Repair of DNA Breaks by Break-Induced Replication.

Double-strand DNA breaks (DSBs) are the most lethal type of DNA damage, making DSB repair critical for cell survival. However, some DSB repair pathways are mutagenic and promote genome rearrangements, leading to genome destabilization. One such pathway is break-induced replication (BIR), which repairs primarily one-ended DSBs, similar to those formed by collapsed replication forks or telomere erosion. BIR is initiated by the invasion of a broken DNA end into a homologous template, synthesizes new DNA within the context of a migrating bubble, and is associated with conservative inheritance of new genetic material. This mode of synthesis is responsible for a high level of genetic instability associated with BIR. Eukaryotic BIR was initially investigated in yeast, but now it is also actively studied in mammalian systems. Additionally, a significant breakthrough has been made regarding the role of microhomology-mediated BIR in the formation of complex genomic rearrangements that underly various human pathologies.

BLM helicase unwinds lagging strand substrates to assemble the ALT telomere damage response.

The Bloom syndrome (BLM) helicase is critical for alternative lengthening of telomeres (ALT), a homology-directed repair (HDR)-mediated telomere maintenance mechanism that is prevalent in cancers of mesenchymal origin. The DNA substrates that BLM engages to direct telomere recombination during ALT remain unknown. Here, we determine that BLM helicase acts on lagging strand telomere intermediates that occur specifically in ALT-positive cells to assemble a replication-associated DNA damage response. Loss of ATRX was permissive for BLM localization to ALT telomeres in S and G2, commensurate with the appearance of telomere C-strand-specific single-stranded DNA (ssDNA). DNA2 nuclease deficiency increased 5'-flap formation in a BLM-dependent manner, while telomere C-strand, but not G-strand, nicks promoted ALT. These findings define the seminal events in the ALT DNA damage response, linking aberrant telomeric lagging strand DNA replication with a BLM-directed HDR mechanism that sustains telomere length in a subset of human cancers.

HLTF resolves G4s and promotes G4-induced replication fork slowing to maintain genome stability.

G-quadruplexes (G4s) form throughout the genome and influence important cellular processes. Their deregulation can challenge DNA replication fork progression and threaten genome stability. Here, we demonstrate an unexpected role for the double-stranded DNA (dsDNA) translocase helicase-like transcription factor (HLTF) in responding to G4s. We show that HLTF, which is enriched at G4s in the human genome, can directly unfold G4s in vitro and uses this ATP-dependent translocase function to suppress G4 accumulation throughout the cell cycle. Additionally, MSH2 (a component of MutS heterodimers that bind G4s) and HLTF act synergistically to suppress G4 accumulation, restrict alternative lengthening of telomeres, and promote resistance to G4-stabilizing drugs. In a discrete but complementary role, HLTF restrains DNA synthesis when G4s are stabilized by suppressing primase-polymerase (PrimPol)-dependent repriming. Together, the distinct roles of HLTF in the G4 response prevent DNA damage and potentially mutagenic replication to safeguard genome stability.

TERRA and RAD51AP1 promote alternative lengthening of telomeres through an R- to D-loop switch.

Alternative lengthening of telomeres (ALT), a telomerase-independent process maintaining telomeres, is mediated by break-induced replication (BIR). RAD52 promotes ALT by facilitating D-loop formation, but ALT also occurs through a RAD52-independent BIR pathway. Here, we show that the telomere non-coding RNA TERRA forms dynamic telomeric R-loops and contributes to ALT activity in RAD52 knockout cells. TERRA forms R-loops in vitro and at telomeres in a RAD51AP1-dependent manner. The formation of R-loops by TERRA increases G-quadruplexes (G4s) at telomeres. G4 stabilization enhances ALT even when TERRA is depleted, suggesting that G4s act downstream of R-loops to promote BIR. In vitro, the telomeric R-loops assembled by TERRA and RAD51AP1 generate G4s, which persist after R-loop resolution and allow formation of telomeric D-loops without RAD52. Thus, the dynamic telomeric R-loops formed by TERRA and RAD51AP1 enable the RAD52-independent ALT pathway, and G4s orchestrate an R- to D-loop switch at telomeres to stimulate BIR.

