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7786846
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Ultrastructural study of the optic nerve in blind mole-rats (Spalacidae, Spalax).
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The optic nerve in two species of subterranean mole-rats (Spalacidae) has been examined at the ultrastructural level. The axial length of the eye and the diameter of the optic nerve are 1.9 mm and 52.5 microns in Spalax leucodon, and 0.7 mm and 80.8 microns in Spalax ehrenbergi, respectively. An anti-glial fibrillary acidic protein postembedding procedure was used to distinguish glial cell processes from axons. In both species, the optic nerve is composed exclusively of unmyelinated axons and a spatial distribution gradient according to the size or the density of fibers is lacking. The optic nerve of S. leucodon contains 1790 fibers ranging in diameter from 0.07-2.30 microns (mean = 0.57 microns), whereas in S. ehrenbergi, only 928 fibers, with diameters of 0.04-1.77 microns (mean = 0.53 microns) are observed. In S. ehrenbergi, a higher proportion of glial tissue is present and the fascicular organization of optic fibers is less obvious. Distribution gradients according to size frequency or density of fibers in the optic nerve are absent in both species. Comparison with other mammals suggests that although ocular regression in microphthalmic species is correlated with a significant decrease in the total number of optic fibers and the relative proportion of myelinated fibers, no difference in the absolute size range of unmyelinated axons is observed. The total absence of myelinated fibers in Spalax may be related to the subcutaneous location of the eyes.(ABSTRACT TRUNCATED AT 250 WORDS)
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7786845
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Effects of wavelength on the timing and laminar distribution of illuminance-evoked activity in macaque V1.
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Responses to full-field colored flashes (red, blue, and green) were compared with those to illuminance-matched white flashes in area V1, optic radiations, and the lateral geniculate nucleus of two alert macaques. Laminar profiles of visual evoked potentials (VEPs), current source density, and multiunit activity were obtained using multicontact electrodes capable of sampling from all layers of cortex or lateral geniculate nucleus, simultaneously. In striate cortex, stimulation with colored flash enhanced transmembrane current flow dramatically in both layer 4c and the supragranular laminae. Stimulation with red evoked the largest enhancement in every electrode penetration. The mean peak amplitudes of current sinks evoked by red were 203% and 537% of those evoked by white light in layer 4c and the supragranular laminae, respectively. Color effects in V1 were preceded by an initial epoch of wavelength-insensitive activity. In layer 4c, the red effect reached significance, on average, at 47 ms, or approximately 24 ms after the onset of transmembrane current flow. In the supragranular layers, the red effect reached significance, on average, at 55 ms, or approximately 14 ms after the onset of current flow. Recordings from optic radiations in the white matter below V1 and from lateral geniculate nucleus showed no significant difference in the responses to color and illuminance-matched white light. Enhancement of supragranular current flow with color stimulation increased the contribution of these laminae to the generation of the surface VEP. Comparison of the surface VEP wave forms evoked by white and color stimuli may, therefore, help to differentiate the responses of the granular and supragranular laminae.
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7786844
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The VEP thresholds for full-field stimuli in dark-adapted infants.
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Dark-adapted adults' electroretinographic b-wave thresholds are approximately 2 log units below a-wave thresholds and approximately 3 log units above the perceptual threshold, and their perceptual and the visually evoked cortical potential (VEP) thresholds are similar. Dark-adapted infants' scotopic a- and b-wave thresholds for full-field stimuli are both about 0.5 log units above those of adults, but their scotopic VEP thresholds for such stimuli have not been studied. We obtained scotopic VEP thresholds for brief, full-field stimuli from dark-adapted, infants and adults to consider the relationships of the cortical responses to the responses of more distal structures, namely the rod photoreceptors (scotopic a-wave) and ON-bipolars (scotopic b-wave). The median VEP threshold of infants is 0.5 log unit above that of adults. Thus, the relationships of a- and b-wave and VEP thresholds in infants are similar to those in adults. These results are consistent with rod cell immaturities being the primary determinant of the difference between infants' and adults' thresholds.
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7786843
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Expression of the proto-oncogene, trk, receptors in the developing rat retina.
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The neurotrophins, including nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3) and NT-4/5 are important in a variety of developmental processes in the peripheral and central nervous systems. These molecules bind to a low-affinity receptor and to distinct high-affinity receptors. The high-affinity receptor for NGF is the proto-oncogene product, p140trkA(trkA). Isoforms of p140trkA, p145trkB(trkB), and p140trkC(trkC), are the primary high-affinity receptors for BDNF and NT-3, respectively. We evaluated the developmental regulation of the high-affinity neurotrophin receptors in the rat retina using polyclonal antibodies directed to a highly conserved region of the C-terminus of the p140trkA isoforms (pantrk) and antibodies directed to unique amino-acid sequences of p140trkA, p145trkB, and p140trkC. Immunoreactivities for trkA and trkB, as well as pantrk, were detected in the developing retina and showed similar distributions. At similar antibody concentrations, trkC immunoreactivity was not detected. In the embryo, immunoreactivties were present in cells located throughout the neuroblastic retina, especially in the inner retinal layers, and in fibers in the nerve fiber layer and optic nerve. In the newborn retina, immunoreactivities for these two receptor isoforms were localized to numerous somata in the inner nuclear layer (INL), as well as to cells in the ganglion cell layer (GCL) and axons in the nerve fiber layer and optic nerve. A similar pattern of immunostaining persisted throughout the first postnatal week. By postnatal day-10, immunostaining was confined to large-diameter cells in the GCL, both heavily stained and lightly stained cells in the INL and a plexus of processes in the inner plexiform layer (IPL).(ABSTRACT TRUNCATED AT 250 WORDS)
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7786842
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How task-related are the responses of inferior temporal neurons?
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The responses of inferior temporal (IT) neurons may depend on the behavioral context of the stimuli; e.g. in Konorski tasks responses to two successively presented physically identical stimuli can be markedly different. This effect has been interpreted as being linked to the behavioral task, and to be involved in short-term memory and/or the temporal comparison of successively presented stimuli. We tested whether this behavioral context effect also occurs when the monkey is not executing a Konorski task, i.e. no temporal comparison of stimuli is being performed. Responses of the same IT neurons under two behavioral conditions were compared using the same temporal stimulus sequence (but different stimuli): a Konorski task and a Fixation task. We found that the occurrence of the behavioral context effect did not depend on the execution of the short-term memory task. The observed decline in the level of responses to repeated presentation of similar stimuli is interpreted as being a passive mechanism involved in recency detection, which occurs even if the recency information is not useful for the task. The importance of these results in the interpretation of "task-related" neuronal responses is discussed.
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7786841
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Adaptation aftereffects in single neurons of cat visual cortex: response timing is retarded by adapting.
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Extracellular single-unit recordings were made from simple cells in area 17 of anesthetized cats. Cells were tested with drifting gratings under control and adapted conditions. Response amplitude and phase were measured as a function of either contrast or temporal frequency. Adapting not only reduces amplitude, but also retards phase. Adaptation alters the responses of simple cells in a particular way: the onset of the response to each cycle of a sinusoidally modulate stimulus is delayed. Once cells start to respond during each cycle, however, they generally recover to control levels, and the offset of the response is unaffected by adapting. The timing aftereffects are independent of the amplitude aftereffects. Timing aftereffects are tuned around the adapting temporal frequency, with a bias toward lower temporal frequencies. Adaptation thus modifies cortical responses even more specifically then previously thought. Firing rates are depressed primarily at response onset, even after several stimulus cycles have occurred following the end of adapting. Because all cells appear to adapt in this way, the data offer an opportunity to theorize about cortical connectivity. One implication is that inhibition onto a simple cell arises from other simple cells with similar response properties that fire a half-cycle out of phase with the target cell.
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7786839
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Intravenous cibenzoline in the management of acute supraventricular tachyarrhythmias.
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Intravenous cibenzoline was evaluated in 37 patients with acute supraventricular tachyarrhythmias and a ventricular rate > 120 beats/min. The presenting arrhythmia was atrial fibrillation in 15 patients, atrial flutter in 5, ectopic atrial tachycardia in 11, and paroxysmal atrioventricular (AV) junctional reentrant tachycardia in 6 patients. Intravenous cibenzoline was administered as a bolus given over 2 minutes, at a dose of 1 mg/kg in the first 26 patients and 1.2 mg/kg in the subsequent 11 patients, 15 minutes following failure of placebo (isotonic glucose). The results were evaluated 15 minutes after the intravenous injection. Restoration of sinus rhythm was obtained in 3 out of 6 patients with paroxysmal AV junctional tachycardia (50%) and in 7 out of 31 patients (23%) with atrial tachyarrhythmias (5 out of 15 patients with atrial fibrillation and 2 out of 16 patients with ectopic atrial tachycardia or atrial flutter). Five additional patients with atrial tachyarrhythmias had slowing of ventricular rate below 100 beats/min. Therefore, a satisfactory result, that is, restoration of sinus rhythm or slowing of ventricular rate, occurred in 15 patients (40.5%). Side effects were transient, including visual disturbance (one patient), asymptomatic widening of QRS complex (three patients), incessant reciprocating tachycardia (one patient), and acceleration of ventricular rate (eight patients), resulting in 1:1 flutter, with poor tolerance in two patients.(ABSTRACT TRUNCATED AT 250 WORDS)
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7786840
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Reduction of ischemic events with angiotensin-converting enzyme inhibitors: lessons and controversy emerging from recent clinical trials.
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Angiotensin-converting enzyme (ACE) inhibitor therapy has been associated with a substantial (> or = 20%) reduction in the risk of major ischemic events in two recent clinical trials with long-term follow-up: Studies of Left Ventricular Dysfunction (SOLVD) and the Survival and Ventricular Enlargement (SAVE) study. Participants in these studies included patients with a low ejection fraction (< or = 0.35 in SOLVD and < or = 0.40 in SAVE), generally without symptoms of congestive heart failure. Approximately 80% of patients enrolled in SOLVD and all participants in SAVE had histories of ischemic heart disease or acute myocardial infarction (SAVE). In both SOLVD and SAVE the risk of experiencing a major ischemic event such as myocardial infarction was reduced significantly following prolonged ACE inhibitor therapy. In the SOLVD trial, this effect was evident across a range of patient subgroups, including varying concomitant drug therapies. In both studies, several months elapsed before this benefit became apparent, suggesting an effect on underlying ischemic pathophysiology. A third trial of ACE inhibitor therapy postinfarction, the Acute Infarction Ramipril Efficacy (AIRE) Study, demonstrated a 27% reduction in all cause mortality but no effect on myocardial infarction after a 15-month mean follow-up. No effect of ACE inhibition on risk of survival or reinfarction was reported in the Cooperative New Scandinavian Enalapril Survival Study (CONSENSUS-II), which began the drug within 24 hours of infarction and terminated follow-up at 6 months, a time not likely to demonstrate infarction reduction benefit based on the SOLVD and SAVE observations. Neither AIRE nor CONSENSUS-II had objectively determined left ventricular dysfunction as an entry criterion, as did SOLVD and SAVE, but AIRE mandated "clinical" congestive heart failure prior to randomization. More recently, preliminary results from the third Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico (GISSI-3), the Fourth International Study of Infarct Survival (ISIS-4), and the Chinese Captopril Trial suggested that angiotensin-converting enzyme (ACE) inhibitor mortality benefits post-myocardial infarction would be detected in these megatrials as early as 35 days after the event.(ABSTRACT TRUNCATED AT 400 WORDS)
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7786838
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Elastic properties and Windkessel function of the human aorta.
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An understanding of the role of the aortic elastic properties indicates their relevance at several sites of cardiovascular function. Acting as an elastic buffering chamber behind the heart (the Windkessel function), the aorta and some of the proximal large vessels store about 50% of the left ventricular stroke volume during systole. In diastole, the elastic forces of the aortic wall forward this 50% of the volume to the peripheral circulation, thus creating a nearly continuous peripheral blood flow. This systolic-diastolic interplay represents the Windkessel function, which has an influence not only on the peripheral circulation but also on the heart, resulting in a reduction of left ventricular afterload and improvement in coronary blood flow and left ventricular relaxation. The elastic resistance (or stiffness), which the aorta sets against its systolic distention, increases with aging, with an increase in blood pressure, and with pathological changes such as atherosclerosis. This increased stiffness leads to an increase in systolic blood pressure and a decrease in diastolic blood pressure at any given mean pressure, an increase in systolic blood velocity, an increase in left ventricular afterload, and a decrease in subendocardial blood supply during diastole, and must be considered a major pathophysiological factor, for example, in systolic hypertension. The elastic properties of the aortic Windkessel can be assessed in vivo in humans in several ways, most easily by measuring the pulse wave velocity along the aorta. The higher this velocity, the higher the elastic resistance, that is, the stiffness. Other methods depend on assessment of the ratio between pulse pressure and aortic volume changes (delata P/delta V), which can be assessed noninvasively by ultrasonic or tomographic methods. All assessments of vessel stiffness have to take into account the direct effect of current blood pressure, and thus judgements about influences of interventions rely on an unchanged blood pressure. Alternatively, to derive the "intrinsic" stiffness of the aortic wall one has to correct for the effect of the blood pressure present. Recently reports about pharmacologic influences on the elastic properties of the aorta have emerged in the literature.(ABSTRACT TRUNCATED AT 400 WORDS)
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7786837
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Muscarinic receptors and drugs in cardiovascular medicine.
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The parasympathetic system and its associated muscarinic receptors have been the subject of a renaissance of interest for the following two main reasons: (1) the association of endothelial muscarinic receptors and the nitric oxide (NO) pathway; (2) the discovery of several muscarinic receptor subtypes and drugs interacting with them. In the present survey modern insights into the subdivision of muscarinic receptors have been dealt with as the basis for a description of the muscarinic receptor agonists and antagonists thus far known. There are at least four pharmacologically defined M receptors (M1, M2, M3, M4) in primary tissues, and five muscarinic receptors have been cloned (m1, m2, m3, m4, m5). Selective agonists for M-receptor subtypes hardly exist, and all classical agonists (acetylcholine, carbachol, etc.) are clearly nonselective. A few selective antagonists for M1 (pirenzepine) and M2 receptors (AF-DX 116) have been introduced, although selective M3 receptors are hardly available. Finally, the potential therapeutic use of M-receptor agonists (myocardial ischemia, hypertension) and muscarinic antagonists (certain forms of bradycardia, coronary spasm) has been critically discussed. Although only in a preliminary stage, this development appears to be promising and at least of great fundamental interest.
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7786836
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Distinct modulation of myocardial performance, energy metabolism, and [Ca2+]i transients by positive inotropic drugs in normal and severely failing hamster hearts.
