Preoperative elevated eosinophils in peripheral blood for prediction of postoperative recurrence of chronic subdural hematoma.

OBJECTIVE: Chronic subdural hematoma (CSDH) is a common neurological disease with a significant postoperative recurrence rate. There are numerous reported studies of the development of CSDH. In recent years, fibrinolysis, angiogenesis, and inflammation have all been identified as relevant factors in the development of CSDH. While several authors have reported risk factors associated with CSDH recurrence, differential blood count of leukocytes has not yet been discussed. Therefore, in this study the authors aimed to retrospectively investigate the association between differential blood leukocyte count and the rate of CSDH recurrence. METHODS: The authors retrospectively reviewed 476 patients with 529 CSDHs who underwent surgery at a single institution between January 2011 and December 2021. After exclusion of patients who had not undergone a differential blood test of leukocytes preoperatively, CSDHs in 517 cerebral hemispheres of 466 patients were included in the study. Peripheral blood eosinophil counts ≥ 100/µL were considered eosinophil rich. RESULTS: CSDHs in 494 cerebral hemispheres of 445 patients were followed up postoperatively for at least 3 months or until resolution indicated by CSDH disappearance. Postoperative recurrence of CSDH was observed in 46 cerebral hemispheres (9.3%). Among the preoperative differential blood counts of all leukocytes, eosinophils alone were significantly associated with CSDH recurrence (median [IQR] 76/µL [30-155/µL] vs 119/µL [39-217/µL]; p = 0.03). Multivariable regression analysis showed thrombocytopenia (adjusted OR [aOR] 5.23, 95% CI 1.85-14.79; p = 0.002), use of anticoagulant drugs (aOR 2.51, 95% CI 1.17-5.38; p = 0.02), hematoma volume (10 mL per increase) (aOR 1.08, 95% CI 1.00-1.16; p = 0.04), and eosinophil-rich peripheral blood (aOR 2.22, 95% CI 1.17-4.23; p = 0.02) were all independent predictors for CSDH recurrence. CONCLUSIONS: This study showed that preoperative peripheral blood eosinophil count was an independent risk factor for CSDH recurrence. Therefore, patients with CSDH who have elevated eosinophils preoperatively in peripheral blood require careful follow-up.

Effect of decreased platelets on postoperative recurrence of chronic subdural hematoma.

Introduction: Chronic subdural hematoma (CSDH) is commonly treated using simple burr hole surgery. However, postoperative recurrence occurs at a relatively high rate of 10-20%. A decrease in platelet count (PC) may be associated with recurrence via a hemostasis disorder; however, this association has not been well-studied. Therefore, this study aimed to investigate the association between PC and postoperative CSDH recurrence. Methods: We retrospectively reviewed the data for CSDHs in 488 cerebral hemispheres of 431 patients who underwent burr hole surgery at our institution between January 2013 and December 2022. The association between preoperative PC and postoperative CSDH recurrence was investigated. We used the first quartile of PC, PC < 170 × 103/µL to define a threshold for decreased PC. Results: In total, 459 cerebral hemispheres with CSDHs in 405 patients were followed up postoperatively for at least 3 months or until CSDH disappeared. CSDH recurred in 39 (8.5%) cerebral hemispheres. The recurrence rate was gradually increased in parallel with a decreasing PC. Among 109 CSDHs with a decreased PC (<170 × 103/µL), 15 (13.8%) recurred, whereas only 24 (6.9%) of 350 CSDHs without a decreased PC recurred (p = 0.03). In univariable logistic analysis, eosinophil-rich blood (≥100/µL eosinophils in peripheral blood) and a decreased PC were significant risk factors. Multivariable analysis showed that eosinophil-rich blood (adjusted odds ratio, 2.51; 95% confidence interval, 1.26-4.99; p = 0.009) and a decreased PC (adjusted odds ratio, 2.15; 95% confidence interval, 1.07-4.35; p = 0.03) were independent risk factors for recurrence. Conclusion: Our study showed that a decrease in PC was associated with postoperative CSDH recurrence. Patients with CSDH and a decreased PC require careful postoperative follow-up.

Variations and management for patients with craniocervical junction arteriovenous fistulas: Comparison of dural, radicular, and epidural arteriovenous fistulas.