A unified alternative telomere-lengthening pathway in yeast survivor cells.

Alternative lengthening of telomeres (ALT) is a recombination process that maintains telomeres in the absence of telomerase and helps cancer cells to survive. Yeast has been used as a robust model of ALT; however, the inability to determine the frequency and structure of ALT survivors hinders understanding of the ALT mechanism. Here, using population and molecular genetics approaches, we overcome these problems and demonstrate that contrary to the current view, both RAD51-dependent and RAD51-independent mechanisms are required for a unified ALT survivor pathway. This conclusion is based on the calculation of ALT frequencies, as well as on ultra-long sequencing of ALT products that revealed hybrid sequences containing features attributed to both recombination pathways. Sequencing of ALT intermediates demonstrates that recombination begins with Rad51-mediated strand invasion to form DNA substrates that are matured by a Rad51-independent ssDNA annealing pathway. A similar unified ALT pathway may operate in other organisms, including humans.

TSPYL5 Depletion Induces Specific Death of ALT Cells through USP7-Dependent Proteasomal Degradation of POT1.

A significant fraction (∼10%) of cancer cells maintain their telomere length via a telomerase-independent mechanism known as alternative lengthening of telomeres (ALT). There are no known molecular, ALT-specific, therapeutic targets. We have identified TSPYL5 (testis-specific Y-encoded-like protein 5) as a PML body component, co-localizing with ALT telomeres and critical for ALT+ cell viability. TSPYL5 was described as an inhibitor of the USP7 deubiquitinase. We report that TSPYL5 prevents the poly-ubiquitination of POT1-a shelterin component-and protects POT1 from proteasomal degradation exclusively in ALT+ cells. USP7 depletion rescued POT1 poly-ubiquitination and loss, suggesting that the deubiquitinase activates POT1 E3 ubiquitin ligase(s). Similarly, PML depletion suppressed POT1 poly-ubiquitination, suggesting an interplay between USP7 and PML to trigger POT1 degradation in TSPYL5-depleted ALT+ cells. We demonstrate that ALT telomeres need to be protected from POT1 degradation in ALT-associated PML bodies and identify TSPYL5 as an ALT+ cancer-specific therapeutic target.

Consequences of telomere replication failure: the other end-replication problem.

Telomeres are chromosome-capping structures that protect ends of the linear genome from DNA damage sensors. However, these structures present obstacles during DNA replication. Incomplete telomere replication accelerates telomere shortening and limits replicative lifespan. Therefore, continued proliferation under conditions of replication stress requires a means of telomere repair, particularly in the absence of telomerase. It was recently revealed that replication stress triggers break-induced replication (BIR) and mitotic DNA synthesis (MiDAS) at mammalian telomeres; however, these mechanisms are error prone and primarily utilized in tumorigenic contexts. In this review article, we discuss the consequences of replication stress at telomeres and how use of available repair pathways contributes to genomic instability. Current research suggests that fragile telomeres are ultimately tumor-suppressive and thus may be better left unrepaired.

Telomeric C-circles localize at nuclear pore complexes in Saccharomyces cerevisiae.

As in human cells, yeast telomeres can be maintained in cells lacking telomerase activity by recombination-based mechanisms known as ALT (Alternative Lengthening of Telomeres). A hallmark of ALT human cancer cells are extrachromosomal telomeric DNA elements called C-circles, whose origin and function have remained unclear. Here, we show that extrachromosomal telomeric C-circles in yeast can be detected shortly after senescence crisis and concomitantly with the production of survivors arising from "type II" recombination events. We uncover that C-circles bind to the nuclear pore complex (NPC) and to the SAGA-TREX2 complex, similar to other non-centromeric episomal DNA. Disrupting the integrity of the SAGA/TREX2 complex affects both C-circle binding to NPCs and type II telomere recombination, suggesting that NPC tethering of C-circles facilitates formation and/or propagation of the long telomere repeats characteristic of type II survivors. Furthermore, we find that disruption of the nuclear diffusion barrier impairs type II recombination. These results support a model in which concentration of C-circles at NPCs benefits type II telomere recombination, highlighting the importance of spatial coordination in ALT-type mechanisms of telomere maintenance.

