Supplementation of parenteral nutrition with glutamine (GLN) has been suggested to improve the efficacy of nutritional support by stimulating protein synthesis and improving immunocompetence. In the present study we investigated the impact of infusing the dipeptide glycyl-glutamine (GLY-GLN) at increasing dosages on plasma amino acid concentrations in patients with polytrauma. Nine polytraumatized patients were randomly assigned according their age and their trauma score to three experimental groups. Group 1 received 280, group II 450, and group III 570 mg GLY-GLN per kg body weight/day for a period of four days (3rd to 7th posttraumatic day), resulting in a maximum daily GLN administration (calculated for a 70 kg patient) of 14 g, 21 g and 28 g, respectively. Seven polytraumatized patients receiving the nutrition solution without GLY-GLN supplementation served as controls. All patients received total parenteral nutrition with an average amino acid administration of 1.1 g/kg/day and a total energy intake of 30 kcal/kg/day. GLY-GLN infusion did not evoke any side effects. In comparison with the control group, arterial plasma GLN concentrations increased significantly on day I after start of infusion in groups II and III, but remained raised throughout the study period only in group III (p < 0.003). Similarly, plasma GLY concentrations were also significantly raised in group III (p < 0.04). The maximum increase of plasma GLY was found on the second infusion day, after which plasma concentrations of GLY fell to concentrations even below those observed in the control group at the end of the study period. Excretion of GLY-GLN, GLN or GLY in the urine during the GLY-GLN infusions was negligible. We conclude from this first available dose finding study on glutamine-containing dipeptides that in polytraumatized patients infusion of 570 mg/kg/day of GLY-GLN (corresponding to 28 g glutamine or 40 g dipeptide/70 kg, respectively) is necessary to induce a sustained effect on plasma glutamine concentrations. No pathological accumulation of free glycine or of the dipeptide was seen with any of the three dosage steps of GLY-GLN. Thus, the administration of even high doses of GLY-GLN is feasible and safe in patients with polytrauma and is not associated with any relevant renal substrate loss.

Adult↗

PubMed1995

Position of jugular oxygen saturation catheter in patients with head trauma: assessment by use of plain films.

OBJECTIVE: The purpose of this study was to establish a plain radiographic technique for the assessment of the position of a jugular oxygen saturation catheter in patients with head trauma. MATERIALS AND METHODS: In the experimental study, jugular oxygen saturation catheters were introduced into the internal jugular veins of four cadavers. Correct positioning of the catheter tips was monitored by CT. Concurrent anteroposterior radiographs of the skulls were obtained with the tubes angled in a transverse plane and in a sagittal plane at intervals of 5 degrees and within a total range of 70 degrees for each plane. Three radiologists judged the visibility of the catheter tips and measured the distance of the catheter tips to previously determined bony landmarks of the skull. Then, preliminary radiologic criteria for correct positioning of the catheters were defined. In the clinical study, we prospectively evaluated radiographs for 32 patients who received jugular oxygen saturation catheters. Eleven patients had digital radiographs done, and 21 patients had radiographs with a conventional screen film system done. Radiographs were analyzed for consistency of findings with the experimental results and for consistency of the suspected catheter position with laboratory data. RESULTS: Results of the cadaveric study showed that catheter position is best assessed on strict anteroposterior radiographs with the orbitomeatal-basal line perpendicular to the plane of the film. A correctly positioned catheter tip should lie cranial to a line extending from the atlantooccipital joint space and caudal to the lower margin of the orbit. The catheter tip also should lie cranial to a line connecting the tips of the mastoid processes, with a catheter tip-to-line distance averaging 20% of the overall distance between the tips of the mastoid processes. According to these criteria, the catheter was properly positioned in 26 of 32 patients. In three patients, the catheter obviously was improperly positioned. Catheter position was equivocal in three other patients; in two of these patients, the catheter was looped within the internal jugular vein. Whereas for all 26 patients with properly positioned catheters values for jugular venous oxygen saturation were congruent with other laboratory data, incongruent saturation values were recorded for five of the six patients with equivocally or obviously improperly positioned catheters. CONCLUSION: Accurate assessment of the position of a jugular oxygen saturation catheter can be made by use of specific bony landmarks seen on anteroposterior radiographs of the skull.

