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Biomedical subjects

D Newton

Publications and source records attributed to D Newton.

At least 19 recordsLinked to original sources
PubMed2004

Leptin deficiency produces contrasting phenotypes in bones of the limb and spine.

Leptin is a hormone secreted by adipocytes that can regulate bone mass through a central, neuroendocrine signaling pathway. We tested the hypothesis that the response of bone tissue to altered leptin signaling is not uniform throughout the skeleton, but may vary between different skeletal regions and between cortical and trabecular moieties. We investigated the effects of leptin deficiency on muscle mass and bone architecture in obese, leptin-deficient (ob/ob) mice, and in lean controls. Results indicate that the obese mice weigh approximately twice as much as the lean mice, but the quadriceps muscles of the ob/ob mice are 40% smaller than those of controls. Leptin-deficient mice have significantly shorter femora, lower femoral bone mineral content (BMC), bone mineral density (BMD), cortical thickness, and trabecular bone volume compared to lean mice. Marrow tissue from the femora of ob/ob mice also shows a marked increase in adipocyte number compared to that of normal mice. In contrast to the pattern observed in the femur, ob/ob mice have significantly increased vertebral length, lumbar BMC, lumbar BMD, and trabecular bone volume compared to lean controls. Few adipocytes are observed in bone marrow from lumbar vertebrae of ob/ob mice, despite being numerous in marrow of the femur. However, like the femur, significant cortical thinning is also observed in the spine. These results indicate that the effects of altered leptin signaling on bone differ significantly between axial and appendicular regions, and may be mediated in part by muscle mass. The muscle hypoplasia, increased marrow adipogenesis, and decreased bone mass observed in the hindlimbs of ob/ob mice are also observed with aging in humans, suggesting that the ob/ob mouse may be a new and useful animal model for studying the relationship between bone marrow adipogenesis and osteopenia.

Animals↗
PubMed2004

Radionuclide biokinetics database (RBDATA-EULEP): an update.

The main activity of the RBDATA-EULEP project is the development of an electronic database of information on the biokinetics of radionuclides after intake by inhalation, ingestion or injection. It consists of linked tables of publications and experiments, with details and comments on the materials, procedures and results. By March 2004 it contained information on more than 1600 experiments from 600 publications. It will be extended and Internet access will also be provided.

Body Burden↗
PubMed2003

RBDATA-EULEP: providing information to improve internal dosimetry.

The overall aim of the concerted action RBDATA-EULEP is to provide information to improve the assessments of intakes of radionuclides and of the resulting doses. This involves a review of the behaviour of radionuclides following intake, and the transfer of expertise on methodology by organising small training workshops. The main activity is the development of an electronic database, effectively an annotated bibliography, but the electronic format used facilitates extension, updating and information retrieval. It consists of linked tables of references and experiments, with details and comments on the materials, procedures and results. By June 2002 it contained information on 524 inhalation, 282 ingestion and 164 injection experiments from 391 references. It will be extended, and Internet access provided. Prospective users include groups developing standards for internal dosimetry, scientists conducting research on radionuclide biokinetics and health physicists assessing the consequences of accidental intakes.

Body Burden↗
PubMed2003

Human biokinetics of inhaled terbium oxide.

Four healthy men inhaled a monodisperse aerosol of 160Tb-labelled terbium oxide particles. The behaviour of the tracer was studied through measurements of body radioactivity and of its urinary and faecal excretion. Estimated early faecal losses in the four subjects ranged from 3% to 31% of the initial respiratory-tract deposit; most of the residue had become systemic within a year, with the principal deposit apparently in bone. Interference from this systemic deposit prevented accurate determination of the long-term pulmonary clearance kinetics, but the pattern was broadly what would be expected for Type M materials in the ICRP's Human Respiratory Tract Model. Averaged trends in the whole-body residue after approximately 1 year suggest a clearance half-life of approximately to 5 y.

Administration, Inhalation↗
PubMed2001

Long-term retention of injected barium-133 in man.

Data are presented on the whole-body retention of 133Ba (half-life 10.74 y), over periods of up to 13 y after injection into six healthy male volunteers aged 25-81, and on their levels of biochemical markers for bone turnover. The results are relevant to propositions underlying the ICRP's current (Publication 67) and former (Publication 20) models of alkaline earth metabolism. The tracer was predominantly skeletal within weeks of the injection, as predicted in the current model. The mean retention accorded satisfactorily throughout with predictions based on the current model, but this accord does not necessarily validate the model, for two reasons. First, parameter values attributed to barium were influenced by data emerging during the early years of this study. Second, bone resorption rates in these subjects, as indicated by urinary markers, appear insufficient to explain the long-term reductions in skeletal retention which, in the present model, arise exclusively through this mechanism.

