Essential roles for Pot1b in HSC self-renewal and survival

Maintenance of mammalian telomeres requires both the enzyme telomerase and shelterin, which protect telomeres from inappropriately activating DNA damage response checkpoints. Dyskeratosis congenita is an inherited BM failure syndrome disorder because of defects in telomere maintenance. We have previously shown that deletion of the shelterin component Pot1b in the setting of telomerase haploinsufficiency results in rapid telomere shortening and fatal BM failure in mice, eliciting phenotypes that strongly resemble human syskeratosis congenita. However, it was unclear why BM failure occurred in the setting of Pot1b deletion. In this study, we show that Pot1b plays an essential role in HSC survival. Deletion of Pot1b results in increased apoptosis, leading to severe depletion of the HSC reserve. BM from Pot1b(Δ/Δ) mice cannot compete with BM from wild-type mice to provide multilineage reconstitution, indicating that there is an intrinsic requirement for Pot1b the maintenance of HSC function in vivo. Elimination of the p53-dependent apoptotic function increased HSC survival and significantly extended the lifespan of Pot1b-null mice deficient in telomerase function. Our results document for the first time the essential role of a component of the shelterin complex in the maintenance of HSC and progenitor cell survival.     

Coenzyme Q as an antiadipogenic factor

Coenzyme Q (CoQ) is not only the single antioxidant synthesized in humans but also an obligatory element of mitochondrial functions. We have previously reported CoQ deficiency in white adipose tissue of ob/ob mice. We sought to determine (i) whether this deficit exists in all species and its relevance in human obesity and (ii) to what extent CoQ could be involved in adipocyte differentiation. Here we identified in rodents as well as in humans a specific very strong nonlinear negative correlation between CoQ content in subcutaneous adipose tissue and obesity indexes. This striking correlation reveals a threshold value similar in both species. This relative deficit in CoQ content in adipose tissue rapidly took place during the time course of high-fat-diet-induced obesity in mice. Adipocyte differentiation was assessed in vitro using the preadipocyte 3T3-F442A cell line. When CoQ synthesis was inhibited by a pharmacological approach using chlorobenzoic acid, this strongly triggered adipose differentiation. In contrast, adipogenesis was strongly inhibited when a long-term increase in CoQ content was obtained by overexpressing human 4-hydroxy benzoate acid polyprenyltransferase gene. Altogether, these data suggest that a strict level of CoQ remains essential for adipocyte differentiation, and its impairment is associated with obesity.     

Innate and adaptive interferons suppress IL-1α and IL-1β production by distinct pulmonary myeloid subsets during Mycobacterium tuberculosis infection

Interleukin-1 (IL-1) receptor signaling is necessary for control of Mycobacterium tuberculosis (Mtb) infection, yet the role of its two ligands, IL-1α and IL-1β, and their regulation in vivo are poorly understood. Here, we showed that both IL-1α and IL-1β are critically required for host resistance and identified two multifunctional inflammatory monocyte-macrophage and DC populations that coexpressed both IL-1 species at the single-cell level in lungs of Mtb-infected mice. Moreover, we demonstrated that interferons (IFNs) played important roles in regulating IL-1 production by these cells in vivo. Type I interferons inhibited IL-1 production by both subsets whereas CD4(+) T cell-derived IFN-γ selectively suppressed monocyte-macrophages. These data provide a cellular basis for both the anti-inflammatory effects of IFNs and probacterial functions of type I IFNs during Mtb infection and reveal differential regulation of IL-1 production by distinct cell populations as an additional layer of complexity in the activity of IL-1 in vivo.     

Providers as weight coaches: using practice guides and motivational interview to treat obesity in the pediatric office

Motivational interview techniques combined with an evidence-based guideline provide valuable tools for the treatment of childhood obesity. The National Association of Pediatric Nurse Practitioners' Healthy Eating and Activity Together guidelines were adopted in a rural pediatric office. After a 6-month pilot, effectiveness of treatment was evaluated with a retrospective chart review. The results suggest that children were motivated for healthy lifestyle changes but had difficulty maintaining motivation and compliance with healthy change choices after 1-2 months; however, with consistent use of motivational interviewing techniques combined with diet and exercise counseling, there was a trend toward lowered body mass index and waist measurements.     

When should a diagnosis of influenza be considered in adults requiring intensive care unit admission? Results of population-based active surveillance in Toronto

Introduction

There is a paucity of data about the clinical characteristics that help identify patients at high risk of influenza infection upon ICU admission. We aimed to identify predictors of influenza infection in patients admitted to ICUs during the 2007/2008 and 2008/2009 influenza seasons and the second wave of the 2009 H1N1 influenza pandemic as well as to identify populations with increased likelihood of seasonal and pandemic 2009 influenza (pH1N1) infection.

