Biomedical subjects

J Hilton

Publications and source records attributed to J Hilton.

At least 19 recordsLinked to original sources

PubMed2002

PET imaging of brain acetylcholinesterase using [11C]CP-126,998, a brain selective enzyme inhibitor.

PET and [(11)C]CP-126,998, an N-benzylpiperidinebenzisoxazole, were used to image brain acetylcholinesterase (AChE) distribution in healthy controls before and after administration of 5 mg donepezil p.o., a reversible AChE inhibitor. Logan plots were used to compute distribution volumes (V(T)). The V(T) of [(11)C]CP-126,998 was highest in the basal ganglia and cerebellum and lowest in the cerebral cortex, thalamus, amygdala, and hippocampus. The regional V(T) values correlated well with AChE concentration measured in vitro. Donepezil, given 4 h before PET scanning, induced a substantial inhibition of [(11)C]CP-126,998 binding (43-62%) in all brain regions when compared to the baseline PET study. The results of this study indicate that PET imaging of [(11)C]CP-126,998 may be useful in quantifying the distribution of regional brain AChE. This new PET radiotracer may potentially be employed in the diagnosis and treatment of patients with disorders of cholinergic neurotransmission, such as Alzheimer's disease.

Acetylcholinesterase↗

PubMed2002

Modelling the long-term dynamics of radiocaesium in closed lakes.

During the years after the Chernobyl accident the radioceasium activity concentration in most contaminated aquatic ecosystems decreased markedly. Lakes with no permanent inflows and outflows (closed lakes), however, still present a radioecological problem which is expected to continue for some time. In this paper, a mechanistic model for the long-term prediction of radiocaesium behaviour in closed lakes is developed. The model of Prokhorov (Radiokhimiya (Radiochemistry) 11 (1969) 317) was modified to describe the effects of bottom sediment bioturbation, surface runoff from the catchment and suspended solids formation and sedimentation. The model input parameters are the effective diffusion coefficient in bottom sediments, depth of the completely mixed layer, the distribution coefficient in the sediment-water system, the runoff coefficient, sedimentation rate, and deposition density. Values of all these parameters can be independently estimated or measured in a short-term experiment. Given negligible runoff and sedimentation, the dynamics of radiocaesium in lake water is described by a simple equation with only one unknown parameter. This allows us to make long-term predictions on the basis of a series of measurements carried out during the relatively short period. The model was tested against 137Cs activity concentrations measured between 1993 and 1999 in Svyatoe lake in the Bryansk region of Russia. Calculated and measured activity concentrations are in good agreement.

Cesium Radioisotopes↗

PubMed2001

Generation of dual resistance to 4-hydroperoxycyclophosphamide and methotrexate by retroviral transfer of the human aldehyde dehydrogenase class 1 gene and a mutated dihydrofolate reductase gene.

The genetic transfer of drug resistance to hematopoietic cells is an attractive approach to overcoming myelosuppression caused by high-dose chemotherapy. Because cyclophosphamide (CTX) and methotrexate (MTX) are commonly used non-cross-resistant drugs, generation of dual drug resistance in hematopoietic cells that allows dose intensification may increase anti-tumor effects and circumvent the emergence of drug-resistant tumors. We constructed a retroviral vector containing both a human cytosolic ALDH-1 cDNA and a human doubly mutated DHFR cDNA (Phe22/Ser31; termed F/S in the description of constructs) to generate increased resistance to both CTX and MTX. Infection of NIH3T3 cells resulted in increased resistance to both 4-hydroperoxycyclophosphamide (4HC) (1.9 +/- 0.1-fold) and MTX (73 +/- 2.8-fold). Transduced human CD34(+) enriched hematopoietic progenitor cells were also resistant to both 4HC and MTX by CFU-GM readout. Lethally irradiated mice transplanted with SFG-ALDH-IRES-F/S or mock-transduced bone marrow cells were treated with high-dose pulse CTX or high-dose CTX/MTX. Animals receiving marrow not transduced with ALDH-1 or mutated DHFR cDNA died from CTX or CTX/MTX toxicity, whereas mice transduced with ALDH-1 and mutated DHFR cDNA-containing marrow were able to tolerate the same doses of CTX or CTX/MTX treatment posttransplant. These data taken together indicate that ALDH-1 overexpression and mutant DHFR increased both 4HC and MTX resistance in vitro and in the in vivo mouse model. This construct may be useful for protecting patients from high-dose CTX- and MTX-induced myelosuppression.

