SEARCH · Search PubMed

Results for “Osteogenesis”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

SourceResearch connectionFrom yearThrough year

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 775 records · Page 43Linked to original sources

PubMed2006

Classical osteogenesis imperfecta and allegations of nonaccidental injury.

We report 12 patients with osteogenesis imperfecta initially diagnosed with nonaccidental injuries. As a result, formal hearings, care proceedings, and criminal proceedings ensued and seven of the children were removed from their parents. The features suggestive of osteogenesis imperfecta at the time of the initial investigation included a positive family history in six patients, scleral discoloration in nine, abnormally large anterior fontanels in four, excessive numbers of wormian bones in four, abnormal bone texture in two, and abnormal biochemical findings in three. There were discrepancies between the fractures and other clinical evidence of inflicted trauma. The seven patients removed from their homes eventually were returned. Five patients remained at home. Information was available on the subsequent history of the patients for an average of 4.8 years. Although seven patients have had additional fractures, there have been no additional allegations of nonaccidental injury. When investigating children with unexplained fractures, it is important to review carefully their clinical history, family history, physical examination findings, and radiographic findings. Misdiagnosing patients with nonaccidental injuries causes substantial harm to the family and particularly to the child.

Child Abuse↗

PubMed2007

Distraction osteogenesis promotes angiogenesis in the surrounding muscles.

Distraction osteogenesis is used to treat atrophic nonunion and focal osteomyelitis. It enhances blood vessel formation in the distracted callus and in the surrounding soft tissues. Long-term angiogenesis, however, is not well described. We hypothesized newly formed blood vessels persist in the surrounding muscles until the late consolidation period. We performed unilateral tibial lengthening in eight adult Beagles. Seven days after tibial osteotomy, we began lengthening for 30 days, following which consolidation was allowed to proceed for another 60 days. We took bilateral microangiograms of the bilateral tibialis anterior, extensor digitorum longus, and gastrocnemius muscles. We determined the blood vessel volume density and the longitudinal and transverse microangiographic scores. The number of blood vessels in specified diameter ranges was determined histologically. The blood vessel volume density of the distracted limb was higher in all three muscles. The longitudinal microangiographic score was higher for the tibialis anterior and extensor digitorum longus muscles on the distracted side, whereas the transverse microangiographic score was not higher. Histologically, the number of blood vessels less than 100 mum in diameter on the distracted side was higher in the tibialis anterior and extensor digitorum longus muscles. Our data suggest distraction osteogenesis activates angiogenesis and maintains increased vascularity until the late consolidation period.

Angiography↗

PubMed2003

Perthes' disease associated with osteogenesis imperfecta.

Primary hip disorders, such as congenital hip dislocation, have rarely been reported in children with osteogenesis impefecta (OI). Protrusio acetabuli and coxa vara secondary to severe osteopenia and recurrent fractures are common. Perthes' disease in association with osteogenesis imperfecta has not been reported previously. Epiphyseal and growth plate changes may occur in the more severe forms of OI. There was no evidence of growth plate disruption or severe osteopenia in our case. Approximately two-thirds of OI patients have a tendency to bleed easily but the association of clotting and bleeding disorders with Perthes' disease has yet to be clarified.

Child↗

PubMed2006

Surgery versus surgery plus pamidronate in the management of osteogenesis imperfecta patients: a comparative study.

The aim of this study was to evaluate the efficacy of pamidronate in the management of osteogenesis imperfecta patients. This study was carried out in two groups. The first was treated only surgically whereas the second was treated by a combined approach, medical and surgical. Forty patients, divided into two groups, were surgically treated in order to correct bony deformities secondary to osteogenesis imperfecta. Group 1: twenty patients were operated at an average age of 6.5 years. Nine were type I, five type III and six type IV. Group 2: this group consisted of 20 patients to whom intermittent intravenous pamidronate were given at regular intervals for an average of 2 years postoperatively. The average age at surgery was 8.5 years. Four patients were type I, six type III, eight type IV, one type V and the remaining one type VII. The results were assessed according to a scoring system suggested and used by the authors since 1999. Group 1: we had three good, nine fair and eight poor results. Group 2: we had 11 excellent, four good and five fair results. The Bone mineral dens (BMD) increased by an average of 35.2% (22.7-112%), and the rate of refracture decreased. Best results in the management of patients can be obtained through the combined approach (surgical and medical treatment). We now advise preoperative and postoperative pamidronate for these patients.

