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Australia↗
Biomedical subjects
M Schramm
Publications and source records attributed to M Schramm.
Radiographic evaluation of the upper cervical spine in rheumatoid arthritis: a retrospective analysis.
We analysed retrospectively 295 lateral roentgenograms of the cervical spine in 150 patients with classic or definite rheumatoid arthritis. In addition to measuring the atlantodental interval, measurements of the different vertical parameters described by McGregor, Ranawat and Redlund-Johnell and a new measurement method with high reproducibility were described and their results compared statistically. As a control group we analysed 100 lateral roentgenograms of the cervical spine in patients with no inflammatory disease, posttraumatic lesion, tumour or osseous deformity.
Adult↗
Resuscitation of brain neurons in the presence of Ca2+ after toxic NMDA-receptor activity.
Cultured cerebellar granule cells were subjected to toxic activation of the NMDA receptor that was terminated by MK-801. Subsequent resuscitation experiments were mostly conducted in the presence of a physiological concentration of Ca2+. Addition of pyruvate and inorganic phosphate, in addition to glucose, which was always present, rescued approximately 40% of the dying neurons. La3+ and ruthenium red were also effective resuscitating agents. The combination of pyruvate, inorganic phosphate, and ruthenium red rescued 65% of the dying neurons. Parallel studies with 45Ca indicated that La3+ and ruthenium red facilitated the decrease of 45Ca in the neurons, whereas inorganic phosphate, supported by energy-yielding pyruvate, formed perhaps, a less harmful Ca complex inside the neurons.
Animals↗
[DACS--a cost-advantageous nuclear medical document archiving and communication system].
A simple and inexpensive solution for the complete digital management of a nuclear medical institution is presented. The starting point was provided by five different gamma cameras, one of which was equipped with a PC-based ICON computer. The remaining cameras were first adapted to ICONs and subsequently integrated into a Macintosh LAN, of 15 computers, allowing the entire image acquisition, processing, interpretation, documentation and archiving to be performed on the same comfortable menu-guided surface. Complete patient management is accomplished by a specific commercially available data base to which a specially developed image and document archive was connected. The system described provides complete digital management without the conventional filing systems at the moderate price of approximately DM 11 x 10(4) plus the cost of the new camera computers.
Computer Graphics↗
The energy expenditure of actomyosin-ATPase, Ca(2+)-ATPase and Na+,K(+)-ATPase in guinea-pig cardiac ventricular muscle.
1. The rate of heat production (heat rate) and isometric twitch tension of ventricular trabeculae isolated from guinea-pig heart were measured at 37 degrees C in order to determine the relative contributions of actomyosin-ATPase, Ca(2+)-ATPase and Na+,K(+)-ATPase to myocardial energy metabolism. 2. The increase in heat rate recorded during isometric contractions at optimal length (contraction-related heat production) was 19.1 +/- 1.2 mW cm-3 at a stimulation rate of 2 Hz. The tension-time integral of individual contractions measured under the same conditions was 147 +/- 15 mM s cm-2. 3. The heat production of the actomyosin-ATPase was determined by inhibiting the contractile proteins with 2,3-butanedione monoxime (BDM). Contraction-related heat production was reduced by 0.219 +/- 0.010 and the isometric tension-time integral was reduced by 0.288 +/- 0.016 in the presence of 1 mM BDM. From these data an estimate of 0.76 for the relative contribution of the actomyosin-ATPase to contraction-related heat production was derived. 4. The heat production related to actomyosin-ATPase plus Ca(2+)-ATPase was studied by blocking Ca2+ influx into the myocardial cells with a solution containing 100 microM Ca2+ and 400 microM Ni2+. In this solution contraction-related heat production was reduced by 0.907 +/- 0.012. Comparison of this value with the component attributable to the actomyosin-ATPase yields an estimate of 0.15 for the relative contribution of the Ca(2+)-ATPase to contraction related heat production. 5. The heat production related to the Na+,K(+)-ATPase in resting preparations was studied by blocking the sodium pump with 400 microM dihydro-ouabain (DHO). DHO produced a transient decrease in heat rate lasting 1-2 min, which was followed by a secondary increase. From the heat transient produced by DHO the heat rate related to the Na+,K(+)-ATPase in the steady state was extrapolated. The relative contribution of the sodium pump to resting heat production was estimated to be 0.17. 6. The heat production related to the Na+,K(+)-ATPase in contracting preparations was studied by first blocking Ca2+ influx with 100 microM Ca2+ and 400 microM Ni2+, and then inhibiting the sodium pump with 400 microM dihydro-ouabain (DHO). The relative contribution of the sodium pump to contraction-related heat production extrapolated from these data was 0.10, which agreed well with the fraction of contraction-related heat production persisting after blockage of actomyosin-ATPase and Ca(2+)-ATPase (0.09).(ABSTRACT TRUNCATED AT 400 WORDS)
Adenosine Triphosphate↗
The quantity of calcium that appears to induce neuronal death.
