Inhibition of transforming growth factor-beta1 signaling attenuates ataxia telangiectasia mutated activity in response to genotoxic stress

Ionizing radiation causes DNA damage that elicits a cellular program of damage control coordinated by the kinase activity of ataxia telangiectasia mutated protein (ATM). Transforming growth factor beta (TGFbeta)-1, which is activated by radiation, is a potent and pleiotropic mediator of physiologic and pathologic processes. Here we show that TGFbeta inhibition impedes the canonical cellular DNA damage stress response. Irradiated Tgfbeta1 null murine epithelial cells or human epithelial cells treated with a small-molecule inhibitor of TGFbeta type I receptor kinase exhibit decreased phosphorylation of Chk2, Rad17, and p53; reduced gammaH2AX radiation-induced foci; and increased radiosensitivity compared with TGFbeta competent cells. We determined that loss of TGFbeta signaling in epithelial cells truncated ATM autophosphorylation and significantly reduced its kinase activity, without affecting protein abundance. Addition of TGFbeta restored functional ATM and downstream DNA damage responses. These data reveal a heretofore undetected critical link between the microenvironment and ATM, which directs epithelial cell stress responses, cell fate, and tissue integrity. Thus, Tgfbeta1, in addition to its role in homoeostatic growth control, plays a complex role in regulating responses to genotoxic stress, the failure of which would contribute to the development of cancer; conversely, inhibiting TGFbeta may be used to advantage in cancer therapy.     

Videolaparoscopic orchiectomy and nephrectomy: training model in rats

OBJECTIVE: Videolaparoscopic surgery conducted on small animals has proved to be of great importance for the improvement of surgical skills. This is a report utilizing an experimental model for laparoscopic orchiectomy and nephrectomy in training courses for urologists. MATERIAL AND METHODS: Of 350 American Wistar rats enrolled, 319 animals underwent laparoscopic orchiectomy and nephrectomy under intraperitoneal general anesthesia. Graspers, dissectors, and a 0-degree telescope were introduced into the peritoneal cavity by two trocars of 5 mm and one of 10 mm, respectively. RESULTS: Of 350 rats enrolled, 15 (4.2%) died due to anesthetic complications and 16 (4.5%) due to cannibalism and stress during transport. A total of 319 rats were operated on, 178 underwent bilateral orchiectomy, two per model (356 operations), and in 141 animals one nephrectomy per model (141 operations) was performed. A total of 497 operations were performed involving 140 urologists. The animals were easy to handle providing adequate practice without the occurrence of any major intraperitoneal lesion and hemorrhage. CONCLUSION: Nephrectomy and orchiectomy are feasible in rats, and this model can be utilized for training videolaparoscopic surgeries.     

Long-term outcomes of early-onset wheeze and asthma

Evidence from longitudinal cohort studies demonstrates that wheezing that begins in early life and continues into the school years generally persists into adulthood. This persistent wheezing is associated with lung function deficits and airways hyperresponsiveness that appear to be established in the first few years of life. Allergic sensitization early in life, early-life infection with rhinovirus, or colonization with any of a number of bacteria have been associated with increased risk of persistent wheeze. Early life, whether in utero or in the first few years of life, presents a window of vulnerability during which airway injury results in persistent airways dysfunction. Available data further suggest that a second such window of vulnerability might be present in the preadolescent and adolescent years. Lung function growth patterns established by age 6 years generally continue into early adulthood to middle adulthood, typically leaving groups of subjects with wheezing that persists into or relapses during adulthood with a mean FEV(1) of about 10% of predicted value less than their peers who do not wheeze. Subgroups of patients with persistent asthma, however, can have progressive decreases in lung function and enter adulthood with even lower lung function. The concern exists that these deficits in lung function apparent in early adulthood might put subjects at risk for the later development of chronic obstructive pulmonary disease.     

Maxillary Sinus Augmentation by the Crestal Core Elevation Technique

Background: The crestal core elevation (CCE) technique is reportedly a less invasive procedure than the lateral window elevation technique. We retrospectively evaluated long‐term outcomes of CCE procedures over an 11‐year time period. Methods: Core preparations were made after extractions of 57 upper molars in 45 patients. Extraction sites were drilled with a calibrated trephine bur to an estimated distance of 1 mm from the sinus membrane. The trephined interradicular bone and underlying sinus membrane were imploded into the sinus. The surgical crater and residual extraction socket were filled with deproteinized bovine bone mineral or freeze‐dried bone allograft, stabilized, and protected with an absorbable collagen membrane and fully covered with coronally positioned flaps. Implants were placed 4 months later. Success was defined if ≥9 mm available bone height was available. Where the available bone height varied between 7 and 9 mm, implant placement was complemented using the bone‐added osteotome sinus floor elevation technique; those sites were defined as a “partial success.” Results: The CCE technique was successful in 31 (68.9%) out of 45 sites, and partially successful in six (13.3%) out of 45 sites. Eight sites failed (17.8%). Surgical failures were caused by core detachment resulting in large tears of the sinus membrane. Implants placed in successful sites presented a 100% survival rate during the study duration. Conclusions: CCE implemented simultaneously with molar extractions provided therapeutic benefits and clinical limitations. The subsequent implant placement using CCE revealed an excellent survival rate in the study population evaluated.