Limb Growth Research Articles

Proximal Humerus Reconstruction in Skeletally Immature Patients

Proximal humerus reconstruction after oncologic resection is complex, with numerous muscular attachments, proximity of critical neurovascular structures, and dynamic stability granting multidirectional motion at the glenohumeral articulation. In skeletally immature patients, additional factors increase the complexity, including remaining limb growth and humerus size. Limb length discrepancy affects the limb's esthetics and function while the humerus size can limit fixation strategies and intramedullary device use. Reconstruction options used in isolation or combination include endoprostheses, osteoarticular allografts, allograft-prosthetic composites, autografts, and arthrodesis. Unique limb salvage options to address the unique factors in young, skeletally immature patients include vascularized fibular epiphyseal transfer, claviculo pro humeri, and expandible endoprostheses. Each option has advantages and disadvantages for anticipated function, durability, shoulder stability, and complications. This review aims to aid preoperative planning and decision making for surgeons and patients undergoing proximal humerus resection and reconstruction with notable remaining growth potential.

Genomic regions underlying variation in wattles, horns, and supernumerary teats phenotypes in Egyptian goats

Goats play a crucial role in providing humans with various types of valuable products including milk and meat. The underlying genetic mechanisms of important morphological aspects remain largely unknown in goats, highlighting the need for further investigation. A genome-wide association analysis (GWAS) was conducted for three morphological phenotypes in Egyptian goats. All animals were genotyped using the Illumina 65 K SNP BeadChips. Results of GWAS for wattles identified two significant ( P ≤ 1.4 × 10–6, false discovery rate (FDR) ≤ 0.05) single nucleotide polymorphisms (SNPs) on chromosome 10 within a region (72–74 Mb) containing FMN1 and GREM1 genes that are important for limb development and growth. For horns, three significant SNPs were identified on chromosome 1 (119–131 Mb) harbouring candidate genes for embryonic development and tissue differentiation, such as CEP70, DZIP1L, CLDN18, SOX14, and SLC35G2. For supernumerary teats, four significant SNPs located on chromosomes 25 (8.7 Mb), 9 (47.8 Mb), 17 (45.1 Mb), and 28 (6.7 Mb) were identified, harbouring candidate genes involved in morphogenesis and reproductive traits such as EMP2, MDN1, PCDH10, and GHITM. This study identified novel candidate genes alongside previously reported ones in other goat breeds, suggesting their potential as candidate genes for the studied traits in Egyptian goats.

Research progress of genetic research on Char syndrome

Char syndrome is a rare autosomal dominant genetic disorder characterized by patent ductus arteriosus, facial dysmorphism, and dysplasia of fingers/toes. It may also be associated with multiple papillae, dental dysplasia, and sleep disorders. TFAP2B has proven to be a pathogenic gene for neural crest derivation and development, and several variants of this gene have been identified. Bone morphogenetic protein signaling plays an important role in embryonic development by participating in limb growth and patterning, and regulation of neural crest cell development. TFAP2B is an upstream regulatory gene for bone morphogenetic proteins 2 and 4. Variants of the TFAP2B gene may lead to abnormal proliferation of neural crest cells by affecting the expression of bone morphogenetic proteins, resulting in multiple organ dysplasia syndrome. In addition, TFAP2B variants may only lead to patent ductus arteriosus instead of typical Char syndrome.

Current perspective on medical management, orthopedic treatment, and the use of the Ilizarov method in children with X-linked hypophosphatemic rickets

Hypophosphatemic rickets encompasses a group of rare metabolic diseases that cause lower limb bowing and growth impairment. The mainstay of its management rests in frequent dosages of oral phosphate salts and active vitamin D derivatives. Recent developments in therapy reduced severe pathology progression. However, there remains a substantial number of patients suffering from persisting or recurring deformities. Treatment of those resistant to conventional therapy is the domain of orthopedic surgery. Although multiple recommended approaches exist, no single method has been proven superior to others. In this article, the authors review the effectiveness of several surgical techniques, with a focus on the Ilizarov frame. The method allows for a noninvasive and accurate correction but is technically demanding and imposes a prolonged treatment period. Modern alterations of both the procedure and the original construct aim to improve patient compliance while maintaining the same healing index. Nevertheless, research carried out on small groups of patients and the utilization of different assessment tools for each technique hinders the determination of standardized guidelines. The choice of a given method boils down to an individual approach and strongly depends on the surgeon’s experience and preferences.