Excessive entry of Ca2+ through the NMDA receptor is thought to be the major cause of glutamate toxicity in brain neurons. However, actual quantitation of the calcium overload has not been achieved. Here we show that the absolute amount of 45Ca2+ taken up via the NMDA receptor correlates quantitatively with the amount of acute cell death in cultured cerebellar granule cells of the rat. Analysis of 9- and 16-day cultures reveals that the NMDA-induced Ca2+ uptake is about the same at these ages, whereas the Ca-dependent lethal process is more developed in the older neurons. The calculated lethal concentration of 45Ca taken up exceeds by approximately 10,000 times the maximal concentration of [Ca2+]i that can be measured by fluorescence imaging. It is suggested that the Ca2+ taken up induces the lethal process in a subcellular structure in which it has been segregated.
Animals↗
Down-regulation of NMDA receptor activity by NMDA.
Rat cerebellar granule cells were cultured in a medium containing 25 mM KCl. The presence of NMDA during culture caused strong down-regulation of 45Ca uptake through the NMDA receptor channel. The process affected neither the viability nor the protein content of the cells. The developmental program of NMDA receptor activity was resumed after removal of NMDA from the culture medium, dependent apparently on protein synthesis. The down-regulation also rendered the neurons resistant to NMDA toxicity. It permitted replenishment of the culture with fresh medium, which is extremely toxic for cells cultured in absence of NMDA. Such down-regulation might perhaps play a role in adjusting the activity of post synaptic NMDA receptors, following synaptogenesis.
Animals↗
Iodine-123 labelling of atrial natriuretic peptide and its analogues: initial results.
Receptors for atrial natriuretic peptide (ANP) are known to be present in many organs, e.g. brain, liver and kidney. The aim of this study was to optimize the labelling method for ANP analogues with iodine-123 and to describe their pharmakokinetics. ANP 99-126, atriopeptin III, Tyr-atriopeptin II and urodilatin were labelled by the Iodogen method. Of the various labelling conditions tested, the Iodogen procedure with 10 micrograms Iodogen, 10 micrograms peptides in 100 microliters phosphate buffer (pH 7.2) and a reaction time of 60 min proved to be optimal. Separation was performed using a Sep-pak reversed-phase extraction cartridge. In all cases quality control by thin-layer chromatography resulted in a radiochemical purity higher than 98%. After intravenous administration of 15 MBq/kg kinetic profiles of various organs in rabbits were investigated by whole-body scintigraphy with a gamma camera. Organ kinetics showed accumulation and excretion via the kidney. No bowel accumulation was observed. Interestingly, increasing tracer uptake in the head region was registered with three of the four tested tracers. Liver accumulation decreased rapidly during the first 40 min. No tracer degradation was registered over the whole time period, as shown by the low thyroid accumulation with a maximum of only 1%. Thus, labelling of ANF and its analogues is possible. These compounds seem to be of interest for further experiments and perhaps clinical studies because of their potential for brain receptor imaging.
Animals↗
Monitoring of Ca(2+)-transients in electrically stimulated A7r5 vascular smooth muscle cells fills the experimental gap between KCL-induced depolarization and patch-clamp studies.
