• 1

    Beaver PC, Rosen L, 1945. Memorandum on the first report of Angiostrongylus in man by Nomura and Lin. Am J Trop Med Hyg 13 :589–590.

  • 2

    Rosen L, Chappell R, Laqueur GL, 1962. Eosinophilic meningo-encephalitis caused by a metastrongylid lung worm of rats. JAMA 179 :620–624.

    • Search Google Scholar
    • Export Citation
  • 3

    Punyagupta S, Juttijudata P, Bunnag T, 1975. Eosinophilic meningitis in Thailand: clinical studies of 484 typical cases probably caused by Angiostrongylus. Am J Trop Med Hyg 24 :921–931.

    • Search Google Scholar
    • Export Citation
  • 4

    Yii CY, 1976. Clinical observations on eosinophilic meningitis and meningoencephalitis caused by Angiostrongylus cantonensis on Taiwan. Am J Trop Med Hyg 25 :233–249.

    • Search Google Scholar
    • Export Citation
  • 5

    Tsai HC, Liu YC, Kunin CM, Lee SS, Chen YS, Lin HH, Tsai TH, Lin WR, Huang CK, Yen MY, Yen CM, 2001. Eosinophilic-meningitis caused by Angiostrongylus cantonensis: report of 17 cases. Am J Med 111 :109–114.

    • Search Google Scholar
    • Export Citation
  • 6

    Tsai HC, Liu YC, Kunin CM, Lai PH, Lee SS, Chen YS, Wann SR, Lin WR, Huang CK, Ger LP, Lin HH, Yen MY, 2003. Eosinophilic meningitis caused by Angiostrongylus cantonensis associated with eating raw snails: correlation of brain magnetic resonance imaging scans with clinical findings. Am J Trop Med Hyg 68 :281–285.

    • Search Google Scholar
    • Export Citation
  • 7

    Lee JD, Tsai LY, Chen CH, Wang JJ, Hsiao JK, Yen CM, 2006. Blood-brain barrier dysfunction occurring in mice infected with Angiostrongylus cantonensis. Acta Trop 97 :204–211.

    • Search Google Scholar
    • Export Citation
  • 8

    Tsai HC, Liu YC, Susan Lee SJ, Chen ER, Yen CM, 2007. Vascular endothelial growth factor is associated with blood brain barrier dysfunction in eosinophilic meningitis caused by Angiostrongy-lus cantoenesis infection. Am J Trop Med Hyg 76 :592–595.

    • Search Google Scholar
    • Export Citation
  • 9

    Tsai HC, Chung LY, Chen ER, Liu YC, Lee SS, Chen YS, Sy CL, Wann SR, Yen CM, 2008. Association of matrix metalloprotei-nase-9 and tissue inhibitors of metalloproteinase-4 in cerebro-spinal fluid with blood-brain barrier dysfunction in patients with eosinophilic meningitis caused by Angiostrongylus cantonensis. Am J Trop Med Hyg 78 :20–27.

    • Search Google Scholar
    • Export Citation
  • 10

    Morishita R, Aoki M, Hashiya N, Yamasaki K, Kurinami H, Shimizu S, Makino H, Takesya Y, Azuma J, Ogihara T, 2004. Therapeutic angiogenesis using hepatocyte growth factor (HGF). Curr Gene Ther 4 :199–206.

    • Search Google Scholar
    • Export Citation
  • 11

    Gohda E, Tsubouchi H, Nakayama H, Hirono S, Takahashi K, Koura M, Hashimoto S, Daikuhara Y, 1986. Human hepatocyte growth factor in plasma from patients with fulminant hepatic failure. Exp Cell Res 166 :139–150.

    • Search Google Scholar
    • Export Citation
  • 12

    Nakamura T, Nawa K, Ichihara A, Kaise N, Nishino T, 1987. Purification and subunit structure of hepatocyte growth factor from rat platelets. FEBS Lett 224 :311–316.