Protein signaling and morphological development of the tail fluke in the embryonic beluga whale (Delphinapterus leucas).

During the land-to-sea transition of cetaceans (whales, dolphins, and porpoises), the hindlimbs were lost and replaced by an elaborate tail fluke that evolved 32 Ma. All modern cetaceans utilize flukes for lift-based propulsion, and nothing is known of this organ's molecular origins during embryonic development. This study utilizes immunohistochemistry to identify the spatiotemporal location of protein signals known to drive appendage outgrowth in other vertebrates (e.g., Sonic Hedgehog [SHH], GREMLIN [GREM], wingless-type family member 7a [WNT], and fibroblast growth factors [FGFs]) and to test the hypothesis that signals associated with outgrowth and patterning of the tail fluke are similar to a tetrapod limb. Specifically, this study utilizes an embryo of a beluga whale (Delphinapterus leucas) as a case study. Results showed epidermal signals of WNT and FGFs, and mesenchymal/epidermal signals of SHH and GREM. These patterns are most consistent with vertebrate limb development. Overall, these data are most consistent with the hypothesis that outgrowth of tail flukes in cetaceans employs a signaling pattern that suggests genes essential for limb outgrowth and patterning shape this evolutionarily novel appendage. While these data add insights into the molecular signals potentially driving the evolution and development of tail flukes in cetaceans, further exploration of the molecular drivers of fluke development is required.

Rheb1 is required for limb growth through regulating chondrogenesis in growth plate

Ras homology enriched in the brain (Rheb) is well established as a critical regulator of cell proliferation and differentiation in response to growth factors and nutrients. However, the role of Rheb1 in limb development remains unknown. Here, we found that Rheb1 was dynamically expressed during the proliferation and differentiation of chondrocytes in the growth plate. Given that Prrx1+ limb-bud-like mesenchymal cells are the source of limb chondrocytes and are essential for endochondral ossification, we conditionally deleted Rheb1 using Prrx1-Cre and found a limb dwarfism in Prrx1-Cre; Rheb1fl/fl mice. Normalized to growth plate height, the conditional knockout (cKO) mice exhibited a significant decrease in column count of proliferative zones which was increased in hypertrophic zones resulting in decreased growth plate size, indicating abnormal endochondral ossification. Interestingly, although Rheb1 deletion profoundly inhibited the transcription factor Sox9 in limb cartilage; levels of runx2 and collagen type 2 were both increased. These novel findings highlight the essential role of Rheb1 in limb growth and indicate a complex regulation of Rheb1 in chondrocyte proliferation and differentiation.

Multi-species atlas resolves an axolotl limb development and regeneration paradox

Humans and other tetrapods are considered to require apical-ectodermal-ridge (AER) cells for limb development, and AER-like cells are suggested to be re-formed to initiate limb regeneration. Paradoxically, the presence of AER in the axolotl, a primary model organism for regeneration, remains controversial. Here, by leveraging a single-cell transcriptomics-based multi-species atlas, composed of axolotl, human, mouse, chicken, and frog cells, we first establish that axolotls contain cells with AER characteristics. Further analyses and spatial transcriptomics reveal that axolotl limbs do not fully re-form AER cells during regeneration. Moreover, the axolotl mesoderm displays part of the AER machinery, revealing a program for limb (re)growth. These results clarify the debate about the axolotl AER and the extent to which the limb developmental program is recapitulated during regeneration.

