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Biomedical subjects

A Gorman

Publications and source records attributed to A Gorman.

At least 19 recordsLinked to original sources
PubMed2005

A potent nonporphyrin class of photodynamic therapeutic agent: cellular localisation, cytotoxic potential and influence of hypoxia.

We have developed a totally new class of nonporphyrin photodynamic therapeutic agents with a specific focus on two lead candidates azadipyrromethene (ADPM)01 and ADPM06. Confocal laser scanning microscopy imaging showed that these compounds are exclusively localised to the cytosolic compartment, with specific accumulation in the endoplasmic reticulum and to a lesser extent in the mitochondria. Light-induced toxicity assays, carried out over a broad range of human tumour cell lines, displayed EC50 values in the micro-molar range for ADPM01 and nano-molar range for ADPM06, with no discernable activity bias for a specific cell type. Strikingly, the more active agent, ADPM06, even retained significant activity under hypoxic conditions. Both photosensitisers showed low to nondeterminable dark toxicity. Flow cytometric analysis revealed that ADPM01 and ADPM06 were highly effective at inducing apoptosis as a mode of cell death. The photophysical and biological characteristics of these PDT agents suggest that they have potential for the development of new anticancer therapeutics.

Apoptosis↗
PubMed2002

The contribution of transfusion to HCV infection in England.

The English HCV lookback programme has identified some individuals with transfusion-transmitted HCV infection. The path from the collection of donations from HCV-infected donors to the identification of infected recipients was constructed. The probability of different outcomes at each branch was derived from data collected during this programme. This path of probabilities was then used to produce a complete estimate of the number of recipients infected by blood transfusions (dead and alive at the end of 1995) by re-entry of blood components that fell out of the lookback at various steps prior to recipient testing, and entry of components from HCV-infected donations that were never identified for lookback. Less than 14,000 recipients were estimated to have been infected with HCV during the decade prior to the start of donation testing. Over 60% of these were expected to have died by the end of 1995. Transfusion has infected a large group of individuals. However, this group constitutes a very small, and declining, proportion of all HCV infections in the population.

Blood Transfusion↗
PubMed1997

Role of peroxide and superoxide anion during tumour cell apoptosis.

Apoptosis or programmed cell death was induced in the human promyelocytic leukemia cell line HL-60 by UV irradiation or treatment with cytotoxic drugs (etoposide, camptothecin, melphalan or chlorambucil). These treatments caused a rapid increase in intracellular peroxide levels. Preincubation of HL-60 cells with the hydrogen peroxide-scavenging enzyme catalase (500 U/ml) inhibited apoptosis due to UV irradiation or low concentrations of camptothecin, etoposide or melphalan, but did not protect against higher concentrations. In contrast, superoxide anion levels in the cells remained unchanged upon treatment with cytotoxic drugs, while UV irradiation led to a transient doubling in superoxide levels. Exogenous superoxide dismutase (400 U/ml) provided modest protection against UV irradiation and had no effect on cytotoxic drug-induced apoptosis. The results suggest that both hydrogen peroxide and superoxide anion may be involved in the induction of apoptosis by UV irradiation. On the other hand, while exposure to cytotoxic drugs induces a large increase in intracellular peroxide levels, catalase is able to protect the cells from apoptosis only when low concentrations of these compounds are used, thus indicating the involvement of other factors in this process, particularly at higher drug concentrations.

Anions↗
PubMed1994

L-trans-pyrrolidine-2,4-dicarboxylate and cis-1-aminocyclobutane-1,3-dicarboxylate behave as transportable, competitive inhibitors of the high-affinity glutamate transporters.

