Disposition of the Highly Fat Distributed Compound 1-(4-Methoxyphenyl)-4-(2,2,4,6,7-Pentamethyl -2,3-Dihydro-1-Benzofuran-5-yl)Piperazine (TAK-357) in Rats and Dogs.

The non-clinical pharmacokinetics (PK) of TAK-357, a highly lipophilic (clogP>6) potential agent for the amelioration of Alzheimer's disease, was investigated in rats and dogs. A long half-life (t1/2) in plasma was observed in animals and a low total body clearance with high distribution volume was consistent with the long t1/2. The absorption, distribution, metabolism and excretion (ADME) studies using radiolabeled TAK-357 revealed that the total radioactivity was highly distributed to the adipose tissues and sustained with high concentration for over 4 weeks after oral administration. The metabolite analysis also revealed that the main component in the plasma and adipose tissues was unchanged TAK-357. The major elimination route of absorbed TAK-357 was suggested to be by metabolism. An ADME study indicated that the adipose tissue is the main depot of remaining TAK-357 in the body and slow release from the adipose tissues contributes to the long t1/2. The PK of highly lipophilic compounds have a tendency to be affected by body weight changes especially changes in the adipose tissues. Therefore, it is considered that the relationship between the plasma levels of TAK-357 and the body weight should be evaluated carefully during the clinical trials.

Risk assessment of recent Egyptian H5N1 influenza viruses.

Highly pathogenic avian influenza (HPAI) viruses of the H5N1 subtype are enzootic in poultry populations in different parts of the world, and have caused numerous human infections in recent years, particularly in Egypt. However, no sustained human-to-human transmission of these viruses has yet been reported. We tested nine naturally occurring Egyptian H5N1 viruses (isolated in 2014-2015) in ferrets and found that three of them transmitted via respiratory droplets, causing a fatal infection in one of the exposed animals. All isolates were sensitive to neuraminidase inhibitors. However, these viruses were not transmitted via respiratory droplets in three additional transmission experiments in ferrets. Currently, we do not know if the efficiency of transmission is very low or if subtle differences in experimental parameters contributed to these inconsistent results. Nonetheless, our findings heighten concern regarding the pandemic potential of recent Egyptian H5N1 influenza viruses.

Characterization of Transporters in the Hepatic Uptake of TAK-475 M-I, a Squalene Synthase Inhibitor, in Rats and Humans.

TAK-475 (lapaquistat acetate) is a squalene synthase inhibitor and M-I is a pharmacologically active metabolite of TAK-475. Preclinical pharmacokinetic studies have demonstrated that most of the dosed TAK-475 was hydrolyzed to M-I during the absorption process and the concentrations of M-I in the liver, the main organ of cholesterol biosynthesis, were much higher than those in the plasma after oral administration to rats. In the present study, the mechanism of the hepatic uptake of M-I was investigated.The uptake studies of (14)C-labeled M-I into rat and human hepatocytes indicated that the uptakes of M-I were concentrative, temperature-dependent and saturable in both species with Km values of 4.7 and 2.8 µmol/L, respectively. M-I uptake was also inhibited by cyclosporin A, an inhibitor for hepatic uptake transporters including organic anion transporting polypeptide (OATP). In the human hepatocytes, M-I uptake was hardly inhibited by estrone 3-sulfate as an inhibitor for OATP1B1, and most of the M-I uptake was Na(+)-independent. Uptake studies using human transporter-expressing cells revealed the saturable uptake of M-I for OATP1B3 with a Km of 2.13 µmol/L. No obvious uptake of M-I was observed in the OATP1B1-expressing cells.These results indicated that M-I was taken up into hepatocytes via transporters in both rats and humans. OATP1B3 would be mainly involved in the hepatic uptake of M-I in humans. These findings suggested that hepatic uptake transporters might contribute to the liver-selective inhibition of cholesterol synthesis by TAK-475. This is the first to clarify a carrier-mediated hepatic uptake mechanism for squalene synthase inhibitors.

Pharmacokinetics of TAK-475, a Squalene Synthase Inhibitor, in Rats and Dogs.

