Anti-citrullinated protein antibody titre as a predictor of abatacept treatment persistence in patients with rheumatoid arthritis: a prospective cohort study in Japan.

Objective: Successful rheumatoid arthritis (RA) outcome depends on treatment efficacy in the early stages of the disease and its sustainability. It is thus critical to identify factors predicting treatment persistence with biological agents, such as abatacept. We compared clinical profiles, including early changes in autoantibody titres at 3 months, between patients with RA demonstrating sustained persistence and those discontinuing abatacept treatment.Method: We prospectively enrolled 71 and 78 active RA patients treated with abatacept and tumour necrosis factor inhibitors (TNF-Is), respectively, who had previous disease-modifying anti-rheumatic drug) failure. Clinical characteristics were compared between non-continuation and continuation groups stratified according to abatacept or TNF-I persistence for at least 12 months from treatment initiation.Results: Significantly larger decreases in rheumatoid factor titre and anti-citrullinated protein autoantibody (ACPA) titre were observed in the continuation group of abatacept therapy at 3 months, and early reduction in ACPA titre remained a significant and independent predictor of sustained persistence with abatacept in multivariate analysis. In addition, we obtained the area under the receiver operator characteristics curve of 0.904 from a model including baseline ACPA titre and reduction of ACPA titre at 3 months. Sustained reduction of RA disease activity score at 12 months was significantly and independently associated with reduced ACPA titre at 3 months.Conclusions: Persistence with abatacept and sustained therapeutic response are associated with an early reduction in ACPA titre. Prediction of abatacept continuation and efficacy will facilitate the optimal design of therapy in the early stages of RA.

Complete renal response at 12 months after induction therapy is associated with renal relapse-free rate in lupus nephritis: a single-center, retrospective cohort study.

BACKGROUND: Lupus nephritis (LN) is a major risk factor for overall morbidity and mortality in systemic lupus erythematosus (SLE). METHODS: We retrospectively analyzed cases of proliferative and membranous LN patients who underwent a renal biopsy at our hospital in 1993-2016. We analyzed the association between complete renal response (CR) rates at 12 months after induction therapy and predictive factors for CR and their association with renal flares. RESULTS: Of the 95 cases analyzed, we were able to track the therapeutic responses of 81 patients at 12 months after their induction therapy. The median follow-up duration after renal biopsy was 51 months (interquartile range: 16.5-154.5 months). The Cox proportional hazards model showed that, compared to not attaining CR at 12 months, the attainment of CR at 12 months was correlated with being free from renal flares. The multivariate logistic analysis revealed that the predictive factors for CR at 12 months were the anti-La/SSB antibodies (U/ml) (odds ratio (OR) 1.22, 95% confidence interval (CI) 1.01-1.63, p = 0.0220), blood urea nitrogen (BUN) (OR 0.68, 95% CI 0.44-0.90, p = 0.00048) and serum ß2 microglobulin (MG) (OR 0.26, 95% CI 0.06-0.74, p = 0.00098) levels. CONCLUSIONS: Among LN patients, being free from renal flares was associated with attaining CR at 12 months after induction therapy. Anti-La/SSB antibodies were a positive predictive factor, and BUN and serum ß2MG levels were negative predictive factors of CR at 12 months.

Factors predictive of long-term mortality in lupus nephritis: a multicenter retrospective study of a Japanese cohort.

