Evaluation of the Glasgow Prognostic Score in patients receiving chemoradiotherapy for stage III and IV esophageal cancer.

High Glasgow Prognostic scores (GPSs) have been associated with poor outcomes in various tumors, but the values of GPS and modified GPS (mGPS) in patients with advanced esophageal cancer receiving chemoradiotherapy (CRT) has not yet been reported. We have evaluated these with respect to predicting responsiveness to CRT and long-term survival. Between January 2002 and December 2011, tumor responses in 142 esophageal cancer patients (131 men and 11 women) with stage III (A, B and C) and IV receiving CRT were assessed. We assessed the value of the GPS as a predictor of a response to definitive CRT and also as a prognostic indicator in patients with esophageal cancer receiving CRT. We found that independent predictors of CRT responsiveness were Eastern Cooperative Oncology Group (ECOG) performance status, GPS and cTNM stage. Independent prognostic factors were ECOG performance status and GPS for progression-free survival and ECOG performance status, GPS and cTNM stage IV for disease-specific survival. GPS may be a novel predictor of CRT responsiveness and a prognostic indicator for progression-free and disease-specific survival in patients with advanced esophageal cancer. However, a multicenter study as same regime with large number of patients will be needed to confirm these outcomes.

Palmdelphin, a novel target of p53 with Ser46 phosphorylation, controls cell death in response to DNA damage.

The tumor suppressor gene p53 regulates apoptosis in response to DNA damage. Promoter selectivity of p53 depends on mainly its phosphorylation. Particularly, the phosphorylation at serine-46 of p53 is indispensable in promoting pro-apoptotic genes that are, however, poorly determined. In the current study, we identified palmdelphin as a pro-apoptotic gene induced by p53 in a phosphorylated serine-46-specific manner. Upregulation of palmdelphin was observed in wild-type p53-transfected cells, but not in serine-46-mutated cells. Expression of palmdelphin was induced by p53 in response to DNA damage. In turn, palmdelphin induced apoptosis. Intriguingly, downregulation of palmdelphin resulted in necroptosis-like cell death via ATP depletion. Upon DNA damage, palmdelphin dominantly accumulated in the nucleus to induce apoptosis. These findings define palmdelphin as a target of serine-46-phosphorylated p53 that controls cell death in response to DNA damage.

Functional immunocytochemistry of Tragulus placenta: implications for ruminant evolution.

INTRODUCTION AND METHODS: Tragulus, the mouse deer, is considered the most primitive ruminant, with a diffuse placenta grossly quite unlike the cotyledonary type of the other ruminants. This immunocytochemical investigation of placental transporters was designed to elucidate possible mechanisms of evolution to the cotyledonary form. RESULTS AND DISCUSSION: Tragulus expresses several of the major transport systems characteristic of the ruminants: the trophoblast binucleate cell (BNC) dynamics, the requirement for two isoforms, GT1 and GT3, for glucose transport, the provision of Aquaporin 3 for water control, and uterine milk and histiotrophic secretion from uterine glands. However whereas the expression of the 9 kD Calcium Binding Protein (9 CBP) for calcium transport in ruminants is restricted to the intercotyledonary trophoblast with its areolae, Tragulus, having no intercotyledonary area, expresses 9 CBP throughout the villus trophoblast. There is some localised development of areolar-like structures in the mid term Tragulus but it is insignificant at term. The strong expression of Glucose Transporter 1 (GT1) in the BNC granules is unique to Tragulus. CONCLUSION: Tragulus relies on essentially similar transport and BNC dynamics as the other ruminants. Thus the evolutionary pressures driving the development of the cotyledonary placenta probably lie in the increase in body size and the consequent need for a larger placental area to ensure sufficient glucose for the fetus. The delivery in Tragulus of GT1 to the maternal facing side may be this species unique solution to maintain the glucose supply.

BXSB-type genome causes murine autoimmune glomerulonephritis: pathological correlation between telomeric region of chromosome 1 and Yaa.

