Osteoarthritis (OA) is a degenerative joint disease that affects more than 60% of Americans 65 and older. Because human subjects and samples are not readily available for research, animal models are an invaluable resource for the study of OA. Disproportionate micromelia (Dmm) is one such model that develops OA early in life due to a deletion in the c-propeptide of the Col2a1 gene. Light microscope analysis of the articular cartilage in Dmm has been completed, but is insufficient to show the cellular effects of the deletion mutation in Dmm in adequate detail. The present study explores the changes that occur in the rough endoplasmic reticulum (ER) of chondrocytes in the articular cartilage of Dmm heterozygous mutants (D/+). Immunohistochemical analysis in Dmm has shown that type II collagen is absent extracellularly in articular cartilage of Dmm homozygous mutants and reduced in the heterozygotes. Because preprocollagens are processed through the endoplasmic reticulum (ER), it has been hypothesized that due to improper folding this mutation prevents newly synthesized collagen from leaving the ER, as a result large dilations are seen in the ER of Dmm mice. Furthermore, matrix area fractions should be reduced in the D/+ group if indeed type II collagen is not secreted. Data collected indicated that at 4 months and older, large distensions in the ER disappear. At age 0 months, there is significant dilation in the ER of the D/+ (p=.0013), and at .75 months significant dilation is also observed (p=.0063). In pooled age groups, the D/+ has a 1.77% greater ER fraction than the +/+ (p=.0022). The matrix area fraction was also significantly lower in the D/+ compared to the +/+ (p=.0037). Apoptosis was prominent in older ages, but did not appear to be different between +/+ and D/+ mice. Because decreased matrix and dilation of ER have been documented in OA, Dmm is a good model of OA that can be further used to study the molecular changes and deficiencies that occur in the pathogenesis of OA.

Le monde grec antique nous a transmis l'image d'une civilisation imprégnée de beauté à travers ses œuvres artistiques, cette image étant renforcée par la richesse et la qualité de ses productions littéraires. La quête de la beauté suprême atteint son apogée durant la période classique, et dans ce contexte où tout semble tendre vers cet idéal, la laideur d'apparence est très peu évocatrice; les quelques personnages grecs laids ou difformes auxquels nous pouvons penser, Thersite, Socrate ou Héphaïstos, semblent constituer la minorité d'exceptions qui confirme la règle tellement ils sont présentés comme des cas à part. Cette image que nous avons des Grecs est évidemment trompeuse: les maladies, les difformités et les différentes formes de laideur devaient naturellement faire partie de leur vie quotidienne. Travailler sur ce sujet encore peu exploré nous a paru fort intéressant; pour tenter de saisir ce que les Grecs eux-mêmes ont peu exprimé, nous avons couvert le plus d'aspects possibles en ayant recours à l'ensemble des textes de la période classique sans oublier l'iconographie, indispensable pour une étude sur l'esthétique. / The ancient Greek world passed on to us the image of a civilization filled with beauty through its artistic works, this image being strengthened by the richness and quality of its literary productions. The quest for supreme beauty reached its peak during the classical period, and in this context where everything seems to tend towards this ideal, physical ugliness is not something we generally equate with Greek thought; a few ugly or deformed Greek characters of whom we can think, Thersite, Socrates or Hephæstus, are so isolated that they seem to be the exception rather than the rule. Thus, this image is clearly incorrect since sickness, deformity, and other kinds of ugliness were natural parts of their lives. This little investigated subject is full of interest to us. In our efforts to seize what the Greeks themselves failed to express, we covered every relevent aspect possible by using all the texts of the classical period, not leaving the iconography behind, which is indispensable for a study on aesthetics.

