A new vision of ocean biogeochemistry after a decade of the Joint Global Ocean Flux Study (JGOFS).
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Carbon↗
Biomedical subjects
R Anderson
Publications and source records attributed to R Anderson.
Transdisciplinary teams: lessons learned.
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Humans↗
Localized biphasic changes in phosphatidylinositol-4,5-bisphosphate at sites of phagocytosis.
Phagocytosis requires localized and transient remodeling of actin filaments. Phosphoinositide signaling is believed to play an important role in cytoskeletal organization, but it is unclear whether lipids, which can diffuse along the membrane, can mediate the focal actin assembly required for phagocytosis. We used imaging of fluorescent chimeras of pleckstrin homology and C1 domains in live macrophages to monitor the distribution of phosphatidylinositol-4,5-bisphosphate (4,5-PIP(2)) and diacylglycerol, respectively, during phagocytosis. Our results reveal a sequence of exquisitely localized, coordinated steps in phospholipid metabolism: a focal, rapid accumulation of 4,5-PIP(2) accompanied by recruitment of type Ialpha phosphatidylinositol phosphate kinase to the phagosomal cup, followed by disappearance of the phosphoinositide as the phagosome seals. Loss of 4,5-PIP(2) correlated with mobilization of phospholipase Cgamma (PLCgamma) and with the localized formation of diacylglycerol. The presence of 4, 5-PIP(2) and active PLCgamma at the phagosome was shown to be essential for effective particle ingestion. The temporal sequence of phosphoinositide metabolism suggests that accumulation of 4,5-PIP(2) is involved in the initial recruitment of actin to the phagocytic cup, while its degradation contributes to the subsequent cytoskeletal remodeling.
Actins↗
Fossil fuels, transport, and public health.
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Air Pollution↗
Apparent involvement of the A(2A) subtype adenosine receptor in the anti-inflammatory interactions of CGS 21680, cyclopentyladenosine, and IB-MECA with human neutrophils.
This study was undertaken to identify the adenosine receptor (AR) subtypes which down-regulate the proinflammatory activities of human neutrophils, as well as the involvement of adenosine 3',5'-cyclic monophosphate (cAMP) and its relationship to cellular handling of Ca(2+) in mediating these effects. Neutrophils were treated with varying concentrations (0.01-1 microM) of AR agonists operative at A(1) (N(6)-cyclopentyladenosine, CPA), A(2A) (2(4-[(2-carboxyethyl)phenyl]ethylamino)-5'-N-ethylcarboxamidoadenosi ne, CGS 21680), and A(3) (N(6)-(3-iodobenzyl-5'-N-methylcarbamoyladenosine, IB-MECA) receptors, after which they were activated with the chemoattractant, N-formyl-L-methionyl-L-leucyl-L-phenylalanine (FMLP, 1 microM). Intracellular cAMP, superoxide, and elastase were assayed using radioimmunoassay, lucigenin-enhanced chemiluminescence (LECL), and colorimetric procedures, respectively, while changes in the concentrations of cytosolic Ca(2+) were monitored by fura-2-based spectrofluorimetry. CGS 21680, at all concentrations tested, inhibited superoxide production in a dose-related manner, while CPA and IB-MECA were effective only at the highest concentrations tested (0.5-1 microM). The release of elastase from activated neutrophils was also inhibited by all three AR agonists, but was more sensitive to CGS 21680 and IB-MECA than was superoxide production. The inhibitory effects of all 3 agonists on superoxide production and elastase release were associated with accelerated clearance of Ca(2+) from the cytosol of activated neutrophils, and were effectively neutralized by pretreatment of the cells with the highly selective A(2A)R antagonist, ZM 241385 (4-(2-[7-amino-2-(2-furyl)[1, 2,4]triazolo[2,3-a][1,3,5]triazin-5yl amino]ethyl)phenol). Increased cAMP was detected in neutrophils treated with CGS 21680 and IB-MECA (1 microM). These data support the involvement of the A(2A)R subtype in the suppression of superoxide production and degranulation by activated human neutrophils, probably by cAMP-mediated alterations in Ca(2+) handling.