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The present study compared the effects of amrinone, dobutamine, dibutyryl cAMP, digoxin, and isoproterenol on mechanical performance, the high energy phosphate metabolites, and the [Ca2+]i transients in normal and cardiomyopathic hamster hearts with severe heart failure. In normal hearts dobutamine, dibutyryl cAMP, and isoproterenol increased left ventricular developed pressure, while amrinone and digoxin did not. However, the amplitude of [Ca2+]i transients was augmented with all drugs. Diastolic [Ca2+]i level was increased with dobutamine and lowered with dibutyryl cAMP and isoproterenol. In cardiomyopathic hearts with severe heart failure, left ventricular developed pressure, the amplitude of [Ca2+]i transients, the phosphorylation potential, and [cAMP]i were significantly depressed and left ventricular end-diastolic pressure and diastolic [Ca2+]i were significantly elevated when compared with normal hearts. Amrinone, dibutyryl cAMP, and isoproterenol improved mechanical performance while increasing [cAMP]i and the amplitude of [Ca2+]i transients, and decreasing diastolic [Ca2+]i. On the other hand, with dobutamine and digoxin diastolic [Ca2+]i was further increased and mechanical performance deteriorated with digoxin. Thus, distinct differences exist in modulation of mechanical performance, high-energy phosphate metabolism, and [Ca2+]i transients by positive inotropic drugs between normal and cardiomyopathic hearts with severe heart failure.
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7786835
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"Escape" of aldosterone production in patients with left ventricular dysfunction treated with an angiotensin converting enzyme inhibitor: implications for therapy.
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Despite the findings in randomized trials of a significant effect of angiotensin-converting enzyme (ACE) inhibitors in reducing morbidity and mortality of patients with symptomatic left ventricular dysfunction, the morbidity and mortality of these patients remains relatively high. One potential strategy to further improve morbidity and mortality in these patients is blockade of a aldosterone. Many clinicians have assumed that ACE inhibitors would block both angiotensin II and aldosterone. However, there are data to suggest that aldosterone production may "escape" despite the use of an ACE inhibitor. An escape of aldosterone production has several important consequences, including: sodium retention, potassium and magnesium loss, myocardial collagen production, ventricular hypertrophy, myocardial norepinephrine release, endothelial dysfunction, and a decrease in serum high density lipoprotein cholesterol. Due to the potential importance of these mechanisms, the finding that there is a significant correlation between aldosterone production and mortality in patients with heart failure, as well as evidence that an aldosterone antagonist, spironolactone, when administered to patients with heart failure treated with conventional therapy including an ACE inhibitor results in increased diuresis and symptomatic improvement, an international prospective multicenter study has been organized, the Randomized Aldactone Evaluation Study (RALES Pilot Study), to evaluate the safety of blocking the effects of aldosterone in patients with heart failure treated with an ACE inhibitor.
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7786834
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Comparative effects of fosinopril and nifedipine on regression of left ventricular hypertrophy in hypertensive patients: a double-blind study.
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The effects of fosinopril and nifedipine on left ventricular (LV) mass were evaluated in 35 hypertensive patients with LV mass index greater than 110 g/m2 in female and 130 g/m2 in male patients. The goal of therapy was also to obtain a seated diastolic blood pressure (SDBP) of less than 90 mmHg. The patients were studied by echocardiography after 2 weeks of placebo treatment and 4, 12, and 24 weeks of monotherapy with active drugs. Both fosinopril and nifedipine reduced SDBP to a normal level after 6 months of treatment (p < .001). Regression of LV hypertrophy was achieved by either agent (p < .001), with fosinopril being more effective than nifedipine (p < .002). In conclusion, both fosinopril and nifedipine effectively reduce SDBP and achieve important regression of LV hypertrophy.
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7786833
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Effect of beta-blockade on exercise capacity in hypertensive subjects: a one-year double-blind study of celiprolol and metoprolol.
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To assess the effect of beta-blocker antihypertensive therapy on exercise capacity, 40 patients randomized to celiprolol 200 mg and metoprolol 100 mg daily in a double-blind fashion were studied after a month of placebo and a year of active treatment. Both drugs normalized office blood pressure and produced echocardiographic and electrocardiographic left ventricular hypertrophy regression. In symptom-limited maximal stress tests before and after treatment, exercise duration increased with (p < 0.0001) celiprolol (513-700 seconds) and metoprolol (520-634 seconds), although more with the former (p = 0.02). Resting heart rate was reduced with both, more with metoprolol (p < 0.001), while heart rate at peak exercise was reduced similarly with both medications (p < 0.005). Blood pressure at peak exercise was reduced with both celiprolol (217-184 mmHg; p = 0.0002) and metoprolol (218-185 mmHg, p < 0.0001) to a similar degree (p = NS). Exercise parameters were not related to patient age or the degree of left ventricular hypertrophy regression (p = NS). It is concluded that beta-blocker antihypertensive therapy improves exercise capacity, decreasing heart rate and blood pressure responses to stress, irrespective of left ventricular structural changes.
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7786832
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Effects of growth hormone in rats with postinfarction left ventricular dysfunction.
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Growth hormone may affect cardiac function. In rats, chronic hypersecretion of growth hormone leads to increased maximum isometric contractile force of the left ventricular papillary muscle in vitro. In humans, administration of growth hormone can increase myocardial contractility. However, cardiac effects of growth hormone in heart failure or cardiac dysfunction have not been studied to date. The current study was to evaluate the cardiac effects of growth hormone in conscious rats with postinfarction left ventricular dysfunction and sham controls. Ligation of the left coronary artery or sham operation was performed, then 4 weeks after surgery, recombinant human growth hormone (2 mg/kg/day, SC) or vehicle was administered for 15 days. Catheters were implanted 13 days after treatment with growth hormone or vehicle. Hemodynamic parameters were measured in conscious rats 2 days after catheterization. In vehicle-treated rats, left ventricular systolic pressure, maximum dP/dt, and arterial pressure were significantly decreased and left ventricular end-diastolic pressure was significantly increased in the ligation group compared with sham controls. Growth hormone treatment increased left ventricular systolic pressure (p < 0.05) and dP/dt (p < 0.05) and reduced left ventricular end-diastolic pressure (p < 0.05), significantly in the ligated rats. In sham rats, growth hormone tended to decrease arterial pressure but did not alter ventricular contractility. Neither ligation nor growth hormone significantly altered heart rate and right atrial pressure. These results suggest that growth hormone treatment may improve cardiac function by increasing myocardial contractility in cardiac dysfunction or heart failure.
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7786831
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Preconditioning with a single short episode of global ischemia in the isolated working rat heart: effect on structure, mechanical function, and energy metabolism for various durations of sustained global ischemia.
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Preconditioning in the setting of global ischemia, using functional recovery during reperfusion as the endpoint, has recently been demonstrated in the isolated perfused rat heart. It has been suggested that its beneficial actions have a metabolic basis. The isolated rat heart has not been fully characterized with respect to the metabolic, functional, and structural changes associated with this phenomenon in the setting of global ischemia. The purpose of this study was to determine (1) the time course of protection conferred by a single episode (5 minutes) of preconditioning; (2) changes in tissue high energy phosphates, lactate, and glycogen levels at different time intervals; and (3) morphological appearance of the heart at the end of ischemia as well as after reperfusion. Isolated perfused working rat hearts were used. Preconditioning consisted of a single episode of 5 minutes of global ischemia and 15 minutes of reperfusion. Preconditioned and non-preconditioned hearts were subjected to global ischemia of 20-35 minutes duration. Functional recovery, energy metabolism (high energy phosphates, lactate, and glycogen), and structural appearance were studied at different stages. The functional recovery of the preconditioned hearts was significantly higher than in the corresponding nonpreconditioned group during reperfusion for all durations of ischemia longer than 25 minutes. The degree of protection observed was less than reported previously. A minor degree of energy sparing was reflected by differences in the rate of depletion of glycogen and accumulation of tissue lactate during the sustained episode of ischemia. Semiquantitative light microscopy evaluation revealed that ischemia-induced structural damage was less in the preconditioned hearts, both at the end of the sustained ischemic episode as well as after reperfusion. A single episode of global ischemia successfully preconditions the isolated working rat heart. The protection elicited was demonstrated on a functional and structural level, and was accompanied by a small energy-sparing effect.
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7786826
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Phase I study of weekly high-dose cisplatin combined with long-term oral etoposide in advanced solid tumors.
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In a previous phase I study we showed that single-agent cisplatin can be given weekly for six weeks at a dose of 80 mg/m2/wk. It has been suggested that etoposide has synergistic activity with cisplatin and the drug can be given orally continuously. We therefore performed a phase I study with weekly cisplatin combined with oral etoposide. Nineteen patients with metastases of a solid tumor were entered in the study. Cisplatin was administered in hypertonic saline (NaCl 3%). Etoposide was administered as 50-mg capsules. The starting dose was cisplatin weekly at a dose of 70 mg/m2 for six weeks combined with daily oral etoposide at a dose of 50 mg. At the maximum tolerable dose of cisplatin 75 mg/m2/wk and etoposide 50 mg/m2 daily, leukocytopenia and thrombocytopenia were dose-limiting toxic effects which resulted in frequent treatment delays. Other toxicities were mild. Finally, a dose of cisplatin 70 mg/m2/wk weeks 1-2-3 and weeks 5-6-7 in combination with etoposide 50 mg orally days 1-15 and days 29-43 combined a high median cisplatin dose intensity of 52.5 mg/m2/wk with a good patient tolerance. It is feasible to administer frequently dosed cisplatin in combination with oral etoposide. Leukocytopenia and thrombocytopenia are dose-limiting toxicities. The schedule will be explored further in phase II studies.
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7786825
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A phase II trial of vinorelbine and thiotepa in metastatic breast cancer.
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Vinorelbine as single-agent has achieved an overall response rate of > 20% as second-line treatment and 40%-50% as first-line treatment. The aim of this study was to evaluate the activity and toxicity of the combination of vinorelbine and thiotepa as second-line treatment in patients with metastatic breast cancer. Thirty-three patients (31: anthracycline-based chemotherapy, 16: high-dose epirubicin) were given vinorelbine 30 mg/m2 and thiotepa 12 mg/m2 d 1 and 8 every 21 days. Among the 32 evaluable patients two complete responses and seven partial responses were observed, for an overall response rate of 28% (C.I. 12-44). The median duration of response was 9 months and the median time to progression 6 months. Significant toxicity was primarily leukopenia (72%); anemia was also frequent (48%) as well as local phlebitis (39%). The present study has shown this combination to be active as second-line treatment, and its toxic effects have been well tolerated. It should be considered a reasonable option for patients with metastatic disease who have already been treated with anthracyclines.
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7786824
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ChlVPP therapy for Hodgkin's disease: experience of 960 patients. The International ChlVPP Treatment Group.
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Combination chemotherapy or combined chemo-radiotherapy is the treatment of choice for patients with advanced stage Hodgkin's disease and for patients failing curative radiotherapy. Increasingly, particularly in Europe, patients with early stage disease with poor prognostic features are also primarily treated with chemotherapy or combined chemo-radiotherapy. We analyzed the experience of 4 research groups which used ChlVPP, with or without radiotherapy, as standard chemotherapy for Hodgkin's disease. Patients with Hodgkin's disease were treated with ChlVPP chemotherapy: days 1-14: chlorambucil: 6 mg/m2/day, procarbazine: 100 mg/m2/day, prednisone or prednisolone: 40 mg/day; Days 1, 8: vinblastine: 6 mg/m2/day. The use of radiotherapy varied across research groups, with many, but not all, patients receiving radiotherapy. A total of 960 patients were treated. 60% were male, 25% were aged 50+, 59% had nodular sclerosis histology. Failure-free survival (time to first occurrence of progression, relapse after response or death from any cause) at 5 years by stage was: Stage I/IIA (231 patients), 75%; I/IIB (152 patients), 62%; IIIA (180 patients), 67%; IIIB/IV (397 patients), 51%. Adverse prognostic factors for all patients included age 50+ and 'B' symptoms. Patients aged 50+ of all stages did especially poorly on ChlVPP therapy. The 34 stage IIIB/IV patients with lymphocyte depleted histology also did poorly. These results compare favorably with other reported series. ChlVPP is an appropriate alternative to other chemotherapy regimens for some Hodgkin's disease patients, often with a reduced toxicity profile. Other chemotherapy may be preferred in patients greater than 50 years of age.
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7786823
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Early versus late alternating chemotherapy in small-cell lung cancer. Swiss Group for Clinical Cancer Research (SAKK).
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From 1984 to 1989, the Swiss Group for Clinical Cancer Research (SAKK) performed a randomized phase III trial comparing early versus late alternating chemotherapy in patients with small-cell lung cancer. 406 eligible patients were entered into the trial. Regimen A consisted of PAV (cisPlatin, Adriamycin, VP 16-213, and Regimen B of CyMOC (Cyclophosphamide, Methotrexate, Oncovin, CCNU). Cycles were repeated as rapidly as possible. patients were randomized to receive either ABABAB (early alternating chemotherapy) or AAABBB (late alternating chemotherapy). After six cycles patients with limited disease in complete or partial remission and those with extensive disease in complete remission received irradiation to the primary (45 Gy) and the CNS (36 Gy). The overall remission rate was 87% with 31% complete remissions. The median survival of all 406 eligible patients was 346 days with 15% of the patients alive at two years. The overall remission rate, the rate of complete remission, the median survival and the rate of long-term survival were not significantly different in the two treatment arms. In limited disease the estimated percentages of survival at 2 years were 33% in the early and 24% in the late alternating chemotherapy arms. Patients with extensive disease survived significantly longer with late alternating chemotherapy than on the early alternation regimen (median survival 336 days versus 301 days, p = 0.01). In the latter patients the received dose intensities (RDI) of cisplatin, adriamycin and etoposide were significantly higher in the late-alternation arm. Patients treated with early alternating chemotherapy rated their tumor symptoms, functional states, fatigue/malaise and restriction of social activity significantly better, reflecting an improved subjective adjustment. Alternating chemotherapy with PAV-CyMOC plus consolidating radiotherapy is a feasible and effective treatment for small-cell lung cancer, with acceptable toxicity. Whereas patients with early alternating chemotherapy achieve a better subjective adjustment, late alternating chemotherapy allows for a higher RDI of cisplatin, adriamycin and etoposide, which results in a significantly longer median survival of patients with extensive disease.
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7786821
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Phase I and pharmacokinetic study of irinotecan (CPT-11) administered daily for three consecutive days every three weeks in patients with advanced solid tumors.
