Decisive gene strategy on osteoarthritis: a comprehensive whole-literature based approach for conclusive gene targets.

BACKGROUND: Previous meta-analyses only examined the association between single or several gene polymorphisms and osteoarthritis (OA), whereas no studies have concluded that there are existing all gene loci that associate with OA. OBJECTIVE: To assess whether a definite conclusion of the association between the gene loci and OA can be drawn. METHODS: Decisive gene strategy (DGS), a literature-based approach, was used to search PubMed, Embase, and Cochrane databases for all meta-analyses that associated gene polymorphisms and OA. Trial Sequential Analysis (TSA) examined the sufficiency of the cumulative sample size. Finally, we assessed the importance of gene loci in OA based on whether there were enough sample sizes and the heterogeneity of the literatures with I2 value. RESULTS: After excluding 179 irrelevant publications, 80 meta-analysis papers were recruited. Among Caucasians, SMAD3 rs12901499 (OR = 1.20, 95% CI: 1.12-1.29) was a risk factor with validation of sufficient sample sizes through TSA model. Among Asians, there were 3 gene loci risk factors with validation of sufficient sample sizes through TSA model: ESR1 rs2228480, SMAD3 rs12901499, and MMP-1 rs1799750 (OR = 1.35, 95% CI: 1.08-1.69; OR = 1.34, 95% CI: 1.07-1.69; OR = 1.43, 95% CI: 1.18-1.74, respectively). Besides, 3 gene loci, DVWA rs7639618, GDF5 rs143383, and VDR rs7975232 (OR = 0.78, 95% CI: 0.67-0.90; OR = 0.74, 95% CI: 0.67-0.81; OR = 0.56, 95% CI: 0.35-0.90, respectively) were identified as protective factors through TSA model. CONCLUSIONS: We used DGS to identify conclusive gene loci associated with OA. These findings provide implications of precision medicine in OA and may potentially advance genetic therapy.

Perioperative complications of using freezing nitrogen ethanol composite to treat bone tumors: Clinical experience from a single center.

BACKGROUND: The cryoablation efficacy of semisolid freezing nitrogen ethanol composite (FNEC) has been demonstrated. We aimed to investigate the feasibility of adjuvant FNEC-assisted cryoablation in different bone cavity types by assessing the perioperative complication rates. METHODS: The medical charts of patients who received intraoperative adjuvant cryoablation using semisolid FNEC for bone tumors from December 2013 to January 2018 were reviewed. The bone cavities were categorized into three types according to liquid spill potential (type 1, able to hold liquid without limb manipulation; type 2, required extensive limb manipulation to retain liquid; type 3, unable to retain liquid). The overall complication rate and the complication rates stratified by bone cavity type were determined. RESULTS: Among the 76 patients, 30.3%, 57.9%, and 11.8% had type 1, 2, and 3 bone cavities, respectively. The mean follow-up time for perioperative complications was 43.5 ± 24.1 days. Five patients experienced complications, including two cases of skin damage, two cases of skin infection, and one case of fracture, yielding an overall perioperative complication rate of 6.4%. All cases of skin damage and skin infection were superficial and manageable by oral antibiotics. The patient with a pathologic fracture recovered well after being treated with open reduction and plate fixation. No neuropraxia was noted within the first few days postsurgery in any patient. The complication rates in type 1, 2, and 3 bone cavities were 13%, 4.6%, and 0%, respectively. CONCLUSION: All bone cavity types had a low incidence of perioperative complications after treatment with adjuvant FNEC-assisted cryoablation. Semisolid FNEC-assisted cryoablation is a feasible alternative to overcome the liquid spill potential in bone cavities resulting from tumor resection and intralesional curettage.

A functional chicken-liver hydrolysate-based supplement ameliorates alcohol liver disease via regulation of antioxidation, anti-inflammation, and antiapoptosis.

Tons of broiler livers are produced yearly in Taiwan but always considered waste. Our team has successfully patented and characterized a chicken-liver hydrolysate (CLH) with several biofunctions. Chronic alcohol consumption causes hepatosteatosis or even hepatitis, cirrhosis, and cancers. This study was to investigate the hepatoprotection of CLH-based supplement (GBHP01™) against chronic alcohol consumption. Results showed that GBHP01™ could reduce (p < .05) enlarged liver size, lipid accumulation/steatosis scores, and higher serum AST, ALT, γ-GT, triglyceride, and cholesterol levels induced by an alcoholic liquid diet. GBHP01™ reduced liver inflammation and apoptosis in alcoholic liquid-diet-fed mice via decreasing TBARS, interleukin-6, interleukin-1ß, and tumor necrosis factor-α levels, increasing reduced GSH/TEAC levels and activities of SOD, CAT and GPx, as well as downregulating CYP2E1, BAX/BCL2, Cleaved CASPASE-9/Total CASPASE-9 and Active CASPASE-3/Pro-CASPASE-3 (p < .05). Furthermore, GBHP01™ elevated hepatic alcohol metabolism (ADH and ALDH activities) (p < .05). In conclusion, this study prove the hepatoprotection of GBHP01™ against alcohol consumption.

