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A critical issue with the SiC UMOSFET is the need to develop a shielding structure for the gate oxide at the trench bottom without any increase in the JFET resistance. This study describes our new UMOSFET named IE-UMOSFET, which we developed to cope with this trade-off. A simulation showed that a low on-resistance is accompanied by an extremely low gate oxide field even with a negative gate voltage. The low RonA was sustained as Vth increases. The RonA values at VG=25 V (Eox=3.2 MV/cm) and VG=20V (Eox=2.5 MV/cm), respectively, for the 3mm x 3mm device were 2.4 and 2.8 mWcm2 with a lowest Vth of 2.4 V, and 3.1 and 4.4 mWcm2 with a high Vth of 5.9 V.

We investigate the determining mechanisms of the inversion-layer capacitance Cinv in the high-k/metal gate stacks, focusing on the two perturbative effects related with the dielectric properties. Those effects are the penetration of inversion-layer carriers into the dielectrics with a finite potential barrier and the image potential acting on the carriers adjacent to the dielectrics with permittivity different from that of the silicon substrate. The experimental and the theoretical analyses of the Cinv dependency on the crystal orientation of silicon substrates enable us to separate the two effects and to prove that the observed Cinv modulation in the high- k/metal gate stacks is attributable not to the image potential effect, but to the penetration effect. Moreover, we investigate the reduction of the total gate capacitance due to the Cinv in the advanced gate stacks scaled down to 0.66-nm equivalent oxide thickness. The influence of the elementary composition, the physical thickness, and the interface layer on a scaling loss due to the Cinv is experimentally evaluated.

Nerve agents have only ever been used in Iran and Japan: in the Iran-Iraq war and the Matsumoto and Tokyo subway sarin attacks. When discussing responses to nerve agent attacks in peace-time, it is important to maximize the lessons learned from these two incidents. The golden standard for the treatment of nerve agents has conventionally been the combination of atropine sulfate, oxime, and diazepam as recommended. While this recommendation also applies to civil defense for terrorism in peace-time, there is nonetheless a need to re-evaluate the golden standard. In addition, factors such as cost-effectiveness must be considered.

Human T-lymphotropic virus type I (HTLV-I) provirus load was examined in a cohort of a population in Guinea-Bissau among whom human immunodeficiency virus (HIV) type 2 is endemic. Geometric mean of HIV-2 RNA load among HTLVI –coinfected subjects was significantly lower than that in subjects infected with HIV-2 alone (212 vs. 724 copies/mL; P=.02). Adjusted for age sex and HIV status the risk of death increased with HTLV-I provirus load; mortality hazard ratio was 1.59 for each log/10 increase in HTLV-I provirus copies (P=.038). There is no enhancing effect of HTLV-I coinfection on HIV-2 disease but high HTLV-I provirus loads may contribute to mortality. (authors)

Carcinosarcoma of the ovary is a rare, highly aggressive neoplasm comprising histologically of both epithelial and mesenchymal components. The aim of this study was to evaluate the clinicopathological prognostic factors in ovarian carcinosarcoma, including the immunohistochemical expression of p53 protein and Ki67. Methods and results: Twenty-three cases of carcinosarcoma of the ovary were studied retrospectively. The clinicopathological and immunohistochemical parameters including p53 and Ki67 staining were statistically analysed to investigate the prognostic significance of this tumour. The overall 5-year survival rate was 27.1%; 100% for stage I, 31.3% for stage II, 10.9% for stage III and 0% for stage IV. The low-stage group (stages I and II) was found to be a significant prognostic factor for patient survival (P = 0.0113). None of the other factors (tumour size, histological type of carcinomatous and sarcomatous components, mitotic count, vascular space invasion and immunoreactivity for p53 protein and Ki67) was found to be a statistically significant prognostic indicator. Conclusions: Ovarian carcinosarcoma is a rare malignancy with poor prognosis. In this study, advanced stage appears to be poor prognostic indicator of survival in patients with ovarian carcinosarcoma.

Summarybackground In developed countries, 50–75% of AIDS patients develop retinal complications and about 20–40% acquire cytomegalavirus (CMV) retinitis. We conducted a cross-sectional survey to determine prevalence of these in The Gambia where both HIV-1 and HIV-2 infection are present and the prevalence of HIV-1 is rising. method All patients attending hospital whose percentage CD4 + cells (CD4%) was below 14, the level associated typically with an AIDS diagnosis, and one half of those whose CD4% was 14 or above were asked to join the study. Fifty-six HIV-1, 52 HIV-2 and 12 dually infected patients were recruited. Photographs of the fundi were taken and interpreted independently. The findings were related to the patients' percentage CD4 + cells. results The CD4% was

