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Atezolizumab; Isatuximab; Solid tumors Atezolizumab; Isatuximab; Tumores sólidos Atezolizumab; Isatuximab; Tumors sòlids Background The anti-CD38 antibody isatuximab is approved for the treatment of relapsed/refractory multiple myeloma, but there are no data on its efficacy in solid tumors. This phase I/II study (NCT03637764) assessed the safety and activity of isatuximab plus atezolizumab (Isa + Atezo), an anti-programmed death-ligand 1 (PD-L1) antibody, in patients with immunotherapy-naive solid tumors: epithelial ovarian cancer (EOC), glioblastoma (GBM), hepatocellular carcinoma (HCC), and squamous cell carcinoma of the head and neck (SCCHN). Patients and methods Phase I assessed safety, tolerability, pharmacokinetics, pharmacodynamics, and the recommended phase II dose (RP2D) of isatuximab 10 mg/kg intravenously (i.v.) every week for 3 weeks followed by once every 3 weeks + atezolizumab 1200 mg i.v. every 3 weeks. Phase II used a Simon’s two-stage design to assess the overall response rate or progression-free survival rate at 6 months (GBM cohort). Interim analysis was carried out at 6 months following first dose of the last enrolled patient in each cohort. Pharmacodynamic biomarkers were tested for CD38, PD-L1, tumor-infiltrating immune cells, and FOXP3+ regulatory T cells (Tregs) in the tumor microenvironment (TME). Results Overall, 107 patients were treated (EOC, n = 18; GBM, n = 33; HCC, n = 27; SCCHN, n = 29). In phase I, Isa + Atezo showed an acceptable safety profile, no dose-limiting toxicities were observed, and RP2D was confirmed. Most patients experienced ≥1 treatment-emergent adverse event (TEAE), with ≤48.5% being grade ≥3. The most frequent TEAE was infusion reactions. The study did not continue to stage 2 based on prespecified targets. Tumor-infiltrating CD38+ immune cells were reduced and almost cleared after treatment. Isa + Atezo did not significantly modulate Tregs or PD-L1 expression in the TME. Conclusions Isa + Atezo had acceptable safety and tolerability. Clinical pharmacodynamic evaluation revealed efficient target engagement of isatuximab via treatment-mediated reduction of CD38+ immune cells in the TME. Based on clinical data, CD38 inhibition does not improve responsiveness to PD-L1 blockade in these patients. This work was sponsored by Sanofi (no grant number).

This case–control study was aimed to assess the effect of genetic variants of tumor necrosis factor (TNF) α−308 and lymphotoxin (LT) α+252 on development of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). Their gene–gene interaction was also investigated. We enrolled 200 pairs of age- and sex-matched patients with cirrhotic HBV-HCC and unrelated patients with HBV-cirrhosis alone. Polymorphisms of TNFα −308 and LTα +252 were genotyped. Synergy index was used to calculate interaction between the variant genotypes. The results indicated that the frequency distribution of the variant genotypes ( TNFα −308 G/A and LTα +252 G/G) in patients with HCC were significantly higher than those in patients with cirrhosis alone. Multivariate analysis indicated that TNFα −308 G/A (odds ratio [OR], 2.34) and LTα +252 G/G (OR, 2.04) were independent risk factors for HCC. By the clinical characteristics of study population, multivariate analysis demonstrated that independent factors associated with harboring the variant genotypes included cirrhosis with Child-Pugh C (OR = 6.47 in cases and OR = 11.56 in controls) and thrombocytopenia (OR = 8.86 in cases and OR = 7.74 in controls). Calculation of synergy index (SI) indicated that there are additive interaction between TNFα −308 G/A and LTα +252 G/G on risk of HCC (SI = 1.29). In conclusion: There are independent and additive interactions between TNFα −308 G/A and LTα +252 G/G on risk for HBV-HCC. They correlated with advanced hepatic fibrosis and severe liver damage, which might contribute to a higher risk for HCC.