The ability of two conformationally restricted analogues of L-glutamate to function as non-transportable inhibitors of plasma membrane L-glutamate transport was investigated in primary cultures of cerebellar granule cells and cortical astrocytes. L-trans-Pyrrolidine-2,4-dicarboxylic acid (L-trans-PDC) and cis-1-aminocyclobutane-1,3-dicarboxylic acid (cis-ACBD) behaved as linear competitive inhibitors of the uptake of D-[3H]aspartate (used as a non-metabolizable analogue of L-glutamate) exhibiting Ki values between 40 and 145 microM; L-trans-PDC being the more potent inhibitor in each preparation. However, both L-trans-PDC and cis-ACBD, over a concentration range of 1 microM-5 mM, dose-dependently stimulated the release of exogenously supplied D-[3H]aspartate from granule cells maintained in a continuous superfusion system. The stimulated release was independent of extracellular calcium ions; essentially superimposable dose-response profiles being obtained in the absence and presence of 1.3 mM CaCl2 and yielding EC50 values of 16-25 microM and 180-220 microM for L-trans-PDC and cis-ACBD, respectively. Stimulated release of D-[3H]aspartate was unaffected by either 300 microM D-(-)-2-amino-5-phosphonopentanoic acid [D-APV; a selective antagonist of the N-methyl-D-aspartate (NMDA) receptor] or by 25 microM 6-cyano-7-nitroquinoxaline-2,3-dione [CNQX; a selective antagonist of the alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptor]. The release of D-[3H]-aspartate following stimulation by either L-trans-PDC or cis-ACBD was however markedly attenuated following substitution in the superfusion medium of sodium ions by choline ions. Taken together, these results support an action of L-trans-PDC and cis-ACBD consistent with that of being competitive substrates rather than non-transportable blockers of the plasma membrane L-glutamate uptake system.

Amino Acid Transport System X-AG↗
PubMed1994

Sulphur-containing excitatory amino acid-stimulated inositol phosphate formation in primary cultures of cerebellar granule cells is mediated predominantly by N-methyl-D-aspartate receptors.

The stimulatory effect of excitatory sulphur-containing amino acids on inositol phosphate formation was investigated in primary cultures of cerebellar granule cells. L-Cysteine sulphinate (CSA), L-cysteate (CA), L-homocysteine sulphinate (HCSA), L-homocysteate (HCA) and S-sulpho-L-cysteine (SSC) dose-dependently stimulated the formation of [3H]inositol phosphates exhibiting EC50 values in the range 60-200 microM and maximal effects of six- to 17-fold that of basal [3H]inositol phosphate levels. Endogenous L-glutamate spontaneously released into the extracellular medium or following exposure of cells to HCSA, HCA or SSC did not contribute significantly to formation of [3H]inositol phosphates, whereas 10% of the total [3H]inositol phosphates accumulated following exposure to CSA and CA was due to released L-glutamate. The selective N-methyl-D-aspartate receptor antagonist, D,L-2-amino-5-phosphonopentanoic acid (APV, 500 microM) attenuated by 20% (HCSA) to between 80 and 100% (CSA, CA, SSC, HCA) the formation of [3H]inositol phosphates induced by 1 mM sulphur-containing amino acids. When, however, HCSA was used at 100 microM (a concentration near to its EC50 for phosphoinositide hydrolysis), APV inhibited induced responses by 70%. Sulphur-containing amino acid-stimulated [3H]inositol phosphate formation was unaffected by the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX, 10 microM). Inhibition of sulphur-containing amino acid-stimulated [3H]inositol phosphate formation by co-administration of APV and CNQX was similar to that obtained in the presence of APV alone. CSA-, CA-, SSC- and HCA-stimulated [3H]inositol phosphate formation was markedly reduced by removal of Ca2+ from the extracellular medium whereas that stimulated by HCSA was less affected. A similar inhibitory profile was observed when the levels of sulphur-containing amino acid-induced increases in intracellular free calcium ([Ca2+]i) were measured in the presence of 500 microM APV; 1 mM HCSA-induced responses being inhibited by only 30% whereas responses to the remaining sulphur-containing amino acid (also at 1 mM) were inhibited by > 45%. When the sulphur-containing amino acids were used at concentrations approximating their EC50 values for phosphoinositide hydrolysis, APV inhibited the induced increases in [Ca2+]i by 70-100%. HCA and SSC co-administered with the less efficacious but selective metabotropic glutamate receptor agonist, (+-)-1-aminocyclopentane-trans-1,3-dicarboxylic acid (trans-ACPD) at maximally effective concentrations (1 mM) of each agonist stimulated [3H]inositol phosphate formation in an additive manner.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1990

Identifying priorities of psychosocial need in cancer patients.