    • Search Google Scholar
    • Export Citation
  • 13

    Birchmeier C, Gherardi E, 1998. Developmental roles of HGF/SF and its receptor, the c-Met tyrosine kinase. Trends Cell Biol 8 :404–410.

  • 14

    Paumelle R, Tulasne D, Kherrouche Z, Plaza S, Leroy C, Reveneau S, Vandenbunder B, Fafeur V, 2002. Hepatocyte growth factor/ scatter factor activates the ETS1 transcription factor by a RAS-RAF-MEK-ERK signaling pathway. Oncogene 21 :2309–2319.

    • Search Google Scholar
    • Export Citation
  • 15

    Date I, Takagi N, Takagi K, Kago T, Matsumoto K, Nakamura T, 2004. Hepatocyte growth factor attenuates cerebral ischemia-induced learning dysfunction. Biochem Biophys Res Commun 319 :1152–1158.

    • Search Google Scholar
    • Export Citation
  • 16

    Date I, Takagi N, Takagi K, Kago T, Matsumoto K, Nakamura T, Takeo S, 2004. Hepatocyte growth factor improved learning and memory dysfunction of microsphereembolized rats. J Neurosci Res 78 :442–453.

    • Search Google Scholar
    • Export Citation
  • 17

    Isogawa K, Akiyoshi J, Kodama K, Matsushita H, Tsutsumi T, Funakoshi H, Nakamura T, 2005. Anxiolytic effect of hepatocyte growth factor infused into rat brain. Neuropsychobiology 51 :34–38.

    • Search Google Scholar
    • Export Citation
  • 18

    Bhargava M, Joseph A, Knesel J, Halaban R, Li Y, Pang S, Goldberg I, Setter E, Donovan MA, Zarnegar R, Michalopoulos GA, Nakamura T, Faletto D, Rosen EM, 1992. Scatter factor and hepatocyte growthfactor—activities, properties, and mechanism. Cell Growth Differ 3 :11–20.

    • Search Google Scholar
    • Export Citation
  • 19

    Honda S, Kagoshima M, Wanaka A, Tohyama M, Matsumoto K, Nakamura T, 1995. Localization and functional coupling of HGF and c-Met/HGF receptor in rat brain: implication as neurotrophic factor. Brain Res Mol Brain Res 32 :197–210.

    • Search Google Scholar
    • Export Citation
  • 20

    Kern MA, Bamborschke S, Nekic M, Schubert D, Rydin C, Lindholm D, Schirmacher P, 2001. Concentrations of hepatocyte growth factor in cerebrospinal fluid under normal and different pathological conditions. Cytokine 14 :170–176.

    • Search Google Scholar
    • Export Citation
  • 21

    Nayeri F, Nilsson I, Hagberg L, Brudin L, Roberg M, Söderström C, Forsberg P, 2000. Hepatocyte growth factor levels in cerebrospinal fluid: a comparison between acute bacterial and nonbacterial meningitis. J Infect Dis 181 :2092–2094.

    • Search Google Scholar
    • Export Citation
  • 22

    Ozden M, Kalkan A, Demirdag K, Denk A, Kilic SS, 2004. Hepatocyte growth factor (HGF) in patients with hepatitis B and meningitis. J Infect 49 :229–235.

    • Search Google Scholar
    • Export Citation
  • 23

    Tsai HC, Lee SS, Huang CK, Yen CM, Chen ER, Liu YC, 2004. Outbreak of eosinophilic meningitis associated with drinking raw vegetable juice in southern Taiwan. Am J Trop Med Hyg 71 :222–226.

    • Search Google Scholar
    • Export Citation
  • 24

    Chye SM, Chang JH, Yen CM, 2000. Immunodiagnosis of human eosinophilic meningitis using an antigen of Angiostrongylus cantonensis L5 with molecular weight 204KD. Acta Trop 75 :9–17.

    • Search Google Scholar
    • Export Citation
  • 25

    Fenton H, Finch PW, Rubin JS, Rosenberg JM, Taylor WG, Kuo-Leblanc V, Rodriguez-Wolf M, Baird A, Schipper HM, Stopa EG, 1998. Hepatocyte growth factor (HGF/SF) in Alzheimer’s disease. Brain Res 779 :262–270.

