Search PubMed⌕ Search

Biomedical subjects

A Harris

Publications and source records attributed to A Harris.

At least 127 records · Page 7Linked to original sources
PubMed2000

Androgen-induced growth inhibition of androgen receptor expressing androgen-independent prostate cancer cells is mediated by increased levels of neutral endopeptidase.

Androgen-mediated growth repression of androgen-independent prostate cancer (AIPC) cells has been reported in androgen-independent PC-3 cells overexpressing the androgen receptor, and in androgen-independent derivatives of LNCaP cells that develop following prolonged culture in androgen-free media. Using two models of AIPC, PC3/AR cells and LNCaP-OM1 cells, a subclone of LNCaP cells derived by prolonged culturing in charcoal-stripped media, we investigated whether expression of neutral endopeptidase 24.11 (NEP), a cell-surface peptidase that cleaves and inactivates neuropeptides implicated in the growth of AIPC, is induced by androgen, and whether NEP contributes to the observed androgen-mediated growth repression. These cell lines each express high levels of androgen receptor. Culturing in dihyrotestosterone (DHT) resulted in a 30-56% (PC3) and 35-43% (LNCaP-OM1) decrease in cell number over 7 days concomitant with a significant increase in NEP enzyme specific activity. Northern analysis detected an increase in NEP transcripts following DHT treatment in PC3/AR cells. The addition of the NEP enzyme inhibitor phosphoramidon to PC3 and LNCaP-OM1 or the NEP competitive inhibitor CGS 24592 to LNCaP-OM1 blocked the increase in NEP enzyme activity and reversed the DHT-induced growth inhibition. Neither phosphoramidon or CGS 24592 alone inhibited cell growth. Furthermore, the reversal of growth inhibition in LNCaPOM1 cells was dose dependent on the concentration of CGS 24592. These data indicate that androgen-induced growth repression of AIPC cells PC3 and LNCaP-OM1 results in part from androgen-induced expression of NEP in these cells.

Androgens↗
PubMed1999

3-O-Desacyl monophosphoryl lipid A derivatives: synthesis and immunostimulant activities.

The synthesis of a series of novel analogues of lipid A, the active principle of lipopolysaccharide, is reported. In these compounds, the 1-O-phosphono and (R)-3-hydroxytetradecanoyl moieties of native Salmonella minnesota R595 lipid A have been replaced with hydrogen and the length of the normal fatty acyl residues has been systematically varied. Normal fatty acid chain length in the 3-O-desacyl monophosphoryl lipid A (MLA) series is shown to be a critical determinant of iNOS gene expression in activated mouse macrophages and the induction of proinflammatory cytokines in human peripheral monocytes. Examination of pyrogenicity in rabbits and lethal toxicity in D-galactosamine-treated mice shows that toxic effects in the MLA series can be ameliorated by modifying fatty acid chain length. When used as an adjuvant for tetanus toxoid vaccines, certain MLA derivatives enhance the production of tetanus toxoid-specific antibodies in mice.

Adjuvants, Immunologic↗
PubMed1999

Chloride-bicarbonate exchangers in the human fetal pancreas.

Cystic fibrosis (CF) is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene that encodes a small conductance cAMP-activated chloride ion channel. In the CF pancreatic duct, mutations in CFTR cause a reduction in bicarbonate secretion. This is thought to result from CFTR operating in parallel with a chloride-bicarbonate (Cl(-)/HCO(-)(3)) exchanger, located in the apical membrane of pancreatic duct cells. The molecular basis of this Cl(-)/HCO(-)(3) exchanger has not been identified. A combination of screening cDNA libraries, RNase protection, and 5' RACE analysis was used to identify Cl(-)/HCO(-)(3) exchangers in human fetal pancreas. An AE2 Cl(-)/HCO(-)(3) exchanger was shown to be expressed in human fetal pancreas from the midtrimester of gestation, at a time when CF-associated pathology commences. In addition, an AE1 Cl(-)/HCO(3) was identified in fetal pancreas but was absent from the adult pancreas and cultured ductal epithelial cells from fetal and adult pancreas.