BACKGROUND: Craniocervical junction arteriovenous fistulas (CCJAVFs) are known to be rare, but variations and clinical behaviors remain controversial. METHODS: A total of 11 CCJAVF patients (M: F=9:2, age 54-77 years) were investigated. Based on the radiological and intraoperative findings, they were categorized into three types: dural AVF (DAVF), radicular AVF (RAVF), and epidural AVF (EDAVF). RESULTS: There were four symptomatic patients (subarachnoid hemorrhage in two, myelopathy in one, and tinnitus in one) and seven asymptomatic patients in whom coincidental CCJAVFs were discovered on imaging studies for other vascular diseases (arteriovenous malformation in one, intracranial DAVF in two, ruptured cerebral aneurysm in two, and carotid artery stenosis in two). Of these 11 patients, 2 (18.2%) had multiple CCJAVFs. Of 14 lesions, the diagnoses were DAVF in 5, RAVF in 3, and EDAVF in 6 (C1-C2 level ratio =5:0, 2:1, 3:3). Patients with DAVF/RAVF in four lesions with intradural venous reflux underwent surgery, although an RAVF remained in one lesion after embolization/radiation. Since all six EDAVFs, two DAVFs, and one RAVF had neither feeder aneurysms nor significant symptoms, no treatment was provided; of these nine lesions, one DAVF and one RAVF remained unchanged, whereas six EDAVFs showed spontaneous obliteration within a year. Unfortunately, however, one DAVF bled before elective surgery. CONCLUSION: CCJAVFs have many variations of shunting site, angioarchitecture, and multiplicity, and they were frequently associated with coincidental vascular lesions. For symptomatic DAVF/RAVF lesions with intradural drainage, surgery is preferred, whereas asymptomatic EDAVFs without dangerous drainage may obliterate during their natural course.

Improvement of Hemifacial Spasm after Stent-assisted Coil Embolization for Ipsilateral Vertebral Artery Dissecting Aneurysm.

Microvascular decompression (MVD) is the gold standard in the treatment of hemifacial spasm (HFS), and endovascular surgery has been described as a treatment only for aneurysm-induced HFS in several previous cases. We describe symptomatic HFS caused by a normal vertebral artery (VA) trunk adjacent to the ipsilateral dissecting VA aneurysm completely cured after stent-assisted coil embolization. A 52-year-old man presented with a 2-month history of gradually worsening left HFS. Magnetic resonance imaging (MRI) and cerebral angiography revealed a dissecting VA aneurysm on the left side. Based on the findings from preoperative MRI, not the aneurysmal dome itself, but the VA trunk just distal to the aneurysmal dome was considered likely to be compressing the root exit zone (REZ) of the facial nerve. Stent-assisted coil embolization was conducted for the VA aneurysm, and the stent was deployed to cover the wide neck of the aneurysm and offending zone of the VA trunk simultaneously. HFS started to show improvement just after the procedure and complete disappearance within 1 year. HFS was completely resolved by stenting of the offending artery. Stents may show efficacy for "intra-arterial decompression" by reducing pulsatility against the REZ of the facial nerve due to the thickness and rigidity of the stent metal and delayed endothelialization.

Relationship between gut environment, feces-to-food ratio, and androgen deficiency-induced metabolic disorders.

Androgen action generates sex-related differences that include changes in the gut microbiota composition. Hypoandrogenism and hyperandrogenism in males and females, respectively, are associated with the prevalence of metabolic disorders. Our recent work showed that male androgen receptor knockout (ARKO) mice developed high-fat diet (HFD)-dependent sarcopenic abdominal obesity, hyperglycemia, and hepatic steatosis, leading to early death. The ARKO mice also exhibited alterations in intestinal microbiota but did not experience metabolic abnormalities when administered with antibiotics. Here, we show that time-dependent changes in feed efficiency (ratio of body weight gain to food intake) and weight of dried feces-to-food ratio could be good markers for changes in gut microbiota. Turicibacter spp., Lactobacillus spp., and L. reuteri increased in the gut in both HFD-fed ARKO and castrated mice having metabolic abnormalities. HFD-fed ARKO mice showed increased plasma levels of aspartate, but not alanine, aminotransferase. Changes in the gut microbiome appear to provoke androgen deficiency-induced metabolic diseases, leading to early mortality.

Role of gut microbiota in sex- and diet-dependent metabolic disorders that lead to early mortality of androgen receptor-deficient male mice.

