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Distribution of CuZn superoxide dismutase and Mn superoxide dismutase in human tissues and extracellular fluids.

Among various human tissues liver had the highest content of both CuZn superoxide dismutase and Mn superoxide dismutase. There were comparatively small differences in CuZn superoxide dismutase among other organs. The Mn superoxide dismutase contents were roughly half as large as the CuZn superoxide dismutase contents. The total amount of CuZn superoxide dismutase in the body was estimated to be 3900 mg. The superoxide dismutase activities of serum and cerebrospinal fluid corresponded to between 0.2-0.3 mg CuZn superoxide dismutase per liter. CuZn superoxide dismutase was apparently the source of the superoxide dismutase activity in cerebrospinal fluid, whereas this enzyme only accounted for about 15% of the serum activity. The superoxide dismutase activities of ceruloplasmin, transferrin and ferritin were very low, 40 000, 350 000 and 330 000 times lower than that of human CuZn superoxide dismutase. These factors contributed very little to serum superoxide dismutase activity. The activity of lymph was more than twice that of serum. Sera from patients with severely impaired renal function or bilaterally nephrectomized had a very high superoxide dismutase activity.

Female↗

Analgesic response and plasma and brain extracellular fluid pharmacokinetics of morphine and morphine-6-beta-D-glucuronide in the rat.

The analgesic effects of subcutaneously administered morphine and morphine-6-beta-D-glucuronide (M6G) were determined in male Sprague-Dawley rats. Morphine produced a dose-dependent (2.5 to 10.0 mg/kg) analgesic response as measured by the tail-flick test. M6G in the same doses as morphine produced a greater degree of analgesia with longer duration of action. The concentrations of M6G and morphine were determined in plasma as the protein unbound form after the use of an equilibrium dialysis technique and in BECF after administration of the drugs (10.0 mg/kg s.c.). The concentrations of morphine and M6G in BECF were determined by using microdialysis. The concentration of M6G in plasma and BECF at each time interval after its administration was much higher than morphine. The maximal concentrations in plasma and AUC0-infinity values for M6G were, thus, significantly higher for M6G than for morphine in plasma and BECF. In BECF, the Tmax value for M6G was lower than for morphine, but the t1/2 beta values did not differ. In plasma, Tmax and T1/2 values for M6G and morphine did not differ, but volume of distribution and total clearance values for M6G were lower than for morphine. It is concluded that per milligram, M6G has a much higher analgesic potency than morphine in the rat and these differences may be related, in part, to the higher levels of M6G in comparison to morphine in plasma and BECF.

Analgesia↗

Idiopathic chorioretinal effusion: An analysis of extracellular fluids.

A case of nonrhegmatogenous retinal detachment with choroidal detachment was seen 3 weeks after onset and was evaluated clinically with emphasis on the fluid contents from one eye. The right eye showed slight subretinal fluid and minimal RPE pigmentary mottling. The left eye was severely involved with a near flat anterior chamber, a 360 degrees peripheral serous retinal detachment with shifting fluid and 360 degrees choroidal separations. Fluorescein showed mottled retinal pigment epithelium changes in each eye. Cell free samples of the subretinal fluid were high in protein (16.5 gm/100 ml) with a near absence of the alpha-2 fraction. Epichoroidal fluid from the choroidal detachments exhibited a protein content and makeup similar to that of normal plasma. The concentration of protein in the cerebrospinal fluid was elevated (0.096 gm/100 ml) without evidence of inflammatory changes. Ultrastructural examinations of sclera revealed a normal structure. There was no indication of the cause of the elevated protein content of the subretinal and spinal fluids. Following subretinal and epichoroidal fluid evacuation, the patient was treated with systemic steroids. The retinal and choroidal separations subsided slowly over several months, leaving multiple retinal pigment epithelial pigmentary clumps with drusen-like centers. A more appropriate name for this entity is idiopathic chorioretinal effusion.

Blood Proteins↗

Central nervous system magnesium deficiency.