3T3 Cells↗

PubMed2001

An Early Permian plant assemblage from the Taiyuan Formation of northern China with compression/impression and permineralized preservation.

A small but diverse fossil flora is described from the Early Permian Taiyuan Formation occurring at the Yangshuling mine in Pingquan district of Hebei Province, northern China. Fossils occur as compression/impressions within mudrocks and fine-grained sandstones and also as carbonate permineralizations within volcaniclastic tuffs. All are fragmentary and contain lycopsids, sphenopsids, ferns and seed plants, and include several new species. In the compression assemblage sphenopsid and pteridosperm foliage accounts for the majority of the fossils recognised with only a few other kinds of plant organs present. In contrast, the permineralized assemblage is dominated by cordaitaleans with a composition similar to that occurring in coal-ball assemblages elsewhere in the Taiyuan Formation. From the taxonomic synthesis presented it is apparent that the Yangshuling permineralized assemblage contains many of the plant taxa diagnostic of the northern realm of the Early Permian Cathaysian flora, and preserves a representative sample of the wetland coal-swamp vegetation of this time. The permineralized assemblage at Yangshuling represents the first example of anatomically preserved plants from volcaniclastic lithologies from the Palaeozoic of China, raising the possibility of similarly preserved plant-fossil assemblages elsewhere in the Cathaysian realm.

Journal Article↗

PubMed2001

A critical review of measures to reduce radioactive doses from drinking water and consumption of freshwater foodstuffs.

Following a radioactive fallout event, there are a number of possible intervention measures to reduce radioactive doses to the public via the surface water pathway. We have critically reviewed the options available to decision-makers in the event of radioactive contamination of surface waters. We believe that the most effective and viable measures to reduce radioactivity in drinking water are those which operate at the water treatment and distribution stage. Intervention measures to reduce concentrations of radioactivity in rivers and reservoirs are expected to be much less viable and efficient at reducing doses via the drinking water pathway. Bans on consumption of freshwater fish can be effective, but there are few viable measures to reduce radioactivity in fish prior to the preparation stage. Lake liming and biomanipulation have been found to be ineffective for radiocaesium, although the addition of potassium to lakewaters appears promising in some situations. Lake liming may be effective in reducing radiostrontium in fish, though this has not, to our knowledge, been tested. De-boning fish contaminated by strontium is probably the most effective food preparation measure, but salting and freezing can also reduce radiocaesium concentrations in fish. The provision of accurate information to the public is highlighted as a key element of countermeasure implementation.

Animals↗

PubMed2001

[125/123I] 5-Iodo-3-pyridyl ethers. syntheses and binding to neuronal nicotinic acetylcholine receptors.

Three 3-pyridyl ether nicotinic ligands-(S)-5-Iodo-3-[(2-pyrrolidinyl)-methoxy]pyridine (5-iodo-A-85865), (S)-5-Iodo-3-[1-(methyl)-2-pyrrolidinyl-methoxy]pyridine (5-Iodo-A-84543), and (S)-5-iodo-3-[1-methyl-(2-azetidinyl)-methoxy]pyridine (5-iodo-N-Me-A-85380) were labeled with I-125/I-123, and their ability to label high-affinity brain nicotinic acetylcholine receptors (nAChRs) was evaluated. The most promising ligand, [123/125I] 5-iodo-A-85865, showed approximately 65% inhibition of radioactivity uptake in thalamus in mice pretreated with cytisine. Preliminary SPECT imaging studies with [123I] 5-iodo-A-85865 revealed a distribution profile consistent with nAChRs (thalamus > frontal cortex > cerebellum) and a more rapid pharmacokinetic profile relative to azetidinyl 3-pyridyl ether based ligands.

Animals↗

PubMed2001

HIV-related oral manifestations among adolescents in a multicenter cohort study.