The gut microbiota is involved in metabolic disorders induced by androgen deficiency after sexual maturation in males (late-onset hypogonadism). However, its role in the energy metabolism of congenital androgen deficiency (e.g., androgen-insensitive syndrome) remains elusive. Here, we examined the link between the gut microbiota and metabolic disease symptoms in androgen receptor knockout (ARKO) mouse by administering high-fat diet (HFD) and/or antibiotics. HFD-fed male, but not standard diet-fed male or HFD-fed female, ARKO mice exhibited increased feed efficiency, obesity with increased visceral adipocyte mass and hypertrophy, hepatic steatosis, glucose intolerance, insulin resistance, and loss of thigh muscle. In contrast, subcutaneous fat mass accumulated in ARKO mice irrespective of the diet and sex. Notably, all HFD-dependent metabolic disorders observed in ARKO males were abolished after antibiotics administration. The ratios of fecal weight-to-food weight and cecum weight-to-body weight were specifically reduced by ARKO in HFD-fed males. 16S rRNA sequencing of fecal microbiota from HFD-fed male mice revealed differences in microbiota composition between control and ARKO mice. Several genera or species (e.g., Turicibacter and Lactobacillus reuteri, respectively) were enriched in ARKO mice, and antibiotics treatment spoiled the changes. Furthermore, the life span of HFD-fed ARKO males was shorter than that of control mice, indicating that androgen deficiency causes metabolic dysfunctions leading to early death. These findings also suggest that AR signaling plays a role in the prevention of metabolic dysfunctions, presumably by influencing the gut microbiome, and improve our understanding of health consequences in subjects with hypogonadism and androgen insensitivity.

Peripartum myocardial infarction associated with coronary spasm and acquired protein S deficiency: A case report.

RATIONALE: Coronary angiography (CAG) findings of acute myocardial infarction (AMI) in pregnant women are characterized by a high incidence of normal coronary arteries. This is the first report of AMI with normal coronary arteries during pregnancy, showing coronary spasm and pregnancy-related acquired protein S (PS) deficiency. PATIENT CONCERNS: A 30-year-old Japanese woman was admitted to an emergency department. One hour before admission, she developed sudden onset of precordial discomfort, back pain, and dyspnea. She was a primigravida at 39 weeks' gestation and had no abnormality in the pregnancy thus far. She had no history of heart disease, diabetes, hypertension, dyslipidemia, deep vein thrombosis (DVT), smoking, or oral contraceptive use and no family history of ischemic heart disease, hemostasis disorder, or DVT. She did not take any medication. DIAGNOSIS: Electrocardiography showed ST-segment elevations in leads II, III, aVF, and V2-V6. Heart-type fatty acid-binding protein was positive. Echocardiography showed hypokinesis of the anterior interventricular septum and inferior wall. Continuous intravenous infusion of isosorbide dinitrate was initiated. Coronary computed tomography angiography revealed diffuse narrowing of the apical segment of the left anterior descending coronary artery. Three hours after admission, troponin T became positive, and the following enzymes reached their peak levels: creatine kinase (CK), 1,886 U/L; CK-muscle/brain, 130 U/L. She was diagnosed with transmural AMI due to severe coronary spasm and administered benidipine hydrochloride. Five hours after admission, premature membrane rupture occurred. INTERVENTIONS: Emergency cesarean section was performed. There were no anesthetic or obstetrical complications during the operation. On postpartum day 1, the free PS antigen level was low (29%). On postpartum day 18, she was discharged with no reduction in physical performance. OUTCOMES: Four months after the infarction, CAG showed normal coronary arteries. Acetylcholine provocation test showed diffuse vasospasm in the coronary artery. She was advised that her next pregnancy should be carefully planned. Two years after delivery, free PS antigen level was within normal range, at 86%. She had not experienced recurrence of angina during the 2-year period. Her child was also developing normally. LESSONS: In addition to coronary spasm, pregnancy-related acquired PS deficiency may be involved in AMI etiology.

Desflurane inhalation before ischemia increases ischemia-reperfusion-induced vascular leakage in isolated rabbit lungs.

