Periodontal disease is a risk factor for many systemic diseases such as Alzheimer’s disease and adverse pregnancy outcomes.Cleft palate(CP),the most common congenital craniofacial defect,has a multifaceted etiology i...Periodontal disease is a risk factor for many systemic diseases such as Alzheimer’s disease and adverse pregnancy outcomes.Cleft palate(CP),the most common congenital craniofacial defect,has a multifaceted etiology influenced by complex genetic and environmental risk factors such as maternal bacterial or virus infection.A prior case-control study revealed a surprisingly strong association between maternal periodontal disease and CP in offspring.However,the precise relationship remains unclear.In this study,the relationship between maternal oral pathogen and CP in offspring was studied by sonicated P.gingivalis injected intravenously and orally into pregnant mice.We investigated an obvious increasing CP(12.5%)in sonicated P.gingivalis group which had inhibited osteogenesis in mesenchyme and blocked efferocytosis in epithelium.Then glycolysis and H4K12 lactylation(H4K12la)were detected to elevate in both mouse embryonic palatal mesenchyme(MEPM)cells and macrophages under P.gingivalis exposure which further promoted the transcription of metallopeptidase domain17(ADAM17),subsequently mediated the shedding of transforming growth factor-beta receptor 1(TGFBR1)in MEPM cells and mer tyrosine kinase(MerTK)in macrophages and resulted in the suppression of efferocytosis and osteogenesis in palate,eventually caused abnormalities in palate fusion and ossification.The abnormal efferocytosis also led to a predominance of M1 macrophages,which indirectly inhibited palatal osteogenesis via extracellular vesicles.Furthermore,pharmacological ADAM17 inhibition could ameliorate the abnormality of P.gingivalis-induced abnormal palate development.Therefore,our study extends the knowledge of how maternal oral pathogen affects fetal palate development and provides a novel perspective to understand the pathogenesis of CP.展开更多
Background: In developing countries, charity cleft surgical mission is always operated by sporadic surgical teams without systematic follow up and quality assurance. In the past few decades, many mission projects have...Background: In developing countries, charity cleft surgical mission is always operated by sporadic surgical teams without systematic follow up and quality assurance. In the past few decades, many mission projects have been held regularly in China. The purpose of this audit was a retrospective analysis of a 9-year cleft lip and palate charity project operated in a tertiary hospital in China Shenzhen Area to evaluate perioperative and postoperative complications. Nevertheless, understanding the risk profile is essential for establishing a sustainable in-house cleft service in Shenzhen. Methods: A detailed analysis of hospital centralized record in the The University of Hong Kong-Shenzhen Hospital (HKUSZH) was reviewed since the first charity project held in 2015. The parameters of this audit were focused on perioperative complications including anesthesia related problems, early postoperative complications in patients who underwent primary or secondary cleft surgeries. A total of 430 consecutive admitted cases of 311 non-syndromic cleft lip & palate patients were enrolled into the charity project from June 2015 to July 2024. The main anesthesia related complications that occurred during general anesthesia were respiratory tract problems, while intraoperative complication was excessive bleeding, so as wound local infection and reaction were the main early postoperative complications. Results: In our 9-year clinical audit of 430 cleft lip and palate charity surgeries in Shenzhen, we observed no mortalities and a anesthesia-related complication rate of 1.16%. Specific intraoperative complications included excessive bleeding, while early postoperative issues were dominated by wound infections. The fistula rate of 18.7% post palate repair and the average hospital stay of 3.71 days complete the profile of our surgical outcomes. These data underscore the project’s efficacy and offer a reference for international cleft missions aiming for safe and efficient surgical care. Conclusions: This study provides a thorough data review of the complications in the past 9 years charity missions for cleft lip and palate surgery in a well-structured hospital infrastructure and logistic support by local surgical team. There were no perioperative or postoperative death during the study period and the overall short-term complication rate was low. Therefore, it could be a reference model for other international cleft mission in developing country for a safe and efficient service in future.展开更多
Introduction: Pleomorphic adenoma or mixed salivary gland tumor is a heterogeneous benign tumor of the salivary glands. The most common site is the parotid gland. Its extra-parotid locations, particularly in the acces...Introduction: Pleomorphic adenoma or mixed salivary gland tumor is a heterogeneous benign tumor of the salivary glands. The most common site is the parotid gland. Its extra-parotid locations, particularly in the accessory salivary glands, are rarer. We report a case of a pleomorphic adenoma of the posterior palate which posed management problems. Observation: This is an 85-year-old patient who consulted for a tumor of the posterior palate that had been evolving for 3 years. The examination revealed a globular tumor of the posterior palate extending beyond the midline by approximately 7 cm in long axis, shooting towards the oropharynx and hindering breathing, speech and eating, indicating a life-saving tracheotomy. A CT scan of the facial area revealed a well-circumscribed tumor at the expense of the soft palate, with multiple sites of bone lysis. The biopsy performed was in favor of a pleomorphic adenoma. The patient underwent total surgical excision of a huge tumor on the palate. The aftermath of the operation was marked by a loosening of the sutures with an oronasal fistula requiring the creation of an obturator plate due to the patient’s refusal to have another operation. Conclusion: Large pleomorphic adenoma of the posterior palate is a rare entity that can cause respiratory problems and surgical difficulties. His prognosis is generally good.展开更多
BACKGROUND Congenital palate perforation is extremely rare. There is controversy about its exact etiology and appropriate management. Here, a case of congenital palatal perforation is reported. The diagnosis and treat...BACKGROUND Congenital palate perforation is extremely rare. There is controversy about its exact etiology and appropriate management. Here, a case of congenital palatal perforation is reported. The diagnosis and treatment of the disease are summarized.CASE SUMMARY A full-term neonate boy was referred for oral and craniomaxillofacial surgery with a finding of a hole in the palate at birth. The operation was postponed after pediatric consultation because of the patient’s poor nutrition and underweight for his age. At the age of 10 mo, the patient underwent modified von Langenbeck palatoplasty. He was followed for four years after surgery without any signs of re-rupture. His speech was satisfactory.CONCLUSION Considering the anatomy and etiology, congenital palate perforation can be classified as isolated or associated with submucous cleft palate, and the treatment procedure should be altered accordingly.展开更多
