Biomedical subjects
R A Knight
Publications and source records attributed to R A Knight.
Cell death in muscle pathology.
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Assessment of relative brain iron concentrations using T2-weighted and T2*-weighted MRI at 3 Tesla.
In this paper a new method is presented for the relative assessment of brain iron concentrations based on the evaluation of T2 and T2*-weighted images. A multiecho sequence is employed for rapid measurement of T2 and T2*, enabling calculation of the line broadening effect (T2'). Several groups have failed to show a correlation between T2 and brain iron content. However, quantification of T2', and the associated relaxation rate R2', may provide a more specific relative measure of brain iron concentration. This may find application in the study of brain diseases, which cause associated changes in brain iron levels. A new method of field inhomogeneity correction is presented that allows the separation of global and local field inhomogeneities, leading to more accurate T2* measurements and hence, T2' values. The combination of T2*, and T2-weighted MRI methods enables the differentiation of Parkinson's disease patients from normal age-matched controls based on differences in iron content within the substantia nigra.
A low flip angle spin-echo technique for producing rapid diffusion weighted MR images.
A method is described for producing rapid diffusion-weighted images using a modified low flip angle imaging technique. Utility of the method is demonstrated by the quantification of diffusion coefficients in a rat model of focal ischemia. The method may be readily applied to animal research studies using NMR research systems with modest gradient capabilities.
Correction of motional artifacts in diffusion-weighted MR images using navigator echoes.
Patient motion can seriously degrade the quality of diffusion-weighted MR images obtained using standard 2DFT imaging procedures. The main source of error arises from an MR signal phase-shift error which is proportional to the magnitude of the motion. A modified pulse sequence is proposed which uses the phase information from an additional spin echo to correct for patient motion. Application of this technique is demonstrated for a human brain study, which greatly improves the quantification of diffusion values from regions of brain tissue.
Magnetic resonance imaging assessment of evolving focal cerebral ischemia. Comparison with histopathology in rats.
BACKGROUND AND PURPOSE: This study was performed to document the progression of ischemic brain damage after middle cerebral artery occlusion in the rat using magnetic resonance imaging and histopathologic methods. METHODS: Cerebral ischemia was induced through permanent tandem occlusion of ipsilateral middle cerebral and common carotid arteries. The evolution of magnetic resonance imaging and histopathologic parameter changes was studied, both short term (1.5 to 8 hours) and long term (24 to 168 hours), in five specific brain regions within the middle cerebral artery territory. RESULTS: Significant changes in proton nuclear magnetic resonance spin-lattice and spin-spin relaxation times and the "apparent" diffusion coefficient of water could be detected within hours after the onset of permanent focal cerebral ischemia, whereas significant alterations in proton spin-density ratios were not apparent until approximately 48 hours. Histological changes were evident within 12 hours, with a significant loss of neurons seen in the most severely damaged regions at 7 days. Diffusion-weighted imaging was the most sensitive technique for visualizing acute ischemic alterations. The water diffusion coefficient was the only magnetic resonance imaging parameter studied to indicate significant alterations within the first 4 hours after arterial occlusion in all five brain regions. CONCLUSIONS: The degree of change for a particular magnetic resonance imaging parameter appeared to be related to the location and extent of neuronal injury, with the most dramatic changes occurring within the areas displaying the most severe histological damage. These results indicate that complete specification of all brain regions affected by ischemic brain injury may require a combination of imaging strategies applied over a period of days and suggest the possibility of using magnetic resonance imaging to distinguish between permanent and reversible cell damage.
Alveolar macrophage-induced suppression of peripheral blood mononuclear cell responsiveness is reversed by in vitro allergen exposure in bronchial asthma.
Little information is available on the specific role of alveolar macrophages (AMs) in modulating local cellular reactions to inhaled allergens in atopic asthma. We investigated the influence of alveolar macrophages obtained by bronchoalveolar lavage (BAL) on the proliferative responses of lavage and peripheral lymphocytes from 12 patients with atopic asthma, 6 nonasthmatic symptomatic atopic subjects, and 6 nonatopic normal volunteers, in the context of in vitro exposure to relevant and nonrelevant allergens. Fresh nonadherent bronchoalveolar lavage cells from atopic asthmatic patients, depleted of alveolar macrophages, proliferated spontaneously more than nonadherent bronchoalveolar lavage cells from normal subjects. Addition of autologous asthmatic alveolar macrophages reduced this endogenous "activation". Asthmatic and normal alveolar macrophages also inhibited phytohaemagglutinin-stimulated proliferation of both autologous and allogeneic nonadherent peripheral blood mononuclear cells (PBMC). In contrast, autologous asthmatic alveolar macrophages induced strong proliferation of peripheral blood mononuclear cells when stimulated with allergen to which the patient was skin test and radio allergosorbent test (RAST) reactive; however, no response was seen with allergens to which the patient was insensitive. No such allergen-specific proliferation was seen with alveolar macrophages from nonasthmatic atopic subjects. These data support the presence of functionally-active alveolar macrophages within the airways of atopic asthmatic patients, that under normal stable conditions suppress the induction of peripheral blood mononuclear cell responses, and which only on contact with specific allergen appear to switch to inducer alveolar macrophages, with consequent peripheral blood mononuclear cell hyperactivation.
