[Self-assessment of treatment urgency on presentation to a neurological emergency department : Results of a patient survey]. / Selbsteinschätzung der Behandlungsdringlichkeit bei Vorstellung in einer neurologischen Notfallambulanz : Ergebnisse einer Patientenbefragung.

BACKGROUND: The proportion of patients with neurological disorders as well as the absolute number of patients in German emergency departments is rising. OBJECTIVE: This article presents the results of a survey among patients with self-referral to a dedicated neurological emergency department (ED). We sought to find out if the individual evaluation of urgency for treatment was comparable for patients and physicians. METHODS: During a prospective trial to validate a new and specific neurological triage system over a time period of three months (October 2015 to January 2016), patients who presented themselves to the ED were handed a questionnaire and asked to provide information on the symptoms, including duration and the subjective urgency for evaluation by a physician (priority 1-4, 1 = emergency, 4 = elective). The results were descriptively evaluated and the subjective assessment of urgency was compared to the physicians' evaluation. RESULTS: From a total of 836 questionnaires, handed out to each patient with self-referral to the neurological ED, 528 (63%) were returned and analyzed. The most common symptoms were headaches, vertigo, paralysis and sensory deficits. In 24% of the patients the symptoms had lasted less than 24 h, while in 35% the symptoms had persisted for over 1 week. Over half of the patients (55%) indicated that the symptoms needed an emergency evaluation by a physician, while only 3% actually required immediate medical attention according to the retrospective assessment by physicians. This discrepancy was similar even after classification into symptoms and symptom duration. Only 2.6% of the patients stated that the reason for presenting to the ED was the inability to obtain an outpatient appointment. DISCUSSION: Patients regarded their symptoms as being a medical emergency much more often than physicians did. This was independent of the symptoms and their duration. An objective triage for patients in an ED is necessary.

Mesangial function in ureteral obstruction in the rat. Blockade of the efferent limb.

The kinetics for mesangial uptake and transport of radiolabeled aggregated human immunoglobulin (Ig)G (AHIgG(125)I) deviated markedly from normal in male Sprague-Dawley rats with ureteral obstruction. Four experimental groups, each containing 25 rats, were used: (a) bilateral ureteral ligation (BUL) with release of one ureter 24 h later; (b) unilateral ureteral ligation with release 24 h later [UUL(R)]; (c) unilateral ureteral ligation without release (unreleased) [UUL(U)]; (d) uremia-control, which consisted of rats with ligated left ureter and a severed right ureter. A similar number of sham-operated rats served as control for each group. AHIgG(125)I (45 mg/100 g body wt) was given intravenously 1 h after release of the ureteral obstruction (25 h after ureteral obstruction or sham surgery). Groups of five control and five experimental animals were sacrificed at 2, 4, 8, 16, and 24 h after injection. At all time intervals, concentrations of AHIgG(125)I in isolated glomeruli from control animals were similar to values obtained from nonobstructed kidneys of UUL(U) and UUL(R) rats: a linear decrease in concentration over a period of 24 h was observed when the logarithm of glomerular AHIgG(125)I concentration was plotted against time. Aberrations in the kinetics were apparent in obstructed kidneys but not in liver, spleen, or blood concentrations of AHIgG(125)I: (a) At 2 h in all obstructed kidneys, glomerular concentration of AHIgG(125)I was markedly reduced. (b) In BUL (released or unreleased), glomerular concentrations of AHIgG(125)I from 4 to 16 h were congruent with 10-fold those in UUL(U) or UUL(R) kidneys. (c) The significant decline in glomerular concentration between 4 and 16 h in control and nonobstructed kidneys was not observed in UUL(R), UUL(U), or BUL (released or unreleased) kidneys; in all obstructed kidneys, a plateau in glomerular concentrations of AHIgG(125)I was observed between 4 and 16 h. (d) After 16 h at a time when the blood level of AHIgG(125)I had decreased to 3% of initial values, there was progressive fall in glomerular AHIgG(125)I. Similar results were obtained in the uremia-control group in rats, which indicated that uremia per se had no measurable effect on mesangial kinetics. These studies demonstrate that ureteral occlusion induces alterations in mesangial uptake (afferent limb) and egress (efferent limb) of macromolecules. Particularly evident is the "blockade" of the efferent limb which is demonstrable at high blood levels of AHIgG(125)I. These alterations in the transit of macromolecules through the mesangium may be mediated in part by the hemodynamic changes that accompany ureteral obstruction.