Brain Edema↗

PubMed1994

Barbiturate attenuation of agonist affinity in cerebral arteries correlates with anesthetic potency and lipid solubility.

Barbiturates are known to reduce agonist sensitivity (EC50) in vascular smooth muscle; we provide evidence that the reduced agonist sensitivity can be correlated with a reduction in agonist affinity for its receptor. The histamine receptor was chosen since this agonist caused a consistent and maximum contraction of the cerebral artery used in this study. Segments of the basilar artery of white New Zealand male rabbits were set up in a small-vessel myograph in physiological salt solution, kept at 37 degrees C, pH 7.4, and bubbled with a 95% oxygen and 5% carbon dioxide gas mixture. The equilibrium dissociation constant (KA) of histamine for its receptor was calculated according to Furchgott's method by making three concentration-response curves to histamine: control, in the presence of phenoxybenzamine (0.02 microM), and after addition of a barbiturate in concentrations between 0.1 and 1.0 mM. All barbiturates tested, i.e., thiamylal, thiopental, pentobarbital, and phenobarbital, significantly reduced both histamine sensitivity and affinity. There is a significant correlation between histamine sensitivity and receptor affinity for histamine in a series of arterial segments from different animals. The attenuation of both pharmacological properties was consistent with the known rank order of anesthetic potency and with lipophilicity (r = 0.98; p < 0.05). Receptor reserve did not correlate with sensitivity. Thus, most of the change in receptor sensitivity was due to a change in agonist affinity. We suggest that barbiturates alter agonist receptor affinity by causing a perturbation in the membrane lipid environment of the receptor, leading to a conformational change, although alterations in intracellular mechanisms cannot be excluded.

Animals↗

PubMed1994

Neurogenically evoked cerebral artery constriction is mediated by neuropeptide Y.

We examined the proposal that neuropeptide Y (NPY) released from nerve endings constricts cerebral arteries. Neurogenic vasoconstriction of rabbit basilar arteries is of adrenergic origin but is resistant to blockade by classical alpha-adrenoceptor antagonists. Tetrodotoxin-sensitive contractions of the rabbit basilar artery were elicited by transmural stimulation of nerves. The contractions were inhibited by incubation of tissues with an antiserum to NPY (0.32 microL undiluted immune serum/mL); addition of prazosin (0.1 microM) did not further attenuate the nerve-mediated contraction. The antiserum to NPY also antagonized vasoconstriction due to exogenously administered NPY and was without effect on responses due to histamine or angiotensin. Our results indicate that neurogenic vasoconstriction of the rabbit basilar artery is largely due to the release of NPY and that it is unlikely that other vasoconstrictors contribute significantly to the increased tone.

Animals↗

PubMed1993

Right ventricular function in early septic shock states.

OBJECTIVES: To define a variable which could reliably predict when fluid resuscitation as monotherapy is not expected to improve organ perfusion pressure, owing to limitations in cardiac output responsiveness in patients with severe sepsis. DESIGN: Prospective controlled trial. SETTING: Anesthesiological ICU in a university hospital. PATIENTS: Twenty seven patients in early septic shock states (MAP < 60 mmHg). INTERVENTIONS: Infusion therapy was titrated until no further increase in cardiac index and mean arterial pressure could be achieved. Fluid resuscitation as monotherapy was deemed unsuccessful at the end of 2 h if inotropic or vasoactive pharmacologic support was required to maintain a mean arterial pressure > 60 mmHg. MEASUREMENTS AND RESULTS: We investigated the hemodynamic course during fluid resuscitation (2850 +/- 210 ml crystalloids) with special emphasis on right heart function using the thermodilution technique. Eleven patients (group A) had a right ventricular (RV) ejection fraction below 45%. In this group positive inotropic and/or vasoactive drugs were obligatory to achieve and maintain a sufficient perfusion pressure (MAP > 60 mmHg) after fluid challenge. CONCLUSIONS: In 27 septic shock patients investigated, we diagnosed right ventricular dysfunction in 41%. In this specific patient population fluid replacement alone did not succeed in stabilizing hemodynamic variables, therefore necessitating catecholamine therapy.

Adult↗

PubMed1992

Peri-operative liver graft function: monitoring using the relationship between blood glucose and oxygen consumption during anaesthesia.

