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8039850
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Lipids and lipoproteins during antihypertensive drug therapy. Comparison of doxazosin and atenolol in a randomized, double-blind trial: the Alpha Beta Canada Study.
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A randomized double-blind trial comparing the alpha-adrenergic blocker doxazosin and the beta-adrenergic blocker atenolol was completed by 131 patients with mild to moderate hypertension. Blood pressure and fasting blood lipids were determined at baseline and 4, 12, and 24 weeks of treatment. At entry, plasma lipids and lipoproteins were similar in those patients randomized to doxazosin or atenolol. After 24 weeks of treatment with atenolol, there were significant (P < .05) decreases in high-density lipoprotein cholesterol (HDL-C) and increases in triglycerides and very-low-density triglycerides (VLDL-T). In contrast, doxazosin was associated with significant (P < .05) increases in HDL-C and decreases in triglycerides and VLDL-T. There were no significant differences in HDL apolipoprotein (apo) A-I or low-density lipoprotein apoB between the drugs, but atenolol decreased the ratio of HDL-C to apoA-I, and doxazosin increased this ratio, differences that were statistically significant (P < .002). Neither apoA-I nor apoB concentration at baseline nor apoE phenotype was predictive of the lipid responses during antihypertensive treatment with either drug. Thus, there are significant favorable changes in HDL-C, total triglycerides, and VLDL-T between patients with mild to moderate hypertension and normal plasma lipids when treated with the alpha-blocker doxazosin compared with the beta-blocker atenolol. Plasma lipid or apo concentrations were not predictive of their lipid response during antihypertensive therapy with either of these agents.
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8039849
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How should diastolic blood pressure be defined during pregnancy?
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Controversy exists concerning the most accurate method for defining diastolic blood pressure in pregnancy. Both disappearance (phase V) and muffling (phase IV) of Korotkoff sounds have been advocated. We previously reported an objective noninvasive method for measuring blood pressure, called K2 analysis, which in nonpregnant subjects was not different from intra-arterial diastolic blood pressure and was more accurate than the auscultatory technique. For determination of the relation of diastolic blood pressure (using K2) in pregnancy with muffling and disappearance of Korotkoff sounds, 58 women (42 hypertensive, 16 normotensive) underwent 556 blood pressure evaluations in the supine position at various stages of pregnancy. K2 analysis was compared with simultaneous auscultation by two observers, A1 (n = 461 observations; 364 hypertensive, 97 normotensive) and A2 (n = 415; 316 hypertensive, 99 normotensive). Overall, muffling was detected by observer A1 52.9% (244/461) and by observer A2 44.3% (184/415) of the time. When evaluated by clinical classification, muffling was found by both observers to be present less often in the hypertensive group (A1: 47.5%; A2: 37.3%) compared with the normotensive group (A1: 73.2%; A2: 66.7%) (P < .0001). When both observers were present (n = 348), they agreed that muffling was present only 112 times. Disappearance of sound was detected by both observers 98.3% (A1: 453/461; A2: 408/415) of the time. Muffling overestimated K2 diastolic pressure by 7 to 10 mm Hg, whereas there was no statistically significant difference between disappearance and K2 diastolic pressure for hypertensive subjects and a 2.5-mm Hg underestimation of K2 diastolic pressure for normotensive subjects.(ABSTRACT TRUNCATED AT 250 WORDS)
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8039848
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Phosphoramidon-sensitive conversion of big endothelin-1 and degradation of endothelin-1 in rat kidney.
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We investigated the intrarenal conversion of big endothelin-1 (ET-1) to ET-1 in the isolated perfused rat kidney. Big ET-1 caused a concentration-dependent increase in perfusion pressure, and the pressor molar potency of the peptide was 50-fold less than that of ET-1. The big ET-1 (2 x 10(-8) mol/L)-induced pressor action was accompanied by increases in immunoreactive endothelin levels in both the perfusate and renal tissues. Phosphoramidon (10(-4) mol/L), a metalloproteinase inhibitor, significantly suppressed the big ET-1-induced pressor action and the accumulation of immunoreactive endothelin in renal tissues. On the other hand, phosphoramidon slightly but significantly sustained the ET-1-induced pressor effect. The effect of kelatorphan (10(-4) mol/L), a specific inhibitor of neutral endopeptidase 24.11, on the ET-1-induced pressor effect was the same as that seen with phosphoramidon. When ET-1 was exogenously added to the perfusate, phosphoramidon or kelatorphan significantly increased the immunoreactive endothelin levels in renal tissues after perfusion, without affecting the disappearance rate of immunoreactive endothelin from the perfusate. Therefore, the phosphoramidon-sensitive ET-1-converting enzyme in the kidney seems to contribute to the functional local conversion of big ET-1 to ET-1, and neutral endopeptidase 24.11 may be responsible for the proteolytic degradation of ET-1 in the kidney. In addition, immunoreactive endothelin levels in renal tissues but not in the perfusate can account for the functional conversion of big ET-1 to ET-1 and for the local proteolytic degradation of ET-1 in the kidney.
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8039847
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Nitric oxide increases renal blood flow by interacting with the sympathetic nervous system.
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To investigate whether changes in renal blood flow induced by nondepressor doses of L-arginine, the precursor of nitric oxide, are mediated by a sympathetic neural mechanism, we examined the following in conscious rabbits: (1) the effects of intravenous infusion of L- or D-arginine (15 to 200 mumol/kg per minute) on renal blood flow and renal sympathetic nerve activity with or without intravenous infusion of a nonpressor dose of NG-monomethyl-L-arginine (L-NMMA), a nitric oxide synthase inhibitor, and (2) the effects of L-arginine on renal blood flow after renal denervation with or without L-NMMA pretreatment. In renal innervated rabbits, L-arginine (100 and 200 mumol/kg per minute) increased renal blood flow by 9 +/- 2 and 16 +/- 3 mL/min (P < .05, respectively) and decreased renal sympathetic nerve activity by 12 +/- 4% and 19 +/- 3% of control (P < .05, respectively). In contrast, no changes occurred in any variable during D-arginine infusion. L-NMMA attenuated the renal blood flow and renal sympathetic nerve activity responses to L-arginine (P < .05). In renal denervated rabbits, L-NMMA also attenuated the renal blood flow responses to L-arginine (P < .05) and abolished them (P < .05) compared with those in renal innervated rabbits. All renal blood flow responses to L-arginine were accompanied by parallel changes in plasma L-citrulline concentration.(ABSTRACT TRUNCATED AT 250 WORDS)
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8039846
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Coronary artery constriction caused by the cold pressor test in human hypertension.
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Hypertensive patients with angiographically normal coronary arteries may have myocardial ischemia when metabolic demand increases. Abnormal epicardial coronary artery vasomotion in response to sympathetic stimulation may contribute to ischemia in such patients. We studied the vasomotor response of smooth coronary arteries to a cold pressor test in 10 hypertensive patients without other risk factors and in 9 control subjects. Vessel dimensions were measured by quantitative angiography, and blood flow was calculated using an intracoronary Doppler catheter in the left anterior descending coronary artery. In response to cold pressor stimulation, arteries of control subjects dilated 13.0 +/- 5.9% (P < .001), and they constricted 8.2 +/- 8.5% in hypertensive patients (P < .001). Rate-pressure product increased from 9466 +/- 1677 to 12,547 +/- 2367 beats per minute (bpm).mm Hg in control subjects (P < .001) and from 13,720 +/- 1823 to 17,353 +/- 2037 bpm.mm Hg in hypertensive patients (P < .001). Coronary blood flow velocity and blood flow increased 51 +/- 26% (P < .05) and 87 +/- 27% (P < .001), respectively, in control subjects and 68 +/- 52% (P < .05) and 36 +/- 33% (P < .01) in hypertensive patients. At peak cold pressor test, despite a significant higher rate-pressure product in hypertensive patients, blood flow was similar in both groups, suggesting an uncoupling between myocardial metabolic demand and supply. Thus, hypertension impairs the vasodilator response of angiographically normal coronary arteries to a cold pressor test. This abnormal response may be due to enhanced catecholamine reactivity and/or impairment of endothelial flow-mediated vasodilator response.
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8039845
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Effect of nifedipine on coronary capillary geometry in normotensive and hypertensive rats.
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The aim of this study was to describe quantitatively changes in the coronary capillary network resulting from hypertrophy in spontaneously hypertensive rats (SHR) and a potential effect of long-term treatment of these animals with nifedipine. Age-matched male SHR and Wistar-Kyoto (WKY) rats were treated for 27 weeks. Four experimental groups were analyzed: (1) untreated SHR, (2) nifedipine-treated SHR, (3) untreated control WKY rats, and (4) nifedipine-treated WKY rats. Treatment significantly decreased systolic blood pressure in SHR, although normotensive pressures were not reached. SHR had significantly higher cardiac weight, which decreased in nifedipine-treated rats, but values remained above those in control animals. Morphometric evaluation revealed lower capillary density and larger capillary domain area in hearts from SHR, which were partially attenuated by treatment with nifedipine. Capillary domain area was also significantly larger at arteriolar portions compared with domains supplied at venular portions. Capillary segment length was consistently shorter on the venular than arteriolar portion of the capillary, whereas no differences were observed between hearts from WKY rats and SHR. Treatment with nifedipine resulted in a prolongation of segment length. Reconstruction of the three-dimensional capillary supply unit (capillary domain area times capillary segment length) revealed significant differences between the amount of tissue supplied by a capillary at its arteriolar portion than more distally, which was detectable in all experimental groups. In hypertrophic hearts from SHR this tissue volume is increased mainly because of longer intercapillary distances and larger domains, especially on arteriolar portions.(ABSTRACT TRUNCATED AT 250 WORDS)
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8039844
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Role of angiotensin II in renal injury of deoxycorticosterone acetate-salt hypertensive rats.
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To investigate the role of angiotensin II (Ang II) in hypertension-induced tissue injury, we gave TCV-116 (1 mg/kg per day PO), a nonpeptide Ang II type I receptor antagonist, or enalapril (10 mg/kg per day PO) to deoxycorticosterone acetate (DOCA)-salt hypertensive rats for 3 weeks and examined the effects on tissue mRNA levels for transforming growth factor-beta 1 (TGF-beta 1) and extracellular matrix components. Tissue mRNA levels were measured by Northern blot analysis. Renal mRNA levels for TGF-beta 1; types I, III, and IV collagen; and fibronectin in DOCA-salt hypertensive rats were increased by severalfold (P < .01) compared with sham-operated rats. In the aorta of DOCA-salt hypertensive rats, TGF-beta 1 and fibronectin mRNA levels were increased, but types I, III, and IV collagen mRNAs did not increase. In the heart, increased mRNA was found only for fibronectin. Thus, these gene expressions are regulated in a tissue-specific manner. TCV-116 or enalapril did not lower blood pressure in DOCA-salt hypertensive rats. However, the increase in renal mRNAs for TGF-beta 1 and extracellular matrix components in DOCA-salt hypertensive rats was significantly inhibited by treatment with TCV-116 or enalapril, which was associated with a significant decrease in urinary protein and albumin excretions and histological improvement of renal lesions. In contrast, in the aorta and heart these gene expressions were not affected by TCV-116 or enalapril. Thus, local Ang II may contribute to renal injury of DOCA-salt hypertension by stimulating the gene expression of TGF-beta 1 and extracellular matrix components.
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8039843
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Inhibitory effect of ammonium chloride on acetylcholine-induced relaxation.
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We designed the present study to clarify whether the intracellular pH change by ammonium chloride influences endothelium-dependent relaxation in thoracic aorta of 9-week-old Sprague-Dawley rats. Intracellular alkalinization with 3 mmol/L ammonium chloride, which did not affect resting vascular tone, attenuated acetylcholine-induced relaxation but not nitroglycerin vasodilation. Acetylcholine relaxation was more inhibited by a shorter duration of treatment. Thus, change in intracellular pH may be important in the effect because the alkalinizing effect of ammonium chloride disappears gradually. In support of this, the proton ionophore nigericin abolished the effect. Also, amiloride shortened the effect of ammonium chloride, suggesting that intracellular pH plays a role: sodium-proton antiport antagonizes the disappearance of ammonium chloride-induced intracellular alkalinization. The synthesis of vasoconstrictor prostaglandins, such as thromboxane A2, may be stimulated during acetylcholine treatment, resulting in the attenuation of acetylcholine relaxation, because the relaxation was abolished by treatment with the phospholipase A2 inhibitor quinacrine, cyclooxygenase inhibitor indomethacin, prostaglandin H2/thromboxane A2 receptor antagonist S1452, and thromboxane A2 synthase inhibitor dazmegrel. Phospholipase A2 may contribute to the effect of intracellular alkalinization, which is compatible with the fact that the optimal pH of phospholipase A2 is neutral to alkaline. In addition, superoxide dismutase attenuated the effect of ammonium chloride. In conclusion, intracellular alkalinization by ammonium chloride attenuated acetylcholine-induced relaxation, possibly through the interrelated production of both thromboxane A2 and superoxide radicals.
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8039842
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Effect of a nonselective endothelin antagonist on vascular remodeling in deoxycorticosterone acetate-salt hypertensive rats. Evidence for a role of endothelin in vascular hypertrophy.
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We have previously shown that the endothelin content in arteries of deoxycorticosterone acetate (DOCA)-salt hypertensive rats is increased. We designed this study to examine, using the new orally active nonselective endothelin receptor antagonist bosentan, whether this increase in vascular endothelin may contribute to elevated blood pressure and vascular hypertrophy in DOCA-salt hypertensive rats. Rats received bosentan (100 mg/kg body wt per day) for 3 weeks mixed with their food. Systolic blood pressure of DOCA-salt hypertensive rats rose to 197 +/- 5 mm Hg, and that of bosentan-treated DOCA-salt hypertensive rats was 177 +/- 4 mm Hg (P < .01). Mesenteric resistance arteries were studied on a wire myograph. The media width, ratio of media width to lumen diameter, and cross-sectional area of the media of resistance arteries of bosentan-treated DOCA-salt hypertensive rats were significantly smaller than those of untreated DOCA-salt hypertensive rats. The lumen diameter and cross-sectional area of the media of vessels of bosentan-treated rats were not different from those of uninephrectomized control rats. Vasoconstrictor responses, which were altered in DOCA-salt hypertensive rats, approached control in the bosentan-treated rats. We conclude that these results with a nonselective endothelin receptor antagonist may suggest a role for endothelin in the elevation of blood pressure and vascular hypertrophy and remodeling in DOCA-salt hypertensive rats.
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8039841
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In vivo effect of calcitriol on calcium transport and calcium binding proteins in the spontaneously hypertensive rat.
