A presente pesquisa analisou, pelos aspectos fisiológicos e acústicos, a voz metálica visando sua compreensão. Vinte e um cantores profissionais foram avaliados com nasofaringolaringofibroscopia, emitindo a vogal /e/ no modo oral e metal. Avaliaram-se imagens da velofaringe, faringe e laringe e analisaram-se acusticamente as amostras vocais. Na voz metálica não houve mudança significativa de freqüência nem de amplitude de F1; houve aumento significativo de amplitude de F2, F3 e F4 e de freqüência de F2; voz metálica mais forte foi correlacionada significativamente com elevação de amplitude de F3 e F4; observaram-se ajustes consistentes do trato vocal tais como abaixamento velar, medialização de paredes faríngeas, elevação laríngea, constrição ariepiglótica e lateral / Metallic voice was studied by means of physiological and acoustical analyses in order to understand its production. Fiberscopic video pharyngolaryngoscopy was performed on 21 professional singers while speaking vowel /e/ in normal and metallic modes to observe muscular movements and structural changes of the velopharynx, pharynx and larynx, Vocal samples were acoustically analyzed. There were no significant changes in frequency and amplitude of F1 in metallic voice; there were significant increases in amplitudes of F2, F3 and F4 and in frequencies for F2; metallic voice perceived as louder was correlated to increase in amplitude of F3 and F4; vocal tract adjustments like velar lowering, pharyngeal wall narrowing, laryngeal raising, aryepiglottic and lateral laryngeal constriction were frequently found

Com o objetivo de avaliar a hipótese de redução da sensibilidade do hemicampo nasal do campo visual, o que aumentaria a assimetria temporal-nasal dos hemicampos, nos pacientes com estrabismo convergente de aparecimento precoce (antes de dois anos de idade) em comparação aos normais, foram estudados os dois olhos de 66 pacientes, 33 estrábicos e 33 normais, com idade que variou de 7 a 30 anos, com o método da perimetria estática, utilizando-se o programa SITA Standard, do perímetro Humphrey HFA-II Série 700. / With the objective of analysing the hypothesis that a reduction in sensitivity of the nasal hemifield, that in turn would lead to an increase in the nasotemporal asymmetry of the visual field, in patients with early onset convergent strabismus - before 2 years of age - if compared to normal patients, both eyes of 66 patients - 33 esotropes and 33 normal - were studied. Patient's age varied from 7 - 30 years. The method of examination was that of Static Perimetry utilizing the Sita Standard program, of the Humphrey perimeter HFA II 700 Series. The results depicted a clear accentuation of the nasotemporal asymmetry in esotropes if compared to normal patients. This asymmetry was due to the evident decrease of sensitivity in the most peripheral of the chosen points of study. The quantitative sum of values of sensitivity of these points exhibited an average reduction of -15,71% in relation to the normal patients. For both groups, normal and esotropes, there was no difference in values of sensitivity between the to eyes.

A retroalimentação por eletromiografia é uma técnica de aprendizado para controle voluntário de respostas fisiológicas pelo condicionamento operante. Compararam-se os sinais eletromiográficos dos músculos quadríceps de duas séries de retroalimentação pelo "Método Brucker" com duração de 50 minutos semanais durante quatro semanas com um intervalo de três meses em 20 pacientes com trauma raquimedular cervical na posição sentado e na transição da posição sentado para a ortostática. Demonstrou aumento amplitude do potencial eletromiográfico na segunda série. Comprovou que na transição de sentado para a posição ortostática consegue-se arregimentar um maior número de fibras do quadríceps do que na sentado / Electromyography biofeedback is a learning technique for voluntary control of physiological responses through operant conditioning. The electromyographic signals from the quadriceps muscles of two biofeedback series were compared using the Brucker method, with a 50-minute weekly session during four weeks and a three-month interval, in 20 patients with cervical spinal cord injury, in the sitting position and during the transition from the sitting to the orthostatic position. An increase in the amplitude of the electromyographic potential was shown in the second series. It was proven that during the transition from the sitting to the orthostatic position it is possible to gather a larger number of fibers of the quadriceps as compared to the sitting position