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We conducted a phase I and pharmacokinetic study to determine the maximum tolerable dose (MTD), toxicities, pharmacokinetic profile, and antitumor activity of Irinotecan (CPT-11) in patients with refractory solid malignancies. Forty-six patients were entered in this phase I study. CPT-11 was administered intravenously over 30 minutes for 3 consecutive days every 3 weeks. Dose levels ranged from 33 mg/m2/day to 115 mg/m2/day on days 1 through 3. The pharmacokinetics of total CPT-11 and its active metabolite SN-38 were assayed by HPLC. The combination of leukopenia and diarrhea was dose-limiting toxicity at 115 mg/m2/day dose level, since 50% of the patients (5/10) experienced either grade 3-4 leukopenia, or diarrhea, or both. Leukopenia appeared to be a cumulative toxicity, with a global increase in its incidence and severity upon repeated administration of CPT-11. Other toxicities included nausea, vomiting, fatigue and alopecia. CPT-11 and active metabolite SN-38 pharmacokinetics were determined in 21 patients (29 courses). Both CPT-11 and SN-38 pharmacokinetics presented a high interpatient variability. CPT-11 mean maximum plasma concentrations reached 2034 ng/ml at the MTD (115 mg/m2). The terminal-phase half-life was 8.3 h and the mean residence time 10.2 h. The mean volume of distribution at steady state was 141 l/m2/h. CPT-11 rebound concentrations were observed in many courses at about 0.5 to 1 hour following the end of the i.v. infusion, which is suggestive of enterohepatic recycling. Total body clearance did not vary with increased dosage (mean = 14.3 l/h/m2), indicating linear pharmacokinetics within the dose range administered in this trial. The total area under the plasma concentration versus time curve (AUC) increased proportionally to the CPT-11 dose. Mean metabolite SN-38 peak levels reached 41 ng/ml at the MTD. A significant correlation was observed between CPT-11 area under the curve (AUC) and its corresponding metabolite SN-38 AUC (r = 0.52, p < 0.05). SN-38 rebound concentrations were observed in many courses at about 0.5 to 1 hour following the end of the i.v. infusion, which is suggestive of enterohepatic recycling. Mean 24-h urinary excretion of CPT-11 accounted for 10% of the administered dose by the third day, whereas SN-38 urinary excretion accounted for 0.18% of the CPT-11 dose. In this phase I trial, the hematological toxicity correlated with neither CPT-11 nor SN-38 AUC. Diarrhea grade correlated significantly with CPT-11 AUC. Two partial (breast adenocarcinoma and carcinoma of unknown primary) and 2 minor (hepatocarcinoma and pancreatic adenocarcinoma) responses were observed. The MTD for CPT-11 administered in a 3 consecutive-days-every-3 weeks schedule in this patient population is 115 mg/m2/day. The recommended dose for phase II studies is 100 mg/m2/day.
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7786822
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Population pharmacokinetics and pharmacodynamics of irinotecan (CPT-11) and active metabolite SN-38 during phase I trials.
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Irinotecan (CPT-11) is a novel water-soluble camptothecin derivative selected for clinical testing based on its good in vitro and in vivo activity in various experimental systems, including pleiotropic drug-resistant tumors. Its mechanism of action appears mediated through topoisomerase I inhibition. The purpose of this study was to describe CPT-11 and active metabolite SN-38 population pharmacokinetics, examine patient characteristics that may influence pharmacokinetics, and to investigate pharmacokinetic-pharmacodynamic relationships that may prove useful in the future clinical management of this drug. As part of 3 Phase I studies including 235 patients, pharmacokinetics of CPT-11 and metabolite SN-38 were determined in 107 patients. CPT-11 was administered as a 30-min i.v. infusion according to 3 different schedules: daily for 3 consecutive days every 3 weeks, weekly for 3 weeks, and once every 3 weeks. Patients characteristics were the following: median age 53 years; 62 men, 45 women; 105 caucasians, 2 blacks; performance status was 0-1 in 96 patients; tumor sites were predominantly colon, rectum, head and neck, lung, ovary and breast; with the exception of 6 patients, all had been previously treated with surgery, chemotherapy and/or radiotherapy. CPT-11 and metabolite SN-38 were simultaneously determined by HPLC using fluorescence detection. Pharmacokinetic parameters were determined using model-independent and model-dependent analyses. 168 pharmacokinetic data sets were obtained in 107 patients (97 first courses, 43 second courses, 23 third courses, 4 fourth courses, and 1 fifth course). Rebound concentrations of CPT-11 were frequently observed at about 0.5 to 1 h following the end of the i.v. infusion, which is suggestive of enterohepatic recycling of the drug. Model-independent analysis yielded the following mean population pharmacokinetic parameters for CPT-11: a terminal half-life of 10.8 h, a mean residence time (MRT) of 10.7 h, a volume of distribution at steady state (Vdss) of 150 L/m2, and a total body clearance of 14.3 L/m2/h. Model-dependent analysis disclosed a CPT-11 plasma disposition as either biphasic or triphasic with a mean terminal half-life of 12.0 h. The volume of distribution Vdss (150 L/m2) and total body clearance (14.8 L/m2/h) yielded almost identical values to the above model-independent analysis. The active metabolite SN-38 presented rebound concentrations in many courses at about 1 h following the end of the i.v. infusion which is suggestive of enterohepatic recycling. The mean time at which SN-38 maximum concentrations was reached was at 1 h since the beginning of the 0.5 h infusion (i.e., 0.5 h post i.v.). SN-38 plasma decay followed closely that of the parent compound with a mean apparent terminal half-life of 10.6 h. Mean 24 h CPT-11 urinary excretion represented 16.7% of the administered dose, whereas metabolite SN-38 recovery in urine was minimal (0.23% of the CPT-11 dose). The number of CPT-11 treatments did not influence pharmacokinetic parameters of either the parent compound or metabolite SN-38. Although CPT-11 pharmacokinetics presented an important interpatient variability, both CPT-11 maximum concentrations (Cmax) and the CPT-11 area under the plasma concentration versus time curves (AUC) increased proportionally and linearly with dosage (Cmax, r = 0.78, p < 0.001); CPT-11 AUC, r = 0.88, p < 0.001). An increase in half-life and MRT was observed at higher dosages, although this did not influence the linear increase in AUC as a function of dose. The volume of distribution at steady state (Vdss) and the total body clearance (CL) were not affected by the CPT-11 dose. Metabolite SN-38 AUC increased proportionally to the CPT-11 dose (r = 0.67, p < 0.001) and also with the parent compound AUC (r = 0.75, p < 0.001) (ABSTRACT TRUNCATED)
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7786820
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Phase II trial of CPT-11 in patients with advanced pancreatic cancer, an EORTC early clinical trials group study.
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CPT-11 (irinotecan) is a semi-synthetic derivative of camptothecin and exerts its activity by inhibiting DNA topoisomerase I. A phase II study of this drug was performed in patients with pancreatic cancer. Eligibility criteria included advanced non-chemotherapy-pretreated pancreatic cancer. CPT-11 was administered as a 30-minute i.v. infusion at a dose of 350 mg/m2 diluted in 250 ml normal saline every 3 weeks. Thirty-four eligible patients were enrolled in the study, thirty-two of them were evaluated, and three achieved partial responses (9%; 95% C.I. = 3%-25%). The duration of response was 7.2, 7.5 and 7.8 months, respectively. Thirteen patients had no change, fourteen patients had progressive disease and two had early progressive disease. The median duration of survival for all patients treated was 5.2 months. The main toxicities (CTC grade > or = 3) were diarrhea, leukocytopenia, asthenia, nausea and vomiting in, respectively, 7%, 16%, 8%, 6%, 4% of the courses. These toxicities were reversible and manageable with anti-emetics and prophylactic or curative antidiarrheal agents. CPT-11 is an interesting moderately effective drug in pancreatic cancer.
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7786814
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Decreased E-cadherin expression correlates with poor survival in patients with gastric cancer.
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E-cadherin, Ca(2+)-dependent intracellular adhesion molecule, is known to be an invasion suppressor gene. To elucidate the correlation between E-cadherin expression and invasion or metastasis in gastric cancer, we examined E-cadherin tissue status immunohistochemically. Ninety-eight primary gastric cancer, prepared by AMeX method, were retrospectively analyzed with anti-E-cadherin monoclonal antibody. In normal gastric epithelium, E-cadherin is expressed homogeneously with a typical membranous staining at cell-cell borders. Decreased and heterogeneous expression is found in 70 of 98 tumours. Tumours with decreased E-cadherin expression had a tendency to infiltrate more deeply in stomach wall, and metastasize in lymph nodes or peritoneal surface. More importantly, decreased E-cadherin expression correlates with shorter survival (z = 3.98, P = 0.00086). These results may indicate that E-cadherin tissue status is a powerful prognostic indicator in gastric cancer. The high malignant potential of tumours with decreased E-cadherin expression may be associated with high potential of lymph node metastasis and peritoneal dissemination.
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7786813
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Changes in the activities of signal transduction and transport membrane enzymes in CEM lymphoblastoid cells by glucocorticoid-induced apoptosis.
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The behaviour of the membrane enzymes PIP2-phospholipase C (PLC), that modulates the extracellular signals, and gamma-glutamyltransferase (gamma-GT), involved in metabolite transport, was followed during the early and active phases of apoptosis induced in CCRF-CEM cells by glucocorticoid (10(-6) M dexamethasone, DEX). The activities of gamma-GT and PLC increased significantly at 15 and 30 s after dexamethasone addition. Both activities decreased to the control level after 2 min but increased again at 5 min. The enzyme activities were high in apoptotic cells. Apoptosis was seen after incubation with 10(-6)M dexamethasone for 48 h, with decreased cell number, cellular activation (MTT) and S-phase percentage; enhanced DNA fragmentation and propidium iodide uptake; and ultrastructural changes in the chromatin and cell membranes. The changes in enzyme activity are indicators which occur much earlier than the cellular events related to the apoptotic death in CD4(+)-T CEM lymphoblastoid cells.
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7786812
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Grading of transitional cell bladder carcinoma by image analysis of histological sections.
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Image analysis of histological sections was used to achieve a more objective malignancy grading of transitional cell carcinoma of the bladder. Images from Feulgen-stained sections from a clinical material of 197 tumours were analyzed. Features at various levels of analysis, e.g. mainly related to individual objects, neighbouring objects and the entire image, were analyzed. The features used were based on relational rather than individual nuclear features. With this technique, typical tissue architecture and degree of order/disorder can be described. These characteristics were compared by means of multivariate statistical methods with the subjective grading of the pathologists at our institution. This comparison provided the best subset of features and the agreement between the subjective and computer-based classification was 73%. The size, orientation and variation of the grey scale of the nuclei were particularly powerful. On a continuous scale, from grade 1 to 2A and 2B to 3, the four grades formed two distinct classes, low and high grade. In this distribution, the intermediate grade 2A was identified as a displaced grade 1 and the other intermediate grade 2B as a displaced grade 3.
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7786811
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Automated grading of astrocytomas based on histomorphometric analysis of Ki-67 and Feulgen stained paraffin sections. Classification results of neuronal networks and discriminant analysis.
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In stereotactically obtained astrocytoma biopsies, four morphometric nuclear parameters were determined with the use of an image analysis system. A special Ki-67 (MIB1)/Feulgen stain made it possible to quantify the essential characteristics of gliomas of the astrocytoma/glioblastoma group: growth pattern, cellularity, proliferation tendency and nucleus pleomorphism. A grading scale based on a cluster analysis resembling the WHO-scheme, which is suitable for automated astrocytoma grading, was developed. Large back propagation neural networks were used and their results compared with those of a classical multivariate discriminant classification analysis. It is possible to show that the neural network technology is superior to the statistical approach for automated astrocytoma grading. Based on the results of our study we believe neural network technology to be useful for tumour grading problems. The presented approach can be generalized for the automated grading of other tumour entities.
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7786810
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The Sunrise Technique: the correction of occipital plagiocephaly using bandeau occipital plate and radial osteotomies.
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Posterior plagiocephaly secondary to lambdoid suture stenosis requires surgical release and repair to prevent progressive deformational changes associated with a suture stenosis. A surgical technique is described for release of the stenosed lambdoid suture and asterion region, followed by occipital reconstruction. This technique provides excellent cosmetic results. Using a standard biparietal incision, most of the occipital bone is removed en bloc. The asymmetric occiput is then reconstructed using an autologous bone bandeau and Marchac forehead template graft. The remaining bone is cut into longitudinal strips and placed in a centrifugal fashion around this construct. This technique creates a stable unit that provides immediate symmetry to the occipital area. The operative time and blood loss are comparable to that of similar procedures. With this technique there have been no complications or need for reoperation.
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7786808
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Pediatric cervical spine instrumentation using screw fixation.
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From July 1986 to August 1993 we performed 24 pediatric cervical spine screw fixation procedures on 23 patients 16 years of age or less. The types of cervical instrumentation procedures performed were as follows: anterior cervical plates 12, posterior C1-2 screw fixations 8, posterior lateral mass plates 2, odontoid screw fixations 2. The mean age of all patients was 14.2 years (range 6-16). Indications for operation included traumatic instability in 20 cases, congenital instability in 1 case, 2 cases of postoperative swan neck deformity, and one reoperation for early graft and hardware failure. Six of the 23 patients had persistent instability following previous failed fusions (3 with 1 prior surgery, 2 with 2 prior surgeries, and 1 with 3 prior surgeries). Eight patients had improvement of their neurological status following operation and 15 remained at their preoperative level of neurological function. No patient was worse neurologically after their procedure. There were no long-term instrumentation, graft or fusion failures. Two complications occurred. One was the aforementioned graft and hardware failure requiring reoperation, the other was a superficial wound infection treated successfully with antibiotics. We feel that cervical spine fixation techniques have increased our ability to stabilize the pediatric cervical spine and have proven to be safe and effective.
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7786809
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Spinal intradural arteriovenous fistula: a case with an unusual presentation.
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Spinal intradural arteriovenous fistula is a rare type of spinal vascular malformation. It is usually fed by the anterior spinal artery and causes episodic myelopathy in young adults. We present a pediatric patient with such a vascular malformation which was fed directly by a medullary artery. The clinical course, complete radiological study and the excellent outcome will be described in detail. This rare subtype of spinal vascular malformation will be discussed.
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7786807
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Radiographic imaging requirements following ventriculoperitoneal shunt procedures.
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The requirements for radiographic imaging of the ventricles after a ventricular shunt procedure are not well defined. At British Columbia's Children's Hospital, the standard protocol included an ultrasound examination or CT scan at 6-8 weeks postoperatively, and a delayed CT scan at 6 months to 2 years, with additional scans only if the patient had symptoms of shunt malfunction. This study was performed to determine if the delayed scan could be omitted without compromising patient care. The study comprised 86 children with ventriculoperitoneal shunt operations, who had early CT scans or ultrasound examinations less than 20 weeks postoperatively, delayed postoperative CT scans between 20 weeks and 2 years, and who were asymptomatic at the time of these radiographic studies. In 39 of the 86 patients a change in ventricular size occurred between the early and delayed imaging studies, and in these patients the delayed scan was felt to be required. In patients in whom the early imaging study was done at more than 12 weeks postoperatively, and probably in patients with small ventricles preoperatively, there was no added information gained by doing a delayed scan. It is concluded that a radiographic examination of ventricular size at 12 weeks after a shunt operation may provide an adequate baseline study. If the early postoperative radiographic study is done less than 12 weeks after surgery, we would advise that in asymptomatic patients, with the exception of patients with very small ventricles preoperatively, a CT scan be repeated at a later date to obtain an appropriate baseline assessment of ventricular size for the future.
