Impact of enteral nutrition on intestinal bacterial translocation and mortality in burned mice

The aim of these experiments was to study the effect of early enteral nutrition with either standard or enriched (arginine, n-3 fatty acids, RNA) enteral formulas on translocation of bacteria from the gut and acute mortality rate following thermal injury. In the first experiment 60 Balb c mice were gavaged with 10(10)Escherichia coli and received a 20% burn injury. In 40 mice enteral nutrition (20 standard, 20 enriched) was started immediately after injury and stopped 36 h later. In the control group (n = 20) aliquotes of Ringer's solution was administered intragastrically. Mortality rate was observed for 10 days post-injury. In the second experiment 60 Balb c mice were gavaged with 10(10)E. coli labelled with biotin(111) Indium and then burned. In 40 mice enteral nutrition (20 standard, 20 enriched) was started immediately after burn. The control group (n = 20) received aliquotes of Ringer's solution. 4 h after injury all animals were sacrificed and liver, lungs, kidneys, spleen and systemic blood were harvested, and radionuclide counts were measured. No animal died after day 3 post-burn. The mortality rate was significantly lower at day 1 in the groups infused with both enteral solutions (15%) compared to controls (30%; p = 0.05). At day 3 the animals fed with the enriched diets showed a lower mortality (5%) versus the standard and control groups (10%). Bacterial translocation to the liver and lungs was significantly higher in Ringer's group than in both enterally fed groups. Early post-burn enteral nutrition reduces both translocation and acute mortality. Supplementation of the diets with specific nutrients appears to exert additional advantages on outcome.     

Autoradiographic localization of dopamine D2-like receptors in the rabbit pulmonary vascular tree

In the present study, the pharmacological characteristics and the anatomical localization of dopamine D₂-like receptor sites in the extraparenchymal and in the intraparenchymal portion of the rabbit pulmonary artery were investigated using combined radioligand binding and light microscope autoradiography with [³H]-spiroperidol (spiperone) as a ligand. The ligand was bound to sections of the pulmonary artery in a manner consistent with the labelling of dopamine D₂-like receptors with an equilibrium dissociation constant (K _d) of about 2.4±0.07 nmol/l and a maximum density of binding sites of 65±4.5 fmol/mg tissue. In contrast, binding experiments made with sections of rabbit lung did not allow the evaluation of specific binding. Light microscope autoradiography showed the development of specific silver grains within the tunica adventitia of extraparenchymal branches of rabbit pulmonary artery and of large and, to a lesser extent, of medium-sized intraparenchymal branches of the pulmonary artery. No silver grains were found within small branches of the pulmonary artery or of the pulmonary vein. Development of adventitial silver grains was inhibited by compounds active at dopamine receptors. The greater sensitivity to displacement by domperidone, haloperidol, (–)-sulpiride and bromocriptine than to displacement byN-propyl-norapomorphine, quinpirole or clozapine suggests that the [³H]-spiroperidol binding sites observed in extraparenchymal, large and medium-sized branches of the pulmonary artery belong, probably, to the dopamine D₂ receptor subtype. The possible pre-junctional localization of these sites is discussed. Correspondence to: R Amenta     

Protein binding of brequinar in the plasma of healthy donors and cancer patients and analysis of the relationship between protein binding and pharmacokinetics in cancer patients

The protein binding of weakly acidic and basic drugs has been shown to be altered in cancer patients. Brequinar is a weakly acidic, low-clearance, and highly protein-bound (>98% bound) antitumor agent. The pharmacokinetic parameters of brequinar are subject to large interpatient variability. This large interpatient variability may be related to brequinar's plasma protein-binding capacity (assuming no change in the intrinsic clearance of the unbound drug). The objectives of this study, therefore, were (a) to characterize brequinar's protein binding in the plasma of healthy donors and cancer patients and (b) to examine the relationships between brequinar's plasma protein binding and its pharmacokinetics in patients. Brequinar protein binding was determined in human serum albumin (HSA) solution, drug-free donor plasma, and brequinar-free, predose plasma samples obtained from a phase I cancer trial. Pharmacokinetic results from this study were used to examine relationships between plasma protein binding and drug disposition. In HSA solution and healthy donor plasma, brequinar's protein binding as determined using spiked samples was concentration-dependent. The unbound brequinar fraction increased by a factor of 3 (from 0.3% to 0.9% free) in 4% HSA solution and by a factor of 4 (from 0.4% to 1.6% free) in donor plasma as the brequinar concentrations increased from 0.1 to 2.3 mM in the HSA solution and from 0.076 to 1.5 mM in the donor plasma. Analysis of brequinar binding characteristics using the binding ratio and Rosenthal binding plots showed that albumin was the primary protein for brequinar binding in human plasma. The addition of various concentrations of ₁-acid glycoprotein to 4% HSA solution did not affect the protein binding of brequinar to HSA. The protein binding determined in the plasma of cancer patients was not quantitatively different, except for variability, from that observed in the plasma of healthy donors. Examination of relationships between the unbound brequinar fraction and pharmacokinetics suggested that plasma protein binding was not a major determinant of brequinar disposition in cancer patients.     