Birth complications and subsequent negative symptoms in schizophrenia.
A sample of 29 men with an initial psychotic episode and diagnosis of schizophrenia as young adults were followed into middle adulthood. All had prior child guidance clinic contact. The negative symptoms of affect deficit in young adulthood but not the positive symptoms of thought disorder were predicted by a history of birth complications. Subjects with birth complications who developed negative symptoms had a stable deficit over the follow-up period.
Modulation of POMC expression in human neuroectodermal cells.
Neuroblastoma cell lines have been reported to contain two proopiomelanocortin (POMC) mRNA transcripts. We have now shown by immunocytochemistry and radioimmunoassay (RIA) that a number of neuroectodermally derived cell lines contain immunoreactive beta-endorphin although cell concentrations were not characteristic of any tumour type. To explore further the functional significance of beta-endorphin expression, we analysed neuroblastoma cell lines having intermediate (I), substrate adherent (S) and neuronal (N) phenotypes. No differences in cell beta-endorphin content were detected. However, the expression of POMC mRNA and of immunoreactive beta-endorphin was reduced within a few hours of treatment of these cell lines with retinoic acid. Culture of the cell lines in the presence of beta-endorphin resulted in small but significant increases in growth. Although the POMC gene is in the same chromosomal segment as N-myc, which is normally amplified in neuroblastoma, no corresponding amplification of POMC could be demonstrated. The data suggest that POMC gene products may contribute to the autocrine/paracrine growth of neuroectodermal tumours.
Temporal evolution and spatial distribution of the diffusion constant of water in rat brain after transient middle cerebral artery occlusion.
The regional distribution and temporal evolution of the diffusion coefficient (Dw) of water in rat brain was measured during and after transient middle cerebral artery (MCA) occlusion. Male Wistar rats (n = 14) were subjected to 2 h of middle cerebral artery occlusion, induced by intracarotid insertion of a filament. Diffusion (n = 14) and perfusion (n = 7) weighted magnetic resonance imaging were performed before, and at various time points after MCA occlusion, ranging from 30 min up to 7 days. Our data demonstrate that the temporal profiles of Dw differ between the severely and the least damaged regions of tissue. In the core of the lesion, where the tissue evolved to necrosis, Dw declined significantly (P < 0.001) within 0.5 h after onset of ischemia, and remained depressed until 24 h after withdrawal of the suture. However, no statistically significant decline in Dw was found in the perifocal regions containing morphologically intact cells. Perfusion MRI qualitatively exhibited a hypoperfusion and reperfusion during, and after 2 h MCA occlusion, respectively. A significant (r > or = 0.71, P < 0.01) correlation was found between delta Dw (the difference in Dw between the ipsilateral ischemic and homologous contralateral control regions) obtained immediately before withdrawal of the suture (2 h of ischemia) and at specific early time points after withdrawal of the suture, and the degree of ischemic cell damage. No significant (P > 0.01) correlation was detected at an early time points of ischemia or at other time points after withdrawal of the suture.(ABSTRACT TRUNCATED AT 250 WORDS)
CRF mRNA in normal and stress conditions.
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Modulation of IGF-2 expression during growth and differentiation of human neuroblastoma cells: retinoic acid may induce IGF-2.
Insulin-like growth factor 2 (IGF-2) is the major autocrine growth factor for neuroblastoma. IGF-2 mRNA can just be detected in SK-N-BE(2) cell line; higher levels are present in two clones derived from it [BE(2)-C; BE(2)-M17]. IGF-2 mRNA is increased by retinoic acid (RA) only in the clones. IGF-2 expression/induction is more marked in BE(2)-M17, which shows more RA-resistance (evaluated as growth inhibition, neurite outgrowth and induction of programmed cell death). Under RA exposure, the parental line shows a more pronounced growth inhibition, neurite outgrowth and programmed cell death, as compared to its clones. BE(2)-C cells also express type 1 IGF receptor mRNA, though with a different time course than for expression of IGF-2. The data suggest that IGF-2 expression is correlated with growth, and may counteract the growth retardation, neurite outgrowth and programmed cell death effects of retinoic acid. Therefore the autocrine pattern of IGF-2 production by neuroblastoma cells may promote RA-resistance.
