Shizuko Kosugi

Harvard University, Cambridge, Massachusetts, United States

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Publications (24)53.82 Total impact

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    ABSTRACT: Since hyperglycemia-induced cellular dysfunction could be associated with alterations of the immune system, we tested the hypothesis that hyperglycemia augments the aberrant immune responses such as inflammation and differentiation of CD4(+) T lymphocytes in the mesenteric lymph nodes (MLNs), and induces alterations of microbiota both under physiological and pathological conditions. Male Wistar rats were randomly allocated into 4 groups: Control and Endotoxemia (lipopolysaccharide, LPS 1 mg/kg) with or without hyperglycemia. The hyperglycemia groups were administered glucose solution (10-40 %), while the normoglycemia groups were administered saline. Alterations of the mRNA expressions of inflammatory cytokines and CD4(+) T lymphocyte transcriptional factor expressions in the MLNs, and those of the intestinal microbiota were analyzed at 24 hr. Hyperglycemia was kept approximately 250-350 mg/dL during the 24 hr study period. At the end of 24 hr, hyperglycemia augmented the mRNA expressions of interleukin (IL)-1β and IL-6 in the MLNs, while both the helper T (Th) 2 and regulatory-T (Treg) transcriptional factors were simultaneously up-regulated under non-endotoxemic condition. LPS injection significantly modulated the obligate anaerobe bacterial populations of the Bacteroidetes class, and altered the population sizes of the Clostridium perfringens and the Bacteroides fragilis subgroup. Hyperglycemia did not enhance these alterations of the microbiota evoked by LPS, although it did modify the bacterial populations of the L. reuteri subgroup and staphylococci in healthy condition without endotoxemia. The present study indicates that both gut immune function and microbiota are significantly modulated by persistent hyperglycemia.
    Full-text · Article · Dec 2015
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    ABSTRACT: Background: Hydrogen sulfide (H2S) exhibits protective effects in various disease models including cerebral ischemia-reperfusion (I/R) injury. Nonetheless, mechanisms and identity of molecules responsible for neuroprotective effects of H2S remain incompletely defined. In the current study, we observed that thiosulfate, an oxidation product of H2S, mediates protective effects of an H2S donor compound sodium sulfide (Na2S) against neuronal I/R injury. Methods and results: We observed that thiosulfate in cell culture medium is not only required but also sufficient to mediate cytoprotective effects of Na2S against oxygen glucose deprivation and reoxygenation of human neuroblastoma cell line (SH-SY5Y) and murine primary cortical neurons. Systemic administration of sodium thiosulfate (STS) improved survival and neurological function of mice subjected to global cerebral I/R injury. Beneficial effects of STS, as well as Na2S, were associated with marked increase of thiosulfate, but not H2S, in plasma and brain tissues. These results suggest that thiosulfate is a circulating "carrier" molecule of beneficial effects of H2S. Protective effects of thiosulfate were associated with inhibition of caspase-3 activity by persulfidation at Cys163 in caspase-3. We discovered that an SLC13 family protein, sodium sulfate cotransporter 2 (SLC13A4, NaS-2), facilitates transport of thiosulfate, but not sulfide, across the cell membrane, regulating intracellular concentrations and thus mediating cytoprotective effects of Na2S and STS. Conclusions: The protective effects of H2S are mediated by thiosulfate that is transported across cell membrane by NaS-2 and exerts antiapoptotic effects via persulfidation of caspase-3. Given the established safety track record, thiosulfate may be therapeutic against ischemic brain injury.