An optimal dosage of nitrogen has long been known to play important roles in governing nitrogen-use efficiency and improving the yield of plants. However, there is limited information on the isolation and expression profiles of genes related to nitrogen metabolism in peach (Prunus persica L. Batsch). This study isolated five genes involved in nitrogen metabolism and evaluated the effects of a single foliar application of urea on levels of expression of these genes in the leaves of ‘Dazhenbaochiyue’ peach. Cloning resulted in the isolation of 1,767, 1,236, 1,074, 1,758, and 2,721 nt-long cDNAs with full-length open reading frames encoding 588, 411, 357, 585, and 906 amino acids representing the asparagine synthetase (AS), glutamate dehydrogenase (GDH), glutamine synthetase (GS), nitrite reductase (NiR), and nitrate reductase (NR) genes in peach, respectively. An alignment of multiple amino acid sequences revealed that the AS, GDH, GS, and NR proteins in peach shared high levels of sequence conserva...

MicroRNA166 (miR166) is known to have highly conserved targets that encode proteins of the class III homeodomain-leucine zipper (HD-ZIP III) family, in a broad range of plant species. To further understand the relationship between HD-ZIP III genes and miR166, four HD-ZIP III family genes (PpHB14, PpHB15, PpHB8, and PpREV) were isolated from peach (Prunus persica) tissue and characterized. Spatio-temporal expression profiles of the genes were analyzed. Genes of the peach HD-ZIP III family were predicted to encode five conserved domains. Deduced amino acid sequences and tertiary structures of the four peach HD-ZIP III genes were highly conserved, with corresponding genes in Arabidopsis thaliana. The expression level of four targets displayed the opposite trend to that of miR166 throughout fruit development, with the exception of PpHB14 from 35 to 55 days after full bloom (DAFB). This finding indicates that miR166 may negatively regulate its four targets throughout fruit development. As for leaf and phloem, the same trend in expression level was observed between four targets and miR166 from 75 to 105 DAFB. However, the opposite trend was observed for the transcript level between four targets and miR166 from 35 to 55 DAFB. miRNA166 may negatively regulate four targets in some but not all developmental stages for a given tissue. The four genes studied were observed to have, exactly or generally, the same change tendency as individual tissue development, a finding that suggests genes of the HD-ZIP III family in peach may have complementary or cooperative functions in various tissues.

This case–control study aimed to assess the interactive effect between polymorphisms of lymphotoxin (LT) α +252 and habitual substance use on risk of hepatocellular carcinoma (HCC). We enrolled 150 pairs of sex- and age-matched HCC patients and unrelated healthy controls. LTα genotypes were detected with polymerase-chain reaction and restrictive fragment length polymorphisms. Information about habits of substance use was obtained through personal interview. Multivariate analysis indicated that LTα +252 G/G genotypes [odds ratio (OR) = 3.36], Hepatitis B surface antigen (OR = 16.68), antibodies to hepatitis C virus (OR = 34.88) and having at least two habits of substance use (OR = 2.50) were independent risk factors for HCC. There were additive interactions among LTα +252 G/G genotype, chronic viral hepatitis, and habit of each substance use. In conclusion: There are independent and additive interactions between LTα +252 G/G genotype, chronic viral hepatitis, and habits of substance use on risk of HCC.

DNA markers have useful applications in cultivar identification. A novel analysis approach called cultivar identification diagram (CID) was developed using DNA markers in the separation of plant individuals. This new strategy is less time- and cost-consuming, has reliable results, and was constructed for fingerprinting. Ten 11-mer primers were used to amplify the genotypes; all 95 peach genotypes (from the National Peach Germplasm Repository, in Nanjing, China) were distinguished by a combination of 54 primers. The utilization of the CID among these 95 peach cultivars was also verified by the identification of three randomly chosen groups of cultivars. This identification showed some advantages including the use of fewer primers and easy separation of all cultivars by the corresponding primers marked in the right position on the CID. This peach CID could provide the information to separate any peach cultivars of these 95, which may be of help to the peach industry in China and for the utilization of DNA markers to identify other plant species.