PURPOSE: To describe baseline prevalence of oral mucosal diseases among HIV infected adolescents in relationship to biological and behavioral risk factors. METHODS: Participants in Reaching for Excellence in Adolescent Care and Health (REACH), a multicenter longitudinal observational study of HIV/AIDS in adolescents, received physical examinations, blood tests, and oral examinations at 3-month intervals. We evaluated participants for oral conditions commonly seen in relationship to HIV, and explored the association of the most common lesion with selected biological and behavioral variables at baseline using contingency tables and Fisher's Exact test. RESULTS: Among 294 HIV infected adolescents recruited between March 1996 and March 1999, the majority were female (75%), aged 17 to 18 years (69%), and African-American (73%). More than 90% had a CD4(+) T-lymphocyte count > 200 cells/mm(3) at baseline and 57% had a plasma HIV-1 RNA concentration <or=5000 copies/mL. The most common condition was oral candidiasis (6%), predominantly the pseudomembranous type. The only variable found to be associated with oral candidiasis was elevated plasma HIV-1 RNA concentration (p = .03). Aside from 2 cases of hairy leukoplakia and aphthous ulcers, no other oral mucosal lesions were identified in this subject population with apparently early HIV disease. CONCLUSION: Similar types of oral lesions were observed in HIV infected adolescents as have been seen in adults, although the prevalence of these lesions was low. Elevated plasma HIV-1 RNA concentration was found to be associated with the baseline prevalence of oral candidiasis, and appeared to be a better predictor of HIV-related oral disease than CD4(+) T cell count in this cohort at early stage of HIV disease.

Adolescent↗

PubMed2000

Determination of radionuclide exchangeability in freshwater systems.

Two freshwater sediments were spiked with 57Co, 85Sr and 134Cs and left for adsorption times ranging from 1 day to over 60 days. Following adsorption, the 'exchangeable' pool of each radionuclide was measured using ammonium acetate extractions and a sequential leach procedure (Tessier et al., 1979), and the results were compared. Exchangeability was found to depend upon the sediment, radionuclide, sorption time and the identity of extracting agent. All three radionuclides showed a shift with increasing adsorption time from regular exchange sites to sites which are sterically hindered, but a fixation within the sediment was only observed for 57Co and 134Cs, with similar ammonium acetate extraction yields for both radionuclides. Misleading results were obtained during the sequential leach procedure due to redistribution and, therefore, the inclusion of a NH4+ leach after the MgCl2 extraction step was suggested. A mathematical model of element speciation was fairly successful at defining the 'exchangeable' fraction, suggesting that the chemically- and mathematically-defined fractions were similar.

Adsorption↗

PubMed2000

Zhutheca Liu, Li et Hilton gen. nov., the fertile pinnules of Fascipteris densata Gu et Zhi and their significance in marattialean evolution.

The morphology of the fertile pinnules of Fascipteris densata Gu et Zhi have been subjected to a detailed morphological investigation based on recently collected specimens from the Upper Permian of Yunnan Province, south China. These investigations have revealed that this species possesses synangia of the Asterotheca-type, situated in two or three rows either side of the midrib on a Fascipteris-type pinnule. This arrangement of Asterotheca-type synangia is extremely unusual considering that all other reports of this genus are with a single row of synangia located on each side of the midrib of a pecopteroid-type pinnule. As a consequence of this unique morphological arrangement, a new genus, Zhutheca densata Liu, Li et Hilton gen. et comb. nov. has been created to distinguish this material from other specimens of the Asterotheca and Fascipteris types. The structure and arrangement of the fertile pinnule of Zhutheca are compared with other Palaeozoic and Mesozoic marattialean taxa with which it shares certain features of its morphology. In addition, the stratigraphic, evolutionary and phylogenetic significance of Zhutheca are considered in detail.

Journal Article↗

PubMed2000

Column-switching HPLC for the analysis of plasma in PET imaging studies.

A column-switch high performance liquid chromatography method for the analysis of 4 mL of plasma is described with six examples of chromatography of [(11)C]-labeled positron-emission tomography imaging agents. Complete extraction of all but the most polar metabolites by the reverse phase capture column is achieved by disruption of plasma protein binding by 8 M urea.