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7786806
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Reflections on the natural history of lipomyelomeningocele.
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A retrospective analysis of patients with lipomyelomeningocele cared for at two referral centers was completed to derive relationships between neurological function and patient age. Thirty-seven percent of 177 patients had intact neurological function on initial examination. Neurological deficits were progressive and linked with a logarithmic relationship to increasing patient age. Each child with intact examination retained normal bladder function following lipomyelomeningocele repair and release of cord tethering; complications of surgery were limited. Our analysis suggests that surgery on patients with intact function offers greater long-term protection of critical function than is offered by conservative management and expectant care. We recommend repair of lipomyelomeningocele at the time of diagnosis regardless of patient age or neurological function.
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7786805
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Contemporaneous shunting with repair of myelomeningocele.
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The combination of overt hydrocephalus and an open myelomeningocele in a newborn has prompted some authors to advocate the repair of the myelomeningocele and the performance of a shunt procedure during the same anesthetic procedure. Advocates of this approach stress the merits of administering only one anesthetic, diminution in incidence of cerebrospinal fluid leaks from the repair, and shortened hospital stay and the resultant cost-effectiveness. This study was performed to assess the complication rate of shunts inserted at the time of myelomeningocele repair as well as of those inserted at a later date as a separate procedure. It would later appear that the insertion of a ventriculoperitoneal shunt, contemporaneous with the repair of the myelomeningocele, does not increase the risks of shunt infection or shunt malfunction within the 1st year of life.
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7786804
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Electrophysiological studies on brainstem function in patients with myelomeningocele.
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We investigated the brainstem auditory evoked potentials (BAEPs), somatosensory evoked potentials (SEPs), and electrically elicited blink reflexes (BRs) to evaluate the brainstem function in 31 patients with meyelomeningocele (MMC) including 22 with Chiari type-II malformation. The I-III interpeak latency (IPL) of the BAEPs and the N9-N13 IPL of the SEPs tended to become gradually prolonged from the normal range with increasing age. The III-V IPL of the BAEPs and the N13-N20 IPL of the SEPs were initially prolonged and decreased progressively to the normal range. These findings indicated a gradual latency shortening of the brainstem components and latency prolongation of the peripheral components. Thus, while primary brainstem dysfunction may improve with age, secondary dysfunction due to stretching and elongation of the lower cranial nerves and cervical nerve roots may intensify. The BRs showed an abnormal R2 in 90% of the cases, disclosing subclinical lesions in the medulla oblongata which were not detected by BAEPs alone. BAEPs, SEPs and BRs were combined to yield a functional evaluation of the brainstem and lower cranial nerves that could not be done by magnetic resonance imaging alone. No close relation was found between electrophysiological abnormalities and the degree of hindbrain anomaly by neuroimaging.
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7786803
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Predicting outcome in the tethered cord syndrome: a study of cord motion.
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Thirty-two children with spinal dysraphism have been studied with phase MRI to assess longitudinal cord motion. Seventeen children who were asymptomatic and who had normal or slightly decreased motion were not operated. Fifteen had signs and symptoms of spinal cord tethering as well as decreased cord motion and underwent surgery. None of the nonsurgical patients have become symptomatic. The children with markedly decreased cord motion did not improve after surgery. A trend was seen toward a better outcome in younger patients with slight or moderate decrease in cord motion. All children with worse outcome were previously operated meningomyeloceles who had markedly decreased cord motion and who were greater than 10 years old.
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7786802
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Over-expression and amplification of the CDC2 gene in leukaemia cells.
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The expression and structure of the cdc2 gene, one of the master regulators of the eukaryotic cell cycle, were investigated in fresh leukaemic cells from 51 cases of various types of leukaemia. Cdc2 mRNA transcripts were detectable in approximately 40% (21/51) of cases by Northern blotting. Over-expression of cdc2 mRNA as compared to normal bone marrow cells was noted in 10/21 cases with detectable cdc2 mRNA transcripts. Amplification of the cdc2 gene was found in three cases. Cdc2 mRNA was over-expressed in these three cases, suggesting that gene amplification is a direct cause of mRNA over-expression in a subset of cases. Cell proliferative capacity was well correlated with the amount of cdc2 mRNA transcripts, i.e. 3H-thymidine incorporation was highest in cases with cdc2 mRNA over-expression and was significantly higher in cdc2-positive cases than in cdc2-negative cases. These results suggest that over-expression of CDC2, which is due to the gene amplification in some cases, might play a role in altered growth of leukaemic cells.
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7786801
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Assessment of clonal evolution at Ig/TCR loci in acute lymphoblastic leukaemia by single-strand conformation polymorphism studies and highly resolutive PCR derived methods: implication for a general strategy of minimal residual disease detection.
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Junctional sequences of immunoglobulin (Ig)/T-cell receptor (TCR) gene rearrangements are used as patient-specific PCR targets for the detection of minimal residual disease (MRD) in acute lymphoblastic leukaemias (ALLs). Clonal evolution of gene rearrangements is a major pitfall of this strategy. Using high-resolution PCR-based analyses (including denaturing gel electrophoresis and single-stranded conformation polymorphism (SSCP)) we have compared Ig/TCR gene rearrangements at presentation and relapse in a series of ALLs. These methods allow an unambigous comparison of rearrangements taking into account junctional size and nucleotide sequence information and allow a precise assessment of the clonal evolution. V gamma-J gamma and V delta 1-J delta 1 rearrangements were analysed in 12 T-ALLs. VH-JH, V gamma-J gamma, V delta 2-D delta 3 and, in selected cases, DH-JH rearrangements were studied in 14 B-lineage ALLs. Clonal evolution, regarding major rearrangements, occurs for at least one of these loci in 2/12 T-ALLs and in 5/14 B-lineage ALLs. Clonal evolution is more marked for minor rearrangements than for major ones. As shown using SSCP analysis, rearrangements observed at relapse are sometimes found in minor clones at presentation which are therefore selected in vivo by a proliferative advantage. These data, as well as those from the available literature, suggest the use of at least two patient-specific probes to detect MRD in ALLs. A general strategy including selected Ig/TCR rearrangements and chromosomal abnormalities as PCR targets is proposed.
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7786800
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Modulation of cell kinetics and cell cycle status by treating CD34+ chronic myeloid leukaemia cells with p53 antisense phosphorothioate oligonucleotides.
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Mutations of the p53 tumour suppressor gene occur in 20% of chronic myeloid leukaemia (CML) patients in blastic crisis, but it is still uncertain whether this inactivation plays a role in the pathogenesis of blastic transformation or in maintaining the leukaemic proliferation in CML, as it does in several solid tumours. We have previously shown that more than 50% of both normal and CML CD34+ cells express the p53 protein. However, haemopoietic cells at different phases of the cell cycle express p53 with different conformations, suggesting that the function of p53 may be closely regulated during the cell cycle. In order to elucidate the mechanism by which p53 suppresses cell proliferation, we evaluated the effects of inhibiting p53 expression on cell cycle and cell kinetics of chronic phase CML (n = 12) and normal (n = 7) bone marrow light-density cells and purified CD34+ progenitors by using an 18-mer modified antisense oligonucleotide which targets the region covering the six base pairs immediately before the first codon and the first four coding codons of p53. We found that the number of cells positive for the cell cycle-specific nuclear antigen Ki67 and for the BrdU monoclonal antibody (McAb) was significantly increased after p53 antisense olignucleotide treatment. At the same time, p53 protein expression was completely abrogated in both light-density and CD34+ cells. In addition, DNA analysis by flow cytometry demonstrated that the number of cells in quiescent phases of the cell cycle (G0-G1) was significantly decreased after exposure of light-density cells to p53 antisense oligomers, whereas the number of cells in S or G2-M phases was increased. Furthermore, the longer the incubation time the higher the increase in cell proliferation. Treatment of CML, cells with p53 antisense oligomers also resulted in significantly increased numbers of CFU-GM colonies. Our data suggest that p53 is a negative regulator of cell proliferation and its action is mediated through changes in cell cycle kinetics, mainly before the S phase. We can further speculate that the loss of p53 function, at the time of blastic crisis of CML, may play a role, in combination with other genetic changes (p210 BCR/ABL, Rb gene abnormality, others to be defined), in inducing disturbances in cell proliferation, differentiation, and apoptosis.
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7786799
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Leukaemic non-Hodgkin's lymphomas with hyperdiploid cells and t(11;14)(q13;q32): a subtype of mantle cell lymphoma?
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The present study describes five patients with leukaemic non-Hodgkin's lymphoma (NHL) detected on the basis of particular morphology and cytogenetic findings. With respect to histological, immunological and cytogenetic features these NHL are closely related to mantle cell lymphoma/intermediate differentiated lymphocytic lymphoma. However, the presence of unusual large cells associated with the t(11;14)(q13;q32) translocation and numerical chromosome changes, in the near triploid or near tetraploid range, could delineate a particular subtype of mantle cell lymphoma.
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7786798
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Haemoglobin Tunis-Bizerte: a new alpha 1 globin 129 Leu-->Pro unstable variant with thalassaemic phenotype.
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A Leu-->Pro substitution at position 129 of the alpha 1 globin gene was detected in three members of a Tunisian family by sequencing the whole alpha 2 and alpha 1 DNA. The mutation was verified by dot-blot allele-specific hybridization as well as by digestion of PCR and RT-PCR products with Nci I, since the alpha 1(129) T-->C mutation creates an additional recognition site for the above-mentioned enzyme. The alpha 1(129)(H12)Leu-->Pro substitution disturbs helix H resulting in alpha-thal trait most probably because the unstable alpha-globin chain variant cannot form alpha beta dimers. A search for the abnormal Hb and for the abnormal alpha globin chain by isoelectric focusing, carboxymethyl cellulose chromatography and electrospray ionization mass spectrometry was negative. In the heterozygous state, the alpha 1(129)(H12) Leu-->Pro variant is manifested by microcytosis (MCV approximately 73 fl), whereas in the homozygous state there is moderate anaemia with marked microcytosis (Hb 11.6 g/dl, MCV 65 fl).
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7786797
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Low plasma heparin cofactor II levels in thalassaemia syndromes are corrected by chronic blood transfusion.
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Low plasma heparin cofactor II (HCII) levels are associated with a thrombotic tendency, and we have previously shown these to be decreased in a variety of haemolytic conditions. The risk of thrombosis is recognized to be increased in both thalassaemia major (TM) and intermedia (TI), although the exact mechanisms are poorly understood. HCII levels have therefore been compared in 20 untransfused patients with TI and 20 regularly transfused TM patients to determine the influence of transfusion on HCII. Additionally, untransfused TI patients have been commenced on regular red cell transfusion and the effects on correction of low HCII levels investigated. HCII levels were significantly lower in the untransfused TI patients (mean 0.56 +/- 0.06 U/ml) compared to TM patients (mean 0.85 +/- 0.1 U/ml; P < 0.001). Levels in TI were significantly less than in healthy age-matched controls (P < 0.001) and correlated with Hb values (r = 0.8), whereas levels in TM were at the lower end of the normal range. ATIII values were within the normal reference range in both TI and TM, and HCII antigen showed a parallel reduction to HCII activity, indicating that reduction in HCII is not a consequence of increased thrombin consumption. Three patients with TI were commenced prospectively on hypertransfusion programmes which resulted in a slow normalization of their levels taking 2-3 months. These findings support a hypothesis that the low HCII levels are related to increased red cell turnover and can be normalized once this turnover has been suppressed by hypertransfusion. The thrombotic risk to patients with low HCII levels in the presence of haemolysis might in principle be decreased by such transfusion regimes.
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7786795
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Clonal and non-clonal karyotypically abnormal cells in haemophagocytic lymphohistiocytosis.
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We studied chromosomes in bone marrow (BM) or peripheral blood cells of nine patients with haemophagocytic lymphohistiocytosis (HLH); three of them had a family history of HLH and four others underwent concurrent Epstein-Barr virus (EBV) infection. In addition to a large population of normal mitotic cells, karyotypically abnormal clonal cells were found in two patients, abnormal clonal cells and a nonclonal (single) abnormal cell in one, and nonclonal abnormal cells in three. All the six patients with chromosome abnormalities died of progressive disease; one of them also had EBV infection and EBV-associated clonal proliferation. Two of three patients with EBV infection and only normal mitotic cells in BM completely recovered from the disease. Although HLH did not show histological and/or haematological evidence of a neoplastic disease, clonal chromosome abnormalities and the fatal clinical outcome found in some of the patients suggest that the disease may be heterogenous and include malignancy. HLH patients with karyotypically abnormal clonal cells in BM should warrant more intensive chemotherapy than that presently being applied to them and should be considered as candidates for BM transplantation.
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7786796
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Enhanced Mg(2+)-ATPase activity in ghosts from HS erythrocytes and in normal ghosts stripped of membrane skeletal proteins may reflect enhanced aminophospholipid translocase activity.
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Hereditary spherocytosis (HS) is a congenital haemolytic anaemia which is characterized by a great variety of structural defects in the red cell's membrane skeleton and/or deficiencies in particular membrane (skeletal) proteins. Enhanced (Mg2+)-dependent adenosine triphosphatase (Mg(2+)-ATPase) activities, varying from 115% to 160%, were invariably found in erythrocyte ghosts derived from 13 HS patients. Similarly, an enhancement of Mg(2+)-ATPase activity by 30% is observed in normal red cell ghosts that have been stripped of the greater part of their membrane skeletal proteins by treatment with a low ionic strength buffer. Reassociation of those stripped ghosts with spectrin reduces the enhanced Mg(2+)-ATPase activity to its original level. Since in both cases, HS ghosts and stripped normal ghosts, the stabilizing effects that the membrane skeleton exerts on the maintenance of an endofacial localization of the aminophospholipids are impaired, the enhanced Mg(2+)-ATPase activity is interpreted to reflect an increased activity of the aminophospholipid translocase. The present observations therefore support a role of the membrane skeleton in the stabilization of phospholipid asymmetry in the red cell membrane and consequently in reducing the energy consumption of the translocase.
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7786794
|
Haemoglobin Dhofar is linked to the codon 29 C-->T (IVS-1 nt-3) splice mutation which causes beta+ thalassaemia.
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Investigations of a young man with apparent thalassaemia minor showed that he was a heterozygote for a rare abnormal haemoglobin variant, Hb Dhofar. The amino acid replacement is in the beta-globin chain (beta 58 Pro-->Arg) and is therefore not consistent with the observed proportion of Hb Dhofar, as in both this and the original case, it constituted only 15% of the total haemoglobin. We have determined the basis of the low expression of this mutant, which is due to its linkage to a thalassaemic splicing mutation on the same beta-globin gene at codon 29 (C-->T). The finding of this thalassaemia mutation linked to Hb Dhofar not only explains the low level of Hb Dhofar, but also provides evidence that the codon 29 C-->T, IVS-1 splice junction mutation causes a beta+ form of thalassaemia.
