Endothelin receptor blockade prevents the rise in pulmonary vascular resistance after cardiopulmonary bypass in lambs with increased pulmonary blood flow

BACKGROUND: Children with increased pulmonary blood flow may experience morbidity as the result of increased pulmonary vascular resistance after operations in which cardiopulmonary bypass is used. Plasma levels of endothelin-1, a potent vasoactive substance implicated in pulmonary hypertension, are increased after cardiopulmonary bypass. OBJECTIVES: In a lamb model of increased pulmonary blood flow after in utero placement of an aortopulmonary shunt, we characterized the changes in pulmonary vascular resistance induced by hypothermic cardiopulmonary bypass and investigated the role of endothelin-1 and endothelin-A receptor activation in postbypass pulmonary hypertension. METHODS: In eleven 1-month-old lambs, the shunt was closed, and vascular pressures and blood flows were monitored. An infusion of a selective endothelin-A receptor blocker (PD 156707; 1.0 mg/kg/h) or drug vehicle (saline solution) was then begun 30 minutes before cardiopulmonary bypass and continued for 4 hours after bypass. The hemodynamic variables were monitored, and plasma endothelin-1 concentrations were determined before, during, and for 6 hours after cardiopulmonary bypass. RESULTS: After 90 minutes of hypothermic cardiopulmonary bypass, both pulmonary arterial pressure and pulmonary vascular resistance increased significantly in saline-treated lambs during the 6-hour study period (P <.05). In lambs pretreated with PD 156707, pulmonary arterial pressure and pulmonary vascular resistance decreased (P <. 05). After bypass, plasma endothelin-1 concentrations increased in all lambs; there was a positive correlation between postbypass pulmonary vascular resistance and plasma endothelin-1 concentrations (P <.05). CONCLUSIONS: This study suggests that endothelin-A receptor-induced pulmonary vasoconstriction mediates, in part, the rise in pulmonary vascular resistance after cardiopulmonary bypass. Endothelin-A receptor antagonists may decrease morbidity in children at risk for postbypass pulmonary hypertension. This potential therapy warrants further investigation.     

Suppression of inward-rectifying K+ channels KAT1 and AKT2 by dominant negative point mutations in the KAT1 alpha-subunit

Na(+)-glucose transport and transepithelial permeability were investigated during symptomatic acute cryptosporidiosis in newborn rats. The infection resulted in a significant (P < 0.01) decrease in the ileal short-circuit current and a nonsignificant fall in the transepithelial potential difference and conductance. In glucose-stimulated conditions, the rise in ileal short-circuit current and transepithelial permeability were significantly lower in Cryptosporidium parvum-infected rats than in controls (delta Isc = 3.24 +/- 1.21 microA.cm-2 vs delta Isc = 5.09 +/- 2.23 microA.cm-2 in infected and control animals, respectively; P < 0.001; delta PD = -0.35 +/- 0.13 mV vs delta PD = -0.44 +/- 0.14 mV for infected and control animals, respectively; P < 0.01). Electrical parameters were not affected by addition of the cyclooxygenase inhibitor indomethacin in either Cryptosporidium-infected newborn rats or controls. Horseradish peroxidase and mannitol flux studies demonstrated a significant decrease (P < 0.05) in transepithelial molecular permeability in infected enterocyte rats, HRP flux = 380, range 68-5570 ng.cm-2, and mannitol flux = 1.06, range, 0.34-1.44%.cm-2.min-1, compared with controls rats, HRP flux = 4446 range, 1121-124,363 ng.cm-2, and mannitol flux = 1.99, range, 0.57-5.09%.cm-2.min-1; P < 0.05. These effects could originate from C. parvum-induced alteration of intracellular trafficking of pinocytosis vesicles and therefore account for the decrease in permeability to solute and macromolecules, together with impaired transcellular nutrient transport, in suckling rats.     

Role of the endothelium in placental dysfunction after fetal cardiac bypass

BACKGROUND: Fetal cardiac bypass causes placental dysfunction, characterized by increased placental vascular resistance, decreased placental blood flow, hypoxia, and acidosis. Vasoactive factors produced by the vascular endothelium, such as nitric oxide and endothelin 1, are important regulators of placental vascular tone and may contribute to this placental dysfunction. METHODS: To investigate the role of the vascular endothelium in placental dysfunction related to fetal cardiac bypass, we studied 3 groups of fetal sheep. In the first group (n = 7) we determined placental hemodynamic responses before and after bypass to an endothelium-dependent vasodilator (acetylcholine), an endothelium-independent vasodilator (nitroprusside), and endothelin 1. In the second group (n = 8) a nonspecific endothelin receptor blocker (PD 145065) was administered and placental hemodynamic values were measured before and after bypass. In the third group (n = 5) endothelin 1 levels were measured before and after bypass. RESULTS: Before fetal cardiac bypass exogenous endothelin 1 decreased placental blood flow by 9% and increased placental resistance by 9%. After bypass endothelin 1 decreased placental flow by 47% and increased resistance by 106%. There was also a significant attenuation of the placental vascular relaxation response to acetylcholine after bypass, whereas the response to nitroprusside was not significantly altered. In fetuses that received the PD 145065, placental vascular resistance increased significantly less than in control fetuses (28% versus 62%). Similarly, placental blood flow decreased significantly more (from 6. 3 +/- 3.1 to 28.3 +/- 10.4 pg/mL; P =.01) in control fetuses than in fetuses receiving PD 145065 (33% versus 20%). Umbilical venous endothelin 1 levels increased significantly in fetuses exposed to fetal bypass but did not change in control fetuses. CONCLUSIONS: The basal endothelial regulatory mechanisms of placental vascular tone were deranged after fetal cardiac bypass. Endothelin receptor blockade, which substantially reduced postbypass placental dysfunction, and other interventions aimed at preserving endothelial function may be effective means of optimizing fetal outcome after cardiac bypass.     