Objective: To address the effect of intrinsic factors on craniofacial growth by analyzing the craniofacial morphology of unoperated isolated cleft palate in Chinese adult. Materials and Methods: This study included ...Objective: To address the effect of intrinsic factors on craniofacial growth by analyzing the craniofacial morphology of unoperated isolated cleft palate in Chinese adult. Materials and Methods: This study included 37 nonsyndromic isolated cleft palate and 39 age and gender matched non-clefts. Twenty-six cephalometric measurements were employed to evaluate the facial morphology. Independent samples T test and Mann- Whitney U were used for comparison. Significant difference was defined at 95% level. Results: Data from this study showed patients with unoperated isolated cleft palate have a reduced maxillary sagittal length (ANS-PMP, A-PMP, P〈0.05), a smaller ANB angle (ANB, P〈0.05) and a retrusive ANS point (S-N-ANS, P〈0.05; Ba-N-ANS, P〈0.05). Measurements descripted position of maxilla (S-Ptm, P〉0.05), depth of bony pharynx (Ba-PMP, P〉0.05), anterior and posterior maxillary height (N-ANS, P〉0.05; R-PMP, P〉0.05) and mandible morphology (including linear measurements and angle measurements) did not show any significant difference between case and control groups. Conclusions: Patients with isolated cleft palate were characterized by maxillary retrusion. Mandible morphology and cranial basal morphology in isolated cleft palate showed no significant difference with nonclefts. Patients with isolated cleft palate are more vulnerable to cross bite than nonclefts. Intrinsic deficiencies did detrimental effect on maxilla sagittal length, but did no detrimental effect on maxilla position, mandible size and position.展开更多
In this paper, the authors present airflow field characteristics of human upper airway and soft palate movement attitude during breathing. On the basis of the data taken from the spiral computerized tomography images ...In this paper, the authors present airflow field characteristics of human upper airway and soft palate movement attitude during breathing. On the basis of the data taken from the spiral computerized tomography images of a healthy person and a patient with Obstructive Sleep Apnea-Hypopnea Syndrome (OSAHS), three-dimensional models of upper airway cavity and soft palate are reconstructed by the method of surface rendering. Numerical simulation is performed for airflow in the upper airway and displacement of soft palate by fluid-structure interaction analysis. The reconstructed threedimensional models precisely preserve the original configuration of upper airways and soft palate. The results of the pressure and velocity distributions in the airflow field are quantitatively determined, and the displacement of soft palate is presented. Pressure gradients of airway are lower for the healthy person and the airflow distribution is quite uniform in the case of free breathing. However, the OSAHS patient remarkably escalates both the pressure and velocity in the upper airway, and causes higher displacement of the soft palate. The present study is useful in revealing pathogenesis and quantitative mutual relationship between configuration and function of the upper airway as well as in diagnosingdiseases related to anatomical structure and function of the upper airway.展开更多
Non-syndromic cleft lip with or without cleft palate (nsCL/P) is among the most common major birth defects, with complex inheritance involving multiple genes and environmental factors. Numerous studies of MTHFR, enc...Non-syndromic cleft lip with or without cleft palate (nsCL/P) is among the most common major birth defects, with complex inheritance involving multiple genes and environmental factors. Numerous studies of MTHFR, encoding methylenetetrahydrofolate reductase, which catalyzes the rate-limiting step of folic acid biosynthesis, have shown inconsistent association of two common hypomorphic allelic variants, C677T and A1298C, in nsCL/P patients and, in some cases, their mothers. We have studied the MTHFR C677T and A1298C polymorphisms in nsCL/P patients, their mothers, and population-matched controls from northern Venezuela. We found no evidence for contribution of the MTHFR C677T and A1298C variants to the risk of nsCL/P in northern Venezuela. Overall, our findings fail to support a causal role of either the MTHFR C677T or A 1298C variants in the pathogenesis of nsCL/P in northern Venezuela.展开更多
Low-grade myofibroblastic sarcoma (LGMS) is a rare, malignant tumor with myofibroblastic differentiation. Despite it being classified as a distinct entity by the World Health Organization, a few cases were reported ...Low-grade myofibroblastic sarcoma (LGMS) is a rare, malignant tumor with myofibroblastic differentiation. Despite it being classified as a distinct entity by the World Health Organization, a few cases were reported in the oral and maxillofacial region. Here, a LGMS developed on the palate of a 73-year-old man who presented with a 1-cm tumor on the posterior border of the palate. Based on the histological and immunohistochemical features, a diagnosis of LGMS was established. The tumor was resected, and no recurrence was observed over 2 years. Although the tongue is the most preferred site for LGMS, it may occur in any region of the oral cavity.展开更多
The purpose of this study was to investigate the effect of vitamin B12 on palatal development by co-administration of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and dexamethasone (DEX). We examined the morphologic...The purpose of this study was to investigate the effect of vitamin B12 on palatal development by co-administration of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and dexamethasone (DEX). We examined the morphological and histological features of the palatal shelf and expression levels of key signaling molecules (trans- forming growth factor-β3 (TGF-β3) and TGF-β3 type I receptor (activin receptor-like kinase 5, ALK5)) during pala- togenesis among a control group (Group A), TCDD+DEX exposed group (Group B), and TCDD+DEX+vitamin B12 exposed group (Group C). While we failed to find that vitamin B12 decreased the incidence of cleft palate induced by TCDD+DEX treatment, the expression levels of key signaling molecules (TGF-~3 and ALK5) during palatogenesis were significantly modulated. In TCDD+DEX exposed and TCDD+DEX+vitamin B12 exposed groups, palatal shelves could not contact in the midline due to their small sizes. Our results suggest that vitamin B12 may inhibit the expression of some cleft palate inducers such as TGF-β3 and ALK5 in DEX+TCDD exposed mice, which may be beneficial against palatogenesis to some degree, even though we were unable to observe a protective role of vitamin B12 in morphological and histological alterations of palatal shelves induced by DEX and TCDD.展开更多
