Osborn Waves: History and Significance

The Osborn wave is a deflection with a dome or hump configuration occurring at the R-ST junction (J point) on the ECG (Fig. 1). In the historical view, different names have been used for this wave in the medical literature, such as “camel-hump sign”, “late delta wave”, “hathook junction”, “hypothermic wave”, “J point wave”, “K wave”, “H wave” and “current of injury”.1 Although there is no definite consensus about terminology of this wave, either “Osborn wave” or “J wave” are the most commonly used names for this wave in the current clinical and experimental cardiology. The Osborn wave can be generally observed in hypothermic patients,1,2,3,4 however, other conditions have been reported to cause Osborn waves, such as hypercalcemia,5 brain injury,6 subarachnoid hemorrhage,7 cardiopulmonary arrest from oversedation,8 vasospastic angina,9 or idiopathic ventricular fibrillation.10,11,12 Our knowledge about the link between the Osborn waves and cardiac arrhythmias remains sparse and the arrhythmogenic potential of the Osborn waves is not fully understood. In this paper, we present a historic review of Osborn waves and discuss their clinical significance in the various clinical settings

Electrical Excitation of the Pulmonary Venous Musculature May Contribute to the Formation of the Last Component of the High Frequency Signal of the P Wave

Pulmonary veins (PVs) have been shown to play an important role in the induction and perpetuation of focal AF. Fifty-one patients with AF, and 24 patients without AF as control subjects, were enrolled in this study. Signal-averaged P-wave recording was performed, and the filtered P wave duration (FPD), the root-mean-square voltage for the last 20, 30 and 40 ms (RMS20, 30, and 40, respectively) were compared. In 7 patients with AF, these parameters were compared before and after the catheter ablation. The FPD was significantly longer and the RMS20 was smaller in the patients with AF than those without AF. Because RMS30 was widely distributed between 2 and 10 µV, the AF group was sub-divided into two groups; Group 1 was comprised of the patients with an RMS30 ≧5.0 µV, and group 2, <5.0 µV. In group 1, short-coupled PACs were more frequently documented on Holter monitoring, and exercise testing more readily induced AF. After successful electrical disconnection between the LA and PVs, each micropotential parameter was significantly attenuated. These results indicate that the high frequency signal amplitude of the last component of the P wave is relatively high in patients with AF triggered by focal repetitive excitations most likely originating from the PVs. That is, attenuation by the LA-PV electrical isolation, and thus the high frequency P signals of the last component, may contain the electrical excitation of the PV musculature

Enhanced O-GlcNAcylation Mediates Cytoprotection under Proteasome Impairment by Promoting Proteasome Turnover in Cancer Cells

The proteasome is a therapeutic target in cancer, but resistance to proteasome inhibitors often develops owing to the induction of compensatory pathways. Through a genome-wide siRNA screen combined with RNA sequencing analysis, we identified hexokinase and downstream O-GlcNAcylation as cell survival factors under proteasome impairment. The inhibition of O-GlcNAcylation synergistically induced massive cell death in combination with proteasome inhibition. We further demonstrated that O-GlcNAcylation was indispensable for maintaining proteasome activity by enhancing biogenesis as well as proteasome degradation in a manner independent of Nrf1, a well-known compensatory transcription factor that upregulates proteasome gene expression. Our results identify a pathway that maintains proteasome function under proteasome impairment, providing potential targets for cancer therapy

The mechanism of SO2 -induced stomatal closure differs from O3 and CO2 responses and is mediated by nonapoptotic cell death in guard cells.

Plants closing stomata in the presence of harmful gases is believed to be a stress avoidance mechanism. SO2 , one of the major airborne pollutants, has long been reported to induce stomatal closure, yet the mechanism remains unknown. Little is known about the stomatal response to airborne pollutants besides O3 . SLOW ANION CHANNEL-ASSOCIATED 1 (SLAC1) and OPEN STOMATA 1 (OST1) were identified as genes mediating O3 -induced closure. SLAC1 and OST1 are also known to mediate stomatal closure in response to CO2 , together with RESPIRATORY BURST OXIDASE HOMOLOGs (RBOHs). The overlaying roles of these genes in response to O3 and CO2 suggested that plants share their molecular regulators for airborne stimuli. Here, we investigated and compared stomatal closure event induced by a wide concentration range of SO2 in Arabidopsis through molecular genetic approaches. O3 - and CO2 -insensitive stomata mutants did not show significant differences from the wild type in stomatal sensitivity, guard cell viability, and chlorophyll content revealing that SO2 -induced closure is not regulated by the same molecular mechanisms as for O3 and CO2 . Nonapoptotic cell death is shown as the reason for SO2 -induced closure, which proposed the closure as a physicochemical process resulted from SO2 distress, instead of a biological protection mechanism

