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Sixty-four patients aged 16-74 years with total body surface area burns (TBSA) ranging from 30 to 90 per cent, were given one bathing in 0.04 M cerium nitrate within 4 h of admission to hospital. Of 21 patients aged 16-30 years, one died (aged 28 with 90 per cent TBSA), and of those aged 31-74 years, two died, one (aged 50 years with 55 per cent TBSA) had multiple internal injuries, the other (aged 51 years with 55 per cent TBSA) had a pulmonary embolism at day 19. Two risk scores, developed from data on 11,200 burn patients treated by standard methods (Roi et al. 1983), were applied to the analysis of risk for 59 patients for whom both total burn surface (TB) and full thickness (FT) areas had been recorded. About 20 patients bore risk of 0.8 or greater on the FT scale and 1.0 on the TB scale, yet instead of 80 per cent deaths among these, only two died. No FT assessment had been made on the multiple injury death whose TB risk score was 0.66. Such survival results in high-risk patients should encourage the use of cerium nitrate for treating serious burn injury.

The investigation compares 136 insomniacs with 102 healthy controls with respect to their coping strategies. Coping strategies are evaluated with the questionnaire FKBS. This questionnaire measures 5 different coping strategies: TAS--turning against subject; TAO--turning against object; REV--reversal; PRN--prinzipialisation; PRO projection. Insomniacs seem to react less aggressive than healthy controls. They also show less projections, i.e. they do not believe in a hostile intention of a situation or a counterpart. These differences could be shown on the level of behaviour as well as experience. With the personality traits of the FPI (Freiburger Persönlichkeitsinventar FPI-R) there are some significant correlations. Finally there exists also a correlation between the strategy TAS and the incidence and intensity of depressive symptoms (i.e. state-variabels).

The lipid-protein complex (LPC) formed by thermal injury to skin, which has been shown to have a toxic effect on mice, and which suppresses the immune response, was tested for its specific influence on monocytes. Growth of bacterial endotoxin-stimulated peripheral blood mononuclear cells (PBMC) was inhibited in the presence of LPC, however, the inhibition was less at the time of the optimal rate of cell proliferation. Inhibition was proportional to LPC concentration. ConA-stimulated PBMC were also inhibited by LPC in a dose-related manner. PBMC, in the presence of LPC, secreted interleukin 1 (IL1) at an increasing rate as LPC concentration rose from 5 to 40 micrograms/ml, and the levels of IL1 which could be induced by endotoxin were increasingly amplified in the presence of LPC. In comparison to LPC, the native tissue proteins which were isolated from unburned skin by the same techniques which produced LPC from burned skin, were tested for their effect on PBMC. Native proteins had no effect on IL1 secretion, whether on background or endotoxin-stimulated levels. Thus, the thermally induced change in skin proteins has a specific effect on monocyte IL1 secretion which is not matched by the native proteins, indicating that burn injury to skin specifically affects the lymphokine cascade and consequent immune function.

Lipid peroxides, formed as a consequence of oxygen free radical formation, are responsible for tissue damage in a great variety of pathological conditions including thermal injury. 'Cutaneous burn toxin', formed by application of heat to skin, is thought to be specific to the burn injury. It causes dose-dependent damage to mitochondrial and red cell membranes, and dose-dependent inhibition of interleukin-2-dependent growth of lymphocytes. The possibility that the toxicity of 'cutaneous burn toxin', a lipid-protein, is exerted through lipid peroxides, was examined by measuring the levels of both agents in plasmas of eight burn patients during the first week after their injury. It was observed that plasma lipid peroxides did not appear in parallel with absorption into the circulation of 'cutaneous burn toxin'. Lipid peroxide levels equally common to very low and very high burn toxin levels, were recorded. The pair of agents correlated negatively (r = -0.26) at a significance of only 0.1. In addition, isolated purified 'cutaneous burn toxin' contained no measurable lipid peroxide. No relationship was therefore demonstrated between plasma levels of 'cutaneous burn toxin' and lipid peroxides.

