Neither All-Inside, nor Inside-Out, nor Outside-In Repair Demonstrates Superior Biomechanical Properties for Vertical Meniscal Tears: A Systematic Review of Human Cadaveric Studies.

PURPOSE: To systematically review the literature regarding the biomechanical properties of different repair techniques and fixation methods for vertically oriented meniscal tears. METHODS: Human cadaveric studies evaluating the biomechanical properties of different repair techniques for vertically oriented meniscal tears were identified using the PubMed, EMBASE, and Cumulative Index to Nursing & Allied Health databases. Primary outcomes included load to failure, displacement, stiffness, peak contact pressure, and contact area of repaired menisci. Repair techniques from included studies were reclassified into a total of 19 distinct all-inside (AI), inside-out (IO), or outside-in (OI) techniques. RESULTS: Sixteen studies were included (420 total menisci). Contact pressure and area were restored to intact-state values across all 5 compressive load studies at low knee flexion angles but not at greater knee flexion angles (i.e., >60°). There were no significant differences in contact pressure or area between AI, IO, and OI techniques across all studies. Some studies demonstrated statistically significant advantages in tensile properties with IO techniques when compared with AI techniques, whereas others found AI techniques to be superior. No studies directly compared tensile properties of OI techniques with those of AI or IO techniques. Vertical mattress suture configurations resulted in significantly greater load to failure and decreased displacement compared with horizontal mattress configurations in 67% of studies comparing the 2 techniques. There was no difference in the rate of tissue failure in AI (66.97%), IO (60.38%), or OI (66.67%, χ2 = 0.83, P = .66) techniques. CONCLUSIONS: Contact mechanics are reliably restored after repair of vertical meniscal tears at low flexion angles but inconsistently restored at greater flexion angles, regardless of technique. Vertical mattress configurations outperformed horizontal mattress configurations under tensile load. There are conflicting data regarding the comparison of tensile properties between AI and IO techniques. Ultimately, neither AI, IO, nor OI repair demonstrated superior biomechanical properties in the present literature. CLINICAL RELEVANCE: Several repair techniques demonstrate favorable biomechanical properties for vertical meniscal tears under tensile and compressive loads. Neither AI, IO, nor OI repair techniques demonstrate superior biomechanical properties at this time.

The subacromial bursa modulates tendon healing after rotator cuff injury in rats.

Rotator cuff injuries result in more than 500,000 surgeries annually in the United States, many of which fail. These surgeries typically involve repair of the injured tendon and removal of the subacromial bursa, a synovial-like tissue that sits between the rotator cuff and the acromion. The subacromial bursa has been implicated in rotator cuff pathogenesis and healing. Using proteomic profiling of bursa samples from nine patients with rotator cuff injury, we show that the bursa responds to injury in the underlying tendon. In a rat model of supraspinatus tenotomy, we evaluated the bursa's effect on the injured supraspinatus tendon, the uninjured infraspinatus tendon, and the underlying humeral head. The bursa protected the intact infraspinatus tendon adjacent to the injured supraspinatus tendon by maintaining its mechanical properties and protected the underlying humeral head by maintaining bone morphometry. The bursa promoted an inflammatory response in injured rat tendon, initiating expression of genes associated with wound healing, including Cox2 and Il6. These results were confirmed in rat bursa organ cultures. To evaluate the potential of the bursa as a therapeutic target, polymer microspheres loaded with dexamethasone were delivered to the intact bursae of rats after tenotomy. Dexamethasone released from the bursa reduced Il1b expression in injured rat supraspinatus tendon, suggesting that the bursa could be used for drug delivery to reduce inflammation in the healing tendon. Our findings indicate that the subacromial bursa contributes to healing in underlying tissues of the shoulder joint, suggesting that its removal during rotator cuff surgery should be reconsidered.

RPM: An open-source Rotation Platform for open- and closed-loop vestibular stimulation in head-fixed Mice.

