Mammalian pre-mRNA 3' end processing factor CF I m 68 functions in mRNA export

Export of mRNA from the nucleus is linked to proper processing and packaging into ribonucleoprotein complexes. Although several observations indicate a coupling between mRNA 3' end formation and export, it is not known how these two processes are mechanistically connected. Here, we show that a subunit of the mammalian pre-mRNA 3' end processing complex, CF I(m)68, stimulates mRNA export. CF I(m)68 shuttles between the nucleus and the cytoplasm in a transcription-dependent manner and interacts with the mRNA export receptor NXF1/TAP. Consistent with the idea that CF I(m)68 may act as a novel adaptor for NXF1/TAP, we show that CF I(m)68 promotes the export of a reporter mRNA as well as of endogenous mRNAs, whereas silencing by RNAi results in the accumulation of mRNAs in the nucleus. Moreover, CF I(m)68 associates with 80S ribosomes but not polysomes, suggesting that it is part of the mRNP that is remodeled in the cytoplasm during the initial stages of translation. These results reveal a novel function for the pre-mRNA 3' end processing factor CF I(m)68 in mRNA export.

Prostate specific antigen doubling time as auxiliary end point in hormone refractory prostatic carcinoma

In hormone refractory prostatic carcinoma (HRPCa), the majority of patients have bone metastases only, which are by definition non-measurable. This makes objective evaluation of chemotherapeutic agents difficult. Prostate specific antigen (PSA) as a dynamic model was analyzed as potential auxiliary end point in HRPCa.

Effect of calcium-channel blockers on calcium-phosphate metabolism in patients with end-stage renal disease

After EDTA-induced hypocalcaemia, healthy volunteers treated with diltiazem display more severe hyperparathyroidism than subjects on felodipine studied under identical conditions. Therefore patients with end-stage renal disease (ESRD) and severe secondary hyperparathyroidism might be particularly sensitive to this side-effect.

The end of the corporate life cycle

This paper asks how takeover and failure hazards change as listed firms get older. The hypothesis is that they increase because firms gradually run out of growth opportunities. We find the opposite. Both takeover and failure hazard drop significantly with age. The decline in takeover hazard can be explained with Loderer, Stulz, and Waelchli’s (2013) “buggy whip makers” hypothesis: Because old firms are comparatively well-managed and are affected by limited agency problems, on average, they offer little value added potential to acquirers. Failure hazard drops because to learning. The results are robust to various alternative interpretations and cannot be explained by unobserved heterogeneity. While hazards decline with age, they do not go to zero. This explains why, eventually, all listed firms disappear

The end of the corporate life cycle

This paper asks how takeover and failure hazards change as listed firms get older. The hypothesis is that they increase because firms gradually run out of growth opportunities. We find the opposite. Both takeover and failure hazard drop significantly with age. The decline in takeover hazard can be explained with Loderer, Stulz, and Waelchli’s (2013) “buggy whip makers” hypothesis: Because old firms are comparatively well-managed and are affected by limited agency problems, on average, they offer little value added potential to acquirers. Failure hazard drops because to learning. The results are robust to various alternative interpretations and cannot be explained by unobserved heterogeneity. While hazards decline with age, they do not go to zero. This explains why, eventually, all listed firms disappear

The end of the corporate life cycle

This paper asks how takeover and failure hazards change as listed firms get older. The hypothesis is that they increase because firms gradually run out of growth opportunities. We find the opposite. Both takeover and failure hazard drop significantly with age. The decline in takeover hazard can be explained with Loderer, Stulz, and Waelchli’s (2013) “buggy whip makers” hypothesis: Because old firms are comparatively well-managed and are affected by limited agency problems, on average, they offer little value added potential to acquirers. Failure hazard drops because to learning. The results are robust to various alternative interpretations and cannot be explained by unobserved heterogeneity. While hazards decline with age, they do not go to zero. This explains why, eventually, all listed firms disappear

