The efficacy of synthetic pseudo-ceramide for dry and rough lips.

OBJECTIVE: Lips can easily become dry and rough, one reason being the characteristics of their ceramide (CER) profile. Lips have lower levels of total ceramides, higher percentages of CER[NS] and CER[AS], and lower percentages of CER[NP] and CER[NH] than skin in other regions of the body. The purpose of this study was to clarify the effects of synthetic pseudo-ceramide (pCer; Cetyl-PG hydroxyethyl palmitamide) to improve the dryness and roughness of the lips of healthy subjects in a formulation that exclude an occlusive effect. METHODS: Thirty-one Japanese female subjects with normal skin (age range 21-37 years; mean 28.6) were enrolled in this study. A four-week continuous use test was conducted using samples with or without 0.5% or 2.0% pCer. The degree of lip roughness was scored, and values of capacitance, transepidermal water loss (TEWL) and lip surface elasticity were measured. Endogenous CER profiles and absorption levels of pCer in the stratum corneum (SC) were analysed in tape-stripped skin specimens. RESULTS: Treatment with the pCer-2.0% sample significantly improved the visual roughness score after 2 and 4 weeks compared to 0 weeks and compared to the Blank. Moreover, an improvement in TEWL was observed after 4 weeks of treatment with the pCer-2.0% sample. CER[NP] showed a significant increase in pCer-2.0% treated lips after 4 weeks compared to the Blank. Both pCer-0.5% and pCer-2.0% were significantly absorbed after 2 weeks compared with the Blank. CONCLUSION: The effect of the synthetic pseudo-ceramide pCer to improve the roughness of lips was shown excluding the effect of occlusiveness derived from the formulation for the first time. Since the improvement of TEWL and absorption of pCer was observed, we concluded that pCer was first absorbed in rough lip areas, improved the ceramide profile and consequently restored the barrier function.

OBJECTIF: Les lèvres peuvent facilement devenir sèches et rugueuses, l'une des raisons étant les caractéristiques de leur profil de céramide (CER). Les lèvres présentent des taux plus faibles de céramides totaux, des pourcentages plus élevés de CER[NS] et de CER[AS] et des pourcentages plus faibles de CER[NP] et CER[NH] que la peau des autres régions de l'organisme. L'objectif de cette étude visait à clarifier les effets du pseudo-céramide synthétique (pCer; cétyl-PG hydroxyéthyl palmitamide) pour améliorer la sécheresse et la rugosité des lèvres de sujets en bonne santé avec une formulation excluant un effet occlusif. MÉTHODES: Trente et un sujets de sexe féminin japonais ayant une peau normale (tranche d'âge: 21 à 37 ans; moyenne: 28,6 ans) ont été inclus dans cette étude. Une analyse d'utilisation continue de quatre semaines a été effectuée en employant des échantillons avec ou sans pCer à 0,5 % ou 2,0 %. Le degré de rugosité des lèvres a été noté et les valeurs de capacitance, de perte d'eau transépidermique (transepidermal water loss, TEWL) et d'élasticité de la surface des lèvres ont été mesurées. Les profils CER endogènes et les niveaux d'absorption de pCer de la couche cornée (stratum corneum, SC) ont été analysés dans des échantillons cutanés fixés par bande adhésive. RÉSULTATS: Le traitement avec l'échantillon pCer-2,0% a amélioré de façon significative le score de rugosité visuelle après 2 et 4 semaines par rapport à 0 semaine et par rapport au groupe témoin. En outre, une amélioration de la TEWL a été observée après 4 semaines de traitement avec l'échantillon pCer-2,0%. Après 4 semaines, le CER[NP] a aumenté de manière significative dans les lèvres traitées avec pCer-2,0% par rapport au groupe témoin. Le pCer-0,5 % et le pCer-2,0% ont tous deux été absorbés de manière significative après 2 semaines par rapport au groupe témoin. CONCLUSION: L'effet du pseudo-céramide synthétique pCer pour améliorer la rugosité des lèvres a été démontré, excluant l'effet de l'occlusion dérivé de la formulation pour la première fois. Puisque l'amélioration de la TEWL et l'absorption du pCer ont été observées, nous avons conclu que le pCer était d'abord absorbé dans les zones rugueuses des lèvres, améliorait le profil du céramide et, par conséquent, rétablissait la fonction barrière.