Head fixation allows the recording and presentation of controlled stimuli and is used to study neural processes underlying spatial navigation. However, it disrupts the head direction system because of the lack of vestibular stimulation. To overcome this limitation, we developed a novel rotation platform which can be driven by the experimenter (open-loop) or by animal movement (closed-loop). The platform is modular, affordable, easy to build and open source. Additional modules presented here include cameras for monitoring eye movements, visual virtual reality, and a micro-manipulator for positioning various probes for recording or optical interference. We demonstrate the utility of the platform by recording eye movements and showing the robust activation of head-direction cells. This novel experimental apparatus combines the advantages of head fixation and intact vestibular activity in the horizontal plane. The open-loop mode can be used to study e.g., vestibular sensory representation and processing, while the closed-loop mode allows animals to navigate in rotational space, providing a better substrate for 2-D navigation in virtual environments. The full build documentation is maintained at https://ranczlab.github.io/RPM/.

Hedgehog Activation for Enhanced Rotator Cuff Tendon-to-Bone Healing.

BACKGROUND: Rotator cuff repair is a common orthopaedic procedure, yet the rate of failure to heal after surgery is high. Repair site rupture is due to poor tendon-to-bone healing and lack of regeneration of the native fibrocartilaginous enthesis. During development, the enthesis is formed and mineralized by a pool of progenitors activated by hedgehog signaling. Furthermore, hedgehog signaling drives regenerative enthesis healing in young animals, in contrast to older animals, in which enthesis injuries heal via fibrovascular scar and without participation of hedgehog signaling. HYPOTHESIS: Hedgehog activation improves tendon-to-bone healing in an animal model of rotator cuff repair. STUDY DESIGN: Controlled laboratory study. METHODS: A total of 78 adult Sprague-Dawley rats were used. Supraspinatus tendon injury and repair were completed bilaterally, with microsphere-encapsulated hedgehog agonist administered to right shoulders and control microspheres administered to left shoulders. Animals were sacrificed after 3, 14, 28, or 56 days. Gene expression and histological, biomechanical, and bone morphometric analyses were conducted. RESULTS: At 3 days, hedgehog signaling pathway genes Gli1 (1.70; P = .029) and Smo (2.06; P = .0173), as well as Runx2 (1.69; P = .0386), a transcription factor of osteogenesis, were upregulated in treated relative to control repairs. At 14 days, transcription factors of tenogenesis, Scx (4.00; P = .041), and chondrogenesis, Sox9 (2.95; P = .010), and mineralized fibrocartilage genes Col2 (3.18; P = .031) and Colx (1.85; P = .006), were upregulated in treated relative to control repairs. Treatment promoted fibrocartilage formation at the healing interface by 28 days, with improvements in tendon-bone maturity, organization, and continuity. Treatment led to improved biomechanical properties. The material property strength (2.43 vs 1.89 N/m2; P = .046) and the structural property work to failure (29.01 vs 18.09 mJ; P = .030) were increased in treated relative to control repairs at 28 days and 56 days, respectively. Treatment had a marginal effect on bone morphometry underlying the repair. Trabecular thickness (0.08 vs 0.07 mm; P = .035) was increased at 28 days. CONCLUSION: Hedgehog agonist treatment activated hedgehog signaling at the tendon-to-bone repair site and prompted increased mineralized fibrocartilage production. This extracellular matrix production and mineralization resulted in improved biomechanical properties, demonstrating the therapeutic potential of hedgehog agonism for improving tendon-to-bone healing after rotator cuff repair. CLINICAL RELEVANCE: This study demonstrates the therapeutic potential of hedgehog agonist treatment for improving tendon-to-bone healing after rotator cuff injury and repair.

The Posterior Cranial Vertical Line: A Novel Radiographic Marker for Classifying Global Sagittal Alignment.

OBJECTIVE: To define a novel radiographic measurement, the posterior cranial vertical line (PCVL), in an asymptomatic adult population to better understand global sagittal alignment. METHODS: We performed a multicenter retrospective review of prospectively collected radiographic data on asymptomatic volunteers aged 20-79. The PCVL is a vertical plumb line drawn from the posterior-most aspect of the occiput. The horizontal distances of the PCVL to the thoracic apex (TA), posterior sagittal vertical line (PSVL, posterosuperior endplate of S1), femoral head center, and tibial plafond were measured. Classification was either grade 1 (PCVL posterior to TA and PSVL), grade 2 (PCVL anterior to TA and posterior to PSVL), or grade 3 (PCVL anterior to TA and PSVL). RESULTS: Three hundred thirty-four asymptomatic patients were evaluated with a mean age of 41 years. Eighty-three percent of subjects were PCVL grade 1, 15% were grade 2, and 3% were grade 3. Increasing PCVL grade was associated with increased age (p < 0.001), C7-S1 sagittal vertical axis (SVA) (p < 0.001), C2-7 SVA (p < 0.001). Additionally, it was associated with decreased SS (p = 0.045), increased PT (p < 0.001), and increased knee flexion (p < 0.001). CONCLUSION: The PCVL is a radiographic marker of global sagittal alignment that is simple to implement and interpret. Increasing PCVL grade was significantly associated with expected changes and compensatory mechanisms in the aging population. Most importantly, it incorporates cervical alignment parameters such as C2-7 SVA. The PCVL defines global sagittal alignment in adult volunteers and naturally distributes into 3 grades, with only 3% being grade 3 where the PCVL lies anterior to the TA and PSVL.

