon cusp in individuals born with oral clefts.

Management of Oronasal Fistulas in Patients With Cleft Lip and Palate.

BACKGROUND: The oronasal fistula in cleft patients is one of the complications that can be found after primary surgeries due to a failure of healing of the surgical repair that causes the communication between the oral and nasal cavities. A number of procedures can be implemented to correct the fistula and it is not clear if a particular technique is the best to be recommended. OBJECTIVE: This study aims to systematically analyze the scientific evidence regarding the treatment of oronasal fistulas located in the lingual-alveolar and labial-alveolar regions in patients with cleft lip and palate who have undergone primary surgeries. MATERIAL AND METHODS: A bibliographic search of articles published until September 2018 without restricted year and language of publication, in PubMed (Medline), Scopus, Cochrane, Web of science, and BVS databases. The MeSHterms "Fistula," "Oral Fistula," and "Cleft Lip" were used, which were related to each other and with other keywords related to the subject of the review through the "OR" and "AND" operators. The quality of the publications was evaluated according to the guidelines of the Methodological Index for Nonrandomized Studies. RESULTS: After applying the eligibility criteria, a total of 18 articles were selected for the extraction of data and qualitative analysis. CONCLUSION: All publications analyzed in this review reported the fistula treatment at the same surgical time as the bone graft, independently of the donor area, the type of cleft treated and the patient's age at operation. There was no consensus among the studies on the best treatment type for oronasal fistulas located in the alveolar region, and further comparative studies between the existing techniques will be necessary to address this question.

An analysis of third molar mineralization in Brazilian patients with cleft lip and palate.

Purpose: This study investigated the third molar mineralization in patients with cleft lip and palate.Materials and methods: From a total of 253 digital panoramic radiographs from patients with cleft lip and palate within the age range of 7-21 years, 97 radiographs were selected (cleft group). A control group was formed from same sex individuals, without malformation and chronological age matched within 30 days. The analysis of third molar mineralization was carried out by three calibrated examiners using Demirjian's and Nolla's methods. McNemar and Wilcoxon test for paired samples were used for pairwise comparisons between the groups. The Likelihood Ratio test was used to check for an association between the type of cleft and tooth calcification.Results: In both methods, the mineralization means were smaller in the case group than in the control, with significant differences for all third molars (p < .05). The type of cleft affected dental mineralization. There was no significant difference when comparing the left or right sides, but maxillary molars showed earlier mineralization.Conclusions: A significant delay in third molar mineralization was observed in patients with cleft lip and palate according to Demirjian's and Nolla's methods.

Digital resources in the monitoring of patients with cleft lip and palate: protocol for a scoping review.

INTRODUCTION: Cleft lip and/or palate (CL+/-P) is a congenital malformation affecting the lip and palate, requiring long-term treatment due to potential associated complications. For this reason, it is important for the patient to be continuously monitored and followed for health promotion and prevention, as well as improving the quality of life. The aim of this scoping review protocol is to identify and map the available evidence regarding the application of digital resources and technologies in the monitoring and follow-up of patients with CL+/-P. METHODS AND ANALYSIS: This scoping review protocol follows the guidelines recommended by the Joanna Briggs Institute Manual, employing the PCC acronym (Patient/Concept/Context). Searches will be conducted, in May 2024, of PubMed, Web of Science, Scopus, Latin American and Caribbean Health Sciences Literature, ScienceDirect, as well as grey literature indexed in ProQuest Open Access Dissertations & Theses and Google Scholar. The review will consider all types of published studies, including grey literature, in English, Portuguese and Spanish languages, and will consider studies regardless of publication date. Exclusions will apply to studies that do not address the use of digital resources and technologies in CL+/-P monitoring and follow-up. ETHICS AND DISSEMINATION: As this is a scoping review, no ethics committee approval is required. After completion, the plan is to publish results in scientific journals on craniofacial malformations. STUDY REGISTRATION: Open Science Framework, DOI:10.17605/OSF.IO/Y6AG8.

Prevalence of dental anomalies in patients with cleft lip and palate, Paraiba, Brazil: clinic and radiographic study.

