Daily energy expenditure, cardiorespiratory fitness and glycaemic control in people with type 1 diabetes.

Published onlineJournal ArticleResearch Support, Non-U.S. Gov'tThis is the final version of the article. Available from Public Library of Science via the DOI in this record.OBJECTIVE: Encouraging daily physical activity improves cardiorespiratory fitness and many cardiovascular risk factors. However, increasing physical activity often creates a challenge for people with type 1 diabetes, because of difficulties maintaining euglycemia in the face of altered food intake and adjustments to insulin doses. Our aim was to examine the triangular relationship between glucose control measured by continuous glucose monitoring system (CGMS), objective measures of total daily energy expenditure (TEE) recorded by a multi-sensory monitoring device, and cardiorespiratory fitness (CRF), in free-living subjects with type 1 diabetes. RESEARCH DESIGN AND METHODS: Twenty-three individuals (12 women) with type 1 diabetes who were free from micro- and macrovascular complications were recruited. TEE and glucose control were monitored simultaneously for up to 12 days, using a multi-sensory device and CGMS respectively. CRF was recorded as V02 max from a maximal treadmill test with the Bruce protocol. RESULTS: Subjects (mean±SD) were aged 37±11 years, with BMI = 26.5±5.1 kg.m⁻², HbA1c = 7.7±1.3% (61±14 mmol/mol) and V02 max (ml.min⁻¹.kg⁻¹)  = 39.9±8.4 (range 22.4-58.6). TEE (36.3±5.5 kcal.kg⁻¹.day⁻¹) was strongly associated with CRF(39.9±8.4 ml.min⁻¹.kg⁻¹) independently of sex (r = 0.63, p<0.01). However, neither TEE (r = -0.20, p = 0.36) nor CRF (r = -0.20, p = 0.39; adjusted for sex), were significantly associated with mean glycaemia measured by CGMS. CONCLUSION: Higher levels of energy expenditure (due to a more active lifestyle) are associated with increased cardiorespiratory fitness, but not necessarily better glycaemic control. Since increased levels of energy expenditure and good glycaemic control are both needed to protect against diabetes-related complications our data suggest they need to be achieved independently.Diabetes UK funded this work under grant BDA: RD06/0003306. JJV also gratefully acknowledges the support of the UK EPSRC PhD plus programme. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

Enhanced flow-motion complexity of skin microvascular perfusion in Sherpas and lowlanders during ascent to high altitude

An increased and more effective microvascular perfusion is postulated to play a key role in the physiological adaptation of Sherpa highlanders to the hypobaric hypoxia encountered at high altitude. To investigate this, we used Lempel-Ziv complexity (LZC) analysis to explore the spatiotemporal dynamics of the variability of the skin microvascular blood flux (BF) signals measured at the forearm and finger, in 32 lowlanders (LL) and 46 Sherpa highlanders (SH) during the Xtreme Everest 2 expedition. Measurements were made at baseline (BL) (LL: London 35 m; SH: Kathmandu 1300 m) and at Everest base camp (LL and SH: EBC 5,300 m). We found that BF signal content increased with ascent to EBC in both SH and LL. At both altitudes, LZC of the BF signals was significantly higher in SH, and was related to local slow-wave flow-motion activity over multiple spatial and temporal scales. In SH, BF LZC was also positively associated with LZC of the simultaneously measured tissue oxygenation signals. These data provide robust mechanistic information of microvascular network functionality and flexibility during hypoxic exposure on ascent to high altitude. They demonstrate the importance of a sustained heterogeneity of network perfusion, associated with local vaso-control mechanisms, to effective tissue oxygenation during hypobaric hypoxia

A New Method for Isolation of Interstitial Fluid from Human Solid Tumors Applied to Proteomic Analysis of Ovarian Carcinoma Tissue

Major efforts have been invested in the identification of cancer biomarkers in plasma, but the extraordinary dynamic range in protein composition, and the dilution of disease specific proteins make discovery in plasma challenging. Focus is shifting towards using proximal fluids for biomarker discovery, but methods to verify the isolated sample's origin are missing. We therefore aimed to develop a technique to search for potential candidate proteins in the proximal proteome, i.e. in the tumor interstitial fluid, since the biomarkers are likely to be excreted or derive from the tumor microenvironment. Since tumor interstitial fluid is not readily accessible, we applied a centrifugation method developed in experimental animals and asked whether interstitial fluid from human tissue could be isolated, using ovarian carcinoma as a model. Exposure of extirpated tissue to 106 g enabled tumor fluid isolation. The fluid was verified as interstitial by an isolated fluid:plasma ratio not significantly different from 1.0 for both creatinine and Na+, two substances predominantly present in interstitial fluid. The isolated fluid had a colloid osmotic pressure 79% of that in plasma, suggesting that there was some sieving of proteins at the capillary wall. Using a proteomic approach we detected 769 proteins in the isolated interstitial fluid, sixfold higher than in patient plasma. We conclude that the isolated fluid represents undiluted interstitial fluid and thus a subproteome with high concentration of locally secreted proteins that may be detected in plasma for diagnostic, therapeutic and prognostic monitoring by targeted methods

The lancet weight determines wheal diameter in response to skin prick testing with histamine

