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PubMed1997

Palatal thickening and facial form in Paranthropus: examination of alternative developmental models.

Paranthropus is distinctive among hominoids in its possession of a greatly thickened hard palate. Although traditionally considered a structural adaptation to counter high-magnitude masticatory stress, alternative developmental models are equally viable. Three models of palatal thickening were evaluated in this study. A mechanical model interprets palatal thickening as a compensatory response to increased instability of the midpalatal suture effected by an anterior placement of the masseteric muscle mass. This model predicts that palatal thickness is correlated with the length of the palate posterior to the masseteric tubercle. Two non-mechanical models consider the thickness of the hard palate to be structurally related to and therefore correlated with either 1) the degree to which the premaxilla overlaps the hard palate in the subnasal region or 2) the height of the posterior facial skeleton. The correlation of craniofacial variables was assessed intraspecifically in ontogenetic series of great ape and human crania. Tests of correlation were performed for each comparison using both residuals calculated from reduced major axis regression of the variable of interest against a measure of cranial size and shape ratios. A significant correlation of palatal thickness with posterior facial height in Pan suggests that the unusually thick hard palate of Paranthropus is directly related to the increased posterior facial height characteristic of this taxon. Further evaluation suggests that extreme palatal thickening in these specimens occurred by virtue of their possession of a nasal septum morphology in which the vomer extends onto the superior and nasal surface of the premaxilla. Such a morphology would have constrained the palatal nasal lamina to maintain the approximate level of the premaxillary nasal lamina throughout the growth process thereby promoting palatal thickening.

Animals↗
PubMed2006

Analysis of Meox-2 mutant mice reveals a novel postfusion-based cleft palate.

Cleft palate represents a common human congential disease involving defects in the development of the secondary palate. Major steps in mammalian palatogenesis include vertical growth, elevation, and fusion of the palate shelves. Our current study with the homeobox gene Meox-2 during mouse secondary palate development reveals a novel postfusion-based mechanism for cleft palate. Meox-1 and Meox-2 are two functionally related homeobox genes playing important roles in somitogenesis and limb muscle differentiation. We found that the expression of Meox-2, not Meox-1, marks the specification of early mouse palatal mesenchymal cells in the maxillary processes at embryonic day 11.5 (E11.5). From E12.5 to E15.5, the expression of Meox-2 occupies only the posterior part of the palate, providing an early molecular marker for the anterior-posterior polarity in mouse secondary palate formation. A total of 35.3% of Meox-2-/- (n = 17) and 25.5% of Meox-2+/- (n = 55) mouse embryos display a cleft palate phenotype at E15.5, indicating that the reduction of Meox-2 function is associated with susceptibility to cleft palate. Unlike previously reported clefts, none of the clefts found in Meox-2 mutants contain any epithelial sheets in the medial edge areas, and detailed examination revealed that the clefts resulted from the breakdown of newly fused palates. This article is the first report of a gene required to maintain adherence of the palatal shelves after fusion.

Animals↗
PubMed1995

Patterns of cyclic AMP-dependent protein kinase gene expression during ontogeny of the murine palate.

Normal growth and differentiation of embryonic palatal tissue depends on regulated levels of intracellular cAMP. Cyclic AMP-dependent protein kinases (PKA) act to mediate the biological activities of cAMP. PKA isozyme protein profiles demonstrate a clear pattern of temporal alterations in embryonic palatal tissue during its development. In order to ascertain the molecular basis for changing PKA isozyme profiles during palatal ontogeny, the spatial and temporal expression of mRNAs for regulatory (RI alpha, RII alpha, and RII beta) and catalytic (C alpha) subunits of PKA was examined. RNA extracted from murine embryonic palatal tissue (days 12-14 of gestation) was examined by Northern blot analysis. Significant levels of constitutively expressed RI alpha and C alpha mRNA were seen on all days of gestation examined. RI alpha transcripts were substantially less abundant in palate mesenchymal cells in vitro than in palatal tissue in vivo. Levels of RII alpha and RII beta mRNA were highest on gestational day (GD) 12, a period characterized by pronounced palatal tissue growth. In addition, patterns of tissue distribution of RII beta, not previously described, were examined in the developing embryonic palate. A dramatic developmental shift in tissue distribution of RII beta was seen. The isozyme was evenly distributed between palatal epithelial and mesenchymal cells on GD 12 but by GD 14, RII beta was predominantly localized to palatal epithelial cells. Direct activation of adenylate cyclase with forskolin in murine embryonic palate mesenchymal (MEPM) cells resulted in an increase in RII alpha mRNA levels but had no effect on steady state levels of RII beta or C alpha mRNA. In addition, elevation of intracellular levels of cAMP resulted in a shift in the transcriptional profile of RI alpha mRNAs. Results of this study document specific patterns of expression for the genes encoding the various cAMP-dependent protein kinase regulatory and C alpha subunits in murine embryonic palatal tissue. In addition, we have demonstrated adaptational changes of this kinase in MEPM cells in response to conditions of increased intracellular levels of cAMP.