The aim of this study is to investigate the prevalence of dental anomalies in a group of individuals with different types of clefts attending the reference service in orthodontics for the care of patients with clefts in Paraiba state, northeastern Brazil. This was a cross-sectional, observational study. Two previously trained examiners (kappa = 0.89) performed the clinical examination of 76 patients with post and incisive transforamen unilateral or bilateral clefts, of both sexes, aged 4 to 32 years, and the analysis of periapical and panoramic radiographs from archived records of these patients. Only the upper front teeth were evaluated. Data were processed by descriptive statistics and subjected to statistical Chi-square test considered significant at 5%. Among the patients evaluated, males (57.9%) and left unilateral transforamen clefts (40.8%) were prevalent. Of the total 76 patients examined, 56 (73.68%) had at least one dental anomaly, the most frequent being agenesis (31.6%) and conical teeth (28.9%). The presence of anomalies differed significantly between the cleft and the contralateral sides (p<0.00001). The diagnosis and treatment of patients with clefts should therefore receive more attention. It is suggested that clinical and radiographic examination be performed together with careful planning and implementation of specialist services in an effort to provide early and adequate detection and treatment.

Retrognathic maxilla in individuals born with oral clefts is due to intrinsic factors and not only due to early surgical treatment.

OBJECTIVES: To determine if the skeletal form of individuals born with oral clefts was associated with maxillary position. MATERIALS AND METHODS: Lateral cephalometric radiographs of 90 individuals 8 to 12 years old born with or without cleft lip and palate paired by age and sex were used. Skull base length, cranial base angle, cranial deflection angle, and maxillary skeletal length and position were studied. Also, mandibular skeletal length and position, lower anterior facial height, and dental position were defined. Individuals were divided into three groups: 30 individuals born with cleft lip and palate with Class III malocclusion (UCLP Class III), 30 individuals born with cleft lip and palate with Class I malocclusion (UCLP Class I), and 30 individuals born without cleft lip and palate with Class III malocclusion (non-cleft Class III). RESULTS: When comparing the UCLP Class III group with the UCLP Class I group, there were differences in maxillary position (P < .001) and mandibular position (P = .004) found. No differences were found when comparing the UCLP Class III group with the non-cleft Class III group. CONCLUSIONS: There are intrinsic factors that affect craniofacial morphology of individuals born with cleft lip and palate.

Distinct Patterns of Dental Age and Chronological Age: Longitudinal Evaluation of Individuals Born with or without Oral Clefts.

Purpose: Dental development is delayed in individuals born with oral clefts. The purpose of this study was to determine: (1) the proportion of individuals with severe delays in dental maturation; and (2) if there are different patterns of dental development timing, taking into consideration the chronological age of the individual.
Methods: Dental maturation was estimated by the Demirjian method in children aged seven to 12 years with and without clefts. The differences between dental age and chronological age between groups were compared using the Mann-Whitney test, with an alpha of 0.05. A subset of 50 individuals in each group had at least two panoramic radiographs at least two years apart. These were analyzed to determine dental maturation trajectories in comparison with chronological age to identify individuals with different patterns of development.
Results: The sample consisted of 201 children with oral clefts and 201 without clefts. Individuals born with clefts had, on average, two months of delay in dental maturation compared to those without a cleft. Five patterns of differences were identified between dental and chronological age. These distributions were statistically significant statistically (P <0.001).
Conclusion: Children born with cleft lip and palate have delayed tooth maturation and a high frequency of greater delays in tooth maturation over time compared to individuals born without clefts.

Identification of dental calcification stages as a predictor of skeletal development phase.