BACKGROUND: Lupus nephritis (LN) is a major determinant of mortality in systemic lupus erythematosus (SLE). Here we evaluated the association between complete renal response (CR) and mortality in LN. METHODS: We retrospectively analyzed the cases of 172 of 201 patients with LN for whom data on the therapeutic response at 6 and 12 months after induction therapy were available. The patients underwent a renal biopsy at Nagasaki University Hospital and community hospitals in Nagasaki between the years 1990 and 2016. We determined the CR rates at 6 and 12 months after induction therapy initiation and evaluated the predictive factors for CR and their relationship with mortality. We performed univariate and multivariable competing risks regression analyses to determine the factors predictive of CR. The patients' survival data were analyzed by the Kaplan-Meier method with a log-rank test. RESULTS: The median follow-up duration after renal biopsy was 120 months (interquartile range: 60.3-191.8 months). The 5-, 10-, 15- and 20-year survival rates of our cohort were 99.3, 94.6, 92.0 and 85.4%, respectively. During follow-up, nine patients (5.2%) died from cardiovascular events, infection, malignancy and other causes. The multivariate analysis revealed that the following factors were predictive of CR. At 6 months: male gender (odds ratio (OR) 0.23, 95% confidence interval (CI) 0.08-0.65, p = 0.0028), proteinuria (g/gCr) (OR 0.83, 95% CI 0.71-0.97, p = 0.0098) and index of activity (0-24) (OR 0.84, 95% CI 0.71-0.99, p = 0.0382). At 12 months: male gender (OR 0.25, 95% CI 0.09-0.67, p = 0.0043) and index of activity (0-24) (OR 0.82, 95% CI 0.69-0.98, p = 0.0236). The Kaplan-Meier analysis showed that compared to not achieving CR at 12 months, achieving CR at 12 months was significantly correlated with the survival rate (OR 0.18, 95% CI 0.04-0.92, p = 0.0339). CONCLUSIONS: Our results suggest that the survival rate of patients with LN is associated with the achievement of CR at 12 months after induction therapy, and that male gender and a higher index of activity (0-24) are the common predictive factors for failure to achieve CR at 6 and 12 months.

Once-weekly glucagon-like peptide-1 receptor agonist dulaglutide significantly decreases glycated haemoglobin compared with once-daily liraglutide in Japanese patients with type 2 diabetes: 52 weeks of treatment in a randomized phase III study.

AIMS: To examine the efficacy and safety of once-weekly dulaglutide 0.75 mg monotherapy compared with once-daily liraglutide 0.9 mg in Japanese patients with type 2 diabetes (T2D) for 52 weeks. METHODS: We conducted a phase III, randomized, 52-week (26-week primary endpoint), active- and placebo-controlled trial comparing 492 Japanese patients (dulaglutide, n = 281; liraglutide, n = 141; and placebo, n = 70). Participants and investigators were blinded to treatment assignment for dulaglutide and placebo but not for liraglutide (open-label comparator); after 26 weeks, patients randomized to placebo were switched to once-weekly dulaglutide 0.75 mg (open-label). The present paper reports results for patients treated with dulaglutide and patients treated with liraglutide for 52 weeks. RESULTS: At week 52, dulaglutide decreased HbA1c significantly from baseline compared with liraglutide [least squares mean difference: -0.20; 95% confidence interval (CI) -0.39, -0.01; p = 0.04]. At week 52 (last observation carried forward), dulaglutide significantly decreased pre- and post-dinner blood glucose (BG) levels, the mean of seven-point self-monitored BG profiles, the mean of all postprandial BG levels and circadian variation compared with liraglutide. Body weight was generally stable in both groups through 52 weeks. The most frequently reported adverse events were nasopharyngitis, constipation, nausea and diarrhoea. Eight dulaglutide-treated (2.9%) and four liraglutide-treated (2.9%) patients reported hypoglycaemia, with no event being severe. CONCLUSIONS: Monotherapy with once-weekly dulaglutide 0.75 mg was effective and safe in Japanese patients with T2D, with better glycaemic control compared with once-daily liraglutide 0.9 mg.

Once-weekly glucagon-like peptide-1 receptor agonist dulaglutide is non-inferior to once-daily liraglutide and superior to placebo in Japanese patients with type 2 diabetes: a 26-week randomized phase III study.

AIMS: To examine the efficacy and safety of once-weekly dulaglutide monotherapy (0.75 mg) compared with placebo and once-daily liraglutide (0.9 mg) in Japanese patients with type 2 diabetes. METHODS: This was a phase III, 52-week (26-week primary endpoint), randomized, double-blind, placebo-controlled, open-label comparator (liraglutide) trial comparing 492 Japanese patients with type 2 diabetes (dulaglutide, n = 281; liraglutide, n = 141; and placebo, n = 70) who were aged ≥20 years. Patients and investigators were blinded to treatment assignment for dulaglutide and placebo but not for liraglutide. The primary objective evaluated the superiority of dulaglutide versus placebo on change from baseline in glycated haemoglobin (HbA1c) at 26 weeks. Analyses were performed on the full analysis set. RESULTS: At 26 weeks, once-weekly dulaglutide was superior to placebo and non-inferior to once-daily liraglutide for HbA1c change from baseline [least squares mean difference: dulaglutide vs placebo -1.57% (95% confidence interval -1.79 to -1.35); dulaglutide vs liraglutide -0.10% (95% confidence interval -0.27 to 0.07)]. The most frequently reported adverse events were nasopharyngitis, constipation, diarrhoea, nausea, abdominal distension and decreased appetite; only decreased appetite was different between the dulaglutide and liraglutide groups [dulaglutide, n = 2 (0.7%); liraglutide, n = 8 (5.8%); p = 0.003]. Nine (1.8%) patients experienced hypoglycaemia [dulaglutide, n = 6 (2.1%); liraglutide, n = 2 (1.5%); placebo, n = 1 (1.4%)], with no event being severe. CONCLUSIONS: In Japanese patients with type 2 diabetes, once-weekly dulaglutide (0.75 mg) was superior to placebo and non-inferior to once-daily liraglutide (0.9 mg) for reduction in HbA1c at 26 weeks. Dulaglutide was safe and well tolerated.

