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B Background: b No standard of care for elderly patients with aggressive adult T-cell leukemia/lymphoma (ATL) has been established yet. B Conclusions: b This study demonstrated that Moga-CHOP-14 significantly improved PFS in elderly patients with aggressive CCR4-positive ATL who were ineligible for allo-HSCT. ATL subtypes included 31, 9, and 8 patients for the acute, lymphoma, and unfavorable chronic type, respectively. [Extracted from the article]

Abstract: Introduction: Antithrombin resistance (ATR) is a novel thrombotic risk in abnormal prothrombins. A manual ATR assay using Oxyuranus scutellatus (Ox) venom as a prothrombin activator was established for detecting antithrombin‐resistant prothrombin. However, this assay was limited because of Ox snake venom availability and its throughput capacity. Here, we have improved the ATR assay using bovine factors Xa and Va (FXa/Va) as prothrombin activators and have optimised assay conditions for an automated instrument (ACL TOP 500). Methods: Diluted plasma was incubated with a prothrombin activator mix (phospholipids, CaCl2, and bovine FXa/Va), followed by inactivation with antithrombin for 10, 20 and 30 minutes. We added a chromogenic substrate S‐2238, and assessed changes in absorbance/min at 405 nm. We also adapted assay conditions for ACL TOP 500. Results: Optimum conditions for FXa/Va treatment were 6.25% phospholipids, 5 mM CaCL2, 0.01 μg/mL FXa and 0.1 μg/mL FVa. ATR assay kinetics with the FXa/Va activator was comparable with that with the Ox activator in heterozygous reconstituted plasma with the recombinant wild‐type or antithrombin‐resistant prothrombin. Using ACL TOP 500, optimum conditions for the FXa/Va treatment were 10.0% phospholipids, 5 mM CaCl2, 0.02 μg/mL FXa and 0.2 μg/mL FVa. The automated ATR assay with the FXa/Va activator demonstrated good detectability for antithrombin‐resistant prothrombin in plasma from a heterozygous carrier with prothrombin Yukuhashi or Belgrade. Conclusion: We optimised the ATR assay with the FXa/Va activator and adapted the assay for ACL TOP 500; the assay showed the ability to clearly detect antithrombin‐resistant prothrombin in manual and automated procedures. [ABSTRACT FROM AUTHOR]

The article discusses an increased frequency of a rare bleeding disorder, which is a combined deficiency of two blood coagulation factors, in regions where consanguineous marriage is practiced. According to the author, this rare bleeding disorder, which is a combination of parahaemophilia and haemophilia A is usually caused by mutations of lectin mannose binding 1 (LMAN1) and multiple coagulation factor deficiency 2 (MCFD2).

Triple therapy with telaprevir, pegylated interferon and ribavirin has been reported to improve antiviral efficacy but have potentially severe adverse effects in patients with chronic hepatitis C. To avoid the severe effects of telaprevir, lowering the dose has been suggested. However, impact of dosage changes on antiviral and adverse effects remains unclear. One hundred and sixty-six Japanese patients with HCV genotype 1 were treated with triple therapy. The drug exposure of each medication was calculated by averaging the dose actually taken. The overall SVR rate was 82%. The telaprevir discontinuation rate was 26%. The factors associated with discontinuation were an older age (≥65 y.o.) and a higher average dose during treatment. The telaprevir discontinuation rates were 42%, 25% and 14% in patients at ≥35, 25-35 and <25 mg/kg/day of telaprevir and 58% in older patients at ≥35 mg/kg/day of TVR. The factors associated with SVR were treatment-naïve, relapse to previous treatment, higher average telaprevir dose during treatment and completion of treatment. The SVR rate was higher, at 91%, in patients at 25-35 mg/kg/day of telaprevir than the 71% and 78% observed in those at <25 and ≥35 mg/kg/day of drug. In Japanese patients, a mean telaprevir dose of 25-35 mg/kg/day during treatment can augment its efficacy in triple therapy for patients with HCV genotype 1. [ABSTRACT FROM AUTHOR]