OBJECTIVE: This study aimed to establish a correlation between the stages of tooth calcification of mandibular canines and second molars with the phases of skeletal development. METHODS: In a consecutive series of panoramic, cephalometric and hand-wrist radiographs of 113 individuals (60 females and 53 males) with an average age of 12.24 ± 1.81 years, the stages of mandibular canine and second molar calcification, cervical vertebrae maturation indicators (CVMI) and skeletal maturity indicators (SMI) were classified. The variables were correlated by means of the Spearman's Rank test: chronological age, SMI, CVMI and tooth calcification stages. In order to assess whether the CVMI and tooth calcification stages were significant predictors of the SMI, an ordinal regression analysis was carried out. RESULTS: The stages of CVMI (OR = 16.92; CI 95% = 6.45-44.39; p< 0.001) and calcification of the second molars (OR = 3.22; CI 95% = 1.50-6.92; p= 0.003) were significant predictors of SMI, however similar result was not observed for canines (OR = 0.52, CI 95% = 0.18-1.54; p= 0.239). Calcification stage E for boys, and E and F for girls corresponded to the pre-peak phase of pubertal growth. Stages G and H for boys, and F and G for girls coincided with peak of growth. In the final growth phase, the majority of second molars presented with root apex closure (stage H). CONCLUSION: The stages of calcification of the second molar may be considered predictors of the stage of skeletal development in the population studied.

Maxillary incisor enamel defects in individuals born with cleft lip/palate.

Cleft lip with or without cleft palate (CLP) is considered the most frequent congenital malformations of the head and neck, with cleft individuals exhibiting more chances of presenting abnormalities such as developmental defects of enamel (DDE). Matrix metallopeptidase 2 (MMP2) is a membrane-bound protein with collagen-degrading ability and has important roles in tooth formation and mineralization. The aim of this study was to evaluate the frequency, location, severity and extent of DDE found in the maxillary incisors for groups of individuals born with CLP, as well as understanding their relationship with the cleft side. Besides, this study addresses the hypothesis that DDE can be influenced by variation in the MMP2 genes (rs9923304). Individual samples, clinical history, intraoral photographs and panoramic radiographs were obtained from 233 patients under treatment at the Cleft Lip and Palate Service of the University Hospital Lauro Wanderley at the Federal University of Paraíba. Digital images were examined by the same evaluator using the Classification of Defects According to the Modified DDE Index, and then loaded into the Image Tool software, where two measurements were made: total area of the buccal surface (SA) and the area of the DDE (DA), obtaining the percentage of the surface area affected (%SAD) (ICC = 0.99). Genomic DNA was extracted from saliva samples from 124 participants. Genotyping was carried out using TaqMan chemistry for one marker in MMP2 (rs9923304). Statistical analyses were performed by The Jamovi Project software. The Shapiro-Wilk test was applied, followed by the Student's t-test and the Mann-Whitney test. Chi-square and Fisher's exact tests, and odds ratio (OR) with 95% confidence interval (CI) calculations were used to determine Hardy-Weinberg equilibrium and statistically significant differences with an alpha of 0.05. No significant differences in the prevalence and extent of enamel defects were found between male and female individuals born with CLP (p = 0.058256). The frequency of individuals presenting teeth with DDE, in relation to the cleft and non-cleft side, was statistically different (p <0.001; OR = 7.15, CI: 4.674> 7.151> 10.942). However, the averages of %SAD were similar (p = 0.18). The highest means of the %SAD were found in individuals with bilateral cleft lip with or without cleft palate (BCLP) when compared to individuals with unilateral cleft lip with or without cleft palate (UCLP), for the teeth inside (IA) and outside the cleft area (OA) (p <0.001). Regardless of the cleft side, individuals with BCLP were 7.85 times more likely to have more than one third of the tooth surface affected, showing more frequently defects in the three thirds (OA: p <0.001) (IA: p = 0.03), as well as a higher frequency of more than one type of defect (OA: p = 0.000358) (IA: p = 0.008016), whereas in UCLP, defects were isolated and restricted to only one third, more frequently, the incisal third (OA: p = 0.009) (IA: p = 0.001), with greater frequency of milder defects, such as demarcated (p = 0.02) and diffuse (p = 0.008) opacities. A higher frequency of the T allele, less common, was observed in the group of CLP individuals who had all the affected teeth or at least two teeth with %SAD greater than 20% (p = 0.019843). Our results suggest that MMP2 may have a role in the cases that presented DDE and genotyping rs9923304 could serve as the basis for a genomic approach to define risks for individuals born with CLP. Frequency and severity of DDE is strongly related to the CLP phenotype, since the highest values were found for BCLP. However, the extent of the DDE is independent of its relationship with the side of the cleft.

