Meat toughening does not occur when rigor shortening is prevented

The objective of this experiment was to test the hypothesis that meat toughening during the first 24 h postmortem results from sarcomere shortening during rigor mortis development. Eleven market-weight lambs were used to measure changes in shear force of clamped longissimus during rigor development. Within 15 min of exsanguination, while attached at both ends, each longissimus was separated from the vertebrae body and clamped between three sets of metal plates to prevent muscle shortening (six clamped sections per lamb). Five of the clamped sections were placed at -1.1 degrees C for 0, 3, 6, 12, or 24 h. After storage at their respective times at -1.1 degrees C, the samples were placed at -30 degrees C for 90 min and then at -5 degrees C for 8 d. The sixth section (168-h section) was stored at -1.1 degrees C for the first 24 h, at 4 degrees C for 144 h, and then treated the same as other sampling times. Sections were sampled for pH, sarcomere length, shear force, and Western blot analyses before and after storage at -5 degrees C. Shear force values were the same (P > .05) from 0 to 24 h (4.5 kg at 0 h to 4.9 kg at 24 h) then declined (P < .05) to 3.3 kg at 168 h postmortem. As evident by lack of statistical difference in the sarcomere lengths, we were successful in holding the muscle length constant. Western blot analyses of nebulin, vinculin, and troponin-T indicated that minimum degradation occurred through 12 h, was slightly increased by 24 h, and was relatively extensive by 168 h postmortem. Although limited proteolysis occurred during storage at -5 degrees C for 8 d, this by itself had no effect on shear force. Results indicate that shear force values do not increase during rigor development when muscle is prevented from shortening; thus, the toughening that occurs during the first 24 h of slaughter is most likely due to sarcomere shortening.     

Estrogen receptor does not directly regulate the murine Muc-1 promoter

Muc-1 is a heavily O-glycosylated, type 1 membrane glycoprotein present on the surface of polarized secretory uterine epithelial cells. Previous studies have shown that treatment of ovariectomized mice with 17-beta-estradiol (E2) strongly induces Muc-1 mRNA expression in an estrogen receptor (ER)-mediated fashion in the uterus. In this study, the 5.4 kb Muc-1 gene promoter has been isolated from a mouse genomic library and the proximal 1.85 kb region has been sequenced. Sequence analysis revealed the presence of one potential full estrogen response element (ERE) (GCTCGCGGTGACC) located at -748 to -735 bp in the Muc-1 promoter and several potential ERE half sites. Electrophoretic mobility shift assays (EMSA) showed that neither ERalpha nor ERbeta bind efficiently to this sequence. Transient cotransfection assays using constructs containing various deletion mutations of the 5' Muc-1 flanking sequences showed that E2 had no direct stimulation on promoter-driven reporter in NMuMG cells or primary mouse uterine epithelial cells, but did stimulate a consensus ERE CAT-reporter gene activity. In addition, E2-treatment of Weg-ER cells, a mouse uterine epithelial cell line stably expressing human ERalpha, did not restore endogenous Muc-1 expression or activate Muc-1 promoter-driven CAT activity. These results indicate that regions of the Muc-1 gene promoter within -1838 to +43 bp do not respond to E2 and ER stimulation and that ER alone is not sufficient to restore Muc1 gene expression. Deletion analyses also revealed that the sequence between -73 and +43 bp of the Muc-1 promoter is the minimal promoter region required for maximal Muc-1 promoter activity. Collectively, these results demonstrate that ER does not directly regulate the 1.85 kb murine Muc-1 gene promoter. Therefore, E2 control of uterine Muc-1 gene expression is likely to be indirect, i.e. mediated by stromal cell-derived factors.     