BACKGROUND:Skin prick test (SPT) is a common test for diagnosing immunoglobulin E-mediated allergies. In clinical routine, technicalities, human errors or patient-related biases, occasionally results in suboptimal diagnosis of sensitization. OBJECTIVE:Although not previously assessed qualitatively, lancet weight is hypothesized to be important when performing SPT to minimize the frequency of false positives, false negatives, and unwanted discomfort. METHODS:Accurate weight-controlled SPT was performed on the volar forearms and backs of 20 healthy subjects. Four predetermined lancet weights were applied (25 g, 85 g, 135 g and 265 g) using two positive control histamine solutions (1 mg/mL and 10 mg/mL) and one negative control (saline). A total of 400 SPTs were conducted. The outcome parameters were: wheal size, neurogenic inflammation (measured by superficial blood perfusion), frequency of bleeding, and the lancet provoked pain response. RESULTS:The mean wheal diameter increased significantly as higher weights were applied to the SPT lancet, e.g. from 3.2 ± 0.28 mm at 25 g to 5.4 ± 1.7 mm at 265 g (p<0.01). Similarly, the frequency of bleeding, the provoked pain, and the neurogenic inflammatory response increased significantly. At 265 g saline evoked two wheal responses (/160 pricks) below 3 mm. CONCLUSION AND CLINICAL RELEVANCE:The applied weight of the lancet during the SPT-procedure is an important factor. Higher lancet weights precipitate significantly larger wheal reactions with potential diagnostic implications. This warrants additional research of the optimal lancet weight in relation to SPT-guidelines to improve the specificity and sensitivity of the procedure

The maize root stem cell niche: a partnership between two sister cell populations

Using transcript profile analysis, we explored the nature of the stem cell niche in roots of maize (Zea mays). Toward assessing a role for specific genes in the establishment and maintenance of the niche, we perturbed the niche and simultaneously monitored the spatial expression patterns of genes hypothesized as essential. Our results allow us to quantify and localize gene activities to specific portions of the niche: to the quiescent center (QC) or the proximal meristem (PM), or to both. The data point to molecular, biochemical and physiological processes associated with the specification and maintenance of the niche, and include reduced expression of metabolism-, redox- and certain cell cycle-associated transcripts in the QC, enrichment of auxin-associated transcripts within the entire niche, controls for the state of differentiation of QC cells, a role for cytokinins specifically in the PM portion of the niche, processes (repair machinery) for maintaining DNA integrity and a role for gene silencing in niche stabilization. To provide additional support for the hypothesized roles of the above-mentioned and other transcripts in niche specification, we overexpressed, in Arabidopsis, homologs of representative genes (eight) identified as highly enriched or reduced in the maize root QC. We conclude that the coordinated changes in expression of auxin-, redox-, cell cycle- and metabolism-associated genes suggest the linkage of gene networks at the level of transcription, thereby providing additional insights into events likely associated with root stem cell niche establishment and maintenance

BOLITA, an Arabidopsis AP2/ERF-like transcription factor that affects cell expansion and proliferation/differentiation pathways

The BOLITA (BOL) gene, an AP2/ERF transcription factor, was characterized with the help of an activation tag mutant and overexpression lines in Arabidopsis and tobacco. The leaf size of plants overexpressing BOL was smaller than wild type plants due to a reduction in both cell size and cell number. Moreover, severe overexpressors showed ectopic callus formation in roots. Accordingly, global gene expression analysis using the overexpression mutant reflected the alterations in cell proliferation, differentiation and growth through expression changes in RBR, CYCD, and TCP genes, as well as genes involved in cell expansion (i.e. expansins and the actin remodeling factor ADF5). Furthermore, the expression of hormone signaling (i.e. auxin and cytokinin), biosynthesis (i.e. ethylene and jasmonic acid) and regulatory genes was found to be perturbed in bol-D mutant leave

B cell depletion in autoimmune diabetes:insights from murine models

INTRODUCTION: The incidence of type 1 diabetes (T1D) is rising for reasons that largely elude us. New strategies aimed at halting the disease process are needed. One type of immune cell thought to contribute to T1D is the B lymphocyte. The first Phase II trial of B cell depletion in new onset T1D patients indicated that this slowed the destruction of insulin-producing pancreatic beta cells. The mechanistic basis of the beneficial effects remains unclear. AREAS COVERED: Studies of B cell depletion and deficiency in animal models of T1D. How B cells can influence T cell-dependent autoimmune diabetes in animal models. The heterogeneity of B cell populations and current evidence for the potential contribution of specific B cell subsets to diabetes, with emphasis on marginal zone B cells and B1 B cells. EXPERT OPINION: B cells can influence the T cell response to islet antigens and B cell depletion or genetic deficiency is associated with decreased insulitis in animal models. New evidence suggests that B1 cells may contribute to diabetes pathogenesis. A better understanding of the roles of individual B cell subsets in disease will permit fine-tuning of therapeutic strategies to modify these populations

Interstitial fluid: the overlooked component of the tumor microenvironment?

Background: The interstitium, situated between the blood and lymph vessels and the cells, consists of a solid or matrix phase and a fluid phase, together constituting the tissue microenvironment. Here we focus on the interstitial fluid phase of tumors, i.e., the fluid bathing the tumor and stromal cells. Novel knowledge on this compartment may provide important insight into how tumors develop and how they respond to therapy. Results: We discuss available techniques for interstitial fluid isolation and implications of recent findings with respect to transcapillary fluid balance and uptake of macromolecular therapeutic agents. By the development of new methods it is emerging that local gradients exist in signaling substances from neoplastic tissue to plasma. Such gradients may provide new insight into the biology of tumors and mechanistic aspects linked to therapy. The emergence of sensitive proteomic technologies has made the interstitial fluid compartment in general and that of tumors in particular a highly valuable source for tissue-specific proteins that may serve as biomarker candidates. Potential biomarkers will appear locally at high concentrations in the tissue of interest and will eventually appear in the plasma, where they are diluted. Conclusions: Access to fluid that reliably reflects the local microenvironment enables us to identify substances that can be used in early detection and monitoring of disease