Pegylated interferon ( Peg- IFN) plus ribavirin combination therapy is effective in patients with hepatitis C virus ( HCV) infection and normal alanine aminotransferase levels ( NALT). However, it remains unclear whether the risk of hepatocellular carcinoma ( HCC) incidence is actually reduced in virological responders. In this study, HCC incidence was examined for 809 patients with NALT ( ALT ≤ 40 IU/mL) treated with Peg- IFN alpha-2b and ribavirin for a mean observation period of 36.2 ± 16.5 months. The risk factors for HCC incidence were analysed by Kaplan- Meier method and Cox proportional hazards model. On multivariate analysis among NALT patients, the risk of HCC incidence was significantly reduced in patients with sustained virological response ( SVR) or relapse compared with those showing nonresponse ( NR) ( SVR vs NR, hazard ratio ( HR): 0.16, P = 0.009, relapse vs NR, HR: 0.11, P = 0.037). Other risk factors were older age (≥65 years vs <60 years, HR: 6.0, P = 0.032, 60-64 vs <60 years, HR: 3.2, P = 0.212) and male gender (HR: 3.9, P = 0.031). Among 176 patients with PNALT ( ALT ≤ 30 IU/mL), only one patient developed HCC and no significant risk factors associated with HCC development were found. In conclusion, antiviral therapy for NALT patients with HCV infection can lower the HCC incidence in responders, particularly for aged and male patients. The indication of antiviral therapy for PNALT ( ALT ≤ 30 IU/mL) patients should be carefully determined. [ABSTRACT FROM AUTHOR]

Introduction Platelet activation in circulation is considered to be associated with thrombosis and inflammation; thus, sensitive and easy-to-use markers are necessary. In this study, we established a simple and rapid protocol to clinically examine leukocyte-platelet aggregate formation associated with activated platelets in circulation. Methods Whole blood was stained with PC5-conjugated anti- CD45 monoclonal antibody and fluorescent isothiocyanate-conjugated anti- CD41 monoclonal antibody for leukocyte-platelet aggregate analysis. For platelet activation, 5 μ m thrombin receptor-activated peptide ( TRAP) or 2 μg/mL collagen was added. Samples were analyzed by EPICS XL (Beckman Coulter, Miami, FL, USA). Monocytes, neutrophils, and lymphocytes were gated based on differences in CD45 fluorescence intensity and side scatter. For each gate, the percentage (%) of platelets expressing CD41 was analyzed. Same drawing sample was stained with anti- CD62P monoclonal antibody. Platelet CD62P expression was then analyzed with gating for platelet cell population. Results We analyzed leukocyte-platelet aggregates and platelet CD62P expression in 18 healthy individuals. Leukocyte-platelet aggregates, mainly monocyte-platelet aggregates, increased when platelets were activated by platelet agonists. Monocyte-platelet aggregates and neutrophil-platelet aggregates also increased over time with mild platelet activation. Conclusion Leukocyte-platelet aggregates, mainly monocyte-platelet aggregates, appear to be a sensitive marker of platelet activation in circulation. [ABSTRACT FROM AUTHOR]

Background: GM2 gangliosidosis variant 0 (human Sandhoff disease) is a lysosomal storage disorder caused by deficiencies of acid β-hexosaminidase (Hex) A and Hex B because of an abnormality of the β-subunit, a common component in these enzyme molecules, which is coded by the HEXB gene. Objective: To describe the clinical, pathological, biochemical, and magnetic resonance imaging (MRI) findings of Sandhoff-like disease identified in a family of Toy Poodles. Animals: Three red-haired Toy Poodles demonstrated clinical signs including motor disorders and tremor starting between 9 and 12 months of age. The animals finally died of neurological deterioration between 18 and 23 months of age. There were some lymphocytes with abnormal cytoplasmic vacuoles detected. Methods: Observational case study. Results: The common MRI finding was diffuse T2-hyperintensity of the subcortical white matter in the cerebrum. Bilateral T2-hyperintensity and T1-hypointensity in the nucleus caudatus, and atrophic findings of the cerebrum and cerebellum, were observed in a dog in the late stage. Histopathologically, swollen neurons with pale to eosinophilic granular materials in the cytoplasm were observed throughout the central nervous system. Biochemically, GM2 ganglioside had accumulated in the brain, and Hex A and Hex B were deficient in the brain and liver. Pedigree analysis demonstrated that the 3 affected dogs were from the same family line. Conclusions and Clinical Importance: The Sandhoff-like disease observed in this family of Toy Poodles is the 2nd occurrence of the canine form of this disease and the 1st report of its identification in a family of dogs. [ABSTRACT FROM AUTHOR]