Animals↗
PubMed2002

Laser soft palate "stiffening": an alternative to uvulopalatopharyngoplasty.

BACKGROUND AND OBJECTIVE: Habitual snoring is best treated surgically, with uvulopalatophayngoplasty, but the standard "cutting" procedure poses potential morbidity. In this study, a new approach, stiffening of the soft palate with a low energy laser, was studied as a less invasive alternative. Study Design In an in vitro study, five fresh palates of canines were used to see acute thermal effect on the palatal tissue after laser treatment. The same laser irradiation was conducted in three living canines to observe a delayed response of the palate to the laser. MATERIALS AND METHODS: With the use of a non-contact 1.44 microm Nd:YAG laser at 0.1 J and 20 Hz, the mucosa on the marginal area of the soft palate was irradiated for 2-3 minutes. Following Outcome were Measured Acute shrinkage of the soft palate and thermal effect on the mucosa, and delayed stiffening and elevation of the palate after laser irradiation. RESULTS: There was immediate shrinkage of the palate of about 3.0 mm in the in vitro study. In the in vivo study, a delayed palatal stiffening with 6.0-7.0 mm elevated palatal arch was found at 5 weeks. There was no morbidity after the treatment. CONCLUSION: Laser stiffening of soft palate is simple, safe and effective for reduction of length and fluttering of the soft palate in the canine model. Clinical studies are warranted to evaluate its efficacy as an office treatment for snoring.

Animals↗
PubMed1996

Timing of hard palatal closure: a critical long-term analysis.

The controversy about timing of cleft palate surgical procedures is focused on early palatoplasty for improved speech versus delayed hard palate repair for undisturbed facial growth. Timing and technique of palate repair are the most important influences on speech and facial growth, yet there is no consensus on the age or technique for surgery. The Oxford Cleft Palate Study was initiated to evaluate critically the long-term follow-up of 44 patients with early versus late closure of the hard palate. A multidisciplinary approach was used to determine the incidence of speech deficiencies, palatal fistulas, maxillofacial growth disturbances, and hearing abnormalities and to assess objectively the long-term effects of two different treatment modalities on the cleft palate patient. The 44 patients were selected randomly, interviewed, and examined by the multidisciplinary Oxford Cleft Palate Study team. The average age at follow-up in the early closure group was 17.0 years versus 18.2 years in the late closure group. There was a similar number of unilateral and bilateral clefts in both the early and late closure groups. The hard palate was closed in the early group at an average age of 10.8 months versus 48.6 months in the late closure group. All operative procedures in each group were performed by the same senior plastic surgery consultant. Both consultants have since retired and did not participate in the study. Each patient was evaluated by the same plastic surgeon, speech pathologist, orthodontist, and otologist. All examiners were blinded in that they were unaware of the type or timing of the surgical technique and had no prior knowledge of or access to the patient's medical records. Furthermore, none of the examiners participated in the initial care and surgery of these patients. Statistically significant greater speech deficiencies were noted with delayed hard palate closure, especially in articulation, nasal resonance, intelligibility, and substitution pattern assessment (overall intelligibility, p < 0.01). Likewise, the persistent palatal fistula rate in the late closure group was 35 percent in comparison with 5 percent for the early closure group (p <0.02). No significant differences in hearing or maxillofacial growth impairment were delineated in either group. Our data suggest that delaying hard palate closure results in significant speech impairment without a beneficial maxillofacial growth response.

