Background-Takotsubo cardiomyopathy is an acute heart failure syndrome characterized by myocardial hypocontractility from the mid left ventricle to the apex. It is precipitated by extreme stress and can be triggered by intravenous catecholamine administration, particularly epinephrine. Despite its grave presentation, Takotsubo cardiomyopathy is rapidly reversible, with generally good prognosis. We hypothesized that this represents switching of epinephrine signaling through the pleiotropic  2 -adrenergic receptor ( 2 AR) from canonical stimulatory G-protein-activated cardiostimulant to inhibitory G-protein-activated cardiodepressant pathways. Methods and Results-We describe an in vivo rat model in which a high intravenous epinephrine, but not norepinephrine, bolus produces the characteristic reversible apical depression of myocardial contraction coupled with basal hypercontractility. The effect is prevented via G i inactivation by pertussis toxin pretreatment.  2 AR number and functional responses were greater in isolated apical cardiomyocytes than in basal cardiomyocytes, which confirmed the higher apical sensitivity and response to circulating epinephrine. In vitro studies demonstrated high-dose epinephrine can induce direct cardiomyocyte cardiodepression and cardioprotection in a  2 AR-Gi-dependent manner. Preventing epinephrine-G i effects increased mortality in the Takotsubo model, whereas -blockers that activate  2 AR-G i exacerbated the epinephrine-dependent negative inotropic effects without further deaths. In contrast, levosimendan rescued the acute cardiac dysfunction without increased mortality. Conclusions-We suggest that biased agonism of epinephrine for  2 AR-G s at low concentrations and for G i at high concentrations underpins the acute apical cardiodepression observed in Takotsubo cardiomyopathy, with an apical-basal gradient in  2 ARs explaining the differential regional responses. We suggest this epinephrine-specific  2 AR-G i signaling may have evolved as a cardioprotective strategy to limit catecholamine-induced myocardial toxicity during acute stress. (Circulation. 2012;126:697-706.)Key Words: acute heart failure Ⅲ catecholamines Ⅲ receptors, adrenergic, beta Ⅲ Takotsubo syndrome T here has been a rapid increase in the recognition of a syndrome of acute and severe but reversible heart failure called Takotsubo or stress cardiomyopathy, 1-3 also known as broken heart syndrome, which usually follows within hours of an identifiable emotional, psychological, or physical stress. Takotsubo cardiomyopathy mimics symptoms of acute myocardial infarction but is distinguished by the lack of coronary occlusion and by characteristic regional wall-motion abnormalities, classically a virtual apical ballooning appearance caused by a hypercontractile base of the heart relative to hypokinetic or akinetic apical and mid left ventricular myocardium, the latter extending beyond a single coronary artery territory. Clinical Perspective on p 706The pathophysiological mechanisms for this increasingly recogn...
Primary Sjögren's syndrome is one of the most common autoimmune diseases. So far, genetic studies of Sjögren's syndrome have relied mostly on candidate gene approaches. To identify new genetic susceptibility loci for primary Sjögren's syndrome, we performed a three-stage genome-wide association study in Han Chinese. In the discovery stage, we analyzed 556,134 autosomal SNPs in 542 cases and 1,050 controls. We then validated promising associations in 2 replication stages comprising 1,303 cases and 2,727 controls. The combined analysis identified GTF2I at 7q11.23 (rs117026326: Pcombined = 1.31 × 10(-53), combined odds ratio (ORcombined) = 2.20) as a new susceptibility locus for primary Sjögren's syndrome. Our analysis also confirmed previously reported associations in Europeans in the regions of STAT4, TNFAIP3 and the major histocompatibility complex (MHC). Fine mapping of the region around GTF2I showed that rs117026326 in GTF2I had the most significant association, with associated SNPs extending from GTF2I to GTF2IRD1-GTF2I.
A modified diet was formulated for Arizona inland shrimp farming and tested as a method for reducing moult-associated mortalities presumed due to trace mineral deficiencies. The experimental diet was supplemented with additional dietary magnesium, potassium, phospholipids and cholesterol to a commercial shrimp feed (Rangen 45/10, which was also used as the control diet). The modified diet was tested at Arizona Mariculture Associates (AMA), while the control diet was used at a nearby inland shrimp farm, Desert Sweet Shrimp Farm (DSSF). Both feeds were used throughout the culture season of 2001. Earthen pond-reared Litopenaeus vannamei at intermoult stages (C-D 0 ) and ranging from 7 to 30 g were sampled at intervals for determination of haemolymph osmolality (HO). Results showed that the modified diet had not only resulted in larger size shrimp at harvest, but also improved osmoregulatory capacity (OC). HO of DSSF shrimp decreased as shrimp grew bigger, whereas HO of AMA shrimp was maintained at a stable level, or showed a slightly positive linear relationship with weight. The hyper-OC of shrimp from AMA (462 mOsm kg )1 ) was greater than that from DSSF (398 mOsm kg )1 ). Shrimp at AMA fed the experimental diet presented no mass moult-associated mortalities. To further investigate the iso-osmotic point of shrimp reared in AMA, a group of six salinity gradients were designed by mixing oceanic salts into the well water to form 5, 8.5, 11.4, 14.4, 17.8, 20.7 p.p.t. medium. HO of subadult shrimp (25 g in average) were then evaluated 48 h after they had been transferred from 5 p.p.t. pond water to the medium. Shrimp HO increased with external salinity, and a plateau formed as salinity reached at 11.4 p.p.t. and higher. The iso-osmotic point of shrimp was estimated to be 695.5 mOsm kg )1 , equivalent to 26.1 p.p.t. in AMA well water. KEY WORDS
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