A esteato-hepatite não alcoólica (EHNA) consiste em esteatose e inflamação lobular hepática, em indivíduos não alcoolistas. Ocorre associada a obesidade, hiperlipidemia, diabetes mellitus, sexo feminino, medicamentos e ‘bypass’ jejunoileal. Recentemente, a sobrecarga de ferro, secundária a mutações no gene HFE da hemocromatose hereditária, também vem sendo evidenciada nos pacientes com EHNA do sexo masculino, não obesos e não diabéticos. O presente estudo, envolvendo pacientes com EHNA do Ambulatório de Gastroenterologia do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, teve como objetivos traçar seu perfil clínico, laboratorial e histopatológico, pesquisar a presença de mutações do gene HFE, buscar associações entre esses resultados e rever a literatura a respeito. Trinta e dois indivíduos foram caracterizados quanto a 14 aspectos clínicos, 12 parâmetros laboratoriais e 11 variáveis histopatológicas. Em 31 destes pesquisaram-se as mutações C282Y e H63D pela técnica de PCR-RFLP, utilizando-se as enzimas de restrição SnaB I e Bcl I, respectivamente. As idades variaram entre 32 e 76 anos, com média de 49,2 anos. Sexo feminino (59%), obesidade (50%), hiperlipidemia (53%) e diabetes mellitus (31%) ocorreram em taxas inferiores às das primeiras séries publicadas. Outras condições encontradas foram uso de amiodarona e prednisona, inalação de substâncias químicas industriais e enterectomia extensa. As etnias branca (72%) e asiática (12%) ocorreram em percentagens maiores que da população geral; ao contrário, a negra (ausente) e mulatos (12%), em menores. A fibrose perivenular ocorreu em todos os casos, proporcional ao grau de atividade necroinflamatória. Os hialinos de Mallory foram identificados em 78% dos casos, mas a siderose em apenas 9%. Cerca de dois terços da casuística não apresentou queixas relacionadas ao aparelho digestivo. Dentre as enzimas hepáticas, a ALT foi a que se alterou com maior freqüência e magnitude, e a relação AST/ALT foi menor que dois em todos os casos. As incidências das mutações pesquisadas corresponderam às da população geral. A sobrecarga de ferro em sangue periférico não se correlacionou estatisticamente com a agressão histológica, nem com a presença das mutações. EHNA é um diagnóstico que engloba múltiplas condições, mas, na população estudada, não houve associação com a sobrecarga de ferro hepático, tampouco com as mutações conhecidas do gene HFE. / Non-alcoholic steatohepatitis (NASH) consists of steatosis and hepatic lobular inflammation in non-alcoholic individuals. It occurs in association to obesity, hyperlipidemia, diabetes mellitus, female sex, drug therapy and jejunoileal bypass. Recently, iron overload, secondary to mutations in the HFE gene in hereditary hemochromatosis has also been evidenced in nonobese, non-diabetic male patients with NASH. This study involves patients with NASH from the outpatient clinic of Hospital das Clinicas of the University of São Paulo School of Medicine, and its objective was to define patients’ clinical, laboratory and histological profiles and search for mutations in the HFE gene, compare results for associations and review the literature. Thirtytwo individuals were characterized for 14 clinical features, 12 laboratory parameters and 11 histopathological variables. The C282Y and H63D mutations in 31 of these individuals were searched using PCR-RFLP techniques, using restriction enzymes SnaB I and BcI I, respectively. Age varied from 32 to 76 yrs old, with an average of 49,2 yrs. Female sex (59%), obesity (50%), hyperlipidemia (53%) and diabetes mellitus (31%) had a lower incidence than those in the first series in the literature. Other features observed were amiodarone and prednisone use, inhalation of industrial chemical substances and extensive enterectomy. Its incidence was higher among Caucasians (72%) and Asians (12%) than in the general population, contrary to other ethnic types such as Black (absent) and Mulattos (12%) which presented lower incidences. Perivenular fibrosis was present in all cases, proportional to the degree of necroinflammatory activity. Mallory’s hyalines were identified in 78% of the cases, but hepatic siderosis was identified in only 9%. Around two-thirds of the casuistic did not have abdominal complaints. Among the hepatic enzymes, ALT was the most frequently altered with the highest magnitude and the AST/ALT ratio was < 2 in all cases. The incidence of the mutations studied was similar to those found in the general population. The iron overload in peripheral blood was neither statistically correlated to the histological aggression, nor to the presence of mutations. NASH diagnosis depends on multiple features, but in the population studied, there was no association with hepatic iron overload as well as with the known mutations in the HFE gene.