The effects of electrical field stimulation on [Ca2+]i in the A7r5 vascular smooth muscle cell line have been monitored with the Ca(2+)-sensitive dye fura-2. The experimental set-up allowed high-temporal resolution of the [Ca2+]i-measurements and fast application of test solutions. Electrical field stimulation of A7r5 cells in the confluent growth state resulted in a transient increase in [Ca2+]i from resting values below 100 nM to values in the range of some hundred nM. For a given cell, the electrically induced Ca(2+)-transients were highly reproducible. The requirement for the presence of extracellular Ca2+ and the sensitivity to the Ca(2+)-antagonist nifedipine and the Ca(2+)-agonist BAY K 8644 suggest that the Ca(/+)-transients reflect [Ca2+]i-changes based on Ca(2+)-influx through voltage-dependent L-type Ca(2+)-channels. Therefore, electrical field stimulation of confluent A7r5 cells provides an easy-to-establish and highly reproducible method for the investigation of the physiology and pharmacology of voltage-dependent Ca(2+)-channels in intact vascular smooth muscle cells, which fills the gap between KCl-induced depolarization and the patch-clamp technique.
Animals↗
Potentiation of 45Ca uptake and acute toxicity mediated by the N-methyl-D-aspartate receptor: the effect of metal binding agents and transition metal ions.
The activities mediated by the N-methyl-D-aspartate (NMDA) receptor were studied in cultured rat cerebellar granule cells. Micromolar concentrations of the metal binding compounds, EDTA, cysteine, and histidine, as well as serum albumin strongly potentiated receptor activity in the presence of millimolar concentrations of Ca2+ and Mg2+. The findings indicated that these agents remove an endogenous metal, probably Zn2+, which attenuates NMDA receptor-mediated 45Ca uptake and toxicity. Several added metal ions were therefore tested at low micromolar concentrations. Zn2+ was found to be the most potent inhibitor of NMDA-induced 45Ca uptake, followed by Cu2+ and Fe2+.Co2+, Cd2+, Fe3+, and Al3+ had no significant effect, whereas Ni2+ potentiated the 45Ca uptake but inhibited at much higher concentrations. The potentiating agents that remove the endogenous metal had a particularly dramatic effect in the presence of Mg2+, the voltage-dependent suppressor of the NMDA receptor. Mg2+ also played an important role in the inhibitory effect of added Zn2+. Much lower concentrations of Zn2+ were needed to achieve inhibition of NMDA-induced 45Ca uptake in the presence of Mg2+. Under a variety of conditions, a very good correlation was found between NMDA receptor-mediated 45Ca uptake and the magnitude of acute neurotoxicity.
Animals↗
Kinetics of ATP-induced Ca2+ transients in cultured pig aortic smooth muscle cells depend on ATP concentration and stored Ca2+.
1. Single cultured pig aortic smooth muscle cells were studied using fura-2 and dual excitation wavelength microfluometry. 2. Extracellular ATP in micromolar concentrations induced a transient increase of [Ca2+]i due to Ca2+ release from internal stores. In the same concentration range application of ATP resulted in an increase of intracellular inositol phosphate level. 3. In a medium range of ATP concentrations (2-10 microM) the Ca2+ signal was oscillating, whereas at higher and lower concentrations only a Ca2+ transient with a single peak was elicited. 4. The rank order of potency for the tested purine and pyrimidine nucleotides was: UTP > ATP > ADP >> AMP = adenosine = alpha,beta-methylene ATP = 0. The response to the nucleotides could be abolished by the P2-purinoceptor antagonist suramin. 5. The latency between agonist application and onset of the Ca2+ transients as well as their amplitude and rate of rise are dependent on ATP concentration. 6. Removal of Ca2+ from the extracellular solution led to a progressive decrease of amplitude and prolonged latency of the Ca2+ transients. This shows that depletion of the Ca2+ stores affects kinetics of the ATP-induced Ca2+ release. 7. The inorganic Ca(2+)-influx blockers Ni2+ and Co2+ affected amplitude and latency in a manner similar to Ca2+ removal, while the Ca2+ antagonist nifedipine was ineffective up to a concentration of 10(-6) M. 8. These results reveal a dual dependency of the InsP3-induced Ca2+ release on agonist concentration and filling state of the Ca2+ stores, which supports the hypothesis of a feedback amplification between InsP3 and released Ca2+.
