Biomedical subjects

J Hilton

Publications and source records attributed to J Hilton.

At least 19 recordsLinked to original sources

PubMed1999

Ablation of renal tumors in a rabbit model with interstitial saline-augmented radiofrequency energy: preliminary report of a new technology.

OBJECTIVES: To evaluate the efficacy of interstitial saline radiofrequency energy for reproducibly ablating nonmalignant (control) and malignant (the VX-2 tumor) renal tissue in a rabbit model, and to determine the ability of conventional gray-scale and power sonography to image the tumor and ablative process in real time before, during, and after treatment. METHODS: The VX-2 tumor was implanted beneath the renal capsule in 18 rabbit kidneys. Twelve days after implantation, 50 W of 500-kHz radiofrequency energy was delivered into the surgically externalized renal tumor and contralateral control kidney for 30 or 45-second treatment intervals using an interstitial saline-augmented radiofrequency probe (the virtual electrode). Localization of the tumor and response to treatment were imaged with gray-scale and power Doppler ultrasonography. The effect of radiofrequency and extent of the destructive process on benign and malignant renal tissue were evaluated histologically. RESULTS: Mean tumor size was 1.3 x 0.7 cm. Both 30 and 45-second treatment intervals provided marked tissue/tumor ablation. Gross anatomic and histologic analysis showed time-dependent ablated lesions averaging 1.4+/-0.3 x 1.0+/-0.3 cm (30-second treatment) and 1.8+/-0.4 x 1.5+/-0.3 cm (45-second treatment), with clear demarcation of the surrounding parenchyma. Conventional gray-scale sonography allowed visualization of the ablative process, and power Doppler ultrasound demonstrated changes in the vascular pattern of the tumor both before and after ablation. No immediate treatment-related complications were observed. CONCLUSIONS: These preliminary studies in a rabbit model demonstrate the feasibility of using the interstitial saline-augmented electrode to ablate small renal tumors and the ability to simultaneously visualize the ablative process using real-time ultrasonography. This technology may have the potential to treat small renal tumors in a minimally invasive manner in the clinical setting.

Animals↗

PubMed1998

New prodrug activation gene therapy for cancer using cytochrome P450 4B1 and 2-aminoanthracene/4-ipomeanol.

Vector-mediated transfer of prodrug-activating genes provides a promising means of cancer gene therapy. In a search for more selective and more potent bioactivating enzymes for gene therapy of malignant brain tumors, the toxicity-generating capacity of the rabbit cytochrome P450 isozyme CYP4B1 was investigated. Rabbit CYP4B1, but not rat or human isozymes, efficiently converts the inert prodrugs, 2-aminoanthracene (2-AA) and 4-ipomeanol (4-IM), into highly toxic alkylating metabolites. Toxicity of these two prodrugs was evaluated in culture in parental and genetically modified rodent (9L) and human (U87) glioma cell lines stably expressing CYP4B1, and in vivo in a subcutaneous 9L tumor model in nude mice. The most sensitive CYP4B1-expressing glioma clone, 9L4B1-60, displayed an LD50 of 2.5 microM for 2-AA and 4-IM after 48 h of prodrug incubation, whereas 20 times higher prodrug concentrations did not cause any significant toxicity to control cells. Substantial killing of control tumor cells by 2-AA was achieved by co-culturing these cells with CYP4B1-expressing cells at a ratio of 100:1, and toxic metabolites could be transferred through medium. In both CYP4B1-expressing cells and co-cultured control cells, prodrug bioactivation was associated with DNA fragmentation, as assayed by fluorescent TUNEL assays and by annexin V staining. Alkaline elution of cellular DNA after exposure to 4-IM revealed extensive protein-DNA crosslinking with single-strand breakage. Growth of 9L-4B1 tumors in nude mice was inhibited by intraperitoneal injection of 4-IM with minimal side effects. Potential advantages of the CYP4B1 gene therapy paradigm include: the low concentrations of prodrug needed to kill sensitized tumor cells; low prodrug conversion by human isozymes, thus reducing toxicity to normal cells; a tumor-killing bystander effect that can occur even without cell-to-cell contact; and the utilization of lipophilic prodrugs that can penetrate the blood-brain barrier.

Animals↗

PubMed1998

Assessment of the skin sensitization potential of topical medicaments using the local lymph node assay: an interlaboratory evaluation.