Introdução: A hiperidrose primária (HP) é uma desordem que afeta negativamente a qualidade de vida de seus portadores. A fisiopatologia da HP não é bem compreendida e acredita-se que uma complexa disfunção do sistema nervoso simpático esteja relacionada com sua etiologia. A ressecção de um ou mais gânglios da cadeia simpática torácica constitui-se como o método mais eficiente de controle da HP; apesar disso, pouco se sabe sobre o funcionamento dos gânglios simpáticos em indivíduos normais e em portadores de HP. Objetivos: Analisar a expressão de acetilcolina e das subunidades 3 e 7 de seu receptor nicotínico neuronal em gânglios da cadeia simpática torácica de portadores de HP palmar e comparar estes resultados com os obtidos de não portadores; avaliar se existe diferença de tamanho entre esses gânglios. Métodos: Estudo transversal, no qual foram analisados dois grupos de 20 participantes: no grupo Hiperidrose, portadores de HP palmar, candidatos a simpatectomia torácica; no grupo Controle, doadores falecidos de órgãos sem história prévia de sudorese excessiva. Em todos os indivíduos foram realizados: ressecção do 3º gânglio simpático esquerdo; aferição do maior diâmetro do gânglio; avaliação imunohistoquímica pela quantificação das áreas de expressão forte e fraca de anticorpos primários contra acetilcolina e contra as subunidades 3 e 7 de seu receptor nicotínico neuronal. Resultados: A mediana da idade dos participantes foi menor no grupo Hiperidrose em relação ao Controle; a proporção de homens e mulheres foi de 3:17 no grupo Hiperidrose e 9:11 no Controle. A expressão da subunidade 3 foi semelhante em ambos os grupos (p = 0,78 para expressão forte e p = 0,31 para expressão fraca). A área de expressão forte da subunidade 7 correspondeu a 4,85% da área total em portadores de HP e a 2,34% nos controles (p < 0,001), enquanto a área de expressão fraca foi de 11,48% no grupo Hiperidrose e de 4,59% no Controle (p < 0,001). Expressão forte da acetilcolina foi encontrada em 4,95% da área total no grupo Hiperidrose e 1,19% no Controle (p < 0,001); expressão fraca foi encontrada em 18,55% e 6,77%, respectivamente (p < 0,001). O diâmetro dos gânglios ressecados foi de 0,71cm no grupo Hiperidrose e de 0,53cm no Controle (p < 0,001). Conclusões: Existe um aumento da expressão de acetilcolina e da subunidade 7 do seu receptor nos gânglios simpáticos de portadores de HP; a subunidade 3 do receptor nicotínico de acetilcolina tem expressão semelhante em gânglios simpáticos de portadores de HP e de não portadores; gânglios da cadeia simpática torácica apresentam diâmetro maior em portadores de HP / Introduction: Primary hyperhidrosis (PH) is a disorder that impairs the quality of life of its bearers. The PH physiopathology is not well understood and a complex sympathetic nervous system dysfunction seems to be related with its etiology. The resection of one or more thoracic sympathetic chain ganglia is the most effective PH treatment; however sympathetic ganglia function in normal subjects and in PH patients is unknown. Objectives: Analyzing the immunohistochemical expression of acetylcholine and its neuronal nicotinic receptors 3 and 7 subunits in thoracic sympathetic ganglia of PH patients and compare the results with those obtained from subjects without this disorder; identifying possible differences in size of these ganglia. Methods: Cross-sectional study, in which two groups of 20 subjects were analyzed: the Hyperhidrosis group, with palmar PH patients eligible to thoracic sympathectomy and the Control group, with organ donators after brain death without hyperhidrosis historical. For each subject it were performed: resection of the third left sympathetic ganglion; measurement of the ganglions diameter; immunohistochemical evaluation by quantification of intense and mild expression areas of primary antibodies against acetylcholine and its neuronal nicotinic receptors 3 and 7 subunits. Results: The median of participants age was smaller in Hyperhidrosis group than in Control; the male/female ratio was 3:17 in Hyperhidrosis group and 9:11 in Control. The 3 subunit expression was similar in both groups (p = 0.78 for intense expression and p = 0.31 for mild expression). Intense 7 subunit expression area was 4.85% in PH patients and 2.34% in controls (p < 0.001) whereas mild expression area was 11.48% in Hyperhidrosis group and 4.59% in Control (p < 0.001). Intense acetylcholine expression was found in 4.95% of total area in Hyperhidrosis group and in 1.19% in Control (p < 0.001); mild expression was found in 18.55% and 6.77%, respectively (p < 0.001). Ganglia diameter was 0.71cm in Hyperhidrosis group and 0.53cm in Control (p < 0.001). Conclusions: There is a higher expression of acetylcholine and its neuronal nicotinic receptors 7 subunit in sympathetic ganglia of PH patients; the 3 subunit of the neuronal nicotinic acetylcholine receptor shows similar expression in sympathetic ganglia of PH patients and subjects without this disorder; thoracic sympathetic chain ganglia diameter is bigger in PH patients