Polymerized hemoglobin restores cardiovascular and kidney function in endotoxin-induced shock in the rat.

Sepsis and its complications, hypotension, shock, and multiorgan failure continue to represent a significant cause of mortality among hospitalized patients, affecting approximately 200,000 patients per year in the US and 100,000 in Europe (Dal Nogare, A.R. 1991. Am. J. Med. Sci. 302:50-65.). Incidence rates appear to be increasing, probably due to an increase in the population with risk factors such as diabetes or invasive procedures. Activation of cytokines by endotoxins and subsequent formation of nitric oxide is of central pathogeneic importance in sepsis. In this study we show that polymerized bovine hemoglobin (Biopure 2) restores both cardiovascular and renal functions in an endotoxin-induced shock model in rats. These effects are compared to those of the nitric oxide synthase inhibitor N(G)-nitro-L-arginine, and hydroxyethyl starch, the latter currently in clinical use for intravenous volume replacement. Our results clearly indicate that polymerized hemoglobin but not nitric oxide synthase inhibition or volume replacement normalize cardiovascular and kidney function in acute septic shock. This new therapeutic approach is readily applicable to controlled clinical trials because polymerized hemoglobin has been tested in humans and is therefore available for such studies.

Adenosine metabolism and its effect on methylation potential in cultured cells: methodological considerations.

Cell culture models are frequently used to study the role of adenosine in several physiological and pathological processes. In the present study, we have shown that adenosine deaminase activity in medium supplemented with calf serum significantly reduces adenosine concentration in culture medium. In the presence of HepG2 cells, the adenosine concentration in culture medium is decreased much faster, because a large amount of exogenous adenosine is metabolized by cellular enzyme. In order to measure intracellular adenosine, inosine, adenine nucleotides, S-adenosylhomocysteine (AdoHcy) and Sadenosylmethionine (AdoMet) contents, two methods for cell harvesting were compared. First, cells were removed with trypsin/EDTA, second, cells were lysed in cell culture dishes immediately after removing culture medium. Our results show that exact determination of adenosine metabolites requires immediate inactivation of metabolism by cell lysis in culture dishes. Application of adenosine (1mM) resulted in a time-dependent increase in intracellular adenosine, inosine, AMP, ATP, AdoHcy and AdoMet concentration. Since AdoHcy levels increased to a larger extent than AdoMet, the methylation potential, expressed as the ratio of AdoMet/AdoHcy, was reduced from 51.8 (control) to 2.9 (adenosine 1 mM, 2 hrs), suggesting that AdoMet-dependent methylation reactions might be impaired. In conclusion our data demonstrate that extracellular adenosine concentration and intracellular metabolite concentration strongly depend on the methods used to culture and harvest the cells.

Effect of endothelin-1 on erythropoietin production in a rat model under normoxia and functional carbon monoxide-induced hypoxia.

It has been hypothesized that autacoids, such as endothelin-1 (ET), may modulate erythropoietin (Epo) secretion. Therefore, we studied the effect of ET-1 infusion and of a nonselective ET(A/B) receptor antagonist on Epo secretion under carbon monoxide (CO) exposure. Anesthetized rats were supplied with room temperature air containing increasing concentrations of CO by an aerating cap. A CO-Epo dose-response curve over the range of 0.02-0.14 vol% CO was conducted. Subpressor doses of ET-1 (3 pmol/min/kg BW) and the ET(A/B) receptor antagonist LU302872 (LU; 30 mg/kg) were applied to anaesthetized rats under normoxia (controls CON, ET, LU) and following hypoxia (CO exposure; H-CON, H-ET, H-LU). Mean arterial blood pressure (MAP), glomerular filtration rate (GFR, inulin clearance), Epo and ET-1 serum concentrations (ELISA) and renal Epo mRNA (Light Cycler) were determined. The EC50 value for CO was 0.1 vol% with a 70-fold increase in Epo serum concentrations. CO exposure increased Epo serum and Epo mRNA concentrations in the expected range in all groups. None of the treatments with ET or LU influenced the effect of hypoxia on Epo serum concentrations and renal Epo mRNA content. Under hypoxia, administration of ET-1 as well as LU prevented the hypoxia-induced decrease in MAP (p<0.05). Under hypoxia, GFR was reduced by 50% except for H-LU with values comparable to normoxia. Taken together, the influence of hypoxia exceeds by far the effect of ET-1 on Epo production, irrespective of the presence or absence of exogenous ET-1. Thus, ET-1 does not appear to be a major modulator of Epo production.