Reducing the dose of drug affects treatment efficacy in pegylated interferon (Peg-IFN) and ribavirin combination therapy for patients with hepatitis C virus (HCV) genotype 1. The aim of this study was to investigate the impact of drug exposure, as well as the baseline factors and the virological response on the treatment efficacy for genotype 2 patients. Two-hundred and fifty patients with genotype 2 HCV who were to undergo combination therapy for 24 weeks were included in the study, and 213 completed the treatment. Significantly more patients who achieved a rapid virological response (RVR), defined as HCV RNA negativity at week 4, achieved a sustained virological response (SVR) (92%, 122/133) compared with patients who failed to achieve RVR (48%, 38/80) ( P < 0.0001). Multivariate logistic-regression analysis showed that only platelet counts [odds ratio (OR), 1.68; confidence interval (CI), 1.002–1.139] and RVR (OR, 11.251; CI, 5.184–24.419) were independently associated with SVR, with no correlation being found for the mean dose of Peg-IFN and ribavirin for RVR and SVR. Furthermore, in the stratification analysis of the timing of viral clearance, neither mean dose of Peg-IFN ( P = 0.795) nor ribavirin ( P = 0.649) affected SVR in each group. Among the patients with RVR, the lowest dose group of Peg-IFN (0.77 ± 0.10 μg/kg/week) and ribavirin (6.9 ± 0.90 mg/kg/day) showed 100% and 94% of SVR. Hence, RVR served as an important treatment predictor, and drug exposure had no impact on both SVR and RVR in combination therapy for genotype 2 patients. [ABSTRACT FROM AUTHOR]

This study was undertaken to investigate the effect of interferon (IFN) monotherapy on the risk of hepatocellular carcinoma (HCC) in aged-patients with chronic hepatitis C. Seven hundred and twenty-five patients with histologically proven chronic hepatitis C were enrolled in this retrospective cohort study; 531 received IFN monotherapy for 6 months between 1992 and 1995, and 157 were collected as a historical control. The effect of IFN therapy on the development of HCC was compared between the patients with chronic hepatitis C under 60 years old (non-aged group, n = 531) and those 60 and over (aged group, n = 194). A stepwise Cox proportional-hazards regression analysis in the non-aged group revealed that IFN therapy (risk ratio 0.52, 95% CI 0.33–0.81, P = 0.004), older age ( P = 0.001), and higher histological stage ( P < 0.001) were independent factors associated with the development of HCC. In the aged-group, only higher histological stage ( P = 0.002) and male gender ( P = 0.011), but not IFN therapy (risk ratio 0.77, 95% CI 0.42–1.40, P = 0.386), were identified as independent risk factors for HCC, although HCC was significantly reduced when sustained virological response (SVR) was obtained (risk ratio 0.23, 95% CI 0.08–0.64, P = 0.005). In conclusion, inhibitory effect of IFN on development of HCC in the patients with chronic hepatitis C aged 60 and over was limited to the patients achieving SVR when treated with 6 months-IFN monotherapy. [ABSTRACT FROM AUTHOR]

The impact of ribavirin exposure on virologic relapse remains controversial in combination therapy with pegylated interferon (Peg-IFN) and ribavirin for patients with chronic hepatitis C (CH-C) genotype 1. The present study was conducted to investigate this. Nine hundred and eighty-four patients with CH-C genotype 1 were enrolled. The drug exposure of each medication was calculated by averaging the dose actually taken. For the 472 patients who were HCV RNA negative at week 24 and week 48, multivariate logistic regression analysis showed that the degree of fibrosis ( P = 0.002), the timing of HCV RNA negativiation ( P < 0.001) and the mean doses of ribavirin ( P < 0.001) were significantly associated with relapse, but those of Peg-IFN were not. Stepwise reduction of the ribavirin dose was associated with a stepwise increase in relapse rate from 11% to 60%. For patients with complete early virologic response (c-EVR) defined as HCV RNA negativity at week 12, only 4% relapse was found in patients given ≥12 mg/kg/day of ribavirin and ribavirin exposure affected the relapse even after treatment week 12, while Peg-IFN could be reduced to 0.6 μg/kg/week after week 12 without the increase of relapse rate. Ribavirin showed dose-dependent correlation with the relapse. Maintaining as high a ribavirin dose as possible (≥12 mg/kg/day) during the full treatment period can lead to suppression of the relapse in HCV genotype 1 patients responding to Peg-IFN alpha-2b plus ribavirin, especially in c-EVR patients. [ABSTRACT FROM AUTHOR]