High-resolution copy number variation analysis of schizophrenia in Japan.

Recent schizophrenia (SCZ) studies have reported an increased burden of de novo copy number variants (CNVs) and identified specific high-risk CNVs, although with variable phenotype expressivity. However, the pathogenesis of SCZ has not been fully elucidated. Using array comparative genomic hybridization, we performed a high-resolution genome-wide CNV analysis on a mainly (92%) Japanese population (1699 SCZ cases and 824 controls) and identified 7066 rare CNVs, 70.0% of which were small (<100 kb). Clinically significant CNVs were significantly more frequent in cases than in controls (odds ratio=3.04, P=9.3 × 10-9, 9.0% of cases). We confirmed a significant association of X-chromosome aneuploidies with SCZ and identified 11 de novo CNVs (e.g., MBD5 deletion) in cases. In patients with clinically significant CNVs, 41.7% had a history of congenital/developmental phenotypes, and the rate of treatment resistance was significantly higher (odds ratio=2.79, P=0.0036). We found more severe clinical manifestations in patients with two clinically significant CNVs. Gene set analysis replicated previous findings (e.g., synapse, calcium signaling) and identified novel biological pathways including oxidative stress response, genomic integrity, kinase and small GTPase signaling. Furthermore, involvement of multiple SCZ candidate genes and biological pathways in the pathogenesis of SCZ was suggested in established SCZ-associated CNV loci. Our study shows the high genetic heterogeneity of SCZ and its clinical features and raises the possibility that genomic instability is involved in its pathogenesis, which may be related to the increased burden of de novo CNVs and variable expressivity of CNVs.

Abnormal asymmetries in subcortical brain volume in schizophrenia.

Subcortical structures, which include the basal ganglia and parts of the limbic system, have key roles in learning, motor control and emotion, but also contribute to higher-order executive functions. Prior studies have reported volumetric alterations in subcortical regions in schizophrenia. Reported results have sometimes been heterogeneous, and few large-scale investigations have been conducted. Moreover, few large-scale studies have assessed asymmetries of subcortical volumes in schizophrenia. Here, as a work completely independent of a study performed by the ENIGMA consortium, we conducted a large-scale multisite study of subcortical volumetric differences between patients with schizophrenia and controls. We also explored the laterality of subcortical regions to identify characteristic similarities and differences between them. T1-weighted images from 1680 healthy individuals and 884 patients with schizophrenia, obtained with 15 imaging protocols at 11 sites, were processed with FreeSurfer. Group differences were calculated for each protocol and meta-analyzed. Compared with controls, patients with schizophrenia demonstrated smaller bilateral hippocampus, amygdala, thalamus and accumbens volumes as well as intracranial volume, but larger bilateral caudate, putamen, pallidum and lateral ventricle volumes. We replicated the rank order of effect sizes for subcortical volumetric changes in schizophrenia reported by the ENIGMA consortium. Further, we revealed leftward asymmetry for thalamus, lateral ventricle, caudate and putamen volumes, and rightward asymmetry for amygdala and hippocampal volumes in both controls and patients with schizophrenia. Also, we demonstrated a schizophrenia-specific leftward asymmetry for pallidum volume. These findings suggest the possibility of aberrant laterality in neural pathways and connectivity patterns related to the pallidum in schizophrenia.

Evaluation of the relationship between salivary concentration of anti-heat shock protein immunoglobulin and clinical manifestations of Behçet's disease.