Risk-adjusted therapy for pediatric non-T cell ALL improves outcomes for standard risk patients: results of JACLS ALL-02

This study was a second multicenter trial on childhood ALL by the Japan Childhood Leukemia Study Group (JACLS) to improve outcomes in non-T ALL. Between April 2002 and March 2008, 1138 children with non-T ALL were enrolled in the JACLS ALL-02 trial. Patients were stratified into three groups using age, white blood cell count, unfavorable genetic abnormalities, and treatment response: standard risk (SR), high risk (HR), and extremely high risk (ER). Prophylactic cranial radiation therapy (PCRT) was abolished except for CNS leukemia. Four-year event-free survival (4yr-EFS) and 4-year overall survival (4yr-OS) rates for all patients were 85.4% ± 1.1% and 91.2% ± 0.9%, respectively. Risk-adjusted therapy resulted in 4yr-EFS rates of 90.4% ± 1.4% for SR, 84.9% ± 1.6% for HR, and 66.5% ± 4.0% for ER. Based on NCI risk classification, 4yr-EFS rates were 88.2% in NCI-SR and 76.4% in NCI-HR patients, respectively. Compared to previous trial ALL-97, 4yr-EFS of NCI-SR patients was significantly improved (88.2% vs 81.2%, log rank p = 0.0004). The 4-year cumulative incidence of isolated (0.9%) and total (1.5%) CNS relapse were significantly lower than those reported previously. In conclusion, improved EFS in NCI-SR patients and abolish of PCRT was achieved in ALL-02

Gene Knockout and Metabolome Analysis of Carnitine/Organic Cation Transporter OCTN1

金沢大学医薬保健研究域薬学系Purpose: Solute carrier OCTN1 (SLC22A4) is an orphan transporter, the physiologically important substrate of which is still unidentified. The aim of the present study was to examine physiological roles of OCTN1. Methods: We first constructed octn1 gene knockout (octn1-/-) mice. Metabolome analysis was then performed to identify substrates in vivo. The possible association of the substrate identified with diseased conditions was further examined. Results: The metabolome analysis of blood and several organs indicated complete deficiency of a naturally occurring potent antioxidant ergothioneine in octn1-/- mice among 112 metabolites examined. Pharmacokinetic analyses after oral administration revealed the highest distribution to small intestines and extensive renal reabsorption of [3H]ergothioneine, both of which were much reduced in octn1-/- mice. The octn1-/- mice exhibited greater susceptibility to intestinal inflammation under the ischemia and reperfusion model. The blood ergothioneine concentration was also much reduced in Japanese patients with Crohn\u27s disease, compared with healthy volunteers and patients with another inflammatory bowel disease, ulcerative colitis. Conclusions: These results indicate that OCTN1 plays a pivotal role for maintenance of systemic and intestinal exposure of ergothioneine, which could be important for protective effects against intestinal tissue injuries, providing a possible diagnostic tool to distinguish the inflammatory bowel diseases. © 2010 Springer Science+Business Media, LLC

Attentional Set-Shifting Deficit in Parkinson’s Disease Is Associated with Prefrontal Dysfunction: An FDG-PET Study

The attentional set-shifting deficit that has been observed in Parkinson’s disease (PD) has long been considered neuropsychological evidence of the involvement of meso-prefrontal and prefrontal-striatal circuits in cognitive flexibility. However, recent studies have suggested that non-dopaminergic, posterior cortical pathologies may also contribute to this deficit. Although several neuroimaging studies have addressed this issue, the results of these studies were confounded by the use of tasks that required other cognitive processes in addition to set-shifting, such as rule learning and working memory. In this study, we attempted to identify the neural correlates of the attentional set-shifting deficit in PD using a compound letter task and 18F-fluoro-deoxy-glucose (FDG) positron emission tomography during rest. Shift cost, which is a measure of attentional set-shifting ability, was significantly correlated with hypometabolism in the right dorsolateral prefrontal cortex, including the putative human frontal eye field. Our results provide direct evidence that dysfunction in the dorsolateral prefrontal cortex makes a primary contribution to the attentional set-shifting deficit that has been observed in PD patients

Effects of protein phosphatase and kinase inhibitors on the cardiac L-type Ca current suggest two sites are phosphorylated by protein kinase A and another protein kinase.

