Pulmonary endothelin-1 clearance in human pulmonary arterial hypertension.
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Endothelin-1↗
Biomedical subjects
A Caron
Publications and source records attributed to A Caron.
Dielectric study of the molecular mobility and the isothermal crystallization kinetics of an amorphous pharmaceutical drug substance.
During the development of new pharmaceutical products based on drug substances in their amorphous form, the molecular mobility of an amorphous active ingredient was characterized in detail within a very broad time-temperature range. The relation between the isothermal crystallization kinetics and the dynamics of this amorphous substance was investigated. First, dynamic dielectric spectroscopy (DDS) and the thermostimulated current (TSC) techniques were used to analyze the molecular mobility of the amorphous drug substance over a wide frequency and temperature range (the drug substance is referred to as SSR in this text and was chosen as a model glass-forming system). Two relaxation processes, corresponding to different molecular motions, were identified. The beta(a)-relaxation process, associated with intramolecular oscillation of small dipolar groups, followed Arrhenius temperature behavior over the entire time-temperature domain that was studied. However, the main alpha(a)-relaxation process, assigned to the dielectric manifestation of the dynamic glass transition of the amorphous phase, was described by Vogel-Fulcher-Tammann (VFT) and Arrhenius behavior above and below the glass transition temperature (T(g)) respectively. The physical meaning of these complex dynamics is explained in the context of the Adam and Gibbs (AG) model, by the temperature dependence of the size of cooperatively rearranging regions (CRR) that govern the time scale of delocalized molecular motions. The distinction between the molecular mobility and the structural relaxation of amorphous systems below T(g) is discussed. This work shows that the complementary nature of both DDS and TSC techniques is essential to directly analyze the intramolecular and molecular motions of disordered phases over a wide time-temperature range above and below the T(g). Second, real-time dielectric measurements were carried out to determine the isothermal crystallization kinetics of the SSR amorphous drug. Whatever the crystalline form obtained over time in the crystallization process, the decrease of the dielectric response of amorphous phase, which is characteristic of the isothermal crystallization, was studied to monitor the time dependence of the degree of crystallinity. The characteristic crystallization time, derived from Kohlrausch-Williams-Watt (KWW)-Avrami analyses performed at different temperatures, followed an Arrhenius temperature dependence. Behaviors specific to the molecular mobility of the amorphous drug substance were compared with the characteristic crystallization time. It was concluded that the crystal growth process of the SSR drug seems to be controlled by the intramolecular motions involving the beta(a)-relaxation mode and not by the molecular motions responsible for the alpha(a)-relaxation mode in the range of temperatures >T(g). Subsequent studies will focus on the crystallization process of the SSR drug in the glassy state (T < T(g)).
Calorimetry, Differential Scanning↗
E2F3 contributes both to the inappropriate proliferation and to the apoptosis arising in Rb mutant embryos.
The E2F transcription factors are thought to be key downstream targets of the retinoblastoma protein (pRB) tumor suppressor. It is widely believed that E2F1, E2F2, and E2F3 can all activate cellular proliferation but that E2F1 is the specific inducer of apoptosis. Here we show that the E2f3 mutation completely suppresses both the inappropriate proliferation and the p53-dependent apoptosis arising in the Rb mutant embryos. Through the analysis of Rb(-/-);E2f3(+/-) embryos, we have been able to separate E2F3's role in the induction of apoptosis from its ability to induce proliferation. Thus, contrary to the prevailing view of E2F action, E2F3 makes a major contribution to the apoptosis resulting from pRB loss.
Animals↗
Measurement of blood volume after haemodilution with haemoglobin-based oxygen carriers by a radiolabelled-albumin method.
Recent studies have shown that the use of haemoglobin-based oxygen-carrying solutions (HBOCs) for perioperative haemodilution could significantly reduce the need for packed red blood cells in clinical practice. Though the effects of HBOCs on plasma volume have been characterized in experimental models of volume resuscitation from hypovolaemic shock, little is known about their action in normovolaemic haemodilution conditions. We therefore applied a radiolabelled serumalbumin method to determine blood volume after haemodilution with crosslinked or conjugated haemoglobin, in comparison with a reference solution of hydroxyethyl starch (HES). Three groups of New Zealand white rabbits were studied (n = 7 each group) subjected to moderate exchange transfusion with low molecular weight HES, bis(3,5-dibromosalicyl)fumarate crosslinked haemoglobin (alphaalpha-Hb), or dextran-conjugated haemoglobin (Hb-Dex-BTC). HES induced no changes in heart rate and blood pressure. The amplitude and duration of blood pressure increase and bradycardia were similar in both haemoglobin groups. A significant contraction of blood volume (12%) was observed 60 min after haemodilution with alphaalpha-Hb, compared to HES and Hb-Dex-BTC. At the same time point, a decrease in absolute haemoglobin (plasma haemoglobin x plasma volume) was also noted. This study suggests that in haemodilution conditions, the specific oncotic properties and circulating persistence of crosslinked and conjugated haemoglobin solutions affect the pattern of blood volume distribution differently.