Adolescent↗

PubMedDate not supplied

Efficacy of oral alendronate in children with osteogenesis imperfecta.

The purpose of this study was to investigate the efficacy of oral alendronate for children with osteogenesis imperfecta. Nine boys and seven girls of average age 9.5 years were given oral alendronate for an average of 4 years. Fracture frequency decreased, and in more than half of the patients the ambulatory/mobility status improved. Bone mineral density improved significantly, and restoration of collapsed vertebral bodies was observed. Urinary excretion of calcium and a bone resorption marker decreased significantly. Iliac crest physis biopsy showed an expanded primary spongiosa area with numerous multinucleated cells. This study reveals that oral alendronate caused biochemical, radiologic, and histologic changes along with clinical improvement. Oral alendronate treatment, which is convenient for the school-age group, was found to be a tolerable and efficacious treatment for children with moderate or severe osteogenesis imperfecta.

Administration, Oral↗

PubMed2005

Effects of growth hormone transgene expression on vertebrae in a mouse model of osteogenesis imperfecta.

STUDY DESIGN: A human growth hormone transgene was bred into mice of the Cola2oim (oim) lineage. Caudal (tail) vertebrae from male and female mice at early skeletal maturity and at midlife were evaluated for physical and biomechanical properties. OBJECTIVE: To test whether constant low-level growth hormone expression within the marrow could improve structural or material properties of caudal vertebrae in oim mice. SUMMARY OF BACKGROUND DATA: A spontaneous genetic defect in a type I procollagen gene created the oim mouse model for osteogenesis imperfecta. Bones of heterozygous oim mice are biomechanically inferior to wild-type controls. Bone marrow expression of human growth hormone was demonstrated previously to enhance bone deposition and structural biomechanical properties in caudal vertebrae of transgenic mice. METHODS: Compression tests were performed individually on three caudal vertebrae (Ca4, 5, and 6) from each mouse to determine their structural biomechanical properties. Volumetric and mineral content measurements were also made. In a subset of vertebrae, the ashing measurements were confirmed and extended by peripheral quantitative tomographic scanning, which also allowed calculation of the failure stress. RESULTS: Heterozygous oim mouse vertebrae had structural and material properties inferior to the wild-type controls. Growth hormone transgene expression increased the size and mineral content of the vertebrae from mutant mice, and increased biomechanical structural values for maximum load and energy to failure. Failure stress was not improved. CONCLUSIONS: Growth hormone stimulation of size and bone mineral content of osteogenesis imperfecta mutant mouse caudal vertebrae contributed to their improved performance in axial compression. There was no evidence for improved material properties, however.

Animals↗

PubMed2005

De novo osteogenesis from human ligamentum flavum by adenovirus-mediated bone morphogenetic protein-2 gene transfer.

STUDY DESIGN: In vitro and in vivo experiment using degenerated human ligamentum flavum (LF) and Type 5 adenovirus construct with bone morphogenetic protein-2 (BMP-2) cDNA. OBJECTIVES: To demonstrate in vitro and in vivo osteogenic effect of BMP-2 gene transfer to human LF and to propose genetically modified LF as a substitute for autogenous bone graft in spinal fusion. SUMMARY OF BACKGROUND DATA: Spinal fusion is still considered to be an important option for treating various spinal disorders. To induce solid spinal fusion, osteoinductive and/or osteoconductive agents have been widely adopted. Autogenous LF, however, has never been seriously considered as a carrier for ex vivo osteoinductive gene therapy for spinal fusion. METHODS: In vitro experiment: Degenerated human LF was harvested and cultured. Type 5 adenovirus lacZ (Ad/lacZ) and BMP-2 construct (Ad/BMP-2) were produced. LF cell cultures were then exposed to Ad/BMP-2. Expressions of osteocalcin and BMP-2 mRNA were analyzed by reverse transcriptase-polymerase chain reaction (RT-PCR). Western blot analysis was performed to detect osteocalcin protein. Alkaline phosphatase and von Kossa stains were used to detect osteogenic markers and bone nodule formation, respectively. In vivo experiment: Human LF tissues treated with Ad/lacZ, Ad/BMP-2, and saline were implanted into the subcutaneous tissue of nude mice. After 4 weeks, nude mice were radiographed and killed. Implanted LF tissues were harvested and histologically stained. RESULTS: LF cell cultures with Ad/BMP-2 revealed strong expression of BMP-2 and osteocalcin mRNA in RT-PCR and osteocalcin protein in western blot analysis. LF cell culture with saline showed baseline expression of BMP-2, osteocalcin mRNA, and osteocalcin protein, respectively. Furthermore, LF cell culture with Ad/BMP-2 demonstrated the expression of alkaline phosphatase and bone nodule formation in the aforementioned histochemical stain. LF tissues with Ad/BMP-2 revealed de novo osteogenesis in nude mice, whereas LF with Ad/lacZ or saline showed only remaining LF tissue without sign of bone formation. CONCLUSION: Human LF cells transduced with Ad/BMP-2 exhibited the expression of osteogenic phenotype and bone nodule formation. Additionally, genetically modified human LF with BMP-2 cDNA clearly demonstrated de novo osteogenesis, which supports the concept that biologically modified LF can be a substitute for autogenous bone graft in spinal fusion surgery.