Low serum bilirubin concentration in haemodialysis patients with Type 2 diabetes.

AIMS: Previous studies have implicated reduced serum bilirubin concentrations in the development of cardiovascular disease. The aim of this study was to examine whether bilirubin may explain the high incidence of vascular complications in haemodialysis patients with Type 2 diabetes. METHODS: We compared serum bilirubin concentrations, as well as other known aetiological risk factors for cardiovascular disease, in 206 Type 2 diabetes patients on haemodialysis with those in 741 Type 2 diabetes patients not receiving haemodialysis, and evaluated the association between serum bilirubin concentration and cardiovascular disease incidence. RESULTS: Incidences of cardiovascular disease and systolic blood pressure were higher; however, BMI and serum total cholesterol were lower in haemodialysis patients compared with those in patients without haemodialysis. Serum total (0.30 ± 0.10 vs. 0.74 ± 0.26 mg/dl, 0.005 ± 0.002 vs. 0.013 ± 0.004 mmol/l, P < 0.0001) and indirect (0.17 ± 0.08 vs. 0.70 ± 0.23 mg/dl, 0.003 ± 0.001 vs. 0.012 ± 0.004 mmol/l, P < 0.0001) bilirubin were lower in haemodialysis patients compared with those in patients without haemodialysis. Stepwise regression analysis demonstrated that age (ß = 0.109, F = 5.959, P < 0.05), duration of diabetes (ß = -0.112, F = 6.048, P < 0.05), sex (ß = -0.123, F = 8.623, P < 0.05), cardiovascular disease events (ß = -0.099, F = 5.131, P < 0.05) and presence of haemodialysis (ß = -0.626, F = 201.727, P < 0.01) were independent factors for serum total bilirubin. Logistic regression demonstrated that age (OR 1.089, 95% CI 1.044-1.136; P < 0.0001), duration of diabetes (OR 1.029, 95% CI 1.001-1.059; P = 0.0423), body mass index (OR 1.115, 95% CI 1.001-1.242; P = 0.0487), habit of smoking (OR 2.445, 95% CI 1.046-5.716; P = 0.0391) and serum total bilirubin (OR 0.192, 95% CI 0.037-0.989; P = 0.0484) were independent factors for cardiovascular disease events. CONCLUSIONS: Low serum bilirubin concentration could be one of the important factors for the high incidence of cardiovascular disease in Type 2 diabetes patients receiving haemodialysis.

Evaluation and modification of the formalin-ether sedimentation technique.

Formalin-ether sedimentation (MGL) is a well-known technique for the examination of faeces for parasites, but some recent reports have indicated that its efficiency is not as high as originally thought. We reevaluated the recovery efficiency of the original MGL (O-MGL) technique to modify it. We subsequently adopted the following modified MGL technique (M-MGL): filtration by three layers of gauze and washing, adjustment to pH 3, retreatment of plug, and use of 1.5 g of faeces. We also compared five faecal examination techniques (including the O-MGL and the M-MGL) for three parameters: recovery efficiency, sensitivity, and mean number of eggs detected. The highest sensitivity was obtained by the M-MGL (95%), followed by the commercially available kit (Kit; 90%), O-MGL (76%), Kato-Katz (KK; 57%), and direct smear (DS; 50%). The mean numbers of Ascaris lumbricoides eggs recovered by the techniques were in order M-MGL (148 eggs), Kit (97), O-MGL (41), KK (11), and DS (6). This M-MGL technique has the advantage not only of the above-mentioned three parameters, but also the ease of microscopic observation and the concentration index. The parameters of the O-MGL technique were not necessarily sufficient compared with the other techniques. It seems that the improved M-MGL technique in the present study is applicable for field surveys, particularly when the survey is done in areas of low parasite endemicity.

