Current role of liver transplantation for the treatment of urea cycle disorders: a review of the worldwide English literature and 13 cases at Kyoto University.

To address the current role of liver transplantation (LT) for urea cycle disorders (UCDs), we reviewed the worldwide English literature on the outcomes of LT for UCD as well as 13 of our own cases of living donor liver transplantation (LDLT) for UCD. The total number of cases was 51, including our 13 cases. The overall cumulative patient survival rate is presumed to be more than 90% at 5 years. Most of the surviving patients under consideration are currently doing well with satisfactory quality of life. One advantage of LDLT over deceased donor liver transplantation (DDLT) is the opportunity to schedule surgery, which beneficially affects neurological consequences. Auxiliary partial orthotopic liver transplantation (APOLT) is no longer considered significant for the establishment of gene therapies or hepatocyte transplantation but plays a significant role in improving living liver donor safety; this is achieved by reducing the extent of the hepatectomy, which avoids right liver donation. Employing heterozygous carriers of the UCDs as donors in LDLT was generally acceptable. However, male hemizygotes with ornithine transcarbamylase deficiency (OTCD) must be excluded from donor candidacy because of the potential risk of sudden-onset fatal hyperammonemia. Given this possibility as well as the necessity of identifying heterozygotes for other disorders, enzymatic and/or genetic assays of the liver tissues in cases of UCDs are essential to elucidate the impact of using heterozygous carrier donors on the risk or safety of LDLT donor-recipient pairs. In conclusion, LT should be considered to be the definitive treatment for UCDs at this stage, although some issues remain unresolved.     

Impact of portal venous pressure on regeneration and graft damage after living-donor liver transplantation.

Several reports claim that portal hypertension after living-donor liver transplantation (LDLT) adversely affects graft function, but few have assessed the impact of portal venous pressure (PVP) on graft regeneration. We divided 32 adult LDLT recipients based on mean PVP during the 1st 3 days after LDLT into a group with a PVP > or = 20 mm of Hg (H Group; n = 17), and a group with a PVP < 20 mm of Hg (L Group; n = 15). Outcome in the H Group was poorer than in the L Group (58.8 vs. 92.9% at 1 year). Peak peripheral hepatocyte growth factor (HGF) during the 1st 2 weeks was higher in the H Group (L: 1,730 pg/mL, H: 3,696 pg/mL; P < .01), whereas peak portal vascular endothelial growth factor (VEGF) level during the 1st week was higher in the L Group (L: 433 pg/mL, H: 92 pg/mL; P < .05). Graft volume (GV) / standard liver volume (SLV) was higher in the H Group (L / H, at 2, 3, and 4 weeks, and at 3 months: 1.02 / 1.24, .916 / 1.16, .98 / 1.27, and .94 / 1.29, respectively; P < .05). Peak serum aspartate aminotransferase, bilirubin levels, and international normalized ratio after LDLT were significantly higher in the H Group, as was mean ascitic fluid volume. In conclusion, early postoperative PVP elevation to 20 mm of Hg or more was associated with rapid graft hypertrophy, higher peripheral blood HGF levels, and lower portal VEGF levels; and with a poor outcome, graft dysfunction with hyperbilirubinemia, coagulopathy, and severe ascites. Adequate liver regeneration requires an adequate increase in portal venous pressure and flow reflected by clearance of HGF and elevated VEGF levels.     

Binding of Clostridium botulinum type C neurotoxin to different neuroblastoma cell lines.

Binding of type C neurotoxin (C1 toxin) from Clostridium botulinum (strain Stockholm) to neuroblastoma cell lines was studied by using biotinylated anti-toxin antibody and avidin-biotinylated peroxidase complex. The neurotoxin bound with high efficiency to mouse neuroblastoma (NS-20Y and NIE-115) cells and to hybridomas of rat glioblastoma and mouse neuroblastoma (NG108-C15) cells. The toxin bound little to human neuroblastoma, rat astrocytoma, and nonneural cell lines. Binding of the neurotoxin to NG108-C15 cells was inhibited by gangliosides (GT1b and GM1) and by monoclonal antibodies (CA-12 and C-9), although inhibition was not complete. Sequential preincubation of C1 toxin with GT1b and CA-12 caused complete inhibition. A Scatchard plot of binding of 125I-labeled C1 toxin to NG108-C15 cells showed a hyperbolic curve. Monoclonal antibody CA-12 but not C-9 neutralized the lethal activity of the toxin toward mice. Only C-9 clearly inhibited toxin binding to GT1b. These results suggest that NG108-C15 cells have at least two kinds of receptors for C1 toxin. From the results of binding tests with neuraminidase-, pronase-, and trypsin-treated NG108-C15 cells, the chemical nature of the high-affinity site was presumed to be a glycoprotein containing sialic acid. GT1b may have an important role in low-affinity sites.     

