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Biomedical subjects

J Morgan

Publications and source records attributed to J Morgan.

At least 91 records · Page 5Linked to original sources
PubMed1999

Imaging of tumour therapy responses by dynamic CT.

The objective of this study was to investigate whether functional CT with Patlak analysis could be used to demonstrate acute changes associated with radiotherapy. Patlak analysis yields fractional vascular volume and contrast clearance per unit volume (a measure of permeability). Four tumour types (prostate, bronchus, breast and cervix) were studied pre-radiotherapy and at 1-2 weeks and 6-12 weeks post-therapy. Significant rises in fractional vascular volume and contrast clearance were shown at 1-2 weeks. These indices were still significantly elevated at 6-12 weeks post-therapy. In the prostates perfusion values were also elevated reflecting a hyperemic response to radiotherapy. Dynamic CT with Patlak analysis can be used to measure important pathophysiological indices which may prove useful in assessing response to therapy of tumours.

Breast Neoplasms↗
PubMed1999

Plant 'hairy root' culture.

Due to their fast growth rates and biochemical stability, 'hairy root' cultures remain unsurpassed as the choice for model root systems and have promise as a bioprocessing system. Applications are wide-ranging, from the production of natural products and foreign proteins to a model for phytoremediation of organic and metal contaminants. Hairy roots will have a continuing role as an experimental model in plant metabolic engineering.

Biodegradation, Environmental↗
PubMed1999

Noninvasive continuous monitoring of cerebral oxygenation periictally using near-infrared spectroscopy: a preliminary report.

PURPOSE: To report on the use of near-infrared spectroscopy (NIRS) to examine the changes in cerebral oxygenation in the periictal period in patients with seizures. METHODS: Cerebral hemoglobin oxygen availability was monitored continuously and noninvasively with NIRS in three patients (one in the pediatric intensive care unit (ICU) and two in epilepsy-monitoring units) in conjunction with continuous EEG monitoring. Ictal events were recorded and compared with the pre-, intra-, and postictal periods for cerebral oxygen availability, as defined by oxygenated hemoglobin (HbO2), deoxygenated hemoglobin (Hb), and the redox state of cytochrome oxidase (cytox). RESULTS: Several important preliminary observations were made by using this technology. First, a preictal increase in cerebral oxygenation began between 1 and 2 h and >10 h before the ictal event. Second, despite adequate perfusion, based on an observed increased HbO2, reduction in cytox indicates a perfusion-metabolism mismatch during seizure activity. Third, continued seizure activity and even isolated ictal events were associated with decreased cerebral oxygen availability. Fourth, differences in cerebral oxygen availability were noted between different types of seizures (e.g., electrographic seizures were accompanied by rapid reductions in HbO2 and cerebral blood volume without reduction of cytox, whereas electroclinical seizures were characterized by marked increases in HbO2 with or without reduction of cytox). CONCLUSIONS: In this preliminary report on the use of NIRS for patients with seizures, we believe that NIRS allows continuous and noninvasive monitoring of changes in cerebral oxygenation periictally, thereby permitting investigations into the pathophysiology of seizures and the exploration of the potential of cerebral oximetry as a tool for seizure localization.

Brain↗
PubMed1999

The meaning and significance of the equilibrium phase in enhanced computed tomography of the liver.

The "equilibrium phase" (EP) in liver contrast enhancement in CT is generally held to be a potential pitfall by way of loss of intrinsic lesion conspicuity. Unfortunately, the definitions extant in the literature are not firmly rooted in a pharmacokinetic basis. Such a basis is developed in this article and a method is described for estimating the time of onset of the EP. It is shown that this may be, effectively, as early as 120 s or so after the beginning of a typical infusion of contrast agent. This means that incremental scanning protocols are likely to result in later slices being acquired in the EP. It is further shown that the pharmacokinetic model does predict a danger of loss of lesion conspicuity in EP scanning. Fortunately, rapid helical/spiral scanning makes it a danger that is easily avoided.

Contrast Media↗
PubMed1999

Deletion of alloantigen-activated cells by aminolevulinic acid-based photodynamic therapy.