The murine local lymph node assay (LLNA) is a method for the predictive identification of chemicals that have a potential to cause skin sensitization. Activity is measured as a function of lymph node cell (LNC) proliferative responses stimulated by topical application of test chemicals. Those chemicals that induce a threefold or greater increase in LNC proliferation compared with concurrent vehicle controls are classified as skin sensitizers. In the present investigations we have evaluated further the reliability and accuracy of the LLNA. In the context of an international interlaboratory trial the sensitization potentials of six materials with a history of use in topical medicaments have been evaluated: benzoyl peroxide, hydroquinone, penicillin G, streptomycin sulfate, ethylenediamine dihydrochloride, and methyl salicylate. Each chemical was analyzed in the LLNA by all five laboratories. Either the standard LLNA protocol or minor modifications of it were used. Benzoyl peroxide and hydroquinone, both human contact allergens, elicited strong LLNA responses in each laboratory. Penicillin G, another material shown previously to cause allergic contact dermatitis in humans, was also positive in all laboratories. Streptomycin sulfate induced equivocal responses, in that this material provoked a positive LLNA response in only one of the five laboratories, and then only at the highest concentration tested. Ethylenediamine dihydrochloride dissolved in a 3:1 mixture of acetone with water, or in 4:1 acetone:olive oil (one laboratory), was uniformly negative. However, limited further testing with the free base of ethylene diamine yielded a positive LLNA response when applied in acetone:olive oil (AOO). Finally, methyl salicylate, a nonsensitizing skin irritant, was negative at all test concentrations in each laboratory. Collectively these data serve to confirm that the local lymph node assay is sufficiently robust to yield equivalent results when performed independently in separate laboratories and indicate also that the LLNA is of value in assessing the skin sensitization potential of topical medicaments.

Administration, Topical↗

PubMed1998

The partitioning of phosphoramide mustard and its aziridinium ions among alkylation and P-N bond hydrolysis reactions.

NMR (1H and 31P) and HPLC techniques were used to study the partitioning of phosphoramide mustard (PM) and its aziridinium ions among alkylation and P-N bond hydrolysis reactions as a function of the concentration and strength of added nucleophiles at 37 degrees C and pH 7.4. With water as the nucleophile, bisalkylation accounted for only 10-13% of the product distribution given by PM. The remainder of the products resulted from P-N bond hydrolysis reactions. With 50 mM thiosulfate or 55-110 mM glutathione (GSH), bisalkylation by a strong nucleophile increased to 55-76%. The rest of the PM was lost to either HOH alkylation or P-N bond hydrolysis reactions. Strong experimental and theoretical evidence was obtained to support the hypothesis that the P-N bond scission observed at neutral pH does not occur in the parent PM to produce nornitrogen mustard; rather it is an aziridinium ion derived from PM which undergoes P-N bond hydrolysis to give chloroethylaziridine. In every buffer studied (bis-Tris, lutidine, triethanolamine, and Tris), the decomposition of PM (with and without GSH) gave rise to 31P NMR signals which could not be attributed to products of HOH or GSH alkylation or P-N bond hydrolysis. The intensities of these unidentified signals were dependent on the concentration of buffer.

Alkylation↗

PubMed1998

Use of a satellite-derived land cover map to estimate transport of radiocaesium to surface waters.

During the weeks to months after the deposition of radioactive fallout, the initial concentration of radioactivity in rivers and lakes declines as a result of flushing and removal to bottom sediments. In the long-term, however, radioactivity in the water body can remain at significant levels as a result of secondary contamination processes. In particular, it is known that soils contaminated by long-lived radionuclides such as 137Cs and 90Sr provide a significant source to surface waters over a period of years after fallout. Using The Land Cover Map of Great Britain, a satellite-derived land cover map as a surrogate indicator of soil type, we have related catchment land cover type to long-term 137Cs activity concentrations in 27 lakes in Cumbria, UK. The study has shown that satellite-derived maps could be used to indicate areas vulnerable to high long-term 137Cs transport to surface waters in the event of a nuclear accident. In these Cumbrian lakes, it appears that residual 137Cs levels are determined by transfers of 137Cs from contaminated catchments rather than within-lake processes. Only three of the cover types, open shrub moor, bog and dense shrub moor, as identified by the satellite, are needed to explain over 90% of the variation in long-term 137Cs activity concentrations in the lakes, and these have been shown to correlate spatially with occurrence of organic soils.