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7786793
|
Detection of the BCR-ABL gene by reverse transcription/polymerase chain reaction and fluorescence in situ hybridization in a patient with Philadelphia chromosome negative acute lymphoblastic leukaemia.
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The Philadelphia (Ph) chromosome is detected in leukaemia cells in approximately 20% of adults with acute lymphoblastic leukaemia (ALL). When treated with chemotherapy alone, Ph-positive ALL has a poor prognosis, and patients may benefit from bone marrow transplantation in first remission. Here we report a patient with chromosomally normal bone marrow, in all 60 cells analysed, who was found to have the p210-type BCR-ABL chimaeric transcript by RT/PCR. Fluorescence in situ hybridization was labelled cosmid probes for BCR and ABL showed the presence of BCR-ABL juxtaposition on a normal chromosome 22 in leukaemia cell metaphases. We conclude that molecular and cytogenetic methods should be used in conjunction to detect the BCR-ABL gene rearrangement in ALL.
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7786792
|
The fusion of TEL and ABL in human acute lymphoblastic leukaemia is a rare event.
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We have recently identified a common ALL patient which harboured a chromosomal fusion between the TEL gene on chromosome 12 and the ABL gene on chromosome 9. We designed an RT-PCR assay to screen 186 adult ALL and 30 childhood ALL patients for this novel translocation. We were unable to identify any additional cases with a TEL/ABL fusion product.
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7786791
|
Scintigraphic evaluation of the haemopoietic bone marrow using a 99mTc-anti-granulocyte antibody: a validation study with 52Fe.
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To specify the validity of bone marrow scanning using a monoclonal anti-granulocyte antibody labelled with 99mTc (BW 250/183) for the functional assessment of haemopoiesis, we compared this method with 52Fe scan in 16 patients with haematological disorders. The examinations were performed using a rectilinear whole-body scanner and the distribution of the two tracers was assessed visually and quantitatively in anatomical bone marrow segments, the spleen and liver. Qualitative comparison showed concordance in the bone marrow distribution of the two tracers in 83% of the segments. Discrepancies were found in six patients with hypoplastic or aplastic marrow. The spleen was visualized in all cases with the 99mTc-Moab, including nine patients without splenic haemopoiesis (i.e. without spleen uptake of 52Fe). The uptake of the two tracers, quantified in bone marrow segments and the spleen, correlated well (P < 0.001), but not in the liver (NS). The correlation between the uptake values for each patient was excellent, except in cases of aplastic bone marrow. In conclusion, bone marrow scanning using a 99mTc labelled anti-granulocyte monoclonal antibody enables functional evaluation of the distribution of haemopoiesis. Limitations include the evaluation of bone marrow aplasia and identification of splenic haemopoiesis, for which 52Fe remains the tracer of choice.
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7786790
|
Expression of an erythropoietin-like gene in the trout.
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Cross-species Northern blot hybridization and radioimmunoassay have provided evidence for the expression of an erythropoietin (EPO)-like gene in the rainbow trout. The principal site of EPO-like mRNA and antigen expression in the adult trout appears to be the kidney which also acts as the major erythropoietic organ. The data suggest that a locally produced EPO-like factor may regulate renal erythropoiesis in bony fish and, furthermore, they identify a possible evolutionary origin for renal EPO production in mammals.
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7786789
|
Refractory cytopenia with t(1;7),+8 abnormality and dysplastic eosinophils showing intranuclear Charcot-Leyden crystals: a fluorescence in situ hybridization study.
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A case of refractory cytopenia and marrow eosinophilia showing t(1;7) translocation and concomitant trisomy 8 is reported. The eosinophils were dysplastic, and showed the unique feature of intranuclear Charcot-Leyden crystal formation, giving rise to a 'lip-like' appearance. We speculate that this unusual cytologic feature resulted from abnormal precipitation of Charcot-Leyden crystal protein in the eosinophils. By fluorescence in situ hybridization using a chromosome 8 specific alpha-satellite probe, the abnormal eosinophils were shown to have derived from the abnormal clone. We postulate that the dysplastic clone might have retained a differentiation potential and be responsive to normal haemopoietic stimuli.
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7786788
|
Successful bone marrow transplantation for idiopathic hypereosinophilic syndrome.
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A 21-year-old man who had an increased number of eosinophils with morphological abnormalities, bone marrow fibrosis and multiple organ dysfunction failed to respond to methylprednisolone and hydroxyurea. He was diagnosed with hypereosinophilic syndrome (HES) probably due to myeloproliferative disorder, and underwent allogeneic bone marrow transplantation (allo-BMT) from an HLA-identical sibling. The engraftment was confirmed on day 21 after BMT, but the patient developed acute graft-versus-host disease (GVHD) with grade I veno-occlusive disease, and transient increase of eosinophils of the donor type followed by chronic GVHD of the extensive type. These complications were eventually controlled with cyclosporin A. The patient survived free of disease for more than a year after BMT. Allo-BMT seems to be a possible treatment of HES/MPD.
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7786787
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Random X chromosome inactivation in a female with a variant of Wiskott-Aldrich syndrome.
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A 15-month-old female presented with eczema, thrombocytopenia, recurrent infections and failure to thrive. She had low serum IgM and IgG subclasses and an abnormal lymphocyte proliferative response to periodate in vitro. Molecular X chromosome inactivation analysis, using the polymorphic HUMARA DNA probe, showed that the infant has random X chromosome inactivation. We conclude that she has an atypical form of Wiskott-Aldrich syndrome which may be inherited in an autosomal recessive manner.
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7786786
|
Acquired hypochromic and microcytic sideroblastic anaemia responsive to pyridoxine with low value of free erythrocyte protoporphyrin: a possible subgroup of idiopathic acquired sideroblastic anaemia (IASA).
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Patients with idiopathic acquired sideroblastic anaemia (IASA) usually show macrocytic or normocytic anaemia and increased free erythrocyte protoporphyrin (FEP). The mean cell haemoglobin concentration is normal or slightly low. Here we report a pyridoxine-responsive IASA patient with microcytic and hypochromic anaemia and low FEL level; these features are usually seen in cases of hereditary sideroblastic anaemia. Microcytosis increased during therapy. There may be a subgroup of IASA with microcytic and hypochromic anaemia, low normal FEP and some response to pyridoxine like hereditary sideroblastic anaemia.
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7786785
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Resistance to activated protein C activity of an anti-beta 2-glycoprotein I antibody in the presence of beta 2-glycoprotein I.
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Some researchers claim that lupus anticoagulant-positive plasma may cause a false-positive reaction in the test for activated protein C (APC) resistance, a hereditary thrombophilic state characterized by abnormal factor V, which frequently causes venous thrombosis. We investigated whether anti-beta 2-glycoprotein I antibody (aGPI), which has recently come to be regarded as an anti-cardiolipin antibody (aCL) itself, might have an effect on the APC resistance test.
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7786784
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Fibrin degradation product (FnDP) assays: analysis of standardization issues and target antigens in plasma.
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The in vivo formation of fibrin and its subsequent secondary fibrinolytic digestion yields a variety of crosslinked fibrin degradation products (XL/FnDP). One of these is known as D-dimer and a variety of ELISA-type commercial kits using monoclonal antibodies to D-dimer have been developed. We have investigated the possibility of establishing a standard such that these various kits might indicate the same levels of D-dimer in the same samples. We have concluded that because it seems that each individual monoclonal antibody to D-dimer targets a unique and distinct epitope in the FnDP fraction the notion of introducing a standard D-dimer which will respond uniformly to each D-dimer monoclonal antibody is not feasible. Using various monoclonal and polyclonal antibodies in conjunction with gel exclusion chromatography we have examined human plasma derived from patients with disseminated intravascular coagulation (DIC) which contained high levels of fibrin degradation products (FnDP). The data suggested that the FnDP fraction in plasma contained mostly high molecular weight (> 2 x 10(6) daltons) crosslinked fragments which contain high levels of fibrinopeptide A. Many of these crosslinked fragments crossreact with antibodies to D-dimer because they each contain D-dimer as a structural component. On the basis of this data, a novel sequence of events is proposed which may occur during the aggregation of fibrin in vivo.
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7786783
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A low M(r) GTP-binding protein, Rap1, in human platelets: localization, translocation and phosphorylation by cyclic AMP-dependent protein kinase.
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Subcellular fractions were prepared from human platelet membranes by sucrose density gradient centrifugation and the localization of a low M(r) GTP-binding protein, rap1 protein (Rap1) was analysed by immunoblotting using a specific antibody. Rap1, which has been purified from human platelets, was found to be located in plasma membrane and alpha-granule fractions in resting platelets. Treatment of isolated alpha-granules with pronase led to proteolysis of Rap1, indicating that this protein is exposed to the cytoplasmic face of the granules. Degranulation of alpha-granules consists of translocation and subsequent fusion of the granules with the open canalicular system. Activation of this process by thrombin induced the redistribution of Rap1 on the alpha-granules to plasma membranes. On the other hand, Rap1 is known to be phosphorylated by cyclic AMP-dependent protein kinase (A-kinase) in vitro and in vivo. In intact human platelets, phosphorylation of Rap1 by A-kinase in response to prostaglandin E1 (PGE1) was observed only in Rap1 localized in plasma membranes and not on alpha-granules, although Rap1 was phosphorylated in a cell-free system when plasma membranes and alpha-granule membranes were exposed to A-kinase as substrates. These results strongly suggest that Rap1 in plasma membranes and the protein on alpha-granules are regulated by different mechanisms, and have different functions.
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7786782
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Evidence for a light chain restriction of glycoprotein Ib/IX and IIb/IIIa reactive antibodies in chronic idiopathic thrombocytopenic purpura (ITP).
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To address the assumption of clonally restricted antibodies in immune thrombocytopenias we studied sera from 19 patients with chronic ITP known to possess antibodies reactive with glycoprotein (GP) Ib/IX and/or GPIIb/IIIa. These sera were re-analysed using the standard monoclonal antibody immobilization of platelet antigens (MAIPA) assay and 16 patients exhibited IgG antibodies reactive with GPIIb/IIIa; seven patients showed also a reactivity with GPIb/IX. Employing a light-chain-specific MAIPA assay, 75% (12/16) of these sera displayed GPIIb/IIIa-specific antibodies that were light chain restricted; only 13% (2/16) of the GPIIb/IIIa reactive sera showed a mixed kappa and lambda phenotype. A light-chain-restricted phenotype was also seen for the GPIb/IX reactive antibodies. To further substantiate these findings, the MAIPA assay was modified in order to avoid interference from human anti-mouse antibodies. A high frequency of light-chain restricted platelet antibodies was also found using the modified MAIPA technique. These results support the hypothesis of a clonal B-cell expansion in immune thrombocytopenias, producing antibodies with a restricted idiotype repertoire and reacting with a limited number of epitopes.
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7786778
|
Effects of interleukin-12 on natural killer cell cytotoxicity and the production of interferon-gamma and tumour necrosis factor-alpha in patients with myelodysplastic syndromes.
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The effects of interleukin 12 (IL-12) on natural killer (NK) cell cytotoxicity and on the production of interferon-gamma (IFN-gamma) and tumour necrosis factor-alpha (TNF-alpha) were examined in 15 patients with myelodysplastic syndromes (MDS), which are well known to have immunologic defects, and in 11 normal subjects. The NK cell cytotoxicity of all of the normal subjects was augmented by incubation with IL-12 alone, and co-incubation with interleukin 2 (IL-2) further augmented it (type A response). The MDS patients showed varied responses to IL-12/IL-2. Seven patients showed the type A response, resulting in augmented NK cell cytotoxicity which was similar to that in the normal subjects. In five other patients the cytotoxicity was not increased by IL-12 alone, but the combination of IL-12 and IL-2 did augment the cytotoxicity (type B response). The augmented cytotoxicity in these type B patients was lower than that in the normal subjects. In the final three MDS patients the cytotoxicity was low and not affected by IL-12 and/or IL-2 (type C response). All patients with refractory anaemia with excess blasts (RAEB) and patients with RAEB in transformation showed a type B or C response. Conversely, six of eight refractory anaemia patients showed a type A response. In MDS patients there was a positive correlation between the percentage of CD3- CD56+ cells in pre-incubated cells and the cytotoxicity of cells incubated with IL-12/IL-2. The combination of IL-12 and IL-2 augmented IFN-gamma and TNF-alpha production by nonadherent mononuclear cells in a synergistic or cumulative manner, respectively, in most patients. These results suggest that IL-12, alone or with IL-2, may modulate these important immunologic functions in most MDS patients.
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7786781
|
Attenuated-dose idarubicin in acute myeloid leukaemia of the elderly: pharmacokinetic study and clinical results.
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AML in the elderly is characterized by intrinsic biological features implying an enhanced chemoresistance. Intensive chemotherapy should be the treatment of choice, but the standard doses could induce unacceptable rates of aplastic deaths. We evaluated the efficacy of an induction protocol with attenuated-dose idarubicin (IDA) 8 mg/m2 for 3 d plus cytarabine and etoposide in 26 AML patients aged > 60. 18 patients (69%) achieved CR, five (19%) were non-responders and three (12%) died during induction. To compare the pharmacokinetics of IDA between elderly and young patients, we assayed daily the serum level of the drug and of its metabolite (idarubicinol, IDAol) in a group of eight elderly patients who received a dose of 8 mg/m2 (group A) and in a group of nine younger AML patients treated with 12 mg/m2 (group B). The apparent terminal half-life of IDAol was significantly longer in the elderly than in the younger patients (mean half-life 59.7 h versus 41.4 h, P < 0.05). The values of the area under the serum concentration curve of IDAol indicated that the two patient groups received a very similar exposure to the drug despite the different doses. In conclusion, this protocol, based on attenuated doses of IDA, compares well with the results obtained previously in similar age-matched patient series.
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7786779
|
Evidence for a paracrine pathway of B-cell stimulation in hairy cell leukaemia.
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It is a well-known phenomenon that the growth of malignant B-lymphocytes, i.e. hairy cells, is regulated by cytokines. Several investigators have suggested that the stimulating cytokines are produced by the malignant B cells themselves, indicating an autocrine growth regulation. In this paper we demonstrate that T-lymphocyte clones produce soluble mediators which stimulate the growth of malignant B lymphocytes. The incidence of the growth-stimulating T-cell clones derived from peripheral blood is identical in patients with hairy cell leukaemia (HCL) and healthy controls. About 50% of the clones stimulate the growth of hairy cells, but not the growth of purified B lymphocytes of healthy donors. The stimulating activity of a single clone varies when tested on different hairy cells. Interferon alpha (IFN alpha), but not antibodies against tumour necrosis factor alpha (TNF alpha) or interleukin-2 (IL-2), completely inhibit the growth-stimulating activity. Our results indicate that a paracrine growth regulation has to be considered in addition to the postulated autocrine loop in the growth regulation of malignant B cells.