The pharmacokinetics of TAK-475 (lapaquistat acetate), a squalene synthase inhibitor, was investigated in rats and dogs. After oral administration of (14)C-labeled TAK-475 ([(14)C]TAK-475) to rats and dogs at a dose of 10 mg/kg, the bioavailability (BA) was relatively low at 3.5 and 8.2%, respectively. The main component of the radioactivity in the plasma was M-I, which has a comparable pharmacological activity to TAK-475 in vitro. The radioactivity in the portal plasma after intraduodenal administration of [(14)C]TAK-475 to portal vein-cannulated rat was also mainly M-I, suggesting that most of the TAK-475 was hydrolyzed to M-I during the permeable process in the intestine. The concentrations of M-I in the liver, the main organ of cholesterol biosynthesis, were much higher than those in the plasma after oral administration of [(14)C]TAK-475 to rats. The main elimination route of the radioactivity was fecal excretion after oral administration of [(14)C]TAK-475 to rats and dogs, and the absorbed radioactivity was mainly excreted via the bile as M-I in rats. M-I excreted into the bile was partially subjected to enterohepatic circulation. These results suggest that although the BA values of TAK-475 are low, M-I can exert compensatory pharmacological effects in the animals. These pharmacokinetic characteristics in animals were also confirmed in the clinical studies. The evaluation of M-I disposition is important for the pharmacokinetics, pharmacodynamics and toxicity of TAK-475 in animals and humans.

Histophilus somni Stimulates Expression of Antiviral Proteins and Inhibits BRSV Replication in Bovine Respiratory Epithelial Cells.

Our previous studies showed that bovine respiratory syncytial virus (BRSV) followed by Histophilus somni causes more severe bovine respiratory disease and a more permeable alveolar barrier in vitro than either agent alone. However, microarray analysis revealed the treatment of bovine alveolar type 2 (BAT2) epithelial cells with H. somni concentrated culture supernatant (CCS) stimulated up-regulation of four antiviral protein genes as compared with BRSV infection or dual treatment. This suggested that inhibition of viral infection, rather than synergy, may occur if the bacterial infection occurred before the viral infection. Viperin (or radical S-adenosyl methionine domain containing 2--RSAD2) and ISG15 (IFN-stimulated gene 15--ubiquitin-like modifier) were most up-regulated. CCS dose and time course for up-regulation of viperin protein levels were determined in treated bovine turbinate (BT) upper respiratory cells and BAT2 lower respiratory cells by Western blotting. Treatment of BAT2 cells with H. somni culture supernatant before BRSV infection dramatically reduced viral replication as determined by qRT PCR, supporting the hypothesis that the bacterial infection may inhibit viral infection. Studies of the role of the two known H. somni cytotoxins showed that viperin protein expression was induced by endotoxin (lipooligosaccharide) but not by IbpA, which mediates alveolar permeability and H. somni invasion. A naturally occurring IbpA negative asymptomatic carrier strain of H. somni (129Pt) does not cause BAT2 cell retraction or permeability of alveolar cell monolayers, so lacks virulence in vitro. To investigate initial steps of pathogenesis, we showed that strain 129Pt attached to BT cells and induced a strong viperin response in vitro. Thus colonization of the bovine upper respiratory tract with an asymptomatic carrier strain lacking virulence may decrease viral infection and the subsequent enhancement of bacterial respiratory infection in vivo.

Successful treatment of severe refractory lupus hepatitis with mycophenolate mofetil.

Systemic lupus erythematosus-related hepatitis, known as lupus hepatitis, is a rare manifestation of systemic lupus erythematosus, and is usually subclinical with mild abnormalities of serum liver enzymes. While cases with clinically significant and refractory lupus hepatitis are uncommon, treatment options for lupus hepatitis are to be established. Here, we report the case of a 45-year-old man with progressive lupus hepatitis accompanied by autoimmune haemolytic anaemia. Lupus hepatitis of this patient was refractory to tacrolimus, azathioprine and cyclophosphamide, but was successfully treated by mycophenolate mofetil. Mycophenolate mofetil might be an effective therapeutic option for refractory lupus hepatitis.

Pharmacokinetics and Urinary Excretion Mechanism of Orteronel (TAK-700), A Novel 17,20-Lyase Inhibitor, in Animals.