Pan-cancer analysis of telomere maintenance mechanisms.

Telomeres, protective caps at chromosome ends, maintain genomic stability and control cell lifespan. Dysregulated telomere maintenance mechanisms (TMMs) are cancer hallmarks, enabling unchecked cell proliferation. We conducted a pan-cancer evaluation of TMM using RNA sequencing data from The Cancer Genome Atlas for 33 different cancer types and analyzed the activities of telomerase-dependent (TEL) and alternative lengthening of telomeres (ALT) TMM pathways in detail. To further characterize the TMM profiles, we categorized the tumors based on their ALT and TEL TMM pathway activities into five major phenotypes: ALT high TEL low, ALT low TEL low, ALT middle TEL middle, ALT high TEL high, and ALT low TEL high. These phenotypes refer to variations in telomere maintenance strategies, shedding light on the heterogeneous nature of telomere regulation in cancer. Moreover, we investigated the clinical implications of TMM phenotypes by examining their associations with clinical characteristics and patient outcomes. Specific TMM profiles were linked to specific survival patterns, emphasizing the potential of TMM profiling as a prognostic indicator and aiding in personalized cancer treatment strategies. Gene ontology analysis of the TMM phenotypes unveiled enriched biological processes associated with cell cycle regulation (both TEL and ALT), DNA replication (TEL), and chromosome dynamics (ALT) showing that telomere maintenance is tightly intertwined with cellular processes governing proliferation and genomic stability. Overall, our study provides an overview of the complexity of transcriptional regulation of telomere maintenance mechanisms in cancer.

The alternative lengthening of telomeres mechanism jeopardizes telomere integrity if not properly restricted.

A substantial number of human cancers are telomerase-negative and elongate physiologically damaged telomeres through a break-induced replication (BIR)-based mechanism known as alternative lengthening of telomeres (ALT). We recently demonstrated that inhibiting the transcription of the telomeric long noncoding RNA TERRA suppresses telomere damage and ALT features, indicating that telomere transcription is a main trigger of ALT activity. Here we show that experimentally increased TERRA transcription not only increases ALT features, as expected, but also causes rapid loss of telomeric DNA through a pathway that requires the endonuclease Mus81. Our data indicate that the ALT mechanism can endanger telomere integrity if not properly controlled and point to TERRA transcription as a uniquely versatile target for therapy.

Conserved mammalian muscle mechanics during eccentric contractions.

Skeletal muscle has a broad range of biomechanical functions, including power generation and energy absorption. These roles are underpinned by the force-velocity relationship, which comprises two distinct components: a concentric and an eccentric force-velocity relationship. The concentric component has been extensively studied across a wide range of muscles with different muscle properties. However, to date, little progress has been made in accurately characterising the eccentric force-velocity relationship in mammalian muscle with varying muscle properties. Consequently, mathematical models of this muscle behaviour are based on a poorly understood phenomenon. Here, we present a comprehensive assessment of the concentric force-velocity and eccentric force-velocity relationships of four mammalian muscles (soleus, extensor digitorum longus, diaphragm and digastric) with varying biomechanical functions, spanning three orders of magnitude in body mass (mouse, rat and rabbits). The force-velocity relationship was characterised using a hyperbolic-linear equation for the concentric component a hyperbolic equation for the eccentric component, at the same time as measuring the rate of force development in the two phases of force development in relation to eccentric lengthening velocity. We demonstrate that, despite differences in the curvature and plateau height of the eccentric force-velocity relationship, the rates of relative force development were consistent for the two phases of the force-time response during isovelocity lengthening ramps, in relation to lengthening velocity, in the four muscles studied. Our data support the hypothesis that this relationship depends on cross-bridge and titin activation. Hill-type musculoskeletal models of the eccentric force-velocity relationship for mammalian muscles should incorporate this biphasic force response. KEY POINTS: The capacity of skeletal muscle to generate mechanical work and absorb energy is underpinned by the force-velocity relationship. Despite identification of the lengthening (eccentric) force-velocity relationship over 80 years ago, no comprehensive study has been undertaken to characterise this relationship in skeletal muscle. We show that the biphasic force response seen during active muscle lengthening is conserved over three orders of magnitude of mammalian skeletal muscle mass. Using mice with a small deletion in titin, we show that part of this biphasic force profile in response to muscle lengthening is reliant on normal titin activation. The rate of force development during muscle stretch may be a more reliable way to describe the forces experienced during eccentric muscle contractions compared to the traditional hyperbolic curve fitting, and functions as a novel predictor of force-velocity characteristics that may be used to better inform hill-type musculoskeletal models and assess pathophysiological remodelling.

