Molecular and functional characterizations of the association and interactions between nucleophosmin-anaplastic lymphoma kinase and type I insulin-like growth factor receptor.

Nucleophosmin-anaplastic lymphoma kinase (NPM-ALK) is aberrantly expressed in a subset of T cell lymphoma that commonly affects children and young adults. NPM-ALK possesses significant oncogenic potential that was previously documented using in vitro and in vivo experimental models. The exact mechanisms by which NPM-ALK induces its effects are poorly understood. We have recently demonstrated that NPM-ALK is physically associated with type I insulin-like growth factor receptor (IGF-IR). A positive feedback loop appears to exist between NPM-ALK and IGF-IR through which these two kinases interact to potentiate their effects. We have also found that a single mutation of the Tyr(644) or Tyr(664) residue of the C terminus of NPM-ALK to phenylalanine decreases significantly, but does not completely abolish, the association between NPM-ALK and IGF-IR. The purpose of this study was to determine whether the dual mutation of Tyr(644) and Tyr(664) abrogates the association and interactions between NPM-ALK and IGF-IR. We also examined the impact of this dual mutation on the oncogenic potential of NPM-ALK. Our results show that NPM-ALK(Y644,664F) completely lacks association with IGF-IR. Importantly, we found that the dual mutation of Tyr(644) and Tyr(664) diminishes the oncogenic effects of NPM-ALK, including its ability to induce anchorage-independent colony formation and to sustain cellular transformation, proliferation, and migration. Furthermore, the association between NPM-ALK and IGF-IR through Tyr(644) and Tyr(664) appears to contribute to maintaining the stability of NPM-ALK protein. Our results provide novel insights into the mechanisms by which NPM-ALK induces its oncogenic effects through interactions with IGF-IR in this aggressive lymphoma.

La experiencia de la Sociedad Española de Neumología y Cirugía Torácica (SEPAR) en la formación post-grado en tabaquismo / No disponible

La formación en diagnóstico y tratamiento del tabaquismo es una disciplina sobre la que cada día existe mayor interés. El área de tabaquismo de la Sociedad Española de Neumología y Cirugía Torácica, SEPAR, fue pionera en la organización y desarrollo del primer curso de Experto en Tabaquismo proporcionado por una sociedad científica española. Hasta el momento actual se han realizado un total de siete cursos. El objetivo primordial de este artículo es comentar la metodología docente que se ha desarrollado y exponer los resultados. Metodología. El principal objetivo docente de los cursos ha sido dotar de conocimientos, aptitudes y habilidades al alumno para realizar una correcta prevención, diagnóstico y tratamiento del tabaquismo. El curso se estructura en dos módulos, teórico y práctico, con 25 y 15 horas lectivas de duración, respectivamente. Los alumnos reciben diverso material docente. Al final del curso se realizan dos tipos de evaluaciones: una del curso, por parte de los alumnos y otra, de los alumnos, por parte del profesorado. Los alumnos que superen todas las evaluaciones obtendrán el diploma de la Sociedad Española de Neumología y Cirugía Torácica (SEPAR) que les titula como Expertos en Tabaquismo. Resultados. A lo largo de los siete años de realización del curso, se han formado a un total de 235 alumnos, de los cuales 173 ( 73,4%) eran mujeres y el resto hombres. La edad media del grupo fue de 35,2 (12,56) años. Otros resultados de interés han sido los siguientes: a) el 96,6% de los discentes consideró que los objetivos que se habían planteado con la realización del curso se habían cumplido de manera muy alta o alta, b) hasta el 80% de alumnos consideró que la calidad de los materiales docentes que se distribuyeron fue muy alta, c) entre el 70 y el 73% de los alumnos valoró como alta, la calidad de la metodología para la adquisición de conocimientos teóricos y prácticos, d) el 80% de los discentes valoró al profesorado con calidad alta o muy alta y f) todos los alumnos superaron el examen tipo test, aunque sólo el 64,6% de ellos realizó el trabajo de investigación tutorizado. Conclusiones. La experiencia nos ha mostrado que la metodología utilizada es la adecuada y que sirve para el cumplimiento de los objetivos. La evaluación final del curso ha sido superada por el 64,5% de los alumnos (AU)

