Improved primary surgical and dental treatment of clefts

The improved combination of surgical and dental teamwork in the primary treatment of clefts presented here is consistent with principles. In fact, this is a staged design for correction of classic clefts of the lip and palate that, based on biological principles, facilitates the continuance of the failed embryonic "migrations" toward a normal end point. Positioning of the alveolar segments, dissection of mucoperiosteum out of the cleft, and union of mucoperiosteum across the alveolar and anterior hard palate cleft make it possible to create a periosteal tunnel across the bony gap and set up a condition conducive to bone formation and eventual tooth eruption in the cleft area. Lip closure by adhesion reduces the tension of the primary lip closure and allows gentle molding until solidification of the arch occurs. Thus a complete cleft has been rendered an incomplete cleft. With a balanced, stabilized maxillary platform, the definitive lip and nose corrections can be carried to completion early (by 2 to 4 years of age). These planned actions bypass a persistent cleft, fistulas, raw areas, malposition of alveolar segments, and probably the necessity for later bone grafting. The only question not totally answered is the effect of this approach on final growth. Although most reports seem to indicate that growth has and will proceed within normal limits, another 10 years of careful follow-up is indicated and, in fact, is in progress.     

Interdental distraction osteogenesis and rapid orthodontic tooth movement: a novel approach to approximate a wide alveolar cleft or bony defect

The closure of a wide alveolar cleft and fistula in cleft patients and the reconstruction of a maxillary dentoalveolar defect in traumatic patients are challenging for both orthodontists and surgeons. This is due to the difficulty in achieving complete closure by using local attached gingiva and the great volume of bone required for the graft. In this article, the authors propose using interdental distraction osteogenesis to create a segment of new alveolar bone and attached gingiva for the complete approximation of a wide alveolar cleft/fistula and the reconstruction of a maxillary dentoalveolar defect. They performed this procedure on one patient with a traumatic maxillary dentoalveolar defect and 10 patients with unilateral or bilateral cleft lips and palates who had varied dentoalveolar clefts/fistulas. Interdental and maxillary osteotomies were performed on one side of the dental arch by the cleft or defect. After a latency period of 3 days, the osteotomized distal segment of the dental arch was then distracted and transported toward the cleft or defect by using a toothborne intraoral distraction device. The alveoli and gingivae on both ends of the cleft or defect were approximated after distraction osteogenesis. The need for extensive alveolar bone grafting was eliminated. A segment of new edentulous alveolus and attached gingiva was created interdentally at a site distant to the cleft or defect. In the cleft patients, teeth were moved orthodontically into the regenerate (newly formed alveolar bone) dental crowding 1 week after distraction. The orthodontic tooth movement was rapidly completed in 3 months, and the edentulous space was eliminated. Interdental distraction osteogenesis minimizes an alveolar cleft/fistula and helps reconstruct a maxillary dentoalveolar defect by approximating the native alveoli and gingivae; it also creates new alveolar bone and gingiva for rapid orthodontic tooth movement.     

3-D model analysis of the maxilla of infants with lip-jaw-palate clefts]

For the investigation of three-dimensional morphological changes in the maxilla of children with cleft lip and palate, the use of two-dimensional test analysis is inadequate. Since no standardised three-dimensional method has so far been available, a three-dimensional digital, computer-aided procedure was developed to visualize and metrically analyse the growth of the edentulous maxilla of infants with cleft lip and palate. Chronologically consecutive casts of the maxillas (obtained at the ages of one week, and three, six and twelve months) of five children with complete unilateral CLP were measured optically with the instrument Micromeasure 70. Following digitation, the casts were reconstructed in the computer, aligned and superimposed using the Orthosurf program. The distances between the surfaces were then measured; in addition, the surfaces were segmented perpendicular to the alveolar crest at reference points C1, C1', C2, C2' and I. The volumes of the resulting segments were determined and compare with one another. Specially designed software automated the following steps: 1. identification of reference points; 2. alignment of the cloud of points in a system of coordinates, and 3. identification of the alveolar crest. Our initial results show that (1) the new method enables visualization of the extent and direction of morphological changes of the mucosal surface, and (2) reproducible quantification of these changes via the determination of changes in the volume of defined alveolar segments. The three-dimensional analysis presented here permits a comprehensive three-dimensional measurement of the models of the edentulous maxilla of infants with cleft lip and palate.     

