Circulant partial triallel crosses.
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It has been shown in various mammal species that clonidine, a well known centrally acting hypotensive agent, acts through the activation of imidazoline receptors (IRs) in the nucleus reticularis lateralis (NRL) of the brainstem. Specific binding sites sensitive to imidazolines and insensitive to catecholamines have been detected in rat and bovine, as well as human brains. An endogenous ligand, other than catecholamines, should exist for these IRs. Such a ligand could play a role in the pathophysiology of human essential hypertension. Therefore, we developed two RIAs with polyclonal and monoclonal anticlonidine antibodies. These antibodies presented specificity spectra similar to that of the IRs: they bound imidazolines and not catecholamines at all. These RIAs were used to detect imidazoline-like immunoreactivity in the human serum. Immunoreactive substance was measured in 26 normotensive subjects' sera, and specificity of interaction between antibodies and sera was verified. None of the known endogenous substances tested so far were able to interact with the two antibodies. Immunoreactivity in 32 essential hypertensive patients' sera proved higher in approximately 30% of cases. Values of immunoreactivity positively correlated with the mean arterial pressure values. This study demonstrates the existence of an "imidazoline-like" immunoreactive substance in the human serum with high levels in some hypertensive patients.
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Two infants with cerebral arteriovenous malformation (CAVM), both initially seen with persistent fetal circulation, were studied with cross-sectional echo. The descending aorta, which is dilated in infants with CAVM, was identified in the subxiphoid four-chamber and short-axis views in both infants. In both infants the arteriovenous malformation was readily identified by cross-sectional echo as a lucency within the brain. Pulsation of the cranial lucency was noted in one infant, but only still frames from the head echo were preserved in the other infant, and pulsation was not commented on in that case.
Progestogens appear to influence breast density more than estrogens in postmenopausal women taking hormone replacement therapy (HRT), but little is known about the effect of circulating hormones on mammographic density among premenopausal women. This cross-sectional study explores the relationship of body weight and sex steroids with breast density. Luteal serum samples were analyzed for progesterone, estrone, estradiol, and sex hormone-binding globulin (SHBG). Mammograms were assessed for density using a computer-assisted method. We performed mediation tests using multiple linear regression models. Significant associations of SHBG and estradiol with percentage density disappeared after adjustment for body weight and other covariates, whereas the relationship between progesterone and breast density remained borderline significant. The mediation tests indicated that progesterone has a direct and an indirect effect on mammographic density. Our finding that progesterone shows a stronger association with percentage of mammographic density than estrogen agrees with clinical reports describing denser mammographic patterns among women taking HRT, although these women differ in menopausal status.
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Concentrations of cross-linked fibrin degradation products (XL-FDPs) in plasma, measured by enzyme-linked immunosorbent assays (ELISAs) based on monoclonal antibodies (MAbs) raised against fragment D-dimer of cross-linked fibrin, increase when patients are given fibrinolytic agents. Whether XL-FDPs derive from circulating cross-linked fibrin polymers in plasma, compared with clot-associated fibrin, has been questioned because increases in XL-FDP are measured by some assays after fibrinolysis in vitro in the absence of clot. We characterized the source of XL-FDP immunoreactivity in plasma of patients with acute myocardial infarction and ischemic heart disease and the response to plasminogen activation in vitro induced by pharmacological concentrations of tissue-type plasminogen activator (t-PA) and streptokinase. XL-FDPs were measured with two different ELISA. One, "pan-specific tag ELISA," was based on a capture MAb specific for XL-FDP and a tag MAb that recognizes an epitope exposed in the fragment D region of both fibrin and fibrinogen, whereas the other, "fibrin-specific tag ELISA," was based on a capture and tag MAbs both specific for fibrin. After plasminogen activation was induced in vitro in plasma from patients with myocardial infarction, increased concentrations of XL-FDP were measured by the pan-specific tag ELISA; however, concentrations measured with the fibrin-specific tag ELISA were not increased. To determine the mechanism for this discrepancy, plasma was subjected to immunoadsorption with a MAb specific for fragment D-dimer before and after in vitro activation of the fibrinolytic system and immunoblotting with a fragment D-dimer-specific MAb and with the pan-specific MAb. Increased concentrations of fragment D-dimer, as well as fibrinogen fragment D at high concentrations, were recognized by the specific MAb. Non-cross-linked fragments were also shown by immunoblotting with the pan-specific MAb to coprecipitate with cross-linked fibrin fragments. This suggested the increased concentrations of XL-FDP measured by the pan-specific tag ELISA after in vitro activation of the fibrinolytic system were due to detection of non-cross-linked fibrinogen fragments. However, fibrin fragment D-dimer concentrations were found to increase in plasma of 15 patients given t-PA for acute myocardial infarction. We conclude fragment D-dimer in plasma of patients during thrombolysis does not originate from circulating soluble cross-linked fibrin but rather is a marker of solid-phase fibrin dissolution, which may be quantitated with assays based on capture and tag antibodies that do not detect fibrinogen or its degradation products.
