Perioperative factor concentrate therapy

Transfusion of allogeneic plasma has been a life-saving measure for decades in patients with severe trauma or suffering from major surgical blood loss. The safety of allogeneic blood components has improved in terms of pathogen transmission, but haemostatic efficacy of plasma is hindered by the large volume and time required for thawing and infusion. Several plasma-derived and recombinant factor concentrates are clinically available and indicated for targeted replacement of missing coagulation elements in hereditary disorders of thrombosis and haemostasis. When used appropriately, factor concentrate therapy can rapidly restore deficient factor(s) without causing volume overload. The haemostatic defect in perioperative patients is often multifactorial, and therefore careful clinical judgement and timely coagulation testing must be exercised before the administration of factor concentrates. In this review, the rationale for including factor concentrates in perioperative haemostatic management will be discussed in conjunction with the limitations of plasma transfusio

Glycaemic control in the perioperative period

The prevalence of type 2 diabetes mellitus and the potential for perioperative dysglycaemia (hyperglycaemia, hypoglycaemia, stress-induced hyperglycaemia, or glucose variability) continue to increase dramatically. The majority of investigations on perioperative glycaemic control focused on critically ill patients and concentrated on goals of therapy, level of intensity of insulin infusion, feeding regimes, concerns over hypoglycaemia, and promulgation of recent guidelines calling for less strict glucose control. Areas of perioperative glycaemic control that deserve further investigation include preoperative identification of patients with undiagnosed type 2 diabetes and other forms of dysglycaemia, determination of appropriate intraoperative glucose goals, and establishment of the impact and natural history of perioperative abnormalities in glucose homeostasis. In the heterogeneous adult perioperative population, it is unlikely that one standard of perioperative glycaemic control is appropriate for all patients. This review presents recent evidence and expert guidance to aid preoperative assessment, intraoperative management, and postoperative care of the dysglycaemic adult patien

Nuclear Dbf2-related protein kinases (NDRs) in isolated cardiac myocytes and the myocardium: activation by cellular stresses and by phosphoprotein serine-/threonine-phosphatase inhibitors

The nuclear Dbf2-related protein kinases 1 and 2 (NDR1/2) are closely-related AGC family kinases that are strongly conserved through evolution. In mammals, they are activated inter alia by phosphorylation of an hydrophobic domain threonine-residue [NDR1(Thr-444)/NDR2(Thr-442)] by an extrinsic protein kinase followed by autophosphorylation of a catalytic domain serine-residue [NDR1(Ser-281)/NDR2(Ser-282)]. We examined NDR1/2 expression and regulation in primary cultures of neonatal rat cardiac myocytes and in perfused adult rat hearts. In myocytes, transcripts for NDR2, but not NDR1, were induced by the hypertrophic agonist, endothelin-1. NDR1(Thr-444) and NDR2(Thr-442) were rapidly phosphorylated (maximal in 15-30 min) in myocytes exposed to some phosphoprotein Ser-/Thr-phosphatase 1/2 inhibitors (calyculin A, okadaic acid) and, to a lesser extent, by hyperosmotic shock, low concentrations of H(2)O(2), or chelerythrine. In myocytes adenovirally-transduced to express FLAG-NDR2 (which exhibited a mainly-cytoplasmic localisation), the same agents increased FLAG-NDR2 activity as assessed by in vitro protein kinase assays, indicative of FLAG-NDR2(Ser-282/Thr-442) phosphorylation. Calyculin A-induced phosphorylation of NDR1(Thr-444)/NDR2(Thr-442) and activation of FLAG-NDR2 were inhibited by staurosporine, but not by other protein kinase inhibitors tested. In ex vivo rat hearts, NDR1(Thr-444)/NDR2(Thr-442) were phosphorylated in response to ischaemia-reperfusion or calyculin A. From a pathological viewpoint, we conclude that activities of NDR1 and NDR2 are responsive to cytotoxic stresses in heart preparations and this may represent a previously-unidentified response to myocardial ischaemia in vivo

NDR Kinases Are Essential for Somitogenesis and Cardiac Looping during Mouse Embryonic Development