Proviral load as well as lymphocyte phenotype and function were compared in peripheral blood and lymph node compartments of 17 HIV-1, 12 HIV-2 and three dually infected patients with lymphadenopathy. The mean percentage (95% confidence interval (CI)) of CD4+ cells was higher in lymph node mononuclear cells (LNMC) than in peripheral blood mononuclear cells (PBMC) in both infections, being 26.7% (21.1%, 32.3%) and 15.3% (10.4%, 20.2%), respectively, for HIV-1-infected patients (P = 0.0001) and 32.3% (22.7%, 41.9%) and 22.1% (13.6%, 30.6%), respectively, for HIV-2-infected patients (P = 0.02). In both types of infection, proviral load adjusted for number of CD4+ cells was higher in LNMC than in PBMC: the geometric mean (95% CI) was 8937 (4991; 16 003) and 4384 (2260; 8503), respectively, for HIV-1 patients (P = 0.02) and 1624 (382; 6898) and 551 (147; 2058) DNA copies, respectively, for HIV-2 patients (P = 0.05). Proviral load in both compartments was closely correlated (HIV-1, r = 0.60, P = 0.01; and HIV-2, r = 0.83, P = 0.0003). In both infections, proliferation and interferon-gamma (IFN-γ) production in response to purified protein derivative (PPD) was lower in LNMC than in PBMC, both of which, in turn, were lower than in healthy controls. These results indicate that in HIV-2 as in HIV-1 infection, infected cells have a tropism for the lymph nodes resulting in higher viral load in this compartment and lower lymphocyte responses to the recall antigen PPD which may increase susceptibility to tuberculosis.

Objective To improve the detection rate of HIV-2 proviral DNA in primary uncultured peripheral blood mononuclear cells (PBMC) of HIV-2-seroreactive and HIV-1-HIV-2 dually seroreactive individuals. Materials and methods Two newly designed HIV-2 PCR primer pairs in the long terminal repeat (LTR) gag and gag-pol regions and a previously described env and LTR HIV-2 PCR primer pairs were tested on samples from 66 confirmed HIV-2-seropositive individuals (The Gambia, 40; Cote d'Ivoire, 17; Guinea-Bissau, nine), 209 dually seroreactive individuals (The Gambia, 82; Cote d'Ivoire, 127), 24 genetically characterized isolated HIV-1 strains (group M subtypes A-H and group O), one simian immunodeficiency virus (SIV) strain cpz, 10 HIV-2 isolates (subtype A, B and unidentified), two SIVsm isolates, and 10 seronegative samples. Results All HIV-2 primers evaluated showed 100% specificity since there was no amplification observed with 24 HIV-1, one SIVcpz and 10 seronegative samples. One single copy of the HIV-2 genome could be detected with all outer primer pairs as well as all inner primer pairs on one PCR round used. Sensitivity of primers (at least one of the four primer pairs was positive) to HIV-2-seropositive samples was 100% (all nine) in Guinea-Bissau, 71% (12/17) in Cote d'Ivoire, 100% (all 20) in Gambian AIDS patients, and 85% (17/20) in Gambian pregnant women. Doubling the PBMC of dually seroreactive individuals from 7.5 x 10(4) to 1.5 x 10(5) in the PCR revealed the presence of both HIV-1 and 2 proviral DNA in 72% (92/127) in Cote d'Ivoire and 72% (59/82) in The Gambia. By doubling the number of PBMC, HIV-2 detection in dually seroreactive individuals by PCR was increased from 65 to 77% in Cote d'Ivoire and from 67 to 83% in The Gambia. Conclusions The use of 1.5 x 10(5) primary uncultured PBMC and the newly designed HIV-2 primer pairs allowed us to document the highest percentage (72%) ever reported of HIV-1-HIV-2 dual infections amongst HIV-1-HIV-2 dually seroreactive individuals in Cote d'Ivoire and The Gambia. Improved detection of HIV-2 proviral DNA, rather than exposure to both viruses, infection with only one virus, or infection with a unique third virus containing epitopes common to both HIV-1 and HIV-2, contributes to a more accurate monitoring of the prevalence of HIV-1-HIV-2 dual infections.

We evaluated saquinavir, an orally active, selective inhibitor of HIV proteinase, in a randomised, double-blind, dose-ranging study in 49 zidovudine-naive HIV-positive patients with few or no symptoms and CD4 cell counts of 500 or less. The study was designed to assess the antiviral activity and tolerability of saquinavir. Patients were randomised to receive 25, 75, 200, or 600 mg of saquinavir three times daily for 16 weeks. No serious adverse events ocurred. CD4 cell counts showed a trend indicative of a dose response in favour of the 600 mg dosage, the maximum increase being seen around week 4. In none of the 8 patients with positive plasma viraemia at baseline did cultures become negative after treatment; peripheral blood mononuclear cell and plasma-viral load by culture and DNA and RNA PCR all showed a trend towards reduction at higher doses of saquinovir. Saquinavir was well tolerated in this group of previously untreated patients with few or no symptoms; this study shows that an HIV-proteinase inhibitor is active in HIV-infected patients.

A simple and rapid assay for the quantification of infectious HIV-1 in plasma was developed using short-term culture and DNA PCR. This method, called culture PCR, allows detection and quantification of infectious HIV-1 viraemia within 48 hours, and measures the number of infectious cell-free HIV-1 particles, expressed as culture PCR infectious doses (CPID/ml). 42 HIV infected subjects were assessed by this method. The titres obtained by CPID closely correlated with CD4+ count and clinical status. CPID titres had significant correlation with infectious virus titre determined by conventional limiting dilution tissue-culture methods. This culture-PCR technique permits rapid assessment of infectious plasma viraemia, and is comparable to longer culture based assay methods.

