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The use of cell membrane stability (CMS) technique to screen for salt tolerant wheat varieties.

Cell membrane stability (CMS) technique was used to screen salt tolerant (V1, V2), salt sensitive (V5) and two salt/water deficiency tolerant wheat genotypes (V3 and V4) using 100-250 mM NaCl salinity maintained in pots containing gravel and nutrient solution. The objectives were to study: (i) the reliability of CMS technique for screening wheat under high salinity, (ii) factors that impart stability and/or injury to the cell membrane, and (iii) the relationship of CMS with other physiological parameters affected by the salt stress. Generally, cellular injury increased with increasing salinity levels. In V5, it was the highest (74.2%) at 250 mM, probably due to combined effect of Na+ toxicity and low (54%) relative water content (RWC). In V1, RWC was similar to that in V5 but injury was comparatively low possibly due to low concentration of Na+. The difference between V1 and V2 was significant, either due to the highest concentration of K+ or the lowest reduction in RWC in V2. In V3 and V4, injury was the lowest at all salinity levels and was within the range of values observed earlier for drought tolerance. A significant negative correlation was detected between cellular injury and RWC for V1 and V5 but not for V3 and V4. Cellular injury also showed a significant positive correlation with Na+ and a negative correlation with K+ and grain yield (GY). It appeared that CMS technique is suitable for screening wheat under high salinity levels and for detecting differences that may arise due to cumulative effects of salinity and reduced water contents.

Carbohydrate Metabolism↗

Intranasal challenge with aspirin induces cell influx and activation of eosinophils and mast cells in nasal secretions of ASA-sensitive patients.

BACKGROUND: Although the mechanism of aspirin-sensitivity seems to be related to inhibition of cyclo-oxygenase by aspirin (ASA), the chain of biochemical events leading to the ASA-induced adverse reaction is not clear, and the contribution of particular mediators and inflammatory cells has not been elucidated. OBJECTIVES: To investigate the involvement of secretory, vascular and cellular mechanisms in the pathophysiology of nasal reactions to aspirin. METHODS: Six patients with ASA-sensitive asthma/rhinosinusitis and seven ASA-tolerant patients were challenged intranasaly with saline and lysine-acetylsalicylic acid (Lys-ASA) 12 mg, on separate occasions. Nasal lavages were obtained before, and then every 15 min after challenges, and analysed for biochemical and cellular composition. RESULTS: Lys-ASA challenge caused rhinorrhoea, sneezing and nasal congestion with parallel increases in total protein and albumin concentration, albumin % and lysozyme activity in the nasal secretions of ASA-sensitive patients. Concomitant with clinical symptoms, an influx of leucocytes into nasal secretions occurred with significant enrichment in eosinophils (mean prechallenge: 24 +/- 12%, postsaline 27 +/- 9%, postLys-ASA 51 +/- 10%; P < 0.03). The influx of eosinophils into nasal secretions was associated with a remarkable increase in Eosinophil Cationic Protein (ECP) immunoreactivity in five of six patients (mean 9.3 +/- 3.8 micrograms/L and 140.9 +/- 45.8 micrograms/mL before and after Lys-ASA, respectively). At the peak of ASA-induced symptoms an increase in the tryptase level was also observed in five of six patients (mean pre-challenge: 2 +/- 0.1 U/L; postLys-ASA 16 +/- 5 U/L; P < 0.01) suggesting activation of mucosal mast cells. In ASA-tolerant patients Lys-ASA did not induce significant symptoms or changes in the biochemical and cellular composition of nasal secretions. CONCLUSION: The results show that the ASA-induced nasal adverse reaction involves changes in vascular permeability and serous cell secretion. Both activated eosinophils and mast cells may contribute to the pathophysiology of the ASA-induced reaction in the nasal mucosa.

Administration, Intranasal↗

Morphine sensitivity and tolerance: a genetic investigation in the mouse.

Sensitivity and tolerance to morphine were determined in 2 strains of mice, BALB/cBy and C57BL/6By, their reciprocal F1 hybrids and seven of their recombinant inbred strains. Sensitivity was established based on locomotor activity following the administration of saline, 10 or 20 mg/kg of morphine hydrochloride while tolerance was established according to the "hot plate" method following the single or repeated administration of saline, 5, 10, or 20 mg/kg of morphine hydrochloride. Results indicate that both sensitivity and tolerance to morphine are genotype-dependent and their inheritance is characterized by dominance or partical dominance. Further clarification of the genetic relationship of sensitivity, tolerance and analgesia to morphine must await analysis of the brain morphine-binding protein currently being conducted.

