Clinical value of additional resection of a margin-positive distal bile duct in perihilar cholangiocarcinoma.

BACKGROUND: Little is known about the effect of additional resection for a frozen-section-positive distal bile duct margin (DM) in perihilar cholangiocarcinoma. METHODS: Patients who underwent surgical resection for perihilar cholangiocarcinoma between 2001 and 2015 were analysed retrospectively, focusing on the DM. RESULTS: Of 558 consecutive patients who underwent frozen-section examination for a DM, 74 (13·3 per cent) had a frozen-section-positive DM with invasive cancer or carcinoma in situ. Eventually, 53 patients underwent additional resection (bile duct resection in 44 and pancreatoduodenectomy in 9), whereas the remaining 21 patients did not. Ultimately, R0 resection was achieved in 30 of the 53 patients (57 per cent). No patient who underwent additional resection died from surgical complications. The 44 patients with additional bile duct resection had a 5-year overall survival rate of 31 per cent. Overall survival of the nine patients who had pancreatoduodenectomy was better, with a 10-year rate of 67 per cent. Survival of the 21 patients without additional resection was dismal: all died within 5 years. Multivariable analyses identified nodal status and additional resection as independent prognostic factors (lymph node metastasis: hazard ratio (HR) 2·26, 95 per cent c.i. 1·26 to 4·07; bile duct resection versus no additional resection: HR 0·32, 0·17 to 0·60; pancreatoduodenectomy versus no additional resection: HR 0·08, 0·02 to 0·29). CONCLUSION: Additional resection for frozen-section-positive DM in perihilar cholangiocarcinoma frequently yields R0 margins. It offers a better chance of long-term survival, and thus should be performed in carefully selected patients.

Benign hilar bile duct strictures resected as perihilar cholangiocarcinoma.

BACKGROUND: Differentiation between perihilar cholangiocarcinoma (PHCC) and benign strictures is frequently difficult. The aim of this study was to investigate the incidence and long-term outcome of patients with tumours resected because of suspicion of PHCC, which ultimately turned out to be benign (malignancy masquerade). METHODS: Patients who underwent surgical resection with a diagnosis of PHCC between 2001 and 2016 were reviewed retrospectively. RESULTS: Among 707 consecutive patients, 685 had PHCC and the remaining 22 (3·1 per cent) had benign biliary stricture. All patients with benign disease underwent major hepatectomy, with no deaths. Preoperative histological assessment using bile duct biopsy or aspiration cytology had a high specificity (90 per cent), low sensitivity (62 per cent) and unsatisfactory accuracy (63 per cent). Despite the increasing use of histological assessment, the incidence of benign strictures resected did not decrease over time, being 0·9 per cent in 2001-2004, 4·0 per cent in 2005-2008, 3·8 per cent in 2009-2012 and 2·9 per cent in 2013-2016. The final pathology of benign strictures included IgG4-related sclerosing cholangitis (9 patients), hepatolithiasis (4), granulomatous cholangitis (3), non-specific chronic cholangitis (3), benign strictures after cholecystectomy (2), and a benign stricture possibly caused by parasitic infection (1). The 10-year overall survival rate for the 22 patients with benign stricture was 87 per cent, without recurrence of biliary stricture. CONCLUSION: The incidence of benign strictures resected as PHCC as a proportion of all resections was relatively low, at 3·1 per cent. Currently, unnecessary surgery for suspected PHCC is unavoidable.