BACKGROUND: Isoflurane and sevoflurane protect lungs with ischemia-reperfusion (IR) injury. We examined the influence of desflurane on IR lung injury using isolated rabbit lungs perfused with a physiological salt solution. METHODS: The isolated lungs were divided into three groups: IR, desflurane-treated ischemia-reperfusion (DES-IR), and ventilation/perfusion-continued control (Cont) groups (n = 6 per group). In the DES-IR group, inhalation of desflurane at 1 minimum alveolar concentration (MAC) was conducted in a stable 30-min phase. In the IR and DES-IR groups, ventilation/perfusion was stopped for 75 min after the stable phase. Subsequently, they were resumed. Each lung was placed on a balance, and weighed. Weight changes were measured serially throughout this experiment. The coefficient of filtration (Kfc) was determined immediately before ischemia and 60 min after reperfusion. Furthermore, bronchoalveolar lavage fluid (BALF) was collected from the right bronchus at the completion of the experiment. After the completion of the experiment, the left lung was dried, and the lung wet-to-dry weight ratio (W/D) was calculated. RESULTS: The Kfc values at 60 min after perfusion were 0.40 ± 0.13 ml/min/mmHg/100 g in the DES-IR group, 0.26 ± 0.07 ml/min/mmHg/100 g in the IR group, and 0.22 ± 0.08 (mean ± SD) ml/mmHg/100 g in the Cont group. In the DES-IR group, the Kfc at 60 min after the start of reperfusion was significantly higher than in the other groups. In the DES-IR group, W/D was significantly higher than in the Cont group. In the DES-IR group, the BALF concentrations of nitric oxide metabolites were significantly higher than in the other groups. In the DES-IR group, the total amount of vascular endothelial growth factor in BALF was significantly higher than in the Cont group. CONCLUSIONS: The pre-inhalation of desflurane at 1 MAC exacerbates pulmonary IR injury in isolated/perfused rabbit lungs.

Phosphoenolpyruvate administration protects ischemia-reperfusion injury in isolated rabbit lungs.

Phosphoenolpyruvate (PEP) is an intermediate metabolite of the glycolytic pathway and an in vivo high-energy phosphate compound. We have examined the protective effects of PEP on ischemia-reperfusion lung injury in isolated rabbits lungs perfused with a physiological salt solution. The lungs were divided into three treatment groups: (1) ischemia-reperfusion (IR), (2) ischemia-reperfusion with PEP treatment (PEP-IR), in which 1 mM PEP was pre-administered into the perfusate during the stable period, and (3) ventilation-perfusion continued without interruption (Cont). In the IR and PEP-IR groups, ventilation-perfusion was discontinued for about 60 min after a 30-min stable period and then restarted. The capillary filtration coefficients (K fc) and pyruvate concentration in the perfusate were determined immediately before ischemia and 30 and 60 min after reperfusion. The left lungs were dried at the end of the experiment to calculate the tissue wet-to-dry weight ratio (W/D). The K fc values after reperfusion were significantly higher in the IR group than in the other two groups. Pyruvate concentrations were significantly higher at three time-points in the PEP-IR group than in the other two groups. The W/D was significantly higher in the IR group than in the other two groups. Based on these results, we conclude that the administration of PEP prior to lung ischemia alleviates lung ischemia-reperfusion injury.

Clinical outcome in patients with rheumatoid arthritis switched to tocilizumab after etanercept or infliximab failure.

The present study retrospectively assessed the efficacy of tocilizumab in patients with rheumatoid arthritis (RA) who failed to respond to treatment with etanercept or infliximab. A retrospective study of 33 RA patients who did not respond to etanercept or infliximab was conducted. Responses of subjects switching from etanercept to tocilizumab (n = 17) were compared with those switching from infliximab to tocilizumab (n = 16). Treatment with disease-modifying antirheumatic drugs before the switch, especially methotrexate (MTX), was maintained. Disease activity was assessed by the Disease Activity Score 28-C Reactive Protein (DAS28-CRP), the Simplified Disease Activity Index (SDAI), and the Clinical Disease Activity Index (CDAI). Patients who switched from etanercept were significantly less likely to have used MTX and were significantly older than patients who switched from infliximab. In both groups, there was a significant reduction from baseline in DAS28-CRP, SDAI, and CDAI values at 24 weeks with no significant differences between groups. However, at week 52, DAS28-CRP, SDAI, and CDAI values in the group switched from etanercept were significantly worse than those in the group switched from infliximab. All patients switched from infliximab were using MTX. In the evaluation between patients who switched from etanercept monotherapy, etanercept plus MTX, and infliximab plus MTX, a significant improvement from baseline was seen in DAS28-CRP, SDAI, and CDAI for all patients at 24 weeks with no significant differences between groups. Disease activity was maintained at 52 weeks in the group that switched from etanercept plus MTX and infliximab plus MTX. However, the efficacy of tocilizumab was decreased in the group that switched from etanercept monotherapy. Switching from etanercept plus MTX or from infliximab plus MTX to tocilizumab plus MTX improved response to therapy, but switching from etanercept monotherapy to tocilizumab monotherapy did not improve response to therapy.

Repeat etanercept administration restores clinical response of patients with rheumatoid arthritis.

