Survival without disability to age 5 years after neonatal caffeine therapy for apnea of prematurity

Very preterm infants are prone to apnea and have an increased risk of death or disability. Caffeine therapy for apnea of prematurity reduces the rates of cerebral palsy and cognitive delay at 18 months of age.

Histone deacetylase 3 is critical in endothelial survival and atherosclerosis development in response to disturbed flow

Histone deacetylase 3 (HDAC3) is known to play a crucial role in the differentiation of endothelial progenitors. The role of HDAC3 in mature endothelial cells, however, is not well understood. Here, we investigated the function of HDAC3 in preserving endothelial integrity in areas of disturbed blood flow, ie, bifurcation areas prone to atherosclerosis development.

Mesenchymal stem cells enhance survival and bacterial clearance in murine Escherichia coli pneumonia

Rationale: Bacterial pneumonia is the most common infectious cause of death worldwide and treatment is increasingly hampered by antibiotic resistance. Mesenchymal stem cells (MSCs) have been demonstrated to provide protection against acute inflammatory lung injury; however, their potential therapeutic role in the setting of bacterial pneumonia has not been well studied.

Objective: This study focused on testing the therapeutic and mechanistic effects of MSCs in a mouse model of Gram-negative pneumonia.

Methods and results: Syngeneic MSCs from wild-type mice were isolated and administered via the intratracheal route to mice 4 h after the mice were infected with Escherichia coli. 3T3 fibroblasts and phosphate-buffered saline (PBS) were used as controls for all in vivo experiments. Survival, lung injury, bacterial counts and indices of inflammation were measured in each treatment group. Treatment with wild-type MSCs improved 48 h survival (MSC, 55%; 3T3, 8%; PBS, 0%; p<0.05 for MSC vs 3T3 and PBS groups) and lung injury compared with control mice. In addition, wild-type MSCs enhanced bacterial clearance from the alveolar space as early as 4 h after administration, an effect that was not observed with the other treatment groups. The antibacterial effect with MSCs was due, in part, to their upregulation of the antibacterial protein lipocalin 2.

Conclusions: Treatment with MSCs enhanced survival and bacterial clearance in a mouse model of Gram-negative pneumonia. The bacterial clearance effect was due, in part, to the upregulation of lipocalin 2 production by MSCs

Translation suppression promotes stress granule formation and cell survival in response to cold shock

Cells respond to different types of stress by inhibition of protein synthesis and subsequent assembly of stress granules (SGs), cytoplasmic aggregates that contain stalled translation preinitiation complexes. Global translation is regulated through the translation initiation factor eukaryotic initiation factor 2a (eIF2a) and the mTOR pathway. Here we identify cold shock as a novel trigger of SG assembly in yeast and mammals. Whereas cold shock-induced SGs take hours to form, they dissolve within minutes when cells are returned to optimal growth temperatures. Cold shock causes eIF2a phosphorylation through the kinase PERK in mammalian cells, yet this pathway is not alone responsible for translation arrest and SG formation. In addition, cold shock leads to reduced mitochondrial function, energy depletion, concomitant activation of AMP-activated protein kinase (AMPK), and inhibition of mTOR signaling. Compound C, a pharmacological inhibitor of AMPK, prevents the formation of SGs and strongly reduces cellular survival in a translation-dependent manner. Our results demonstrate that cells actively suppress protein synthesis by parallel pathways, which induce SG formation and ensure cellular survival during hypothermia.

Long-term graft survival in patients with flexible open-loop anterior chamber intraocular lenses

Purpose. To evaluate the long-term graft survival in patients with flexible open-loop anterior chamber intraocular lenses (AC IOL). Methods. We retrospectively reviewed the records of patients with aphakic/pseudophakic bullous keratopathy who underwent penetrating keratoplasty and flexible open-loop AC IOL implantation in our institution from 1983 to 1988. Results. 79 eyes from 77 patients were included in the study. Mean follow-up was 50 months (range 1 to 123 months). At last follow-up 61 eyes (77.2%) had clear grafts. Among them, the visual acuity was = 20/40 in 14 eyes (23.0%), 20/50-20/100 in 22 eyes (36.1%), 20/200-20/400 in 9 eyes (14.8%) and = CF in 16 (26.2%). Increment of glaucoma medications and/or glaucoma surgery was the most frequent complication (37 eyes, 46,8%). Cystoid macular edema was newly diagnosed in 10 eyes (12.7%). Conclusions. Flexible, open-loop anterior chamber lens are a viable option in the treatment of patients with aphakic or pseudophakic bullous keratopathy undergoing penetrating keratoplasty.