OBJECTIVE: This study investigated the relationship between the concentration of anti-heat shock protein (HSP) 60 antibody in resting saliva and the severity of Behçet's disease (BD). METHOD: Sixty-five patients diagnosed with BD at Tokyo Medical and Dental University Hospital were enrolled in this study. Based on clinical severity scores, patients were categorized as having mild, moderate, or severe BD. Periodontal status was evaluated with the Community Periodontal Index (CPI), and anti-HSP60 antibody concentrations in resting saliva were measured with an enzyme-linked immunosorbent assay. RESULTS: The mean antibody concentration in patients in the moderate group was significantly higher than concentrations in the mild and severe groups. No significant difference was found between the mild and severe groups. Gingival inflammation, identified with the CPI, was associated with a higher antibody concentration. The antibody concentration in patients who had stomatitis for more than 2 weeks was significantly higher than in those with stomatitis for less than 2 weeks. The antibody concentration in patients who had taken colchicine was significantly lower than that in subjects who had not. CONCLUSION: These results suggest that the concentration of anti-HSP60 antibody in resting saliva may be effective as a non-invasive indicator for the diagnosis (screening) and prognostication of BD.

Upper-normal waist circumference is a risk marker for metabolic syndrome in normal-weight subjects.

BACKGROUND AND AIMS: To elucidate implication of upper-normal waist circumference (WC), we examined whether the normal range of WC still represents a risk of metabolic syndrome (MetS) or non-adipose MetS components among normal-weight subjects. METHODS AND RESULTS: A total of 173,510 persons (100,386 men and 73,124 women) with normal WC (<90/80 cm in men/women) and body mass index (BMI) of 18.5-24.9 were included. Subjects were categorized as having low, moderate, and upper-normal WC for those with WC < 80, 80-84, and 85-89 cm in men and <70, 70-74, and 75-79 cm in women, respectively. The prevalence of all the non-adipose MetS components (e.g. prediabetes and borderline dyslipidemia) was significantly higher in subjects with upper-normal WC on comparison with those with low WC. Overall, the prevalence of MetS (having three or more of four non-adipose MetS components) gradually increased with increasing WC (12%, 21%, and 27% in men and 11%, 14%, and 19% in women for low, moderate, and upper-normal WC, respectively). Moreover, the risk of having a greater number of MetS components increased in subjects with upper-normal WC compared with those with low WC (odds ratios for the number of one, two, three, and four MetS components: 1.29, 1.81, 2.53, and 2.47 in men and 1.16, 1.55, 1.49, and 2.20 in women, respectively). CONCLUSION: Upper-normal WC represents a risk for acquiring a greater number of MetS components and the early stage of MetS components (prediabetes and borderline dyslipidemia), after adjusting for BMI, in a large general population with normal WC and BMI.

Comparison of preoperative chemotherapy using docetaxel, cisplatin and fluorouracil with cisplatin and fluorouracil in patients with advanced carcinoma of the thoracic esophagus.

We retrospectively compared preoperative docetaxel, cisplatin, and fluorouracil (DCF) with cisplatin and fluorouracil (CF) in patients with esophageal cancer. The study included patients with advanced thoracic esophageal carcinoma (excluding T4 tumors) receiving preoperative chemotherapy. In the DCF group, five patients received two courses of treatment every 4 weeks, and 33 patients received three courses every 3 weeks. In the CF group, 38 patients received two courses of treatment every 4 weeks. Patients underwent curative surgery 4-5 weeks after completing chemotherapy. Patient demographic characteristics did not differ between the two study groups. The incidence of a grade 3 or 4 hematologic toxicity was significantly higher in the DCF group (33 patients) than in the CF group (five patients; P < 0.001). Curative resection was accomplished in 79% of patients in the DCF group and 66% in the CF group (P = 0.305). There were no in-hospital deaths. The incidence of perioperative complications did not differ between the groups. A grade 2 or 3 histological response was attained in a significantly higher proportion of patients in the DCF group (63%) than in the CF group (5%; P < 0.001). Progression-free survival and overall survival were significantly higher in the DCF group (P = 0.013, hazard ratio 0.473; P = 0.001, hazard ratio 0.344). In conclusion, a grade 3 or 4 hematologic toxicity was common in the DCF group but was managed by supportive therapy. Histological response rate, progression-free survival, and overall survival were significantly higher in the DCF group compared with the CF group.

