CSF1R-dependent macrophages control postnatal somatic growth and organ maturation.

Homozygous mutation of the Csf1r locus (Csf1rko) in mice, rats and humans leads to multiple postnatal developmental abnormalities. To enable analysis of the mechanisms underlying the phenotypic impacts of Csf1r mutation, we bred a rat Csf1rko allele to the inbred dark agouti (DA) genetic background and to a Csf1r-mApple reporter transgene. The Csf1rko led to almost complete loss of embryonic macrophages and ablation of most adult tissue macrophage populations. We extended previous analysis of the Csf1rko phenotype to early postnatal development to reveal impacts on musculoskeletal development and proliferation and morphogenesis in multiple organs. Expression profiling of 3-week old wild-type (WT) and Csf1rko livers identified 2760 differentially expressed genes associated with the loss of macrophages, severe hypoplasia, delayed hepatocyte maturation, disrupted lipid metabolism and the IGF1/IGF binding protein system. Older Csf1rko rats developed severe hepatic steatosis. Consistent with the developmental delay in the liver Csf1rko rats had greatly-reduced circulating IGF1. Transfer of WT bone marrow (BM) cells at weaning without conditioning repopulated resident macrophages in all organs, including microglia in the brain, and reversed the mutant phenotypes enabling long term survival and fertility. WT BM transfer restored osteoclasts, eliminated osteopetrosis, restored bone marrow cellularity and architecture and reversed granulocytosis and B cell deficiency. Csf1rko rats had an elevated circulating CSF1 concentration which was rapidly reduced to WT levels following BM transfer. However, CD43hi non-classical monocytes, absent in the Csf1rko, were not rescued and bone marrow progenitors remained unresponsive to CSF1. The results demonstrate that the Csf1rko phenotype is autonomous to BM-derived cells and indicate that BM contains a progenitor of tissue macrophages distinct from hematopoietic stem cells. The model provides a unique system in which to define the pathways of development of resident tissue macrophages and their local and systemic roles in growth and organ maturation.

Creating a collaborative program for the care of children with colorectal and pelvic problems.

The treatment of patients with colorectal disorders and their associated urologic, gynecologic, gastrointestinal, spinal, and orthopedic anomalies requires care from various medical and surgical specialties over the course of their lifetime. This is ideally handled by a collaborative center which facilitates the assessment and development of a long-term patient care plan among multiple specialties which can enhance the quality of care, improve communication among different specialties, and improve patient satisfaction and outcomes. We describe the process, as well as lessons learned in developing such a center.

Overgrowth syndromes and new therapies.

Overgrowth syndromes represent a diverse group of disorders with overlapping features. Interdisciplinary management by a team of experts in vascular anomalies is crucial for establishing the correct diagnosis and optimizing outcomes for these patients. Unique management considerations include increased risk for thrombosis and in some cases, cancer. In recent years, research has demonstrated that these disorders are primarily caused by somatic mutations in growth pathways, particularly the PI3K-mTOR pathway. This improved understanding had led to promising new therapies for this group of patients.

Orthopedic issues in vascular anomalies.

Vascular anomalies impact the musculoskeletal system dependent on the tissue involved (skin, subcutis, muscle, cartilage, or bone), the extent of involvement, and the type of anomalous vessels (arteries, capillaries, veins, or lymphatics). These malformations can cause a multitude of musculoskeletal problems for the patient. Leg-length discrepancy, intra-articular involvement, muscular lesions, and primary or secondary scoliosis are amongst the issues that patients face. All of these problems can cause pain, deformity, and a range of functional limitations. Surgical and nonsurgical treatment plans have a role in patient care. Patients with vascular anomalies may also suffer from life-threatening cardiovascular and hematologic abnormalities. For those patients who undergo surgery, the thromboembolic risk is elevated, wound breakdown and infection are much more common, and bleeding risk continues well into the postoperative course. Because of the complex nature of these disorders, the clinician must have a full understanding of the types of lesions, their natural history, appropriate diagnostic studies, associated medical problems, indications for treatment, and treatment options. For severe malformations, especially syndromes such as CLOVES and Klippel- Trenaunay syndrome, interdisciplinary team management is essential for the best outcomes.