Localization of S-adenosylhomocysteine hydrolase in the rat kidney.

S-adenosylhomocysteine (SAH) hydrolase is a cytosolic enzyme present in the kidney. Enzyme activities of SAH hydrolase were measured in the kidney in isolated glomeruli and tubules. SAH hydrolase activity was 0.62 +/- 0.02 mU/mg in the kidney, 0.32 +/- 0.03 mU/mg in the glomeruli, and 0.50 +/- 0.02 mU/mg in isolated tubules. Using immunohistochemical methods, we describe the localization of the enzyme SAH hydrolase in rat kidney with a highly specific antibody raised in rabbits against purified SAH hydrolase from bovine kidney. This antibody crossreacts to almost the same extent with the SAH hydrolase from different species such as rat, pig, and human. Using light microscopy, SAH hydrolase was visualized by the biotin-streptavidin-alkaline phosphatase immunohistochemical procedure. SAH hydrolase immunostaining was observed in glomeruli and in the epithelium of the proximal and distal tubules. The collecting ducts of the cortex and medulla were homogeneously stained. By using double immunofluorescence staining and two-channel immunofluorescence confocal laser scanning microscopy, we differentiated the glomerular cells (endothelium, mesangium, podocytes) and found intensive staining of podocytes. Our results show that the enzyme SAH hydrolase is found ubiquitously in the rat kidney. The prominent staining of SAH hydrolase in the podocytes may reflect high rates of transmethylation. (J Histochem Cytochem 48:211-218, 2000)

Neuromodulatory effects of the renin-angiotensin system on the cat electroretinogram.

PURPOSE: Angiotensin-converting-enzyme (ACE) catalyses the formation of angiotensin II (ANGII), which presumably acts as a central neurotransmitter/modulator. ANGII-related effects have also been observed in the retina. Present in vivo experiments were designed to investigate further ANGII-related effects on retinal neuromodulation. METHODS: In 12 anesthetized cats, electroretinographic measurements were carried out in the dark-adapted state using corneal contact lens electrodes and a Ganzfeld stimulator. Quinapril was used to inhibit ACE. RESULTS: Reducing ANGII-concentration increased sensitivity (0.5 log units) and gain (50%) of the rod b-wave amplitude. The b-wave implicit time was stimulus dependent, shortening at high intensities. The scotopic threshold response and the oscillatory potentials were also influenced by ACE inhibition. However, a-wave and 30 Hz flicker remained unaffected. Effects of Quinapril on ERG-amplitudes were reversed by subsequent ANGII administration, except for the implicit time of the b-wave and scotopic threshold response. CONCLUSIONS: Although these results are accompanied by alterations in systemic blood pressure, several findings support the evidence that the renin-angiotensin system might have a neurophysiologic effect on retinal neurons outside the vascular system. These results are in accordance with immunohistochemical data found by others that point to angiotensinergic cell involvement and thereby further support the concept of angiotensinergic processes in the inner retina from a functional point of view.

Stereospecific inhibition of 5-HT-induced increase of intracellular free calcium by (+)- and (-)-desmethoxyverapamil in human platelets.

The concentration of intracellular free calcium [Ca2+]i in human platelets was measured by the quin-2 method. 5-Hydroxytryptamine (5-HT) at 10(-5) M induced a rapid transient increase of [Ca2+]i which was antagonized by 10(-7) M ketanserin or cyproheptadine. The verapamil derivative, desmethoxyverapamil (D888), showed stereospecific inhibition of the 5-HT-induced [Ca2+]i increase. The IC50 for (-)-D888 was approx. 2 X 10(-8) M; (+)-D888 was almost 50 times less potent.

Inhibition of noradrenaline release by omega-conotoxin GVIA in the rat tail artery.