Summary Background Peginterferon-α–based therapy frequently leads to neutropenia. It remains unclear whether neutropenia is associated with bacterial infection in chronic hepatitis C (CHC). Aim To evaluate the risk of bacterial infection and neutropenia in patients with CHC treated with peginterferon-α/ribavirin. Methods In all, 207 patients with CHC with (group A, n = 30) and without (group B, n = 177) baseline neutropenia were treated with peginterferon-α/ribavirin. Results Group A had significantly higher rates of moderate (

The KT/HAK/KUP family members encoding high-affinity potassium (K(+)) transporters mediate K(+) transport across the plasma membranes of plant cells to maintain plant normal growth and metabolic activities. In this paper, we identified 16 potassium transporter genes in the peach (Prunus persica) using the Hidden Markov model scanning strategy and searching the peach genome database. Utilizing the Arabidopsis KT/HAK/KUP family as a reference, phylogenetic analysis indicates that the KT/HAK/KUP family in the peach can be classified into 3 groups. Genomic localization indicated that 16 KT/HAK/KUP family genes were well distributed on 7 scaffolds. Gene structure analysis showed that the KT/HAK/KUP family genes have 6-9 introns. In addition, all of the KT/HAK/KUP family members were hydrophobic proteins; they exhibited similar secondary structure patterns and homologous tertiary structures. Putative cis-elements involved in abiotic stress adaption, Ca(2+) response, light and circadian rhythm regulation, and seed development were observed in the promoters of the KT/HAK/KUP family genes. Subcellular localization prediction indicated that the KT/HAK/KUP members were mainly located in the plasma membrane. Expression levels of the KT/HAK/ KUP family genes were much higher in the fruit and flower than those in the other 7 tissues examined, indicating that the KT/HAK/KUP family genes may have important roles in K(+) uptake and transport, which mainly contribute to flower formation and fruit development in the peach.

The fruit peach originated in China and has a history of domestication of more than 4000 years. Numerous local cultivars were selected during the long course of cultivation, and a great morphological diversity exists. To study the diversity and genetic background of local peach cultivars in China, a set of 158 accessions from different ecological regions, together with 27 modern varieties and 10 wild accessions, were evaluated using 49 simple sequence repeats (SSRs) covering the peach genome. Broad diversity was also observed in local cultivars at the SSR level. A total of 648 alleles were amplified with an average of 13.22 observed alleles per locus. The number of genotypes detected ranged from 9 (UDP96015) to 58 (BPPCT008) with an average of 27.00 genotypes per marker. Eight subpopulations divided by STRUCTURE basically coincided with the dendrogram of genetic relationships and could be explained by the traditional groups. The 8 subpopulations were juicy honey peach, southwestern peach I, wild peach, Buddha peach + southwestern peach II, northern peach, southern crisp peach, ornamental peach, and Prunus davidiana + P. kansuensis. Most modern varieties carried the genetic backgrounds of juicy honey peach and southwestern peach I, while others carried diverse genetic backgrounds, indicating that local cultivars were partly used in modern breeding programs. Based on the traditional evolution pathway, a modified pathway for the development of local peach cultivars in China was proposed using the genetic background of subpopulations that were identified by SSRs. Current status and prospects of utilization of Chinese local peach cultivars were also discussed according to the SSR information.

To evaluate the diagnostic application of serum insulin-like growth factor-II (IGF-II) and alpha-fetoprotein (AFP) levels in hepatocellular carcinoma (HCC), IGF-II and AFP were determined in 100 cirrhotic patients with HCC, 100 sex- and age-matched patients with cirrhosis alone and 50 healthy controls. The results indicated that IGF-II and AFP levels in patients with HCC were higher than in those with cirrhosis alone (p = 0.0001). There is an inverse correlation between IGF-II and (log)AFP (r = -0.410, p = 0.0001) in patients with HCC. Multivariate analysis indicated that IGF-II and AFP were closely associated, in a dose-related fashion, with the presence of HCC. Receiver operating characteristic curves were used to determine the optimal cutoff values of IGF-II (4.5 mg/g prealbumin) and AFP (100 ng/ml), respectively. Both IGF-II and AFP show a high specificity and positive likelihood ratio. The sensitivity was 42.0% for IGF-II and 73.0% for AFP. Determination of both markers in parallel significantly increased the diagnostic accuracy (96.5%) and sensitivity (97.9%), with a high specificity (95.1%) and positive likelihood ratio (19.9). In conclusion, IGF-II and AFP may be used as complementary tumor markers to discriminate HCC from cirrhosis.