Untersuchungen haben gezeigt, dass unterdurchschnittlich leichte Neugeborene für zahlreiche Erkrankungen ein erhöhtes Risiko tragen. Beschrieben ist unter anderem das vermehrte Auftreten psychosozialer Probleme sowie metabolischer und kardiovaskulärer Spätfolgen. Inzwischen sind zahlreiche mögliche Ursachen einer intrauterinen und postnatalen Wachstumsretardierung beschrieben worden. Unter diesen Ursachen finden sich auch genetische Veränderungen von Proteinen der endokrinologischen Wachstumsregulierung. So wurden Mutationen im GH1 Gen, in Entwicklungsgenen von GH produzierenden Zellen, im IGF-I Gen und schließlich auch im IGF-I Rezeptor Gen identifiziert. Mutationen im letztgenannten Gen stellen den neuesten Forschungszweig dar und wurden bisher weltweit bei lediglich 19 Patienten festgestellt. Mit dieser Arbeit wird ein weiterer Patient mit einer heterozygoten IGF-I Rezeptormutation beschrieben. Neben einer ausführlichen klinischen Beschreibung war die Analyse der Kausalzusammenhänge von Mutation und klinischem Bild Hauptziel dieser Studie. Über eine ausgeprägte intrauterine und postnatale Wachstumsretardierung hinaus präsentierte die betroffene Patientin eine mentale Entwicklungsverzögerung. Durch verschiedene molekularbiologische Methoden konnte eine gestörte intrazelluläre Prozessierung des veränderten Rezeptorproteins nachgewiesen werden. Beobachtet wurde eine fehlende Zelloberflächenexpression aufgrund einer Retention von Rezeptorvorstufen im Endoplasmatischen Retikulum. Damit wurde ein neuer Mechanismus der IGF-I Resistenz beschrieben.

No description available.

Ce mémoire porte sur une étude du corps dans sa dimension socioculturelle. À partir d’entrevues sous le mode du récit de vie, je cherche à comprendre les manières dont les différences qui passent par le corps participent à définir les individus, en fonction des connotations culturelles qui y sont rattachées. Ces différences sont définies comme des composantes du corps qui sont perçues comme une déviation de la norme sachant que celle-ci est établie par une culture dominante. Trois corps différents ont fait l’objet de cette étude : un corps de petite taille, un corps de race noire et un corps tatoué. Cette démarche est essentiellement ancrée dans un cadre théorique faisant écho aux études culturelles telles que définies par Stuart Hall (1997) et aux études de genres selon Judith Butler (2001). Elle émerge du principe d’après lequel le corps est un réservoir de signes dont les connaissances produites à l’intérieur du système social contribuent à créer des sujets. Ce travail s’organise autour de questions qui touchent aux pratiques culturelles qui participent à la construction du corps, à la production des différences, à l’inscription des différences dans le corps et au processus de subjectivation des individus. De plus, il est suggéré que les connotations négatives associées aux différences créent des systèmes de classification hiérarchisés marqués par des formes de discrimination des groupes dominés. Ce travail aboutit à une mise en évidence des différences comme des éléments organisant les relations sociales à travers des rapports de pouvoir dont l’exercice rappelle la structure de la société disciplinaire telle qu’étudiée par Michel Foucault (1975). / This thesis deals with issues related to the body considered as a socio-cultural construct. Based on interviews inspired by the life-story method, I try to understand the ways in which body differences contribute to individual identification, in relation to the cultural connotations attached to them. These differences are defined as components of the body, perceived as a deviation from the norm established by the dominant culture. Three different bodies have been the subject of this study: one short, one black, and one tattooed. This approach is essentially rooted in a theoretical framework of Cultural Studies, as defined by Stuart Hall (1997), and in one of Gender Studies, as per Judith Butler (2001). It derives from the idea that the body is a reservoir of signs, producing meaning within a social system which contributes in transforming individuals into subjects. This work is organized around issues affecting cultural practices involved in the construction of the body, in the production of differences, in the writing of those differences in the body, and in the process of subjectification of individuals. Moreover, it argues that the negative connotations associated with differences create hierarchical classification systems marked by forms of discrimination of dominated groups. This work focuses on differences as organizing elements of social relations through power struggles whose presence is reminiscent of Michel Foucault's study of the structure of the disciplinary society (1975).

