Scoring system for throat infection.
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Humans↗
Biomedical subjects
M Moore
Publications and source records attributed to M Moore.
The role of HIV counseling and testing in the developing world.
The role of voluntary HIV counseling and testing is still under debate, especially in the developing world. HIV counseling-and-testing (HIV CT) services are a major component of HIV and AIDS control programs in the industrialized world and are increasingly being advocated in the developing world. In the United States, voluntary HIV CT has been a major component of HIV prevention efforts since the HIV antibody test became available in 1985. Yet even in the United States, questions about the management, cost, and effectiveness of voluntary HIV CT services continue to be raised. Because HIV CT has multiple goals, the evaluation of its effectiveness is a complicated task. Worldwide, a broad range of ethical, social, policy, technical, and economic issues encompass this HIV prevention activity. This article identifies the substantial barriers and serious concerns that are raised about HIV CT services and attempts to highlight the potential advantages of providing HIV CT as part of a developing country's comprehensive HIV prevention strategy.
AIDS Serodiagnosis↗
Introduction of the "Simple Delivery Kit" in East Hararghe Zone and the effect on traditional practices in Ethiopia.
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Circumcision, Female↗
Regulation of neuronal and recombinant GABA(A) receptor ion channels by xenovulene A, a natural product isolated from Acremonium strictum.
Xenovulene A (XR368) is a natural product exhibiting little structural resemblance with classical benzodiazepines yet is able to displace high-affinity ligand binding to the benzodiazepine site of the gamma-aminobutyric acid (GABA)A receptor. We have characterized this compound and an associated congener (XR7009) by use of radioligand binding and electrophysiological methodologies with native neurons and the Xenopus oocyte expression system. Xenovulene A, and the more potent XR7009, inhibited [3H]flunitrazepam binding to rat forebrain with Ki values of 7 and 192 nM, and 1.7 and 42 nM, respectively, each site accounting for approximately 50% of the total specific binding. In cerebellar and spinal cord membranes, these ligands identified only single binding sites. These ligands demonstrated no intrinsic agonist activity at recombinant GABA(A) receptors comprising alpha1beta1gamma2S subunits expressed in Xenopus oocytes, yet at 1 microM both significantly potentiated the GABA-induced response and reduced the GABA EC50 from 10.9 (control) to 5.1 (Xenovulene A) or 2.7 microM (XR7009). The rank potency order for enhancement of the 10 microM GABA response is: XR7009 (EC50, 0.02 microM) > diazepam (0.03) > Xenovulene A (0.05) > flurazepam (0.17). The activity of XR368 and XR7009 was reduced by the benzodiazepine antagonist, flumazenil, and absent in receptors devoid of the gamma2 subunit. These agents exhibited receptor subtype selectivity because alpha3beta1gamma2S receptors were less sensitive to these compounds relative to alpha1 subunit-containing receptors, whereas alpha6beta1gamma2S receptors were completely insensitive. Potentiation of the response to GABA on native GABA(A) receptors in cortical neurons substantiates the profile of the novel structures of Xenovulene A and XR7009 as specific benzodiazepine agonists.
Acremonium↗
Clinical experience with gemcitabine in pancreatic carcinoma.
The treatment of advanced pancreatic carcinoma has been viewed with pessimism. Because of the lack of activity of commonly used agents, there is no consensus regarding a standard chemotherapy regimen. Assessment of response is neither uniform nor reproducible. Debilitating tumor-related symptoms, including pain, anorexia, weight loss, and impaired performance status, are common. Many studies have failed to evaluate the palliative benefit of treatments, although many patients consider such benefit to be of the utmost importance. Tools have been developed to uniformly assess tumor-related symptoms, and the concept of clinical benefit response has been developed as an end point to quantify symptomatic improvement utilizing these tools. Clinical benefit response incorporates palliative measures, such as pain control, analgesic consumption, performance status, and weight gain. In early phase I and II trials, gemcitabine (Gemzar) has shown activity in patients with chemotherapynaive advanced pancreatic carcinoma. In addition to producing some responses and symptomatic benefit, gemcitabine has a favorable toxicity profile. Two recent trials using clinical benefit response as the primary end point have demonstrated that gemcitabine significantly improves disease-related symptoms in approximately one-quarter of patients. These trials also showed improved survival with gemcitabine, as compared with fluorouracil. Additional studies are required to fully assess the role of gemcitabine in both adjuvant and advanced disease settings.