In this study, 33 homeodomain-leucine zipper (HD-ZIP) genes were identified in peach using the HD-ZIP amino acid sequences of Arabidopsis thaliana as a probe. Based on the phylogenetic analysis and the individual gene or protein characteristics, the HD-ZIP gene family in peach can be classified into 4 subfamilies, HD-ZIP I, II, III, and IV, containing 14, 7, 4, and 8 members, respectively. The most closely related peach HD-ZIP members within the same subfamilies shared very similar gene structure in terms of either intron/exon numbers or lengths. Almost all members of the same subfamily shared common motif compositions, thereby implying that the HD-ZIP proteins within the same subfamily may have functional similarity. The 33 peach HD-ZIP genes were distributed across scaffolds 1 to 7. Although the primary structure varied among HD-ZIP family proteins, their tertiary structures were similar. The results from this study will be useful in selecting candidate genes from specific subfamilies for functional analysis.

This paper describes a system for the recognition of legal amounts on bank checks written in the Chinese language. It consists of subsystems that perform preprocessing, segmentation, and recognition of the legal amount. In each step of the segmentation and recognition phases, a list of possible choices are obtained. An approach is adopted whereby a large number of choices can be processed effectively and efficiently in order to achieve the best recognition result. The contribution of this paper is the proposal of a grammar checker for Chinese bank check amounts. It is found to be very effective in reducing the substitution error rate. The recognition rate of the system is 74.0%, the error rate is 10.4%, and the reliability is 87.7%.

One of the most important uses of DNA markers is cultivar identification. However, no DNA fingerprint analysis strategy is available for making DNA markers helpful in practical plant cultivar identification, especially for the identification of a large number of cultivars. We developed a manual cultivar identification diagram strategy for efficient identification of plant cultivars, from which a cultivar identification diagram (CID) of genotyped plant individuals can be constructed manually. This CID could be used as a reference for quick identification of plant cultivars of interest. We used 11-mer RAPD primers to amplify DNA samples of 32 ornamental peach genotypes; all the cultivars were well distinguished by fingerprints from 6 primers. The utility of this CID was verified by identification of three randomly chosen groups of cultivars among the 32 ones that we selected. This CID generated will be useful for the identification of commercially important ornamental peach cultivars.

This case–control study aimed to evaluate the diagnostic application of urinary transforming growth factor (TGF) α and serum α-fetoprotein (AFP) in hepatocellular carcinoma (HCC). TGFα and AFP were determined in 90 pairs of age- and gender-matched patients with cirrhotic HCC and patients with cirrhosis alone and 60 healthy controls. The results indicated that TGFα and AFP levels in patients with HCC were higher than in those with cirrhosis alone or healthy controls (each P = 0.0001). Multivariate analysis indicated that TGFα (odds ratio (OR) 1.03, 95 % confidence interval (CI) 1.05–1.16) and AFP (OR 1.03, 95 % CI 1.01–1.06) were closely associated, in a dose-related fashion, with the development of HCC. The optimal cutoff values, determined with the receiver operating characteristic (ROC) curves, were 29 μg/g creatinine for TGFα and 100 ng/ml for AFP, respectively. The areas under ROC curve (AUC) were 0.74 for TGFα and 0.78 for AFP, respectively. Both biomarkers showed the same sensitivity (52.2 %), high specificity, high positive predictive value, and moderate positive likelihood ratio. Determination of both markers in parallel significantly increased the AUC (0.91) and diagnostic accuracy (92.2 %), with a high sensitivity (86.7 %), specificity (97.8 %), positive predictive value (PPV; 97.5 %), and moderate positive likelihood ratio (PLR; 39.4). Among 31 cirrhotic HCC with AFP ≤ 20 ng/ml, the calculated AUC for TGFα was 0.79, with a sensitivity of 64.5 %, specificity of 96.7 %, PPV of 87.0 %, and PLR of 19.5. In conclusion, urinary TGFα and serum AFP are complementary tumor markers for detection of HCC with low AFP production.