Inhibition of HIV-1 replication and syncytium formation by synthetic CD4 peptides

Summary Only one peptide of CD₄ (amino acid residues 70–132) among 16 synthetic peptide fragments selectively inhibited HIV-1 replication and HIV-1-induced syncytium formation. Several smaller peptides within this region did not show any activity, except for the peptide (86–132) which showed somewhat lower activity.     

Modulation of infection-induced inflammation and locomotive deficit and longevity in senescence-accelerated mice-prone (SAMP8) model by the oligomerized polyphenol Oligonol.

Oligonol is produced from the oligomerization of polyphenols (typically proanthocyanidin from a variety of fruits such as lychees, grapes, apples, persimmons, etc.) and contains catechin-type monomers and oligomers of proanthocyanidins. The ability of Oligonol to affect infection-dependent eye inflammation, locomotion and longevity in senescence-accelerated prone mice (SAMP8) (a model of senescence acceleration and geriatric disorders with increased oxidative stress and neuronal deficit) was investigated. Oligonol (60mg/kg) significantly modulated the extent of inflammation scores in the eye of SAMP8 mice. Examination of the mice indicated infection with mouse hepatitis virus and pinworm (Syphacia obvelata) in both males and females and with the intestinal protozoa (trichomonad) in males. A comparison of the two groups (using log-rank test) and the difference in the mean life span between groups (using Student's t-test) indicated significant differences in survival (p=0.043) and the mean life span (p=0.033) in male SAMP8 mice. Oligonol increased the mean life span and this was statistically significant. In the open-field locomotive test, the 7-week-old SAMP8 mice crossed more than 40 partitioned lines in 1min. At 48-week-old control untreated male SAMP8 crossed 2 lines. The Oligonol-treated 48-week-old male SAMP8 mice crossed 17 lines however. The improved locomotive activity was statistically significant even after 36weeks in the Oligonol-treated male SAMP8 but this was not the case throughout the time course of the study in the Oligonol-treated female SAMP8. Thus Oligonol treatment to SAMP8 mice modulated the severity of infection-dependent inflammation, prolonged life-span and significantly improved locomotive activity indicating potential benefit to aging-associated diseases such as Alzheimer's or Parkinson's diseases. This presents potential for further research to define infection-dependent inflammation associated with degenerative conditions and the molecular mechanism of dietary antioxidant protection.     

Experimental autoimmune uveoretinitis (EAU) in rats: isolation of S-antigen, EAU susceptibility of rat strains, genetic control of EAU induction, and effects of cyclophosphamide and irradiation on EAU

Highly purified S-antigen was isolated from bovine retinas by high performance liquid chromatography (HPLC), and was used to induce experimental autoimmune uveoretinitis (EAU) in various rat strains. Studies were then made of the genetic control of EAU, the effects of cyclophosphamide or irradiation on EAU, and the correlation between the EAU incidence and the serum levels of antibody to S-antigen. Lewis rats were the most susceptible to EAU followed by Wistar rats. F344 rats and BN rats were resistant to EAU. (Lewis X BN)F1 rats and (LBNF1 X Lewis) rats were susceptible to EAU, while (LBNF1 X BN) rats were resistant. These results indicate that susceptibility to EAU was inherited as an autosomal dominant trait. Treatment of rats with cyclophosphamide or irradiation (200 rad/rat) on the day before immunization markedly suppressed EAU development. On the other hand, the same dose of irradiation 7 days after the immunization did not affect the disease induction, yet the antibody levels to S-antigen were very high in the rats. In addition, BN rats resistant to EAU exhibited very high levels of antibody to S-antigen. Therefore, the antibody to S-antigen seems to play a minor role, if any, in the immunopathogenic mechanisms of EAU.     

Near-infrared spectroscopy for monitoring cerebral ischemia during selective cerebral perfusion.

OBJECTIVE: To minimize the neurological complications following cardiovascular surgery, it is essential to prevent an occurrence of cerebrovascular embolism and to detect and solve cerebral malperfusion without delay in the operating theater. Although we have introduced near-infrared spectroscopy (NIRS) monitoring for the purpose of detecting cerebral malperfusion, no criterion has been available. We searched for this criterion by examining the relationship of sustained drop in the regional oxygen saturation (rSO2) of the frontal lobes to the occurrence of neurological events. METHODS: The 59 consecutive patients undergoing aortic surgery with selective cerebral perfusion (SCP) were examined. The rSO2 was monitored throughout the surgery and the durations of drops in rSO2 to below 55% and those below 60% were determined for each patient. The durations of rSO2 drop and other surgery-related parameters were compared between the patients in whom neurological events occurred and those without such events. RESULTS: A total of 16 cases (27.1%) presented with neurological events. Newly developed cerebral infarction was documented in 6 of these 16 cases. Operation time and the durations for which rSO2 dropped were significantly longer for the 16 patients with neurological events than for the 43 patients without events (Op time: 546.8 versus 448.1 min, P=0.0064; rSO2 below 60%: 141.2 versus 49.8 min, P=0.0032; rSO2 below 55%: 66.6 versus 10.6 min, P=0.0011), while there was no significant difference in age, bypass time, aortic clamping time, SCP time, and circulatory arrest time between the two groups. In the 3 patients with infarcts suggestive to hypoperfusion, sustained decrease in rSO2 was observed, while it was not significant in the remaining 3 patients with infarcts suggestive to embolism. Among the 53 patients without infarction, transient neurological events occurred more frequently in patients with sustained drop in rSO2 below 55% for over 5 min (44.4% versus 5.7%, P=0.0014). CONCLUSIONS: A sustained drop in rSO2 during aortic surgery is closely related to the occurrence of neurological events following surgery. We recommend that recovery of drop in rSO2 below 55% should be addressed without delay. However, use of NIRS is limited for detecting embolic events or hypoperfusion in the basilar region.     

