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Relief of pain following upper abdominal operations by thoracic epidural block with etidocaine.

Bupivacaine and etidocaine were compared in 0.375% and 0.5% solutions (without adrenaline) in a double-blind study in thoracic epidural analgesia following upper abdominal surgery. Special regard was taken to duration and adequacy of analgesia and changes in motor function. Duration of analgesia was roughly comparable for all four solutions. Bupivacaine 0.375% and etidocaine 0.5% seemed to be appropriate concentrations for adequate pain relief. Motor function, as assessed by changes in FVC, FEV1 and PEFR was not influenced to any greater extent. A progressive fall in FVC with successive injections, indicating increasing motor weakness, did not occur.

Abdomen↗

Lysosomal degradation of cell organelles. II. Ultrastructural analysis of uptake and digestion of intravenously injected microsomes and ribosomes by Kupffer cells.

Rough and smooth microsomes, "mixed" or total microsomes, and ribosomes were isolated from one single rat liver and subsequently injected intravenously into a series of inbred rats. The uptake and the degradation of the injected organelles by Kupffer cells were followed by means of electron microscopic analysis. By 1 minute after injection, microsomes were seen attached to the surface of Kupffer cells separated by a gap of 200 to 300 A. No attachment to hepatocytes, fat-storing cells, or endothelial cells was seen. By 5 and 10 minutes, most microsomes were phagocytosed and sequestered in large numbers within single membrane-enclosed vacuoles or phagosomes. The engulfment proceeded by two mechanisms: (1) most frequently, flaplike processes of cytoplasm embraced aggregates of microsomes, concomitant with the formation of indention of the cytoplasm; (2) occasionally, single microsomal profiles were taken up by bristle-coated endocytic vacuoles. Ribosomes were also seen penetrating into the wormlike structures (micropinocytosis vermiformis) at the cell surface. At 30 minutes after injection, clear signs of alteration were noted starting with vesicle aggregation, clumping, and elongation of the microsomal profiles. The ribosomes were quickly stripped from their microsomal membranes and marginated to the inside of the vacuoles but separated from the limiting membrane by a distance of 200 to 300 A. By 1 and 2 hours, disruption of the vesicles into membrane fragments and formation of dense material in and between the profiles occurred. By 8 hours it was difficult to recognize the degradation products as membrane derivatives. The digestive vacuoles retained their size at this time interval. Typical pentalaminar structures were observed. By 14 to 24 hours the digestive vacuoles became electron lucent and appeared to shrink, and in addition to containing various types of granular material, many were laden with lipid-like droplets presumed to be conglomerates of phospholipid remnants. Rough microsomes, when compared to smooth microsomes, gave rise to more granular material within the digestive vacuoles. Ribosomes were still identifiable 24 hours after injection, indicative of a somewhat slower rate of degradation. Accumulation of various types of lipid-like droplets in the "residual bodies" was typical after microsomal injections. It is concluded that although microsomes appear to be phagocytosed at a quicker rate than mitochondria, they are digested within the lysosomal apparatus of the Kupffer cells at a somewhat slower rate. This especially seems to be the case for ribosomes. Heterophagy of microsomes is one source of residual bodies.

Animals↗

The matrix of the optic vesicle-presumptive lens interface during induction of the lens in the chicken embryo.

The cell coats of the presumptive lens cells and the extracellular interface between the lens rudiment and optic vesicle were investigated in the chicken embryo throughout the period during which lens induction is presumed to take place. Histochemical methods showed that the cell coats contained both glycoproteins and glycosaminoglycans. Autoradiography after [3H]glucosamine injection indicated incorporation of the precursor with subsequent localization primarily at the cell surface. No obvious changes in the properties of the coat were noted with the progression of early lens morphogenesis. The extracellular matrix at the interface between ectoderm and optic vesicle also contained glycoprotein and glycosaminoglycan. There was a heavy concentration of [3H]glucosamine-containing macromolecules in the area. Electron microscopy revealed that the interface consisted of the basement membrane systems of lens and optic vesicle, fused with their external fibrillar layers. In contrast to the findings on cell coats the density of the interfacial matrix increases appreciably during the lens induction period. Evidence suggests that the cells of the two ocular epithelia are themselves the source of the matrix materials. It is proposed that the macromolecules excreted by the epithelial cells into the interface interact at different concentrations to form aggregates of various structure by a process of self-assembly. This may be reflected in the different ultrastructure of the layers of the interfacial matrix. Quantitative changes in the density of the matrix, leading to increased adhesion between lens rudiment and optic vesicle, may restrict the lateral spreading of the lens cells and so fix the basal area of the lens rudiment. This, together with continued cell replication, may produce the cell crowding, placode formation and invagination characteristic of lens morphogenesis.