Adult↗
PubMed2001

Human biokinetics of injected bismuth-207.

A healthy male volunteer received an intravenous injection of 207Bi as citrate. Levels of the tracer in blood and in excretion samples, and its retention and distribution within the body, were investigated by appropriate radioactivity measurements. Levels in blood fell very rapidly, with only 1% of the injection remaining at 7 h and only ca. 0.1% at 18 days. There was rapid initial excretion, with 55% lost during the first 47 h, principally in urine; however, longer-term losses were much slower and 0.6% remained in the body at 924 days, when the contemporary rate of loss implied a half-life of 1.9 years. Integration of the retention pattern suggested that steady exposure to bismuth compounds could lead ultimately to a body content of approximately 24 times the daily systemic uptake. The largest organ deposit was in the liver, which after 3 days contained ca. 60% of the contemporary whole body content, consistent with reports of hepatotoxicity. These findings differ markedly from the metabolic model for bismuth proposed by the International Commission on Radiological Protection, which envisages a terminal half-life in the body of only 5 days and kidney as the site of highest deposition.

Half-Life↗
PubMed1999

Functional food properties of non-digestible oligosaccharides: a consensus report from the ENDO project (DGXII AIRII-CT94-1095).

This paper results from the final phase of the ENDO project (DGXII AIRII-CT94-1095), a European Commission-funded project on non-digestible oligosaccharides (NDO). All participants in the programme met to perform a consensus exercise on the possible functional food properties of NDO. Topics studied during the project (including a workshop on probiotics and prebiotics) and related aspects, for which considerable evidence has been generated recently, were evaluated on the basis of existing published scientific evidence. There was a general consensus that: (1) there is strong evidence for a prebiotic effect of NDO in human subjects. A prebiotic effect was defined as a food-induced increase in numbers and/or activity predominantly of bifidobacteria and lactic acid bacteria in the human large intestine; (2) there is strong evidence for the impact that NDO have on bowel habit; (3) there is promising evidence that consumption of inulin-type fructans may result in increased Ca absorption in man; (4) there are preliminary indications that inulin-type fructans interact with the functioning of lipid metabolism; (5) there is preliminary evidence in experimental animals of a preventive effect against colon cancer. Human nutrition studies are needed to substantiate these findings. It was concluded that the nutritional properties of NDO may prove to be a key issue in nutritional research in the future.

Animals↗
PubMed1999

Middle latency auditory evoked responses and electroencephalographic derived variables do not predict movement to noxious stimulation during 1 minimum alveolar anesthetic concentration isoflurane/nitrous oxide anesthesia.

UNLABELLED: The electroencephalogram (EEG) and middle latency auditory evoked responses (MLAER) have been proposed for assessment of the depth of anesthesia. However, a reliable monitor of the adequacy of anesthesia has not yet been defined. In a multicenter study, we tested whether changes in the EEG and MLAER after a tetanic stimulus applied to the wrist could be used to predict subsequent movement in response to skin incision in patients anesthetized with 1 minimum alveolar anesthetic concentration (MAC) isoflurane in N2O. We also investigated whether the absolute values of any of these variables before skin incision was able to predict subsequent movement. After the induction of anesthesia with propofol and facilitation of tracheal intubation with succinylcholine, 82 patients received 1 MAC isoflurane (0.6%) in N2O 50% without an opioid or muscle relaxant. Spontaneous EEG and MLAER to auditory click-stimulation were recorded from a single frontoparietal electrode pair. MLAER were severely depressed at 1 MAC isoflurane. At least 20 min before skin incision, a 5-s tetanic stimulus was applied at the wrist, and the changes in EEG and MLAER were recorded. EEG and MLAER values were evaluated before and after skin incision for patients who did not move in response to tetanic stimulation. Twenty patients (24%) moved after tetanic stimulation. The changes in the EEG or MLAER variables were unable to predict which patients would move in response to skin incision. Preincision values were not different between patients who did and did not move in response to skin incision for any of the variables. MLAER amplitude increased after skin incision. We conclude that it is unlikely that linear EEG measures or MLAER variables can be of practical use in titrating isoflurane anesthesia to prevent movement in response to noxious stimulation. IMPLICATIONS: Reliable estimation of anesthetic adequacy remains a challenge. Changes in spontaneous or auditory evoked brain activity after a brief electrical stimulus at the wrist could not be used to predict whether anesthetized patients would subsequently move at the time of surgical incision.

