Orthopedic management of the extremities in patients with Morquio A syndrome.

BackgroundMusculoskeletal involvement in Morquio A syndrome (mucopolysaccharidosis IVA; MPS IVA) contributes significantly to morbidity and mortality. While the spinal manifestations of the disorder have received considerable attention in the literature, there have been few reported studies to date to guide the management of the orthopedic problems associated with the lower and upper extremities.PurposeThe objective was to develop recommendations for the management of the extremities in patients with Morquio A syndrome.MethodsA group of specialists in orthopedics, pediatrics and genetics with experience in the management of Morquio A patients convened to review and discuss current clinical practices and to develop preliminary recommendations. Evidence from the literature was retrieved. Recommendations were further refined until consensus was reached.Results and conclusionsThis present article provides a detailed review and discussion of the lower and upper extremity deformities in Morquio A syndrome and presents recommendations for the assessment and treatment of these complications. Key issues, including the importance of early diagnosis and the implications of medical therapy, are also addressed. The recommendations herein represent an attempt to develop a uniform and practical approach to managing patients with Morquio A syndrome and improving their outcomes

Transgastric Pancreatic Necrosectomy: How I Do It

Necrotizing pancreatitis is a serious medical problem that often requires intervention to debride necrotic pancreatic and peripancreatic tissue. Recently, minimally invasive approaches have been applied to pancreatic necrosectomy. The purpose of this report is to review the history of transgastric pancreatic debridement, identify appropriate patient selection criteria, and highlight technical “pearls.” We present this subject matter in the context of our own clinical experience, with a primary focus on a “How I Do It” type of technical description

Microsurgery in pediatric upper limb reconstructions: An overview

Pediatric microsurgery; Brachial plexus palsy; Upper limbMicrocirugía pediátrica; Parálisis del plexo braquial; Extremidad superiorMicrocirurgia pediàtrica; Paràlisi del plexe braquial; Extremitat superiorThe use of microsurgery has spread during the last decades, making resolvable many complex defects considered hitherto inapproachable. Although the small vessel diameter in children was initially considered a technical limitation, the increase in microsurgical expertise over the past three decades allowed us to manage many pediatric conditions by means of free tissue transfers. Pediatric microsurgery has been shown to be feasible, gaining a prominent place in the treatment of children affected by limb malformations, tumors, nerve injuries, and post-traumatic defects. The aim of this current concepts review is to describe the more frequent pediatric upper limb conditions in which the use of microsurgical reconstructions should be considered in the range of treatment options

Impact of elosulfase alfa in patients with morquio A syndrome who have limited ambulation: An open-label, phase 2 study.

Efficacy and safety of elosulfase alfa enzyme replacement therapy (ERT) were assessed in an open-label, phase 2, multi-national study in Morquio A patients aged ≥5 years unable to walk ≥30 meters in the 6-min walk test. Patients received elosulfase alfa 2.0 mg/kg/week intravenously for 48 weeks. Efficacy measures were functional dexterity, pinch/grip strength, mobility in a modified timed 25-foot walk, pain, quality of life, respiratory function, and urine keratan sulfate (KS). Safety/tolerability was also assessed. Fifteen patients received elosulfase alfa, three patients discontinued ERT due to adverse events (two were grade 3 drug-related adverse events, the other was not drug-related), and two patients missed >20% of planned infusions; 10 completed treatment through 48 weeks and received ≥80% of planned infusions (Modified Per Protocol [MPP] population). The study population had more advanced disease than that enrolled in other trials. From baseline to week 48, MPP data showed biochemical efficacy (urine KS decreased 52.4%). The remaining efficacy results were highly variable due to challenges in test execution because of severe skeletal and joint abnormalities, small sample sizes, and clinical heterogeneity among patients. Eight patients showed improvements in one or more outcome measures; several patients indicated improvements not captured by the study assessments (e.g., increased energy, functional ability). The nature of adverse events was similar to other elosulfase alfa studies. This study illustrates the considerable challenges in objectively measuring impact of ERT in very disabled Morquio A patients and highlights the need to examine results on an individual basis. © 2016 The Authors. American Journal of Medical Genetics Part A Published by Wiley Periodicals, Inc