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.     

Reconstruction of late craniofacial deformities after irradiation of the head and face during childhood

Little is known about the results of surgical management of late craniofacial abnormalities arising after irradiation of the head and face for treatment of childhood cancers. The clinical records of 10 children (4 males and 6 females) who received 4500 to 6500 rads (mean 5160 rads) of craniofacial radiation between birth and 8 years of age (mean 5 years) and who subsequently had reconstructive surgery were reviewed. Six of the 10 patients received orbital radiation, 3 received maxillary-midfacial radiation, and 1 patient underwent radiation to the frontal bone. Histologic tumor types included retinoblastoma (4), rhabdomyosarcoma (3), Ewing's sarcoma (2), and neurofibrosarcoma (1). In addition to radiation, 7 of the 10 patients underwent surgical resection or debulking of their tumors and 6 received adjuvant chemotherapy. All patients presented from 4 to 20 years after treatment (mean 10 years) with varying, but severe degrees of soft-tissue and bony hypoplasia of the irradiated territories. Onlay bone grafting with soft-tissue reconstruction by a combination of local pedicle flaps and dermal-fat grafts was initially performed in 9 patients, and an occipitoparietal bone-flap switch procedure was done in 1 patient. Late follow-up ranged from 11 months to 7.5 years (mean 34 months). A total of 8 secondary procedures were necessary in 4 of the 10 patients (40 percent). Of these 4 patients, major revisions were performed in 3 and minor adjustments in 1. In addition, 2 patients in whom secondary procedures had not been done would benefit from further reconstruction. Therapy for cancer of the head and face during childhood has profound and ongoing effects on the growth of soft tissue and bone.(ABSTRACT TRUNCATED AT 250 WORDS)     

Regeneration in surgically produced cleft palate in rabbits. A microscopical study

In order to study the effects of surgical procedures on the regeneration process in cleft palate, an artificial cleft was made in 4-weeks old female New Zealand rabbits. The 47 animals were divided into 5 groups: group 1: controls, group 2: cleft made in the bony palate, using a dental burr (phi 3 mm), group 3: cleft as in group 2, oral mucosa stitched, group 4: cleft made without perforating the nasal mucosa; oral mucosa stitched ("Veau"), group 5: cleft made as in group 4; before stitching the oral mucosa pieces of autologous rib bone were introduced into the cleft ("Schuchardt"). At the ages of 4, 5, 6, 8, 12, 18 and 24 weeks, one or two animals per group were sacrificed. The palatal region was microscopically studied using 10 mu paraffin sections stained according to Herovici. It was found that it is difficult to make a reproducible cleft on the histological level. A large interindividual variation in local damage due to the surgical procedure was observed; this might contribute to the variation in growth results of the facial skeleton reported in literature. Signs of excessive bone resorption were found. The presence of bone in places where sutural tissue should be present, observed in some growing animals, will contribute to reduction of palatal width, medial collapse of the palate and asymmetry of the facial skeleton. There appeared to be no striking differences between the three methods of repair, used in group 3, 4 and 5 respectively.     

Wnt signalling in oral and maxillofacial diseases

Wnts include more than 19 types of secreted glycoproteins that are involved in a wide range of pathological processes in oral and maxillofacial diseases. The transmission of Wnt signalling from the extracellular matrix into the nucleus includes canonical pathways and noncanonical pathways, which play an important role in tooth development, alveolar bone regeneration, and related diseases. In recent years, with the in-depth study of Wnt signalling in oral and maxillofacial-related diseases, many new conclusions and perspectives have been reached, and there are also some controversies. This article aims to summarise the roles of Wnt signalling in various oral diseases, including periodontitis, dental pulp disease, jaw disease, cleft palate, and abnormal tooth development, to provide researchers with a better and more comprehensive understanding of Wnts in oral and maxillofacial diseases.     