Analgesia↗

Contingent suppression of tolerance to haloperidol: a dose-response analysis.

Rats were given injections of haloperidol (HAL; 0.625 or 2.5 mg/kg) either before (Before groups) or after (After groups) access to sweetened milk on alternate days. Controls (Saline groups) were given injections of saline. At biweekly intervals ("test days"), all groups were given pretest injections of the drug in order to monitor the development of tolerance in the After and Saline groups. Rats in the Before groups showed no tolerance to the initial suppression of milk intake. In contrast, rats in the After groups had greater intakes, although the level of intake declined on subsequent test days in the group given the lower dose. Rats in the Saline groups drank less on the test days than any of the other groups, suggesting that sensitization occurred. These results are consistent with previous findings (29) that tolerance to HAL is suppressed following pretest injections of the drug. The degree of suppression appears to be inversely related to the frequency of such injections.

Animals↗

Prenatal administration of morphine to the rat: tolerance to the analgesic effect of morphine in the offspring.

The analgesic activity of morphine was assessed by the hot-plate technique in the offspring of female CFE rats that had received morphine twice daily on days 5 to 12 of pregnancy. A dose of 5.0 mg/kg of morphine was administered for the first 3 injections; 10 mg/kg was used for each of the remaining 13. Morphine dose-response curves were determined in the offspring at 5 weeks of age. The analgesic effect of morphine in the offspring of morphine-treated females (morphine offspring) was attenuated by as much as 50% compared to the offspring of saline-treated females (saline offspring). This same relationship between the morphine and saline offspring was also observed in offspring rendered tolerant to the analgesic effect of morphine. A diminished analgesia in the morphine offspring compared to the saline offspring was also observed after the injection of graded doeses of levorphanol in both nontolerant and morphine-tolerant offspring. The analgesic effect of a single dose of morphine was also attenuated in 3-, 5- and 11-week-old morphine offspring. No differences were found in either brain or plasma concentration of morphine between the morphine and saline offspring. The long-term effect of prenatal morphine administration could not be explained on the basis of maternal influences since cross-fostering procedures failed to abolish it. It is concluded that the administration of moderate doses of morphine to gestating rats can induce a long-lasting tolerance to the analgesic effect of morphine in the offspring.

Aging↗

Comparison of lidocaine and saline for epidural top-up during combined spinal-epidural anesthesia in volunteers.

This study was designed to determine the efficacy of saline as an epidural top-up to prolong spinal anesthesia during combined spinal-epidural anesthesia (CSEA). Eight volunteers received three separate CSEAs with intrathecal lidocaine (50 mg). After two-segment regression, each subject received either a saline (10 mL), lidocaine 1.5% (10 mL), or control sham (0.5 mL saline) epidural injection in a randomized, double-blind, triple cross-over fashion. Sensory block was assessed by pinprick and tolerance to transcutaneous electrical stimulation (TES) equivalent to surgical stimulation at the knee and ankle. Motor strength was assessed with iso-metric force dynamometry. Data were analyzed with a repeated measures analysis of variance and a paired t-test. Sensory block to pinprick was prolonged in the thoracolumbar dermatomes only by lidocaine (P < 0.05). Neither lidocaine nor saline prolonged the duration of tolerance to TES at the tested sites. Instead, saline decreased the duration of tolerance to TES by 20 and 24 min at the knee and ankle (P < 0.05). Recovery from motor block at the quadriceps was prolonged by an epidural injection of lidocaine (P < 0.05). We conclude that when 10 mL of epidural saline is administered after two-segment regression, it is an ineffective top-up and may decrease the duration of spinal anesthesia during CSEA.

Adult↗

Preoperative local infiltration with ropivacaine for postoperative pain relief after inguinal hernia repair. A randomised controlled trial.