Management of Critical Bone Defects.

Bone defects may occur after trauma, infection, or oncologic resection. A critical sized defect is any defect that is unable to spontaneously heal and will require secondary procedure(s) to obtain union. Autologous grafting is widely used, but may be insufficient to obtain union in these situations. Other options include the induced membrane technique, bone transport through distraction osteogenesis, or free vascularized bone transfer. This chapter will review options for obtaining graft, and the aforementioned special techniques for managing these challenging problems.

Knee orthopedic problems in newborns and infancy: a review.

PURPOSE OF REVIEW: We present the reader with insight on the most common disorders of the knee in newborns and infants. Knee issues in this population may confuse the first contact physicians due to certain peculiarities of the immature immune system, small size and underdevelopment of joint anatomy. Data presented here are recent and significant, and something to bear in mind when caring for children of this age. RECENT FINDINGS: With the advent of new diagnostic methods, a shift in the causative agent of pediatric knee infections has been noted. Minimally invasive methods such as arthrocentesis and arthroscopy are successfully employed in treatment of knee problems in newborns and infants. A trial of conservative therapy in congenital patellar instability can give good results, and obviate the need for surgery in some cases. Various syndromes that affect the knee have specific characteristics that need to be recognized early to avoid problems in the future. SUMMARY: Although rare, knee problems in infants can and do occur. Their cause varies significantly and good outcomes require a multidisciplinary approach. Early diagnosis, referral and initiation of treatment protocols can significantly influence the fate of the joint and with it the patients' functional status for life.

Effect of horse riding equipment in activity of trunk and lower limb muscles in equine-assisted therapy

Equine-assisted therapy uses the horse in rehabilitation and/or education of people, such as Down syndrome(SD), cerebral palsy(PC)and intellectual disability(DI). In context, the rehabilitation program and horse riding equipment should be usedaccording to the specific characteristics of each individual, becoming an ally in the quest for excellence in equine-assisted therapy programs. The aim was to evaluate the effect of riding equipment used in equine-assisted therapy on the muscular activityof trunk and lower limb of individuals with SD, PC and DI. The study included 15 individuals equally assigned to each group: SD, PC and DIwith a mean age of 16.2 (±1.10), 16 (±1.22)e 16 (±0) years,respectively. The analysis of muscle activity was performed through surface electromyography, using four variations of horse riding equipment: saddle with and without feet supported on the stirrups and blanket with and without feet supported on the stirrups. Sigma Stat 3.5®software was used for statistical analysis.The Shapiro Wilk's test was used for normality of the data, the Bartlett test for homogeneity of the variances and the Kruskal-Wallis test for repeated measures with no normal distribution.Statistically significant differences were observed forp<0.05.The SDgroup presented a greater muscular activity of trunk and lower limbs with blanket equipment without the feet supported in the stirrups (H = 15.078, p = 0.002), as in the DI group (H=8.302, p = 0.040), while inPCgroup was the saddle with feet supported in the stirrups (H=11.137,p = 0.011). The choice of riding equipment used in equine-assisted therapy interferes differently in the pattern of muscular activation of the trunk and the lower limbs, according to the pathological processes of the practitioners. It should be an important aspect to consider when planninga treatment.

What's New in Genetic Skin Diseases.

The discoveries of new genes underlying genetic skin diseases have occurred at a rapid pace, supported by advances in DNA sequencing technologies. These discoveries have translated to an improved understanding of disease mechanisms at a molecular level and identified new therapeutic options based on molecular targets. This article highlights just a few of these recent discoveries for a diverse group of skin diseases, including tuberous sclerosis complex, ichthyoses, overgrowth syndromes, interferonopathies, and basal cell nevus syndrome, and how this has translated into novel targeted therapies and improved patient care.

Best practice guidelines regarding diagnosis and management of patients with type II collagen disorders.