Adenoviridae↗

PubMed2006

All pedicle screw fixation technique in correcting severe kyphoscoliosis in an osteogenesis imperfecta patient: a case report.

Spinal deformity in patients with osteogenesis imperfecta demonstrates a high prevalence. The surgical treatment of this problem had numerous difficulties, which included breakage of bone, dislodgement of implants, and late loss of correction. We reported the correction of severe kyphoscoliosis in a patient with osteogenesis imperfecta using 3-rod all pedicle screw fixation technique. In this case, the 2 main goals of spinal operation, stabilization and correction of spinal curvatures, were achieved. The Cobb angles of scoliosis and thoracic kyphosis were corrected from 110 degrees to 68 degrees and from 107 degrees to 39 degrees, respectively. One and a half years after the operation, spinal radiographs showed no loss of correction, either on coronal or sagittal planes. The predicted forced vital capacity, predicted forced expiratory volume in 1 second and vital capacity of the lung of the patient had improved 2-fold. The usage of pedicle screw, with its conical core and cylindrical thread design, and 3-rod technique in fixation, together with cyclic intravenous bisphosphonate administration and halo-gravity traction preoperatively, contributed to the success in this case.

Adolescent↗

PubMed2003

Bone graft augmentation and dental implant treatment in a patient with osteogenesis imperfecta: review of the literature with a case report.

This case report with a review of the literature describes a patient with osteogenesis imperfecta who was treated with dental implants. To our knowledge, only one case report has been published in the English dental literature describing implant treatment in the osteogenesis imperfecta patient. The uncertainty in treatment confronted by all clinicians is the density of bone, which is essential for implant survival.

Adult↗

PubMed2003

Volumetric change of the medial pterygoid following distraction osteogenesis of the mandible: an example of the associated soft-tissue changes.

Mandibular distraction osteogenesis lengthens not only the affected skeleton but also the associated muscles of mastication. The purpose of this study was to determine medial pterygoid volume before and after distraction by using computed tomography. Using computed tomographic scans, the volume of the medial pterygoid muscle was determined before and after mandibular distraction in six pediatric patients. In four unilateral distraction patients (average age, 65 months), the average increase of the medial pterygoid muscle on the distracted side of the mandible was 29 percent, and on the contralateral nondistracted side, 10 percent. The average increase in medial pterygoid muscle volume in two bilateral distraction patients (each aged 8 months) was 75 percent. Results of this study demonstrate that distraction osteogenesis of the human mandible not only lengthens deficient bone, but it also increases the volume of the attached musculature.

Child↗

PubMed2004

Comparison of canine mandibular bone regeneration by distraction osteogenesis versus acute resection and rigid external fixation.