OBJECTIVE: To assess the effect of preoperative local anaesthesia with ropivacaine and find out if there was a dose-response relationship with postoperative pain after inguinal hernia repair. DESIGN: Randomised, double-blind, placebo-controlled trial. SETTING: Two Swedish and two Norwegian hospitals. SUBJECTS: 131 Male patients undergoing elective inguinal hernia repair. INTERVENTION: Infiltration of the inguinal field before operation with 0.5% ropivacaine 40 ml (200 mg), 0.25% ropivacaine 40 ml (100 mg) or saline 40 ml. MAIN OUTCOME MEASURES: Wound pain at rest and during mobilisation, pressure exerted to reach pain threshold and maximum pain tolerance after 3, 6, 10, and 24 hours, and after 7 days; consumption of analgesics; and Quality of Life assessed by two independent questionnaires before and after operation. RESULTS: Pain scores after 3 hours were significantly lower in the ropivacaine groups compared with the saline group for all variables (p < 0.05). At 6 hours pain scores were significantly lower for ropivacaine 0.5% compared with saline for wound pain during mobilisation and pressure exerted to reach maximum pain tolerance. Patients given saline made their first request for analgesics significantly sooner than in the other two groups (p < 0.05), and a significantly larger percentage of them requested analgesics during the first 24 hours (p < 0.05). Evaluation of the Quality of Life questionnaires showed no significant differences between the groups. CONCLUSION: Ropivacaine has a significant, dose-related pain-reducing effect in the immediate postoperative period but we could find no support for the theory that preoperative infiltration analgesia reduces long term pain.

Adolescent↗

Effects of ethanol on carbohydrate metabolism in the elderly.

We have previously reported that in young men, ethanol caused acute insulin resistance, but compensatory insulin secretion prevented deterioration of glucose tolerance (1). In this study, we tested the hypothesis that elderly men, because of their pre-existing insulin resistance and compromised insulin secretory capacity, may experience worsening of their glucose tolerance after ethanol. Nine elderly men (65.7 +/- 0.8 yr, BMI 25.8 +/- 1.4 kg/m2) received ethanol (13 mmol/kg for 30 min i.v.) or saline followed 30 min later by i.v. glucose (2.8 mmol/kg for 5 min). To determine the mechanism of the ethanol effect, six of the men underwent euglycemic-hyperinsulinemic (approximately 350 pM) clamping with simultaneous infusion of ethanol or saline. Muscle biopsies were obtained before and 1 and 4 h after insulin infusion. In all nine men, glucose concentrations after i.v. glucose were higher after ethanol than after saline, whereas insulin was the same and glucose tolerance decreased by 23% (Kg 2.41 +/- 0.2 vs. 1.86 +/- 0.1%/min, P < 0.01). Ethanol reduced insulin-stimulated glucose uptake from 40.6 +/- 3.1 to 25.6 +/- 1.9 mumol.kg-1.min-1 (-37%, P < 0.05), glucose oxidation from 11.7 +/- 1.1 to 7.0 +/- 0.7 mumol.kg-1.min-1 (-33%, P < 0.01), and glucose storage from 28.7 +/- 2.4 to 18.6 +/- 1.7 mumol.kg-1.min-1 (-35%, P < 0.01). Ethanol increased muscle lactate concentration from 0.49 +/- 0.14 to 1.99 +/- 0.99 mumol/mg protein (P < 0.05), but had no effects on muscle concentration of free glucose, G-6-P, and citrate concentrations, nor did it affect muscle GS activity.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗

A major QTL conditioning salt tolerance in S-100 soybean and descendent cultivars.