INTRODUÇÃO: O hipopituitarismo está associado, em cerca de 40% dos casos, à ectopia da neuro-hipófise observada em imagem por ressonância magnética (RM). Nestes pacientes a visualização da haste ocorre predominantemente nos que têm deficiência isolada de GH (DIGH), enquanto a não visualização da mesma está mais associada à deficiência hipofisária múltipla (DHM). A etiologia deste quadro, no entanto, permanece indeterminada na maioria dos pacientes. A elevada freqüência de parto pélvico e de complicações neonatais sugere uma causa traumática, enquanto que relatos de casos familiares, associação com outras patologias do SNC e descrição de mutações nos genes HESX1, LHX4 e SOX3 apontam para uma causa genética. O LHX4 é um fator de transcrição envolvido na embriogênese hipofisária fundamental para a formação da bolsa de Rathke definitiva. O LHX4 está localizado no cromossomo 1q 25, possui 6 éxons e estende-se por mais de 45 kb de DNA genômico. A única mutação publicada neste gene em humanos é a IVS4-1G>C, associada a um fenótipo caracterizado por baixa estatura, deficiências de GH, TSH e ACTH, neuro-hipófise ectópica e malformação Arnold-Chiari tipo I. O objetivo do estudo é analisar as regiões exônicas e éxon-íntron do LHX4 e caracterizar o perfil hormonal, correlacionando com os achados de RM, em 63 pacientes com hipopituitarismo associado a neurohipófise ectópica. MÉTODOS: Os pacientes foram submetidos à avaliação hormonal e por imagem através de ressonância magnética. A análise molecular incluiu amplificação do gene por PCR, seqüenciamento automático e uso de enzima de restrição. RESULTADOS: A visualização da haste ocorreu em 21 pacientes; destes, 10 (48%) apresentaram DIGH. A não visualização da haste foi mais associada a DHM, o que ocorreu em 40 (95%) dos 42 pacientes. Não encontramos diferença significativa quando comparamos pacientes com haste visualizada e não visualizada quanto à freqüência de partos vaginais em apresentação pélvica, à freqüência de malformações do SNC e à posição precisa da neuro-hipófise ectópica. Identificamos 6 variações alélicas no gene LHX4 em nossos pacientes: GGT>GGC, no códon 21; GAC>GAT, no códon 128; AAC>AAT, no códon 150; AGC>AGT, no códon 230; GGA>GGT, no códon 283 e AAT>AGT no códon 329 (N329S), esta já descrita como polimorfismo no GenBank. Nenhuma das outras variações determina troca de aminoácidos, altera o sítio de \"splice\" ou se correlaciona com um padrão de deficiência hormonal característico. As variações alélicas nos códons 21, 128 e 150 foram caracterizadas como polimorfismos. Não foi possível estabelecer uma relação entre as variações alélicas e o fenótipo dos pacientes. CONCLUSÃO: Mutações no LHX4 são causas raras de hipopituitarismo / INTRODUCTION: Ectopic posterior pituitary lobe (EPL) is observed using magnetic resonance imaging (MRI) scans in about 40% of patients with hypopituitarism. In these patients, the pituitary stalk is visualized mainly in patients with isolated GH deficiency (IGHD), whilst it is not visualized predominantly in patients with combined pituitary hormone deficiency (CPHD). Nevertheless, the etiology of EPL remains undetermined in most of the patients. A traumatic etiology is proposed for this figure, which presents a high frequency of breech delivery and perinatal damages. On the other hand, a genetic cause is suggested by associations to other CNS abnormalities and reports of gene mutations in HESX1, LHX4 and SOX3, as well as familial cases. LHX4 is a transcription factor implicated in pituitary embryogenesis which is essential to definitive Rathke\'s pouch development. It is located in chromosome 1q25, has 6 exons and is stretched out for more than 45 kb of genomic DNA. The only documented human mutation in this gene, IVS4-1G>C, is associated to a phenotype characterized by short stature, GH, TSH and ACTH deficiencies, EPL and Arnold-Chiari type I malformation. The aim of this study is to analyze exonic and exon-intron regions of LHX4 gene and characterize the hormonal deficiency profiles, establishing relationships to MRI findings in 63 patients with hypopituitarism associated to EPL. METHODS: All patients were submitted to hormonal evaluation and MRI scans. The molecular analysis included amplification of the gene