OptoPi: An open source flexible platform for the analysis of small animal behaviour.

Behaviour is the ultimate output of neural circuit computations, and therefore its analysis is a cornerstone of neuroscience research. However, every animal and experimental paradigm requires different illumination conditions to capture and, in some cases, manipulate specific behavioural features. This means that researchers often develop, from scratch, their own solutions and experimental set-ups. Here, we present OptoPi, an open source, affordable (∼ £600), behavioural arena with accompanying multi-animal tracking software. The system features highly customisable and reproducible visible and infrared illumination and allows for optogenetic stimulation. OptoPi acquires images using a Raspberry Pi camera, features motorised LED-based illumination, Arduino control, as well as irradiance monitoring to fine-tune illumination conditions with real time feedback. Our open-source software (BioImageProcessing) can be used to simultaneously track multiple unmarked animals both in on-line and off-line modes. We demonstrate the functionality of OptoPi by recording and tracking under different illumination conditions the spontaneous behaviour of larval zebrafish as well as adult Drosophila flies and their first instar larvae, an experimental animal that due to its small size and transparency has classically been hard to track. Further, we showcase OptoPi's optogenetic capabilities through a series of experiments using transgenic Drosophila larvae.

The subacromial bursa is a key regulator of the rotator cuff and a new therapeutic target for improving repair.

Rotator cuff injuries result in over 500,000 surgeries performed annually, an alarmingly high number of which fail. These procedures typically involve repair of the injured tendon and removal of the subacromial bursa. However, recent identification of a resident population of mesenchymal stem cells and inflammatory responsiveness of the bursa to tendinopathy indicate an unexplored biological role of the bursa in the context of rotator cuff disease. Therefore, we aimed to understand the clinical relevance of bursa-tendon crosstalk, characterize the biologic role of the bursa within the shoulder, and test the therapeutic potential for targeting the bursa. Proteomic profiling of patient bursa and tendon samples demonstrated that the bursa is activated by tendon injury. Using a rat to model rotator cuff injury and repair, tenotomy-activated bursa protected the intact tendon adjacent to the injured tendon and maintained the morphology of the underlying bone. The bursa also promoted an early inflammatory response in the injured tendon, initiating key players in wound healing. In vivo results were supported by targeted organ culture studies of the bursa. To examine the potential to therapeutically target the bursa, dexamethasone was delivered to the bursa, prompting a shift in cellular signaling towards resolution of inflammation in the healing tendon. In conclusion, contrary to current clinical practice, the bursa should be retained to the greatest extent possible and provides a new therapeutically target for improving tendon healing outcomes. One Sentence Summary: The subacromial bursa is activated by rotator cuff injury and regulates the paracrine environment of the shoulder to maintain the properties of the underlying tendon and bone.

A low-cost device for cryoanesthesia of neonatal rodents.

Studying the development of neural circuits in rodent models requires surgical access to the neonatal brain. Since commercially available stereotaxic and anesthetic equipment is designed for use in adults, reliable targeting of brain structures in such young animals can be challenging. Hypothermic cooling (cryoanesthesia) has been used as a preferred anesthesia approach in neonates. This commonly involves submerging neonates in ice, an approach that is poorly controllable. We have developed an affordable, simple to construct device - CryoPup - that allows for fast and robust cryoanesthesia of rodent pups. CryoPup consists of a microcontroller controlling a Peltier element and a heat exchanger. It is capable of both cooling and heating, thereby also functioning as a heating pad during recovery. Importantly, it has been designed for size compatibility with common stereotaxic frames. We validate CryoPup in neonatal mice, demonstrating that it allows for rapid, reliable and safe cryoanesthesia and subsequent recovery. This open-source device will facilitate future studies into the development of neural circuits in the postnatal brain.