Adult↗
PubMed1999

The protein kinase C inhibitor CGP41251 suppresses cytokine release and extracellular signal-regulated kinase 2 expression in cancer patients.

Components of cell signaling pathways provide important targets for anticancer drugs. Protein kinase C (PKC) is a serine/threonine-specific kinase that regulates cell growth and differentiation. It is also implicated in tumor promotion. The staurosporine analogue CGP41251 is a PKC inhibitor, and it is currently in a Phase I clinical trial for treatment of advanced cancer. However, it is difficult to define its biological activity. We have used two approaches to measure the in vivo biological response to CGP41251: (a) sequential whole blood samples were taken from 27 patients before and during treatment and incubated with mitogen (PHA), and cytokine [tumor necrosis factor (TNF)-alpha and interleukin (IL)-6] release was measured ex vivo; and (b) peripheral blood lymphocytes were isolated from seven of these patients, and the levels of extracellular signal-regulated kinase 2 were measured by Western blotting. Response to PHA was significantly lowered during treatment (P < 0.001 for TNF-alpha production; P < 0.03 for IL-6). This was most evident at 7 and 28 days after the start of treatment in patients receiving higher doses (150-300 mg/day; P = 0.002 and P = 0.02, respectively, for TNF-alpha and P = 0.001 and P = 0.003, respectively, for IL-6 release). Whole blood cytokine production returned to pretreatment levels after drug administration ceased. The levels of extracellular signal-regulated kinase 2 were reduced by 50-97% during treatment in all seven patients tested. These results show for the first time that a PKC inhibitor can block in vivo signaling pathways in cancer patients. The assays we describe complement toxicity studies in selecting relevant doses for Phase II trial of novel agents, particularly when biological activity occurs at doses below those that cause obvious side effects.

Adult↗
PubMed1999

Analysis of DNase-I-hypersensitive sites at the 3' end of the cystic fibrosis transmembrane conductance regulator gene (CFTR).

The cystic fibrosis transmembrane conductance regulator gene (CFTR) exhibits a complex pattern of expression that shows temporal and spatial regulation, although the control mechanisms are not fully known. We have mapped DNase-I-hypersensitive sites (DHSs) flanking the CFTR gene with the aim of identifying potential regulatory elements. We previously characterized DHSs at -79.5 and -20.9 kb with respect to the CFTR translational start site and a regulatory element in the first intron of the gene at 185+10 kb. We have now mapped five DHSs lying 3' to the CFTR gene at 4574+5.4, +6.8, +7.0, +7.4 and +15.6 kb that show some degree of tissue specificity. The DHSs are seen in chromatin extracted from human primary epithelial cells and cell lines; the presence of the +15.6 kb site is tissue-specific in transgenic mice carrying a human CFTR yeast artificial chromosome. Further analysis of the 4574+15.6 kb DHS implicates the involvement of CCAAT-enhancer-binding protein (C/EBP), cAMP-response-element-binding protein (CREB)/activating transcription factor (ATF) and activator protein 1 (AP-1) family transcription factors at this regulatory element.

Animals↗
PubMed1999

The duct cell in cystic fibrosis.

The pancreatic duct cell is central to the etiology of cystic fibrosis (CF) and is the site where pathology commences in utero. We have evaluated expression of the cystic fibrosis transmembrane conductance regulator gene (CFTR) through human development and shown it to be expressed from the early mid-trimester, with highest levels in the most distal portion of the developing duct system and in centroacinar cells. The precise cause of pancreatic destruction in CF is thought to be the obstruction of pancreatic ducts with inspissated secretions. We have shown that the MUC6 mucin is a significant component of the material that obstructs the ducts and that the MUC6 gene shows a very similar pattern of expression to that of CFTR in the developing pancreas. These observations provide a starting point for investigating how mutations in CFTR lead to obstruction of the pancreatic ducts in CF.