The central nervous system concentration of magnesium (Mg++) appears to have a critical level below which neurologic dysfunction occurs. Observations presented suggest that the interchange of the Mg++ ion between the cerebrospinal fluid, extracellular fluid, and bone is more rapid and dynamic than is usually believed. This is especially so when the hypertrophied parathyroid gland is associated with significant skeletal depletion of Mg++ as judged by history rather than serum level. Magnesium, much like calcium, has a large presence in bone and has a negative feedback relationship with the parathyroid gland. A decline in central nervous system Mg++ may occur when the skeletal buffer system orchestrated largely by the parathyroid glands is activated by an increase in serum calcium. Observations in veterinary medicine and obstetrics suggest that the transfer of Mg++ from the extracellular fluid into bone during mineralization processes may be extensive. If the inhibition of the hypertrophied parathyroid gland is prolonged and the skeletal depletion of Mg++ extreme, serious neurologic symptoms, including seizures, coma, and death, may occur. Noise, excitement, and bodily contact appear to precipitate neurologic symptoms in Mg+(+)-deficient human subjects as it has been documented to occur in Mg+(+)-deficient experimental animals. The similarity of the acute central nervous system demyelinating syndromes with reactive central nervous system Mg++ deficiency is reviewed.

Adolescent↗

[Volume replacement solutions--pharmacology and clinical use].

PHYSIOLOGY AND PATHOPHYSIOLOGY: Total body water represents 60% of body weight (BW), consisting of 40% BW intra- and 20% BW extracellular fluid. Extracellular fluid is divided into 16% BW interstitial fluid and 4% BW plasma volume (Fig. 1). The colloid oncotic pressure (COP) of the plasma proteins, which is about 25 mmHg (Fig. 2), is the main factor for the retention of intravascular volume and the prevention of interstitial edema. Within a defined range, oxygen transport capacity can be improved by normovolaemic haemodilution. Under strictly normovolaemic conditions ("controlled haemodilution"), the critical haemoglobin concentration for intensive care patients is about 10.0 g/dl, and 8-6 g/dl in patients with satisfactory compensatory mechanisms under stable clinical conditions. Larger blood volume deficits are replaced step by step with volume replacement solutions (crystalloids and synthetic colloids), packed red cells, fresh-frozen plasma, and platelets (Fig. 3). VOLUME REPLACEMENT WITH CRYSTALLOID AND COLLOID SOLUTIONS: Crystalloid solutions do not contain any macromolecules. Due to their lack of intrinsic COP, they spread rapidly over the intravascular and interstitial space. To achieve a comparable volume effect like colloid solutions, a fourfold infusion volume is necessary. Thus, crystalloids should be used in addition to colloid solutions to compensate the interstitial fluid deficit. Hyperosmotic-hyperoncotic solutions have not yet been established, and their benefit seems doubtful. Synthetic colloid solutions contain gelatin, dextran, or hydroxyethyl starch (HES) molecules. Due to their intrinsic COP, fluid is fixated in the intravascular space (Fig. 4). Solutions with high COP increase the intravascular volume due to resorption of interstitial fluid (plasma expanders). Pharmacological characterisation of synthetic colloids includes concentration [%], mean molecular weight [x1,000 Dalton] and degree and position of substitution (HES only). Main clinical features are the maximal volume effect and the duration of a 100% and a 50% volume effect (Fig. 5). For economic reasons, 5% albumin should not be used for volume replacement. The use of 20% albumin in intensive care patients is also limited and recommended only if a capillary leck is unlikely and the dose limits of synthetic colloids are reached. Gelatin is a polypeptide of bovine origin and achieves a shortlasting isovolaemic volume effect. When compared with dextran or HES, negative effects on haemostatis are less, and the renal function is not impaired. Thus, gelatin is first of all indicated in patients with limited volume demand, and secondly in situations with massive blood losses, when the dose limits of HES are reached. Dextran has no specific benefits. HES is a polysaccharide of maize or potato origin. By substitution of glucose molecules with hydroxyethyl groups, starch molecules are protected against fast amylase degradation. Metabolism depends on the degree and position of substitution and mean molecular weight. Smaller molecules are eliminated via the kidneys, but a certain amount of larger molecules is stored in the reticulo-endothelial system. HES is available in very different preparations (concentration 3-10%, mean molecular weight 70,000-450,000 Dalton, substitution 50-70%). Special indications of 10% HES 200/0.5 are rapid hypervolaemic replacement of massive blood losses and increase of COP in intensive care patients without capillary leak. Synthetic colloids as well as albumin may lead to adverse reactions, which are generally very rare. In large-scala studies, no significant differences have been found with regard to incidence and severity.

Animals↗

[Reaction of the middle ear mucous membrane in tubal obstruction].