La transplantation cardiaque est aujourd'hui la seule option de traitement à long terme pour les patients souffrant d'insuffisance cardiaque terminale. Malgré des progrès considérables dans les traitements immunosuppresseurs, le rejet d'allogreffe reste une cause majeure de la perte du greffon. Dans ce domaine, des études récentes ont souligné l'importance du rejet humoral (AMR) comme un facteur contributif important à l’évolution, précoce ou tardive, de la maladie vasculaire du greffon et, in fine, à la perte de ce greffon. La pierre angulaire du diagnostic de rejet repose sur la biopsie endomyocardique (BEM) et l'évaluation histopathologique classique. Cependant, les épisodes de rejet observés sont aujourd'hui plus rares et plus complexes qu'auparavant, du fait de la présence de formes tronquées, indolentes et mixtes empêchant un diagnostic précis avec une évaluation conventionnelle. En outre, la BEM est une procédure invasive, entrainant des coûts importants, un inconfort pour le patient et un risque non négligeable de complications graves. Par conséquent, l'évaluation histologique conventionnelle ne reflète pas la complexité du rejet de greffe cardiaque et a besoin d'améliorations en termes de diagnostic. Le travail présenté dans cette thèse explore deux types de biomarqueurs, la voie mTOR, marqueur in situ, et les micro-ARNs, marqueurs circulants, qui permettraient une meilleure classification du rejet et constitueraient une aide diagnostique et/ou prédictive à la pratique clinique quotidienne lors du suivi des patients transplantés. / Cardiac transplantation is currently the only option for long-term treatment for patients with terminal heart failure. Despite considerable advances in immunosuppressive therapy, allograft rejection remains a major cause of graft loss. In this regard, recent studies have highlighted the importance of antibody-mediated rejection (AMR) as an important contributory factor in the evolution of vascular graft disease and, ultimately, graft loss. The cornerstone of the rejection diagnosis is based on endomyocardial biopsy (EMB) and the classical histopathological evaluation. However, rejection episodes observed today are becoming scarce and more complex than before, due to the presence of truncated, indolent and mixed forms preventing an accurate diagnosis with a conventional assessment. In addition, the biopsy is an invasive procedure, resulting in significant costs, discomfort for the patient and a significant risk of serious complications. Therefore, conventional histological assessment does not reflect the complexity of cardiac transplant rejection and needs improvement in terms of diagnosis. The work presented in this thesis explores two types of biomarkers, the mTOR pathway, an in situ marker, and the micro-RNAs, circulating markers that would allow a better classification of rejection and provide diagnosis and/or predictive help to daily clinical practice during the monitoring of transplant patients.

L'ostéochondrose (OC) est une affection ostéo-articulaire juvénile caractérisée par une perturbation locale de la maturation du cartilage créant des zones de fragilité. L'OC a été décrite chez de nombreuses espèces dont l'Homme, le Chien, le Porc, le Poulet et le Cheval. Chez le cheval les lésions s'installent progressivement, sans symptômes, avant l'âge d'un an et les manifestations cliniques ne se manifestent que tardivement, souvent à l'entraînement. L'OC affecte 10 à 30 % de la population équine représentant ainsi un souci majeur pour la filière tant sur le plan du bien être animal que sur le plan économique. Son étiologie, multifactorielle, est encore mal comprise et implique des composantes génétiques et environnementales ainsi que traumatiques. Les objectifs des travaux présentés étaient d'améliorer la compréhension de la physiopathologie de l'OC équine et de mettre en évidence les processus biologiques perturbés. L'ensemble des résultats a permis de préciser la définition des différentes entités de l'OC et pourraient également être pertinentes dans l'amélioration du diagnostic et le dévelopement de nouveaux traitements. Un défaut constitutif de l'os et du cartilage a été mis en évidence chez les individus atteints d'OC, notamment associé à une perturbation du métabolisme énergénique et un stress du reticulum endoplasmique. De plus, selon le type de lésions, des mécanismes moléculaires sous-jacents différents sont impliqués dans leur développement. D'autre part, les microARNs (miRNAs) semblent également jouer un rôle dans la physiopathologie de l'OC et certains d'entre eux pourraient constituer de bonnes cibles thérapeutiques ou être utilisés comme biomarqueurs diagnostics. / Osteochondrosis (OC) is a juvenile osteo-articular disease characterized by a focal failure of cartilage maturation leading to weak areas. OC has been described in several species including Human, Dog, Swine, Poultry and Horse. In horse, lesions develop gradually without symptoms before one year old and clinical manifestations occur tardily during training. OC affects 10 to 30% of equine population and constitutes a major concern in terms of animal welfare and economy. Its multifactorial etiology remains poorly understood and involved several factors including genetics, environment and traumas. The aim of this current work was to improve the comprehension of equine OC physiopathology and highlight biological pathways disrupted. Taken together, our results made it possible to refine the definition of OC entities and our data could be relevant to improve diagnosis and develop new therapies. A constitutive defect was found in cartilage and bone of OC-affected horses and particularly a defective energy metabolism and a endoplasmic reticulum stress. Moreover, in function of lesion type, different underlying molecular mechanisms are involved in their development. Secondly, mircoRNAs (miRNAs) seem to take part in the OC physiopathology and some miRNAs could constitute a relevant therapeutic target or be used as diagnosis biomarkers.