Comparing radial lengthening osteotomy with ulnar shortening osteotomy to treat ulnar impaction syndrome after distal radius fracture malunion.

INTRODUCTION: Distal radius mal-unions often cause radius shortening and ulnar impaction syndrome. The modern treatments of ulnar impaction syndrome following distal radius mal-union are ulnar shortening osteotomy (USO) and distal radius lengthening osteotomy (DRLO). However, there are few studies to compare long-term outcomes of these two treatments. This study compares isolated USO to DRLO for the treatment of ulnar impaction syndrome following distal radius mal-union. MATERIALS AND METHODS: We retrospectively reviewed 68 patients with extra-articular distal radius mal-unions treated by isolated USO in 36 patients and DRLO in 32 patients. Pain visual analog scale (VAS), wrist motion, grip strength, radiographic parameters including sigmoid inclination, DASH score, and perioperative complications were analyzed. Mean follow-up was 62.6 months. RESULTS: The postoperative VAS scores for pain on exertion were less in the DRLO group than the USO group (1.2 vs. 2.8, p = 0.02). The DASH scores were 16.7 and 29.8 in the DRLO and USO groups, respectively (p = 0.02). The reduction of pain and improvement of function showed significantly better in the DRLO group. The mean operative time was shorter in the USO group. Most of the sigmoid inclinations were changed in DRLO. There were two re-operations following USO for painful nonunion and two patients had subsequent DRUJ osteoarthritis at the last follow-up. CONCLUSION: Although both treatments improved range of motion, grip strength, and VAS for pain, DRLO was found in better reduction of pain and improvement of function. USO is a simpler procedure with a shorter operative time but it has an increased potential to cause subsequent osteoarthritis of the DRUJ as its incongruity of DRUJ after USO especially in reverted inclination. DRLO can be a preferred method for treating USWP in relevant distal radial mal-union.

Comparison of the Confluence-Initiated Neurogenic Differentiation Tendency of Adipose-Derived and Bone Marrow-Derived Mesenchymal Stem Cells.

Adipose-derived mesenchymal stem cells (ADSCs), which tended to neurogenically differentiate spontaneously after achieving high confluence, were observed. Human ADSCs reaching 80% confluence were cultured in DMEM without an inducing factor for 24 h and then maintained in DMEM plus 1% FBS medium for 7 days. The neurogenic, adipogenic, and osteogenic genes of the factor-induced and confluence-initiated differentiation of the ADSCs and bone marrow-derived mesenchymal stem cells (BMSCs) at passages 3 to 5 were determined and compared using RT-qPCR, and the neurogenic differentiation was confirmed using immunofluorescent staining. In vitro tests revealed that the RNA and protein expression of neuronal markers, including class III ß-tubulin (TUBB3), microtubule-associated protein 2 (MAP2), neurofilament medium polypeptide (NEFM), neurofilament heavy polypeptide (NEFH), and neurofilament light polypeptide (NEFL), had been enhanced in the confluence-initiated differentiation of the ADSCs. In addition, the expressions of neurotrophins, such as the nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and glial cell-derived neurotrophic factor (GDNF), were also elevated in the confluence-initiated differentiation of the ADSCs. However, the confluent ADSCs did not show a tendency toward spontaneous adipogenic and osteogenic differentiation. Moreover, compared with the confluent ADSCs, the tendency of spontaneous neurogenic, adipogenic, and osteogenic differentiation of the confluent human bone marrow mesenchymal stem cells (BMSCs) was not observed. The results indicated that ADSCs had the potential to spontaneously differentiate into neuron-like cells during the confluent culture period; however, this tendency was not observed in BMSCs.

Prognostic factors and survival in conventional chondrosarcoma: A single institution review.