Intracerebral recombinant HSV-1 vector does not reactivate latent HSV-1

Herpes simplex virus type-1 (HSV-1) has been used for gene delivery in the nervous system for the treatment of brain tumors and other neurological diseases. In most protocols, recombinant viruses containing the gene of interest are directly injected into the brain. Since many people harbor latent wild-type HSV-1 virus in sensory ganglia and other regions of the nervous system, there is a potential risk that the injected recombinant virus may reactivate the latent wild-type virus to cause severe encephalitis. The present study used two rat latent infection models to evaluate this risk. Adult rats were infected with wild-type kos by cornea scarification or by intracerebral injection, and after the establishment of latency, the ICP6(-) strain hrR3 was injected intracerebrally. In the control group, the latent virus was reactivated by treatment of cadmium sulfate. Viral shedding from tears was detected by incubation with Vero cells, and the trigeminal ganglia, cortical tissue and the eyes were collected to detect reactivated wild-type virus by RT-PCR. Our results showed that while the reactivated wild-type virus was readily detectable in the cadmium-sulfate-treated animals, intracerebrally infected hrR3 did not reactivate the latent virus in either the corneal model or the cerebral model. These results indicate that intracranial injection of partially defective recombinant virus may bear little risk of reactivating latent wild-type virus harbored in the sensory ganglia or the brain in our animal model.     

Adrenalectomy does not affect the nocturnal peak of Fos expression within hypothalamic pro-opiomelanocortin neurons

Clinical and evoked-potential studies in internal capsule and corona radiata infarction are lacking. We report the results of a clinical and central motor conduction time (CMCT) study in 16 patients with internal capsule and 17 with computed tomography (CT)-proven corona radiata infarction. Patients's outcome was defined at the end of 3 months on the basis of the Barthel Index score. Four patients with type A capsular infarction (middle third of posterior limb of internal capsule) all had severe weakness, while 2 also had persistently unrecordable CMCT and poor outcome. Twelve patients with type B internal capsular infarction (genu, anterior limb, anterior or posterior third of posterior limb) had a milder degree of weakness, and CMCT was recordable in 9. At 3 months' follow-up, however, CMCT was recordable in all 12 patients. All of these patients had a partial (n = 4) or complete (n = 5) recovery. Thirteen patients with type A corona radiata infarction (middle third of corona radiata) had more pronounced weakness, and CMCT was unrecordable in all of these patients except 1 on initial examination. Follow-up after 3 months was possible in 8 patients, and CMCT became recordable in 3. One of these patients had complete, 3 partial, and 4 poor recovery. In type B corona radiata infarction (anterior or posterior third of corona radiata), the clinical signs and CMCT did not follow a regular pattern. Clinical and CMCT abnormalities in internal capsular infarction followed a more predictable pattern compared with those in corona radiata infarction. A less predictable pattern of weakness and CMCT change in corona radiata infarction may be attributed to a less definite organisation of motor pathways compared with the internal capsule.     

Behavioral testing does not exacerbate ischemic CA1 damage in gerbils

BACKGROUND AND PURPOSE: Previous research studying ablative lesions has suggested that functional use may exacerbate brain injury. If true, this would have considerable ramifications not only for the mechanistic understanding of neuronal injury but also for the clinical use of physiotherapy. In this report the hypothesis that behavioral use of brain tissue exacerbates ischemic hippocampal injury was tested. METHODS: Gerbils were subjected to sham operation or 5 minutes of normothermic ischemia. To produce borderline hippocampal CA1 injury and enhance susceptibility to exacerbation, 2 of 3 ischemic groups were cooled (>48 hours) beginning at 6 hours after ischemia. Increased use of the hippocampus was produced by a battery of tests involving 3 novel small mazes, a T maze, and an open field. One hypothermic group was not tested and served as a control. RESULTS: Behavioral testing failed to worsen ischemic damage since neuronal loss in the behaviorally tested and untested hypothermic groups was 12% and 8%, respectively, while that in the untreated ischemic group was 81% at a 1-month survival. Accordingly, protected CA1 cells tolerated the neuronal activity associated with behavioral testing. Concomitant with marked CA1 neuroprotection, a significant reduction in behavioral deficits with the hypothermic treatment was observed. Importantly, behavioral testing was found to transiently elevate brain temperature. CONCLUSIONS: CA1 neuronal survival was unaffected by behavioral testing or the associated mild fever. Hypothermia delayed for 6 hours provided sustainable CA1 neuroprotection.     