Subclinical hypothyroidism and cardiovascular risk: how to end the controversy

The indications for screening and TSH threshold levels for treatment of subclinical hypothyroidism have remained a clinical controversy for over 20 years. Subclinical thyroid dysfunction is a common finding in the growing population of older adults, occurring in 10–15% among those age 65 and older, and may contribute to multiple common problems of older age, including cardiovascular disease, muscular impairment, mood problems, and cognitive dysfunction (1). In 2004, both the U.S. Preventive Services Task Force (2) and a clinical consensus group of experts (3) concluded that the existing evidence about the association between subclinical hypothyroidism and cardiovascular risks, primarily cross-sectional or case-control studies (4), was insufficient. For example, a frequently cited analysis from the Rotterdam study found a cross-sectional association between subclinical hypothyroidism and atherosclerosis, as measured by abdominal aortic calcification (odds ratio, 1.7; 95% confidence interval [CI], 1.1–2.6) and prevalent myocardial infarction (MI) (odds ratio, 2.3; 95% CI, 1.3–4.0) (5). Conversely, the prospective part of this study included only 16 incident MIs; the hazard ratio (HR) for subclinical hypothyroidism was 2.50, with broad 95% CIs (0.70–9.10). Potential mechanisms for the associations with cardiovascular diseases among adults with subclinical hypothyroidism include elevated cholesterol levels, inflammatory markers, raised homocysteine, increased oxidative stress, insulin resistance, increased systemic vascular resistance, arterial stiffness, altered endothelial function, and activation of thrombosis and hypercoagulability that have all been reported to be associated with subclinical hypothyroidism (1, 6).

Is there good simulation basic training for end-to-side vascular microanastomoses?

BACKGROUND Microvascular anastomosis is the cornerstone of free tissue transfers. Irrespective of the microsurgical technique that one seeks to integrate or improve, the time commitment in the laboratory is significant. After extensive previous training on several animal models, we sought to identify an animal model that circumvents the following issues: ethical rules, cost, time-consuming and expensive anesthesia, and surgical preparation of tissues required to access vessels before performing the microsurgical training, not to mention that laboratories are closed on weekends. METHODS Between January 2012 and April 2012, a total of 91 earthworms were used for 150 microsurgical training exercises to simulate vascular end-to-side microanastomosis. The training sessions were divided into ten periods of 7 days. Each training session included 15 simulations of end-to-side vascular microanastomoses: larger than 1.5 mm (n=5), between 1.0 and 1.5 mm (n=5), and smaller than 1.0 mm (n=5). A linear model with the main variables being the number of weeks (as a numerical covariate) and the size of the animal (as a factor) was used to determine the trend in time of anastomosis over subsequent weeks as well as the differences between the different size groups. RESULTS The linear model shows a significant trend (p<0.001) in time of anastomosis in the course of the training, as well as significant differences (p<0.001) between the groups of animals of different sizes. For microanastomoses larger than 1.5 mm, the mean anastomosis time decreased from 19.3±1.0 to 11.1±0.4 min between the first and last week of training (decrease of 42.5%). For training with smaller diameters, the results showed a decrease in execution time of 43.2% (diameter between 1.0 and 1.5 mm) and 40.9% (diameter<1.0 mm) between the first and last periods. The study demonstrates an improvement in the dexterity and speed of nodes execution. CONCLUSION The earthworm appears to be a reliable experimental model for microsurgical training of end-to-side microanastomoses. Its numerous advantages are discussed here and we predict training on earthworms will significantly grow and develop in the near future. LEVEL OF EVIDENCE III This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Macular hole surgery in patients with end-stage choroideremia

OBJECTIVE To assess macular hole surgery in patients with end-stage choroideremia with regard to anatomic closure and visual outcome. DESIGN Retrospective, interventional case series. PARTICIPANTS Thirty adult male patients with a diagnosis of advanced choroideremia were reviewed and underwent spectral domain optical coherence tomography (OCT) as part of the screening process for a gene therapy clinical trial. From within that cohort, 3 were identified as having a full-thickness macular hole (FTMH). METHODS A 23-gauge pars plana vitrectomy was performed with peeling of the inner limiting membrane and gas tamponade. Preoperative best-corrected visual acuity ranged from perception of light to 6/24. MAIN OUTCOME MEASURES Prevalence of FTMH in advanced choroideremia, morphologic phenotype characteristics of FTMH in OCT, pre- and postoperative best-corrected visual acuity, and closure rate after surgery. RESULTS The prevalence of FTMH in advanced choroideremia in our cohort was 10%. One hole was associated with significant macular schisis, presumed to be attributable to degeneration of outer retinal layers. Anatomic closure was achieved in all 3 patients and confirmed with spectral domain OCT. Gas tamponade lasted approximately twice as long as might be expected compared with standard FTMH surgery. Objective visual acuity did not improve; however, perceived vision improved in all patients. CONCLUSIONS Although FTMH in choroideremia is a rare finding, it could potentially mask central progression of the disease. Regular screening may help to diagnose holes at an earlier stage when the visual prognosis after surgery may be better. Standard macular hole surgery seems to be effective in gaining anatomic closure, which would be significant for patients who subsequently require macula detachment for subretinal gene therapy. FINANCIAL DISCLOSURE(S) The authors have no proprietary or commercial interest in any of the materials discussed in this article.