The present study was performed (1) to explore the mechanism of skeletal healing following distraction osteogenesis of the mandible and to evaluate whether the same process is involved following acute mandibular resection and rigid external fixation, and (2) to examine the role of the periosteum in skeletal healing in both models. The study was performed using 16 mongrel dogs divided into two equal groups. In the first group, distraction of 20 mm was performed at a rate of 1 mm/day. In the second group, bone resection of 20 mm was performed, followed by rigid external fixation. The buccal periosteum was stripped in four dogs from each group, and the periosteum was left intact in the remaining four dogs. Dogs were euthanized after a survival period of either 2 or 3 months, and the new bone regenerate was evaluated. Analysis consisted of three-dimensional computed tomography scanning, histometric analysis, and immunostaining. Analysis of bone mineral content in the residual gap was conducted. Bone mineral content was increased in 3- versus 2-month survival for all groups (p < 0.05). The distracted groups had greater bone mineral content than their acutely resected counterparts, with the difference achieving statistical significance by 3-month survival (p < 0.05). Although periosteal preservation resulted in increased bone mineral content over time for all groups (p = 0.044), periosteal preservation had no significant effect on bone mineral content in the distracted groups. After periosteal stripping, however, bone mineral content was significantly increased in dogs that underwent distraction rather than acute resection and rigid external fixation (p = 0.022). Regarding histometric analysis, analysis of fibrous tissue content in the bone regenerate demonstrated that by 3 months the distracted groups had significantly less fibrous tissue in the new bone regenerate than did the acutely resected groups (p < 0.001). Regarding immunostaining, diffuse localization of transforming growth factor-beta1 was observed in all groups at 2 months, returning to nearly baseline levels by 3 months. These data demonstrate that significant bone formation in a segmental gap can be achieved after acute mandibular resection and rigid external fixation if the periosteum is preserved. However, after periosteal injury or stripping, significant bone formation can only be achieved by distraction osteogenesis. In both processes, bone formation is preceded by up-regulation of transforming growth factor-beta1.

Animals↗

PubMed2006

Simultaneous maxillo-mandibular distraction osteogenesis in hemifacial microsomia: a new technique using two distractors.

BACKGROUND: The goal of this study was to prospectively evaluate the use of two distractors for a simultaneous maxillo-mandibular distraction osteogenesis without the use of intermaxillary fixation in the restorative treatment of hemifacial microsomia. METHODS: The authors analyzed the clinical and radiological data of five patients with type I hemifacial microsomia (one patient), type IIa hemifacial microsomia (two patients), and Goldenhar syndrome (two patients). Follow-up examinations were performed at 1, 3, 6, and 12 months. RESULTS: All the patients had satisfactory correction of the facial asymmetry without complications. Complete horizontalization of the occlusal plane was achieved in three patients, whereas a cant of 2 degrees persisted in two patients. None of the children in this study were noncompliant with the prescribed duration of the active distraction period, nor did they experience technical problems with the two devices. CONCLUSIONS: Simultaneous maxillo-mandibular distraction osteogenesis resulted in a high rate of success in correcting facial asymmetry as well as occlusal plane cant. It offered good aesthetic satisfaction.

Cephalometry↗

PubMed2006

Distraction osteogenesis in adolescents with maxillary arch deficiency and dental crowding: a 3-year follow-up.

BACKGROUND: In this study, the authors evaluated the long-term results after using anterior segmental osteotomy and distraction osteogenesis for the correction of sagittal maxillary deficiency associated with dental crowding. METHODS: Six young adolescents (four boys and two girls) underwent surgery and distraction at a mean age of 11.2 years (range, 10 to 12 years) and were followed up for 3 years. A tooth-borne distraction device was used for interdental distraction. The evaluation consisted of hard- and soft-tissue profile analysis and dental arch measurements before, immediately after, and 3 years after distraction. RESULTS: The results showed that the facial profile, the occlusion, and the dental crowding could be successfully corrected and that the results were stable after 3 years' follow-up. The mean facial convexity angle was changed from 1 to 8 degrees. The average advancement at point A was 4 mm and the SNA increased by an average of 4 degrees. Lengthening of the dental arch by an average of 4 mm created approximately 8 mm of new space, sufficient to resolve the dental crowding in all patients, thus avoiding an extraction of healthy teeth. CONCLUSION: The results of this study demonstrated that anterior segmental maxillary osteotomy combined with distraction osteogenesis offers an alternative for the treatment of adolescents suffering from sagittal maxillary deficiency with dental crowding.

Child↗

PubMed2006

Monobloc advancement by distraction osteogenesis decreases morbidity and relapse.

