Hospital hypoglycemia: From observation to action

Background: A preponderance of evidence indicates that when treatment of hyperglycemia with insulin is provided for certain hospitalized populations, the attainment of appropriate glycemic targets improves nonglycemic outcomes such as mortality rates, morbidities (eg, wound infection, critical illness polyneuropathy, bacteremia, new renal insufficiency), duration of ventilator dependency, transfusion requirements, and length of hospital stay. Nevertheless, randomized controlled trials (RCTs) of intensive insulin therapy and studies of outcomes before and after implementation of tight glycemic control have consistently recognized an increased incidence of hypoglycemia as a complication associated with the use of lower glycemic targets and higher doses of insulin.Objectives: This commentary compares the quality of the available evidence on the clinical impact of iatrogenic hypoglycemia. We present treatment strategies designed to prevent iatrogenic hypoglycemia in the hospital setting.Methods: The PubMed database and online citations of articles tracked subsequent to publication were searched for articles on the epidemiology, clinical impact, and mechanism of harm of hypoglycemia published since 1986. In addition, we searched the literature for RCTs conducted since 2001 concerning intensive insulin therapy in the hospital critical care setting, including meta-analyses; letters to the editor were excluded. The retrieved studies were scanned and chosen selectively for full-text review based on the study size and design, novelty of findings, and evidence related to the possible clinical impact of hypoglycemia. Reference lists from the retrieved studies were searched for additional studies. Reports were summarized for the purpose of comparing and contrasting the qualitative nature of information about iatrogenic hypoglycemia in the hospital.Results: Eight RCTs of intensive glycemic management, 16 observational studies of hospitalized patients with hypoglycemia (including studies of outcomes before and after implementation of tight glycemic control), and 4 case reports on patients with hypoglycemia were selected for discussion of the incidence of hypoglycemia, significance of hypoglycemia as a marker or cause of poor prognosis, and clinical harm of hypoglycemia. Hypoglycemia was identified in clinical trials as either a category of adverse events or a complication of intensified insulin treatment. For example, a recent meta-analysis found that the incidence of severe hypoglycemia was higher among critically ill patients treated with intensive insulin therapy than among control patients, with a pooled relative risk of 6.0 (95% CI, 4.5–8.0). In the largest multisite RCT on glycemic control among patients in intensive care units (ICUs) conducted to date, deaths were reported for 27.5% (829/3010 patients) in the intensive-treatment group and 24.9% (751/3012 patients) in the conventional-treatment group (odds ratio, 1.14; 95% CI, 1.02–1.28; P = 0.02). In another multisite ICU study, although the intensive and control groups had similar mortality rates, the mortality rate was higher among hypoglycemic participants than among nonhypoglycemic participants (32.2% vs 13.6%, respectively; P < 0.01). Pooled data from 2 singlesite studies in medical and surgical ICUs revealed an increased risk of hypoglycemia in the intensive-treatment group compared with the conventional-treatment group (11.3% [154/1360] and 1.8% [25/1388], respectively; P < 0.001), but the hospital mortality rate was similar for the 2 groups (50.6% [78/154] and 52.0% [13/25], respectively). Specific sequelae of hypoglycemia affecting individual patients were described in the RCTs as well as in the observational studies. New guidelines for glycemic control have recently been issued, but results of the studies using the new targets are not yet available. We propose treatment strategies designed to prevent iatrogenic hypoglycemia in the hospital setting.Conclusions: In response to the growing evidence on the risk of hypoglycemia during intensified glycemic management of hospitalized patients, professional organizations recently revised targets for glycemic control. It is appropriate for institutions to reevaluate hospital protocols for glycemic management with intravenous insulin and, on general wards, to implement standardized order sets for use of subcutaneous insulin to achieve beneficial targets using safe strategies.     

Comparative analysis of the Metarhizium anisopliae secretome in response to exposure to the greyback cane grub and grub cuticles

Metarhizium anisopliae is a well-characterized biocontrol agent of a wide range of insects including cane grubs. In this study, a two-dimensional (2D) electrophoresis was used to display secreted proteins of M. anisopliae strain FI-1045 growing on the whole greyback cane grubs and their isolated cuticles. Hydrolytic enzymes secreted by M. anisopliae play a key role in insect cuticle-degradation and initiation of the infection process. We have identified all the 101 protein spots displayed by cross-species identification (CSI) from the fungal kingdom. Among the identified proteins were 64-kDa serine carboxypeptidase, 1,3 beta-exoglucanase, Dynamin GTPase, THZ kinase, calcineurin like phosphoesterase, and phosphatidylinositol kinase secreted by M. ansiopliae (FI-1045) in response to exposure to the greyback cane grubs and their isolated cuticles. These proteins have not been previously identified from the culture supernatant of M. anisopliae during infection. To our knowledge, this the first proteomic map established to study the extracellular proteins secreted by M. ansiopliae (FI-1045) during infection of greyback cane grubs and its cuticles.     

Pain perception, aversion and fear in fish

There is now compelling evidence that teleost fish possess similar nociceptive processing systems to those found in terrestrial vertebrates. Noxious stimulation of these nociceptors--specialised pain receptors -in the skin around the snout of fish generates neural activity that can be electrophysiologically recorded, and induces a number of behavioural and physiological changes. To determine whether changes in behaviour are more than simple responses to the noxious stimulation it is necessary to demonstrate that higher order cognitive processes such as mental state or 'affective state' are involved. However, quantifying the 'motivational affected state' of an animal--a concept encompassing not just pain but also fear, hunger, thirst and pleasure - is difficult owing to its subjectivity. Recent empirical work is beginning to test these concepts in fish, and we review a number of these studies and suggest how these general methodologies could be used to further our understanding of fish cognition and the capacity for fish to experience mental states such as fear or suffering.     

Population differences in spatial learning in three-spined sticklebacks

In a changing environment, learning and memory are essential for an animal''s survival and reproduction. The role played by the environment in shaping learning and memory is now attracting considerable attention. Until now, studies have tended to compare the behaviour of two, or at best a few species but interspecific comparisons can be misleading as many life history variables other than environment may differ between species. Here we report on an experiment designed to determine how learning varies between different populations of the same species, the three-spined stickleback. We found differences between the populations in their ability to solve a spatial task and also in the spatial strategies they used. A second simple learning task showed that these differences were not the result of gross differences in learning ability or adaptation to laboratory conditions. We discuss these results and suggest that the behavioural differences may relate to features of the respective habitats from which the fish were sampled.     

Some p53-binding proteins that can function as arbiters of life and death

Four sets of p53-binding proteins are discussed in this review. These are the E2F family, the ASPP family, Y-box-binding protein YB1, and the prolyl isomerase Pin1. Each appears to play a role in the decision by p53 to induce an arrest of cell proliferation or apoptosis and they may also be independent markers of cancer. Their activities appear to be linked with the cell cycle and they may also interact with each other. In this review, the properties of each protein class are discussed as well as how they affect p53 functions. A model is proposed as to how their activities might be coordinated.