Vascularized Fibular Epiphyseal Transfer for Pediatric Limb Salvage: Review of Applications and Outcomes

Summary: Vascularized fibular epiphyseal transfer (VFET) offers a functional advantage in pediatric limb salvage due to the preservation of growth potential and an articular surface for remodeling. This review summarizes the available evidence on the clinical characteristics and outcomes of pediatric reconstruction applying VFET at different recipient sites and with varying techniques. VFET was used to reconstruct the proximal humerus, distal radius or ulna, proximal femur, distal fibula, calcaneus, and mandible. Although most often harvested on the anterior tibial artery, VFET has also been performed using the peroneal artery, the inferior lateral genicular artery, and a dual pedicle. Recipient site flap inset most often involved fixation with plates and/or screws as well as soft tissue reconstruction using a retained slip of biceps femoris tendon. Outcomes included limb growth, range of motion, and strength. The most common reported complications were bone flap fracture and peroneal nerve palsy. The anterior tibial artery was the most applied pedicle with reliable limb growth, but with the added risk of postoperative peroneal palsy. Bone flap fracture most often occurred at the proximal humerus and femur recipient sites. Plate fixation and the combined use of allograft had lower instances of bone flap fracture. This review highlights how the anticipated dynamic growth and remodeling this free flap offers in the long term must be weighed against its complexity and potential complications.

MicroRNA sequencing analysis reveals injury-induced immune responses of Scylla paramamosain against cheliped autotomy

During pond culture or intensive culture system of crabs (mainly Eriocheir sinensis, Portunus trituberculatus and Scylla paramamosain), high-density farming has typically contributed to a higher limb autotomy level in juvenile animals, especially in S. paramamosain which has a high level of cannibalism. Due to the high limb autotomy level, the survival and growth rates in S. paramamosain farming are restricted, which limit the growth of the mud crab farming industry. MicroRNAs (miRNAs) are small noncoding RNAs that regulate a series of biological processes including innate immune responses by post-transcriptional suppression of their target genes. MiRNAs are believed to be crucial for innate immune process of host wound healing. Many miRNAs have been verified to be required in host immune responses to repair wound and to defense pathogen after tissue damage. However, to our best knowledge, the miRNAs functions of crustacean innate immune reactions against injury induced by limb autotomy have not been studied yet. Here in this study, for the first time, miRNAs involved in the S. paramamosain immune reactions against injury induced by cheliped autotomy were obtained by high-throughput sequencing. A total of 575 miRNAs (518 known miRNAs and 57 novel predicted miRNAs) were obtained, of which 141 differentially expressed microRNAs (93 up-regulated microRNAs and 48 down-regulated microRNAs) were revealed to be modified against cheliped autotomy, and the qPCR results of randomly selected miRNAs confirmed the expression patterns in the miRNAs sequencing data. Numerous immune-related target genes associated with innate immune system were mediated by miRNAs to induce host humoral immune and cellular immune defense to minimize acute physical damage. Furthermore, the genes expression in hemolymph coagulation and melanization pathways, as well as Toll and Imd signaling pathways were mediated by miRNAs to activate host immune responses including melanization and antimicrobial peptides for rapid wound healing and killing invaded pathogens. These results will help to understand injury-induced immune responses in crabs and to develop an effective control strategy of autotomy rate in crabs farming.

Physeal distraction prior to excision of metaphyseal malignant bone tumors in children: Preserving joint function and limb growth

BackgroundImprovements in imaging methods and adjuvant chemotherapy have increased survival rates in children with bone sarcomas up to 80%, therefore long-lasting limb salvage procedures are needed. PurposeTo describe a case series of pediatric patients who have undergone physeal distraction prior to tumor resection for treatment of metaphyseal malignant bone tumors. MethodsBetween January 2007 to December 2020, 8 patients (5 boys and 3 girls) with a mean age of 7.2 years (2–13), underwent physeal distraction as the first stage of a tumor resection protocol. Six patients had Ewing's sarcoma and two had osteosarcoma. Tumor locations were: proximal tibia (4 cases), distal femur, proximal humerus, distal radius, and distal fibula (1 case each). The affected bones were replaced with cadaver allograft in 6 patients; there was also one fibula autograft and one vascularized fibula graft. Chemotherapy was administered pre- and post-surgery; one patient received adjuvant radiotherapy. Average follow-up was 62.6 months (8–152). ResultsPhyseal distraction lasted an average of 10.6 days (3–15); delay to definitive resection was 17 days (range 13–22). Mean length of resection was 10.7 ​cm (range 5–14) and all had negative margins. There were no local recurrences. Three patients suffered disease progression with metastasis and died. Surgical complications included: pin infection (1 patient), surgical site infection (2 patients), allograft fracture (1 patient), and nonunion of the diaphyseal junction (3 patients). Final lower limb length discrepancy was 1.5 ​cm (range 1–2 ​cm). Normal joint function was achieved in 6 patients. The mean MSTS score was 75% (53%–97%). ConclusionsPhyseal distraction technique is an oncologically safe limb salvage procedure with good functional results, and it should be considered in the treatment of metaphyseal pediatric malignant tumors.