1. The perivascular nerves of isolated tail arteries from Wistar rats were stimulated with field pulses (1 Hz, 2 pulses, every 2 min). omega-Conotoxin 10 nmol l-1 depressed neurogenically mediated contractions, but did not influence the contractions to noradrenaline 0.1-0.3 mumol l-1. 2. The inhibitory effect of omega-conotoxin was concentration-dependent (IC50 = 3.8 nmol l-1). It did not reach a steady-state during 30 min incubation and could not be reversed upon subsequent washout for another 60 min. 3. A gradual increase in the Ca2+ concentration of the medium from 1.25 mmol l-1 to 10 mmol l-1 enhanced vasoconstriction and attenuated the action of omega-conotoxin 10 nmol l-1. When a low stimulation intensity (120 mA) was used at high external Ca2+ (10 mmol l-1), similar contractile responses were obtained as under normal conditions (200 mA current, 2.5 mmol l-1 Ca2+). However, the inverse relationship between the effect of the toxin and external Ca2+ remained unchanged. 4. The time-course and degree of the inhibition by omega-conotoxin 3 nmol l-1 was identical in tail arteries of spontaneously hypertensive rats (SHR) and their normotensive controls (WKY). 5. When tail arteries of Wistar rats were preincubated with [3H]-noradrenaline, field stimulation (0.4 Hz, 24 pulses, every 16 min) evoked tritium overflow and vasoconstriction. omega-Conotoxin 30 nmol l-1 inhibited both responses to a similar extent. 6. Our results suggest that omega-conotoxin selectively blocks Ca2+ channels in the terminals of perivascular nerves and thereby reduces the release, but not the contractile effect of the sympathetic transmitter.

Eukaliuric diuresis and natriuresis in response to the KATP channel blocker U37883A: micropuncture studies on the tubular site of action.

1. Systemic application of U37883A, a blocker of ATP sensitive potassium (KATP) channels, elicits diuresis and natriuresis without significantly altering urinary potassium excretion. 2. To elucidate tubular sites of action upstream to the distal nephron, micropuncture experiments were performed in nephrons with superficial glomeruli of anaesthetized Munich-Wistar-Frömter rats during systemic application of U37883A (1, 5 or 15 mg kg-1 i.v.). 3. The observed eukaliuric diuresis and natriuresis in response to U37883A at 15 mg kg-1 was accompanied by an increase in early distal tubular flow rate (VED) from 10 - 18 nl min(-1) reflecting a reduction in fractional reabsorption of fluid up to this site (FR-fluid) of 13%. The latter proposed an effect on water-permeable segments such as the proximal tubule which could fully account for the observed reduction in fractional reabsorption of Na+ up to the early distal tubule (FR-Na+) of 8% and the increase in early distal tubular Na+ concentration ([Na+]ED) from 35 - 51 mM whereas [K+]ED was left unaltered. 4. In comparison, furosemide (3 mg kg-1 i.v.), which acts in the water-impermeable thick ascending limb, elicited diuresis, natriuresis and kaliuresis which were associated with a fall in FR-Na+ of 10% with no change in FR-fluid, and a rise in [Na+]ED from 42 - 117 mM and [K+]ED from 1.2 - 5.7 mM with no change in VED. 5. Direct late proximal tubular fluid collections confirmed a significant inhibition of fluid reabsorption in proximal convoluted tubule in response to systemic application of U37883A. 6. These findings suggest that the diuretic and natriuretic effect upstream to the distal tubule in response to systemic application of U37883A involves actions on water-permeable segments such as the proximal convoluted tubule.

Sodium reabsorption in thick ascending limb of Henle's loop: effect of potassium channel blockade in vivo.