Pharmacological effects of novel cross-linked hyaluronate, Gel-200, in experimental animal models of osteoarthritis and human cell lines.

OBJECTIVE: To study the pharmacological effects of Gel-200, cross-linked hyaluronate. EXPERIMENTAL DESIGN: We examined the chondroprotective, anti-inflammatory and analgesic effects of Gel-200 in experimental animal models for osteoarthritis (OA) and in a human synovial sarcoma cell line and normal human articular chondrocytes. RESULTS: In the OA model, a single-dose intra-articular (IA) injection of Gel-200 significantly suppressed cartilage degeneration and reduced synovitis of the knee joint. In the joint pain model, Gel-200 significantly suppressed pain responses for 4 weeks after injection. The residual property of Gel-200 in the knee joint tissue was investigated in rabbits. The mean residual ratio of injected Gel-200 in the synovium was 3.3% (95% confidence interval [CI], 2.4-4.2) at 28 days after the injection. The long-lasting analgesic effect of Gel-200 might be explained by its high residual ratio in the joint. In addition, we investigated the mechanism of action of Gel-200 in a human synovial sarcoma cell line and normal human articular chondrocytes. Gel-200 inhibited IL-1ß-induced production of MMP-1, 3 and 13 in human chondrocytes and production of prostaglandin E2 in human synoviocytes in a concentration-dependent manner, respectively. CONCLUSION: A single-dose IA injection of Gel-200 exerts chondroprotective and anti-inflammatory effects in the experimental OA model, and long-lasting analgesia in the joint pain model, suggesting the beneficial multimodal function of Gel-200 against symptomatic OA patients.

The number of metabolic syndrome components is a good risk indicator for both early- and late-stage kidney damage.

BACKGROUND AND AIMS: Renal hyperfiltration (early-stage kidney damage) and hypofiltration (late-stage kidney damage) are common in populations at high risk of chronic kidney disease. This study investigated the associations of renal hyperfiltration and hypofiltration with the number of metabolic syndrome (MetS) components. METHODS AND RESULTS: The study subjects included 205,382 people aged 40-74 years who underwent Specific Health Checkups in Aichi Prefecture, Japan. The prevalence of renal hyperfiltration [estimated glomerular filtration rate (eGFR) above the age-/sex-specific 95th percentile] and hypofiltration (eGFR below the 5th percentile) was compared according to the number of MetS components. We found that the prevalence of both hyperfiltration and hypofiltration increased with increasing number of MetS components (odds ratios for hyperfiltration: 1.20, 1.40, 1.42, 1.41, and 1.77; odds ratios for hypofiltration: 1.07, 1.25, 1.57, 1.89, and 2.21 for one, two, three, four, and five components, respectively, compared with no MetS components). These associations were observed in both normal weight [body mass index (BMI) < 25 kg/m(2)] and overweight (BMI ≥ 25 kg/m(2)) subjects. Renal hyperfiltration was associated with prehypertension and prediabetes, while hypofiltration was associated with dyslipidemia, abdominal obesity, overt hypertension, and overt diabetes. CONCLUSION: The number of MetS components is a good risk indicator of early- and late-stage kidney damage. Therefore, kidney function should be monitored in subjects with MetS components. MetS components should be treated as early as possible to prevent the development of kidney damage and cardiovascular diseases in people with hyperfiltration, regardless of their body weight.

Effect of membrane solubilization on the inhibition of rat and hamster liver microsomal type I 11ß-hydroxysteroid dehydrogenase by bile acids.