using PCR, direct automatic sequencer and digestion with restriction enzymes. RESULTS: The pituitary stalk was visualized in 21 patients; of these, 10 (48%) exhibited IGHD. The stalk was not visualized in 42 patients, most of them with CPHD (95%). We did not find a statistical difference, when patients with and without visualized pituitary stalk were compared, regarding breech deliveries, CNS malformations and exact position of EPL. We identified 6 allelic variations in LHX4 gene: GGT>GGC in codon 21, GAC>GAT in codon 128, AAC>AAT in codon 150, AGC>AGT in codon 230, GGA>GGT in codon 283 and AAT>AGT in codon 329 (N329S), this already related as a polymorphism in GenBank. None of the former variations determine amino acid changes, nor splicing site changes, not even are related to a typical profile of hormonal deficiency. The allelic variations in codons 21, 128 and 150 were described as polymorphisms. It was not possible to establish a relationship between the allelic variations and the phenotype. CONCLUSION: LHX4 gene mutations are rare causes of hypopituitarism

Ce mémoire porte sur une étude du corps dans sa dimension socioculturelle. À partir d’entrevues sous le mode du récit de vie, je cherche à comprendre les manières dont les différences qui passent par le corps participent à définir les individus, en fonction des connotations culturelles qui y sont rattachées. Ces différences sont définies comme des composantes du corps qui sont perçues comme une déviation de la norme sachant que celle-ci est établie par une culture dominante. Trois corps différents ont fait l’objet de cette étude : un corps de petite taille, un corps de race noire et un corps tatoué. Cette démarche est essentiellement ancrée dans un cadre théorique faisant écho aux études culturelles telles que définies par Stuart Hall (1997) et aux études de genres selon Judith Butler (2001). Elle émerge du principe d’après lequel le corps est un réservoir de signes dont les connaissances produites à l’intérieur du système social contribuent à créer des sujets. Ce travail s’organise autour de questions qui touchent aux pratiques culturelles qui participent à la construction du corps, à la production des différences, à l’inscription des différences dans le corps et au processus de subjectivation des individus. De plus, il est suggéré que les connotations négatives associées aux différences créent des systèmes de classification hiérarchisés marqués par des formes de discrimination des groupes dominés. Ce travail aboutit à une mise en évidence des différences comme des éléments organisant les relations sociales à travers des rapports de pouvoir dont l’exercice rappelle la structure de la société disciplinaire telle qu’étudiée par Michel Foucault (1975). / This thesis deals with issues related to the body considered as a socio-cultural construct. Based on interviews inspired by the life-story method, I try to understand the ways in which body differences contribute to individual identification, in relation to the cultural connotations attached to them. These differences are defined as components of the body, perceived as a deviation from the norm established by the dominant culture. Three different bodies have been the subject of this study: one short, one black, and one tattooed. This approach is essentially rooted in a theoretical framework of Cultural Studies, as defined by Stuart Hall (1997), and in one of Gender Studies, as per Judith Butler (2001). It derives from the idea that the body is a reservoir of signs, producing meaning within a social system which contributes in transforming individuals into subjects. This work is organized around issues affecting cultural practices involved in the construction of the body, in the production of differences, in the writing of those differences in the body, and in the process of subjectification of individuals. Moreover, it argues that the negative connotations associated with differences create hierarchical classification systems marked by forms of discrimination of dominated groups. This work focuses on differences as organizing elements of social relations through power struggles whose presence is reminiscent of Michel Foucault's study of the structure of the disciplinary society (1975).