PURPOSE: Skeletal dysplasias comprise a heterogeneous group of inherited disorders of development, growth, and maintenance of the human skeleton. Because of their relative rarity and wide phenotypic variability, patients should be accurately identified, uniformly assessed, and managed by clinicians who are aware of their potential complications and possess the knowledge and resources to treat them effectively. This study presents expert guidelines developed to improve the diagnosis and management of patients with type II collagen skeletal disorders to optimize clinical outcomes. METHODS: A panel of 11 multidisciplinary international experts in the field of skeletal dysplasia participated in a Delphi process, which comprised analysis of a thorough literature review with subsequent generation of 26 diagnosis and care recommendations, followed by two rounds of anonymous voting with an intervening face-to-face meeting. Those recommendations with more than 80% agreement were considered as consensual. RESULTS: After the first voting round, consensus was reached to support 12 of 26 (46%) statements. After the panel discussion, the group reached consensus on 22 of 24 revised statements (92%). CONCLUSIONS: Consensus-based, expert best practice guidelines developed as a standard of care to assist accurate diagnosis, minimize associated health risks, and improve clinical outcomes for patients with type II collagen skeletal dysplasias.

Pulmonary thromboembolic events in patients with congenital lipomatous overgrowth, vascular malformations, epidermal nevi, and spinal/skeletal abnormalities and Klippel-Trénaunay syndrome.

OBJECTIVE: Patients with Klippel-Trénaunay syndrome (KTS) and congenital lipomatous overgrowth, vascular malformations, epidermal nevi, and spinal/skeletal abnormalities (CLOVES) syndrome have central phlebectasia and enlarged persistent embryonic veins that are often incompetent and prone to thromboembolism. The purpose of the study was to determine the presence of phlebectasia and the incidence of symptomatic pulmonary embolism (PE). METHODS: A retrospective review was conducted of patients referred to the Vascular Anomalies Center at our institution during a 21-year period who were diagnosed with KTS and CLOVES syndrome. Of these, the patients who had PE were screened for thromboembolic risk factors in addition to phlebectasia and the presence of persistent embryonic veins. Treatment outcomes following subsequent endovascular and medical therapies were reported. RESULTS: A total of 12 KTS patients of 96 (12.5%) and 10 CLOVES syndrome patients of 110 (9%) suffered PE. Fourteen patients (64%) developed PE after surgery or sclerotherapy. All of the patients had abnormally dilated central or persistent embryonic veins; 20 patients were treated with anticoagulation (1 died at the time of presentation, and no information was available for 1) after PE, and 14 (66%) patients underwent subsequent endovascular treatment. Five patients developed recurrent PE despite anticoagulation. Two of the patients died of PE. No patients treated with endovascular closure of dilated veins had subsequent evidence of PE. CONCLUSIONS: Patients with KTS and CLOVES syndrome are at high risk for PE, particularly in the postoperative period.

Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA)-related overgrowth spectrum: A brief report.

A patient with extensive multisystem overgrowth caused by a somatic gain of function PIK3CA-mutation is described. This case is an example of the clinical diversity of the PIK3CA-Related Overgrowth Spectrum (PROS) as the patient had overlapping features of Congenital Lipomatous Overgrowth Vascular malformations Epidermal nevi and Skeletal abnormalities (CLOVES) syndrome and Megalencephaly-Capillary malformation Polymicrogyria (MCAP) syndrome and underlines the utility of this umbrella term.

Aplasia cutis congénita con defecto óseo subyacente: evolución favorable tras manejo conservador.

La aplasia cutis congénita es una rara alteración caracterizada por la ausencia de áreas localizadas de piel en el momento del nacimiento. Suele manifestarse como una lesión solitaria localizada principalmente en el cuero cabelludo, que puede estar asociada con otras malformaciones congénitas. Las complicaciones pueden ser fatales, por lo que es necesario un tratamiento individualizado que vendrá determinado por el tamaño, localización y grado de afectación de estructuras subyacentes. Presentamos un caso de aplasia cutis congénita del cuero cabelludo con múltiples lesiones y defecto óseo subyacente de 3 × 1.5 cm de tamaño, pero sin otras anomalías asociadas. El manejo conservador permitió una adecuada y completa epitelización cutánea con cierre del defecto óseo subyacente sin necesidad de procedimientos invasivos.