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The abnormal intestinal Ca2+ transport reported in spontaneously hypertensive rats (SHR) has been attributed to decreased responsiveness to calcitriol. We reexamined this hypothesis by studying the calcitriol regulation of SHR duodenal calbindin-D9K and calmodulin and the relation of calcitriol to Ca2+ uptake by isolated enterocytes. SHR and normotensive Wistar-Kyoto (WKY) rats were injected with either 50 ng/d calcitriol (vit-D) or vehicle alone (control) for 3 days. Decreased calbindin-D9K (P < .001) and cellular Ca2+ flux (P < .001) were observed in control SHR. Calcitriol increased total cell and brush border calbindin-D9K (P < .0001); this variation paralleled plasma calcitriol levels in both strains. In contrast, Ca2+ flux, which increased in vit-D animals, remained lower in SHR for plasma calcitriol levels similar to those in WKY rats. Immunoreactive calmodulin was similar in both strains whether assayed in total cell or brush border membranes. In contrast, when measured by ligand blotting (45Ca), calmodulin was lower in SHR than in WKY rats (P < .01), suggesting the existence of a calmodulin pool with reduced Ca2+ binding capacity in the hypertensive strain. Calcitriol had no effect on calmodulin in either strain. In conclusion, Ca2+ binding protein regulation by calcitriol is normal in the SHR, and decreased hormone responsiveness cannot account for the defective duodenal calcium transport of this experimental model of hypertension.
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8039840
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Effects of pioglitazone on calcium channels in vascular smooth muscle.
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Pioglitazone, an insulin-sensitizing, antidiabetic agent, has blood pressure-lowering effects in insulin-resistant hypertensive rats and attenuates growth factor-induced increases of intracellular Ca2+ in rat aortic vascular smooth muscle cells. To determine whether modulation of voltage-dependent Ca2+ channels plays a role in this association, we investigated the effects of pioglitazone on voltage-dependent current in cultured rat aortic (a7r5) and freshly dissociated rat tail artery vascular smooth muscle cells. Both cell types were studied with whole-cell patch-clamp techniques. Current through L-type Ca2+ channels was elicited with a voltage ramp in the presence of Ba2+ substituted for Ca2+. T-type Ca2+ current was studied using a two-pulse protocol that enabled the isolation of transient current. In a7r5 vascular smooth muscle cells, 2-minute application of pioglitazone (5 and 10 mumol/L) reduced L-type current by 7.9 +/- 1.0% (n = 8) (mean +/- SEM, number of cells) and 14.5 +/- 3.0% (n = 9) (P < .01, two-tailed paired t test), respectively. In contrast, 2-minute application of pioglitazone had no significant effect on T-type Ca2+ current. In freshly dissociated tail artery vascular smooth muscle cells, 2-minute application of 10 mumol/L pioglitazone had an insignificant effect (4.8 +/- 5.6% reduction); however, 25 mumol/L pioglitazone reduced L-type current by 27.3 +/- 7.2% (n = 5) (P < .01). Two-minute application of 0.1% or 0.2% dimethyl sulfoxide (vehicle) alone had no significant effects on currents in either type of vascular smooth muscle cell.(ABSTRACT TRUNCATED AT 250 WORDS)
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8039839
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Ciprokiren (Ro 44-9375). A renin inhibitor with increasing effects on chronic treatment.
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The present study characterizes the new transition-state renin inhibitor ciprokiren (Ro 44-9375) in squirrel monkeys. Arterial blood pressure was monitored by telemetry in freely moving, chronically instrumented conscious animals. In vitro at pH 7.4, ciprokiren inhibited human renin in buffer and human plasma with an IC50 of 0.07 and 0.65 nmol/L, respectively. It was equipotent against primate plasma renin and also inhibited plasma renin from dog and guinea pig in the nanomolar range (IC50, 29 and 65 nmol/L, respectively). After acute oral administration it reduced arterial blood pressure dose dependently in normotensive sodium-depleted and cyclosporin-induced hypertensive squirrel monkeys, starting with the minimal oral dose of 3 micrograms/kg. Daily oral doses of 1 microgram/kg showed a progressive blood pressure decrease, with a maximal response reached after 1 week. The drug could also be applied transdermally with similar hemodynamic effects without any decrease of plasma renin activity or plasma immunoreactive angiotensin II. Thus, ciprokiren is characterized in squirrel monkeys as a renin inhibitor with high in vivo potency that might act mainly in the tissular compartment.
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8039838
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Interrelation between renin mRNA levels, renin secretion, and blood pressure in two-kidney, one clip rats.
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To examine the interrelation between renin mRNA levels, renin secretion, and blood pressure in rats, we clipped the left renal arteries of rats and measured renin mRNA levels in both kidneys, plasma renin activity, and blood pressure. One and 2 days after clipping, renin mRNA levels increased 3-fold and 4.3-fold in the stenosed kidney and were suppressed to 52% and 26% of controls in the intact kidneys; plasma renin activity increased from 8 to 16.5 and to 30.5 ng angiotensin I.h-1.mL-1 and systolic blood pressure rose from 114 to 123 and to 137 mm Hg. We found a strong correlation (P < .001) between plasma renin activity and renin mRNA levels in the clipped kidneys. We also found significant correlations (P < .05) between mRNA levels in the clipped and intact kidneys and between plasma renin activity and blood pressure for the individual animals. Treatment of normal rats with the converting enzyme inhibitor ramipril (5 mg/kg twice a day) for 2 days increased renin mRNA levels in both kidneys fourfold. In animals with unilateral clips, additional treatment with ramipril increased renin mRNA levels 6.4-fold in the stenosed and 3.3-fold in the intact kidneys. These findings suggest that endogenous angiotensin II exerts an inhibitory effect on renin mRNA expression in normal kidneys, clipped kidneys, and their contralaterals. Suppression of the renin gene in contralateral kidneys seems not to be directly mediated by the rise of plasma renin activity or by the rise of blood pressure in two-kidney, one clip rats.
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8039837
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Adaptation, allometry, and hypertension.
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Essential hypertension is a "disease of civilization" but has a clear genetic component. From an evolutionary perspective, persistence in the human genome of elements capable of raising blood pressure presupposes their adaptive significance. Recently, two hypotheses that explicitly appeal to selectionist arguments, the "slavery" and "thrifty gene" theories, have been forwarded. We find neither completely successful, and we advance an alternative explanation of the adaptive importance of genes responsible for hypertension. We propose that blood pressure rises during childhood and adolescence to subserve homeostatic needs of the organism. Specifically, we contend that blood pressure is a flexible element in the repertoire of renal homeostatic mechanisms serving to match renal function to growth. The effect of modern diet and lifestyle on human growth stimulates earlier and more vigorous development, straining biologically necessary relationships between renal and general somatic growth and requiring compensation via homeostatic mechanisms preserved during evolution. Prime among such mechanisms is blood pressure, which rises as a compensation to maintain renal function in the face of greater growth. Since virtually all members of acculturated societies share in the modern lifestyle, the demands imposed by accelerated growth and development result in a populational shift to higher blood pressures, with a consequent increase in the prevalence of hypertension. We propose that hypertension is the product of maladaptation of highly genetically conserved mechanisms subserving important biological homeostatic needs. Elucidation of the mechanisms underlying hypertension will require approaches that examine the developmental processes linking growth to blood pressure.
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8039829
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The immunoglobulin repertoire of the rainbow trout (Oncorhynchus mykiss): definition of nine Igh-V families.
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An Igh-V library was constructed from the head kidney cytoplasmic RNA of an 8.5-month-old non-immunized rainbow trout, Oncorhynchus mykiss, using the 5' RACE polymerase chain reaction. Six new Igh-V segments were identified, bringing to nine the number of Igh-V families actually defined in that species. A phylogenetic analysis shows that these nine Igh-V families can be classified into three major groups. The first includes the Igh-V1, Igh-V3, Igh-V4, and Igh-V7 families, and is homologous to the human and mouse Group III Igh-V families. The second includes the Igh-V5, Igh-V8, and Igh-V9 families and is more closely related to the Group I and Group II human and mouse Igh-V families. The third group includes the Igh-V2 and Igh-V6 families, which are not closely related to any other vertebrate Igh-V gene. Six Igh-J segments were characterized. They can recombine with Igh-V segments belonging to different families and there is a high level of junctional diversity between the Igh-V and Igh-J segments.
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8039828
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Two different IFN-gamma nonresponsive variants derived from the B-cell lymphoma 70Z/3.
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The kappa immunoglobulin (Igk) light chain locus is transcriptionally silent in the mouse B-cell lymphoma 70Z/3. However, exposure to lipopolysaccharide (LPS) or interferon-gamma (IFN) causes a marked increase in Igk transcription. By immunoselection, we isolated two variants that are nonresponsive to IFN. One variant, AT7.2, has retained its response to LPS (IFN-LPS+), whereas the other, AT3.3, is also nonresponsive to LPS (IFN-LPS-). Stable transfection of an intact Igk gene does not rescue the phenotype of either variant. Both variants have intact Igk genes and neither is deficient in the binding or uptake of IFN. Nuclear extracts from LPS-treated wild-type 70Z/3 cells show strong increases in three transcription factors: OTF-2, NF-kappa B, and kBF-A. Remarkably, when the IFN-LPS- variant is treated with LPS, all three transcription factors are still observed in the nuclear extracts. Treatment of wild-type cells with either LPS or IFN also causes a decrease in nuclear complexes that bind to two other regions of the Igk intron enhancer, the octenh and the E kappa MHCIC regions. Both of these changes are also observed after LPS or IFN treatment of the IFN-LPS- variant. Thus, this variant transduces the IFN and LPS signals at least into the nuclear compartment, but still fails to activate Igk transcription. In contrast, the IFN-LPS+ variant decreases neither the octenh nor the E kappa MHCIC binding complexes in response to IFN. This variant may be defective in transducing the IFN signal to the nucleus. These variants will be useful in studying the activation of Igk transcription and the IFN signaling pathway in B cells.
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8039827
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The peptide binding specificity of HLA-B27 subtypes.
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Five HLA-B27 subtypes, B*2701, B*2703, B*2704, B*2705, and B*2706, were tested for direct binding with twenty-six synthetic nonapeptides carrying the primary anchor residue motifs (combination of amino residues at positions 2 and 9) relevant to B*2705. The peptide sequences were derived from human HSP89 alpha, P53 and MBP. The alpha chains were immunospecifically isolated from LH (B*2701), CH (B*2703), WE1 (B*2704), BTB (B*2705), and LIE (B*2706) cells and their peptide binding was measured by the HLA class I alpha chain refolding assay. The data obtained indicated that the B27 subtypes tested can bind a common set of peptides carrying several different anchor residue motifs. The motifs, R-K and R-R, reported for B*2705 and a new motif H-R were accepted by B*2703, B*2704, and B*2706, but not by B*2701. However, other motifs, including known B*2702 and/or B*2705 motifs, R-H, R-L, R-A, and R-F, and a new motif found here, R-G, were apparently accepted by all B27 subtypes tested. The observed cross-peptide binding in the B27 subgroup is compatible with the so-called arthritogenic peptide hypothesis in the pathogenesis of ankylosing spondylitis.
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8039826
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Structure, diversity, and evolution of the T-cell receptor VB gene repertoire in primates.
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AB T-cell receptors (TCR) that recognize major histocompatibility complex (MHC)/peptide antigen complexes regulate humoral and cellular arms of the adaptive immune response. Antigen binding sites of MHC and immunoglobulin heavy chain variable regions (Igh-V) are subject to diversity enhancing selection. We sought to establish whether positive Darwinian selection has driven diversity of TCRBV chains in the primate lineage by sequencing rearranged TCR from rhesus monkeys and chimpanzees and comparing them with those of humans. Rates of synonymous (silent) and nonsynonymous (replacement) substitutions indicate selection against amino acid replacements in TCRBV frameworks, and relaxation of these constraints in putative MHC/peptide contact sites. The lack of positive selection for variability in likely ligand contact sites suggests that mechanisms generating somatic diversity in TCR junctional regions have relaxed the pressure for selection of variability in the TCR V region encoded in the germline.
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8039824
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The cotton-top tamarin revisited: Mhc class I polymorphism of wild tamarins, and polymorphism and allelic diversity of the class II DQA1, DQB1, and DRB loci.
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Cotton-top tamarins (Saguinus oedipus) in captivity are unusual in that they exhibit low levels of polymorphism and allelic diversity at the major histocompatibility complex (Mhc) class I loci. Since the polymorphism has previously only been examined in captive tamarins, we analyzed the Mhc class I alleles of a population of wild tamarins. These wild tamarins, like their captive counterparts, exhibited limited class I polymorphism. We also assessed the levels of polymorphism and allelic diversity at the Mhc class II DQA1, DQB1, DQB2, and the DRB loci in captive populations of cotton-top tamarins. In contrast to the extensive polymorphism in Old World monkeys, only two alleles were detected at each of DQA1 and DQB1. Also, the DQB2 locus was monomorphic and conserved between New and Old World monkeys. Sequences derived from four putative DRB loci were obtained, and extensive polymorphism was found at all four loci. Phylogenetic analysis did not indicate that any of the tamarin DRB loci, with the possible exception of Saoe-DRB3, were orthologous to the human DRB loci. At three of the DRB loci (Saoe-DRB11, Saoe-DRB*W12, Saoe-DRB*W22), the number of nonsynonymous changes was higher than the number of synonymous changes in the putative antigen recognition sites, indicative of positive selection. We found no support for a restriction on the polymorphism at the cotton-top tamarin class II loci. However, the allelic diversity at some of the Saoe-DRB loci is more limited than for the HLA-DRB1, consistent with a restriction imposed by the bone marrow-chimerical lifestyle.
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8039825
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Mapping of the human lambda immunoglobulin variable gene subgroup 1.
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We describe the cloning and mapping of 20 putative members of the IGLV subgroup 1. These gene segments are contained on 26 phage clones which fall into 7 contigs plus one solitary phage. This represents approximately 240 kilobases (kb) of cloned DNA. Like IGLC gene segments, the IGLV gene segments were found to be oriented proximal to distal on the chromosome, indicating IGL somatic rearrangement is by deletion. The gene segments were placed on a long-range map of the IGL locus, which covers at least 800 kb. Clones were further ordered by pulsed field gel electrophoresis analysis of B-cell lines known to produce IGL-containing immunoglobulins. DNA deletions ranged from 120 to 570 kb.
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8039822
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Miliary mottling in non-Hodgkins lymphoma.
