Hisanari Ishii

6-formylpterin, a xanthine oxidase inhibitor, intracellularly generates reactive oxygen species involved in apoptosis and cell proliferation.

The chemical property of 6-formylpterin and its biological functions were examined. Polarographic studies revealed that 6-formylpterin reacted with NAD(P)H and consumed oxygen. In contrast, other conjugated pterins, such as biopterin and neopterin, showed no consumption of oxygen. The production analysis using high-performance liquid chromatography documented that 6-formylpterin catalyzes the conversion from NADH to NAD. Electroparamagnetic resonance spin trapping experiments demonstrated that this reaction is accompanied with the generation of reactive oxygen species (ROS), superoxide anion and hydrogen peroxide. When 6-formylpterin was administered to HL-60 cells, intracellular ROS generation was observed and apoptosis was induced. In contrast, other conjugated pterins induced neither intracellular ROS generation nor apoptosis in HL-60 cells. The intracellular ROS generation by 6-formylpterin was observed in other cells, such as PanC-1 cells and Jurkat cells. 6-formylpterin suppressed cell proliferation in PanC-1 cells and inhibited Fas-mediated apoptosis in Jurkat cells. These findings indicate that, among conjugated pterins, 6-formylpterin has the unique property to transfer electron from NAD(P)H to oxygen and that the property brings about intracellular ROS generation, which exerts various biological functions such as induction of apoptosis, suppression of cell proliferation, and inhibition of Fas-mediated apoptosis.

Neuroprotective effects of pterin-6-aldehyde in gerbil global brain ischemia : comparison with those of α-phenyl-N-tert-butyl nitrone

The superoxide (O2.-) scavenging activity and the neuroprotective effects of pterin-6-aldehyde (P6A), a xanthine oxidase inhibitor, were examined and compared with those of alpha-phenyl-N-tert-butyl nitrone (PBN), a spin trapping agent. The scavenging activity of P6A was more potent than that of PBN by 150-fold in neutrophil/phorbol myristate acetate O2.- generating system. P6A attenuated the neuronal damage with a much smaller dose and a greater efficiency than PBN in global brain ischemia in gerbils. These findings suggest that P6A is a more potent neuroprotective agent than PBN and has possible therapeutic effects against various diseases in which O2.- is involved.

Effects of blood sugar level on rat transient focal brain ischemia consecutively observed by diffusion-weighted EPI and 1H echo planar spectroscopic imaging

The effects of blood sugar level on transient focal brain ischemia were examined by consecutive diffusion‐weighted EPI and 1H echo planar spectroscopic imaging. A remote‐controlled rat intraluminal suture middle cerebral artery occlusion (MCAO) model was prepared. Animals were divided into three experimental groups: control, 1 g/kg, and 2 g/kg glucose groups (n = 6 for each). Saline or glucose was infused intraperitoneally 30 min prior to MCAO. The glucose‐loaded groups showed increased lactate accumulation and marked decreases in average diffusion coefficient in the ischemic region during 40‐min MCAO. These changes were correlated with blood sugar levels at the onset of MCAO. After reperfusion, all rats in the control and 1 g/kg groups recovered from the ischemic changes, but three rats with marked hyperglycemia in the 2 g/kg group showed irreversible changes. The adverse effects of hyperglycemia on transient focal brain ischemia were clearly demonstrated by sequential 2D images. Magn Reson Med 42:895–902, 1999.

Evaluation of Focal Cerebral Ischemia in Rats by Magnetic Resonance Imaging and Immunohistochemical Analyses

Correlation of focal ischemia-induced brain damage evidenced by magnetic resonance imaging (MRI) and by staining with microtubule-associated protein 2 (MAP2) was studied in rats. Ischemia was produced by transient occlusion of the middle cerebral artery (MCAO). The damage was assessed at 6 to 8 hours after MCAO and 1 week later. The area of damage assessed by MRI agreed with that by MAP2 staining at 6 to 8 hours after MCAO, which was smaller (P < 0.001) than that defined by MAP2 staining 1 week after MCAO. Glial staining indicated that glial infiltration affected the signal intensity of MRI in the area of damage.