ANTECEDENTES: La diferenciación entre colangiocarcinoma perihilar (perihilar colangiocarcinoma, PHCC) y estenosis benignas es con frecuencia difícil. El objetivo de este estudio fue investigar la incidencia y el resultado a largo plazo de los tumores resecados con sospecha diagnóstica de PHCC, que finalmente resultaron ser benignos (malignidad enmascarada). MÉTODOS: Se revisaron retrospectivamente los pacientes con diagnóstico de PHCC que se sometieron a resección quirúrgica entre 2001 y 2016. RESULTADOS: Entre 707 pacientes consecutivos, 685 pacientes presentaban PHCC y los 22 restantes (3,1%) tenían una estenosis biliar benigna. Todos los pacientes con patología benigna se sometieron a una hepatectomía mayor, sin mortalidad. La evaluación histológica preoperatoria mediante biopsia de conducto biliar o citología por aspiración tuvo una alta especificidad (90%), una baja sensibilidad (62%) y una exactitud diagnóstica insatisfactoria (63%). A pesar del uso creciente de la evaluación histológica, la incidencia de estenosis benignas resecadas no disminuyó con el tiempo, con un 0,9% en 2001-2004, un 4,0% en 2005-2008, un 3,8% en 2009-2012 y un 2,9% en 2013-2016. La patología final de las estenosis benignas incluyó colangitis esclerosante relacionada con IgG4 (n = 9), hepatolitiasis (n = 4), colangitis granulomatosa (n = 3), colangitis crónica no específica (n = 3), estenosis benignas tras una colecistectomía (n = 2) y una estenosis benigna posiblemente causada por una infección parasitaria (n = 1). Los resultados a largo plazo de los 22 pacientes con estenosis benigna fueron mejores (tasa de supervivencia a 10 años; 87,4%) sin recidiva de la estenosis biliar. CONCLUSIÓN: La incidencia de pacientes con estenosis benignas resecadas como PHCC en comparación con todas las resecciones fue relativamente baja, del 3,1%. Actualmente, la cirugía "innecesaria" por sospecha de PHCC es inevitable.

Precision Analysis of the

We present a precision analysis of the ^{136}Xe two-neutrino ßß electron spectrum above 0.8 MeV, based on high-statistics data obtained with the KamLAND-Zen experiment. An improved formalism for the two-neutrino ßß rate allows us to measure the ratio of the leading and subleading 2νßß nuclear matrix elements (NMEs), ξ_{31}^{2ν}=-0.26_{-0.25}^{+0.31}. Theoretical predictions from the nuclear shell model and the majority of the quasiparticle random-phase approximation (QRPA) calculations are consistent with the experimental limit. However, part of the ξ_{31}^{2ν} range allowed by the QRPA is excluded by the present measurement at the 90% confidence level. Our analysis reveals that predicted ξ_{31}^{2ν} values are sensitive to the quenching of NMEs and the competing contributions from low- and high-energy states in the intermediate nucleus. Because these aspects are also at play in neutrinoless ßß decay, ξ_{31}^{2ν} provides new insights toward reliable neutrinoless ßß NMEs.

Localization of muscle damage within the quadriceps femoris induced by different types of eccentric exercises.

This study examined localization of muscle damage within the quadriceps femoris induced by different types of eccentric exercises by using transverse relaxation time (T2 )-weighted magnetic resonance imaging (MRI). Thirty-three young males performed either of the following three exercises: single-joint eccentric contraction of the knee extensors (KE), eccentric squat (S), or downhill walking (DW) (n=11/exercise). KE and S consisted of 5-set×10-lowering of 90% one-repetition maximum load. DW was performed for 60 minutes with -10% slope, 6 km/h velocity, and 20% body mass load carried. At pre- and 24-, 48-, and 72-hours post-exercise, T2 -MRI was scanned and T2 values for the rectus femoris (RF), vastus intermedius (VI), vastus lateralis (VL), and vastus medialis (VM) at proximal, middle, and distal sites were calculated. Additionally, soreness felt when static pressure was applied to these sites and maximal isometric knee extension torque were measured. Maximal torque significantly (P<.05) decreased (7%-15%) at 24-48 hours after all exercises. T2 significantly increased (3%-9%) at 24-72 hours after all exercises, with heterogeneities within the muscles found in each exercise. Effect size and peak change of T2 , as well as soreness, overall indicated that the proximal RF after KE and middle VM after S and DW were most affected by these exercises. The VL did not show any significant T2 increase after all exercises. These results suggest that muscle damage specifically localizes at the proximal RF by KE and at the middle VM by S and DW, while the VL is least damaged regardless of the exercises.