This study examined the dynamic characteristics of upper airway collapse at soft palate level in patients with obstructive sleep apnea/hypopnea syndrome(OSAHS) by using dynamic 3-Dimensional(3-D) CT imaging.A tota...This study examined the dynamic characteristics of upper airway collapse at soft palate level in patients with obstructive sleep apnea/hypopnea syndrome(OSAHS) by using dynamic 3-Dimensional(3-D) CT imaging.A total of 41 male patients who presented with 2 of the following symptoms,i.e.,daytime sleepiness and fatigue,frequent snoring,and apnea with witness,were diagnosed as having OSAHS.They underwent full-night polysomnography and then dynamic 3-D CT imaging of the upper airway during quiet breathing and in Muller's maneuver.The soft palate length(SPL),the minimal cross-sectional area of the retropalatal region(mXSA-RP),and the vertical distance from the hard palate to the upper posterior part of the hyoid(hhL) were compared between the two breathing states.These parameters,together with hard palate length(HPL),were also compared between mild/moderate and severe OSAHS groups.Association of these parameters with the severity of OSAHS [as reflected by apnea hypopnea index(AHI) and the lowest saturation of blood oxygen(LSaO2)] was examined.The results showed that 31 patients had severe OSAHS,and 10 mild/moderate OSAHS.All the patients had airway obstruction at soft palate level.mXSA-RP was significantly decreased and SPL remarkably increased during Muller's maneuver as compared with the quiet breathing state.There were no significant differences in these airway parameters(except the position of the hyoid bone) between severe and mild/moderate OSAHS groups.And no significant correlation between these airway parameters and the severity of OSAHS was found.The position of hyoid was lower in the severe OSAHS group than in the mild/moderate OSAHS group.The patients in group with body mass index(BMI)≥26 had higher collapse ratio of mXSA-RP,greater neck circumference and smaller mXSA-RP in the Muller's maneuver than those in group with BMI26(P0.05 for all).It was concluded that dynamic 3-D CT imaging could dynamically show the upper airway changes at soft palate level in OSAHS patients.All the OSAHS patients had airway obstruction of various degrees at soft palate level.But no correlation was observed between the airway change at soft palate level and the severity of OSAHS.The patients in group with BMI≥26 were more likely to develop airway obstruction at soft palate level than those with BMI26.展开更多
This study investigated the role of long non‐coding RNAs(lnc RNAs) in the development of the palatal tissues. Cleft palates in mice were induced by 2,3,7,8‐tetrachlorodibenzo‐p‐dioxin(TCDD). Expression levels ...This study investigated the role of long non‐coding RNAs(lnc RNAs) in the development of the palatal tissues. Cleft palates in mice were induced by 2,3,7,8‐tetrachlorodibenzo‐p‐dioxin(TCDD). Expression levels of long non‐coding RNA H19(lncR NA H19) and insulin‐like growth factor 2(IGF2) gene were measured by quantitative real‐time polymerase chain reaction(q RT‐PCR). The rate of occurrence of cleft palate was found to be 100% by TCDD exposure, and TCDD could cause short upper limb, cerebral fissure, webbed neck, and short neck. The expression levels of lnc RNA H19 and IGF2 gene specifically showed embryo age‐related differences on E13, E14, and E15 in the palatal tissues. The expression levels of lnc RNA H19 and IGF2 gene showed an inverse relationship on E13, E14, and E15. These findings demonstrated that lnc RNA H19 and IGF2 can mediate the development of mouse cleft palate.展开更多
Objective To evaluate the effects of retinoic acid (RA) on expression of bone morphogenetic protein 7 ( BMP-7 ) in rat fetus with cleft palate, and the effects of RA on proliferation and apoptosis of osteoblasts. ...Objective To evaluate the effects of retinoic acid (RA) on expression of bone morphogenetic protein 7 ( BMP-7 ) in rat fetus with cleft palate, and the effects of RA on proliferation and apoptosis of osteoblasts. Methods All-trans RA (ATRA) was used to induce congenital cleft palate in Wistar rat. BMP-7 mRNA expression in maxillary bone tissue of fetal rats was measured by Northern blotting analysis. Flow cytometry and MTF assay were used to measure the apoptosis and proliferation of ATRA-treated MC-3T3-E1 cells. BMP-7 mRNA and protein expressions in ATRA-treated MC-3T3-E1 cells were detected by RT-PCR and Western blotting analysis. Remilts ATRA could induce cleft palate of rat fetus. The incidence rate of cleft palate induced by 100 mg/kg AT-RA (45.5%) was significantly higher than 50 mg/kg ATRA ( 12.5%, P 〈 0. 05 ). BMP-7 mRNA expression decreased in maxillary bone tissue of rat fetus with cleft palate. MC-3T3-E1 cells proliferation treated with 1 × 10^-6 mol/L ATRA decreased by 60%, the cell apoptosis increased by 2 times. BMP-7 mRNA and protein levels in MC-3T3-E1 cells treated with 1 × 10^-6 mol/L ATRA decreased by 60% and 80%, respectively, compared with ATRA-untreated cells ( P 〈 0.05 ). Conclusions BMP-7 may play an important role in embryonic palate development. RA may possess the ability to down-regulate cell proliferation through regulation of BMP-7 gene expression.展开更多
Cleft lip with or without cleft palate(CP) is one of the most common congenital malformations. Ultrasonographers involved in the routine 20-wk ultrasound screening could encounter these malformations. The face and pal...Cleft lip with or without cleft palate(CP) is one of the most common congenital malformations. Ultrasonographers involved in the routine 20-wk ultrasound screening could encounter these malformations. The face and palate develop in a very characteristic way. For ultrasonographers involved in screening these patients it is crucial to have a thorough understanding of the embryology of the face. This could help them to make a more accurate diagnosis and save time during the ultrasound. Subsequently, the current postnatal classification will be discussed to facilitate the communication with the CP teams.展开更多
Objective Convincing evidence suggests a link between increased risk of nonsyndromic cleft lip with or without cleft palate (NSCL/P) and low intake of folic acid by the mother during pregnancy. The present study was...Objective Convincing evidence suggests a link between increased risk of nonsyndromic cleft lip with or without cleft palate (NSCL/P) and low intake of folic acid by the mother during pregnancy. The present study was designed to explore if genetic variation in the betaine‐homocysteine methyltransferase (BHMT) gene contributes to NSCL/P. Methods DNA was obtained from 166 individuals with NSCL/P and 285 healthy subjects. Three known single nucleotide polymorphisms (SNPs) present in the BHMT gene (rs651852, rs3797546, and rs3733890) were investigated by real‐time PCR‐based TaqMan genotyping. Results Neither allelic nor genotypic association was found between NSCL/P and SNPs rs651852 and rs3733890. SNP rs3797546 did not show allelic association with NSCL/P; however, a higher proportion of NSCL/P patients carry the CC genotype compared with the TT+CT genotype (P=0.020, OR=2.10, 95% CI=1.11‐3.95). Conclusion Our study suggests that polymorphism rs3797546 in the BHMT gene may confer genetic risk of NSCL/P in a recessive manner.展开更多