    No preview · Article · Nov 2015 · Journal of the American Heart Association
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    ABSTRACT: Since neutrophil gelatinase-associated lipocalin (NGAL) is known to provide significant bacteriostatic effects during infectious conditions, we tested the hypothesis that this protein is up-regulated and secreted into the intraluminal cavity of the gut under critically ill conditions and is thus responsible for the regulation of bacterial overgrowth. With our institutional approval, male C57BL/6 J mouse (6-7 weeks) were enrolled and applied for lipopolysaccharide or peritonitis model compared to naïve control. We assessed NGAL protein concentrations in intestinal lumen and up-regulation of NGAL expression in intestinal tissues in in vivo as well as ex vivo settings. Simultaneously, we examined the effects of NGAL protein administration on the growth of Escherichia coli (E.coli) in in vivo and in vitro experimental settings. The localization of NGAL in intestinal tissues and lumen was also assessed by immunohistological approach using NGAL antibody. Both LPS and peritonitis insults evoked the marked up-regulation of NGAL mRNA and protein levels in gut tissues such as crypt cells. In addition, the administration of NGAL protein significantly inhibited the outgrowth of enteric E. coli under both in vitro and in vivo conditions, accompanied by histological evidence. NGAL protein accompanied by apparent bacteriostatic action accumulated in the intestinal wall and streamed into the mucosal layer during critically ill state, thereby possibly shaping microbiota homeostasis in the gut. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    No preview · Article · Jul 2015 · Journal of Gastroenterology and Hepatology
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    ABSTRACT: In this randomized controlled trial, we examined whether intra- and postoperative infusion of low-dose ketamine decreased postoperative morphine requirement and morphine-related adverse effects as nausea and vomiting after scoliosis surgery. After IRB approval and informed consent, 36 patients, aged 10-19 years, undergoing posterior correction surgery for adolescent idiopathic scoliosis, were randomly allocated into two groups: intra- and postoperative ketamine infusion at a rate of 2 μg/kg/min until 48 h after surgery (ketamine group, n = 17) or infusion of an equal volume of saline (placebo group, n = 19). All patients were administered total intravenous anesthesia with propofol and remifentanil during surgery and intravenous morphine using a patient-controlled analgesia device after surgery. The primary outcome was cumulative morphine consumption in the initial 48 h after surgery. Pain scores (Numerical Rating Scale, NRS, 0-10), sedation scales, incidence of postoperative nausea and vomiting (PONV), and antiemetic consumption were recorded by nurses blinded to the study protocol for 48 h after surgery. Patient characteristics did not differ between the two groups. Cumulative morphine consumption for 48 h after surgery was significantly lower in the ketamine group compared to the placebo group (0.89 ± 0.08 mg/kg vs. 1.16 ± 0.07 mg/kg, 95% confidence interval for difference between the means, 0.03-0.48 mg/kg, P = 0.019). NRS pain, sedation scales, and incidence of PONV did not differ between the two groups. Antiemetic consumption was significantly smaller in ketamine group. Intra- and postoperative infusion of low-dose ketamine reduced cumulative morphine consumption and antiemetic requirement for 48 h after surgery. © 2015 The Acta Anaesthesiologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.
    No preview · Article · Jun 2015 · Acta Anaesthesiologica Scandinavica
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    Full-text · Dataset · May 2015
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    ABSTRACT: Neutrophil-derived lipocalin-2 exerts bacteriostatic effects through retardation of iron uptake by the Gram-negative organisms like Escherichia coli. We tested the hypothesis that the expression of lipocalin-2, a bacteriostatic protein, was upregulated by induction of surgical site infection (SSI) with E coli in healthy and diseased rats and that epidural anesthesia modulated its expression. Male Wistar rats were randomized into a healthy or disease group, the latter of which was administered lipopolysaccharide. Both groups were further divided into 3 subgroups, the control, saline, and lidocaine groups: group healthy control (n = 10), healthy saline (n = 10), and healthy lidocaine (n = 10) versus group disease control (n = 15), disease saline (n = 18), and disease lidocaine (n = 19), respectively. While saline was epidurally administered to the control and saline groups, lidocaine was administered to the lidocaine groups. Except for the control groups, E coli was injected to the pseudosurgical site to mimic SSI after abdominal surgery. Plasma concentrations of inflammatory cytokine and lipocalin-2 were measured. At 72 hours, the surgical site tissues were obtained to evaluate mRNA expression of lipocalin-2 and E coli DNA expression. All disease subgroups showed markedly increased plasma inflammatory cytokines versus the healthy subgroups. Among the disease subgroups, plasma concentrations of lipocalin-2 and tissue mRNA expression of lipocalin-2 were significantly increased in group disease lidocaine versus the others. Concurrently, E coli DNA expression in the tissue specimens was also significantly lower in group disease lidocaine as compared with group disease saline. Epidural anesthesia was associated with an increase in the expression lipocalin-2 and a decrease in the expression of E coli DNA at pseudosurgical sites in sick but not healthy rats. These observations suggest a potential mechanism by which epidural anesthesia could reduce the risk of SSI.
