DUSP6/MKP-3 is identified as a candidate tumor suppressor gene for pancreatic cancer. The aim of this study was to elucidate the roles of DUSP6 in the pancreatic carcinogenesis through the pancreatic intraepithelial neoplasia and/or intraductal papillary-mucinous neoplasms, both of which are considered to be precursor lesions of invasive carcinoma of the pancreas, by comparing with involvements of other major tumor suppressive pathways. Expressions of DUSP6, CDKN2A, TP53, and SMAD4 were investigated by immunohistochemistry in a total of 206 lesions of dysplastic ductal precursors and carcinomas retrieved from 52 pancreata with invasive ductal carcinomas and 51 of those with intraductal papillary-mucinous neoplasms. The intensity of staining was evaluated in lesions at different atypical grades and statistically compared among them. Mutations of KRAS2 were analyzed by methods of the allele-specific oligonucleotide hybridization and nucleotide sequencing. In pancreata with invasive ductal carcinomas, expressions of DUSP6 were abrogated exclusively in the invasive carcinoma cells in contrast to its fairly preserved expressions in pancreatic intraepithelial neoplasia. In pancreata with intraductal papillary-mucinous neoplasms, abrogated expressions of DUSP6 were observed in a relatively small fraction of intraductal adenoma/borderlines and intraductal carcinomas. Most of the intraductal adenoma/borderline lesions with abrogation of DUSP6 harbored mutations of KRAS2. None of the molecules was associated with each other in any grade of lesions. Morphological variations of papillae of the intraductal papillary-mucinous neoplasms were evaluated and analyzed for their associations with abrogations of the molecules, which resulted in finding of no significant associations. Our results suggest that the abrogation of DUSP6 is associated exclusively with progression from pancreatic intraepithelial neoplasia to the invasive ductal carcinoma while it is potentially associated with initiation of intraductal papillary-mucinous neoplasms with mutated KRAS2, which is independent of other major tumor suppressive pathways in both types of neoplasms.

Early aggressive hemodynamic resuscitation using elevated plasma lactate as a marker is an essential component of managing critically ill patients. Therefore, measurement of blood lactate is recommended to stratify patients based on the need for fluid resuscitation and the risks of multiple organ dysfunction syndrome and death. Hyperlactatemia is common among critically ill patients, and lactate levels and their trend may be reliable markers of illness severity and mortality. Although hyperlactatemia has been widely recognized as a marker of tissue hypoxia/hypoperfusion, it can also result from increased or accelerated aerobic glycolysis during the stress response. Additionally, lactate may represent an important energy source for patients in critical condition. Despite its inherent complexity, the current simplified view of hyperlactatemia is that it reflects the presence of global tissue hypoxia/hypoperfusion with anaerobic glycolysis. This review of hyperlactatemia in critically ill patients focuses on its pathophysiological aspects and recent clinical approaches. Hyperlactatemia in critically ill patients must be considered to be related to tissue hypoxia/hypoperfusion. Therefore, appropriate hemodynamic resuscitation is required to correct the pathological condition immediately. However, hyperlactatemia can also result from aerobic glycolysis, unrelated to tissue dysoxia, which is unlikely to respond to increases in systemic oxygen delivery. Because hyperlactatemia may be simultaneously related to, and unrelated to, tissue hypoxia, physicians should recognize that resuscitation to normalize plasma lactate levels could be over-resuscitation and may worsen the physiological status. Lactate is a reliable indicator of sepsis severity and a marker of resuscitation; however, it is an unreliable marker of tissue hypoxia/hypoperfusion.

on behalf of the J-RHYTHM Registry Investigators* Background--To clarify the influence of hypertension and blood pressure (BP) control on thromboembolism and major hemorrhage in patients with nonvalvular atrial fibrillation, a post hoc analysis of the J-RHYTHM Registry was performed.

Achieving a balance between organ perfusion and hemostasis is critical for optimal fluid resuscitation in patients with severe trauma. The concept of "permissive hypotension" refers to managing trauma patients by restricting the amount of resuscitation fluid and maintaining blood pressure in the lower than normal range if there is continuing bleeding during the acute period of injury. This treatment approach may avoid the adverse effects of early, high-dose fluid resuscitation, such as dilutional coagulopathy and acceleration of hemorrhage, but does carry the potential risk of tissue hypoperfusion. Current clinical guidelines recommend the use of permissive hypotension and controlled resuscitation. However, it is not mentioned which subjects would receive most benefit from this approach, when considering factors such as age, injury mechanism, setting, or the presence or absence of hypotension. Recently, two randomized clinical trials examined the efficacy of titrating blood pressure in younger patients with shock secondary to either penetrating or blunt injury; in both trials, overall mortality was not improved. Another two major clinical trials suggest that controlled resuscitation may be safe in patients with blunt injury in the pre-hospital setting and possibly lead to improved outcomes, especially in patients with pre-hospital hypotension. Some animal studies suggest that hypotensive resuscitation may improve outcomes in subjects with penetrating injury where bleeding occurs from only one site. On the other hand, hypotensive resuscitation in blunt trauma may worsen outcomes due to tissue hypoperfusion. The influence of these approaches on coagulation has not been sufficiently examined, even in animal studies. The effectiveness of permissive hypotension/ hypotensive resuscitation and restricted/controlled resuscitation is still inconclusive, even when examining systematic reviews and meta-analyses. Further investigation is needed to elucidate the effectiveness of these approaches, so as to develop improved treatment strategies which take into account coagulopathy in the pathophysiology of trauma.

Cardiac thrombosis due to atrial fibrillation (AF) has been recognized as the most common cause of cerebral embolism. However, sometimes no macroscopic thrombus is found at autopsy in the heart of a victim of this type of cerebral embolism. We investigated morphological changes in the left atrial endocardium of 31 patients (including 21 cases with AF) who had died of cerebral embolism. "Rough endocardium" (RE) seen macroscopically provided evidence for the existence of atrial thrombosis. The RE that appeared in AF cases was due to a granular and wrinkled appearance of the endocardium associated with oedematous and fibrous thickening. Fibrin-thread deposits were also always distinguishable. Mural thrombi and oedema with neutrophil infiltration in the subendocardium could be seen under the microscope. Small areas of endothelial denudation and thrombotic aggregations were commonly observed by scanning electron microscopy (SEM). These SEM lesions were significantly more frequent in cases with AF than in controls (P < 0.001). The diagnostic success rate for atrial thrombosis among cases with AF increased from 33.3% to 81% when thrombi proven by histological investigation of the areas with RE were added. Left atrial RE may be an anatomically relevant finding for the existence of atrial thrombosis with AF, when the thrombosis cannot be detected upon gross observation at autopsy.