Adolescent↗
PubMed2004

A comparison of the effects of the Latham-Millard procedure with those of a conservative treatment approach for dental occlusion and facial aesthetics in unilateral and bilateral complete cleft lip and palate: part I. Dental occlusion.

The purpose of this study was to compare the effect of the Latham-Millard presurgical orthopedics, gingivoperiosteoplasty, and lip adhesion protocol with conservative treatment (nonpresurgical orthopedics without gingivoperiosteoplasty) for palatal and dental occlusion in complete bilateral and complete unilateral cleft lip and palate. All patients were from the South Florida Cleft Palate Clinic. A retrospective dental occlusal study was conducted using serial dental casts that had been taken of patients from birth to 12 years of age. All surgical procedures, except for the secondary alveolar bone grafts in the conservative, nonpresurgical orthopedics group, were performed by D. Ralph Millard, Jr. Ralph Latham supervised the presurgical orthopedics cases. Samuel Berkowitz collected and analyzed all the serial records from 1960 to 1996. Among the patients with complete unilateral cleft lip and palate, 30 patients were treated with presurgical orthopedics, gingivoperiosteoplasty, and lip adhesion (the Latham-Millard protocol) and 51 patients were treated conservatively (i.e., nonpresurgical orthopedics without gingivoperiosteoplasty). Among the patients with complete bilateral cleft lip and palate, 21 patients were treated with the Latham-Millard protocol and 49 patients were treated conservatively. Conservative treatment was performed between 1960 and 1980. In patients with bilateral cleft lip and palate, a head bonnet with an elastic strip was used to ventroflex the protruding premaxilla. In all patients (unilateral and bilateral cleft), lip adhesion was performed at 3 months followed by definitive lip surgery at 6 to 8 months and palatal cleft closure between 18 and 24 months of age, in most cases. The Latham-Millard procedure was performed from 1980 to 1996; in bilateral cleft patients, it involved the use of a fixed palatal orthopedic appliance to bodily retract the protruding premaxilla and align it within the alveolar segments soon after birth. In all patients (unilateral and bilateral cleft), palatal alignment was also followed by gingivoperiosteoplasty and lip adhesion. Definitive lip surgery was performed between 6 and 8 months of age, and palatal closure was performed between 8 and 24 months of age using the von Langenbeck procedure with a modified vomer flap. All of the study participants had cleft lips and palates of either the unilateral or bilateral type; the unilateral and bilateral groups were further subdivided based on whether they had received the Latham-Millard protocol or the conservative treatment. It was then determined how many in each of these four basic groups had either anterior or buccal crossbites at four different age levels, when they were approximately 3, 6, 9, and 12 years of age. Although several children entered the study at or just before age 6, every patient in the 9-year-old and 12-year-old sample groups had been in the 6-year-old group and all of the 12-year-olds had been included in the immediate preceding age sample. Two-by-two chi-square tests were carried out within each cleft type (unilateral or bilateral) at each of the four age levels separately, to test whether the treatment groups (protocol versus conservative) differed in the frequency of cases with a given kind of crossbite (rather than not having that kind of crossbite). At every age level, a greater percentage of patients treated with the Latham-Millard protocol developed crossbites than did those treated more conservatively. This difference existed for both the anterior and buccal crossbites and for both unilateral and bilateral clefts. Chi-square tests of the treatment differences in crossbite frequency showed that in three quarters of the Latham-Millard protocol versus conservative treatment comparisons (12 out of 16), a significantly greater frequency of crossbite cases occurred after the Latham-Millard protocol treatment as compared with after the conservative procedure. The chi-square values for the differences in outcome between the two kinds of treatment procedures were greater for the anterior crossbites than for the buccal crossbites, suggesting that the Latham-Millard protocol, relative to the conservative method, was more likely to have an adverse effect on the anterior crossbites than on the buccal crossbites. For those patients born with a bilateral cleft, the differences in crossbite frequency between the protocol and the conservative treatment were statistically significant for patients with an anterior crossbite but not for patients with a buccal crossbite. The analysis shows that in complete bilateral and unilateral cleft lip and palate, the frequency of the anterior crossbite and (except for ages 3 and 12) the buccal crossbite is significantly higher with the Latham-Millard presurgical orthopedics, gingivoperiosteoplasty, and lip adhesion protocol compared with the conservative, nonpresurgical orthopedics without gingivoperiosteoplasty treatment. The exception in the bilateral buccal case may be attributed to the small experimental sample size, which brings down the confidence level.