Spatially Correlated Cluster Populations in the Outer Disk of NGC 3184

We use deep (~27.5 mag V-band point-source limiting magnitude) V- and U-band LBT imaging to study the outer disk (beyond the optical radius R_25) of the non-interacting, face-on spiral galaxy NGC 3184 (D = 11.1 Mpc; R_25 = 11.1 kpc) and find that this outer disk contains >1000 objects (or marginally-resolved 'knots') resembling star clusters with masses ~10^2 - 10^4 M_sun and ages up to ~1 Gyr. We find statistically significant numbers of these cluster-like knots extending to ~1.4 R_25, with the redder knots outnumbering bluer at the largest radii. We measure clustering among knots and find significant correlation to galactocentric radii of 1.5 R_25 for knot separations <1 kpc. The effective integrated surface brightness of this outer disk cluster population ranges from 30 - 32 mag arcsec^-2 in V. We compare the HI extent to that of the correlated knots and find that the clusters extend at least to the damped Lyman-alpha threshold of HI column density (2e20 cm^-2; 1.62 R_25). The blue knots are correlated with HI spiral structure to 1.5 R_25, while the red knots may be correlated with the outer fringes of the HI disk to 1.7 R_25. These results suggest that outer disks are well-populated, common, and long-lasting features of many nearby disk galaxies.Comment: Accepted for publication in The Astrophysical Journal. 12 pages, 10 figure

The enigmatic pair of dwarf galaxies Leo IV and Leo V: coincidence or common origin?

We have obtained deep photometry in two 1x1 degree fields covering the close pair of dwarf spheroidal galaxies (dSph) Leo IV and Leo V and part of the area in between. We find that both systems are significantly larger than indicated by previous measurements based on shallower data and also significantly elongated. With half-light radii of r_h=4'.6 +- 0'.8 (206 +- 36 pc) and r_h=2'.6 +- 0'.6 (133 +- 31 pc), respectively, they are now well within the physical size bracket of typical Milky Way dSph satellites. Their ellipticities of epsilon ~0.5 are shared by many faint (M_V>-8) Milky Way dSphs. The large spatial extent of our survey allows us to search for extra-tidal features with unprecedented sensitivity. The spatial distribution of candidate red giant branch and horizontal branch stars is found to be non-uniform at the ~3 sigma level. This substructure is aligned along the direction connecting the two systems, indicative of a possible `bridge' of extra-tidal material. Fitting the stellar distribution with a linear Gaussian model yields a significance of 4 sigma for this overdensity, a most likely FWHM of ~16 arcmin and a central surface brightness of ~32 mag arcsec^{-2}. We investigate different scenarios to explain the close proximity of Leo IV and Leo V and the possible tidal bridge between them. Orbit calculations demonstrate that they are unlikely to be remnants of a single disrupted progenitor, while a comparison with cosmological simulations shows that a chance collision between unrelated subhalos is negligibly small. Leo IV and Leo V could, however, be a bound `tumbling pair' if their combined mass exceeds 8 +- 4 x 10^9 M_sun. The scenario of an internally interacting pair appears to be the most viable explanation for this close celestial companionship. (abridged)Comment: 9 pages, 8 figures, small number of minor textual changes, accepted for publication in Astrophysical Journa

Human Adipose-Derived Stem Cells Suppress Elastase-Induced Murine Abdominal Aortic Inflammation and Aneurysm Expansion Through Paracrine Factors