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7786780
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Analysis of heat-shock protein expression in myeloid leukaemia cells by flow cytometry.
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Expression of heat-shock proteins (hsp) was analysed in the leukaemic cells of 12 patients with acute myeloid leukaemia (AML) and nine patients with chronic myeloid leukaemia (CML). Using monoclonal antibodies to hsp70, hsp90 and hsp60 (ML30, a mycobacterial antigen with homology to human hsp60), we measured hsp levels by flow cytometry of permeabilized cells. Mononuclear cells from 10 healthy volunteers were also examined. The results demonstrate that hsp expression is significantly increased (P < 0.01) in the circulating cells of patients with AML compared with cells from CML patients, and compared with normal peripheral blood mononuclear cells. This increased pattern of expression was found for all three heat-shock protein families included in this study. Mononuclear cells from leukaemic patients showed a heterogenous pattern of hsp expression, between different patients, between cells from individual patients, and between the different hsp proteins examined. It is possible that hsp expression relates to the differentiation state or proliferative potential of these leukaemic cells.
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7786776
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Characterization of genomic BCR-ABL breakpoints in chronic myeloid leukaemia by PCR.
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In order to understand better the mechanism of translocation between the BCR and ABL genes in CML, we have exploited a 'bubble PCR' technique to clone genomic breakpoints. BCR-ABL junction fragments were successfully amplified and sequenced in 14/32 (43%) patients tested. Breakpoints were dispersed throughout the major breakpoint cluster region without any clustering or hot spots. In three cases Alu sequences were found at or near the breakpoint on the ABL side of the translocation but no other obvious sequence homologies were found either in BCR or ABL. The translocation event was characterized further in three other patients by amplifying the reciprocal ABL-BCR junction on the 9q+ chromosome and also normal ABL around breakpoints. In two of these patients a few nucleotides of BCR and ABL were either duplicated or deleted on translocation, suggesting that staggered cuts had been made in the DNA strand prior to recombination. In the third patient 50 bp of ABL was deleted and 159 bp of M-BCR including exon b3 was duplicated, indicating either that the single-stranded cuts may span a larger distance than previously thought or that another mechanism, perhaps involving gene conversion, may be involved in this instance.
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7786777
|
Hemizygous expression of the wild-type p53 allele may confer a selective growth advantage before complete inactivation of the p53 gene in the progression of chronic myelogenous leukaemia.
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We analysed the expression of the p53 gene in various clinical phases of chronic myelogenous leukaemia (CML) by quantitative reverse transcriptase (RT) polymerase chain reaction (PCR). Hemizygous expression of the wild-type p53 allele was observed in two samples showing the loss of one p53 allele, and affected p53 expression was associated with p53 allelic loss rather than the clinical phase of CML. In four patients with CML showing p53 inactivation, we performed a detailed sequential analysis of p53 allelic loss, p53 mutation and expression from the onset of the disease to the patients' death. Consequently, we demonstrated that the loss of a wild-type p53 allele preceded mutation of the remaining allele, and that cells hemizygous for the wild-type p53 allele dominated those with both wild-type alleles, then were replaced by cells with complete p53 inactivation. These observations indicate that not only complete p53 inactivation but also hemizygous expression of the wild-type p53 allele may confer a selective growth advantage, and that the former is implicated in a more malignant phase than the latter. Alternatively, the inactivation of another undefined anti-oncogene on chromosome 17p may allow selective growth before the p53 mutation occurs.
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7786775
|
Clonal analysis of haemopoietic cells in essential thrombocythaemia.
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Essential thrombocythaemia (ET) is a myeloproliferative disease (MPD) predominantly involving the platelet lineage, with a diagnosis often difficult to establish in practice. The demonstration of a clonal haemopoiesis can contribute to diagnosis. The clonal origin of blood cells can be assessed in female patients using X-chromosome-linked polymorphisms, assuming a random inactivation of the X chromosome. The human androgen receptor gene HUMARA has been used for this purpose, taking advantage of a highly polymorphic trinucleotide repeat in the first exon. The close proximity of the polymorphic trinucleotide repeat to four methylation sites permits a clonal analysis based on the polymerase chain reaction. We have used this technique to study the clonality of haemopoietic cells in 32 patients with ET and 23 age-matched control heterozygotes for the HUMARA polymorphism. A monoclonal pattern of haemopoiesis was detected in unfractionated nucleated blood cells from 22 patients, suggesting that haemopoiesis is essentially monoclonal in a majority of cases in this disease. In some patients a monoclonality of granulocytes was documented, whereas the mononuclear fraction had a polyclonal pattern of X-inactivation. Finally, in two patients for whom a polyclonality had been found in unfractionated blood, analysis of G6PD transcripts in platelets revealed a clonal megakaryocytopoiesis. These findings confirm the heterogeneity of haematological abnormalities in ET patients and the potential utility of a multifaceted laboratory approach to investigate these patients.
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7786774
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Prognostic relevance of serum thymidine kinase in primary myelodysplastic syndromes: relationship to development of acute myeloid leukaemia.
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The aim of this study was to evaluate the possible prognostic relevance of thymidine kinase serum levels (s-TK), an indirect marker of proliferative activity, in myelodysplastic syndromes (MDS). S-TK levels were monitored by means of a radioenzyme assay in 90 patients affected by MDS (22 refractory anaemia, RA; 17 RA with ring sideroblasts, RARS; 21 RA with blast excess, RAEB; 15 RAEB in transformation, RAEB-T; 15 chronic myelomonocytic leukaemia, CMMoL). Mean s-TK levels (U/microliter) measured at diagnosis were 11.9 +/- 12.6 for RA, 11.4 +/- 13.6 for RARS, 19.9 +/- 28.4 for RAEB, 39.6 +/- 34.3 for RAEB-T and 77.7 +/- 69.7 for CMMoL (normal values < 5 U/microliter). With the only exception of a weak relationship with lactate dehydrogenase, no correlation was found between initial s-TK values and other clinical or laboratory parameters, such as age, haemoglobin, white blood cell or platelet count, percentage of bone marrow blasts. MDS patients with s-TK > 38 U/microliters, a cut-off level selected by means of ROC statistical analysis, showed a significantly shorter survival than those with s-TK < 38 U/microliter (8.2 v 37.4 months, respectively; P < 0.0001). In particular, transformation in acute myeloid leukaemia (AML) occurred in 17/21 (81%) of patients with s-TK > 38 U/microliters and 9/69 (13%) of those with lower levels at diagnosis (P < 0.0001), independently of FAB subtype. High s-TK levels were also useful to predict evolution in AML during the course of the disease in patients with normal initial values. Multivariate analysis confirmed the independent prognostic value of s-TK on both overall survival and risk of acute transformation. We conclude that s-TK may be an important prognostic factor in MDS, strongly correlated with development of AML.
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7786773
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Der(16)t(1;16)(q11;q11) in myelodysplastic syndromes: a new non-random abnormality characterized by cytogenic and fluorescence in situ hybridization studies.
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The der(16)t(1;16)(q11;q11) is a frequent recurrent rearrangement in solid tumours such as breast carcinomas and Ewings sarcomas. Recently, this abnormality was described also in multiple myeloma. We identified a der(16)t(1;16)(q11;q11) in three patients with myelodysplastic syndrome, either during preleukaemic phase (n = 2) or at the time of blastic transformation (n = 1). Breakpoints were ascertained by fluorescence in situ hybridization (FISH) using specific centromeric alpha-satellite probes and whole chromosome painting for chromosome 1 and chromosome 16. These observations, combined with isolated cases of the literature, suggest that der(16)t(1;16)(q11; q11) is a nonrandom abnormality associated with myelodysplastic syndromes.
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7786772
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Idiotypic oligonucleotide probes to detect myeloma cells by mRNA in situ hybridization.
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An mRNA in situ hybridization (ISH) method which used non-radioactive idiotypic oligonucleotide probes has been used to detect malignant cells in the bone marrow and peripheral blood of patients with multiple myeloma. For each of two patients with multiple myeloma a pair of biotinylated antisense oligonucleotide probes (18-22mer) was prepared from non-germline sequences of the rear-ranged immunoglobulin heavy chain (IgH) gene. These oligonucleotide sequences were not homologous with any previously published sequence. The probes from each patient were specific as shown by a failure to hybridize to any cells from six other myeloma patients and four normal individuals. Specific staining of IgH gene mRNA occurred only when the myeloma cells and the sequence of the probe used were from the same patient. Using simultaneous fluorescent immunocytochemistry it was shown that more than 95% of the ISH-positive cells expressed the malignant light chain in their cytoplasm. ISH positive cells were found in 1-4% of the peripheral blood mononuclear fraction of these two patients. These studies show that idiotypic oligonucleotide IgH gene probes can be used to identify individual cells belonging to the malignant clone and offer the possibility of developing innovative tumour-specific therapeutic procedures using antisense technology for patients with myeloma.
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7786771
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Prognostic implications of DNA aneuploidy in 156 untreated multiple myeloma patients. Castelano-Leonés (Spain) Cooperative Group for the Study of Monoclonal Gammopathies.
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In this study the incidence of DNA aneuploidy in a large series of untreated multiple myeloma (MM) patients was assessed in order to determine its clinical and prognostic significance. A total of 156 MM patients were included in the study. DNA measurements were performed in all cases at diagnosis using two different flow cytometry methods: (1) propidium iodide (PI) staining on isolated nuclei, and (2) CD38/PI double staining on whole cells. The DNA ploidy status was correlated with the most relevant clinical and haematological disease characteristics. From the 156 cases analysed, 91 (58%) were aneuploid (56% hyperdiploid and 2% hypodiploid). The correlation between the two techniques on the detection of DNA aneuploidy was excellent, although CD38/PI double staining would be preferable in cases with < 5% of DNA aneuploid plasma cells (PC). Upon comparing the clinical and haematological disease characteristics of hyperdiploid versus diploid cases, the former group was characterized by a lower age, reduced incidence of anaemia, lower beta 2M levels, higher proliferative activity within the residual normal haemopoietic cells, increased expression of CD56 antigen in PC, and higher proportion of PB CD4+ T cells. In contrast, diploid cases had a higher expression of the CD10, CD20 and CD15 antigens and greater numbers of PB CD56+CD3- NK cells (P < 0.05). Circulating PC were identified in six cases, all being diploid. Overall survival was significantly longer in hyperdiploid compared to diploid MM (P = 0.02). These results show that over 50% of MM patients are aneuploid, almost all of them being hyperdiploid. This characteristic is associated with better prognosis.
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7786770
|
Clinical significance of serum thymidine kinase in adult T-cell leukaemia and acute myeloid leukaemia.
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To clarify the clinical and biological significance of serum thymidine kinase (TK) in adult T-cell leukaemia (ATL) associated with human lymphotropic virus type-I (HTLV-I) and in acute myeloid leukaemia (AML), TK was measured in 52 patients with ATL (acute ATL, 35 patients; lymphoma ATL, two patients; chronic ATL, 12 patients; smouldering ATL, three patients), and in 27 patients with AML (one FAB MO, one M1, 10 M2, seven M3, five M4, one M5, one M6, one MU). In ATL patients, statistical analysis disclosed a close correlation between TK level and the leucocyte count (P < 0.01), and absolute number of abnormal lymphocytes (P < 0.01). However, no correlation was observed between serum lactic dehydrogenase (LDH) level and these items. Concerning the therapeutic response, a statistical difference was present in TK between complete remission and no response (P < 0.05), but not in LDH. We also investigated a significant inverse correlation between TK level as well as LDH level and the length of survival after the initial diagnosis (P < 0.01). In AML patients a close correlation of TK level with the count of leucocytes (P < 0.01), percentage of blasts in the blood (P < 0.05), therapeutic response (P < 0.01) and the length of survival after the initial diagnosis (P < 0.05) was present. Therefore the TK level may indicate the aggressiveness of leukaemic cells and predict the response to the chemotherapy and the length of survival in ATL and AML.
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7786768
|
Differential decline of rabbit chondrocytic dehydrogenases with age.
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We have previously found that the restoration of cartilage matrical proteoglycans is preceded by markedly increased activity of uridine diphosphoglucose dehydrogenase (UDPGD), an enzyme directly associated with glycosaminoglycan (GAG) synthesis, and by increased activity of enzymes of the major energy yielding pathways (glucose-6-phosphate dehydrogenase (G6PD), glyceraldehyde-3-phosphate dehydrogenase (GAPD) and succinate dehydrogenase (SDH)). We did not find an increase in lactate dehydrogenase (LDH). In the present longitudinal study of rabbits (from 5 weeks to 42 months of age), we looked for age related changes in the activity of these enzymes in auricular chondrocytes, as well as for collagen and GAG content. Collagen content (micrograms/wet weight) increased up to 12 months and remained stable; total GAG content (micrograms/wet weight) reached its maximal value at growth and then declined gradually, reducing the GAG/collagen ratio dramatically from 36 to 8. At any age LDH was two to three times more active than either G6PD, aldolase, or GAPD. SDH and UDPGD activities were even lower. The age related changes varied: (1) LDH and GAPD were stable and did not change with either growing or aging; (2) G6PD and aldolase reached their maximal activity at 3-9 months, followed by a sharp drop at 12 months. G6PD remained stable, while aldolase continued to decline, although more slowly; (3) Maximal activity of SDH and UDPGD was measured at 5 weeks. Thus, the changes in enzyme activity in chondrocytes with age were specific for each enzyme. The significant decline in G6PD, aldolase, the rate-limiting enzymes of the pentose shunt and classic glycolysis, and SDH markedly reduced the ability of chondrocytes to generate energy.(ABSTRACT TRUNCATED AT 250 WORDS)
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7786767
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Increased Na+,K(+)-pump activity in erythrocytes of rabbits fed cholesterol.
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Na+,L(+)-pump activity, intracellular sodium, potassium and magnesium concentrations and membrane cholesterol content were studied in erythrocytes of rabbits fed cholesterol. The average activity of the Na+,K(+)-pump in erythrocytes of rabbits with high plasma cholesterol was twice that in erythrocytes of control animals. Analysis showed a positive correlation between the pump activity and plasma cholesterol. The sodium content in erythrocytes correlated negatively with plasma cholesterol, as well as with the Na+,K(+)-pump activity. No significant differences in potassium and magnesium concentrations or in the membrane cholesterol content were observed between the two groups. The results indicate that modulation of the pump activity by cholesterol is not necessarily mediated by changes in the membrane viscosity.
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7786765
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Mycobacterial granulomatous inflammation in the ulcerated caecum of indomethacin-treated rats.