Adenosine↗
Use of lignocaine (lidocaine) in food animals.
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Anesthesia↗
AIDS in a new millennium.
As we enter the new millennium the world is still facing the challenge of responding to the AIDS pandemic. A new report from the Joint United Nations Programme on HIV/AIDS presents the latest statistics on prevalence, spread, and impact of the disease. In their Perspective, Schwartländer and his colleagues discuss the newly released statistics and the strategies needed to combat the further spread of HIV/AIDS and to reduce prevalence in the most severely affected countries.
Acquired Immunodeficiency Syndrome↗
Theiler's murine encephalomyelitis virus induces rapid necrosis and delayed apoptosis in myelinated mouse cerebellar explant cultures.
Infection with the Daniel strain of Theiler's murine encephalomyelitis (TMEV-DA) virus induces persistent demyelinating lesions in mice and serves as a model for multiple sclerosis. During the acute phase of the disease, however, viral infection leads to cell death in vivo. Viral-induced death may result directly from viral infection of neural cells, or indirectly, by activation of the immune system. To examine the direct effects of TMEV infection on neural cells, myelinated explant cultures of the murine cerebellum were infected with 10(5) pfu of TMEV-DA for periods ranging from 1 to 72 h. Our results indicate that TMEV-DA replicates in cultured neural tissue. Initially, viral antigen is localized to a few isolated neural cells. However, within 72 h antigen was observed in multiple foci that included damaged cells and extracellular debris. Viral infection led to a rapid and cyclical induction of necrosis with a time period that was consistent with the lytic phase of the viral life-cycle. Simultaneously, we observed an increase in apoptosis 48 h post-infection. Electron micrographic analysis indicated that viral-infected cultures contained cells with fragmented nuclei and condensed cytoplasm, characteristic of apoptosis. The localization of apoptosis to the cerebellar granule cell layer, identified these cells as presumptive granule neurons. Viral infection, however, did not lead to myelin damage, though damaged axons were visible in TMEV-infected cultures. These results suggest that during the acute phase of infection, TMEV targets neural cells for apoptosis without directly disrupting myelin. Myelin damage may therefore result from the activation of the immune system.
Animals↗
Medical therapy, symptoms, and the distress the cause: relation to quality of life in patients with angina pectoris and/or hypertension.
BACKGROUND: Adverse events during drug therapy can be assessed through measurement of 2 features: their frequency and their severity. Their severity, in turn, can be measured by assessing the distress that they cause. Our goal was to relate the magnitude of the distress induced by treatment with calcium-channel blocking agents to the change in quality of life assessed through psychosocial instruments in patients treated with calcium-channel blocking agents, either for hypertension or for angina pectoris. METHODS: Four hundred seventy-five patients with angina pectoris were randomized to double-blind treatment with PPR (physiological pattern release) verapamil hydrochloride, amlodipine besylate, amlodipineatenolol combination, or placebo. In addition, 557 hypertensive patients were randomized either to PPR verapamil or nifedipine GITS (gastrointestinal system). Both studies were double-blind. RESULTS: Significant differences in treatment of angina pectoris or hypertension, were not found between the regimens. Overall quality of life also failed to show a significant difference in either group. In both groups, however, remarkable concordance was found between the degree of distress associated with specific symptoms and a change in quality of life. An unchanged, stable symptom distress was associated with a significant improvement in the quality of life of about 0.1 SD. Improvement or erosion of symptom distress represented by 1 step was associated with a 0.1- to 0.2-SD change. The extreme change in symptom distress was associated with a substantially larger change in global quality of life. CONCLUSIONS: The magnitude of symptom distress or relief associated with symptoms in 2 patient populations correlated strongly with a shift in quality of life. The assessment of distress associated with symptoms provides valuable additional information on drug therapy.
Adult↗
Antibiotic prescribing for dental conditions: general medical practitioners and dentists compared.