    No preview · Article · Mar 2015 · Anesthesia and analgesia
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    Preview · Article · Nov 2014 · Pain Medicine
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    ABSTRACT: Background Acute kidney injury (AKI) is one of the major morbidities after surgical repair of abdominal aortic aneurysm (AAA); however, precise pathogenesis of this morbidity has not been well determined. Since prothrombotic coagulation abnormality may precede organ dysfunction in systemic inflammatory state, we examined the kinetics of von Willebrand factor (VWF) and a disintegrin-like metalloprotease with thrombospondin type 1 motif 13 (ADAMTS13), a cleaving enzyme of VWF, on the development of AKI after AAA surgery. Methods The kinetics of ADAMTS13 and VWF were examined in ten patients who underwent surgical repair of AAA. The changes in plasma neutrophil gelatinase-associated lipocalin (NGAL), a novel biomarker for AKI, and serum creatinine concentration were also examined at four points until seventh postoperative day (POD). Clinical diagnosis of AKI was based on the change in serum creatinine concentration and urine output according to Acute Kidney Injury Network (AKIN) criteria. Results ADAMTS13 activity was significantly lower than normal level before the surgery and showed a trend of decrease toward 3POD. The VWF/ADAMTS13 ratio showed a significant increase on 1POD, which persisted until 7POD. None of patents was diagnosed as AKI based on AKIN criteria, although two patients received furosemide and/or carperitide therapy because of decreased urine output less than 0.5 ml/kg/h for several hours in ICU. Plasma NGAL showed a trend to increase after the surgery, which was significant on 3POD. The change in plasma NGAL was significantly correlated with VWF/ADAMTS13 ratio (P < 0.01). Conclusions This study has shown that patients undergoing AAA surgery were prothrombotic after the surgery because of high VWF/ADAMTS13 ratio. Correlation between VWF/ADAMTS13 ratio and NGAL might indicate contribution of thrombotic event to subclinical AKI in the patients undergoing AAA surgery.
    Full-text · Article · Jul 2014
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    ABSTRACT: It remains to be clarified if the application of noninvasive positive pressure ventilation (NPPV) is effective after extubation in patients with hypoxemic respiratory failure who require the sufficient level of positive end-expiratory pressure (PEEP). This study was aimed at examining the effect and the safety of NPPV application following extubation in patients requiring moderate PEEP level for sufficient oxygenation after cardiovascular surgery. With institutional ethic committee approval, the patients ventilated invasively for over 48 h after cardiovascular surgery were enrolled in this study. The patients who failed the first spontaneous breathing trial (SBT) at 5 cmH2O of PEEP, but passed the second SBT at 8 cmH2O of PEEP, received NPPV immediately after extubation following our weaning protocol. Respiratory parameters (partial pressure of arterial oxygen tension to inspiratory oxygen fraction ratio: P/F ratio, respiratory ratio, and partial pressure of arterial carbon dioxide: PaCO2) 2 h after extubation were evaluated with those just before extubation as the primary outcome. The rate of re-intubation, the frequency of respiratory failure and intolerance of NPPV, the duration of NPPV, and the length of intensive care unit (ICU) stay were also recorded. While 51 postcardiovascular surgery patients were screened, 6 patients who met the criteria received NPPV after extubation. P/F ratio was increased significantly after extubation compared with that before extubation (325 ± 85 versus 245 ± 55 mmHg, p < 0.05). The other respiratory parameters did not change significantly. Re-intubation, respiratory failure, and intolerance of NPPV never occurred. The duration of NPPV and the length of ICU stay were 2.7 ± 0.7 (SD) and 7.5 (6 to 10) (interquartile range) days, respectively. While further investigation should be warranted, NPPV could be applied effectively and safely after extubation in patients requiring the moderate PEEP level after cardiovascular surgery.