Macrophage-dominant sialadenitis in human T-cell leukemia virus type I-associated myelopathy after living-donor liver transplantation.

A 64-year-old man who suffered from human T-cell leukemia virus type I (HTLV-I)-associated myelopathy (HAM) after living-donor liver transplantation (LDLT) for liver cirrhosis due to hepatitis C virus infection complained of xerostomia. Although exocrine function test results were positive, autoantibodies including anti-SS-A/SS-B antibodies and sialography showed negative findings. Labial salivary gland biopsy revealing infiltration of 60 counts of mononuclear cells (MNCs) in minor salivary glands led to a diagnosis of Sjögren's syndrome-like sialadenitis. Immunohistochemistry demonstrated dominant CD68 staining and major histocompatibility complex class II on the surface of infiltrating MNCs. Herein we have reported a rare condition of macrophage-dominant sialadenitis in a patient with HAM after LDLT.

Association of distinct clinical subsets with myositis-specific autoantibodies towards anti-155/140-kDa polypeptides, anti-140-kDa polypeptides, and anti-aminoacyl tRNA synthetases in Japanese patients with dermatomyositis: a single-centre, cross-sectional study.

OBJECTIVE: To determine the association of distinct clinical subsets with myositis-specific autoantibodies (MSAs) towards anti-155/140-kDa polypeptides [anti-155/140 antibodies (Abs)], anti-140-kDa polypeptides (anti-140 Abs), and anti-aminoacyl tRNA synthetases (ARS Abs) in Japanese patients with dermatomyositis (DM). METHODS: We compared the clinical features and short-term prognoses of 30 DM patients whose serological status included these MSAs. The MSAs were determined by immunoprecipitation. RESULTS: Anti-155/140 Abs (n = 5), anti-140 Abs (n = 8), and anti-ARS Abs (n = 7) did not overlap each other. All of the anti-155/140 Ab-positive patients (n = 5) were complicated by malignancies, as were all of the anti-140 Ab-positive patients (n = 8), who showed rapidly progressive interstitial lung disease (ILD). The survival rate at 6 months from the diagnosis of DM was significantly lower in the anti-140 Ab-positive patients than in the other patients. CONCLUSION: This is the first study to report, in a single cohort of DM patients, that distinct clinical subsets are distributed in an anti-155/140 Ab-positive group, an anti-140 Ab-positive group, or an anti-ARS Ab-positive group. Our data also confirm previous evidence that anti-155/140 Abs are involved in malignancies and that anti-140 Abs are involved in rapidly progressive ILD.

Calcium/calmodulin-dependent protein kinase II (CaMKII) regulates tumour necrosis factor-related apoptosis inducing ligand (TRAIL)-mediated apoptosis of fibroblast-like synovial cells (FLS) by phosphorylation of Akt.

OBJECTIVE: We tried to determine whether calcium/calmodulin-dependent protein kinase II (CaMKII) regulates tumour necrosis factor-related apoptosis inducing ligand (TRAIL)-mediated apoptosis of fibroblast-like synovial cells (FLS). METHODS: CaMKII expression in FLS was studied by both western blotting and real time reverse transcription polymerase chain reaction (RT-PCR). TRAIL-mediated apoptosis of FLS was quantified by disruption of mitochondrial transmembrane potential (DeltaPsim), Leu-Glu-His-Asp (IETD) ase activity and DNA degradation. Involvement of CaMKII and other kinases, including extracellular signal-regulated kinase (ERK), p38, c-Jun N-terminal kinase (JNK) and Akt during TRAIL-mediated apoptosis of FLS was estimated by the use of specific each kinase chemical inhibitor. RESULTS: Predominant expression of delta and gamma isoform of CaMKII, especially delta isoform, was determined in cultured FLS. TRAIL rapidly induced apoptosis of FLS as well as the phosphorylation of extracellular signal-regulated kinase (ERK), p38, c-Jun N-terminal kinase (JNK) and Akt. Chemical kinase inhibitor toward CaMKII and Akt significantly augmented TRAIL-mediated apoptosis of FLS whereas those toward ERK, p38 and JNK did not. Notably, CaMKII chemical inhibitor abrogated TRAIL-induced phosphorylation of Akt. Elevation of Leu-Glu-His-Asp (IETD) ase activity was associated with the apoptotic phenomena, which was almost suppressed by IETD competitive peptides. CONCLUSION: Our results suggest a first observation that CaMKII regulates TRAIL-mediated apoptosis of FLS through Akt, standing an upstream of caspase-8-dependent cascades. Furthermore, CaMKII is suggested to be a new therapeutic target molecule of rheumatoid arthritis (RA).

