The Glutaredoxin-like Cysteine-rich Family of Genes, Grxcr1 and Grxcr2, in Stereocilia Development and Function.

Grxcr1 encodes an evolutionarily conserved cysteine-rich protein with sequence similarity to the glutaredoxin family of proteins. Mutations in this Grxcr1 are associated with deafness and vestibular dysfunction in the pirouette mouse, a model for human deafness segregating at the DFNB25 locus. In this thesis, I characterize spontaneous loss of function mutations in Grxcr1 and a paralogous gene, Grxcr2, in vivo, and explore structure-function relationships between genes to provide insight into their functions in the inner ear. Mice homozygous for null alleles of Grxcr1 exhibit abnormally thin stereocilia on the apical surface of sensory cells in the inner ear, indicating a role for this gene in the control of stereocilia dimensions. Despite defects in stereocilia maturation, sensory hair cells exhibit relatively normal mechanotransduction at early postnatal time points. The vertebrate specific paralog, Grxcr2, encodes a protein that is localized to stereocilia of sensory cells in the cochlea and vestibular organs, similar to GRXCR1. Generation and analysis of a targeted mutation of mouse Grxcr2 indicated a similar requirement for this gene in the normal maturation of stereocilia bundles and in auditory function. Mice homozygous for the Grxcr2 mutation exhibited severe hearing loss associated with abnormal stereocilia bundle orientation and organization. Later onset hearing loss in mice homozygous for the Grxcr2 hypomorphic allele suggests that this gene may also be required to maintain auditory function in the mature cochlea. The different stereocilia morphologies identified in Grxcr1 and Grxcr2 mutants and the lack of an overt vestibular phenotype in Grxcr2 mutants, are consistent with distinct roles for these genes during inner ear development. Structure-function analysis of GRXCR1 and GRXCR2 indicated a conserved role for the N-terminus in localization of these proteins to actin filament-rich structures and for the C-terminal Cysteine-rich domain in mediating multimer formation. These studies suggest a model in which multimeric complexes of GRXCR1 and GRXCR2 play a local role to coordinate proper stereocilia development.Ph.D.Human GeneticsUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/91447/1/avenarim_1.pd

Reconstructing institutional complexity in practice: A relational model of institutional work and complexity

This article develops a relational model of institutional work and complexity. This model advances current institutional debates on institutional complexity and institutional work in three ways. First, it provides a relational and dynamic perspective on institutional complexity by explaining how constellations of logics - and their degree of internal contradiction - are constructed rather than given. Second, it refines our current understanding of agency, intentionality and effort in institutional work by demonstrating how different dimensions of agency interact dynamically in the institutional work of reconstructing institutional complexity. Third, it situates institutional work in the everyday practice of individuals coping with the institutional complexities of their work. In doing so, it reconnects the construction of institutionally complex settings to the actions and interactions of the individuals who inhabit them

Two Iranian families with a novel mutation in GJB2 causing autosomal dominant nonsyndromic hearing loss

Mutations in GJB2 , encoding connexin 26 (Cx26), cause both autosomal dominant and autosomal recessive nonsyndromic hearing loss (ARNSHL) at the DFNA3 and DFNB1 loci, respectively. Most of the over 100 described GJB2 mutations cause ARNSHL. Only a minority has been associated with autosomal dominant hearing loss. In this study, we present two families with autosomal dominant nonsyndromic hearing loss caused by a novel mutation in GJB2 (p.Asp46Asn). Both families were ascertained from the same village in northern Iran consistent with a founder effect. This finding implicates the D46N missense mutation in Cx26 as a common cause of deafness in this part of Iran mandating mutation screening of GJB2 for D46N in all persons with hearing loss who originate from this geographic region. © 2011 Wiley-Liss, Inc.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/83755/1/33209_ftp.pd

Proton nuclear magnetic resonance spectroscopic detection of oligomannosidic n glycans in alpha-mannosidosis: a method of monitoring treatment

In Alpha-mannosidosis (MIM 248500) the patients accumulate mainly unbranched oligosaccharide chains in the lysosomes in all body tissues, including the brain. With ensuing therapeutic modalities in man (BMT and ERT) non-invasive methods of monitoring the effect of treatment are needed. Paramount is the possible effect of the treatment on the brain, since this organ is regarded as difficult to reach because of the blood-brain barrier. We therefore performed proton nuclear magnetic resonance spectroscopy (MRS) of the brain in two untreated patients, and a 16-year-old patient treated with BMT at the age of 10 to assess whether this non-invasive method could be applied in the monitoring of the accumulation of abnormal chemicals in the brain of patients. We found an abnormal peak that was not present in the treated patient. A similar pattern was also found in MRS of urine from patients, reflecting the concentration of oligosaccharides in serum and tissues. We therefore conclude that MRS can be a useful method to monitor the effect of treatment for Alpha-Mannosidosis

Stereocilia-staircase spacing is influenced by myosin III motors and their cargos espin-1 and espin-like

Hair cells tightly control the dimensions of their stereocilia, which are actin-rich protrusions with graded heights that mediate mechanotransduction in the inner ear. Two members of the myosin-III family, MYO3A and MYO3B, are thought to regulate stereocilia length by transporting cargos that control actin polymerization at stereocilia tips. We show that eliminating espin-1 (ESPN-1), an isoform of ESPN and a myosin-III cargo, dramatically alters the slope of the stereocilia staircase in a subset of hair cells. Furthermore, we show that espin-like (ESPNL), primarily present in developing stereocilia, is also a myosin-III cargo and is essential for normal hearing. ESPN-1 and ESPNL each bind MYO3A and MYO3B, but differentially influence how the two motors function. Consequently, functional properties of different motor-cargo combinations differentially affect molecular transport and the length of actin protrusions. This mechanism is used by hair cells to establish the required range of stereocilia lengths within a single cell