Protoporphyrin IX (PpIX), an endogenously synthesized photosensitizer, can transiently accumulate in activated lymphocytes following administration of the heme precursor 5-aminolevulinic acid (ALA). One possible mechanism of this in lymphocyte accumulation is that actively dividing cells use intracellular iron stores for cytochrome and DNA synthesis and thus do not inactivate PpIX, the photoactive precursor of heme, by iron incorporation. This selective accumulation in activated cells should allow targeting by photodynamic therapy (PDT). To determine the effect of this accumulation, we studied PDT effects on the in vitro correlate of transplantation rejection: the one-way mixed lymphocyte reaction (MLR). Selective phototoxicity was determined by photoirradiating ALA-treated, MLR-activated cells and measuring subsequent stimulation either in a secondary MLR or with phytohemagglutinin (PHA). We found that proliferation of MLR-activated lymphocytes incubated with ALA and treated with light was only 12-20% of controls (ALA+, no light) after rechallenge with the stimulator cells (P < 0.05), although their response to nonspecific PHA stimulation was similar to controls. Thus alloantigen-specific depletion was shown. The data suggest a role for ALA-PDT in the treatment of diseases that require the selective elimination of activated lymphocytes and possibly as an immunomodulator.

Aminolevulinic Acid↗
PubMed1999

Subcellular localization patterns and their relationship to photodynamic activity of pyropheophorbide-a derivatives.

To determine if subcellular localization is important to photodynamic therapy (PDT) efficacy, an in vitro fluorescence microscopy study was conducted with a congeneric series of pyropheophorbide-a derivatives in human pharyngeal squamous cell carcinoma (FaDu) cells and murine radiation-induced fibrosarcoma (RIF) mutant cells. In the FaDu cells the octyl, decyl and dodecyl ether derivatives localized to the lysosomes at extracellular concentrations less than needed to produce a 50% cell kill (LD50). At extracellular concentrations equal or greater than the LD50 the compounds localized mainly to mitochondria. The propyl, pentyl, hexyl and heptyl ether derivatives localized mainly to the mitochondria at all concentrations studied. This suggested that mitochondria are a sensitive PDT target for these derivatives. Similar experiments were performed with two Photofrin-PDT resistant RIF cell lines, one of which was found to be resistant to hexyl ether derivative (C6) mediated-PDT and the other sensitive to C6-PDT relative to the parent line. At extracellular concentrations of C6 below the LD50 of each cell line, the mutants exhibited lysosomal localization. At concentrations above these values the patterns shifted to a mainly mitochondrial pattern. In these cell lines mitochondrial localization also correlated with PDT sensitivity. Localization to mitochondria or lysosomes appeared to be affected by the aggregation state of the congeners, all of which are highly aggregated in aqueous medium. Monomers apparently were the active fraction of these compounds because equalizing the extracellular monomer concentrations produced equivalent intracellular concentrations, photoxicity and localization patterns. Compounds that were mainly aggregates localized to the lysosomes where they were rendered less active. Mitochondria appear to be a sensitive target for pyropheophorbide-a-mediated photodamage, and the degree of aggregation seems to be a determinant of the localization site.

Animals↗
PubMed1998

Quantification of metabolites in the indole alkaloid pathways of catharanthus roseus: implications for metabolic engineering

In this article, we present a review of the current state of metabolic engineering in Catharanthus roseus. A significant amount of research has contributed to characterization of several individual steps in the biosynthetic pathway of medicinally valuable alkaloids. However, knowledge of the regulation of these pathways is still sparse. Using hairy root cultures, we studied the responses of alkaloid metabolism to environmental stimulation such as light and elicitation. Through precursor feeding studies, the putative rate-limiting steps of the terpenoid pathway in hairy root cultures also have been examined. Relating this knowledge to specific events at the molecular level, and the cloning of corresponding genes are the next key steps in metabolic engineering of the C. roseus alkaloids. Copyright 1998 John Wiley & Sons, Inc.

Journal Article↗
PubMed1998

"Depression" increases "craving" for sweet rewards in animal and human models of depression and craving.