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Pulmonary parenchymal involvement and mediastinal lymphadenopathy are less common manifestations of non-Hodgkin's lymphoma as compared to Hodgkin's lymphoma. The pattern of pulmonary disease varies with histological type of non-Hodgkin's lymphoma. We are presenting an uncommon case of diffuse histiocytic lymphoma having miliary mottling who responded well to chemotherapy.
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8039823
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Cryptococcosis: involvement of more than one system.
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We report a 37-year-old female patient with pulmonary cryptococcosis who presented with a one week old history of cough and fever. Within a week of admission, she developed cryptococcal meningitis and 5 months later cryptococcomas of the brain were detected. She was successfully treated with 2 courses of amphotericin-B at an interval of 5 months. 5-flucytosine was also administered initially along with amphotericin-B. The pulmonary lesions resolved completely whereas the cryptococcomas reduced in number.
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8039821
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Wegener's vasculitis: diagnostic and therapeutic problems.
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A case of Wegener's granulomatosis (WG) presenting with pulmonary manifestation which were initially suspected to be due to tuberculosis is being reported. Renal involvement appeared later. He developed complications of antitubercular treatment and of immunosuppression. The difficulties in distinguishing pulmonary manifestation of WG from tuberculosis and other diagnostic and therapeutic problems are discussed.
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8039818
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Role of mechanical ventilation in acute severe asthma.
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During the last 4 years, fifty-seven patients of acute severe asthma (ASA) were admitted to intensive care unit (ICU). Twenty-three patients required mechanical ventilation (MV) on 25 occasions. Indications to intubate were persistent hypoxia (PaO2 < or = 55 mm Hg) or hypercapnia with respiratory acidosis (64%), abnormal mentation (24%) and respiratory arrest (12%). All the patients were monitored for clinical features, arterial blood gases (ABG) and peak airway pressure (PAP). During MV, there was one case of pneumothorax (4%), seven (28%) cases of transient hypertension and one (4%) patient died. Mean duration of MV was 3 days and the outcome was favourable. Therefore, resorting to aggressive treatment early in the course of disease proves life saving in acute severe asthma.
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8039819
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Multivariate analysis of byssinosis risk assessment.
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Multiple logistic regression model was used considering byssinosis as an independent variable, and dustiness, smoking, exposure years and age as explanatory variables. Dustiness and length of exposure to the dust were found to be the most important contributory factors to byssinosis prevalence. The risk of byssinosis among workers in card room, blow room and waste plant sections and those who had exposure of more than 5 years was nearly three times than that among workers of other sections of the mill and/or with less than 5 years of exposure.
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8039817
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On the contribution of height to predict lung volumes, capacities and diffusion in healthy school children of 10-17 years.
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Lung volumes, capacities, diffusion and alveolar volumes with physical characteristics (age, height and weight) were recorded for 186 healthy school children (96 boys and 90 girls) of 10-17 years age group. The objective was to study the relative importance of physical characteristics as regressor variables in regression models to estimate lung functions. We observed that height is best correlated with all the lung functions. Inclusion of all physical characteristics in the models have little gain compared to the ones having just height as regressor variable. We also find that exponential models were not only statistically valid but fared better compared to the linear ones. We conclude that lung functions covary with height and other physical characteristics but do not depend upon them. The rate of increase in the functions depend upon initial lung functions. Further, we propose models and provide ready reckoners to give estimates of lung functions with 95 per cent confidence limits based on heights from 125 to 170 cm for the age group of 10 to 17 years.
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8039816
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Comparison of salbutamol dry powder aerosol with pressurised aerosol.
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The bronchodilator efficacy of two doses of dry salbutamol powder (rotacap) was compared with the conventional dose of metered dose inhaler (MDI). The doses used were: 200 micrograms rotacaps, 400 micrograms rotacaps and 200 micrograms MDI. All the three doses resulted in a significant bronchodilation, increasing the FEV1. The increase in FEV1 was 11.4%, 23.2% and 24% respectively. The improvement following 400 micrograms rotacap was similar to that seen after 200 micrograms MDI. Both 200 micrograms MDI and 400 micrograms rotacap resulted in significantly greater increase in FEV1 as compared to 200 micrograms rotacaps. It was concluded that bronchodilator effect is superior with an MDI and a double dose of powder aerosol is required to achieve the same results.
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8039815
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Cellular specificity of murine renal C3 expression in two models of inflammation.
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The expression of the complement protein C3 in extrahepatic tissues is highly regulated during the course of inflammation. Hence, systemic acute phase stimuli such as bacterial lipopolysaccharide (LPS) and autoimmune nephritis in aged 'lupus mice' (MRL-lpr/lpr and NZB x NZW F1) both lead to increased C3 mRNA expression in whole kidney. In situ hybridization was used to determine the intrarenal cell type(s) capable of constitutive and regulated C3 mRNA expression. Normal mice injected with Escherichia coli LPS show a marked increase in whole kidney C3 mRNA over control (saline-injected) animals. The renal C3 mRNA in LPS-stimulated mice was found in cortical tubular epithelium. By contrast, in aged (18 week) MRL-lpr/lpr mice, which develop lupus nephritis, the increased intrarenal C3 messenger RNA was localized to perivascular inflammatory cells surrounding medium-sized arteries. Similar perivascular infiltrates were seen in the lungs of the MRL-lpr/lpr mice, and focal inflammatory cell infiltrates were also found in the myocardium. Leucocytes in these infiltrates accounted for the increased C3 expression in these tissues. These findings suggest cell as well as tissue specificity of the response to inflammatory stimuli in the local extrahepatic production of the third component of complement.
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8039813
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T-helper 1-like subset selection in Mycobacterium bovis bacillus Calmette-Guérin-infected resistant and susceptible mice.
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The Bcg gene has been shown to control natural resistance of mice to intravenous infection with low doses of Mycobacterium bovis (bacillus Calmette-Guérin; BCG). In the present study, we evaluated the impact of the Bcg gene on the development of T-cell reactivity during the early stages of infection. Congenic strains of mice, bearing 'r' and 's' alleles of the Bcg gene on B10.A and BALB/c backgrounds, were studied at different time-points for 2 weeks after infection. The in vitro proliferative response of spleen cells, induced by mycobacteria or concanavalin A, was depressed in the Bcgs mice compared to the Bcgr congenic mice 14 days after infection with 10(5) colony-forming units (CFU) of BCG. Polymerase chain reaction (PCR)-based methodology was used to compare the level of lymphokine gene expression in the spleens of infected congenic mice both ex vivo and after in vitro stimulation. In both cases, preferential expression of interferon-gamma (IFN-gamma), lymphotoxin, interleukin-2 (IL-2) and IL-2 receptor genes was observed. The lymphokine gene expression profiles indicated that T lymphocytes activated in the course of the BCG infection preferentially expressed the T-helper 1-specific pattern, irrespective of the allele of the Bcg gene. We showed that this bias in T-cell differentiation could not be attributed to either down-regulation of IL-4 gene expression or modulation of the macrophage co-stimulatory activity by live M. bovis BCG. We conclude that the mechanism of phenotypic expression of the Bcg gene resides in the differential ability of macrophages to be activated by lymphokines produced by protective T cells, rather than in the lack of these lymphokines in susceptible animals.
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8039814
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The importance of interferon-gamma in an early infection of Chlamydia psittaci in mice.
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Athymic mice (nu/nu) and their hairy littermates (nu/+) were infected experimentally with Chlamydia psittaci and the role of endogenous interferon-gamma (IFN-gamma) on the resolution of the infection was studied. The pathological changes produced in the spleen, liver and lung were exacerbated by administration of a monoclonal antibody (mAb) to IFN-gamma and an increased number of viable chlamydiae were recovered from the tissues of both nu/+ and nu/nu mice treated in this way.
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8039812
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Signal transduction via Fc gamma R and Mac-1 alpha-chain in monocytes and polymorphonuclear leucocytes.
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Some (VIM12, Leu-15, 5A4.C5), but not all, Mac-1-specific monoclonal antibodies (mAb) induced a clear respiratory burst in unprimed monocytes but not in unprimed polymorphonuclear leucocytes (PMN). We showed that this monocyte stimulation occurred via formation of Mac-1 mAb-Fc gamma RI or Mac-1 mAb-Fc gamma RII complexes, as human monomeric IgG1 could completely block the respiratory burst induced by the murine IgG2a subclass anti-Mac-1 mAb Leu-15 and the Fc gamma RII-specific mAb IV.3 inhibited respiratory burst formation by IgG1 subclass anti-Mac-1 mAb VIM12 and 5A4.C5, respectively. F(ab')2 fragments of mAb VIM12 did not stimulate. This association between Mac-1 and Fc gamma RII may be due to a near spatial association between these molecules in monocytes, as we observed partial inhibition of FITC-labelled anti-Fc gamma RII mAb IV.3 binding after prior incubation with mAb VIM12. If monocytes were preincubated with mAb IV.3 or aggregated IgG, there was partial inhibition of mAb VIM12 binding. The non-stimulating anti-Mac-1 mAb (JML.H11,44, OKM1, LM2/1, Mo1) did not show any significant competition with mAb IV.3 binding to Fc gamma RII. Both non-stimulating CD18-specific mAb, however, showed strong competition with mAb IV.3 binding to Fc gamma RII. On unprimed PMN, the situation was different. No Mac-1-specific mAb induced a respiratory burst and there was no competitive inhibition between anti-Mac-1 mAb and antibodies binding to Fc gamma RII. In interferon-gamma (IFN-gamma)-primed PMN, however, we observed a functional association between Mac-1 and Fc gamma RI as IgG2a subclass mAb Leu-15 induced a respiratory burst which could be inhibited by monomeric human IgG1, as observed in monocytes. However, no other anti-Mac-1 mAb was able to induce a respiratory burst in IFN-gamma-primed PMN. Therefore, a similar signal transducing capability may exist between Mac-1 and Fc gamma RI on both monocytes and PMN, despite a different relationship between Mac-1 and Fc gamma RII on these cell populations. As no Mac-1 beta-chain-specific (CD18)mAb were able to induce a respiratory burst in monocytes, despite being able to interact with Fc gamma R via their Fc regions, as detected by competition with mAb IV.3 for binding to Fc gamma RII, we conclude that intracellular signalling via Mac-1 mAb-Fc gamma RII complexes requires the alpha-chain.
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8039811
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Prostaglandins inhibit lipoprotein lipase gene expression in macrophages.
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In the present investigation of the effects of prostaglandin E2 (PGE2) on lipoprotein lipase (LPL) gene expression in macrophages, we observed that treatment of macrophages with PGE2 increased the levels of adenosine 3',5'-cyclic monophosphate (cAMP), while the addition of exogenous 5-bromo-cAMP to macrophage cultures resulted in down-regulation of LPL expression. Using indomethacin (INDO), an inhibitor of cyclo-oxygenase and prostaglandins production, we determined that PGE2 acts as a feedback inhibitor of LPL expression. We found that inhibited secretion of LPL protein in lipopolysaccharide (LPS)-treated macrophages could be restored to control levels by the addition of INDO to the medium. In contrast, INDO did not reverse the inhibition of LPL mRNA induced by LPS. Overall, our results have demonstrated that PGE2 is a potent inhibitor of LPL gene expression and indicated that its action may play an important physiological role in the regulation of LPL gene expression during bacterial infections.
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8039810
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Influence of suramin on the expression of Fc receptors and other markers on human monocytes and U937 cells, and on their phagocytic properties.
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Suramin, a polyanionic and polycyclic compound, was initially used for the treatment of trypanosomiasis and onchocerciasis. In the last decade, it has been used in therapy of cancer and acquired immune deficiency syndrome (AIDS). The influence of suramin on the expression of various markers by human mononuclear phagocytes is not known and was, therefore, presently investigated. Suramin inhibited the proliferation of U937 cells and mitogen-induced T-cell proliferation in a dose-dependent manner. The constitutive and cytokine-driven expression of Fc receptors for IgG (Fc gamma RI and Fc gamma RII), IgE (Fc epsilon RII) and IgA (Fc alpha R) on blood monocytes and U937 cells was suppressed by suramin. The basal level, as well as cytokine-induced major histocompatibility complex (MHC) class II antigens, was markedly diminished on suramin-treated monocytes. Furthermore, suramin dramatically reduced expression of CD14 and partially reduced complement receptor type 3 (CR3) and CR4 expression on monocytes. In contrast, suramin slightly induced MHC class I antigens on monocytes and CD71 on U937 cells. The capacity of monocytes to phagocytose IgG-sensitized ox erythrocytes, opsonized Escherichia coli, or fluorescein isothiocyanate (FITC)-conjugated latex beads was significantly inhibited. Northern blot analysis showed that the amount of Fc epsilon RII-specific mRNA was only partially reduced, suggesting that other mechanisms may be involved in the regulation of Fc epsilon RII expression. Our data demonstrate that suramin suppresses the expression of various cell-surface structures on human mononuclear phagocytes and impairs their phagocytic capacity.
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8039809
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Interferon-gamma enhances monocyte cytotoxicity via enhanced reactive oxygen intermediate production. Absence of an effect on macrophage cytotoxicity is due to failure to enhance reactive nitrogen intermediate production.
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Interferon-gamma (IFN-gamma) enhanced the cytotoxic capability of freshly isolated human blood monocytes but failed to enhance the tumoricidal competence of monocyte-derived macrophages. Treatment of monocytes with IFN-gamma (100 U/ml) caused a significant increase (P < 0.001) in lucigenin-dependent chemiluminescence and O2- production stimulated by N-formyl-L-methionyl-L-leucyl-L-phenylalanine (FMLP) during the first few days in culture but IFN-gamma was unable to prevent the decline to negligible levels of chemiluminescence and O2- production which occurred during the later days in vitro. Culture of monocytes in the presence of IFN-gamma had no effect on phorbol 12-myristate 13-acetate (PMA)-stimulated O2- production. However, IFN-gamma decreased PMA-stimulated lucigenin-dependent chemiluminescence during the first 24 hr in vitro but then significantly enhanced (P < 0.001) chemiluminescence after 2-4 days in culture. IFN-gamma was unable to prevent the eventual decline to undetectable levels in PMA-stimulated chemiluminescence during the later days in vitro. Nitrite production by macrophages was unaffected by IFN-gamma treatment. It is concluded therefore, that IFN-gamma enhanced the cytotoxicity of freshly isolated human blood monocytes by increasing reactive oxygen intermediate generation but was unable to enhance the tumoricidal competence of macrophages as reactive nitrogen intermediate production was unaffected.
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8039808
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Proliferative and cytolytic responses of human gamma delta T cells display a distinct specificity pattern.