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.

Pathogenetic role of an autoimmune susceptibility locus derived from MRL/MpJ strain chromosome 1 in chronic pancreas inflammation.

We examined the role of Mag, an autoimmune susceptibility locus encoded by the telomeric region of MRL/MpJ mouse chromosome 1, in the pathogenesis of autoimmune exocrinopathy. At nine to 12 months of age, strain-specific differences were observed in the pancreas of the animals. B- and T-cell-containing periductal/perivascular cell infiltrations in the pancreases of MRL/MpJ and B6.MRLc1 congenic C57BL/6-background Mag-carrying strains were more severe than were those of C57BL/6. Pancreatic periductal/perivascular cell infiltration was observed frequently in A/J, AKR/N, B6.MRLc1, C57BL/6, and MRL/MpJ, moderately in DBA/1 and DBA/2, and rarely in BALB/c and C3H/He strains. Females tended to have greater pancreatic periductal/perivascular cell infiltration than males. C57BL/6 mice possessed defined borders between cell infiltrations and acini, but borders were indistinct in MRL/MpJ and B6.MRLc1 mice. We attributed this to the invasion of inflammatory cells between each acinus and the disruption of acinar cells around cell infiltrations in the latter strains. No strain-specific differences were observed in the appearance of fibrotic lesions and high endothelial venules in the cell infiltrates. The levels of serum anti-dsDNA antibodies and amylase, and mRNA expression of tumor necrosis factor-α and Fc gamma receptor III (encoded on Mag) in the pancreases, were elevated in MRL/MpJ- and B6.MRLc1-strain mice relative to C57BL/6. These results emphasized the crucial roles of Mag in the molecular and genetic pathogenesis of autoimmune-mediated pancreatitis.

Effect of cooling during inter-exercise periods on subsequent intramuscular water movement and muscle performance.

To evaluate the effects of cooling between exercise sessions on intramuscular water movement and muscle performance, the lower extremities of nine untrained men were assigned to either a cooling protocol (20-min water immersion, 15 °C) or a noncooling protocol. Each subject performed two exercise sessions involving maximal concentric knee extension and flexion (three repetitions, 60°/s; followed by 50 repetitions, 180°/s). The peak torque at 60°/s and total work, mean power, and decrease rate of torque value at 180°/s were evaluated. Axial magnetic resonance diffusion-weighted images of the mid-thigh were obtained before and after each exercise session. Apparent diffusion coefficient (ADC) values for the quadriceps and hamstrings were calculated for evaluating intramuscular water movement. Both groups exhibited significantly increased ADC values for the quadriceps and hamstrings after each exercise session. These ADC values returned to the pre-exercise level after water immersion. No significant difference was observed in muscle performance from first exercise session to the next in either group, except for increased total work and mean power in knee flexion in the cooled group. Cooling intervention between exercise sessions decreased exercise-induced elevation of intramuscular water movement and had some beneficial effects on muscle endurance of knee flexors, but not knee extensors.

Major hepatectomy with combined vascular resection for perihilar cholangiocarcinoma.