The autoimmune-prone BXSB/MpJ-Yaa mouse is a model of membranous proliferative glomerulonephritis (MPGN). Severe MPGN has been reported only in male BXSB/MpJ-Yaa mice because of the Y-linked autoimmune accelerator (Yaa) locus. However, we show that female BXSB/MpJ mice develop age-related MPGN without Yaa. Female BXSB/MpJ mice clearly developed MPGN characterized by increased mesangial cells, thickening of the glomerular basement membrane (GBM), double contouring and spike formation of GBM with T-cell infiltrations and podocyte injuries corresponding with increased autoantibody production and albuminuria. Analysis of the renal levels of the Fc gamma receptor (Fcgr) and interferon-activated gene 200 (Ifi200) family genes, which are MPGN candidate genes localized to the telomeric region of chromosome 1 (Chr.1), showed that Fcgr2b levels decreased, whereas Fcgr3 and Ifi202b levels increased in female BXSB/MpJ mice compared with healthy C57BL/6 mice. Furthermore, in isolated glomeruli, microarray analysis revealed that Fcgr3, Fcgr4 and Ifi202b expression was higher in male BXSB/MpJ-Yaa mice than in male BXSB/MpJ mice. These findings indicate that the BXSB/MpJ-type genome causes age-related MPGN with significant contribution from the telomeric region of Chr.1, and Yaa enhances the expression of genes localizing to this locus, thereby leading to severe MPGN in male mice.

Green tea ingestion greatly reduces plasma concentrations of nadolol in healthy subjects.

This study aimed to evaluate the effects of green tea on the pharmacokinetics and pharmacodynamics of the ß-blocker nadolol. Ten healthy volunteers received a single oral dose of 30 mg nadolol with green tea or water after repeated consumption of green tea (700 ml/day) or water for 14 days. Catechin concentrations in green tea and plasma were determined. Green tea markedly decreased the maximum plasma concentration (C(max)) and area under the plasma concentration-time curve (AUC(0-48)) of nadolol by 85.3% and 85.0%, respectively (P < 0.01), without altering renal clearance of nadolol. The effects of nadolol on systolic blood pressure were significantly reduced by green tea. [(3)H]-Nadolol uptake assays in human embryonic kidney 293 cells stably expressing the organic anion-transporting polypeptides OATP1A2 and OATP2B1 revealed that nadolol is a substrate of OATP1A2 (Michaelis constant (K(m)) = 84.3 µmol/l) but not of OATP2B1. Moreover, green tea significantly inhibited OATP1A2-mediated nadolol uptake (half-maximal inhibitory concentration, IC(50) = 1.36%). These results suggest that green tea reduces plasma concentrations of nadolol possibly in part by inhibition of OATP1A2-mediated uptake of nadolol in the intestine.

Effects of green tea extract and (-)-epigallocatechin-3-gallate on pharmacokinetics of nadolol in rats.

Green tea catechins have been shown to affect the activities of drug transporters in vitro, including P-glycoprotein and organic anion transporting polypeptides. However, it remains unclear whether catechins influence the in vivo disposition of substrate drugs for these transporters. In the present study, we investigated effects of green tea extract (GTE) and (-)-epigallocatechin-3-gallate (EGCG) on pharmacokinetics of a non-selective hydrophilic ß-blocker nadolol, which is reported to be a substrate for several drug transporters and is not metabolized by cytochrome P450 enzymes. Male Sprague-Dawley rats received GTE (400 mg/kg), EGCG (150 mg/kg) or saline (control) by oral gavage, 30 min before a single intragastric administration of 10 mg/kg nadolol. Plasma and urinary concentrations of nadolol were determined using high performance liquid chromatography. Pharmacokinetic parameters were estimated by a noncompartmental analysis. Pretreatment with GTE resulted in marked reductions in the maximum concentration (Cmax) and area under the time-plasma concentration curve (AUC) of nadolol by 85% and 74%, respectively, as compared with control. In addition, EGCG alone significantly reduced Cmax and AUC of nadolol. Amounts of nadolol excreted into the urine were decreased by pretreatments with GTE and EGCG, while the terminal half-life of nadolol was not different among groups. These results suggest that the coadministration with green tea catechins, particularly EGCG, causes a significant alteration in the pharmacokinetics of nadolol, possibly through the inhibition of its intestinal absorption mediated by uptake transporters.