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The function and physiological role of gamma delta T cells are still unknown. Concerning the specificity of these cells, a proliferative response towards microbial ligands has been noted, whereas in terms of effector functions in humans a cytolytic activity against a variety of tumour targets is most prominent. Here we show data demonstrating that the cytolytic activity of activated human gamma delta T cells does not reflect the specificity of these cells in primary in vitro stimulation; moreover, we provide evidence that the recognition of target cells by gamma delta T cells can have different qualities. gamma delta T cells proliferate vigorously in primary in vitro reaction upon stimulation with various B-cell tumour lines but not with the T-cell lines Jurkat or Molt-4. However, gamma delta T cells stimulated primarily with phytohaemagglutinin or with cells from B-cell lines gain unrestricted cytolytic activity against a broad set of tumour targets, including Jurkat and Molt-4; the same set of targets is capable of inducing release of serine esterases (SE) from gamma delta T-effector cells. Whereas the cytolytic activity in the 51Cr-assay against the B-cell lines and against Molt-4 depends on the presence of Ca2+ ions in the assay, the lysis of Jurkat cells is only slightly reduced upon removal of Ca2+ from the medium; the SE release, however, is Ca2+ dependent in all cases. Taken together, these data suggest several different ways of target cell recognition by gamma delta T cells leading to either proliferation or triggering of cytolytic activity, and argue against an involvement of the gamma delta T-cell receptor in the cytotoxic activity of gamma delta T cells.
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8039807
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Inducible interleukin-4-secreting cells provoked in mice during chemical sensitization.
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It has been demonstrated previously that chemical contact and respiratory allergens differ with respect to the quality of immune responses they will provoke in mice. Trimellitic anhydride (TMA), a human respiratory allergen, induces in mice responses consistent with the preferential activation of Th2-type cells, resulting in the production of IgE anti-hapten antibody and an increase in the serum concentration of IgE. In contrast, oxazolone (OX), a potent contact allergen considered not to cause respiratory hypersensitivity, induces instead Th1-type responses in mice characterized by vigorous IgG2a antibody production and a failure to elicit IgE. In the present study we have extended these investigations and have examined the capacity of these chemicals to stimulate inducible interleukin-4 (IL-4) production by draining lymph node cells (LNC). IL-4 was measured in the supernatants of draining LNC cultured for various periods in the presence or absence of concanavalin A (Con A). Following primary topical exposure to the chemical allergens, Con A-stimulated LNC from OX-treated mice secreted significantly more IL-4 than did LNC from mice exposed to trimellitic anhydride (TMA). A different pattern of IL-4 secretion was observed following culture with Con A of LNC prepared from lymph nodes draining the sites of secondary exposure to these chemicals. In this case significantly higher concentrations of IL-4 were produced by TMA-treated mice. Detectable levels of IL-4 (> 300 pg/ml) were not found following culture of draining LNC from sensitized mice in the absence of Con A or following culture of LNC from naive mice with or without Con A. These data demonstrate that chemical allergens of different types stimulate discrete and changing patterns of inducible IL-4 synthesis consistent with the selective activation of Th-cell subpopulations.
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8039806
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Effect of serine/threonine kinase inhibitors on motility of human lymphocytes and U937 cells.
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Mononuclear cell migration across the endothelium and through connective tissue into inflammatory sites is a multi-step process. After adhesion to the endothelium, there is an initial change in shape from spherical to irregular, followed by the migratory phase itself in which the cells constantly change in shape. In this paper we have investigated the possibility that the shape-changing in this latter phase is controlled by serine/threonine phosphorylation. For this purpose, we used a spontaneously shape-changing variant of U937 monocytoid cells as well as human peripheral blood lymphocytes that had been previously activated by anti-CD3. To test the role of phosphorylation in shape-changing, a wide range of serine/threonine kinase inhibitors was tested, including ML-7, KT5720, KT823, H7, H8, staurosporine, calphostin C, sphingosine, bisindolylmaleimide, chelerythrine and KN-62. Only those compounds which inhibited protein kinase C prevented lymphocyte and U937 shape-change and transmigration across polycarbonate filters. However, one specific protein kinase C inhibitor, bisindolylmaleimide, stimulated lymphocyte shape-change. In conclusion, these studies show that activation of a serine/threonine kinase is necessary for the constant shape-changing required for motility of mononuclear cells. The kinase may be a protein kinase C isotype or a closely related enzyme.
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8039805
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Purified excretory-secretory component of filarial parasite enhances Fc epsilon RII/CD23 expression on human splenic B and T cells and IgE synthesis while potentiating T-helper type 2-related cytokine generation from T cells.
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The CD23-bearing cells are known to be involved in multiple biological activities, including IgE synthesis and IgE-dependent cytotoxicity to parasites. The factors that regulate interleukin-4 (IL-4)-induced IgE synthesis in helminthic infection were analysed by using an excretory-secretory component (ESC) of Dirofilaria immitis (DI). Human splenic B and T cells significantly enhanced the expression of low-affinity Fc receptors for IgE (Fc epsilon RII/CD23) by stimulation with ESC, either acting alone or in synergy with IL-4. On B cells, ESC potentiated the CD23 expression in synergy with IL-4, whereas ESC alone was unable to modulate CD23 expression. In contrast, ESC directly induced CD23 expression on T cells by acting alone and no further enhancement was observed in the presence of IL-4. Furthermore, IL-4-induced IgE synthesis by splenic mononuclear cells (SMNC) was greatly enhanced in the presence of ESC. Of particular interest, T cells primed by ESC significantly produced a set of cytokines including IL-3, IL-4, IL-5 and IL-6. Inasmuch, IL-4-induced IgE synthesis in helminthic infection may be selectively modulated by parasite protein(s) acting on the generation of T-helper type 2 (Th2)-related cytokines.
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8039804
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Oligoclonality of T cells in salivary glands of autoimmune MRL/lpr mice.
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The aim of this study was to obtain further information about exocrine glandular immunopathology and the potential of the MRL/lpr strain as a model of Sjögren's syndrome. Immunoenzyme staining (ABC technique) and monoclonal antibodies defining CD3 T-cell receptor (TcR) alpha beta, gamma delta and TcR V beta 2, V beta 4, V beta 6, V beta 7, V beta 8.1,2, V beta 10b and V beta 11 were used to identify the mononuclear cells (MNC) in salivary gland infiltrates and lymph nodes of 2- and 4-5-month-old female MRL/lpr mice. TcR alpha beta + cells dominated clearly over TcR gamma delta + cells in both salivary glands and lymph nodes. In addition, to be expressed on lymphocyte-like cells, TcR gamma delta + cells also had a dendritic appearance. The frequency pattern of TcR expression in early inflammation (2 months) was V beta 8.1, 2 > V beta 6 > V beta 4 > V beta 10b > V beta 2 > V beta 7 > V beta 11. Clear differences in frequencies could be found between salivary glands and lymph nodes in established sialadenitis (4-5 months). Particularly V beta 4, V beta 8.1,2 and V beta 10b showed expansion in salivary glands at > or = 4 months. In conclusion, this study shows a diverse repertoire of TcR at local sites of MNC infiltration in autoimmune MRL/lpr mice. However, with increasing age it also shows a preferential utilization of certain V beta gene products.
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8039802
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Polymorphism of delta-aminolevulinate dehydratase in the upper Silesian population, Poland.
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The delta-aminolevulinate dehydratase (ALADH) polymorphism was studied in the Upper Silesian population, Poland. The frequency of ALADH*1 was 0.9417, and ALADH*2 was 0.0583. No rare or anomalous phenotype was found. The distribution of phenotypes in 148 mother-child pairs was determined. Comparison with other world populations was made.
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8039801
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Low frequency of the delta F508 mutation in Finno-Ugrian and Baltic populations.
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The frequency of carriers of the delta F508 mutation at the cystic fibrosis (CF) locus was studied in population samples of Finns, Lithuanians, Saamis (Lapps) and Swedes from northern Sweden. The carrier frequencies in northern Sweden (1:200) and in Lithuanians (1:143) were significantly lower than in southern Scandinavia (Denmark; 1:38). No delta F508 carriers were found in Finns (n = 171) and Saamis (n = 151). The results indicate that the frequency of delta F508 is low in Finno-Ugrian and Baltic populations, and the decreased frequency of delta F508 in northern Sweden may be due to Finnish and Saamish admixture.
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8039800
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Within-pair differences in a-b ridge count asymmetry in monozygotic twins: evidence for a placental proximity effect.
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Asymmetry of a-b ridge count, a dermatoglyphic trait in the second interdigital (ID II) palmar area was studied in 314 identical (MZ) twin-pairs of known placental type. Statistically significant differences were observed for the variability of a-b ridge count with respect to placentation. Monochorionic MZ pairs displayed more within-pair variability than dichorionic MZ twins. Within dichorionic pairs, greater variability was observed in MZ twins when pairs with fused placentas were compared with those with separate placentas. A similar pattern of greater variability in dichorionic fused versus dichorionic separate placentas was also found in 121 same sex dizygotic twin-pairs. The pattern of within-pair differences was consistent with a placental proximity effect like that known for the variability in birth weight in twins.
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8039799
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Human enzyme polymorphism in the Canary Islands. VI. Northwest African influence.
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The genetic polymorphism of eight red cell enzymes was analyzed in population samples from the Northwest African Continent and from the South of Spain in order to study their genetic relationships with the Canarian population. The Moroccan, Berber and Spanish populations, although geographically more distant from the Canary Islands than the Saharan and Mauritanian ones, are genetically more closely related to the Canarian population. The glucose-6-phosphate dehydrogenase Gc allele earlier found only in the Canary Islands was detected in the Berber sample. The Spanish, Berber and African Black contributions to the Canarian hybrid population was estimated to 70, 20 and 10%, respectively.
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8039798
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HLA-DQ alpha genotype and allele frequencies in Malays, Chinese, and Indians in the Malaysian population.
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The HLA-DQ alpha genotype and allele frequencies in 130 Malays, 125 Chinese, and 137 Indians in the Malaysian population were determined using a commercial HLA-DQ alpha DNA amplification and typing kit which distinguishes 6 alleles (DQA1.1, DQA1.2, DQA1.3, DQA2, DQA3, and DQA4) and 21 possible genotypes at this locus. All 21 genotypes were encountered in the Malay and Indian samples, but DQA1.1,DQA1.3 and DQA2,DQA2 genotypes were absent in the Chinese sample. In all three ethnic groups, the numbers observed for the various DQ alpha genotypes were in accordance with those expected from Hardy-Weinberg equilibrium. The allele frequencies observed in these three groups were significantly different to allow them to be distinguished as distinct populations. For the Malays, Chinese, and Indians, heterozygosity values at this locus were 0.77, 0.77, and 0.83, respectively, and values of the power of discrimination were 0.91, 0.90, and 0.94, respectively. These population data will enable the HLA-DQ alpha locus to be used as a marker in forensic identity testing in Malaysia.
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8039796
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Parallelization of general-linkage analysis problems.
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We describe a parallel implementation of a genetic-linkage analysis program that achieves good speed improvement, even for analyses on a single pedigree and with a single starting recombination fraction vector. Our parallel implementation has been run on three different platforms: an Ethernet network of workstations, a higher-bandwidth asynchronous transfer mode (ATM) network of workstations, and a shared-memory multiprocessor. The same program, written in a shared-memory programming style, is used on all platforms. On the workstation networks, the hardware does not provide shared memory, so the program executes on a distributed shared memory system that implements shared memory in software. These three platforms represent different points on the price/performance scale. Ethernet networks are cheap and omnipresent, ATM networks are an emerging technology that offers higher bandwidth, and shared-memory multiprocessors offer the best performance because communication is implemented entirely by hardware. On 8 processors and for the longer runs, we achieve speedups between 3.5 and 5 on the Ethernet network and between 4.8 and 6 on the ATM network. On the shared-memory multiprocessor, we achieve speedups in the 5.5-6.5 range for all runs.
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8039797
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Beta-globin gene cluster haplotypes of Amerindian populations from the Brazilian Amazon region.
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We have determined the beta-globin cluster haplotypes for 80 Indians from four Brazilian Amazon tribes: Kayapó, Wayampí, Wayana-Apalaí, and Arára. The results are analyzed together with 20 Yanomámi previously studied. From 2 to 4 different haplotypes were identified for each tribe, and 7 of the possible 32 haplotypes were found in a sample of 172 chromosomes for which the beta haplotypes were directly determined or derived from family studies. The haplotype distribution does not differ significantly among the five populations. The two most common haplotypes in all tribes were haplotypes 2 and 6, with average frequencies of 0.843 and 0.122, respectively. The genetic affinities between Brazilian Indians and other human populations were evaluated by estimates of genetic distance based on haplotype data. The lowest values were observed in relation to Asians, especially Chinese, Polynesians, and Micronesians.
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8039795
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Clinical heterogeneity of skeletal dysplasia in Roberts syndrome: a review.
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Roberts syndrome is a rare autosomal recessive disorder with highly variable clinical features. The most notable manifestations include pre- and postnatal growth retardation, craniofacial anomalies and improper development of all four extremities. We reviewed 50 cases whose clinical evaluation has been vigorously pursued. A relationship of deformities exists between humerus versus femur, and radius and ulna versus tibia and fibula. Only six cases had clubfoot. The number of fingers and toes was variable. The sex ratio was 1:1. Most individuals died in early infancy, although the longest follow-up survival was 13 years in one case. Premature centromere separation, centromere splitting and puffing were common chromosomal abnormalities. An annotated bibliography on notable cases is also provided which should serve as an aid for clinicians who wish to further understand the genetic and clinical heterogeneity noted in their cases.
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8039789
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The history of venereology in Norway.
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Syphilis became a problem at the beginning of the eighteenth century when a virulent microbe was brought to Norway. This new disease was called "radesyken", a Nordic name for "the wicked disease". "Rade" hospitals were built and this was the beginning of the Norwegian hospital system. Professor Caesar Boeck refused to use mercury in the treatment of syphilis; 2000 of his patients were included in the Oslo study of untreated syphilis. With the use of penicillin and other antibiotics, syphilis and gonorrhoea decreased. More frequent now are the viral diseases, herpes genitalis and condylomata acuminata. HIV is seldom found in the STD clinic in Oslo: only 5-6 HIV-positive persons per year; that is, about 0.09% of all new patients.
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8039786
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Seroprevalence, risk factors and attitude to HIV-1 in a representative sample of lesbians in Turin.