    • Search Google Scholar
    • Export Citation
  • 26

    Miyazawa T, Matsumoto K, Ohmichi H, Katoh H, Yamashima T, Nakamura T, 1998. Protection of hippocampal neurons from ischemia-induced delayed neuronal death by hepatocyte growth factor: a novel neurotrophic factor. J Cereb Blood Flow Metab 18 :345–348.

    • Search Google Scholar
    • Export Citation
  • 27

    Dorta-Contreras AJ, Reiber H, 1998. Intrathecal synthesis of immunoglobulins in eosinophilic meningoencephalitis due to Angiostrongylus cantonensis. Clin Diagn Lab Immunol 5 :452–455.

    • Search Google Scholar
    • Export Citation
  • 28

    Chang EE, Yen CM, 2004. Eosinophil chemoattracted by eotaxin from cerebrospinal fluid of mice infected with Angiostrongylus cantonensis assayed in a microchamber. Kaohsiung J Med Sci 20 :209–215.

    • Search Google Scholar
    • Export Citation
  • 29

    Sugaya H, Abe T, Yoshimura K, 2001. Eosinophils in the cerebrospinal fluid of mice infected with Angiostrongylus cantonensis are resistant to apoptosis. Int J Parasitol 31 :1649–1658.

    • Search Google Scholar
    • Export Citation
  • 30

    Sugaya H, Aoki M, Abe T, Ishida K, Yoshimura K, 1997. Cytokine responses in mice infected with Angiostrongylus cantonensis. Parasitol Res 83 :10–15.

    • Search Google Scholar
    • Export Citation

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Dynamic Changes of Hepatocyte Growth Factor in Eosinophilic Meningitis Caused by Angiostrongylus cantonensis Infection

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  • 1 Section of Infectious Diseases, Department of Medicine, Kaohsiung Veterans General Hospital, Kaohsiung City, Taiwan and National Yang-Ming University, Taipei, Taiwan, Republic of China; Department of Parasitology and Graduate Institute of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan, Republic of China; Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohisung, Taiwan, Republic of China

Hepatocyte growth factor (HGF) is a member of the angiogenic growth factor family, which exerts a variety of effects on epithelial, endothelial, and neuronal cells by binding to the c-MET receptor tyrosine kinase. It was reported that HGF attenuates cerebral ischemia-induced increase in permeability of the blood-brain barrier (BBB) and decreases in expression of tight junction proteins in cerebral vessels of rats. Studies on the localization of the c-Met/HGF receptor in the rat brain and the interaction with HGF after brain injuries show that HGF plays an important role as a neurotrophic factor in the brain. To assess the role of HGF in patients with eosinophilic meningitis, a retrospective, cohort study was conducted to measure the dynamic changes of HGF in the cerebrospinal fluid (CSF) and blood of nine patients with eosinophilic meningitis. The mean HGFCSF at presentation, 1 week, 2 weeks, and 3 weeks after admission was 539 pg/mL, 540 pg/mL, 376 pg/mL, and 279 pg/mL, respectively. The mean level of HGFCSF at presentation (539 ± 242 pg/mL) and 1 week after admission (540 ± 213 pg/mL) was significantly higher than in controls (162 ± 207 pg/mL)(P = 0.02 and P = 0.01, respectively). The CSF/blood ratio of HGF at presentation (0.61) was higher when compared with physiologic situations in uninfected individuals (0.51). The levels of HGF in CSF were not correlated with the amount of CSF cells or proteins. All patients recovered without neurologic sequelae. These results indicate that high concentrations of HGF in the CSF occur in eosinophilic meningitis, and may have a role in protecting against endothelial injury and reducing BBB dysfunction.