Training on smoking cessation is getting interest. The smoking prevention group of the Spanish Respiratory Society, SEPAR was the pioneer in organizing this type of courses. The main objective of this paper is to show the methodology and the results of these courses. Methodology. The main objective of these training courses was to increase the knowledge and to improve the skills on smoking control of the different health professionals. The course is comprised of two modules: theory and practice. Each module has 25 and 15 hours, respectively. At the end of the course there are two kind of evaluations: the course is evaluated by the pupils and the pupils are evaluated by the professors. Pupils who approve the exam and write up a small research in some aspects of smoking control will get an Accreditation from Spanish Respiratory Society, SEPAR as "Expert on Smoking Control". Results. We have undertaken seven training courses. 235 pupils have participated, 173 ( 73.4%) were women. Mean age 35.2 (12.56). Other results were as follows: a) 96.6% of pupils considered that the objectives had been accomplished, b) 96% of pupils qualified as high quality the contents of the courses , c) around 73% of pupils qualified as high quality the methodology of the course, d) 80% of pupils qualified as high quality the teachers of the course and f) all pupils approved the final exam but only 64.6% of them wrote up the research. Conclusions. The methodology is adequate and it helps to comply with the objectives. The final evaluation has been approved by 64.5% of pupils (AU)

Autoimmunity to the M(r) 32,000 subunit of replication protein A in breast cancer.

PURPOSE: We sought to identify autoantigens recognized by antibodies in breast cancer patient sera with potential diagnostic or prognostic significance. EXPERIMENTAL DESIGN: Serum from a female breast cancer patient exhibiting a high titer antinuclear antibody was used to screen a HeLa cDNA expression library, leading to the cloning of a cDNA for the M(r) 32,000 subunit of replication protein A (RPA32). RPA32 expression and localization were assayed in autologous tumor by monoclonal antibody staining. A specific ELISA using recombinant protein was used to screen sera from 801 breast cancer patients and 65 controls. RESULTS: A relationship between anti-replication protein A (RPA) antibodies and the ductal breast carcinoma of the proband was suggested by overexpression and aberrant localization of RPA32 in tumor cells as compared with surrounding normal ductal tissue and by the presence of anti-RPA32 antibodies before the diagnosis. The prevalence of anti-RPA32 antibodies was significantly higher (P < 0.01) among breast cancer patients (87 of 801 patients) than among noncancer controls (0 of 65 controls). Similarly, anti-RPA32 antibodies were present in 4 of 39 patients with intraductal in situ carcinoma. No associations were found between anti-RPA antibodies and survival, occurrence of a second tumor, metastases, or antibodies to p53. Reactivity to RPA32 also was detected in sera from 3 of 47 patients with other cancers. CONCLUSIONS: In view of the central role of RPA in DNA replication, recombination, and repair, we suggest that autoimmunity to RPA32 may reflect molecular changes involved in the process of tumorigenesis. The finding of antibodies to RPA32 before diagnosis and their prevalence in in situ carcinoma suggest that they are potentially useful markers of early disease.

Síndrome de cushing por hiperplasia adrenal macronodular bilateral ACTH-independiente / Cushing's syndrome due to ACTH-independent bilateral macronodular adrenal hyperplasia

La hiperplasia suprarrenal macronodular bilateral ACTH-independiente (HAMAI) se considera hoy día una entidad diferente y separada del resto de causas de síndrome de Cushing. Su etiología es incierta aunque en los últimos años se ha demostrado la existencia de respuesta anormal de glándulas suprarrenales a distintas hormonas que estimulan la secreción de cortisol. En este artículo presentamos un caso de hipercortisolismo no suprimible con dexametasona, cifras de ACTH indetectables, hiperplasia suprarrenal bilateral de aspecto nodular y resonancia magnética nuclear hipofisaria normal. Se realizó suprarrenalectomía bilateral, objetivando cifras detectables de ACTH a los 3 meses (AU)

Antinuclear antibodies as potential markers of lung cancer.