Zero-strain insertion material of lithium titanium oxide (Li[Li1/3Ti5/3]O4) is used as a negative electrode in lithium-ion batteries and as a positive electrode in lithium batteries. It is crystallized as a defect spinel structure having space group symmetry of Fd3¯m (a=8.36 A). The material is topotactically reduced to Li2[Li1/3Ti5/3]O4, and it is oxidized to Li[Li1/3Ti5/3]O4 at 1.55 V against a lithium electrode in nonaqueous lithium cells. The lattice dimension is virtually unchanged during the reaction, and therefore the material is ideal for long-life lithium-ion battery application. Some trials for modification of Li[Li1/3Ti5/3]O4 are also described, and recent application of the material to backup memory in solar cells for digital watches, solid-state batteries, asymmetric hybrid supercapacitors, and ‘lead-free’ accumulators is also highlighted.

Web documents usually have complicated layouts and the overall information content can be huge. All these documents are designed for viewing in large screen devices, such as a computer monitor. In recent times, a large number of small screen portable devices, such as personal digital assistants (PDA) and cellular phones, have been made available for mobile browsing. Viewing a Web page originally written for large screen devices using these very small screen devices can be extremely cumbersome. This paper discusses this issue of small viewing form factor of electronics devices from the perspective of Web browsing and proposes an approach to automatically summarize and transform Web documents into a meaningful, readable and above all, browsable format.

Objective: To assess and compare the mortality rates of patients with HIV-1, HIV-2 or both infections (HIV-D) in the same population. Design: Clinic-based cohort study. Methods: HIV-seropositive patients aged 15 years and older who attended the Medical Research Council clinics in Fajara between May 1986 and September 1997 were recruited. Clinical assessment using the Karnofsky score, CDC cell staging, WHO staging, and CD4 cell counts was performed at baseline. Patients attended clinic every 3 months; if they did not attend, they were visited at home by field workers to ascertain survival status. No patient was on antiretroviral therapy during the study period. Results: Data from 1519 HIV-positive adult patients were analysed. A total of 746 patients had HIV-1, 666 HIV-2, and 107 patients had HIV-D. A total of 828 patients (55%) died, and 161 (11%) were lost to follow-up. The median follow-up was 12 months (range 0-128). CD4 cell counts were available for 894 patients. Compared with HIV-1, the adjusted hazards ratio for mortality in the CD4 cell count category 500 cells/mul or greater was 0.50 for HIV-2 (95% CI 0.28-0.88) and 1.27 (95% CI 0.51-3.7) for HIV-D. Among those with CD4 cell counts less than 500 cells/mul the mortality rates in HIV-2 and HIV-D were similar to those in HIV-1. Discussion: HIV-2-infected patients with CD4 cell counts of 500 cells/mul and greater had a significantly lower mortality rate than HIV-1-infected patients. HIV-2-infected patients with advanced disease had the same poor prognosis as patients with HIV-1. Dually infected patients had mortality rates similar to HIV-1. (C) 2002 Lippincott Williams Wilkins.

Mycoplasmas have been suggested as a co-factor to explain various puzzling features of infection by human immunodeficiency virus 1 (HIV-1). We sought Mycoplasma fermentans by means of a semi-nested polymerase chain reaction (PCR) in samples of peripheral-blood mononuclear cells (PBMC), throat swabs, and urine samples from 117 HIV-seropositive patients (of whom 114 were homosexual men). M fermentans was detected in 12 (10%) PBMC samples, 15 (23%) of 65 throat samples, and 4 (8%) of 55 urine samples from the seropositive subjects. The organism was detected in similar proportions among 73 HIV-seronegative patients recruited from a sexually transmitted diseases clinic (9%, 20%, and 6%, respectively); again, most of the men (40 of 50) in this group were homosexual. We found no association between infection by the mycoplasma and stage of disease, CD4 count, or HIV-1 load. These findings do not, however, eliminate the possibility that the mycoplasmal infection could affect the speed of disease progression.

Aim: There is no standard medical treatment or method of care for patients with advanced cancers of the head and neck. However, because the treatment received by terminally ill patients with head and neck cancers differ among institutions, evaluations and examinations are not being adequately performed. We aimed to clarify the symptoms in these patients contributing to changes in quality of life (QOL). In the future, we aim to reduce the suffering of these patients as far as possible by establishing a systematic method for care. Methods: This multicenter, prospective, observational study included 100 patients with advanced head and neck cancers in 11 oncology units. We evaluated changes in global QOL (European Organisation for Research and Treatment of Cancer Quality-of-Life Questionnaire–Palliative 15), respiratory tract morphology, tumor site, bleeding, pulmonary metastasis, nutritional course, phonation ability, edema, and respiratory tract secretions. Results: of the 100 patients who met the entry criteria, 71 could be observed until death. Average survival from entry was 33.5 days (range, 0–167 days). Patients with worse performance status were shorter-lived. Questionnaires on QOL were answered by 48 of the 71 patients. There was no significant difference in global QOL between entry and 3 weeks later. 32 patients (45.1%) were breathing with a tracheostoma, and 15 patients needed a cuffed endotracheal tube. 26 patients (36.6%) needed a change of dressing because of bleeding or oozing, and 5 patients had severe bleeding. 17 patients (23.9%) had head and neck edema at entry, and 26 patients (36.6%) had edema at the time of death. 53 patients (74.6%) had received enteral nutrition. Conclusions: With this prospective study we have clarified symptoms in terminally ill patients with head and neck cancers. On the basis of this study, we plan to establish a care system for terminally ill patients with head and neck cancers and prepare further prospective studies. Disclosure: All authors have declared no conflicts of interest.

