Akibumi Omi

Cyclophilin D-Sensitive Mitochondrial Permeability Transition in Adult Human Brain and Liver Mitochondria

The mitochondrial permeability transition (mPT) is considered to be a major cause of cell death under a variety of pathophysiological conditions of the central nervous system (CNS) and other organs. Pharmacological inhibition or genetic knockout of the matrix protein cyclophilin D (CypD) prevents mPT and cell degeneration in several models of brain injury. If these findings in animal models are translatable to human disease, pharmacological inhibition of mPT offers a promising therapeutic target. The objective of this study was to validate the presence of a CypD-sensitive mPT in adult human brain and liver mitochondria. In order to perform functional characterization of human mitochondria, fresh tissue samples were obtained during hemorrhage or tumor surgery and mitochondria were rapidly isolated. Mitochondrial calcium retention capacity, a quantitative assay for mPT, was significantly increased by the CypD inhibitor cyclosporin A in both human brain and liver mitochondria, whereas thiol-reactive compounds and oxidants sensitized mitochondria to calcium-induced mPT. Brain mitochondria underwent swelling upon calcium overload, which was reversible upon calcium removal. To further explore mPT of human mitochondria, liver mitochondria were demonstrated to exhibit several classical features of the mPT phenomenon, such as calcium-induced loss of membrane potential and respiratory coupling, as well as release of the pro-apoptotic protein cytochrome c. We concluded that adult viable human brain and liver mitochondria possess an active CypD-sensitive mPT. Our findings support the rationale of CypD and mPT inhibition as pharmacological targets in acute and chronic neurodegeneration.

Evaluation of putative inhibitors of mitochondrial permeability transition for brain disorders ― Specificity vs. toxicity

Inhibition of mitochondrial permeability transition (mPT) has emerged as a promising approach for neuroprotection and development of well-tolerated mPT inhibitors with favorable blood-brain barrier penetration is highly warranted. In a recent study, 28 clinically available drugs with a common heterocyclic structure were identified as mPT inhibitors e.g. trifluoperazine, promethazine and nortriptyline. In addition, neuroprotection by structurally unrelated drugs e.g. neurosteroids, 4-hydroxy-tamoxifen and trimetazidine has been attributed to direct inhibition of mPT. The regulation of mPT is complex and highly dependent on the prevailing experimental conditions. Several features of mPT, such as swelling, depolarization or NADH oxidation, can also occur independently of the mPT phenomenon. Here, in isolated rodent brain-derived and human liver mitochondria, we re-evaluate drugs promoted as potent mPT inhibitors. We address the definition of an mPT inhibitor and present strategies to reliably detect mPT inhibition in vitro. Surprisingly, none of the 12 compounds tested displayed convincing mPT inhibition or effects comparable to cyclophilin D inhibition by the non-immunosuppressive cyclophilin inhibitor D-MeAla(3)-EtVal(4)-Cyclosporin (Debio 025). Propofol and 2-aminoethoxydiphenyl borate (2-APB) inhibited swelling in de-energized mitochondria but did not increase calcium retention capacity (CRC). Progesterone, trifluoperazine, allopregnanolone and 4-hydroxy-tamoxifen dose-dependently reduced CRC and respiratory control and were thus toxic rather than beneficial to mitochondrial function. Interestingly, topiramate increased CRC at high concentrations likely by a mechanism separate from direct mPT inhibition. We conclude that a clinically relevant mPT inhibitor should have a mitochondrial target and increase mitochondrial calcium retention at concentrations which can be translated to human use.

The Effectiveness of the Fukuhara Laryngeal Mask Airway Holding Forceps (F Forceps)

The laryngeal mask airway (LMA) was introduced more than two decades ago cl), and a comprehensive review article on the LMA has been published (2). The LMA has many advantages over the endotracheal tube (3), including increased speed in establishing an airway, reduced anesthetic requirements for airway tolerance, and lower frequency of coughing during emergence. Insertion of the LMA is performed blindly so that the LMA cuff is placed to cover the laryngeal inlet. The technique of LMA insertion described by Brain (4,5) has been widely accepted and used. Fukuhara (6) had designed and developed the J-shaped LMA holding forceps, named the Fukuhara (F) forceps, for easy and accurate placement of the LMA. The current study was undertaken to evaluate the effectiveness of the F forceps, which have been approved by the Food and Drug Administration.

Are the incidences of cardiac events during noncardiac surgery in Japan the same as in the United States and Europe

In Japan, an ever-present problem in the preoperative evaluation of patients with ischemic heart disease is that although such evaluations are based on Western data, these data serve as the basis for determining perioperative risk in Japanese patients. To remedy this problem, the Cardiac Ischemia and Anesthesia Research Committee was formed in 1997 and has conducted studies of perioperative complications in noncardiac surgery in Japan. In two retrospective studies in 1997, the proportions of patients with ischemic heart disease were 3.9% and 3.1%, approximately one tenth the rates reported in Europe and the United States. The incidences of perioperative cardiac complications in patients with ischemic heart disease were 16.4% and 13.2%, not widely divergent from rates reported in Europe and the United States. To investigate the baseline characteristics involved in perioperative complications, we conducted a prospective study of 237 patients classified as having intermediate risk for perioperative cardiac complications according to the American College of Cardiology/American Heart Association Guidelines for Perioperative Cardiovascular Evaluation for Noncardiac Surgery. We found that the prominent factor in intraoperative cardiac complications was the presence of hypertension (odds ratio = 2.911). Factors contributing to postoperative cardiac complications included those reflecting coronary lesion severity and cardiac dysfunction (history of heart failure; odds ratio = 6.884, coronary risk index grade; odds ratio = 2.884, and a history of intervention; odds ratio = 4.774).