Cesium Radioisotopes↗

PubMed1998

Estimation of relative skin sensitizing potency using the local lymph node assay: a comparison of formaldehyde with glutaraldehyde.

BACKGROUND: Chemicals vary considerably in their intrinsic ability to cause allergic contact dermatitis. Presently, there are no experimental methods available for the quantitative assessment of the relative sensitizing potency of chemical allergens. OBJECTIVE: The objective of the investigations described here was to evaluate the use of the local lymph node assay for determining the relative skin sensitizing potential of chemicals. This has been addressed by comparing the sensitizing potency of formaldehyde with glutaraldehyde. METHODS: Dose responses induced by formaldehyde and glutaraldehyde in the local lymph node assay, using either acetone or dimethylformamide (DMF) as the application vehicle, have been measured. Relative skin sensitizing potency was estimated as a function of the amount of chemical required to induce a threefold increase in lymph node cell proliferative activity, a mathematically derived EC3 value (estimated concentration required to induce a stimulation index of 3). RESULTS: In both vehicles, glutaraldehyde induced substantially more vigorous responses in the local lymph node assay (EC3 values of 0.006mol/L in acetone and 0.002mol/L in DMF) than did formaldehyde (EC3 values of 0.18mol/L in acetone and 0.11mol/L in DMF). CONCLUSIONS: These results demonstrate that glutaraldehyde has a considerably greater potential to induce skin sensitization than does formaldehyde; the data are consistent with what is known of the ability of these chemicals to cause allergic contact dermatitis in humans. Using formaldehyde and glutaraldehyde as examples, the results here illustrate the utility of EC3 values derived from local lymph node assay responses for the estimation of the relative potency of skin sensitizing chemicals.

Allergens↗

PubMed1997

Home birth in New Zealand 1973-93: incidence and mortality.

AIMS: To determine for the period 1973-93, national and regional (1991 and 1992 only) incidence of home birth in New Zealand, with home birth defined as home being the intended place of birth at the onset of labour, to calculate perinatal and maternal mortality rates for home birth, and to categorise the cause of perinatal death. METHODS: Data sheets for 9776 planned home births were analysed. These had been collected by the Home Birth Associations of New Zealand/Aotearoa. National perinatal data and data from National Women's Hospital, Auckland were used for comparison. Trend analysis was performed by Poisson regression allowing for overdispersion. RESULTS: Planned home birth made up 2% of the total births in 1993, up from 0.04% in 1973. The home birth perinatal mortality rate for this period was 2.97 per 1000 total births, with no change over time. This was not significantly different from the rate for a selected low risk group at National Women's Hospital. Lethal anomalies caused 31% of the perinatal deaths. There was one maternal death (maternal mortality rate: 1.02 per 10,000 total births). There were significant differences in the rate of home birth in separate area health board regions for 1991 and 1992. CONCLUSION: Home birth was a safe and increasingly popular: though minor, option for New Zealand women from 1973-93.

Cause of Death↗

PubMed1997

Going it alone.

Explore the source record for details and available documents.

Entrepreneurship↗

PubMed1997

A re-appraisal of the skin-sensitizing activity of 2,4-dinitrothiocyanobenzene.

A debate continues regarding the immunological properties of 2,4-dinitrothiocyanobenzene (DNTB). In some investigations this chemical was shown not to cause skin sensitization when applied topically but to induce instead hyporesponsiveness or immunological tolerance. In other studies DNTB was found to cause skin sensitization, but not tolerance. However, this chemical continues to be used to discriminate between the properties of skin sensitizing and non-sensitizing chemicals. This study demonstrates that topical exposure of mice to DNTB induces skin sensitization in mice and that this is associated with the accumulation of dendritic cells in draining lymph nodes and the stimulation of lymph node cell proliferation; the latter responses being of equivalent magnitude to those stimulated by 2,4-dinitrochlorobenzene (DNCB), a chemical known to cause contact sensitization. Moreover, exposure of mice to DNTB, as with exposure to DNCB, resulted in the development of a cytokine secretion pattern by draining lymph node cells (LNC) characteristic of contact allergens. Thus, DNTB and DNCB each induced the production by LNC of high levels of interferon-gamma, but little or no interleukin 4 or interleukin 10. Finally, DNTB was shown in the guinea pig maximization test to behave as an extreme skin sensitizer. These results confirm that DNTB should not be regarded as a universal tolerogen and that it possesses a significant potential to induce contact sensitization. The use of this chemical as a presumptive non-sensitizer and/or tolerogen for the evaluation of the selectivity of new predictive test methods for the identification of contact allergens is therefore considered to be inappropriate.