Long-term graft survival in patients with flexible open-loop anterior- chamber intraocular lenses

Purpose. To evaluate the long-term graft survival and complications of flexible, open-loop anterior-chamber intraocular lenses in patients with penetrating keratoplasty for pseudophakic or aphakic bullous keratopathy. Methods. We reviewed charts of all consecutive patients who underwent penetrating keratoplasty for pseudophakic or aphakic bullous keratopathy combined with implantation of a flexible, open-loop, anterior-chamber intraocular lens at our institution between 1983 and 1988. One-hundred one eyes of 99 patients were evaluated. Graft-survival rates were calculated by using the Kaplan-Meier actuarial method. Results. Mean follow-up was 49.8 months (range. 1-144). The probability of graft survival at 1, 2, 4, 6, and 8 years was 93, 87, 78, 65, and 65%, respectively. A total of 25 (24.8%) grafts failed. Progressive corneal edema without signs of rejection was the most common finding in patients with failed grafts (10 eyes, 40%). The most frequent complication observed was newly diagnosed or worsening of preexisting glaucoma (46 eyes, 45.5%). Conclusions. Our long-term results support flexible, open-loop anterior-chamber intraocular lenses as a reasonable option, at the time of penetrating keratoplasty, in patients with pseudophakic and aphakic bullous keratopathy.

US Credit Unions: Survival, Consolidation and Growth

This study uses hazard function estimations and time-series and cross-sectional growth regressions to examine the impact of exit through merger and acquisition (M&A) or failure, and internally-generated growth, on the firm-size distribution within the US credit union sector. Consolidation through M&A was the principal cause of a reduction in the number of credit unions, but impact on concentration was small. Divergence between the average internally-generated growth of smaller and larger credit unions was the principal driver of the rise in concentration.

A literature review of end-stage renal disease and cachexia:Understanding experience to inform evidence-based healthcare

Introduction: Cachexia is a major cause of morbidity and mortality in people who have end-stage renal disease (ESRD). The majority of research into cachexia in ESRD has focused on the biological aspects of the syndrome and potential treatment modalities. While this research is necessary, it predominately focuses on the physical impact of cachexia in ESRD. The multi-dimensional psychosocial ramifications of this syndrome have been highlighted in other end-stage illness trajectories, but have not been systematically explored in persons who have ESRD. Aim: This paper discusses why this research is necessary, alongside further studies to help define the pathophysiology of this syndrome. Conclusion: The rich insightful data gained from understanding the patients' illness experience will positively contribute to the limited knowledge base available and inform future holistic patient-centred care delivery which recognises and responds to not only the biological but also the psychosocial impact of cachexia. © 2013 European Dialysis and Transplant Nurses Association/European Renal Care Association.

Combined genomic and phenotype screening reveals secretory factor SPINK1 as an invasion and survival factor associated with patient prognosis in breast cancer

Secretory factors that drive cancer progression are attractive immunotherapeutic targets. We used a whole-genome data-mining approach on multiple cohorts of breast tumours annotated for clinical outcomes to discover such factors. We identified Serine protease inhibitor Kazal-type 1 (SPINK1) to be associated with poor survival in estrogen receptor-positive (ER+) cases. Immunohistochemistry showed that SPINK1 was absent in normal breast, present in early and advanced tumours, and its expression correlated with poor survival in ER+ tumours. In ER- cases, the prognostic effect did not reach statistical significance. Forced expression and/or exposure to recombinant SPINK1 induced invasiveness without affecting cell proliferation. However, down-regulation of SPINK1 resulted in cell death. Further, SPINK1 overexpressing cells were resistant to drug-induced apoptosis due to reduced caspase-3 levels and high expression of Bcl2 and phospho-Bcl2 proteins. Intriguingly, these anti-apoptotic effects of SPINK1 were abrogated by mutations of its protease inhibition domain. Thus, SPINK1 affects multiple aggressive properties in breast cancer: survival, invasiveness and chemoresistance. Because SPINK1 effects are abrogated by neutralizing antibodies, we suggest that SPINK1 is a viable potential therapeutic target in breast cancer.

Lipoxins attenuate renal fibrosis by inducing let-7c and suppressing TGFβR1

Lipoxins, which are endogenously produced lipid mediators, promote the resolution of inflammation, and may inhibit fibrosis, suggesting a possible role in modulating renal disease. Here, lipoxin A4 (LXA4) attenuated TGF-ß1-induced expression of fibronectin, N-cadherin, thrombospondin, and the notch ligand jagged-1 in cultured human proximal tubular epithelial (HK-2) cells through a mechanism involving upregulation of the microRNA let-7c. Conversely, TGF-ß1 suppressed expression of let-7c. In cells pretreated with LXA4, upregulation of let-7c persisted despite subsequent stimulation with TGF-ß1. In the unilateral ureteral obstruction model of renal fibrosis, let-7c upregulation was induced by administering an LXA4 analog. Bioinformatic analysis suggested that targets of let-7c include several members of the TGF-ß1 signaling pathway, including the TGF-ß receptor type 1. Consistent with this, LXA4-induced upregulation of let-7c inhibited both the expression of TGF-ß receptor type 1 and the response to TGF-ß1. Overexpression of let-7c mimicked the antifibrotic effects of LXA4 in renal epithelia; conversely, anti-miR directed against let-7c attenuated the effects of LXA4. Finally, we observed that several let-7c target genes were upregulated in fibrotic human renal biopsies compared with controls. In conclusion, these results suggest that LXA4-mediated upregulation of let-7c suppresses TGF-ß1-induced fibrosis and that expression of let-7c targets is dysregulated in human renal fibrosis.