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We report mycobacterial granulomatous inflammation in the ulcerated caecum of rats that received indomethacin. Two groups of male rats were treated with dietary indomethacin 3 mg/kg/day or untreated diet for 3 weeks. Six out of 8 indomethacin treated rats showed both ulceration and inflammation of the caecal mucosa. Two of the rats showing caecal ulceration also showed distinct granulomatous inflammation of the caecal mucosa and acid-fast bacilli were identified within granulomata. None of the other indomethacin treated or control rats contained acid-fast bacilli within caecal tissue sections but they were present, in the same sections, within the lumen of most rats in both groups. Polymerase chain reaction analysis identified the mycobacterial 65 kDa GroEL gene within control and granulomatous caecal tissue. In a repeat of indomethacin administration to a third group of rats, culture of both non-granulomatous caecal tissue (containing histologically identified luminal acid-fast bacilli) and faecal samples for mycobacteria was negative.
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7786766
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Anti-glomerular basement membrane glomerulonephritis in the mouse: the role of macrophages.
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An immunohistochemical study was undertaken on fixed, paraffin-embedded mouse kidney in order to elucidate the role and significance of infiltrating macrophages in a mouse model of anti-glomerular basement membrane glomerulonephritis (anti-GBM GN). Tissue was available representing the full gamut of histological features seen in this model. The mouse macrophage-specific antigen F4/80 was detected in tissue sections of glomerulonephritic kidney and the pattern and extent of staining was compared with normal mouse kidney. In glomerulonephritic kidney, an increase in the number of F4/80-positive cells was evident in close proximity to and surrounding Bowman's capsule of those glomeruli which were severely damaged, with extensive fibrin deposition and well developed cellular crescents. F4/80-positive cells did not feature in the glomerular tuft or in the region of the parietal epithelium of Bowman's capsule even when extensive cellular crescents were present. Breaks in Bowman's capsule were not demonstrated. We conclude that F4/80-positive macrophages are not a major constitutive cell type of developing crescents in this mouse model of anti-GBM GN but, by virtue of their peri-glomerular localization, may be involved in the destructive process, perhaps producing signalling molecules which contribute to the inflammatory reaction.
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7786764
|
Pulmonary capillaries are smaller in the centre than in the periphery of the guinea-pig lung lobule: possible contributory mechanism for the centrilobular location of emphysema?
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We used scanning electron microscopic morphometry of microvascular corrosion casts to compare the capillary structure in the centre and periphery of the lung lobule in the guinea-pig. Capillaries in the centre of the lobule had a lesser diameter than in the periphery (8.6 +/- 1.6 vs 10.4 +/- 1.9 microns respectively, P < 0.001). The polygonal capillary rings differed in structure between the centre and periphery of the lobule, although the number of branches remained constant. Capillary density in the centre of the lung (0.71 +/- 0.05) was significantly less than in its periphery (0.78 +/- 0.06, P < 0.001). We conclude that the capillary structure of the centre of the lung lobule is markedly different from that seen in the periphery. The smaller capillary diameter seen in the centre might be important in trapping polymorphonuclear leucocytes that lose the ability to deform after contact with cigarette smoke components; such an effect could explain why cigarette smoke induced emphysema tends to involve the centre of the lung lobule.
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7786762
|
Sexually differentiated response to choline in choline deficiency and ethionine intoxication.
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A sex difference exists in the response of rats to a choline deficient diet and to ethionine intoxication. Female rats are less susceptible than males to the acute effects of choline deficiency, such as fatty liver and impaired secretion of triglycerides into blood plasma, while they are more susceptible to inhibition of liver protein synthesis and triglyceride accumulation by ethionine. These differences have been ascribed to sex differences in the biosynthesis of phosphatidylcholine in the liver of rats. The available data indicate that females are more dependent than males on the stepwise methylation of phosphatidylethanolamine rather than the direct incorporation of preformed choline. Continuous prefeeding with choline for three weeks was able to shift the female pattern of response to choline deficiency and ethionine intoxication towards that observed in males; thus, choline caused accumulation of hepatic triglycerides and a decrease in plasma triglycerides after choline deficiency, while it protected against ethionine induced triglyceride accumulation and protein synthesis inhibition in the liver. These results suggest that choline prefeeding in females makes them more dependent on choline availability and, thus, more susceptible to a choline deficient diet and less sensitive to ethionine intoxication, as are males. No effect of choline was observed in either choline deficient or ethionine intoxicated male rats.
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7786763
|
Site of localization of Mycoplasma pulmonis and Mycoplasma hominis in the genital tract of female mice demonstrated by culture and scanning and immuno-electron microscopy.
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Thirty young adult mice, of strain BALB/c, treated previously with progesterone, were inoculated intravaginally (10 mice) or directly into the uterus (10 mice) with Mycoplasma pulmonis and 10 mice remained uninoculated. Ten mice not treated with the hormone were also inoculated intrauterinely with M. pulmonis. The same numbers of mice treated with oestradiol were inoculated in the same ways with M. hominis. Vaginal swab specimens were obtained from all mice 7, 14 and 28 days after inoculation and samples of genital tract tissue were collected from pairs of mice at the same time intervals. Large numbers of M. pulmonis and M. hominis organisms were isolated from the vagina throughout the course of the experiments and they were cultured also from the cervix and uterine horns. Mycoplasma-like bodies were demonstrated by scanning electron microscopy in the cervix and in the uterus, but neither mycoplasmal species was found attached to vaginal epithelium. The results of silver-enhanced immunogold labelling in conjunction with scanning microscopy provided assurance that the mycoplasma-like bodies were, in fact, mycoplasmas. The importance of hormone treatment was indicated by the diminished susceptibility of untreated mice to M. pulmonis and the almost complete insusceptibility to M. hominis, shown by culture and scanning electron microscopy.
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7786761
|
Studies on early events of Borrelia burgdorferi-induced cytokine production in immunodeficient SCID mice by using a tissue chamber model for acute inflammation.
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Lyme arthritis, one of the common features of Borrelia burgdorferi infection in the human, is associated with the production of various monocyte derived cytokines. To investigate the expression and regulation of cytokines during the acute phase of spirochete induced inflammation, a perforated Teflon chamber was implanted under the dorsal skin of severe combined immunodeficiency (SCID) and immunocompetent co-isogenic C.B-17 mice. The histology of the surrounding chamber tissue exhibited sterile inflammation with several features reminiscent of an inflamed synovium, i.e. infiltration of polymorphonuclear and mononuclear cells, fibroblast-like cells and neovascularization. The experimental inoculation of Borrelia burgdorferi into the chamber resulted in the production of TNF-alpha, IL-1 and IL-6 into the chamber exudate, in both the immunodeficient, disease susceptible SCID and the immunocompetent, disease resistant C.B-17 mice. Peak levels of TNF-alpha were reached at 2 hours and of IL-1 and IL-6 at 6 hours after infection; by 24 hours, cytokine levels were only marginal (IL-1, IL-6) or non-detectable (TNF-alpha). Experimental infection by s.c. injection distant from the tissue chamber led to colonization of the spirochetes into the chamber, suggesting a tropism of the bacteria for this tissue. Thus, this model provides a system for studying acute events of Borellia burgdorferi induced cytokine regulation in a complex cellular, synovium-like environment that the bacterium encounters in vivo.
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7786760
|
Viruria during acute Japanese encephalitis virus infection.
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In this study, viruria following Japanese encephalitis virus (JEV) infection in mice has been shown to appear earlier in pregnant than in normal mice with proteinuria and haematuria. This was related to the production of splenic macrophage derived neutrophil chemotactic factor (MDF) following JEV infection. Intravenous inoculation of MDF in mice resulted in leakage of cells, proteins and erythrocytes in the urine as a result of altered capillary permeability. The isolation of virus from kidney did not correlate with the shedding of virus in the urine. The histological examination of sections of kidneys showed no morphological damage; however, ultrastructural degenerative changes in the mesangial cells were observed following JEV infection. These data suggest that JEV-induced macrophage derived factor regulates the leakage of proteins, erythrocytes and cells into the urine.
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7786744
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Using benchmarking to improve practice.
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Benchmarking is a relatively new addition to NHS quality initiatives. This article describes how a group of paediatric nurses set up a project to introduce benchmarking across units in the north west of England, and explores the benefits and disadvantages of this approach for nursing in general.
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7786746
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Consent to surgery: the role of the nurse.
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In the first of two articles relating to consent issues, the author examines the role of the nurse in helping patients to have a more equal relationship with doctors when they sign a consent form. It is based on sociological research studies of consent to surgery (1-3). Next week, the author will look at issues relating to consent to research.
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7786742
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The really useful guide to portfolios and profiles (continuing education credit).
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It is generally accepted that there is value in developing personal professional portfolios within nursing. This assumption is based on its inclusion as one of the main features of the UKCC's Standards for Education and Practice Following Registration (1): the requirement that all practitioners should maintain a personal professional profile. The fundamental purpose of the personal professional profiel is to 'provide a means for showing that nurses, midwives and health visitors have maintained and developed their professional knowledge and competence' (1). However, there is the potential to achieve much more than this rudimentary outcome. This Unit is relevant to UKCC Professional Development category Educational Development.
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7786737
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Menorrhagia: care and treatment.
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Approximately one tenth of women in this country experience menorrhagia. This can cause considerable discomfort, distress and curtailment of lifestyle. Hysterectomy is a common treatment, but morbidity and convalescence can be prolonged. Alternative surgical and pharmacological treatments are currently being developed which, it is hoped, will be available in the future. In the meantime, nurses have an important role to play in investigating, diagnosing and treating menorrhagia, and in supporting the women who experience it.
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7786736
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Pain management: a review of the uses of epidural analgesia.
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Epidural analgesia can be a valuable method of pain control in a variety of situations. It can facilitate early mobilisation and enhance recovery from surgery. This article describes the physiology of epidural pain relief and the nurse's role in monitoring patients effectively, recognising complications and minimising risk.
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7786735
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Identifying the coping behaviours used by nurses in intensive care.
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This study examines the use and perceived effectiveness among nurses of five coping styles: problem-focused coping, positive appraisal, help seeking, avoidance and aggression. Subjects were asked how they would cope with a conflict between themselves and a physician in the ward. The relationship between the coping behaviour and subjects' professional characteristics was explored. The subjects were 128 intensive cardiac care unit (ICCU) nurses. The results indicate that more experienced nurses use coping strategies less and may experience more burnout. The study also shows that nurses who participate in professional extra-curricular activities tend to choose more effective coping strategies.
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7786734
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Using care plans to replace the handover.
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This article describes the attempts of an NDU to make better use of written nursing care plans. It had been found that care plans were used more as historical records than as they were intended--to direct and plan care. The author outlines how staff identified the problem and then used primary nursing to enable the care plan to replace the oral handover.
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7786726
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Nurses' attire in a special hospital: perceptions of patients and staff.
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Nurses' uniforms have been the subject of ongoing debate in many areas. Following the Ashworth Hospital inquiry, two wards at the hospital piloted the wearing of casual clothes by nurses. Patients and nurses in these wards completed questionnaires to evaluate the effects of the change. The results showed that the patients felt casual clothes helped remove a 'them and us' distinction and enhanced nurse/patient relationships. Nurses found casual clothes to be more comfortable and practical. Although concern was expressed that, without uniform, nurses might not be readily identifiable in an emergency situation, the change to casual clothing was generally viewed positively by both patients and nurses.
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7786725
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Traumatic stress: a nurse therapist role?
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The study of people who experience post-traumatic stress disorder (PTSD) is still in its infancy. Yet it is already clear that victims of more common traumatic events are as much at risk of suffering short- and long-term psychological consequences as the victims of major disasters. Nurse therapists and specialists clinics could have a key role in working with people experiencing PTSD and in educating others about the problems.
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7786724
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Learning theories made easy: humanism.
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This is the last of three articles explaining theories of learning with particular relevance to clinical areas. In the story so far, the Director of Nursing Education at the St Elsewhere Academy of Nursing is trying to create the ultimate programme of nursing education. In order to ensure that the very highest standards of teaching and learning are achieved, the DNE has decided to employ a theorist of learning. She first interviewed the candidate representing the school of behaviourism, and last week the cognitivist candidate made his presentation. The series now concludes with the humanist candidate--and the final decision.
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7786723
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Long-term catheter use in the community.
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This article discusses the advantages and disadvantages of long-term urinary catheters and explores patients' attitudes to catheterisation. The author argues that, with careful selection of equipment, long-term catheterisation can be acceptable to patients and a useful method of management for people whose lives are severely restricted by incontinence.
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7786707
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Symptomatic subclavian steal syndrome four decades after operation for dysphagia lusoria.
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Congenital abnormalities of the aortic arch may lead to signs and symptoms of tracheal and esophageal obstruction secondary to a restrictive vascular ring. There are many case reports and monographs concerning the surgical management of dysphagia lusoria. This case provides the first example of long-term follow-up of surgical intervention for relief of dysphagia lusoria. A 45-year-old laborer presented with a several year history of episodic bilateral blindness and a more recent onset of "drop attacks." Notably this patient had presented at the age of 18 months with difficulty breathing and eating since birth. The patient also had frequent upper respiratory infections and episodes of pneumonia. Workup revealed a right-sided aortic arch with a left ligamentum arteriosum. When he was first seen in our clinic, history and physical examination revealed claudication and diminished pulses in the left upper extremity. Arteriography and duplex studies confirmed reversal of flow in the patient's left vertebral artery. The arteriogram demonstrated the presence of a right-sided aortic arch and descending aorta along with the proximal stump of the previously ligated left subclavian artery. He underwent left carotid to left axillary artery bypass for the treatment of symptomatic subclavian steal syndrome. His symptoms have resolved with return of antegrade vertebral flow and the presence of normal pulses in the left arm. Congenital aortic abnormalities that lead to tracheal and esophageal compromise are numerous and varied. Surgical management requires a thorough understanding of the person's anatomy and preoperative planning. The life expectancy of patients with dysphagia lusoria necessitates consideration of the long-term consequences of surgical intervention.
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7786706
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Tumor embolism after pneumonectomy for primary pulmonary neoplasia.
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We report a case of tumor embolism of the lower right extremity after right pneumonectomy. This is an infrequent complication and in most cases occurs during the intraoperative or immediate postoperative period. Our patient underwent surgery for primary pulmonary neoplasia (squamous cell carcinoma) and 4 hours later showed clinical signs of acute arterial occlusion in the lower right extremity. An emergency embolectomy was performed and a thrombus with tumor characteristics was extracted from the right common femoral artery. The pathologic features of this thrombus were identical to those of the pulmonary tumor.
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7786705
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Infrapopliteal polytetrafluoroethylene and composite bypass: factors influencing patency.