Chronic hepatitis C (CH-C) genotype 1 patients who achieved early virologic response have a high probability of sustained virologic response (SVR) following pegylated interferon (Peg-IFN) plus ribavirin therapy. This study was conducted to evaluate how reducing drug doses affects complete early virologic response (c-EVR) defined as hepatitis C virus (HCV) RNA negativity at week 12. Nine hundred eighty-four patients with CH-C genotype 1 were enrolled. Drug doses were evaluated independently on a body weight base from doses actually taken. From multivariate analysis, the mean dose of Peg-IFN α-2b during the first 12 weeks was the independent factor for c-EVR ( P = 0.02), not ribavirin. The c-EVR rate was 55% in patients receiving ≥1.2 μg/kg/week of Peg-IFN, and declined to 38% at 0.9–1.2 μg/kg/week, and 22% in patients given <0.9 μg/kg/week ( P < 0.0001). Even with stratified analysis according to ribavirin dose, the dose-dependent effect of Peg-IFN on c-EVR was observed, and similar c-EVR rates were obtained if the dose categories of Peg-IFN were the same. Furthermore, the mean dose of Peg-IFN during the first 12 weeks affected HCV RNA negativity at week 24 ( P < 0.0001) and SVR ( P < 0.0001) in a dose-dependent manner. Our results suggest that Peg-IFN was dose-dependently correlated with c-EVR, independently of ribavirin dose. Thus, maintaining the Peg-IFN dose as high as possible during the first 12 weeks can yield HCV RNA negativity and higher c-EVR rates, leading to better SVR rates in patients with CH-C genotype 1. [ABSTRACT FROM AUTHOR]

Background Processing milk leads to changes in clinical allergenicity. However, the mechanism by which heat treatment affects the allergenicity of milk proteins is not fully understood. Objective We investigated the effect of heat treatment and enzymatic digestion on the allergenicity of B cell epitopes of milk proteins using a histamine release assay. Methods Human basophils were passively sensitized using sera from 10 patients with allergies to cow's milk. All the patients experienced symptoms immediately after ingesting milk. The human basophils were obtained from umbilical cord blood mononuclear cells after culturing the mononuclear cells for 3–4 weeks in the presence of IL-3. After sensitization with 10% patient sera for 48 h, the cells were stimulated with untreated, heat-treated, or heat-treated and pepsin-and-trypsin-digested β-lactoglobulin or α-casein for 1 h. The histamine concentrations in the supernatants were then measured by radioimmunoassay. Results Heat treatment alone did not alter the molecular weight of β-lactoglobulin or α-casein. Heat treatment of β-lactoglobulin significantly increased its susceptibility to enzymatic digestion in a time- and temperature-dependent manner and reduced its ability to induce histamine release from sensitized basophils. Similar findings were not observed for α-casein. The combination of heat treatment and enzymatic digestion reduced the abilities of both β-lactoglobulin and α-casein to induce histamine release from passively sensitized basophils. Conclusions Heat treatment reduced the allergenicity of β-lactoglobulin by inducing conformational changes and by increasing its susceptibility to enzymatic digestion, both of which disrupted B cell epitopes, whereas heat treatment alone did not alter the allergenicity of α-casein. [ABSTRACT FROM AUTHOR]

Introduction: The effects of Streptococcus salivarius on the competence-stimulating peptide (CSP)-dependent biofilm formation by Streptococcus mutans were investigated. Methods: Biofilms were grown on 96-well microtiter plates coated with salivary components in tryptic soy broth without dextrose supplemented with 0.25% sucrose. Biofilm formations were stained using safranin and quantification of stained biofilms was performed by measuring absorbance at 492 nm. Results: S. mutans formed substantial biofilms, whereas biofilms of S. salivarius were formed poorly in the medium conditions used. Furthermore, in combination cultures, S. salivarius strongly inhibited biofilm formation when cultured with S. mutans. This inhibition occurred in the early phase of biofilm formation and was dependent on inactivation of the CSP of S. mutans, which is associated with competence, biofilm formation, and antimicrobial activity of the bacterium, and is induced by expression of the comC gene. Comparisons between the S. mutans clinical strains FSC-3 and FSC-3Δ glrA in separate dual-species cultures with S. salivarius indicated that the presence of the bacitracin transport ATP-binding protein gene glrA caused susceptibility to inhibition of S. mutans biofilm formation by S. salivarius, and was also associated with the regulation of CSP production by com gene-dependent quorum sensing systems. Conclusion: It is considered that regulation of CSP by glrA in S. mutans and CSP inactivation by S. salivarius are important functions for cell-to-cell communication between biofilm bacteria and oral streptococci such as S. salivarius. Our results provide useful information for understanding the ecosystem of oral streptococcal biofilms, as well as the competition between and coexistence of multiple species in the oral cavity. [ABSTRACT FROM AUTHOR]