Angiostrongylus cantonensis is the most common cause of eosinophilic meningitis in the Pacific Islands and Southeast Asia. Human infection occurs after ingestion of the worms in raw snails or fish that serve as intermediate hosts. Rats serve as the definitive host of the nematode. If an infection occurs in non-permissive hosts, including humans and mice, the development of the parasites will terminate at the young-adult worm stage in the brain and cause eosinophilic meningitis or menin-goencephalitis.16 Lee and others7 showed that dysfunction of the blood-brain barrier (BBB) occurred in mice infected with A. cantonensis, evident by the high concentrations of protein and albumin, high leukocyte counts in the cerebrospinal fluid (CSF), a high ratio of CSF/serum protein and albumin, and high permeability of the BBB. Infection in the CSF causes a severe inflammatory reaction, mediated by pathogen products and host cytokines. This inflammatory reaction compromises the function of BBB, resulting in the exudation of plasma proteins and development of vasogenic brain edema, which contributes to cerebral dysfunction and brain damage. 8,9

Hepatocyte growth factor (HGF) is a potent mitogen for hepatocytes and is a member of the angiogenic growth factor family. 10 This secreted protein, originally purified from rat platelets and plasma from a patient with fulminant hepatic failure, 11,12 exerts a variety of effects on many cell types by binding to the c-MET receptor tyrosine kinase. 13,14 It can also improve learning and memory dysfunction 15,16 and exert anxiolytic effects in rats. 17 The HGF not only preserves from neuronal cells after cerebral ischemia induced by middle cerebral artery occlusion 18 or microsphere embolism, 15 but also protects against endothelial injury and reduces BBB disruption in rats. 15 From studies on the localization of the c-Met/HGF receptor in the rat brain and the interaction with HGF after brain injuries, which HGF plays an important role as a neurotrophic factor in the brain. 19 So far, large increases of HGF concentrations in the CSF have only been described in acute bacterial meningitis 20,21 and tuberculous meningitis. 22 We surmise that HGF may act as a neurotrophic factor in eosinophilic meningitis. To research the role of HGF in eosinophilic meningitis, a retrospective cohort study was conducted to measure dynamic changes in HGF levels in the CSF and serum of patients with eosinophilic meningitis.

A case of eosinophilic meningitis was defined as clinical presentation with an acute onset of headache, eosinophilic pleocytosis in the blood/CSF, and accompanied by at least one of the following: fever, ataxia, visual disturbances, photophobia, nuchal rigidity, neck pain, hyperesthesias, or paresthesias.5 Three outbreaks of eosinophilic meningitis, caused by A. cantonensis occurred in Kaohsiung, Taiwan, in 1998, 1999, and 2001. 5,6,23 Most of the patients (77%) were adult, male, Thai laborers who had eaten raw golden apple snails (Ampullarium canaliculatus) within 3 weeks of presentation. Study subjects were derived from the second outbreak in 1999. 5,6 Each patient underwent a physical, neurologic, and ophthalmic examination. Laboratory tests were performed at the time of admission and lumbar spinal taps were performed on all patients. All CSF samples were obtained immediately at admission and before treatment. The CSF analysis included cell count, glucose and protein levels, gram and acid-fast stains, India ink preparation, wet mount preparations for larvae, and measurement of cryptococcal antigen. The patients were observed daily during their hospital course. The CSF and blood were examined weekly until discharge. The common source of the outbreak was raw snails that were eaten as a delicacy, seasoned with lemon juice and red pepper. The mean incubation period was 13 days. Antibodies to A. cantonensis were detected at admission in either the serum (8, 90%) and/or the CSF (3, 33%) of the patients. Details of the clinical manifestations and laboratory findings have been described in detail elsewhere.5 All of the nine Thai laborers received only analgesics and/or glycerol as treatment. No patients died of this infection and neurologic sequelae were not observed after 6 months follow-up. The CSF control group (N = 12) consisted of patients presenting with headache or disturbance of consciousness, who underwent a diagnostic lumbar spinal tap that resulted in normal CSF parameters. All of the CSF/serum samples were centrifuged and the supernatants were frozen at −80°C until assayed. Antibodies to A. cantonensis were detected in serum and CSF by a microenzyme-linked immunosorbent assay (ELISA) using young-adult worm antigen, with a molecular weight 204 kD, and purified by monoclonal antibody. 24 The study protocol was reviewed and approved by the Commission on Medical Ethics of the Kaohsiung Veterans General Hospital (KVGH).