Development of the secondary palate displays molecular heterogeneity along the anterior-posterior axis;however, the underlying molecular mechanism remains largely unknown. MSX1 is an anteriorly expressed transcription...Development of the secondary palate displays molecular heterogeneity along the anterior-posterior axis;however, the underlying molecular mechanism remains largely unknown. MSX1 is an anteriorly expressed transcription repressor required for palate development. Here, we investigate the role of Msx1 in regional patterning of the secondary palate. The Wnt1-Cre-mediated expression of Msx1(Rosa Msx1^(Wnt1-Cre))throughout the palatal mesenchyme leads to cleft palate in mice, associated with aberrant cell proliferation and cell death. Osteogenic patterning of the hard palate in Rosa Msx1^(Wnt1-Cre)mice is severely impaired, as revealed by a marked reduction in palatine bone formation and decreased expression of the osteogenic regulator Sp7. Overexpression and knockout of Msx1 in mice show that the transcription repressor promotes the expression of the anterior palate-specific Alx1 but represses the expression of the medialposterior palate genes Barx1, Meox2, and Tbx22. Furthermore, Tbx22 constitutes a direct Msx1 target gene in the secondary palate, suggesting that Msx1 can directly repress the expression of medial-posterior specific genes. Finally, we determine that Sp7 is downstream of Tbx22 in palatal mesenchymal cells,suggesting that a Msx1/Tbx22/Sp7 axis participates in the regulation of palate development. Our findings unveil a novel role for Msx1 in regulating the anterior-posterior growth and patterning of the secondary palate.展开更多
Cleft lip and/or palate(CLP)are the most common craniofacial malformations in humans.Speech problems often persist even after cleft repair,such that follow-up articulation training is usually required.However,the neur...Cleft lip and/or palate(CLP)are the most common craniofacial malformations in humans.Speech problems often persist even after cleft repair,such that follow-up articulation training is usually required.However,the neural mechanism behind effective articulation training remains largely unknown.We used fMRI to investigate the differences in brain activation,functional connectivity,and effective connectivity across CLP patients with and without articulation training and matched normal participants.We found that training promoted task-related brain activation among the articulation-related brain networks,as well as the global attributes and nodal efficiency in the functional-connectivity-based graph of the network.Our results reveal the neural correlates of effective articulation training in CLP patients,and this could contribute to the future improvement of the post-repair articulation training program.展开更多
Objectives To identify the loci involved in nonsyndromic cleft lip with or without cleft palate (NSCL/P) in Northern Chinese people in Shenyang by using genomewide and interaction linkage scan.Methods Two multiplex ...Objectives To identify the loci involved in nonsyndromic cleft lip with or without cleft palate (NSCL/P) in Northern Chinese people in Shenyang by using genomewide and interaction linkage scan.Methods Two multiplex families in Shenyang from North China were ascertained through probands with NSCL/P.Blood of every member was drawn for DNA extraction and analysis.Genotypes were available for 382 autosomal short tandem repeat (STR) markers from the ABI Prism Linkage Mapping Set version 2.5.Linkage between markers and NSCL/P was assessed by 2-point parametric LOD scores,multipoint heterogeneity parametric LOD scores (HLODs),and multipoint nonparametric linkage score (NPL).Results The initial scan suggested linkage on Chromosomes 1,2,and 15.In subsequent fine mapping,1q32-q42 showed a maximum multipoint LOD score of 1.9(empirical P=0.013) and an NPL score of 2.35 (empirical P=0.053).For 2p24-p25,the multipoint NPL increased to 2.94 (empirical P=0.007).2-locus interaction analysis obtained a maximum NPL score of 3.73 (P=0.00078) and a maximum LOD score of 3 for Chromosome 1 (at 221 cM) and Chromosome 2 (at 29 cM).Conclusion Both parametric and nonparametric linkage scores greatly increased over the initial linkage scores on 1q32-q42,suggesting a susceptibility locus in this region.Nonparametric linkage gave a strong evidence for a candidate region on chromosome 2p24-p25.The superiority of 2-locus linkage scores compared to single-locus scores gave additional evidence for linkage on 1q32-q42 and 2p24-p25,and suggested that certain genes in the two regions may contribute to NCSL/P risks with interaction.展开更多
Cleft palate, including complete or incomplete cleft palates, soft palate clefts, and submucosal cleft palates, is the most frequent congenital craniofacial anomaly in humans. Multifactorial conditions, including gene...Cleft palate, including complete or incomplete cleft palates, soft palate clefts, and submucosal cleft palates, is the most frequent congenital craniofacial anomaly in humans. Multifactorial conditions, including genetic and environmental factors, induce the formation of cleft palates. The process of palatogenesis is temporospatially regulated by transcription factors, growth factors, extracellular matrix proteins, and membranous molecules; a single ablation of these molecules can result in a cleft palate in vivo. Studies on knockout mice were reviewed in order to identify genetic errors that lead to cleft palates. In this review, we systematically describe these mutant mice and discuss the molecular mechanisms of palatogenesis.展开更多
In this study, we sought to determine the association between environmental factors and nonsyndromic cleft of the lip and/or palate (NSCLP) to understand the etiology of the disease. A total of 200 NSCLP cases and 3...In this study, we sought to determine the association between environmental factors and nonsyndromic cleft of the lip and/or palate (NSCLP) to understand the etiology of the disease. A total of 200 NSCLP cases and 327 controls were recruited at the Maternal and Child Health Hospital of Xuzhou City. We conducted face-to-face interviews with the mothers of both cases and controls. The factors increasing the risk of NSCLP were a positive family history [odds ratio (OR)=56.74], pesticide exposure (OR=8.90), and indoor decoration pollution (OR= 4.32). On the other hand, the factors decreasing the risk of NSCLP were a high education level (OR=0.22) and supplementation of folic acid (OR=0.23) and multivitamins (OR=0.16). Positive family history, pesticide exposure, and indoor decoration pollution are associated with the risk of NSCLP. In contrast, high education level and folic acid and multivitamin supplementation are protective factors against NSCLP.展开更多
Orofacial clefts(OFCs),particularly cleft lip with or without cleft palate(CL/P)and cleft palate only(CPO),are among the most common birth defects in humans(Mossey et al.,2009;Dixon et al.,2011).The birth prevalence r...Orofacial clefts(OFCs),particularly cleft lip with or without cleft palate(CL/P)and cleft palate only(CPO),are among the most common birth defects in humans(Mossey et al.,2009;Dixon et al.,2011).The birth prevalence rate of OFCs in China is reported to be as high as 1.66 per thousand newborns.展开更多
基金funded by grants from the National Natural Science Foundation of China(grant numbers 82170912 and 82370910)the Beijing Stomatological Hospital,Capital Medical University Young Scientist Program(No.YSP202404).