Hyperextended telomeres promote formation of C-circle DNA in telomerase positive human cells.

Telomere length maintenance is crucial to cancer cell immortality. Up to 15% of cancers utilize a telomerase-independent, recombination-based mechanism termed alternative lengthening of telomeres (ALT). Currently, the primary ALT biomarker is the C-circle, a type of circular DNA with extrachromosomal telomere repeats (cECTRs). How C-circles form is not well characterized. We investigated C-circle formation in the human cen3tel cell line, a long-telomere, telomerase+ (LTT+) cell line with progressively hyper-elongated telomeres (up to ∼100 kb). cECTR signal was observed in 2D gels and C-circle assays but not t-circle assays, which also detect circular DNA with extrachromosomal telomere repeats. Telomerase activity and C-circle signal were not separable in the analysis of clonal populations, consistent with C-circle production occurring within telomerase+ cells. We observed similar cECTR results in two other LTT+ cell lines, HeLa1.3 (∼23 kb telomeres) and HeLaE1 (∼50 kb telomeres). In LTT+ cells, telomerase activity did not directly impact C-circle signal; instead, C-circle signal correlated with telomere length. LTT+ cell lines were less sensitive to hydroxyurea than ALT+ cell lines, suggesting that ALT status is a stronger contributor to replication stress levels than telomere length. Additionally, the DNA repair-associated protein FANCM did not suppress C-circles in LTT+ cells as it does in ALT+ cells. Thus, C-circle formation may be driven by telomere length, independently of telomerase and replication stress, highlighting limitations of C-circles as a stand-alone ALT biomarker.

Is human height based on a Lucas sequence relationship between the foot height, tibial length, femur length and upper body length?

This is a retrospective chart and radiographic review of 145 patients who underwent full-body EOS imaging; 109 males and 36 females. The mean ages of the female and male subsets are 28.8 (SD = 11.6) years and 29.5 (SD = 11.8) years, respectively. The sum of the foot height (Ft) and the tibial length (T) for each subject was compared to their femur length (Fe). Subsequently, the sum of the tibial (T) and femoral lengths (Fe) were compared to their respective upper body lengths (UB), as measured from the tops of the femoral heads. A linear regression test was performed to determine whether a Lucas sequence-based relationship exists between Ft + T and Fe, and between T + Fe and UB. The regression for the relationship between Ft + T and Fe for the entire cohort (R = 0.82, R2 = 0.70), the female subset (R = 0.94, R2 = 0.88) and the male subset (R = 0.75, R2 = 0.57), all demonstrated a strong positive correlation between Ft + T and Fe and showed that Ft + T is a likely predictor of Fe. The regression test for the entire cohort demonstrated a moderately positive correlation between T + Fe and UB (R = 0.41, R2 = 0.17, F(1, 145) = 29.42, p = 2.4E-07). A stronger correlation was found for the relationship between T + Fe and UB (R = 0.57, R2 = 0.32, F(1, 35) = 16.64, p = 2.5E-05) for the female subset relative to the male subset (R = 0.20, R2 = 0.038, F(1, 35) = 4.37, p = 0.04). There appears to be a Lucas sequence relationship between the lengths of the foot height, tibial length, femoral length and upper body length, which together make up standing height. This mathematical proportion relationship is stronger in females than males.