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Between January 1, 1979, and December 31, 1988, 149 infrapopliteal polytetrafluoroethylene (PTFE) bypasses were performed in 145 patients with chronic, critical, limb-threatening ischemia. These operations represented 27.9% of 534 infrapopliteal bypasses performed during the same period. There were 92 males and 53 females. Mean age was 71.8 +/- 12.3 years. Signs and symptoms of critical ischemia were gangrene, ulceration, and isolated rest pain in 101 (69%), 23 (15.3%), and 25 (16.7%) cases, respectively. A composite (PTFE-saphenous vein) graft was used in 53 (35%) cases. In 96 prosthetic bypasses the distal anastomosis was performed using vein patch angioplasty in 65 (44%) cases and directly in 31 (21%). The in-hospital mortality rate was 3.3%. Patency, limb salvage, and patient survival rates were plotted according to the actuarial method and the curves obtained were compared using the log-rank test. Actuarial survival rates were 68% +/- 5% and 57% +/- 7% at 3 and 5 years, respectively. Primary patency and lower limb salvage rates were 41% +/- 5% and 68% +/- 6% at 3 years and 35% +/- 9% and 65% +/- 10% at 5 years, respectively. There was no statistically significant difference noted in primary patency rates at 3 years according to the type of bypass (composite or all-prosthetic: 36% vs. 44%), the type of distal anastomosis (direct or vein patch angioplasty: 43% vs. 45%), the site of distal anastomosis (upper or lower half of the leg: 38% vs. 46%), lateral or medial placement of the bypass (39% vs. 43%), or according to whether or not it was a repeat operation (40% vs. 44%). In conclusion, patency rates using infrapopliteal PTFE bypasses are low. Certain technical approaches, although they do not seem to improve patency, definitely increase the feasibility of bypass and in our opinion decrease the risk of early failure in unfavorable anatomic settings. The limb salvage rates following infrapopliteal PTFE and composite bypass are encouraging and justify the use of routine distal revascularization, even in the absence of autogenous vein graft.
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7786702
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Hemodynamics of stenotic infrainguinal vein grafts: theoretic considerations.
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We developed a theoretic model of arterial stenosis to study the relationship between perfusion pressure and regional hemodynamics in stenotic infrainguinal vein grafts in an attempt to identify grafts at high risk for failure. Our model was based on the concept of energy and mass conservation of the flowing blood. We used the modified Bernoulli equation (delta P = 4 delta V2) to calculate the maximum possible intrastenotic peak systolic velocity (PSV) from the systolic blood pressure. PSV was measured by means of duplex ultrasonography in infrainguinal bypasses up to the time of revision (nine grafts) or spontaneous thrombosis (two grafts). We related arm systolic blood pressure, intrastenotic PSV, and prestenotic PSV obtained from duplex examinations conducted prior to graft thrombosis or revision and applied our model to these stenotic vein grafts. Intrastenotic PSV was consistently lower than maximum PSV predicted from the Bernoulli equation. The highest measured intrastenotic PSV of 600 cm/sec would require a minimum perfusion pressure of 144 mm Hg. The lowest measured PSV (20 cm/sec) was considered the minimum "thrombotic threshold velocity." This model predicts that for parabolic profile flow in an 80% diameter-reducing axisymmetric stenosis (96% cross-sectional area reduction), a prestenotic PSV of 20 cm/sec would produce an intrastenotic PSV of 500 cm/sec requiring the equivalent potential energy of 100 mm Hg systolic blood pressure. Our theory implies that in patients with nocturnal hypotension thrombosis of stenotic vein grafts may occur.
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7786704
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Intraoperative fibrinolytic therapy for salvage of limbs with acute arterial ischemia: an adjunct to thromboembolectomy.
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The purpose of this prospective study was to determine the value of intraoperative intra-arterial fibrinolytic therapy (IIFT) in patients with acute arterial ischemia as an adjunct to mechanical thromboembolectomy. Sixty-six femoropopliteal or distal acute arterial occlusions were assessed by means of arteriography and Doppler imaging pre- and postoperatively. Two groups of patients were compared: one (n = 35) in which mechanical thromboembolectomy was applied as the single technique and another (n = 31) in which 250,000 IU of urokinase diluted in 250 ml of normal saline solution was instilled at the end of mechanical thromboembolectomy over a 30-minute period with the arterial inflow occluded. Candidates for IIFT were selected according to a nonrandomized method. Intraoperative arteriography showed residual thrombus in 20 (30.3%) patients and unsuspected arterial lesions in 23 (34.8%). Thrombosis recurrence was associated with residual thrombus (p < 0.001) and amputation (p < 0.001). The ankle/brachial index increased significantly (p < 0.05) in the patients who received IIFT (0.88 +/- 0.03) in comparison with those who underwent mechanical thromboembolectomy (0.75 +/- 0.05). Although the percentages of distal revascularization and amputation did not differ significantly between the two groups, quantitatively the results were better in the IIFT group (80.65% success and 9.68% failure) compared to the mechanical thromboembolectomy group (60% success and 22.86% failure). There was no bleeding due to IIFT. Significant variables in our study were diabetes (p < 0.05), the time period of 12 to 24 hours before the surgery (p < 0.05), and the severity of the ischemia in association with rest pain (p < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)
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7786703
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Is infrapopliteal bypass compromised by distal origin of the proximal anastomosis?
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Distal origination of the proximal anastomosis (DOPA) of an infrapopliteal bypass beyond the adductor hiatus minimizes the length of graft required and optimizes use of scarce autogenous conduit. Sixty-two DOPA infrapopliteal revascularizations using autogenous vein performed for limb salvage over a 7-year period were reviewed and compared with 203 concurrent infrapopliteal bypasses originating more proximally (POPA). Life-table analysis revealed no difference at 54 months between DOPA and POPA bypass with regard to primary patency (57% vs. 50%, respectively) or secondary patency (67% vs. 65%, respectively). Differences in limb salvage at 54 months between DOPA and POPA bypasses did not reach statistical significance (53% vs. 66%, p = 0.12), although DOPA fared worse. Inferior limb salvage results in all infrapopliteal bypasses were correlated with the presence of tissue necrosis (52% vs. 70%, p < 0.001), which was more prevalent in patients undergoing DOPA bypass (71% vs. 49%, p < 0.01). The long-term patency of infrapopliteal bypass appears only marginally affected by DOPA. However, the prognosis for limb salvage in this setting is compromised as a result of the virulent behavior of the atherosclerotic disease that spares the superficial femoral artery while predominantly involving the popliteal and tibial vessels.
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7786700
|
Early inflammatory response to gelatin- and collagen-sealed Dacron prostheses.
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The immediate inflammatory response following aortic reconstruction with two types of sealed Dacron grafts was studied in a prospective, randomized manner. C-reactive protein (CRP) levels were measured before surgery and on days 2 and 8 postoperatively. In the collagen-sealed group (n = 10) CRP levels were 10 +/- 9.6, 180.2 +/- 48.3, and 54.3 +/- 34.3 mg/L, respectively. In the gelatin-impregnated group (n = 10) the values were 10.5 +/- 8.7, 200.7 +/- 27.3, and 80.3 +/- 30.2 mg/L, respectively. The slight differences were not significant according to the analysis of variance test for repeated measurements. These findings suggest that implantation of a knitted Dacron graft sealed with collagen does not lead to a higher inflammatory reaction compared with a gelatin-sealed graft.
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7786701
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Characteristics of patients at risk for perioperative myocardial infarction after infrainguinal bypass surgery: an exploratory study.
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Patients requiring infrainguinal bypass surgery often have diffuse atherosclerotic disease, and perioperative myocardial infarction (MI) is a potentially lethal complication that is not uncommon in these patients. To establish additional clinical characteristics that might be useful in identifying patients who require more extensive cardiac evaluation, we conducted an exploratory case-control study comparing 22 patients who had a perioperative MI following elective infrainguinal bypass surgery with 191 control subjects whose bypasses were uneventful. In addition to previously recognized risk factors (e.g., history of angina or prior MI), we examined the association of perioperative MI with (1) results of common preoperative laboratory tests and ECG, (2) preoperative use of certain medications, and (3) intraoperative factors that might be anticipated prior to surgery (e.g., duration of surgery or type of anesthesia). Perioperative MI was associated not only with a history of angina, prior MI, or coronary artery disease but also with the need for certain cardiac medications, higher white blood cell (WBC) counts, ST-segment depression, left bundle branch block, and lengthy surgical procedures. Multiple logistic regression analysis identified the following factors as being independently associated with perioperative MI: preoperative antiarrhythmic agents (odds ratio [OR] = 26.4, p = 0.006), nitrates (OR = 8.4, p = 0.006), calcium channel blockers (OR = 5.5, p = 0.04), and aspirin (OR = 6.8, p < 0.01) and ST-segment depression (OR = 11.8, p = 0.01), WBC count (OR = 1.27/1000, p = 0.005), and duration of surgery (OR = 2.2/hr, p = 0.0001).(ABSTRACT TRUNCATED AT 250 WORDS)
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7786699
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The effect of aging on the transarterial wall oxygen gradient.
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Atherosclerosis is associated with aging based on numerous epidemiologic studies, whereas arterial wall hypoxia has been associated with other risk factors for atherosclerosis. We studied the effect of age on the transarterial wall oxygen gradient in the rat using an oxygen microelectrode. A decrease in oxygen tension in the outer 35% of the artery wall was noted in 36- to 40-week-old rats when compared to 3- to 4-week-old rats. These findings were noted despite no difference in arterial blood oxygen tension between the two groups and prior to any histologic evidence of atherosclerotic lesion formation. Our observations suggest that aging decreases the delivery of oxygen to the outer artery wall.
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7786698
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Preliminary evaluation of a technique for inhibiting intimal hyperplasia: implantation of a resorbable luminal collagen membrane.
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Pharmacologic control of intimal hyperplasia has been attempted through oral and intravenous administration of smooth muscle cell inhibitors. We report a more direct method of altering arterial healing using a novel bioresorbable membrane that can be applied to the lumen of an artery or anastomosis following endarterectomy or vascular reconstruction. Following a standard balloon injury, the infrarenal aortas of 3 kg female New Zealand white rabbits were opened and a thin membrane composed of collagen/chondroitin 6-sulfate copolymer was sutured to the posterior wall of each artery. Animals were killed at intervals of up to 3 months. All arteries remained patent. By 24 hours the membrane had become infiltrated with fibrin and red blood cells. An inflammatory response ensued and by 8 days the membrane was filled with mononuclear cells. At 3 months only a small remnant of the membrane remained. Intimal hyperplasia developed throughout the injured aorta. However, the hyperplastic response beneath the membrane was no greater than that observed in the adjacent injured aorta. A bioresorbable membrane can be sutured into the lumen of a small-diameter vessel without inducing thrombosis and without locally increasing intimal hyperplasia. A prosthesis of this type might be used to deliver inhibitors of smooth muscle cell proliferation and migration to the injured arterial wall.
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7786695
|
Magnesium and therapeutics.
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Two different types of therapy with magnesium are used: physiological oral magnesium supplementation which is totally atoxic since it palliates magnesium deficiencies by simply normalizing the magnesium intake and pharmacological magnesium therapy which may induce toxicity since it creates iatrogenic magnesium overload. Primary and secondary magnesium deficiencies constitute the sole indication of physiological oral magnesium therapy. It is therefore necessary to be well acquainted with the clinical and paraclinical pattern of magnesium deficit and to discriminate between magnesium deficiency due to an insufficient magnesium intake which only requires oral physiological supplementation and magnesium depletion related to a dysregulation of the control mechanisms of magnesium status which requires more or less specific regulation of its causal dysregulation. Physiological oral magnesium load constitutes the best tool for diagnosis of magnesium deficiency and the first step of its treatment. Physiological oral magnesium supplementation (5 mg/kg/day) is easy and can be carried out in the diet or with magnesium salts, with practically only one contra-indication: overt renal failure. Specific and aspecific treatments of magnesium depletion are tricky using for example magnesium sparing diuretics, pharmacological doses of vitamin B6, physiological doses of vitamin D and of selenium. In order to use the pharmacological properties of induced therapeutic hypermagnesaemia, high oral doses of magnesium (> 10 mg/kg/day) are advisable for chronic indications and the parenteral route is suitable for acute indications. There are 3 types of indications: specific (for the treatment of some forms of magnesium deficit i.e. acute), pharmacological (i.e. without alterations of magnesium status) and mixed--pharmacological and aetiopathogenic--(for example complications of chronic alcoholism). Today pharmacological magnesium therapy mainly concerns the obstetrical, cardiological and anaesthesiological fields. The main indications are eclampsia, some dysrhythmias (torsades de pointe particularly) and myocardial ischaemias. But it is now difficult to situate the exact place of the pharmacological indications of magnesium. Magnesium infusions can only be envisaged in intensive care units with careful monitoring of pulse, arterial pressure, deep tendon reflexes, hourly diuresis, electrocardiogram and respiratory recordings. High oral magnesium doses besides their laxative action may bring latent complications which may reduce lifespan. There may remain some indications of the laxative and antacid properties of non soluble magnesium, particularly during intermittent haemodialysis. Lastly local use of the mucocutaneous and cytoprotective properties of magnesium is still valid, in cardioplegic solutions and for preservation of transplants particularly.
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7786694
|
New concepts in the cardioprotective action of magnesium and taurine during the calcium paradox and ischaemia of the heart.
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A rise in intracellular sodium during periods of exposure to calcium free media would seem to be the critical step that predisposes the mammalian heart to the damaging effects of the calcium paradox. The damage which is seen in both single cells and multicellular preparations, occurs on reperfusion with calcium containing media and results from calcium loading via the sodium/calcium exchanger where the rise in intracellular calcium provokes hypercontraction as well as activating hydrolytic enzymes. Because the rise in intracellular sodium is a critical step in inducing damage, manoeuvres which reduce this rise during calcium depletion are expected to protect the heart against the calcium paradox. Raising extracellular magnesium concentration is one such manoeuvre which by blocking the influx of sodium through the L-type calcium channels, reduces the rise in intracellular sodium during calcium depletion. The beta-amino acid taurine is another agent capable of opposing a rise in intracellular sodium. Taurine is present at high concentration in mammalian heart cells and is maintained against high concentration gradient. During calcium depletion, heart cells use this energy to efflux taurine and sodium via a taurine/sodium symport and therefore protect against the calcium paradox. A similar mechanism may also be used by the ischaemic heart to reduce the rise in intracellular sodium. In contrast to the changes seen during the calcium paradox the ischaemic heart shows a rise in intracellular magnesium concentration. This rise will have several and diverse cellular effects including the modulation of intracellular calcium mobilisation and of several membrane transporters. The potential significance of these effects remains to be evaluated. On the other hand elevated levels of extracellular magnesium may protect the ischaemic heart by reducing the influx of calcium by suppressing the L-type calcium channels and possibly the sodium/calcium exchanger. Finally evidence suggests that the rat heart may not be identical to that of other species in its response to the calcium paradox and to the protective role of intracellular taurine and extracellular magnesium. The reason for this species difference would seem to be due to different metabolic activity and the activity of the sodium, potassium-ATPase.
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