Between March 1991 and October 1992, 21 consecutive patients underwent aortic arch reconstruction without aortic cross-clamping using separate extracorporeal circulation in combination with retrograde blood cardioplegia (Non-clamping selective cerebral perfusion). Twelve patients had true arch aneurysm, 3 had acute aortic dissection and 6 had chronic aortic dissection including 2 redo cases. Cardiopulmonary bypass (CPB) was instituted with an arterial cannula in the femoral artery and 2 cannulae in both vena cavae. When tympanum temperature was lowered to 20 degrees C by central cooling, CBP was stopped temporarily. As soon as the aortic arch was incised longitudinally together with aneurysm, flexible 12 Fr. balloon cannulae were inserted into the three arch arteries via their orifices and selective cerebral perfusion was started. The perfusion flow was kept between 0.3 L/m2/min and 0.35 L/m2/min with the pressure of catheter tip from 30 to 60 mmHg to keep tympanum temperature 18 degrees C. Heart was protected by retrograde continuous cold blood cardioplegia. During arch correction, the descending aorta was occluded by a balloon then abdominal viscera were perfused via a femoral return cannula and rewarming to 25 degrees C was started to prevent visceral organ failure and coagulopathy. The time of separate perfusion ranged 20 to 161 minutes with a mean of 99.9 minutes. Except one patient who died of pneumonia, 20 patient (95.2%) were discharged and doing well. No cerebral complication, myocardial infarction, lung bleeding and coagulopathy occurred. In order to prevent the infarction by debris and to protect vital organs, this method is reliable for aortic arch reconstruction.
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Diaspirin cross-linked hemoglobin (DCLHb), a hemoglobin-based blood substitute, has been found to improve systemic hemodynamics, cutaneous oxygen tension, and normalization of blood lactate levels and acid-base equilibrium after hemorrhage in animals. The present study was conducted to determine the dose-dependent effect of a 10% solution of DCLHb (20, 50, and 100% of shed blood volume; SBV) on regional blood circulation in hemorrhaged rats. Hemorrhage was induced in urethane-anesthetized rats by bleeding them at a rate of approximately .5 to 1 mL/min until a mean arterial pressure of 35-40 mmHg was achieved. This was maintained for up to 90 min to reach a base deficit of more than -12 mmol/L. Hemorrhage significantly decreased oxygen consumption, mean arterial pressure, cardiac output, stroke volume, and regional blood circulation, but increased total peripheral resistance. The vehicle Ringer's lactate (RL at 20% of SBV, intravenously) did not produce any improvements in oxygen consumption, base deficit, systemic hemodynamics, and regional blood circulation. DCLHb increased oxygen consumption, decreased base deficit, and produced significant improvements in systemic hemodynamics and regional blood flow in a dose-dependent manner. The increase in blood flow was highly significant until 60 min, but was less marked at 120 min, after resuscitation with DCLHb. Resuscitation with RL (300% of SBV) significantly improved systemic and regional blood circulation. However, the improvement was greater after resuscitation with DCLHb (50 or 100% of SBV) as compared with RL at 300% SBV. DCLHb in the dose of 50% of SBV produced maximal resuscitative effects, which were comparable to a DCLHb dose of 100% of SBV. The effect of DCLHb at 50% of SBV on renal cortical blood perfusion, concentration of moving red blood cells (CMBC), and blood velocity was also studied using laser Doppler flowmetry. Hemorrhage produced a decrease in renal cortical blood perfusion (85.3%), which was due to a decrease in the CMBC (61.0%) and their velocity (64.2%). Resuscitation with the RL did not produce any improvement in renal cortical perfusion. However, resuscitation with DCLHb significantly increased renal cortical perfusion (364.7%) due to an increase in both CMBC (123.4%) and their velocity (109.9%). It is concluded that DCLHb in a dose of 50% of SBV produces maximal improvement in regional blood circulation of hemorrhaged rats.