Magnetic resonance imaging with implanted neurostimulators: an in vitro and in vivo study

OBJECTIVE: The goal was to assess the safety of magnetic resonance imaging (MRI) with implanted neurostimulators, in an in vitro and in vivo study. METHODS: Two different implantable pulse generators (IPGs) (ITREL II and 3; Medtronic, Minneapolis, MN) and different leads (separately and connected to an IPG) were tested in three different MRI scanners (0.2, 0.25, and 1.5 T). Measurements of the induced voltages (using an external oscilloscope) and the induced heat (using an infrared camera) were performed in an in vitro study. Finally, 38 patients with implanted neurostimulator systems (leads and IPGs) underwent MRI in 50 examinations, with continuous monitoring by a physician with uninterrupted visual and vocal contact with the patient. Twenty-five patients were studied prospectively, with documented printouts of the parameter settings before and after MRI. RESULTS: An induced voltage of 2.4 to 5.5 V was measured in the experimental configuration with a lead connected to an IPG. The voltage was higher with the leads alone, compared with the leads connected to the IPG, and was dependent on the MRI scanner, the sequences, and the type of lead. No heat induction was observed in any part of the hardware. No change of pulse shape or change of IPG parameters was observed during MRI. No adverse effects occurred in patients with chronically implanted deep brain leads connected to an IPG. CONCLUSION: MRI can be safely performed in patients with implanted neurostimulation systems with the tested deep brain leads connected to an IPG (ITREL II and 3), with running parameters. No heat induction was detected, and the experimentally measured induced voltage did not seem to harm the patients. Only the reed switch of the IPGs was activated; the other parameters remained unchanged. Further investigations must be performed to study the local electrical effects in larger plate electrodes; these effects might cause slight discomfort. There is no danger with any type of electrode during MRI examinations if the electrodes lie outside the region of interest. These observations are restricted to the tested devices. A conscientious estimation of the risks and benefits of MRI for patients with implanted devices is recommended. If the type of device is not known to the examiner, MRI should still be considered to be contraindicated.     

Clinical manifestations and treatment of intestinal dysbacteriosis in patients with Flexner's dysentery

Flexner's dysentery is often accompanied with intestinal dysbacteriosis. Disbiotic changes in the intestine contribute to specific shigella endotoxins entering blood flow thus prolonging clinical symptoms of the underlying disease. Administration of bacterial biological preparations (bifidumbacterin forte, lactobacterin) relieves specific endotoxemia, reduces the duration of the disease and has an immunomodulating action.     

Temperament as a prerequisite of creative capabilities

Temperamental and creative characteristics were compared in three groups of subjects who manifested a bent for creative activity. The groups differed in their age: 14-year-old schoolchildren of architectural class (n = 20), 18 to 20-year-old students of architectural institute (n = 94), and 25 to 45-year-old professional architects (n = 25). The temperamental properties were measured using the STQ method. The creative characteristics were evaluated by E. P. Torrance's non-verbal tests of creative thinking. In the structure of creative abilities, only two creative characteristics, i.e., fluency and flexibility, correlated at the statistically significant level with temperamental properties in all the age-specific groups under study. The closest correlations were found with plasticity and emotionality of temperament both in object-related and subject-related spheres.     

Suppression of anchorage-independent growth and matrigel invasion and delayed tumor formation by elevated expression of fibulin-1D in human fibrosarcoma-derived cell lines

Using differential display, we identified an mRNA that is markedly down-regulated in cell line 6A/SB1, derived from a fibrosarcoma formed in an athymic mouse following injection of carcinogen-transformed MSU-1.1 cells. The nontumorigenic parental cell strain, MSU-1.1, expresses high levels of this mRNA. Sequencing of the corresponding cDNA fragment revealed that it corresponded to an expressed sequence tag, which ultimately led to its identification as the fibulin-1D gene. Fibulin-1 is a cysteine-rich, calcium-binding extracellular matrix and plasma protein, which has four isoforms, A-D, derived from alternative splicing. Northern and Western blotting analysis of 16 cell lines established from tumors formed in athymic mice by MSU-1.1-derived cell strains independently transformed in culture showed that 44% exhibited low level or lack of expression of fibulin-1D mRNA and protein. In a similar analysis of 15 malignant cell lines derived from patients, 80% showed low level or no expression. To study the role of fibulin-1D in transformation, we transfected 6A/SB1 cells and a human fibrosarcoma-derived cell line (SHAC) with a fibulin-1D cDNA expression construct. Transfectants displaying high levels of fibulin-1D were isolated and characterized. Elevated expression of fibulin-1D led to reduced ability to form colonies in soft agar and reduced invasive potential as tested in a matrigel in vitro invasion assay. Furthermore, expression of fibulin-1D resulted in a markedly extended latency in tumor formation in athymic mice. These results indicate that low expression of fibulin-1D plays a role in tumor formation and invasion.