Orientadores: Jose Antonio Rocha Gontijo, Sarah Monte Alegre / Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas / Made available in DSpace on 2018-08-24T10:43:55Z (GMT). No. of bitstreams: 1 Almeida_AmandaRobertade_D.pdf: 2198169 bytes, checksum: 7c24ef7c416a9b7492db15a314337669 (MD5) Previous issue date: 2013 / Resumo: A obesidade é considerada um importante problema de saúde pública, sendo classificada como uma epidemia global, podendo ser definida como uma doença que pode causar ou exacerbar problemas de saúde. Nos últimos anos, o crescimento do número de indivíduos com sobrepeso e obesidade revela um quadro epidemiológico preocupante. Este aumento de peso causa hipertrofia e/ou hiperplasia dos adipócitos, podendo constituir situações relacionadas à gênese do processo fisiopatológico da obesidade e suas complicações. Dentre as complicações, o aumento na produção de citocinas corrobora para o desenvolvimento de um quadro inflamatório, que está associado à resistência à insulina e hipertensão arterial, caracterizado como Síndrome Metabólica. Este processo inflamatório está também relacionado à função renal, sugerindo que o rim desempenha um papel no clearance das citocinas envolvidas no processo inflamatório. Observa-se também a hiperinsulinemia presente em grande parcela de indivíduos obesos, contribuindo para alterações na função renal. A patologia renal em paciente obeso é conhecida como glomerulopatia relacionada à obesidade. No obeso a taxa de filtração elevada leva a uma vasodilatação da arteríola aferente com consequente elevação da fração de filtração, como resultado de uma hiperfiltração glomerular seguido de dano renal. Este trabalho procurou entender as implicações da obesidade, sem qualquer outra co-morbidade associada, sobre a função tubular renal, a pressão arterial, os perfis metabólico e inflamatório em um grupo de voluntários obesos comparados a um grupo de controles eutróficos. Os voluntários foram submetidos ao clearance de lítio e creatinina, juntamente com o teste de tolerância oral à glicose. Foi avaliada a função tubular renal, os perfis metabólico, lipídico e inflamatório. Os voluntários obesos apresentaram fenótipos diferentes para a resistência à insulina e pressão arterial, contudo, o perfil inflamatório e a função tubular renal foram similares. O perfil insulinêmico mostrou diferença importante entre os grupos de obesos quando comparados ao controle. O presente estudo demonstrou que a obesidade no grupo estudado, pode ocorrer com poucas alterações fisiopatológicas. Nós aventamos a hipótese que estas alterações, particularmente as metabólicas, são acentuadas ou associadas à elevação do status inflamatório dos voluntários obesos, mas por outro lado, são atenuadas possivelmente pela elevada concentração sérica de adiponectina no grupo normo-insulinêmico, quando comparado aos voluntários hiperinsulinêmicos. Assim, é possível, que os indivíduos do grupo obeso normo-insulinêmicos possam tardiamente evoluir para hiperinsulinemia reciprocamente à redução dos níveis de adiponectina / Abstract: Obesity is considered an important public health problem, being classified as a global epidemic, which can be defined as a disease that can cause or exacerbate health problems. In recent years, the growth in the number of individuals with overweight and obesity reveals an epidemiological framework concern. This increase in weight cause hypertrophy and/or Adipocyte hyperplasia and may constitute situations related to the genesis of the pathophysiological process of obesity and its complications. Among its complications, the increase in the production of cytokines supports for the development of an inflammatory process, which is associated with insulin resistance and hypertension, characterized as metabolic syndrome. This inflammatory process is also related to kidney function, suggesting that the kidney plays a role in the clearance of cytokines involved in the inflammatory process. It is also observed hyperinsulinemic present in large proportion of obese individuals, contributing to changes in renal function. Renal changes in obese patient is known as glomerulopathy related to obesity. In the obese high filtration rate leads to vasodilation of the afferent arteriole with consequent elevation of the filtration fraction, as a result of glomerular Hyperfiltration followed by renal damage. Thus, this work sought to understand the implications of obesity, with no other