Chromatography, High Pressure Liquid↗

PubMed2000

Thymidine kinase activation of ganciclovir in recurrent malignant gliomas: a gene-marking and neuropathological study.

OBJECT: The gene therapy paradigm of intratumoral activation of ganciclovir (GCV) following transduction of tumor cells by retroviral vectors bearing the thymidine kinase (tk) gene has produced dramatic remissions of malignant gliomas in animal models. In human trials, although the technique has been deemed safe, little antitumor effect has been demonstrated. To evaluate the basis of this inefficacy in human gliomas, the authors conducted a gene-marking trial involving neuropathological and biochemical studies of treated tumor specimens. METHODS: Five patients with malignant recurrent gliomas underwent stereotactic biopsy sampling and intratumoral implantation procedures with three aliquots of 10(6) vector-producing cells (VPCs) in columns. After 5 days, the tumor was resected and the tumor bed reimplanted with VPCs, and a course of GCV was given. Patients received clinical and radiological follow up for 6 months. Tumor specimens were analyzed neuropathologically and for tk gene expression by anti-TK immunohistochemistry and TK enzymatic activity. Four patients tolerated the treatment well but experienced tumor progression. The other developed an abscess after the second operation and died. Increased TK enzymatic activity was demonstrated in the one tumor specimen analyzed. Immunohistochemical evidence of tk gene expression was limited to VPCs. Transduction of tumor cells was not seen. Viable tumor cells were seen near VPCs containing TK. The lymphocytic immune response was mild. CONCLUSIONS: Except for the risk of infection inherent in reoperation, this tk-GCV paradigm was both feasible and safe. Pathological studies indicated that limited dissemination of VPCs and vector from the infusion site and failure to transduce tumor cells with the tk gene are major barriers to efficacy.

Adult↗

PubMed1999

Detection of pyrogenic toxins of Staphylococcus aureus in sudden infant death syndrome.

It has been suggested that pyrogenic toxins of Staphylococcus aureus are involved in the series of events leading to some cases of sudden infant death syndrome (SIDS). The objectives of the study were to screen tissues from SIDS infants for pyrogenic toxins and to compare incidence of identification of these toxins among these infants from different countries. An enzyme-linked immunosorbent assay (ELISA) and a flow cytometry method were used to screen body fluids and frozen or formalin-fixed tissues for pyrogenic toxins of S. aureus, toxic shock syndrome toxin 1 (TSST), staphylococcal enterotoxins A (SEA), B (SEB), and C1 (SEC). Toxins were identified in tissues of 33/62 (53%) SIDS infants from three different countries: Scotland (10/ 19, 56%); France (7/13, 55%); Australia (16/30, 53%). In the Australian series, toxins were identified in only 3/19 (16%) non-SIDS deaths (chi2 = 5.42, P < 0.02). The flow cytometry method was useful for toxin detection in both frozen and fixed tissues, but ELISA was suitable only for frozen tissues or those fixed for less than 12 months. Identification of pyrogenic toxins in > 50% of SIDS infants from three different countries indicated further investigation into the role the toxins play in cot deaths might result in development of additional measures to reduce further the incidence of these infant deaths.

Bacterial Toxins↗

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↗

PubMed1999

Distribution of the parathyroid hormone 2 receptor in rat: immunolocalization reveals expression by several endocrine cells.

The PTH2 receptor is a G protein-coupled receptor selectively activated by PTH. We are studying the receptors distribution to guide the investigation of its physiological function. We have now generated an antibody from a C-terminal peptide sequence of the PTH2 receptor and used this to study its cellular distribution. Labeling with the antibody identified a number of endocrine cells expressing the PTH2 receptor, including thyroid parafollicular cells, pancreatic islet D cells, and some gastrointestinal peptide synthesizing cells. There was complete overlap of PTH2 receptor labeling with somatostatin in pancreatic islets, and partial overlap with somatostatin in thyroid parafollicular cells and in the gastrointestinal tract. Furthermore, observations made previously by in situ hybridization histochemistry, including expression throughout the cardiovascular system, as well as by discrete populations of cells within the gastrointestinal tract and reproductive system were confirmed. These data suggest a broad role for the PTH2 receptor, especially within the endocrine system, and provide a basis for experimental exploration of its physiology.

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↗