The aim of this study was to investigate the differences between rats and hamsters, Two of the most widely used experimental animals, with respect to the effects of microsomal membrane solubilization on the inhibition of liver 11ß-hydroxysteroid dehydrogenase (11ß-HSDI) enzyme by bile acids. Liver microsome fractions were prepared, and the 11ß-HSDI enzymatic activity was measured using cortisone as a substrate. The substrate and various concentrations of bile acids were added to the assay mixtures. After incubation, the products were extracted and analyzed using high-performance liquid chromatography. To investigate the effect of detergent on the inhibitory effects of bile acids, we conducted inhibition tests using Triton X-100-solubilized animal liver microsomes. When solubilized microsomes were used, all bile acids inhibited 11ß-HSDI from rats and hamsters to various degrees. 7α-Hydroxycholanoic acids (cholic acid and chenodeoxycholic acid) in particular had strong inhibitory activities. In hamsters, 7ß-hydroxycholanoic acid (ursodeoxycholic acid) was the strongest inhibitor among the bile acids tested, although its effect was not very strong. When nonsolubilized microsomes were used, deoxycholic acid did not inhibit but rather enhanced the enzymatic activity in both animals. Microsomal content of cholesterol and phospholipids are significantly different between rats and hamsters. Species differences in bile acid inhibition of nonsolubilized microsomes might be reflected not only by structural difference of bile acids, which affect membrane solubilization and enzyme activity directly, but also species difference in microsomal membrane lipid content.

Impact of diabetes and glycaemic control on peripheral artery disease in Japanese patients with end-stage renal disease: long-term follow-up study from the beginning of haemodialysis.

AIMS/HYPOTHESIS: End-stage renal disease (ESRD) patients with diabetes have been regarded as being at the highest risk of cardiovascular disease. We therefore investigated the relationship between diabetes and the incidence of peripheral artery disease (PAD) in new haemodialysis patients. METHODS: We enrolled 1,513 ESRD patients who had just begun haemodialysis therapy. They were divided into two groups: those with (n = 739) and those without diabetes (n = 774). The endpoint was the development of PAD, defined as ankle brachial pressure index ≤ 0.9 or toe brachial pressure index <0.7 in patients with an ankle brachial pressure index >0.9. RESULTS: According to the Kaplan-Meier method, the 10 year event-free rate for development of PAD and lower limb amputation was significantly lower in the diabetes group than in the non-diabetes group (60.3% vs 82.8%, HR 2.99, 95% CI 2.27, 3.92, p<0.0001 and 93.9% vs 98.9%, HR 5.59, 95% CI 2.14, 14.7, p = .0005 for PAD and lower limb amputation, respectively). In patients with diabetes, quartile analysis of HbA1c levels showed that the highest quartile group (≥ 6.8% [51 mmol/mol]) had significant development of PAD and lower limb amputation compared with lower quartile groups (PAD HR 1.63, 95% CI 1.17, 2.28, p = .0038; lower limb amputation HR 2.99, 95% CI 1.17, 7.70, p = .023). CONCLUSIONS/INTERPRETATION: Diabetes was a strong predictor of PAD after initiation of haemodialysis therapy in patients with ESRD. In addition, higher HbA1c levels were associated with increased risk of developing PAD and requiring limb amputation in such diabetic populations.

Interventional radiology for hepatic artery complications soon after living donor liver transplantation in a neonate.

Early hepatic artery complications after liver transplantation in children, having undergone LDLT, can directly affect graft and recipient outcomes, making early diagnosis and treatment essential. In the past, laparotomy (thrombectomy or reanastomosis) was generally employed to treat early hepatic artery complications. Recently, favorable outcomes of IR have been reported. In children, however, the number of such reports is small. To the best of our knowledge, there is no published report on IR applied to neonates with early hepatic artery complications. We recently succeeded in safely using IR for a neonate with early hepatic artery complications after LDLT and obtained a favorable outcome. This case is presented herein.