文摘Periodontal disease is a risk factor for many systemic diseases such as Alzheimer’s disease and adverse pregnancy outcomes.Cleft palate(CP),the most common congenital craniofacial defect,has a multifaceted etiology influenced by complex genetic and environmental risk factors such as maternal bacterial or virus infection.A prior case-control study revealed a surprisingly strong association between maternal periodontal disease and CP in offspring.However,the precise relationship remains unclear.In this study,the relationship between maternal oral pathogen and CP in offspring was studied by sonicated P.gingivalis injected intravenously and orally into pregnant mice.We investigated an obvious increasing CP(12.5%)in sonicated P.gingivalis group which had inhibited osteogenesis in mesenchyme and blocked efferocytosis in epithelium.Then glycolysis and H4K12 lactylation(H4K12la)were detected to elevate in both mouse embryonic palatal mesenchyme(MEPM)cells and macrophages under P.gingivalis exposure which further promoted the transcription of metallopeptidase domain17(ADAM17),subsequently mediated the shedding of transforming growth factor-beta receptor 1(TGFBR1)in MEPM cells and mer tyrosine kinase(MerTK)in macrophages and resulted in the suppression of efferocytosis and osteogenesis in palate,eventually caused abnormalities in palate fusion and ossification.The abnormal efferocytosis also led to a predominance of M1 macrophages,which indirectly inhibited palatal osteogenesis via extracellular vesicles.Furthermore,pharmacological ADAM17 inhibition could ameliorate the abnormality of P.gingivalis-induced abnormal palate development.Therefore,our study extends the knowledge of how maternal oral pathogen affects fetal palate development and provides a novel perspective to understand the pathogenesis of CP.
文摘Background: In developing countries, charity cleft surgical mission is always operated by sporadic surgical teams without systematic follow up and quality assurance. In the past few decades, many mission projects have been held regularly in China. The purpose of this audit was a retrospective analysis of a 9-year cleft lip and palate charity project operated in a tertiary hospital in China Shenzhen Area to evaluate perioperative and postoperative complications. Nevertheless, understanding the risk profile is essential for establishing a sustainable in-house cleft service in Shenzhen. Methods: A detailed analysis of hospital centralized record in the The University of Hong Kong-Shenzhen Hospital (HKUSZH) was reviewed since the first charity project held in 2015. The parameters of this audit were focused on perioperative complications including anesthesia related problems, early postoperative complications in patients who underwent primary or secondary cleft surgeries. A total of 430 consecutive admitted cases of 311 non-syndromic cleft lip & palate patients were enrolled into the charity project from June 2015 to July 2024. The main anesthesia related complications that occurred during general anesthesia were respiratory tract problems, while intraoperative complication was excessive bleeding, so as wound local infection and reaction were the main early postoperative complications. Results: In our 9-year clinical audit of 430 cleft lip and palate charity surgeries in Shenzhen, we observed no mortalities and a anesthesia-related complication rate of 1.16%. Specific intraoperative complications included excessive bleeding, while early postoperative issues were dominated by wound infections. The fistula rate of 18.7% post palate repair and the average hospital stay of 3.71 days complete the profile of our surgical outcomes. These data underscore the project’s efficacy and offer a reference for international cleft missions aiming for safe and efficient surgical care. Conclusions: This study provides a thorough data review of the complications in the past 9 years charity missions for cleft lip and palate surgery in a well-structured hospital infrastructure and logistic support by local surgical team. There were no perioperative or postoperative death during the study period and the overall short-term complication rate was low. Therefore, it could be a reference model for other international cleft mission in developing country for a safe and efficient service in future.
文摘Introduction: Pleomorphic adenoma or mixed salivary gland tumor is a heterogeneous benign tumor of the salivary glands. The most common site is the parotid gland. Its extra-parotid locations, particularly in the accessory salivary glands, are rarer. We report a case of a pleomorphic adenoma of the posterior palate which posed management problems. Observation: This is an 85-year-old patient who consulted for a tumor of the posterior palate that had been evolving for 3 years. The examination revealed a globular tumor of the posterior palate extending beyond the midline by approximately 7 cm in long axis, shooting towards the oropharynx and hindering breathing, speech and eating, indicating a life-saving tracheotomy. A CT scan of the facial area revealed a well-circumscribed tumor at the expense of the soft palate, with multiple sites of bone lysis. The biopsy performed was in favor of a pleomorphic adenoma. The patient underwent total surgical excision of a huge tumor on the palate. The aftermath of the operation was marked by a loosening of the sutures with an oronasal fistula requiring the creation of an obturator plate due to the patient’s refusal to have another operation. Conclusion: Large pleomorphic adenoma of the posterior palate is a rare entity that can cause respiratory problems and surgical difficulties. His prognosis is generally good.
基金Supported by Shanghai Science and Technology Commission Project,No.17410710500,No.19441906000,No.YG2015MS02,No.PW2016E-1,and No.JYJX03201810
文摘BACKGROUND Congenital palate perforation is extremely rare. There is controversy about its exact etiology and appropriate management. Here, a case of congenital palatal perforation is reported. The diagnosis and treatment of the disease are summarized.CASE SUMMARY A full-term neonate boy was referred for oral and craniomaxillofacial surgery with a finding of a hole in the palate at birth. The operation was postponed after pediatric consultation because of the patient’s poor nutrition and underweight for his age. At the age of 10 mo, the patient underwent modified von Langenbeck palatoplasty. He was followed for four years after surgery without any signs of re-rupture. His speech was satisfactory.CONCLUSION Considering the anatomy and etiology, congenital palate perforation can be classified as isolated or associated with submucous cleft palate, and the treatment procedure should be altered accordingly.