1. Tubal obstruction causes a rapid rise in transepithelial cytopempsis. The squamous epithelial cells show numerous vesicles carrying subepithelial fluid (extracellular fluid) to the middle ear cavity. 24 hours following tubal obstruction a widespread rupture of the epithelial junctions can be observed. Subepithelial fluid, consisting of lymphfluid, transsudate and later exsudate, enters the middle ear cavity without passing a cellular barrier. 2. Long lasting negative pressure provoces a cellular differentiation (metaplasia!) of the formerly squamous epithelium to a high, cylindric cell layer with new functions: ciliary movement and secretory activity. 3. Ablation of the tympanic membrane to expose the middle ear to air after 2-4 days, causes a stop in the epithelial differentiation but no regeneration to the normal histological flat formation. 4. Studies of samples of human middle ear mucosa in serous otitis or sero-mucous otitis show exactly the same results as during the different stages of our animal experiments.

Animals↗

Implantable devices for chronic access and drug delivery to the central nervous system.

This is a review of implantable devices for chronic access and drug delivery to the central nervous system (CNS) via the cerebrospinal fluid, extracellular fluid, and vascular pathways. The current applications of such devices in the management of mycotic meningitis, meningeal leukemia and carcinomatosis, solid malignant tumors of the CNS, intractable cancer-associated pain, unresectable cystic tumors and in cytologic, pharmacologic, and experimental studies on the cerebrospinal fluid (CSF) are assessed. Specific attention is paid to the applications of the most commonly used device, a subcutaneous reservoir and pump (SRP), including its major uses and complications. A new system for local chemotherapy of malignant gliomas, the tumor cyst device (TCD), is also described.

Animals↗

Growth of shigellae in monolayer tissue cultures.

Gerber, Dolores F. (University of California, Berkeley) and H. M. S. Watkins. Growth of shigellae in monolayer tissue cultures. J. Bacteriol. 82:815-822. 1961.-The influence of environment on virulence, antigenicity, and antibiotic susceptibility of infectious agents is well recognized. The development of tissue culture monolayer techniques has stimulated new interest in manifestations of these attributes at the cellular level. Shigella flexneri and S. sonnei were grown intracellularly in Henle epithelial cell monolayer tissue cultures; uptake of the bacteria was induced by 50% normal horse serum in the infection medium. Since preliminary experiments indicated that streptomycin in the extracellular fluid depressed intracellular multiplication of these organisms, the antibiotic was later omitted from the tissue culture growth fluid. Extracellular multiplication of shigellae was controlled by thorough washing of the infected monolayers and replacement with fresh medium at 2-hr intervals during incubation. Intracellular growth patterns of two S. flexneri and two S. sonnei strains were established. Differences in the capacity of strains to adapt to the intracellular environment was reflected in the number of organisms subsequently produced, and appeared to be associated with the degree of intracellular resistance to streptomycin. No such variation was seen in cultures grown in broth. Microscopic examination of stained monolayers showed that intracellular bacterial growth was confined to the cytoplasm, which became filled with organisms prior to cellular disintegration.Biological implications of the variable response of Shigella strains to the intracellular environment are discussed.

Anti-Bacterial Agents↗

Pleural fluid as nutrient substratum for Aspergillus fumigatus and A. flavus. Submerged growth in pleural fluid and extracellular proteolysis in pleural fluid agar. A preliminary report.

Pleural fluid in liquid and agar form from a patient with adenocarcinoma of the lung was used as a nutrient medium for culturing Aspergillus fumigatus and A, flavus. The extracellular proteolytic activity of both strains could be demonstrated after an incubation period of 5 d at 37 degrees C by the agar block method using pleural fluid agar (protein content ca. 0.1-0.5% and initial pH values of 7.0 and 5.0) and protein staining with naphthalene black. In the undiluted pleural fluid, after stationary culture at 37 degrees C for 8 days, compact white granule-like colonies of a size of ca. 0.5-1.0 mm were found near the surface of the liquid and as sediment. Microscopically, these colonies consisted of radially arranged septate hyphae, similar in size and form to those seen in invasive aspergillosis.

Adult↗

[Pathophysiologic role of the level of taste sensitivity to table salt and its determination during treatment of hypertension with diuretics].