Risk factors for anterior open bite: A case-control study.

BACKGROUND: Anterior open bite (AOB) is noteworthy because it is a complex dysplasia, and clinical studies on this malocclusion are usually epidemiological studies or experimental models with small samples and no control group, which renders the data on AOB incomplete and therefore inconclusive. The objective this study was to assess the risk factors involved in developing AOB. MATERIALS AND METHODS: A case-control study was provided with a total of 96 lateral cephalometric radiographs of male and female patients aged between 8 and 14 years were used, regardless of facial type. The dependent variable was the presence or absence of AOB, which divided the participants into case and control groups, respectively; these groups were matched for gender and age. The case and control groups data were analyzed by descriptive and inferential analysis by binary logistic regression using at the 5% significance level. RESULTS: The occurrence of AOB was associated with the presence of deleterious oral habits (P = 0.014; Chi-square test) and was approximately three times (odds ratio = 3.04) more likely to occur in participants with AOB. No significant association between the presence of mouth breathing and the occurrence of AOB was found (P = 0.151; Chi-square test). The odds associated with tongue interposition were 10.51 times higher than those of participants with no such deglutition. The odds associated with the dolichofacial pattern were 5.74 times those of participants with a nondolichofacial pattern. CONCLUSION: Tongue interposition and dolichocephalic facial pattern were risk factors for developing AOB.

Analysis of permanent second molar development in children born with cleft lip and palate.

OBJECTIVE: The study of dental development in individuals born with cleft lip and palate (CLP) serves to determine when orthodontic intervention should start. To evaluate the permanent second molar development in children born with cleft lip and palate according to Demirjian's and Nolla's methods. METHODOLOGY: Out of a total of 513 digital panoramic radiographs, 113 pairs of children aged 3 to 16 years were selected. The exams were from children born with or without cleft lip and palate, of the same sex, with an age difference of up to 30 days. The images were analyzed by three examiners and reliability was checked through intra-examiner agreement by the Kappa test. The data were analyzed by Wilcoxon's and Mann-Whitney tests according to each dataset. RESULTS: The findings indicated delayed development of the permanent second molars in children with CLP (P<0.001). The development of the right permanent second molar was delayed compared to the left molar in children with CLP. Moreover, mandibular teeth showed significantly earlier development than maxillary teeth in both the case and control groups. There was no significant difference in the development of permanent second molars between sexes. CONCLUSION: Children with CLP presented delay in the development of permanent second molars.

A new 500 kb haplotype associated with high CD8+ T-lymphocyte numbers predicts a less severe expression of hereditary hemochromatosis.

BACKGROUND: Hereditary Hemochromatosis(HH) is a common genetic disorder of iron overload where the large majority of patients are homozygous for one ancestral mutation in the HFE gene. In spite of this remarkable genetic homogeneity, the condition is clinically heterogeneous, varying from a severe disease to an asymptomatic phenotype with only abnormal biochemical parameters. The recent recognition of the variable penetrance of the HH mutation in different large population studies demands the need to search for new modifiers of its phenotypic expression. The present study follows previous observations that MHC class-I linked genetic markers, associated with the setting of CD8+ T-lymphocyte numbers, could be clinically relevant modifiers of the phenotypic expression in HH, and aimed to find new markers that could be used as more reliable prognostic variables. METHODS: Haplotype analysis, including seven genetic markers within a 1 Mb region around the microsatellite D6S105 was performed in a group of 56 previously characterized C282Y homozygous Portuguese patients. Parameters analyzed in this study were total body iron stores, clinical manifestations related with HH and immunological parameters (total lymphocyte numbers, CD4+ and CD8+ T-lymphocyte numbers). An independent group of 10 C282Y homozygous patients from Vancouver, Canada, were also included in this study and analyzed for the same parameters. RESULTS: A highly conserved ancestral haplotype defined by the SNP markers PGBD1-A, ZNF193-A, ZNF165-T (designated as A-A-T) was found associated with both abnormally low CD8+ T-lymphocyte numbers and the development of a severe clinical expression of HH. In a small proportion of patients, another conserved haplotype defined by the SNP markers PGBD1-G, ZNF193-G, ZNF165-G (designated as G-G-G) was found associated with high CD8+ T-lymphocyte numbers and a milder clinical expression. Remarkably, the two conserved haplotypes defined in Portuguese patients were also observed in the geographically different population of Canadian patients, also predicting CD8+ T-lymphocyte numbers and the severity of disease. CONCLUSION: These results may have important implications not only for approaching the question of the penetrance of the hemochromatosis gene in different world populations but also to further narrow the region of interest to find a candidate gene involved in the setting of CD8+ T-lymphocyte numbers in humans.

