Search PubMed⌕ Search

Biomedical subjects

A Todd

Publications and source records attributed to A Todd.

At least 19 recordsLinked to original sources
PubMed2006

Mobilisation and attenuation of boron during coal mine rehabilitation, Wangaloa, New Zealand.

Environmental mobility and fate of boron has been traced from source to discharge waters through the rehabilitated Wangaloa coal mine in southern New Zealand. The boron is derived initially from coal, which has up to 450 mg/kg B. The coal also contains pyrite (2-5 wt.% S), which oxidizes to yield a low-pH environment (typical pH 2-5). Weathering of coal-bearing waste rock liberates B into rainwater that infiltrates into waste rock or evaporates to leave a gypsum crust enriched in B, possibly as boric acid or colemanite as inferred from geochemical modelling. Surface waters dissolve this evaporative material periodically, yielding total B concentrations up to 6 mg/L, at pH<4.5. Some of the available B is taken up by plants that have been established on the waste rock, resulting in foliage B concentrations of up to 230 mg/kg (dry weight). Partial attenuation of dissolved B by adsorption to iron oxyhydroxide occurs as groundwater passes through waste rock, but this is inhibited by adsorption competition with dissolved sulphate (up to 600 mg/L). Groundwater flows from the mine through a pit lake and wetland, with total dissolved B near 1 mg/kg after dilution and limited adsorption attenuation has occurred. Despite the widespread B mobility throughout the rehabilitated mine, there is little evidence of B toxicity in plants. The B concentrations in discharging waters are in the environmentally safe range for most aquatic organisms, being neither deficient in B as a micronutrient, nor boron-toxic.

Boron↗
PubMed2006

Characterization of neurons that express preprotachykinin B in the dorsal horn of the rat spinal cord.

Although it is established that neurokinin B is expressed by some neurons in laminae I-III of the rat spinal dorsal horn, little is known about the proportions of cells in these laminae that express neurokinin B, or whether these are excitatory or inhibitory neurons. Neurokinin B is derived from preprotachykinin B, and we have used an antibody against preprotachykinin B to address these issues. We found that preprotachykinin B-immunoreactive neurons were present throughout laminae I-III, constituting 10-11% of the neuronal population in laminae I-II, and 4% of that in lamina III. They formed a prominent band in the ventral half of lamina II (where they made up 16% of the population) and the dorsalmost part of lamina III. The great majority (99%) of preprotachykinin B-immunoreactive axonal boutons contained the vesicular glutamate transporter 2, while none contained glutamic acid decarboxylase. Since most of these boutons are likely to be derived from local preprotachykinin B-expressing cells, these observations suggest that most of the latter are excitatory interneurons. Although 9% of preprotachykinin B-labeled axonal varicosities were substance P-immunoreactive, none contained calcitonin gene-related peptide, which is consistent with reports that neurokinin B is not expressed by primary afferent axons. Many of the preprotachykinin B-immunoreactive cells contained compounds that are present in putative excitatory neurons in laminae I-III: calbindin (84%), protein kinase Cgamma (76%) or somatostatin (31%). However, there was little or no overlap between preprotachykinin B and three other markers associated with excitatory neurons in these laminae: the mu opioid receptor MOR-1, the neurokinin 1 receptor and neurotensin. These results suggest that neurokinin B is expressed by specific populations of excitatory neurons in the superficial dorsal horn. By examining expression of Fos protein in response to intraplantar injection of formaldehyde we provide evidence that many of the preprotachykinin B cells in lamina I and the outer part of lamina II respond to noxious stimulation.

Animals↗
PubMed2004

Reducing red cell transfusion by audit, education and a new guideline in a large teaching hospital.