associated co-morbidity, on renal tubular function, blood pressure, and inflammatory and metabolic profiles in a group of obese volunteers compared to a group of eutrophic controls. Obese volunteers showed different phenotypes for insulin resistance, blood pressure, inflammatory profile and renal tubular function were similar. Insulinemia profile showed significant difference for the obese groups compared to controls. The present study showed that obesity, at least in a specific group, can occur without major patho-physiological changes. We may state the hypothesis that these amendments, particularly the metabolic, are accentuated or associated with elevation of inflammatory status of obese volunteers, but on the other hand, are attenuated possibly by the high concentration of serum adiponectin in normo-insulinemic group when compared to the hyperinsulinemic volunteers. Thus, it is possible however, that individuals of the obese group normo-insulinemic can later evolve to hyperinsulinemic reciprocally to reduction of adiponectin levels / Doutorado / Fisiopatologia Médica / Doutora em Ciências

The main concern of this thesis is with desmoplasia - a process in which excessive connective tissue is deposited in a neoplasm. This is a common phenomenon in neoplasia but one whose mechanisms are poorly understood. To study the process, I used a human malignant melanoma cell line (UCT-Mel 7) that was established in this laboratory and that, when injected into athymic mice, gave rise to tumours that showed a number of interesting features. Firstly, the tumour induced a marked desmoplastic response as evidenced by a high content of hydroxyproline in tumour lysates, intense staining for reticulin in sections of the tumour and infiltration of the tumour by host mesenchymal cells. Secondly, the desmoplasia was associated in UCT-Mel 7-derived tumours with an unusual phasic pattern of growth that was related to the in vitro passage number of the melanoma cells. On occasions, murine tumours developed at the site of inoculation of human tumour cells. I have identified 2 possible mechanisms by which UCT-Mel 7 cells could have induced the desmoplastic response: either the tumour cells could have exerted their effect indirectly, i.e. via macrophages, or they could have stimulated the host's stromal cells directly. UCT-Mel 7 cells were shown to be chemotactic for mouse macrophages and human foreskin fibroblasts were stimulated, in a dose-dependent manner, to synthesize increased amounts of collagen when co-cultured with mouse peritoneal exudate cells. Stimulation could only be effected by direct cell:cell contact; medium conditioned by macrophages was not effective. The amount of stimulation was not dependent on the state of activation of the peritoneal cells nor on the strain of mouse used. Tumour cells were also found to act directly. Co-culture of UCT-Mel 7 cells and fibroblasts resulted in increased collagen synthesis by the fibroblasts. Increased synthesis of the protein was reflected in an increase in the amount of collagen mRNA. UCT-Mel 7 cell stimulated in a dose-dependent manner with an absolute requirement for intimate cell:cell contact with the fibroblasts. DNA synthesis was not required. Dexamethasone, retinoic acid and the tumour promoter, phorbol myristate acetate, had significant primary effects on fibroblast collagen synthesis but did not modify the response to melanoma cells. Indomethacin, however, had a minimal primary effect upon the fibroblasts but significantly augmented the melanoma cell effect. The nature of the stimulatory cell:cell contact is still uncertain. The gap junction inhibitor, α-glycyrrhetinic acid, did not diminish the melanoma cell effect. Preliminary findings suggested that cell-surface proteoglycans may be important. Removal of the proteoglycans with the inhibitor of proteoglycan assembly, 4-methylumbelliferyl-β-D-xyloside, abrogated the melanoma cell:fibroblast interaction. Recombinant basic fibroblast growth factor did. not seem to be involved in the desmoplastic response. It was of incidental interest to note that this compound inhibited fibroblast collagen synthesis in a manner that was augmented by the concomitant addition of heparin. A surprising finding was the production of a potent inhibitor of collagen synthesis by superinduced cells of the mouse macrophage cell line, P388D₁. This inhibitor has not been fully characterised.

No description available.