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To estimate the HIV-1 seroprevalence, behavioural risks and attitude to HIV-1 infection among lesbians. Institute of Infectious Diseases, University of Turin, Italy. From March 1992 to May 1993, 181 lesbians were tested for HIV-1 and included in the study. Sociodemographic details, nonsexual risks for HIV-1, sexual behaviour, STD history and attitude to HIV-1 were obtained from an anonymous, standardised, self-administered, 30-item questionnaire. Snow-ball techniques were used to recruit the largest possible number of participants. 11 lesbians (6.1%) were found to be HIV-1 antibody positive. Of them, 10 were intravenous (i.v.) drug users. STD episodes were higher among lesbians with HIV-1 than without (p = 0.04), increasing in both groups over time. Syphilis, genital herpes and viral hepatitis were highly associated with HIV-1 (p = 0.000). In univariate analysis, i.v. drug use, bisexual behaviour, history of STDs, sex during menses and vaginal/anal manipulation were significantly linked to HIV-1 (p = 0.000). In multivariate analysis only history of i.v. drug use (p = 0.04) and bisexual behaviour (p = 0.06) remained independently associated with HIV-1. Seventy-one participants (39.3%) had already undergone AIDS testing. Only 3.5% admitted to be at risk for HIV-1 and 11% changed their sex habits after first hearing of AIDS. No lesbian had ever practised safe-sex. Television was the most important source of information on HIV-1 (84%). I.v. drug use was the most likely means of HIV-1 infecting the lesbians of Turin. The high rate of STDs and the low perceived risk to HIV-1 require programmes of STD prevention and AIDS information to be targeted at the lesbian community.
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8039785
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An outbreak of a penicillin-sensitive strain of gonorrhoea in Sydney men.
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To describe an outbreak of gonorrhoea caused by penicillin sensitive Wild type 1B2-Wt/1B2(FS), in homosexual men in Sydney. The study sample comprised all gonococcal isolates referred to the Gonococcal Reference Laboratory (GRL), New South Wales, Australia between 1 January 1990 and 30 June 1992. Demographic data on Wt/1B2(FS) were sought by review of all request forms accompanying specimens to the GRL. Detailed review was undertaken of the clinical records of all men with gonorrhoea which had been differentiated by auxotype and serotype (A/S) from two large STD clinics in Sydney. The first isolation of Wt/1B2(FS) was made in April 1990 and by the end of July 1992, 140 such isolates were identified in 131 patients. The male:female ratio was 130:1 suggesting male homosexual transmission, which was confirmed in 55 of 57 evaluable cases. There was a higher proportion of pharyngeal and anal infections among Wt/1B2(FS) isolates compared with all other male gonorrhoea. Demographic information showed that 60% of men with Wt/1B2(FS) were under the age of 30, and 80% lived in Central or Eastern Sydney. An outbreak of a penicillin sensitive strain of gonorrhoea has occurred in Sydney, primarily among gay men living in the inner city. The extent to which the outbreak represents an increase in the risk of HIV transmission is unclear.
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8039784
|
The value of primary colposcopy in genitourinary medicine--a six year review.
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To evaluate the effectiveness of primary colposcopy in the genitourinary medicine setting by comparing the cervical cytology and punch biopsy results for women identified as having an abnormal cervical transformation zone. A retrospective audit of six years' findings in primary colposcopy was carried out. The punch biopsy findings of 1338 women were compared with their last cervical cytology results. A small sample of biopsies were subjected to in situ hybridisation for human papilloma virus types 6, 11, 16, 18 and cytomegalovirus. The tabulated results demonstrated the variability between histology and cytology. This was explored with reference to other studies. The viral typing showed the dominance of low oncogenic risk human papilloma virus types. The findings are discussed against the overall concept of sexual health. Primary colposcopy facilitates empowerment of the patient and her partner through the opportunity for demonstration and explanation of disease processes and options for management. Experience and expertise gathered in six years of primary colposcopy confirm the value of primary colposcopy not only in improved diagnosis and management but also in teaching, audit and research.
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8039783
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Unsatisfactory performance of the leukocyte esterase test of first voided urine for rapid diagnosis of urethritis.
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The objective of this study was to determine the performance characteristics of a dipstick test for leukocyte esterase (LE), (Chemstrip 2LN, Boehringer Mannheim) in predicting the presence of urethritis and urethral pathogens in men presenting to a busy sexually transmitted disease clinic and to street outreach facilities. Urethral swabs for polymorphonuclear (pmn) cell count, gonorrhoea culture and chlamydia enzyme immunoassay (EIA) as well as 15 ml of first voided urine (FVU) were collected from 737 symptomatic and 726 asymptomatic men. Gonorrhoea cultures and pmn counts were processed according to standard methods. Either Abbott Chlamydiazyme EIA (confirmed) or Syva Microtrak EIA (confirmed) test was employed to detect C trachomatis. The LE test was immediately dipped in FVU, read after 60-120 seconds by the clinician and considered positive if trace, 1+ or 2+. Microscopic evidence of urethritis (> or = = 4 pmn cells per 1000 x field) was found on urethral smear of 782 (53.5%) patients. Chlamydia, gonorrhoea or both were present in 104 (7.1%) patients. Performance characteristics of the LE test were as follows: (table below) The LE test did not have adequate sensitivity to be considered a reliable rapid diagnostic test for urethritis or urethral pathogens, particularly in the asymptomatic portion of this STD clinic population.
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8039782
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Immunohistochemical study of in vivo and in vitro IgA coating of candida species in vulvovaginal candidiasis.
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To evaluate whether quantitative or qualitative IgA deficiencies in cervicovaginal secretions can be identified in patients with recurrent vulvovaginal candidiasis. Prospective and controlled study. Department of Dermatology, University of Vienna. 30 patients with symptomatic and recurrent vulvovaginal candidiasis at the time of their presentation. 30 healthy women as a control group. Blood samples were drawn for measurement of serum IgA levels. Smears of the cervix and vagina were taken for direct microscopy and microbiological culture. Lavage of the vagina and ectocervix was performed with sterile saline solution for measurement of cervicovaginal IgA levels. IgA levels of serum and cervicovaginal secretion evaluated by Single Radial Immunodiffusion. IgA labelling was demonstrated on fungal elements in vaginal smears and subcultured blastospores after incubation with vaginal secretions by immunohistochemistry. We could not find any significant difference of IgA levels in serum and cervicovaginal secretions between the symptomatic group and healthy controls (p value for serum = 0.5796, p value for secretion = 0.2381). In vaginal smears yeasts revealed IgA coating on their surfaces, whereas three of the 61 subcultures were negative. Negative subcultures were assigned to three patients with recurrent candidiasis. No correlation was found between IgA levels of cervicovaginal secretions and staining intensity of subcultured blastospores after incubation with vaginal secretions (r = -0.0578). IgA levels of serum and vaginal secretion showed no correlation (r = -0.00012). Recurrent vulvovaginal candidiasis cannot be attributed to IgA deficiency. In some cases an IgA coating defect of yeasts might be involved. In addition inactivation of the IgA molecule by candida proteases might be of pathogenetic importance.
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8039781
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Papillomavirus-associated balanoposthitis.
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To assess whether there might be an association between genital papillomavirus infection (GPVI) and balanoposthitis. Retrospective HPV DNA examination of biopsy specimens from 23 men suffering from balanoposthitis and exhibiting acetowhite lesions that were penoscopically and histologically concurrent with HPV infection. The STD clinics at Karolinska Hospital and South Hospital, Stockholm, Sweden. Randomly selected men attending with long-lasting and/or recurrent penile symptoms and exhibiting a clinical picture of balanoposthitis, who revealed a penoscopical and histopathological picture of epidermal lesions that were concordant with accepted criteria for typical or conspicuous GPVI. Asymptomatic controls were selected retrospectively on the basis of identical penoscopy and histology criteria. A history of previous condylomata was obtained in eight (35%) of 23 men. At penoscopic evaluation tiny condylomatous lesions were observed in five (22%) patients. The in situ hybridisation (ISH) assay using specific probes for the HPV types 6/11, 16/18, 31/33 and 42 was positive in 13/23 (56%) of the patient samples, but in only 26% of the 19 control samples. In patient biopsies the oncogenic HPV types 16/18 and/or 31/33 were found in 7/13 samples, whereas HPV 6/11 and/or 42 were present in another six cases. PCR performed on the ten ISH negative patient biopsies, were negative in all cases. Symptoms included redness, itching, burning, tenderness, dyspareunia, fissuring and in two cases penile oedema and inguinal adenopathy. All patients fulfilled penoscopical and histopathological criteria for HPV infection. We demonstrate some tentative evidence that HPV might be associated with long-lasting balanoposthitis, although our data still are circumstantial for a causative association. The results also elucidate the diversity in clinical presentation of GPVI.
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8039780
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The detection of HPV DNA, the size of tampon specimens and the menstrual cycle.
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To determine if HPV detection or the size of a tampon specimen is affected by the menstrual cycle. Two hundred and eighty women between 18-35 years of age attending a gynaecology clinic at The Royal Women's Hospital were enrolled. Each woman completed a questionnaire on the risk factors of HPV infection and provided a tampon specimen. Specimens were analysed for the presence of HPV DNA (polymerase chain reaction with the L1 consensus primers) after the pellet volume and number of cells was assessed. The mean age of the 298 women enrolled in this study was 27.0 years (SD 4.5, range 18-35). Ninety two (30.9%) of the tampon specimens were positive for HPV using the L1 consensus primer. The detection of HPV DNA was not associated with the quartiles of the menstrual cycle (p = 0.32). Both the pellet volume and the number of cells from a tampon specimen were greater during the mid cycle, although this was significant for the pellet volume only (p = 0.002 and 0.1 respectively). The pellet volume was not significantly associated with other variables assessed by the questionnaire. The number of cells from a tampon specimen increased with the numbers of life time sexual partners (p = 0.02) and was higher for a single marital status (p = 0.0008). The timing of the menstrual cycle effects the size of tampon specimens but not the probability of detecting HPV DNA.
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8039779
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HPV and p53 in cervical cancer.
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To determine the prevalence of HPV 16 and 18 E6 by DNA detection and p53 abnormal protein expression in cervical cancers in Hong Kong. Seventy-three squamous cell cervical cancer biopsy were analysed. Detection of HPV DNA was carried out by the polymerase chain reaction and Southern blotting (PCR/SB) technique using primers to the HPV16 & 18 E6 region and consensus primers to the L1 region. Abnormal expression of the p53 protein was detected by immunohistochemical staining (IHS) using the antibody CM1 on frozen sections of 55 cervical cancer samples. Forty-six samples were analysed for both the presence of HPV DNA and abnormal expression of p53. 67.2% of the 64 samples showed the presence of HPV 16 E6 DNA and 39.1% showed the presence of HPV 18 E6 DNA. 32.8% showed the presence of both HPV 16 and 18 E6 DNA. No HPV DNA was shown in 10.9% of samples. Only 3.6% (2) of 55 samples showed positive IHS with CM1. One occurred in a HPV negative sample and the other in a HPV positive sample. A high prevalence of HPV DNA was detected in cervical cancer in Hong Kong using the PCR/SB technique. However, abnormal expression of p53 was uncommon amongst patients with or without HPV 16 or 18 infection.
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8039777
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Risk factors for gonorrhoea, syphilis, and trichomonas infections among women attending family planning clinics in Nairobi, Kenya.
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To identify the risk factors for gonorrhoea, syphilis, and trichomonas infections among low risk women in Nairobi, Kenya. In a cross-sectional study, 4,404 women attending two peri-urban family planning clinics between 1989 and 1991 were interviewed using a structured questionnaire and examined for signs of sexually transmitted disease (STD) infection. Cervical cultures for gonorrhoea, PAP smear (including microscopy for trichomonas), RPR and HIV testing were done. Positive cervical cultures for gonorrhoea were found in 3.2% of women, positive syphilis serology in 1.9%, and positive trichomonas microscopy in 5.2%. Genital ulcers were found in 1.9% of women. Although unmarried status and reporting more than one sex partner in the previous year were both significantly associated with each disease in the crude analysis, these associations were attenuated after controlling for each other and for other risk factors. The population attributable risks (PARs) for these factors were low (7-16%) owing to the high proportion of cases who were married and monogamous. The majority of women with microbiological evidence of infection had normal pelvic examinations. Clinical diagnostic algorithms for STDs in this population had a low sensitivity and positive predictive value. Nevertheless, a strong association between HIV seropositivity and STDs was observed. The low population attributable risks found in this study suggest that behaviour change messages directed to women, particularly if they are married have a low potential for preventing STDs. The poor performance of clinical diagnostic algorithms illustrates the desirability of testing these algorithms in a variety of populations and reinforces the need for low-cost methods of microbiologic diagnosis if populations with relatively low prevalences of these infections are to be included in programmes to diagnose and treat STDs.
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8039778
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Evaluation of the Amplicor Chlamydia trachomatis test versus culture in genital samples in various prevalence populations.
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To evaluate a newly developed polymerase chain reaction (PCR) assay, Amplicor C trachomatis for the detection of C trachomatis in genital samples using cell culture for comparison. 501 patients (431 women and 70 men) attending an STD clinic in Hôpital Pellegrin (high-risk population) and gynaecological clinics (low-risk population) in Bordeaux, France. The genital samples (cervical and urethral) were tested for the presence of C trachomatis using the Amplicor test and using standard cell culture identified by the immunofluorescence test using a monoclonal antibody to C trachomatis. Discrepancies between the results of culture and Amplicor were further analysed by major outer membrane protein gene (omp1)-PCR of the specimens taken in transport media and by direct fluorescent antibody (DFA) staining of elementary bodies in culture transport tubes. After analysis of discrepancies, the revised sensitivity and specificity of PCR were 95.3% and 100% and the positive and negative predictive values were 100% and 99.5%, respectively. The present results indicate that the Amplicor assay is rapid, specific and more sensitive than the culture method. This test provides an excellent non-culture method for the detection of C trachomatis in various prevalence populations.
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8039775
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Zopiclone poisoning: tissue distribution and potential for postmortem diffusion.