Transthoracic 2D echo color Doppler assessment of internal mammary artery to left anterior descending coronary artery graft

For noninvasive evaluation of anatomy and flow characteristics of internal mammary artery graft (IMA-graft), 2D echo-Color-Doppler (CDE) was performed in 60 patients (54 M, 6 F, mean age 54.1±6.9 y), who underwent coronary angiography 20.1 ±13 months after a coronary artery bypass graft (CABG).CDE was performed, using an echocardiographic unit equipped with a 5 MHz linear transducer.In all patients, measurements of IMA-graft diameter (mm), and peak systolic and diastolic flow velocity (cm/sec) were obtained at baseline and also in 16 patients after dipyridamole infusion (0.54 mg/Kg/min) and in 10 patients after sublingual nitroglycerin (NTG) (0.4 mg). Angiography showed the IMA-graft patency in 58/60 patients (96.8%).A typical biphasic flow was displayed by CDE in 49/58 patients (84.4%) with angiographic patency.Dipyridamole infusion increased both IMA-graft diameter and peak diastolic flow velocity (PDFV) from 2.28 ±0.51mm to 2.9 ±0.42mm and from 19.4 ±6.2 cm/sec to 93.9 ±29 cm/sec, respectively (p<0.0001).No significant modifications of peak systolic flow velocity (PSFV) were observed.NTG increased PDFV from 29.11 ±8 cm/sec to 41.88 ±7.20 cm/sec (p<0.005), while diameter and PSFV showed no statistically significant modifications.CDE is a useful diagnostic tool for noninvasive evaluation of IMA-graft patency both early after surgery and during long-term follow-up. CDE pharmacological stress improves the sensibility of the technique and it can provide indirect information about pathophysiology of recipient coronary vessel.     

Identification of the central vestibular projections in man: a positron emission tomography activation study

The cerebral representation of space depends on the integration of many different sensory inputs. The vestibular system provides one such input and its dysfunction can cause profound spatial disorientation. Using positron emission tomography (PET), we measured regional cerebral perfusion with various vestibular stimulations to map central vestibular projections and to investigate the cerebral basis of spatial disorientation. We showed that the temporoparietal cortex, the insula, the putamen, and the anterior cingulate cortex are the cerebral projections of the vestibular system in man and that the spatial disorientation caused by unilateral vestibular stimulation is associated with their asymmetric activation.     

Short-term neurobehavioural effects in anaesthetists with low exposure to nitrous oxide

The aim of this study was to assess whether a sample of 37 anaesthetists occupationally exposed only to N2O showed any deterioration in vigilance and/or mood. The anaesthetists were examined with three neurobehavioural tests (Simple Reaction Time and Colour Word Vigilance to measure the vigilance and Mood Rating Scale to evaluate the level of stress and arousal) and underwent N2O biological monitoring (to correlate the test results with the N2O exposure) on the first and on the last day of the work week, before and after work in the operating room. No significant relationship was found between the biological monitoring and the test results. The only significant statistical difference was found between the beginning and the end of each workday in the arousal level, regardless of the result of the biological monitoring.     

Antihypertensive drug therapy and hypoglycemia in elderly diabetic patients treated with insulin and/or sulfonylureas

We performed this case–control study to evaluate the risk of hypoglycemia associated with the use of antihypertensive drugs in older hospitalized diabetic patients treated with sulfonylureas and/or insulin. All diabetic patients admitted during 4 months in 1988, 1 month in 1991, 4 months in 1993 and 4 months in 1995 (n = 3477, mean age 71.4 ± 0.2 years, 1542 males and 1935 females) were enrolled in the study. During the four annual surveys 86 patients (mean age 71.1 ± 1.4 years, 33 males and 53 females) presented hypoglycemia during hospital stay. The patients who presented hypoglycemia were less frequently users of sulfonylureas and more frequently users of a combination of insulin and sulfonylureas. Use of antihypertensive drugs was similar in the two groups studied, and among potentially interacting drugs considered in the analysis, sulfonamides were more frequently used in patients who experienced hypoglycemia. Moreover, patients with hypoglycemia used a higher number of drugs, had a longer length of stay and had a greater prevalence of hypoglycemia as admission problem. Finally, although not significant, liver and renal diseases were more frequent among patients with hypoglycemia. In the multivariate analysis, contemporary use of insulin and sulfonylureas, liver disease and length of stay were significantly associated with hypoglycemia, while none of the antihypertensive drugs showed a significant association with the occurrence of hypoglycemia during hospital stay. Our results indicate that antihypertensive drugs do not increase the risk of hypoglycemia in elderly diabetic patients.     