In experiments on mice we were able to show that the negative effects attributed to burn toxins could almost completely be prevented by one single early treatment of the burned skin with a 0.04 M solution of cerium nitrate [Ce(NO3)3]. The survival rate was 10% for animals which were grafted with burned skin. Treatment with Ce(NO3)3 increased the survival rate to 74%. A reflection of this protective effect was the prevention of the burn-induced disturbance of the acceptor control ratio in isolated liver cell mitochondria. Repeated use of Ce(NO3)3 showed adverse effects due to an increased absorption. An effective treatment of burns with Ce(NO3)3 is without problems and can be done in any hospital.

In 29 patients with nephroptosis two different methods of nephropexy were compared; nephropexy using sutures passing through the parenchyma (n = 16) and nephropexy using tissue adhesives (n = 13). The first group was mobilized 3.5 days after operation, whereas the second group was mobilized one day after operation. On later follow-up 79% of the patients had no or minor complaints. Those patients who had the same disturbances as preoperatively had all been treated by nephropexy using sutures passing through the parenchyma. In 56% of this group radiological recurrence was seen, whereas in the group using tissue adhesives there was only 8% radiological recurrence. We think therefore that the nephroxepy using tissue adhesive is the simplest and least traumatic method.

Animal experiments confirmed the neuropeptide nature of delta-sleep-inducing-peptide (DSIP) and a species-specific sleep promotion. Five different human studies were carried out with single and repeated intravenous injections of DSIP under double-blind conditions, and with assessing treatment effects by psychophysiological tests and polygraphic recordings. Compatibility of DSIP was good. Slow injection proved essential. A latency of sleep induction of 1 h, but a duration of up to 20 h was found. The somnogenic properties, initially proven in animal studies, were confirmed. Indications of specific effects on chronobiological regulations were found. A complete normalization of disturbed sleep was achieved by four consecutive injections to insomniacs. During the active awake state, DSIP induced higher alertness and better performance. Psychological tests and evaluation by psychotherapists indicated modulation of ego functions by DSIP in the direction of improved stress tolerance and coping ability. The various actions of DSIP might be conceptualized neurophysiologically on the level of 'programming' behavior by means of changing 'local vigilances'. Whereas the somnogenic actions of DSIP appear promising for treating insomnia, other therapeutic perspectives in the field of psychiatry have to be explored.

Daily intravenous evening injections of 30 nmol/kg DSIP (Delta Sleep-Inducing Peptide) in rats adapted to a constant 24 hr light:dark cycle produced changes in the circadian locomotor behavior. After 3 days the normally high locomotor activity during the dark phase was reduced while during the light (sleeping) phase the animals became relatively more active. Similar, but more rapid and more marked changes were observed (with the same schedule of injections) after 0.1 nmol/kg DSIP-P (the analogue of DSIP phosphorylated at the serine in position 7). In fact the peptide and its analogue induced a relative reversal or shift of the circadian locomotor activity phases opposite to the persisting light:dark conditions (=Zeitgeber). This suggests that DSIP exerts rather complex "programming" effects on the circadian activities and has more than just a sleep-inducing activity.

Ultrastructural and metabolic alterations of the liver were studied in mice and rats after standardized "in vivo" burn injuries or i.p. injections of a specific cutaneous burn toxin. The main findings of the ultrastructural investigations were delayed and specific intramitochondrial vacuolizations appearing not before the 5th-7th day after burning or toxin-injections. -By applying the Schimassek model of the isolated and perfused liver for investigating liver metabolism we found a drastically reduced ATP/ADP-quotient on the 5th day after burns or toxin-injection as compared to the normal controls. The total content of adenonucleotides, however, remained unchanged. The urea and glucose release into the perfusate was also significantly decreased in both groups of animals and the glucose synthesis was not adequately stimulated by an additional lactate load. The results show a direct effect on the burn toxin on the hepatic metabolism as well as the hepatic cell structure suggesting a marked alteration of the oxydative phosphorylation.