This study consisted of two experiments, one in rats and one in human volunteers, that used the identical progressive ratio (PR) operant procedure. In both experiments, responding was reinforced under a progressively increasing work requirement, and different groups of subjects received reinforcers that varied in sweetness. In experiment 1, rats were subjected to chronic mild stress, a well-validated animal model of depression. Performance under the PR schedule increased in subjects reinforced with conventional precision pellets (which contain 10% sucrose) or very sweet pellets, but not in subjects reinforced with sugar-free pellets. In experiment 2, volunteers were subjected to a depressive musical mood induction. Performance under the PR schedule increased in subjects reinforced with chocolate buttons, but not in subjects reinforced with with buttons made from the relatively unpalatable chocolate substitute carob. In experiment 2, depressive mood induction also increased chocolate craving, as measured by a novel questionnaire, and there were significant correlations between chocolate craving and chocolate-reinforced PR performance. These results suggest that performance under the PR schedule provides a measure of craving rather than reward, and that craving for sweet rewards is increased by depressive mood induction in both animal and human models. Implications for the interpretation of pharmacological studies using the PR procedure are also discussed.

Adult↗
PubMed1998

Influence of coping style and precolonoscopy information on pain and anxiety of colonoscopy.

BACKGROUND: This study assessed the relationship between patient coping style, precolonoscopy information, and anxiety and pain associated with colonoscopy. METHODS: Eighty consecutive adult patients undergoing initial colonoscopy were classified into two groups on the basis of coping style: information seekers or information avoiders. All were given standardized information about colonoscopy. Half of each group was randomly assigned to receive additional sensory information describing what they could expect to feel. Self-report, physiologic, and behavioral indices of anxiety and pain were measured. RESULTS: Patients given information congruent with coping style experienced significantly less self-report anxiety immediately after the information intervention and spent less time in recovery. In contrast, patients given information not congruent with coping style maintained their pre-intervention anxiety level. Patients given information congruent with coping style scored lower on behavioral indices of pain, but there were no differences with respect to patient perception of pain or the dosage of sedative drugs. Most patients reported that the bowel preparation was the most distressing part of the colonoscopy. CONCLUSIONS: Assessment of coping style and provision of congruent information reduces anxiety, recovery time, and observed behavioral indices of pain of colonoscopy but has no effect on sedation dose or patient perception of pain.

Adaptation, Psychological↗
PubMed1998

Effects of two different fibric acid derivatives on lipoproteins, cholesteryl ester transfer, fibrinogen, plasminogen activator inhibitor and paraoxonase activity in type IIb hyperlipoproteinaemia.