UFT plus gemcitabine combination chemotherapy in patients with advanced non-small-cell lung cancer: a multi-institutional phase II trial.

A multi-institutional phase II trial was conducted to evaluate the efficacy and toxicity of combination chemotherapy consisting of gemcitabine and UFT, which is composed of tegafur and uracil, for non-small-cell lung cancer (NSCLC) patients. Patients with advanced NSCLC received an oral administration of UFT (tegafur 200 mg m(-2)) b.i.d. from days 1 to 14 and intravenous injection of gemcitabine 900 mg m(-2) on days 8 and 15. This treatment was repeated every 4 weeks. A total of 44 patients were enrolled into this trial. The median age of all patients was 74 years, with 23 patients younger than 75 years and 21 patients with 75 years of age or older. A total of 18 patients (41%) achieved a partial response. The median survival time was 13.2 months and the 1-year survival rate was 59%. The most common grade 3-4 toxicity was neutropenia (57%). The frequency of grade 3 nonhaematologic toxicities was less than 5%. In addition, no significant difference in the response, survival or toxicities was observed between the patients younger than and those older than 75 years of age. This combination chemotherapy demonstrated a promising effectiveness and acceptable toxicity in patients with advanced NSCLC, even in patients older than 75 years. .

[Thoracoscopic repair of diaphragmatic thinning for pleuroperitoneal communication; report of a case].

A 53-year-old man presented with massive right hydrothorax just after introduction of continuous ambulatory peritoneal dialysis (CAPD). Because the glucose concentration of pleural fluid was markedly high compared with that of serum, we diagnosed pleuroperitoneal communication. Thoracoscopic surgery was performed and thinning of the diaphragm was found. We sutured the diaphragm to repair the thin portion and performed pleurodesis with 50% glucose solution. He restarted CAPD 1 month post-operatively and continued at home without pleural effusion. Eight months post-operatively, he experienced dyspnea again and chest X-ray showed right hydrothorax. Although the cause of recurrent hydrothorax is unknown, it may be that not only surgical repair but also more intense pleurodesis is needed.

Biosynthesis of Vicia graminea lectin- and Vicia unijuga lectin-binding glycoproteins in human tumor and nontumor cells and an estimation of its epitope structure.

We investigated biosynthesis of Vicia graminea lectin (VGA)- and Vicia unijuga lectin (VUA)-binding (Vgu) glycoproteins, which are human malignant tumor-associated antigens, in cultured human tumor and non-tumor cells by pulse-labeling experiments with [35S]-methionine, followed by immunoprecipitation using immobilized VUA, SDS-PAGE and autofluorography. It was shown that Vgu glycoproteins synthesized by tumor cells were 15-30 times greater than those of non-tumor cells. It was also shown that about 40-70% of Vgu glycoproteins synthesized by non-tumor cells were secreted from the cells while more than 80% of the antigen synthesized by tumor cells was not secreted, and that Vgu glycoproteins consisted of multiple molecular species with the same epitope. To estimate the epitope structure of Vgu glycoproteins, in preliminary experiments we prepared sialoglycoproteins and/or sialoglycopeptides from purified human glycophorin A. Human glycophorins A(M) and A(N) (GPs-A(M) and A(N)) were treated with Clostridium perfringens neuraminidase to remove all sialic acid residues linked to carbohydrate chains, with Newcastle disease virus (NDV) to remove alpha2-3 linked sialic acid residues, and by Edman's degradation to eliminate N-terminal amino acid of GP-As. Partial or complete desialylation reactions resulted in disappearance of the reactivity of GP-A(M) and GP-A(N) with corresponding antisera and in appearance of reactivities with VUA and VGA. Elimination of N-terminal amino acid of GP-As also resulted in appearance of reactivities with VUA. These results show that sialoglycoproteins with similar serological properties of Vgu glycoprotein could be prepared from GP-As, and suggest that the epitope structure of Vgu glycoprotein may be related to the MN blood type-epitope structure and its sialic acid residues at N-terminal moiety of GP-As.