Rerupture and wound complications following Achilles tendon repair: A systematic review.

Despite the relatively high frequency of Achilles ruptures, there is no general consensus on the optimal treatment method. A general trend toward more patients being treated nonoperatively has emerged recently with the advent of functional rehabilitation. However, much of the recent data on this subject has been highly variable. This systematic review focused on Achilles tendon rupture (ATR) treatment outcomes, with a focus on rerupture and complication rates. This systematic review specifically focused on articles regarding ATR treatment that also included rerupture and complication rates. Treatments were divided into three categories: open minimally invasive, open standard, and nonoperative. Bivariate analyses were performed to compare complication and rerupture rates among pairs of treatment options, as well as between early weight bearing versus immobilization. There was significantly higher complications for minimally invasive compared to nonoperative treatment (risk ratio [RR] = 4.4154; p < 0.05), lower complication rates for minimally invasive compared to open treatment (RR = 0.3231; p < 0.05), and higher complications for open standard compared to nonoperative treatment (RR = 5.6350; p < 0.001). There were significantly lower rerupture rates in minimally invasive compared to nonoperative treatment (RR = 0.4085; p < 0.001), a significantly lower rerupture rate in nonoperative treatment compared to open treatment (RR = 0.2282; p < 0.001), and no significant difference in rerupture rates when comparing minimally invasive to open standard treatment. We found that operative treatment is associated with fewer reruptures and more complications than a nonoperative approach. Minimally invasive surgery appears to be associated with a lower rate of complications than open operative treatment.

Risk of distal junctional kyphosis in scheuermann's kyphosis is decreased by selecting the LIV as two vertebrae distal to the first lordotic disc.

PURPOSE: To determine whether (1) distal junctional kyphosis (DJK) is decreased by selecting the stable sagittal vertebra (SSV), versus the vertebra below the 1st lordotic disc (1stLD), as the lowest instrumented level (LIV); (2) DJK is decreased if the LIV is two versus one vertebrae distal to the 1stLD. METHODS: A multi-institution prospective database was queried for SK patients who underwent posterior-only instrumentation and fusion with > 2 year follow-up. DJK was defined as > 10° change in the distal junctional angle postoperative from the preoperative junctional angle. Statistical analysis was performed using t test, chi-square test and logistic regression. RESULTS: Of 94 patients included, 38 (40%) developed radiographic DJK. 31 (39%) patients in whom the LIV was at or distal to the SSV developed DJK, whereas 7 (47%) in whom the LIV was proximal to the SSV developed DJK. 20 (59%) patients in whom the LIV was one vertebra below and 10 (22%) in whom the LIV was two vertebrae below the 1stLD developed DJK. Logistic regression demonstrated a significant increase in DJK development if the LIV was one vertebra below the 1stLD (OR = 3.2 (1.28-8.18)). There was not a significant relationship between DJK development and LIV position relative to the SSV. CONCLUSION: In SK surgery, LIV selection/fusion to two vertebrae below the 1stLD decreased the development of DJK. A significant relationship was not found between DJK development and location of distal fusion level in regards to the SSV, possibly due to the small number of patients who had LIV proximal to SSV.

¿Qué variables facilitan el alta terapéutica en servicios residenciales de tratamiento de las drogodependencias? Estudio en dos comunidades terapéuticas en Cataluña / What variables facilitate therapeutic discharge in residential drug treatment services? A study in two therapeutic communities in Catalonia