Hepatic artery reconstruction with the jejunal artery of the Roux-en-Y limb in pediatric living donor liver re-transplantation.

When re-anastomosis and re-transplantation becomes necessary after LDLT, arterial reconstruction can be extremely difficult because of severe inflammation and lack of an adequate artery for reconstruction. Frequently, the recipient's HA is not in good condition, necessitating an alternative to the HA. In such cases, the recipient's splenic artery, right gastroepiploic artery or another vessel can be safely used for arterial reconstruction. There have, however, been few reports on using the jejunal artery. Herein, we report our experience with arterial reconstruction using the jejunal artery of the Roux-en-Y limb as an alternative to the HA. A three-yr-old girl who had developed graft failure due to early HA thrombosis after LDLT required re-transplantation. At re-transplantation, an adequate artery for reconstruction was lacking. We reconstructed the artery by using the jejunal artery of the Roux-en-Y limb, as we judged it to be the most appropriate alternative. After surgery, stent was deployed because hepatic blood flow had reduced due to kinking of the anastomosed site, and a favorable outcome was obtained. In conclusion, when an alternative to the HA is required, using the jejunal artery is a feasible alternative.

Living donor liver transplantation from an asymptomatic mother who was a carrier for ornithine transcarbamylase deficiency.

Liver transplantation (LT) has been adopted as a radical treatment for ornithine transcarbamylase deficiency (OTCD), yielding favorable outcomes. Despite the fact that it is an inheritable disease, a blood relative who is heterozygous for the disorder must sometimes be used as a liver donor for living donor LT. There is ongoing discussion regarding the use of heterozygous donors, however, to our knowledge, no cases where donation was determined based on the Ornithine transcarbamylase (OTC) activity before LT have been reported. Between May 2001 and April 2011, 17 patients were indicated for living donor LT because of OTCD at our facility. There were three cases with heterozygous donor candidate (17.6%). All heterozygous candidates underwent a liver biopsy to measure their OTC activity before LT and made efforts to secure the safety of the both donor and recipient. Two of 3 candidates had headaches sometimes, and their activity was less than 40%, and thus they were not employed as the donor. One candidate with 104.4% activity was employed, yielding favorable outcomes. Our current experience supported the effectiveness of our donation criteria, however it is necessary to collect sufficient data on a large number of patients to confirm the safety of the procedure.

Temporal and sequential changes of glial cells and cytokine expression during neuronal degeneration after transient global ischemia in rats.

BACKGROUND: How glial cells and cytokines are associated with the progression of delayed neuronal death induced by transient global ischemia is still unclear. To further clarify this point, we studied morphological changes in glial cells (microglial cells and astrocytes), and cytokine protein levels, during the progression of neuronal cell loss in CA1 (Cornu Ammonis 1) of the hippocampus after transient global ischemia. METHODS: Morphological changes in glial cells were studied immuno-histochemically. Nine cytokines (IL-1α, IL-1ß, IL-2, IL-4, IL-6, IL-10, GM-CSF, IFN-γ and TNF-α) were simultaneously measured by a multiplexed bead-based immunoassay from 6 h to day21 after transient four vessel occlusion (4VO) in rats. RESULTS: During the process of neuronal loss, we observed four distinct phases: (1) lag phase day0-2 (no NeuN+ cell loss observed), (2) exponential phase day2-7 (NeuN+ cells reduced in number exponentially), (3) deceleration phase day7-14 (reduction rate of NeuN+ cells became low), (4) stationary phase day14 onward (NeuN+ cell loss progressed no longer). In the lag phase, activated glial cells were observed in the entire hippocampus but later were gradually restricted to CA1. Cytokine protein levels in the lag and exponential phases were lower than in the deceleration and stationary phases. IL-1α, IL-1ß, IL-4, IL-6 and IFN-γ in 4VO were significantly higher in all four phases than in sham. Compared with sham level, GM-CSF was significantly high in the deceleration phase. TNF-α was significantly high in both the deceleration and stationary phases. CONCLUSION: Ischemic stress in 4VO activated glial cells in areas beyond CA1 in the lag phase. Pyramidal neurons were injured in CA1 from the end of the lag phase and then neuronal cells reduced in CA1 in the exponential phase. After neuronal death began, the influence of dead cells on glial cells and cytokine expression gradually became stronger than the influence by ischemic stress. Therefore, from the deceleration phase, changes in glial cells and cytokine production were likely caused by dead cells. Cytokine interaction in the microenvironment may determine the functions of IL-1α, IL-1ß, IL-4, IL-6 and IFN-γ in all four phases. The function of GM-CSF and TNF-α in the deceleration phase may be neurotrophic.