We identified 131 AP2/ERF (APETALA2/ethylene-responsive factor) genes in material from peach using the gene sequences of AP2/ERF amino acids of Arabidopsis thaliana (Brassicaceae) as probes. Based on the number of AP2/ERF domains and individual gene characteristics, the AP2/ERF superfamily gene in peach can be classified broadly into three families, ERF (ethylene-responsive factor), RAV (related to ABI3/VP1), and AP2 (APETALA2), containing 104, 5, and 21 members, respectively, along with a solo gene (ppa005376m). The 104 genes in the ERF family were further divided into 11 groups based on the group classification made for Arabidopsis. The scaffold localizations of the AP2/ERF genes indicated that 129 AP2/ERF genes were all located on scaffolds 1 to 8, except for two genes, which were on scaffolds 17 and 10. Although the primary structure varied among AP2/ERF superfamily proteins, their tertiary structures were similar. Most ERF family genes have no introns, while members of the AP2 family have more introns than genes in the ERF and RAV families. All sequences of AP2 family genes were disrupted by introns into several segments of varying sizes. The expression of the AP2/ERF superfamily genes was highest in the mesocarp; it was far higher than in the other seven tissues that we examined, implying that AP2/ERF superfamily genes play an important role in fruit growth and development in the peach. These results will be useful for selecting candidate genes from specific subgroups for functional analysis.

DNA markers have useful applications in cultivar identification. A novel analysis approach called cultivar identification diagram (CID) was developed using DNA markers in the separation of plant individuals. This new strategy is less time- and cost-consuming, has reliable results, and was constructed for fingerprinting. Ten 11-mer primers were used to amplify the genotypes; all 95 peach genotypes (from the National Peach Germplasm Repository, in Nanjing, China) were distinguished by a combination of 54 primers. The utilization of the CID among these 95 peach cultivars was also verified by the identification of three randomly chosen groups of cultivars. This identification showed some advantages including the use of fewer primers and easy separation of all cultivars by the corresponding primers marked in the right position on the CID. This peach CID could provide the information to separate any peach cultivars of these 95, which may be of help to the peach industry in China and for the utilization of DNA markers to identify other plant species.

Distributed simulation of circuits in which the process interactions form a cyclic graph is addressed. The method described uses a dataflow network synthesized on the basis of the connectivity of the circuit components. The algorithm, called Yaddes (which stands for yet another asynchronous distributed discrete-event simulation algorithm), computes for each component a quantity time of next event, which permits the corresponding model to execute asynchronously as far ahead in simulation time as possible. The network ensures that a simulation process executing in a distributed processing environment will not deadlock. The algorithm, which also offers acceptable performance and provable correctness, is compared with the two other principal algorithms proposed to avoid deadlocks: the deadlock recovery algorithm and the exception-mode algorithm. Performance results for Yaddes are presented. >

The long-term benefits of interferon-based therapy on preventing cirrhosis at non-cirrhotic stage in chronic hepatitis C patients are not fully clarified.To evaluate the effectiveness of interferon-based therapy regarding to cirrhosis prevention in non-cirrhotic chronic hepatitis C patients.A total of 1386 biopsy-proven, non-cirrhotic chronic hepatitis C patients (892 received interferon-based therapy and 494 untreated) were enrolled.Fifty-six untreated and 51 treated (24 sustained virologic responders and 27 non-responders) patients developed cirrhosis during a mean follow-up period of 5.0 (1-16) and 5.1 (1-15.3) years, respectively. The annual incidences of cirrhosis in untreated and treated groups were 2.26 and 1.11% (non-responders: 1.99%, sustained responders: 0.74%), respectively. The 15-year cumulative incidence of cirrhosis was significantly lower in treated (9.9%) than untreated patients (39.8%, P = 0.0008, log-rank test). The 14.5-year cumulative incidence of cirrhosis was significantly lower in sustained responders (4.8%) compared with non-responders (21.6%, P = 0.0007) and untreated patients (36.6%, P0.0001). The difference was not significant between non-responders and untreated controls. Cox proportional hazards regression showed sustained virologic responders and younger age were independent negative factors for cirrhosis development.A sustained virologic response secondary to IFN-based therapy could reduce cirrhosis development in chronic hepatitis C patients.