Cystic Fibrosis↗
PubMed1999

The fusiform face area is selective for faces not animals.

To test whether the human fusiform face area (FFA) responds not only to faces but to anything human or animate, we used fMRI to measure the response of the FFA to six new stimulus categories. The strongest responses were to stimuli containing faces: human faces (2.0% signal increase from fixation baseline) and human heads (1.7%), with weaker but still strong responses to whole humans (1.5%) and animal heads (1.3%). Responses to whole animals (1.0%) and human bodies without heads (1.0%) were significantly stronger than responses to inanimate objects (0.7%), but responses to animal bodies without heads (0.8%) were not. These results demonstrate that the FFA is selective for faces, not for animals.

Adult↗
PubMed1999

Electrodermal activity in schizophrenia: a quantitative study using a short interstimulus paradigm.

BACKGROUND: Electrodermal activity in response to short interstimulus interval (ISI) stimulation allows aspects of information processing to be examined, but such paradigms cause skin conductance responses (SCRs) to overlap. A signal decomposition method was developed and employed to score the overlapped SCRs. This is the first application of the method to the study of schizophrenia. METHODS: Electrodermal activity of 30 medicated patients with schizophrenia and 50 normal controls was obtained using a conventional auditory oddball paradigm with an ISI of 1.3 sec. Tonic skin conductance level (SCL), phasic SCRs, SCR temporal dynamics, and a range of SCR variables in response to target tones were examined. RESULTS: The schizophrenic group showed reduced response rate, proportion of responders, SCR amplitude, rise time, peak latency, and steady-state response amplitude, over the trial compared with controls. There were no between-group differences in SCL or SCR onset time. CONCLUSIONS: The combined use of a conventional short ISI paradigm and the new SCR scoring method demonstrated new facets of electrodermal hyporeactivity in medicated patients with schizophrenia. The hyporeactivity could not be attributed to changes in tonic arousal or dysfunctions in peripheral sympathetic nerve conductance.

Acoustic Stimulation↗
PubMed1999

[Retinal hemodynamics in patients with normal pressure glaucoma. Quantification with digital laser scanning fluorescein angiography].

UNLABELLED: Chronic ischemia of the retina and the optic nerve head seems of importance especially in patients with normal-tension glaucoma (NTG). The purpose of this study was to examine the retinal hemodynamics in patients with NTG. PATIENTS: Twenty-five patients with NTG were examined (3 weeks washout period) in this study (age 58 +/- 16 years). The arteriovenous passage (AVP) time and arterial and venous diameters from scanning laser fluorescein angiograms were evaluated by means of digital image analysis. RESULTS: The AVP time in patients with NTG (2.78 +/- 1.1 s) was significantly prolonged (P < 0.0001) compared with healthy subjects (1.58 +/- 0.4 s). No significant correlation was found between arterial and venous diameters, intraocular pressure, blood pressure or calculated perfusion pressure and retinal arteriovenous passage time. CONCLUSION: Patients with NTG showed prolonged retinal passage, which could cause chronic hypoxia. This prolongation of circulation is not correlated with any of the clinical parameters. Thus, a circulatory defect might be a primary factor in the pathogenesis of NTG.

Angiography, Digital Subtraction↗
PubMed1999

Comprehensive assessment of retinal, choroidal and retrobulbar haemodynamics during blood gas perturbation.

