No abstract

-Heat shock protein 90 (Hsp90) is a constitutively expressed molecular chaperone and plays an important role in the folding of client proteins with key regulatory roles in growth, survival, differentiation and metastasis. Because inhibition of Hsp90 degrades multiple oncogenic client proteins, it is considered to be an attractive anticancer therapy, and clinical trials of several Hsp90 inhibitors have been carried out. In the present study, two structurally distinct Hsp90 inhibitors, CH5164840 and CH5449302, were orally administered to beagle dogs to evaluate systemic toxicity. CH5164840 induced symptoms that suggest visual disorder, and ophthalmological observation and electroretinography (ERG) revealed loss of pupillary light reflex and abnormal waveforms, respectively. Histopathological examination showed changes in the photoreceptor cell layer and the outer nuclear layer of retina. On the other hand, while there were no clinical symptoms related to visual disorder, animals treated with CH5449302 showed similar abnormalities of ERG responses and histopathological changes in the photoreceptor cell layer and the outer nuclear layer of retina. The visual symptoms and abnormalities of ERG responses were noted at an earlier stage or lower dose than other toxicities in both compounds. Considering that two structurally distinct Hsp90 inhibitors induced a retinal toxicity in dogs after repeated administration, and that visual disorders were also reported in some clinical trials of Hsp90 inhibitors, it would seem highly likely that Hsp90 inhibition induces retinal toxicity. Also, our study indicated that a detailed ocular examination to evaluate the safety of Hsp90 inhibitors would be useful in both preclinical and clinical studies.

A 17-year-old male with tachycardia-induced cardiomyopathy presented with persistent, drug-resistant atrial tachycardia (AT). An electrophysiological study suggested focal abnormal automaticity, and localized the AT origin to the left atrial appendage. Radiofrequency catheter ablation at the site of the earliest endocardial activation during AT failed. A minimally invasive, video-assisted thoracoscopic (VAT) atrial appendectomy terminated the AT and restored left ventricular contractility. The patient remained free of AT and normal left ventricular function was maintained over a 24-month follow-up period. To our knowledge, we are the first to use VAT atrial appendectomy to treat focal AT.

Introduction: To our knowledge, no studies have investigated the histological comparison between primary injured anterior cruciate ligament (ACL), initially anatomically reconstructed grafts and non-anatomically reconstructed grafts at the time of revision ACL reconstruction. The purpose of this study was to histologically clarify the differences between ACL remnant tissue, reconstructed graft after anatomic double-bundle ACL reconstruction, and reconstructed graft after non-anatomic single-bundle ACL reconstruction. Methods: This histological study included five patients after anatomic double-bundle ACL reconstruction, three patients after non-anatomic single-bundle ACL reconstruction performed who injured their operated knees again, and five patients who injured their ACL for the first time and agreed to participate. All of the grafts and ACL remnant tissue were harvested, stained with hematoxylin and eosin, S-100, and alpha smooth muscle actin and evaluated using light microscopy. Results: There was no area of necrosis in the reconstructed graft after an anatomic double-bundle ACL reconstruction. However, there were obvious areas of necrosis in the reconstructed graft after non-anatomic single-bundle ACL reconstruction. Additionally, the collagen fibers were more longitudinally oriented, and most cells were spindle shaped like those in ACL remnant tissue after an anatomic double-bundle ACL reconstruction in contrast with the finding of the grafts after non-anatomic single-bundle ACL reconstruction. Conclusion: Initially reconstructed graft after an anatomic double-bundle ACL reconstruction may be beneficial if preserved at the time of the revision surgery.

No abstract