Adenocarcinoma↗
A glass fiber/diethylaminoethyl double filter binding assay that measures apoptotic internucleosomal DNA fragmentation.
A filter binding assay that measures internucleosomal DNA fragmentation associated with apoptosis is described. The assay is based on a novel principle that consists of using simultaneously two kinds of glass fiber filters to harvest [3H]thymidine-prelabeled cells following their incubation with inducers of apoptosis. One filter, which is neutral, traps intact chromatin and high-molecular-weight DNA. The other filter, which is positively charged with DEAE active groups, traps low-molecular-weight DNA fragments. DNA fragmentation is quantified by measuring the radioactivity retained by each of the filters. The assay was evaluated with the histiocytic lymphoma cell line U937 and the topoisomerase inhibitors camptothecin, etoposide, and doxorubicin. These agents caused a dose-dependent decrease of radioactivity in the neutral filter and a parallel increase of radioactivity in the DEAE filter. Irradiation-induced single strand breaks and topoisomerase-mediated primary DNA damage were not detected by this method. Consistent with the detection of internucleosomal DNA fragmentation, the effects measured by this assay were prevented by the endonuclease inhibitor zinc acetate and by the metabolic inhibitor sodium azide. Results obtained using this assay were validated by observation of DNA ladders on agarose gels and by morphologic examination of apoptotic features. Evaluation of the assay in a mock screen demonstrated that the introduction of the DEAE filter increases the assay sensitivity and eliminates false positives. Thus, this assay may be used in high-throughput screening approaches to discover novel modulators of apoptosis.
Antineoplastic Agents↗
Oncogenic potential of the adenovirus E4orf6 protein.
The group C adenovirus E4orf6 protein has previously been shown to bind to the p53 cellular tumor suppressor protein and block its ability to activate transcription. Here we show that the E4orf6 protein blocks the induction of p53-mediated apoptosis when AT6 cells, which harbor a temperature-sensitive p53, are shifted to the permissive temperature. The E4orf6 protein does not, however, prevent the induction of apoptosis in p53-deficient H1299 cells by treatment with tumor necrosis factor alpha and cycloheximide. The E4orf6 protein also cooperates with the adenovirus E1A protein to transform primary baby rat kidney cells, and it cooperates with the adenovirus E1A plus E1B 19-kDa and E1B 55-kDa proteins to increase the number of baby rat kidney cell transformants and enhance the rate at which they arise. The level of p53 is substantially reduced in transformed cells expressing the E4orf6 protein in comparison to adenovirus transformants lacking it. The E4orf6 gene also accelerates tumor formation when transformed baby rat kidney cells are injected subcutaneously into the nude mouse, and it converts human 293 cells from nontumorigenic to tumorigenic in nude mice. In addition to the well-studied E1A and E1B oncogenes, group C adenoviruses harbor a third oncogene, E4orf6, which functions in some respects similarly to the E1B oncogene.
Adenoviridae↗
Gastrointestinal parasite infections.
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Adult↗
Topotecan, a topoisomerase I inhibitor, is active in the treatment of myelodysplastic syndrome and chronic myelomonocytic leukemia.
The aim of this study was to evaluate the activity of topotecan in patients with myelodysplastic syndrome (MDS) and chronic myelomonocytic leukemia (CMML). Forty-seven patients with a diagnosis of MDS (n = 22) or CMML (n = 25) were treated. The median age was 66 years. Chromosomal abnormalities were present in 70% and thrombocytopenia less than 50 x 10(3)/microL in 51%. Evaluation of outcome and of differences among subgroups was performed according to standard methods; the criteria for response were those used for acute leukemia. Topotecan was administered as 2 mg/ m2 by continuous infusion over 24 hours daily for 5 days (10 mg/m2 per course) every 3 to 4 weeks until remission, then once every month for a maximum of 12 courses. Thirteen patients (28%) achieved a complete response (CR) and six (13%) had hematologic improvement. A CR was achieved in six of 22 patients with MDS (27%) and in seven of 25 with CMML (28%). All eight patients who presented with cytogenetic abnormalities (five chromosome 5 or 7 abnormalities) who achieved CR were cytogenetically normal in CR. Characteristics for which there was evidence of association with a higher response rate were lack of prior chemotherapy, less than 10% marrow monocytes, and absence of RAS oncogene mutations. In contrast, CR rates were similar in patients with or without abnormal karyotypes. Mucositis occurred in 64% of patients (severe in 19%) and diarrhea in 32% (severe in 13%). Febrile episodes occurred in 85% of patients and documented infections in 47%. With a median follow-up duration of 8 months, the 12-month survival rate was 38%, median survival time 10.5 months, and median remission duration 7.5 months. We conclude that topotecan has significant activity in MDS and CMML, with acceptable side effects. Future studies will investigate topotecan combined with topoisomerase II reactive agents, cytarabine, or hypomethylating agents (azacytidine and decitabine).