Sixty hypertensive patients (stage IIB, no complications) were studied. Gustatory sensitivity threshold to salt was determined and body fluid volume, extracellular fluid volume, intracellular fluid volume, circulating plasma volume and interstitial fluid volume were measured in the control period and 2-3 weeks after treatment with diuretics. 27, 63 and 10% of patients had low, moderate and high gustatory sensitivity threshold, respectively. Patients with different gustatory sensitivity threshold to salt were identical in body fluid volume with peculiar extracellular fluid distribution between intravascular and interstitial spaces. In patients (72%) with a favourable hypotensive effect of diuretic therapy the reduction in gustatory threshold to salt was significant.

Adult↗

Secretion of D-aspartic acid by the rat testis and its role in endocrinology of the testis and spermatogenesis.

The D-isomer of aspartic acid (D-Asp) has been found in rat testes. In the present study, samples of testicular venous blood plasma, rete testis fluid, interstitial extracellular fluid, luminal fluid from the seminiferous tubules, testicular parenchymal cells, epididymal spermatozoa and peripheral blood plasma were collected and analyzed for D-Asp by two methods, an enzymatic and a chromatographic HPLC method. The two methods gave very similar results for all samples. The highest concentrations of D-Asp (about 120 nmol/ml) were found in testicular venous blood plasma, with slightly lower concentrations in rete testis fluid (95 nmol/ml) and epididymal spermatozoa (80 nmol/g wet weight). Lower levels were found in testicular parenchymal cells (which would comprise mostly spermatids and spermatocytes), luminal fluid from the seminiferous tubules and interstitial extracellular fluid (26, 23 and 11 nmol/ml respectively). However, these values were all higher than those for peripheral blood plasma (6 nmol/ml). It would appear that D-Asp is being secreted by the testis mostly into the venous blood, passing thence into the rete testis fluid and being incorporated into the spermatozoa at the time or after they leave the testis. The distribution of D-Asp is thus quite different from that of testosterone, and its role and the reason for its high concentration in the male reproductive tract remain to be elucidated.

Animals↗

Effectiveness of the aldosterone-sodium and -potassium feedback control system.

This study was conducted to determine the quantitative importance of the aldosterone feedback mechanism in controlling each one of three major factors that have often been associated with aldosterone, namely, extracellular fluid sodium concentration, extracellular fluid potassium concentration, and extracellular fluid volume. To do this, the ability of the body to control these three factors in the face of marked changes in daily sodium or potassium intake was studied under two conditions: 1) in the normal dog, and 2) in the dog in which the aldosterone feedback mechanism was prevented from functioning by removing the adrenal glands and then providing a continuous fixed level of supportive aldosterone and glucocorticoids during the low and high electrolyte intake periods. Under these conditions, removal of feedback control of aldosterone secretion decreased the effectiveness of plasma potassium control by nearly fivefold (39% vs. 8% change in plasma potassium concentration), fluid volume by sixfold (12% vs. 2% change in sodium space) and had no effect on control of plasma sodium concentration (2% change with and without feedback control of aldosterone secretion.)

Adrenalectomy↗

Distributional transport kinetics of zidovudine between plasma and brain extracellular fluid/cerebrospinal fluid in the rabbit: investigation of the inhibitory effect of probenecid utilizing microdialysis.

The effect of probenecid (PBD) on the distributional transport of zidovudine (AZT) between plasma, cerebrospinal fluid (CSF) and brain extracellular fluid (ECF) was investigated by using microdialysis. New Zealand White rabbits received AZT, in a crossover design, during control and treatment periods. PBD was coadministered at one of two rates. One additional study involved a repeated control to investigate the possible existence of a period effect. In the low- and high-dose treatment groups, PBD decreased the total body clearance of AZT by 47.7 +/- 8.9 and 51.7 +/- 9.7%, respectively. PBD also decreased the clearance of AZT from CSF and thalamus ECF, prolonging the half-lives of AZT disappearance from the brain. Additionally, PBD elevated the AZT area under the concentration-time curve in the ventricular CSF 3- to 5-fold and the area under the thalamic ECF concentration-time curve by 5- to 6-fold, whereas the area under the plasma concentration-time curve increased only 2-fold. During PBD treatment the ratio area under the thalamic ECF concentration-time curve/area under the ventricular CSF concentration-time curve approached unity. These results provide evidence that AZT is actively transported outwardly across the CSF- and brain ECF-blood barriers, and this transport system is sensitive to PBD. A pharmacokinetic model that considers the effect of PBD on the AZT clearance from brain to plasma suggests that 73% of this pathway is subject to competitive inhibition by PBD.

Animals↗