文摘Objective: To address the effect of intrinsic factors on craniofacial growth by analyzing the craniofacial morphology of unoperated isolated cleft palate in Chinese adult. Materials and Methods: This study included 37 nonsyndromic isolated cleft palate and 39 age and gender matched non-clefts. Twenty-six cephalometric measurements were employed to evaluate the facial morphology. Independent samples T test and Mann- Whitney U were used for comparison. Significant difference was defined at 95% level. Results: Data from this study showed patients with unoperated isolated cleft palate have a reduced maxillary sagittal length (ANS-PMP, A-PMP, P〈0.05), a smaller ANB angle (ANB, P〈0.05) and a retrusive ANS point (S-N-ANS, P〈0.05; Ba-N-ANS, P〈0.05). Measurements descripted position of maxilla (S-Ptm, P〉0.05), depth of bony pharynx (Ba-PMP, P〉0.05), anterior and posterior maxillary height (N-ANS, P〉0.05; R-PMP, P〉0.05) and mandible morphology (including linear measurements and angle measurements) did not show any significant difference between case and control groups. Conclusions: Patients with isolated cleft palate were characterized by maxillary retrusion. Mandible morphology and cranial basal morphology in isolated cleft palate showed no significant difference with nonclefts. Patients with isolated cleft palate are more vulnerable to cross bite than nonclefts. Intrinsic deficiencies did detrimental effect on maxilla sagittal length, but did no detrimental effect on maxilla position, mandible size and position.
基金The project supported by the National Natural Science Foundation of China(10672036,10472025 and 10421002)the Natural Science Foundation of Liaoning Province(20032109)
文摘In this paper, the authors present airflow field characteristics of human upper airway and soft palate movement attitude during breathing. On the basis of the data taken from the spiral computerized tomography images of a healthy person and a patient with Obstructive Sleep Apnea-Hypopnea Syndrome (OSAHS), three-dimensional models of upper airway cavity and soft palate are reconstructed by the method of surface rendering. Numerical simulation is performed for airflow in the upper airway and displacement of soft palate by fluid-structure interaction analysis. The reconstructed threedimensional models precisely preserve the original configuration of upper airways and soft palate. The results of the pressure and velocity distributions in the airflow field are quantitatively determined, and the displacement of soft palate is presented. Pressure gradients of airway are lower for the healthy person and the airflow distribution is quite uniform in the case of free breathing. However, the OSAHS patient remarkably escalates both the pressure and velocity in the upper airway, and causes higher displacement of the soft palate. The present study is useful in revealing pathogenesis and quantitative mutual relationship between configuration and function of the upper airway as well as in diagnosingdiseases related to anatomical structure and function of the upper airway.
基金supported by the grant DE13571 from the National Institutes of Health (R.A.S.),USAthe support from Rotaplast International, Inc. (M.M.T.),USA
文摘Non-syndromic cleft lip with or without cleft palate (nsCL/P) is among the most common major birth defects, with complex inheritance involving multiple genes and environmental factors. Numerous studies of MTHFR, encoding methylenetetrahydrofolate reductase, which catalyzes the rate-limiting step of folic acid biosynthesis, have shown inconsistent association of two common hypomorphic allelic variants, C677T and A1298C, in nsCL/P patients and, in some cases, their mothers. We have studied the MTHFR C677T and A1298C polymorphisms in nsCL/P patients, their mothers, and population-matched controls from northern Venezuela. We found no evidence for contribution of the MTHFR C677T and A1298C variants to the risk of nsCL/P in northern Venezuela. Overall, our findings fail to support a causal role of either the MTHFR C677T or A 1298C variants in the pathogenesis of nsCL/P in northern Venezuela.
文摘Low-grade myofibroblastic sarcoma (LGMS) is a rare, malignant tumor with myofibroblastic differentiation. Despite it being classified as a distinct entity by the World Health Organization, a few cases were reported in the oral and maxillofacial region. Here, a LGMS developed on the palate of a 73-year-old man who presented with a 1-cm tumor on the posterior border of the palate. Based on the histological and immunohistochemical features, a diagnosis of LGMS was established. The tumor was resected, and no recurrence was observed over 2 years. Although the tongue is the most preferred site for LGMS, it may occur in any region of the oral cavity.
基金Project supported by thc National Natural Science Foundation of China (Nos. 81000425 and 30530730) and the Sichuan Key Tech- nology R&D Program (No. 2010SZ0098), China
文摘The purpose of this study was to investigate the effect of vitamin B12 on palatal development by co-administration of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and dexamethasone (DEX). We examined the morphological and histological features of the palatal shelf and expression levels of key signaling molecules (trans- forming growth factor-β3 (TGF-β3) and TGF-β3 type I receptor (activin receptor-like kinase 5, ALK5)) during pala- togenesis among a control group (Group A), TCDD+DEX exposed group (Group B), and TCDD+DEX+vitamin B12 exposed group (Group C). While we failed to find that vitamin B12 decreased the incidence of cleft palate induced by TCDD+DEX treatment, the expression levels of key signaling molecules (TGF-~3 and ALK5) during palatogenesis were significantly modulated. In TCDD+DEX exposed and TCDD+DEX+vitamin B12 exposed groups, palatal shelves could not contact in the midline due to their small sizes. Our results suggest that vitamin B12 may inhibit the expression of some cleft palate inducers such as TGF-β3 and ALK5 in DEX+TCDD exposed mice, which may be beneficial against palatogenesis to some degree, even though we were unable to observe a protective role of vitamin B12 in morphological and histological alterations of palatal shelves induced by DEX and TCDD.