Primary cilia support cartilage regeneration after injury

In growing children, growth plate cartilage has limited self-repair ability upon fracture injury always leading to limb growth arrest. Interestingly, one type of fracture injuries within the growth plate achieve amazing self-healing, however, the mechanism is unclear. Using this type of fracture mouse model, we discovered the activation of Hedgehog (Hh) signaling in the injured growth plate, which could activate chondrocytes in growth plate and promote cartilage repair. Primary cilia are the central transduction mediator of Hh signaling. Notably, ciliary Hh-Smo-Gli signaling pathways were enriched in the growth plate during development. Moreover, chondrocytes in resting and proliferating zone were dynamically ciliated during growth plate repair. Furthermore, conditional deletion of the ciliary core gene Ift140 in cartilage disrupted cilia-mediated Hh signaling in growth plate. More importantly, activating ciliary Hh signaling by Smoothened agonist (SAG) significantly accelerated growth plate repair after injury. In sum, primary cilia mediate Hh signaling induced the activation of stem/progenitor chondrocytes and growth plate repair after fracture injury.

Developmental regulation of conserved non-coding element evolution provides insights into limb loss in squamates.

Limb loss shows recurrent phenotypic evolution across squamate lineages. Here, based on three de novo-assembled genomes of limbless lizards from different lineages, we showed that divergence of conserved non-coding elements (CNEs) played an important role in limb development. These CNEs were associated with genes required for limb initiation and outgrowth, and with regulatory signals in the early stage of limb development. Importantly, we identified the extensive existence of insertions and deletions (InDels) in the CNEs, with the numbers ranging from 111 to 756. Most of these CNEs with InDels were lineage-specific in the limbless squamates. Nearby genes of these InDel CNEs were important to early limb formation, such as Tbx4, Fgf10, and Gli3. Based on functional experiments, we found that nucleotide mutations and InDels both affected the regulatory function of the CNEs. Our study provides molecular evidence underlying limb loss in squamate reptiles from a developmental perspective and sheds light on the importance of regulatory element InDels in phenotypic evolution.

Look who's TORking: mTOR-mediated integration of cell status and external signals during limb development and endochondral bone growth.

The balance of cell proliferation and size is key for the control of organ development and repair. Moreover, this balance has to be coordinated within tissues and between tissues to achieve robustness in the organ's pattern and size. The tetrapod limb has been used to study these topics during development and repair, and several conserved pathways have emerged. Among them, mechanistic target of rapamycin (mTOR) signaling, despite being active in several cell types and developmental stages, is one of the least understood in limb development, perhaps because of its multiple potential roles and interactions with other pathways. In the body of this review, we have collated and integrated what is known about the role of mTOR signaling in three aspects of tetrapod limb development: 1) limb outgrowth; 2) chondrocyte differentiation after mesenchymal condensation and 3) endochondral ossification-driven longitudinal bone growth. We conclude that, given its ability to interact with the most common signaling pathways, its presence in multiple cell types, and its ability to influence cell proliferation, size and differentiation, the mTOR pathway is a critical integrator of external stimuli and internal status, coordinating developmental transitions as complex as those taking place during limb development. This suggests that the study of the signaling pathways and transcription factors involved in limb patterning, morphogenesis and growth could benefit from probing the interaction of these pathways with mTOR components.