The HGF levels were determined by a commercial kit (Hu HGF ELISA Kit, BioSource Europe S.A, Belgium) using a solid phase sandwich ELISA. The assay was performed following the manufacturer’s instructions. Results in the CSF concentrations of HGF between patient and control group were compared by using the Mann-Whitney U test. Correlations were quantified by using the Pearson correlation test. All results were presented as mean ± SD. A P value of < 0.05 was considered statistically significant.

A total of 23 lumbar spinal taps were performed in these nine patients. The HGFCSF can be detected in all of the patients at presentation. The mean HGFCSF at presentation, 1 week, 2 weeks, and 3 weeks after admission was 539 ± 242 pg/mL (N = 9), 540 ± 213 pg/mL (N = 9), 376 ± 216 pg/mL (N = 3), and 279 ± 137 pg/mL (N = 2), respectively. The HGFserum levels were higher than the HGFCSF in our patients. The mean HGFserum at presentation, 1 week, 2 weeks, and 3 weeks after admission was 883 ± 252 pg/mL, 1311 ± 310 pg/mL, 1426 ± 387 pg/mL, and 1240 ± 502 pg/mL, respectively. The CSF/ blood ratio of HGF at presentation, 1 week, 2 weeks, and 3 weeks after admission was 0.61, 0.41, 0.26, and 0.23, respectively. The CSF/blood ratio of HGF at presentation (0.61) was higher when compared with the physiologic situations in uninfected patients (0.51). 20 The CSF/blood ratio of HGF at the convalescent stage of meningitis was much lower than the normal ratio. The HGFCSF levels at presentation and 1 week after admission were significantly increased when compared with the controls (N = 12, 162 ± 207 pg/mL) (P = 0.02 and P = 0.01, respectively, Mann-Whitney U test). There was no association between HGFCSF, total CSF protein concentrations (P = 0.36), white cell counts (P = 0.56), and eosinophil counts (P = 0.84) at presentation and 1 week after admission (P = 0.80, 0.93, 0.29, respectively).

In this study, we showed that HGFCSF levels were significantly increased in patients with eosinophilic meningitis at presentation and 1 week after admission, when compared with the controls (P = 0.02 and P = 0.01, respectively). The localization and function of HGF in brain diseases have been reported by several authors. Fenton and others 25 have reported a widespread HGF-like immunoreactivity in both the cerebral cortex and the white matter in patients with Alzheimer’s disease. Miyazawa and others 26 showed that HGF successfully prevented the postischemically delayed death of hippocampal neurons in rats. Date and others 15,16 found that HGF can protect against endothelial injury and reduce BBB dysfunction in animals. These results indicated that HGF may act as a neurotrophic factor in eosinophilic meningitis, with possible roles of preventing from endothelial damage and BBB dysfunction.

The time-dependent decrease in the CSF/blood ratio of HGF found in our study that was not correlated with the amount of CSF cells or proteins, suggests that this rapid decline at 1 week after admission may be explained by clinical recovery rather than the merely passive transfer from the serum. This postulation is supported with a study by Dorta-Contreras and others, 27 which showed that during the first 3 days of acute phase of eosinophilic meningoencephalitis, a blood-CSF barrier dysfunction occurred, usually resulting from a reduced CSF flow rate. 27 However, at the time of early clinical recovery the blood-CSF barrier dysfunction was normalized in 75% of the patients. Moreover, Nayeri and others 21 also showed that the HGF levels were very low at 1 week after treatment in patients with bacterial meningitis.