Stereocilia-staircase spacing is influenced by myosin III motors and their cargos espin-1 and espin-like

Hair cells tightly control the dimensions of their stereocilia, which are actin-rich protrusions with graded heights that mediate mechanotransduction in the inner ear. Two members of the myosin-III family, MYO3A and MYO3B, are thought to regulate stereocilia length by transporting cargos that control actin polymerization at stereocilia tips. We show that eliminating espin-1 (ESPN-1), an isoform of ESPN and a myosin-III cargo, dramatically alters the slope of the stereocilia staircase in a subset of hair cells. Furthermore, we show that espin-like (ESPNL), primarily present in developing stereocilia, is also a myosin-III cargo and is essential for normal hearing. ESPN-1 and ESPNL each bind MYO3A and MYO3B, but differentially influence how the two motors function. Consequently, functional properties of different motor-cargo combinations differentially affect molecular transport and the length of actin protrusions. This mechanism is used by hair cells to establish the required range of stereocilia lengths within a single cell

Stereocilia-staircase spacing is influenced by myosin III motors and their cargos espin-1 and espin-like

Hair cells tightly control the dimensions of their stereocilia, which are actin-rich protrusions with graded heights that mediate mechanotransduction in the inner ear. Two members of the myosin-III family, MYO3A and MYO3B, are thought to regulate stereocilia length by transporting cargos that control actin polymerization at stereocilia tips. We show that eliminating espin-1 (ESPN-1), an isoform of ESPN and a myosin-III cargo, dramatically alters the slope of the stereocilia staircase in a subset of hair cells. Furthermore, we show that espin-like (ESPNL), primarily present in developing stereocilia, is also a myosin-III cargo and is essential for normal hearing. ESPN-1 and ESPNL each bind MYO3A and MYO3B, but differentially influence how the two motors function. Consequently, functional properties of different motor-cargo combinations differentially affect molecular transport and the length of actin protrusions. This mechanism is used by hair cells to establish the required range of stereocilia lengths within a single cell

The strengths and limitations of routine staging before treatment with abdominal CT in colorectal cancer

<p>Abstract</p> <p>Background</p> <p>Advanced colorectal cancer (CRC), either locally advanced, metastasized (mCRC) or both, is present in a relevant proportion of patients. The chances on curation of advanced CRC are continuously improving with modern multi-modality treatment options. For incurable CRC the focus lies on palliation of symptoms, which is not necessarily a resection of the primary tumor. Both situations motivate adequate staging before treatment in CRC. This prospective observational study evaluates the outcomes after the introduction of routine staging with abdominal CT before treatment.</p> <p>Methods</p> <p>In a prospective observational study of 612 consecutive patients (2007-2009), the ability of abdominal CT to find liver metastases (LM), peritoneal carcinomatosis (PC) and T4 stage in colon cancer (CC) was analysed.</p> <p>Results</p> <p>Advanced CRC was present in 58% of patients, mCRC in 31%. The ability to find LM was excellent (99%), cT4 stage CC good (86%) and PC poor (33%). In the group of surgical patients with emergency presentations, the incidences of both mCRC (51%) and locally advanced colon cancer (LACC) (69%) were higher than in the elective group (20% and 26% respectively). Staging tended to be omitted more often in the emergency group (35% versus 12% in elective surgery).</p> <p>Conclusions</p> <p>The strengths of staging with abdominal CT are to find LM and LACC, however it fails in diagnosing PC. On grounds of the incidence of advanced CRC, staging is warranted in patients with emergency presentations as well.</p

Imaging assessment of children presenting with suspected or known juvenile idiopathic arthritis : ESSR-ESPR points to consider

Juvenile idiopathic arthritis (JIA) is the most common paediatric rheumatic disease. It represents a group of heterogenous inflammatory disorders with unknown origin and is a diagnosis of exclusion in which imaging plays an important role. JIA is defined as arthritis of one or more joints that begins before the age of 16 years, persists for more than 6 weeks and is of unknown aetiology and pathophysiology. The clinical goal is early suppression of inflammation to prevent irreversible joint damage which has shifted the emphasis from detecting established joint damage to proactively detecting inflammatory change. This drives the need for imaging techniques that are more sensitive than conventional radiography in the evaluation of inflammatory processes as well as early osteochondral change. Physical examination has limited reliability, even if performed by an experienced clinician, emphasising the importance of imaging to aid in clinical decision-making. On behalf of the European Society of Musculoskeletal Radiology (ESSR) arthritis subcommittee and the European Society of Paediatric Radiology (ESPR) musculoskeletal imaging taskforce, based on literature review and/or expert opinion, we discuss paediatric-specific imaging characteristics of the most commonly involved, in literature best documented and clinically important joints in JIA, namely the temporomandibular joints (TMJs), spine, sacroiliac (SI) joints, wrists, hips and knees, followed by a clinically applicable point to consider for each joint. We will also touch upon controversies in the current literature that remain to be resolved with ongoing research

From practice to field:a multi-level model of practice-driven institutional change

This article develops a model of practice-driven institutional change - or change that originates in the everyday work of individuals but results in a shift in field-level logic. In demonstrating how improvisations at work can generate institutional change, we attend to the earliest moments of change, which extant research has neglected; and we contrast existing accounts that focus on active entrepreneurship and the contested nature of change. We outline the specific mechanisms by which change emerges from everyday work, becomes justified, and diffuses within an organization and field, as well as precipitating and enabling dynamics that trigger and condition these mechanisms. © Academy of Management Journal