Adolescent↗
PubMed1998

Uptake by man of aluminium in a public water supply.

1. After overnight fasting, two young male adults each received a single oral dose of 100 Bq 26Al in tap water. Coincidence gamma-ray spectrometry and accelerator mass spectrometry were used to determine the 26Al content of excretion collections and of blood samples. 2. Close to 100% of the intake was recovered in faeces during the first 7 days. Gastro-intestinal uptake, determined by comparing urinary excretion with patterns previously established following intravenous administration of 26Al, averaged 0.22% in the two subjects. 3. Uptake fractions based on comparisons of blood concentration following ingestion and injection were much lower, but were judged to be unreliable. It is concluded that aluminium present in most water supplies is unlikely to contribute as much as 1% of a typical daily uptake of 10 microg from food.

Adult↗
PubMed1996

Regulation of superantigen-induced T cell activation in the absence and the presence of MHC class II.

To study MHC class II-dependent and -independent SAg2 activation and the relative importance of CD80/CD28 costimulation, staphylococcal enterotoxin A (SEA) was presented to T cells as a fusion protein containing the Fab fragment of an mAb directed against the CA215 glycoprotein. Chinese hamster ovary (CHO) cells transfected with HLA-DR4, CA215, and CD80, individually or in combinations, were used as presenting cells. A strong T cell proliferation was obtained when C215Fab-SEA fusion proteins were presented by CHO-DR/CD80 or CHO-CA215/CD80 double transfectants, whereas only low levels of proliferation were seen in the absence of CD80. Large amounts of IL-2, IFN-gamma, and TNF were produced in addition to an increase in IL-2 mRNA as a result of CD80 costimulation. Only approximately 50% of the SEA-reactive T cells responded by expression of IL-2 receptor chains and by blast formation when activated with SEA in the absence of MHC class II. Reverse transcription-PCR-assisted repertoire analysis of SEA-reactive TCR V beta families showed that the CA215-dependent activation involved an expansion of fewer TCR V beta families compared with MHC class II-dependent activation. One-half of the six analyzed TCR V beta families were expanded independently of class II. This indicates that MHC class II has only a partial influence on the TCR V beta repertoire imprinted by SAg. This finding redefines the role of MHC class II in SAg presentation. It is suggested that MHC class II molecules are selected as SAg-binding molecules mainly as a suitable targeting receptor for professional APC expressing costimulatory molecules such as CD80 and CD86.

Animals↗
PubMed1995

Selective depletion of V beta-bearing T cells in patients with severe invasive group A streptococcal infections and streptococcal toxic shock syndrome. Ontario Streptococcal Study Project.

The V beta repertoire of T cells of patients with gram-positive group A streptococcal (GAS) and non-GAS infections was analyzed to seek evidence for the role of superantigens in streptococcal toxic shock syndrome. No evidence of V beta overexpression but a consistent pattern of depletion of V beta 1, V beta 5.1, and V beta 12 was observed in patients with severe GAS infections. This pattern of V beta depletion was not observed in patients with nonsevere GAS infections or with severe non-GAS gram-positive infections. T cells from patients with severe GAS infections showed evidence of apoptosis; no apoptosis was found when there was no evidence of V beta depletion. There was no correlation with streptococcal M or T serotype or known spe genes. The depletion of specific V beta-bearing T cells in patients with severe GAS infections supports the role of a superantigen in these infections. The in vivo pattern of V beta specificity implicates a novel superantigen(s) in this disease.

Adolescent↗
PubMed1995

Human metabolism of aluminium-26 and gallium-67 injected as citrates.

1. 26Al and 67Ga were given as citrates to a healthy male volunteer by intravenous injection. The retention of both tracers was studied by body radioactivity measurement. Levels in blood and excreta were determined by gamma-ray spectrometry and/or accelerator mass spectrometry. 2. More than half of the 26Al had left the blood after 15 min and the decline continued, leaving < 1% in blood after 2 d; the losses occurred both to renal excretion and through uptake by other compartments. Estimated excretion up to 13 d was 83% (urine) and 1.8% (faeces). Whole-body retention of 15% at 13 d declined to approximately 4% at 1178 d, when the daily reduction corresponded to a biological half-life of 7 y, suggesting that sustained intake of dietary aluminium may lead to a progressively increasing internal deposit. 3. The metabolism of 67Ga differed markedly from that of 26Al in all aspects studied.