La retención en el tratamiento residencial de drogodependencias es el mejor predictor deléxito terapéutico. Quienes finalizan sus tratamientos con una alta terapéutica (AT) presentanuna mejor evolución en su tratamiento integral que quienes no lo hacen. El objetivo de esteestudio fue analizar las variables relacionadas con el alta terapéutica (u otros motivos no deseados de salida precoz del tratamiento) en dos comunidades terapéuticas (CT) profesionales enCataluña. La muestra estuvo conformada por las personas que iniciaron tratamiento en las CTentre marzo de 2018 y marzo de 2020. Para ello se hicieron comparaciones de medias, varianzas y tablas de contingencia. Se ajustó un modelo de regresión logística binaria para determinarvariables predictoras relacionadas con el AT. De 223 pacientes, un 32,8% consiguieron AT. Losdependientes de cocaína y de heroína presentaron un menor número de AT, contrariamente alos consumidores exclusivos de alcohol. Quienes tenían antecedentes de tratamientos previospresentaron un mayor riesgo de abandono. Las personas que refirieron peor estado de saludgeneral, peor calidad de vida, mayor ansiedad, peor estado de ánimo, mayor puntuación en STAI(rasgo o estado), mayor puntuación en el inventario de depresión de Beck o mayor impulsividadobtuvieron menos AT. En conclusión, se identificaron algunas variables capaces de pronosticaruna mayor posibilidad de altas terapéuticas en el tratamiento residencial de las adicciones. Losdías en tratamiento, la percepción de la calidad de vida y el diagnóstico exclusivo de dependenciade alcohol resultaron las variables que mejor predijeron, de forma independiente, el AT. (AU)

Retention is the best predictor of therapeutic success in community-based substance abusetreatment. Those that finalize the treatment having therapeutic discharge (TD) have best resultsafter the treatment than those who don’t get the TD. The objective of this study was analysedvariables related with TD (or another drop-off reasons) in two professionalized therapeuticcommunities (TC) in Catalonia (Spain). The sample included people who started treatment inthe TC between March 2018 and March 2020. Median and variances comparison and contingence tables were performed. A logistic regression was adjusted to determine variables with capacity to predict TD. 223 patients were included and the 32,8% had TD. Patients with exclusivelyalcohol-dependence diagnose had more TD than patients with diagnoses of cocaine-dependence and heroin-dependence. Those who had previous experiences of treatment were riskierof drop-off. Patients who referred worst health status and quality of live, more anxiety, worstmood situation, more punctuation in the STAI test, more punctuation in the Beck depressioninventor or more impulsivity, had less TD. In conclusion some variables with capacity to predicthigh probability of TD in community-based substance abuse treatment were identified. The timespent under treatment, perception of quality of live and the diagnose of alcohol-dependenceexclusively were independent variables that predict better the TD. (AU)

Hedgehog signaling underlying tendon and enthesis development and pathology.

Hedgehog (Hh) signaling has been widely acknowledged to play essential roles in many developmental processes, including endochondral ossification and growth plate maintenance. Furthermore, a rising number of studies have shown that Hh signaling is necessary for tendon enthesis development. Specifically, the well-tuned regulation of Hh signaling during development drives the formation of a mineral gradient across the tendon enthesis fibrocartilage. However, aberrant Hh signaling can also lead to pathologic heterotopic ossification in tendon or osteophyte formation at the enthesis. Therefore, the therapeutic potential of Hh signaling modulation for treating tendon and enthesis diseases remains uncertain. For example, increased Hh signaling may enhance tendon-to-bone healing by promoting the formation of mineralized fibrocartilage at the healing interface, but pathologic heterotopic ossification may also be triggered in the adjacent tendon. Further work is needed to elucidate the distinct functions of Hh signaling in the tendon and enthesis to support the development of therapies that target the pathway.

Intraoperative Scrub Nurse Handoffs Are Associated with Increased Operative Times for Lower Extremity Orthopaedic Sports Procedures.

PURPOSE: The purpose of this study was to evaluate the effect of intraoperative scrub nurse handoffs on surgical times for arthroscopically-assisted anterior cruciate ligament (ACL) reconstructions and hip arthroscopies. METHODS: A retrospective chart review was done at a major, urban academic medical center for all patients who underwent arthroscopically-assisted ACL reconstructions and hip arthroscopies for femoroacetabular impingement syndrome between May 2014 and May 2020. All ACL reconstructions were performed by 1 of 6 sports medicine fellowship-trained surgeons, and all hip arthroscopies were performed by a single surgeon. Operative times, number of scrub nurse handoffs, surgeon, patient demographics, and procedure-specific information were recorded. The association between patient characteristics and the number of handoffs, as well as the association between patient characteristics and operative times, stratified by scrub nurse handoffs, were calculated. A multivariable linear regression was performed to assess the association between intra-operative handoffs and operative times. RESULTS: Eight hundred twenty ACL reconstructions and 269 hip arthroscopies were identified. Multivariable linear regression demonstrated increasing intraoperative scrub nurse handoffs were associated with increased operative times for all patients. For ACL reconstructions, when including all possible covariates, 1 scrub nurse handoff increased operative times by 21.1 minutes (95% confidence interval [CI]: 15.36 to 26.89; P < .001), and 2+ handoffs increased operative times by 34.2 minutes (95% CI: 26.28 to 42.15; P < .001). For hip arthroscopies, 1 scrub nurse handoff increased operative times by 7.0 minutes (95% CI: 0.31 to 13.74; P = .04). CONCLUSION: Although a causal link cannot be made, intraoperative scrub nurse handoffs were associated with statistically significant increase in operative times for both ACL reconstructions and hip arthroscopies. LEVEL OF EVIDENCE: Level III, retrospective cohort study.