Animals↗
Effects of three Hb-based oxygen-carrying solutions on neutrophil activation in vitro: quantitative measurement of the expression of adherence receptors.
BACKGROUND: Hb-based oxygen carriers (HbOCs) are currently under investigation as RBC substitutes. These solutions have vasoactive properties and may modify the behavior of the RBC in vitro. The effects of these agents on other blood cells have not been extensively investigated. The aim of this study was to evaluate the potential effect(s) of three differently modified HbOCs on the activation of PMNs. STUDY DESIGN AND METHODS: Whole blood from humans was incubated with Hb dextran-benzene-tetracarboxylate, alphaalpha-Hb, or o-raffinose-poly-Hb for 15, 30, and 60 minutes. The expression of adherence receptors CD62L, CD18, and CD11b, which reflects the activation state of the neutrophils, was assessed in vitro by a direct immunofluorescence method using calibration beads measured by flow cytometry. RESULTS: The observed expression of each of the three adherence receptors for each solution at each time point was similar to that noted with the RPMI control. Decreases in CD62L and increases in CD18 expression were noted at 15 minutes of incubation but, when those values were compared to the values obtained with TNFalpha as the positive control of PMN activation, the profile of expression of adherence receptors obtained with HbOC solutions did not conform to the expected activation profile of PMNs. CONCLUSION: Hb solutions modified by a variety of methods, as obtained and employed in this study, did not appear to activate neutrophils in vitro.
Aspirin↗
Vasoconstrictive response of rat mesenteric arterioles following infusion of cross-linked, polymerized, and conjugated hemoglobin solutions.
Infusion of hemoglobin-based oxygen-carrying solutions (HBOCs) produce an immediate rise in blood pressure with most solutions, both in animals and humans, as a result of systemic and pulmonary vasoconstriction. Autoregulation of the O2 supply by the microvasculature has been proposed as a phenomenon involved in the vasoconstriction elicited by HBOCs. Nevertheless, little is known about the ability of various HBOCs to induce constriction in the microcirculation according to their specific physicochemical properties (viscosity, molecular weight, P50, etc.). This study was therefore designed to assess the effects of three HBOCs, that is, bis(3.5-dibromosalicyl) fumarate-crosslinked hemoglobin (alphaalpha-Hb), dextran-benzene-tetracarboxylate-conjugated hemoglobin (Hb-Dex-BTC) and o-raffinose-oligomerized hemoglobin (o-raffinose-Hb), on the vascular tone of rat mesenteric arterioles (diameter, 15-25 microm) viewed microscopically in moderate hemodilution conditions. The effects of HBOCs were compared to those elicited by a reference solution of hydroxyethyl starch (HES-200) infused in the same conditions. In each experimental group, a fall in arteriolar diameter was observed 2 min and 5 min after infusion of the solution. The maximum changes were observed in Hb-Dex-BTC and o-raffinose-Hb groups, in which diameter decreased from 6.9 +/- 0.5% and 5.2 +/- 0.7%, respectively, 2 min after infusion. The changes in arteriolar diameter induced by Hb-Dex-BTC and o-raffinose-Hb were significantly higher than those elicited by HES-200 and alphaalpha-Hb. In conclusion, our data indicate that moderate hemodilution with HBOCs induces instantaneous constriction in rat mesenteric arterioles, with amplitudes depending on both pharmacological and physicochemical properties of the hemoglobin solution infused.
Animals↗
Health care organization improvement reports using control charts for key quality characteristics: ORYX measures as examples.
Some medical centers have developed quarterly quality performance reports consisting of key quality characteristics reported in the form of annotated control charts. The content of these reports needs to be linked with the mission, vision, values, and the structure of the organization. A partial example using one hospital's Joint Commission on Accreditation of Healthcare Organizations' ORYX measures is presented along with comments. The examples have been chosen to show the use of different types of control charts (XmR, P, and rare events) and different clinical conditions (congestive heart failure, low birth weight, and chronic obstructive pulmonary disease).