BACKGROUND: Treatment of midface hypoplasia and forehead retrusion with monobloc advancement is associated with significant complications, including meningitis, prolonged intubation, and frontal bone flap necrosis. To see whether distraction of the monobloc segment offered decreased morbidity, the authors compared clinical outcomes of patients who underwent conventional monobloc advancement with those of patients who underwent monobloc distraction. METHODS: Group 1 (conventional monobloc; n = 12) underwent traditional monobloc advancement with bone grafting. Group 2 (modified monobloc; n = 11) did not receive ventriculoperitoneal shunts and underwent the above procedures with placement of a pericranial flap and fibrin glue over the midline defect. Group 3 (monobloc distraction; n = 24) underwent advancement of the monobloc segment by distraction osteogenesis using internal distraction devices. Complications included meningitis, cerebrospinal fluid leak, frontal bone flap loss, and wound infection. Preoperative, postoperative, and follow-up lateral cephalograms were used to assess horizontal changes of the forehead, midface, and maxilla. RESULTS: Group 3 (distraction monobloc) had the lowest complication rate (8 percent), followed by groups 2 (modified monobloc; 43 percent) and 1 (conventional monobloc; 61 percent) (p < 0.05). Group 3 achieved greater advancement (12.6 mm) than did group 2 (9.4 mm) or group 1 (9.1 mm) (p < 0.05). Relapse was least in group 3 (8 percent) compared with groups 2 (67 percent) and 1 (45 percent). CONCLUSIONS: Monobloc advancement by distraction osteogenesis had less morbidity and achieved greater advancement with less relapse compared with conventional methods of acute monobloc advancement with bone grafting. Monobloc distraction is superior to conventional methods of acute monobloc advancement and is an alternative to staged fronto-orbital advancement followed by Le Fort III advancement.

Adolescent↗

PubMed2005

Colocalization of c-Src (pp60src) and bone morphogenetic protein 2/4 expression during mandibular distraction osteogenesis: in vivo evidence of their role within an integrin-mediated mechanotransduction pathway.

Craniofacial distraction osteogenesis (DO) is an evolving reconstructive technique with expanding applications for the treatment of bony deficiencies of the facial skeleton. Mechanical force has been known to play a fundamental role in modulating sustained osteogenic response and therefore is believed to function as a critical regulator of DO. We hypothesize that key clustering components of an integrin-mediated signaling pathway, including c-Src (pp60), are necessary for mediating the response to mechanical force. The specific aim of this study is to demonstrate up-regulation of a key focal adhesion molecule, c-Src, selectively in new bone formation subject to the mechanical forces of distraction and to demonstrate a lack of that same up-regulation in new bone formation associated with simple fracture healing. An additional specific aim is to demonstrate colocalization of c-Src expression and bone morphogenetic protein (BMP 2/4) expression during mandibular DO. Using a rat model of mandibular DO, c-Src and BMP 2/4 expression were evaluated in critical size defects, subcritical size defects, and mandibles undergoing gradual distraction. Osseous regeneration was observed in the course of gradual distraction; this process was associated with increased expression of c-Src. Furthermore, the presence of BMP 2/4 closely approximated c-Src expression spatially and temporally, suggesting a link between cytoplasmic focal adhesion activation and the resultant nuclear regulation of osteogenic protein expression. In significant contradistinction, minimal c-Src expression was found in the subcritical-sized defects where the fractures healed secondarily but where no gradual distraction was performed. Instead, the new bone formation inherent in the secondarily healed subcritical-sized defects demonstrated expected BMP 2/4 expression but was devoid of an up-regulation of c-Src. Finally, as expected, minimal expression of both c-Src and BMP was found in fibrous nonunion specimens. C-src expression was observed during gradual distraction; furthermore, minimal c-Src expression was visualized during subacute and critical-size defect fracture healing. C-Src expression also closely approximated BMP expression during DO. These findings that c-Src expression is found primarily only during conditions of cyclic distraction forces strongly implicates that mechanical force during gradual distraction is associated with c-Src expression. These results provide in vivo support for previous in vitro evidence that mechanical force profoundly influences osseous regeneration during distraction osteogenesis by means of a c-Src dependent mechanotransduction pathway, resulting in increased expression of osteogenic proteins, including BMP 2/4.