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Zopiclone is the first cyclopyrrolone hypnotic and is chemically unrelated to any existing drug. The authors studied the tissue distribution and postmortem redistribution of zopiclone in a fatal suicidal overdose. A 29-year-old female weighing 64 kg had cardiac blood ethanol 153 mg% and zopiclone blood concentrations in the range 0.9-2.0 microgram/ml in 10 distinct sampling sites. After 40 h at room temperature the range was 0.9-1.8 micrograms/ml in 15 samples. Portal venous blood and urine concentrations were 3.0 and 10.5 micrograms/ml, respectively. Tissue concentrations (microgram/g) were spleen 5.8, peri-renal fat 5.0, psoas muscle 3.3, brainstem 2.8, gastrocnemius muscle 1.9, myocardium 1.6, and kidney 1.7. Eight liver samples had concentrations in the range 0.5-4.9 micrograms/g, with highest concentrations in the left lobe and adjacent to the gallbladder, probably reflecting postmortem diffusion from gastric residue (700 ml, 55.1 micrograms/ml) and bile (14.1 micrograms/ml). Of six lung samples, paired upper and middle samples had concentrations in the range 2.1-2.3 micrograms/g, the right postero-basal 1.3 micrograms/g and the left postero-basal 3.4 micrograms/g. Drug concentration in putrefactive pleural fluid was also higher on the left (2.1 micrograms/ml) than the right (1.4 micrograms/ml), probably reflecting postmortem diffusion from gastric residue. The authors conclude that zopiclone showed little preferential concentration in solid organs and consequently has relatively stable postmortem blood concentrations, with little drug redistribution artefacts. Postmortem diffusion from gastric drug residue elevates drug levels in the left lobe of the liver and left lung lower lobe.
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8039776
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Development of an instrument to measure postmortem lividity and its preliminary application to estimate the time since death.
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A degree of postmortem lividity was related to a subcutaneous hemoglobin concentration, which can be measured by using light absorption. On the basis of this theory, the authors have developed an instrument utilizing a light to measure the degree of postmortem lividity. By using 42 corpses whose postmortem intervals were known, the authors examined the relationship between the actual postmortem intervals and the measurements, and found that there was significant correlation between them.
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8039774
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Analysis of short tandem repeat (STR) HUMVWA in the Spanish population.
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Amplification by polymerase chain reaction (PCR) of variable number of tandem repeat (VNTR) loci and subsequent typing by electrophoresis and silver staining has become a useful tool for identity testing. One viable group of genetic markers amenable to amplification by PCR is the short tandem repeat (STR) loci. A horizontal discontinuous polyacrylamide gel electrophoresis (PAGE) method was used to type the amplified products of the STR HUMVWA. Typing for VWA of 120 unrelated Spanish Caucasians was done. Six alleles were observed with frequencies in the range 0.096-0.242. The genotype distribution meets Hardy-Weinberg expectations (0.25 < P < 0.50). The heterozygosity was 73.3% and the discrimination power (DP) 0.94. Simultaneously, in a small sample of families (n = 24) no new mutations could be found.
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8039773
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Characteristics of imprisoned wife-beaters.
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The aim of this study is to present the authors' recent findings concerning the wife-beater and to discuss the existing state of knowledge as well as practical implications concerning the treatment of these men. The study presents interview and register data as well as some endocrinological findings in 18 wife-beaters sentenced to prison. These men generally lived under unfavourable socio-economic conditions, half of them were immigrants and most of them had been maltreated as children. Drug and alcohol abuse was common. The men showed an overconsumption of both somatic in-patient and out-patient care but had virtually no previous psychiatric history. Depressive symptoms were common, however, as were anti-social personality traits, reflected in a marked involvement in both violent and non-violent offences. The levels of testosterone were generally high. It is argued that the most efficient therapeutic approach would be to treat alcohol and drug addiction, an aspect of rehabilitation that has often been underestimated or overlooked in previous treatment programmes. The period of imprisonment could be utilized for these purposes, as an alcoholic who becomes sober is probably less prone to abuse his wife.
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8039772
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Analysis of cocaine and metabolites in brain using solid phase extraction and full-scanning gas chromatography/ion trap mass spectrometry.
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A method is described for the determination of cocaine, benzoylecgonine and cocaethylene in the human brain using Clean Screen solid phase extraction cartridges and gas chromatography/ion trap mass spectrometry with electron impact and full scan analysis. The procedure uses deuterated internal standards. Run-to-run and within-run coefficients of variation are < 7% and the sensitivity proved to be 50 ng/g from 1 g of sample. The procedure has been applied to a number of forensic cases involving cocaine intoxication. Cocaine was relatively unstable in brain tissue stored at 4 degrees C when compared to storage at -80 degrees C.
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8039771
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[Heterotrimeric G proteins and ion channels].
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Direct G protein regulation of ion channels is one of the major mechanisms of the functional regulation of excitable cells by hormones and neurotransmitters. Recent extensive studies indicate that a number of channels are directly regulated by G proteins. In this short review, we focus on the molecular mechanism underlying G protein (GK) regulation fo cardiac muscarinic K+ channels. This channel was reported to be activated in the inside-out configuration by both exogenously applied alpha- and beta gamma-subunits of pertussis toxin-sensitive G proteins. There has been a longstanding controversy as to which of the subunits physiologically mediate the effect of GK on this channel. We have established the notion that GK physiologically activates cardiac muscarinic K+ channels through its beta gamma-subunit but not its alpha-subunit.
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8039770
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[Phospholipid metabolism regulated by heterotrimeric G proteins].
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Phosphoinositide-specific phospholipase C (PI-PLC) catalyzes the hydrolysis of phosphatidylinositol 4,5-bisphosphate to inositol 1,4,5-trisphosphate (IP3) and diacylglycerol. IP3 induces the release of Ca2+ from intracellular stores, and diacylglycerol acts as the physiological activator of protein kinase C. Several distinct PI-PLC enzymes have been identified from various cells. Based on the primary sequences, PI-PLC isozymes are divided into three families: PLC-beta, PLC-gamma, and PLC-delta. Substantial evidence has strongly suggested that G proteins regulate PI-PLC in various cell-stimulation systems and that there might be two distinct pathways (pertussis toxin-sensitive and pertussis toxin-insensitive). Recently, it has become apparent that beta-type PLC isoforms are activated by the heterotrimeric G protein subfamily Gq. Careful studies using in vitro and in vivo reconstitution systems have further suggested that the alpha-subunits of Gq/11/16 specifically regulate PLC-beta 1 and PLC-beta 3 and that the beta gamma -subunits of the Gi subfamily interact with PLC-beta 2, which are considered to be responsible for the pertussis toxin-insensitive and the pertussis toxin-sensitive pathways, respectively. In this paper, involvement of G proteins in the regulation of phospholipase A2 and phosphatidylcholine-specific PLC and PLD is also discussed.
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8039769
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[Multiplicity of adenylylcyclase and regulation of G-protein].
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Adenylylcyclase is a membrane bound enzyme that catalyzes the conversion of ATP to cyclic AMP. Studies on the regulation of adenylylcyclase have been hampered by the small amount of this enzyme in the cell as well as by the instability of the catalytic activity. Cloning of multiple adenylylcyclase isoforms (types I though VIII) has indicated the presence of a large enzyme family, which is further subdivided into several smaller groups. Members within the same group share similar biochemical properties. The multiplicity of adenylylcyclase is made through at least three distinct mechanisms. First, each isoform is encoded by a distinct gene. Second, multiple isoforms are generated through possible alternative splicing from the same gene. Third, there is a mechanism to generate a half-molecule of adenylylcyclase via alternative polyadenylation. Overexpression of a distinct isoform in insect cells followed by purification has enabled researchers to examine the role of each specific isoform in vitro. The results have suggested that each isoform is regulated through distinct mechanisms. For example, type I adenylylcyclase is inhibited in the presence of beta gamma-subunits, while type II is stimulated. Other isoforms such as types V and VI are not affected. On the other hand, Gi alpha may directly inhibit each adenylylcyclase isoform. Further characterization of adenylylcyclase would be feasible using those clones in the future.
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8039768
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[Regulation of G proteins by receptors].
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Receptors located on the cell surface are responsible for recognition of extracellular first messengers. The largest number of receptors belongs to a G protein-coupled receptor superfamily. They showed common structural features characterized by seven transmembrane regions and three connecting extracellular and intracellular loops. Stimulation of a receptor by an agonist activates the coupled G protein. From in vitro mutagenesis analyses of beta 2-adrenergic, muscarinic acetylcholine and alpha 1-adrenergic receptors, it was shown that the intracellular third loop and carboxyl terminus of the receptor molecule are involved in coupling with a G protein. One intriguing observation was that mutation at a single site of the intracellular third loop could induce the active state of receptors without agonist stimulation. Receptor heterogeneity generated from distinct genes or alternative splicing can be seen at the intracellular third loop and carboxyl terminus that is assumed to play an important role of coupling with G proteins. There are several examples that receptor isoforms arising from alternative splicing have their own counterparts of G proteins.
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8039767
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[Covalent lipid modifications of heterotrimeric G proteins].
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Guanine nucleotide-binding regulatory proteins (heterotrimeric G proteins) are composed of alpha-, beta- and gamma- subunits, and they mediate a variety of intracellular signal transductions by coupling activated membrane receptors with effector enzymes and channels. Activated receptors catalyze the exchange of GDP bound to the alpha-subunits for cytosolic GTP, and GTP-bound alpha-subunits in turn regulate activities or functions of the effectors. The beta gamma-complex is not dissociable under physiological conditions, and it is indispensable for the GDP/GTP exchange reaction on the alpha-subunit. Recently, three kinds of lipid modifications have been found in the alpha- and gamma-subunits. The first is the attachment of fatty acids, myristate (C14:0) or structurally related fatty acids to the N-terminal glycine residues of some members of the alpha-subunits. Another type of fatty acylation to be characterized is the linkage of palmitate (C16:0) to a number of alpha-subunits via a thioester bond at their cysteine residues. The third type of modification is polyisoprenylation (farnesylation or geranylgeranylation) and alpha-carboxyl methylation at the C-terminal cysteine residue of the gamma-subunit. These modifications on the two subunits have been shown to play a critical role in not only protein-membrane interaction but also proper protein-protein interaction, both of which are required for the G protein function.
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8039766
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[Structure and function of heterotrimeric G-proteins].
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In mammals, G-protein alpha, beta, gamma polypeptides are encoded by at least 16, 4 and 7 genes, respectively. G alpha-subunits bind and hydrolyze GTP and have the sites for bacterial toxin-catalyzed ADP-ribosylation. A structural model of G alpha-subunits can be defined on the basis of similarities between G alpha and other members of the GTP-binding proteins. The resulting G alpha model specifies the spatial relationship among the guanine nucleotide binding site, the binding site of the G beta gamma-subunit complex, likely regions of effector and receptor interaction, and sites of cholera or pertussis toxin-induced modification. The architecture of the G alpha core is the same as that of p21ras. Experimental evidence from immunological, molecular genetic and biochemical studies support the G alpha model. The G alpha-subunits alone were previously thought to act on the effector enzymes; However, recent evidence indicates that the G beta gamma-dimer also plays an important part in effector activation.
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8039765
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[Role of heterotrimeric GTP-binding proteins in cellular signaling].
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The GTP-binding protein (G protein) is a heterotrimeric protein composed of an alpha-, a beta- and a gamma-subunit. The G protein is functionally located between membrane receptors whose structures are characterized by seven membrane-spanning domains and effectors that are enzymes responsible for the generation of intracellular second messengers or ionic channels, thereby playing its essential role as a molecular switch for intracellular signal initiation. The switch turns on when GTP binds, in exchange for prebound GDP, to the alpha-subunit (G alpha), whereas it turns off upon the GTP hydrolysis due to the G alpha GTPase activity. The beta gamma-component plays a supporting role for the molecular switching and is also involved in signal transduction to certain effectors. One of the most exciting subjects to be currently studied as to the physiological roles of G proteins will be the mechanism by which the G protein-mediated second messenger system interacts (crosstalks) with the tyrosine kinase-mediated signaling system arising from other types of growth factor receptors.
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8039764
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Fulminant sepsis in adults splenectomized for Hodgkin's disease.
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Laparotomy with splenectomy still remains important for staging Hodgkin's disease (HD). The risk of fulminant sepsis (FS) after splenectomy is well known, but the incidence of FS in splenectomized HD adult patients has not been accurately assessed. In this study we have tried to assess this risk and its duration and to evaluate the role of HD "per se" in causing FS. Six cases of FS were traced in a group of 226 splenectomized adults, with a crude incidence of 2.65%. Age at the time of the event ranged from 23 to 41 years and time after splenectomy from 46 to 98 months. Four patients were disease-free when sepsis occurred. In 4 cases the causative agent was isolated (3 Streptococcus Pneumoniae, 1 Streptococcus alpha Haemolyticus). The mortality rate was 66%, while net probability of death (life table) at 10 years was 2.6%. M/F rate was 0/6 (P = 0.01). The incidence of FS was 0.33 cases per 100 patient-years (I.C. 95% = 0.12-0.72). There seems to be no relationship to histological type, clinical stage or age at splenectomy. No case of sepsis occurred in a control group of 281 non-splenectomized HD adults (P = < 0.01), despite the more advanced disease present in these cases on the average. The frequency of FS, the causative agents, the mortality rate, the duration of risk are similar to those previously reported. Prompt treatment of any febrile disease in HD splenectomized patients and a policy of antipneumococcal (and possibly of anti-meningococcal) vaccination seem advisable.
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8039763
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Single step immunophenotyping of acute leukemias not classifiable by standard morphology and cytochemistry: a practical approach.
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Immunophenotyping is at present a useful aid and often an essential step for correct diagnosis of acute leukemia and for this purpose some investigators have proposed several immunomarker panels. This approach is particularly important in the differential diagnosis of acute leukemias not classifiable by standard morphology and cytochemistry. We have tested peripheral blood and/or bone marrow samples from 125 patients not classifiable by FAB criteria. In all the cases, the reactivities of the same panel of 17 monoclonal antibodies were analyzed by flow cytometry, using both single and double fluorescent labeling. Of the 125 patients investigated, 75 (60%) were classifiable as ALL, 58 as B-lineage ALL and 17 as T-lineage ALL; 33 (26.4%) as AML, of which 2 M7; 6 (4.8%) as biphenotypic and 11 (8.8%) as immunophenotypically undifferentiated. From a critical analysis of our cases and a review of the literature, we suggest that a panel of 9 monoclonal antibodies (CD2, CD5, CD7, CD10, CD19, CD20, CD13, CD33, CD41), is sufficient for reliable, rapid and reasonably low cost typing of acute leukemia, useful for an immediate therapeutic decision.
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8039762
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Hematologic and cytogenetic analyses of 99 cases of de novo myelodysplastic syndromes.
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BACKGROUND. The myelodysplastic syndromes (MDS) are a heterogeneous group of clonal hematopoietic stem cell disorders characterized by peripheral pancytopenia, abnormal bone marrow differentiation and a high risk of leukemic transformation. The role of karyotypic abnormalities in the pathogenesis of MDS is still unclear. In this paper we present the hematologic and cytogenetic findings in 99 patients with de novo MDS. RESULTS AND CONCLUSIONS. Fifty-three cases had chromosomal abnormalities nor complex karyotypes were associated with the morphologic subsets described by the FAB criteria. Nevertheless, the karyotypic profile is prognostically important, as indicated by the fact that patients with complex karyotype abnormalities have very short survival.