Deployment of salt tolerant cultivars is an effective approach to minimize yield loss in a saline soil. In soybean, Glycine max (L.) Merr., substantial genetic variation exists for salt response. However, breeding for salt tolerance is hampered because no economically viable screening method has been developed for practical breeding. To facilitate the development of an effective screening method for salt tolerance in soybean, the present study was conducted to determine the heritability of salt tolerance and to identify associated quantitative trait loci (QTL). F2:5 lines from the cross of 'S-100' (salt tolerant) x 'Tokyo' (salt sensitive) were evaluated in a saline field in Hyde County, N.C., USA, in 1999 and in a greenhouse located in Raleigh, N.C., USA, in 2001. S-100 and Tokyo are ancestors of popular soybean cultivars released for the southern USA. The visual salt tolerance ratings of the F2:5 lines ranged from 0 (complete death) to 5 (normal healthy appearance). The entry-mean heritability for salt tolerance was 0.85, 0.48, and 0.57 in the field (four replications), greenhouse (two replications), and combined environments, respectively. The genotypic correlation between field and greenhouse ratings was 0.55, indicating reasonably good agreement between the two screening environments. To identify QTL associated with salt tolerance, each line was characterized with RFLP markers and an initial QTL single-factor analysis was completed. These results were used to identify genomic regions associated with the trait and to saturate the selected genomic regions with SSR markers to improve mapping precision. Subsequently, a major QTL for salt tolerance was discovered near the Sat_091 SSR marker on linkage group (LG) N, accounting for 41, 60, and 79% of the total genetic variation for salt tolerance in the field, greenhouse, and combined environments, respectively. The QTL allele associated with tolerance was derived from S-100. Pedigree tracking was used to examine the association between the salt tolerance QTL and flanking SSR marker alleles in U.S. cultivars descended from S-100 or Tokyo through 60 years of breeding. The presence of alleles from S-100 at the Sat_091 and Satt237 marker loci was always associated with salt tolerance in descendants. Alleles from Tokyo for these same markers were generally associated with salt sensitivity in descendent cultivars. The strong relationship between the SSR marker alleles and salt tolerance suggests that these markers could be used for marker-assisted selection in commercial breeding.

Adaptation, Physiological↗

Ketamine retards chronic but not acute tolerance to ethanol.

Motor impairment (tilt-plane test) was used to investigate whether the noncompetitive N-methyl-D-aspartate (NMDA) antagonist ketamine prevents the development of chronic and acute tolerance to ethanol. Rats were treated with ethanol or saline in the presence and absence of ketamine (separate groups) for 10 days and tested for ethanol tolerance in the absence of ketamine on the fifth and tenth days. In other studies, the effect of ketamine on acute tolerance to ethanol was examined. Rats that received ethanol daily without ketamine showed significant tolerance to ethanol on days 5 and 10, but those receiving ethanol plus ketamine daily showed significantly less tolerance to ethanol. Thus, ketamine interfered with the development of chronic tolerance just as it had been found previously to prevent rapid tolerance. In contrast, ketamine failed to block acute tolerance to ethanol. These results would suggest that the phenomena of acute tolerance and chronic tolerance have differences not previously reported.

Animals↗

Activation of trout gill AMP deaminase by an endogenous proteinase--III. Comparative studies on the gill AMP deaminase from different fresh water and sea water teleosts.

The effects of monovalent cations and inorganic phosphate, on gill AMP deaminase, were compared in different fresh water and sea water stenohaline and euryhaline Teleosts. Generally, sea water species displayed a lower sensitivity to these effectors than fresh water species. During salinity changes, the sensitivity of gill AMP deaminase to cations and phosphate were modified proportionally to the tolerance of a given species to variations of environmental salinity. In particular, these parameters were modified in the weak euryhaline, Salmo gairdneri, but not in the real euryhaline, Anguilla anguilla. In sea water adapted trout, the appearance of a modified AMP deaminase form, with similar properties to that found in sea water species, is suggested. When compared with the conclusions from the preceeding papers [Raffin (1986) Comp. Biochem. Physiol. 85B, 157-162; 85B, 163-171], the results suggest that modification of gill AMP deaminase by limited proteolysis should be a rather general adaptation mechanism to stress.

AMP Deaminase↗

Intravenous endotoxin suppresses the cytokine response of peripheral blood mononuclear cells of healthy humans.