Dwarfism is considered one of the most recognized congenital defects of animals and humans and can be hereditary or sporadic in cause and expression. There are two general morphologic categories within this vastly diverse disease. These categories are disproportionate and proportionate dwarfism and within each of these there are numerous phenotypes which have been extensively described in humans, and to a lesser extent in dogs, cattle, mice, chickens, and other domestic species. Ponies and Miniature horses largely differ from full size horses only by their stature. Ponies are often defined as those whose height is not greater than 14.2 hands; however the maximum height for Miniature horses is constitutionally defined as 8.2 hands. Dwarfism is not considered a desirable genetic trait for Miniature horses. A majority of these conformationally inferior horses showed consistent physical abnormalities typical of disproportionate dwarfisms as seen in other mammal species. A whole genome scan with the Illumina Equine SNP50 chip clearly implicated a region on ECA1 as being associated with dwarfism of horses. The region implicated on the horse chromosome 1 (Equus Caballus; ECA1) contained a candidate gene for dwarfism, aggrecan (ACAN). Mutations were found in Exons 2, 6, 11 and 15 with each mutation associated with a distinct type of dwarfism. These mutations are independently transmitted throughout the population. Absence of normal homozygotes for these mutations and absence of normal horses which were heterozygous for these mutations indicated that these alleles caused dwarfism in those genotypes. These genotypes did not explain all observed dwarves in this population.

INTRODUÇÃO: O hipopituitarismo está associado, em cerca de 40% dos casos, à ectopia da neuro-hipófise observada em imagem por ressonância magnética (RM). Nestes pacientes a visualização da haste ocorre predominantemente nos que têm deficiência isolada de GH (DIGH), enquanto a não visualização da mesma está mais associada à deficiência hipofisária múltipla (DHM). A etiologia deste quadro, no entanto, permanece indeterminada na maioria dos pacientes. A elevada freqüência de parto pélvico e de complicações neonatais sugere uma causa traumática, enquanto que relatos de casos familiares, associação com outras patologias do SNC e descrição de mutações nos genes HESX1, LHX4 e SOX3 apontam para uma causa genética. O LHX4 é um fator de transcrição envolvido na embriogênese hipofisária fundamental para a formação da bolsa de Rathke definitiva. O LHX4 está localizado no cromossomo 1q 25, possui 6 éxons e estende-se por mais de 45 kb de DNA genômico. A única mutação publicada neste gene em humanos é a IVS4-1G>C, associada a um fenótipo caracterizado por baixa estatura, deficiências de GH, TSH e ACTH, neuro-hipófise ectópica e malformação Arnold-Chiari tipo I. O objetivo do estudo é analisar as regiões exônicas e éxon-íntron do LHX4 e caracterizar o perfil hormonal, correlacionando com os achados de RM, em 63 pacientes com hipopituitarismo associado a neurohipófise ectópica. MÉTODOS: Os pacientes foram submetidos à avaliação hormonal e por imagem através de ressonância magnética. A análise molecular incluiu amplificação do gene por PCR, seqüenciamento automático e uso de enzima de restrição. RESULTADOS: A visualização da haste ocorreu em 21 pacientes; destes, 10 (48%) apresentaram DIGH. A não visualização da haste foi mais associada a DHM, o que ocorreu em 40 (95%) dos 42 pacientes. Não encontramos diferença significativa quando comparamos pacientes com haste visualizada e não visualizada quanto à freqüência de partos vaginais em apresentação pélvica, à freqüência de malformações do SNC e à posição precisa da neuro-hipófise ectópica. Identificamos 6 variações alélicas no gene LHX4 em nossos pacientes: GGT>GGC, no códon 21; GAC>GAT, no códon 128; AAC>AAT, no códon 150; AGC>AGT, no códon 230; GGA>GGT, no códon 283 e AAT>AGT no códon 329 (N329S), esta já descrita como polimorfismo no GenBank. Nenhuma das outras variações determina troca de aminoácidos, altera o sítio de \"splice\" ou se correlaciona com um padrão de deficiência hormonal característico. As variações alélicas nos códons 21, 128 e 150 foram caracterizadas como polimorfismos. Não foi possível estabelecer uma relação entre