Endothelin-1 receptor antagonism does not influence myocardial function in hypertensive dogs

BACKGROUND: As endothelin-1 exerts positive inotropic effects, the present study evaluated whether the hypotensive effects of the endothelin-1 receptor antagonist bosentan were partially related to a decrease in myocardial performance. METHODS: In group I, eight anaesthetized open-chest dogs with perinephritic hypertension received four cumulative doses of bosentan (B1-B4). In group II, eight animals received the same doses of bosentan after autonomic blockade. Indices of heart function were derived from the pressure-length loops obtained during vena cava occlusion. RESULTS: In group I, bosentan decreased left ventricular systolic pressure (LVSP) and mean aortic pressure (MAP) dose dependently, reaching 21% and 23% respectively at B4 (LVSP from 190 +/- 8 to 150 +/- 5 mmHg, P < 0.001; MAP from 167 +/- 7 to 128 +/- 5 mmHg, P < 0.001). These effects were only related to peripheral vasodilatation, without depression of myocardial contractility, as systemic vascular resistance dropped (from 670 +/- 83 to 446 +/- 53 mmHg mL-1 min-1 x 10(4); P < 0.05), and the end-systolic pressure-length relationship (ESPLR) remained unchanged (4.0 +/- 0.4 vs. 4.3 +/- 0.7 mmHg mm-1 kg-1). Concomitantly with pressure decline, heart rate tended to increase in this group (from 150 +/- 4 to 156 +/- 6 beats min-1). When autonomic system was blocked (group II), administration of bosentan induced similar hypotensive effects as in group I (26% and 28% reduction in LVSP and MAP respectively, P < 0.001) whereas ESPLR did not change (3.0 +/- 0.9 vs. 3.1 +/- 0.5mmHg-1 mm kg-1 ). Under these sympathetically blocked conditions, heart rate significantly fell after bosentan infusion (from 120 +/- 4 to 110 +/- 6 beats min-1, P < 0.001). CONCLUSIONS: Without influencing heart function, bosentan is an efficient and safe therapy that opens up new therapeutic perspectives in human essential hypertension.     

Endothelin-1 does not mediate the endothelium-dependent hypoxic contractions of small pulmonary arteries in rats

Various pulmonary artery preparations in vitro demonstrate sustained endothelium-dependent contractions upon hypoxia. To determine whether endothelin-1 could mediate this phenomenon, we examined the effect of bosentan, a new antagonist of both the ETA and ETB subtypes of the endothelin receptor. Small (300 pm) pulmonary arteries from rats were mounted on a myograph, precontracted with prostaglandin F2 alpha and exposed to hypoxia (PO2, 10 to 15 mm Hg, measured on-line) for 45 min. Endothelium-intact control rings exhibited a biphasic response, with a transient initial vasoconstriction (phase 1) followed by a second slowly developing sustained contraction (phase 2). Expressed in percent of the maximal response to 80 mmol/L KCl, the amplitudes of phase 1 (peak tension) and 2 (tension after 45 min of hypoxia) averaged 37 +/- 12% and 17 +/- 14%, respectively (n = 11). In endothelium-denuded rings, phase 1 persisted while the amplitude of phase 2 was reduced to 2 +/- 12% (p < 0.05, n = 8), showing the endothelium dependence of this contraction. Neither phase was significantly decreased in rings treated with 10(-5) mmol/L bosentan (38 +/- 15% and 17 +/- 12%, respectively, n = 6). The PO2 threshold for onset of hypoxic contraction was not significantly different among these three groups and averaged 32 +/- 24 mm Hg. In a separate experiment, we assessed the inhibitory effect of 10(-5) mol/L bosentan on the response to 10(-8) mol/L endothelin-I. Rings treated for 45 min with 10(-8) mol/L endothelin-1 alone exhibited a maximal contraction of 75 +/- 27% (n = 6). This was reduced to 4 +/- 17% (p < 0.01, n = 6) in rings treated with both 10(-8) mol/L endothelin-1 and 10(-5) mol/L bosentan. We conclude that complete blockade of all endothelin receptor subtypes has no effect on either endothelium-dependent or -independent hypoxic contractions in this preparation. This suggests that endothelial factors other than endothelin-I mediate the acute hypoxic contractions of small pulmonary arteries in the rat.     