A toxic extent has been isolated and partially purified from burnt human and mouse skin and also from sera of severely burnt patients, which causes disturbances of energy metabolism and decreased synthesis rates for glucose and urea in the perfused rat liver. Enzymatically isolated hepatocytes from rat livers were used to study the toxic effects on hormonal sensitivity, synthetic functions and ultrastructure of the cells. A decreased synthesis of urea and glycogen was found in cells from rats treated 5 days before with "toxin" and in cells, which were directly incubated with the toxic factor. Glucagon increased urea synthesis in normal cells by 33%, and a decrease of 25% was caused by insulin. Cells of rats treated with the nontoxic precursor of the toxic factor from normal skin were similar, while those treated with "toxin" produced less urea and did not react to glucagon or insulin. Glycogen synthesis was reduced in cells directly incubated with the "toxin", however, the hormonal effects were still observed. Surface alterations of "toxin" treated cells and cells of "toxin" treated rats were found by scanning electronmicroscopy. These findings provide evidence of a direct cytotoxic effect of the toxic factor from burnt skin. It is proposed that the "toxin" acts on the cellular membrane with destruction of surface and receptorproteins.

Modern intensive care combined with current improvements in the specific, systemic and local therapy of burns has delayed the mortal effects of severe burns. Nor has there been any significant improvement in this mortality during the last decade. The occurrence of uncontrollable infection and sepsis due to gram-negative bacteria or fungi as the basic cause of death was not a satisfactory explanation. So, progress should only be expected from a new concept in burn treatment. This new concept should be to view the burn disease as being caused by toxic factors induced by thermal injury to the skin. Electron-microscope studies in mice and rats have revealed similar mitochondrial alterations in hepatocytes after either a sublethal controlled burn injury or an intraperitoneal application of an equivalent dose, of a cutaneous burn toxin. The intraperitoneal injection of different amounts of the burn toxin indicated, that the extent of the mitochondrial changes correlated directly with the dose of toxin. Investigations of liver metabolism suggested an inhibition of the oxygenation chain. The incubation of isolated liver cells together with the burn toxin demonstrated by scanning electron microscopy a direct cytotoxic effect of the burn toxin. In animal tests the pathogenic effect of the burn toxin could be prevented by treatment with an antitoxic IgG generated in sheep. The fatal sepsis of severely burned patients is the consequence of a decreased host defence against infections, which is caused by a primary and general toxic alteration of the whole organism. One important aspect of treatment should therefore be the elimination of burn toxins. To achieve this management should include primary excision of the burns, local application of nonabsorbable protein-complex-binding substances and specific passive immunotherapy with an antitoxic IgG.

The nonapeptide delta-sleep-inducing peptide (DSIP) has been isolated from venous blood of rabbits induced to sleep. Numerous reports have described sleep as well as extra-sleep effects. Radiochemical and immunochemical data suggest a relationship of DSIP with the pineal gland supported by interactions of this peptide with pineal functions such as the serotonin N-acetyltransferase activity. In order to demonstrate the natural occurrence of DSIP-like material associated with high Mr proteins in the ovine pineal, organs were water-extracted and fractionated by ultrafiltration and gel filtration. Radioimmunoassay (RIA) for DSIP-like fragments of the fractions revealed considerable amounts of pineal DSIP-like immunoreactivity (DSIP-LI) apparently existing in small as well as large molecular forms. Acidification of large DSIP-LI forms resulted in the elution from Sephadex G-50 of Mr less than or equal to 1,000 DSIP-like material. This free DSIP-LI form coeluted with the synthetic DSIP nonapeptide from microBondapak C18 on high-performance liquid chromatography. The results, therefore, appear to indicate the presence of a (biospecific) noncovalent intermolecular interaction of DSIP (1-9) with proteins (Mr greater than or equal to 10,000) of the ovine pineal gland.