We have investigated the effects of two fibric acid derivatives, bezafibrate mono (400 mg daily) and gemfibrozil (600 mg b.d.), in 29 patients with type IIb hyperlipoproteinaemia. All patients received placebo and each drug for 8 weeks in randomised order in a double-blind, cross-over study designed to evaluate any different effects of the drugs on serum lipoproteins, cholesteryl ester transfer protein (CETP), cholesteryl ester transfer activity (CETA), plasma fibrinogen, plasminogen activator inhibitor-I (PAI-1) or paraoxonase. Serum cholesterol decreased (P < 0.05) with gemfibrozil, but the effect of bezafibrate on serum cholesterol did not achieve statistical significance (placebo 8.34 +/- 1.05 (mean +/- S.D.), gemfibrozil 7.70 +/- 1.23 and bezafibrate 7.8 +/- 1.37 mmol/l). Both drugs decreased the serum triglyceride concentration (both P < 0.001) (placebo 4.39 (3.13-5.75) (median (interquartile range)), bezafibrate 2.26 (1.89-3.89) and gemfibrozil 2.00 (1.30-3.30) mmol/l) and very low density lipoprotein (VLDL) cholesterol (both P < 0.001) (placebo 1.18 (0.74-2.30), bezafibrate 0.59 (0.34-0.85) and gemfibrozil 0.48 (0.34-0.68) mmol/l). Discontinuous gradient ultracentrifugation (DGU) revealed that Sf 60-400 (large VLDL) decreased by more than 50% and Sf 20-60 (small VLDL) by more than 30% with each of the drugs (both P < 0.001), neither of which affected the composition of these lipoproteins. Gemfibrozil decreased the concentration of Sf 12-20 lipoprotein (intermediate density lipoprotein; IDL) by 23% (P < 0.01), whereas the effect of bezafibrate on this lipoprotein did not achieve statistical significance. Neither drug altered the concentration of apolipoprotein B or of total Sf 0-12 lipoproteins (low density lipoprotein, (LDL)). Both, however, significantly increased the quantity of free cholesterol in Sf 0-12 lipoproteins (P < 0.05). Overall the concentration of triglycerides decreased significantly in all lipoproteins isolated by DGU (Sf 0-12, Sf 12-20, Sf 20-60, Sf 60-400) on gemfibrozil treatment, but only in Sf 20-60 and Sf 60-400 on bezafibrate (all P < 0.05). Both drugs also increased serum high density lipoprotein (HDL) cholesterol (placebo 1.15 +/- 0.29, bezafibrate 1.27 +/- 0.38 (P < 0.01) and gemfibrozil 1.26 +/- 0.49 (P < 0.05) mmol/l) and HDL3 cholesterol concentration (placebo 0.59 +/- 0.12, bezafibrate 0.72 +/- 0.23 (P < 0.001) and gemfibrozil 0.70 +/- 0.24 (P < 0.01) mmol/l). Serum apolipoprotein A1 (apo A1) was increased (P < 0.05) by bezafibrate compared to gemfibrozil (placebo 103 +/- 26, bezafibrate 111 +/- 28 and gemfibrozil 102 +/- 25 mg/dl) and CETA from HDL to VLDL and LDL was decreased (P < 0.05) by bezafibrate compared to placebo, but the apparent decrease with gemfibrozil did not achieve statistical significance (placebo 39.6 +/- 17.7, bezafibrate 32.3 +/- 14.7 and gemfibrozil 33.8 +/- 15.0 nmol/ml/h). Neither drug affected the circulating concentration of CETP. Plasma fibrinogen was increased (P < 0.05) by gemfibrozil (placebo 4.16 (3.38-4.71) and gemfibrozil 4.65 (4.05-5.77) g/l) and was significantly lower (P < 0.001) on bezafibrate (3.60 (3.18-4.54) g/l) than on gemfibrozil treatment. There was a significant (P < 0.05) increase in PAI-1 activity with bezafibrate and a similar trend with gemfibrozil (placebo 41.2 (25.6-64.5), bezafibrate 50.5 (35.1-73.9) and gemfibrozil 48.5 (31.5-5.4 U/l). Neither fibrate influenced plasma concentrations of PAI-1 nor were the activities of lecithin:cholesterol acyl transferase or paraoxonase affected. The major difference in the action of the two drugs on lipoprotein metabolism was the greater effect of gemfibrozil in decreasing the overall serum concentration of Sf 12-20 lipoproteins and the triglycerides in Sf 12-20 and 0-12 lipoproteins. Bezafibrate, however, increased serum apo A1 concentration and significantly decreased CETA. The two drugs also had different effects on the plasma fibrinogen levels, which increased with gemfibrozil and tended to decrea

Adult↗
PubMed1998

Mice deficient for 5-lipoxygenase, but not leukocyte-type 12-lipoxygenase, display altered immune responses during infection with Schistosoma mansoni.

Periovular granuloma formation during Schistosoma mansoni infection is a complex, multifaceted immunologic response. Products of arachidonic acid metabolism have been shown to contribute to this response through studies in which general inhibitors of lipoxygenase function reduce granulomatous inflammation. To determine which lipoxygenases are important for granuloma development in schistosomiasis, wild type mice or mice deficient for 5-lipoxygenase (5-LO) or "leukocyte-type" 12-lipoxygenase (12-LO) were infected with S. mansoni and studied for responses to schistosome eggs and egg antigens. At the acute stage of infection, when granuloma formation is usually maximal, 5-LO deficient mice developed smaller granulomas around liver-deposited schistosome eggs compared with wild type or 12-LO deficient mice. 5-LO mice also displayed less antibody-mediated (5 h) and cell-mediated, delayed-type (24 h) hypersensitivity to schistosome egg antigens than did the other two infection groups. In an attempt to determine possible mechanisms for the reduced inflammatory responses, we also measured hepatic mRNA levels of cytokines that have been shown to influence granuloma size (IL-4, IL-10, and IFN-gamma). The mRNA levels for IL-10 were significantly lower in 5-LO-deficient mice, but SEA-stimulated spleen cells did not demonstrate a significant difference in IL-10 production between wild type and 5-LO mice. These data suggest that 5-LO plays a role in host responses to schistosomiasis via a mechanism that cannot be explained solely by changes in expression of these cytokines.

Animals↗
PubMed1998

Antigen specific and nonspecific modulation of the immune response by aminolevulinic acid based photodynamic therapy.