Orteronel is newly identified as a selective 17,20-lyase inhibitor for an agent for castration resistant prostate cancer. The absorption and disposition of [(14)C]orteronel were investigated in rats and monkeys. Orteronel was extensively excreted into rat and monkey urine in an unchanged form after oral administration. The unbound based renal clearances in rats and monkeys were greater than the respective glomerular filtration rates (GFR), suggesting that urinary tubular secretion plays an important role in the renal excretion of orteronel. Therefore, the uptake of [(14)C]orteronel was investigated using rat kidney slices to estimate the contribution of carrier-mediated transport on the urinary tubular secretion. The uptake study using rat kidney slices suggested that the transport of orteronel from the blood circulation to the kidney was mediated by a digoxin sensitive transport system represented by Oatp4c1 and non-saturable components. Furthermore, the saturable component accounted for a limited fraction of the total renal uptake by rat kidney slices. These results suggested that non-saturable uptake mainly contributed to the renal excretion of orteronel in rats.

Miniature quartz crystal-resonator-based thermogravimetric detector.

In this work, a new design for a microheater combined with a quartz crystal microbalance (QCM) array for thermogravimetric analysis is presented. Each QCM consists of two electrodes to excite thickness-shear-mode vibrations and one microheater to increase the temperature on the crystal backside. In addition, all the electrode pads are patterned on the crystal backside, making the design of the QCM compact and user-friendly. Finally, the proposed QCM array was employed to separate ethanol from methanol. This was successfully achieved via thermal desorption spectra calculated by differentiating the frequency changes.

Disposition of the new potent acetylcholinesterase inhibitor 8-[3-[1-[(3-fluorophenyl)methyl]-4-piperidiny]-1-oxopropyl]-1, 2, 5, 6-tetrahydro-4H-pyrrolo [3, 2, 1-ij] quinolin-4-one (TAK-802) in rats, dogs and monkeys.

The pharmacokinetics of TAK-802, a potential agent of amelioration for voiding dysfunction, were investigated in rats, dogs and monkeys after a single oral administration of 14C-labeled TAK-802. The values of the bioavailability for the compound ranged from 10.2 to 19.9% and the extent of absorption of 14C were higher than the values for the bioavailability in the tested animals. TAK-802 and its related compounds distributed widely in the tissues including the target organ, the urinary bladder, in rats. TAK-802 was highly bound to the plasma proteins and the protein-binding % was independent of the spiked concentrations in all the species tested. Meanwhile, the erythrocyte distribution decreased significantly with the increase in the TAK-802 concentrations. After oral dosing, the dosed 14C was predominantly excreted into the feces of the test animals and the hepato-biliary route mainly contributed to the excretion of 14C in rats. The major components of 14C in the plasma and excreta were unidentified polar metabolites in the test animals. These results indicated that TAK-802 was extensively metabolized by first-pass metabolism during the absorption process and its related metabolites were excreted predominantly into the feces via the bile in the test animals. The concentration-dependent erythrocyte distribution was characterized as the most influential property on the pharmacokinetics of TAK-802. For the clinical safety in the development of TAK-802, the effect of the concentration-dependent erythrocyte distribution on the pharmacokinetics of TAK-802 in animals and humans should be addressed.

Characteristic activities of lower limbs with body weight support ratio.

In this study, we investigated a lower limbs muscle activity during body weight support treadmill training (BWSTT). Informed consent was obtained from 16 healthy men. Experimental system consists of force plate, treadmill, three-dimensional motion analysis system, electromyograph, and body weight support device. Body weight support (BWS) was set every 15% increase from 0% to 45%. Walking speed was 4.17 km/h. The measurement data were reaction forces, joint angles, joint moments and lower limbs muscle activities. The vertical reaction force shows two peaks. Two peaks decreased with increase of BWS together. Joint angles did not show significant changes with BWS. However, only the extension of hip angle was decreased with BWS. The peaks of joint moment were decreased. Decrease of ankle joint moment was greatest compared with other moment. Decrease of peaks of muscle activity by BWS was observed during stance phase, and did not almost change during swing phase.

p27 deregulation by Skp2 overexpression induced by the JAK2V617 mutation.

Janus kinase 2 (JAK2) V617F mutation has been regarded as the major cause of myeloproliferative disorders (MPD). However, the mechanisms of abnormal cell growth by JAK2V617F have not been elucidated. In this study, cell cycle regulatory protein expression was analyzed using JAK2V617F-Ba/F3 and mock-Ba/F3. JAK2V617F-Ba/F3, but not mock-Ba/F3, showed IL-3 independent cell growth and constitutive STATs activation. Deregulation of p27(Kip1), the cell cycle regulator at the G1 to S transition, was observed in JAK2V617F-Ba/F3 but not in mock-control. p27(Kip1) deregulation was not due to p27(Kip1) mRNA level but due to high Skp2 expression, a subunit of ubiquitin E3 ligase, through the STAT binding in the Skp2 promoter. Like JAK2V617F overexpression, constitutively active STAT5 or STAT3 induced aberrant p27(Kip1) expression of Ba/F3 cells. Similar findings were observed in BCR/ABL-transfected Ba/F3. Our results elucidate the regulatory mechanism by which JAK2V617F modulates Skp2 gene expression through the STAT transcription factors.