When administered parenterally, endotoxin stimulates the synthesis of IL-1, TNF-alpha, and IL-6. However, this initial injection induces tolerance; a second injection of endotoxin results in lower levels of circulating cytokines. In our study, five healthy male volunteers between the ages of 18 and 30 were injected with Escherichia coli endotoxin. Four subjects received only saline. Immediately before the injection and 3, 6, and 24 h afterward, PBMC were isolated and stimulated in vitro with endotoxin, IL-1, or toxic shock syndrome toxin-1. Inasmuch as CD14+ monocytes are the primary source of the cytokines induced by these stimuli, results are expressed as cytokine production per 10(6) CD14+ cells. Six h after endotoxin injection, endotoxin-stimulated CD14+ cells synthesized 66% less IL-1 beta (p < 0.01), 47% less TNF-alpha (p < 0.001), 56% less IL-6 (p < 0.01), and 49% less IL-8 (p < 0.01) than cells obtained before the injection. This suppression was not specific for endotoxin; IL-1 beta-induced IL-1 alpha and TNF-alpha were reduced by 84% (p = 0.01) and 68% (p < 0.001), respectively. A decrease in cytokine synthesis was also observed using toxic shock syndrome toxin-1 as a stimulus: 57% for IL-1 beta (p = 0.06), 70% for TNF-alpha (p < 0.01), 56% for IL-6 (p < 0.05), and 71% for IL-8 (p = 0.001). When data were expressed as cytokine production per 10(6) PBMC, cells isolated 3 h after endotoxin injection synthesized significantly less stimulus-induced IL-1, TNF-alpha, IL-6, and IL-8 than did PBMC from saline-injected controls. We conclude that endotoxin tolerance is due, in part, to changes in the stimulus-induced cytokine response of circulating CD14+ cells.

Antigens, CD↗

Failure of oral tolerance in (NZB X NZW)F1 mice is antigen specific and appears to parallel antibody patterns in human systemic lupus erythematosus (SLE).

Primary oral antigen exposure normally induces mucosal immunity and an active suppression of the systemic immune response. Patients with systemic lupus erythematosus (SLE) have increased antibodies to bovine gamma-globulin (BGG), which suggested a possible failure of oral tolerance in SLE. We examined this possibility in murine lupus. NZB/W females were fed BGG or saline and were subsequently immunized ip. Primary and secondary responses were assessed. At 1 month of age the mice tolerized normally in response to feeding with BGG but, at 4 months of age, not only did they not tolerize, the mice fed BGG had a 5- to 7-fold higher response to parenteral immunization than did the saline-fed mice. Control strain mice tolerized normally at both ages (a 5- to 10-fold lower response). Conversely, when fed ovalbumin, NZB/W females tolerized normally at both 1 and 4 months of age, and patients with SLE had normal levels of antibody to this antigen. However, we also found increased levels of antibodies to bovine casein in SLE patients, and found that NZB/W mice failed to orally tolerize with this antigen at either 1 or 4 months of age. Thus, the failure of oral tolerance in the NZB/W mice appears to be antigen specific and age dependent and, at least with respect to these three antigens, appears to parallel the antibody patterns seen in human SLE.

Administration, Oral↗

Analog of neuropeptide FF attenuates morphine tolerance.

Previous studies suggest that neuropeptide FF (NPFF) plays a role in opiate dependence and subsequent abstinence syndrome. Endogenous NPFF also appears to play a role in opiate tolerance since third ventricle injection of IgG from NPFF antiserum selectively restores morphine sensitivity in morphine-tolerant rats. The NPFF analog, desamino YFLFQPQRamide (daY8Ra) has previously antagonized behavioral effects of NPFF and has attenuated morphine dependence. The present study assessed whether daY8Ra could similarly attenuate morphine tolerance. Third ventricle (i.c.v.) injection of daY8Ra restored the analgesic response to i.c.v. morphine in morphine-tolerant rats (radiant heat tail flick test). Saline injection failed to produce this effect. In opiate-naive rats, however, the same treatment with daY8Ra did not affect the analgesic response to i.c.v. morphine. Thus, daY8Ra appears to selectively restore morphine sensitivity in opiate-tolerant animals. These results further support the hypothesis that endogenous NPFF contributes to opiate tolerance.

Amino Acid Sequence↗

Caffeine's neuroprotection against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine toxicity shows no tolerance to chronic caffeine administration in mice.

We investigated the effect of chronic daily caffeine treatment on caffeine's neuroprotection against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced dopaminergic toxicity. Mice received either caffeine (20 mg/kg) or saline daily for 9 days. Caffeine-induced locomotion tolerance developed within 3 days of treatment and persisted for the duration of the experiment. On day 10, mice were treated with MPTP (20 mg/kg, x4). Caffeine (20 mg/kg) or saline was administered 10 min before each MPTP dose. Acute pretreatment with caffeine attenuated MPTP-induced loss of striatal dopamine and dopamine transporter binding sites, and this attenuation was identical in mice pretreated chronically with caffeine or with saline. Thus, in contrast to the locomotor stimulant effect of caffeine, its neuroprotectant effect did not show tolerance to prior caffeine exposure. These data raise the possibility that caffeine may induce neuroprotection and locomotion by distinct mechanisms.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗

Efficient leaf ion partitioning, an overriding condition for abscisic acid-controlled stomatal and leaf growth responses to NaCl salinization in two legumes.

