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Biomedical subjects

R Anderson

Publications and source records attributed to R Anderson.

At least 55 records · Page 3Linked to original sources
PubMed2002

The effects of pneumolysin and hydrogen peroxide, alone and in combination, on human ciliated epithelium in vitro.

We have investigated the effects of pneumolysin and H2O2, putative virulence factors of Streptococcus pneumoniae, on the ciliary beat frequency and structural integrity of human ciliated epithelium in vitro. Human ciliated epithelium was obtained by brushing the inferior nasal turbinate of healthy human volunteers. Ciliary slowing (CS) was measured using a photo-transistor technique and epithelial damage (ED) was documented using a visual scoring index. Effects of recombinant pneumolysin (100 ng/ml), a mutant pneumolysin preparation with markedly reduced haemolytic activity (100 ng/ml) and reagent H2O2 (100 microM) were measured alone and in combination, in the absence and presence of catalase (1000 units/ml). When used individually, both recombinant pneumolysin and H2O2 caused significant (P < 0.05) CS and ED. The effects of H2O2 but not those of pneumolysin were almost completely attenuated by catalase, while the mutant pneumolysin preparation did not cause significant CS or ED. When used in combination, the effects of pneumolysin and H2O2 on CS and ED were additive as opposed to synergistic. These actions of pneumolysin and H2O2 may contribute to the pathogenesis of respiratory tract infections caused by the pneumococcus.

Bacterial Proteins↗
PubMed2002

Electrical impedance scanning used in addition to ultrasound for the verification of submandibular and parotid lesions: initial results.

OBJECTIVES: Different dielectric properties of cancerous tissues are correlated with increased conductance potentially measurable using Electrical Impedance Scanning (EIS). Sonographically based differentiation of lesions in the salivary glands remains difficult. The clinical value of EIS used additionally to Ultrasound was investigated. METHODS: Sonographically suspicious lesions of parotid (n = 25) and submandibular (n = 16) glands were examined using TransScan TS2000 (TransScan Medical, Israel; distributed by Siemens, Sweden). Bright focal spots representing areas of high conductance were read as positive; absence of a focal spot (ie, homogeneous gray) was read as negative. All lesions were histopathologically proved. RESULTS: 14/15 malignant (93.3%) and 13/26 benign lesions (50.0%) were correctly detected using EIS, NPV 93%, PPV 52%. All cases of squamous cell carcinoma were correctly identified. Lymph node relapse of T-cell lymphoma, lymph node relapse of malignant melanoma, malignant hemangioendothelioma and 2/3 adenocystic carcinoma (primary metastases) were correctly detected. CONCLUSIONS: Our initial results suggest EIS to be of interest when used adjunctively to ultrasound for the identification of malignant lesions of the salivary glands. However, low specificity induced in part by current technical restrictions (bone interference, skin alterations, contact artifacts, prominence of the lesions) limit this clinical application.

Electric Impedance↗
PubMed2002

Regulation of calcium homeostasis in activated human neutrophils--potential targets for anti-inflammatory therapeutic strategies.

OBJECTIVES: The objectives of the current study were to: (i) present an integrated model for the restoration of calcium homeostasis in activated human neutrophils based on current knowledge and recent research; and (ii) identify potential targets for the modulation of calcium fluxes in activated neutrophils based on this model and to investigate the effects of intracellular probes which target key processes involved in calcium homeostasis and pro-inflammatory activity in these cells. DESIGN AND SETTING: Laboratory-based experimental research using purified human neutrophils from healthy, adult human volunteers. OUTCOME MEASURES: Calcium metabolism and pro-inflammatory activity of neutrophils. RESULTS: Modulation of calcium fluxes in activated human neutrophils can be achieved by cAMP-dependent upregulation of the activity of the endomembrane Ca(2+)-ATPase which resequesters cytosolic Ca2+. Formoterol, a long-acting beta 2-agonist, elevates intracellular cAMP levels, accelerates Ca2+ restoration in activated neutrophils and downregulates the pro-inflammatory responses of these cells. Alterations in the membrane potential of activated neutrophils may play a role in regulating calcium reuptake into the cells as attenuation of the membrane depolarisation response is associated with accelerated calcium influx. CONCLUSIONS: Modulation of the activity of the endomembrane Ca(2+)-ATPase in human neutrophils represents an important target for anti-inflammatory

Adrenergic beta-Agonists↗
PubMed2002

Immunotherapy for Hodgkin's disease.

