Autosomal-dominant isolated growth hormone deficiency (IGHD type II) with normal GH-1 gene

BACKGROUND: Autosomal-dominant isolated GH deficiency (IGHD) is a rare disorder that is commonly believed to be due to heterozygous mutations in the GH-1 gene (GH-1). These mutations cause the production of a protein that affects the release of the product of the normal allele. Rarely, heterozygous mutations in the gene encoding for HESX-1 gene (HESX-1) may cause autosomal-dominant IGHD, with penetrance that has been shown to be variable in both humans and mice. SUBJECTS AND METHODS: We have sequenced the whole GH-1 in the index cases of 30 families with autosomal-dominant IGHD. In all the families other possible causes of GH deficiency and other pituitary hormones deficits were excluded. We here describe the clinical, biochemical and radiological picture of the families without GH-1 mutations. In these families, we also sequenced the HESX-1. RESULTS: The index cases of the five families with autosomal-dominant IGHD had normal GH-1, including the intronic sequences. They had no HESX-1 mutations. CONCLUSION: This study shows that GH-1 mutations are absent in 5/30 (16.6%) of the families with autosomal-dominant IGHD and raises the possibility that mutations in other gene(s) may be involved in IGHD with this mode of transmission.

Allelic Heterogeneity at the Equine KIT Locus in Dominant White (W) Horses

White coat color has been a highly valued trait in horses for at least 2,000 years. Dominant white (W) is one of several known depigmentation phenotypes in horses. It shows considerable phenotypic variation, ranging from approximately 50% depigmented areas up to a completely white coat. In the horse, the four depigmentation phenotypes roan, sabino, tobiano, and dominant white were independently mapped to a chromosomal region on ECA 3 harboring the KIT gene. KIT plays an important role in melanoblast survival during embryonic development. We determined the sequence and genomic organization of the approximately 82 kb equine KIT gene. A mutation analysis of all 21 KIT exons in white Franches-Montagnes Horses revealed a nonsense mutation in exon 15 (c.2151C>G, p.Y717X). We analyzed the KIT exons in horses characterized as dominant white from other populations and found three additional candidate causative mutations. Three almost completely white Arabians carried a different nonsense mutation in exon 4 (c.706A>T, p.K236X). Six Camarillo White Horses had a missense mutation in exon 12 (c.1805C>T, p.A602V), and five white Thoroughbreds had yet another missense mutation in exon 13 (c.1960G>A, p.G654R). Our results indicate that the dominant white color in Franches-Montagnes Horses is caused by a nonsense mutation in the KIT gene and that multiple independent mutations within this gene appear to be responsible for dominant white in several other modern horse populations.

Exon splice enhancer mutation (GH-E32A) causes autosomal dominant growth hormone deficiency

CONTEXT AND OBJECTIVE: Alteration of exon splice enhancers (ESE) may cause autosomal dominant GH deficiency (IGHD II). Disruption analysis of a (GAA) (n) ESE motif within exon 3 by introducing single-base mutations has shown that single nucleotide mutations within ESE1 affect pre-mRNA splicing. DESIGN, SETTING, AND PATIENTS: Confirming the laboratory-derived data, a heterozygous splice enhancer mutation in exon 3 (exon 3 + 2 A-->C) coding for GH-E32A mutation of the GH-1 gene was found in two independent pedigrees, causing familial IGHD II. Because different ESE mutations have a variable impact on splicing of exon 3 of GH and therefore on the expression of the 17.5-kDa GH mutant form, the GH-E32A was studied at the cellular level. INTERVENTIONS AND RESULTS: The splicing of GH-E32A, assessed at the protein level, produced significantly increased amounts of 17.5-kDa GH isoform (55% of total GH protein) when compared with the wt-GH. AtT-20 cells coexpressing both wt-GH and GH-E32A presented a significant reduction in cell proliferation as well as GH production after forskolin stimulation when compared with the cells expressing wt-GH. These results were complemented with confocal microscopy analysis, which revealed a significant reduction of the GH-E32A-derived isoform colocalized with secretory granules, compared with wt-GH. CONCLUSION: GH-E32A mutation found within ESE1 weakens recognition of exon 3 directly, and therefore, an increased production of the exon 3-skipped 17.5-kDa GH isoform in relation to the 22-kDa, wt-GH isoform was found. The GH-E32A mutant altered stimulated GH production as well as cell proliferation, causing IGHD II.