文摘This study examined the dynamic characteristics of upper airway collapse at soft palate level in patients with obstructive sleep apnea/hypopnea syndrome(OSAHS) by using dynamic 3-Dimensional(3-D) CT imaging.A total of 41 male patients who presented with 2 of the following symptoms,i.e.,daytime sleepiness and fatigue,frequent snoring,and apnea with witness,were diagnosed as having OSAHS.They underwent full-night polysomnography and then dynamic 3-D CT imaging of the upper airway during quiet breathing and in Muller's maneuver.The soft palate length(SPL),the minimal cross-sectional area of the retropalatal region(mXSA-RP),and the vertical distance from the hard palate to the upper posterior part of the hyoid(hhL) were compared between the two breathing states.These parameters,together with hard palate length(HPL),were also compared between mild/moderate and severe OSAHS groups.Association of these parameters with the severity of OSAHS [as reflected by apnea hypopnea index(AHI) and the lowest saturation of blood oxygen(LSaO2)] was examined.The results showed that 31 patients had severe OSAHS,and 10 mild/moderate OSAHS.All the patients had airway obstruction at soft palate level.mXSA-RP was significantly decreased and SPL remarkably increased during Muller's maneuver as compared with the quiet breathing state.There were no significant differences in these airway parameters(except the position of the hyoid bone) between severe and mild/moderate OSAHS groups.And no significant correlation between these airway parameters and the severity of OSAHS was found.The position of hyoid was lower in the severe OSAHS group than in the mild/moderate OSAHS group.The patients in group with body mass index(BMI)≥26 had higher collapse ratio of mXSA-RP,greater neck circumference and smaller mXSA-RP in the Muller's maneuver than those in group with BMI26(P0.05 for all).It was concluded that dynamic 3-D CT imaging could dynamically show the upper airway changes at soft palate level in OSAHS patients.All the OSAHS patients had airway obstruction of various degrees at soft palate level.But no correlation was observed between the airway change at soft palate level and the severity of OSAHS.The patients in group with BMI≥26 were more likely to develop airway obstruction at soft palate level than those with BMI26.
基金supported by the grants of the National Natural Science Foundation of China(81502843)college students’research and innovation program of Xinxiang Medical UniversityHenan Province Xinxiang Key Laboratory of medical tissue regeneration program
文摘This study investigated the role of long non‐coding RNAs(lnc RNAs) in the development of the palatal tissues. Cleft palates in mice were induced by 2,3,7,8‐tetrachlorodibenzo‐p‐dioxin(TCDD). Expression levels of long non‐coding RNA H19(lncR NA H19) and insulin‐like growth factor 2(IGF2) gene were measured by quantitative real‐time polymerase chain reaction(q RT‐PCR). The rate of occurrence of cleft palate was found to be 100% by TCDD exposure, and TCDD could cause short upper limb, cerebral fissure, webbed neck, and short neck. The expression levels of lnc RNA H19 and IGF2 gene specifically showed embryo age‐related differences on E13, E14, and E15 in the palatal tissues. The expression levels of lnc RNA H19 and IGF2 gene showed an inverse relationship on E13, E14, and E15. These findings demonstrated that lnc RNA H19 and IGF2 can mediate the development of mouse cleft palate.
基金Supported by National Natural Science Foundation of China(30500414)Scientific Research Project in Department of Education of Liaoning Province(05L508,20061010)
文摘Objective To evaluate the effects of retinoic acid (RA) on expression of bone morphogenetic protein 7 ( BMP-7 ) in rat fetus with cleft palate, and the effects of RA on proliferation and apoptosis of osteoblasts. Methods All-trans RA (ATRA) was used to induce congenital cleft palate in Wistar rat. BMP-7 mRNA expression in maxillary bone tissue of fetal rats was measured by Northern blotting analysis. Flow cytometry and MTF assay were used to measure the apoptosis and proliferation of ATRA-treated MC-3T3-E1 cells. BMP-7 mRNA and protein expressions in ATRA-treated MC-3T3-E1 cells were detected by RT-PCR and Western blotting analysis. Remilts ATRA could induce cleft palate of rat fetus. The incidence rate of cleft palate induced by 100 mg/kg AT-RA (45.5%) was significantly higher than 50 mg/kg ATRA ( 12.5%, P 〈 0. 05 ). BMP-7 mRNA expression decreased in maxillary bone tissue of rat fetus with cleft palate. MC-3T3-E1 cells proliferation treated with 1 × 10^-6 mol/L ATRA decreased by 60%, the cell apoptosis increased by 2 times. BMP-7 mRNA and protein levels in MC-3T3-E1 cells treated with 1 × 10^-6 mol/L ATRA decreased by 60% and 80%, respectively, compared with ATRA-untreated cells ( P 〈 0.05 ). Conclusions BMP-7 may play an important role in embryonic palate development. RA may possess the ability to down-regulate cell proliferation through regulation of BMP-7 gene expression.
文摘Cleft lip with or without cleft palate(CP) is one of the most common congenital malformations. Ultrasonographers involved in the routine 20-wk ultrasound screening could encounter these malformations. The face and palate develop in a very characteristic way. For ultrasonographers involved in screening these patients it is crucial to have a thorough understanding of the embryology of the face. This could help them to make a more accurate diagnosis and save time during the ultrasound. Subsequently, the current postnatal classification will be discussed to facilitate the communication with the CP teams.
基金supported by the National Natural Science Foundation of China (grant number 307009907)Beijing Natural Science Foundation (grant number 7082038)Beijing Foundation for Excellent Elite (grant number 2010D003034000013)
文摘Objective Convincing evidence suggests a link between increased risk of nonsyndromic cleft lip with or without cleft palate (NSCL/P) and low intake of folic acid by the mother during pregnancy. The present study was designed to explore if genetic variation in the betaine‐homocysteine methyltransferase (BHMT) gene contributes to NSCL/P. Methods DNA was obtained from 166 individuals with NSCL/P and 285 healthy subjects. Three known single nucleotide polymorphisms (SNPs) present in the BHMT gene (rs651852, rs3797546, and rs3733890) were investigated by real‐time PCR‐based TaqMan genotyping. Results Neither allelic nor genotypic association was found between NSCL/P and SNPs rs651852 and rs3733890. SNP rs3797546 did not show allelic association with NSCL/P; however, a higher proportion of NSCL/P patients carry the CC genotype compared with the TT+CT genotype (P=0.020, OR=2.10, 95% CI=1.11‐3.95). Conclusion Our study suggests that polymorphism rs3797546 in the BHMT gene may confer genetic risk of NSCL/P in a recessive manner.