Abdominal aortic aneurysm (AAA) is a potentially lethal disease associated with immune activation-induced aortic degradation. We hypothesized that xenotransplantation of human adipose-derived stem cells (hADSCs) would reduce aortic inflammation and attenuate expansion in a murine AAA model. Modulatory effects of ADSCs on immune cell subtypes associated with AAA progression were investigated using human peripheral blood mononuclear cells (hPBMNCs) cocultured with ADSCs. Murine AAA was induced through elastase application to the abdominal aorta in C57BL/6 mice. ADSCs were administered intravenously, and aortic changes were determined by ultrasonography and videomicrometry. Circulating monocytes, aortic neutrophils, CD28− T cells, FoxP3+ regulatory T cells (Tregs), and CD206+ M2 macrophages were assessed at multiple terminal time points. In vitro, ADSCs induced M2 macrophage and Treg phenotypes while inhibiting neutrophil transmigration and lymphocyte activation without cellular contact. Intravenous ADSC delivery reduced aneurysmal expansion starting from day 4 [from baseline: 54.8% (saline) vs. 16.9% (ADSCs), n = 10 at baseline, n = 4 at day 4, p < 0.001], and the therapeutic effect persists through day 14 (from baseline: 64.1% saline vs. 24.6% ADSCs, n = 4, p < 0.01). ADSC administration increased aortic Tregs by 20-fold (n = 5, p < 0.01), while decreasing CD4+CD28− (-28%), CD8+CD28− T cells (-61%), and Ly6G/C+ neutrophils (-43%, n = 5, p < 0.05). Circulating CD115+CXCR1−LY6C+-activated monocytes decreased in the ADSC-treated group by day 7 (-60%, n = 10, p < 0.05), paralleled by an increase in aortic CD206+ M2 macrophages by 2.4-fold (n = 5, p < 0.05). Intravenously injected ADSCs transiently engrafted in the lung on day 1 without aortic engraftment at any time point. In conclusion, ADSCs exhibit pleiotropic immunomodulatory effects in vitro as well as in vivo during the development of AAA. The temporal evolution of these effects systemically as well as in aortic tissue suggests that ADSCs induce a sequence of anti-inflammatory cellular events mediated by paracrine factors, which leads to amelioration of AAA progression

Recommendations for the management of MPS IVA: systematic evidence- and consensus-based guidance.

IntroductionMucopolysaccharidosis (MPS) IVA or Morquio A syndrome is an autosomal recessive lysosomal storage disorder (LSD) caused by deficiency of the N-acetylgalactosamine-6-sulfatase (GALNS) enzyme, which impairs lysosomal degradation of keratan sulphate and chondroitin-6-sulphate. The multiple clinical manifestations of MPS IVA present numerous challenges for management and necessitate the need for individualised treatment. Although treatment guidelines are available, the methodology used to develop this guidance has come under increased scrutiny. This programme was conducted to provide evidence-based, expert-agreed recommendations to optimise management of MPS IVA.MethodsTwenty six international healthcare professionals across multiple disciplines, with expertise in managing MPS IVA, and three patient advocates formed the Steering Committee (SC) and contributed to the development of this guidance. Representatives from six Patient Advocacy Groups (PAGs) were interviewed to gain insights on patient perspectives. A modified-Delphi methodology was used to demonstrate consensus among a wider group of healthcare professionals with experience managing patients with MPS IVA and the manuscript was evaluated against the validated Appraisal of Guidelines for Research and Evaluation (AGREE II) instrument by three independent reviewers.ResultsA total of 87 guidance statements were developed covering five domains: (1) general management principles; (2) recommended routine monitoring and assessments; (3) disease-modifying interventions (enzyme replacement therapy [ERT] and haematopoietic stem cell transplantation [HSCT]); (4) interventions to support respiratory and sleep disorders; (5) anaesthetics and surgical interventions (including spinal, limb, ophthalmic, cardio-thoracic and ear-nose-throat [ENT] surgeries). Consensus was reached on all statements after two rounds of voting. The overall guideline AGREE II assessment score obtained for the development of the guidance was 5.3/7 (where 1 represents the lowest quality and 7 represents the highest quality of guidance).ConclusionThis manuscript provides evidence- and consensus-based recommendations for the management of patients with MPS IVA and is for use by healthcare professionals that manage the holistic care of patients with the intention to improve clinical- and patient-reported outcomes and enhance patient quality of life. It is recognised that the guidance provided represents a point in time and further research is required to address current knowledge and evidence gaps

Recommendations for the management of MPS VI: systematic evidence- and consensus-based guidance.