Alveolar Process↗
PubMed1995

A comparative study of palatal height in a Saudi and Egyptian population.

The present study constitutes an attempt to compare normal traits for palatal height and width at different stages of dentition development of two ethnic groups of the Middle East. The observations were obtained from 346 randomly selected normal subjects, 188 Saudis and 158 Egyptians. The stone models were divided into three categories in both groups--primary, mixed and permanent dentitions. Palatal index values were calculated at two levels. Vernier calipers were used to measure the palatal width. Palatal depth was measured by profile Gauge by Vitrex. The results of this study demonstrate no significant difference between ethnic groups at levels 1 and 2 in relation to the palatal height, width and index. For both groups, palatal index increased significantly from the primary to mixed and permanent dentition at level 1. At level 2, palatal index and height showed decreases in measurement in the mixed dentition compared with the primary and the permanent dentitions. Subjective assessment of the palatal height correlated with palatal index. The casts were then labelled so that the shallow group had the smallest palatal index followed by the normal and the deep group had the largest palatal index. The results contribute to the information available on the development of palatal shape within two Middle Eastern populations. Knowledge of the normal range in shape can act as a baseline for studies of certain oral developmental abnormalities.

Adolescent↗
PubMed2006

Analysis of cell migration, transdifferentiation and apoptosis during mouse secondary palate fusion.

Malformations in secondary palate fusion will lead to cleft palate, a common human birth defect. Palate fusion involves the formation and subsequent degeneration of the medial edge epithelial seam. The cellular mechanisms underlying seam degeneration have been a major focus in the study of palatogenesis. Three mechanisms have been proposed for seam degeneration: lateral migration of medial edge epithelial cells; epithelial-mesenchymal trans-differentiation; and apoptosis of medial edge epithelial cells. However, there is still a great deal of controversy over these proposed mechanisms. In this study, we established a [Rosa26<-->C57BL/6] chimeric culture system, in which a Rosa26-originated ;blue' palatal shelf was paired with a C57BL/6-derived ;white' palatal shelf. Using this organ culture system, we observed the migration of medial edge epithelial cells to the nasal side, but not to the oral side. We also observed an anteroposterior migration of medial edge epithelial cells, which may play an important role in posterior palate fusion. To examine epithelial-mesenchymal transdifferentiation during palate fusion, we bred a cytokeratin 14-Cre transgenic line into the R26R background. In situ hybridization showed that the Cre transgene is expressed exclusively in the epithelium. However, beta-galactosidase staining gave extensive signals in the palatal mesenchymal region during and after palate fusion, demonstrating the occurrence of an epithelial-mesenchymal transdifferentiation mechanism during palate fusion. Finally, we showed that Apaf1 mutant mouse embryos are able to complete palate fusion without DNA fragmentation-mediated programmed cell death, indicating that this is not essential for palate fusion in vivo.

Animals↗
PubMedDate not supplied

Cytokeratin, vimentin and E-cadherin immunodetection in the embryonic palate in two strains of mice with different susceptibility to glucocorticoid-induced clefting.

An immunohistochemical study analyzing the pattern of distribution of some intermediate filament proteins, keratin and vimentin and, one adhesion molecule, cadherin in different stages of developing secondary palate in two strains of mice with different H-2 backgrounds was undertaken to investigate differences between a strain that is susceptible to glucocorticoid-induced cleft palate (A/Sn) and one that is resistant to glucocorticoid-induced cleft palate (C57/BL). The heads of embryos were processed by standard immunohistochemistry with antipancytokeratin (KAE1), antikeratins 18 (K18) and 19 (K19), antivimentin, and anti E-cadherin antibodies. Immunostaining with KAE1 antibody showed differences between the strains. The reaction was stronger in the medial edge epithelia of palatal processes in the A/Sn strain at all stages of palatogenesis. The C57/BL strain showed a weak immunostain to KAE1. Antivimentin antibody stained the mesenchymal cells of palatal processes and K18 and K19 showed no reaction in either strain of mice. Anti E-cadherin antibody was detected in the medial palatal epithelium of both strains of mice and in all stages of palate development. No differences were observed in E-cadherin and vimentin immunostain in palatal epithelium between the strains. The different expression of some cytokeratins in the embryonic palatal epithelium suggests that these intermediate filament proteins may be involved in different susceptibility to glucocorticoid-induced cleft palate in the mouse. The decreased immunoreaction of cytokeratins observed in the resistant strain would facilitate the disappearance of this molecule during the transformation from an epithelial to a mesenchymal phenotype that takes place during the development of the palate. These results may be related to the loss of cytokeratin expression observed during epithelial-mesenchymal transformation in the embryonic palate.