The purpose of our study was to test the hypothesis that the quotient between plasma glucose and whole body oxygen consumption (VO2) as a 'metabolic index' is a sensitive indicator of early graft function. Arterial levels of glucose and oxygen consumption were determined in 100 consecutive patients during orthotopic liver transplantation performed without anhepatic veno-venous bypass. Patients were divided into survivors with no obvious problems related to graft function and those with primary nonfunction of the graft. The neohepatic increase in VO2 was significantly higher in survivors (112 +/- 4 vs 88 +/- 11 ml.min-1.m-2; p < 0.05), whereas blood glucose levels after reperfusion were higher (352 +/- 18 vs. 287 +/- 36 mg dl-1) in those with primary non-function of the graft. The calculated metabolic index was also higher (4.02 +/- 0.93 vs 2.67 +/- 0.45, p < 0.05) in patients with primary nonfunction of the graft. Our principal conclusion was that 92% of normal functioning liver grafts could be classified correctly by the metabolic index immediately after reperfusion, whereas glucose levels and VO2 alone classified only 67% and 70% of normal functioning liver grafts correctly.

Anesthesia, General↗

PubMed1991

Platelets augment rabbit cerebral artery constriction by activating protein kinase C.

BACKGROUND AND PURPOSE: We tested the hypothesis that activated platelets augment cerebral artery responsiveness to thrombin by activating protein kinase C, a possible intracellular modulator of Ca2+ sensitivity. METHODS: Ring segments of rabbit basilar artery were prepared for in vitro measurements of isometric force. Cumulative concentration-response curves to thrombin were made in the absence or presence of activated platelets. RESULTS: Arteries contracted to thrombin in a concentration-dependent manner; freshly obtained human platelets (8.5 x 10(8) cells/ml) activated with 10 micrograms/ml collagen increased the arteries' sensitivity to thrombin by threefold while augmenting the maximal response from 40 +/- 11% to 66 +/- 12% of the maximal response to 0.3 mM histamine. At 10 nM, staurosporine, an inhibitor of protein kinase C activity, blunted the platelet-induced augmentation of the response to thrombin but did not alter the sensitivity or the maximal contraction to 8-64 mM K+. Removal of the endothelium did not alter the characteristics of the thrombin concentration-response curve. The addition of activated platelets increased the tissue sensitivity of endothelium-denuded arteries to thrombin by a factor of 30, and the maximal response to thrombin was 101 +/- 27% of the histamine response. CONCLUSIONS: Our findings suggest that amplification of the arterial contractile response to thrombin caused by platelet-derived mediators may be due to activation of protein kinase C. There may also be a protective role for the cerebrovascular endothelium since endothelium reduced the extent of augmentation of protein kinase C-mediated tone by vasoactive agents released by activated platelets. Thus, increased vascular responsiveness caused by activated platelets may in part be due to protein kinase C-mediated changes in the intracellular sensitivity to Ca2+.

Alkaloids↗

PubMed1990

New functional cell-culture approach to pulmonary carcinogenesis and toxicology.

Modern pulmonary toxicology (including lung carcinogenesis) has, to assist its rapid development, constantly incorporated the knowledge obtained through cell and tissue-culture studies. While this has been carried out in rather a passive manner until quite recently, the currently necessary multi-disciplinary approach increasingly requires more active involvement of cell/tissue-culture techniques in this area. Our understanding in this regard is that one of such requirements is to establish a cell-culture system consisting of a single population of possible target cells for certain classes of hazardous inhalants. In addition, such target cells in culture should be able to function in a manner as closely resembling the situation in vivo as possible. In view of the culture techniques presently available, this requirement is probably too ideal to be met immediately. Nevertheless, efforts have been made in the last decade to achieve functioning cultures of Clara cells, type II pneumocytes or small mucus granule cells (SMGC), using undifferentiated cells obtained from animal and human fetuses. This attempt forms a sharp contrast to the usual approach, in that while the latter tries to keep the functions of adult cells in an already differentiated state, the former aims at inducing functional differentiation in undifferentiated cells by manipulating culture conditions. In carrying out these efforts, we have shown clear evidence that the type II pneumocytes and Clara cells induced in vitro are closely cognate and share a common precursor cell in culture, and that SMGC are at a pre-stage of differentiation to Clara cells. We have also shown an induced capacity for xenobiotic activation and conjugation in SMGC in culture. Our next plan is to prove similar activity (of mixed-function oxidase) in Clara cells and type II pneumocytes induced to differentiate in culture.

