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The ultrarapid delayed rectifier current ( I K,ur) plays a significant role in human atrial repolarization and is generally believed to show little rate dependence because of slow and partial inactivation. This study was designed to evaluate in detail the properties and consequences of I K,urinactivation in isolated human atrial myocytes. I K,ur inactivated with a biexponential time course and a half-inactivation voltage of −7.5 ± 0.6 mV (mean ± SE), with complete inactivation during 50-s pulses to voltages positive to +10 mV (37°C). Recovery from inactivation proceeded slowly, with time constants of 0.42 ± 0.06 and 7.9 ± 0.9 s at −80 mV (37°C). Substantial frequency dependence was observed at 37°C over a clinically relevant range of frequencies. Inactivation was faster and occurred at more positive voltages at 37°C compared with room temperature. The voltage and time dependencies of Kv1.5 inactivation were studied in Xenopus oocytes to avoid overlapping currents and strongly resembled those of I K,ur in native myocytes. We conclude that, while I K,urinactivation is slow, it is extensive, and slow recovery from inactivation confers important frequency dependence with significant consequences for understanding the role of I K,ur in human atrial repolarization.

The purpose of this study was to understand the clinical significance of the morphology and blood supply of the falciform ligament in laparoscopic surgery. The structure, blood vessel distribution and anastomoses of the falciform ligament were observed in 20 cases of living laparoscopy, 30 cadaveric specimens injected with latex and five cadaveric specimens with Indian ink and hyaline. The falciform ligament was formed by two sides of peritoneum and its length, largest and smallest width were 8.3+/-1.6 cm, 4.9+/-0.8 cm and 1.1+/-0.3 cm, respectively. The left inferior phrenic artery and middle segment artery of the liver formed a vessel that arched and gave off 6-12 branches to the falciform ligament. The veins of the falciform ligament drained into the left inferior phrenic vein, and were not accompanied by any artery. In conclusion, the vessels of the falciform ligament anastomose with multiple vessels and form a significant pathway of the collateral circulation in the liver. The falciform ligament is an important landmark in laparoscopic surgery.

Background One of the most important objectives of modern medical education is to empower medical students to become humanistic clinicians. Human anatomy plays a crucial role in this mission by using cadavers to cause reflections on death, dying, illness, and the role of medical practitioners in humanistic care. The objective of this study was to introduce, describe, and evaluate the impact of a ceremony in honor of the body donors on ethical and humanistic attitudes of medical students. Methods We used a phenomenological research approach to explore and understand the lived experiences of the anatomy teachers as they teach anatomy in the context of humanism and ethics. A separate survey of third-year medical students was carried out to understand their perceptions of changes in themselves, respect for donors and donor families, and their relationship with patients. Data were collected in two phases: a desktop review of teaching materials followed by in-depth interviews of the main anatomy teachers followed by a self-administered, 5-item Likert scaled questionnaire given to students. Results In the present article, we describe the rituals conducted in honor of body donors at our School of Medicine. We also describe the lived experiences of anatomy teachers as they work on improving humanistic education quality through the introduction of the concept of “silent mentor” which refers to a cadaver that quietly allows medical students to learn from it. In turn, a ceremony in honor of body donors who have altruistically donated their bodies so that learning anatomy through dissection would be possible is also introduced. A survey of the impact of the ceremony in honor of body donors on medical students revealed positive responses in terms of promoting studying anatomy (3.96 Vs 3.95) as well as reflections on own death (4.44 Vs 4.35), the life of body donors (4.07 Vs 4.04), and how to humanely view future patients and their significant others (4.32 Vs 4.24) relative to those that did not attend the ceremony (5-item Likert scale). The majority of the students that attended the ceremony also indicated that it had a positive impact on their future doctor-patient relationship, thinking about the possibility of donating their body for teaching as well as about medical ethics. Most of them also think that attending the ceremony helped reduce their anxiety, fear, and disgust of seeing corpses or dissecting and 90% insisted that memorial ceremonies should continue being conducted at Zhongshan Medical School. Conclusion The combination of the anatomy component of the basic medical curriculum and gratitude ceremonies as well as activities to promote body bequeathal programs might help to accomplish the goal of cultivating high-quality medical students and professionals for the future. The long-term benefits would be a medical graduate who exudes empathy, relates well with patients and their significant others, leading to a productive doctor-patient relationship.