Early after liver transplantation, patients are in a hypercoagulable state because of an imbalance between coagulation and fibrinolysis because of the slow recovery of depleted anticoagulant proteins. Antithrombin (AT) is used in anticoagulant protocols to prevent thrombosis. The subjects of the present study were 17 men and eight women that underwent living donor liver transplantation. The initial 15 cases were administered AT concentrate (1500 U/day) on postoperative days (POD) 1 through 3 (AT group) and the following 10 consecutive cases were not administered AT (control). AT, thrombin-AT complex, plasmin-alpha2 plasmin inhibitor complex, thrombomodulin, fibrin degradation product D-dimer (FDP-DD) level, prothrombin time international normalized ratio, activated partial thromboplastin time, and platelet counts were measured. In the AT group, AT activity was maintained at levels >80% for 5 days after transplantation. In the control group, AT activity did not return to normal during the first 2 weeks after the operation. FDP-DD levels were significantly higher in the control group than in the AT group ( P < 0.05). Six patients in the control group and three patients in the AT group required transfusions with platelet concentrate ( P < 0.05). AT supplementation might reduce FDP-DD levels and prevent decreased platelet counts in the early stages after liver transplantation. [ABSTRACT FROM AUTHOR]

Objectives. Pseudomonas aeruginosa infection is a major cause of bacterial infection after deceased-donor liver transplantation. The incidence and risk factors of P. aeruginosa infection after living-donor liver transplantation (LDLT), however, are not known. Methods. We retrospectively reviewed the data from 170 adult patients who underwent LDLT at the University of Tokyo Hospital. The microbiologic and medical records of the patients from admission to 3 months after LDLT were reviewed. Uni- and multivariate analyses were performed to identify the independent risk factors for postoperative P. aeruginosa infection. Result. Preoperative P. aeruginosa carriage was identified in 15 (9%) patients. Only 2 of the 15 patients later presented with postoperative P. aeruginosa infection. Postoperative P. aeruginosa infection occurred in 27 (16%) of 170 patients by median postoperative day 38. Among those 27 patients, surgical site infections were recorded in 8 (30%) and intra-abdominal infections in 14 (52%). In 5 of the 27 (19%) patients, P. aeruginosa isolates were multiple antimicrobial resistant. Postoperative bile leakage independently predicted postoperative P. aeruginosa infection. Conclusion. P. aeruginosa infections were frequently detected after LDLT, including those by multiple antimicrobial-resistant isolates. Postoperative bile leakage predisposed patients to P. aeruginosa infection. Surveillance culture should be checked periodically after LDLT to ensure that appropriate antimicrobials can be administered for postoperative infection. [ABSTRACT FROM AUTHOR]

Background. Methicillin-resistant Staphylococcus aureus (MRSA) infection frequently complicates the postoperative course in deceased-donor liver transplantation. The incidence and risk factors of MRSA infection after Living-donor Liver transplantation (LDLT), however, are unclear. Methods. We retrospectively reviewed the data from 242 adult patients who underwent LDLT at the University of Tokyo Hospital. The microbiologic and medical records of the patients from admission to 3 months after LDLT were reviewed. Uni- and multivariate analyses were performed to identify the independent risk factors for postoperative MRSA infection. Results. Postoperative MRSA infection occurred in 25 of 242 patients by median postoperative day 23. Preoperative MRSA colonization, preoperative use of antimicrobials, operation time (≥16 h), and postoperative apheresis independently predicted postoperative MRSA infection. Conclusion. Surveillance culture should be checked periodically after admission to identify patients at high risk for MRSA infection and to administer appropriate antimicrobials for perioperative infection. Postoperative apheresis, suggesting postoperative liver dysfunction, predisposed patients to MRSA infection. [ABSTRACT FROM AUTHOR]