Amylases↗

Plasma levels following administration of sodium meclofenamate by various routes.

Sodium meclofenamate, an anti-inflammatory and anti-anaphylactic agent, was administered to cattle intravenously, orally and by intraruminal injection. Plasma levels of the free drug were estimated fluorimetrically at intervals after administration by each route. Levels fell rapidly, particularly during the first hour after intravenous injection. Differences between those plasma levels resulting from oral administration and those following intraruminal injection indicated that direct passage into the abomasum was achieved by the former method. Simultaneous intravenous and intrauminal injections achieved immediate high plasma levels and maintained levels adequate for efficacy for 24 h.

Administration, Oral↗

Evaluation of alkylated derivatives of 99mTc-propylene amine oxime (99mTc-PnAO).

Several lipophilic di-alkylated derivatives of propylene amine oxime (PnAO were complexed to 99mTc. Assessment of the 99mTc-PnAO derivatives included biodistribution and qualitative autoradiography. All of the derivatives studied penetrated the intact blood-brain-barrier, with the 99mTc-dibutyl-PnAO complex exhibiting the lowest initial brain uptake while the 99mTc-diethyl-PnAO and the 99mTc-dipropyl-PnAO complexes possessing nearly identical initial brain uptake as compared to 99mTcPnAO. Qualitative autoradiographs revealed significant loss of image resolution with extended time post injection indicative of rapid radiopharmaceutical washout. Although increasing alkyl chain length did not enhance initial brain uptake, the data demonstrates that limited modification of the PnAO ligand structure can be performed without decreasing cerebral uptake of the respective 99mTc complex.

Animals↗

Individual molecular species of phosphatidylcholine and phosphatidylethanolamine in myelin turn over at different rates.

Phosphatidylcholine (PC) and phosphatidylethanolamine (PE) of the myelin membrane exhibit heterogeneity with respect to metabolic turnover rate (Miller, S. L., Benjamins, J. A., and Morell, P. (1977) J. Biol. Chem. 252, 4025-4037). To test the hypothesis that this is due to differential turnover of individual molecular species (which differ in acyl chain composition), we have examined the relative turnover of individual molecular species of myelin PC and PE. Phospholipids were labeled by injection of [2-3H]glycerol into the brains of young rats. Myelin was isolated at 1, 15, and 30 days post-injection, lipids were extracted, and phospholipid classes were separated by thin-layer chromatography. The PC and PE fractions were hydrolyzed with phospholipase C, and the resulting diacylglycerols were dinitrobenzoylated and fractionated by reverse-phase high performance liquid chromatography. The distribution of radioactivity among individual molecular species was determined. The labeled molecular species of myelin PC were 16:0-16:0, 16:0-18:0, 16:0-18:1, and 18:0-18:1, with most of the label present in 16:0-18:1 and 18:0-18:1. Changes in distribution of label with time after injection indicated that 16:0-18:1 turned over more rapidly than 18:0-18:1. The labeled molecular species of myelin PE were 18:0-20:4, 18:1-18:1, 16:0-18:1, 18:0-18:2, and 18:0-18:1. As with myelin PC, 16:0-18:1 (and 18:1-18:1) turned over more rapidly than 18:0-18:1. The relative turnover of individual molecular species of PC in the microsomal fraction from forebrain was also examined. The molecular species profile was different from myelin PC, but again, 16:0-18:1 turned over more rapidly than the other molecular species. Thus, within the same membrane, individual molecular species of a phospholipid class are metabolized at different rates. Comparison of our results with previous studies of turnover of molecular classes of phospholipids indicates that in addition to polar head group composition (Miller et al., 1977), fatty acid composition is very important in determining the metabolic fate of a phospholipid.