Predicting Success of Deformity Correction With Tension Band Plating in Early-Onset Tibia Vara.

Angular deformity correction with tension band plating has not been as successful in early-onset tibia vara (EOTV) as it has been in other conditions. Our hypothesis is that perioperative factors can predict the success of lateral tibial tension band plating (LTTBP) in patients with EOTV. A retrospective review was performed at 7 centers evaluating radiographic outcomes of LTTBP in patients with EOTV (onset <7y of age). Single-event tibial LTTBP outcome was assessed through medial proximal tibial angle (MPTA). The final limb alignment following comprehensive limb growth modulation (CLGM), which could include multiple procedures, was assessed by mechanical axis zone (MAZone), mechanical tibio-femoral angle (mTFA), and mechanical axis deviation (MAD). Preoperative age, weight, deformity severity, medial physeal slope, and Langenskiöld classification +/- modification were investigated as predictors of outcome. Success was defined as the correction or overcorrection to normal age-adjusted alignment. The minimum follow-up was 2 years except when deformity correction, skeletal maturity, or additional surgery occurred. Fifty-two patients with 80 limbs underwent 115 tibial LTTBP procedures at a mean age of 5.3y, including 78 primary, 21 implant revisions, and 15 reimplantations for recurrence. Tibial LTTBP resulted in a mean change of +8.6 o in MPTA and corrected 53% of tibias. CLGM resulted in MAD correction for 54% of limbs.Univariate analysis showed that success was best predicted by preoperative age, weight, MPTA, and MAD. Multivariate analysis identified that preoperative-MPTA/MAD and preoperative-weight<70kg were predictive of MPTA and MAD correction, respectively. The probability of success tables are presented for reference. Successful correction of MPTA to age-adjusted norms following a single-event LTTBP occurred in 53% of tibias and was best predicted by preoperative-MPTA and preoperative body weight <70kg. Comprehensive growth modulation corrected limbs in 54%. The probability of correction to age-adjusted MAD is best estimated by preoperative-MAZone 1 or 2 (MAD ≤40mm). Limbs with preoperative-MAD>80mm improved, but ultimately all failed to correct completely with CLGM. Osteotomy may need to be considered with these severe deformities. While modified Langenskiöld classification and medial physeal slope have been shown to predict the outcome of osteotomy, they were not predictive for LTTBP. Change in MPTA was common after physeal untethering. Level-III.

Bmp-signaling and the finfold size in zebrafish: implications for the fin-to-limb transition.

In tetrapods, BMP-signaling coordinates limb outgrowth, skeleton patterning, and apoptosis during the formation of their typical autopod structures, the digits. In addition, inhibition of BMP signaling during mouse limb development leads to the persistence and enlargement of an important signaling center, the apical ectodermal ridge (AER), and consequent digit defects. Interestingly, during fish fin development there is a natural elongation of the AER, rapidly converted into an apical finfold (FF), in which osteoblasts differentiate into dermal fin-rays used in aquatic locomotion. Previous reports have led us to suggest that upregulation of Hox13 genes in the distal fin mesenchyme, caused by the origin of novel enhancer modules, may have caused an increment of the BMP signaling potentially leading to the apoptosis of these osteoblasts precursors of the fin-rays. To explore this hypothesis, we characterized the expression of several components of the BMP signaling in zebrafish lines with distinct FF sizes (bmp2b, smad1, smoc1, smoc2, grem1a, msx1b, msx2b, Psamd1/5/9). Our data suggest that the BMP signaling is enhanced in shorter FFs and inhibited in longer FFs, as implied by the differential expression of several components of this network. In addition, we detected an earlier expression of several of these BMP-signaling components associated with the development of short FFs and the opposite tendency during the development of longer FFs. Thus, our results suggest that a heterochronic shift, involving enhanced Hox13 expression and BMP signaling may have caused the reduction of the FF size during the evolutionary transition from fish fins to tetrapod limbs.