Animals↗
PubMed1992

Factors affecting speech in patients with isolated cleft palate. A methodic, clinical and instrumental study.

The present study deals with various factors affecting speech, particularly its resonance, in patients with isolated cleft palate. For that purpose a method to evaluate hypernasality was developed. The degree of hypernasality was assessed in terms of hypernasality indexes by means of a modified cul-de-sac hypernasality test. The phonetic content of the test words was chosen so as not to bias the evaluations by compensatory articulations. The reliability and validity of four variations of hypernasality indexes were examined. All these four indexes proved reliable, valid and feasible for evaluating hypernasality. The hypernasality indexes were compared with nasalance scores derived from the Model 6200 Nasometer (The Nasometer 1987, Fletcher et al. 1989). Reference nasalance scores for normal Finnish speech were measured. The mean percent nasalance and the standard deviation were 13 and 8, respectively. In addition to the present hypernasality test modification, more traditional descriptive speech analysis was used in some studies. The effect of the age at primary palatal repair on speech was examined in three year old children with isolated cleft palate. The effect on speech of two techniques for primary palatal repair - a Veau-Wardill-Kilner V to Y push back procedure and the Cronin modification - were compared in young adults with isolated cleft palate. The effect on speech of two techniques for a secondary velopharyngeal flap - a Sanvenero-Rosselli and modified Honig flap - were compared in patients with various ages and cleft types. One third had cleft lip and palate or submucous cleft palate. The rest had isolated cleft palate. The quality of speech was significantly dependent on the age at primary palatal repair. The children, whose palatal repair was performed at the average age of 22 months demonstrated, significantly more frequently, hypernasality and misarticulations related to velopharyngeal insufficiency than the children operated upon earlier. The children operated upon between the average ages of 12-18 months, demonstrated normal speech in about 3/4 of the cases. If the palate was operated on later, about 1/4 of the patients demonstrated normal speech. The technique for primary palatal repair had a significant influence on the quality of speech. Hypernasality assessed in terms of hypernasality indexes was less frequent in the speech of patients with the Cronin modification than with the Veau-Wardill-Kilner push back procedure. The technique for the secondary velopharyngeal flap also affected speech significantly. The patients with a modified Honig velopharyngeal flap eliminated more efficiently hypernasality from their speech than those with a Sanvenero-Rosselli flap.(ABSTRACT TRUNCATED AT 400 WORDS)

Cephalometry↗
PubMed2005

[Differential expression of Bmp2, Bmp4 and Bmp3 in embryonic development of mouse anterior and posterior palate].

BACKGROUND: The palate is differently regulated and developed along the anterior-posterior axis. The Bmp signal pathway plays a crucial role in palatogenesis. Conditioned-inactivation of Bmp type I receptor Alk2 or Alk3 in the neural crest or craniofacial region leads to palatal cleft in mice. However, how different Bmp members are involved in palatogenesis remains to be elucidated. In the present study, mRNA expression patterns of Bmp2, Bmp3 and Bmp4 in the developing anterior and posterior palates were examined and compared, focusing on the fusion stage. METHODS: To detect the expression of Bmp mRNA, antisense riboprobes were synthesized by in vitro transcription. Radioactive in situ hybridization was performed on sagital and coronal sections of mice head from E13 to E18. RESULTS: The expression of these Bmps were developmentally regulated in the anterior and posterior palates prior to, during and after palatal fusion. During palatal fusion, Bmp4 expression shifted from the anterior to the posterior palate, Bmp2 was highly expressed in both the anterior and posterior palates in this process, whereas Bmp3 was only localized in the posterior palate. They showed generally non-overlapping pattern in their expression domains. Thereafter, their expression was detected in both the anterior and posterior palates regulating osteogenesis and myogenesis respectively. CONCLUSIONS: Bmp signalling is involved in palatogenesis in multiple stages and has multiple roles in regulating anterior and posterior palatal development. Disturbances of Bmp signalling during palatogenesis might be a possible mechanism of cleft palate.