BACKGROUND: Chondrosarcoma is the second most common primary sarcoma of the bone. Surgery remains the gold standard for treatment due to chemotherapy and radiotherapy resistance in chondrosarcoma. The main aim of our study was to analyze patients with primary chondrosarcoma of the bone who were treated in a single tumor center. Our study team identified the prognostic factors for overall survival, metastasis-free survival, and recurrence-free survival. METHODS: From 1998 to 2012, 55 consecutive patients were treated surgically. All patients were followed for local recurrence or distant metastasis. Uni- and multivariate analyses were performed for overall, metastasis-free, and recurrence-free survival. RESULTS: Local recurrence developed in 29 of the 55 patients (52.7%). Recurrence-free survival in the multivariate analysis showed a significant association with the surgical margin, and high-grade lesions were an independent factor for local recurrence. In total, 11 patients died of the disease in the study, and the 5- and 10-year survival rates were 84.4% and 78.1%, respectively. The tumor grade and local recurrence were significant factors in the univariate analysis but were insignificant in the Cox regression with time-dependent covariates (p = 0.327 and p = 0.82, respectively). The development of distant metastasis was a significant poor prognostic factor in both the uni- and multivariate analyses. CONCLUSION: Chondrosarcoma of the bone is a disease with surgery-dependent outcomes; but, however, patients often develop subsequent recurrence of the disease. The surgical margins were statistically associated with the risk of subsequent local recurrence but did not predict survival. The development of distant metastases was an independent prognostic factor for poor survival.

Results of Fabry Disease Screening in Male Pre-End Stage Renal Disease Patients with Unknown Etiology Found Through the Platform of a Chronic Kidney Disease Education Program in a Northern Taiwan Medical Center.

BACKGROUND/AIMS: Fabry disease (FD), a rare x-lined genetic disorder is a cause of renal deterioration. The phenotype of FD is highly variable and nonspecific, and correct diagnosis has always been delayed. We aimed to explore the prevalence and clinical presentation of FD in this high-risk male population in a Northern Taiwan medical center. METHODS: This is the first study to survey the incidence of FD in this high-risk population through the platform of a chronic kidney disease (CKD) education program in Asia. A total of 1,012 male patients with unknown CKD causes were screened using an assay of alpha-galactosidase A activity (α-Gal A) by dried blood spots (DBS). A final GLA gene analysis was also done for those with low enzyme activity. RESULTS: We identified two new patients with classic FD and four patients with late-onset FD. One novel GLA mutation with c.413 G>A was found in one classic FD patient (index 5). The prevalence of FD is about 0.59 % (6 in 1,012) in the high-risk population group with CKD. The clinical symptoms of FD patients are nonspecific except in those with various degrees of renal failure. Those patients' correct diagnosis was delayed, taking years and even decades. Three patients received enzyme replacement therapy and one started regular hemodialysis due to persistent renal function deterioration. Another two patients were found from family screening through a new index. In addition, a false negative result occurred in one patient who was proved to have FD by his kidney pathology as determined by this screening. CONCLUSION: FD is not such as rare a disease and its prevalence is greater in this high-risk male population. Clinicians need to be aware that FD should be included in the differential diagnosis in CKD with unknown etiology.

Intralesional curettage of central low-grade chondrosarcoma: A midterm follow-up study.

BACKGROUND: The aim of this study was to review the experience of surgical treatment of low-grade chondrosarcoma and to assess the long-term oncological and functional outcomes between intralesional curettage and wide excision. METHODS: We included 11 patients with central low-grade chondrosarcoma lesions treated with intralesional curettage or wide excision from 1998 to 2013. Seven patients were treated with intralesional curettage and local adjuvant treatment (Group A), and four patients were treated with wide excision and reconstructive surgery (Group B). The mean age of patients was 43.8±17.6 years (range, 20-71 years), and the mean duration of follow-up was 84.4±47.6 months (range, 48-194 months). RESULTS: Group A had a significantly lower complication rate than Group B; three complications were documented in Group B (0% vs. 75%, p=0.024). The operative time (177.1 hours vs. 366.3 hours, p=0.010) and the hospital stay (6.6 days vs. 12.5 days, p=0.010) were significantly shorter in Group A. There was one local recurrence in Group A without statistical significance. Also, there were no differences between intralesional curettage and wide excision with respect to the blood loss. No metastasis disease occurred in either group during the follow-up period. The Musculoskeletal Tumor Society (MSTS) scores in Groups A and B were 99.0±2.5 and 94.2±4.2, respectively, with statistically significant difference (p=0.048). CONCLUSION: Extended intralesional curettage has the benefits of good MSTS score, shorter operative time, shorter hospital stay, and lower complication rate without increasing local recurrence in central low-grade chondrosarcoma. For central low-grade chondrosarcoma, we suggest extended curettage to decrease soft tissue damage and surgical risk.