There are multiple case reports of antinuclear antibodies (ANAs) in patients with malignancies, yet to date there has not been a systematic survey of ANAs in lung cancer. We have previously reported that autoantibodies to collagen antigens resembling those found in the connective tissue diseases are consistently detected in the sera from lung cancer patients. In this work, we looked for the presence of ANAs in the sera from these same patients. Sera from 64 patients with lung cancer and 64 subjects without a history of cancer were retrospectively tested for reactivity on immunoblots of nuclear extracts of HeLa, small cell carcinoma, squamous cell carcinoma, adenocarcinoma, large cell carcinoma of the lung, and of normal lung cells. Associations were sought between the reactivities on immunoblots and lung cancer cell type, diagnosis, and progression-free survival by the method of classification and regression trees (CARTs). Cross-validated CART analyses indicated that reactivities to certain bands in immunoblots are associated with different types of lung cancer. Some of these autoantibodies were associated with a prolonged survival without disease progression. Our data suggest that autoimmunity is often a prominent feature of lung cancer and that molecular characterization of these antigens may lead to the discovery of proteins with diagnostic and prognostic value.

Periarticular osteoporosis in osteoarthritis of the knee.

OBJECTIVE: To test the hypothesis that bone mineral density (BMD) in periarticular subchondral regions of the knee joint is abnormal in patients with osteoarthritis (OA). METHODS: Sixty-two knees from patients with relatively mild OA (primarily radiographic grades 0, 1, 2) of the knee were compared with 62 knees from normal subjects matched for age, sex, race, and body side (right or left). BMD of the lumbar spine, distal femoral shaft, and several periarticular subchondral regions of the knee were determined by dual energy x-ray absorptiometry (DXA). To facilitate increased accuracy of BMD values, lateral DXA of the knees was also performed and used to provide a third dimension to the usual two-dimensional anterior-posterior g/cm2, producing measurements as g/cm3. Subchondral bone regions included both superficial and deep regions of the medial femoral, medial tibial, and lateral tibial compartments. RESULTS: BMD (g/cm3) was lower than normal in 6 subchondral bone regions of the knees (n=43) of white female patients with OA (average decrease -13.3%), significant in all 6 subchondral regions (p=0.001 to p=0.047). Two-dimensional BMD (g/cm2) was lower than normal in 6 subchondral regions of the knees (n=43) of white female patients with OA (average decrease -7.3%), significant in only 2 of 6 subchondral regions (p=0.011 to p=0.014). BMD (g/cm3) was lower than normal in 6 subchondral regions of the knees (n=19) of African American female patients with OA (average decrease -9.1%), significant in only one of the 6 subchondral regions (p=0.016). There was no significant difference in spinal BMD (L1-L4) or femoral shaft BMD between normal and OA for either racial group. About 13% of the OA patients had osteoporosis at the spine. CONCLUSION: A significant decrease in periarticular subchondral BMD is present in female patients with relatively mild OA of the knee whether or not they had osteoporosis based on a spine BMD measurement.

[Cyclosporin A in the treatment of Eaton-Lambert myasthenic syndrome]. / Ciclosporina-A como tratamiento del síndrome miasteniforme de Eaton-Lambert.

The Lambert-Eaton myasthenic syndrome (LEMS) is a disorder of he cholinergic neurotransmition at the presinaptic terminal of the neuromuscular junction. Clinically it is characterized by muscular weakness, hyporeflexia and autonomic dysfunction. In this entity thet presence of antibodies against calcium channels impair acetylcholine release. Whe used cyclosporin-A in a patient with LEMS and this resulted in a complete clinical and neurophysiological recovery after four months of therapy.