A 3·5-month-old papillon puppy was brought to our clinic with chief complaints of progressive quadriparesis, ataxia and head tremor. Lesions in the cerebellum, brainstem and spinal cord were suspected on the basis of a neurological examination. No abnormality was found in a clinicopathological examination or on magnetic resonance imaging. On the basis of these results differential diagnoses including an inflammatory disease, a degenerative condition or a storage disorder were considered. Subsequently, the signs progressed and glossoplegia and dysphagia developed at six months of age. At a second magnetic resonance imaging, severe atrophy of the entire brain was found. After these examinations, the puppy was euthanased and histopathologically diagnosed with neuroaxonal dystrophy. Because magnetic resonance imaging detected abnormal features that were characteristic of neuroaxonal dystrophy in this case, we speculate that magnetic resonance imaging can assist in the pre-mortem diagnosis of this disease. [ABSTRACT FROM AUTHOR]

Nocardiosis is a serious infection with high mortality. We report a case of subcutaneous and neural lesions due to Nocardia farcinica infection after living-donor liver transplantation. The neural lesion was cured with antibiotics without drainage. [ABSTRACT FROM AUTHOR]

Interferon-α (IFN-α) is widely used in the treatment of chronic hepatitis C (CHC). The suppressor of cytokine signalling (SOCS) family has been implicated in the regulation of JAK–STAT signalling, including IFN signalling. The negative effect of SOCS expression on the response of CHC to IFN-α is demonstrated here. The transcriptional levels of SOCS-1 and -3 in the livers of 21 patients with CHC and eight controls were investigated by quantitative reverse transcription-polymerase chain reaction. We established stable transfectants of SOCS-1 in a human hepatoma cell line, PLC/PRF/5 and analysed the effects of SOCS-1 on the phosphorylation of IFN-α-induced STAT-1 tyrosine by immunoblotting and the expression of antiviral genes by Northern blot. A prospective cohort study on SOCS-1 expression and clinical outcome was carried out in 77 patients with CHC who received IFN therapy. SOCS-1, but not SOCS-3, transcripts in the livers of CHC were significantly higher than controls (P < 0.005). IFN-α-induced STAT-1 phosphorylation and the expression of antiviral genes were inhibited in SOCS-1-transfected cells. Patients showing high SOCS-1 expression in the liver had a significantly lower rate of sustained virological response (SVR) to IFN therapy than those with low SOCS-1 expression (P = 0.0014). A multivariate analysis performed with host factors revealed that SOCS-1 staining in the liver can serve as a significant predictor for IFN SVR (P = 0.004). SOCS-1 expression is enhanced in the livers of CHC patients and might be involved in resistance to IFN therapy. [ABSTRACT FROM AUTHOR]

Interferon therapy for chronic hepatitis C reduces the risk of hepatocellular carcinoma, especially among virological and biochemical responders. However, little is known about the effect of interferon therapy on mortality. We studied the long-term effect of interferon therapy on mortality in patients with chronic hepatitis C. For this retrospective cohort study, 2954 patients with chronic hepatitis C were recruited, of whom 2698 received interferon therapy and 256 did not. The effect of interferon therapy on survival was assessed by standardized mortality ratio (SMR) based on published mortality data for the general Japanese population and by risk ratio calculated by proportional hazard regression. Over 6.0 ± 2.2 years follow-up, death from liver-related diseases was observed in 69 (68%) of 101 deaths among interferon-treated patients and in 42 (81%) of 52 deaths among untreated patients. Compared with the general population, overall mortality was high among untreated patients (SMR: 2.7; 95% CI: 2.0–3.6) but not among interferon-treated patients (SMR: 0.9; 95% CI: 0.7–1.1). Liver-related mortality was extremely high among untreated patients (SMR: 22.2; 95% CI: 16.0–30.0) and less among interferon-treated patients (SMR: 5.5; 95% CI: 4.3–6.9). The risk of death from all causes was lower for interferon-treated than untreated patients (risk ratio: 0.47; 95% CI: 0.261–0.836; P = 0.01). The risk of death from liver-related diseases was significantly lower for sustained virological responders (risk ratio: 0.04; 95% CI: 0.005–0.301; P = 0.002) compared with untreated patients, but not for nonsustained virological responders. Sustained biochemical responders (risk ratio: 0.03; 95% CI: 0.004–0.230; P < 0.001) and transient biochemical responders (risk ratio: 0.18; 95% CI: 0.063–0.532; P = 0.002) showed a significantly reduced risk of death from liver-related death, whereas biochemical nonresponders did not. Hence interferon treatment improved survival in chronic hepatitis C patients showing a biochemical as well as a virological response by preventing liver-related deaths. [ABSTRACT FROM AUTHOR]

