Publisher Correction: Metabolic characteristics of CD8+ T cell subsets in young and aged individuals are not predictive of functionality.

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Metabolic characteristics of CD8+ T cell subsets in young and aged individuals are not predictive of functionality.

Virtual memory T (TVM) cells are antigen-naïve CD8+ T cells that exist in a semi-differentiated state and exhibit marked proliferative dysfunction in advanced age. High spare respiratory capacity (SRC) has been proposed as a defining metabolic characteristic of antigen-experienced memory T (TMEM) cells, facilitating rapid functionality and survival. Given the semi-differentiated state of TVM cells and their altered functionality with age, here we investigate TVM cell metabolism and its association with longevity and functionality. Elevated SRC is a feature of TVM, but not TMEM, cells and it increases with age in both subsets. The elevated SRC observed in aged mouse TVM cells and human CD8+ T cells from older individuals is associated with a heightened sensitivity to IL-15. We conclude that elevated SRC is a feature of TVM, but not TMEM, cells, is driven by physiological levels of IL-15, and is not indicative of enhanced functionality in CD8+ T cells.

A randomized cross-over study of auto-continuous positive airway pressure versus fixed-continuous positive airway pressure in patients with obstructive sleep apnoea.

BACKGROUND AND OBJECTIVES: To compare the efficacy of auto-CPAP (AutoSet Spirit, ResMed) versus fixed-CPAP (S6 Elite, ResMed) in improving daytime sleepiness, health status, objective compliance and the ultimate treatment preference in patients with severe OSA. METHODS: The study recruited 43 subjects aged 18-65 years with newly diagnosed severe OSA (AHI >30/h). Patients were initially treated with either auto-CPAP or fixed-CPAP for 2 months and then crossed over after a washout period of 1 week for another 2 months. RESULTS: The study was completed by 41 patients. Results are presented as mean (SE). Use of auto-CPAP in the first and the second month was significantly higher than that of fixed-CPAP [129.7 (9.9) and 130.5 (10.7) h vs 115.2 (9.5) and 113.2 (9.4) h, P = 0.04 and 0.01], whereas mean hourly use per night was 4.3 and 4.4 h versus 3.8 and 3.7 h, respectively. The Epworth sleepiness scores improved after 1 month in both treatments (13.4 to 8.5 and 8.2, P < 0.01 for both). The Sleep apnoea quality of life index improved in the first month in both compared with baseline [4.6 (0.2) to 5.0 (0.2) for auto-CPAP and 4.9 (0.2) for fixed-CPAP, P = 0.01 and 0.04, respectively], with no difference between the two treatments. Nine and 30 patients preferred auto-CPAP and fixed-CPAP, respectively, at the end of the trial, whereas 14 and 25 patients would have chosen the same treatments if cost had not been a consideration. CONCLUSIONS: Auto-CPAP and fixed-CPAP were equally effective in improving symptoms and health status in patients with severe OSA. Usage was higher with auto-CPAP, but more patients ultimately chose fixed-CPAP.

A comparative study of the cytotoxicity of silver-based dressings in monolayer cell, tissue explant, and animal models.

Over the past decade, a variety of advanced silver-based dressings have been developed. There are considerable variations in the structure, composition, and silver content of these new preparations. In the present study, we examined five commercially available silver-based dressings (Acticoat, Aquacel Ag, Contreet Foam, PolyMem Silver, Urgotul SSD). We assessed their cytotoxicity in a monolayer cell culture, a tissue explant culture model, and a mouse excisional wound model. The results showed that Acticoat, Aquacel Ag, and Contreet Foam, when pretreated with specific solutes, were likely to produce the most significant cytotoxic effects on both cultured keratinocytes and fibroblasts, while PolyMem Silver and Urgotul SSD demonstrated the least cytotoxicity. The cytotoxicity correlated with the silver released from the dressings as measured by silver concentration in the culture medium. In the tissue explant culture model, in which the epidermal cell proliferation was evaluated, all silver dressings resulted in a significant delay of reepithelialization. In the mouse excisional wound model, Acticoat and Contreet Foam indicated a strong inhibition of wound reepithelialization on the postwounding-day 7. These findings may, in part, explain the clinical observations of delayed wound healing or inhibition of wound epithelialization after the use of certain topical silver dressings. Caution should be exercised in using silver-based dressings in clean superficial wounds such as donor sites and superficial burns and also when cultured cells are being applied to wounds.