An ocular infection model using suckling hamsters inoculated with equine herpesvirus 9 (EHV-9): kinetics of the virus and time-course pathogenesis of EHV-9-induced encephalitis via the eyes.

By using a new member of the neurotropic equine herpesviruses, EHV-9, which induced encephalitis in various species via various routes, an ocular infection model was developed in suckling hamsters. The suckling hamsters were inoculated with EHV-9 via the conjunctival route and were sacrificed after 6, 12, 24, 36, 48, 72, 96, 120, and 144 hours (h) post inoculation (PI). Three horizontal sections of the brains, including the eyes and cranial cavity, were examined histologically to assess the viral kinetics and time-course neuropathological alterations using a panoramic view. At 6 to 24 h PI, there were various degrees of necrosis in the conjunctival epithelial cells, as well as frequent mononuclear cell infiltrations in the lamina propria and the tarsus of the eyelid, and frequent myositis of the eyelid muscles. At 96 h PI, encephalitis was observed in the brainstem at the level of the pons and cerebellum. EHV-9 antigen immunoreactivity was detected in the macrophages circulating in the eyelid and around the fine nerve endings supplying the eyelid, the nerves of the extraocular muscles, and the lacrimal glands from 6 h to 144 h PI. At 96 h PI, the viral antigen immunoreactivity was detected in the brainstem at the level of the pons and cerebellum. These results suggest that EHV-9 invaded the brain via the trigeminal nerve in addition to the abducent, oculomotor, and facial nerves. This conjunctival EHV-9 suckling hamster model may be useful in assessing the neuronal spread of neuropathogenic viruses via the eyes to the brain.

Pathological features of Mycobacterium kansasii infection in black bearded sakis (Chiropotes satanas).

Two black bearded sakis (Chiropotes satanas), kept in the same cage in a zoological park, developed multifocal subcutaneous nodular lesions and were diagnosed as having mycobacterial infection by microscopical examination of tissues and 16S rRNA polymerase chain reaction (PCR) and subsequent sequencing of amplicons. One animal died despite both being treated with prolonged antimicrobial therapy. This animal had disseminated disease with lesions in the liver, spleen, lymph nodes and brain. The lesions were granulomatous in nature, but organisms were not identified by acid-fast staining other than on an impression smear of one of the skin nodules. The granulomatous lesions lacked epithelioid macrophages, multinucleated giant cells and fibrous encapsulation. Mycobacterium kansasii was identified by PCR in the lymph nodes of the animal with disseminated disease. Mycobacterial speciation was not as readily achieved in the animal with cutaneous nodules only.

Orbital embryonal rhabdomyosarcoma with metastasis in a young dog.

A 2-year-old male Welsh corgi dog was brought to an animal hospital because of left upper eyelid enlargement with lachrymal gland protrusion. The lachrymal and orbital cavity mass was removed surgically. Microscopically, the orbital mass consisted of a mixture of large rhabdomyoblastic and small round tumour cells. Immunohistochemically, the rhabdomyoblastic cells expressed desmin and myoglobin and the small round cells expressed desmin, myogenin and MyoD1. A diagnosis of embryonal rhabdomyosarcoma (ERS) was made. One month later, multiple masses throughout the body were identified, in particular around the cervical region. One of these lesions was sampled and diagnosed as metastatic ERS. The dog died 84 days after the time of first admission.

Second-line docetaxel plus cisplatin for advanced gastric cancer showing resistance to S-1.

The purpose of this study was to clarify the efficacy and safety of docetaxel and cisplatin as second-line treatment for patients with S-1 refractory advanced gastric cancer. Between 1999 and 2006, 32 patients received docetaxel (60 mg/m²) and cisplatin (60 mg/m²) (Dp regimen) on day 1 every 3 weeks. This regimen was repeated at least three times at 3-week intervals until disease progression or unacceptable toxicity was detected. The overall response rate was 21.9%. Seven patients showed partial response, 17 showed stable disease and 8 showed disease progression. The median survival time was 12.3 months after the start of the first-line treatment. The median survival time and time to progression following the DP regimen was 7.8 months and 4.0 months, respectively. The major adverse effects were leukopenia and neutropnea. Non-hematological toxicities were generally mild to moderate and controllable. this study showed satisfactory therapeutic outcomes for patients with gastric cancer refractory to S- 1 chemotherapy.