Carcinosarcoma of the ovary is a rare, highly aggressive neoplasm comprising histologically of both epithelial and mesenchymal components. The aim of this study was to evaluate the clinicopathological prognostic factors in ovarian carcinosarcoma, including the immunohistochemical expression of p53 protein and Ki67.Twenty-three cases of carcinosarcoma of the ovary were studied retrospectively. The clinicopathological and immunohistochemical parameters including p53 and Ki67 staining were statistically analysed to investigate the prognostic significance of this tumour. The overall 5-year survival rate was 27.1%; 100% for stage I, 31.3% for stage II, 10.9% for stage III and 0% for stage IV. The low-stage group (stages I and II) was found to be a significant prognostic factor for patient survival (P = 0.0113). None of the other factors (tumour size, histological type of carcinomatous and sarcomatous components, mitotic count, vascular space invasion and immunoreactivity for p53 protein and Ki6 7) was found to be a statistically significant prognostic indicator.Ovarian carcinosarcoma is a rare malignancy with poor prognosis. In this study, advanced stage appears to be poor prognostic indicator of survival in patients with ovarian carcinosarcoma.

A patient with acute myeloid leukemia (AML)-M2 with t(8;21)(q22;q22) achieved complete remission with remission-induction chemotherapy followed by consolidation and intensification chemotherapies. T(8;21)(q22;q22) disappeared, but chimeric AML1/MTG8 was continuously detected in bone marrow cells. Following the development of therapy-related leukemia after 1 year, evolution of therapy-related AML-M4 with t(11;17)(q23;q25) and the rearrangement of the MLL gene were observed, while AML/MTG8 disappeared. After reinduction and following intermittent chemotherapies, a subsequent alternative transformation to AML-M2 occurred after detection of t(3;21)(q21;q22), with a break in the AML1 gene shown by interphase fluorescence in situ hybridization analysis. This leukemia transformed to AML-M4 after t(9;22)(q34;q11), with a minor BCR/ABL rearrangement, and then finally to AML-M2. This therapy-related leukemia was resistant to chemotherapy. These findings indicate that alterations in cytogenetic and molecular events caused by chemotherapeutic agents contribute to the sequential evolution of new leukemic clones with different morphology.

Objective: To examine whether the levels of plasma RNA and DNA provirus predict the rate of CD4 cell decline and patient death. Design: Retrospective analysis of HIV-2 cohort subjects. Methods: Fifty-two subjects were recruited between January 1991 and December 1992. HIV-2 RNA levels in plasma and DNA levels in peripheral blood mononuclear cells (PBMC) were measured using in-house quantitative PCR assays. The annual rate of CD4 cell decline was calculated using the least-squares method. The survival data on 31 December 1997 were used. Results: The mean percentage of CD4 cells at baseline was 30.7 (SD, 9.5). In a linear regression model, the annual rate of CD4 cell decline was 1.76 CD4% faster for every increase in one log 10 RNA copies/ml [95% confidence interval (CI), 0.81-2.7; P= 0.0006; r= 0.46; n = 52] and 1.76 CD4% faster for every increase in log 10 DNA copies/10 5 PBMC (95% Cl 0.46-3.1; P = 0.01; r = 0.33; n = 42). In a multiple linear regression model, RNA load was related to CD4 decline independently of DNA load (P = 0.02). The overall mortality rate was 7.29/100 person-years. In a Cox regression model, the hazard rate increased by 2.12 for each log 10 increase in RNA load (95% CI, 1.3-3.5; P = 0.0023) but only by 1.09 for each log 10 increase in DNA load (95% CI, 0.64-1.87; P = 0.8). Conclusion: This longitudinal study shows for the first time that a baseline HIV-2 RNA load predicts the rate of disease progression. HIV-2-infected patients with a high viral load may need to be treated as vigorously as HIV-1 patients.