Animals↗

The effects of intraocular gases on rabbit blood-retinal barrier permeability.

The effects of intravitreal expansile gases, sulfur hexafluoride and octafluoropropane, as well as air and needle insertion alone were assessed by iris fluorescein angiography and blood-retinal barrier permeability determination. Iris angiography, at 3 days after injection, indicated no differences between experimental and paired control eyes. Vitreous fluorophotometry on day 1, day 4 and day 7 after gas or sham injection also showed no differences between paired control and experimental eyes regardless of which experimental condition was employed. The results indicate that these gases are non-toxic to the blood-retinal barrier over a 7 day time course.

Animals↗

Gastric antisecretory and antiulcer actions of interleukin-1. Evidence for the presence of an "immune-brain-gut" axis.

Increasing evidence suggests that interleukin-1 (IL-1), a cytokine mainly produced by activated monocytes/macrophages, has various biological actions in addition to its immunological activities. In the present study, we examined the effect of IL-1 on gastric secretion and gastric ulcer formation in rats. Gastric secretion was assessed in conscious pylorus-ligated rats weighing approximately 200 g. The peripheral injection of IL-1 resulted in a dose-related inhibition of gastric acid output. The central injection of IL-1 similarly reduced gastric acid secretion at 100 times smaller doses than peripherally injected IL-1, suggesting that this gastric antisecretory action of IL-1 is mediated by the central nervous system. In addition, it was found that this inhibitory effect of IL-1, either peripherally or centrally administered, was still evident at 8 h after injection, indicating the long-lasting property of this IL-1 action. On the basis of these antisecretory actions of IL-1, we determined whether or not pretreatment with IL-1 would prevent experimentally induced gastric ulcer formation. As expected, the central administration of IL-1 dose-dependently suppressed the development of gastric mucosal lesions induced by water-immersion restraint stress, a well-established ulcerogenic procedure. These results clearly demonstrated that IL-1 has potent antisecretory and antiulcer effects that are mediated by the central nervous system. Moreover, these findings suggest that there may exist an "immune-brain-gut" axis, which is involved in the regulation of gastric secretion and mucosal homeostasis, especially under certain pathophysiological conditions that activate the immune system to release various cytokines including IL-1.

Animals↗

In vivo pulmonary metabolism of bradykinin, angiotensin I and 5-hydroxtryptamine in the rat.

Involvement of the pulmonary vasculature of the rat in the in vivo metabolism of bradykinin, angiotensin I and 5-hydroxytryptamine was studied by monitoring the systemic blood pressure response of the test animal during intravenous or intraarterial administration of these substances. Observation of essentially the same blood pressure response regardless of the route of injection indicated that neither agiotensins I or II nor 5-hydroxytryptamine was metabolized by the pulmonary vasculature, while bradykinin was inactivated to the extent of 95+% on one passage through the lung. In the rat the major portion of bradykinin inactivation and angiotensin conversion apparently occur at different places in the vascular tree and therefore could not be carried out by the same enzyme. Differential inhibition by 2-mercaptoethanol and the bradykinin potentiating peptide, Pyr-Lys-Trp-Ala-Pro, support this postulate. One rat was found which had no pulmonary kininase but could convert angiotensin I to angiotensin II. In addition, infusion of large doses of known inhibitors of lung converting enzyme had no effect on either angiotensin I conversion or bradykinin inactivation in this system. These results support the idea that the pulmonary vasculature is not a major site for conversion of angiotensin I in the rat.

Angiotensin II↗

Myocardial capillary permeability for small hydrophilic indicators during normal physiological conditions and after ischemia and reperfusion.

