Therapeutic Neonatal Hepatic Gene Therapy in Mucopolysaccharidosis VII Dogs

Dogs with mucopolysaccharidosis VII (MPS VII) were injected intravenously at 2–3 days of age with a retroviral vector (RV) expressing canine β-glucuronidase (cGUSB). Five animals received RV alone, and two dogs received hepatocyte growth factor (HGF) before RV in an attempt to increase transduction efficiency. Transduced hepatocytes expanded clonally during normal liver growth and secreted enzyme with mannose 6-phosphate. Serum GUSB activity was stable for up to 14 months at normal levels for the RV-treated dogs, and for 17 months at 67-fold normal for the HGF/RV-treated dog. GUSB activity in other organs was 1.5–60% of normal at 6 months for two RV-treated dogs, which was likely because of uptake of enzyme from blood by the mannose 6-phosphate receptor. The body weights of untreated MPS VII dogs are 50% of normal at 6 months. MPS VII dogs cannot walk or stand after 6 months, and progressively develop eye and heart disease. RV- and HGF/RV-treated MPS VII dogs achieved 87% and 84% of normal body weight, respectively. Treated animals could run at all times of evaluation for 6–17 months because of improvements in bone and joint abnormalities, and had little or no corneal clouding and no mitral valve thickening. Despite higher GUSB expression, the clinical improvements in the HGF/RV-treated dog were similar to those in the RV-treated animals. This is the first successful application of gene therapy in preventing the clinical manifestations of a lysosomal storage disease in a large animal

Views of institutional leaders on maintaining humanism in today’s practice

Objective To explore leadership perspectives on how to maintain high quality efficient care that is also person-centered and humanistic. Methods The authors interviewed and collected narrative transcripts from a convenience sample of 32 institutional healthcare leaders at seven U.S. medical schools. The institutional leaders were asked to identify factors that either promoted or inhibited humanistic practice. A subset of authors used the constant comparative method to perform qualitative analysis of the interview transcripts. They reached thematic saturation by consensus on the major themes and illustrative examples after six conference calls. Results Institutional healthcare leaders supported vision statements, policies, organized educational and faculty development programs, role modeling including their own, and recognition of informal acts of kindness to promote and maintain humanistic patient-care. These measures were described individually rather than as components of a coordinated plan. Few healthcare leaders mentioned plans for organizational or systems changes to promote humanistic clinician-patient relationships. Conclusions Institutional leaders assisted clinicians in dealing with stressful practices in beneficial ways but fell short of envisaging systems approaches that improve practice organization to encourage humanistic care

How Physicians Draw Satisfaction and Overcome Barriers in their Practices: “It Sustains Me”

Objective Major reorganizations of medical practice today challenge physicians’ ability to deliver compassionate care. We sought to understand how physicians who completed an intensive faculty development program in medical humanism sustain their humanistic practices. Methods Program completers from 8 U.S. medical schools wrote reflections in answer to two open-ended questions addressing their personal motivations and the barriers that impeded their humanistic practice and teaching. Reflections were qualitatively analyzed using the constant comparative method. Results Sixty-eight physicians (74% response rate) submitted reflections. Motivating factors included: 1) identification with humanistic values; 2) providing care that they or their family would want; 3) connecting to patients; 4) passing on values through role modelling; 5) being in the moment. Inhibiting factors included: 1) time, 2) stress, 3) culture, and 4) episodic burnout. Conclusions Determination to live by one’s values, embedded within a strong professional identity, allowed study participants to alleviate, but not resolve, the barriers. Collaborative action to address organizational impediments was endorsed but found to be lacking. Practice implications Fostering fully mature professional development among physicians will require new skills and opportunities that reinforce time-honored values while simultaneously partnering with others to nurture, sustain and improve patient care by addressing system issues