EBV proteins present in the malignant Hodgkin Reed-Sternberg (HR-S) cells of about 40% of patients with Hodgkin's Disease (HD) provide targets for immunotherapy with virus-specific cytotoxic T lymphocytes (CTL). However, Hodgkin tumors use multiple strategies to avoid CTL, including down-regulation of immunodominant EBV antigens, and secretion of cytokines and chemokines such as TGF-beta, that inhibit the activation of CTL and professional antigen-presenting cells (APC). To be effective against this tumor, CTL must resist some or all of these strategies. Thirteen patients with multiply-relapsed HD received EBV-specific CTL, generated ex vivo using the autologous EBV-transformed B cells (LCL) as stimulator cells. After CTL infusion, EBV-specific immunity increased, virus load decreased, CTL homed to sites of malignancy and persisted for up to ten months. Clinically, CTL produced resolution of B symptoms and mixed tumor responses including one complete remission of residual disease remaining after autologous bone marrow transplant. However, no complete remission of bulky disease was achieved. Although LMP2-specific CTL activity could be detected in some of the infused CTL lines, they were present in low frequency. In pre-clinical studies, LMP1 and LMP2-specific CTL could be produced by stimulating PBMC from patients and normal donors with autologous dendritic cells expressing LMP1 or LMP2 from adenoviral vectors. Further, CTL could be rendered resistant to the devastating effects of TGF-beta by transduction with a retrovirus vector expressing a dominant-negative TGF-beta receptor, while transgenic IL-12 could increase the expression of Th1 and decrease that of Th2 cytokines. Future clinical studies will test the efficacy of CTL with improved antigen-specificity and resistance to Hodgkin immune evasion strategies.

Antigens, Viral↗
PubMed2001

Randomized, double-blind comparison of two nelfinavir doses plus nucleosides in HIV-infected patients (Agouron study 511).

OBJECTIVE: To evaluate the safety and antiretroviral activity of nelfinavir mesylate at two doses as part of a combination regimen in HIV-infected, antiretroviral-naive patients. DESIGN: Phase III, multicenter, double-blind, placebo-controlled trial. PATIENTS AND METHODS: Two-hundred and ninety-seven patients were randomized to one of three treatment groups: nelfinavir 750 mg three times daily (tid), nelfinavir 500 mg tid, or matching placebo, each in combination with open-label zidovudine (ZDV) 200 mg tid and lamivudine (3TC) 150 mg twice daily (bid). Data were analyzed on an intent-to-treat basis. RESULTS: Sixty-seven percent of patients receiving nelfinavir 750 mg tid, and 50% receiving nelfinavir 500 mg tid in combination with ZDV/3TC achieved HIV RNA < 400 copies/ml compared to 7% receiving ZDV/3TC plus placebo (P < 0.001); 55% and 30% of patients in the nelfinavir-containing arms achieved HIV RNA < 50 copies/ml at week 24. This compared with 4% in the placebo-containing arm. For patients continuing nelfinavir treatment (750 mg or 500 mg tid as treated) for a further 6 months, the proportions achieving < 400 copies/ml at week 48 were 75% and 54% (P = 0.001) and < 50 copies/ml 61% and 37%, respectively (P = 0.004). The mean increases from baseline in CD4 cell counts were also durable in patients receiving the triple combination nelfinavir therapy. The range and incidence of adverse events was similar for the two nelfinavir-containing arms, with diarrhea being the most common adverse event. CONCLUSIONS: Nelfinavir plus ZDV/3TC was superior to ZDV/3TC/placebo. In addition, the 750 mg tid nelfinavir dose was better than the 500 mg tid dose. Virologic responses were sustained over 12 months.