DNA damage response and Ku80 function in the vertebrate embryo.

Cellular responses to DNA damage reflect the dynamic integration of cell cycle control, cell-cell interactions and tissue-specific patterns of gene regulation that occurs in vivo but is not recapitulated in cell culture models. Here we describe use of the zebrafish embryo as a model system to identify determinants of the in vivo response to ionizing radiation-induced DNA damage. To demonstrate the utility of the model we cloned and characterized the embryonic function of the XRCC5 gene, which encodes Ku80, an essential component of the nonhomologous end joining pathway of DNA repair. After the onset of zygotic transcription, Ku80 mRNA accumulates in a tissue-specific pattern, which includes proliferative zones of the retina and central nervous system. In the absence of genotoxic stress, zebrafish embryos with reduced Ku80 function develop normally. However, low dose irradiation of these embryos during gastrulation leads to marked apoptosis throughout the developing central nervous system. Apoptosis is p53 dependent, indicating that it is a downstream consequence of unrepaired DNA damage. Results suggest that nonhomologous end joining components mediate DNA repair to promote survival of irradiated cells during embryogenesis.

The zebrafish dog-eared mutation disrupts eya1, a gene required for cell survival and differentiation in the inner ear and lateral line.

To understand the molecular basis of sensory organ development and disease, we have cloned and characterized the zebrafish mutation dog-eared (dog) that is defective in formation of the inner ear and lateral line sensory systems. The dog locus encodes the eyes absent-1 (eya1) gene and single point mutations were found in three independent dog alleles, each prematurely truncating the expressed protein within the Eya domain. Moreover, morpholino-mediated knockdown of eya1 gene function phenocopies the dog-eared mutation. In zebrafish, the eya1 gene is widely expressed in placode-derived sensory organs during embryogenesis but Eya1 function appears to be primarily required for survival of sensory hair cells in the developing ear and lateral line neuromasts. Increased levels of apoptosis occur in the migrating primordia of the posterior lateral line in dog embryos and as well as in regions of the developing otocyst that are mainly fated to give rise to sensory cells of the cristae. Importantly, mutation of the EYA1 or EYA4 gene causes hereditary syndromic deafness in humans. Determination of eya gene function during zebrafish organogenesis will facilitate understanding the molecular etiology of human vestibular and hearing disorders.

Lymphodepletion in the ApcMin/+ mouse model of intestinal tumorigenesis.

Germ line mutations in the Adenomatous polyposis coli tumor suppressor gene cause a hereditary form of intestinal tumorigenesis in both mice and man. Here we show that in Apc(Min/+) mice, which carry a heterozygous germ line mutation at codon 850 of Apc, there is progressive loss of immature and mature thymocytes from approximately 80 days of age with complete regression of the thymus by 120 days. In addition, Apc(Min/+) mice show parallel depletion of splenic natural killer (NK) cells, immature B cells, and B progenitor cells in bone marrow due to complete loss of interleukin 7 (IL-7)-dependent B-cell progenitors. Using bone marrow transplantation experiments into wild-type recipients, we have shown that the capacity of transplanted Apc(Min/+) bone marrow cells for T- and B-cell development appears normal. In contrast, although the Apc(Min/+) bone marrow microenvironment supported short-term reconstitution with wild-type bone marrow, Apc(Min/+) animals that received transplants subsequently underwent lymphodepletion. Fibroblast colony-forming unit (CFU-F) colony assays revealed a significant reduction in colony-forming mesenchymal progenitor cells in the bone marrow of Apc(Min/+) mice compared with wild-type animals prior to the onset of lymphodepletion. This suggests that an altered bone marrow microenvironment may account for the selective lymphocyte depletion observed in this model of familial adenomatous polyposis.