The novel idea of water Cherenkov calorimeter made of water tanks as the next generation neutrino detector for nu factories and nu beams is investigated. A water tank prototype with a dimension of 1*1*13m^3 is constructed, its performance is studied and compared with a GEANT4 based Monte Carlo simulation. By using measured parameters of the water tank, including the light collection efficiency, attenuation length, angular dependent response etc, a detailed Monte Carlo simulation demonstrates that the detector performance is excellent for identifying neutrino charged current events while rejecting neutral current and wrong-flavor backgrounds., 19 pages, 14 figures, submitted to NIM

TT virus (TTV) is a newly isolated DNA virus from the serum of a patient with posttransfusion hepatitis of unknown etiology in 1997. To evaluate the clinical and molecular characteristics of TT virus (TTV) in a hepatitis C virus (HCV) and B (HBV) hyperendemic area (Masago), 200 residents were enrolled in the study. The sera were tested for alanine aminotransferase (ALT), HCV RNA and GB virus C/Hepatitis G virus (HGV) RNA, TTV DNA, HBsAg, anti-HCV and antibodies to HGV E2-protein (anti-E2). TTV DNA was positive in 99 of the 200 sera with a prevalence rate of 49.5%. The prevalence of HBsAg, anti-HCV, HCV RNA, HGV RNA, anti-E2 and HGV exposure (defined as positive for serum HGV RNA and/or anti-E2) was 38.9%, 69.5%, 64.5%, 17.0%, 25.5% and 39.5%, respectively. Neither clinical nor virological factors were associated with TTV viremia. The rate of ALT abnormality was significantly elevated in HCV RNA-positive (34.9%) than -negative (7.0%) residents (p0.001). HCV viremia was the only factor significantly associated with ALT elevation by multiple logistic regression (odds ratio: 6.96; 95% C.I.: 2.60-18.7). We concluded that in this HCV/HBV hyperendemic area, the prevalence of TTV DNA was high. No significant clinical factor was observed to be associated with TTV infection. TTV infection is not related to abnormal ALT levels and ALT abnormality was mainly attributable to HCV but not TTV, HBV or HGV infection.

To investigate the genotype distribution of hepatitis C virus (HCV) in southern Taiwan, the sera from 56 patients with chronic HCV infection were studied. Twenty-nine patients were men and 27 were women. Age ranged from 22 to 65 years (mean, 47.3 +/- 11.4). Eighteen of them had chronic persistent hepatitis, 27 had chronic active hepatitis, and 11 had liver cirrhosis. HCV RNA was detected by reverse transcription-nested polymerase chain reaction using primers derived from the 5'-noncoding region. The genotypes of HCV were determined by amplification of the core region with the type-specific primers as described by Okamoto et al.. All sera were positive for HCV RNA. The prevalence rates of genotypes were as follows: 1b/II, 44.6%(25/56); 2a/III, 41.1%(23/56); 2b/IV, 3.6%(2/56); mixed 1b/I + 2a/III, 5.4%(3/56): mixed 1b/II + 2b/IV, 1.8%(1/56) and type unclassified 3.6%(2/56). The distribution of genotypes was not related to the patients' age, sex, and histological changes. Nevertheless, patients having past history of blood transfusion had a significantly higher rate of HCV type 2a/III infection (72.2% versus 34.2%, p.05, chi-square test). We concluded that both of the HCV genotypes 1 b/II and 2a/III are predominant types in southern Taiwan and regional HCV genotype distribution may differ even within this island. Selective transmission of specific genotypes may pass along different infectious routes.

Interferon alpha (IFN-alpha) has been indicated to be dramatically effective in some but not all patients with chronic hepatitis C virus (HCV) infection. We investigated prospectively 27 patients of chronic hepatitis C, 12 females and 15 males, treated with IFN-alpha for a better regimen of the therapy and for any effective predictor of response to the treatment. All patients were treated with 3 to 6 million units (MU) of recombinant IFN-alpha 2b (n = 15) or lymphoblastoid IFN-alpha (n = 12) given 3 times weekly for 12 to 36 weeks. Patients with normal alanine aminotransferase (ALT) value during therapy, who sustained this response throughout 6 months follow-up after treatment was completed, were grouped into the complete responders. Patients with normal ALT value during therapy but who relapsed after treatment completed, were grouped as partial responders. Non-responders were defined as patients without normal ALT value during therapy. The rates of complete response, partial response, and non-response were 29.6%, 40.8%, and 29.6%, respectively. The degree of response to IFN-alpha therapy was not related to age, sex, type of IFN-alpha, history of blood transfusion, the state of liver pathology, or pretreatment level of ALT value. The complete responsive rate to IFN-alpha was higher in patients treated with total dose above 215 MU [38.1% (8/21) vs. 0% (0/6), p = 0.06], in patients treated for at least 24 weeks [40% (8/20) vs. 0% (0/7), p0.05], and in patients with non-genotype 1b/II HCV infection [40% (8/20) vs. 0% (0/7), p0.05]. We concluded that IFN-alpha was effective in the treatment of chronic HCV infection, particularly in those other than HCV genotype 1b/II. A high-dose, and long-duration regimen may be recommended for better response of chronic hepatitis C to IFN-alpha therapy.