Previous reports showed that HGFCSF was increased significantly in patients with bacterial meningitis and some patients with tuberculous meningitis. 2022 The objective of the present study was to research the serial changes of HGF levels in patients with eosinophilic meningitis. We found that HGFCSF levels were significantly higher in the acute stage of eosinophilic meningitis, compared with the controls. This is the first report of elevated levels of HGF found in CSF of patients with eosinophilic meningitis.

The finding that HGFCSF was not associated with CSF parameters may be explained in several ways. First, locally HGF secretion from the cortex and white matter may not be reflected in the CSF level. Second, the timing of sampling may affect HGFCSF detection, because the in vivo half-life of HGFCSF is unknown. Third, not every patient in our study had CSF abnormalities and our case numbers were small. Finally, BBB disruption during eosinophilic meningitis involves a complex interaction between eosinophils and mediators, such as interleukin-4, interleukin-5, platelet-activating factor, nitric oxide, and matrix metalloproteinases, which might induce BBB permeability, independent of HGF. 9,2830

In conclusion, we found that patients with eosinophilic meningitis had elevated HGF levels in the CSF. The clinical significance needs to be clarified further.

*

Address correspondence to Yao-Shen Chen, Section of Infectious Diseases, Department of Medicine, Kaohsiung Veterans General Hospital, 386, Ta-Chung 1st Road, Kaohsiung City, 813, Taiwan. E-mail: hctsai1011@yahoo.com.tw

Authors’ addresses: Hung-Chin Tsai, Yung-Ching Liu, Shue-Ren Wann, Susan Shin-Jung Lee, Min-Hon Shi, and Yao-Shen Chen, Section of Infectious Diseases, Department of Medicine, Kaohsiung Veterans General Hospital 386, Ta-Chung 1st Road, Kaohsiung City, 813, Taiwan and National Yang-Ming University, Taipei, Taiwan, Republic of China. Yen-Lin Huang and Ming-Hong Tai, Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung 804, Taiwan. Eng-Rin Chen, Chuan-Min Yen, and Min-Hon Shi, Department of Parasitology and Graduate Institute of Medicine, Kaohsiung Medical University, No. 100, Shih-Chuan 1st Road, Kaohsiung 80708, Taiwan.

Financial support: This work is supported by grant VGHKS95-014 and VGHKS97-034 from Kaohsiung Veterans General Hospital and by grant NSC-96-2320-B-075B-002 from the National Science Council, Republic of China.

REFERENCES

  • 1

    Beaver PC, Rosen L, 1945. Memorandum on the first report of Angiostrongylus in man by Nomura and Lin. Am J Trop Med Hyg 13 :589–590.

  • 2

    Rosen L, Chappell R, Laqueur GL, 1962. Eosinophilic meningo-encephalitis caused by a metastrongylid lung worm of rats. JAMA 179 :620–624.

    • Search Google Scholar
    • Export Citation
  • 3

    Punyagupta S, Juttijudata P, Bunnag T, 1975. Eosinophilic meningitis in Thailand: clinical studies of 484 typical cases probably caused by Angiostrongylus. Am J Trop Med Hyg 24 :921–931.

    • Search Google Scholar
    • Export Citation
  • 4

    Yii CY, 1976. Clinical observations on eosinophilic meningitis and meningoencephalitis caused by Angiostrongylus cantonensis on Taiwan. Am J Trop Med Hyg 25 :233–249.

    • Search Google Scholar
    • Export Citation
  • 5

    Tsai HC, Liu YC, Kunin CM, Lee SS, Chen YS, Lin HH, Tsai TH, Lin WR, Huang CK, Yen MY, Yen CM, 2001. Eosinophilic-meningitis caused by Angiostrongylus cantonensis: report of 17 cases. Am J Med 111 :109–114.

    • Search Google Scholar
    • Export Citation
  • 6

    Tsai HC, Liu YC, Kunin CM, Lai PH, Lee SS, Chen YS, Wann SR, Lin WR, Huang CK, Ger LP, Lin HH, Yen MY, 2003. Eosinophilic meningitis caused by Angiostrongylus cantonensis associated with eating raw snails: correlation of brain magnetic resonance imaging scans with clinical findings. Am J Trop Med Hyg 68 :281–285.