Reduction and alkylation of human serum albumin (HSA) resulted in molecular aggregation of the protein. The reduced and alkylated antigen (RAHSA) was lacking in the ability to induce delayed-type hypersensitivity (DTH) response as well as antibody response to native HSA in mice, although native HSA induced both responses. On the other hand, RA-HSA could stimulate a priming function that accelerated and enhanced the DTH response to native HSA, which, however, failed to stimulate the function. Thus, DTH-related memory activity was dissociated from DTH-related effector activity. The DTH-related memory activity, manifested by the accelerated and enhanced response in RA-HSA-primed mice, could be transferred antigen-specifically by their spleen cells and T-cell enriched fraction, but not by their T-cell depleted spleen cells. The RA-HSA-primed T cells, however, failed to transfer the effector function for DTH response. These results suggested that DTH related memory T cells belong to different subset(s) of T cells from effector T cells for a DTH response. [ABSTRACT FROM AUTHOR]

Thymus cells from mice primed s.c. with a high dose (10 mg) of lysozyme (Lys) specifically suppressed delayed footpad reaction (FPR) in mice previously immunized with lipid-conjugated lysozyme (D.Lys), and also suppressed the transfer of FPR by D.Lys-immune spleen ceils into normal mice. Furthermore, they inhibited antigen-stimulated DNA synthesis of D.Lys-immune spleen cells in vitro. If the suppressor thymus cells were cultured with Lys in vitro, they produced soluble factor which depressed the ability of D.Lys-immune spleen cells to transfer FPR. Both supernatant of culture without Lys and extract of suppressor thymus cells were inactive in suppression of FPR. The suppressor factor was antigen-specific because its suppressive activity was absorbed with Lys but not with an unrelated antigen, lactalbumin. The factor failed to depress the ability of D.Lys-immune spteen cells to transfer FPR when the spleen cells were depleted of glass-adherent cells. In addition, incubation of peritoneal exudate cells from normal mice with the factor rendered the cells suppressive for passive transfer of FPR. These results suggest that the suppressor factor depresses the effector function of T cells responsible for FPR possibly via macrophages. [ABSTRACT FROM AUTHOR]

Delayed hypersensitivity (DH) response in mice induced by subcutaneous (s.c.) injection of optimal dose of sheep red blood cells (SRBC) (108) was accelerated by s.c. injection of the antigen of 10³ or more doses, given 2 or more days earlier. The accelerated response appeared soon after the injection of optimal antigen dose, that is, 1 or 2 days earlier than the response of non-presensitized control. The acceleration was antigen specific. The accelerated response was generally accompanied by an acceleration and/or enhancement of humoral antibody response. Parallel to the acceleration of DH response, the proliferation of regional lymph node cells in the presensitized mice was induced immediately after the following injection of 108 SRBC, 1 day earlier than that of non-presensitized animals. These results suggest that presensitization of mice with the antigen induces DH-related memory cells which proliferate immediately after the following injection and function as effector cells for DH reactions, and that the development of DH-related memory cells occurs in close relation to that of helper thymus-derived (T) cells for antibody production. [ABSTRACT FROM AUTHOR]

Cholera toxin B subunit (CTB) has been shown to augment the antibody responses to influenza virus haemagglutinin (HA) in BALB/c mice immunized with HA vaccine together with CTB. In this study, mouse strain differences in the adjuvant effect of CTB on anti-HA antibody responses were investigated along with those in the antibody responses to CTB or HA, using various inbred and H-2 congenic strains. The antibody responsiveness to CTB depended on the H-2 haplotype of the strain: strains with the H-2b haplotype were high responders, those with H-2a, H-2k and H-2s were low responders, and those with H-2d were intermediate. The responsiveness to HA was also related to the H-2 haplotype: H-2a and H-2k strains were high responders, H-2b and H-2s strains were low responders, and H-2d stratus were intermediate. However, the degree of the adjuvant effect of CTB on anti-HA antibody responses was almost constant, regardless of the H-2 haplotype or other genetic backgrounds of the strain. The lack of genetic restriction of the adjuvant effect would be favourable for application of CTB-combined HA vaccine to humans, who are genetically diverse. Moreover, these results suggest that the immunogenicity and adjuvanticity of CTB differ essentially in their mechanisms. [ABSTRACT FROM AUTHOR]