1. Based on previous in vitro studies, inhibition of K(+) recycling in thick ascending limb (TAL) is expected to lower Na(+) reabsorption through (i) reducing the luminal availability of K(+) to reload the Na(+)-2Cl(-)-K(+) cotransporter and (ii) diminishing the lumen positive transepithelial potential difference which drives paracellular cation transport. 2. This issue was investigated in anaesthetized rats employing microperfusion of Henle's loop downstream from late proximal tubular site with K(+)-free artificial tubular fluid in nephrons with superficial glomeruli. 3. The unselective K(+) channel blocker Cs(+) (5 - 40 mM) dose-dependently increased early distal tubular delivery of fluid and Na(+) with a maximum increase of approximately 20 and 185%, respectively, indicating predominant effects on water-impermeable TAL. 4. The modest inhibition of Na(+) reabsorption in response to the 15 mM of Cs(+) but not the enhanced inhibition by 20 mM Cs(+) was prevented by luminal K(+) supplementation. Furthermore, pretreatment with 20 mM Cs(+) did not attenuate the inhibitory effect of furosemide (100 microM) on Na(+)-2Cl(-)-K(+) cotransport. 5. Neither inhibitors of large (charybdotoxin 1 microM) nor low (glibenclamide 250 microM; U37883A 100 microM) conductance K(+) channels altered loop of Henle fluid or Na(+) reabsorption. 6. The intermediate conductance K(+) channel blockers verapamil and quinine (100 microM) modestly increased early distal tubular Na(+) but not fluid delivery, indicating a role for this K(+) channel in Na(+) reabsorption in TAL. As observed for equieffective concentrations of Cs(+) (15 mM), Na(+) reabsorption was preserved by K(+) supplementation. 7. The results indicate that modest inhibition of K(+) channels lowers the luminal availability of K(+) and thus transcellular Na(+) reabsorption in TAL. More complete inhibition lowers paracellular Na(+) transport probably by reducing or even abolishing the lumen positive transepithelial potential difference. Under the latter conditions, transcellular Na(+) transport may be restored by paracellular K(+) backleak.

The curative action of hexamethylmelamine on intramuscularly or intracerebrally implanted Yoshida sarcoma.

Curative effects of hexamethylmelamine (HMM, NSC 13875) against intramuscularly or intracerebrally implanted Yoshida sarcoma depend on the schedules. A twice daily oral administration over a 2-week period showed a significant chemotherapeutic advantage over a single daily administration. The observed curative effect depends on the tumour site and on its mass. The Yoshida sarcoma seems to be one of the most suitable test models for HMM or related derivatives.

Suramin enhancement of the chemotherapeutic actions of cyclophosphamide or adriamycin of intramuscularly-implanted Ehrlich carcinoma.

The chemotherapeutic action of cyclophosphamide or adriamycin monotherapy on hyperdiploid Ehrlich carcinoma was compared with that of sequential combinations of suramin and cyclophosphamide and suramin and adriamycin. The chemotherapeutic action of the suramin-cyclophosphamide combination or of the adriamycin-surmin combination was significantly enhanced when the combination partners were applied at definite intervals.

Potentiation of the chemotherapeutic action of bleomycin by combination with inosine on HRS-sarcoma.

The chemotherapeutic action of Bleomycin, applied at a dosage which induced only a non-specific tumor inhibition on HRS-sarcoma, was potentiated by combination with inosine. This combination, without increasing toxicity, effected both a significant tumor inhibition and a significant curative action.

Timing- and sequence-dependent synergism between etoposide and methotrexate or etoposide, methotrexate and 5-fluorouracil in advanced leukemia L1210.

The optimal synergism in combination therapy of leukemia L1210 depends on the sequence and the timing of the agents used. Etoposide (20 mg/kg applied intravenously) 3 h before methotrexate (50 mg/kg administered subcutaneously) results in significantly improved therapeutic action. Simultaneous application of these drugs, or an exceeding of that interval, do not entail synergism. Similar to the results obtained with other transplantable murine tumors, the optimal interval between methotrexate and 5-fluorouracil treatments of leukemia L1210 amounts to 6 h. Sequential treatment with etoposide (20 mg/kg given intravenously) significantly improves the efficacy of combined methotrexate (50 mg/kg applied subcutaneously) and 5-fluorouracil (80 mg/kg administered subcutaneously). The optimal synergism combining etoposide, methotrexate and 5-fluorouracil is achieved when the interval between etoposide and methotrexate amounts to 3 h followed 6 h later by 5-fluorouracil.

Activity of various amphiphilic agents in reversing multidrug resistance of L 1210 cells.