Dissociation between lactate accumulation and acidosis in middle cerebral artery-occluded rats assessed by 31P and 1H NMR metabolic images under A 2-T magnetic field

The relationships among tissue edema, lactate accumulation, and intracellular pH in middle cerebral artery (MCA)-occluded rats were investigated with multiecho 1H magnetic resonance imaging and spatially resolved metabolic images constructed by 1H and 31P nuclear magnetic resonance (NMR) chemical shift imaging (CSI). For the effective and sensitive detection of NMR signals from the brain, outer volume suppression (OVS), reduced k-space sampling and proton irradiation were incorporated into the CSI sequences. The consecutive three measurements of calculated T2 image, lactate image, and pH image which were required for 3.75 h were repeated for four cycles of 1-16 h after MCA occlusion. Tissue edema and lactate accumulation in the infarcted region were gradually and consistently increased during the 15-h observation period. In contrast, severe acidosis was already detected on the first pH image (2-4.7 h after MCA occlusion); thereafter, the degree of acidosis became milder and showed no further progression. The dissociation between the time courses of the lactate accumulation and pH decrease was clearly demonstrated by the NMR metabolic images. Acid-base balance in cerebral infarction might be affected not only by lactate production but also by complicated interactions with tissue edema and some other factors.

Delayed Chest Closure Assessed by Transesophageal Echocardiogram in Single-Lobe Lung Transplantation

A 6-year-old girl with idiopathic interstitial pneumonia successfully underwent living-donor right single-lobe lung transplantation from her mother. Her mothers right lower lobe was 207% bigger than her right chest cavity, and attempting chest closure caused significant compression and narrowing of the right pulmonary vein anastomosis, as assessed by transesophageal echocardiogram. Her chest was temporarily closed without rib approximation. The following day, her chest could be completely closed. The pulmonary vein anastomosis, confirmed by transesophageal echocardiogram, was now patent. Currently, 7 months after the transplantation, she is well without limitations.

Living-donor, single-lobe lung transplantation and simultaneous contralateral pneumonectomy in a child

An 8-year-old girl became ventilator-dependent due to severe bronchiolitis obliterans/interstitial pneumonia caused by cord-blood cell transplantation for neuroblastoma. Her mothers right lower lobe was twice as large as her right chest cavity. She successfully underwent living-donor, right, single-lobe lung transplantation and simultaneous left pneumonectomy under conditions of cardiopulmonary bypass. At 18 months after transplantation, the patient returned to school life and is currently able to carry out daily activities without supplemental oxygen.

Living-donor lobar lung transplantation with sparing of bilateral native upper lobes: a novel strategy.

A 44-year-old man became wheelchair-bound due to sever bronchiolitis obliterans caused by peripheral blood stem cell transplantation for acute myelogenous leukemia. His lung donors, his sister and his wife, were 17 cm shorter than him. He successfully underwent living-donor lobar lung transplantation with sparing of the bilateral native upper lobes to address the size mismatch. Ten months after the transplantation, the patient has returned to a normal lifestyle without supplemental oxygen.

Oxypurinol, a xanthine oxidase inhibitor and a superoxide scavenger, did not attenuate ischemic neuronal damage in gerbils

The superoxide (O2.-) scavenging activity and neuroprotective effects of oxypurinol, a xanthine oxidase inhibitor, were compared with those of alpha-phenyl-N-tert-butyl nitrone (PBN). The rate constant for the reaction of oxypurinol with O2.- at pH 7.4 was 1.71 x 10(3) M(-1) s(-1) which was more than 100-fold that of PBN (1.65 x 10 M(-1) s(-1)). Oxypurinol inhibited the release of O2.- from stimulated neutrophils better than did PBN. However, oxypurinol did not attenuate the ischemic neuronal damage in gerbils, while PBN did. These results indicate that neither xanthine oxidase inhibiting activity nor O2.- scavenging activity correlates to the therapeutic efficacy of neuroprotective agents in ischemic-reperfusion injury.

Takotsubo cardiomyopathy during ambulatory anesthesia for bladder hydrodistension therapy -A case report-

Stress-induced cardiomyopathy, also referred to Takotsubo cardiomyopathy or apical ballooning syndrome presents in perioperative period. We demonstrated a case of Takotsubo cardiomyopathy recognized after general anesthesia for bladder hydrodistension therapy as ambulatory surgery, which we surmise was due to inadequate blockage of surgical stress and sympathetic discharge against noxious stimulus during ambulatory anesthesia.