Safety concerns combined with the greatly increased costs and difficulties of maintaining the blood supply are major considerations for transfusion services. Previous local surveys demonstrated that hospital blood use at our hospital could be improved. Excessive cross-matching, unnecessary transfusion and high return rates of unused blood were commonplace. Transfusion practice was audited over a 3-month period. An education package with guidelines for transfusion was delivered to all clinician groups within the hospital, over the following 9 months. The audit was repeated exactly 1 year later at the same time period. During the second audit, inpatient hospital numbers increased by 1.02% (from n = 7262 to n = 7336) but no differences in length of stay, cardiovascular morbidity or mortality were demonstrated. Twenty percent (n = 254, 2002; n = 316, 2001) fewer patients received blood, and the number of red cell packs used reduced by 19% (from n = 1093 to n = 880). Total number of patients transfused reduced from 4.4% to 3.5% which, as an absolute difference, is a reduction of 0.9% (CI 0.3-1.5, P = 0.006). The audit, guideline and education package had a major impact on red cell use within the hospital with no adverse effects. Blood use can be improved by the implementation of a suitable education package and guideline. If it is possible to replicate the results of this education programme nationwide, the effect on blood use, with subsequent savings and enhanced patient safety could be significant.

Algorithms↗
PubMed2004

Hospital teaching.

Explore the source record for details and available documents.

Attitude of Health Personnel↗
PubMed2003

Association of stress proteins with autoantigens: a possible mechanism for triggering autoimmunity?

Patterns of autoantibody production are diagnostic of many autoimmune disorders; the recent observation of additional autospecificities towards stress-induced proteins may also provide insight into the mechanisms by which such responses arise. Grp78 (also known as BiP) is a target of autoaggressive B and T cell responses in our murine model of anti-Ro (SS-A) autoimmunity and also in rheumatoid arthritis. In this report we demonstrate reciprocal intermolecular spreading occurs between Ro52 and Grp78 in immunized mice, reflecting physiological association of these molecules in vivo. Moreover, we provide direct biochemical evidence that Grp78 associates with the clinically relevant autoantigen, Ro52 (SS-A). Due to the discrete compartmentalization of Ro52 (nucleocytoplasmic) and Grp78 (endoplasmic reticulum; ER) we propose that association of these molecules occurs either in apoptotic cells, where they have been demonstrated indirectly to co-localize in discrete apoptotic bodies, or in B cells themselves where both Ro52 and Grp78 are known to bind to immunoglobulin heavy chains. Tagging of molecules by association with Grp78 may facilitate receptor mediated phagocytotsis of the complex; we show evidence that exogenous Grp78 can associate with cell surface receptors on a subpopulation of murine splenocytes. Given the likelihood that Grp78 will associate with viral glycoproteins in the ER it is possible that it may become a bystander target of the spreading antiviral immune response. Thus, we propose a model whereby immunity elicited towards Grp78 leads to the selection of responses towards the Ro polypeptides and the subsequent cascade of responses observed in human disease.

Animals↗
PubMed2001

Elevated acute-phase protein in stunted Nepali children reporting low morbidity: different rural and urban profiles.

This study examined the associations between severity of stunting, plasma protein concentrations and morbidity of 104 Nepali boys, aged 10-14 years, living in contrasting environments. Boys from a remote village were compared with three similarly aged urban groups: poor squatters, homeless street children, and middle-class schoolchildren. All but the middle-class group were stunted, particularly village boys whose mean height-for-age z-score (-2.97, SD 0.82) indicates severe growth retardation. Stunting was significantly associated with increased plasma levels of the acute-phase protein alpha1-antichymotrypsin itself inversely related to plasma levels of albumin. Plasma ACT levels of village children (mean 1.52 g/l, SD 0.43) were three to four times higher than those of squatters and homeless street children, and five times higher than those of middle-class boys. Despite being the most severely stunted and having the most abnormal plasma protein values, village children reported the lowest burden of disease, a contradiction which may reflect exposure to sub-clinical infections or habituation to illness and low expectation of treatment. This study draws attention to the strikingly high levels of ACT and of stunting in the rural sample, and cautions on the use of uncorroborated morbidity reports across different epidemiological and socio-ecological environments. Possible mechanisms to explain the impact of illness and inflammation on growth faltering are discussed.