We determined whether repeated treatment with the tumor necrosis factor-α (TNF-α) antagonist etanercept can be effective after an initial clinical response to this drug is lost. We describe three female patients with active, refractory rheumatoid arthritis who were administered with a second course of etanercept after eventually becoming refractory to a first course. Disease activity was high in all three patients before initial etanercept therapy, and each of them had clinically responded by 24 weeks. However, the initial clinical effect was lost between 1.5 and 3.5 years thereafter, and tocilizumab was administered, but the effect was lost again between 3 and 18 months later. Two patients did not respond to subsequent treatment with adalimumab and infliximab. Etanercept administered once again reduced disease activity in all three patients, none of whom developed any acute side effects. Etanercept re-administration significantly improved clinical disease activity and inflammatory parameters in three patients with RA who were refractory to biological anti-TNF agents.

Induction of chlorosis, ROs generation and cell death by a toxin isolated from Pyricularia oryzae.

The ethyl acetate extract of the conidia germination fluid from an Avena isolate (Br58) of Pyricularia oryzae had chlorosis-inducing activity on oat leaf segments. The same activity was also present in the acetone extract of an oatmeal agar culture of Br58. Fungal cultures were used for a large-scale preparation. A series of acetone and ethyl acetate extraction monitored by chromatography was used to isolate an active fraction. The active principle was purified by HPLC. We show by NMR and LC/MS that the toxin was an oxidized C18 unsaturated fatty acid named Mag-toxin. Mag-toxin induced chlorosis on oat leaf segments incubated in the light but not in the dark. Reactive oxygen species (ROS) and cell death were induced by Mag-toxin in oat cells. The sub-cellular localization of ROS generation induced by the toxin treatment was correlated with the location of mitochondria. Interestingly, the induction of ROS generation and cell death by Mag-toxin was light-independent.

Polaprezinc Protects Mice against Endotoxin Shock.

Polaprezinc (PZ), a chelate compound consisting of zinc and l-carnosine (Car), is an anti-ulcer drug developed in Japan. In the present study, we investigated whether PZ suppresses mortality, pulmonary inflammation, and plasma nitric oxide (NO) and tumor necrosis factor (TNF)-alpha levels in endotoxin shock mice after peritoneal injection of lipopolysaccharide (LPS), and how PZ protects against LPS-induced endotoxin shock. PZ pretreatment inhibited the decrease in the survival rate of mice after LPS injection. PZ inhibited the increases in plasma NO as well as TNF-alpha after LPS. Compatibly, PZ suppressed LPS-induced inducible NO synthase mRNA transcription in the mouse lungs. PZ also improved LPS-induced lung injury. However, PZ did not enhance the induction of heat shock protein (HSP) 70 in the mouse lungs after LPS. Pretreatment of RAW264 cells with PZ suppressed the production of NO and TNF-alpha after LPS addition. This inhibition likely resulted from the inhibitory effect of PZ on LPS-mediated nuclear factor-kappaB (NF-kappaB) activation. Zinc sulfate, but not Car, suppressed NO production after LPS. These results indicate that PZ, in particular its zinc subcomponent, inhibits LPS-induced endotoxin shock via the inhibition of NF-kappaB activation and subsequent induction of proinflammatory products such as NO and TNF-alpha, but not HSP induction.

[Multiple cerebral infarction by air embolism associated with remarkable low BIS value during lung segmentectomy with video assisted thoracic surgery (VATS) technique: a case report].

A 64-year-old woman (151 cm, 43 kg) with well controlled hypertension was diagnosed as having right lung cancer at S8 segment. She underwent right S8 segmentectomy by video assisted thoracic surgery (VATS) under general anesthesia combined with epidural anesthesia. Her vital signs were stable and BIS value was around 45 before the surgeon injected the air using a syringe with a 22 G needle to confirm the lesion resected. After the injection of air, her systolic blood pressure rapidly increased from 120 to 170 mmHg and the BIS value suddenly decreased to 5. Blood propofol concentration was reduced from 3 microg x ml(-1) to 2 microg x ml(-1) in the target-controlled infusion technique, and thereby the BIS value increased slowly. She did not wake up nor maintain sufficient spontaneous breathing even 2 hours after the discontinuation of opioids, and was transferred to ICU with tracheal intubation. In ICU, she showed clonic convulsions. Urgent CT and MRI confirmed cerebral air embolism. Her vital signs were too unstable to choose hyperbaric oxygen therapy as her first treatment. Her consciousness was recovered and her trachea was extubated on 11th postoperative day. She was discharged with left hemiparalysis from hospital.