A study of 82 extended HLA haplotypes in HFE-C282Y homozygous hemochromatosis subjects: relationship to the genetic control of CD8+ T-lymphocyte numbers and severity of iron overload.

BACKGROUND: It has been recently demonstrated that CD8+ T-lymphocyte numbers are genetically transmitted in association with the MHC class I region. The present study was designed with the objective of narrowing the region associated with the setting of CD8+ T-lymphocyte numbers in a population of C282Y homozygous hemochromatosis subjects, in whom a high prevalence of abnormally low CD8+ T-lymphocyte counts has been described. METHODS: The study includes 43 C282Y homozygous subjects fully characterized both phenotypically and genotypically. Clinical characterization includes measurements of iron parameters at diagnosis (transferrin saturation and serum ferritin), total body iron stores and T-cell immunophenotyping determined by flow cytometry. Genetic characterization includes HLA class I alleles (A, B and C) and four additional microsatellite markers (D6S265, D6S2222, D6S105 and D6S2239) spanning 5 Megabases in the 6p21.3 region. RESULTS: Eighty-two extended C282Y carrying haplotypes were defined. Single-locus analysis revealed that the HLA-A region was associated with CD8+ T-cell numbers. Multivariate analysis showed that the combinations of the most common HLA-A alleles (HLA-A*03, -A*02 and -A*01) were associated with significantly lower numbers of CD8+ T-lymphocytes (0.30 +/- 0.14 x 106/ml), in comparison with subjects carrying only one copy of those alleles (0.46 +/- 0.19 x 106/ml) and subjects without any copy of those alleles (0.79 +/- 0.15 x 106/ml;p = 0.0001). No differences were observed in CD8+ T-cell counts among control subjects carrying the same combinations of HLA-A alleles (0.47 +/- 0.14; 0.45 +/- 0.21 and 0.41 +/- 0.17 x 106/ml, respectively), therefore not supporting a direct effect of HLA specificity but rather an indirect association with a locus close to HLA-A. Multivariate analysis showed that the combination of the most common HLA-A alleles also have an impact on the clinical expression of HH in terms of iron stores, in males(p = 0.0009). CONCLUSION: The present study provides evidence supporting an inextricable link between extended HLA haplotypes, CD8+ T-lymphocyte numbers and severity of iron overload in hereditary hemochromatosis(HH). It gives additional information to better define a candidate region involved in the regulation of CD8+ T-lymphocyte numbers. A new evolutionary hypothesis concerning the inheritance of the phenotype of low CD8+ T-lymphocyte numbers associated with particular ancestral HLA haplotypes carrying the C282Y mutation and its implication on the clinical heterogeneity of HH is discussed.