Adult↗
Frequent infection of peripheral blood CD8-positive T-lymphocytes with HIV-1. Edinburgh Heterosexual Transmission Study Group.
BACKGROUND: Although lymphocytes expressing the CD4 surface receptor for HIV-1 have been identified as the principal target of the virus, the extent to which infection of other cell types of the immune system contributes to immunodeficiency is unknown. We investigated the cell types in peripheral blood infected with HIV and the relation of viral load in different subsets to disease progression. METHODS: The study group consisted of 16 HIV-infected individuals, eight of whom had clinically defined AIDS with CD4 cell counts less than 200/microL blood. The main component subsets of peripheral blood mononuclear cells were purified by magnetic bead separation, and included CD4 and CD8 lymphocytes, B lymphocytes, monocytes, and dendritic cells. HIV proviral sequences within these separate populations were quantified by limiting-dilution nested polymerase chain reaction. FINDINGS: HIV-1 proviral sequences were detected in T-helper cells, cytotoxic T cells, dendritic cells, and monocytes. CD4 T lymphocytes constituted the main reservoir of HIV in all but one of the symptom-free individuals studied (those with CD4 count > 200/microL). However, in all the individuals with CD4 counts of less than 200/microL, most infected cells within the peripheral blood mononuclear cell fraction were either dendritic cells or CD8 lymphocytes. Infection of CD8 cells accounted for between 66% and 97% of total proviral load in five of the eight AIDS patients. A strong inverse relation between total CD8 count and the frequency of CD8 T-lymphocyte infection was found. INTERPRETATION: This study provides evidence for widespread infection of lymphocytes of the CD8 phenotype, indicating that HIV-1 has a broader tropism for different cell types in vivo than described for cultured virus. Infection of CD8 cells may contribute to the decline of this subset upon disease progression in HIV-infected individuals. Infection of CD8 cells may or may not occur by a non-CD4-dependent mechanism of virus entry.
Base Sequence↗
A rationale for expanding the endpoints for clinical trials in advanced pancreatic carcinoma.
BACKGROUND: Using classical endpoints, such as response rate and survival, as the sole measures of benefit, little progress has been made in the treatment of advanced pancreatic carcinoma in the past 30 years. We challenge the assumption that response rate and survival are the only appropriate endpoints for clinical trials in this disease setting. METHOD: A review of the literature and roundtable discussion were undertaken. RESULTS: Using current imaging techniques, it is inherently difficult to distinguish pancreatic tumor from normal pancreas, inflammatory tissue, local fibrosis, and unopacified bowel. As a result, objective tumor measurements are often imprecise, unreliable, and irreproducible. This difficulty may explain the wide variation in response rates reported in clinical trials even when the same therapies are used. Tumor-related symptoms, such as anorexia, weight loss, severe pain (requiring opioid analgesia), and impaired functional status, are prevalent and debilitating characteristics of this disease. Tools that can assess these symptoms in a consistent fashion over time have been developed and have been integrated into clinical trials to evaluate new drugs in this setting. CONCLUSIONS: Systematic assessment of the impact of a new therapy on tumor-related symptoms may provide a sensitive and accurate way to identify useful new treatments for patients with advanced pancreatic carcinoma. Such analyses can be a useful complement to the classical endpoints of response rate and survival.
Clinical Trials as Topic↗
Activity of gemcitabine in patients with advanced pancreatic carcinoma. A review.