The human ether-a-go-go-related gene (HERG) encodes a delayed rectifier K⁺ channel, which is expressed in a variety of tissues and cells. Besides its well-recognized function in cellular electrophysiology, HERG channels have also been implicated in neuronal differentiation and cell cycle regulation. We have recently found that HERG regulates apoptosis. To elucidate the signaling pathways, we performed studies in HEK293 cells stably expressing HERG channels. ELISA was used to quantify DNA fragmentation, a biochemical hallmark of apoptosis. In HERG-transfected HEK cells, the degree of DNA fragmentation was found consistently higher (ñ4-times) than in non-transfected cells. Correspondingly, remarkable activation of caspase 3, caspase 9 and cleavage of PARP were seen in HERG-expressing cells, which were otherwise minimal in non-transfected cells. Exposure of cells to H₂O₂ (10 hrs) at concentrations up to 1 mM, which is known to induce apoptosis in a variety of cells, caused minimal DNA fragmentation in non-transfected cells. HERG expression facilitates DNA fragmentation induced by H₂O₂ at a concentration-dependent fashion, starting at 200 µM and reaching maximum at 1 mM. Selective HERG channel inhibitors, dofetilide or E-4031 (5 µM) prevented DNA fragmentation. Inhibition of p38 by SB-203580 alleviated DNA-F and PD-98059, which inhibited activation of ERKs, nearly abolished DNA-F. Immunoblotting analysis demonstrated that p38, SAPKs and ERKs MAP kinases were all substantially activated (>10-fold higher) in HERG-expressing cells vs. non-transfected cells. Akt activity was ñ4-fold lower in HERG cells vs. non-transfected cells in the absence of H₂O₂ and was slightly increased (ñ2-fold) after H₂O₂ exposure. We conclude that HERG channels facilitate cellular DNA fragmentation in HEK cells via concomitant activation of MAP kinases and inactivation of Akt.

To characterize electrophysiologically the K⁺ currents mediated by various mAChR subtypes, we performed detailed whole-cell patch-clamp studies in canine atrial myocytes. I_KACh was induced by 1 mM ACh (acetylcholine) or by arecaidine but-2-ynyl ester tosylate (100 nM, an M₂ receptor selective agonist) and was blocked by methoctramine (20 nM, an M₂ receptor selective antagonist). Tetramethylammonium (0.5 mM) activated a K⁺ conductance with delayed rectifying properties (I_KM3) and the currents were highly sensitive to 4-diphenylacetoxy-N-methylpiperidine methiodide (2 nM, an M₃ receptor inhibitor). 4-aminopyridine (1 mM) induced a delayed rectifier-like current (I_K4AP) which was selectively suppressed by tropicamide (200 nM, an M₄ receptor blocker). The current waveforms, I-V relationships, steady-state voltage-dependence, kinetics and pharmacological properties of these three currents were different from one another and distinct from the classical delayed rectifier K⁺ currents (I_Kr and I_Ks). Both I_KACh and I_K4AP were sensitive to pertussis ntoxin, whereas I_KM3 was not. Isoproterenol (1 mM) markedly depressed I_KM3, but increased I_K4AP and did not alter I_KACh. The effects of isoproterenol were reversed by propranolol (1 mM); and ACh completely suppressed I_KM3 and I_K4AP. The results suggest that the K⁺ currents mediated by different subtypes of mAChR represent different populations of K⁺ channels and that the cholinergic regulation of the heart’s electrical function is a consequence of activating multiple mAChRs linked to different effector systems with potentially varying signal transduction.