BACKGROUND: Hepatectomy with vascular resection (VR) for perihilar cholangiocarcinoma (PHCC) is a challenging procedure. However, only a few reports on this procedure have been published and its clinical significance has not been fully evaluated. METHODS: Patients undergoing surgical resection for PHCC from 2002-2017 were studied. The surgical outcomes of VR and non-VR groups were compared. RESULTS: Some 238 patients were included. VR was performed in 85 patients. The resected vessels were hepatic artery alone (31 patients), portal vein alone (37 patients) or both (17 patients). The morbidity rates were almost the same in the VR (49.4 per cent) and non-VR (43.8 per cent) groups (P = 0.404). The mortality rates of VR (3.5 per cent) and non-VR (3.3 per cent) were also comparable (P > 0.999). The median survival time (MST) was 45 months in the non-VR group and 36 months in VR group (P = 0.124). Among patients in whom tumour involvement was suspected on preoperative imaging and whose carbohydrate antigen 19-9 (CA19-9) value was 37 U/ml or less, MST in the VR group was significantly longer than that in the non-VR group (50 versus 34 months, P = 0.017). In contrast, when the CA19-9 value was greater than 37 U/ml, MST of the VR and non-VR groups was comparable (28 versus 29 months, P = 0.520). CONCLUSION: Hepatectomy with VR for PHCC can be performed in a highly specialized hepatobiliary centre with equivalent short- and long-term outcomes to hepatectomy without VR.

Utility of remnant liver volume for predicting posthepatectomy liver failure after hepatectomy with extrahepatic bile duct resection.

BACKGROUND: Hepatectomy with extrahepatic bile duct resection is associated with a high risk of posthepatectomy liver failure (PHLF). However, the utility of the remnant liver volume (RLV) in cholangiocarcinoma has not been studied intensively. METHODS: Patients who underwent major hepatectomy with extrahepatic bile duct resection between 2002 and 2018 were reviewed. The RLV was divided by body surface area (BSA) to normalize individual physical differences. Risk factors for clinically relevant PHLF were evaluated with special reference to the RLV/BSA. RESULTS: A total of 289 patients were included. The optimal cut-off value for RLV/BSA was determined to be 300 ml/m2. Thirty-two patients (11.1 per cent) developed PHLF. PHLF was more frequent in patients with an RLV/BSA below 300 ml/m2 than in those with a value of 300 ml/m2 or greater: 19 of 87 (22 per cent) versus 13 of 202 (6.4 per cent) (P < 0.001). In multivariable analysis, RLV/BSA below 300 ml/m2 (P = 0.013), future liver remnant plasma clearance rate of indocyanine green less than 0.075 (P = 0.031), and serum albumin level below 3.5 g/dl (P = 0.015) were identified as independent risk factors for PHLF. Based on these risk factors, patients were classified into three subgroups with low (no factors), moderate (1-2 factors), and high (3 factors) risk of PHLF, with PHLF rates of 1.8, 14.8 and 63 per cent respectively (P < 0.001). CONCLUSION: An RLV/BSA of 300 ml/m2 is a simple predictor of PHLF in patients undergoing hepatectomy with extrahepatic bile duct resection.

Absence of microsatellite instability in extramammary Paget's disease.

Background: Deficiency of DNA mismatch repair (MMR) induces microsatellite instability (MSI). Pembrolizumab, an antibody targeting PD-1 (an immune checkpoint inhibitor), is more effective against MMR-deficient tumours than against MMR-proficient tumours. The status of MMR is a useful biomarker for predicting the effectiveness of pembrolizumab administration. Although the status of MMR has attracted attention in skin tumours, there are few reports on MSI in extramammary Paget's disease (EMPD). Objectives: To evaluate the status of MMR in patients with EMPD. Materials & Methods: One hundred one patients with EMPD were included. MMR status of the genomic DNA of each subject was analysed using Promega panel (approved as a companion diagnostic agent for the administration of pembrolizumab). Results: MSI testing showed the occurrence rates of MSI-high (more than two markers are unstable), MSI-low (one marker is unstable) and MSS (all markers are stable) tumour tissues were 0% (0/101), 1.0% (1/101) and 99.0% (100/101), respectively. Conclusion: The status of MMR may not be useful for the potential therapeutic application of pembrolizumab.

Overexpression of interferon-activated gene 202 (Ifi202) correlates with the progression of autoimmune glomerulonephritis associated with the MRL chromosome 1.