OBJECTIVE: To compare the level of prescribing and types of antibiotics prescribed for dental problems by general medical practitioners and dentists. DESIGN: Secondary analysis of standard consultation data and prescription records from four different settings. SETTING: 30 participating general practices in the General Practice Morbidity Database for Wales in 1996. SUBJECTS: 1,185 attendances for tooth-related problems, at 30 participating practices in the General Practice Morbidity Database for Wales in 1996. Standard consultation records from a GDP emergency dental rota, and two weekend emergency dental clinics: one in a health centre, the other in a dental hospital. RESULTS: More than two thirds (68%) of attendances at general medical practices for tooth-related problems resulted in a prescription for antibiotics. In contrast less than a third (28%) of patients seen by a GDP rota, about half (52%) of patients at a weekend emergency clinic in a health centre, and just more than a third (38%) of patients attending the dental hospital clinic received antibiotics. General medical practitioners were also more likely to prescribe broad-spectrum antibiotics than dentists. CONCLUSION: For acute dental problems general medical practitioners are more likely to prescribe antibiotics than dentists. There also appear to be inter-professional differences in the tendency to prescribe broad spectrum antibiotics. Initiatives to rationalise prescribing for dental conditions may need to target doctors as well as dentists.
Anti-Bacterial Agents↗
Crystal structures of ligand complexes of P450eryF exhibiting homotropic cooperativity.
Several mammalian cytochrome P450 (P450) isoforms demonstrate homotropic cooperativity with a number of substrates, including steroids and polycyclic aromatic hydrocarbons. To identify structural factors contributing to steroid and polycyclic aromatic hydrocarbon binding to P450 enzymes and to determine the location of the allosteric site, we investigated interactions of the macrolide hydroxylase P450eryF from Saccharopolyspora erythraea with androstenedione and 9-aminophenanthrene. Spectroscopic binding assays indicate that P450eryF binds androstenedione with an affinity of 365 microM and a Hill coefficient of 1.31 +/- 0.6 and coordinates with 9-aminophenanthrene with an affinity of 91 microM and a Hill coefficient of 1.38 +/- 0.2. Crystals of complexes of androstenedione and 9-aminophenanthrene with P450eryF were grown and diffracted to 2.1 A and 2.35 A, respectively. Electron density maps indicate that for both complexes two ligand molecules are simultaneously present in the active site. The P450eryF/androstenedione model was refined to an r = 18.9%, and the two androstenedione molecules have similar conformations. The proximal androstenedione is positioned such that the alpha-face of carbon-6 is closest to the heme iron, and the second steroid molecule is positioned 5.5 A distal in the active site. The P450eryF/9-aminophenanthrene model was refined to an r = 19.7% with the proximal 9-aminophenanthrene coordinated with the heme iron through the 9-amino group and the second ligand positioned approximately 6 A distal in the active site. These results establish that homotropic cooperativity in ligand binding can result from binding of two substrate molecules within the active site pocket without major conformational changes in the protein.
Bacterial Proteins↗
Out-of-hours dental services: a survey of current provision in the United Kingdom.
OBJECTIVE: To describe the variety of arrangements for providing out-of-hours dental care in the UK. DESIGN: A telephone interview survey of health authorities and health boards. SETTING: United Kingdom. SUBJECTS: 104 health authority contacts, usually consultants in dental public health, dental advisers or others in a position to describe the local dental service arrangements. RESULTS: At weekends, 25 authorities have no formal dental care arrangements for unregistered patients, 55 have separate arrangements for registered and unregistered patients, and 44 have 'universal access' arrangements--for anyone in an area, regardless of their registration status. On weekday nights over two-thirds (82/124) of UK health authorities have no formal arrangements for unregistered patients. Where there are separate 'safety-net' services intended for unregistered patients only they are usually (in 48 of 55 authorities) emergency treatment sessions. A fifth of authorities reported planned changes to their local out-of-hours arrangements, including the introduction of telephone triage, and moves to make care available at more times, to more people or from centralised premises. CONCLUSIONS: There is extremely wide geographical variation in the organisation of out-of-hours dental services provided in the United Kingdom. In many parts of the UK there are no formal out-of-hours care arrangements for unregistered patients, even at weekends. This unequal provision will mean inequitable access for many unregistered patients. With increasing demands from a growing unregistered population, and various government initiatives to make primary care services more integrated and accessible, the highly fragmented pattern of provision in many areas may no longer be acceptable.