Alteraciones musculoesqueléticas en los niños afectados de pie zambo tratatos con método Ponsetti / No disponible

Introducción: El pie zambo, es una de las malformaciones musculoesqueléticas más frecuentes en la edad infantil. A pesar de los buenos resultados en la corrección biomecánica del pié mediante el método Ponseti, las pequeñas alteraciones musculares no son infrecuentes, interfiriendo en la progresión e incluso en la corrección del pie. La terapia manual osteopática y la fisioterapia son necesarias en el seguimiento de este tipo de pacientes para optimizar los tratamientos. Objetivo: Exponer la relación existente entre el pie zambo y las alteraciones de la pisada en niños, y por tanto la interferencia del captor postural del pie en el desarrollo postural del niño. Material y Métodos: Se ha realizado una revisión bibliográfica comentada de una serie de artículos que relacionan las alteraciones estructurales de los pies equinovaros congénitos, con las alteraciones del desarrollo muscular del pie y de la pierna, así como las diferencias cuantitativas de la baropodometría en niños tratados por pie zambo con el método Ponseti. Resultados: Estudio de revisión sistemática, retrospectivo, con una muestra de análisis bibliográfico integrado por 15 artículos (n=15), que cumplieron criterios de selección en dos fases de análisis, lo cual supone un 24’19 % de los artículos que cumplieron los criterios de selección (n= 62) (inclusión y exclusión), y el 4’02 % del total de artículos encontrados (n= 373). Conclusiones: El estudio de la pisada del niño en las diferentes fases del tratamiento del pie zambo, y la intervención temprana para la optimización del desarrollo del sistema muscular, de los apoyos plantares y de la distribución de cargas, podría aportar no sólo un elemento de mejora a nivel local, sino del desarrollo postural global del niño

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Resgistro Baropodométrico y establiométrico en niños con pie zambo tratados con método Ponsett. Intervención osteopática / No disponible

Introducción: El pie zambo, o Pie Equino Varo Aducto Congénito, es una de las malformaciones musculoesqueléticas más comunes. Los componentes de la deformidad son el equinismo, varismo, supinación del retropié, y aducción del antepié, existiendo una alteración de la morfología de las articulaciones del tarso, debida a las deformidades óseas. Objetivo: Comprobar las alteraciones en los apoyos plantares de los niños afectos de pie zambo, mediante el análisis estabilométrico y baropodométrico. Estudiar las modificaciones en los apoyos plantares de estos niños tras el tratamiento osteopático, mediante la mejora de la movilidad a nivel de la pelvis o la intervención en la musculatura cervical. Material y métodos: Se llevó a cabo un ensayo clínico aleatorizado, doble ciego. Se estudió a 24 niños afectos de pie zambo, divididos en 3 grupos. Se realizó una técnica osteopática a cada uno de los dos grupos de intervención, y el tercer grupo fue un grupo control activo. Se realizó una baropodometría y una estabilometría mediante la plataforma podoprint aluminium antes e inmediatamente después de la aplicación de la técnica. Conclusiones: Los niños afectos de pie zambo unilateral presentan en su mayoría (93’75%) un apoyo de peso sobre el retropié contralateral. En los casos bilaterales, el punto de máxima presión se localiza en el retropié derecho en un 50% de los casos. La modificación de tensiones a nivel pélvico, produjo mayores cambios en la distribución de cargas en los pies, que el tratamiento a nivel cervical

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Smart and Controllable rAAV Gene Delivery Carriers in Progenitor Cells for Human Musculoskeletal Regenerative Medicine with a Focus on the Articular Cartilage.