Data Collection↗
Distinct regulatory elements direct delta1 expression in the nervous system and paraxial mesoderm of transgenic mice.
The Delta1 gene encodes one of the Notch ligands in mice. Delta1 is expressed during early embryogenesis in a complex and dynamic pattern in the paraxial mesoderm and neuroectoderm, and is essential for normal somitogenesis and neuronal differentiation. Molecular components thought to act in response to ligand binding and Notch activation have been identified in different species. In contrast, little is known about the transcriptional regulation of Notch receptors and their ligands. As a first step to identify upstream factors regulating Delta1 expression in different tissues, we searched for cis-regulatory regions in the Delta1 promoter able to direct heterologous gene expression in a tissue specific manner in transgenic mice. Our results show that a 4.3 kb genomic DNA fragment of the Delta1 gene is sufficient in a lacZ reporter transgene to reproduce most aspects of Delta1 expression from the primitive streak stage to early organogenesis. Using a minimal Delta1 promoter we also show that this upstream region contains distinct regulatory modules that individually direct tissue-specific transgene expression in subdomains of the endogenous expression pattern. It appears that expression in the paraxial mesoderm depends on the interaction of multiple positive and negative regulatory elements. We also find that at least some regulatory sequences required for transgene expression in subdomains of the neural tube have been maintained during the evolution of mammals and teleost fish, suggesting that part of the regulatory network that controls expression of Delta genes may be conserved.
Animals↗
In vivo effects of Hb solutions on blood viscosity and rheologic behavior of RBCs: comparison with clinically used volume expanders.
BACKGROUND: Hb-based oxygen carriers (HbOCs) have vasoactive effects that are still poorly understood. Factors known to have vasoactive effects, such as plasma, whole-blood viscosity, and the rheologic behavior of RBCs, are modulated by HbOCs in vitro, but few in vivo studies have been performed. STUDY DESIGN AND METHODS: Rabbits were phlebotomized (30%) and resuscitated with unmodified stroma-free Hb (SFHb), dextran-tetracarboxylate-Hb (Dex-BTC-Hb), O-raffinose-polymerized Hb (OrpHb), HSA, or hydroxyethyl starch 200 (HES). Plasma viscosity was assessed with a capillary viscometer and whole-blood viscosity with a rotational viscosimeter. RBC aggregation kinetics were determined by analysis of back-scattered light in a rotating device. RESULTS: As compared to that in the control RBC suspension, resuscitation with SFHb, OrpHb, or HSA decreased plasma and whole-blood viscosity as well as RBC aggregation; resuscitation with Dex-BTC-Hb increased whole-blood viscosity at low shear rates as well as RBC aggregation, whereas that with HES decreased whole-blood viscosity but increased RBC aggregation. CONCLUSION: HbOCs have different rheologic effects in vitro and in vivo. There are marked differences among the Hb solutions in their in vivo effects on viscosity and RBC rheologic behavior (especially at low shear rates encountered in the venous circulation and the microcirculation), which may be related to the chemical modifications applied to hemoprotein. These results could contribute to an understanding of the vasoactive effects of HbOCs.
Adult↗
Systemic and renal hemodynamics after moderate hemodilution with HbOCs in anesthetized rabbits.
Hb-based O(2)-carrying solutions (HbOCs) have been developed as red blood cell substitutes for use in patients undergoing hemodilution. Variously modified Hb with diverse solution properties have been shown to produce variable hemodynamic responses. We examined, through pulsed-Doppler velocimetry, the systemic and renal hemodynamic effects of dextran-benzene-tetracarboxylate-conjugated (Hb-Dex-BTC), bis(3,5-dibromosalicyl)fumarate cross-linked (alphaalpha-Hb), and o-raffinose-polymerized (o-raffinose-Hb) Hb perfused in rabbits after moderate hemodilution (30% hematocrit), and we compared the effects of these Hb solutions with the effects elicited by plasma volume expanders. In addition, vascular hindrance (resistance/blood viscosity at 128.5 s(-1)) was calculated to determine whether a moderate decrease in the viscosity of blood mixed with HbOCs may impair vasoconstriction as a result of autoregulation after infusion of cell-free Hb. No changes were observed in renal hemodynamics after hemodilution with reference or Hb solutions. Increase in blood pressure and vascular resistance was found with Hb-Dex-BTC and alphaalpha-Hb (for 180 min) and, to a lesser extent, with o-raffinose-Hb (for 120 min). Furthermore, Hb-Dex-BTC (high viscosity) and o-raffinose-Hb (medium viscosity) induced comparable increases in vascular hindrance (from 0.091 to 0. 159 and from 0.092 to 0.162 cm(-1), respectively) but far less than that produced by alphaalpha-Hb (low viscosity, from 0.092 to 0.200 cm(-1)). These results suggest that maintaining the viscosity of blood by infusing solutions with high viscosity makes it possible to limit vasoconstriction due to autoregulation mechanisms and mainly caused by hemodilution per se.
