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Biomedical subjects

E Forbes

Publications and source records attributed to E Forbes.

At least 19 recordsLinked to original sources
PubMed2006

Mechanism of interleukin-25 (IL-17E)-induced pulmonary inflammation and airways hyper-reactivity.

BACKGROUND: IL-25, a novel member of the IL-17 cytokine family, promotes CD4+ T-helper 2 lymphocyte-like (Th type-2) inflammatory responses in the lung. Although IL-25 up-regulates IL-13 in the lung, the contribution of this and other type 2 cytokine signalling pathways to the induction and persistence of airways hyper-reactivity (AHR) and allergic inflammation are unclear. OBJECTIVE: To determine the downstream factors employed by IL-25 to induce Th type-2 pulmonary inflammation and AHR. METHODS: IL-25 was delivered to the airways of BALB/c mice by intra-tracheal (i.t.) instillation and AHR and Th type-2 inflammatory responses were characterized in wild type (WT) and Th type-2-cytokine and -signalling pathway-deficient (-/-) mice. RESULTS: IL-25 treatment resulted in AHR, eosinophilic inflammation, mucus hypersecretion and a progressive increase in the production of Th type-2 cytokines in the lungs. Levels of arginase-I (arg-I) and eotaxin were also elevated by IL-25 treatment. A significant reduction in AHR, and attenuation of mucus production was observed in IL-25-treated IL-13-/-, IL-4 receptor alpha (IL-4Ralpha-/-)- and signal-transducer-and-activator-of-transcription-factor-6 (STAT6-/-)-deficient mice. AHR was also inhibited in IL-4(-/-)- and IL-5/eotaxin(1)(-/-)- deficient mice treated with IL-25, however, mucus hypersecretion was not completely ablated. IL-25 promoted Th type-2 responses by directly acting on naïve T cells. CONCLUSION: IL-25 potently (single dose) induces sustained AHR and acute pulmonary inflammation with eosinophilia. IL-25-induced AHR is dependent on the production of Th type-2 cytokines, and removal of IL-13 and its signal transduction pathway prevents IL-25-induced airways inflammation and AHR. IL-25 potently induces inflammatory cascades that may exacerbate allergic airways inflammation by promoting Th type-2 cytokine responses in conjunction with the up-regulation of factors (eotaxin and arg-I) that can amplify inflammation associated with allergic disorders. Dysregulation in IL-25 production may predispose to features of allergic airways disease.

Animals↗
PubMed2005

Safety and immunogenicity of an oral, inactivated, whole-cell vaccine for Shigella sonnei: preclinical studies and a Phase I trial.

Orally delivered, inactivated whole-cell vaccines are safe methods of inducing local and systemic immunity. To increase surface proteins associated with adherence and invasion, Shigella sonnei were grown in BHI broth containing deoxycholate. A whole-cell vaccine (SsWC) was then produced by formalin inactivation. In pre-clinical studies, the SsWC vaccine was immunogenic and protected against S. sonnei-induced keratoconjunctivitis in the guinea pig model. In a randomized, double-blind, placebo-controlled, Phase I study, 10 evaluable subjects received either three doses of SsWC on Days 0, 14, and 28 (N = 3); five doses of SsWC on Days 0, 2, 4, 6, and 28 (N = 4); or placebo (N = 3). Each dose contained 2.0 x 10(10) inactivated cells. Serum and fecal antibodies against SsWC, LPS, and IpaC were measured by ELISA. A > or = 4-fold increase in titer was considered significant. Both SsWC dosing regimens were well tolerated. No fever or severe gastrointestinal symptoms were noted by any of the vaccinated subjects. Antibody responses were similar in the two dosing groups. Serum IgG or IgA responses to SsWC were seen in six of seven vaccinees (86%), to LPS in four of seven (57%), and to IpaC in five of seven (61%). Fecal IgA responses to these three antigens developed in five of five, three of five, and three of five subjects, respectively. Among the seven vaccinees, geometric mean rises in serum IgA levels to all three immunogens were significant; IgG increases trended toward significance (paired one-tailed t-test). We conclude that SsWC was immunogenic and protective in animal studies and well tolerated and immunogenic in a Phase I trial.

Administration, Oral↗
PubMed2001

The acetylcholinesterase gene and organophosphorus resistance in the Australian sheep blowfly, Lucilia cuprina.