Inconsistent findings on the efficacy of psychosocial interventions in cancer may be due to their lack of specificity. The aim of this study was to identify priorities of psychosocial need among cancer patients currently receiving treatment in Western Sydney (NSW) as a prelude to targeted intervention. A sample of 188 patients (129 female, median age 52 years, median time since diagnosis 12 months), with various solid tumours, completed a self-report ranking questionnaire listing eight major areas of psychosocial need based on a literature search of relevant studies. The resulting ranking of priorities was: family (1), dealing with emotional stress (2), getting information (3), money (4), work (5), social life (6), sex life (7), and dealing with hospital staff (8). These priorities were independent of demographic characteristics, including time since diagnosis, suggesting that support in the areas of major need may be just as important during follow-up as it is at diagnosis. Males reported less distress than females, and patients with cancer of the head/neck or breast reported most distress. To be maximally effective, psychosocial intervention for cancer patients should focus on the principal areas of family interaction, effective stress management, and access to information.

Adult↗
PubMed1988

Effects of aging and alcohol on the biochemical composition of histologically normal human brain.

Human brains were removed at autopsy and examined grossly and histologically for any abnormality or evidence of disease. Sixty-two brains appearing normal by these criteria were examined further. First, a detailed record of alcohol consumption was obtained. Second, frozen punches of gray and white matter were used to determine the compositional change associated with age and drinking patterns. Increased age was associated with an increase in the water content, particularly in the white matter, a decline in RNA content in gray matter, a decline in total protein in white matter, and a decline in both myelin and the myelin-like subfraction. The loss of myelin membrane in white matter corresponded to a similar increase in water content, although there was an additional loss of some nonmyelin protein. There was no significant shift in the density between the myelin and the myelin-like membranes, and the protein composition of myelin was not significantly altered by age. A history of heavy alcohol consumption was associated with a relative increase in total protein in white matter even though heavy drinking accelerated the age-related loss of myelin. Presumably, alcohol produced a lag in the rate at which nonmyelin proteins are lost or accelerated the accumulation of abnormal protein. Alcohol consumption did not influence the myelin composition or the ratio of myelin and myelin-like membranes. The interval between patient death and autopsy was shown to have little or no effect on the samples used in this study. These data show that normal aging, uncomplicated by other disease processes, can have a significant effect on the composition of brain tissue, particularly the white matter, and that heavy alcohol consumption accelerates degenerative change, even in tissue appearing normal by histology.

Aged↗
PubMed1986

Peroxidative aggregation of myelin membrane proteins.

The exposure of CNS myelin to reactive oxygen species (ROS) generated by a Cu2+-H2O2 system results in the aggregation of membrane proteins. Integral and peripheral membrane proteins are equally vulnerable and the denaturation is not mediated by the SH groups. The aggregated proteins retain their original antigenicity as determined by immunoblot technique. The aggregation of proteins is not limited to myelin and can be elicited in the preparation of other cerebral membranes. The effect of ROS on membrane proteins can also be demonstrated in cerebral slices incubated in the presence of the ROS-generating system. Furthermore, the peroxidation inactivates membrane-bound enzymes as exemplified by myelin cyclic nucleotide phosphatase (CNP). Competitive inhibition studies with various scavengers and quenchers of ROS implicate singlet oxygen as a major mediator in the Cu2+-H2O2 oxidizing system responsible for the peroxidative aggregation of membrane proteins.

Animals↗
PubMed1982

Binding of serum ferritin to concanavalin A in patients with iron overload and with chronic liver disease.