Photosensitizers used normally in treating cancers have considerable potential for treatment of other diseases. One such photosensitizer is the endogenously synthesized photosensitizer protoporphyrin IX (PpIX). To better understand how protoporphyrin might be used in transplantation or in treating autoimmune diseases, information must be obtained on how the photosensitizer affects all immune cells. We used a combination of flow cytometry and in vitro activation assays (recall assays and mixed-lymphocyte reactions) to examine the effects of PpIX on the antigen specific component, lymphocytes and the non-antigen specific component, the macrophages/monocytes and dendritic cells of the immune system. Whereas, lymphocytes accumulate PpIX only when activated, both macrophages and dendritic cells accumulated PpIX immediately, without in vitro activation, as measured by flow cytometry. ALA-PDT (aminolevulenic acid-photodynamic therapy) treated adherent cells in the recall assay had a decreased capability to activate lymphocytes. By increasing the light dose in the recall assay, antigen primed lymphocytes were selectively eliminated from a population of cells. Stimulator cells in an MLR had a decreased stimulatory capacity following ALA-PDT treatment. Functional alterations are seen in both the antigen specific

Aminolevulinic Acid↗
PubMed1998

Ex vivo gene transfer using adenovirus-mediated full-length dystrophin delivery to dystrophic muscles.

Duchenne muscular dystrophy (DMD) is an X-linked recessive muscle disease characterized by a lack of dystrophin expression. Myoblast transplantation and gene therapy have the potential of restoring dystrophin, thus decreasing the muscle weakness associated with this disease. In this study we present data on the myoblast mediated ex vivo gene transfer of full-length dystrophin to mdx (dystrophin deficient) mouse muscle as a model for autologous myoblast transfer. Both isogenic primary mdx myoblasts and an immortalized mdx cell line were transduced with an adenoviral vector that has all viral coding sequences deleted and encodes beta-galactosidase and full-length dystrophin. Subsequently, these transduced myoblasts were injected into dystrophic mdx muscle, where the injected cells restored dystrophin, as well as dystrophin-associated proteins. A greater amount of dystrophin replacement occurred in mdx muscle following transplantation of mdx myoblasts isolated from a transgenic mouse overexpressing dystrophin suggesting that engineering autologous myoblasts to express high amounts of dystrophin might be beneficial. The ex vivo approach possesses attributes that make it useful for gene transfer to skeletal muscle including: (1) creating a reservoir of myoblasts capable of regenerating and restoring dystrophin to dystrophic muscle; and (2) achieving a higher level of gene transfer to dystrophic muscle compared with adenovirus-mediated direct gene delivery. However, as observed in direct gene transfer studies, the ex vivo approach also triggers a cellular immune response which limits the duration of trans-gene expression.

Adenoviridae↗
PubMed1998

Cytokine mRNA levels in the hearts of inbred mice that develop different degrees of cardiomyopathy during infection with Trypanosoma cruzi.

Profiles of cytokine mRNA expression were examined by semiquantitative RT-PCR in the hearts of DBA/2 (pathopermissive) and B10.D2 (pathoresistant) mice during infection with the Brazil strain of Trypanosoma cruzi. The levels and time-course profiles of IFNgamma, IL-1beta and IL-10 mRNA expression were similar in each strain. TNFalpha, iNOs, and IL-13 mRNA expression peaked at comparable levels and times after infection in each strain, but declined more rapidly in B10.D2 than in DBA/2 mice. Peak IL-2 mRNA levels were also similar between the two strains, but occurred earlier in DBA/2 than in B10.D2 mice. Levels of IL-4, IL-6 and IL-12 mRNA were significantly higher in DBA/2 than in B10.D2 mice from day 10 through day 50 of infection. With the exception of IL-1beta, which was expressed constitutively in both strains, the levels of mRNA of all other cytokines examined reached their peak no later than day 20 and declined significantly by day 50 after infection. The inflammatory infiltrate paralleled the latter cytokines; starting at day 10 in DBA/2 mice and at day 15 in the B10.D2 s, peaking between days 20 and 30 in both strains, decreasing to minimal levels by day 50 in the pathoresistant mice, but maintaining a mild amount through day 70 in the pathopermissive strain. The inflammation was composed mostly of lymphocytes and histiocytes throughout the entire process. These data demonstrate differences in the profiles of cytokine mRNA that may be related to the differential degree of cardiac pathology that develops in these two strains of mice upon infection with T. cruzi.

Age Factors↗