Early and adequate shock treatment combined with improved systemic and local therapy practically eliminated primary death of patients with severe burns. In contrast the late mortality, i.e. the fatal outcome during the "burn disease" has not been significantly improved during the last decade. A burn toxin has been discussed as reason of this burn disease. Such a toxic factor has been isolated from burnt mouse and human skin and from the serum of burnt patients as well. Electron microscopic studies in rats revealed similar and comparable mitochondrial alterations of hepatocytes after either a sublethal controlled burn injury or an i.p. application of an equivalent dose of this cutaneous burn toxin. These alterations were dose-dependent. Studies of the liver metabolism of these rats (i.e. gluconeogenesis, urea synthesis and energy metabolism) suggested an inhibited oxidative phosphorylation. Incubation of enzymatically isolated hepatocytes with toxin demonstrated a direct cytotoxic effect of the burn toxin by scanning electron microscopy. Glycogen synthesis and urea synthesis were significantly reduced, hormonal sensibility was partially abolished. These results suggest a disturbance of the cellular energy metabolism via a cell membrane damage. This could be the reason of the decreased host defence of burned patients which causes the fatal outcome in severe burns. Therefore, elimination of burn toxin should be an important point in burn treatment.

Studies on isolated perfused rat livers 5 days after either a sublethal burn or an i.p. injection of human/mouse burn toxin showed a significant inhibition of the glucose/urea synthesis and the ATP production concomitantly with ultrastructural mitochondrial damages. A direct specific effect of these burn toxins on enzymatically isolated liver parenchyma cells was found either after direct incubation of the isolated cells with the compound or 5 days after injection of the toxin to the animals followed by the isolation of the cells. Control experiments were performed with the "native" non-toxic precursor from normal skin. Liver cells of rats pretreated with the toxin showed an 100% increase of the amino-acid release while this increase was 70% after direct toxin incubation. Glycogen synthesis from lactate, alanin and fructose was significantly decreased in both toxin groups while the glucose synthesis was not altered. The degree of the inhibition of the glycogen synthesis was directly correlated to the number of ATP-dependent metabolic steps. A disturbance of the oxygen transfer system by structural damages of the mitochondria seems to be the basic mechanism for these specific metabolic alterations due to ultrastructural mitochondrial damages.

Delta sleep-inducing peptide (DSIP) has been found to induce sleep as well as extra-sleep effects. Although the presence of endogenous DSIP-like material has been demonstrated, the metabolic fate of injected DSIP has not been clarified so far. A major obstacle in monitoring degradation of DSIP has been the lack of an easy method to separate DSIP from tryptophan (Trp). Cleavage of the N-terminal Trp apparently represents the first and most important step in the metabolism of the peptide. Adsorption to aluminum oxide has been found to separate the two compounds and optimal conditions for the separation are described. Quantitative determination of the degradation of DSIP in plasma or serum is now rapidly achieved. The method should help to advance metabolic studies of DSIP. Other applications such as extraction of DSIP from solutions are also possible.

Delta sleep-inducing peptide has been shown to exert extra-sleep effects as well as effects on sleep. In this study, the concentrations of DSIP-like immunoreactivity were measured by radioimmunoassay in the plasma of spontaneously hypertensive rats (SHR). They were found to be about 25% higher in SHR plasma than in the plasma of the normotensive Wistar-Kyoto (WK) controls. DSIP was then infused for 10 days by osmotic minipump (200 micrograms/kg/day) into SHR. This resulted in in maintenance of BP at a level of about 200 mm Hg as compared with the significant increase to about 220 mm Hg after 10 days in the SHR controls infused with 0.9% NaCl. After daily SC injection of a single dose of 200 micrograms/kg DSIP for each of 5 days in SHR, findings were similar. The results raise the possibility of an involvement of DSIP in the regulation of BP in SHR.