Kinetics of skeletal muscle regeneration after mild and severe muscle damage induced by electrically-evoked lengthening contractions.

Post-injury skeletal muscle regeneration requires interactions between myogenic and non-myogenic cells. Our knowledge on the regeneration process is mainly based on models using toxic, chemical, or physical (e.g., based on either muscle freezing or crushing) injury. Strikingly, the time course and magnitude of changes in the number of cells involved in muscle regeneration have been poorly described in relation to mild and severe muscle damage induced by electrically-evoked lengthening contractions. We investigated for the first time the kinetics and magnitude of changes in mononuclear cells in relation to the extent of muscle damage. Mild and severe injury were induced in vivo in the mouse gastrocnemius muscle by 1 and 30 electrically-evoked lengthening contractions, respectively. Several days after muscle damage, functional analysis of maximal torque production and histological investigations were performed to assess the related cellular changes. Torque recovery was faster after mild injury than after severe muscle damage. More necrotic and regenerating myofibers were observed after severe muscle damage as compared with mild injury, illustrating an association between functional and histological alterations. The kinetics of changes in muscle stem cells (total, proliferating, and differentiating), endothelial cells, fibro-adipogenic progenitors (FAPs), and macrophages in the regenerating muscle was similar in mild and severe models. However, the magnitude of changes in the number of differentiating muscle stem cells, hematopoietic cells, among which macrophages, and FAPs was higher in severe muscle damage. Collectively, our results show that the amount of myogenic and non-myogenic cells varies according to the extent of skeletal muscle injury to ensure efficient skeletal muscle regeneration while the kinetics of changes is independent of muscle tissue alterations. The possibility to experimentally modulate the extent of muscle damage will be useful to further investigate the cellular and molecular events involved in muscle regeneration.

Effect of high-fat diet on isometric, concentric and eccentric contractile performance of skeletal muscle isolated from female CD-1 mice.

Despite evidence inferring muscle and contractile mode-specific effects of high-fat diet (HFD), no study has yet considered the impact of HFD directly on eccentric muscle function. The present work uniquely examined the effect of 20-week HFD on the isometric, concentric and eccentric muscle function of isolated mouse soleus (SOL) and extensor digitorum longus (EDL) muscles. CD-1 female mice were randomly split into a control (n = 16) or HFD (n = 17) group and for 20 weeks consumed standard lab chow or HFD. Following this period, SOL and EDL muscles were isolated and assessments of maximal isometric force and concentric work loop (WL) power were performed. Each muscle was then subjected to either multiple concentric or eccentric WL activations. Post-fatigue recovery, as an indicator of incurred damage, was measured via assessment of concentric WL power. In the EDL, absolute concentric power and concentric power normalised to muscle mass were reduced in the HFD group (P < 0.038). HFD resulted in faster concentric fatigue and reduced eccentric activity-induced muscle damage (P < 0.05). For the SOL, maximal isometric force was increased, and maximal eccentric power normalised to muscle mass and concentric fatigue were reduced in the HFD group (P < 0.05). HFD effects on eccentric muscle function are muscle-specific and have little relationship with changes in isometric or concentric function. HFD has the potential to negatively affect the intrinsic concentric and eccentric power-producing capacity of skeletal muscle, but a lack of a within-muscle uniform response indicates disparate mechanisms of action which require further investigation.

Experiences of vaginal lengthening treatment and sexual well-being in women with Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome: An interview study.