Animals↗
[Familial myopathy with desmin storage seen as a granulo-filamentar, electron-dense material with mutation of the alphaB-cristallin gene].
Two familial cases of a myopathy remarkable by the presence of a granulo-filamentar, electron dense material were reported in 1978. In a second step, in 1988, it was demonstrated that this material contained an abnormally-phosphorylated desmin. During the last twenty years, the occurrence of new cases in this family confirmed the autosomal dominant inheritance of the disease, and made it potentially informative for molecular genetics studies. This allowed first to map the disease on chromosome11q21-23, and afterwards to identify a mutation within a gene coding for a chaperone protein, alphaBcrystallin. An extensive clinical, pathological and genetic study of this princeps family is herein reported in detail. First, it showed the possible detection of histopathological changes in presymptomatic patients. Second, it allowed to demonstrate the simultaneous occurrence of both alphaBcrystallin and desmin in the granulo-filamentar aggregates. Third, this study provided a precise knowledge of the evolution rate of the disease. The analysis of similar observations reported in the literature clearly shows the clinical, pathological and genetic heterogeneity of this new neuro-muscular disorder.
Actin Cytoskeleton↗
Desmin phosphorylation abnormalities in cytoplasmic body and desmin-related myopathies.
Cytoplasmic body myopathy (CBM) and desmin-related myopathy (DRM) are both characterized by an abnormal accumulation of desmin. To determine whether these abnormalities involve similar or different forms of desmin, we performed desmin two-dimensional electrophoresis: our results showed an increase in the two acidic isoforms in CBM muscles as compared with an increase in the number of acidic isovariants in DRM samples. A process of hyperphosphorylation involved in these acidic forms was confirmed by alkaline phosphatase application onto the muscle samples in both pathological conditions.
Cytoplasm↗
Study of some components of the cytoskeleton in muscular disorders with nonspecific cytoplasmic bodies.
To gain a better understanding of the mechanisms involved in the formation of cytoplasmic bodies (CBs), the immunohistochemical and biochemical features of muscle samples with nonspecific CBs were compared to those previously described by our group in cytoplasmic body myopathy (CBM), a congenital disease in which specific CBs are found. Accordingly, we studied nonspecific CBs found in the muscle biopsies of 15 patients with the following diseases: peripheral neuropathy (n = 5), polymyositis (n = 3), myotonic dystrophy (n = 2), sarcoidosis (n = 1), inclusion body myositis (n = 1), hereditary inclusion body myopathy (n = 1), hypothyroidism (n = 1), and muscle atrophy in a patient with multiple brain infarctions (n = 1). Nonspecific inclusions were stained at their periphery by anti-desmin but not by anti-dystrophin antibodies, except in the case of hypothyroidism in which immunostaining was observed with both antibodies. Biochemical studies showed normal amounts of desmin and phosphorylation pattern (the latter data are available for only four patients) as compared to control specimens. Our results differ from those previously reported in CBM, in which CBs were stained by both antidesmin and anti-dystrophin antibodies and in which a hyperphosphorylation of desmin was found. Hypothyroidism is, thus, the only disease in which nonspecific CBs show the same immunostaining pattern as specific CBs from CBM patients. These findings indicate that CBs may result from different mechanisms, and that one of these mechanisms may be shared by CBM and hypothyroidism.
Actins↗
Potential effect of hemoglobin solutions on blood components.
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Animals↗
The effect of public accountability on hospital performance: trends in rates for cesarean sections and vaginal births after cesarean section in Cleveland, Ohio.
The article reports a study that was designed to identify whether hospitals in the Cleveland, Ohio area have responded to public concern about improving their cesarean section and vaginal birth after cesarean section (VBAC) rates. A 14-item survey based on the Joint Commission on Accreditation of Healthcare Organizations' 1997 Codman Quality Award was administered to 20 hospitals. Respondents self-scored the survey based on a 5-point Likert scale. Three hospitals provided a detailed description of their efforts. Results showed that all hospitals are at various stages of the process to improve their cesarean section and VBAC rates. From this, it is proposed that public accountability encourages quality improvement.