Animals↗
PubMed1985

Palatal dimensions in 45,X-females.

Seventy-two females with 45,X-chromosome complement were examined for palatal dimensions, and the results of the measurements were compared to those of first-degree normal female relatives of the study subjects and population control females. Hard stone casts were prepared for measuring widths and lengths of the maxillary alveolar arch and palatal height between or at the level of the permanent canines, first and second premolars, and first molars with a palatometer and sharp-pointed vernier calipers (0.5 mm). According to the analyses of covariance (history of orthodontic treatment and loss of permanent teeth as cofactors and age as covariate), the differences in palatal dimensions between the groups were statistically significant or highly significant for all dimensions except for palatal height in the posterior segments. The group of the 45,X-females had the highest mean value for palatal height at the level of the canines and systematically the lowest mean values for palatal width in all segments, while no clear difference could be found in the length of the alveolar arch between the 45,X-females and the relatives, the population control group showing the lowest value in the posterior segments. The findings of this study indicate that the narrowed palate rather than the high palate is a frequent but not definite feature in 45,X-females. This may reflect the effect of sex-chromosomes on width but not other dimensions of the palate, resulting in deficiency of transversal growth of the palate possibly through decreased growth of the palatal shelves or through disturbances in the growth of the nasal septum, sutural growth, or--to which the exostosis on the palatal alveolar plates would refer--disturbances in apposition-resorption growth changes of the maxilla.

Adolescent↗
PubMed2000

Using measurements of muscle color, pH, and electrical impedance to augment the current USDA beef quality grading standards and improve the accuracy and precision of sorting carcasses into palatability groups.

This research was conducted to determine whether objective measures of muscle color, muscle pH, and(or) electrical impedance are useful in segregating palatable beef from unpalatable beef, and to determine whether the current USDA quality grading standards for beef carcasses could be revised to improve their effectiveness at distinguishing palatable from unpalatable beef. One hundred beef carcasses were selected from packing plants in Texas, Illinois, and Ohio to represent the full range of muscle color observed in the U.S. beef carcass population. Steaks from these 100 carcasses were used to determine shear force on eight cooked beef muscles and taste panel ratings on three cooked beef muscles. It was discovered that the darkest-colored 20 to 25% of the beef carcasses sampled were less palatable and considerably less consistent than the other 75 to 80% sampled. Marbling score, by itself, explained 12% of the variation in beef palatability; hump height, by itself, explained 8% of the variation in beef palatability; measures of muscle color or pH, by themselves, explained 15 to 23% of the variation in beef palatability. When combined together, marbling score, hump height, and some measure of muscle color or pH explained 36 to 46% of the variation in beef palatability. Alternative quality grading systems were proposed to improve the accuracy and precision of sorting carcasses into palatability groups. The two proposed grading systems decreased palatability variation by 29% and 39%, respectively, within the Choice grade and decreased palatability variation by 37% and 12%, respectively, within the Select grade, when compared with current USDA standards. The percentage of unpalatable Choice carcasses was reduced from 14% under the current USDA grading standards to 4% and 1%, respectively, for the two proposed systems. The percentage of unpalatable Select carcasses was reduced from 36% under the current USDA standards to 7% and 29%, respectively, for the proposed systems. These grading systems, which included requirements for maturity, marbling, hump height, and colorimeter readings, could be implemented into the current USDA beef quality grading standards and improve the accuracy and precision of sorting beef carcasses into palatability groups. At the least, measurements of muscle color or pH could be used in a branded-beef program to increase the palatability consistency of its beef products.

Animals↗
PubMed1993

Effects of 5-fluorouracil on embryonic rat palate in vitro: fusion in the absence of proliferation.