Results of surgical lengthening of the short nose in the bilateral cleft lip patient

Some children with bilateral cleft lips do not grow a long enough nose and require surgical lengthening of the nose. We review our 12-year experience with a one-stage slide operation to achieve this. Seven males and 5 females had this operation at ages 7 through 13 years, and we have followed them from 6 months to 12 years. The results, and the subsequent growth effects are described. In general, good long-term improvement has been achieved and the external scars have not proved to be a major drawback. Subsequent procedures upon the columella, alae, and upper lip are often required to establish an unobtrusive nasal appearance.     

A new transplant bone for maxillary alveolar cleft

An innovative technique with distraction osteogenesis has been developed in our research group to explore autogenous bone transplantation into craniofacial bone defects. This technique was designed to investigate bone-marrow transplantion using a chondroid or fibula bone graft into simulated alveolar bone defects in mice in terms of the osteogenic process and activity. As an experimental model of maxillary alveolar bone cleft available for testing bone-inductive materials, a critical-size defect was formed in the pre-maxillary bone of male mice using a surgical trephine bur with a low-speed dental engine. Distraction osteogenesis was performed using an external fixation device. The osteotomy site was occupied by an external callus consisting of hyaline cartilage with a large quantity of chondroid bone. Moreover, bone remodelling with new bone formation was demonstrated 30 days after the transplantation. Bone adhesion was better in chondroid bone grafting than in fibula bone grafting. The present findings are the first to demonstrate the potential of chondroid bone transplantation as a new therapeutic system of bone grafting, suitable for bone substitutes in craniofacial bone defects.     

Radical correction of secondary nasal deformity in unilateral cleft lip patients presenting late

It is universally acknowledged that correction of a cleft lip nasal deformity continues to be a difficult problem. In developing countries, it is common for patients with cleft lip deformities to present in their early or late teens for correction of severe secondary lip and nasal deformities retained after the initial repairs were carried out in infancy or early childhood. Such patients have never had the benefit of primary nasal correction, orthodontic management, or alveolar bone grafting at an appropriate age. Along with a severe nasal deformity, they present with alveolar arch malalignments and anterior fistulae. In the study presented here, a strategy involving a complete single-stage correction of the nasal and secondary lip deformity was used.In this study, 26 patients (nine male and 17 female) ranging in age from 13 to 24 years presented for the first time between June of 1996 and December of 1999 with unilateral cleft lip nasal deformity. Eight patients had an anterior fistula (diameter, 2 to 4 mm) and 12 patients had a secondary lip deformity. An external rhinoplasty approach was used for all patients. The corrective procedures carried out in a single stage in these patients included lip revision; columellar lengthening; repair of anterior fistula; augmentation along the pyriform margin, nasal floor, and alveolus by bone grafts; submucous resection of the nasal septum; repositioning of lower lateral cartilages; fixation of the alar cartilage complex to the septum and the upper lateral cartilages; augmentation of nasal dorsum by bone graft; and alar base wedge resections. Medial and lateral nasal osteotomies were performed only if absolutely indicated. The median follow-up period was 11 months, although it ranged from 5 to 25 months. Overall results have been extremely pleasing, satisfactory, and stable.In this age group (13 years of age or older), it is not fruitful to use a technique for nasal correction that corrects only one facet of the deformity, because no result of nasal correction can be satisfactory until septal deviations and maxillary deficiencies are addressed along with any alar repositioning. The results of complete remodeling of the nasal pyramid are also stable in these patients because the patients' growth was nearly complete, and all the deformities could be corrected at the same time, leaving no active deforming vector. These results would indicate that aesthetically good results are achievable even if no primary nasal correction or orthodontic management had been previously attempted.     

The role of estrogen receptor-beta, in the early age-related bone gain and later age-related bone loss in female mice