New insight on the biology of neuroectodermal tumors. Workshop report from the University of Rome Tor Vergata and the IDI-IRCCS on the genetics and control of growth, differentiation, and programmed cell death.
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Comparison of DSM-II and DSM-III schizophrenics: a longitudinal perspective.
Patients who meet DSM-III criteria for schizophrenia were compared with those who meet DSM-II, but not DSM-III, criteria. Comparisons included measures of positive symptoms, negative symptoms, and social competence both before extended hospitalization and during a 7-year follow-up. The measure of positive symptoms was the only variable that differed significantly between groups at initial assessment. Positive symptoms were more stable and predictive for DSM-III schizophrenics than for DSM-II schizophrenics. The measure of negative symptoms was the most stable and predictive variable for the DSM-II schizophrenics. Increased homogeneity for the DSM-III schizophrenics was not found for most measures.
The heterogeneous temporal evolution of focal ischemic neuronal damage in the rat.
Male Fisher rats (n = 61) underwent permanent focal cerebral ischemia induced by left middle cerebral artery (MCA) occlusion, in conjunction with ipsilateral common carotid artery ligation. The experiments were terminated at time points ranging from immediately following occlusion to 30 days post MCA occlusion. A coronal histological section, in close proximity to the site of the arterial occlusion, was taken from each brain and divided into six areas encompassing the affected cortex and caudate putamen. Each area was analyzed for ischemic damage according to a grading scale that reflects changes in neuronal morphology. Differential neuronal counts were also made on a 0.5-mm2 field in each of the six areas. The areas closest to the occluded vessel showed accelerated ischemic damage between 8 and 12 h after occlusion, leaving open the possibility that before 8 h, therapeutic intervention may be effective. After 12 h, changes in these areas progressed to complete necrosis and eventual cavitation with a complete loss of neurons after 10 days. The areas more peripheral to the occluded vessel exhibited mild ischemic damage, with an apparent reversal of damage grading at later time points and no loss of neurons. This reversal of ischemic damage in the peripheral areas is suggestive of a histological equivalent of the penumbra.
Histopathological correlations of nuclear magnetic resonance imaging parameters in experimental cerebral ischemia.
Changes in the nuclear magnetic resonance (NMR) parameters of spin-lattice relaxation (T1), spin-spin relaxation (T2), proton density (rho), and water diffusion (DNMR) were measured over time together with the histopathological status in three regions of rat brain cortex after permanent middle cerebral artery occlusion (MCA-O). Histological response ranged from severe irreversible damage (necrosis and cavitation) to relatively mild and apparently reversible damage. DNMR was the only NMR parameter which demonstrated a statistically significant change in all three regions of brain studied. Additionally, rho was significantly increased only in the region of brain studied which eventually progressed to necrosis and cavitation. Finally, data are presented which indicate that changes in T2, DNMR, and rho can occur independently of one another.
Effects of glucocorticoids and chronic inflammatory stress upon anterior pituitary interleukin-6 mRNA expression in the rat.
During development of adjuvant arthritis (AA) in the rat, anterior pituitary interleukin-6 (IL-6) mRNA expression was increased. Following adrenalectomy and AA there was a further increase in the accumulation of pituitary IL-6 transcript. Corticosterone (B) replacement in adrenalectomized (ADX) animals resulted in a dose-dependent reduction in pituitary IL-6 mRNA accumulation, while in ADX plus AA animals these effects of B were less marked. Cyclosporine A (CsA) markedly reduced the AA-induced increase in IL-6 mRNA. These data are consistent with an immunologically-mediated activation of pituitary IL-6 mRNA in AA, which may contribute to the increased activity of the pituitary-adrenal axis seen in this condition.
Direct stimulation of the pituitary by transfer of activated leucocytes.
Some strains of rat develop arthritis, and have profoundly elevated adrenocorticotropin (ACTH) and corticosterone, following intradermal injection of an adjuvant containing heat-killed mycobacteria. Transfer to syngeneic recipients of immune spleen (IS) cells taken from arthritic rats 14 days after injection of the adjuvant, but not of non-immune cells, causes increased circulating ACTH and increased pituitary proopiomelanocortin (POMC) mRNA. Transfer of immune cells does not transfer the disease, but does protect recipients from subsequent challenge with the adjuvant. In these immune-protected rats, the secondary immune response raises ACTH and POMC to levels similar to those seen in arthritic rats. These data show that endogenous inflammatory mediators have direct actions on the neuroendocrine system.