BACKGROUND: A study was performed to evaluate the effect of isoxic hypercapnia on ocular haemodynamics using colour Doppler imaging (CDI), scanning laser Doppler flowmetry (SLDF) and ocular blood flow (OBF) tonography. METHODS: Measurements were taken for one eye of each of 14 healthy subjects (mean age 27 +/- 6 years) during breathing of room air and then during isoxic hypercapnia (breathing CO2 and room air). Using CDI, blood flow velocities and resistance indices were determined for the ophthalmic artery (OA), central retinal artery (CRA) and short posterior ciliary arteries (SPCAs). Using SLDF a 10 x 10 pixel frame was used to measure blood flow, volume and velocity in each quadrant of the peripapillary retina. Pulsatile ocular blood flow (POBF) was measured using the OBF tonograph. RESULTS: Using CDI, peak systolic and end diastolic velocities increased and resistance index decreased significantly in the SPCAs during hypercapnia. Using SLDF, blood flow, volume and velocity increased significantly during hypercapnia in the superior temporal quadrant of the peripapillary retina. No significant difference was observed between baseline and hypercapnia for POBF. CONCLUSIONS: Isoxic hypercapnia resulted in an increase in peripapillary retinal and SPCA blood flow parameters as determined by SLDF and CDI respectively. This implies the presence of autoregulatory activity in these vasculatures. These findings may be of significance in the pathogenesis of ocular disease such as glaucoma where autoregulation is thought to be compromised.

Adolescent↗
PubMed1999

Color Doppler imaging discloses reduced ocular blood flow velocities in nonexudative age-related macular degeneration.

PURPOSE: To study ocular perfusion defects in age-related macular degeneration. METHODS: Twenty-five subjects with nonexudative age-related macular degeneration were compared with 25 age-matched control subjects in studies of flow velocities in several retrobulbar vessels. Color Doppler imaging, which was performed by an examiner who was masked to the subjects' assignment to the control or age-related macular degeneration group, measured peak systolic and end diastolic velocity in the ophthalmic, central retinal, and nasal and temporal posterior ciliary arteries of one eye. A resistive index was calculated from the peak systolic and end diastolic velocity. RESULTS: Subjects with nonexudative age-related macular degeneration showed a consistent trend toward lower peak systolic and end-diastolic velocities in the posterior ciliary arteries. For example, in the nasal posterior ciliary artery, the mean end diastolic velocity measured 1.45 +/- 0.34 cm per sec in the age-related macular degeneration group compared with 1.96 +/- 0.66 cm per sec in the control group, yielding a 26% decrease in the age-related macular degeneration group, which represented the largest difference and was highly statistically significant (P = .0012). The resistive index was not significantly altered in the nasal or temporal posterior ciliary artery. Subjects with nonexudative age-related macular degeneration did not differ from control subjects in peak systolic velocity, end diastolic velocity, or resistive index in the ophthalmic artery. In the central retinal artery, the end diastolic velocity was lower (1.37 +/- 1.95 cm per sec vs 1.95 +/- 0.66 cm per sec), whereas the resistive index was higher (0.83 +/- 0.05 vs 0.76 +/- 0.06 cm per sec), in the age-related macular degeneration group; these results were highly statistically significant (P = .0007 and P < .0001, respectively). CONCLUSIONS: Retrobulbar vascular changes in nonexudative age-related macular degeneration subjects include reduced flow velocities in the nasal and temporal posterior ciliary arteries. The reduced peak systolic velocity, combined with the reduced end diastolic velocity at a constant resistive index, seen in nonexudative age-related macular degeneration, is consistent with reduced bulk flow in these vessels, suggesting that choroidal perfusion is abnormal in this form of age-related macular degeneration. The changes in the central retinal artery suggest there may be a more generalized perfusion abnormality beyond the choroid in patients with age-related macular degeneration or that the central retinal artery exhibits a secondary autoregulatory response to a primary change elsewhere.

Aged↗
PubMed1999

Vascular aspects in the pathophysiology of glaucomatous optic neuropathy.