Effect of volitional relaxation and motor imagery on F wave and MEP: do these tasks affect excitability of the spinal or cortical motor neurons?

OBJECTIVE: To test if simple motor imagery, like thumb abduction, preferentially influences the excitability of the spinal or cortical motoneurons. METHODS: Ten healthy subjects underwent two separate experiments, each consisting of recording F waves and MEPs from abductor pollicis brevis (APB) in three consecutive sessions: (1) baseline, (2) after immobilizing APB for 3 h, and (3) after brief muscle exercise. During the immobilization, the subjects were instructed to volitionally relax APB in experiment 1 (relaxation task), and mentally simulate thumb abduction without actual movement in experiment 2 (imagery task). RESULTS: Relaxation task suppressed both MEPs and F waves. Motor imagery reduced this suppression, restoring F waves nearly completely (94%) and MEPs only partially (77%). Hence, the rest-induced decline of MEPs in part results from cortical modulation. In contrast, statistical analysis revealed no differences in imagery-induced recovery of motoneuron excitabilities whether assessed by F wave or MEP. Thus, increased excitability of spinal motoneurons responsible for F-wave changes also accounts for recovery of MEPs. CONCLUSIONS: Volitional relaxation depresses the spinal and cortical motoneurons, whereas mental simulation counters rest-induced suppression primarily by restoring spinal excitability. SIGNIFICANCE: The present findings help elucidate physiologic mechanisms underlying motor imagery.

Population of follicles and luteal structures during the oestrous cycle of mares detected by three-dimensional internal structure microscopy.

The structure of the equine ovary is different from that of other mammals in its extremely large size, the presence of ovarian fossa and the inverted location of its cortex and medulla. A three-dimensional internal structure microscopy (3D-ISM), which consists of a computer-controlled slicer, a CCD camera, a laser disc recorder and a PC, is very useful for the observation of the internal structures in equine ovaries. In addition, the three-dimensional images of follicles and corpus luteum (CL) reconstructed by the segmentation technique can clarify the spatial arrangement in the equine ovary. In this study, to understand the changes in the ovarian internal structures of the mare during the oestrous cycle, the size and numbers of follicles and luteal structures were analysed by 3D-ISM in addition to the concentrations of progesterone (P(4)) and oestradiol-17beta. As a result, many small follicles (<10 mm in diameter) were detected. It was recognized that the luteal structures were distinguished into three types, such as the corpus haemorragicum (CH), which is formed by blood elements at the cavity after ovulation, CL and corpus albican (CA). There were some CHs and CL in the group, which had the concentration of P(4) > 1 ng/ml. CHs were also observed in the group, which had low level of P(4) (P(4) < 1 ng/ml). CAs were found regardless of the P(4) level. In conclusion, 3D-ISM enabled the internal observation of the ovarian structures in detail, and estimation of the stage of the ovarian cycle with complementary physiological information. The findings by 3D-ISM provide basic information for clinical applications.

Distribution of lectin-bindings in the testis of the lesser mouse deer, Tragulus javanicus.