Catchment Area, Health↗
The onset of germ cell migration in the mouse embryo.
Mouse primordial germ cells (PGCs) are specified between embryonic day 6.5 (E6.5) and E7.5, when they have been visualized as an alkaline phosphatase-positive (AP+) cell population in the developing allantois. By E8.5, they are embedded in the hind-gut epithelium. Previous experiments have suggested different sites for PGCs' origin, and it is unclear how they reach the gut epithelium. We have used transgenic mice expressing GFP under a truncated Oct4 promoter to visualize living PGCs. We find GFP+/AP+ cells in the posterior end of the primitive streak as a dispersed population of cells actively migrating into the allantois, and directly into the adjacent embryonic endoderm. Time-lapse analysis shows these cells to be actively migratory from the time they exit the primitive streak.
Alkaline Phosphatase↗
The role of cadherins during primordial germ cell migration and early gonad formation in the mouse.
Primordial germ cells (PGCs) are the founder cells of the gametes. In mammals, PGCs migrate from the hindgut to the genital ridges, where they coalesce with each other and with somatic cells to form the primary sex cords. We show here that, in both sexes, PGCs express P- and E-cadherins during and after migration, and N-cadherin at post-migratory stages. E-Cadherin is not expressed by PGCs whilst in the hindgut, but is upregulated as they leave. Blocking antibodies against E-, but not P-cadherin cause defective PGC-PGC coalescence, and in some cases, ectopic PGCs.
Animals↗
Phase II placebo-controlled trial of fozivudine tidoxil for HIV infection: pharmacokinetics, tolerability, and efficacy.
Fozivudine tidoxil (FZD) is a thioether lipid-zidovudine (ZDV) conjugate with anti-HIV activity demonstrated in vitro and in pilot phase I studies. To assess its safety, efficacy and pharmacokinetics, we conducted a multicenter, randomized, double-blind, placebo-controlled trial of FZD monotherapy in 72 HIV-infected patients who had not previously received antiretroviral therapy. In each dosage group (200 mg daily, 400 mg daily, 200 mg twice daily, 800 mg daily, 400 mg twice daily, and 600 mg twice daily), 12 patients were randomized to receive in a 10:2 ratio either FZD or a placebo for 4 weeks. Overall, FZD was well tolerated in all dosage groups; only 1 patient discontinued the drug, because of a moderate rise in aminotransaminase activity. HIV viral load fell in all the patients who were receiving FZD, except in the 200 mg daily group. The largest decrease (-0.67 log10) was observed in the 600 mg twice daily group. The plasma half-life was significantly longer (approximately 3.8 hours) than that of the parent drug ZDV. Exposure to ZDV, as reflected by the area under the time-concentration curve, was much lower after FZD than after ZDV administration. FZD thus appears to be as effective as and potentially better tolerated than ZDV during short-term administration and has the advantage of once daily intake.
Adult↗
Liposome encapsulation of a soluble recombinant fragment of the respiratory syncytial virus (RSV) G protein enhances immune protection and reduces lung eosinophilia associated with virus challenge.