Pediatric liver retransplantation from living donors can be considered as a therapeutic option for patients with irreversible living donor graft failure.

Liver retransplantation (re-LT) is required in patients with irreversible graft failure, but it is a significant issue that remains medically, ethically, and economically controversial, especially in living donor liver transplantation (LDLT). The aim of this study was to evaluate the outcome, morbidity, mortality, safety and prognostic factors to improve the outcome of pediatric living donor liver retransplantation (re-LDLT). Six of 172 children that underwent LDLT between January 2001 and March 2010 received a re-LDLT and one received a second re-LDLT. The overall re-LDLT rate was 3.5%. All candidates had re-LDLT after the initial LDLT. The overall actuarial survival of these patients was 83.3% and 83.3% at one and five yr, respectively. These rates are significantly worse than the rates of pediatric first LDLT. Vascular complications occurred in four patients and were successfully treated by interventional radiologic therapy. There were no post-operative biliary complications. One case expired because of hemophagocytic syndrome after re-LDLT. Although pediatric re-LDLT is medically, ethically, and economically controversial, it is a feasible option and should be offered to children with irreversible graft failure. Further investigations, including multicenter studies, are therefore essential to identify any prognostic factors that may improve the present poor outcome after re-LDLT.

Living donor liver transplantation for ornithine transcarbamylase deficiency.

Ornithine transcarbamylase deficiency, the most common urea cycle disorder, causes hyperammonemic encephalopathy and has a poor prognosis. Recently, LT was introduced as a radical OTCD treatment, yielding favorable outcomes. We retrospectively analyzed LT results for OTCD at our facility. Twelve children with OTCD (six boys and six girls) accounted for 7.1% of the 170 children who underwent LDLT at our department between May 2001 and April 2010. Ages at LT ranged from nine months to 11 yr seven months. Post-operative follow-up period was 3-97 months. The post-operative survival rate was 91.7%. One patient died. Two patients who had neurological impairment preoperatively showed no alleviation after LT. All patients other than those who died or failed to show recovery from impairment achieved satisfactory quality-of-life improvement after LT. The outcomes of LDLT as a radical OTCD treatment have been satisfactory. However, neurological impairment associated with hyperammonemia is unlikely to subside even after LT. It is desirable henceforth that more objective and concrete guidelines for OTCD management be established to facilitate LDLT with optimal timing while avoiding the risk of hyperammonemic episodes.

Living donor liver transplantation for neonates using segment 2 monosubsegment graft.

The prognosis of liver transplantation for neonates with fulminant hepatic failure (FHF) continues to be extremely poor, especially in patients whose body weight is less than 3 kg. To address this problem, we have developed a safe living donor liver transplantation (LDLT) modality for neonates. We performed LDLTs with segment 2 monosubsegment (S2) grafts for three neonatal FHF. The recipient age and body weight at LDLT were 13-27 days, 2.59-2.84 kg, respectively. S2 or reduced S2 grafts (93-98 g) obtained from their fathers were implanted using temporary portacaval shunt. The recipient portal vein was reconstructed at a more distal site, such as the umbilical portion, to have the graft liver move freely during hepatic artery (HA) reconstruction. The recipient operation time and bleeding were 11 h 58 min-15 h 27 min and 200-395 mL, respectively. The graft-to-recipient weight ratio was 3.3-3.8% and primary abdominal wall closure was possible in all cases. Although hepatic artery thrombosis occurred in one case, all cases survived with normal growth. Emergency LDLT with S2 grafts weighing less than 100 g can save neonates with FHF whose body weight is less than 3 kg. This LDLT modality using S2 grafts could become a new option for neonates and very small infants requiring LT.