Acute-Phase Proteins↗
PubMed2000

IgG subclass responses to pigeon intestinal mucin in pigeon Fanciers' lung

Pigeon fanciers' lung (PFL) is a form of extrinsic allergic alveolitis caused by exposure to avian antigens. Although the mechanisms involved in the pathogenesis of PFL are unclear it has been suggested that immune complexes formed on the alveolar epithelial surface of the lung initiate the symptoms of the acute stages of discase. Pigeon intestinal mucin has been implicated as an important antigen in the pathogenesis of PFL, and affected fanciers have very high antibody titres against this antigen. In this study we investigated the IgG and IgG subclass responses to both intact and papain digested mucin in 250 pigeon fanciers classified according to the presence of absence of precipitating antibodies and clinical status. Sera were screened by quantitative ELISA for IgG and IgG subclass activity to these antigens. There was no significant difference in the median IgG titre to pigeon mucin in individuals with PFL and asymptomatic antibody positive individuals. IgG1 and IgG2 were the major antibody subclasses against pigeon intestinal mucin with lower titres of IgG3 and negligible IgG4. Patients with PFL had significantly higher titres of anti-mucin IgG1 than asymptomatic antibody positive individuals (p = 0.0019) whilst there was no significant differences in IgG2, IgG3 and IgG4 titres between these two groups. Papain digestion of mucin resulted in a 600 fold decrease in IgG3 titres whilst IgG1 and IgG2 titres were essentially unaffected as compared to undigested mucin. This suggests that both IgG1 and IgG2 are directed against the O-linked oligosaccharides in the papain resistant regions of mucin whilst the majority of IgG3 is directed against papain sensitive protein epitopes (or possibly N-Iinked sugars in the sparsely glycosylated regions). - The difference between symptomatic and asymptomatic sera in the IgG subclass profiles to pigeon intestinal mucin together with the very high titres of anti-mucin antibody in all individuals with PFL confirm pigeon mucin as a major antigen in disease. Differences in antibody subclass profiles are likely to affect the composition and properties of the immune complexes, with consequences for the developmcnt of disease.

Journal Article↗
PubMed2000

Lactation and lead body burden turnover: a pilot study in Mexico.

A pilot study was conducted in Morelos, Mexico in March 1999 to assess the body burden of lead in 24 Mexican women of childbearing age. Lead levels were measured in whole blood and at three bone sites: two primarily trabecular (calcaneus and patella) and one primarily cortical (tibia). Demographic and reproductive characteristics of the women and potential sources of lead exposure were gathered by a direct interview. An inverse relationship was noted between months of lactation and age-adjusted calcaneus lead level (P = 0.001). No association was observed between age-adjusted patella or tibia lead level and months of lactation (P = 0.15). Blood lead levels were positively associated with the use of lead-glazed ceramics (P = 0.01). Bone and blood lead levels were observed to be 77% higher in these rural Mexican women than in urban New York City women. This pilot study provides further limited evidence for the hypothesis that lead mobilization occurs during lactation.

Adult↗
PubMed2000

Phase I and pharmacokinetic study of farnesyl protein transferase inhibitor R115777 in advanced cancer.

PURPOSE: To determine the maximum-tolerated dose, toxicities, and pharmacokinetic profile of the farnesyl protein transferase inhibitor R115777 when administered orally bid for 5 days every 2 weeks. PATIENTS AND METHODS: Twenty-seven patients with a median age of 58 years received 85 cycles of R115777 using an intrapatient and interpatient dose escalation schema. Drug was administered orally at escalating doses as a solution (25 to 850 mg bid) or as pellet capsules (500 to 1300 mg bid). Pharmacokinetics were assessed after the first dose and the last dose administered during cycle 1. RESULTS: Dose-limiting toxicity of grade 3 neuropathy was observed in one patient and grade 2 fatigue (decrease in two performance status levels) was seen in four of six patients treated with 1,300 mg bid. The most frequent clinical grade 2 or 3 adverse events in any cycle included nausea, vomiting, headache, fatigue, anemia, and hypotension. Myelosuppression was mild and infrequent. Peak plasma concentrations of R115777 were achieved within 0.5 to 4 hours after oral drug administration. The elimination of R115777 from plasma was biphasic, with sequential half-lives of about 5 hours and 16 hours. There was little drug accumulation after bid dosing, and steady-state concentrations were achieved within 2 to 3 days. The pharmacokinetics were dose proportional in the 25 to 325 mg/dose range for the oral solution. Urinary excretion of unchanged R115777 was less than 0.1% of the oral dose. One patient with metastatic colon cancer treated at the 500-mg bid dose had a 46% decrease in carcinoembryonic antigen levels, improvement in cough, and radiographically stable disease for 5 months. CONCLUSION: R115777 is bioavailable after oral administration and has an acceptable toxicity profile. Based upon pharmacokinetic data, the recommended dose for phase II trials is 500 mg orally bid (total daily dose, 1, 000 mg) for 5 consecutive days followed by 9 days of rest. Studies of continuous dosing and studies of R115777 in combination with chemotherapy are ongoing.