    Full-text · Article · Jan 2014
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    ABSTRACT: The objective of this study was to examine the long-term outcome of percutaneous radiofrequency thermocoagulation (PRT) of the Gasserian ganglion for the 2nd division and multiple division trigeminal neuralgia (TN), compared to the isolated 3rd division TN. One hundred and forty-eight procedures performed in 89 patients with typical TN between April 2004 and September 2011 in a single pain center were retrospectively analyzed. Baseline characteristics of these patients, immediate outcome, duration pain-free, and complications were obtained from their medical records and questionnaires sent in June 2012. Duration pain-free was assessed by Kaplan-Meier analysis. Of the 148 PRT of the Gasserian ganglion, 37 procedures were performed for isolated 2nd-division TN (V2 TN), 67 procedures were for both 2nd- and 3rd-division TN (V2 + V3 TN), and 38 procedures were for isolated 3rd-division TN (V3 TN). The remaining 6 procedures were performed for V1 + V2 TN and V1 + V2 + V3 TN. Immediate success rates of PRT for V2 TN, V2 + V3 TN, and V3 TN were 100%, 86.6%, and 100%, respectively, whereas the durations pain-free for V2 TN and V2 + V3 TN were significantly shorter than that for V3 TN (9, 12, and 36 months, respectively: P = 0.012). For 2nd-division TN and multiple-division TN, less long-term pain relief after PRT of the Gasserian ganglion can be expected compared with that for isolated trigeminal 3rd-division neuralgia, even if immediate pain relief is achieved.
    No preview · Article · Jan 2014 · Pain Practice

  • Shizuko Kosugi · Hiroshi Morisaki

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    Dataset: JBC 2012

    Full-text · Dataset · May 2013
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    ABSTRACT: Physiological levels of H2S exert neuroprotective effects, whereas high concentrations of H2S may cause neurotoxicity in part via activation of NMDAR. To characterize the neuroprotective effects of combination of exogenous H2S and NMDAR antagonism, we synthesized a novel H2S-releasing NMDAR antagonist N-((1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl)-4-(3-thioxo-3H-1,2-dithiol-4-yl)-benzamide (S-memantine) and examined its effects in vitro and in vivo. S-memantine was synthesized by chemically combining a slow releasing H2S donor 4-(3-thioxo-3H-1,2-dithiol-4-yl)-benzoic acid (ACS48) with a NMDAR antagonist memantine. S-memantine increased intracellular sulfide levels in human neuroblastoma cells (SH-SY5Y) 10-fold as high as that was achieved by ACS48. Incubation with S-memantine after reoxygenation following oxygen and glucose deprivation (OGD) protected SH-SY5Y cells and murine primary cortical neurons more markedly than did ACS48 or memantine. Glutamate-induced intracellular calcium accumulation in primary cortical neurons were aggravated by sodium sulfide (Na2S) or ACS48, but suppressed by memantine and S-memantine. S-memantine prevented glutamate-induced glutathione depletion in SH-SY5Y cells more markedly than did Na2S or ACS48. Administration of S-memantine after global cerebral ischemia and reperfusion more robustly decreased cerebral infarct volume and improved survival and neurological function of mice than did ACS48 or memantine. These results suggest that an H2S-releasing NMDAR antagonist derivative S-memantine prevents ischemic neuronal death, providing a novel therapeutic strategy for ischemic brain injury.