Catch-up growth in autosomal dominant isolated growth hormone deficiency (IGHD type II)

OBJECTIVE: Data on the GH-induced catch-up growth of severely GH-deficient children affected by monogenetic defects are missing. PATIENTS: Catch-up growth of 21 prepubertal children (6 females, 15 males) affected with IGHD type II was analyzed in a retrospective chart review. At start of therapy, mean age was 6.2 years (range, 1.6-15.0), mean height SDS was -4.7 (-7.6 to -2.2), mean IGF-I SDS was -6.2 (-10.1 to -2.2). GH was substituted using a mean dose of 30.5microg/kg*d. RESULTS: Catch-up growth was characterized by a mean height gain of +0.92, +0.82, and +0.61 SDS after 1, 2, and 3 years of GH therapy, respectively. Mean height velocities were 10.7, 9.2 and 7.7cm/year during the first three years. Mean duration of complete catch-up growth was 6 years (3-9). Mean height SDS reached was -0.97 (-2.3 to +1.1), which was within the range of the estimated target height of -0.60 SDS (-1.20 to -0.15). The younger and shorter the children were at start of therapy the better they grew during the first year independent of the dose. Mean bone age was delayed at start by 2.1 years and progressed by 2.5 years during the first two years of therapy. Incomplete catch-up growth was caused by late initiation or irregular administration of GH in four cases. CONCLUSIONS: Our data suggest that GH-treated children with severe IGHD show a sustained catch-up growth over 6 years (mean) and reach their target height range. This response to GH is considered to be characteristic for young children with severe growth retardation due to IGHD.

[Hypophyseal incidentaloma in a patient with autosomal dominant polycystic kidney disease]

The prevalence of incidentally discovered lesions within the pituitary (pituitary incidentalomas) is about 10%. The most common form of sellar mass are clinically nonfunctioning adenomas (less than 10 mm); functioning adenomas, however, are rare. Incidentally discovered pituitary microadenomas causing growth hormone hypersecretion are uncommon. In addition, the association of autosomal dominant polycystic kidney disease with acromegaly is exceptional and has not yet been reported to our knowledge.

A pedigree with autosomal dominant thrombocytopenia, red cell macrocytosis, and an occurrence of t(12:21) positive pre-B acute lymphoblastic leukemia

Sampling and analyzing new families with inherited blood disorders are major steps contributing to the identification of gene(s) responsible for normal and pathologic hematopoiesis. Familial occurrences of hematological disorders alone, or as part of a syndromic disease, have been reported, and for some the underlying genetic mutation has been identified. Here we describe a new autosomal dominant inherited phenotype of thrombocytopenia and red cell macrocytosis in a four-generation pedigree. Interestingly, in the youngest generation, a 2-year-old boy presenting with these familial features has developed acute lymphoblastic leukemia characterized by a t(12;21) translocation. Tri-lineage involvement of platelets, red cells and white cells may suggest a genetic defect in an early multiliear progenitor or a stem cell. Functional assays in EBV-transformed cell lines revealed a defect in cell proliferation and tubulin dynamics. Two candidate genes, RUNX1 and FOG1, were sequenced but no pathogenic mutation was found. Identification of the underlying genetic defect(s) in this family may help in understanding the complex process of hematopoiesis.

Interrogating the spaces of personal photography : women, identity, and the cultural formation of photographic practice