VCAM-1 expression and leukocyte trafficking to the CNS occur early in infection with pathogenic isolates of SIV

This study reports on the endothelial expression of vascular cell adhesion molecule-1 (VCAM-1) in the central nervous system (CNS) early after experimental infection of rhesus monkeys (Macaca mulatta) with pathogenic and nonpathogenic simian immunodeficiency virus (SIV). Diffuse endothelial expression of VCAM-1 was observed in the CNS in all animals receiving pathogenic SIV. These findings demonstrate the rapidity with which pathogenic SIV is able to enter the CNS and induce endothelial cell activation.     

Calcium-induced intercellular adhesion of keratinocytes does not involve accumulation of beta 1 integrins at cell-cell contacts and does not involve changes in the levels or phosphorylation of catenins

The development of the lymphatic system in the rat diaphragm was studied from embryonic day 16 to 25 weeks after birth by histochemistry for 5'-nucleotidase, scanning electron microscopy of KOH-treated or intact tissues, and transmission electron microscopy of thin sections. On embryonic day 16, distinct lymphatics were noted in the subpleural space of the diaphragm periphery. The endothelial cells at this stage contained an abundance of rough endoplasmic reticulum, a developed Golgi apparatus and mitochondria, and fewer pinocytotic vesicles than those in adults. The subpleural lymphatics subsequently increased and formed a polygonal network. They possessed many valves, and by postnatal week 6, some thick collecting lymphatics became endowed with smooth muscle cells. On embryonic day 19, some lymphatics appeared in the subperitoneal space. They extended centripetally and had many lateral projections that subsequently became elongated and connected with those from adjacent lymphatics, thus forming a lattice-like network. During the early postnatal days, the subperitoneal lymphatics projected many bulges that subsequently became elongated, and came into contact with the pores among the mesothelial cells, thus forming lymphatic stomata connecting the lymphatic lacunae to the peritoneal cavity. The lymphatic stomata increased until postnatal week 10. The results show that lymphatics appear as early as embryonic day 16 in the subpleural space of the diaphragm periphery, and develop with age by sprouting to form networks in both the subpleural and the subperitoneal spaces, and that the direct connection of the lymphatic lacunae to the peritoneal cavity is formed after birth.     

Citrate anticoagulation does not correct cuprophane bioincompatibility as evaluated by the expression of leukocyte surface molecules

BACKGROUND: Citrate, used for the anticoagulation of the extracorporeal dialysis circuit, reduces ionized calcium by chelation and has been claimed to attenuate dialyser membrane bioincompatibility. Dialysis with complement-activating cuprophane membranes is associated with leukopenia which has been related to an increase in adhesion molecule expression on the surface of circulating leukocytes. METHODS: The effect of citrate anticoagulation on the expression of CD11b, CD11c and CD45 on the surface of granulocytes and CD14 on monocytes during haemodialysis with cuprophane membranes, was evaluated by flow cytometric analysis. A comparison of standard heparin vs citrate was performed in 14 chronic haemodialysis patients. During citrate anticoagulation a calcium-free dialysate was used and citrate was infused to obtain a concentration of 4.3 mmol/l blood. The unchallenged 'baseline state' expression of the surface molecules and the increase after ex vivo stimulation with phorbol 12-myristate 13-acetate (delta-PMA) or formyl-methionyl-leucyl-phenylalanine (delta-fMLP) was studied. RESULTS: With heparin, as well as with citrate, a sharp fall in granulocyte and monocyte count was observed after 15 min of dialysis, followed by a recovery at the end of the session. The expression of CD11b, CD11c and CD45 on granulocytes increased markedly during cuprophane dialysis with a peak at 15 min; there were no differences in response between heparin and citrate anticoagulation. Delta-PMA and delta-fMLP for CD45, CD11c and CD14 showed a decrease during cuprophane dialysis vs t0; again there were no differences between heparin and citrate. CONCLUSION: We conclude that the use of citrate was not associated with reduced leukocyte activation as measured by the expression of surface molecules during cuprophane dialysis and that no effect on dialysis leukocytopenia could be registered.     