BACKGROUND: In early phase II trials in advanced pancreatic cancer, gemcitabine demonstrated modest antitumor activity. The investigators in these studies reported that gemcitabine should be studied further in view of the degree and frequency of symptomatic improvement observed, the durability of some of the remissions, and the favorable toxicity profile. METHODS: In order to quantify such symptomatic improvement, a rigorous endpoint of Clinical Benefit was developed that incorporated measures including pain intensity, analgesic consumption and performance status, which have been shown to be reliable and valid endpoints in other studies. RESULTS: Two trials have been conducted using this methodology in patients with advanced pancreatic carcinoma. CONCLUSIONS: The results of these studies suggest that gemcitabine is the first cytotoxic agent with any meaningful impact on survival and disease-related symptoms in advanced pancreatic adenocarcinoma. The degree of improvement seen is one which patients with cancer often consider to be most important. Further studies will be required to define more fully the role of gemcitabine in the treatment of pancreatic cancer.
Antimetabolites, Antineoplastic↗
Treatment of sarcoptic mite infestation and mite hypersensitivity in pigs with injectable doramectin.
Thirty-two pigs were infested experimentally with Sarcoptes scabiei var suis and allocated randomly to a medicated group (injected intramuscularly with 300 micrograms doramectin/kg) or an unmedicated group (injected intramuscularly with 1 ml saline/33 kg). They were observed daily for 15 minutes for signs of pruritus, and the ear lesions were assessed and skin scrapings examined for mites on days 7, 14, 21 and 28 after treatment. In the 16 pigs treated with doramectin the ear lesions resolved completely within 14 days, no mites were recorded on 15 of them on day 7 or on any of them on days 14, 21 and 28; pruritus was greatly reduced from day 7 onwards (range 0 to 0-62 rubbing episodes per pig per day) and papular skin lesions were absent from 15 of the pigs at slaughter on day 28. In comparison, the ear lesions in the 16 unmedicated pigs failed to resolve in 15 of them. Mites were present on 15 of them at different times during the experiment; the numbers of rubbing episodes ranged from 0.88 to 4.65 per pig per day and all the pigs had papular skin lesions at slaughter. In the unmedicated pigs, both the degree of pruritus and the presence and severity of papular skin lesions at slaughter were greater in those with zero or low mite counts than in those with high mite counts.
Animals↗
Differentiation of follicular dendritic cells and full antibody responses require tumor necrosis factor receptor-1 signaling.
Using mice double deficient for tumor necrosis factor (TNF) and lymphotoxin alpha (LT alpha), we demonstrated that TNF and/or LT alpha are necessary for development of a normal splenic microarchitecture and for isotype switch after immunization with sheep red blood cells (SRBC). In the present study, we extended these observations by determining which TNF receptor (TNFR) is involved in morphological and functional differentiation of the spleen. Spleen morphology and antibody response were investigated in wild-type, TNFR1-/-, TNFR2-/- and TNF/LT alpha-/- mice immunized with SRBC. TNF/LT alpha-/- mice, which have a complete disruption of the TNF/LT alpha signaling system including the LT beta-receptor pathway, displayed an abnormal microarchitecture, and isotype switch did not take place. TNFR1-/- and TNFR2-/- mice displayed a normal spleen microarchitecture and mounted an IgM and IgG antibody response to SRBC. However, the IgG production in TNFR1-/- mice was minimal, with citers leveling off 6 d after immunization. In this strain, immunofluorescence revealed a lack of follicular dendritic cells (FDC) network, detected with FDC-M1 as well as anti-CR1, and a lack of germinal centers, detected with peanut agglutinin. In conclusion, whereas normal splenic microarchitecture and isotype switch might require the LT beta receptor, differentiation of FDC network, development of germinal centers, and full IgG response depend on signaling via TNFR1.
Animals↗
Isolation and characterization of variant benzo[a]pyrene-resistant T47D human breast-cancer cells.