To determine the rates of, and risk factors for, mother-to-child transmission (MCT) of HIV-1 and HIV-2 infection in The Gambia.A blinded, prospective, community-based cohort study of 29.549 pregnant women attending the eight largest antenatal clinics in The Gambia.Women were tested for HIV-1 and HIV-2 infection. Infected subjects and a group of HIV-seronegative women were followed with their babies until 18 months after delivery. Maternal CD4 cell count percentages were measured before and 18 months after delivery, and the antenatal plasma viral load was determined. Babies were tested for HIV by the polymerase chain reaction and/or serology at 2, 9 and 18 months of age.The study enrolled 144 women positive for HIV-1 and 294 for HIV-2 plus 565 seronegative pregnant women: the mean antenatal percentage CD4 cell counts of 96 HIV-1-positive, 223 HIV-2-positive and 125 HIV-seronegative mothers were 31% [95% confidence interval (CI) 28-33], 41% (95% CI 39-42) and 47% (95% CI 45-49), respectively. The geometric mean antenatal plasma viral load of 94 HIV-1-infected women was 15,100 copies x 10(3) ml (95% CI 10,400-19,000) which was much higher than that of 60 randomly selected HIV-2-infected women, which was 410 copies x 10(3) ml (95% CI 150-910) (P0.001). The estimated transmission rate of HIV-1 was 24.4% (95% CI 14.6-33.9) and that of HIV-2 was 4.0% (95% CI 1.9-7.4). Five of 17 HIV-1-positive and three of eight HIV-2-positive babies were infected after 2 months of age. Birth in the rainy season [odds ratio (OR) 2.9; 95% CI 1.2-7.2], a low postnatal CD4 cell percentage (OR for a 10% fall 2.4; 95% CI 1.1-5.1) and a high maternal plasma viral load (OR for a 10-fold increase 2.9; 95% CI 1.1-7.8) were risk factors for transmission that applied equally to both viruses.Low maternal HIV-2 RNA levels, which on average are 37-fold less than in HIV-1 infection, relate to the low MCT rate of HIV-2.

We recently identified several constitutively active forms of signal transducers and activators of transcription 5 (STAT5) using polymerase chain reaction-driven random mutagenesis followed by retrovirus-mediated expression screening. All constitutively active STAT5 showed constitutive phosphorylation on their tyrosine residues and induced factor-independent growth in a mouse interleukin-3-dependent cell line, Ba/F3. Sequence analysis of these active STAT5 revealed two important mutations: S710F and N642H. The N642H mutation localized in the SH2 domain was able to induce autonomous growth of Ba/F3 cells by itself, whereas S710F in the effector domain was able to induce autonomous growth of Ba/F3 cells in concert with a second mutation including H298R and E150G. Recently, constitutive activation of STAT5 has been reported in patients' leukemic cells and is implicated in leukemogenesis. We attempted to clarify whether leukemic cells harbored activating mutations primarily in STAT5 proteins, and analyzed the sequence of STAT5 derived from 49 leukemic patients. No mutations were found, however, in the regions surrounding S710 and N642 of STAT5A and corresponding residues of STAT5B. We also cloned full-length cDNAs for STAT5s from three patients whose leukemic cells exhibited constitutive tyrosine phosphorylation of the STAT5 protein and expressed the derived STAT5 proteins in Ba/F3 cells. However, none of these clones exhibited constitutive tyrosine phosphorylation or gave rise to FI proliferation of Ba/F3 cells. These results indicate that constitutive activation of STAT5 is a secondary event in most leukemias.

To elucidate why the virulence of HIV-1 and HIV-2 infections differ in West African populations.Peripheral blood plasma virion RNA and cellular proviral DNA levels were measured in a cross-section of 59 HIV-1 and 49 HIV-2 singly infected individuals representing all stages of infection in The Gambia, West Africa. Novel reverse transcriptase polymerase chain reaction (RT-PCR) assays specific and sensitive for virus quantification of non-clade B HIV-1 and HIV-2 infections were used.HIV-1 and HIV-2 proviral and plasma RNA levels were inversely correlated with CD4+ count for both infections with cellular proviral load similar at each stage of infection. Critically, up to three-fourths of HIV-2-infected individuals with high CD4 percentages (28%) had undetectable (500 copies/mL) levels of peripheral blood HIV-2 RNA in contrast to HIV-1-infected individuals who had readily detectable plasma virus at all stages of infection (P.0001). Plasma RNA levels were similar in the intermediate and end stages of infection, indicating similar replication potential for both viruses. In the cross-section of HIV-1- and HIV-2-infected patients studied, the data indicate a wider dynamic range of HIV-2 RNA in vivo compared with HIV-1.Low levels of HIV-2 replication and virion expression characterize individuals with high CD4+ lymphocyte counts, suggesting that a very different dynamic equilibrium exists between virus and host for HIV-2 compared with HIV-1. By analogy with HIV-1, our data implicate a considerably lower turnover of HIV-2 virion RNA in vivo with a markedly reduced production of infectious genomes in individuals during the subclinical phase of infection.The lower levels of virion expression of HIV-2 infections in vivo are compatible with observed differences in the natural history of HIV-1 and HIV-2 infections, relating to overall differences in the pathogenesis and disease progression of the two infections.