Species-specificity of a panel of prion protein antibodies for the immunohistochemical study of animal and human prion diseases.

Monoclonal antibodies to the prion protein (PrP) have been of critical importance in the neuropathological characterization of PrP-related disease in men and animals. To determine the influence of species-specific amino-acid substitutions recognized by monoclonal antibodies, and to investigate the immunohistochemical reactivity of the latter, analyses were carried out on brain sections of cattle with bovine spongiform encephalopathy, sheep with scrapie, mice infected with scrapie, and human beings with Creutzfeldt-Jakob disease (CJD) or Gerstmann-Sträussler-Sheinker disease (GSS). Immunoreactivity varied between the antibodies, probably as the result of differences in the amino-acid sequence of the prion protein in the various species. Some monoclonal antibodies against mouse recombinant PrP gave strong signals with bovine, ovine and human PrP(Sc), in addition to murine PrP(Sc), even though the amino-acid sequences determined by the antibody epitope are not fully identical with the amino-acid sequences proper to the species. On the other hand, in certain regions of the PrP sequence, when the species-specificity of the antibodies is defined by one amino-acid substitution, the antibodies revealed no reactivity with other animal species. In the region corresponding to positions 134-159 of murine PrP, immunohistochemical reactivity or species-specificity recognized by the antibodies may be determined by one amino acid corresponding to position 144 of murine PrP. Not all epitopes recognized by a monoclonal antibody play an important role in antigen-antibody reactions in immunohistochemistry. The presence of the core epitope is therefore vital in understanding antibody binding ability.

Comparative study on adhesive performance of functional monomers.

Mild self-etch adhesives demineralize dentin only partially, leaving hydroxyapatite around collagen within a submicron hybrid layer. We hypothesized that this residual hydroxyapatite may serve as a receptor for chemical interaction with the functional monomer and, subsequently, contribute to adhesive performance in addition to micro-mechanical hybridization. We therefore chemically characterized the adhesive interaction of 3 functional monomers with synthetic hydroxyapatite, using x-ray photoelectron spectroscopy and atomic absorption spectrophotometry. We further characterized their interaction with dentin ultra-morphologically, using transmission electron microscopy. The monomer 10-methacryloxydecyl dihydrogen phosphate (10-MDP) readily adhered to hydroxyapatite. This bond appeared very stable, as confirmed by the low dissolution rate of its calcium salt in water. The bonding potential of 4-methacryloxyethyl trimellitic acid (4-MET) was substantially lower. The monomer 2-methacryloxyethyl phenyl hydrogen phosphate (phenyl-P) and its bond to hydroxyapatite did not appear to be hydrolytically stable. Besides self-etching dentin, specific functional monomers have additional chemical bonding efficacy that is expected to contribute to their adhesive potential to tooth tissue.

Platelet-derived endothelial cell growth factor expression is an independent prognostic factor in colorectal cancer patients after curative surgery.

AIMS: Platelet-derived endothelial cell growth factor (PD-ECGF) is an angiogenic factor that undergoes increased expression in colorectal carcinomas, but its prognostic value is a topic of debate. The aim of this study is to clarify the prognostic value of PD-ECGF expression in colorectal carcinomas. METHODS: PD-ECGF expression was measured by enzyme-linked immunosorbent assay in frozen materials from 134 colorectal cancer patients who had received curative resections. Patients were divided into high expression and low expression groups based upon selected cut-off value. Correlations among PD-ECGF expression, clinicopathologic features, and disease-free interval were studied by univariate and multivariate analysis. To evaluate the origin of PD-ECGF, serial sections of the 134 tumours were stained for PD-ECGF and CD68. RESULTS: PD-ECGF expression in the normal mucosa was 34.4+/-15.5 (Units/mg protein) and the cut-off value was 65.4 (mean+2SD). There were no significant correlations between clinicopathological features and PD-ECGF expression. The disease-free interval for the high PD-ECGF expression group was significantly longer than that of the low expression group (P=0.05). A multivariate Cox's regression analysis revealed that high PD-ECGF expression is an independent factor for better outcome. In immunohistochemical study, almost all tumour cells were negative for PD-ECGF, but stromal macrophages were predominantly positive for PD-ECGF. CONCLUSIONS: The PD-ECGF expression originated from stromal macrophages was a predictor for favorable outcome after curative resections for colorectal cancer.