Geranylgeranylacetone ameliorates inflammatory response to lipopolysaccharide (LPS) in murine macrophages: inhibition of LPS binding to the cell surface.

We investigated whether pretreatment with geranylgeranylacetone (GGA), a potent heat shock protein (HSP) inducer, could inhibit proinflammatory cytokine liberation and nitric oxide (NO) production in lipopolysaccharide (LPS)-treated murine macrophages. The levels of NO and tumor necrosis factor-alpha (TNF-alpha) released from murine macrophage RAW 264 cells were increased dose- and time-dependently following treatment with LPS (1 microg/ml). GGA (80 microM) treatment 2 h before LPS addition significantly suppressed TNF-alpha and NO productions at 12 h and 24 h after LPS, respectively, indicating that GGA inhibits activation of macrophages. However, replacement by fresh culture medium before LPS treatment abolished the inhibitory effect of GGA on NO production in LPS-treated cells. Furthermore, GGA inhibited both HSP70 and inducible NO synthase expressions induced by LPS treatment despite an HSP inducer. When it was examined whether GGA interacts with LPS and/or affects expression of Toll-like receptor 4 (TLR4) and CD14 on the cell surface, GGA inhibited the binding of LPS to the cell surface, while GGA did not affect TLR4 and CD14 expressions. These results indicate that GGA suppresses the binding of LPS to the cell surface of macrophages, resulting in inhibiting signal transduction downstream of TLR4.

Geranylgeranylacetone protects against acetaminophen-induced hepatotoxicity by inducing heat shock protein 70.

Geranylgeranylacetone (GGA), an anti-ulcer drug, has been reported to induce heat shock protein (HSP) 70 in several animal organs. The present study was performed to determine whether GGA protects mouse liver against acetaminophen (APAP)-induced injury and whether it has potential as a therapeutic agent for APAP overdose. Hepatic damage was induced by single oral administration of APAP (500 mg/kg). GGA at 400 mg/kg was given orally 4 or 8h before, or 0.5h after APAP administration. Treatment of mice with GGA 4h before or 0.5h after APAP administration suppressed increases in transaminase activities and ammonia content in blood as well as hepatic necrosis. Such GGA treatment significantly increased hepatic HSP70 accumulation after APAP administration. Furthermore, GGA inhibited increases in hepatic lipid peroxide content and hepatic myeloperoxidase activity after APAP administration. In contrast, GGA neither inhibited hepatic cytochrome P450 2E1 activity nor suppressed hepatic glutathione depletion after APAP administration. The protective effect of GGA treatment 4h before APAP on hepatotoxicity induced by APAP was completely inhibited with quercetin, known as an HSP inhibitor. In conclusion, GGA has been identified as a new antidote to APAP injury, acting by induction of HSP70. The potential of GGA as a therapeutic tool is strongly supported by its ability to inhibit hepatic injury even when administered after ingestion of APAP.

Oral administration of geranylgeranylacetone improves survival rate in a rat endotoxin shock model: administration timing and heat shock protein 70 induction.

The present study was performed to determine whether oral pretreatment with geranylgeranylacetone (GGA) inhibits proinflammatory cytokine liberation and nitric oxide (NO) production in lipopolysaccharide (LPS)-treated rats and protects rats against death from LPS-induced endotoxin shock, and whether such protection by GGA is related to heat shock protein (HSP) 70 induction in multiple organs of rats. GGA (200 mg/kg) was given orally to rats. LPS (20 mg/kg) was administered intraperitoneally 4, 8, 16, or 24 h after GGA administration. The survival of rats was monitored over 24 h after LPS administration. GGA treatment at 8 or 16 h before LPS dramatically improved the survival rate of LPS-treated rats. Plasma levels of proinflammatory cytokines (tumor necrosis factor-alpha and interleukin-6) and NO 6 h after LPS administration in these GGA-pretreated rats were less than one-half of those in rats treated with LPS alone. A GGA challenge 8 or 16 h before LPS administration enhanced HSP70 expression in rat organs after LPS. Treatment with GGA 8 h before LPS minimized hepatic and renal damage. Furthermore, the protective effect of GGA on mortality in LPS-treated rats was inhibited with quercetin, known as an HSP70 inhibitor. These results suggest that oral administration of GGA at an optimal time before LPS injection induces and enhances HSP70 expression in several organs, inhibits proinflammatory cytokine and NO production, and prevents organ damage, resulting in an improved survival rate.