ShcA promotes chondrocyte hypertrophic commitment and osteoarthritis in mice through RunX2 nuclear translocation and YAP1 inactivation.

OBJECTIVE: Chondrocyte hypertrophic differentiation, a key process in endochondral ossification, is also a feature of osteoarthritis leading to cartilage destruction. Here we investigated the role of the adaptor protein Src homology and Collagen A (ShcA) in chondrocyte differentiation and osteoarthritis. METHODS: Mice ablated for ShcA in osteochondroprogenitor cells were generated by crossing mice carrying the Twist2-Cre transgene with ShcAflox/flox mice. Their phenotype (n = 5 to 14 mice per group) was characterized using histology, immuno-histology and western-blot. To identify the signaling mechanisms involved, in vitro experiments were conducted on wild type and ShcA deficient chondrocytes (isolated from n = 4 to 7 littermates) and the chondroprogenitor cell line ATDC5 (n = 4 independent experiments) using western-blot, cell fractionation and confocal microscopy. RESULTS: Deletion of ShcA decreases the hypertrophic zone of the growth plate (median between group difference -11.37% [95% confidence interval -17.34 to -8.654]), alters the endochondral ossification process, and leads to dwarfism (3 months old male mice nose-to-anus length -1.48 cm [-1.860 to -1.190]). ShcA promotes ERK1/2 activation, nuclear translocation of RunX2, the master transcription factor for chondrocyte hypertrophy, while maintaining the Runx2 inhibitor, YAP1, in its cytosolic inactive form. This leads to hypertrophic commitment and expression of markers of hypertrophy, such as Collagen X. In addition, loss of ShcA protects from age-related osteoarthritis development in mice (2 years old mice OARSI score -6.67 [-14.25 to -4.000]). CONCLUSION: This study reveals ShcA as a new player in the control of chondrocyte hypertrophic differentiation and its deletion slows down osteoarthritis development.

Anti-Donor HLA Antibody Response After Pancreatic Islet Grafting: Characteristics, Risk Factors, and Impact on Graft Function.

Pancreatic islet grafting restores endogenous insulin production in type 1 diabetic patients, but long-term outcomes remain disappointing as a result of immunological destruction of allogeneic islets. In solid organ transplantation, donor-specific anti-HLA antibodies (DSA) are the first cause of organ failure. This retrospective multicentric study aimed at providing in-depth characterization of DSA response after pancreatic islet grafting, identifying the risk factor for DSA generation and determining the impact of DSA on graft function. Forty-two pancreatic islet graft recipients from the Groupe Rhin-Rhône-Alpes-Genève pour la Greffe d'Ilots de Langerhans consortium were enrolled. Pre- and postgrafting sera were screened for the presence of DSA and their ability to activate complement. Prevalence of DSA was 25% at 3 years postgrafting. The risk of sensitization increased steeply after immunosuppressive drug withdrawal. DSA repertoire diversity correlated with the number of HLA and eplet mismatches. DSA titer was significantly lower from that observed in solid organ transplantation. No detected DSA bound the complement fraction C3d. Finally, in contrast with solid organ transplantation, DSA did not seem to negatively affect pancreatic islet graft survival. This might be due to the low DSA titers, specific features of IgG limiting their ability to activate the complement and/or the lack of allogenic endothelial targets in pancreatic islet grafts.

Pulmonary function in paracoccidioidomycosis (South American blastomycosis). An analysis of the obstructive defect.

Comparison of the mean results of routine pulmonary function studies of 17 patients with diffuse pulmonary paracoccidioidomycosis (PM) and manifestations of chronic obstructive pulmonary disease (COPD) to those of 17 matched patients with pure COPD showed no significant differences. These findings were interpreted as fresh evidence suggesting that expiratory obstruction in PM may be secondary to underlying COPD. Other evidence to that effect is discussed.

Pulmonary function changes in the acute stage of histoplasmosis, with follow-up. An analysis of eight cases.

We have studied eight patients, six children and two adults, during a microepidemic of soil- and patient-proven histoplasmosis. Pulmonary function tests were performed between the 15th and 23rd days after the onset of symptoms, and repeated between the fifth and sixth, the ninth and tenth and the 15th and 22nd months afterward. Initial abnormalities were mild in seven cases and severe in one. There was a restrictive pattern in three cases and an obstructive pattern in two. The fraction of CO extraction was reduced in five cases and the diffusing capacity for CO was reduced in five of six cases so tested. Hypoxemia was present in three cases. On follow-up, the obstructive defect had disappeared by the sixth month, the restrictive pattern by the tenth month, and the diffusing defect still remained in three cases by the end of follow-up. Hypoxemia remained only in the severe case.

[Respiratory symptoms and spirometric tests of quarry workers in Rio de Janeiro]. / Sintomas respiratórios e testes espirográficos dos funcionários de uma pedreira do Rio de Janeiro.

Respiratory symptoms and past history of chest disease as well as spirometric tests were investigated in 72 of 86 (83.7%) employees of a middle sized quarry in Rio de Janeiro, Brazil. Seventy one were men (98.6%), and the mean age was 36.2 +/- 9.3 years (20-65). Forty two (58.3%) had occupations considered as highly exposed to dust, and 30 (44.7%) were considered as lightly exposed. Forty (55.6%) were smokers, 20 (27.8%) never had been smokers and 12 (16.7%) were former smokers. Symptoms and past history were investigated with a questionnaire based on international models, and adapted for the Brazilian public. A high prevalence of symptoms (except for dyspnea) was noted: 47 (65.3%) had one or more symptoms-there was cough in 31.9%, expectoration in 41.7% dyspnea in 9.7% and wheezing in 33.3%. The symptoms were found to be associated mostly with a past history of chest disease, and also with smoking, factors which explained, in part, the presence of the symptoms. No association with a higher exposure to dust was found. The exposure to dust did not explain the symptoms. The spirometric tests were performed on a 6 liter bell spirometer. The means of the parameters were lower than one would expect in a non selected population sample--89.9 +/- 11.2% of predicted for the Forced Vital Capacity (FVC), 90.1 +/- 12.9% for the Forced Expiratory Volume in 1 second (FEV1) and 92.9 +/- 32.7% for the Forced Expiratory Flow between 25% and 75% of the FVC (FEF25-75). However, the proportions of abnormal results were comparable to the reported ones from unselected samples. There was no statistically significant influence of higher dust exposure, past history or smoking on the means of the results. It is concluded that, in this sample of quarry employees, no association between respiratory symptoms or spirometric results and dust exposure could be demonstrated. There was an association between the symptoms, but not with the spirometric results, and a past history of chest disease, as well as with smoking.