The molecular and cellular mechanism of estrogen action in skeletal tissue remains unclear. The purpose of this study was to understand the role of estrogen receptor-beta, (ERbeta) on cortical and cancellous bone during growth and aging by comparing the bone phenotype of 6- and 13-month-old female mice with or without ERbeta. Groups of 11-14 wild-type (WT) controls and ERbeta knockout (BERKO) female mice were necropsied at 6 and 13 months of age. At both ages, BERKO mice did not differ significantly from WT controls in uterine weight and uterine epithelial thickness, indicating that ERbeta does not regulate the growth of uterine tissue. Femoral length increased significantly by 5.5% at 6 months of age in BERKO mice compared with WT controls. At 6 months of age, peripheral quantitative computerized tomography (pQCT) analysis of the distal femoral metaphysis (DFM) and femoral shafts showed that BERKO mice had significantly higher cortical bone content and periosteal circumference as compared with WT controls at both sites. In contrast to the findings in cortical bone, at 6 months of age, there was no difference between BERKO and WT mice in trabecular density, trabecular bone volume (TBV), or formation and resorption indices at the DFM. In 13-month-old WT mice, TBV (-41%), trabecular density (-27%) and cortical thickness decreased significantly. while marrow cavity and endocortical circumference increased significantly compared with 6-month-old WT mice. These age-related decreases in cancellous and endocortical bone did not occur in BERKO mice. At 13 months of age, BERKO mice had significantly higher total, trabecular and cortical bone, while having significantly lower bone resorption, bone formation and bone turnover in DFM compared with WT mice. These results indicate that deleting ERbeta protected against age-related bone loss in both the cancellous and endocortical compartments by decreasing bone resorption and bone turnover in aged female mice. These data demonstrate that in female mice, ERbeta plays a role in inhibiting periosteal bone formation, longitudinal and radial bone growth during the growth period, while it plays a role in stimulating bone resorption, bone turnover and bone loss on cancellous and endocortical bone surfaces during the aging process.     

Early palatal changes in complete and incomplete cleft lip and/or palate.

Early palatal development in various complete and incomplete forms of cleft lip and/or palate (CLP) was studied from birth to 3 months of age by means of dental casts. Palatal morphology (shape) and dimensions--based on reproducible reference points--were determined in a group of 128 CLP children and 68 normal children who served as controls. Substantial normal palatal growth during the first 3 months of life was observed. Round arch forms changed into oval arch forms. Growth mainly takes place in the sagittal direction (+4 mm) (transverse: +1 mm). Palates of CLP children differed significantly dependent on the type of cleft and whether the cleft was complete or incomplete. Cleft lip and alveolus children and bilateral cleft lip and palate children had more elongated palatal arches, whereas unilateral cleft lip and palate children and cleft palate children had wider palatal arches than the control group. Incomplete clefts differed from the control group in the same direction as their complete cleft forms, though less distinctly. Preoperative orthopedics used in CLP patients does not stimulate growth. On the contrary, it even restricts growth.     

Dental replacement resorption after bone grafting to the alveolar cleft

In a review of 100 consecutively performed bone grafts to the alveolar cleft, replacement resorption was found in 7 teeth adjacent to the cleft. Damage to the periodontal tissues during surgery is considered to be the main cause of this complication: granulation tissue from the bone graft may have some influence. Treatment of the affected teeth eventually includes extraction or surgical removal. To minimize the risk for this complication, we suggest that bone grafting should be done when the canine (or lateral incisor) is in an early stage of eruption and that orthodontic uprighting of the medial incisor should be done after surgery.     

New biomaterials and methods for craniofacial bone defect: chondroid bone grafts in maxillary alveolar clefts

The purpose of this study was to evaluate autogenous osteogenic marrow within chondroid bone grafts in simulated alveolar defects of mice in order to determine the ability of the graft material to effectively close the cleft from an osseous standpoint and to observe the effect of the grafting procedure. Critical-sized defects were made in the premaxillary bones of male mice using a surgical trephine and a low-speed dental engine as a model of the maxillary alveolar cleft for testing bone-inductive agents. Premaxillary trephine defects were not repaired by fibrous tissue or bone formation 30 days after operation. This nonhealing bony wound of the premaxilla in mice may be useful as a model for studying the effect of bone-inductive agents on the healing of alveolar clefts. Distraction osteogenesis is a recently advanced principle of bone lengthening in which a long bone separated by osteotomy is subjected to slow progressive distraction using an external fixation device. The osteotomy site was surrounded by an external callus consisting of hyaline cartilage. The callus contained a lot of chondroid bone. The transplant bone within chondroid bone was characterized by bone formation and remodeling 30 days after transplantation. Throughout the experiment, our findings demonstrated, for the first time, that the transplant bone that contains chondroid bone may be used clinically in relation to craniofacial bone defects to improve the treatment of bone grafts.     