Molecular characterization of mitotic cyclins in rice plants.

Cyclins are known to activate cyclin-dependent protein kinases, which are essential for cell cycle progression in eukaryotes. We isolated full-length cDNAs encoding rice mitotic cyclins named CycA1; os; 1 and CycB2;os;1, which are related to A- and B-type cyclins, respectively, from animals. To characterize the function of these mitotic cyclins, as well as that of another B-type cyclin, CycB2;os;2, each cDNA was introduced into yeast cells. When cDNAs encoding CycA1;os;1, CycB2;os; or CycB2;os;2 were overexpressed in the yeast mutant DLI, which is deficient in G1 cyclins, the mutant phenotype was rescued, indicating that these mitotic cyclins are functional in yeast cells. When the cDNA encoding CycB2;os;1 was expressed in the wild-type yeast strain, the cells lost the ability to grow, whereas the expression of either cycA1;os: 1 or cycB2;os;2 did not inhibit growth. In situ hybridization of these mitotic cyclin genes with rice root apices and counterstaining of chromosomes with a DNA-specific dye revealed that cycA1;os;1 is expressed from the G2 phase to the early M phase, while transcripts of cycB2:os;1 and cycB2;os;2 accumulated until the end of mitosis. Our results indicate that these B2-type cyclins may be involved in the control of mitosis, in combination with a G2/M-phase CDK.

Postoperative outcome of 37 patients with lobar intracerebral hemorrhage related to cerebral amyloid angiopathy.

BACKGROUND AND PURPOSE: Several recent studies have suggested that neurosurgical procedures are not contraindicated in patients with cerebral amyloid angiopathy (CAA). The purpose of this study was to elucidate the clinical factors influencing the outcome of patients with CAA-related intracerebral hemorrhage (ICH) treated surgically. METHODS: A total of 50 neurosurgical procedures (42 intracerebral hematoma evacuations, 4 ventriculoperitoneal shunts, 3 ventricular drainages, and 1 brain biopsy) were performed in 37 patients with CAA-related ICH. To ascertain the clinical factors that may influence their postoperative outcome, their clinical data (demographics, medical history, recurrent lobar hemorrhage, radiographic characteristics, multiple lobar hemorrhage, surgical details, and postoperative hemorrhage) were examined retrospectively and subjected to multivariate analysis. RESULTS: Twenty patients (54%) had a good outcome, and only 4 (11%) died. Parietal hematomas, advanced age (>/=75 years), and intraventricular hemorrhages had significant adverse influence on the postoperative outcome. Clinically significant postoperative hemorrhage requiring evacuation occurred after 2 (5%) of 42 intracerebral hematoma evacuations. Postoperative hemorrhage did not have significant adverse influence on the outcome. CONCLUSIONS: Neurosurgery can be performed relatively safely in patients with CAA-related ICH, and their postoperative outcome is better than that reported previously. Surgical treatment should be considered for such patients aged <75 years without a parietal hematoma and intraventricular hemorrhage.

Presence of Vicia graminea lectin- and Vicia unijuga lectin-binding (Vgu) glycoproteins in human fetal membranes and some of their biochemical properties.

We have previously reported that Vicia graminea lectin (VGA)- and Vicia unijuga lectin (VUA)-binding glycoproteins (Vgu glycoproteins), malignant tumor-associated antigens, exist in human meconium and amniotic fluid. To examine the origin of Vgu glycoprotein, their presence, some of their chemical and serological properties and their biosynthesis in the human fetal membrane, amnion and chorion laeve and accompanying membrane cells were examined. Perchloric acid-soluble fractions were prepared from human amnion and chorion laeve, after which VUA-binding components (Vgu glycoproteins) were separated by HPLC and affinity chromatography using immobilized VUA. Biosynthesis of the antigens in primary cultured cells prepared from the amnion and chorion laeve were examined by pulse-labeling and immunoprecipitation using immobilized VUA and compared with those in cultured human cancer cells. The results indicated that the serological properties of VUA-binding components in fetal membranes were similar to those of meconium and amniotic fluid, that many molecular species of VUA-binding components were synthesized in amnion and chorion laeve cells and that about 40-50% of antigens synthesized are secreted from cells while antigens synthesized in cultured cancer cells human were hardly secreted with more than 95% of the antigens remaining in the cells. From these results, we concluded that a large part of Vgu glycoproteins found in amniotic fluid is synthesized in cells of the amnion and chorion laeve and secreted into the fluid, and that Vgu glycoproteins synthesized in cancer cells were not secreted, rather they were retained in the cells.