Animals↗

PubMed1990

Evaluation of the carcinogenic potency of 4 environmental polycyclic aromatic compounds following intrapulmonary application in rats.

The carcinogenic potential of 4 highly purified polycyclic aromatic compounds (PAC) was studied in the respiratory tract of rats. Using a beeswax/trioctanoin mixture as vehicle, 10, 3 and 1 mg phenanthrene (PHE), 3 and 1 mg chrysene (CHR), 0.1 mg dibenz(a,h)anthracene (DBahA) and 6, 3 and 1 mg benzo(b)naphto(2,1-d)thiophene (BNT) were injected into the lungs of 35 female Osborne-Mendel rats per group. Benzo(a)pyrene (BaP, 0.3, 0.1 and 0.03 mg) was used as the reference substance. Whereas only one squamous cell carcinoma developed at the highest PHE dose, a dose-dependent tumor incidence was found for CHR. BNT showed a carcinogenic effect similar to CHR, but an increasing incidence of neoplasms was not seen between the median and high dose. DBahA induced carcinomas in even more than half of the animals at the dose level of 0.1 mg and, therefore, has to be classified as the most potent PAC under investigation. BaP resulted in a clear dose-response relationship. According to probit analysis of the results, the carcinogenic potencies of the PAC relative to BaP (1.00) rank as follows: DBahA, 1.91; CHR, 0.03; BNT, 0.02; and PHE, 0.001. The estimated ED10- values were 0.031 mg for BaP, 0.016 mg for DBahA, 1.02 mg for CHR, 1.65 mg for BNT and 22.84 mg for PHE.

Animals↗

PubMed1990

Dietary fish oil intake: effects on glomerular prostanoid formation, hemodynamics, and proteinuria in nephrotoxic serum nephritis.

Dietary fish oil intake improves glomerular pathology and proteinuria in murine models of autoimmune disease. We evaluated glomerular prostanoid formation, glomerular hemodynamics, and proteinuria in rats with nephrotoxic serum nephritis (NSN) to test whether this beneficial effect of marine lipids also applies to other animal models of glomerular immune injury. Rats were fed diets (8 weeks) containing either cod liver oil or sunflower oil. NSN was induced with a rabbit anti-rat glomerular basement membrane antiserum. Antibody injection significantly stimulated glomerular thromboxane B2 (TxB2) formation in animals fed cod liver oil and sunflower oil at 2 hours, 24 hours, and 7 days. TxB2 production in glomeruli of sunflower oil rats, however, was five to seven times higher when compared with that in rats fed cod liver oil. The dietary regimen led to a significant decrease of glomerular TxB2 and prostaglandin E2 formation in the animals receiving cod liver oil when compared with those fed sunflower oil. Induction of NSN resulted in a significant fall of inulin clearance (Cin) and paraaminohippurate clearance at 2 hours, 24 hours, and 7 days in both groups. The decrease in Cin at 2 hours was greater in rats fed cod liver oil when compared with animals receiving sunflower oil (p less than 0.02); it was not different, however, at 24 hours and 7 days. Animals with NSN developed proteinuria. There was no difference in protein excretion between rats fed cod liver oil or those fed sunflower oil (days 2 and 7).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1989

Functional culture of hamster and human airway epithelial cells and its application to pulmonary toxicology.

Explore the source record for details and available documents.

Animals↗

PubMed1989

The selective potentiation of noradrenaline-induced tone by Bay K 8644 in the rabbit basilar artery.