SUMMARY It is well-established that in heart, both the L-type Ca 2ϩ channel and the cystic fibrosis transmembrane conductance regulator Cl Ϫ channel are regulated by cAMP-dependent phosphorylation. However, it is not clear whether both of these channels are regulated in concert by protein kinase A (PKA) or whether there are mechanisms that independently control the phosphorylation of these two PKA targets. The purpose of this study was to compare the effects of various protein phosphatase and protein kinase inhibitors on these two ionic currents (I Ca and I Cl ) in guinea pig ventricular myocytes to gain insight into these questions. We found that both the stimulation and washout of the effects of isoproterenol on I Cl are about twice as fast as the effects on I Ca , probably because the dephosphorylation reaction for I Cl is faster than that for I Ca . In contrast, inhibition of protein phosphatases with 10 M microcystin stimulated both I Ca and I Cl , but the stimulation of I Cl was much slower and smaller than the stimulation of I Ca . The effect of microcystin was inhibited by staurosporine (K i ϭ 171.5 and 161 nM for I Ca and I Cl , respectively), suggesting that the stimulation was due to a kinase. The kinase was not protein kinase C (PKC) because it was not inhibited by the specific pseudosubstrate inhibitor of PKC, PKC (19 -31) , and it was not PKA because it was not inhibited by adenosine 3Ј,5Ј-cyclic phosphorothioate. These results suggest that although both the Ca 2ϩ and Cl Ϫ channels are regulated by cAMP-dependent phosphorylation, another protein kinase may also regulate these channels, and the kinetics of the response of the channels to phosphorylation can be modulated independently by protein phosphatases. In mammalian cardiac myocytes, ␤-adrenergic agonists regulate a variety of ionic currents, including I Ca and I Cl (1-3). Both currents are stimulated by cAMP-dependent phosphorylation via the G s /adenylyl cyclase/cAMP/PKA cascade, but both of these currents may be regulated by phosphorylation of more than a single phosphorylation site. In the case of I Ca , Tsien et al. (4) proposed that two different phosphorylation sites were responsible for the ␤-adrenergic regulation of Ca 2ϩ channel availability (N) and channel gating (P o ). Support for this hypothesis has come from studies on rabbit ventricular myocytes in which different concentrations of okadaic acid selectively affect N and p o (5) and from our studies on frog ventricular myocytes in which the amplitude of I Ca is regulated by two phosphorylation sites that can be distinguished by the phosphatases that dephosphorylate them (6). One site is dephosphorylated by phosphatase 2A, and the other site is dephosphorylated by a phosphatase with a low sensitivity to the phosphatase inhibitors microcystin, okadaic acid, and calyculin A. The regulation of I Cl is even more complicated (3). The regulation of this channel, like that of the Ca 2ϩ channel, involves two phosphorylation sites. One site is dephosphorylated by protein phosphatase 2A, and the other is dephosphorylated by a phosphatase with a low sensitivity to microcystin and okadaic acid, which may be protein phosphatase 2C (7). In addition, the channel is regulated by ATP binding and hydrolysis by its two nucleotide binding domains. The singly phosphorylated channel exhibits brief openings that correspond to hydrolysis of ATP by the first nucleotide binding site. The doubly phosphorylated channel exhibits a much longer channel open time that involves ATP binding to the second nucleotide binding site and stabilization of channel open state. Although it is clear that both channels are regulated by PKA, there is evidence that other protein kinases may also be involved in their regulation as well. For example, PKC can regulate cardiac Ca 2ϩ channels (8), and the CFTR Cl Ϫ channel may also be regulated by PKC (3). Furthermore, we have recently shown that in frog ventricular myocytes there is a novel protein kinase, which we have termed PKX, that ca