Adult↗
PubMed2001

The anti-inflammatory interactions of epinephrine with human neutrophils in vitro are achieved by cyclic AMP-mediated accelerated resequestration of cytosolic calcium.

This study was designed to evaluate the effects of epinephrine (0.01-1 microM) on superoxide production by, and release of elastase from human neutrophils activated with the chemotactic tripeptide, N-formyl-L-methionyl-L-leucyl-L-phenylalanine (FMLP) (1 microM) in vitro, and to relate alterations in these responses to changes in adenosine 3,5' cyclic monophosphate (cAMP) and cytosolic free Ca(2+). Cyclic AMP, superoxide production and elastase release were measured by radioimmunoassay, lucigenin-enhanced chemiluminescence, and a colorimetric procedure respectively. Cytosolic Ca(2+) fluxes were measured by fura-2 spectrofluorimetry in combination with radiometric procedures that enable distinction between net efflux and influx of the cation. Epinephrine treatment of neutrophils resulted in increased cAMP and dose-related inhibition of both superoxide production and elastase release, which was potentiated by the type 4 phosphodiesterase inhibitor, rolipram, and attenuated by propranolol, but not by selective beta(1)-, alpha(1)- or alpha(2)-adrenoreceptor antagonists. Although epinephrine did not affect the FMLP-activated abruptly-occurring increase in fura-2 fluorescence intensity, indicating no effects on the release of Ca(2+) from neutrophil intracellular stores, this agent accelerated the rate of decline in fluorescence in the setting of decreased efflux and a reduction in store-operated influx of Ca(2+). These effects of epinephrine on the clearance of Ca(2+) from the cytosol of FMLP-activated neutrophils were attenuated by propranolol, and are compatible with enhancement of the activity of the cAMP-dependent Ca(2+) sequestering/resequestering endo-membrane Ca(2+)-ATPase. We conclude that epinephrine down-regulates the pro-inflammatory activities of neutrophils by cAMP-mediated enhancement of the clearance of cytosolic Ca(2+).

Adult↗
PubMed2001

Crystal structure of the mitotic spindle kinesin Eg5 reveals a novel conformation of the neck-linker.

Success of mitosis depends upon the coordinated and regulated activity of many cellular factors, including kinesin motor proteins, which are required for the assembly and function of the mitotic spindle. Eg5 is a kinesin implicated in the formation of the bipolar spindle and its movement prior to and during anaphase. We have determined the crystal structure of the Eg5 motor domain with ADP-Mg bound. This structure revealed a new intramolecular binding site of the neck-linker. In other kinesins, the neck-linker has been shown to be a critical mechanical element for force generation. The neck-linker of conventional kinesin is believed to undergo an ordered-to-disordered transition as it translocates along a microtubule. The structure of Eg5 showed an ordered neck-linker conformation in a position never observed previously. The docking of the neck-linker relies upon residues conserved only in the Eg5 subfamily of kinesin motors. Based on this new information, we suggest that the neck-linker of Eg5 may undergo an ordered-to-ordered transition during force production. This ratchet-like mechanism is consistent with the biological activity of Eg5.

Adenosine Diphosphate↗
PubMed2001

Cancer screening guidelines.