    Full-text · Article · Jul 2012 · Journal of Biological Chemistry
  • Kanako Makito · Shizuko Kosugi · Koichi Tsuzaki
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    ABSTRACT: Spinal epidural hematoma following neuraxial anesthesia is a rare condition that usually presents with acute and, if any, progressive neurological symptoms including pain, sensory/motor impairment, and bladder/ rectal disturbance. Although possible pathogenesis is mainly considered to be a direct injury of Batson's venous plexus, preoperative coagulation status and anticoagulant therapy also play some role in its development. Therefore, to prevent such a disastrous complication, one must choose an appropriate anesthetic technique and monitor neurological function of the patient at a regular time interval. In addition, it is highly recommended to carefully follow the recently revised regional anesthesia guideline for the patient receiving antithrombotic or thrombolytic therapy, although we still need further understanding and investigation of the complexity around this issue.
    No preview · Article · Nov 2011 · Masui. The Japanese journal of anesthesiology
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    ABSTRACT: Sudden cardiac arrest (CA) is a leading cause of death worldwide. Breathing nitric oxide (NO) reduces ischemia/reperfusion injury in animal models and in patients. The objective of this study was to learn whether inhaled NO improves outcomes after CA and cardiopulmonary resuscitation (CPR). Adult male mice were subjected to potassium-induced CA for 7.5 minutes whereupon CPR was performed with chest compression and mechanical ventilation. One hour after CPR, mice were extubated and breathed air alone or air supplemented with 40 ppm NO for 23 hours. Mice that were subjected to CA/CPR and breathed air exhibited a poor 10-day survival rate (4 of 13), depressed neurological and left ventricular function, and increased caspase-3 activation and inflammatory cytokine induction in the brain. Magnetic resonance imaging revealed brain regions with marked water diffusion abnormality 24 hours after CA/CPR in mice that breathed air. Breathing air supplemented with NO for 23 hours starting 1 hour after CPR attenuated neurological and left ventricular dysfunction 4 days after CA/CPR and markedly improved 10-day survival rate (11 of 13; P=0.003 versus mice breathing air). The protective effects of inhaled NO on the outcome after CA/CPR were associated with reduced water diffusion abnormality, caspase-3 activation, and cytokine induction in the brain and increased serum nitrate/nitrite levels. Deficiency of the α1 subunit of soluble guanylate cyclase, a primary target of NO, abrogated the ability of inhaled NO to improve outcomes after CA/CPR. These results suggest that NO inhalation after CA and successful CPR improves outcome via soluble guanylate cyclase-dependent mechanisms.
    Full-text · Article · Sep 2011 · Circulation
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    ABSTRACT: Assessments of tracheal diameter (TD) are important to select proper endotracheal tubes. Previous studies have used X-ray and physical indices to estimate tracheal diameter but these may not reflect the actual TD. We compared TD measured by X-ray (TD-XP) and by computer tomography (TD-CT) in 200 patients. Also, we analyzed correlation of TD-CT with physical indices such as age, height, weight, and BMI. TD-XP and TD-CT were significantly correlated (male: n = 55, P = .0146; female: n = 91, P = .001). TD-XP was 0.4 mm wider in male and 1.0 mm wider in female than TD-CT. However, correlation coefficients of TD-XP and TD-CT are very weak (male: r = 0.36; female: r = 0.653). TD-CT did not correlate with age, height, weight, or BMI. Our findings suggest that correlations of TD-XP and TD are statistically significant but not clinically significant. Physical indices are not useful to estimate TD.