    • Search Google Scholar
    • Export Citation
  • 7

    Lee JD, Tsai LY, Chen CH, Wang JJ, Hsiao JK, Yen CM, 2006. Blood-brain barrier dysfunction occurring in mice infected with Angiostrongylus cantonensis. Acta Trop 97 :204–211.

    • Search Google Scholar
    • Export Citation
  • 8

    Tsai HC, Liu YC, Susan Lee SJ, Chen ER, Yen CM, 2007. Vascular endothelial growth factor is associated with blood brain barrier dysfunction in eosinophilic meningitis caused by Angiostrongy-lus cantoenesis infection. Am J Trop Med Hyg 76 :592–595.

    • Search Google Scholar
    • Export Citation
  • 9

    Tsai HC, Chung LY, Chen ER, Liu YC, Lee SS, Chen YS, Sy CL, Wann SR, Yen CM, 2008. Association of matrix metalloprotei-nase-9 and tissue inhibitors of metalloproteinase-4 in cerebro-spinal fluid with blood-brain barrier dysfunction in patients with eosinophilic meningitis caused by Angiostrongylus cantonensis. Am J Trop Med Hyg 78 :20–27.

    • Search Google Scholar
    • Export Citation
  • 10

    Morishita R, Aoki M, Hashiya N, Yamasaki K, Kurinami H, Shimizu S, Makino H, Takesya Y, Azuma J, Ogihara T, 2004. Therapeutic angiogenesis using hepatocyte growth factor (HGF). Curr Gene Ther 4 :199–206.

    • Search Google Scholar
    • Export Citation
  • 11

    Gohda E, Tsubouchi H, Nakayama H, Hirono S, Takahashi K, Koura M, Hashimoto S, Daikuhara Y, 1986. Human hepatocyte growth factor in plasma from patients with fulminant hepatic failure. Exp Cell Res 166 :139–150.

    • Search Google Scholar
    • Export Citation
  • 12

    Nakamura T, Nawa K, Ichihara A, Kaise N, Nishino T, 1987. Purification and subunit structure of hepatocyte growth factor from rat platelets. FEBS Lett 224 :311–316.

    • Search Google Scholar
    • Export Citation
  • 13

    Birchmeier C, Gherardi E, 1998. Developmental roles of HGF/SF and its receptor, the c-Met tyrosine kinase. Trends Cell Biol 8 :404–410.

  • 14

    Paumelle R, Tulasne D, Kherrouche Z, Plaza S, Leroy C, Reveneau S, Vandenbunder B, Fafeur V, 2002. Hepatocyte growth factor/ scatter factor activates the ETS1 transcription factor by a RAS-RAF-MEK-ERK signaling pathway. Oncogene 21 :2309–2319.

    • Search Google Scholar
    • Export Citation
  • 15

    Date I, Takagi N, Takagi K, Kago T, Matsumoto K, Nakamura T, 2004. Hepatocyte growth factor attenuates cerebral ischemia-induced learning dysfunction. Biochem Biophys Res Commun 319 :1152–1158.

    • Search Google Scholar
    • Export Citation
  • 16

    Date I, Takagi N, Takagi K, Kago T, Matsumoto K, Nakamura T, Takeo S, 2004. Hepatocyte growth factor improved learning and memory dysfunction of microsphereembolized rats. J Neurosci Res 78 :442–453.

    • Search Google Scholar
    • Export Citation
  • 17

    Isogawa K, Akiyoshi J, Kodama K, Matsushita H, Tsutsumi T, Funakoshi H, Nakamura T, 2005. Anxiolytic effect of hepatocyte growth factor infused into rat brain. Neuropsychobiology 51 :34–38.

    • Search Google Scholar
    • Export Citation
  • 18

    Bhargava M, Joseph A, Knesel J, Halaban R, Li Y, Pang S, Goldberg I, Setter E, Donovan MA, Zarnegar R, Michalopoulos GA, Nakamura T, Faletto D, Rosen EM, 1992. Scatter factor and hepatocyte growthfactor—activities, properties, and mechanism. Cell Growth Differ 3 :11–20.