Administration, Topical↗

PubMed1997

Characteristics of antibody responses induced in mice by protein allergens.

Whereas many foreign proteins are immunogenic, only a proportion is also allergenic, having the capacity to induce the quality of immune response necessary to support the production of IgE antibody. We have demonstrated previously that intraperitoneal administration to mice of proteins such as ovalbumin (OVA) or the industrial enzyme A. oryzae lipase, which possess significant allergenic potential, stimulates the production of both IgG and IgE antibody. Identical exposure to bovine serum albumin (BSA), a protein with limited potential to cause immediate respiratory or gastrointestinal hypersensitivity reactions, induced IgG responses only. In the current investigations, the quality of immune responses induced following exposure to these proteins via mucosal tissue (intranasal) has been compared with those provoked following administration via a non-mucosal (intraperitoneal) route of exposure. Intranasal or intraperitoneal administration of BSA, OVA or A. oryzae lipase elicited in each case vigorous IgG and IgG1 antibody responses. For all three proteins, at every concentration tested, and via both routes of exposure, IgG1 antibody titres paralleled closely IgG titres. However, the three materials displayed a differential potential to provoke IgE responses and this correlated with their known allergenic potential in humans. Thus, OVA and A. oryzae lipase stimulated strong IgE antibody responses, whereas BSA provoked low titre IgE only at the highest concentration tested (5% administered intraperitoneally). The quality of induced responses was not affected by the route of exposure. It would appear, therefore, that the stimulation of IgG and IgG1 antibody responses is a reflection of protein immunogenicity whereas protein allergenicity is associated with the induction of strong IgE responses.

Administration, Intranasal↗

PubMed1997

Towards a generalized model for the primary and secondary contamination of lakes by Chernobyl-derived radiocesium.

As part of the UK Ministry of Agriculture Fisheries and Food Directorate of Fisheries Research (MAFF/DFR) post-Chernobyl monitoring program, a detailed study was carried out of the change over time in dissolved-phase 137Cs concentrations in a number of lakes in Cumbria, UK. These measurements have been combined with published data on 137Cs in Cumbrian and other European lakes in order to develop and test a "double exponential" model for changes in lakewater concentrations: A exp(-k1t) + B exp(-k2t) where the exponential terms correspond, respectively, to the initial fast flush of activity through the system followed by longer-term transfers (timescale, years) from the catchment. Parameter values have been determined for this model by curve-fitting to the set of measurements of post-Chernobyl 137Cs activities in lakes. Values of fitted parameters are shown to be related, in a simple manner, to the physical characteristics of the system, in particular water residence time and mean lake depth. These parameters are generalized to give a simple empirical model for the full set of study lakes. The model is shown to give estimates of 137Cs activity to within a factor of 5 of field data for a period of several years after the fallout. Initial fractional losses of activity from catchment to lake were determined to be within the range 0.44-8.7% per year, declining exponentially with a mean rate constant 0.98 x 10(-3) d(-1).

Biophysical Phenomena↗

PubMed1997

Dinitrohalobenzenes: evaluation of relative skin sensitization potential using the local lymph node assay.

The dinitrohalobenzenes are known to cause skin sensitization and have been used in many seminal investigations of the relationships between physicochemical characteristics and sensitizing potential. The electrophilic theory of skin sensitization implies that contact allergic potential should correlate positively with ability of chemicals to react with proteins to form immunogenic hapten-protein conjugates. It is intriguing, therefore, that previous studies in guinea pigs and mice have suggested that such correlations do not apply to dinitrohalobenzenes. To address this, we have examined, using the murine local lymph node assay (LLNA), the sensitizing activity of 2,4-dinitrofluorobenzene (DNFB), 2,4-dinitrochlorobenzene (DNCB), 2,4-dinitrobromo-benzene (DNBB) and 2,4-dinitroiodobenzene (DNIB). In contrast to previous investigations, it was found that the ability of these chemicals to provoke responses in the LLNA correlated closely with their reported protein reactivity. On the basis of these data, it is proposed that dinitrohalobenzenes conform to the electrophilic theory of skin sensitization and that they should be regarded as direct acting haptens.