Adventitial stripping does not strip the adventitia

This study investigates the process of stripping the adventitia off a blood vessel, which is a normal procedure prior to performing a microvascular anastomosis. In five rats, the common carotid and the superficial femoral arteries of one side were stripped sharply, whereas the arteries of the other side were left unstripped to serve as controls. In a further set of five rats, the arteries were stripped bluntly. Immediately following stripping, experimental and control arterial segments were removed. Histology of cross sections of the segments was studied. In no case was there complete removal of the adventitia. When stripped and control arterial sections were compared, no significant difference between cross-sectional adventitial areas could be demonstrated. Morphologic study revealed that stripping mainly removes large collagen fibers from the adventitia. The small collagen fibrils that are still in place fan out in such a way that although considerable tissue is removed, the volume that the adventitia occupies remains the same. Stripping the adventitia does not cause complete removal of the adventitia, and in this study no significant reduction in the adventitial volume could be found. Stripping does, however, allow a better view of the cut edge of the vessel wall under an operating microscope. Since blunt stripping could cause damage to other vessel wall layers, sharp stripping is to be preferred.     

Endothelin-1 does not contribute to ischemia/reperfusion-induced vasoconstriction in skeletal muscle

The experiment reported was designed to investigate whether endothelin-1 (ET-1) contributes to vasospasm and poor perfusion during the reperfusion after prolonged ischemia in skeletal muscle. Male Sprague-Dawley rats weighting 100 to 120 g were anesthetized with Nembutal. The vascular isolated rat cremaster muscle, coupled with local interarterial infusion, was the model used in this study. The diameters of feeding arterioles and terminal arterioles were measured utilizing intravital microscopy. The number of terminal arterioles with temporary cessation of flow were counted in each cremaster. Group 1: ET-dose response (8 rats)--various concentrations of ET-1 (from 10(-8) M to 10(-5) M) were infused into the cremaster to test whether this muscle was responsive to the agent in a dose-dependent manner. Group 2: ET-antagonist response (12 rats)--PD-142893, 10(-4) M (ETab receptor antagonist) plus ET-1 10(-7) M were infused into the cremaster to test whether vasospasm caused by exogenous ET-1 could be prevented by pretreatment with this specific ETab receptor antagonist. Group 3: ischemia/reperfusion response (12 rats)--PD-142893, 10(-4) M was infused into the cremaster before ischemia (4 hr warm ischemia) and during reperfusion to test whether ETab receptor antagonism was effective in preventing the vasospasm associated with ischemia/reperfusion injury. The results from this study show that a mixed ETab endothelin antagonist, PD-142893, infused before ischemia and during reperfusion at a dose which virtually abolished the vasoconstriction produced by a high concentration of exogenous endothelin-1, had no effect on ischemia/reperfusion-induced vasoconstriction in this model. These results suggest that ET-1 probably does not contribute to the ischemia/reperfusion-induced vasoconstriction and poor reflow in rat skeletal muscle.     