Many people who remain persistently seronegative despite frequent HIV exposure have HIV-specific immune responses. The study of these may provide information about mechanisms of natural protective immunity to HIV-1. We describe the specificity of cytotoxic T lymphocyte responses to HIV in seronegative prostitutes in Nairobi who are apparently resistant to HIV infection. These women have had frequent exposure to a range of African HIV-1 variants, primarily clades A, C, and D, for up to 12 yr without becoming infected. Nearly half of them have CTL directed towards epitopes previously defined for B clade virus, which are largely conserved in the A and D clade sequences. Stronger responses are frequently elicited using the A or D clade version of an epitope to stimulate CTL, suggesting that they were originally primed by exposure to these virus strains. CTL responses have been defined to novel epitopes presented by HLA class I molecules associated with resistance to infection in the cohort, HLA-A*6802 and HLA-B18. Estimates using a modified interferon-gamma Elispot assay indicate a circulating frequency of CTL to individual epitopes of between 1:3,200 and 1:50,000. Thus, HIV-specific immune responses-particularly cross-clade CTL activity- may be responsible for protection against persistent HIV infection in these African women.

HIV-1 infection is increasing in many countries where HIV-2 is endemic so the potential interaction between the two strains which differ at the nucleotide level by 40--60% is important. HIV-2 infection is less aggressive than HIV-1 and may protect against HIV-1 infection but this theory is controversial. HIV-specific cytotoxic T lymphocytes (CTL) recognizing conserved viral proteins could mediate cross-immunity. We described extensive cross-reactivity between HIV-1 and HIV-2 CTL epitopes from gag pol and nef presented by HLA-B35. Cross-reactivity was also reported for an HLA-B*2705-restricted HIV-1 epitope; however most CTL epitopes are not cross-reactive (e.g. those presented by HLA-B8 in p17 by HLA-B8 and B14 in gp41 by HLA-CW4 in gp120 and by HLA-B53 in HIV-2 gag). Amino-acid substitutions between HIV-1 and HIV-2 can prevent binding to the HLA molecule or interfere with T-cell receptor (TCR) recognition and may also interfere with recognition of the index sequence. This process of TCR antagonism has been described for naturally occurring variants of HIV-1 hepatitis B virus Epstein--Barr virus and Plasmodium falciparum. (excerpt)

A 59-year-old female suffering from malignant lymphoma developed therapy-related acute myeloblastic leukemia (t-AML) after chemotherapy consisting of treatment with DNA-topoisomerase II inhibitors, etoposide and mitoxantrone, and an alkylating agent, cyclophosphamide. The cumulative dose of etoposide administration was 5500 mg; 1500 mg given intravenously and 4000 mg orally. One year later, she suddenly developed AML of FAB M2. Cytogenetic analysis of bone marrow cells revealed deletion of 7q and a rare translocation, t(16;21)(q24;q22). Southern blot analysis of bone marrow cells did not detect rearrangement of the AML1 gene, however, fluorescence in situ hybridization (FISH) analysis of bone marrow cells at interphase and metaphase revealed a translocational splitting between chromosome 21 involving AML1 gene and chromosome 16. These results suggest that the breakpoint is not located in the breakpoint cluster region for t(8;21). The patient was treated with chemotherapy and entered complete remission.

Co-infections such as Mycobacterium tuberculosis (TB) and Pneumocystis pneumonia may affect the progress of HIV infection and speed the onset of death. As malaria and syphilis are both endemic in West Africa we examined their effects on HIV-2 infection, for these may also accelerate the progress of disease. A community-based case-control study was undertaken in a rural village in Guinea-Bissau, West Africa. One hundred and fifty asymptomatic subjects seropositive for HIV-2 and 154 age- and sex-matched controls were enrolled. Venous blood samples taken into EDTA were stained within six hours of collection with CD4 and CD8 monoclonal antibodies and processed by Q-Prep machine in the field. The stained cells were then transported on ice by road and analysed by FACS-can at the base laboratory in The Gambia within a week. The mean CD4% was significantly lower and geometric mean neopterin and beta 2-microglobulin levels were significantly higher in the HIV-2-infected subjects than in the controls (P0.01 for all cases versus all controls). The mean CD4% was lower and beta 2-microglobulin level was higher in both HIV-2 and control subjects with active or past syphilis when compared with subjects with no syphilis; however, syphilis did not have a marked effect on plasma neopterin level. Malaria infection raised neopterin levels, but had little effect on CD4%. Overall multiple regression analysis allowing for HIV-2 infection and other variables showed that syphilis lowered CD4% (P = 0.01) and raised beta 2-microglobulin levels (P = 0.05) and malaria raised neopterin levels (P = 0.05). The conclusions are that HIV-2 infection is associated with lower CD4% and higher neopterin and beta 2-microglobulin levels than controls, and co-infection with syphilis is associated with a further lowering of CD4%, suggesting a worse suppression of the immune system. Co-infection with malaria is associated with a modest immune disturbance.