The effect of infrarenal cross-clamping of the aorta on regional splanchnic and renal circulations was studied in seven dogs. Regional blood flow was determined with differentially labeled microspheres (9 and 15 micron in diameter) that were injected simultaneously into the left atrium. Blood flow was measured 30 minutes after surgical preparation was completed (stage I), 20 minutes after infrarenal aortic cross-clamping (stage II), and 20 minutes after supplemented sodium nitroprusside infusion (stage III). Infrarenal aortic cross-clamping was accompanied by a slight increase in the cardiac output (CO) without significant changes in mean arterial pressure (MAP). Blood flow through the gut, hepatic artery, and cortical layer of the kidneys, as determined with 15-micron spheres, was not changed. Nonentrapment of 9-micron spheres in the gut and renal cortex was increased substantially. Blood flow through the juxtamedullary layer of the kidneys was increased. Sodium nitroprusside supplementation decreased MAP by 30%; CO values returned to baseline level. Hepatic artery blood flow, compared with both baseline values and values during aortic cross-clamping, increased significantly. Blood flow, determined with 15-micron spheres, through the gut and renal cortex did not change, and nonentrapment of 9-micron spheres decreased to baseline values. The data suggest a certain shift of blood flow to the juxtamedullary layer of the kidneys during aortic cross-clamping and normalization of intrarenal blood flow distribution during supplemented sodium nitroprusside infusion. Controlled vasoplegia with sodium nitroprusside may help modify peripheral circulatory disturbances in the kidneys and splanchnic system during infrarenal aortic cross-clamping.
In experiments on dogs, application of the cross-over circulation method revealed that mildronate increased coronary blood flow due to active coronary dilation. In experiments on cats, a cardioprotective effect of mildronate was found, which prevented the development of acute ischemic heart failure by stabilizing the major hemodynamic parameters. Clinical studies of patients with Functional Classes I-III angina provided evidence for positive effects of mildronate on coronary blood flow.
A 24-h rhythm has been demonstrated in fetal and maternal melatonin plasma concentrations in pregnant sheep in the last third of gestation. Melatonin in the maternal circulation can cross the placenta and is the major source of melatonin in the fetal circulation. Melatonin has been postulated to act as a prostaglandin (PG) synthetase inhibitor in the uterus. PG synthetase inhibitors decrease myometrial contractility. To assess transplacental passage of melatonin and potential influences of melatonin on uterine contractility, we infused melatonin continuously into the maternal jugular vein in seven pregnant sheep at 138-142 days gestation (term in our instrumented animals is 147 days gestation) at three infusion rates for successive 1-h periods during the late morning to late afternoon. There was no change in the total time during which the myometrium was active, as indicated by myometrial electromyographic activity or the myometrial contracture frequency during the 3 h before and after melatonin infusions and for each hour of the infusions. The MCR for melatonin in the ewe was 4128 +/- 410 ml/min (mean +/- SE; n = 7; weight, 50-70 kg). The resting maternal to fetal melatonin concentration ratio was 0.8; this ratio was maintained at 2.28 during melatonin infusion to the ewe at a wide range of maternal melatonin concentrations. Melatonin concentrations in the range of 3-200 times normal had no effect on the maternal plasma PGF2 alpha metabolite concentration, but caused a 40.4% fall in fetal plasma PGE2 (P less than 0.05). We conclude that changes in maternal and fetal plasma melatonin concentrations within the physiological range observed throughout the day do not alter myometrial contractility, but do alter fetal PGs.
Preceding studies showed that fibrin-monomer of the type lacking only fibrinopeptide A (alpha-fibrin) cleared from the circulation more rapidly than a tighter aggregating form of monomer that lacks both fibrinopeptides A and B (alpha beta-fibrin). The rapid clearance of alpha-fibrin may be related to the high dissociability of the soluble complexes that it forms with fibrinogen in blood. In this study, we use cross-linking by factor XIIIa to suppress dissociation of fibrin complexes and examine the effect of the cross-linking on the circulatory half-life of the fibrin. Incubation of alpha-fibrin-monomer/fibrinogen solutions with factor XIIIa before injection in rabbits increased the circulatory half-life of the fibrin (range, 2 to 16 hours) in proportion to the percentage conversion of monomer to cross-linked dimers and small oligomers. Electrophoretic analyses of plasma samples confirmed that, compared with non-cross-linked monomer, cross-linked dimers and small oligomers were long lived and, further, were not degraded. The inhibition of clearance through cross-linking occurs only under conditions that produce partial cross-linking of the fibrin. An opposite effect occurs when cross-linking is allowed to approach completion, as a result of polymerization of the fibrin into large fibers that disappear almost immediately after injection. Cross-linking elicited in vivo with injected factor XIIIa has an inhibitory effect on clearance of injected monomer similar to the effect produced by partial cross-linking in vitro. It is proposed that the prolonged survival of cross-linked dimers and small oligomers in the circulation provides a partial explanation for the frequent prevalence of cross-linked rather than non-cross-linked complexes in blood of human subjects with vascular disease.