    Full-text · Article · Aug 2010 · Anesthesiology Research and Practice
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    ABSTRACT: Hepatic cryosurgery is an alternative therapeutic choice for patients who are not eligible for surgical liver resection. As this procedure sometimes causes postoperative bleeding tendency, we investigated indication of intravenous patient-controlled analgesia (IVPCA) after this surgery. We measured pre- and postoperative platelet counts, coagulation profile and postoperative pain with IVPCA in 8 patients. Platelet counts decreased from 9.83 +/- 5.38 (x 10(3) x ml(-1)) to 5.91 +/- 4.56 (x10(3) x ml(-1)) postoperatively (P<0.01) and the maximum relative decrease was 72%. Platelet counts reached the maximum depression from 1 to 3 POD and in two patients it did not recover by 7 POD. Percentage of prothrombin activity decreased from 79.5 +/- 10.4 to 65.9 +/- 13.2 (P<0.01), with the nadir observed from 0 POD to 2 POD. In this study it was difficult to predict the extent of postoperative bleeding tendency beforehand. IVPCA with morphine provided adequate analgesia at rest. Althogh pain on moving seemed rather difficult to treat in two patients, IVPCA also helped patients walk with VAS score less than 55 mm in other patients. Considering the risk of bleeding tendency and epidural hematoma, we recommend IVPCA with opioid for postoperative pain in patients after hepatic cryosurgery instead of epidural analgesia and non-steroidal anti-inflammatory drugs.
    No preview · Article · Jun 2010 · Masui. The Japanese journal of anesthesiology
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    ABSTRACT: The purpose of the present study was to determine the effects of magnesium sulfate (MgSO(4)) on the neuromuscular function and spontaneous breathing of patients under sevoflurane and spinal anesthesia. Twenty-two patients with a history of arrhythmia undergoing elective knee surgery were randomly assigned to two groups: group M (n = 11), administered with MgSO(4) 40, and group S (n = 11), administered with saline. A combination of spinal anesthesia with 2% sevoflurane inhalation was applied to all patients under spontaneous breathing. Tidal volume (VT: ), respiratory rate (RR) and end-tidal carbon dioxide (ET(CO) (2)) were measured before the MgSO(4) or saline injection and measurements were repeated at 5, 15, 30, and 45 min after the injection. Neuromuscular function was continuously monitored with an acceleromyograph to record the acceleration of the adductor pollicis by stimulating the ulnar nerve at a frequency of 0.1 Hz. The VT: , RR, and ET(CO) (2) showed little change in either group, and there was no significant difference between, the groups. The single-twitch response showed significant differences between the two groups (P = 0.0006). The present study indicated that the MgSO(4) had a minimal effect on spontaneous breathing in patients undergoing sevoflurane and spinal anaesthesia, but that it attenuated the safety margin of neuromuscular function.
    No preview · Article · Feb 2007 · Journal of Anesthesia
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    ABSTRACT: Although it has side effects, succinylcholine is still widely used in rapid sequence induction. The aim of the present study is to evaluate the effects of pretreat ment with magnesium and precurarization of vecuroni um on succinylcholine-induced fasciculation and subse quent tracheal intubation-induced hemodynamic changes during rapid sequence induction. Fifty-five patients were allocated to three groups by a blinded randomization: Group M received saline 100 ml with magnesium 40 mg x kg(-1) for 5 min at 6.5 min before induction and sub sequently administered saline 1-2 ml at 1.5 min before induction; Group V received saline 100 ml for 5 min at 6.5 min before induction and subsequently administered vecuronium 0.02 mg x kg(-1) at 1.5 min before induction; Group C received saline 100 ml for 5 min at 6.5 min before induction and then saline 1-2 ml at 1.5 min before induction. Fasciculation scores and mean percent changes of heart rate, systolic blood pressure and rate pressure product between baseline and after induction were significantly lower in group M than those in group C and group V. Pretreatment with magnesium is more effective to limit succinylcholine-induced fasciculation and subsequent tracheal intubation-induced hemody namic changes in rapid sequence induction compared with vecuronium pretreatment, although magnesium does not prevent the elevation of serum potassium con centration after induction.
    No preview · Article · Feb 2006 · Acta anaesthesiologica Belgica

Publication Stats

110 Citations
53.82 Total Impact Points


  • 2015
    • Harvard University
      Cambridge, Massachusetts, United States
  • 2002-2015
    • Keio University
      • Department of Anesthesiology
      Edo, Tokyo, Japan
  • 2011-2012
    • Massachusetts General Hospital
      • Department of Anesthesia, Critical Care and Pain Medicine
      Boston, Massachusetts, United States