Chromosomal imbalances associated with acquired resistance to fluoropyrimidines in human colorectal cancer cells.

The chromosomal aberrations underlying the development of resistance to fluoropyrimidines have not yet been identified. To characterise the genomic changes that induce the development of resistance to fluoropyrimidines, we used comparative genomic hybridisation (CGH) to analyse and compare the parent DLD-1 human colorectal cancer cell line and two cell lines, DLD-1/5-FU and DLD-1/FdUrd, which were resistant to 5-fluorouracil (5-FU) and 5-fluoro-2'-deoxyuridine (FdUrd), respectively. Both resistant cell lines showed a genetic aberration derived from the parental cell line DLD-1. Losses of 3p and 3q were also detected as additional genetic changes in the two resistant cell lines. Both resistant cell lines showed decreased orotate phosphoribosyltransferase (OPRT) activity, which is associated with the activity of the uridine monophosphate (UMP) synthase gene (3q13). These results suggested that the loss of 3q might be a genetic change responsible for the decreased OPRT activity and fluoropyrimidine cytotoxic response in cancer cells. Amplification of 18p11.2-p11.3 containing the thymidine synthase (TS) gene (18p11.32) was observed only in the DLD-1/FdUrd-resistant cell line, which overexpresses TS. These findings suggested that 18p amplification represents a genetic change associated with the overexpression of the TS protein. Our results indicate that chromosomal aberrations identified by CGH could explain, at least in part, acquired fluoropyrimidine resistance.

Localization of major gangliosides in the PNS: implications for immune neuropathies.

Antibodies targeting major gangliosides that are broadly distributed in the nervous system are sometimes associated with clinical symptoms that imply selective nerve damage. For example, anti-GD1a antibodies are associated with acute motor axonal neuropathy (AMAN), a form of Guillain-Barré syndrome that selectively affects motor nerves, despite reports that GD1a is present in human axons and myelin and is not expressed differentially in motor versus sensory roots. We used a series of high-affinity monoclonal antibodies (mAbs) against the major nervous system gangliosides GM1, GD1a, GD1b and GT1b to test whether any of them bind motor or sensory fibres differentially in rodent and human peripheral nerves. The following observations were made. (i) Some of the anti-GD1a antibodies preferentially stained motor fibres, supporting the association of human anti-GD1a antibodies with predominant motor neuropathies such as AMAN. (ii) A GD1b antibody preferentially stained the large dorsal root ganglion (DRG) neurones, in keeping with the proposed role of human anti-GD1b antibodies in sensory ataxic neuropathies. (iii) Two mAbs with broad structural cross-reactivity bound to both gangliosides and peripheral nerve proteins. (iv) Myelin was poorly stained; all clones stained axons nearly exclusively. Our findings suggest that anti-ganglioside antibody fine specificity as well as differences in ganglioside accessibility in axons and myelin influence the selectivity of injury to different fibre systems and cell types in human autoimmune neuropathies.

Prognostic significance of the null genotype of glutathione S-transferase-T1 in patients with acute myeloid leukemia: increased early death after chemotherapy.

We investigated the prognostic significance of genetic polymorphism in glutathione-S transferase mu 1 (GSTM1), glutathione-S transferase theta 1 (GSTT1), NAD(P)H:quinone oxidoreductase (NQO1) and myeloperoxidase (MPO), the products of which are associated with drug metabolism as well as with detoxication, in 193 patients with de novo acute myeloid leukemia (AML) other than M3. Of the patients, 64.2% were either homozygous or heterozygous for GSTT1 (GSTT1(+)), while 35.8% showed homozygous deletions of GSTT1 (GSTT1(-)). The GSTT1(-) group had a worse prognosis than the GSTT1(+) group (P = 0.04), whereas other genotypes did not affect the outcome. Multivariate analysis revealed that GSTT1(-) was an independent prognostic factor for overall survival (relative risk: 1.53; P = 0.026) but not for disease-free survival of 140 patients who achieved complete remission (CR). The rate of early death after the initiation of chemotherapy was higher in the GSTT1(-) group than the GSTT1(+) group (within 45 days after initial chemotherapy, P = 0.073; within 120 days, P = 0.028), whereas CR rates and relapse frequencies were similar. The null genotype of GSTT1 might be associated with increased toxicity after chemotherapy.