CurQ+, a Next-Generation Formulation of Curcumin, Ameliorates Growth Plate Chondrocyte Stress and Increases Limb Growth in a Mouse Model of Pseudoachondroplasia.

Mutations in cartilage oligomeric matrix protein (COMP) causes protein misfolding and accumulation in chondrocytes that compromises skeletal growth and joint health in pseudoachondroplasia (PSACH), a severe dwarfing condition. Using the MT-COMP mice, a murine model of PSACH, we showed that pathological autophagy blockage was key to the intracellular accumulation of mutant-COMP. Autophagy is blocked by elevated mTORC1 signaling, preventing ER clearance and ensuring chondrocyte death. We demonstrated that resveratrol reduces the growth plate pathology by relieving the autophagy blockage allowing the ER clearance of mutant-COMP, which partially rescues limb length. To expand potential PSACH treatment options, CurQ+, a uniquely absorbable formulation of curcumin, was tested in MT-COMP mice at doses of 82.3 (1X) and 164.6 mg/kg (2X). CurQ+ treatment of MT-COMP mice from 1 to 4 weeks postnatally decreased mutant COMP intracellular retention, inflammation, restoring both autophagy and chondrocyte proliferation. CurQ+ reduction of cellular stress in growth plate chondrocytes dramatically reduced chondrocyte death, normalized femur length at 2X 164.6 mg/kg and recovered 60% of lost limb growth at 1X 82.3 mg/kg. These results indicate that CurQ+ is a potential therapy for COMPopathy-associated lost limb growth, joint degeneration, and other conditions involving persistent inflammation, oxidative stress, and a block of autophagy.

Indications and Timing of Guided Growth Techniques for Pediatric Upper Extremity Deformities: A Literature Review.

Osseous deformities in children arise due to progressive angular growth or complete physeal arrest. Clinical and radiological alignment measurements help to provide an impression of the deformity, which can be corrected using guided growth techniques. However, little is known about timing and techniques for the upper extremity. Treatment options for deformity correction include monitoring of the deformity, (hemi-)epiphysiodesis, physeal bar resection, and correction osteotomy. Treatment is dependent on the extent and location of the deformity, physeal involvement, presence of a physeal bar, patient age, and predicted length inequality at skeletal maturity. An accurate estimation of the projected limb or bone length inequality is crucial for optimal timing of the intervention. The Paley multiplier method remains the most accurate and simple method for calculating limb growth. While the multiplier method is accurate for calculating growth prior to the growth spurt, measuring peak height velocity (PHV) is superior to chronological age after the onset of the growth spurt. PHV is closely related to skeletal age in children. The Sauvegrain method of skeletal age assessment using elbow radiographs is possibly a simpler and more reliable method than the method by Greulich and Pyle using hand radiographs. PHV-derived multipliers need to be developed for the Sauvegrain method for a more accurate calculation of limb growth during the growth spurt. This paper provides a review of the current literature on the clinical and radiological evaluation of normal upper extremity alignment and aims to provide state-of-the-art directions on deformity evaluation, treatment options, and optimal timing of these options during growth.

Emerged donor limb growth morbidity and malalignment after combined ipsilateral tibial and fibular cortical harvest graft in children. Early follow-up report.

The quantity of bone grafts required in certain pediatric conditions is sometimes substantial. This retrospective study details the radiological changes occurring in the donor leg and ankle following the simultaneous harvest of large diaphyseal cortical grafts from the tibia and fibula in 14 children (16 legs). The following preoperative and follow-up radiological parameters were measured and compared for donor legs: the longitudinal continuous regeneration of fibula, distal fibular station, medial proximal tibial angle, lateral distal tibial angle, posterior proximal tibial angle (PPTA), anterior distal tibial angle and interphyseal angle (tibia diaphyseal angulation) in both coronal and sagittal planes. Additionally, the impact of fibular regeneration in combined harvests was separately analyzed. Children were operated at the mean age of 52 months. Mean follow-up of 25.2 months was available. At follow-up, the donor tibia healed completely in all legs whereas fibular regeneration was complete only in 10 legs (62.5%). At follow-up, ankle valgus was present in 6 out of 16 legs (37%) and tibia valga increased in all legs except one (94%). Procurvatum was present in 7 legs. The fibular nonregeneration group was prone to ankle valgus deformity ( P = 0.014), valgus angulation of tibial diaphysis ( P = 0.0076) and lower mean PPTA ( P = 0.026) when compared to the regenerate group. There was a complication of stress fracture in one donor tibia. Combined tibial and fibular harvest is a major surgical undertaking in children. The donor limbs have their share of complications postharvest, more so when the fibula remains nonregenerated. Serial monitoring of donor sites is emphasized.