Iliac crest bone graft harvesting techniques: a comparison

This study was undertaken to compare the morbidity of traditional iliac bone graft harvesting techniques for grafting alveolar clefts to minimally invasive techniques. Fifty-five age-matched patients, ages 6.5 to 16 years (mean, 11.2 years), 22 girls and 33 boys, were divided into three groups. The traditional bone window open harvesting technique served as the control group. Two different minimally invasive techniques, one that used a bone grinder and another that used a trephine, for bone harvesting were compared with the control. Both invasive techniques were statistically superior, p < 0.05, in terms of total time pain medication was necessary (mean of 12.0 hours for bone grinder, 17.6 hours for trephine, 26.0 hours for control), operative time for bone harvest (mean of 11 minutes for bone grinder and trephine, 20 minute for control), and mean incision length (2 cm for bone grinder and trephine, 5 cm for control). Patients exposed to the minimally invasive techniques had fewer complications, a trend toward earlier ambulation, and shorter hospital stays when compared with the bone grinder technique. The patients exposed to the bone grinder demonstrated earlier ambulation and fewer requirements for analgesia when compared with the trephine technique, although these results did not reach statistical significance. The trephine technique was useful when maxillary osteotomies were combined with alveolar bone grafting, because it provided structural bone grafts and cancellous bone. On the basis of these findings, the bone grinder is the preferred technique for harvesting alveolar bone grafts when no structural support is required. These authors no longer use the traditional bone window open harvesting technique.     

Precocious puberty secondary to cranial irradiation for tumors distant from the hypothalamo-pituitary area

This retrospective study is the first report of the occurrence of central precocious puberty in 6 children having received cranial irradiation. Pubertal development took place at a mean age of 7 5/12 years (6 10/12-7 10/12 years in 5 girls and at 9 years in 1 boy). They had received 2,400-4,500 rad at a mean age of 5 2/12 years. In addition, 5 children had GH deficiency so that their growth spurt was blunted and 3 of them were left with an extremely short stature. This condition would require a therapeutic approach combining the use of an LHRH analogue and hGH therapy when necessary in order to protect from too rapidly progressing bone maturation.     

OSFE植骨与不植骨种植修复的临床效果对比研究

目的:比较上颌窦挤压内提升(OSFE)植骨与不植骨种植修复的临床效果。方法:选择上颌后牙区种植修复的35例患者,其剩余牙槽嵴高度(RBH)为4~8 mm,共植入43颗种植体。A组16例患者为植骨组,20个种植位点,牙槽骨可用骨高度平均(5.87±1.19)mm,植入人工骨粉后植入种植体;B组19例患者为不植骨组,23个种植位点,缺牙区牙槽骨可用骨高度平均(5.67±1.10)mm,上颌窦提升后直接植入种植体。6个月后行二期手术完成修复。采用临床检查、X线检查及视觉模拟评分法(visual analogue scale,VAS)进行效果评价。结果:两组病例的牙槽嵴高度差异比较无统计学意义。在平均约36.7个月的随访期内,A组种植体的存留率为100%(20/20),B组中有1枚种植体因咬合力过大及口腔卫生较差脱落,种植体的存留率为95.6%(22/23),两组病例的存留率比较无统计学差异。两组患者的VAS值比较亦相当。所有种植体骨结合良好,种植体周围软组织无炎症,种植义齿咀嚼功能良好。结论:在严格控制适应症、准确掌握种植技巧的前提下,RBH在4~8 mm之间的病例无需额外植入骨代替材料即可取得理想的修复效果,简化了手术的操作,减少了手术的风险和创伤,节省了手术的时间和费用,易被患者接受。     

Metabolomics Reveals Dynamic Metabolic Changes Associated with Age in Early Childhood

Objectives

A detailed understanding of the metabolic processes governing rapid growth in early life is still lacking. The aim of this study was to investigate the age-related metabolic changes in healthy children throughout early childhood.

Methods

Healthy children from a birth cohort were enrolled in this study from birth through 4 years of age. Urinary metabolites were assessed at 6 months, and 1, 2, 3, and 4 yr of age by using ¹H-nuclear magnetic resonance (NMR) spectroscopy coupled with multivariate statistical analysis including principal components analysis (PCA) and partial least-squares discriminant analysis (PLS-DA). Metabolic pathway analysis was performed using the MetPA web tool.