    • Search Google Scholar
    • Export Citation
  • 19

    Honda S, Kagoshima M, Wanaka A, Tohyama M, Matsumoto K, Nakamura T, 1995. Localization and functional coupling of HGF and c-Met/HGF receptor in rat brain: implication as neurotrophic factor. Brain Res Mol Brain Res 32 :197–210.

    • Search Google Scholar
    • Export Citation
  • 20

    Kern MA, Bamborschke S, Nekic M, Schubert D, Rydin C, Lindholm D, Schirmacher P, 2001. Concentrations of hepatocyte growth factor in cerebrospinal fluid under normal and different pathological conditions. Cytokine 14 :170–176.

    • Search Google Scholar
    • Export Citation
  • 21

    Nayeri F, Nilsson I, Hagberg L, Brudin L, Roberg M, Söderström C, Forsberg P, 2000. Hepatocyte growth factor levels in cerebrospinal fluid: a comparison between acute bacterial and nonbacterial meningitis. J Infect Dis 181 :2092–2094.

    • Search Google Scholar
    • Export Citation
  • 22

    Ozden M, Kalkan A, Demirdag K, Denk A, Kilic SS, 2004. Hepatocyte growth factor (HGF) in patients with hepatitis B and meningitis. J Infect 49 :229–235.

    • Search Google Scholar
    • Export Citation
  • 23

    Tsai HC, Lee SS, Huang CK, Yen CM, Chen ER, Liu YC, 2004. Outbreak of eosinophilic meningitis associated with drinking raw vegetable juice in southern Taiwan. Am J Trop Med Hyg 71 :222–226.

    • Search Google Scholar
    • Export Citation
  • 24

    Chye SM, Chang JH, Yen CM, 2000. Immunodiagnosis of human eosinophilic meningitis using an antigen of Angiostrongylus cantonensis L5 with molecular weight 204KD. Acta Trop 75 :9–17.

    • Search Google Scholar
    • Export Citation
  • 25

    Fenton H, Finch PW, Rubin JS, Rosenberg JM, Taylor WG, Kuo-Leblanc V, Rodriguez-Wolf M, Baird A, Schipper HM, Stopa EG, 1998. Hepatocyte growth factor (HGF/SF) in Alzheimer’s disease. Brain Res 779 :262–270.

    • Search Google Scholar
    • Export Citation
  • 26

    Miyazawa T, Matsumoto K, Ohmichi H, Katoh H, Yamashima T, Nakamura T, 1998. Protection of hippocampal neurons from ischemia-induced delayed neuronal death by hepatocyte growth factor: a novel neurotrophic factor. J Cereb Blood Flow Metab 18 :345–348.

    • Search Google Scholar
    • Export Citation
  • 27

    Dorta-Contreras AJ, Reiber H, 1998. Intrathecal synthesis of immunoglobulins in eosinophilic meningoencephalitis due to Angiostrongylus cantonensis. Clin Diagn Lab Immunol 5 :452–455.

    • Search Google Scholar
    • Export Citation
  • 28

    Chang EE, Yen CM, 2004. Eosinophil chemoattracted by eotaxin from cerebrospinal fluid of mice infected with Angiostrongylus cantonensis assayed in a microchamber. Kaohsiung J Med Sci 20 :209–215.

    • Search Google Scholar
    • Export Citation
  • 29

    Sugaya H, Abe T, Yoshimura K, 2001. Eosinophils in the cerebrospinal fluid of mice infected with Angiostrongylus cantonensis are resistant to apoptosis. Int J Parasitol 31 :1649–1658.

    • Search Google Scholar
    • Export Citation
  • 30

    Sugaya H, Aoki M, Abe T, Ishida K, Yoshimura K, 1997. Cytokine responses in mice infected with Angiostrongylus cantonensis. Parasitol Res 83 :10–15.

    • Search Google Scholar
    • Export Citation
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