T47D human breast cancer cells were grown in 1 microM benzo[a]pyrene (BaP) for 3.5 months, and 2 BaP-resistant (BaPr) variant cell lines (CS and C10) were isolated. Decreased aryl hydrocarbon (Ah)-responsiveness in the CS and C1O BaPr cells was characterized by lower (80 to 900/o) induction of CYP1A1-dependent activity by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), lower levels of the nuclear Ah receptor complex and significantly decreased Ah receptor mRNA levels. Nuclear estrogen receptor (ER) binding and ER mRNA levels were similar in wild-type and mutant cell lines, whereas epidermal growth factor receptor mRNA levels were significantly decreased in the variant BaPr T47D cells. 17beta-Estradiol induced proliferation of both wild-type and BaPr T47D cells, and TCDD inhibited this response but did not down-regulate nuclear ER levels. The unique characteristics of the BaPr T47D variant cells will be used to further elucidate the mechanism of interaction between the ER and Ah receptor signalling pathways.
Base Sequence↗
A phase I study of combined radiation therapy with 5-fluorouracil and low dose folinic acid in patients with locally advanced pancreatic or biliary carcinoma.
PURPOSE: To evaluate the toxicities of a Phase I study of radiation therapy with concurrent 5-fluorouracil (5FU) and low dose folinic acid in patients with locally advanced pancreatic or biliary carcinoma. METHODS AND MATERIALS: Twenty-seven patients with locally advanced carcinoma of the pancreas (n = 19), bile duct (n = 7), and gall bladder (n = 1) were entered into a Phase I study of combined radiation therapy, 5FU, and folinic acid. Radiation was given as a split course of 40 Gy in 20 daily fractions with a gap of 2 weeks after 20 Gy. 5-Fluorouracil, 300 to 375 mg/m2/day and folinic acid, 20 mg/m2/day were given as an i.v. bolus daily for 5 days beginning on day 1 and again on day 29. RESULTS: Eight patients developed Grade 3 or 4 toxicities (National Cancer Institute common toxicity criteria) including nausea and vomiting (n = 4), oral mucositis (n = 4), myelosuppression (n = 2), infection (n = 2), and diarrhea (n = 1). Four patients did not complete the planned protocol due to treatment toxicities. There were two treatment deaths secondary to septic neutropenia. Treatment toxicity appeared to be related to age (> 70), performance status (ECOG = 2), and 5FU dose (> 350 mg/m2/day). CONCLUSION: This protocol is poorly tolerated by elderly patients or those with poor performance status, and 350 mg/m2/day is our recommended dose for 5FU as given in this protocol.
Adult↗
Hematopoietic defects in mice lacking the sialomucin CD34.
Although the pluripotent hematopoietic stem cell can only be definitively identified by its ability to reconstitute the various mature blood lineages, a diversity of cell surface antigens have also been specifically recognized on this subset of hematopoietic progenitors. One such stem cell-associated antigen is the sialomucin CD34, a highly O-glycosylated cell surface glycoprotein that has also been shown to be expressed on all vascular endothelial cells throughout murine embryogenesis as well as in the adult. The functional significance of CD34 expression on hematopoietic progenitor cells and developing blood vessels is unknown. To analyze the involvement of CD34 in hematopoiesis, we have produced both embryonic stem (ES) cells and mice that are null for the expression of this mucin. Analysis of yolk saclike hematopoietic development in embryoid bodies derived from CD34-null ES cells showed a significant delay in both erythroid and myeloid differentiation that could be reversed by transfection of the mutant ES cells with CD34 constructs expressing either a complete or truncated cytoplasmic domain. Measurements of colony-forming activity of hematopoietic progenitor cells derived from yolk sacs or fetal livers isolated from CD34-null embryos also showed a decreased number of these precursor cells. In spite of these diminished embryonic hematopoietic progenitor numbers, the CD34-null mice developed normally, and the hematopoietic profile of adult blood appeared typical. However, the colony-forming activity of hematopoietic progenitors derived from both bone marrow and spleen is significantly reduced in adult CD34-deficient animals, and these CD34-deficient progenitors also appear to be unable to expand in liquid cultures in response to hematopoietic growth factors. Even with these apparent progenitor cell deficiencies, CD34-null animals showed kinetics of erythroid, myeloid, and platelet recovery after sublethal irradiation that are indistinguishable from wild-type mice. These data strongly suggest that CD34 plays an important role in the formation of progenitor cells during both embryonic and adult hematopoiesis. However, the hematopoietic sites of adult CD34-deficient mice may still have a significant reservoir of progenitor cells that allows for normal recovery after nonmyeloablative peripheral cell depletion.
Animals↗