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8039761
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Erwinia- and E. coli-derived L-asparaginase have similar effects on hemostasis. Pilot study in 10 patients with acute lymphoblastic leukemia.
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L-asparaginase (L-ase) affects the synthesis of several hemostatic factors, including the naturally occurring clotting inhibitors antithrombin III, protein C and S, and thromboembolic events are a well-recognized complication of the hypercoagulable state resulting from this treatment. Recently, in addition to the widely used E. Coli-derived L-ase, a new L-ase derived from Erwinia Carotovora has been introduced into clinical studies. This formulation seems to have lesser side-effects, but data on its effects on the hemostatic system are very limited. We report here the hemostatic changes observed in 10 adult patients with acute lymphoblastic leukemia (ALL) treated with Erwinia- or with E. Coli-derived L-ase. The decreases (percentages of basal level) of antithrombin III, protein C and plasminogen (functional assays) were similar in both groups of patients (about 50% of the basal value 6 or 8 days after starting L-ase) and so were the number of instances in which the level of these proteins fell below 70% of normal. On the contrary, the fibrinogen level (PT-derived method) was less severely decreased by Erwinia L-ase (34% of basal value for E. Coli L-ase versus 58% for Erwinia L-ase; P = 0.048) and there were more instances in which the fibrinogen level was less than 100 mg/dL than with E. Coli L-ase (40% versus 16%; P = 0.051). Thrombin-AT-III complexes (ELISA) showed similar pattern during both treatments. Two patients treated with Erwinia L-ase had moderate hyperglycemia, requiring insulin treatment but not L-ase discontinuation. No allergic reaction or pancreatitis was observed. A patient in the Erwinia L-ase-treated group developed deep venous thrombosis on day 7 after the start of L-ase and was treated with subcutaneous heparin (12,500 U x 2/day), with prompt improvement. This study shows that the two L-ase formulations have similar effects on hemostasis. Patients treated with Erwinia L-ase may develop thrombotic symptoms, as already reported for E. Coli-L-ase.
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8039760
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Fibrinogen survival and fibrinopeptide A in acute leukemia.
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BACKGROUND. Hypofibrinogenemia and increased fibrin(ogen) degradation products in acute leukemia have been attributed to intravascular thrombin generation triggered by leukemic cells. However, the strict relationship between fibrinogen catabolism and turnover of fibrinopeptide A (FPA), which is a sensitive and specific marker of thrombin activity, has not been evaluated in acute leukemia (AL) with or without disseminated intravascular coagulation (DIC) to see whether mechanisms other than thrombin activity could be responsible for fibrinogen consumption. We report here the 125I-fibrinogen kinetics and FPA measurements in 19 patients with AL, 6 of them with DIC. METHODS AND RESULTS. Radiolabelled fibrinogen kinetics were studied in all the patients concomitantly with the start of chemotherapy. Fibrinopeptide A was measured by a radioimmunoassay at time of diagnosis and during chemotherapy. The kinetics of disappearance of radiolabelled fibrinogen where biphasic, with a rapid phase in the first 1-3 days of chemotherapy and a subsequent slow phase associated with the reduction or disappearance of blast cells. Patients with DIC had a significantly shorter half-life and turnover than patients without DIC. The latter group had significant shortening of these parameters in comparison to normal subjects. The thrombin-dependent catabolic rate of fibrinogen, calculated from the mean level of FPA during the first phase of disappearance curve and by assuming 2 moles of FPA generated per mole of fibrinogen, was similar in patients without DIC and in normal subjects, whereas patients with DIC had a significantly higher catabolic rate, even though the increase was not sufficient to account for all the turnover of fibrinogen. No relationship was observed between fibrinogen turnover and FPA turnover.
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8039759
|
Acquired plasma factor XIII deficiencies.
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Coagulation factor XIII (FXIII) is of paramount importance in the process of fibrin stabilization, which is the final step of the coagulation cascade. The clinical significance of defective fibrin stabilization is highlighted by the severe hemorrhagic manifestations of congenital FXIII deficiency. In this paper we review the pathophysiology, clinical presentation and therapy of acquired plasma FXIII deficiencies, caused by specific inhibitors or associated with other clinical conditions. For acquired severe FXIII deficiency caused by factor-specific inhibitors, the need for prompt diagnosis and treatment is emphasized by the high hemorrhagic risk and mortality. For moderate reduction of FXIII secondary to other conditions, we discuss the relative importance of FXIII reduction in the development of clinical symptoms and the role of substitution treatment.
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8039758
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Adult patients with the nephrotic syndrome: really at high risk for deep venous thromboembolism? Report of a series and review of the literature.
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The reported incidence of thromboembolic episodes in people with nephrotic syndrome (NS) ranges from 6% to 44% and it has been ascribed to the presence of a hypercoagulable state, as suggested by abnormalities of several hemostatic parameters in these patients. However, the results of the studies are often contradictory and fragmented and are rarely based on prospective studies. To assess the incidence of venous thrombosis and the pattern of abnormalities of the hemostatic parameters in NS, we planned a prospective study of a group of patients with NS. Thirty-six consecutive patients with NS were enrolled during a 9-month period. Every 4-6 months, clinical history was collected and physical examination was carried out. Blood samples for laboratory investigation were taken at entry into the study and 24 months later. A critical review of the literature was also carried out (Medline database and Current Contents). During the follow-up (mean 45.2 months), no thrombotic symptoms were recorded, PTT, PT, TT and mean AT-III levels were within the normal range, whereas fibrinogen, plasminogen, protein C and S, heparin cofactor II levels were significantly higher than normal both at entry into the study and 24 months later. No patient was positive for antiphospholipid antibodies. Slightly decreased levels of AT-III and heparin cofactor II were found in only two cases. Our study confirms neither the high incidence of thrombotic complications in NS nor the presence of abnormalities of hemostatic parameters commonly associated with venous thromboembolism.
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8039757
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The clinical significance of the antiplatelet antibody test based on results for 265 thrombocytopenic patients.
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The usefulness of measuring antiplatelet antibodies by ELISA or cytofluorimetric techniques for the diagnosis of idiopathic thrombocytopenic purpura is still uncertain. We evaluated the clinical significance of two widely applicable antiplatelet antibody tests for a series of 265 patients evaluated consecutively in our Department for the diagnosis or follow-up of thrombocytopenia. Flow cytofluorimetry was used to measure platelet-associated immunoglobulins (PAIg) and the enzyme-linked immunosorbent assay (ELISA) was used to detect antiplatelet antibodies in patients sera (S-PBIg). The significance of antiplatelet antibody testing was addressed by studying the factors that influence test positivity, the diagnostic value of a positive test and the prognostic implication of a positive test. The platelet count was found to be strongly associated with positive PAIg or S-PBIg (P < 0.001), while neither splenectomy nor corticosteroid treatment affected PAIg or S-PBIg positivity. Both PAIg and S-PBIg were limited diagnostic value for the differential diagnosis of idiopathic thrombocytopenic purpura (ITP) from secondary thrombocytopenia for patients with platelet counts between 25,000 and 100,000 platelets/microliters, but the percentages of misclassified patients based on only the PAIg or S-PBIg test were 32 and 54%. We found no relationship between PAIg and/or S-PBIg at time of diagnosis and the patient's clinical response to corticosteroid therapy. We conclude that antiplatelet antibodies are strongly correlated with platelet counts, discriminate poorly between ITP and secondary thrombocytopenia and have negligible prognostic value. Therefore, we do not recommend performing antiplatelet antibody tests as a routine laboratory test in the diagnostic workup of thrombocytopenia.
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8039756
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Adverse reactions after high-dose intravenous immunoglobulin: incidence in 83 patients treated for idiopathic thrombocytopenic purpura (ITP) and review of the literature.
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High dose intravenous immunoglobulin (h.d. Ig) is increasingly used in several hematological diseases. There are few data on the safety and no review of side effects after this treatment is available. We review here the literature on reported adverse reactions after h.d. Ig and report our own experience in the management of 83 patients with idiopathic thrombocytopenic purpura (ITP). Computer assisted (Medline) and manual searches of the cumulative Index Medicus were undertaken to retrieve articles reporting side effects after infusion of h.d. Ig, published between 1981 and August 1993. Our own experience is based on clinical records of 83 patients, 56 females, 27 male, with a median age of 61 years (range 8-84), treated with h.d. Ig for acute or chronic ITP between 1985 and June 1993. Major adverse reactions included aseptic meningitis (14 cases), hemolytic anemia (8 cases) and renal dysfunction (12 cases). The most frequently reported mild side effect was headache. We have had 2 cases of severe skin reactions, 1 case of acute renal failure, 3 cases of severe headache and 1 case of chills and fever. For other 3 cases, an anaphylactic/oid reaction, caused by a too rapid infusion rate, occurred. Thus, 10/83 (12%) patients, 7 female and 3 male, developed side effects, but they were unpredictable and severe in only 3 cases (4%). Side effects developed only in 21/480 (4%) infusions.
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8039755
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Treatment of idiopathic thrombocytopenic purpura (ITP) in patients with refractoriness to or with contraindication for corticosteroids and/or splenectomy with immunosuppressive therapy and danazol.
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The best treatment for patients with idiopathic thrombocytopenic purpura (ITP) who are refractory to or have contraindications for splenectomy and corticosteroid remains uncertain. We report here our experience with vinca alkaloids (VA), azathioprine (Azp) and danazol in 33 such patients (6 M/27 F), median age 66 (23-83). Group A (n = 19), Group B (n = 11), Group C (n = 17) patients were treated with VA, Azp and danazol. Fourteen patients were given more than one immunosuppressor agent. Sixteen patients were given 2 mg/week bolus infusions of vincristine (Vcr), while weekly slow infusions of vinblastine (Vnb, 0.1 mg/kg), for 2-4 weeks, were administered to the remaining 3 cases of Group A. Azp was administered at a daily dose of 150 mg for a median duration of 6 months. Danazol was administered at a median daily dose of 400 mg (400-800 mg), for a median length of 5 months. Response was defined as any increase of platelet count to higher than 30 x 10(9)/l, when platelet count was < 20 x 10(9)/l or any doubling of the basal platelet count otherwise. Remission, any increase of platelet count to higher than 100 x 10(9)/l lasting for 3 months or longer without therapy. In Group A, there was a response rate of 63%, with 2 remissions (10%). All responses were observed after the first infusion. Two additional patients, who responded transitorily to VA, went into spontaneous remission 19 and 51 months after the last infusion of VA. In Group B, the response rate was 45%, with 1 remission (9%). The response was never observed before one month. One additional patient went into spontaneous remission 60 months after stopping Azp. In Group C, the response rate was 56% with 2 remissions (12%); 2 patients relapsed while on therapy, 4 continue to require therapy and 1 died from a stroke while on therapy. Four patients in Group A and two in Group B discontinued the therapy because of severe side effects. Danazol was generally well tolerated but for one patient was interrupted after only 5 days because of severe dyspepsia. In conclusion, the clinical usefulness of VA and Azp is very limited and burdened by severe side-effects. Danazol seems to be safer but no more effective and its long-term toxicity is not known. There were two hemorrhagic deaths in this series of patients.
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8039754
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Twenty years experience with treatment of idiopathic thrombocytopenic purpura in a single department: results in 490 cases.
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All patients with idiopathic thrombocytopenic purpura (ITP), diagnosed in our Department between June 1970 and December 1989, have been analyzed to evaluate the efficacy of treatment, incidence of spontaneous remission and see whether or not there are some parameters that may be indicative of the clinical outcome of these patients. A total of 93 children and 397 adults have been evaluated. Response to treatment was any increase in platelet count to above 30 x 10(9)/1, when the platelet count was < 20 x 10(9)/l, or any doubling of the basal platelet count otherwise. Remission was defined as any platelet count higher than 100 x 10(9)/l lasting for 3 months or longer without treatment. For duration of the response and remission, the last check-up with a favorable platelet count was considered or the midpoint between the last favorable check-up and relapse. In children, short-term responses to prednisone were obtained in 78% of acute patients and 67% of chronic patients, while stable remissions or long-term responses were found in 49% and 17% (p = 0.01). In adults, a short term response to prednisone was obtained in 71% of acute and in 72% of chronic patients, while stable remissions or long-term responses in 30% and 5% (p = 0.000003). In 40/45 children (89%), splenectomy induced a stable remission or a long-term response, while in adults, remissions or a long-term responses were achieved in 100/133 (75%) (p = 0.003). Age below 40 was found to be a significant determinant of a better response (p = 0.0013). Of the 92 evaluable adult patients with borderline thrombocytopenia, 8 developed a severe thrombocytopenia (9%). Spontaneous remissions or spontaneous rises to safe levels of platelet counts were recorded in 9% of adult cases presenting with severe thrombocytopenia: among refractory patients, spontaneous remission occurred significantly more frequently in younger patients (p = 0.003). An overall rate of 19% of adult patients continue to need therapy or have become refractory to any treatment. Among these cases, 7 died from cerebral hemorrhage, 6/7 were older than 50 years. Thus, the overall crude rate of thrombocytopenia-related death for our series of patients was 1.8%.
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8039753
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Is ticlopidine a safe alternative to aspirin for management of myeloproliferative disorders?
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Bleeding and thrombosis are frequent complications in patients with chronic myeloproliferative disorders (cMPD). Antiplatelet therapy is extensively used by many physicians for primary prophylaxis of thrombotic events, even though there have been no prospective trials that demonstrate clinical benefit. The use of aspirin has been associated with a heavy incidence of serious hemorrhages, particularly of gastrointestinal origin. This evidence is mainly based on data from patients treated with dosages far higher than those presently recommended. Moreover, patients with bleeding symptoms or prolonged bleeding time (BT) had not usually been excluded from treatment. In this study 58 patients with cMPD and thrombocytosis were treated with aspirin (325-500 mg/day, 31 patients) or with ticlopidine (500 mg/day 27 patients). Only patients with negative bleeding histories and normal BT were considered. Ticlopidine, a drug not extensively investigated in cMPD, was reserved only for patients with histories of gastritis, gastric discomfort, peptic ulcer and/or intolerance to aspirin. All other patients were given aspirin combined with antacids in a buffered preparation. Average follow-up was 2 years. Aspirin was associated with a high incidence of gastrointestinal hemorrhages (5/31). Ticlopidine was tolerated better and no bleeding complications were recorded. Both drugs were similarly effective in relieving erythromelalgia and painful paresthesia in almost all cases with these symptoms within 24-48 hours.