B6.MRLc1(82-100) congenic mice carrying the telomeric region of lupus-prone MRL chromosome 1 develop autoimmune glomerulonephritis (GN). The GN susceptibility locus of B6.MRLc1(82-100) contains the interferon activated gene 200 (Ifi200) family, which consists of Ifi202, 203, 204, and 205. Recently, Ifi202 was suggested as a candidate gene for murine lupus. In this study, we assessed the association between Ifi200 family and GN in several disease models. We compared the expression of Ifi200 family members in 24 organs between the C57BL/6 and B6.MRLc1(82-100). The expressions of Ifi200 family members differed between strains, and the most dramatic differences appeared in Ifi202 expression. Briefly, in the blood, immune organs, lungs, and testes mRNA expression was higher in B6.MRLc1(82-100) mice. In the kidney and immune organs, only Ifi202 expression increased with the development of GN in B6.MRLc1(82-100), and significant differences from C57BL/6 were observed even before disease onset. Ifi202 expression in the kidneys of BXSB, NZB/WF1, and MRL/lpr was also significantly high in the early- and late-disease stages. Furthermore, laser microdissection-reverse-transcriptase-polymerase chain reaction analysis confirmed the high Ifi202 expression in all areas of B6.MRLc1(82-100) kidneys. In conclusion, in the Ifi200 family, Ifi202 expressions in the kidney and immune organs significantly increased with GN progression.

PGE2 signal via EP2 receptors evoked by a selective agonist enhances regeneration of injured articular cartilage.

OBJECTIVE: The effect of the prostaglandin E2 (PGE2) signal through prostaglandin E receptor 2 (EP2) receptors on the repair of injured articular cartilage was investigated using a selective agonist for EP2. METHODS: Chondral and osteochondral defects were prepared on the rabbit femoral concave in both knee joints, and gelatin containing polylactic-co-glycolic acid microspheres conjugated with or without the EP2 agonist was placed nearby. Animals were sacrificed at 4 or 12 weeks post-operation, and regenerated cartilage tissues and subchondral structure remodeling were evaluated by histological scoring. The quality of regenerated tissues was also evaluated by the immunohistochemical staining of EP2, type II collagen, and proliferating cell nuclear antigen (PCNA). As an evaluation of side effects, the inflammatory reaction of the synovial membrane was analyzed based on histology and the mRNA expression of matrix metalloproteinase3 (MMP3), tissue inhibitor of metalloproteinase 3 (TIMP3), and interleukin-1 beta (IL-1 beta). Also, the activity of MMP3 and the amount of tumor necrosis factor-alpha (TNF-alpha) and C-reactive protein in joint fluid were measured. RESULTS: In both models, the EP2 agonist enhanced the regeneration of the type II collagen-positive tissues containing EP2- and PCNA-positive chondrocytes, and the histological scale of regenerated tissue and subchondral bone was better than that of on the control side, particularly at 12 weeks post-operation. No inflammatory reaction in the synovial membrane was observed, and no induction of pro-inflammatory cytokines was found in joint fluid. CONCLUSION: Selective stimulation of the PGE2 signal through EP2 receptors by a specific agonist promoted regeneration of cartilage tissues with a physiological osteochondral boundary, suggesting the potential usefulness of this small molecule for the treatment of injured articular cartilages.

Genetic diversity of gamma-hexachlorocyclohexane-degrading sphingomonads isolated from a single experimental field.