Apoptosis resistance of blood cells from patients with paroxysmal nocturnal hemoglobinuria, aplastic anemia, and myelodysplastic syndrome.

Bone marrow (BM) hypoplasia is a major cause of death in paroxysmal nocturnal hemoglobinuria (PNH). However, little is known about the molecular events leading to the hypoplasia. Considering the close pathologic association between PNH and aplastic anemia (AA), it is suggested that a similar mechanism operates in the development of their BM failure. Recent reports have indicated apoptosis-mediated BM suppression in AA. It is thus conceivable that apoptosis also operates to cause BM hypoplasia in PNH. If this is the case, PNH clones need to survive apoptosis and show considerable expansion leading to clinical manifestations. We report here that granulocytes obtained from 11 patients with PNH were apparently less susceptible than those from 20 healthy individuals to both spontaneous apoptosis without any ligands and that induced by anti-FAS (CD95) antibody in vitro. The patients' BM CD34+ cells were also resistant to apoptosis induced by treatment with tumor necrosis factor-alpha, interferon-gamma, and subsequently with anti-FAS antibody. In lymphocytes, the pathologic resistance was not discriminated from inherent resistance to apoptosis. Granulocytes from 13 patients with AA and 12 patients with myelodysplastic syndrome (MDS) exhibited similar resistance to apoptosis. CD34+ cells from MDS-BM also showed similar tendency. Thus, the comparative resistance to apoptosis supports the pathogenic implication of apoptosis in marrow injury of PNH and related stem cell disorders.

[Clinical results of combination chemotherapy with cisplatin, vinblastine and bleomycin (pvb) for advanced testicular cancer: evaluation of risk criteria].

Between 1982 and 1991, 24 patients with advanced testicular germ cell tumor were treated by combination chemotherapy with cisplatin, vinblastine and bleomycin (PVB). Based on short-term efficacy of the PVB regimen and long-term prognosis in our patients, we evaluated 4 risk criteria proposed by Indiana University, National Cancer Institute (NCI), Memorial Sloan-Kettering Cancer Center (MSKCC) and European Organization for Research and Treatment of Cancer (EORTC). Clinical staging were IIA in 8 patients, IIB in 8, IIIA in 1, IIIB in 5 and IIIC in 2. Metastases included retroperitoneal lymph node in 20 cases (> 5 cm in 10), lung in 6, bone and liver in each 1. Complete response (CR) was obtained in 12 (50%) patients and partial response (PR) in 9 (38%). According to the stage and metastatic site, CR was achieved in 75%, 38% and 38%of the stage IIA, IIB and III tumors, respectively, and in 60% and 50% of retroperitoneal and pulmonary metastases, respectively. However, neither CR nor PR was recognized for live and bone metastases. Prognosis was assessed with a mean followup period of 88.5 months. Although all 12 patients with CR were alive, 4 of the 9 with PR and all patients on whom the drug was ineffective died of cancer. Accuracy in predicting prognosis was 82%, 75%, 74%, and 63% using the MSKCC, Indiana, NCI and EORTC risk criteria, respectively.

Quenching of nitric oxide by an oral carbonaceous adsorbent.

The ability of carbonaceous particles (AST-120), originally developed as an enteral adsorbent of uremic toxins, to quench nitric oxide (NO) was tested. NO in solutions prepared by two methods [NO gas bubbling and NO generating system, i.e., decomposition of 1-hydroxy-2-oxo-3-(aminopropyl)-3-isopropyl-1-triazene] were determined by a NO-specific reduction of carboxy-2-phenyl-4,4,5,5-tetramethyl-imidazoline-1-oxyl-3-oxide using an electron paramagnetic resonance spectrometry. NO concentrations were less in samples containing increasing concentrations of AST-120. In a separate study, nitrite concentrations in lipopolysaccharide-treated RAW264 cells were significantly less in incubation medium containing AST-120. Thus, AST-120 may be applicable as an enteral anti-NO agent.