Hemolysis-induced acute kidney injury following cardiac surgery: a case report and review of the literature.

Acute kidney injury is a common complication following cardiac surgery. Even small increases in creatinine levels are associated with increases in morbidity and mortality. Numerous factors such as hemolysis can contribute to the development of acute kidney injury after cardiac surgery. We present a rare case of severe hemolysis related to cardiopulmonary bypass resulting in kidney injury and requiring dialysis. The patient's renal function gradually recovered when hemolysis was improved. After follow-up for 3 months, his creatinine levels returned to normal. We discussed the pathogenesis of this hemolysis-related kidney dysfunction, the causes of hemolysis during cardiac surgery, and a new treatment option.

DR-70 immunoassay for the surveillance of hepatocellular carcinoma.

BACKGROUND AND AIM: Although alpha-fetoprotein (AFP) is a widely used serological marker for hepatocellular carcinoma (HCC), its utility is limited due to its unsatisfactory sensitivity. Meanwhile, a newly developed immunoassay-DR-70-has been reported to have a good sensitivity for HCC in a small-scale study. The aim of this study was to determine the clinical value of DR-70 for the surveillance of HCC. METHODS: Serum levels of DR-70 and AFP were measured in 103 patients with HCC, 50 healthy volunteers, and 33 patients with chronic liver disease. In addition, we investigated the prognostic value of DR-70 in patients with HCC correlating with the clinical staging-Cancer of the Liver Italian Program (CLIP) score and Barcelona Clinic Liver Cancer (BCLC) classification. RESULTS: Based on the receiver operating characteristic curve with area under the curve of 0.836, the DR-70 cut-off value for detecting HCC was determined to be 0.75 µg/mL. DR-70 provided a sensitivity of 81.6% and a specificity of 77.1%, and correlated well with the CLIP score and BCLC classification. The combination of DR-70 and AFP increased the sensitivity to 91.2%. The prognosis for patients with HCC with DR-70 level > 0.75 µg/mL was worse than that for those with DR-70 ≤ 0.75 µg/mL. Among the patients with early stage HCC (CLIP score 0-2), DR-70 > 0.75 µg/mL independently predicted a poor survival. CONCLUSIONS: DR-70 immunoassay is complementary to AFP for the detection of HCC and has a good correlation with clinical staging and prognosis.

Comparison of parenteral iron sucrose and ferric chloride during erythropoietin therapy of haemodialysis patients.

AIM: To compare the effects of i.v. iron sucrose and Fe chloride on the iron indices of haemodialysis patients with anaemia. METHODS: One hundred and eight haemodialysis patients receiving recombinant human erythropoiesis-stimulating agent (ESA) (mean age 59.37 years) were enrolled and randomly assigned to an iron sucrose or an Fe chloride group. Iron supplements were administered at 100 mg/week during the first 4 weeks (loading dose). Ferritin and transferrin saturation (TSAT) were then measured and dose adjusted. Ninety-eight subjects completed treatment; 51 in the iron sucrose group and 47 in the Fe chloride group. Ferritin, TSAT, haematocrit (Hct), reticulocyte count, serum albumin, fractional clearance of urea (Kt/V) and intact parathyroid hormone (iPTH) were measured. RESULTS: There was no significant difference in baseline characteristics between the groups. Significant differences between the groups were observed in both iron indices and ESA dosage. Hct at week 24 (31.1% vs 29.7%, P = 0.006) and ferritin at week 20 (731.3 vs 631.7 ng/mL, P = 0.006) in the iron sucrose group were significantly higher than in the Fe chloride group. ESA dosage used in the iron sucrose group at week 8 was significantly lower than in the Fe chloride group (244.9 vs 322.6 U/kg per month, P = 0.003), and iron sucrose group received significantly lower iron dose than the Fe chloride group at week 8 (P = 0.005). CONCLUSION: Although the differences in ESA dosage, ferritin and iron dosage between two groups were found during the study period while similar results were shown at the end of 24 week study. Thus, iron sucrose and Fe chloride are safe and work equally well for haemodialysis patients.

Chronic thalidomide administration enhances vascular responsiveness to vasopressin in portal-systemic collaterals of bile duct-ligated rats.