Results

A total of 105 urine samples from 30 healthy children were collected and analyzed. Metabolites contributing to the discrimination between age groups were identified by using supervised PLS-DA (Q² = 0.60; R² = 0.66). A significantly higher urinary trimethylamine N-oxide (TMAO) and betaine level was found in children aged 6 months. Urinary glycine and glutamine levels declined significantly after 6 months of age and there was a concomitant compensatory increase in urinary creatine and creatinine. Metabolic pathway analysis using MetPA revealed similar nitrogen metabolism associated energy production across all ages assessed. Pathways associated with amino acid metabolism were significantly different between infants aged 6 months and 1 year, whereas pathways associated with carbohydrate metabolism were significantly different between children at ages 2 and 3 years.

Conclusions

Urine metabolomics ideally represents dynamic metabolic changes across age. Urinary metabolic profiles change significantly within the first year of life, which can potentially provide crucial information about infant nutrition and growth.     

IL10 deficiency promotes alveolar enlargement and lymphoid dysmorphogenesis in the aged murine lung

The connection between aging‐related immune dysfunction and the lung manifestations of aging is poorly understood. A detailed characterization of the aging IL10‐deficient murine lung, a model of accelerated aging and frailty, reconciles features of both immunosenescence and lung aging in a coherent model. Airspace enlargement developed in the middle‐aged (12 months old) and aged (20–22 months old) IL10‐deficient lung punctuated by an expansion of macrophages and alveolar cell apoptosis. Compared to wild‐type (WT) controls, the IL10‐deficient lungs from young (4‐month‐old) mice showed increased oxidative stress which was enhanced in both genotypes by aging. Active caspase 3 staining was increased in the alveolar epithelial cells of aged WT and mutant lungs but was greater in the IL10‐deficient milieu. Lung macrophages were increased in the aged IL10‐deficient lungs with exuberant expression of MMP12. IL10 treatment of naïve and M2‐polarized bone marrow‐derived WT macrophages reduced MMP12 expression. Conditioned media studies demonstrated the secretome of aged mutant macrophages harbors reduced AECII prosurvival factors, specifically keratinocyte growth factor (KGF) and hepatocyte growth factor (HGF), promotes cell death, and reduces survival of primary alveolar epithelial cells. Compared to WT controls, aged IL10‐deficient mice have increased parenchymal lymphoid collections comprised of a reduced number of apoptotic cells and B cells. We establish that IL10 is a key modulator of airspace homeostasis and lymphoid morphogenesis in the aging lung enabling macrophage‐mediated alveolar epithelial cell survival and B‐cell survival within tertiary lymphoid structures.     

Cognitive and adaptive functioning of children with infantile Pompe disease treated with enzyme replacement therapy: long-term follow-up

This report documents the long-term cognitive and adaptive outcome of children with infantile Pompe disease. Specifically, we describe the cognitive and adaptive functioning of seven children with classic infantile Pompe disease and two children with atypical infantile Pompe disease who have received enzyme replacement therapy (Myozyme?) for an average of 6 years, 8 months and 4 years, 1. 5 months, respectively. Multiple assessments of cognitive functioning were completed over time by means of individualized intelligence (IQ) testing. Adaptive functioning was measured by means of the Vineland Adaptive Behavior Scales-Second Edition (VABS-II). Consistent with our earlier findings regarding infants treated with ERT, children with classic infantile Pompe disease (ages 4 years, 11 months to 8 years, 11 months) were functioning at the lower end of the average range in comparison to their typical peers on their most recent IQ test. There was no evidence of a decline in their cognitive abilities over time. In contrast, the two children with atypical infantile Pompe disease (ages 5 years, 4 months and 5 years, 11 months) obtained above average IQ scores and demonstrated significant gains in IQ over time. For all children where adaptive functioning was assessed, their overall level of adaptive functioning on the VABS-II was lower than their Full Scale IQ scores on cognitive testing. Motor function appears to be an important factor impacting on reduced adaptive behavior. The implication of these findings on our understanding of a possible relationship between CNS status in children with Pompe and their adaptive and cognitive function is discussed.