as variações alélicas e o fenótipo dos pacientes. CONCLUSÃO: Mutações no LHX4 são causas raras de hipopituitarismo / INTRODUCTION: Ectopic posterior pituitary lobe (EPL) is observed using magnetic resonance imaging (MRI) scans in about 40% of patients with hypopituitarism. In these patients, the pituitary stalk is visualized mainly in patients with isolated GH deficiency (IGHD), whilst it is not visualized predominantly in patients with combined pituitary hormone deficiency (CPHD). Nevertheless, the etiology of EPL remains undetermined in most of the patients. A traumatic etiology is proposed for this figure, which presents a high frequency of breech delivery and perinatal damages. On the other hand, a genetic cause is suggested by associations to other CNS abnormalities and reports of gene mutations in HESX1, LHX4 and SOX3, as well as familial cases. LHX4 is a transcription factor implicated in pituitary embryogenesis which is essential to definitive Rathke\'s pouch development. It is located in chromosome 1q25, has 6 exons and is stretched out for more than 45 kb of genomic DNA. The only documented human mutation in this gene, IVS4-1G>C, is associated to a phenotype characterized by short stature, GH, TSH and ACTH deficiencies, EPL and Arnold-Chiari type I malformation. The aim of this study is to analyze exonic and exon-intron regions of LHX4 gene and characterize the hormonal deficiency profiles, establishing relationships to MRI findings in 63 patients with hypopituitarism associated to EPL. METHODS: All patients were submitted to hormonal evaluation and MRI scans. The molecular analysis included amplification of the gene using PCR, direct automatic sequencer and digestion with restriction enzymes. RESULTS: The pituitary stalk was visualized in 21 patients; of these, 10 (48%) exhibited IGHD. The stalk was not visualized in 42 patients, most of them with CPHD (95%). We did not find a statistical difference, when patients with and without visualized pituitary stalk were compared, regarding breech deliveries, CNS malformations and exact position of EPL. We identified 6 allelic variations in LHX4 gene: GGT>GGC in codon 21, GAC>GAT in codon 128, AAC>AAT in codon 150, AGC>AGT in codon 230, GGA>GGT in codon 283 and AAT>AGT in codon 329 (N329S), this already related as a polymorphism in GenBank. None of the former variations determine amino acid changes, nor splicing site changes, not even are related to a typical profile of hormonal deficiency. The allelic variations in codons 21, 128 and 150 were described as polymorphisms. It was not possible to establish a relationship between the allelic variations and the phenotype. CONCLUSION: LHX4 gene mutations are rare causes of hypopituitarism

Untersuchungen haben gezeigt, dass unterdurchschnittlich leichte Neugeborene für zahlreiche Erkrankungen ein erhöhtes Risiko tragen. Beschrieben ist unter anderem das vermehrte Auftreten psychosozialer Probleme sowie metabolischer und kardiovaskulärer Spätfolgen. Inzwischen sind zahlreiche mögliche Ursachen einer intrauterinen und postnatalen Wachstumsretardierung beschrieben worden. Unter diesen Ursachen finden sich auch genetische Veränderungen von Proteinen der endokrinologischen Wachstumsregulierung. So wurden Mutationen im GH1 Gen, in Entwicklungsgenen von GH produzierenden Zellen, im IGF-I Gen und schließlich auch im IGF-I Rezeptor Gen identifiziert. Mutationen im letztgenannten Gen stellen den neuesten Forschungszweig dar und wurden bisher weltweit bei lediglich 19 Patienten festgestellt. Mit dieser Arbeit wird ein weiterer Patient mit einer heterozygoten IGF-I Rezeptormutation beschrieben. Neben einer ausführlichen klinischen Beschreibung war die Analyse der Kausalzusammenhänge von Mutation und klinischem Bild Hauptziel dieser Studie. Über eine ausgeprägte intrauterine und postnatale Wachstumsretardierung hinaus präsentierte die betroffene Patientin eine mentale Entwicklungsverzögerung. Durch verschiedene molekularbiologische Methoden konnte eine gestörte intrazelluläre Prozessierung des veränderten Rezeptorproteins nachgewiesen werden. Beobachtet wurde eine fehlende Zelloberflächenexpression aufgrund einer Retention von Rezeptorvorstufen im Endoplasmatischen Retikulum. Damit wurde ein neuer Mechanismus der IGF-I Resistenz beschrieben.