Administration, Oral↗
PubMed1999

BiP-binding sequences in HIV gp160. Implications for the binding specificity of bip.

BiP, a resident endoplasmic reticulum member of the HSP70 family of molecular chaperones, associates transiently with a wide variety of newly synthesized exocytotic proteins. In addition to immunoglobulin heavy and light chains, the first natural substrates identified for BiP, a number of viral polypeptides including the human immunodeficiency virus type 1 envelope glycoprotein gp160 interact with BiP during their passage through the endoplasmic reticulum. We have used a computer algorithm developed to predict BiP-binding sites within protein primary sequences to identify sites within gp160 that might mediate its association with BiP. Analysis of the ability of 22 synthetic heptapeptides corresponding to predicted binding sites to stimulate the ATPase activity of BiP or to compete with an unfolded polypeptide for binding to BiP indicated that about half of them are indeed recognized by the chaperone. All of the confirmed binding sites are localized within conserved regions of gp160, suggesting a conserved role for BiP in the folding of gp160. Information on the characteristics of confirmed BiP-binding peptides gained in this and previous studies has been utilized to improve the predictive power of the BiP Score algorithm and to investigate the differences in peptide binding specificities of HSP70 family members.

Adenosine Triphosphatases↗
PubMed1999

Medulloblastoma - late outcome.

Long-term survivors of medulloblastoma do occur, even in high-risk groups. Infants and toddlers surviving past the age of 21 years can expect significant intellectual impairment if their radiation therapy was given at approximately 2 years of age. If radiation therapy is delayed or avoided, most of those who survive long term are in a regular school classroom. All of the latter had complete tumor resection. Sixty-two percent of children who received conventional radiation therapy (mean 24 Gy) developed primary hypothyroidism. Tumor markers and improved understanding of tumor biology may lead to more effective surveillance monitoring.

Journal Article↗
PubMed1999

Pigeon fanciers' lung: identification of disease-associated carbohydrate epitopes on pigeon intestinal mucin.

Pigeon intestinal mucin, a complex high molecular weight glycoprotein, is a key antigen in the development of pigeon fanciers' lung (PFL). We have studied the specificity of antibodies to mucin in patients with PFL and asymptomatic antibody-positive individuals. Extensive papain digestion, which removes the non-glycosylated regions of the mucin leaving the heavily glycosylated 'bottle brush' regions, resulted in a 600-fold decrease in IgG3 antibody titres with little effect on IgG1 and IgG2 titres. This suggests that IgG1 and IgG2 are directed against the region rich in O-linked sugar chains whilst the majority of the IgG3 is directed against epitopes which are proteinase-sensitive. Lectin mapping of the carbohydrates present on pigeon intestinal mucin demonstrated high levels of exposed N-acetyl neuraminic acid, N-acetyl galactosamine and N-acetyl glucosamine, with lower levels of fucose and some galactose. Sera from pigeon fanciers inhibited binding of lectins specific for N-acetyl neuraminic acid, N-acetyl galactosamine, internal N-acetyl glucosamine and fucose. Sera from people with PFL, compared with sera from asymptomatic antibody-positive fanciers, had significantly higher titres of antibody that inhibited binding of four lectins specific for N-acetyl galactosamine and one fucose-specific lectin, suggesting that these sugars may play a dominant role in disease-associated epitopes. The results suggest that different IgG subclasses recognize different epitopes on mucin and that the epitopes recognized by the major subclasses are present on the O-linked oligosaccharides. Further, the carbohydrate-specific anti-mucin antibodies produced by PFL patients may differ in their specificity from those found in asymptomatic individuals.

Animals↗