5-Fluorouracil (5-FU) inhibits the enzyme thymidylate synthetase (TS) which results in inhibition of DNA synthesis. 5-FU is teratogenic in many species, inducing cleft palate, limb, and tail defects. In the present study, gestation day (GD) 14 embryonic rat craniofacial explants were exposed to 5-FU in organ culture with increasing concentrations and durations of exposure. Palates exposed to 5-FU were morphologically abnormal and craniofacial shape, size, and palatal fusion pattern were affected with the severity of effects dependent on concentration and duration of exposure. Cleft palate was induced in vitro as opposing palates overlapped in a narrowed oral cavity. Palates exposed to higher levels of 5-FU were growth inhibited, but fused even though proliferation ceased and few cells were available to participate in elevation and fusion. This was demonstrated as a biphasic concentration-response profile for palatal fusion in which 0.05 to 0.15 micrograms 5-FU/ml produced decreasing rates of palatal fusion, while exposure to 0.15 to 3.0 micrograms/ml resulted in progressively increasing rates of fusion. The effects of 5-FU were detected biochemically as a reduction in TS activity which was concentration and time dependent during the first 12 hours, with a return to control levels by 24 hours. During the first day, 5-FU did not alter protein levels, but DNA levels significantly decreased at the high concentration, 2.0 micrograms/ml. After 5 days in culture, both DNA and protein decreased with increasing 5-FU concentration and duration of exposure. Also by the end of the culture period, 3H-TdR incorporation had decreased in a concentration dependent manner. It is concluded that progressive inhibition of proliferation and growth in organ culture results in two different morphological outcomes: cleft palate resulting from a narrowed oral cavity and increased incidence of anterior palatal fusion under conditions of strong growth reduction. This study demonstrates that elevation and fusion can occur in the absence of growth and proliferation. Based on these observations, severe inhibition of growth or proliferation would not necessarily be sufficient to induce cleft palate.

Animals↗
PubMed2004

Nomograms of sonographic measurements throughout gestation of the fetal hard palate width, length and area.

OBJECTIVE: To assess the feasibility of sonographic depiction of the fetal hard palate and secondarily to create nomograms throughout gestation of its sonographic width, length and area. METHODS: This was a cross-sectional study of pregnant patients between 15 and 41 weeks' gestation. Inclusion criteria consisted of well-established dates (confirmed by early ultrasound), and singleton, non-anomalous fetuses. Sonographic measurements obtained included biparietal diameter, head circumference, abdominal circumference and femur length. Fetal hard palate measurements included maximum width, maximum length and the calculated area. Tables were prepared depicting the estimated mean +/- SD and 5(th), 50(th) and 95(th) centiles at each gestational week between 15 and 41 weeks. Pearson's correlation coefficient and associated P-values for the relationships between fetal hard palate measurements and other sonographic measurements and coefficients of variation for each of the fetal hard palate measurements were calculated. RESULTS: The study included 602 consecutive patients. The mean maternal age was 28.7 +/- 6.3 years, with median gravidity of 2 (range, 1-12) and parity 1 (range, 0-8). All attempts at obtaining fetal hard palate ultrasound measurements were successful. Mean fetal hard palate width (cm) = -0.73579345 + 0.11370432 x GA - 0.00083919 x GA(2) and SD = -0.017842055 + 0.005142475 x GA, where GA is gestational age in weeks. Mean fetal hard palate length (cm) = -0.82020463 + 0.11767777 x GA - 0.00092801 x GA(2) and SD = -0.043064317 + 0.006378869 x GA. Mean fetal hard palate area (cm(2)) = -2.40090641 + 0.17136556 x GA + 0.00097308 x GA(2) and SD = -0.603647741 + 0.040740282 x GA. Sonographic measurements of the fetal hard palate width, length and area correlated significantly and strongly with gestational age (all P < 0.001) and significantly but less strongly with femur length (P = 0.004). CONCLUSION: The fetal hard palate may be depicted sonographically with relative ease between 15 and 41 weeks' gestation and measurements of the fetal hard palate width, length and area correlate well with gestational age, biparietal diameter, abdominal circumference, sonographic estimated fetal weight, and femur length.

Adult↗
PubMed2004

Tgf-beta3-induced palatal fusion is mediated by Alk-5/Smad pathway.