Metalloradical activation of carbonyl azides for enantioselective radical aziridination.

Organic azides have been increasingly employed as nitrogen sources for catalytic olefine aziridination due to their ease of preparation and generation of benign N2 as the only byproduct. Among common organic azides, carbonyl azides have not been previously demonstrated as effective nitrogen sources for intermolecular olefin aziridination despite the synthetic utilities of N-carbonyl aziridines. As a new application of metalloradical catalysis, we have developed a catalytic system that can effectively employ the carbonyl azide TrocN3 for highly asymmetric aziridination of alkenes at room temperature. The resulting enantioenriched N-Trocaziridines have been shown as valuable chiral synthons for stereoselective synthesis of other chiral aziridines and various chiral amines. The Co(II)-based metalloradical system, which proceeds with distinctive stepwise radical mechanism, may provide a general method for asymmetric synthesis of chiral aziridines from alkenes with organic azides.

Roles and Regulation of Voltage-gated Calcium Channels in Arrhythmias.

Calcium flowing through voltage-dependent calcium channels into cardiomyocytes mediates excitation-contraction coupling, controls action-potential duration and automaticity in nodal cells, and regulates gene expression. Proper surface targeting and basal and hormonal regulation of calcium channels are vital for normal cardiac physiology. In this review, we discuss the roles of voltage-gated calcium channels in the heart and the mechanisms by which these channels are regulated by physiological signaling pathways in health and disease.

Cocaine addiction is associated with abnormal prefrontal function, increased striatal connectivity and sensitivity to monetary incentives, and decreased connectivity outside the human reward circuit.

Cocaine addiction has been associated with increased sensitivity of the human reward circuit to drug-related stimuli. However, the capacity of non-drug incentives to engage this network is poorly understood. Here, we characterized the functional sensitivity to monetary incentives and the structural integrity of the human reward circuit in abstinent cocaine-dependent (CD) patients and their matched controls. We assessed the BOLD response to monetary gains and losses in 30 CD patients and 30 healthy controls performing a lottery task in a magnetic resonance imaging scanner. We measured brain gray matter volume (GMV) using voxel-based morphometry and white matter microstructure using voxel-based fractional anisotropy (FA). Functional data showed that, after monetary incentives, CD patients exhibited higher activation in the ventral striatum than controls. Furthermore, we observed an inverted BOLD response pattern in the prefrontal cortex, with activity being highest after unexpected high gains and lowest after losses. Patients showed increased GMV in the caudate and the orbitofrontal cortex, increased white matter FA in the orbito-striatal pathway but decreased FA in antero-posterior association bundles. Abnormal activation in the prefrontal cortex correlated with GMV and FA increases in the orbitofrontal cortex. While functional abnormalities in the ventral striatum were inversely correlated with abstinence duration, structural alterations were not. In conclusion, results suggest abnormal incentive processing in CD patients with high salience for rewards and punishments in subcortical structures but diminished prefrontal control after adverse outcomes. They further suggest that hypertrophy and hyper-connectivity within the reward circuit, to the expense of connectivity outside this network, characterize cocaine addiction.

Non Random Distribution of DMD Deletion Breakpoints and Implication of Double Strand Breaks Repair and Replication Error Repair Mechanisms.