Studies of mammalian tissue culture cells indicate that the conserved and distinct NDR isoforms, NDR1 and NDR2, play essential cell biological roles. However, mice lacking either Ndr1 or Ndr2 alone develop normally. Here, we studied the physiological consequences of inactivating both NDR1 and NDR2 in mice, showing that the lack of both Ndr1/Ndr2 (called Ndr1/2-double null mutants) causes embryonic lethality. In support of compensatory roles for NDR1 and NDR2, total protein and activating phosphorylation levels of the remaining NDR isoform were elevated in mice lacking either Ndr1 or Ndr2. Mice retaining one single wild-type Ndr allele were viable and fertile. Ndr1/2-double null embryos displayed multiple phenotypes causing a developmental delay from embryonic day E8.5 onwards. While NDR kinases are not required for notochord formation, the somites of Ndr1/2-double null embryos were smaller, irregularly shaped and unevenly spaced along the anterior-posterior axis. Genes implicated in somitogenesis were down-regulated and the normally symmetric expression of Lunatic fringe, a component of the Notch pathway, showed a left-right bias in the last forming somite in 50% of all Ndr1/2-double null embryos. In addition, Ndr1/2-double null embryos developed a heart defect that manifests itself as pericardial edemas, obstructed heart tubes and arrest of cardiac looping. The resulting cardiac insufficiency is the likely cause of the lethality of Ndr1/2-double null embryos around E10. Taken together, we show that NDR kinases compensate for each other in vivo in mouse embryos, explaining why mice deficient for either Ndr1 or Ndr2 are viable. Ndr1/2-double null embryos show defects in somitogenesis and cardiac looping, which reveals their essential functions and shows that the NDR kinases are critically required during the early phase of organogenesis

Coupling Strongly, Discretely PHYSICS

PERSPECTIVES tein p53 for degradation, show that Mdm2 inhibition can be attained by blocking interaction with its substrate. Yang et al. show that a stable complex forms between TRAF6 and Akt, suggesting that this approach may be a good way to block TRAF6-mediated Akt activation. The potential effectiveness of this approach for tumor therapy is highlighted by the point in the signaling cascade at which TRAF6 contributes to Akt activation-downstream of common mutations observed in the clinic that affect phosphatidylinositol 3-kinase (PI3K) or the phosphatase PTEN, both of which cause hyperactivation of Akt. In support of this, the tumor cell line depleted of TRAF6 that was injected into mice by Yang et al. did not express PTEN and displayed strong Akt activation. TRAF6 could be used to augment the effectiveness of rapamycin analogs (rapalogs), drugs that inhibit the mammalian target of rapamycin complex 1 (mTORC1). Rapalogs are approved for limited antitumor therapy because they may temporarily stabilize tumors in clinical trials but rarely elicit a full response in terms of tumor ablation. Preclinical studies indicate that rapalogs have a cytostatic effect on tumors, due at least in part to increased Akt activation, because a negative feedback loop that normally prevents PI3K signaling is lost. As Yang et al. show, cells lacking TRAF6 display increased spontaneous apoptosis (programmed cell death). Thus, TRAF6 inhibition in conjunction with rapalogs could shift the response of tumors to rapalogs from cytostatic to cytotoxic, increasing the effi cacy of these drugs in cancer therapy. LoPiccolo et al., Drug Resist. Updat. 11, 32 (2008). 4. S. Klein, A. Levitzki, Curr. Opin. Cell Biol. 21, 185 (2009). 5. W.-L. Yang et al., Science 325, 1134). 6. N. Filippa, C. L. Sable, B. A. Hemmings, E. Van Obberghen, Mol. Cell. Biol. 20, 5712 (2000. 7. C. C. Thomas et al., Curr. Biol. 12, 125

Exploring views on satisfaction with life in young children with chronic illness: an innovative approach to the collection of self-report data from children under 11

The objective of this study was to explore young children’s views on the impact of chronic illness on their life in order to inform future development of a patient-based self-report health outcome measure. We describe an approach to facilitating self-report views from young children with chronic illness. A board game was designed in order to obtain qualitative data from 39 children with a range of chronic illness conditions and 38 healthy controls ranging in age from 3 to 11 years. The format was effective in engaging young children in a self-report process of determining satisfaction with life and identified nine domains. The board game enabled children aged 5–11 years with chronic illness to describe the effects of living with illness on home, family, friends, school and life in general. It generated direct, non-interpreted material from children who, because of their age, may have been considered unable or limited their ability to discuss and describe how they feel. Obtaining this information for children aged 4 and under continues to be a challenge

Unhatched eggs represent the invisible fraction in two wild bird populations

Prenatal mortality is typically overlooked in population studies, which biases evolutionary inference by confounding selection and inheritance. Birds represent an opportunity to include this ‘invisible fraction’ if each egg contains a zygote, but whether hatching failure is caused by fertilization failure versus prenatal mortality is largely unknown. We quantified fertilization failure rates in two bird species that are popular systems for studying evolutionary dynamics and found that overwhelming majorities (99.9%) of laid eggs were fertilized. These systems thus present opportunities to eliminate the invisible fraction from life-history data