Cleft palate is among the most common birth defects in humans, caused by a failure in the complex multistep developmental process of palatogenesis. It has been recently shown that transforming growth factor beta3 (Tgf-beta3) is an absolute requirement for successful palatal fusion, both in mice and humans. However, very little is known about the mechanisms of Tgf-beta3 signaling during this process. Here we show that putative Tgf-beta type I receptors, Alk-1, Alk-2, and Alk-5, are all endogenously expressed in the palatal epithelium. Activation of Alk-5 in the Tgf-beta3 (-/-) palatal epithelium is able to rescue palatal fusion, whereas inactivation of Alk-5 in the wild-type palatal epithelium prevents palatal fusion. The effect of Alk-2 is similar, but less pronounced. The induction of fusion by activation of Alk-5 or Alk-2 is stronger in the posterior parts of the palates at the embryonic day 14 (E14), while their activation at E13.5 also restores anterior fusion, reflecting the natural anterior-posterior direction of palate maturation in vivo. We also show that Smad2 is endogenously activated in the palatal midline epithelial seam (MES) during the fusion process. By using a mutant Alk-5 receptor that is an active kinase but is unable to activate Smads, we show that activation of Smad-independent Tgf-beta responses is not sufficient to induce fusion of shelves deficient in Tgf-beta3. Based on these observations, we conclude that the Smad2-dependent Alk-5 signaling pathway is dominant in palatal fusion driven by Tgf-beta3.

Activin Receptors, Type I↗
PubMed2005

The cellular and molecular etiology of the cleft secondary palate in Fgf10 mutant mice.

Mammalian palatogenesis depends on interactions between the stomodium-derived epithelium and the cranial neural crest-derived ectomesenchyme. Fibroblast growth factor 10 (FGF10) is a mesenchymal signaling factor that guides the morphogenesis of multiple organs through tissue-tissue interactions. This is consistent with widespread agenesis and dysgenesis of organs observed in Fgf10-/- mice. In this study, we report the presence of a wide-open cleft secondary palate in Fgf10 homozygous null mutant mice. Fgf10 transcripts were detected in the palatal mesenchyme from E11.5 to E13.5 during normal palatogenesis and were enriched in the anterior and middle portions of the palatal shelves. In Fgf10-/- embryos, histological analyses revealed aberrant adhesion of the palatal shelves with the tongue in the anterior and fusion with the mandible in the middle and posterior beginning at E13.5, which could prevent normal elevation of the palatal shelves leading to a cleft palate. TUNEL and BrdU assays demonstrated significant levels of apoptosis in the medial edge epithelium (MEE) but unaltered cell proliferation in mutant palatal shelves. At the molecular level, we show that Fgf10 is epistatic to Jagged2 and Tgfbeta3 in the developing palate. Notably, the expression of Jagged2 is downregulated throughout the palate epithelium in Fgf10 mutants while Tgfbeta3 is misexpressed in the palatal epithelium at the oral side. Our results demonstrate that mesenchymally expressed Fgf10 is necessary for the survival of MEE cells and for the normal expression of Jagged2 and Tgfbeta3 in the palatal epithelium during mammalian palatogenesis.

Animals↗
PubMedDate not supplied

An in vitro screening system for characterizing the cleft palate-inducing potential of chemicals and underlying mechanisms.

An in vitro organ culture system with developing mouse palates was improved to characterize the cleft palate (CP)-inducing potential of chemicals and underlying mechanisms. Palatal explants collected from gestation day 12 mouse fetuses were cultured with various concentrations of teratogens and examined for palatal development after 48 and 72 h of culture to assess effects of the chemicals on growth and/or fusion of palatal shelves. When the explants were exposed to diphenylhydantoin or 5-fluorouracil, palatal growth was inhibited in a concentration-dependent manner at 48 h. Suppression of the expression of proliferative cell nuclear antigen revealed poor cell proliferation. At 72 h, the incidence of explants with CP was significantly increased in the high-dose groups, suggesting that CP induction is mainly attributable to inhibition of palatal growth. By contrast, retinoic acid and hydrocortisone significantly lowered the rates of fused palates at 72 h in all treated groups, while they exhibited no effects on palatal growth at 48 h even at the highest concentration. Because no apoptosis was found in the epithelial cells at the tip of these palates, these chemicals are suggested to inhibit palatal fusion process by preventing apoptosis.

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