基金supported by grants from the National Natural Scientific Foundation of China (81771028 and 317771593)Medical Health Science and Technology Project of Zhejiang (2021KY891)Medical Health Science and Technology Major Project of Hangzhou (Z20200046)。
文摘Development of the secondary palate displays molecular heterogeneity along the anterior-posterior axis;however, the underlying molecular mechanism remains largely unknown. MSX1 is an anteriorly expressed transcription repressor required for palate development. Here, we investigate the role of Msx1 in regional patterning of the secondary palate. The Wnt1-Cre-mediated expression of Msx1(Rosa Msx1^(Wnt1-Cre))throughout the palatal mesenchyme leads to cleft palate in mice, associated with aberrant cell proliferation and cell death. Osteogenic patterning of the hard palate in Rosa Msx1^(Wnt1-Cre)mice is severely impaired, as revealed by a marked reduction in palatine bone formation and decreased expression of the osteogenic regulator Sp7. Overexpression and knockout of Msx1 in mice show that the transcription repressor promotes the expression of the anterior palate-specific Alx1 but represses the expression of the medialposterior palate genes Barx1, Meox2, and Tbx22. Furthermore, Tbx22 constitutes a direct Msx1 target gene in the secondary palate, suggesting that Msx1 can directly repress the expression of medial-posterior specific genes. Finally, we determine that Sp7 is downstream of Tbx22 in palatal mesenchymal cells,suggesting that a Msx1/Tbx22/Sp7 axis participates in the regulation of palate development. Our findings unveil a novel role for Msx1 in regulating the anterior-posterior growth and patterning of the secondary palate.
基金We are grateful to all the patients and healthy controls for their generous participation in this study.This work was supported by grants from the National Natural Science Foundation of China(81771909,61701323,and 62171300)the Discipline Construction Foundation of Beijing Stomatological Hospital(19-09-24)+1 种基金the Capital Medical University Research and Development Fund(PYZ19081)Beijing Municipal Administration of Hospitals Clinical Medicine Development of Special Funding Support(XML201714).
文摘Cleft lip and/or palate(CLP)are the most common craniofacial malformations in humans.Speech problems often persist even after cleft repair,such that follow-up articulation training is usually required.However,the neural mechanism behind effective articulation training remains largely unknown.We used fMRI to investigate the differences in brain activation,functional connectivity,and effective connectivity across CLP patients with and without articulation training and matched normal participants.We found that training promoted task-related brain activation among the articulation-related brain networks,as well as the global attributes and nodal efficiency in the functional-connectivity-based graph of the network.Our results reveal the neural correlates of effective articulation training in CLP patients,and this could contribute to the future improvement of the post-repair articulation training program.
基金supported by National Natural Science Foundation of China (the research to identify susceptibility genes of nonsyndromic cleft lip and/or palates, 30600676)Program for New Century Excellent Talents of the Ministry of Education of China (NCET-07-0034)
文摘Objectives To identify the loci involved in nonsyndromic cleft lip with or without cleft palate (NSCL/P) in Northern Chinese people in Shenyang by using genomewide and interaction linkage scan.Methods Two multiplex families in Shenyang from North China were ascertained through probands with NSCL/P.Blood of every member was drawn for DNA extraction and analysis.Genotypes were available for 382 autosomal short tandem repeat (STR) markers from the ABI Prism Linkage Mapping Set version 2.5.Linkage between markers and NSCL/P was assessed by 2-point parametric LOD scores,multipoint heterogeneity parametric LOD scores (HLODs),and multipoint nonparametric linkage score (NPL).Results The initial scan suggested linkage on Chromosomes 1,2,and 15.In subsequent fine mapping,1q32-q42 showed a maximum multipoint LOD score of 1.9(empirical P=0.013) and an NPL score of 2.35 (empirical P=0.053).For 2p24-p25,the multipoint NPL increased to 2.94 (empirical P=0.007).2-locus interaction analysis obtained a maximum NPL score of 3.73 (P=0.00078) and a maximum LOD score of 3 for Chromosome 1 (at 221 cM) and Chromosome 2 (at 29 cM).Conclusion Both parametric and nonparametric linkage scores greatly increased over the initial linkage scores on 1q32-q42,suggesting a susceptibility locus in this region.Nonparametric linkage gave a strong evidence for a candidate region on chromosome 2p24-p25.The superiority of 2-locus linkage scores compared to single-locus scores gave additional evidence for linkage on 1q32-q42 and 2p24-p25,and suggested that certain genes in the two regions may contribute to NCSL/P risks with interaction.
基金Supported by The Japan Society for the Promotion of Science(JSPS) through KAKENHI grants 25670774 and 15K11004,awarded to Funato N
文摘Cleft palate, including complete or incomplete cleft palates, soft palate clefts, and submucosal cleft palates, is the most frequent congenital craniofacial anomaly in humans. Multifactorial conditions, including genetic and environmental factors, induce the formation of cleft palates. The process of palatogenesis is temporospatially regulated by transcription factors, growth factors, extracellular matrix proteins, and membranous molecules; a single ablation of these molecules can result in a cleft palate in vivo. Studies on knockout mice were reviewed in order to identify genetic errors that lead to cleft palates. In this review, we systematically describe these mutant mice and discuss the molecular mechanisms of palatogenesis.
基金supported by the National Natural Science Foundations of China(No.81273103)the Priority Academic Program Development of Jiangsu Higher Education Institutions(PAPD)
文摘In this study, we sought to determine the association between environmental factors and nonsyndromic cleft of the lip and/or palate (NSCLP) to understand the etiology of the disease. A total of 200 NSCLP cases and 327 controls were recruited at the Maternal and Child Health Hospital of Xuzhou City. We conducted face-to-face interviews with the mothers of both cases and controls. The factors increasing the risk of NSCLP were a positive family history [odds ratio (OR)=56.74], pesticide exposure (OR=8.90), and indoor decoration pollution (OR= 4.32). On the other hand, the factors decreasing the risk of NSCLP were a high education level (OR=0.22) and supplementation of folic acid (OR=0.23) and multivitamins (OR=0.16). Positive family history, pesticide exposure, and indoor decoration pollution are associated with the risk of NSCLP. In contrast, high education level and folic acid and multivitamin supplementation are protective factors against NSCLP.
基金funded by the National Natural Science Foundation of China(81970904 to MH,81970923 to ZB)Anhui Institute of Translational Medicine(ZHYX2020A005 to LS)+2 种基金the University Synergy Innovation Program of Anhui Province(GXXT-2020-064 to LS)Clinical medicine discipline construction project of Anhui Medical University(2021lcxk008 to LS)the National Key Research and Development Program(2016YFC1000505 to ZB)。
文摘Orofacial clefts(OFCs),particularly cleft lip with or without cleft palate(CL/P)and cleft palate only(CPO),are among the most common birth defects in humans(Mossey et al.,2009;Dixon et al.,2011).The birth prevalence rate of OFCs in China is reported to be as high as 1.66 per thousand newborns.