Myocardial capillary permeability for small hydrophilic solutes (51Cr-EDTA or 99mTc-DTPA) has been measured using intracoronary indicator bolus injection and external radioactivity registration (the single injection, residue detection method). The method is based on kinetic separation of the injected indicator molecules in an extracted and a transmitted fraction of molecules. In open chest dog hearts measurements performed during normal physiological conditions gave mean capillary extraction values of 43.5-47.5% and the corresponding calculated PdS values were 47.1 - 57.5 ml.(100g.min)-1. From these PdS values Pd values between 1.57.10(-5) and 1.92.10(-5) cm.s-1 were calculated, in accordance with values obtained by other methods. Similar data have been obtained in myocardium of patients undergoing coronary angiography. Oxygen derived free radicals seems to participate in reperfusion injury including microvascular alterations. In open chest dogs transitory increases in capillary extraction fraction and PdS for small hydrophilic solutes were seen following 20 minutes of regional myocardial ischemia and reperfusion. This response could be inhibited by treatment directed against superoxide radicals.

Animals↗

[The treatment of different forms of B and delta hepatitis with interferon preparations].

A study was made of the therapeutic efficacy of human leukocytic interferon (HLI) and leikinferon in the treatment of HBV- and HDV-infection. 21 patients were placed under observation. Of these, 6 presented with lingering hepatitis B (HB), 8 with chronic HB, 1 was a HBsAg carrier, 4 had Grades I-IV, acute hepatic encephalopathy, and 2 acute hepatitis delta. 15 patients received leikinferon, 6 were given HLI for injections. Indications and schemes for the treatment with interferon preparations are provided as are the clinico-biochemical and serological criteria for estimating the efficacy of interferon therapy. In lingering and chronic forms of HB, leikinferon exerts a beneficial effect. It is not costly, thus enabling one to carry out continuous treatment in patients suffering from chronic forms. HLI may be recommended as an effective agent.

Adolescent↗

[Clinical experience of intramediastinal injection therapy via mediastinoscope for lung cancer].

As local treatments other than surgery, radiation therapy, bronchial artery infusion and intrabronchial injection of anti-cancer drugs have generally been administered to inoperative lung cancer cases. Together with these local therapies, we experienced six cases of intramediastinal injection. Indication of this therapy has been fundamentally limited to the inoperative cases in which patient performance status has deteriorated. Histologically, three cases were squamous cell carcinoma and three cases were adenocarcinoma. Injection therapy was effective in four cases where we noted alleviation of atelectasis and obstructive pneumonia brought on by the tumor, and a tendency of the tumor and swelling lymph nodes to be reduced. No side effects nor complications were evidenced. This therapy is characterized by a wider injection area in which intrabronchial injection is incapable of reaching the upper mediastinum, the bifurcation and the upper side of the hilus. The results suggest that this therapy should be used alone or together with other local therapies and prior to operation.

Adenocarcinoma↗

Cell dynamics in the adult mouse olfactory epithelium: a quantitative autoradiographic study.

The dynamics of cell genesis in the olfactory epithelium of the adult mouse were investigated using 3H-thymidine autoradiography. Mice were injected once with 3H-thymidine, and their olfactory epithelia were examined 7, 14, 30, 60, and 90 d later. The number of silver grains over each nucleus was counted, and the relative distance from the basement membrane was measured for each labeled nucleus. At 7 and 14 d, the average number of labeled cells in each section was about 20 per mm. By 30 d, and for the following 60 d, the average number of labeled cells was only about 6 per mm. Thus, most cells labeled by the injection died 2-4 weeks after injection. When the labeled cells were compared by nuclear grain density, time after injection (the "survival period"), and distance of the nucleus from the basement membrane (the "migration distance"), it was apparent that there was a small population of "nonmigrating" cells that remained close to the basement membrane. These cells, at first heavily labeled, divided a second time about 60 d after the 3H-thymidine injection, indicated by a significant decrease in nuclear grain density. This nonmigrating, slowly dividing basal cell is probably the neural stem cell, which gives rise to another stem cell and an olfactory neuron precursor by an asymmetric division. When the relative numbers of nonmigrating and migrating cells were compared, the results indicated that, after the asymmetric division, there are at least 2 or 3 rapid, symmetric divisions of the precursor cells, producing many immature receptor cells. Most of these die within 4 weeks of the 3H-thymidine injection.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

Clinical and toxicological profile of fluphenazine decanoate in elderly chronic schizophrenia.