To elucidate the status of serum hepatitis B virus (HBV) DNA in HBsAg-positive hepatocellular carcinoma (HCC), 100 type B chronic liver disease (CLD) patients and 19 HCC patients were studied. The positive rate of serum HBV DNA in HBeAg-positive CLD patients was significantly higher than that in HBeAg-negative CLD patients, and the correlation between the presence of serum HBV DNA and patients' age showed a negative trend. In contrast, the positive rates of serum HBV DNA in HCC patients were not related to the status of HBeAg and age, and the positive rate of serum HBV DNA in HBeAg-negative HCC patients was significantly higher than that in HBeAg-negative CLD patients. Nevertheless, the serum concentrations of HBV DNA in HCC patients were significantly lower than those in CLD patients. These results suggest that replication of HBV in HCC patients might differ from that in CLD patients, and that persistent low-level HBV replication might be related to the presence of HCC.

Necrotizing fasciitis is a rare and rapid progression soft tissue infection. The only identifiable feature is tissue necrosis along a single fascia plane. Because the skin is initially spared, it is difficult for early recognition prior to extensive tissue destruction. Ultrasonography was used for early diagnosis of this infection in five cases. All 5 patients presented with severe cellulitis. Under the suspicion of necrotizing fasciitis, ultrasonography was performed before surgical debridement. Tissue biopsy was done for histological confirmation of the diagnosis. Three patients were proven to have necrotizing fasciitis and two cellulitis only. The ultrasonographic findings of necrotizing fasciitis included: 1) irregularity of the fascia; 2) abnormal fluid collections along the fascia plane; and 3) diffuse thickening of the fascia when compared with the control site in the normal limb. However, in severe infectious cellulitis, the above mentioned findings were not observed. Our results indicate the usefulness of the ultrasonography for early diagnosis of necrotizing fasciitis.

Neutrophils (PMN) from 20 patients with atopic disease (atopy), the parents of 8 of the patients and 10 normal controls were studied by light-microscopic cytochemistry. The results revealed that myeloperoxidase (MPO) and acid phosphatase (ACP) activities in PMN in all cases significantly decreased and alkaline phosphatase activity was normal. Parents or parent of 7 of those patients had PMN enzyme deficiency similar to that of the patients. The results indicated that a primary combined and partial deficiency of MPO and ACP in PMN azurophilic granule existed in atopy. It is postulated that the deficiency led to reduction of PMN bactericidal power and delay of bactericidal action. Foreign bodies which were partially degraded could possess antigenic property. This is believed to be the important cytobiological mechanism of the tendency toward infections and formation of sensitive antigen in atopy.

The neutrophils in 2 patients with atopic disease were studied. Ultrastructurally, a number of abnormal azurophilic granules (AG) with low electron-density (Case 1) and secondary lysosomes with "myelinoid membranes" figures (Case 2) were found. Myeloperoxidase (MPO) and acid phosphatase activity were detected by light cytochemical techniques, and showed significantly low values. The deficiency of MPO and abnormal distribution of AG were also demonstrated by electron microscopic cytochemical technique. The neutrophils from the parents revealed changes similar to the patients. This study suggests that since genetic partial deficiency of neutrophil AG enzymes existed, the phagocytosed substances were only partially degraded, leading to accumulation of substances with antigenicity, and became trigger event of atopic disease.