HIV-specific cytotoxic T lymphocytes (CTL) are believed to play a major role in controlling virus levels through the asymptomatic period of HIV infection. For the rational design of an HIV vaccine, we need to know whether protective immunity can ever develop following HIV exposure in people who remain uninfected. We have detected HIV-specific CTL in 5/6 repeatedly exposed, persistently seronegative female sex-workers in The Gambia. Their CTL, repeatedly detected over two years, recognise epitopes presented by HLA-B35 which are cross-reactive between HIV-1HIV-2, suggesting they could have been primed first by HIV-2 exposure and subsequently boosted by exposure to HIV-1. Using previously identified clade B HIV-1 epitope peptides, we have now detected HIV-specific CTL in 6/15 highly exposed and apparently HIV-resistant Kenyan prostitutes, predominantly towards epitopes highly conserved between B and the Kenyan AD clades of HIV-1. This CTL activity towards conserved virus epitopes may represent protective immunity to HIV generated in response to repeated exposure, and prophylactic HIV vaccines should aim to generate similar CTL responses.During the asymptomatic phase of HIV infection, HIV-specific cytotoxic T lymphocytes (CTL) are believed to play a major role in controlling virus levels. The design of an HIV vaccine requires knowledge about whether protective immunity can ever develop after exposure to the virus and the mechanisms underlying such natural immunity. The authors' research has focused on HIV-specific CTL responses in highly HIV-exposed commercial sex workers in The Gambia, West Africa, and in Nairobi, Kenya. HIV CTL was detected in 5 of 6 repeatedly exposed, persistently seronegative female sex workers in The Gambia. Their CTL recognized epitopes presented by HLA-835 that are cross-reactive between HIV-1 and HIV-2, suggesting they could have been primed first by HIV-2 exposure and subsequently boosted by exposure to HIV-1. Through use of previously identified clade B HIV-1 epitope peptides, the authors also detected HIV-specific CTL in 6 of 15 highly exposed and apparently resistant Kenyan prostitutes, predominantly toward epitopes highly conserved between B and Kenyan A and D clades of HIV-1. This CTL activity toward conserved virus epitopes may represent protective immunity to HIV in response to HIV generated by repeated exposure. HIV vaccines should aim to generate similar CTL responses. There is currently no evidence that genetic factors, other than weak HLA associations, influence susceptibility or resistance to HIV infection.

Knowledge of immune mechanisms responsible for the cross-protection between highly divergent viruses such as human immunodeficiency virus type 1 (HIV-1) and HIV-2 may contribute to an understanding of whether virus variability may be overcome in the design of vaccine candidates which are broadly protective across the HIV subtypes. We demonstrate that despite the significant difference in virus amino acid sequence, the majority of HIV-2-infected individuals with different HLA molecules possess a dominant cytotoxic T-cell response which is able to recognize HIV-1 Gag protein. Furthermore, HLA-B5801-positive subjects show broad cross-recognition of HIV-1 subtypes since they mounted a T-cell response that tolerated extensive amino acid substitutions within HLA-B5801-restricted HIV-1 and HIV-2 epitopes. These results suggests that HLA-B5801-positive HIV-2-infected individuals have an enhanced ability to react with HIV-1 that could play a role in cross-protection.

Previous studies have shown the B*2703 subtype of HLA-B27, which differs from B*2705 and other MHC class I molecules by having a His substituted for Tyr at position 59 in the A pocket, inefficiently presents certain B*2705-restricted peptides. The current work investigates the influence of the first peptidic amino acid (P1) on peptide binding to B*2705 and B*2703. Results show P1 has a marked effect for both subtypes, with relative affinities (EC50) of P1-substituted peptides spanning four orders of magnitude. All peptides tested bind better to B*2705 than to B*2703. However, Lys, Arg, Phe, or Trp at P1 result in aor = 2-fold difference between subtypes, while other amino acids produce greater differences (maximum approximately 50-fold for Leu). Self peptides eluted from B*2703, as well as two viral epitopes, have a motif similar to B*2705 peptides, except for a stronger preference for Lys or Arg at P1, consistent with peptide binding data. Computer modeling of B*2703 reveals movement of a water molecule and the alpha1 alpha-helix to allow His at position 59 to maintain important hydrogen bonds with the peptide N terminus in the A pocket. However, these bonds are weaker, and the water molecule movement results in the loss of a hydrogen bond with Glu-45 in the B pocket. We conclude that B*2703, as a consequence of its unique A pocket polymorphism, appears to have a greater dependency on an accessory anchor residue at P1 to maintain tight binding of peptides.

A 18-year old female with acute myelogenous leukemia (AML), M2 had translocation: t(6;9) (p23; q34). The patient entered into hematological complete remission after two courses of BHAC-DMP chemotherapy with disappearance of cytogenetic abnormality. However, minimal residual disease (MRD) detected with DEK/CAN chimeric m-RNA by reverse transcription polymerase chain reaction (RT-PCR) was continuously observed, although decreased quantitatively, following several courses of consolidation and intensification chemotherapies. MRD was detected also in the harvested peripheral blood stem cells (PBSC). Leukemia relapsed with the reappearance of t(6;9) 2 months after the subsequent peripheral blood stem cell transplantation (PBSCT). Leukemia became refractory to chemotherapy, and the patient died 5 months thereafter.