The mechanism by which high doses of estrogen influences lipid metabolism was studied with a microtubular blocking agent. Castrated male rats received oral injection daily for 14 days of 3 mg hexestrol in olive oil, or oil alone as controls. About half of the animals in each group were injected intraperitoneally with 4 mg/100 g body weight colchicine 3 hr before they were killed. Hexestrol treatment caused an accumulation of esterified cholesterol in the liver while it decreased those in serum. Triglyceride concentrations slightly decreased in the liver but were unaffected in serum. On polyacrylamide-gel disc electrophoresis, the peaks of high density lipoproteins (HDL) and low density lipoproteins (LDL) were decreased remarkably. Electron microsopic examination of hepatocytes revealed electron-lucent lipid droplets in the cytoplasm. After a colchicine treatment of the control animals, concentrations of esterified cholesterol and triglycerides markedly increased in the liver, while those in serum decreased. Electron microscopic examination of hepatocytes revealed numerous secretory vesicles filled with nascent VLDL. In hexestrol-treated animals, the colchicine treatment was associated with marked decreases in serumesterified cholesterol and triglyceride as seen in the controls. However, there were no further increases of esterified cholesterol in the liver, and the increase of triglycerides was slight. Electron microscopic examination showed less secretory droplets than in the controls. These data suggest that very low density lipoproteins (VLDL) synthesis in the liver of hexestrol treated rats was inhibited. An accumulation of esterified cholesterol with a marked decrease in serum could not be accounted for by the inhibition of lipoproteins secretion, but rather by their enhanced entry into the liver. [ABSTRACT FROM AUTHOR]

To compare the efficacy of low and relatively high dosages of recombinant interferon (IFN)-α-2a in Japanese patients with chronic hepatitis C, as well as to characterize the type of patients who will respond well to a low-dosage treatment, 88 patients with histologically proven chronic hepatitis C were randomly assigned to two treatment groups; one treated with IFN-α-2a 6 MU daily for 2 weeks followed by 6 MU three times weekly for 22 weeks (6-MU group), and another given the same initial treatment followed by 3 MU three times weekly for 22 weeks (3-MU group). The rate of sustained normalization of ALT 6 months after the cessation of treatment was 33% in the 3-MU group and 40% in the 6-MU group ( p=0.64). In addition, there was no difference in elimination of serum HCV-RNA 6 months after the cessation of treatment between the 3-MU group (26%) and 6-MU group (29%). Multivariate stepwise regression analysis revealed that serum HCV-RNA level ( p=0.0035) and platelet count ( p=0.0009) were independent variables useful in predicting a sustained response of ALT. The sustained response rate of ALT in patients with a serum HCV-RNA level less than 105 copies/ml and serum platelet level above 15×104/μl was 71%, whereas that in patients with a serum HCV-RNA level above 105 copies/ml and serum platelet level less than 15×104/μl was 12%. These results indicate that a high rate of sustained response to IFN therapy can be expected in chronic hepatitis C patients with a low serum level of HCV-RNA and a high level of platelets, even if treated with a low dose of IFN. [ABSTRACT FROM AUTHOR]

Two dogs, a 14-year-old, female American Eskimo dog and a 14-year-old, male Maltese dog, were presented with thalamic syndromes, including lowered levels of consciousness, poor postural responses and presence of masses in the neck region. In both dogs, magnetic resonance imaging revealed multiple masses inside the cranium, including the pituitary gland. One dog died from status epilepticus two days after magnetic resonance imaging and the other died two months after magnetic resonance imaging from respiratory failure. These dogs were histopathologically diagnosed with multiple metastases of thyroid cancer occurring inside the cranium, including the pituitary gland. To the authors’ knowledge, this is the first time this tumour pattern has been reported in dogs, but it is possible that it is not uncommon. [ABSTRACT FROM AUTHOR]