Two tree medics contrasting in salt tolerance, Medicago arborea and Medicago citrina, were compared to evaluate the relative importance of abscisic acid on leaf growth and stomatal responses to salt stress. Plants were grown for 30 d in solution culture with 1, 50, 100 or 200 mM NaCl. Salinized plants of M. citrina had lower Na+ and Cl- uptake and maintained better leaf growth than M. arborea. In M. citrina, stomatal conductance was only slightly affected by salt and, in consequence, the salt treatment had no significant influence, neither on the CO2 fixation rate nor the transpiration rate in these plants. Moreover, leaf photosynthetic pigments and soluble protein in M. citrina were increased by the presence of NaCl, while a decrease of both parameters with salt was found in M. arborea. However, leaf and xylem ABA increased only in salt-treated M. citrina, while no differences were found among treatments in M. arborea. The role of ion compartmentation, gas exchange parameters and ABA concentrations in relation to salt tolerance in M. arborea and M. citrina is discussed.

Abscisic Acid↗

Analgesic properties of meperidine, amitriptyline and phenelzine in mice.

Sixty-three white Swiss Webster mice were divided into seven equal groups. Their tolerance to pain (heat applied to the tail by a test tube containing hot water at a temperature measured by telethermometry) was assessed before and after intraperitoneal injection of (1) physiologic saline; (2) meperidine 14 micrograms X g-1; (3) amitriptyline 6 micrograms X g-1 (4) amitriptyline 12 micrograms X g-1; (5) phenelzine 1.5 micrograms X g-1; (6) phenelzine 3 micrograms X g-1; and (7) amitriptyline 6 micrograms X g-1 plus phenelzine 1.5 micrograms X g-1. All post-injection tests were conducted 45 and 90 minutes after administration, and repeated 24 hours later. No significant difference in pain threshold was noted in any pre-injection test or in any test conducted with physiologic saline. By 90 minutes post-injection, all groups receiving drugs developed increased tolerance to pain. Mice which had received phenelzine plus amitriptyline, or either dose of phenelzine were more tolerant to pain for up to 24 hours than mice which had received physiologic saline. The most marked increases in tolerance to pain were seen with 1.5 micrograms X g-1 and 3 micrograms X g-1 of phenelzine and phenelzine plus amitriptyline. However, phenelzine was more effective and had a longer-lasting effect than either dose of amitriptyline, or meperidine. The combination of phenelzine plus amitriptyline was no more effective than phenelzine alone.

Amitriptyline↗

Feasibility of using intraperitoneal epinephrine and cisplatin in patients with advanced peritoneal carcinomatosis.

Intraperitoneal epinephrine above 1 mg/l concentration has been shown to enhance the intratumoral accumulation and antitumor activity of intraperitoneal cisplatin in rats with advanced peritoneal carcinomatosis. The aim of this study was to determine the tolerance of intraperitoneal epinephrine combined with intraperitoneal cisplatin in patients with advanced peritoneal carcinomatosis (17 ovarian cancers, one peritoneal mesothelioma). Intraperitoneal epinephrine (1-5 mg/l) and cisplatin (50 mg/l; 100 mg total dose) were infused in 2 l of saline solution over 2 h. The maximal tolerated concentration of intraperitoneal epinephrine was not reached at 5 mg/l. Cardiovascular symptoms were infrequent and not strictly related to the epinephrine concentration. Tumor responses were obtained in some patients with disease resistant to intravenous platinum compounds. This work demonstrates for the first time that intraperitoneal epinephrine at sufficient concentration enhances the cisplatin effect and can be safely infused into the peritoneal cavity of patients with peritoneal carcinomatosis. The greatest limitation was abdominal pain and limited intraperitoneal distribution of the peritoneal fluid in this closed-abdomen procedure.

Aged↗