Cell therapy using mesenchymal stem cells (MSCs) is a powerful tool for the treatment of various diseases and injuries. Still, important limitations including the large amounts of cells required for application in vivo and the age-related decline in lifespan, proliferation, and potency may hinder the use of MSCs in patients. In this regard, gene therapy may offer strong approaches to optimize the use of MSCs for regenerative medicine. Diverse nonviral and viral gene vehicles have been manipulated to genetically modify MSCs, among which the highly effective and relatively safe recombinant adeno-associated viral (rAAV) vectors that emerged as the preferred gene delivery system to treat human disorders. Yet, clinical adaptation of such gene vehicles may be limited by several hurdles, including the possibility of dissemination to nontarget sites and the presence of immune and toxic responses in the host organism that may impair their therapeutic actions. The use of smart biomaterials acting as interfaces to enhance the temporal and spatial presentation of therapeutic agents in the target place and/or acting as scaffolding for MSC growth is an innovative, valuable approach to overcome these shortcomings that else restrain the efficacy of such potent cell populations. Here, we provide an overview on the most recent tissue engineering approaches based on the use of biomaterials acting as vehicles for rAAV vectors to target MSCs directly in the recipient (in vivo strategy) or as supportive matrices for rAAV-modified MSCs for indirect cell reimplantation (ex vivo strategy) as means to activate the reparative processes in tissues of the musculoskeletal system.

A less intensive bracing protocol for pectus carinatum.

OBJECTIVES: Despite the widespread use of bracing to correct Pectus carinatum (PC) there is no consensus in the number of hours per day patients are instructed to wear the brace. In our practice, we use a less rigorous protocol of 8-12h/day. We sought to evaluate our results and those in the literature to determine whether more intensive usage is necessary. STUDY DESIGN: We reviewed the outcomes of patients with PC treated at our institution between 2012 and 2015. We searched MEDLINE, EMBASE and Web of Science for studies describing the use of bracing to correct PC. RESULTS: Seventy-five patients presented with PC at our institution. Among those who were offered bracing and had adequate follow-up (n=32), the success rate (full correction or improvement) was 90.6%. The compliance rate was 93.8%. Fifteen studies met our inclusion criteria. Our pooled data combining our results with those of other published data showed that less intensive brace usage (<12h/day), when compared to more intensive usage (≥12h/day), is associated with higher patient compliance (89.6% vs. 81.1%) with a similar time to correction (7.3 vs 7.1months) and success rate (85.3% vs. 83.5%). CONCLUSIONS: Implementing a less intensive bracing protocol for PC is successful, efficient and improves compliance. TYPE OF STUDY: Clinical Research. LEVELS OF EVIDENCE: Oxford Centre for Evidence-Based Medicine Level-of-Evidence rating: Level IV.

Combined endovascular and microsurgical treatment of a complex spinal arteriovenous fistula associated with CLOVES syndrome in an adult patient.

CLOVES (congenital lipomatous overgrowth, vascular malformations, epidermal nevi, and scoliosis/skeletal/spinal anomalies) syndrome is a congenital and almost exclusively pediatric syndrome associated with vascular malformations of the neuroaxis. We report the case of a complex spinal arteriovenous fistula in an adult woman with CLOVES syndrome treated using a multidisciplinary approach with endovascular embolization and microsurgical technique, and review the medical literature on this disease.

Physical therapy management of infants and children with hypophosphatasia.

Hypophosphatasia (HPP) is a rare inborn error of metabolism resulting in undermineralization of bone and subsequent skeletal abnormalities. The natural history of HPP is characterized by rickets and osteomalacia, increased propensity for bone fracture, early loss of teeth in childhood, and muscle weakness. There is a wide heterogeneity in disease presentation, and the functional impact of the disease can vary from perinatal death to gait abnormalities. Recent clinical trials of enzyme replacement therapy have begun to offer an opportunity for improvement in survival and function. The role of physical therapy in the treatment of the underlying musculoskeletal dysfunction in HPP is underrecognized. It is important for physical therapists to understand the disease characteristics of the natural history of a rare disease like HPP and how the impairment and activity limitations may change in response to medical interventions. An understanding of when and how to intervene is also important in order to optimally impact body function, lessen structural impairment, and facilitate increased functional independence in mobility and activities of daily living. Individualizing treatment to the child's needs, medical fragility, and setting (home/school/hospital), while educating parents, caregivers, and school staff regarding approved activities and therapy frequency, may improve function and development in children with HPP.