Twelve (34%) of thirty-five patients with an active infection on the palms or soles caused by Hendersonula toruloidea or Scytalidium hyalinum were found to have circulating antibodies to these organisms by counter immunoelectrophoresis or immunodiffusion, compared with 9% of uninfected controls. In every instance there was cross-reactivity between the positive patients' sera and the heterologous non-dermatophyte antigen. Using crossed and intermediate gel immunoelectrophoresis it was found that cytoplasmic extracts of H. toruloidea and S. hyalinum showed 34 and 41 precipitin peaks respectively, most of which were shared by both organisms. No cross-reactions were observed between the non-dermatophyte cytoplasmic extracts and hyperimmune animal antisera raised to Trichophyton rubrum, Trichophyton interdigitale, Aspergillus fumigatus or Candida albicans. Exoantigens prepared from the two non-dermatophytes showed similar cross-reactivity between the two species. It appears that H. toruloidea and S. hyalinum are very similar in antigenic structure, a finding which lends support to the view that they may be closely related. They are also antigenically distinct from other pathogenic fungi which commonly infect skin, a fact which may be useful in their cultural identification as well as their recognition in tissue specimens.
Peptides derived from proteolytic degradation of the amyloid precursor protein, e.g., amyloid beta (A beta), are considered to be central to the pathology of Alzheimer's disease (AD). Soluble A beta is present in measurable concentrations in cerebrospinal fluid and blood. There are indications that soluble A beta present in circulation can cross the blood-brain barrier via transcytosis mediated by brain capillary endothelial cells. It implies that A beta originating from circulation may contribute to vascular and parenchymal A beta deposition in AD. Enhancing of A beta catabolism mediated by proteolytic degradation or receptor-mediated endocytosis could be a key mechanism to maintain low concentrations of soluble A beta. To launch A beta clearance we have exploited the A beta-degrading activity of diverse alpha 2-macroglobulin (alpha 2-M)-proteinase complexes. Complexes with trypsin, alpha-chymotrypsin, and bromelain strongly degrade (125)I-A beta 1--42 whereas complexes with endogenous proteinases, e.g., plasmin and prostate-specific antigen, were not effective. A beta degradation by the complexes was not inhibited by alpha 1-antichymotrypsin and soybean trypsin inhibitor which normally would inactivate the free serine proteinases. A prerequisite for A beta degradation is its binding to specific binding sites in alpha 2-M that may direct A beta to the active site of the caged proteinase. Ex vivo, enhanced degradation of (125)I-A beta 1--42 in blood could be achieved upon oral administration of high doses of proteinases to volunteers. These results suggest that up-regulation of A beta catabolism could probably reduce the risk of developing AD by preventing A beta accumulation in brain and vasculature.
OBJECTIVE: To investigate the effect of cordocentesis on the umbilical and fetal cerebral circulation. DESIGN: Cross sectional study. SETTING: Department of Obstetrics and Gynaecology, Regional Referral Centre for Fetal Medicine, Klagenfurt Hospital, Austria. SUBJECTS: Thirty pregnant women undergoing diagnostic cordocentesis at 18 to 38 weeks' gestation. INTERVENTIONS: The pulsatility index (PI) in the umbilical artery and fetal middle cerebral artery was measured by pulsed Doppler ultrasound before and immediately after cordocentesis. MAIN OUTCOME MEASURES: Change in umbilical artery PI and middle cerebral artery PI. RESULTS: Cordocentesis was associated with a significant decrease in both umbilical artery PI (median -0.18, range -2.21 to 1.5, P < 0.004) and middle cerebral artery PI (mean -0.15, SD 0.32, P < 0.03) and the decrease in umbilical artery PI was most marked when cordocentesis was performed transplacentally. In four cases, there were absent or reversed frequencies at the end of diastole (EDF) in the umbilical artery before cordocentesis, and in all cases there were positive EDF after the procedure. In contrast, one of the 26 cases with positive EDF developed reversed EDF following the procedure. CONCLUSIONS: Acute alterations in the waveforms from both the umbilical and fetal cerebral circulation can be induced by cordocentesis. The decrease in resistance in the fetoplacental circulation could be attributed to the release of vasodilators, and the increase in resistance observed in some cases could be secondary to arterial vasospasm. Better understanding of the underlying mechanisms might help in making cordocentesis a safer procedure.