Bone Marrow Transplantation for Feline Mucopolysaccharidosis I

Severe mucopolysaccharidosis type I (MPS I) is a fatal neuropathic lysosomal storage disorder with significant skeletal involvement. Treatment involves bone marrow transplantation (BMT), and although effective, is suboptimal, due to treatment sequelae and residual disease. Improved approaches will need to be tested in animal models and compared to BMT. Herein we report on bone marrow transplantation to treat feline mucopolysaccharidosis I (MPS I). Five MPS I stably engrafted kittens, transplanted with unfractionated bone marrow (6.3 × 107–1.1 × 109 nucleated bone marrow cells per kilogram) were monitored for 13–37 months post-engraftment. The tissue total glycosaminoglycan (GAG) content was reduced to normal levels in liver, spleen, kidney, heart muscle, lung, and thyroid. Aorta GAG content was between normal and affected levels. Treated cats had a significant decrease in the brain GAG levels relative to untreated MPS I cats and a paradoxical decrease relative to normal cats. The α-l-iduronidase (IDUA) activity in the livers and spleens of transplanted MPS I cats approached heterozygote levels. In kidney cortex, aorta, heart muscle, and cerebrum, there were decreases in GAG without significant increases in detectable IDUA activity. Treated animals had improved mobility and decreased radiographic signs of disease. However, significant pathology remained, especially in the cervical spine. Corneal clouding appeared improved in some animals. Immunohistochemical and biochemical analysis documented decreased central nervous system ganglioside storage. This large animal MPS I study will serve as a benchmark of future therapies designed to improve on BMT

Intervenir sobre la cultura organizacional: ¿qué aspectos se pueden considerar?

La cultura organizacional (co) es un macroconstructo que involucra una gran variedad de componentes y funciones organizacionales (Warner, 2014). Reyes y Moros (2018) señalan que tiene su origen en el estudio realizado en Hawthorne por Elton Mayo y otros investigadores de la Escuela de las Relaciones Humanas de la Administración, en el que buscaban identificar la influencia de las condiciones físicas y ambientales en el desempeño individual. Para Reyes y Moros (2018), la co se siguió desarrollando en los años setenta con Pettigrew, para ser entendida como un sistema de significados que tanto pública como colectivamente es aceptado para operar en un tiempo y por un grupo determinado. Los autores la definen como “… un sistema de significados compartidos por los miembros de la organización, los cuales son el resultado de una construcción social constituida a través de símbolos y como tal deben ser interpretados”1a edició

A Multi-Institutional Longitudinal Faculty Development Program in Humanism Supports the Professional Development of Faculty Teachers

The authors describe the first 11 academic years (2005–2006 through 2016–2017) of a longitudinal, small-group faculty development program for strengthening humanistic teaching and role modeling at 30 U.S. and Canadian medical schools that continues today. During the yearlong program, small groups of participating faculty met twice monthly with a local facilitator for exercises in humanistic teaching, role modeling, and related topics that combined narrative reflection with skills training using experiential learning techniques. The program focused on the professional development of its participants. Thirty schools participated; 993 faculty, including some residents, completed the program

The Lipid A from Vibrio fischeri Lipopolysaccharide: A UNIQUE STRUCTURE BEARING A PHOSPHOGLYCEROL MOIETY*

Vibrio fischeri, a bioluminescent marine bacterium, exists in an exclusive symbiotic relationship with the Hawaiian bobtail squid, Euprymna scolopes, whose light organ it colonizes. Previously, it has been shown that the lipopolysaccharide (LPS) or free lipid A of V. fischeri can trigger morphological changes in the juvenile squid's light organ that occur upon colonization. To investigate the structural features that might be responsible for this phenomenon, the lipid A from V. fischeri ES114 LPS was isolated and characterized by multistage mass spectrometry (MSn). A microheterogeneous mixture of mono- and diphosphorylated diglucosamine disaccharides was observed with variable states of acylation ranging from tetra- to octaacylated forms. All lipid A species, however, contained a set of conserved primary acyl chains consisting of an N-linked C14:0(3-OH) at the 2-position, an unusual N-linked C14:1(3-OH) at the 2′-position, and two O-linked C12:0(3-OH) fatty acids at the 3- and 3′-positions. The fatty acids found in secondary acylation were considerably more variable, with either a C12:0 or C16:1 at the 2-position, C14:0 or C14:0(3-OH) at the 2′-position, and C12:0 or no substituent at the 3′-position. Most surprising was the presence of an unusual set of modifications at the secondary acylation site of the 3-position consisting of phosphoglycerol (GroP), lysophosphatidic acid (GroP bearing C12:0, C16:0, or C16:1), or phosphatidic acid (GroP bearing either C16:0 + C12:0 or C16:0 + C16:1). Given their unusual nature, it is possible that these features of the V. fischeri lipid A may underlie the ability of E. scolopes to recognize its symbiotic partner