A three-dimensional close-packed array of Josephson junctions was successfully produced in the form of a bulk granular superconductor. The granular system is a tightly compressed solid of oxide coated small tin particles in the thousand A range. The three-dimensional array of Josephson junctions thus formed showed coherent Josephson oscillations when external rf radiation was imposed, rf induced constant voltage steps were observed on its I-V characteristics at voltages a few thousand times the Josephson voltage hv/2e. The external rf radiation also induced Stable dc voltages on unbiased bulk samples, suggesting a practical mode of microwave detection. The analogy of this bulk superconducting system with a magnetic spin system will be discussed.

The transport of ATP out of mitochondria and uptake of ADP and Pi into the matrix are coupled to the uptake of one proton (Klingenberg, M., and Rottenberg, H. (1977) Eur. J. Biochem. 73, 125--130). According to the chemiosmotic hypothesis of oxidative phosphorylation this coupling of nucleotide and Pi transport to proton transport implies that the P/O ratio for the synthesis and transport of ATP to the external medium is less than the P/O ratio for the synthesis of ATP inside mitochondria. A survey of previous determinations of the P/O ratio of intact mitochondria showed little convincing evidence in support of the currently accepted values of 3 with NADH-linked substrates and 2 with succinate. We have measured P/O ratios in rat liver mitochondria by the ADP pulse method and by 32 Pi esterification, measuring oxygen uptake with an oxygen electrode, and find values close to 2 with beta-hydroxybutyrate as substrate and 1.3 with succinate as substrate in the presence of rotenone to inhibit NADH oxidation. These values were largely independent of pH, temperature, Mg2+ ion concentration, Pi concentration, ADP pulse size, or amount of mitochondria used. We suggest that these are the true values of the P/O ratio for ATP synthesis and transport by mitochondria, and that previously reported higher values resulted from errors in the determination of oxygen uptake and the use of substrates which lead to ATP synthesis by succinate thiokinase.

The authors examine the limitations of the timing semantics in the conventional behavioral simulators and present a preemptive scheduling mechanism for accurate behavioral simulation results. They consider two signal transitions at the input ports of a component, where the second input transition arrives later than the first transition. The first and second input transitions cause first output signal transitions O/sub 1/ and O/sub 2/, respectively, to be generated at the output port of the component. When the logical values of O/sub 1/ and O/sub 2/ conflict with each other and O/sub 1/ arrives later than O/sub 2/, O/sub 1/ is preempted by O/sub 2/. In addition, an input signal to a component whose pulse duration is smaller than the inertial delay of the component, T/sub mip/, is discarded during simulation. Empirical measures for T/sub mip/ relative to the high-to-low and low-to-high propagation delays of the component for TL (transistor-transistor logic), NMOS, and CMOS technologies are presented. This approach has been implemented in the ADLIB-SABLE simulator at Stanford University. >

A new way to use Josephson junctions for parametric amplification with phase control is proposed. The dc current bias of the junction is adjusted such that the Josephson oscillation automatically synchronizes with the input signal and oscillates at twice the signal frequency with the proper relative phase. The impedance of the junction then has a negative resistive component which can be used for amplification. Extension to other phase sensitive circuits is also discussed.

The transport of ATP out of mitochondria and uptake of ADP and Pi into the matrix are coupled to the uptake of one proton (Klingenberg, M., and Rottenberg, H. (1977) Eur. J. Biochem. 73, 125--130). According to the chemiosmotic hypothesis of oxidative phosphorylation this coupling of nucleotide and Pi transport to proton transport implies that the P/O ratio for the synthesis and transport of ATP to the external medium is less than the P/O ratio for the synthesis of ATP inside mitochondria. A survey of previous determinations of the P/O ratio of intact mitochondria showed little convincing evidence in support of the currently accepted values of 3 with NADH-linked substrates and 2 with succinate. We have measured P/O ratios in rat liver mitochondria by the ADP pulse method and by 32 Pi esterification, measuring oxygen uptake with an oxygen electrode, and find values close to 2 with beta-hydroxybutyrate as substrate and 1.3 with succinate as substrate in the presence of rotenone to inhibit NADH oxidation. These values were largely independent of pH, temperature, Mg2+ ion concentration, Pi concentration, ADP pulse size, or amount of mitochondria used. We suggest that these are the true values of the P/O ratio for ATP synthesis and transport by mitochondria, and that previously reported higher values resulted from errors in the determination of oxygen uptake and the use of substrates which lead to ATP synthesis by succinate thiokinase.