Acetylcholinesterase (AChE), encoded by the Ace gene, is the primary target of organophosphorous (OP) and carbamate insecticides. Ace mutations have been identified in OP resistants strains of Drosophila melanogaster. However, in the Australian sheep blowfly, Lucilia cuprina, resistance in field and laboratory generated strains is determined by point mutations in the Rop-1 gene, which encodes a carboxylesterase, E3. To investigate the apparent bias for the Rop-1/E3 mechanism in the evolution of OP resistance in L. cuprina, we have cloned the Ace gene from this species and characterized its product. Southern hybridization indicates the existence of a single Ace gene in L. cuprina. The amino acid sequence of L. cuprina AChE shares 85.3% identity with D. melanogaster and 92.4% with Musca domestica AChE. Five point mutations in Ace associated with reduced sensitivity to OP insecticides have been previously detected in resistant strains of D. melanogaster. These residues are identical in susceptible strains of D. melanogaster and L. cuprina, although different codons are used. Each of the amino acid substitutions that confer OP resistance in D. melanogaster could also occur in L. cuprina by a single non-synonymous substitution. These data suggest that the resistance mechanism used in L. cuprina is determined by factors other than codon bias. The same point mutations, singly and in combination, were introduced into the Ace gene of L. cuprina by site-directed mutagenesis and the resulting AChE enzymes expressed using a baculovirus system to characterise their kinetic properties and interactions with OP insecticides. The K(m) of wild type AChE for acetylthiocholine (ASCh) is 23.13 microM and the point mutations change the affinity to the substrate. The turnover number of Lucilia AChE for ASCh was estimated to be 1.27x10(3) min(-1), similar to Drosophila or housefly AChE. The single amino acid replacements reduce the affinities of the AChE for OPs and give up to 8.7-fold OP insensitivity, while combined mutations give up to 35-fold insensitivity. However, other published studies indicate these same mutations yield higher levels of OP insensitivity in D. melanogaster and A. aegypti. The inhibition data indicate that the wild type form of AChE of L. cuprina is 12.4-fold less sensitive to OP inhibition than the susceptible form of E3, suggesting that the carboxylesterases may have a role in the protection of AChE via a sequestration mechanism. This provides a possible explanation for the bias towards the evolution of resistance via the Rop-1/E3 mechanism in L. cuprina.

Acetylcholinesterase↗
PubMed1997

Singlet oxygen and superoxide characteristics of a series of novel asymmetric photosensitizers.

The singlet oxygen quantum yields and superoxide quantum yields for a series of novel compounds based on an asymmetrical protoporphyrin molecule have been examined. Electron spin resonance was used to measure superoxide yield and time resolved luminescence for singlet oxygen. A comparison between these results and previously published cell survival data was carried out. A broad association was found between singlet oxygen quantum yield and clonogenic cell kill.

Cyclic N-Oxides↗
PubMed1996

Novel asymmetric photosensitizers: an in vitro study.

A series of compounds based on an asymmetrical protoporphyrin molecule have been examined. The paired groups of sensitizers differed in terms of the presence or absence of a permanent positive charge, in the alkyl side chain length and in having either a primary or secondary amine substituent. The effects of these variables on drug uptake, partition coefficient and photodynamic cell kill were tested. Drug uptake and partition coefficient were shown to be correlated. Differences in gross uptake were found within paired groups of sensitizers although cell-associated uptake alone did not correlate with clonogenic cell survival. Of the compounds tested it was the sensitizers with alkyl side chains, rather than the permanently positively charged compounds, which resulted in the greatest degree of clonogenic cell kill.

Cell Survival↗
PubMed1996

Pilot project on functional outcome in stroke.

The purpose of this pilot project was to compare the outcome of stroke survivors cared for on an Acute Stroke Unit (ASU) to those who received care on a routine medical-surgical unit. The sample included a total of 88 patients, 68 admitted to an acute stroke unit and 20 admitted to a medical-surgical unit. The Functional Index Measure was used to assess in-hospital functional gains in the two groups. There appeared to be a trend toward increased functional gains in the group of stroke patients cared for on the Acute Strike Unit as compared to the group of patients cared for on medical-surgical units. These findings provide a foundation for neuroscience nurses and other health care professionals to study functional gains after stroke.

Activities of Daily Living↗
PubMed1994

Improving information for nuclear medicine department outpatients.

In two large inner city hospitals we have conducted a survey of the letters sent to patients before their attendance at a nuclear medicine department. The majority of questions asked for a graded answer (poor, fair, ok, good, excellent). Patients were handed the survey form when they had completed their test and the survey was continued until 100 valid replies had been received at each hospital. Information leaflets, as recommended by the British Nuclear Medicine Society (BNMS), were subsequently issued to all patients and at one hospital the patient information letters were rewritten. The surveys were then repeated. There was a significant (P < 0.001) improvement in patient satisfaction with the information provided. In some areas, for example, instructions about getting to the hospital, no different information was provided and there was no change between the surveys, as would be expected. Curiously, questions allowing free text answers were more often completed by patients from Dudley Road Hospital, Birmingham, than from Guy's Hospital, London. Some possible explanations for this difference are discussed. Particularly reassuring was that more women understood about precautions regarding pregnancy or breastfeeding as a result of the leaflets. We would recommend the advice of the BNMS to other nuclear medicine departments.

Data Collection↗
PubMed1993

The uptake of porphyrin and zinc-metalloporphyrin by the primate prostate.

The relative distribution of sensitizer drugs in the prostate and its contiguous organs is of importance in the treatment of localized prostatic cancer with photodynamic therapy. Using the primate model, whose prostate is both morphologically and physiologically homologous with its human counterpart, the distribution of hematoporphyrin derivative (HpD) amongst organs of urological interest was determined. Hematoporphyrin derivative levels were comparatively low in both caudal and cranial prostatic lobes (0.93-1.77 micrograms/g) and were similar to those in rectum, urethra and the skin. The reticuloendothelial organs, liver, spleen and also the kidney accumulated the highest quantities of porphyrin (4.76-9.8 micrograms/g, liver > spleen > kidney). Despite a high avidity of prostatic tissue for zinc, a zinc-metalloporphyrin (Zn-HpD) did not concentrate selectively in the prostate. The results are of clinical value in view of the homology between the primate and the human.