BACKGROUND: Arginine vasopressin (AVP) controls gastroesophageal variceal bleeding, partly due to its vasoconstrictive effect on portal-systemic collaterals. It has been shown that chronic thalidomide treatment decreases portal pressure, attenuates hyperdynamic circulation and inhibits vascular endothelial growth factor (VEGF) and tumor necrosis factor (TNF)-alpha in partially portal vein-ligated rats. This study investigated the effects of chronic thalidomide treatment on portal-systemic collateral vascular responsiveness to AVP in common bile duct-ligated (CBDL) cirrhotic rats. METHODS: In the first series, CBDL-induced cirrhotic rats received thalidomide (50 mg/kg/day orally) or distilled water (control) from the 35th to 42nd day after ligation. On the 43rd day after ligation, the body weight, mean arterial pressure, portal pressure, and heart rate were measured. An in situ collateral vascular perfusion model was used to obtain the cumulative concentration-response curves of collateral vessels to AVP (10(-10) to 3 x 10(-7) M). Plasma levels of VEGF and TNF-alpha were measured, and expressions of VEGF and TNF-alpha mRNA in the left adrenal veins were also determined. In the second series, the cumulative concentration-response curves of collateral vessels to AVP in CBDL rats with or without thalidomide (10(-5) M) preincubation in the perfusate were obtained. RESULTS: The thalidomide and control groups were not significantly different in terms of heart rate, mean arterial pressure and portal pressure (p > 0.05). The collateral vascular perfusion pressure change to AVP was significantly enhanced at 10(-8) M after thalidomide treatment (p = 0.041). Compared with the control group, thalidomide-treated rats had significantly lower plasma VEGF levels (p < 0.001), accompanied by an insignificant reduction in plasma TNF-alpha levels (p > 0.05). The expressions of VEGF and TNF-alpha mRNA in the left adrenal veins of thalidomide-treated CBDL rats were not significantly changed compared with those of the control group. In addition, thalidomide did not significantly elicit changes in vascular responsiveness to AVP in collateral vessels of CBDL rats when it was added into the perfusate. CONCLUSION: In cirrhotic rats, chronic thalidomide treatment improves the portal-systemic collateral vascular responsiveness to AVP, which was partly related to VEGF inhibition.

Acute tumor lysis syndrome in a hemodialysis patient with diffuse large B cell lymphoma.

Acute tumor lysis syndrome (TLS) is a life-threatening complication of cancer therapy requiring prompt recognition and aggressive management. It occurs particularly in patients with lymphoproliferative disease during potent myelosuppressive therapy. To our knowledge, acute TLS in end-stage renal disease (ESRD) patients with malignancy is extremely rare and has never been reported in English literature. We report the first case of acute TLS in an ESRD woman with diffuse large B cell lymphoma after chemotherapy. Aggressive treatments with daily hemodialysis and allopurinol rather than hydration benefit the patient. There is neither optimal therapy in treating ESRD patients with TLS nor adequate guidelines for how to adjust the chemotherapy drug in hemodialysis patients. This case provides our experience to clinician how to treat acute TLS in ESRD patients.

Renal cell carcinoma presenting as a huge simple renal cyst.

Simple renal cysts are the most common renal masses, accounting for roughly 65-70% of cases. Transformation of a simple renal cyst into a renal cell carcinoma (RCC), however, is extremely rare. We reported a 48-year-old man with a right huge simple renal cyst from which about 800 ml of dark yellowish fluid with elevated protein and lactic dehydrogenase (LDH) levels was aspirated. Cytological examination disclosed negative for malignant cells. Nephrectomy was performed because of intractable flank pain 3 months after aspiration. The pathology examination confirmed RCC. While this is an extremely unusual finding, one must not exclude the possibility of malignancy in an apparently simple cyst.

Methimazole alleviates hepatic encephalopathy in bile-duct ligated cirrhotic rats.