The concentrations of delta sleep-inducing peptide (DSIP)-like (DSIP-LI) and P-DSIP-like (phosphorylated, Ser7) immunoreactivity (P-DSIP-LI) were measured by specific radioimmunoassay in the cerebrospinal fluid (CSF) of patients with senile dementia of the Alzheimer type [SDAT, subdivided into early (S1), middle (S2) and late dementia (S3)], multi-infarct dementia (MD), Parkinson's disease (PD), vascular disease (VD) and communicating hydrocephalus (H), as well as in control patients (C1, C2). Mean DSIP-LI and P-DSIP-LI concentrations were found to be significantly higher in the elderly control group (C1, mean age 83 +/- 5 years) than in the middle-aged control group (C2, mean age 40 +/- 16 years). DSIP-LI and P-DSIP-LI were positively correlated with age in both control groups. Significant decreases of DSIP-LI compared with age-matched controls (C1) were observed for S2, S3, MD, PD, VD and H. In contrast, no significant differences corresponding to pathology were found for P-DSIP-LI.

By means of light-microscopic autoradiography, binding sites for the delta sleep-inducing peptide (3H-DSIP) were observed on the soma and processes of cultured brain stem neurones but not on glial cells. Unlabelled DSIP at high concentrations inhibited binding of 3H-DSIP, indicating specific binding of this peptide. Our data suggest that brain stem neurones might possess receptors for the sleep-inducing peptide.

Ultrastructural alterations of the liver were examined on the 1st, 2nd, 3rd, 5th, 7th and 14th day after a standard burn in mice. Our results can be divided pathogenetically into two groups: 1. Alterations explained by the primary thermal injury including electron-optically empty vacuoles and sinusendothelium destruction. 2. Alteration due to the influence of a specific burn toxin including mitochondrial changes and the formation of autophagic vacuoles. Evidence of this distinction was produced by a second investigation. Burn toxin isolated from the serum of severely burned patients was injected intraperitoneally (15 mg) into 4 mice. The livers were examined by electron microscopy on the 2nd, 4th, 7th and 14th day. Alterations described in 2 above were not observed in any case of this investigation series. The nature and timing of liver alterations were similar to those described in 2 above. In none of the cases were changes similar to those in 1 above observed.

Daily intravenous injection of 30 nmol/kg DSIP (delta sleep-inducing peptide) in rats under constant illumination produced marked changes of their motor activity as compared to saline controls. Similar marked but distinctly different effects on the circadian pattern of locomotor behavior partially abolished by constant illumination were also obtained after repeated administration of 0.1 nmol/kg DSIP-P (the phosphorylated analogue of DSIP) which enhanced overall motor activity. In both instances the results additionally differed from those reported for a normal 12 hr light:dark cycle. The present results support the hypothesis that DSIP might primarily act by influencing circadian rhythmicity.

The delta sleep-inducing peptide (DSIP) has been shown to induce effects other than only delta sleep. One of these effects was the paradoxical thermoregulatory and locomotor response of rats to amphetamine after DSIP administration. In the present investigation we found similar effects of DSIP on the locomotor activity in mice. However, two different doses of DSIP (30 and 120 nmol/kg) and 3 doses of amphetamine (4, 10, and 15 mg/kg) produced a complex pattern of effects in mice tested at 22 degrees C. In general, DSIP-treated mice showed lower locomotor activity after amphetamine than controls, but under two conditions, both using 15 mg/kg amphetamine, DSIP produced higher scores; this occurred in the first two hours after amphetamine for the 30 nmol/kg DSIP group and in the third hour for mice given 120 nmol/kg DSIP. The results indicate that the effects of DSIP on locomotor behavior were dependent on the dosage of the peptide and the time of measurement as well as the level of amphetamine stimulation.