Cortical reflex myoclonus in adult onset Huntington's disease]

We report a case of cortical reflex myoclonus in adult onset Huntington's disease (HD). The patient is a 51-year-old woman. Chorea and myoclonus were observed on her face and extremities. Neurophysiological tests showed C reflex and abnormal waves preceding myoclonus by jerk-locked back averaging method but no giant somatosensory evoked potential. Gene analysis revealed the prolongation of CAG repeats (13/44) in IT15 gene. Oral administration of clonazepam was transiently effective for myoclonus. We should inscribe that the cortical reflex myoclonus may exceptionally manifest in HD.     

A suspected case of alcoholic pellagra encephalopathy with marked response to niacin showing myoclonus and ataxia as chief complaints]

We report a 47-year-old alcoholic man with alcoholic pellagra encephalopathy (APE) showing myoclonus and ataxia as chief complaints. He had been a heavy drinker for 30 years. He had noticed appetite loss and subsequently showed a subacutely progressive gait disturbance. He had no history of diarrhea, dementia, or dermatitis. On admission, he showed severe alcoholic liver cirrhosis with a large amount of ascites, limbs and truncal ataxia, myoclonus of the limbs and areflexia, although his consciousness was alert and there were no sign of dermatitis. Though the plasma level of ammonia was normal, we started administration of amino acids suspecting hepatic encephalopathy. Symptoms showed no improvement, and subsequent administration of thiamine was also ineffective. A decreased serum level of niacin was demonstrated. After administration of nicotinamide, the symptoms improved gradually. This patient received a diagnosis of APE. Endemic pellagra, characterized by the classical triad of dermatitis, diarrhea and dementia, is known to be caused by a dietary deficiency of the niacin, and has now become very rare in developed countries. At present, pellagra is encountered most often in patients with chronic alcoholism, which is called APE. APE patients often show only disturbance of consciousness. Although several reports has described ataxia and myoclonus in patients with APE, APE patients with myoclonus and ataxia as chief complaints have not previously been reported. On autopsy cases, central chromatolysis of neurons in the dentate nucleus of the cerebellum, gracile and cuneate nuclei, and the Clarke's column has been demonstrated. The APE patients would show myoclonus and ataxia as their first symptoms. In conclusion, we would like to emphasize that administration of niacin should be started for the treatment of chronic alcoholic patients showing myoclonus and ataxia even without the classical triads found in endemic pellagra patients.     

Preoperative chemotherapy increases cytokine production after lung cancer surgery.

OBJECTIVE: Many phase II trials have shown that preoperative chemotherapy for lung cancer is feasible but associated with postoperative morbidity and mortality. However, little is known about the effect of preoperative chemotherapy on surgical stress and postoperative complications associated with surgical intervention. We evaluated the effect of preoperative chemotherapy on perioperative inflammatory cytokine production as a surgical stress marker. METHODS: The study group comprised 38 patients undergoing anatomical lung resection and mediastinal nodal dissection for clinical stage IB/II non-small cell lung cancer during the period October 2001-December 2003. Nineteen patients received a single cycle of cisplatin (80 mg/m(2)) and docetaxel (60 mg/m(2)) chemotherapy prior to surgery (neoadjuvant group), and 19 patients underwent surgery without any previous chemotherapy (control group). White blood cell and neutrophil counts and serum concentrations of C-reactive protein (CRP), interleukin-6 (IL-6), and granulocyte colony-stimulating factor (GCSF) were determined before surgery and on postoperative days 1 and 3. Postoperative complications were reviewed. Differences were assessed by repeated analysis of variance. RESULTS: Serum concentrations of IL-6 and GCSF rose significantly on postoperative days 1 and 3 in the neoadjuvant group in comparison to concentrations in the control group, but white blood cell count, neutrophil count, and CRP did not differ between the groups. No major complication occurred in either group. CONCLUSIONS: A single cycle of cisplatin and docetaxel chemotherapy followed by surgery can exacerbate overproduction of inflammatory cytokines during the perioperative period in lung cancer patients.