Twenty elderly chronic schizophrenic inpatients of both sexes, age ranging from 60 to 73 years (mean age 63 +/- 0.81 years), diagnosed according to DSM III-R, were treated with fluphenazine decanoate, 12.5 mg intramuscularly, administered every 21 days for six months. Psychopathological features were assessed by means of the Brief Psychiatric Rating Scale at time 0 and then weekly. At 0, 6, 12, 24, 36, 48, 72h and 7, 14 and 21 days after each administration, extrapyramidal side-effects were evaluated using the Extrapyramidal Side-Effects Scale. Fluphenazine was significantly effective in treating symptoms such as emotional withdrawal, blunted affect, suspiciousness, thought disturbances, but not hallucinations. The most severe extrapyramidal side-effects occurred within the first two days of administration of fluphenazine, with a peak after 36 h, following the first four administrations of the drug, possibly related to early peak plasma concentrations. The severity of these effects was reduced after the fifth injection indicating the occurrence of tolerance mechanisms during long-term fluphenazine administration.

Aged↗

High concentrations of bacterial lipopolysaccharide, but not microbial infection-induced inflammation, activate macrophage C3 receptors for phagocytosis.

Macrophage C3 receptors are normally immobilized in the plane of the cells' plasma membrane and are unable to promote phagocytosis even though they promote avid particle binding. We have previously identified a lymphokine that activates macrophage C3 receptors for phagocytosis both in vitro and in vivo, and others have found that certain types of nonimmunologically mediated inflammation are also able to activate mononuclear phagocyte C3 receptors. These findings raised the possibility that macrophage C3 receptor activation is a universal consequence of inflammation. We sought in the present experiments to determine whether or not inflammation induced by microbial infection in a nonimmune host resulted in activation of macrophage C3 receptors. We injected mice i.p. with either viable microorganisms, microbe-containing immune complexes, or bacterial LPS. Macrophages were harvested by peritoneal lavage 4 days later; nearly all lavage fluids grew the microorganism with which the mouse had been injected, indicating that an infection had been established. Monolayers of macrophages were established and their interaction with sheep E coated with C3 (EIgMC) was determined. All macrophages bound EIgMC, but only macrophages from mice injected with either very high concentrations of LPS or microbe-containing immune complexes ingested them. C3 receptors of macrophages that ingested EIgMC were mobile; others were not. Thus, inflammation induced by microbial infection does not commonly, if at all, activate macrophage C3 receptors; microbe-containing immune complexes and high concentrations of LPS do. The mechanism of receptor activation in each case is C3 receptor mobilization, which is probably mediated by a lymphokine.

Animals↗

Resiniferatoxin: an ultrapotent selective modulator of capsaicin-sensitive primary afferent neurons.

Resiniferatoxin (RTX) has been shown to function as an ultrapotent analog of capsaicin. It is reported here that RTX, like capsaicin, acts selectively on primary sensory neurons in rats to produce ultrastructural alterations and calcitonin gene-related peptide depletion. To evaluate RTX actions on capsaicin-sensitive nociceptors of vagal origin in the lung, the activation and desensitization of the pulmonary chemoreflex in both rats and cats were examined. In rats, RTX (2 ng-5 micrograms/kg i.v.) failed to elicit the full reflex triad (apnea, systemic hypotension and bradycardia); RTX did, however, desensitize the pulmonary chemosensitive receptors to capsaicin and phenyldiguanide. This effect is not achievable upon acute capsaicin treatment. RTX pretreatment (300 micrograms/kg s.c.) of rats also abolished the neurogenic edema formation, another response mediated via capsaicin-sensitive vagal fibers, in rat trachea to challenge either by capsaicin or ether. The effect of electrical stimulation of vagal nerve was not impaired after RTX injection, indicating that RTX desensitized only the capsaicin-sensitive pathway whereas the parasympathetic pathway remained unaltered. In cats, unlike in the rat, the full pulmonary chemoreflex occurred in response to 0.1 micrograms/kg RTX. It is concluded that RTX is a selective probe for capsaicin-sensitive neural pathways but the spectrum of action of the two compounds is not identical. The failure of RTX to provoke the pulmonary chemoreflex in the rat, which is the main limiting factor in the use of capsaicin, suggests a further advantage to the use of RTX for probing capsaicin-sensitive neural pathways.