AIMS: To isolate gamma-hexachlorocyclohexane (gamma-HCH)-degrading bacteria from a single field and to examine their genetic diversity. METHODS AND RESULTS: Gamma-HCH-degrading bacteria were screened from a long-term experimental field in which gamma-HCH has been continuously applied to, and a gamma-HCH-degrading sphingomonad strain SS86 was isolated from in 1986. As the result, five strains of sphingomonads were newly isolated. The sequences of several housekeeping genes separated the six strains, including SS86, into two genotypes. Among the genes involved in gamma-HCH degradation, the sequences of linC, linD and linE were identical among all six strains, that of linA was identical among five strains, and that of linB was diverse. CONCLUSIONS: We calculated that the gamma-HCH-degrading populations of the two genotypes arose independently. Not just one but diverse sphingomonads that degrade a particular xenobiotic compound possibly tend to arise and/or accumulate in fields, where that compound has been applied. SIGNIFICANCE AND IMPACT OF THE STUDY: This study indicates the potential usefulness of a long-term continuous application of xenobiotic compounds to an experimental field in that it would potentially generate diverse micro-organisms able to degrade the compounds.

Only three mutations account for almost all defective alleles causing adenine phosphoribosyltransferase deficiency in Japanese patients.

We analyzed mutant alleles of adenine phosphoribosyltransferase (APRT) deficiency in Japanese patients. Among 141 defective APRT alleles from 72 different families, 96 (68%), 30 (21%), and 10 (7%) had an ATG to ACG missense mutation at codon 136 (APRT*J allele), TGG to TGA nonsense mutation at codon 98, and duplication of a 4-bp sequence in exon 3, respectively. The disease-causing mutations of only four (3%) of all the alleles among Japanese remain to be elucidated. Thus, a diagnosis can be made for most of the Japanese APRT-deficient patients by identifying only three disease-causing mutations. All of the different alleles with the same mutation had the same haplotype, except for APRT*J alleles, thereby suggesting that alleles with the same mutation in different families were derived from the same ancestral gene. Evidence for a crossover or gene conversion event within the APRT gene was observed in an APRT*J mutant allele. Distribution of mutant alleles encoding APRT deficiency among the Japanese was similar to that seen in cystic fibrosis genes among Caucasians and Tay-Sachs genes among the Ashkenazi Jews.

Characterization of ferritin from human placenta. Implications for analysis of tissue specificity and microheterogeneity of ferritins.

Mammalian ferritins can be resolved into multiple components by isoelectric focusing, and each tissue contains a characteristic subset of isoferritins. Ferritin isolated from human liver was compared to acidic ferritin isolated from mid-gestational human placenta to define a structural basis for ferritin heterogeneity. Placenta ferritin contained several major bands with isoelectric points in the range of pI = 4.7-5.0 which were more acidic than the predominant isoferritins of human liver. Ferritin from each tissue was resistant to denaturation by 10 M urea and appeared to be identical by electron microscopy. Circular dichroism measurements revealed that placenta ferritin had substantially less ordered secondary structure than liver ferritin. Both types of ferritin contained only two subunits when analyzed by electrophoresis in sodium dodecyl sulfate gels, but isoelectric focusing of dissociated subunits in urea revealed 6-7 different components. In this system, placenta ferritin was enriched in the more acidic subunits and it completely lacked the most basic subunits noted in liver ferritin; placental ferritin had no unique components. Differences in isoelectric points among assembled ferritins from these two tissues appear to result from different proportions of these acidic and basic subunits.

Molecular cloning of a cDNA encoding human ribosomal protein L39.

A cDNA clone encoding a human ribosomal protein L39 (hRPL39) was isolated through a random cDNA sequencing approach to a cDNA library constructed from a human colon carcinoma cell line of COLO 205. Although levels of hRPL39 mRNA were different in several cell lines including carcinoma cell lines from different tissues, they were shown not to be cell cycle-dependent in a human fibroblast cell line of TIG-1.

Molecular mechanism of angiotensin II type I and type II receptors in cardiac hypertrophy of spontaneously hypertensive rats.