Identification of dental calcification stages as a predictor of skeletal development phase

ABSTRACT Objective: This study aimed to establish a correlation between the stages of tooth calcification of mandibular canines and second molars with the phases of skeletal development. Methods: In a consecutive series of panoramic, cephalometric and hand-wrist radiographs of 113 individuals (60 females and 53 males) with an average age of 12.24 ± 1.81 years, the stages of mandibular canine and second molar calcification, cervical vertebrae maturation indicators (CVMI) and skeletal maturity indicators (SMI) were classified. The variables were correlated by means of the Spearman's Rank test: chronological age, SMI, CVMI and tooth calcification stages. In order to assess whether the CVMI and tooth calcification stages were significant predictors of the SMI, an ordinal regression analysis was carried out. Results: The stages of CVMI (OR = 16.92; CI 95% = 6.45-44.39; p< 0.001) and calcification of the second molars (OR = 3.22; CI 95% = 1.50-6.92; p= 0.003) were significant predictors of SMI, however similar result was not observed for canines (OR = 0.52, CI 95% = 0.18-1.54; p= 0.239). Calcification stage E for boys, and E and F for girls corresponded to the pre-peak phase of pubertal growth. Stages G and H for boys, and F and G for girls coincided with peak of growth. In the final growth phase, the majority of second molars presented with root apex closure (stage H). Conclusion: The stages of calcification of the second molar may be considered predictors of the stage of skeletal development in the population studied.

RESUMO Objetivo: O presente estudo objetivou estabelecer uma correlação entre os estágios de calcificação dentária de caninos e segundos molares inferiores e as fases do desenvolvimento esquelético. Métodos: Em uma série consecutiva de radiografias panorâmicas, cefalométricas e de mão e punho de 113 indivíduos (60 meninas e 53 meninos) com idade média de 12,24 ± 1,81 anos, foram classificados os estágios de calcificação do canino e do segundo molar inferiores, indicadores de maturação das vértebras cervicais (IMVC) e indicadores de maturação esquelética (IME). As variáveis foram correlacionadas pelo teste de Correlação de Rank de Spearman: idade cronológica, IME, IMVC e estágios de calcificação dentária. A fim de avaliar se os estágios do IMVC e da calcificação dentária foram preditores significativos do IME, foi realizada uma análise de regressão ordinal. Resultados: Os estágios de IMVC (OR = 16,92; IC 95% = 6,45-44,39; p< 0,001) e calcificação dos segundos molares (OR = 3,22; IC 95% = 1,50-6,92; p= 0,003) foram preditores significativos de IME; no entanto, esse não foi o caso com dentes caninos (OR = 0,52, IC 95% = 0,18-1,54; p= 0,239). Os estágios de calcificação E para meninos e E e F para meninas corresponderam à fase pré-pico de crescimento puberal. Os estágios G e H para meninos e F e G para meninas coincidiram com o pico de crescimento. Na fase final de crescimento, a maioria dos segundos molares apresentou fechamento do ápice radicular (estágio H). Conclusão: Os estágios de calcificação do segundo molar podem ser considerados preditores do estágio de desenvolvimento esquelético na população estudada.

Assessment of upper airways measurements in patients with mandibular skeletal Class II malocclusion.

OBJECTIVE: Mandibular Class II malocclusions seem to interfere in upper airways measurements. The aim of this study was to assess the upper airways measurements of patients with skeletal Class II malocclusion in order to investigate the association between these measurements and the position and length of the mandible as well as mandibular growth trend, comparing the Class II group with a Class I one. METHODS: A total of 80 lateral cephalograms from 80 individuals aged between 10 and 17 years old were assessed. Forty radiographs of Class I malocclusion individuals were matched by age with forty radiographs of individuals with mandibular Class II malocclusion. McNamara Jr., Ricketts, Downs and Jarabak's measurements were used for cephalometric evaluation. Data were submitted to descriptive and inferential statistical analysis by means of SPSS 20.0 statistical package. Student's t-test, Pearson correlation and intraclass correlation coefficient were used. A 95% confidence interval and 5% significance level were adopted to interpret the results. RESULTS: There were differences between groups. Oropharynx and nasopharynx sizes as well as mandibular position and length were found to be reduced in Class II individuals. There was a statistically significant positive correlation between the size of the oropharynx and Xi-Pm, Co-Gn and SNB measurements. In addition, the size of the nasopharynx was found to be correlated with Xi-Pm, Co-Gn, facial depth, SNB, facial axis and FMA. CONCLUSION: Individuals with mandibular Class II malocclusion were shown to have upper airways measurements diminished. There was a correlation between mandibular length and position and the size of oropharynx and nasopharynx.