Total serum ferritin and the proportion of serum ferritin binding to concanavalin A (glycosylated ferritin) was measured in 18 healthy volunteers and in 84 patients, eight with primary haemochromatosis, 43 with beta-thalassaemia major and secondary iron overload and 33 with chronic liver diseases without iron overload. The total serum ferritin was either equally or even more closely related than either the non-binding or the concanavalin A binding ferritin, to the liver iron concentration in all patients with iron overload, and with the units of blood transfused in non-chelated thalassaemic patients. The total serum ferritin showed a significant correlation with serum aminotransferase for the group of 84 patients. In the thalassaemic patients the ferritin binding to concanavalin A also correlated with aminotransferase. However, in the other groups it was the ferritin not binding to concanavalin A which showed a significant correlation with aminotransferase activity. These results suggest that measuring the fraction of serum ferritin which binds to concanavalin A does not offer any advantage over estimation of the total serum ferritin concentration in the assessment of iron stores in patients wit iron overload and liver damage.

Binding Sites↗
PubMed1982

Effect of ascorbic acid deficiency on serum ferritin concentration in patients with beta-thalassaemia major and iron overload.

The incidence of ascorbic acid (AA) deficiency and its effect on serum ferritin concentration relative to body iron stores was studied in 61 unchelated patients with beta-thalassaemia major. Thirty-nine (64%) of patients had subnormal leucocyte ascorbate concentrations without clinical evidence of scurvy. The lowest leucocyte ascorbate concentrations tended to occur in the most transfused patients. No correlation was found between the units transfused and serum ferritin concentration in the AA-deficient patients but a close correlation (r = +0.82; p less than 0.005) existed for the AA-replete group. Similarly a close correlation (r = +0.77; p less than 0.005) was obtained between liver iron concentration and serum ferritin in AA-replete patients but only a weak correlation (r = +0.385; p less than 0.025) existed for the AA-deficient group. When AA-deficient patients were treated with ascorbic acid, serum iron and percentage saturation of iron binding capacity rose significantly; serum ferritin rose in 13 of 21 patients despite the simultaneous commencement of desferrioxamine therapy. In contrast all three measurements tended to fall in AA-replete patients with ascorbic acid and desferrioxamine therapy. Thus, AA deficiency is commonly present in beta-thalassaemia patients with iron overload and may give rise to inappropriate serum ferritin concentrations in relation to body iron stores.

Adolescent↗
PubMed1980

Thalassaemia.

Explore the source record for details and available documents.

Fetal Hemoglobin↗
PubMed1980

Mechanical haemolytic anaemia after valve repair operations for non-rheumatic mitral regurgitation.

Two cases are described in which severe mechanical haemolytic anaemia developed shortly after operation for repair of non-rheumatic mitral regurgitation. One patient had a "floppy" valve and the other cleft mitral leaflets, and both had chordal rupture. In both there was residual regurgitation after repair though in one this was initially only trivial. Clinically manifest haemolysis ceased after replacement of the valve by a frame-mounted xenograft. There are two previously reported cases in which haemolytic anaemia followed an unsuccessful mitral valve repair operation. Subclinical haemolysis or mild haemolytic anaemia may occur with unoperated valve lesions, but hitherto frank haemolytic anaemia has been observed only when turbulent blood flow is associated with the presence of a prosthetic valve or patch of prosthetic fabric. In these four cases, however, polyester or Teflon sutures were the only foreign material, and it is suggested that when these are used for the repair of leaflets, particularly in non-rheumatic mitral valve disease, they may increase the damaging effect of turbulence on circulating red blood cells.

Aged↗
PubMed1979

Improvement in iron status and liver function in patients with transfusional iron overload with long-term subcutaneous desferrioxamine.

Subcutaneous desferrioxamine (2--4 g over 12 h) was administered 6 nights each week to 34 patients with transfusional iron overloads who continued to receive regular blood-transfusions. All 34 patients showed a fall in serum-ferritin after 5 to 12 months. In some patients serum-ferritin fell almost to normal. Liver function improved in all the patients, serum-aspartate-transaminase levels fell in all 17 patients tested, and liver-iron fell in 5 of 6 patients tested. These studies show that body-iron stores can be substantially reduced, to normal or near normal levels, by long-term subcutaneous desferrioxamine in patients with transfusional iron overload despite the need for continued blood-transfusion. They also show that removal of iron is accompanied by improved organ function.

Adolescent↗