Inadequate gas supply to patients with an adjustable pressure-limiting valve in the fully opened position

With spontaneous ventilation, sufficient exhaust resistance at the adjustable pressure-limiting (APL) valve when fully opened ensures that the reservoir bag fills and adequately supplies gas to patients. A lack of exhaust resistance with the APL valve fully open caused inadequate gas supply to patients with four types of anesthesia machines: SA2 (Dräger), Excel-210 SE (GE), Fabius (Dräger), and Cato (Dräger). Mechanically, the SA2 and Excel-210 SE APL valve systems, which are of the spring-loaded disc type positioned horizontally, cannot maintain sufficient exhaust resistance with the APL valve fully open. As for the Fabius and Cato, an exhaust valve independent of the APL valve should maintain sufficient exhaust resistance continuously. However, accumulated viscous substances on the thin diaphragm of the exhaust valve contributed to hindrance of diaphragm closure.

Different characteristics of cell volume and intracellular calcium ion concentration dynamics between the hippocampal CA1 and lateral cerebral cortex of male mouse brain slices during exposure to hypotonic stress

The mechanism of brain edema is complex and still remains unclear. Our aim was to investigate the regional differences of cell volume and intracellular Ca2+ concentration ([Ca2+]i) dynamics during hypotonic stress in male mouse hemi‐brain slices. Brain slices were loaded with the fluorescence Ca2+ indicator fura‐2, and cell volume and [Ca2+]i in the lateral cerebral cortex (LCC) and hippocampal CA1 (CA1) region were measured simultaneously during exposure to hypotonic stress using Ca2+ insensitive (F360) and Ca2+ sensitive fluorescence (F380), respectively. Brain cell swelling induced by hypotonic stress was followed by a regulatory volume change that coincided with an increase in [Ca2+]i. The degrees of change in cell volume and [Ca2+]i were significantly different between the LCC and CA1. The increase in cell volume and [Ca2+]i in the LCC, but not in the CA1, was decreased by the transient receptor potential channel blockers LaCl3 and GdCl3. The increase in [Ca2+]i in both the LCC and CA1, was significantly decreased by the intracellular Ca2+ modulators thapsigargin and xestospongin C. The K+ channel activator isoflurane and Cl‐ channel blocker NPPB significantly decreased [Ca2+]i in the LCC. This study demonstrated that, between cells located in the LCC and in the CA1, the characteristics of brain edema induced by hypotonic stress are different. This can be ascribed to the different contribution of volume sensitive G‐protein coupled receptor and stretch sensitive Ca2+ channels.

Dexmedetomidine-based intravenous anesthesia of a pediatric patient with glucose-6-phosphate dehydrogenase (g6pd) deficiency: A case report

Rationale: Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common human enzyme defect, resulting in deficits in nicotinamide adenine dinucleotide phosphate production, an important intracellular antioxidant enzyme. G6PD-deficient subjects present with a susceptibility of erythrocytes to oxidative stress and hemolysis, and should avoid drugs or stressors that have oxidative actions. Dexmedetomidine is an anesthetic agent with antioxidant actions. Patient concerns and diagnoses: A 5-year-old boy with G6PD deficiency. The patient was diagnosed with G6PD deficiency at birth. His red blood cell levels were indicating Class II G6PD activity by the World Health Organization (WHO) classification, but had no history of hemolytic anemia. Intraventions: Because of the patients anxiety and hyperactivity prior to an operation for upper labial frenum resection, we performed perioperative management using intravenous sedation with dexmedetomidine, which provides upper airway patency and has an antioxidant action. Outcomes: There was no abnormal breathing observed during anesthesia, and arousal was smooth with stable hemodynamics. The patient had no symptoms of hemolytic anemia up to 1 week postsurgery. Conclusion: Antioxidant sedatives such as dexmedetomidine may be useful for reducing the risk of hemolysis after surgery in infant G6PD deficiency cases.

Anesthetic Management of Spinal Cord Injury (Unstable Cervical Spine)

Spinal cord injury (SCI) often presents difficult anesthesia management problems. The goals of the perioperative management of SCI are to prevent further spinal cord damage and fatal complications. However, knowledge of the best treatment for neurological injury is limited. In the early management of acute injuries, it is most important to prevent secondary injury by spinal immobilization during transport, airway manipulation, and correct positioning. In addition to spinal immobilization, the current standard of anesthetic management includes support of adequate arterial oxygenation, blood pressure and spinal cord perfusion.