Влияние телескопического интрамедуллярного остеосинтеза большеберцовой кости на рост сегмента: пилотное экспериментальное исследование

Introduction Telescopic intramedullary osteosynthesis (TIO) is used in children with osteogenesis imperfecta and other diseases accompanied by frequent fractures and deformities of long bones due to pathological bone tissue featuring reduced strength properties. Purpose In an animal experiment to study the growth characteristics of an intact tibia under conditions of intramedullary reinforcement with a telescopic rod. Material and methods A non‑randomized controlled study was conducted on 4 animals (puppies, littermates) that underwent TIO of the right limb tibia with a telescopic titanium rod (outer diameter of 4.2 mm) at the age of 5 months. X-ray parameters (length of the tibia, angles of inclination of the articular surfaces, telescoping magnitude) were studied before surgery, on the day of rod placement, and after the end of spontaneous growth of the segment (7 months after surgery). The contralateral left tibia served as a control, and its X-ray parameters were studied at the same time-points. Results Transphyseal reinforcement with a telescopic rod caused growth retardation with loss of length in only one case out of four (8 mm or 4.8 % of residual growth). In other cases, no difference in the length of the tibias of the right and left lower extremities was found. Eccentric insertion of the transphyseal rods into the posterior third of the distal epiphysis (due to the natural anatomy of the canine tibial shaft) formed an angular deformity during growth: a significant increase in the distal anterior and lateral tibial angles of the operated limb compared to the intact limb. The amount of divergenceof the parts of the rods was, on average, 11.3 mm. There were no cases of migration of intramedullary rods or loss of fixation of threaded sections in the epiphyses. Conclusion Under experimental conditions, the slowing down of longitudinal bone growth is not a constantly observed effect. Titanium telescopic rods are not prone to blocking during the limb growth or to losing the position of the threaded parts in the epiphyses. The eccentric passage of the rods through the growth zones causes angular deformities in the course of growth of the segment.

Development and metamorphosis in frogs deficient in the thyroid hormone transporter MCT8

Precisely regulated thyroid hormone (TH) signaling within tissues during frog metamorphosis gives rise to the organism-wide coordination of developmental events among organs required for survival. This TH signaling is controlled by multiple cellular mechanisms, including TH transport across the plasma membrane. A highly specific TH transporter has been identified, namely monocarboxylate transporter 8 (MCT8), which facilitates uptake and efflux of TH and is differentially and dynamically expressed among tissues during metamorphosis. We hypothesized that loss of MCT8 would alter tissue sensitivity to TH and affect the timing of tissue transformation. To address this, we used CRISPR/Cas9 to introduce frameshift mutations inslc16a2, the gene encoding MCT8, inXenopus laevis. We produced homozygous mutant tadpoles with a 29-bp mutation in the l-chromosome and a 20-bp mutation in the S-chromosome. We found that MCT8 mutants survive metamorphosis with normal growth and development of external morphology throughout the larval period. Consistent with this result, the expression of the pituitary hormone regulating TH plasma levels (tshb) was similar among genotypes as was TH response gene expression in brain at metamorphic climax. Further, delayed initiation of limb outgrowth during natural metamorphosis and reduced hindlimb and tail TH sensitivity were not observed in MCT8 mutants. In sum, we did not observe an effect on TH-dependent development in MCT8 mutants, suggesting compensatory TH transport occurs in tadpole tissues, as seen in most tissues in all model organisms examined.