Several compounds (bamipine, chlorphenoxamine, estracyt, hycanthone, quinidine, quinine, tamoxifen, trifluoperazine and verapamil) have a common basic structure with the following features: lipophilic aromatic ring system; linked chain hydrophilic N-alkyl group. They are used medically for varying diseases. Their activity in reversing multidrug-resistance (MDR) with other compounds (diethylstilbestrol, beta-estradiol, methylbiguanide, methylpiperazine, testosterone) lacking one of these chemical features is compared. The in vitro test system we used was the nucleoside incorporation assay using parental L 1210 ascites tumor cells and a doxorubicin resistant subline, which expresses the MDR phenotype. The substances lacking one of these features were not effective in reversing the MDR whereas all other tested substances demonstrated modulating potential in the MDR resistant L 1210 cells.

Decreased HER-2 tyrosine kinase expression in rectal mucosa of FAP patients following low-dose sulindac chemoprevention.

As a part of the mechanisms of action in reversing FAP adenomas by the low-dose sulindac maintenance therapy (2 x 25 mg/patient per day), the extent of HER-2 proto-oncogene expression in the rectal mucosa seems to be of interest. Immunocytochemical analyses were performed in plasma and in rectal tissue of sulindac-treated FAP patients during an 18 months follow-up and compared with rectal tissue of patients with FAP, Crohn's disease, or rectal cancer or with healthy volunteers. HER-2 was significantly reduced and maintained in tissue under sulindac chemoprevention below base line levels of healthy individuals, but not in plasma. Therefore, a direct or indirect effect of sulindac as a tyrosine kinase inhibitor may be implicated. During NSAID treatment HER-2 protein expression as a prognostic tool seems to be of little clinical relevance.

Effects of ions on adenosine binding and enzyme activity of purified S-adenosylhomocysteine hydrolase from bovine kidney.

The present investigation was undertaken to determine the effect of various ions on the characteristics of S-adenosylhomocysteine (SAH) hydrolase from bovine kidney. The binding sites of [3H]-adenosine to purified SAH hydrolase were not influenced by phosphate, magnesium, potassium, sodium, chloride or calcium ions at physiological cytosolic concentrations. To test whether NAD+ in the SAH hydrolase is essential for adenosine binding, we prepared the apoenzyme by removing NAD+ with ammonium sulfate. The resulting apoenzyme did not exhibit any [3H]-adenosine binding. Since the apoenzyme was enzymatically inactive, it is suggested that adenosine binds to the active site and not to an allosteric site of the intact enzyme. The kinetics of the hydrolysis and the synthesis of SAH catalyzed by the enzyme SAH hydrolase were measured in the presence and absence of phosphate and magnesium. Phosphate increased the Vmax for both synthesis and hydrolysis. However, only the affinity of adenosine for SAH synthesis was significantly enhanced from 10.1+/-1.3 microM to 5.4+/-0.5 microM by phosphate. This effect was already maximal at a phosphate concentration of 1 mM. All other tested ions were without effect on the enzyme activity. Our results show that phosphate at physiological concentrations shifts the thermodynamic equilibrium of SAH hydrolase in the direction of SAH synthesis. These findings imply that SAH-sensitive transmethylation reactions are inhibited during renal hypoxia when intracellular levels of phosphate, adenosine, and SAH are elevated.

Overadditive chemotherapeutic synergism of prospidine and inosine when given sequentially to the Sarcoma 180 implanted intramuscularly.

The chemotherapeutic effectiveness of prospidine monotherapy on the Sarcoma 180 implanted i.m. was compared with several prospidine/inosine combinations. The chemotherapeutic action of the combination was enhanced overadditively when inosine was given 6 h after prospidine. This particular combination caused not only a significant curative action and tumor inhibition as compared with prospidine monotherapy, but also decreased the toxic effects.

Overadditive synergism between the intercalators mitoxantrone and lucanthone in advanced L 12010 and P 388 leukemia.

The combination of mitoxantrone with lucanthone, a schistosomicidal and nonmyelotoxic agent, yielded a therapeutic synergism in L 1210 and P 388 leukemia with no increase in toxicity. In that combination the nonmyelotoxic lucanthone enabled the use of the optimal dose of mitoxantrone. The recent hypothesis that planar polycyclic aromatic compounds, mostly comprised by the term intercalators, intercalate with DNA or bind to DNA may need receiving with respect to membrane target sites.