A human cartilage metalloproteinase with elastolytic activity.

A metalloproteinase with elastolytic properties found in human fetal and osteoarthritic cartilage could not be detected in normal adult cartilage. During extraction the enzyme appeared to be mostly associated with cartilage proteoglycans, from which it can be separated by ion exchange chromatography. This enzyme migrated during electrophoresis with an apparent molecular weight of 62,000 daltons and was found to be fully activated in the tissue under the study conditions. The enzyme showed a preference for substrates rich in non-polar amino acid residues and was capable of breaking down elastin and casein at neutral pH. The enzyme activity can be inhibited by chelating agents and specific affinity reagents, chloroketones, and is not inhibited by other proteinase inhibitors such as PMSF, aprotinin and alpha-1-antitrypsin. This enzyme may play a significant role in conditions demanding rapid cartilage matrix turnover and/or remodeling, such as normal embryonic development or osteoarthritis.

[Morbidity caused by accidents in the child population in Cantabria]. / Estudio de la morbilidad por accidentes en la población infantil de Cantabria.

This work presents the morbidity by accident which required medical assistance, covering the population from zero-to-nineteen years of the Autonomic Community of Cantabria between the first of October 1986 and the 30th of September 1987. For this study 1610 families chosen at random depending on the zone's population, were interviewed. The number of registered accidents was of 527 and the number of injured children of 453, which represents the 28.14% of the total of children interviewed. A 42.66% required out-patient medical assistance, a 53.82% required medical assistance at the hospital's emergency units and a 3.5% had to enter hospital. A 5.1% of the accidents were considered very serious, no deaths occurred. The circumstances that defined the accidents were analyzed and the facts that conditioned them, subject, agent and mean.

Influence of antecedent lymphoid surgery on the odds of acquiring rheumatoid arthritis.

The occurrence of rheumatoid arthritis (RA) and the extent of antecedent lymphoid surgeries was examined using case control study methods. Two hundred sixty-four patients with definite or classic RA were considered and 283 patients with rheumatic diseases presumably of nonimmunologic origin were used as controls. The odds for developing RA were found to be significantly higher for patients with multiple lymphoid surgeries (tonsillectomy and adenoidectomy or tonsillectomy and adenoidectomy plus appendectomy) and exhibited a gradient, increasing with more extensive surgery. Significant rank correlations were found in patients with RA between the age at tonsillectomy and the rheumatoid factor (RF) titer. An earlier tonsillectomy correlated with lower titers of RF. A significant decrease of serum RF titer was also seen in patients with RA subjected to tonsillectomy, adenoidectomy and appendectomy. We conclude that antecedent removal of lymphoid tissue from the tonsils, adenoids and appendix constitutes a risk factor predisposing to RA. Moreover, this risk seems related to the quantity of lymphoid tissue removed.

[Cutters and drillers: 2 different coal pneumoconioses?]. / Foreurs et abatteurs: deux pneumoconioses différentes du charbon?

The radiographs of 393 coal-cutters (or hewers) and 187 drillers were read independently by two pneumoconiosis experts following the complete 12 grade classification (BIT 1980). The two groups were comparable for age, tobacco and alcohol consumption, and respiratory symptoms but the VEMS was lower in he drillers (p = 0.05). There were significant radiological differences between the groups as follows: with the coal-cutters predominantly type "p" opacities and Category 1; in the drillers "q" and "v" opacities and category 3 were most frequent, and there were a large number of pseudo-tumoral masses and signs of hyperinflation. The two groups have a quantitative and qualitative differences in exposure; it is necessary to interpret the results as two different types of pneumoconiosis, although there are intermediate types. The coal cutters have coal-workers pneumoconiosis in the strictest sense, while the drillers have silicosis with mixed dusts, the latter being more aggressive and incapacitating. One should take account of the two types in epidemiological evaluations in coal miners. It helps to explain certain contradictory results.