Personal photographs permeate our lives from the moment we are born as they define who we are within our familial group and local communities. Archived in family albums or framed on living room walls, they continue on after our death as mnemonic artifacts referencing our gendered, raced, and ethnic identities. This dissertation examines salient instances of what women “do” with personal photographs, not only as authors and subjects but also as collectors, archivists, and family and cultural historians. This project seeks to contribute to more productive, complex discourse about how women form relationships and engage with the conventions and practices of personal photography. In the first part of this dissertation I revisit developments in the history of personal photography, including the advertising campaigns of the Kodak and Agfa Girls and the development of albums such as the Stammbuch and its predecessor, the carte-de-visite, that demonstrate how personal photography has functioned as a gendered activity that references family unity, sentimentalism for the past, and self-representation within normative familial and dominant cultural groups, thus suggesting its importance as a cultural practice of identity formation. The second and primary section of the dissertation expands on the critical analyses of Gillian Rose, Patricia Holland, and Nancy Martha West, who propose that personal photography, marketed to and taken on by women, double-exposes their gendered identities. Drawing on work by critics such as Deborah Willis, bell hooks, and Abigail Solomon-Godeau, I examine how the reconfiguration, recontextualization, and relocation of personal photographs in the respective work of Christine Saari, Fern Logan, and Katie Knight interrogates and complicates gendered, raced, and ethnic identities and cultural attitudes about them. In the final section of the dissertation I briefly examine select examples of how emerging digital spaces on the Internet function as a site for personal photography, one that both reinscribes traditional cultural formations while offering new opportunities for women for the display and audiencing of identities outside the family.