We administered angiotensin (Ang) II receptor type 1 (AT1) blockade (losartan; 10 or 40 mg/kg per day), type II receptor (AT2) blockades (PD123319; 100 mg/kg per day), or angiotensin-converting enzyme (ACE) inhibitor (enalapril; 30 mg/kg per day) to spontaneously hypertensive rats (SHR) from 10 to 20 weeks of age. At the end of the treatment, high doses of losartan and enalapril significantly reduced the arterial systolic blood pressure compared with the untreated SHR to the level of WKY rats. But low doses of losartan and PD123319 were without effect. High doses of losartan and enalapril also significantly reduced both the left ventricular (LV) weight and the ratio of LV to body weight compared with the untreated SHR, which were still larger than that of WKY rats. However, the collagen concentration of SHR treated with high doses of losartan or enalapril was completely reduced to the level of WKY rats. Using reverse transcription polymerase chain reaction, we examined the mRNA expression for ACE, AT1, and AT2 in experimental animals. The enhanced AT1 mRNA expression was significantly decreased in the SHR treated with a high dose of losartan or PD123319 compared with the untreated SHR. The level of ACE mRNA was also decreased in the SHR treated with a high dose of losartan or enalapril. The level of AT2 mRNA was not significantly different between the Wistar-Kyoto rats and the SHR; however, this expression was decreased significantly after the treatment with a high dose of losartan or PD123319. These results indicate that AT1 receptor and ACE, but not AT2 receptor, play a crucial role in the remodeling of matrix tissue but a smaller role in the development of the hypertrophy of LV myocyte in SHR and that the LV/body weight changes do not fully account for the complete suppression of hypertension.

Interaction of mRNAs for angiotensin II type 1 and type 2 receptors to vascular remodeling in spontaneously hypertensive rats.

We administered angiotensin II (Ang II) receptor type 1 (AT1) blockade (losartan, 40 mg x kg-1 x d-1), type II receptor (AT2) blockade (PD123319, 100 mg x kg-1 x d-1), or angiotensin-converting enzyme (ACE) inhibitor (enalapril, 30 mg x kg-1 x d-1) to spontaneously hypertensive rats (SHR) from 10 to 20 weeks of age. Control SHR and Wister-Kyoto rats (WKY) received a placebo for the same period. At the end of treatment, losartan and enalapril were both found to have significantly reduced the arterial systolic blood pressure and the collagen concentration to the level of WKY, whereas PD123319 had no effect. Enalapril and PD123319 significantly reduced the media cross-sectional area of the aorta in comparison to that of untreated SHR, which was still larger than that of the WKY; however, losartan did not change it. Using reverse transcription-polymerase chain reaction, we next examined the mRNA expressions for ACE, AT1 receptor, and AT2 receptor in experimental animals. We observed significantly enhanced mRNA expression for AT1 and AT2 receptors and ACE in untreated SHR compared with WKY. The AT1 mRNA level was also significantly decreased in the SHR treated with either losartan or enalapril, whereas the AT2 mRNA level was significantly decreased in the SHR treated with either PD123319 or enalapril in comparison to untreated SHR. The level of ACE mRNA was significantly decreased only in the SHR treated with enalapril. These results indicate that AT1 receptor, but not AT2 receptor, plays a crucial role in the remodeling of matrix tissue, while AT2 receptor may play a role in the development of hypertrophy of smooth muscle in aorta in SHR, and that the reduction of hypertrophy of smooth muscle does not fully account for the suppression of hypertension.

Synergy of interleukin-5 with interleukin-2 in the generation of lymphokine-activated killer-cells.

IL-5 synergies with IL-2 to produce increased LAK activity, although IL-5 alone induced little cytotoxic activity. The most dramatic synergy occurred with a suboptimal IL-2 concentration. The kinetics of LAK activity induced by IL-2 plus IL-5 were similar to those induced by IL-2. IL-5 exerted its effects during the late stage of IL-2 induced LAK generation. In the precursor phase, depletion of asialo-GM1+ cells preceding culture eliminated IL-2 plus IL-5 induced LAK activity. In the effector phase, IL-2 plus IL-5 induced LAK activity was eliminated by depletion of Thy1.2+ cells following culture.