OBJECTIVE: To explore how women with Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome experience dilation or surgical vaginal lengthening treatment, and their current sexual well-being. DESIGN: A qualitative interview study. SETTING: Denmark. POPULATION: Women aged ≥25 years diagnosed with MRKH syndrome. METHODS: Semi-structured video interviews were conducted with 18 women. Interviews lasted a median of 92 min and were digitally recorded, transcribed and anonymised. Data were analysed using thematic analysis. MAIN OUTCOME MEASURES: A qualitative analysis of women's experiences. RESULTS: The analysis identified three themes. Firstly, Experiences with dilation treatment revealed dilation as an awkward routine, especially for adolescents living with parents and yet to sexually debut. While some experienced successful vaginal lengthening, others faced treatment failure leading to frustration and self-blame. Secondly, Experiences with neovaginal surgery described the procedure as extremely painful but resulting in a 'normal size' vagina. Some women felt that the procedure had negatively impacted their self-confidence, and all underscored the importance of maturity before opting for surgery. Lastly, Current sex life and sexual well-being indicated a well-functioning sex life for many women, but with reported low sexual confidence and genital self-image due to the perceived 'deviance' of their genitalia. CONCLUSIONS: For women with MRKH syndrome, vaginal lengthening treatment, whether through dilation or surgery, may result in a 'normal size' vagina. However, according to the women's experiences, vaginal lengthening treatment does not adequately foster positive sexual esteem and genital self-image.

Minimum Intensity of Daily Six Eccentric Contractions to Increase Muscle Strength and Size.

Our previous study showed that daily six maximal eccentric contractions that were performed 5 days a week for 4 weeks increased maximal voluntary isometric (MVC-ISO), concentric (MVC-CON), and eccentric contraction (MVC-ECC) strength of the elbow flexors and muscle thickness of biceps brachii and brachialis (MT) by 8.3 ± 4.9%, 11.1 ± 7.4%, 13.5 ± 11.5%, and 10.6 ± 5.1%, respectively. In the present study, we tested the hypothesis that the muscle strength and MT would still increase when the training intensity was reduced to 2/3 or 1/3 of the peak MVC-ECC torque. Thirty-six healthy young (19-24 years) adults who had not performed resistance training were placed to three groups (n = 12/group): 2/3MVC or 1/3MVC that performed six eccentric contractions with 2/3 or 1/3 MVC-ECC load using a dumbbell 5 days a week for 4 weeks or control group that did not perform any training. Changes in the MVC-ISO, MVC-CON, MVC-ECC torque, and MT before and after the 4-week period were compared among the groups and with the group of the previous study in which six maximal eccentric contractions were performed 5 days a week for 4 weeks (MVC group; n = 12). The control and 1/3MVC groups showed no significant changes in any measures. Significant (p < 0.05) increases in MVC-ISO (10.3 ± 11.4%), MVC-CON (10.9 ± 9.5%), and MVC-ECC (9.3 ± 8.8%) torque and MT (10.1 ± 9.2%) were observed for the 2/3MVC group. These changes were not significantly different from those of the MVC group. These results suggest that the 2/3-intensity eccentric contractions with a dumbbell are as effective as maximal-intensity isokinetic eccentric contractions to induce muscle adaptations.

Weekly minimum frequency of one maximal eccentric contraction to increase muscle strength of the elbow flexors.