Nonlinear pharmacokinetics of TAK-044, a new endothelin antagonist, in rats.

The mechanism of the nonlinear pharmacokinetics of TAK-044 in rats was shown from in vivo and in vitro studies to be due to capacity-limited hepatic uptake. In the rats, which were given intravenous injections of (14)C-labeled TAK-044 ([(14)C]TAK-044) (1, 3, 10, 30 and 100 mg/kg), the AUC(inf) per unit dose of unchanged compound increased remarkably. An analysis model indicated that the CL(tot), V(1) and k(12) values of TAK-044 decreased significantly with increasing dose, whereas the k(el) values remained constant over the doses examined. The uptake clearance of [(14)C]TAK-044 by several tissues was investigated by an integration plot at doses from 0.3 to 60 mg/kg. This study showed that the liver played the principal role in the removal of TAK-044 from the plasma, while hepatic uptake was capacity-limited at doses greater than 30 mg/kg. The hepatic uptake study using rat hepatocytes indicated that a carrier-mediated transport system contributed to the hepatic uptake of TAK-044, and this system had high affinity (K(m,in vitro); 8.4 micromol/L) with low capacity (V(max,in vitro); 86.3 pmol/mg protein/min). These results show that the saturation of hepatic uptake by the carrier-mediated transport system could explain the nonlinear pharmacokinetics of TAK-044 in rats.

Monocyte chemotactic protein-1 in the vitreous of patients with proliferative diabetic retinopathy.

PURPOSE: To investigate the correlation between monocyte chemotactic protein-1 (MCP-1) levels in the vitreous and clinical findings in eyes with proliferative diabetic retinopathy (PDR). METHODS: We assayed MCP-1 levels by ELISA in vitreous samples of 88 consecutive patients with PDR (52 eyes) and macular holes or idiopathic epimacular membrane (controls, 36 eyes). RESULTS: The level of MCP-1 in the vitreous was 2,097.5 +/- 1,099.4 pg/ml (mean +/- SD) in PDR, and 504.3 +/- 405.6 pg/ml in the controls. In PDR eyes, multivariate regression analysis revealed a significant association between MCP-1 levels in the vitreous and the degree of proliferative membrane, and a significant negative association between MCP-1 levels and the extent of preoperative retinal photocoagulation. CONCLUSION: The results suggest that MCP-1 may play a role in the development of the proliferative phase of PDR.

Effect of 6-hydroxydopamine on host resistance against Listeria monocytogenes infection.

Recent studies have shown that immunocompetent cells bear receptors of neuropeptides and neurotransmitters and that these ligands play roles in the immune response. In this study, the role of the sympathetic nervous system in host resistance against Listeria monocytogenes infection was investigated in mice pretreated with 6-hydroxydopamine (6-OHDA), which destroys sympathetic nerve termini. The norepinephrine contents of the plasma and spleens were significantly lower in 6-OHDA-treated mice than in vehicle-treated mice. The 50% lethal dose of L. monocytogenes was about 20 times higher for 6-OHDA-treated mice than for vehicle-treated mice. Chemical sympathectomy by 6-OHDA upregulated interleukin-12 (IL-12) and tumor necrosis factor-alpha (TNF-alpha) production in enriched dendritic cell cultures and gamma interferon (IFN-gamma) and TNF-alpha production in spleen cell cultures, whereas chemical sympathectomy had no apparent effect on phagocytic activities, listericidal activities, and nitric oxide production in peritoneal exudate cells and splenic macrophages. Augmentation of host resistance against L. monocytogenes infection by 6-OHDA was abrogated in IFN-gamma(-/-) or TNF-alpha(-/-) mice, suggesting that upregulation of IFN-gamma, IL-12, and TNF-alpha production may be involved in 6-OHDA-mediated augmentation of antilisterial resistance. Furthermore, adoptive transfer of spleen cells immune to L. monocytogenes from 6-OHDA-treated mice resulted in untreated naive recipients that had a high level of resistance against L. monocytogenes infection. These results suggest that the sympathetic nervous system may modulate host resistance against L. monocytogenes infection through regulation of production of IFN-gamma, IL-12, and TNF-alpha, which are critical in antilisterial resistance.