The rescue chain does not stop in the hospital

When a patient is saved from a severe illness or accident, his doctor (family practitioner) must care about many problems which are not really medical but also social, psychologic, financial, occupational or political. The interest must be revealed during education and supported by head doctors in hospitals during vocational training years. Therefore, postgraduate training must discuss not only medical problems; the themes mentioned above are just as important.     

Melatonin does not inhibit estradiol-stimulated proliferation in MCF-7 and BG-1 cells

Melatonin, an indolic pineal hormone, is produced primarily at night in mammals and is important in controlling biological rhythms. Previous research suggested that melatonin can attenuate proliferation in the estrogen-responsive MCF-7 breast cancer cell line. We tested whether these anti-proliferative effects may have physiological consequences upon two estrogen-responsive cell lines, MCF-7 (a breast cancer cell line) and BG-1 (an ovarian adenocarcinoma cell line). Melatonin (10(-9)-10(-5) M) attenuated proliferation of MCF-7 and BG-1 cells by >20% in the absence of estrogen. However, 17beta-estradiol exposure negated the ability of melatonin to inhibit proliferation. To substantiate this finding, cells were estrogen starved followed by multiple treatments with estradiol and melatonin. Melatonin did not inhibit estradiol-stimulated proliferation under this protocol. Estradiol increased MCF-7 and BG-1 cell cycle transition from G1 to S phase, however, melatonin did not inhibit this transition nor did it down-regulate estradiol-induced pS2 mRNA levels measured by northern blotting, further indicating that melatonin was unable to attenuate estradiol-induced proliferation and gene expression. We also examined the effects of melatonin on estradiol-induced proliferation in MCF-7 cell xenografts in athymic nude mice. Melatonin at a dose 28 times greater than 17beta-estradiol did not inhibit estradiol-induced proliferation in vivo. Furthermore, pinealectomy did not increase proliferation. Therefore, we conclude that melatonin does not directly inhibit estradiol-induced proliferation.     

Long-term alpha 1 blockade does not reverse cardiac hypertrophy in spontaneously hypertensive rats

Not all antihypertensive drugs induce regression of left ventricular (LV) hypertrophy in hypertension, although they may equally lower blood pressure. The effects of alpha 1-blockers on regression have been inconsistent. In this study, bunazosin, a selective alpha 1-blocker, (15 mg/kg/day in food) was given to male spontaneously hypertensive rats (SHR) from 15 to 35 weeks of age to evaluate its effects on cardiac hypertrophy, hemodynamics, and neurohumoral factors. Age- and sex-matched SHR served as controls. LV function and cardiac output were determined by a micromanometer and thermodilution, respectively. Bunazosin significantly decreased blood pressure in conscious rats (from 209 to 192 mmHg, p < 0.01) but did not reduce LV mass. Heart rate, LV end-diastolic pressure, dp/dtmax, and cardiac output were similar in the 2 groups. Plasma renin activity was unaltered but plasma norepinephrine levels were higher in the treated rats (p < 0.05). Thus, bunazosin produced a significant relative reduction of blood pressure but did not reverse LV hypertrophy in SHR. Inadequate afterload reduction (8%) due to severe hypertension (> 200 mmHg) may explain the absence of regression. The rise of plasma norepinephrine levels may also offset the beneficial effects of bunazosin.     

Eprosartan does not affect the pharmacodynamics of warfarin

The purpose of this study was to conduct a retrospective analysis of the clinical spectrum, treatment and morbidity of the patients who have suffered high tension electrical injuries with current passage through their body (59 patients). Voltage, localization and surgical treatment seem to be the main factors influencing the lesion and the morbidity. The following points were considered: (1) Is there any relation between known factors such as voltage and the localization of the points of contact with the incidence and the type of complications and sequelae? (2) Do the observations show that wound management and the excision of dead tissues is the most adequate? From factors studied in our patients (voltage, point of entry and pathway of current, associated multiple trauma or flame burns, surgical treatment) we have found that the voltage does not have any influence on the severity of the wound nor on the percentage of sequelae (cataracts, limb amputation, neurologic complications). The current pathway, as well as its points of entry, does not show any relation with the presence of renal failure, cardiac arrhythmia and cataracts. A clear relationship between the point of entry of the current and the appearance of neurologic injury with presence of paralysis and permanent regional anaesthesia at the same level was observed. The presence of associated burns was not related to any other complications or sequelae. For those patients whose length of contact has been shorter we find a lower rate of amputations despite having associated limb fractures. Fasciotomy incisions appear to confer benefit as this series shows that this procedure decreases the rate of limb amputations.     