The distribution of lectin bindings in the testis of the smallest ruminant, lesser mouse deer (Tragulus javanicus), was studied using 12 biotinylated lectins specific for d-galactose (peanut agglutinin PNA, Ricinus communis agglutinin RCA I), N-acetyl-d-galactosamine (Dolichos biflorus agglutinin DBA, Vicia villosa agglutinin VVA, Soybean agglutinin SBA), N-acetyl-D-glucosamine and sialic acid (wheat germ agglutinin WGA, s-WGA), D-mannose and d-glucose (Lens culinaris agglutinin LCA, Pisum sativum agglutinin PSA, Concanavalin A Con A), L-fucose (Ulex europaeus agglutinin UEA I), and oligosaccharide (Phaseolus vulgaris agglutinin PHA-E) sugar residues. In Golgi-, cap-, and acrosome-phase spermatids, lectin-bindings were found in the acrosome (PNA, RCA I, VVA, SBA, WGA and s-WGA), and in the cytoplasm (PNA, RCA I, VVA, SBA, WGA, LCA, PSA, Con A and PHA-E). s-WGA binding was confined to the spermatid acrosome, but other lectins were also observed in spermatocytes. In spermatogonia, VVA, WGA, Con A, and PHA-E bindings were observed. Sertoli cells were intensely stained with DBA and Con A, and weakly with PHA-E. In interstitial Leydig cells, RCA I, DBA, VVA, Con A, PSA, LCA, WGA and PHA-E were positive. UEA I was negative in all cell types including spermatogenic cells. Unusual distribution of lectin-bindings noted in the testis of lesser mouse deer included the limited distribution of s-WGA only in the spermatid acrosome, the distribution of DBA in Sertoli cells, Leydig cells and lamina propria, and the absence of UEA I in all type cells. The present results were discussed in comparison with those of other animals and their possible functional implications.

Involvement of organic anion transporting polypeptides in the toxicity of hydrophilic pravastatin and lipophilic fluvastatin in rat skeletal myofibres.

BACKGROUND AND PURPOSE: There is a discrepancy in the adverse effect of 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors, statins between the clinical reports and the studies using skeletal muscle cell models. In the clinical reports, both hydrophilic and lipophilic statins induce myotoxicity, whereas in in vitro experiments using cell lines of myoblasts, lipophilic, but not hydrophilic, statins exert myotoxicity. We investigated the cause of this discrepancy. EXPERIMENTAL APPROACH: Skeletal myofibres, fibroblasts and satellite cells were isolated from rat flexor digitorum brevis (FDB) muscles. Using these primary cultured cells as well as the L6 myoblast cell line, we compared the toxicity of hydrophilic pravastatin and lipophilic fluvastatin. The mRNA expression levels of possible drug transporters for statins were also examined in these cells using reverse transcriptase-PCR. KEY RESULTS: In the skeletal myofibres, both pravastatin and fluvastatin induced vacuolation and cell death, whereas in the mononuclear cells only fluvastatin, but not pravastatin, was toxic. mRNA of the organic anion transporting polypeptides (Oatp) 1a4 and Oatp2b1 were expressed in the skeletal myofibres, but not in mononucleate cells. Estrone-3-sulphate, a substrate for Oatps, attenuated the effects of pravastatin and fluvastatin in skeletal myofibres; p-aminohippuric acid, a substrate for the organic anion transporters (Oats), but not Oatps, failed to do so. CONCLUSIONS AND IMPLICATIONS: The statin transporters Oatp1a4 and Oatp2b1 are expressed in rat skeletal myofibres, but not in satellite cells, fibroblasts or in L6 myoblasts. This is probably why hydrophilic pravastatin affects skeletal muscle, but not skeletal myoblasts.

Effect of motion imagery to counter rest-induced suppression of F-wave as a measure of anterior horn cell excitability.

OBJECTIVE: To test if motor imagery prevents the rest-induced suppression of anterior horn cell excitability. METHODS: Ten healthy subjects underwent two separate experiments, each consisting of stimulating the median nerve 100 times and recording F-waves from abductor pollicis brevis (APB) in three consecutive sessions: (1) after muscle exercise to standardize the baseline, (2) after immobilization of APB for 3h and (3) after muscle exercise to check recovery. We instructed the subject to volitionally relax APB in experiment 1 (relaxation task), and to periodically simulate thumb abduction without actual movement in experiment 2 (imagery task). RESULTS: F-wave persistence and amplitude declined after relaxation task and recovered quickly after exercise, but changed little with imagery task. F-wave latencies showed no change when analyzed individually. The frequency distribution of collective F-waves recorded from all subjects remained the same after relaxation task, but showed a shift toward longer latencies after imagery task. CONCLUSIONS: Mental imagery without overt motor output suffices to counter the effect of sustained volitional muscle relaxation, which would, otherwise, cause a reversible reduction in anterior horn cell excitability. SIGNIFICANCE: This finding documents the importance of central drive for spinal excitability, which affects F-wave studies of a paretic muscle.