Pharmacokinetic study of the oral administration of procaterol hydrochloride hydrate 50 µg in healthy adult Japanese men.

BACKGROUND: The pharmacokinetics of procaterol, a selective beta2-adrenergic agonist with a high intrinsic efficacy in man, could not be determined in humans when the drug was launched because of the low therapeutic dose and the low sensitivity of the analytical methods available at the time. However, a recently established analytical method using LC-MS/MS has been refined to enable the determination of the pharmacokinetic profile of procaterol and its metabolites in humans. METHODS: Procaterol hydrochloride hydrate 50 µg was administered orally to 8 healthy adult Japanese men. Plasma and urine samples collected from the subjects were analyzed by use of LC-MS/MS for procaterol and its metabolites. RESULTS: Following the oral administration of procaterol hydrochloride hydrate 50 µg, the plasma concentration of procaterol reached a Cmax of 136.4 pg/ml at ~1.44 h post-dose. The mean apparent terminal elimination half-life was ~3.83 h. DM-251 and DM-252, glucuronides of the optical isomers of procaterol, were the main metabolites and both were present in plasma at higher levels than procaterol in the plasma. The 24 h urinary excretion rates of unchanged procaterol, DM-251 and DM-252 were 15.7%, 12.4% and 11.2% of the procaterol administered, respectively. CONCLUSION: This study describes the pharmacokinetic profiles of procaterol and its metabolites following the oral administration of procaterol hydrochloride hydrate 50 µg. Procaterol and its glucuronides were found at high levels in the plasma and urine.

Effect of pituitary adenylate cyclase-activating polypeptide in islet transplantation.

INTRODUCTION: Pituitary adenylate cyclase-activating polypeptide (PACAP) is an islet substance serving as an intra-islet amplifier of glucose-induced insulin secretion similar to exendin-4. It has been reported that systemic administration of PACAP maintained beta-cell mass, delayed the onset of hyperglycemia, and protected beta cells from glucose toxicity. Moreover, PACAP increases glucose-stimulated insulin release in vitro and in vivo. In this study, we investigated the possibility of PACAP use in human islet transplantation. METHODS: Human islets were cultured in the presence or absence of PACAP (10(-12) mol/L) for 48 hours. We assessed beta-cell viability using FACS, cellular composition analysis by iCys/LSC, and glucose-stimulated insulin secretion. In vivo, islets were transplanted beneath the kidney capsule of Streptozotocin-induced diabetic immunodeficient mice. An intravenous glucose tolerance test (IVGTT) was also performed in the presence or absence of PACAP (Peptide International, Louisville, Ky, United States; 1.3 nmol/kg). RESULTS: There were significant improvements in terms of beta-cell viability and cellular composition between islets cultured with or without PACAP, respectively (P < .05). Moreover, glucose-stimulated insulin secretion significantly improved in islets cultured with PACAP compared with controls, respectively (P < .05). Treatment of recipient mice with PACAP resulted in beneficial effects on insulin secretion (PACAP vs control, 13.2 vs 1.9 mU/L), in IVGTT. However, no significant difference was observed in glucose levels between the 2 groups. CONCLUSIONS: Our study indicated that PACAP significantly improved beta-cell viability and survival during culture, and increased insulin secretion in vitro and in vivo. However, blood glucose levels in vivo after an IVGTT did not significantly improve, probably due to increased glucagon secretion from alpha cells. PACAP supplementation to culture medium could be of assistance to improve clinical islet transplantation outcomes.