Animals↗

Effects of prenatal nicotine exposure on biochemical development of rat brain regions: maternal drug infusions via osmotic minipumps.

The effects of a continuous 16-day gestational exposure to nicotine on brain development were examined in the offspring of dams who received a minipump implant on the 4th day of gestation. Maternal viability was unaffected and weight gain was only reduced slightly, but nearly half the dams failed to give birth; dams delivering pups had normal litter sizes. Examination of fetal macromolecules on the 18th day of gestation revealed specific deficits in cell number (DNA) in developing brain tissue as opposed to the rest of the fetus, accompanied by parallel shortfalls in other macromolecules (RNA, protein). After birth, brain development in the nicotine-exposed animals showed persistent abnormalities in the timing of maturational events, with elevated levels of ornithine decarboxylase (an enzymatic marker related to cellular maturation) detectable in all brain regions. Subsequent effects on macromolecules were highly selective regionally, with clear distinctions between areas in which neuronal replication occurs relatively late (cerebellum) compared to early-developing regions (midbrain plus brainstem). Differences apparent between the effects of infused maternal nicotine and those noted previously in studies with nicotine injections indicate that the drug does exert primary effects on developing neural tissues, but that other factors associated with the injection route (such as hypoxia and ischemia consequent to acute effects of nicotine) can interact with the drug to influence brain cell maturation.

Animals↗

Acute pulmonary toxicity of bleomycin: DNA scission and matrix protein mRNA levels in bleomycin-sensitive and -resistant strains of mice.

The severity of bleomycin (BLM)-induced pulmonary fibrosis in mice varies markedly among several different murine strains. We have examined the DNA from lungs of sensitive (i.e., C57BL/6N) and resistant (i.e., BALB/c) strains of mice using a nucleoid sedimentation technique to detect early in vivo changes in the integrity of DNA after intravenous BLM. Mice received intravenous injections of BLM (80 mg/kg) or vehicle; lung nucleoids were prepared 15 min to 6 hr later. BLM produced striking decreases in nucleoid sedimentation distance versus paired controls in both strains within 15 min after injection, indicating extensive DNA scission. Repair of DNA strand breaks was complete in the resistant (BALB/c) mice by 5 hr; in contrast, only partial repair occurred in the sensitive (C57BL/6N) strain during that time. We then examined lungs for subsequent changes in steady state poly-(A)+ RNA levels and mRNA levels for lung matrix proteins (type I procollagen, type III procollagen, and fibronectin). Steady state levels of poly-(A)+ RNA were depressed to 50% of control 1 through 6 days after BLM injection in the lungs of sensitive mice. Resistant mice had pulmonary poly-(A)+ RNA levels similar to those of C57BL/6N mice, except for a 2-fold elevation 1 day after BLM injection. BLM injection affected the steady state levels of mRNA encoding lung matrix proteins differently than total poly-(A)+ RNA. Fibronectin mRNA/poly(A)+ RNA was elevated 2-fold 1 day after BLM treatment only in the sensitive strain and remained elevated at 3 and 6 days. In contrast, alpha 2I procollagen mRNA increased in both murine strains and alpha 1III procollagen mRNA decreased in both strains. Thus, a 7-fold or greater increase in the type I: type III procollagen mRNA ratio was seen in both strains 3 to 6 days after BLM injection. These data demonstrate that BLM treatment rapidly produces extensive pulmonary DNA damage in vivo, that persistence of DNA damage rather than the initial level of strand scission is associated with sensitivity to BLM lung disease in these mice, and that changes in the levels of mRNA encoding pulmonary matrix proteins occur in vivo within 1 to 3 days after intravenous BLM treatment.

Animals↗