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8039752
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Polycythemia vera and essential thrombocythemia in young patients.
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Polycythemia vera (PV) and essential thrombocythemia (ET) in young patients are rarely reported. Their natural histories seem to differ from those of older patients and the best treatment is still uncertain. In this follow-up study we have evaluated a cohort of 64 consecutive patients younger than 40 to determine the incidence of thrombohemorrhagic events and the long-term outcome. Twenty-eight patients (20 M; 8 F) had PV, and 36 ET (21 F, 15 M). Mean follow-up was 8.2 years (range 4 months-16.7 years) in PV and 6.5 years (range 5 months-15 years) in ET. Thrombohemorrhagic symptoms were present at diagnosis in 10/28 patients (35%) with PV and in 12/36 patients (33%) with ET; during follow-up in 15/28 PV patients (53%) and in 13/36 ET patients (36%). Thrombotic events were the most frequent symptoms, both at diagnosis (52% in PV, 65% in ET) and during follow-up (43% in PV, 52% in ET). A total of 19/28 PV patients (67%) and 17/36 ET patients (47%) had thrombotic complications. Hemorrhagic complications at diagnosis were 4% and during follow-up 13% in PV, and 15% and 13% in ET. A total of 5/28 (18%) PV and 6/36 (17%) ET patients had hemorrhagic events. No laboratory parameter, including platelet count, was predictive of these events. Five PV patients had major thrombotic complications (18%). Four PV patients died (14%), 2 because of ANLL (7%), 2 because of thrombotic events (7%). Four ET patients experienced major complications, in three cases thrombotic (8.3%), in one hemorrhagic. No leukemic transformation occurred in ET and no ET patient died. In our experience, severe thrombohemorrhagic complications are present in young patients with PV and ET, which excludes young age as a favorable prognostic factor. Treatment also seems advisable for young patients and myelosuppressive treatment might be required. Prospective studies are urgently needed to assess the best treatment for this particular subset of patients.
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8039737
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Experiential teaching: infection control for certified nurse's aides.
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This article has described a self-care model of teaching infection control to CNAs in nursing homes. How the CNAs know and detect illness in themselves becomes the basis for learning about the presentation of acute illness in nursing home residents. This model begins with a discussion of the different meanings of feelings, then the awareness of changes during acute illness, and the factors affecting nursing home residents that change their perceptions of acute illness. With this knowledge, CNAs empathically detect the changes of common acute infectious illnesses in elderly nursing home residents to accomplish infection control. This model uses self-care as a motivational tool, blending greater knowledge with self-confidence.
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8039732
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Obtaining and maintaining a research sample with cognitively impaired nursing home residents.
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Obtaining and maintaining a research sample of cognitively impaired nursing home residents is a challenging task. One cannot conduct research with this population without the cooperation of the nursing home administration and staff. The initial challenge is identifying and screening potential subjects. The medical record often provides inadequate information, necessitating direct observation and use of screening tools. Once potential subjects have been identified, the researcher must obtain consent. This complicated process may vary from site to site. Because of the potential subjects' cognitive impairment, we must obtain additional consent from a proxy. A variety of persons may function as proxy. Suggested methods of contact include personal contact at the nursing home and phone or written contact. Proxies may raise many issues in deciding whether to consent.
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8039728
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Age-related hearing loss: how to screen for it, and when to intervene.
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Hearing loss is prevalent among older adults and is associated with depression, cognitive decline, reduction in functional status, and emotional and social handicaps. Screening by physicians is important, because older adults tend to underestimate the degree of their hearing impairment. The most important predictor of hearing aid candidacy is not the severity of hearing loss but rather the patient's motivation and perception of the handicapping effects of his/her hearing impairment. A variety of hearing aid styles is available. In-the-ear units and in-the-canal hearing aids are the most popular. New digitally programmable aids are often acoustically superior, but they cost more and require considerable training. Assistive listening devices may be used with or without a hearing aid to amplify sound, television, or telephone conversations.
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8039727
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Chronic renal disease: new therapies to delay kidney replacement.
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Several factors promote the progression of renal disease, including glomerular hypertension and hypertrophy, molecular factors such as cytokines and growth hormones, proteinuria, acidosis, and hyperlipidemia. Regardless of the underlying etiology, many patients with chronic renal insufficiency will ultimately require kidney replacement therapy. Your goal is to delay the progression of renal failure, mainly through aggressive control of blood pressure. Other possible interventions include protein restriction, bicarbonate therapy, and lipid-lowering drugs.
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8039726
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Uveitis: role of the physician in treating systemic causes.
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For older patients with uveitis, defined as any inflammation of ocular structures--including the uvea--there are four typical etiologies: infection, "masquerade syndromes," systemic disease, and idiopathic. Uveitis is associated with a systemic cause in about 40% of cases. It manifests in a number of ways, but common symptoms include sudden onset of pain, redness, and sensitivity to light, chronic floaters, or a gradual decrease in vision. Diagnosis is aimed at finding an underlying cause. Depending on the symptoms, useful diagnostic tests include syphilis serology, chest x-ray, Lyme antibody titer, PPD skin test, and skin test for anergy. Treatment, including the use of corticosteroids or antibiotics, is based on the underlying etiology.
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8039725
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Alzheimer's disease: a comprehensive approach to patient management.
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Despite advances in our understanding of Alzheimer's disease (AD), the diagnosis is still made from the clinical history and assessment of cognitive function. The physical, neurologic exam, and laboratory testing help you look for any other condition that may be contributing to the dementia. Once the diagnosis is made, your role becomes that of a resource to the patient and family. Drug therapies may be needed to manage AD-related depression, sleep/wake cycle alterations, and aggressive behaviors. Some patients with mild to moderate cognitive deficits may be candidates for tacrine or enrollment in clinical trials of experimental therapies. Community resources, advocacy, and driving safety should be discussed with each patient and his/her family.
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8039722
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Structure and expression of a novel rat RegIII gene.
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We have isolated a rat cDNA and a novel gene, Reg (regeneration-promoting gene). The cDNA encodes a 174-amino-acid (aa) RegIII protein with a 25-aa signal peptide. The RegIII gene spans 2.7 kb and consists of six exons and five introns. RegIII was expressed in regenerating pancreatic islets, but not in normal islets.
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8039723
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Cloning and sequencing of the cDNA encoding a human testis phospholipid hydroperoxide glutathione peroxidase.
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A human cDNA that encodes a polypeptide that has 94% deduced amino-acid sequence identity to porcine phospholipid hydroperoxide glutathione peroxidase was cloned from a testis library. The sequence shows preservation of the UGA selenocysteine codon, putative active-site Trp and Glu residues and a Tyr residue that is phosphorylated in the porcine protein. The 3'-UTR shows some conservation of sequences implicated in the insertion of selenocysteine at an opal codon in human glutathione peroxidase-1.
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8039721
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Cloning and characterization of cDNAs coding for heavy and light chains of a monoclonal antibody specific for the S antigen of hepatitis B virus.
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The nucleotide (nt) sequences encoding the variable regions of the heavy and light chains of a murine monoclonal antibody (mAb) have been determined. The mAb recognizes a disulfide-bond-dependent conformational epitope on the hepatitis B virus surface antigen. The sequence analyses revealed that the variable regions of the heavy and light chains are members of mouse heavy-chain subgroup II(A) and kappa light-chain subgroup III, respectively.
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8039720
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Cloning and sequencing of hen magnum cDNAs encoding vitelline membrane outer layer protein I (VMO-I).
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Two cDNAs encoding hen vitelline membrane outer layer protein I (VMO-I), which is classified as a new type of multi-beta-sheet assembly, were cloned and sequenced. Northern blot analysis using vmo-I cDNA as a probe showed the presence of three mRNA species. Strikingly, expression of these mRNAs was restricted to a specific region of the hen oviduct, the area joining the infundibulum to the magnum.
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8039719
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The Drosophila melanogaster ribosomal S6 kinase II-encoding sequence.
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A cDNA encoding the Drosophila melanogaster p90 ribosomal S6 kinase II (RSK) was isolated from an eye-antennal imaginal disc library and sequenced. The conceptually translated protein is 60-63% identical to vertebrate RSK homologs and contains a perfectly conserved mitogen-activated protein kinase phosphorylation site. The gene was mapped to the base of the X chromosome in division 20 by in situ hybridization to polytene chromosomes.
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8039717
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A novel human gene that is preferentially transcribed in heart muscle.
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We have cloned a human cDNA fragment for a gene that is expressed primarily in the heart. To explore its biological function, we have isolated full-length cDNA clones of the gene. DNA sequencing of the 2.7-kb cDNA revealed a 2274-bp ORF. Close to the N terminus of the deduced amino acid sequence is a possible ATP-binding domain that has been assembled by a fusion of B- and A-type adenine nucleotide-binding motifs. In the middle of the sequence is a long stretch of alpha-helical residues that could form a coiled-coil. These features imply that this is a sequence encoding a new human motor protein.
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8039718
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Nine duplicated tRNA genes on the plastid-like DNA of the malaria parasite Plasmodium falciparum.
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A major feature of the plastid-like circular DNA of Plasmodium falciparum is an inverted repeat comprising duplicated genes for rRNA (rrn) and tRNA (trn). We have identified nine putative trn genes in each arm of the repeat on the basis of their potential clover-leaf structures and conserved residues. Northern blots indicate that these trn genes are expressed.
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8039716
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A high-level and regulatable production system for recombinant glycoproteins using a human interferon-alpha promoter-based expression vector.
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A novel expression vector for human cells, pIFP, which expresses a cloned gene under the control of the human interferon-alpha-encoding gene (IFN-alpha) promoter (pIFN) was constructed. As a model of glycoprotein production, a human erythropoietin-encoding cDNA (EPO) inserted downstream from pIFN in pIFP was introduced into human B-cell leukemia-derived BALL-1 cells, and EPO-producing cells were established. Upon stimulation with Sendai virus, the cells produced human EPO at high levels. The highest production level and the highest inducibility were 872 IU/ml and 67-fold, respectively. Simultaneously, the transformed cells also produced IFN-alpha and tumor necrosis factor-alpha (TNF-alpha), as the parental BALL-1 cells did. Comparing the amounts of the substances produced, activity of the exogenous pIFN introduced seemed much higher than that of the endogenous one. Further, the transformed cells could be obtained in a large quantity by being applied to the 'in vivo cell proliferation method (hamster method)'. Human EPO produced by the transformed cells had a molecular mass range of 35 to 42 kDa, similar to that of EPO produced by CHO cells. The processing of EPO seemed to occur properly. The combination of the human pIFN, BALL-1 cells and the hamster method provides us with a useful production system for bioactive glycoproteins of human origin.
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8039715
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Structures of the human and mouse growth inhibitory factor-encoding genes.
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Growth inhibitory factor (GIF) is down-regulated in Alzheimer's disease (AD) brains. To analyze the mechanism of this down-regulation, we isolated the human and mouse GIF genes. These genes consist of three exons, are approx. 1-kb long and show strikingly high homology to metallothionein-encoding genes. A comparison of the human and mouse GIF showed several conserved sequences, including the putative AP-2, SP-1, TATA-binding protein and metal-responsive elements (MRE). A sequence similar to the human gfa common sequence (hgcs), recently identified as the sequence for an astrocyte-specific transcriptional factor, is present in the promoter of these GIF. Characterization of factors associated with the putative regulatory elements in the promoter of GIF should help in determining the mechanism of the down-regulation of GIF in AD brains.
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8039714
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Selection for the expression of one form of Chinese hamster dihydrofolate reductase over another during growth in methotrexate.
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Two mammalian expression plasmids, each carrying a cDNA encoding a different allele of dihydrofolate reductase (DHFR) present in the Chinese hamster lung cell line DC-3F, were constructed. These simian virus 40 promoter-enhancer-based plasmids, designated pSVA75 and pSVMQ19, are identical except for a G-->A transition at nucleotide 286 of the DHFR coding sequence. Due to this change, the enzyme expressed by pSVA75 contains Asp95, while the enzyme expressed by pSVMQ19 has Asn95 [Melera et al., J. Biol. Chem. (1988) 1978-1990]. Both forms of the enzyme are catalytically equivalent and are produced to similar levels in DC-3F cells [Yu and Melera, Cancer Res. (1993) 6031-6035; H.Y., A.H. and P.W.M., in preparation]. Clonal cell lines expressing one or the other DHFR allele were obtained via transfection of DHFR- Chinese hamster ovary cells, and 74 clones of each type isolated. These were pooled and divided into 40 aliquots, each of which was then subjected to selection by growth in sequentially increasing concentrations of methotrexate (MTX). Analysis of the resulting drug-resistant populations revealed that cells producing Asp95 DHFR dominated with an overall frequency of 3:1, and therefore, under these growth conditions, display a selective advantage over those producing Asn95 DHFR. These data extend previous observations showing that independent selections of the heterozygous parent cell line DC-3F in MTX result in threefold more MTX-resistant lines overexpressing the Asp95-encoding DHFR allele than the Asn95-encoding DHFR allele.(ABSTRACT TRUNCATED AT 250 WORDS)
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8039713
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Partial cloning and sequencing of the gene encoding the porcine T-cell receptor delta-chain constant region.
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The polymerase chain reaction (PCR) was utilized to clone the pig T-cell receptor (TCR) delta-chain constant region-encoding gene (C delta). A cDNA was generated from total RNA preparations of normal pig peripheral blood lymphocytes (PBLs) and a miniature pig peripheral blood cell line (PBLCL 62.G4). The cDNA was used to amplify the porcine TCR C delta gene by PCR using primers chosen by comparing other known C delta sequences for sequence identity. Clones were sequenced and used to determine the primary structure of the porcine TCR C delta chain. A comparison of the nucleotide and deduced amino acid (aa) sequences with the known human, mouse, sheep and cattle sequences revealed that the primary structure of the pig TCR C delta chain has been highly conserved. The immunoglobulin (Ig) domain has two conserved Cys residues and contains a high degree of sequence identity, whereas the hinge region is marked by a high level of diversity. The transmembrane and cytoplasmic regions are also highly conserved, including the presence of the two basic aa, Arg and Lys, in the transmembrane domain. Southern blot analysis has confirmed the presence of one TCR C delta gene in the porcine genome, consistent with similar findings in other species. Thus, the successful cloning and sequencing of the porcine TCR C delta gene should facilitate our understanding of the role of gamma delta T-lymphocytes in the swine immune system.
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