BACKGROUND: Acute or chronic liver damage may lead to hepatic encephalopathy. Previous studies have indicated the hemodynamic and hormonal mimicry between portal hypertension and hyperthyroidism. Furthermore, medically or surgically induced hypothyroidism has been found to be beneficial in ameliorating hyperdynamic circulation in the portal hypertensive state and in alleviating acute or chronic liver injury in rats. However, the effect of chronic thyroid hormone inhibition on chronic hepatic encephalopathy in cirrhosis remains unknown. METHODS: Liver cirrhosis was induced by bile-duct ligation (BDL) in male Sprague-Dawley rats. Three weeks after BDL, rats were randomized to receive either tap water (control) or 0.04% methimazole in drinking water for 3 weeks. At the end of 6 weeks after BDL, severity of encephalopathy was assessed by the Opto-Varimex animal activity meter and hemodynamic parameters were measured. Blood samples were collected for determination of thyroid stimulating hormone, ammonia and liver biochemistry. RESULTS: The heart rate of the methimazole-treated group was significantly lower than that of the control group (p = 0.015), whereas there were no differences in the mean arterial pressure and portal pressure. The total amount of movements were significantly increased in the methimazole group (p = 0.029). Plasma levels of ammonia, aspartate aminotransferase and alkaline phosphatase were significantly lower (p = 0.01) and thyroid stimulating hormone significantly higher (p = 0.035) in the methimazole group. CONCLUSION: Chronic methimazole treatment alleviates hepatic encephalopathy and liver damage in rats with BDL-induced hepatic cirrhosis.

Lack of detrimental or therapeutic effects of cyclooxygenase inhibition in bile duct-ligated rats with hepatic encephalopathy.

BACKGROUND: The pathogenetic mechanisms of hepatic encephalopathy (HE) are not fully understood. Cerebral blood flow regulated by cyclooxygenase (COX) may be involved in the development of HE. There are no comprehensive data concerning the effects of COX inhibition on HE in chronic liver disease. METHODS: Male Sprague-Dawley rats weighing 240-270 g at the time of surgery were selected for experiments. Secondary biliary cirrhosis was induced by bile duct ligation (BDL). Those rats were then divided into two groups to receive i.p. injection of indomethacin (5 mg/kg per day) or distilled water for 7 days from day 36 to day 42 after BDL. The control group consisted of rats receiving a sham operation. Severity of encephalopathy was assessed by counts of motor activity. Plasma levels of tumor necrosis factor (TNF)-alpha and 6-keto-prostaglandin F(1alpha) (6-keto-PGF(1alpha)), and liver biochemistry tests were determined after treatment. RESULTS: The motor activity in both groups of BDL rats were significantly lower than that of the control group (P < 0.001). As compared with the BDL rats treated with distilled water, BDL rats treated with indomethacin had significant lower levels of 6-keto-PGF(1alpha), but the motor activity, TNF-alpha levels and serum biochemistry tests were not significantly different between both BDL groups. CONCLUSIONS: Chronic indomethacin administration did not have significantly detrimental or therapeutic effects on the severity of encephalopathy in BDL rats.

Detrimental effects of nitric oxide inhibition on hepatic encephalopathy in rats with thioacetamide-induced fulminant hepatic failure: role of nitric oxide synthase isoforms.

BACKGROUND: Hepatic encephalopathy is a complex neuropsychiatric syndrome. A previous study showed that chronic nitric oxide (NO) inhibition aggravated the severity of encephalopathy in thioacetamide (TAA)-treated rats. The present study investigated the relative contribution of NO synthase (NOS) isoforms on the severity of hepatic encephalopathy in TAA-treated rats. METHOD: Fulminant hepatic failure was induced in male Sprague-Dawley rats by intraperitoneal injection of TAA (350 mg/kg/day) for 3 days. Rats were divided into three groups to receive N(omega)-nitro-L-arginine methyl ester (L-NAME, a non-selective NOS inhibitor, 25 mg/kg/day in tap water), L-canavanine (an inducible NOS inhibitor, 100 mg/kg/day via intraperitoneal injection) or normal saline (N/S) from 2 days prior to TAA administration and lasting for 5 days. Severity of encephalopathy was assessed by the counts of motor activity. Plasma levels of tumor necrosis factor-alpha (TNF- alpha) were determined by enzyme-linked immunosorbent assay (ELISA), and total bilirubin, alanine aminotransferase (ALT) and creatinine were determined by colorimetric assay. RESULTS: Compared with L-canavanine or N/S-treated rats (0% and 4%, respectively), the mortality rate was significantly higher in rats receiving L-NAME administration (29%, P < 0.005). Inhibition of NO created detrimental effects on the counts of motor activities (P < 0.05). Rats treated with L-NAME had significantly higher plasma levels of total bilirubin, ALT, creatinine and TNF- alpha as compared with rats treated with L-canavanine or N/S (P < 0.01). CONCLUSION: Chronic L-NAME administration, but not L-canavanine, had detrimental effects on the severity of hepatic damage and motor activities in TAA-treated rats. These results suggest that constitutive NOS activities play a major protective role in rats with fulminant hepatic failure.