Delayed bile leakage from a remaining part of segment 8 in a posterior section graft after living donor liver transplantation: a common pitfall in harvesting a posterior section graft? A case report.

In Japan and Korea, where availability of deceased donor organs for solid organ transplantation remains rare, living donor liver transplantation (LDLT) using a posterior section graft (PSG; segments VI+VII, according to Couinaud's Nomenclature for liver segmentation) has now been accepted as a standard procedure that balances donor risk and patient benefits for cases in which right hemi-liver donation is too risky, because of marked volume imbalances between right and left hemi-livers. Compared with other types of grafts, however, the procedure requires detailed knowledge concerning hepatic vascular anatomy and meticulous manipulation during donation surgery. We present herein a case of delayed bile leakage from a remaining part of segment 8 in a PSG, which was considered to be a complication peculiar to LDLT using a PSG.

Novel erythrocyte pits in the small tropical ruminant, lesser mouse deer.

We examined unique erythrocyte pits of the peripheral blood and bone marrow in the lesser mouse deer, Tragulus javanicus, using scanning electron microscope (SEM) and transmission electron microscope (TEM). Under the SEM observation, the pit was observed as a hole on both mature erythrocytes of the peripheral blood and immature erythrocytes of the bone marrow. By the TEM, the mature erythrocytes had a vacuole, which showed complicated shape and occupied considerable space within the cytoplasm. The vacuole was communicated extracellularly by perforation, which corresponded to the hole on the cell surface. In the bone marrow, erythroblast and reticulocytes have a cytoplasmic vacuole. This abnormal feature of the erythrocytes is peculiar to the mouse deer, and not found in other tropical ruminants. Despite the disadvantage of volume loss from the small erythrocytes, the mouse deer were healthy and showed no signs of anaemia.

A light and electron microscopical study of the Tragulid (mouse deer) placenta.

The Tragulidae are the living relics of the basal ruminant stock. They have a diffuse placenta, with no aggregations of the placental villi into localised placentomes characteristic of all other ruminants. Despite this difference, this ultrastructural and immunocytochemical investigation demonstrates that in Tragulus the trophoblast binucleate cell (BNC) plays the same central role in development and structure as in all other ruminants. It shows an identical development and ultrastructure, produces granules reactive with bovine placental lactogen and pregnancy associated glycoprotein antibodies, and migrates when mature through the trophoblast tight junction to fuse into a mosaic of syncytial plaques from which the granules are released to the mother and which have replaced the uterine epithelium. Unlike the persistent plaques in the sheep and goat placenta, in Tragulus they are transient, dying by apoptosis with the fragments phagocytosed by the trophoblast. This brings the trophoblast into direct endotheliochorial apposition to maternal tissue until BNC migration and fusion replace the dead plaque. This intimate fetomaternal confrontation has not been shown in any other ruminant, and could be a relic of the evolutionary development of the synepitheliochorial from the original basic eutherian endo- or hemo-chorial placenta.

Immunolocalization of gastrin-releasing peptide (GRP) in the uteroplacenta of the mouse deer.

The considerable phylogenetical differences between mouse deer and other ruminants have been established by means of DNA sequence analysis and anatomical observations. To clarify the physiological role of the uteroplacenta of the mouse deer, immunohistochemical observation was attempted by using GRP, which has been suggested as a novel regulatory peptide in the female reproductive tract, as an indicator to compare with other ruminants. Strong positive reactions for the GRP were detected in the uterine glands of the pregnant animals, but not in the non-pregnant ones. Although the placenta of the mouse deer is categorized as a diffuse placenta that is different from other ruminants' polycotyledonary placenta, in terms of GRP immunoreactivity, the mouse deer placenta can be classified as a synepithecholial placenta like the other ruminants'. The secretion of GRP from the uterine glands is of some importance to the fetus in the mouse deer.