Anti-P-glycoprotein (P-gp) monoclonal antibody, MRK16, and its F(ab')2 fragment were evaluated for its therapeutic efficacy to P-gp-mediated multidrug resistant human colorectal carcinoma cell lines in a nude mouse model. In a blood clearance experiment, 125I-labeled MRK16 had a half-life (16 h) 7 times longer than its F(ab')2 fragment (half-life of 1.8 h) in circulation in nude mice, and approximately 16 and 5% of MRK16 were retained on days 10 and 20 after injection, respectively. In biodistribution experiments using nude mice bearing HCT-15, an intrinsically resistant cell line, 125I-labeled MRK16 accumulated at the tumor site significantly higher than its F(ab')2 fragment as revealed by the percentage of injected dose/g of tissue values (7.4 versus 0.6%) on day 3 after injection. In contrast, the tissue to blood ratio at the tumor site of the MRK16 was significantly lower than that of its F(ab')2 fragment (1.2 versus 10.5). Specific targeting of the MRK16 F(ab')2 fragment to the P-gp-positive tumor (HCT-15) but not to the P-gp-negative tumor (COLO 205) was observed in the nude mice bearing both tumors. In the therapeutic efficacy tests, when administered i.v. 3 times on days 1, 4, and 7 after tumor s.c. inoculation, MRK16 alone showed the significant inhibition of tumor growth of P-gp-positive cell lines, HCT-15, DLD-1, SW480, and SW1417 in contrast to cases of P-gp-negative cell lines, COLO 205 and KM20L2. This inhibitory effect of MRK16 was enhanced in combination with Adriamycin, which alone hardly inhibited the tumor growth. However, MRK16 F(ab')2 fragment alone, even at 1 mg/mouse, had little inhibitory effect on the growth of HCT-15 in the same treatment schedule. When administered at early palpable stage, the degree of HCT-15 tumor growth suppression depended on the number of MRK16 injections. At more progressed stages, treatment with MRK16 alone showed little antitumor activity but when combined with Adriamycin resulted in significant suppression of tumor growth. The present results suggest that MRK16 may be useful for in vivo immunoscintigraphy and immunotherapy of multidrug-resistant colorectal carcinoma.

2'-Iododiazepam (2'-IDZ) is the diazepam analogue iodinated at the 2'-position of C-5 phenyl ring which was synthesized and evaluated as a potential radiopharmaceutical for investigating brain benzodiazepine receptors by SPECT. The 125I-2'-iododiazepam was synthesized by halogen exchange reaction and purified by HPLC. In vitro competitive binding studies with 3H-diazepam, using rat cortical synaptosomal membranes, showed that the affinity of 2'-IDZ for benzodiazepam receptors was higher than that in diazepam and flumazenil (RO15-1788). Biodistribution studies in mice showed that the brain uptake of 2'-iododiazepam was rapid and profound, and in the brain higher accumulation was found in the cortex than in other regions. Furthermore, the cortical uptake was displaced by benzodiazepinergic compounds. In vivo uptake was assessed by autoradiographic studies. Thus, 2'-iododiazepam bound to benzodiazepine receptors in vivo and therefore holds great potential for in vivo benzodiazepine receptor studies.

Publisher Summary Ethylenimine (EI) is an important fine chemical in the chemical industry, which has been used as a raw material of pharmaceuticals and amino resins. EI generally has been produced from monoethanolamine (MEA) in the liquid phase by using H 2 SO 4 and NaOH, but this production process is not attractive from an industrial viewpoint because of the formation of a large quantity of by-product (Na 2 SO 4 ) and hence low productivity. On the other hand, some studies of MEA intramolecular dehydration to EI directly in the vapor phase over various acidic oxides—such as SiO 2 –WO 3 and Nb 2 O 5 -based catalysts—as a new route to EI have been already reported. However, these catalysts did not show any high catalytic performance on selectivity and life, and hence it was not successful to develop the vapor phase process for this reaction. A characteristic feature of present catalysts was that both acid and base strengths of them were adjusted to be very weak (+4.8 0

In an effort to devise an effective treatment for human drug-resistant cancers, we have generated a monoclonal antibody, MRK16, reactive to the multidrug transporter P-glycoprotein. The monoclonal antibody inhibited the growth of human drug-resistant tumor cells in a xenograft model, suggesting its potential usefulness in the immunotherapy of drug-resistant cancers. In this study, we have developed a recombinant chimeric antibody in which the antigen-recognizing variable regions of MRK16 are joined with the constant regions of human antibodies. When human effector cells were used, the chimeric antibody, MH162, was more effective in killing drug-resistant tumor cells than the all-mouse monoclonal MRK16. The chimeric antibody against the multidrug transporter P-glycoprotein will be a useful agent in immunotherapy of human drug-resistant cancers.

The mechanism of clearance of human immunodeficiency virus-1 (HIV-1) viraemia is not fully understood. In two patients with acute HIV-1 infection, initial high titres of free infectious virus in plasma declined rapidly to undetectable levels within 4-8 weeks, an event that was coincident with seroconversion. Neutralising antibodies directed against the first autologous isolates taken during the viraemic periods could not be detected in either patient around the time of disappearance of plasma virus. In the absence of functional neutralising antibody, it is unlikely that humoral factors are responsible for the suppression of primary viraemia in early HIV infection.