Aging↗
PubMed1992

Nitrogen analogues of haematoporphyrin and haematoporphyrin derivative.

The preparation of a number of amines related to haematoporphyrin (HP) and haematoporphyrin derivative (HPD) have been studied and their composition and structure discussed through examination of their 1H, 13C NMR and mass spectral data and other physical properties. In vitro biological studies have been carried out and have shown these amines to have a similar photodynamic efficiency to that of HPD. One of these showed cytotoxic properties at exceptionally low light energy levels.

Cell Survival↗
PubMed1992

Mechanism of action of beta-glycerophosphate on bone cell mineralization.

Experiments were performed to determine whether beta-glycerophosphate (beta-GP) promoted mineralization in vitro by modulating bone cell metabolic activity and/or serving as a local source of inorganic phosphate ions (Pi). Using MC3T3-E1, ROS 17/2.8, and chick osteoblast-like cells in the presence of beta-GP or Pi, we examined mineral formation, lactate generation, alkaline phosphatase (AP) activity, and protein and phospholipid synthesis. Neither beta-GP nor Pi modulated any of the major biosynthetic activities of the bone cells. Thus, we found no change in the levels of phospholipids, and the total protein concentration remained constant. Measurement of lactate synthesis showed that beta-GP did not effect the rate of anaerobic glycolysis. Evaluation of medium Pi levels clearly indicated that beta-GP was hydrolyzed by bone cells; within 24 hours, almost 80% of 10 mM beta-GP was hydrolyzed. It is likely that this local increase in medium Pi concentration promoted rapid mineral deposition. Chemical, energy dispersive X-ray, and Fourier transform infrared analysis of the mineral formed in the presence of beta-GP showed that it was nonapatitic; moreover, mineral particles were also seen in the culture medium itself. Experiments performed with a cell-free system indicated that mineral particles formed spontaneously in the presence of AP and beta-GP and were deposited into a collagen matrix. We conclude that medium supplementation with beta-GP or Pi should not exceed 2 mM. If this value is exceeded, then there will be nonphysiological mineral deposition in the bone cell culture.

Absorptiometry, Photon↗
PubMed1991

Ascorbic acid regulates multiple metabolic activities of cartilage cells.

Bones grow in length because of the activities of cartilage cells in the epiphyseal growth plate. We have examined selected events that occur in the growth cartilage by the use of cultured epiphyseal cells; we have also evaluated the influence of ascorbate on these activities. Our studies indicate that 1) ascorbate induces the expression of a unique collagen isoform, type X collagen; 2) ascorbate stimulates alkaline phosphatase activity of maturing chondrocytes; and 3) ascorbate regulates the energy status of the maturing chondrocyte. We have found that in the presence of ascorbate there is a change in oxidative activity. Thus, lactate formation is inhibited, there is an increase in the adenylate energy charge ratio, and there is an elevation in the activity of isocitrate dehydrogenase. The results of these studies point to multiple effects of vitamin C on chondrocyte maturation involving changes in protein synthesis and energy metabolism.

Alkaline Phosphatase↗
PubMed1989

The Tc3 family of transposable genetic elements in Caenorhabditis elegans.

We describe genetic and molecular properties of Tc3, a family of transposable elements in Caenorhabditis elegans. About 15 Tc3 elements are present in the genomes of several different wild-type varieties of C. elegans, but Tc3 transposition and excision are not detected in these strains. Tc3 transposition and excision occur at high frequencies, however, in strain TR679, a mutant identified because of its highly active Tc1 elements. In TR679, Tc3 is responsible for several spontaneous mutations affecting the unc-22 gene. Tc3-induced mutations are unstable, and revertants result from precise or nearly precise excision of Tc3. Although Tc3 is very active in TR679, it is not detectably active in several other mutator mutants, all of which exhibit high levels of Tc1 activity. Tc3 is 2.5 kilobases long, and except for sequences near its inverted repeat termini, it is unrelated to Tc1. The termini of Tc3 are inverted repeats of at least 70 base pairs; the terminal 8 nucleotides of Tc3 are identical to 8 of the terminal 9 nucleotides of Tc1.

Animals↗
PubMed1988

Systems therapy in a day-treatment setting.

This is a paper about doing systems therapy in a day-treatment facility for children identified as severely emotionally disturbed. Children's emotional problems are seen and treated as aspects of family and larger-system problems. An intervention process has been articulated. Information management is a central team task. All staff are team members. While many theories and therapies inform the intervention process, there is no attempt to integrate approaches. Rather, a consultation process serves as a clearinghouse for information management. The managers of the information process think in systems terms and that thinking is "meta" to other positions. In this paper the thinking, the organization of the workplace, and some of the processes which people experience are explored.

Child↗