Stimulation of muscarinic acetylcholine receptors (mAChRs) can activate an inward rectifier K؉ current (I KACh ), which is mediated by the M 2 subtype of mAChR in cardiac myocytes. Recently, a novel delayed rectifierlike K ؉ current mediated by activation of the cardiac M 3 receptors (designated I KM3 ) was identified, which is distinct from I KACh and other known K ؉ currents. While I KACh is known to be a G i protein-gated K ؉ channel, the signal transduction mechanisms for I KM3 activation remained unexplored. We studied I KM3 with whole-cell patch clamp and macropatch clamp techniques. Whole cell I KM3 activated by choline persisted with minimal rundown over 2 h in presence of internal GTP. When GTP was replaced by guanyl-5-yl thiophosphate, I KM3 demonstrated rapid and extensive rundown. While I KACh (induced by ACh) was markedly reduced in cells pretreated with pertussis toxin, I KM3 was unaltered. Intracellular application of antibodies targeting ␣-subunit of G i/o protein suppressed I KACh without affecting I KM3 . Antibodies targeting the N and the C terminus, respectively, of G q protein ␣-subunit substantially depressed I KM3 but failed to alter I KACh . The antibody against ␤-subunits of G proteins inhibited both I KACh and I KM3 . I KM3 activated by choline in the cell-attached mode of macropatches persisted in the cell-free configuration. Application of purified G q protein ␣-subunit or ␤␥-subunit of G proteins or guanosine 5-O-(thiotriphosphate) to the internal solution activated I KM3 -like currents in inside-out patches. Our findings revealed a novel aspect of receptor-channel signal transduction mechanisms, and I KM3 represents the first G q protein-coupled K ؉ channel. We propose that the G protein-coupled K ؉ channel family could be divided into two subfamilies: G i protein-coupled K ؉ channel subfamily and G q proteincoupled K ؉ channel subfamily.While M 2 receptors are commonly believed to be the only functional mAChRs 1 in cardiac tissues, this concept has been challenged by recent findings revealing the presence of M 3 receptors in the hearts of various species including guinea pig (1, 2), rat (3), dog (4 -6), and human (7-11). We discovered that the cardiac M 3 receptors mediate the activation of a novel delayed rectifier K ϩ current (we have named it I KM3 ) distinct from I KACh and other known K ϩ currents. I KACh is characterized by strong inward rectification, whereas I KM3 conducts a delayed rectifier-like K ϩ current. We also found that M 3 receptors and I KM3 play a significant role in regulating heart rates, cardiac resting membrane potential, and membrane repolarization (1, 2). The findings suggest that we are no longer able to consider parasympathetic control of the heart as due to a simple ACh-M 2 interaction; we have to understand cholinergic effects in terms of the consequence of activating multiple subtypes of mAChRs, with potentially varying signal transduction and effector systems (such as different K ϩ channels) (6). The M 1 and M 3 receptors are characterized biochemica...

Recently, crossdocking techniques have been successfully applied in responsive supply chain management. However, most researches focused on physical layout of a crossdock, or scheduling operations within a crossdock. In this paper, we study a multi-crossdock transshipment service problem with both soft and hard time windows. The flows from suppliers to customers via the crossdocks are constrained by fixed transportation schedules. Cargos can be delayed and consolidated in crossdocks, and both suppliers and customers have specific hard time windows. In addition to hard time windows, customers also have less-restrictive time windows, called soft time windows. The problem to minimize the total cost of the multi-crossdock distribution network, including transportation cost, inventory handling cost and penalty cost, can be proved to be NP-hard in the strong sense and hence efficient heuristics are desired. We propose two types of meta-heuristic algorithms, called Adaptive Tabu Search and Adaptive Genetic Algorithm, respectively, to solve the problem efficiently. We conduct extensive experiments and the results show that both of them outperform CPLEX solver and provide fairly good solutions within realistic timescales. We also perform sensitivity analysis and obtain a number of managerial insights.