From previous investigations with nephroptotic patients increased urinary LDH was assumed to be a reliable marker indicating a renal tissue defect due to the organs descent in erect position. Animal experiments now allowed correlation of this enzymatic activity with controlled changes of anatomical and physiological parameters. Changes of the renal hemodynamics or urinary flow induced in acute experiments in dogs simulated kidney displacement in nephroptotic patients. Both ureters were cannulated for separate urine collection and one kidney was manipulated. The renal arterial or venous flow was reduced or the ureter was occluded under electromagnetic blood-flow control. Arterial constriction alone (30%/15 min) selectively caused a drastic decrease (approximately 80%) of Xenon wash-out (= nutrient-flow) in the renal cortex. Under the same conditions radio-labeled microspheres injected intracardially showed a centralization of the renal capillary blood flow from the outer cortex to the juxtamedullary zone. Urinary LDH activities increased up to 800% immediately after arterial constriction. In accordance with total LDH activity the percentage distribution of isoenzymes changed: LDH-I increased and the LDH-V decreased. Neither constriction of the renal vein nor ureteral occlusion had similar effects. In long-term experiments backward fixation of one kidney in rats would reflect the effects of kidney displacement over years in nephroptotic patients: animals were unilaterally nephrectomized and the remaining kidney was dislocated backwards (approximately 2,5 vertebrae) and fixed to the lateral pelvic wall. "Ptotic" rats showed during the following examinations a constant increase of urinary LDH up to 50% by 26 weeks postoperatively. In accordance with increased LDH the isotope nephrogram was pathological and arteriographies showed a stretched and narrowed renal artery. In a number of rats "ptotic" fixation was not effective enough. All these animals showed normal LDH, isotope nephrograms and arteriographies. Both animal experiments documented that reduced flow/hypoxia is essentially responsible for the tissue damage in the kidney manifested by increased release of urinary LDH.

The influence of delta sleep-inducing peptide (DSIP) on the brain neurotransmitters 5-HT, dopamine and norepinephrine and plasma proteins/corticosterone concentrations for four time points within the 24 hr following IV injection of 30 nmol/kg was investigated in rats. DSIP administered in the morning or in the evening respectively induced changes in nearly all measured parameters. Different effects were observed for different times of administration. The most marked changes were found in the level of serotonin during daytime. In view of the multivariate results obtained by measuring several parameters at multiple time points, a method was developed to describe the time-dependent changes. By means of "circadian rhythm statistics" based on a statistical likelihood analysis we found that multiple and different changes within the factor's daily variation are induced by one injection of DSIP. A multidimensional scaling of the results provides further insights into the correlations of the DSIP-induced effects on plasma and brain factors which are therefore tentatively termed "programming functions." These apparently involve not just sleep induction but also act on multiple parameters within the 24 hr rest-activity period.

The natural occurrence, sleep, and extra-sleep effects of delta sleep-inducing peptide (DSIP) have been shown by different laboratories. However, neither an in vitro assay system nor a probable mechanism of action of the peptide have been conclusively demonstrated so far. The recent finding that DSIP influences the nocturnal rise of N-acetyltransferase (NAT) activity in rat pineal led us to investigate a possible effect on pharmacologically induced NAT activity in vivo and in vitro. Stimulation of the enzyme with adrenergic drugs such as isoproterenol and phenylephrine was reduced by DSIP at doses of 150 and 300 micrograms/kg injected subcutaneously. In vitro, 6, 150 and 300 nM DSIP attenuated isoproterenol stimulation of the enzyme in cultured pineals, whereas 150 nM DSIP effectively reduced stimulation induced by a combination of the two drugs. The peptide alone did not influence NAT activity in vitro, but produced a slight stimulation in vivo. To our knowledge, these results represent the first report of a direct interaction of DSIP with adrenergic transmission. The in vitro system could prove useful for establishing possible mechanism(s) of action of the 'sleep peptide.'