Adenosine Triphosphate↗
[A simple method of digitizing analog scintigrams for quantification and digital archiving].
This study was undertaken to evaluate a quick, reliable and cheap method of digitizing analog scintigrams. 40 whole-body bone scintigrams were obtained simultaneously in analog and genuine digital format. The analog scans on x-ray film were then digitized secondarily by three different methods: 300 dpi flat-bed scanning, high-resolution camera scanning and camcorder recording. A simple exposure approach using a light box, a cheap camcorder, a PC and image grabber hard- and software proved to be optimal. Visual interpretation showed no differences in clinical findings when comparing the analog images with their secondarily digitized counterparts. To test the possibility of quantification, 126 equivalent ROIs were drawn both in the genuine digital and the secondarily digitized images. Comparing the ROI count to whole-body count percentage of the corresponding ROIs showed the correlation to be linear. The evaluation of phantom studies showed the linear correlation to be true within a wide activity range. Thus, secondary digitalization of analog scintigrams is an easy, cheap and reliable method of archiving images and allows secondary digital quantification.
Analog-Digital Conversion↗
An endogenous metal appears to regulate NMDA receptor mediated 45Ca influx and toxicity in cultured cerebellar granule cells.
Glutamate induced 45Ca influx and toxicity were enhanced 2-10 fold by EDTA. A chelator concentration of 10 microM, which was equivalent to less than 1% of the Mg2+ and Ca2+ concentration in the medium, was effective. The chelator revealed no activity on its own and caused potentiation only when present simultaneously with the agonist of the NMDA receptor. Cysteine, which is known to bind certain metals tightly through its sulfhydryl group, and another chelator, O-phenanthroline, produced the same effect as EDTA. The findings indicate that when the N-methyl-D-aspartate receptor is activated, an endogenous metal can become bound to a chelator or to a physiological metal binding agent, such as cysteine, leading to enhanced Ca2+ influx into the neuron and toxicity.
Animals↗
Acute glutamate toxicity in cultured cerebellar granule cells: agonist potency, effects of pH, Zn2+ and the potentiation by serum albumin.
Cell death was due to activation of the receptor responsive to N-methyl-D-aspartate (NMDA). Even during a 30-min incubation, glutamate toxicity was unaffected by 5 microM CNQX and was greater than 90% blocked by 160 nM MK-801, a specific antagonist of the NMDA receptor. The extent of toxicity was dependent on the age of the cultured cells, the concentration of KCl, which determined membrane polarization, the duration of exposure to, and the concentration of, glutamate. Toxicity was critically pH-dependent, increasing from a minimal effect at pH 7.0 to an extremely high level at pH 8.0. Among a number of acidic amino acids tested, glutamate showed the highest potency. Aspartate, cysteine sulfinate and homocysteate reached the same maximal toxicity, but at a 25 times higher concentration. Cysteate and quinolinate were of very low potency. Zn2+, at 0.5 microM, attenuated glutamate toxicity considerably. At concentrations above 5 microM the metal ion showed strong toxicity on its own. Dialysed serum and serum albumin strongly potentiated glutamate and NMDA toxicity in presence and absence of Mg2+. A concentration of 2 mg/ml bovine serum albumin caused maximal potentiation; fatty acid-free bovine serum albumin and human serum albumin were all about equipotent. To be effective, the serum albumin had to act simultaneously with glutamate. Among a number of proteins and other polymers, only casein showed an ability to potentiate glutamate toxicity, similar to serum albumin. It is concluded that minor effects of glutamate toxicity could be considerably aggravated by the potentiating activity of serum albumin, also in pathological situations in vivo.
Amino Acids↗
Acute glutamate toxicity and its potentiation by serum albumin are determined by the Ca2+ concentration.