Pneumoperitoneum does not potentiate the nephrotoxicity of aminoglycosides in rats

OBJECTIVES: Pneumoperitoneum is associated with transient renal dysfunction. To our knowledge, the safety of administering nephrotoxins such as aminoglycosides during pneumoperitoneum has not been studied. Our hypothesis was that pneumoperitoneum potentiates the nephrotoxicity of aminoglycosides. METHODS: From 29 rats we obtained preprocedure 24-hour urine collections. In the pneumoperitoneum group (n = 7), carbon dioxide was insufflated intra-abdominally at 15 mm Hg pressure for 2 hours. In the gentamicin group (n = 7), 10 mg/kg gentamicin was administered intravenously. In the combined pneumoperitoneum/gentamicin group (n = 8), the same dose of gentamicin was administered 10 minutes before pneumoperitoneum. Sham rats (n = 7) received anesthesia only. Urine was collected for the 24 hours after the procedure, and 1 week later blood for creatinine determination and final 24-hour urine collections were obtained. All urine samples were assayed for creatinine and N-acetyl-beta-glucosaminidase (NAG). RESULTS: Only the gentamicin and combined pneumoperitoneum/gentamicin groups presented day 1 values for NAG excretion that were significantly greater than same day sham or paired preprocedure values; the rest of the urinary creatinine and NAG day 1 levels and all the day 7 levels were not significantly different from same day sham or paired preprocedure levels. Day 7 serum creatinine and creatinine clearance did not differ significantly among the groups. CONCLUSIONS: We found that intravenous gentamicin transiently increased urinary excretion of NAG in rats, which resolved within 1 week. Pneumoperitoneum for 2 hours at 15 mm Hg did not increase urinary NAG, either alone or in gentamicin-treated rats. Moreover, our data are sufficient to refute with 95% certainty the possibility that gentamicin plus pneumoperitoneum decreases creatinine clearance more than approximately 60%. These results do not support the hypothesis that pneumoperitoneum potentiates the nephrotoxicity of aminoglycosides.     

Fluid abnormalities occur in the chronically cannulated mid-gestation but not late gestation ovine fetus

Indomethacin, an inhibitor of cyclo-oxygenase given orally, reduced the tumorigenicity of cancer cells in a non-immunogenic murine model of mammary adenocarcinoma (4T1). In the presence of indomethacin, a dose-dependent immune protection could be induced most effectively by immunizing mice with 1 to 3 doses of irradiated tumor cells inoculated at intervals of 7 days prior to challenge with a tumorigenic cell dose. Three immunizations given without indomethacin resulted in tumor growth in 88% of the recipients, and indomethacin treatment started 28 days prior to the challenge dose and given without immunizations led to tumor onset in 83% of mice. In contrast, tumor was documented only in 12% of mice vaccinated with 3 immunization doses and given concomitantly indomethacin. Moreover, 53% of disease-free survivors resisted a second challenge with a high tumorigenic dose. Induction of an anti-tumor immunity in indomethacin-treated mice was further studied as a therapy for tumor-bearing mice. Complete cure was induced in 50% of mice, and a significant reduction in tumor size as well as prolonged survival time were observed in the remaining animals. Immunostimulation by tumor cell vaccination given in the presence of a tolerable dose of indomethacin, therefore, may be incorporated into immunotherapy protocols to activate an anti-tumor response against residual tumor cells that escaped surgery and/or high-dose chemo/radiotherapy.