Serum activin A and B levels predict outcome in patients with acute respiratory failure: a prospective cohort study.

INTRODUCTION: 30 day mortality in patients with Acute Respiratory Failure (ARF) is approximately 30%, defined as patients requiring ventilator support for more than 6 hours. Novel biomarkers are needed to predict patient outcomes and to guide potential future therapies. The activins A and B, members of the Transforming Growth Factor ß family of proteins, and their binding protein, follistatin, have recently been shown to be important regulators of inflammation and fibrosis but no substantial data are available concerning their roles in ARF. METHODS: Specific assays for activin A, B and follistatin were used and the results analyzed according to diagnostic groups as well as according to standard measures in intensive care. Multivariable logistic regression was used to create a model to predict death at 90 days and 12 months from the onset of the ARF. RESULTS: Serum activin A and B were significantly elevated in most patients and in most of the diagnostic groups. Patients who had activin A and/or B concentrations above the reference maximum were significantly more likely to die in the 12 months following admission [either activin A or B above reference maximum: Positive Likelihood Ratio [LR+] 1.65 [95% CI 1.28-2.12, P = 0.00013]; both activin A and B above reference maximum: LR + 2.78 [95% CI 1.96-3.95, P < 0.00001]. The predictive model at 12 months had an overall accuracy of 80.2% [95% CI 76.6-83.3%]. CONCLUSIONS: The measurement of activin A and B levels in these patients with ARF would have assisted in predicting those at greatest risk of death. Given the existing data from animal studies linking high activin A levels to significant inflammatory challenges, the results from this study suggest that approaches to modulate activin A and B bioactivity should be explored as potential therapeutic agents.

Claudin-11 and connexin-43 display altered spatial patterns of organization in men with primary seminiferous tubule failure compared with controls.

OBJECTIVE: To assess the spatial organization of two proteins involved in the Sertoli cell junctional complex in men with primary seminiferous tubule failure. DESIGN: Retrospective study. SETTING: Medical research institute. PATIENT(S): Sixteen men total, six with meiotic arrest, seven with the Sertoli cell-only phenotype, and three with normal spermatogenesis. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Differences in claudin-11 and connexin-43 organization as detected using confocal microscopy. RESULT(S): In men with primary seminiferous tubule failure, four organizational patterns (I-IV) were recognized and quantified for claudin-11. Across these patterns, claudin-11 changed from a basal filamentous staining pattern to a punctate staining pattern with diffuse localization throughout the entire epithelium. Similar changes in staining patterns for connexin-43 were observed. Major differences were seen in the spatial organization of claudin-11 and connexin-43 in tubules from control men compared with tubules with primary seminiferous tubule failure, but we observed no differences in the spatial organization of these proteins in tubules from men with meiotic arrest and Sertoli cell-only phenotypes. CONCLUSION(S): The spatial organization of claudin-11 and connexin-43 is altered in men with primary seminiferous tubule failure. Disorganization of the proteins composing the Sertoli cell junctional complex may be involved in the spermatogenic impairment, possibly via loss of blood-testis barrier function.