Becoming most fully ourselves : gender, voice, and ritual in dissertations

The writing and defense of the dissertation serve both as demonstration one is able to do the work of a scholar and as a rite of initiation. In contrast to much academic writing, dissertations generally adhere to narrowly conceived notions of academic discourse. I explore this within the context of an academic community in which under-representation remains a serious issue. This dissertation is about women writing dissertations. I draw from conversations with fifteen women, in or beyond, the process; friends’ anecdotes; published accounts; and, autobiographically, my experience. I suggest the dissertation’s initiatory role is at least as important as its scholarly role; during the process one establishes a sense of self as scholar, writer, and researcher. Students come to the dissertation with some notion of self as writer and scholar – a culturally negotiated sense that is more, or less, congruent with the culturally established self required for successful completion of the dissertation. The degree of congruence (or alternatively, harmony and dissonance) shapes the process of doing a dissertation. I argue that both the community and the language in which dissertations must generally be written are gendered masculine. Negotiating a voice that is acceptable in a dissertation while maintain fidelity to a sense of who one is seems more problematic as one’s distance from the center of dominant culture increases. Believing that agency lies in altering the reiteration of such processes, I worked with my committee to find ways to alter the process yet still do a dissertation I write in a variety of voices – essay and poetry as well as analytical – play with visual qualities of text, and experiment with non-verbal interpretations. These don’t exhaust possibilities, but do give a sense of how the rich variety of expression found in academe cam be brought into the dissertation. I thus demonstrate that one need not reconstitute herself through characteristic academic discourse in order to be initiated into the community of scholars. I suggest both the desirability of encouraging flexibility in the language, form, and process, of dissertations, and the theoretical necessity for such flexibility if the academic community is to become diverse. The writing and defense of the dissertation serve both as demonstration one is able to do the work of a scholar and as a rite of initiation. In contrast to much academic writing, dissertations generally adhere to narrowly conceived notions of academic discourse. I explore this within the context of an academic community in which under-representation remains a serious issue. This dissertation is about women writing dissertations. I draw from conversations with fifteen women, in or beyond, the process; friends’ anecdotes; published accounts; and, autobiographically, my experience. I suggest the dissertation’s initiatory role is at least as important as its scholarly role; during the process one establishes a sense of self as scholar, writer, and researcher Students come to the dissertation with some notion of self as writer and scholar – a culturally negotiated sense that is more, or less, congruent with the culturally established self required for successful completion of the dissertation. The degree of congruence (or alternatively, harmony and dissonance) shapes the process of doing a dissertation. I argue that both the community and the language in which dissertations must generally be written are gendered masculine. Negotiating a voice that is acceptable in a dissertation while maintain fidelity to a sense of who one is seems more problematic as one’s distance from the center of dominant culture increases. Believing that agency lies in altering the reiteration of such processes, I worked with my committee to find ways to alter the process yet still do a dissertation I write in a variety of voices – essay and poetry as well as analytical – play with visual qualities of text, and experiment with non-verbal interpretations. These don’t exhaust possibilities, but do give a sense of how the rich variety of expression found in academe cam be brought into the dissertation. I thus demonstrate that one need not reconstitute herself through characteristic academic discourse in order to be initiated into the community of scholars. I suggest both the desirability of encouraging flexibility in the language, form, and process, of dissertations, and the theoretical necessity for such flexibility if the academic community is to become diverse. The writing and defense of the dissertation serve both as demonstration one is able to do the work of a scholar and as a rite of initiation. In contrast to much academic writing, dissertations generally adhere to narrowly conceived notions of academic discourse. I explore this within the context of an academic community in which under-representation remains a serious issue. This dissertation is about women writing dissertations. I draw from conversations with fifteen women, in or beyond, the process; friends’ anecdotes; published accounts; and, autobiographically, my experience. I suggest the dissertation’s initiatory role is at least as important as its scholarly role; during the process one establishes a sense of self as scholar, writer, and researcher Students come to the dissertation with some notion of self as writer and scholar – a culturally negotiated sense that is more, or less, congruent with the culturally established self required for successful completion of the dissertation. The degree of congruence (or alternatively, harmony and dissonance) shapes the process of doing a dissertation. I argue that both the community and the language in which dissertations must generally be written are gendered masculine. Negotiating a voice that is acceptable in a dissertation while maintain fidelity to a sense of who one is seems more problematic as one’s distance from the center of dominant culture increases. Believing that agency lies in altering the reiteration of such processes, I worked with my committee to find ways to alter the process yet still do a dissertation I write in a variety of voices – essay and poetry as well as analytical – play with visual qualities of text, and experiment with non-verbal interpretations. These don’t exhaust possibilities, but do give a sense of how the rich variety of expression found in academe cam be brought into the dissertation. I thus demonstrate that one need not reconstitute herself through characteristic academic discourse in order to be initiated into the community of scholars. I suggest both the desirability of encouraging flexibility in the language, form, and process, of dissertations, and the theoretical necessity for such flexibility if the academic community is to become diverse. The writing and defense of the dissertation serve both as demonstration one is able to do the work of a scholar and as a rite of initiation. In contrast to much academic writing, dissertations generally adhere to narrowly conceived notions of academic discourse. I explore this within the context of an academic community in which under-representation remains a serious issue. This dissertation is about women writing dissertations. I draw from conversations with fifteen women, in or beyond, the process; friends’ anecdotes; published accounts; and, autobiographically, my experience. I suggest the dissertation’s initiatory role is at least as important as its scholarly role; during the process one establishes a sense of self as scholar, writer, and researcher Students come to the dissertation with some notion of self as writer and scholar – a culturally negotiated sense that is more, or less, congruent with the culturally established self required for successful completion of the dissertation. The degree of congruence (or alternatively, harmony and dissonance) shapes the process of doing a dissertation. I argue that both the community and the language in which dissertations must generally be written are gendered masculine. Negotiating a voice that is acceptable in a dissertation while maintain fidelity to a sense of who one is seems more problematic as one’s distance from the center of dominant culture increases. Believing that agency lies in altering the reiteration of such processes, I worked with my committee to find ways to alter the process yet still do a dissertation I write in a variety of voices – essay and poetry as well as analytical – play with visual qualities of text, and experiment with non-verbal interpretations. These don’t exhaust possibilities, but do give a sense of how the rich variety of expression found in academe cam be brought into the dissertation. I thus demonstrate that one need not reconstitute herself through characteristic academic discourse in order to be initiated into the community of scholars. I suggest both the desirability of encouraging flexibility in the language, form, and process, of dissertations, and the theoretical necessity for such flexibility if the academic community is to become diverse.