BACKGROUND: Dystrophinopathies are mostly caused by copy number variations, especially deletions, in the dystrophin gene (DMD). Despite the large size of the gene, deletions do not occur randomly but mainly in two hot spots, the main one involving exons 45 to 55. The underlying mechanisms are complex and implicate two main mechanisms: Non-homologous end joining (NHEJ) and micro-homology mediated replication-dependent recombination (MMRDR). OBJECTIVE: Our goals were to assess the distribution of intronic breakpoints (BPs) in the genomic sequence of the main hot spot of deletions within DMD gene and to search for specific sequences at or near to BPs that might promote BP occurrence or be associated with DNA break repair. METHODS: Using comparative genomic hybridization microarray, 57 deletions within the intron 44 to 55 region were mapped. Moreover, 21 junction fragments were sequenced to search for specific sequences. RESULTS: Non-randomly distributed BPs were found in introns 44, 47, 48, 49 and 53 and 50% of BPs clustered within genomic regions of less than 700bp. Repeated elements (REs), known to promote gene rearrangement via several mechanisms, were present in the vicinity of 90% of clustered BPs and less frequently (72%) close to scattered BPs, illustrating the important role of such elements in the occurrence of DMD deletions. Palindromic and TTTAAA sequences, which also promote DNA instability, were identified at fragment junctions in 20% and 5% of cases, respectively. Micro-homologies (76%) and insertions or deletions of small sequences were frequently found at BP junctions. CONCLUSIONS: Our results illustrate, in a large series of patients, the important role of RE and other genomic features in DNA breaks, and the involvement of different mechanisms in DMD gene deletions: Mainly replication error repair mechanisms, but also NHEJ and potentially aberrant firing of replication origins. A combination of these mechanisms may also be possible.

Gender as a Modifying Factor Influencing Myotonic Dystrophy Type 1 Phenotype Severity and Mortality: A Nationwide Multiple Databases Cross-Sectional Observational Study.

BACKGROUND: Myotonic Dystrophy type 1 (DM1) is one of the most heterogeneous hereditary disease in terms of age of onset, clinical manifestations, and severity, challenging both medical management and clinical trials. The CTG expansion size is the main factor determining the age of onset although no factor can finely predict phenotype and prognosis. Differences between males and females have not been specifically reported. Our aim is to study gender impact on DM1 phenotype and severity. METHODS: We first performed cross-sectional analysis of main multiorgan clinical parameters in 1409 adult DM1 patients (>18 y) from the DM-Scope nationwide registry and observed different patterns in males and females. Then, we assessed gender impact on social and economic domains using the AFM-Téléthon DM1 survey (n = 970), and morbidity and mortality using the French National Health Service Database (n = 3301). RESULTS: Men more frequently had (1) severe muscular disability with marked myotonia, muscle weakness, cardiac, and respiratory involvement; (2) developmental abnormalities with facial dysmorphism and cognitive impairment inferred from low educational levels and work in specialized environments; and (3) lonely life. Alternatively, women more frequently had cataracts, dysphagia, digestive tract dysfunction, incontinence, thyroid disorder and obesity. Most differences were out of proportion to those observed in the general population. Compared to women, males were more affected in their social and economic life. In addition, they were more frequently hospitalized for cardiac problems, and had a higher mortality rate. CONCLUSION: Gender is a previously unrecognized factor influencing DM1 clinical profile and severity of the disease, with worse socio-economic consequences of the disease and higher morbidity and mortality in males. Gender should be considered in the design of both stratified medical management and clinical trials.

Muscle magnetic resonance imaging abnormalities in X-linked myopathy with excessive autophagy.

INTRODUCTION: X-linked myopathy with excessive autophagy (XMEA) is an X-linked recessive myopathy due to recently reported mutations in the VMA21 gene. METHODS: Four men from 2 separate families were studied. The clinical presentation, genetic data, muscle biopsy, and muscle MRI were analyzed. RESULTS: A known VMA21 mutation, c.163+4A>G, and a new mutation, c.163+3A>G, respectively, were found in the 2 families. The clinical course was characterized by onset in childhood and progressive muscle weakness with a limb-girdle pattern. Muscle biopsy revealed a mild myopathy with an increased number of giant autophagic vacuoles. Whole-body muscle MRI showed that pelvic girdle and proximal thighs were the most and earliest affected territories, with sparing of rectus femoris muscles. Muscle changes essentially consisted of degenerative fatty replacement. CONCLUSIONS: This study highlights a distinctive MRI pattern of muscle involvement, which can be helpful for diagnosis of XMEA, even before muscle biopsy or genetic analysis.