Two different processes, mediated by the N-methyl-D-aspartate receptor, appear to cause acute cell death in cultured cerebellar granule cells. A Ca(2+)-independent process takes place at zero and very low concentration of the added cation. Under these conditions, the known destabilization of excitable membranes at low extracellular Ca2+ probably plays a major role. A Ca(2+)-dependent process becomes dominant as its concentration is increased above 1.0 mM. The remarkable potentiation of glutamate toxicity by serum albumin is a calcium-dependent reaction.
Calcium↗
Culture of mature hippocampus slices for 4 days in a newly developed medium: preservation of transmitter release and leucine incorporation into protein.
A procedure and a medium for sustaining mature hippocampus slices in vitro for 4 days are described. The ionic composition of the medium, in which the slices were incubated for 1 h of recovery following preparation, strongly affected their ability, 4 days later, to take up and to release D-[3H]aspartate and [14C]GABA. A medium deficient in Na+ and Ca2+ proved best for recovery of the fresh slices prior to transfer to culture medium. The newly developed CSF-like culture medium was the best among several media tested in maintaining the potential of the slices for uptake and for induced release of D-[3H]aspartate and [14C]GABA. Glutamine, present in most culture media, appeared to be particularly toxic. Relative to fresh slices, the slices after 4 days in culture maintained 118% and 97% of the uptake of D-[3H]aspartate and of [14C]GABA respectively. K(+)-induced release of D-[3H]aspartate and of [14C]GABA was 104% and 82% of the respective values in fresh slices. Under the optimal culture conditions worked out, the slices also regained a considerable capacity for incorporation of labelled leucine into protein, which was low in fresh slices.
Animals↗
Synthesis, pharmacological effects, and conformation of 4,4-disubstituted 1,4-dihydropyridines.
4,4-Disubstituted 1,4-dihydropyridines are synthesized by intramolecular addition of sulfinyl carbanions to pyridines. These disubstituted derivatives show a loss of Ca antagonistic potency of up to three powers of 10 both in vitro on aortic rings and in vivo on anaesthetized dogs as compared to examples that are monosubstituted at the 4-position of the DHP ring. As the X-ray structure shows, the 4-aryl substituent is present not in the accustomed axial conformation, but in an equatorial one. This dramatic change in conformation could be the reason for the major loss of activity and would indicate the need for axial conformation of the aryl residue in pharmacologically active 1,4-dihydropyridines. The change in conformation was also confirmed by quantum chemical calculations (AM1).
Animals↗
Serum and depolarizing agents cause acute neurotoxicity in cultured cerebellar granule cells: role of the glutamate receptor responsive to N-methyl-D-aspartate.
The life span of neonatal rat cerebellar granule cells, grown in basal minimal Eagle's medium containing 10% (vol/vol) fetal calf serum, was extended to 21-30 days by weekly supplementation with glucose. Addition of 1% fetal calf serum to the culture at 14 days killed 85% of the cells within 1 hr. This lethal effect could be prevented by the N-methyl-D-aspartate (NMDA) receptor antagonists dibenzocyclohepteneimine (MK-801) and 3-(2-carboxypiperazin-4-yl)propyl-1-phosphonate (CPP). These findings suggested that the glutamate in the serum caused the dramatic neuronal death through action on the NMDA receptor. Indeed, a 5-min incubation in a Locke physiological salt solution containing 20 microM glutamate and 5 microM glycine killed 55-90% of the cells. This acute toxicity could be prevented by a lyso-GM1 ganglioside with N-acetylated sphingosine. The relatively low glutamate content of the sera analyzed suggests that factors in addition to glycine potentiate serum neurotoxicity. The above noted antagonists of the NMDA receptor also greatly reduced the lethal effect of depolarization by 90 mM KCl or 10 microM veratridine. Therefore, it is likely that the toxicity of the depolarizing agents is mediated by glutamate released from the cells. It is concluded that survival of cerebellar neurons in primary culture may be strongly affected by unsuspected neurotoxic phenomena elicited by brief action of a rather low glutamate concentration.
Animals↗