PURPOSE: Our previous study showed that one 3-s maximal eccentric contraction a day performed 5 days a week for 4 weeks (5DW) increased maximal voluntary contraction (MVC) strength of the elbow flexors more than 10%. The present study examined whether muscle strength would still increase when the frequency was reduced to 2 days or 3 days per week. METHODS: Twenty-six healthy young adults were recruited in the present study and placed to two groups (n = 13/group) based on the weekly frequency of the one 3-s maximal eccentric contraction for two (2DW) or three days per week (3DW) for 4 weeks. Changes in MVC-isometric, MVC-concentric, MVC-eccentric torque of the elbow flexors, and muscle thickness of biceps brachii and brachialis (MT) before and after the 4-week training were compared between 2DW and 3DW groups, and also compared to the 5DW group in the previous study. RESULTS: The 2DW group showed no significant changes in MVC torque. Significant (P < 0.05) increases in MVC-concentric (2.5 ± 10.4%) and MVC-eccentric (3.9 ± 4.9%) torque were observed for the 3DW group, but the magnitude of the increase was smaller (P < 0.05) than that presented by the 5DW group (12.8 ± 9.6%, 12.2 ± 7.8%). No significant changes in MT were evident for any of the groups. CONCLUSION: These results suggest that at least three days a week are necessary for the one 3-s maximal eccentric contraction to be effective for increasing muscle strength, and more frequent sessions in a week (e.g., 5 days) appear to induce greater increases in muscle strength.

Ulnar lengthening for children with forearm deformity from hereditary multiple exostoses: a retrospective study from a tertiary medical center.

BACKGROUND: Patients with hereditary multiple exostosis (HME) usually present with forearm deformity with or without radial head dislocation. Ulna lengthening has been proposed to address this condition. Exostosis resection plus ulna lengthening has been adopted in our hospital since 2008, and patients with this condition were retrospectively reviewed. Herein, we aimed to investigate the optimal timing and clinical outcomes of this surgical approach. METHODS: In all, thirty-five patients (40 forearms), including 22 boys and 13 girls, were enrolled in our study from July 2014 to September 2020. We divided the patients into 4 groups based on the age when they received surgery and the status of the radial head. Pronation and supination of the forearm, flexion and extension of the elbow, wrist ulnar deviation and wrist radial deviation, and radiological parameters including ulnar length (UL), ulnar variance (UV), the percentage of radial bowing (RB/RL), radio articular angle (RAA) and carpal slip (CS), were assessed and recorded. RESULTS: The mean UL was significantly improved after surgery in four Groups (P<0.05). In patients with radial head dislocation, we found significant improvement in forearm, wrist function and elbow flexion (p < 0.05). For the patients with radial head dislocation, the juniors demonstrated better improvement in % RB and RAA (p<0.05, p = 0.003 and 0.031). CONCLUSION: Exostosis resection and ulna lengthening with unilateral external fixation can effectively improve the function and radiological parameters of forearm deformity in HME children. For patients with radial head dislocation, early surgery can achieve better results. For patients not associated with radial head dislocation, we recommend regular follow-up and surgical treatment after 10 years of age.

Prospective study of nasal growth in bilateral cleft lip and palate patients after naso-alveolar moulding and primary columella lengthening compared to controls at 5, 10 and 20 years.

INTRODUCTION: A short columella, wide nostrils and a flat nasal tip are common features in patients with bilateral complete cleft lip and palate (BCLP). The objective of this study was to evaluate nasal morphology during growth in patients treated with naso-alveolar moulding (NAM) and primary surgical columella lengthening (PCL) compared with matched non-cleft individuals. STUDY DESIGN: Prospective longitudinal case-control study. PARTICIPANTS AND METHODS: Thirty-four consecutively treated BCLP patients at 5 and 10 years and at the end of growth (19.7 ± 2.0 years) were compared through normalized photogrammetry to a control of 34 age and sex-matched non-cleft individuals. Regression Models for Panel Data assessed how nasal measurements were influenced by surgery, age and gender. RESULTS: Nasal protrusion was equal to non-cleft controls at all ages. Length of the columella was also comparable to controls at 5 and 10 years, but significantly shorter at the end of growth. Inter-alar and nasal tip width and nasolabial angle were significantly wider than controls at all ages: More than 60% of the patients have asked for correction of the nasal width, but no early surgery for columella lengthening was needed. CONCLUSIONS: NAM and PCL have provided a nasal projection close to that of non-cleft individuals until adulthood, while length of the columella was physiological at 5 and 10, but shorter than controls at age 20. Width of the nasal tip and width of the alar bases were significantly wider than the controls and eventually required secondary nasal width correction in over two thirds of the sample.