Methods

Six Toronto acute care hospitals participated in active surveillance for laboratory-confirmed influenza requiring ICU admission during periods of influenza activity from 2007 to 2009. Nasopharyngeal swabs were obtained from patients who presented to our hospitals with acute respiratory or cardiac illness or febrile illness without a clear nonrespiratory aetiology. Predictors of influenza were assessed by multivariable logistic regression analysis and the likelihood of influenza in different populations was calculated.

Results

In 5,482 patients, 126 (2.3%) were found to have influenza. Admission temperature ≥38°C (odds ratio (OR) 4.7 for pH1N1, 2.3 for seasonal influenza) and admission diagnosis of pneumonia or respiratory infection (OR 7.3 for pH1N1, 4.2 for seasonal influenza) were independent predictors for influenza. During the peak weeks of influenza seasons, 17% of afebrile patients and 27% of febrile patients with pneumonia or respiratory infection had influenza. During the second wave of the 2009 pandemic, 26% of afebrile patients and 70% of febrile patients with pneumonia or respiratory infection had influenza.

Conclusions

The findings of our study may assist clinicians in decision making regarding optimal management of adult patients admitted to ICUs during future influenza seasons. Influenza testing, empiric antiviral therapy and empiric infection control precautions should be considered in those patients who are admitted during influenza season with a diagnosis of pneumonia or respiratory infection and are either febrile or admitted during weeks of peak influenza activity.     

Healthy passages. A multilevel, multimethod longitudinal study of adolescent health

PURPOSE: To provide an overview of a multisite, long-term study that focuses on risk and protective factors, health behaviors (e.g., dietary practices, physical inactivity, tobacco use, and violent activity), and health outcomes (e.g., diabetes, obesity, and sexually transmitted diseases) for a fifth-grade cohort to be followed biennially from ages 10 to 20 years. METHODS: A two-stage probability sampling procedure was used to select 5250 fifth-grade students from schools in Birmingham AL, Houston TX, and Los Angeles CA to ensure a sufficient sample size of African Americans, Hispanics, and non-Hispanic whites, to support precise statistical inferences. Computer-assisted technology was used to collect data from children and their primary caregivers. Teachers and other school personnel responded to questionnaires, and observational procedures were used to obtain information about schools and neighborhoods. RESULTS: To exploit the multilevel, multimethod structure of the data, statistical models include latent-growth mixture modeling, multilevel modeling, time-series analysis, survival analysis, latent transition analysis, and structural equation modeling. Analyses focus both on the co-occurrence and predictors of growth trajectories for different health behaviors across time. CONCLUSIONS: By using a prospective research design and studying the predictors and time course of multiple health behaviors with a multilevel, multimethod assessment protocol, this research project could provide an empirical basis for effective social and educational policies and intervention programs that foster positive health and well-being during both adolescence and adulthood.     

Unsustained complete response of less than 24 months after autologous stem cell transplantation predicts aggressive myeloma with short survival

Complete response (CR) predicts superior survivals in myeloma. To define the impact of duration of CR posttransplantation on survivals, 71 myeloma patients, who underwent an intended early (a staged approach) or frontline use of bortezomib‐based induction, followed by autologous stem cell transplantation (ASCT) were studied. Achievement of CR was assessed every 4‐weekly until maximal response after ASCT and then 6‐weekly thereafter. All patients had follow‐up time of ≥24 months from time of best response, of whom 27 failed to attain CR (non‐CR) whereas 44 achieved CR. At 12, 18 and 24 months post‐ASCT, 3 (4.2%), 6 (8.4%) and 11 (15.4%) patients lost CR, respectively, with maximal survival difference observed in the group with CR durations of ≥24 or <24 months. Patients with unsustained CR had survival inferior to those never achieving CR (p = 0.05). Unsustained CR of <24 months was associated with international staging system stage III (p = 0.007) and shorter postrelapse survival (p < 0.001). Both overall survival and event‐free survival were superior in myeloma patients with CR of ≥24 months (p < 0.001). In multivariate analysis, international staging system stage I/II, CR/nCR post‐ASCT and CR duration of ≥24 months remained favourable prognostic factors for both overall survival and event‐free survival. In conclusion, CR of <24 months is an independent adverse risk factor for survival with a short postrelapse survival. Copyright © 2014 John Wiley & Sons, Ltd.     

An outcomes approach to stroke care: the importance of teamwork and evidence-based nursing care

The Quality in Acute Stroke Care (QASC) was a cluster randomised control trial (CRCT) which evaluated the effectiveness of evidence-based clinical treatment protocols for the management of fever, hyperglycaemia and swallowing, in conjunction with multidisciplinary team building workshops, and a standardised interactive staff education program (collectively known as the Fever, Sugar, Swallowing (FeSS) intervention) to improve patient outcomes 90-days. We found that patients cared for in stroke units who received our intervention were 15·7% more likely to be alive and independent 90 days following their stroke. They also had significantly: fewer episodes of fever, lower mean temperatures, lower mean blood glucose levels, and better screening for swallowing difficulties.