Allergens↗

PubMed1996

Mobility of Chernobyl-derived 137Cs in a peatbog system within the catchment of the Pripyat River, Belarus.

The behaviour of Chernobyl-derived 137Cs in a hydrologically isolated bog system in the catchment of the Pripyat River, Belarus was investigated. Measurements were made of 137Cs activities in the solids and pore waters of the bog soils, as well as the variability in activity in water draining from the bog. It was found that the radiocaesium activity of the pore water, and hence the measured distribution coefficient, Kd, was dependent upon the pressure at which the water was removed from the soil. Measured values of Kd were of the order 10(2) l/kg at an extraction pressure of 0.8 MPa, approximately one order of magnitude lower than those measured in a similar system, Devoke Water, in the UK [1]. Results of comparative measurements suggested that this was a result of the different pore water extraction techniques used. The vertical migration of radiocaesium was modelled using a solution of the advection-diffusion equation. Using a mass balance approach, it was estimated that 137Cs was removed from the system at a rate of 0.3% of the catchment inventory per year, approximately 8 years after the Chernobyl accident. It was shown that both vertical migration and removal of 137Cs is best modelled using a Kd based on a measurement of pore water held at low pressure in the soil, approximately 10(3) l/kg. 137Cs activities in soil pore waters and in drainage waters were very strongly related to the aqueous potassium concentration, and both showed concentration minima in drainage water during the spring. It was shown that runoff coefficients of radiocaesium from peat bogs 8 years after the Chernobyl accident were approximately one order of magnitude greater than those from unsaturated soils of higher mineral content.

Cesium Radioisotopes↗

PubMed1996

Characterization of mouse lymphohematopoietic stem cells lacking spleen colony-forming activity.

The classical definition of lymphohematopoietic stem cells (LHSC), the most primitive progenitors of all blood cells, requires that they have the capacity for self-renewal and for the long-term production of all blood cell lineages. However, other characteristics of LHSC have been debated. Our previous data suggested that mouse LHSC are very slowly proliferating cells that generate delayed multilineage engraftment, while "radioprotection" (rapid engraftment that will prevent early death from radiation-induced marrow aplasia) results from more committed progenitors. Alternatively, some groups have reported that mouse LHSC are responsible for both radioprotection and long-term repopulation of all blood cell lineages. A possible explanation for this difference is that cells with the capacity for long-term production of all blood cell lineages are biologically heterogeneous. We now show that 10 LHSC can generate all blood cell lineages for the lifetime of the animal. However, these cells lacked radioprotection and spleen colony-forming activity. LHSC were identified and isolated by their small size, their lack of expression of antigens characteristic of mature blood cell lineages, and their high expression of aldehyde dehydrogenase. In addition, these cells were found to express undetectable or low levels of many antigens presumed to mark LHSC, including Thy-1, Ly-6A/E (Sca-1), c-kit, and CD34. There appears to be at least two classes of LHSC with the capacity for long-term production of all blood cell lineages: one that generates both radioprotection and long-term engraftment and one that produces delayed but durable engraftment. Our data suggest that this latter class may represent a very primitive class of LHSC.

Aldehyde Dehydrogenase↗

PubMed1996

Crystal structure of DMSO reductase: redox-linked changes in molybdopterin coordination.

The molybdoenzyme dimethylsulfoxide (DMSO) reductase contributes to the release of dimethylsulfide, a compound that has been implicated in cloud nucleation and global climate regulation. The crystal structure of DMSO reductase from Rhodobacter sphaeroides reveals a monooxo molybdenum cofactor containing two molybdopterin guanine dinucleotides that asymmetrically coordinate the molybdenum through their dithiolene groups. One of the pterins exhibits different coordination modes to the molybdenum between the oxidized and reduced states, whereas the side chain oxygen of Ser147 coordinates the metal in both states. The change in pterin coordination between the Mo(VI) and Mo(IV) forms suggests a mechanism for substrate binding and reduction by this enzyme. Sequence comparisons of DMSO reductase with a family of bacterial oxotransferases containing molybdopterin guanine dinucleotide indicate a similar polypeptide fold and active site with two molybdopterins within this family.