Glaucoma remains a major eye illness with unknown etiology. Although elevated intraocular pressure is clearly a major risk factor, vascular deficits may contribute to initiation and progression of glaucoma. When intraocular pressure is acutely elevated in healthy individuals, the resistance index (derived from the peak systolic and end-diastolic velocities and an indirect index of vascular resistance distal to the site of measurement) in the central retinal and posterior ciliary arteries increases progressively. This result implies that mechanical and vascular factors may be coupled in such a way that perfusion of the retina and optic nerve head may be influenced by changes in the intraocular pressure. Further, at night, when ophthalmic artery flow velocities fall as arterial blood pressure falls in glaucoma patients, the risk of disease progression may be increased. The constancy of these same flow velocities in age-matched healthy individuals points to a possible vascular autoregulatory defect in glaucoma. In addition, in normal-tension glaucoma, vasodilation (CO2 inhalation) normalizes retrobulbar arterial flow velocities, hinting that some vascular deficits in glaucoma may be reversible. Finally, Ca2+ channel blockade improves contrast sensitivity in patients with normal-tension glaucoma, who also show increased retrobulbar vessel flow velocities, a result suggesting that visual function loss may be linked to ocular ischemia. Emerging evidence points to a role of ischemia in the pathogenesis of glaucoma, suggesting that treatments designed to improve ocular blood flow may benefit glaucoma patients.

Animals↗
PubMed1999

Scanning laser ophthalmoscopy-based evaluation of epipapillary velocities: method and physiologic variability.

PURPOSE: Scanning laser ophthalmoscopy is capable of producing high-resolution fluorescein angiograms. Measurements of capillary blood velocities in the fovea are well established. In this study, we used an identical technique to measure particle velocities in the superficial layers of the optic nerve head. We compared these data with simultaneous velocity measurements in the retinal and macular vasculature. METHODS: Fluorescein angiograms were performed in 30 subjects (12 men, 18 women; mean age, 26 years; standard deviation [SD], 3 years). Off-line, the velocities of hypofluorescent particles through the microvasculature of epipapillary and macular vessels were measured by image-processing techniques. We also assessed the arteriovenous passage (AVP) time of the fluorescein dye front. RESULTS: Epipapillary blood velocities ranged from 2.7 to 6.5 mm/sec (mean, 4.0 mm/sec; SD, 0.99 mm/sec) and differed significantly from macular capillary blood velocities (MCBVs), which ranged from 1.67 to 3.31 mm/sec (mean, 2.53 mm/sec; SD, 0.34 mm/sec). The AVP time in all subjects was 1.74 +/- 0.5 sec (mean +/- SD) and correlated with the MCBV (P < 0.05, r = -0.46). Epipapillary blood velocities showed no correlation with either AVP time or MCBV. CONCLUSIONS: The scanning laser methodology, adapted to objectively assess velocities in the epipapillary vasculature, shows that these measurements are neither correlated with velocities in the perifoveal network, nor inversely correlated with overall retinal transit time. Epipapillary blood velocities were found to be substantially higher than those measured in macular capillaries. This result might be explained by the different anatomy of epipapillary vessels compared with macular capillaries.

Adult↗
PubMed1999

Acute infantile hemorrhagic oedema.

Acute infantile hemorrhagic oedema (AIHO) was first described in 1913 but, despite frequent reports in the European literature, it is not well recognized in the English language literature. It is considered by many to be a variant of Henoch Schonlein Purpura (HSP) because of similarities in cause and histopathology. However, because of the benign nature of this condition and frequent absence of IgA associated with HSP, it may be sensible to consider this as a distinct variety of cutaneous small vessel vasculitis (CSVV). We report this case to highlight the condition and emphasize its benign nature.

Acute Disease↗
PubMed1999

Recurrent anterior uveitis and glaucoma associated with inadvertent entry of ointment into the anterior chamber after radial keratotomy.

Anterior uveitis and elevated intraocular pressure (IOP) occurred after radial keratotomy that was complicated by microperforation and penetration of antibiotic ophthalmic ointment into the anterior chamber. Anterior uveitis and IOP elevation were observed during the early postoperative follow-up and 41 and 61 months after surgery. All 3 attacks responded well to topical anti-inflammatory and antiglaucoma treatment. The probable causes of the uveitis and glaucoma in this case are discussed.

Administration, Topical↗