Animals↗

PubMed2005

Three-dimensional finite element analysis of the mandible and temporomandibular joint during vertical ramus elongation by distraction osteogenesis.

Distraction osteogenesis has been accepted as an alternative treatment modality for hypoplastic mandibles. Knowledge about the changes occurring in the temporomandibular joint region during mandibular distraction osteogenesis is, however, limited and controversial. Stress distribution in the temporomandibular joint region during unilateral vertical mandibular ramus distraction was studied using a finite element model. The finite element model was based on computed tomography scans and magnetic resonance imaging scans of a patient with unilateral hypoplasia of the right mandibular ramus caused by juvenile idiopathic arthritis. The character of stress distribution in the temporomandibular joint and mandible was analyzed quantitatively at different intervals of the vertical mandibular ramus elongation. During the distraction phase, the condyles, articular disks, and glenoid fossa regions were loaded with a differentiated stress pattern. The affected right condyle, disk, and fossa were submitted to increasing loads with increasing elongation compared with the contralateral temporomandibular joint. Loading on the unaffected left side shifted posteriorly and slightly laterally, because the left condyle was the center of rotation. The loading of the temporomandibular joint regions was low during the active distraction phase, although local areas were subjected to elevated peak stresses.

Arthritis, Juvenile↗

PubMed2005

A custom-made distraction device for experimental mandibular distraction osteogenesis.

Distraction osteogenesis has recently become popular in craniofacial reconstruction, after it was first described for long bones. Despite the widespread clinical use of this technique, currently, lack of an ideal experimental model for small animals hampers investigations focused on its molecular basis, which warrants further elucidation. The authors developed a new device for distraction of the rat mandible and, to asses its effectiveness, practiced on 30 animals assigned to either an acute 3-mm distraction group (n = 7) or a gradual distraction group (0.25 mm twice a day for 6 days; n = 23). The authors applied the devices to a localization that allowed them to perform the ostomies posterior to the molar teeth. Because of a U-shaped plate that the authors used for posterior pin fixation, their device maintained its stability until the end of the study, despite the delicate anatomy of the bone at the posterior part of the mandible. Additionally, the authors described a practical and easy method of transient mandibular stabilization method that facilitates the manipulations while the mouth is open for safer airway control during surgery. This new nutrition technique with enteral feeding solution solved the problem of progressive weight loss after surgery. Application of the device was easy and practical, without demanding complex manipulations. The authors did not observe any device dislodgement or a high rate of accidental fractures during the manipulations. They demonstrated that the device works properly and is able to create ossified regenerate bones that fill the entire distraction gap, which can be used for various investigations during distraction osteogenesis.

Animals↗

PubMed2005

Reconstruction with distraction osteogenesis for juxta-articular nonunions with bone loss.

BACKGROUND: Nonunions of a juxta-articular lesion with bone loss, which represent a challenging therapeutic problem, were treated using external fixation and distraction osteogenesis. METHODS: Seven juxta-articular nonunions (five septic and two aseptic) were treated. The location of the nonunion was the distal femur in four patients, the proximal tibia in one patient, and the distal tibia in two patients. All of them were located within 5 cm from the affected joints. Preoperative limb shortening was present in six cases, averaging 2.9 cm (range, 1-7 cm). The reconstructive procedure consisted of refreshment of the nonunion site, deformity correction, stabilization by external fixation, and lengthening to eliminate leg length discrepancy or to fill the defect. Shortening-distraction was applied to six patients and bone transport to one patient for reconstruction. Intramedullary nailing to reduce the duration of external fixation was simultaneously performed in two cases. All the patients had at least 1 year of follow-up evaluation. RESULTS: Osseous union without angular deformity or leg length discrepancy greater than 1 cm was achieved in all patients. The mean amount of lengthening was 5.8 cm (range, 2.2-10.0 cm). The mean external fixation period was 219 days (range, 98-317 days), and the mean external fixation index was 34.4 days/cm (range, 24.5-47.6 days/cm). All patients reported excellent pain reduction. There were no recurrences of infection in five patients with prior history of osteomyelitis. The functional results were categorized as excellent in two, good in three, and fair in two. CONCLUSION: Despite the length of postoperative external fixation, distraction osteogenesis can be a valuable alternative for the treatment of juxta-articular nonunions.

Adolescent↗