Focal electroretinograms and fundus appearance in nonexudative age-related macular degeneration

· Background: The aim of this study was to evaluate the focal electroretinogram (FERG), an objective indicator of outer retinal function, in nonexudative age-related macular degeneration (NE-AMD), and to compare FERG results with morphological lesions assessed by stereoscopic fundus photographs and fluorescein angiograms. · Methods: Twenty-five patients (25 eyes) with bilateral NE-AMD (visual acuity of the study eyes ≥0.4) as well as 10 age- and sex-matched control subjects (10 eyes) were evaluated. FERGs were recorded from the macular region (9°) in response to sinusoidal stimuli flickered at 32 Hz. Amplitude and phase angle of the Fourier-analyzed FERG fundamental component were measured. Fundus lesions were graded from color slides according to the Wisconsin age-related maculopathy grading system [15]. Fluorescein angiograms were evaluated by an image analysis technique to compute the area with pathological hyperfluorescence (associated with drusen and/or retinal pigment epithelial atrophy) within the macular (approximately 9°×9°) region. · Results: Compared to control eyes, NE-AMD eyes had a reduction in the mean FERG amplitude (57% loss, P<0.001) with no phase changes. Amplitudes of individual affected eyes were negatively correlated with either the Wisconsin grading score (r=–0.63, P<0.001) or the percentage area of pathological hyperfluorescence (r=–0.70, P<0.01). Eyes with minimal NE-AMD lesions (Wisconsin score ≤6) and normal acuity had a lower mean amplitude (47% loss, P<0.05) than that of control eyes. · Conclusions: The results indicate that, in NE-AMD, the FERG is altered in parallel with the extent and severity of fundus lesions. However, a functional impairment of outer macular layers, which is detected by FERG losses, could precede morphological changes typical of more advanced disease. Received: 6 March 1998 Revised version received: 5 June 1998 Accepted: 17 June 1998     

Injection of endothelin-1 into the raphe obscurus of rats induces depressor responses predominantly through endothelin ETA receptors

We used in vitro autoradiography to identify the endothelin-1 receptor subtype(s) in the nucleus raphe obscurus of rats. These studies showed dense binding of [¹²⁵I]PD151242 (for endothelin ET_A receptors), while tissues incubated with [¹²⁵I]BQ3020 (for endothelin ET_B receptors) had low binding. In addition, we examined the effects of the endothelin receptor antagonists FR 139317 (endothelin ET_A receptor-selective antagonist), SB 209670 (endothelin ET_A/ET_B receptor-non-selective antagonist) and BQ-788 (endothelin ET_B receptor-selective antagonist) on the blood pressure responses following administration of endothelin-1 into the nucleus raphe obscurus. The basal mean arterial blood pressure (MABP) of the rats was 110 ± 7 mmHg (n = 5). This was decreased in a dose-dependent manner by endothelin-1 (0.1, 1 and 10 pmol) microinjected into the nucleus raphe obscurus. This effect occurred within 1–6 s and recovered within 4 ± 1.2 min at a dose of 10 pmol. The doses of 0.1 pmol and 1 pmol ET-1 had responses which lasted 1 ± 0.4 min and 2 ± 0.2 min, respectively. Small decreases in heart rate accompanied the MAP responses to endothelin-1. For instance, the heart rate decreased by 16 ± 4 beats min^–1 after 10 pmol endothelin-1 (control, 366 ± 6 beats min^–1, n = 5). Decreases in blood pressure induced by endothelin-1 were greatly reduced by pre-administration to the nucleus raphe obscurus of FR139317 (5 nmol/rat) or SB209670 (3 nmol/rat; 97 ± 7% and 95 ± 6%, P < 0.01, n = 5, respectively), but were not affected by BQ-788 (50 nmol/rat; 8 ± 3%, P > 0.05, n = 5). The antagonists did not influence heart rate when injected to the nucleus raphe obscurus prior to endothelin-1. FR139317 (0.5 nmol) and SB209670 (0.3 nmol) had no effects on endothelin-induced changes in arterial blood pressure. Therefore, the autoradiographic study showed that there are binding sites for ET-1 within the nucleus raphe obscurus of rats, which are predominantly of ET_A type. The in vivo study showed that ET_A receptors are the predominant mediators of depressor responses induced by endothelin-1 injected into this nucleus. Received: 6 August 1998 / Accepted: 16 February 1999