Amino Acid Sequence↗

PubMed1996

Sensitization to 2,4-dinitrochlorobenzene: influence of vehicle on absorption and lymph node activation.

Effective skin sensitization is dependent upon immune activation of lymph nodes draining the site of exposure. The influence of vehicle formulation on the vigour of lymph node cell proliferative responses to 2,4-dinitrochlorobenzene (DNCB) has been examined. Mice (BALB/c strain) were exposed topically to 0.5% DNCB dissolved in either acetone or propylene glycol (PG). A significantly greater lymph node cell proliferative response was induced by DNCB in acetone. The observed differences were not attributable to variations in the numbers of immunostimulatory dendritic cells accumulating in the draining nodes following sensitization. In parallel studies, the absorption and cutaneous disposition of DNCB dissolved in acetone or PG were measured in vitro using static diffusion cells and full thickness mouse skin. Although flux of DNCB through the skin was comparable with both vehicles over 24 h, the absorption of the allergen during the first 4 h of exposure was significantly faster when acetone was used as the vehicle. Localization of DNCB demonstrated that much less of the chemical allergen was present in the skin at 4 h when applied in PG vehicle. However, there were no measurable vehicle effects on skin disposition of DNCB at 24 h. These data indicate that the sensitization potential of DNCB is influenced significantly by the nature of the vehicle used, possibly due to consequential effects on chemical absorption and disposition. The studies described in this paper reveal that the application vehicle may have a significant influence on the ability of DNCB to induce immune activation of draining lymph nodes and hence skin sensitization and that this may in turn be associated with important changes in the absorption and/or disposition of the chemical within the skin.

Acetone↗

PubMed1996

Further evaluation of the local lymph node assay in the final phase of an international collaborative trial.

The local lymph node assay (LLNA) is a method used for the prospective identification in mice of chemicals that have the potential to cause skin sensitization. We report here the results of the second and final phase of an international trial in which the performance of the assay has been evaluated using seven test materials in five independent laboratories. The additional chemicals examined here included compounds which are considered less potent allergens than some of those tested in the first phase of the investigation, and includes hexylcinnamic aldehyde (HCA), a chemical recommended by the Organization for Economic Cooperation and Development (OECD) as a positive control for skin sensitization studies. In each laboratory all skin sensitizing chemicals examined (2,4-dinitrochlorobenzene {DNCB}, HCA, oxazolone, isoeugenal and eugenol) elicited positive responses of comparable magnitude as judged by the derived lowest concentration of test chemical required to elicit a 3-fold or greater increase in the proliferative activity of draining lymph node cells compared with vehicle-treated controls. We observed that sodium lauryl sulphate, considered to be a non-sensitizing skin irritant, also induced a positive response in the assay. Para-aminobenzoic acid (pABA), a nonsensitizing chemical, was negative at all test concentrations in each laboratory. Some laboratories incorporated minor modifications into the standard assay procedure, including the evaluation of lymph nodes pooled from individual mice rather than treatment groups and the use of statistical analyses. The use of statistics did not markedly change the determination of the lowest concentration yielding a positive response. These data confirm that the local lymph node assay is robust and yields equivalent results when performed independently.

Animals↗

PubMed1996

Graft-versus-myeloma effect: proof of principle.

The presence of a graft-versus-tumor effect has been well established in leukemia but not in multiple myeloma. A 40-year-old patient with myeloma refractory to standard chemotherapy and autologous transplantation received a matched unrelated T-cell-depleted transplant after conditioning with fractionated total-body irradiation, thiotepa, and cyclophosphamide. This procedure resulted in a transient and incomplete response with evidence of rapidly progressive disease within 2.5 months posttransplantation. The patient then received a small number of donor peripheral blood (PB) mononuclear cells (CD3 cells 1.2 x 10(6)/kg) without any further cytotoxic therapy. A complete remission was attained, lasting now for more than 14 months. The procedure was associated with severe acute and subsequently limited chronic graft-versus-host disease (GVHD). This report provides the first direct evidence of a graft-versus-myeloma effect after allogenic transplantation.

Adult↗