Activated protein C resistance: molecular mechanisms based on studies using purified Gln506-factor V

Gln506-factor V (FV) was purified from plasma of an individual homozygous for an Arg506Gln mutation in FV that is associated with activated protein C (APC) resistance. Purified Gln506-FV, as well as Gln506-FVa generated by either thrombin or FXa, conveyed APC resistance to FV-deficient plasma in coagulation assays. Clotting assay studies also suggested that APC resistance does not involve any abnormality in FV-APC-cofactor activity. In purified reaction mixtures, Gln506-FVa in comparison to normal FVa showed reduced susceptibility to APC, because it was inactivated approximately 10-fold slower than normal Arg506-FVa. It was previously reported that inactivation of normal FVa by APC involves an initial cleavage at Arg506 followed by phospholipid- dependent cleavage at Arg306. Immunoblot and amino acid sequence analyses showed that the 102-kD heavy chain of Gln506-FVa was cleaved at Arg306 during inactivation by APC in a phospholipid-dependent reaction. This reduced but measurable susceptibility of Gln506-FVa to APC inactivation may help explain why APC resistance is a mild risk factor for thrombosis because APC can inactivate both normal FVa and variant Gln506-FVa. In summary, this study shows that purified Gln506- FV can account for APC resistance of plasma because Gln506-FVa, whether generated by thrombin or FXa, is relatively resistant to APC.     

The Effects of Individual and Organisational Characteristics on the Level of Burnout Level: A Research on Physicians and Nurses in Turkey

In the Turkish health care system and hospitals it is very common to witness role conflict and ambiguity among health care personnel. Often this is due to a lack of clarity as to what is expected and required of them. The unfortunate and unavoidable result is a high level of burnout caused by uncertain working conditions in Turkish hospitals. The objectives of this study were to determine the level of role conflict, role ambiguity, and burnout of physicians and nurses working in hospitals, to see the relationship between role conflict, ambiguity and burnout level, to reveal the effects of organisational and indvidual characteristics on the burnout level of physicians and nurses. The study was conducted in three hospitals attached to the Ministry of Health (MoH) of Turkey. 149 nurses and 83 physicians were included in the sample of this study although several efforts of reminders and additional visits to the hospitals to increase the response rate. Structural Equational Modelling (SEM) was chosen to estimate the effects of certain selected individual and organisational variables that were determined by a set of correlation and biovariate analyses on role conflict and ambiguity as well as the burnout level. The SEM results showed that working in surgical units, having less working experience and choosing the profession unwillingly had significant and negative direct effects on the burnout level of the physicians and nurses in the sample of this study. Decreasing the level of role conflict and ambiguity would serve to decrease the level of burnout. In order to decrease the level of role conflict, ambiguity, and burn out level for nurses and physicans, serious efforts must be made to clarify role definitions, increase resources, and employ conflict management methods.     

Calls for Reform to the U.S. Hospice System

The purpose of this paper is to provide a historical perspective of the hospice system within the U.S. In addition, this paper discusses current trends within the U.S. hospice system and provides a platform for discussion about the future of the system in terms of policy standards. The more than 30?year history of hospice in the U.S. has experienced many changes. Originally organized as nonprofit entities, hospices became Medicare funded in the 1980??s and has seen substantial growth in the number of for-profit entities. Hospice has moved from being seen as a ??place to go die?? to being viewed as a viable option for long-term care near the end of life. Changes in the hospice payment system from a per diem reimbursement system and calls for quality measures are at the forefront of the current system and the major issues that the system faces in the future.     

Pressure Wire Used to Measure Gradient in Chronic Mesenteric Ischemia

Chronic mesenteric ischemia is a rare disorder in the United States. Frequently, its symptoms correlate poorly with the angiographically apparent degree of mesenteric artery stenosis. Measuring the pressure gradient with a small-caliber catheter is an established means of determining whether a particular stenosis is flow-limiting, thus guiding the interventional decision when stenoses are of indeterminate angiographic significance. Using a 0.014-in guidewire, however, is potentially more accurate because it eliminates any measurement error attributable to the use of a larger, potentially obstructive catheter. We present a case of chronic mesenteric ischemia in a 70-year-old woman who had abdominal pain with multiple possible causes. We used a 0.014-in pressure wire to calculate pressure gradients and guide our decision to stent tandem lesions in the superior mesenteric artery. After revascularization, the patient''s symptoms improved dramatically. To the best of our knowledge, this is the first published case in which a pressure wire was used to measure a pressure gradient in chronic mesenteric ischemia.Key words: Mesenteric arteries/pathology, mesenteric ischemia, chronic, mesenteric vascular occlusion/diagnosis/therapy, mesentery/blood supply, peripheral vascular diseases/therapy, pressure gradient, pressure wire, splanchnic circulationRecent technical advances in vascular imaging have led to increased recognition of pervasive atherosclerotic plaques. The resulting clinical challenge has been to correlate anatomic findings with the clinical presentation. Using angiography alone may lead one to underestimate or overestimate the significance of visually apparent stenoses.^1,2 Techniques for measuring stenosis severity physiologically have been introduced to help overcome these problems. The pressure gradient across a lesion, measured directly and in vivo, is likely to be the most helpful guide in this regard. The use of small-caliber catheters to measure intravascular gradients has been well established, but the results must be interpreted with caution because of the potential flow obstruction caused by the measuring catheter itself. For this reason, using a 0.014-in pressure wire to measure the translesional pressure gradient can provide more precise information.We present the case of a 70-year-old woman whose symptoms, although atypical, had features that suggested chronic mesenteric ischemia (CMI). We measured the pressure gradient across 2 tandem stenoses of uncertain severity in the proximal superior mesenteric artery (SMA) to guide our decision to stent. We believe that this is the first published case in which a pressure wire was used to measure translesional pressure gradients in a patient with CMI.     

Exploiting PI3K/mTOR signaling to accelerate epithelial wound healing

The molecular circuitries controlling the process of skin wound healing have gained new significant insights in recent years. This knowledge is built on landmark studies on skin embryogenesis, maturation, and differentiation. Furthermore, the identification, characterization, and elucidation of the biological roles of adult skin epithelial stem cells and their influence in tissue homeostasis have provided the foundation for the overall understanding of the process of skin wound healing and tissue repair. Among numerous signaling pathways associated with epithelial functions, the PI3K/Akt/mTOR signaling route has gained substantial attention with the generation of animal models capable of dissecting individual components of the pathway, thereby providing a novel insight into the molecular framework underlying skin homeostasis and tissue regeneration. In this review, we focus on recent findings regarding the mechanisms involved in wound healing associated with the upregulation of the activity of the PI3K/Akt/mTOR circuitry. This review highlights critical findings on the molecular mechanisms controlling the activation of mTOR, a downstream component of the PI3K–PTEN pathway, which is directly involved in epithelial migration and proliferation. We discuss how this emerging information can be exploited for the development of novel pharmacological intervention strategies to accelerate the healing of critical size wounds.