Adult↗
PubMed1995

Inter-subject variability in the metabolism of aluminium following intravenous injection as citrate.

1. Six healthy male volunteers received intravenous injections of 26Al as citrate. Accelerator mass spectrometry and gamma-ray spectrometry were used to determine levels of the tracer in blood and excreta at times up to 5-6 d. 2. There was a rapid clearance from blood (mean 2% of injection remaining after 1 d) and major loss in urine (59% up to 1 d), but 27 +/- 7 (s.d.)% was retained in the body at 5 d. Faecal excretion was negligible (1% up to 5 d). 3. The mean results accord with the early metabolic pattern in the single subject of a previous, more extensive study, who had retained 4% of the injection after 3 y. Together, the two studies point to the likelihood of large inter-subject differences in the long-term accumulation of dietary aluminium by populations receiving a given level of daily intake.

Adult↗
PubMed1994

RNase inhibition of human immunodeficiency virus infection of H9 cells.

Onconase and bovine seminal RNase, two members of the RNase A superfamily, inhibit human immunodeficiency virus type 1 replication in H9 leukemia cells 90-99.9% over a 4-day incubation at concentrations not toxic to uninfected H9 cells. Two other members of the same protein family, bovine pancreatic RNase A and human eosinophil-derived neurotoxin, have no detectable antiviral activity, demonstrating a strikingly selective antiviral activity among homologous ribonucleases. The antiviral RNases do not appear to affect viral particles directly but inhibit replication in host cell cultures. Onconase, already in clinical trials for cancer therapy, and bovine seminal RNase have potential as antiviral therapeutics.

Animals↗
PubMed1994

Characterization of unique human TCR V beta specificities for a family of streptococcal superantigens represented by rheumatogenic serotypes of M protein.

The M protein of Streptococcus pyogenes plays a major role in the virulence of these bacteria. Members of the M protein superfamily are characterized by the presence of tandem segments of repeated amino acid sequences. The NH2-terminal end of the M proteins is a hypervariable region that harbors the type-specific epitopes of the molecule. Pepsin cleaves the molecule into a highly conserved carboxyl terminal half and a variable amino terminal portion referred to as pep M. In some individuals, infection with certain serotypes of group A streptococci is followed by autoimmune disorders such as rheumatic fever and acute glomerulonephritis. The serotypes of M protein that show a high degree of association with acute rheumatic fever are referred to as rheumatogenic serotypes. We have reported that one such serotype, type 5, is a superantigen to human T cells, specifically stimulating T cells bearing V beta 2, V beta 4, and V beta 8 elements. Here we extend our studies by examining other rheumatogenic serotypes for superantigenic properties. Studies with types 6, 18, 19, and 24 M proteins revealed that they are all superantigens to human T cells. The specificity to V beta 4 was shared by the rheumatogenic M proteins tested; however, each pep M serotype has its unique characteristic set of V beta specificity and these are distinct from those reported for the streptococcal pyrogenic exotoxins. The non-rheumatogenic serotype, pep M2, only stimulated V beta 2-bearing T cells. This study establishes that the structurally related M proteins represent a family of streptococcal superantigens analogous to the structurally related family of staphylococcal enterotoxin superantigens.

Amino Acid Sequence↗
PubMed1994

Transcutaneous hydrogen clearance--a new non-invasive technique for assessing blood flow in human skin.

A new technique for the non-invasive assessment of skin blood flow is described using a modified, commercially available transcutaneous oxygen electrode. Initially, experiments were carried out on normal volunteers at skin temperatures of 40 degrees C and 44 degrees C. Transcutaneous H2 (tcpH2) clearances were measured after the subject had breathed a mixture of 2% H2 in air until a saturation value in the skin had been reached. tcpH2 clearance results were compared with laser Doppler flux values measured simultaneously on adjacent sites and at the same temperatures under control and reactive hyperaemic conditions. Good reproducibility for the tcpH2 technique and significant correlation (p < 0.002) between it and laser Doppler flux values at the same temperatures was demonstrated. In further experiments, (I125) 4-iodoantipyrine clearances (IAP) were carried out immediately prior to and at the same sites as tcpH2 clearances in critically ischaemic lower limbs. The correlation between the methods and the differences between tcpH2 values observed in normal and critically ischaemic skin were highly significant (p < 0.002).

Adult↗