Respiratory syncytial virus (RSV) is a leading cause of bronchiolitis and pneumonia in young children and infants. Previous animal studies have shown that immunizing intramuscularly or intraperitoneally with the RSV G protein has elicited protective as well as harmful immune responses upon RSV challenge. In an RSV immunization strategy designed to target the respiratory tract directly (the site of RSV replication), we immunized BALB/c mice intranasally with a liposome-encapsulated, prokaryotically expressed thioredoxin fusion protein consisting of amino acids 128-229 of the RSV G protein (Trx-G(128-229)). Upon intranasal challenge with RSV, a 100 to 500-fold reduction in lung RSV replication was observed in mice immunized with liposome-encapsulated Trx-G(128-229) compared to a sham-immunized control group. Analysis of bronchoalveolar lavage fluids revealed an influx of eosinophils (18% of total cells) in mice immunized with Trx-G(128-229) alone. Such eosinophilic infiltration was diminished (to 4.5% of total cells), however, in mice immunized with liposome-encapsulated Trx-G(128-229). Histological analysis of lung tissue revealed an accumulation of cells around the bronchioles and vessels in mice immunized with Trx-G(128-229) alone followed by RSV challenge which was not increased further in mice immunized with liposome-encapsulated Trx-G(128-229). These results show that intranasal immunization of BALB/c mice with Trx-G(128-229), when encapsulated in liposomes, can reduce the level of RSV replication in the lung as well as specifically reduce the degree of eosinophilic infiltration compared to mice immunized with Trx-G(128-229) alone. This demonstrates the potential of liposomes and particular recombinant fragments of the RSV G protein as an effective combination in RSV vaccine studies.
Animals↗
CGS 21680, dibutyryl cyclic AMP and rolipram attenuate the pro-inflammatory interactions of the Pseudomonas aeruginosa -derived pigment, 1-hydroxyphenazine, with human neutrophils.
The effects of the intracellular adenosine 3':5' cyclic monophosphate (cAMP)-elevating agents, CGS 21680 (0.01- 1 microM) and rolipram (0.01-1 microM), as well as those of dibutyryl cAMP (0. 05-4 mM) on the pro-inflammatory interactions of the P. aeruginosa -derived pigment, 1-hydroxyphenazine (1-hp, 3.1 and 12.5 microM), with human neutrophils have been investigated in vitro. Ca(2+)fluxes in FMLP-activated neutrophils were measured using a fura-2/AM spectrofluorimetric procedure, while a colourimetric method was used to measure release of the primary granule enzyme, elastase, from the cells. Treatment with 1-hp resulted in delayed clearance of Ca(2+)from the cytosol of N -formyl- L -methionyl- L -leucyl- L -phenylalanine (FMLP, 1 microM)-activated neutrophils and increased release of elastase. All 3 test agents caused dose-related antagonism of 1-hp-mediated potentiation of elastase release from activated neutrophils, which was associated with restoration of Ca(2+)homeostasis. These observations demonstrate the potential of cAMP-elevating agents, acting on Ca(2+)clearance mechanisms in activated neutrophils, to attenuate the potentially harmful pro-inflammatory effects of 1-hp.
Adenosine↗
Electrical impedance scanning for classifying suspicious breast lesions: first results.
It has long been established that cancer cells exhibit altered local dielectric properties compared with normal cells. Consequently, different electrical conductivity and capacitance are measurable in malignant vs normal tissues. In this study we evaluated the reliability of electrical impedance scanning (EIS), a new technology, for the classification of suspicious lesions: differentiating benign from malignant, and as a primary means of detection of breast cancer. Fifty-two women with 58 sonographically and/or mammographically suspicious findings were examined using electrical impedance scanning. Two different examination modes of TransScan TS2000 (Siemens, Erlangen, Germany), the standard-resolution mode for a routine overview examination, and the targeted high-resolution mode for a local examination of the suspicious lesion were used. All patients were additionally imaged by MR mammography (MRM) and underwent core-biopsy and/or surgical treatment after the EIS examination. With respect to the histopathological findings (29 malignant and 29 benign lesions) 27 of 29 (93.1%) malignant lesions were correctly identified using the high-resolution mode of EIS, whereas 19 of 29 (65.5%) benign lesions were correctly identified as benign (10 of 29 benign lesions showed as false-positive findings). Negative and positive predictive values of 90.5 and 73.0% were observed, respectively. Using the standard-resolution mode 22 of 29 malignancies were correctly detected (sensitivity 75.9%), whereas 22 of 29 were correctly identified as benign (specificity 72.4%). Electrical impedance scanning appears to be a promising new technology providing a relatively high sensitivity for the verification of suspicious mammographic and/or sonographic lesions especially using the high-resolution mode for local examinations. Artifacts, such as signals from superficial skin lesions, poor contact, and air bubbles, are currently a limitation.
Breast Neoplasms↗