International teachers in the American classroom : deposing the myth of monolingualism

An international graduate teaching assistant‘s way of speaking may pose a challenge for college students enrolled in STEM courses at American universities. Students commonly complain that unfamiliar accents interfere with their ability to comprehend the IGTA or that they have difficulty making sense of the IGTA‘s use of words or phrasing. These frustrations are echoed by parents who pay tuition bills. The issue has provoked state and national legislative debates over universities‘ use of IGTAs. However, potentially productive debates and interventions have been stalemated due to the failure to confront deeply embedded myths and cultural models that devalue otherness and privilege dominant peoples, processes, and knowledge. My research implements a method of inquiry designed to identify and challenge these cultural frameworks in order to create an ideological/cultural context that will facilitate rather than impede the valuable efforts that are already in place. Discourse theorist Paul Gee‘s concepts of master myth, cultural models, and meta-knowledge offer analytical tools that I have adapted in a unique research approach emphasizing triangulation of both analytic methods and data sites. I examine debates over IGTA‘s use of language in the classroom among policy-makers, parents of college students, and scholars and teachers. First, the article "Teach Impediment" provides a particularly lucid account of the public debate over IGTAs. My analysis evidences the cultural hold of the master myth of monolingualism in public policy-making. Second, Michigan Technological University‘s email listserve Parentnet is analyzed to identify cultural models supporting monolingualism implicit in everyday conversation. Third, a Chronicle of Higher Education colloquy forum is analyzed to explore whether scholars and teachers who draw on communication and linguistic research overcome the ideological biases identified in earlier chapters. My analysis indicates that a persistent ideological bias plays out in these data sites, despite explicit claims by invested speakers to the contrary. This bias is a key reason why monolingualism remains so tenaciously a part of educational practice. Because irrational expectations and derogatory assumptions have gone unchallenged, little progress has been made despite decades of earnest work and good intentions. Therefore, my recommendations focus on what we say not what we intend.

Subverting the subject position : toward a new discourse about students as writers and engineering students as technical communicators

There is ample evidence of a longstanding and pervasive discourse positioning students, and engineering students in particular, as “bad writers.” This is a discourse perpetuated within the academy, the workplace, and society at large. But what are the effects of this discourse? Are students aware faculty harbor the belief students can’t write? Is student writing or confidence in their writing influenced by the negative tone of the discourse? This dissertation attempts to demonstrate that a discourse disparaging student writing exists among faculty, across disciplines, but particularly within the engineering disciplines, as well as to identify the reach of that discourse through the deployment of two attitudinal surveys—one for students, across disciplines, at Michigan Technological University and one for faculty, across disciplines at universities and colleges both within the United States and internationally. This project seeks to contribute to a more accurate and productive discourse about engineering students, and more broadly, all students, as writers—one that focuses on competencies rather than incompetence, one that encourages faculty to find new ways to characterize students as writers, and encourages faculty to recognize the limits of the utility of practitioner lore.

Sirolimus ameliorates the enhanced expression of metalloproteinases in a rat model of autosomal dominant polycystic kidney disease

BACKGROUND: Remodelling of matrix and tubular basement membranes (TBM) is a characteristic of polycystic kidney disease. We hypothesized that matrix and TBM degradation by metalloproteinases (MMPs) could promote cyst formation. We therefore investigated the renal expression of MMPs in the Han:SPRD rat model of autosomal dominant polycystic kidney disease (ADPKD) and examined the effect of sirolimus treatment on MMPs. METHODS: 5-week-old male heterozygous (Cy/+) and wild-type normal (+/+) rats were treated with sirolimus (2 mg/kg/day) through drinking water for 3 months. RESULTS: The mRNA and protein levels of MMP-2 and MMP-14 were markedly increased in the kidneys of heterozygous Cy/+ animals compared to wild-type +/+ as shown by RT-PCR and Western blot analyses for MMP-2 and MMP-14, and by zymography for MMP-2. Strong MMP-2 expression was detected by immunoperoxidase staining in cystic epithelial cells that also displayed an altered, thickened TBM. Tissue inhibitor of metalloproteinases-2 (TIMP-2) expression was not changed in Cy/+ kidneys. Sirolimus treatment leads to decreased protein expression of MMP-2 and MMP-14 in Cy/+, whereas MMP-2 and MMP-14 mRNA levels and TIMP-2 protein levels were not affected by sirolimus. CONCLUSION: In summary, in kidneys of the Han:SPRD rat model of ADPKD, there is a marked upregulation of MMP-2 and MMP-14. Sirolimus treatment was associated with a marked improvement of MMP-2 and MMP-14 overexpression, and this correlated also with less matrix and TBM alterations and milder cystic disease.