Numerous medical organizations have developed cancer screening guidelines. Faced with the broad, and sometimes conflicting, range of recommendations for cancer screening, family physicians must determine the most reasonable and up-to-date method of screening. Major medical organizations have generally achieved consensus on screening guidelines for breast, cervical and colorectal cancer. For breast cancer screening in women ages 50 to 70, clinical breast examination and mammography are generally recommended every one or two years, depending on the medical organization. For cervical cancer screening, most organizations recommend a Papanicolaou test and pelvic examination at least every three years in patients between 20 and 65 years of age. Annual fecal occult blood testing along with flexible sigmoidoscopy at five-year to 10-year intervals is the standard recommendation for colorectal cancer screening in patients older than 50 years. Screening for prostate cancer remains a matter of debate. Some organizations recommend digital rectal examination and a serum prostate-specific antigen test for men older than 50 years, while others do not. In the absence of compelling evidence to indicate a high risk of endometrial cancer, lung cancer, oral cancer and ovarian cancer, almost no medical organizations have developed cancer screening guidelines for these types of cancer.

Adolescent↗
PubMed2001

Is the oxidation of high-density lipoprotein lipids different than the oxidation of low-density lipoprotein lipids?

This article gives detailed insight into the kinetics of high-density lipoprotein (HDL) oxidation catalyzed by azobis(2-amidinopropane).dihydrochloride (ABAP) or by copper. ABAP initialized oxidation of human HDL 3-4 times faster than non-human primate HDL with a similar composition. The oxidizability of non-human primate HDL was 1000 times lower than the oxidizability calculated from rate constants derived from liposome oxidation, suggesting that there is a slow step in HDL oxidation not present in liposomes. Saturable binding of copper to HDL was a significant feature of copper-catalyzed oxidation. Binding constants (K(m)) for non-human primate HDL were 2-3-fold lower than those for human HDL. Copper-catalyzed oxidation of non-human primate HDL was slower than that of human HDL, but human HDL(2) and HDL(3) oxidized at about the same rate. Overall, the kinetics describing the oxidation of HDL were mechanistically similar to those reported for LDL, suggesting that HDL lipids were as easily oxidized as LDL lipids and that HDL will be easily oxidized in vivo when exposed to agents that oxidize LDL.

Amidines↗
PubMed2001

Proinflammatory interactions of pneumolysin with human neutrophils.

The effects of pneumolysin on the proinflammatory activity of human neutrophils, as well as on cation fluxes in these cells, have been investigated. Superoxide production, release of elastase, CR3 expression, phospholipase A2 activity, and alterations in membrane potential were measured by use of lucigenin-enhanced chemiluminescence and colorimetric, flow cytometric, radiometric, and spectrofluorimetric procedures, respectively; and cation fluxes were measured by use of 45Ca2+ and 86Rb+ and by fura-2 spectrofluorometry. Pneumolysin at concentrations >1.67 ng/mL caused influx of Ca2+ and increased phospholipase A2 activity and CR3 expression, which were associated with enhanced superoxide production and release of elastase after activation of the cells with the chemotactic tripeptide FMLP. At the same concentrations, pneumolysin caused efflux of K+ and membrane depolarization. The effects of pneumolysin on cation fluxes were not attributable to inhibition of Ca2+-adenosine triphosphatase (ATPase) or Na+, K+-ATPase. Pneumolysin potentiates the proinflammatory activities of neutrophils by a pore-forming mechanism resulting in Ca2+ influx.

Adenosine Triphosphate↗
PubMed2001

Phosphorus quantity-intensity relationships and agronomic measures of P in surface layers of soil from a long-term slurry experiment.