A number of studies indicate that relative to the maximal tone possible, for example, to histamine, noradrenaline produces only weak contractile responses in the rabbit basilar artery. Various factors, including a limited number of alpha-adrenoceptors, have been proposed to account for the reduced response to noradrenaline. We examined the effect of the Ca2+-channel activator, Bay K 8644 (0.1 and 1.0 nM) on dose-response curves to noradrenaline, histamine, calcium (Ca2+) and potassium (K+) in ring preparations of rabbit basilar artery and central ear artery. These concentrations of Bay K 8644 (0.1 and 1.0 nM) increased the magnitude of tension developed by noradrenaline (contractility) in the basilar artery, but did not alter its sensitivity (ED50) to the adrenergic vasoconstrictor. Bay K 8644 (0.1 and 1.0 nM) did not alter the contractility or sensitivity to histamine or K+ of the rabbit basilar artery. When dose-response curves to Ca2+ were made in K+-depolarized rabbit basilar artery rings, Bay K 8644 (0.1 and 1.0 nM) dose-dependently augmented tone generated by readmission of Ca2+. Bay K 8644 (0.1 and 1.0 nM) did not alter responses to noradrenaline, histamine, or K+ in rabbit central ear artery preparations. These results are compatible with a voltage-dependent mechanism of action of Bay K 8644 in the rabbit basilar artery, which may be partially depolarized in the resting state. We propose that in addition to other factors, the contractile response of rabbit basilar arteries is limited by a weak or inefficient coupling of alpha-adrenoceptors to Ca2+ channels.(ABSTRACT TRUNCATED AT 250 WORDS)

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗

PubMed1985

[Uptake and elimination of isoflurane and halothane by children and adults].

The rate of increase of alveolar concentrations (FA/FI) of isoflurane and halothane was studied in children and adults during general anaesthesia and controlled ventilation. After 30 min of body equilibrium, elimination curves of the volatile anaesthetics were determined by measurement of alveolar (FA/FA0; infrared technique) and venous concentrations (gas chromatography). The distribution and elimination half-times (t1/2 alpha, t1/2 beta), clearance (Cl), volume of central and peripheral compartment (V1, Vz) and the volume of distribution at steady state (Vss) were calculated from the intercepts and slopes of a two-compartment model. During the uptake of anaesthetic concentrations of isoflurane and halothane, the FA/FI ratio of each gas was found to rise significantly faster in children than in adults. The reason for the more rapid approach to equilibrium in children seems to be related to physiological differences. Irrespective of age, uptake of isoflurane was more rapid than that of halothane, as it is less soluble. Similarly, isoflurane was eliminated from the lung or blood faster than halothane. Moreover, anaesthetic wash-out in children differed from that in adults. In the paediatric age group t1/2 beta under isoflurane was shorter than in adults, whereas halothane excretion took longer in children. This could be accounted for by the larger volumes of distribution Vz and Vss in the young, due to higher organ affinity of halothane. From our data we conclude that age significantly affects uptake and elimination of volatile anaesthetics and the control of anaesthesia is easiest with isoflurane in paediatric patients.

Adult↗

PubMed1980

Adenosine cyclic 3',5'-monophosphate uptake and regulation of membrane protein kinase in intact human erythrocytes.

The uptake of adenosine cyclic 3',5'-monophosphate (cAMP) and stimulation of membrane-associated protein kinase in mature human erythrocytes were investigated. cAMP transport across the membrane was temperature dependent, and cAMP binding to the isolated membrane had less temperature dependence. More than 99% of the [3H]-cAMP taken up by erythrocytes was nonmembrane bound. Maximal stimulation of membrane protein kinase and maximal occupancy of membrane cAMP binding sites by extracellular cAMP cccurred at 30 degrees C within 30 min after initiation of the incubation of erythrocytes with cAMP. The concentration of extracellular cAMP that gave half-maximal stimulation of membrane protein kinase was 5.4 X 10-4 M, a value consistent with the concentrations of cAMP (5.2 X 10-4 M) found to occupy half-maximally the membrane cAMP binding sites in erythrocytes. Extracellular cAMP and to a lesser extent guanosine cyclic 3',5'-monophosphate and inosine cyclic 3',5'-monophosphate stimulated membrane protein kinase in erythrocytes. The cAMP uptake by human erythrocytes as well as cAMP binding to membranes in the erythrocyte was blocked by an inhibitor [4,4'-bis(isothiocyano)stilbene-2,2-disulfonate] of the anion channel. These studies indicate that cAMP can be transported across membranes into human erythrocytes and can bind to membranes to activate membrane protein kinase. It appears that there is a shared transport channel for cAMP and anion transport.

4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