IntroductionMucopolysaccharidosis (MPS) VI or Maroteaux-Lamy syndrome (253200) is an autosomal recessive lysosomal storage disorder caused by deficiency in N-acetylgalactosamine-4-sulfatase (arylsulfatase B). The heterogeneity and progressive nature of MPS VI necessitates a multidisciplinary team approach and there is a need for robust guidance to achieve optimal management. This programme was convened to develop evidence-based, expert-agreed recommendations for the general principles of management, routine monitoring requirements and the use of medical and surgical interventions in patients with MPS VI.Methods26 international healthcare professionals from various disciplines, all with expertise in managing MPS VI, and three patient advocates formed the Steering Committee group (SC) and contributed to the development of this guidance. Members from six Patient Advocacy Groups (PAGs) acted as advisors and attended interviews to ensure representation of the patient perspective. A modified-Delphi methodology was used to demonstrate consensus among a wider group of healthcare professionals with expertise and experience managing patients with MPS VI and the manuscript has been evaluated against the validated Appraisal of Guidelines for Research and Evaluation (AGREE II) instrument by three independent reviewers.ResultsA total of 93 guidance statements were developed covering five domains: (1) general management principles; (2) recommended routine monitoring and assessments; (3) enzyme replacement therapy (ERT) and hematopoietic stem cell transplantation (HSCT); (4) interventions to support respiratory and sleep disorders; (5) anaesthetics and surgical interventions. Consensus was reached on all statements after two rounds of voting. The greatest challenges faced by patients as relayed by consultation with PAGs were deficits in endurance, dexterity, hearing, vision and respiratory function. The overall guideline AGREE II assessment score obtained for the development of the guidance was 5.3/7 (where 1 represents the lowest quality and 7 represents the highest quality of guidance).ConclusionThis manuscript provides evidence- and consensus-based recommendations for the management of patients with MPS VI and is for use by healthcare professionals that manage the holistic care of patients with the intention to improve clinical- and patient-reported outcomes and enhance patient quality of life. It is recognised that the guidance provided represents a point in time and further research is required to address current knowledge and evidence gaps

Star Cluster Populations in the Outer Disks of Nearby Galaxies

We present a Large Binocular Telescope (LBT) imaging study that characterizes the star cluster component of nearby galaxy outer disks (beyond the optical radius R_25). Expanding on the pilot project of Herbert-Fort et al. (2009), we present deep (~ 27.5 mag V-band point-source limiting magnitude) U- and V-band imaging of six galaxies: IC 4182, NGC 3351, NGC 4736, NGC 4826, NGC 5474, and NGC 6503. We find that the outer disk of each galaxy is populated with marginally-resolved star clusters with masses ~10^3 M_sun and ages up to ~ 1 Gyr (masses and ages are limited by the depth of our imaging and uncertainties are large given how photometry can be strongly affected by the presence or absence of a few stars in such low mass systems), and that they are typically found out to at least 2 R_25 but sometimes as far as 3 to 4 R_25- even beyond the apparent HI disk. The mean rate of cluster formation for 1 R_25<= R <= 1.5R_25 is at least one every ~2.5 Myr and the clusters are spatially correlated with the HI, most strongly with higher density gas near the periphery of the optical disk and with lower density neutral gas at the HI disk periphery. We hypothesize that the clusters near the edge of the optical disk are formed in the extension of spiral structure from the inner disk and are a fairly consistent phenomenon and that the clusters formed at the periphery of the HI disk are the result of accretion episodes.Comment: 23 pages, accepted for publication in Ap