Soils from a long-term slurry experiment established in 1970 at Hillsborough, Northern Ireland, were used in the experiment. The site has a clay loam soil overlying Silurian shale. Seven treatments were used with three replicate plots per treatment. Control plots were treated with mineral fertiliser supplying 200 kg N, 32 kg P and 160 kg K ha(-1) yr(-1). Slurry treatment plots were in two blocks and treated with either pig or cow slurry supplied at 50, 100 or 200 m3 ha(-1) yr(-1). Agronomic measures of P determined on 10-cm soil cores were compared with measured P quantity/intensity (Q/I) parameters from fitted sorption and desorption isotherms. Phosphorus affinity constant was found to be significantly and negatively correlated with P loading of soils. Desorption rate coefficient also increased significantly with increase in P loading from slurry, although there was no significant difference between slurry types (cow vs. pig). In contrast, while agronomic measures of P (water-soluble P, Olsen P, calcium chloride-extractable P, degree of P saturation (DPS)) also correlated significantly with P loading and total P (TP) in the soils, there was a separation and significant differences between the cow and pig slurry treatment blocks, with the former being much lower. Phosphorus inputs to pig slurry treated plots were much higher than to equivalent cow slurry plots over the first 15 years of the study but declined sharply over the most recent 10 years to more or less par. Conventional measures of agronomic P such as Olsen P and DPS, measure only P accumulation over the longer term and indicated only the higher content of P accumulating in soil of pig slurry treatments. Risk of P loss estimated by Q/I parameters appeared to show very similar behaviour between the two slurry types in line with more recent manurial additions but in contradiction of P accumulation statistics.

Absorption↗
PubMed2001

Agronomic measures of P, Q/I parameters and lysimeter-collectable P in subsurface soil horizons of a long-term slurry experiment.

Soils from a long-term slurry experiment established in 1970 at Hillsborough, Northern Ireland, were used in the experiment. The site has a clay loam soil overlying Silurian shale. Seven treatments were used with three replicate plots per treatment under the following manurial regimes: (1) mineral fertiliser supplying 200 kg N, 32 kg P and 160 kg K ha(-1) yr(-1); (2)-(4) pig slurry applied at 50, 100 or 200 m3 ha(-1) yr(-1); (5)-(7) cow slurry applied at 50, 100 or 200 m3 ha(-1) yr(-1). Agronomic measures of P determined on subsurface layers down to 90 cm were compared with sorption isotherm data and rates of desorption. Adsorption isotherms were fitted using a standard Langmuir model. Data were compared with soluble (molybdate-reactive) P levels in soil water collected at 35 and 90 cm using PTFE suction cup lysimeters. Agronomically available P was concentrated in the top 30 cm of soil in all treatments. The accumulation of P in surface layers of the plots was significantly greater in the pig slurry treatments compared to the cow slurry, reflecting the history of P amendments. Nevertheless, over a period of a year, molybdate-reactive phosphorus (MRP) concentrations in lysimeter collections was consistently higher at 35 cm depth in the highest cow slurry treatment (7) compared to the equivalent pig slurry treatment (4). Either the movement of soluble P down the profile is facilitated by the higher organic content of cow slurry or P movement is not directly related to P accumulation in the soils. In addition, it is hypothesised that P movement down the soil profile depends upon two separate mechanisms. First, a 'break' point above which the accumulated P in the surface horizons is less strongly held and therefore amenable to dissolution and movement down the profile. Second, a mechanism by which some solute P from the surface horizons can travel rapidly through horizons of low P status to greater depth in the soil, i.e., by preferential flow.

Adsorption↗
PubMed2001

Cell biology of limb patterning.

Of vertebrate organ systems, the developing limb has been especially well characterized. Morphological studies have yielded a wealth of information describing limb outgrowth and have allowed for the identification of a multitude of important factors. In terms of the latter, key signaling pathways are known to control numerous aspects of limb development, including establishment of the early limb field, determination of limb identity, elongation of the limb bud, specification of digit pattern, and sculpting of the digits. Modification of underlying signaling pathways can thus result in dramatic alterations of the limb phenotype, accounting for many of the diverse limb patterns observed in nature. Given this, it is clear that signaling pathways regulate the highly orchestrated and tightly controlled sequence of cellular events necessary for limb outgrowth; however, exactly how molecular signals interface with the cell biology of limb development remains largely a mystery. In this review we first provide an overview of a number of the morphogenetic signaling pathways that have been identified in the developing limb and then review how a subset of these signals are known to modify cell behaviors important for limb outgrowth.

Animals↗