Cesarean Section↗
Presence of hemoglobin inside aortic endothelial cells after cell-free hemoglobin administration in guinea pigs.
The endothelium is the production site of several potent vasoactive factors that contribute to the modulation of the vascular tone. Because hemoglobin-based oxygen carriers (HBOC) have been demonstrated to cause vasoconstriction and thereby increase arterial pressure by interacting with endothelium-derived factors such as nitric oxide and endothelin-1, we hypothesized that hemoglobin could penetrate into the endothelial cells. Therefore, we investigated the presence of hemoglobin into guinea pig aortic endothelial cells by immunohistochemical staining after exchange transfusion with a hemoglobin-based oxygen carrier. Despite the large molecular size of HBOC due to chemical modifications designed to prevent hemoglobin subunit dissociation and extravascular leakage, hemoglobin was detectable by immunohistochemical staining into the endothelial cells. These findings suggest that the vascular endothelial cells could uptake hemoglobin by endocytosis mechanisms or could help hemoglobin to cross the endothelial barrier toward media by transcytosis mechanisms. These findings are very important to lead future investigations to the mechanisms by which HBOC cause vasoconstriction.
Animals↗
Cardiovascular and hemorheological effects of three modified human hemoglobin solutions in hemodiluted rabbits.
The cardiovascular effects of human albumin (Alb) and three human hemoglobin (Hb) solutions, dextran-benzene-tetracarboxylate Hb, alphaalpha-crosslinked Hb, and o-raffinose-polymerized Hb were compared in anesthetized rabbits undergoing acute isovolemic hemodilution with Hct reduction from 41.4 +/- 2.7 to 28.8 +/- 1.6%. The impact of the vasoconstricting properties of Hb was examined by measuring heart rate (HR), mean arterial pressure (MAP), abdominal aortic, and femoral arterial blood flow, vascular resistance (VR), and aortic distension during the first 3 h after hemodilution. The impact of the hemorheological parameters was assessed by measurements of hemodiluted blood viscosity. In contrast to Alb, the Hb solutions elicited an immediate increase in MAP (20-38%). The effects of Alb and Hb solutions on HR, as well as on aortic and femoral arterial blood flow, were similar. VR decreased with Alb (20-28%) and increased with all three Hb solutions (30-90%), but the MAP and VR rising trends were different with each Hb solution. Aortic distension decreased in Hb groups compared with the Alb group for the first 60 min. The viscosity of hemodiluted blood was similar for all groups at high shear rates but was dependent on the viscosity of the solutions at low shear rates. We conclude that the vasoconstriction elicited by the Hb solutions overrides the vasodilation associated with viscosity changes due to hemodilution and would be the major factor responsible to the cardiovascular changes.
Albumins↗
The effects of stroma-free and dextran-conjugated hemoglobin on hemodynamics and carotid blood flow in hemorrhaged guinea pigs.
Hemoglobin solutions are potential resuscitative fluids with volume expanding and oxygen delivery abilities developed to reduce the use of blood transfusion. Most hemoglobin solutions in clinical trials increase transiently arterial pressure by inhibiting nitric oxide-dependent vasodilation. Our objective was to compare the effects on central hemodynamics and carotid blood flow of two hemoglobin solutions after resuscitation from hemorrhage in anesthetized guinea pigs. After anesthesia and instrumentation, severe hemorrhage was induced by withdrawing 50% of the blood volume. Resuscitation was performed after 15 min of hypovolemia with 5% albumin, stroma-free hemoglobin, or hemoglobin conjugated to dextran-benzenetetracarboxylate (Dex-BTC-Hb). The mean arterial pressure (MAP), carotid blood flow (CBF), vascular resistance index and heart rate (HR) were monitored for 3 hours after resuscitation. After hemorrhage, MAP and CBF dropped to 57.6 +/- 4.4% and 58.9 +/- 3.7% of control values respectively. Albumin failed to maintain hemodynamics in the decompensatory phase of shock. Both hemoglobin solutions gave rise to a transient increase in MAP (35%); stroma-free hemoglobin increased the CBF (150%) and resistance index (24%) whereas Dex-BTC-Hb had no effect on CBF and vascular resistances. None of the solutions affected the HR. Modified hemoglobin has attenuated effects on CBF and resistance index compared to stroma-free hemoglobin. This may be due to a balance between the stimulation of nitric oxide synthesis by shear-stress and the inhibition of vasodilation by nitric oxide trapping.
Animals↗