Dry heat forms a specific burn toxin in mouse and human skin from a naturally occurring precursor by a polymerization process and not by producing breakdown products. Precursor and toxin are both macromolecular lipid-protein complexes with similar chemical composition and physical structure both occurring in mouse and human skin as well as in serum of burned patients. Specific toxicity resides only in the apoprotein of the polymeric toxic form which also has new specific artificially produced antigenic site or sites. This phenomenon makes it possible to jump the species from man to mouse, shown by the success of specific immunotherapy. Neutral apolar lipids of the coat are contributing in an unspecific but significant manner to the toxic effect. Bacteria are not involved in toxin production nor in toxin activity. The target systems of the toxin are the cell wall membranes of all parenchymal cells of paractically all organs. The toxin apparently causes severe damage of the membrane verified by an increased permeability for compounds which otherwise do not penetrate. This basic cell damage itself is able to kill the animal, depending on the ratio of intact to damaged cells. Sublethal doses of toxin, however, prepare the background upon which bacteremia in burn injuries leads to a lethal sepsis. Finally, the direct toxic action as well as the enhancement of the susceptibility for gram-negative organisms both leading to the lethal outcome can be counteracted by specific passive antitoxic immunotherapy.

Experimental results suggested a modulation or 'programming' interaction of delta sleep-inducing peptide (DSIP) with endogenous opioid-peptidergic systems and exogenous intracerebrally or systemically administered morphine and amphetamine. The induction of cerebral MAO-A activity, a pronounced influence on the circadian rhythms of locomotion and intracerebral neurotransmitter as well as plasma protein and cortisol concentrations has been reported. DSIP was also shown to counteract experimentally induced stress situations in animals. An improvement of the psychomotor performance and the concentration capacity in humans beside sleep normalization and pronounced effects on withdrawal symptoms including pain states in alcoholics and opiate addicts was discovered. This encouraged a pilot study for a possible action of the peptide in humans suffering from chronic pronounced pain episodes. We investigated the therapeutic effect in 7 patients with migraine episodes and vasomotor headaches, chronic tinnitus and psychogenic pain attacks. The anamnestic (baseline) values were statistically compared with the katamnestic control period. DSIP lowered significantly the pain levels of 6 out of 7 patients after intravenous administration on 5 consecutive days followed by 5 injections every 48-72 h. Remarkably, a simultaneous significant reduction of the concomitantly occurring depressive states was observed.

The mortality rate of mice after standardized Pseudomonas infection was increased by preinjection of a sublethal dose of burn toxin. This effect was eliminated by a specific antitoxic Ig. After a sublethal burn followed by infection, 60% of the animals died, while treatment with specific Ig reduced the mortality rate to 3.3%. This might be a new way to improve the treatment of severely burned patients.

Two different peptides have been purified from human liver, similar to those previously reported (Schoenenberger, G.A., and Wacker, W.E.C. (1966) Biochemistry 5, 1375--1379) to be present in human urine, which may serve as metabolic regulators of lactate dehydrogenase (EC 1.1.1.27) isoenzymes (LDH-M4 = muscle type; LDH-H4 = heart type). By trichloroacetic acid precipitation, ultrafiltration, Sephadex G-25 and Bio-Gel P-2 columns, affinity chromatography on immobilized LDH-isozymes and HPLC two peptides which differed with respect to molecular weight, retention on the affinity columns and amino acid composition were isolated. No effect was observed when native, tetrameric lactate dehydrogenase was incubated with these peptides. However, when lactate dehydrogenase was dissociated to monomers at low pH and allowed to reassociate by adjusting the pH to 7.5 complete inhibition of the reactivation occurred when the inhibitors were incubated together with respective reassociating monomeric isozymes. The two peptides showed no cross-specificity, i.e. each peptide exhibited inhibitory activity only on one of the two isozymes LDH-M4 or LDH-H4. From the amino acid analyses, gel filtrations and PAGE + SDS, molecular weights of 1800 for the M4 and approximately 2700 for the H4 inhibitor were calculated. An apparent Ki of approximately 3 X 10(-5) mM for the H4 and approximately 7 X 10(-5) mM for the H4 inhibitor was estimated. The interaction of the inhibitors with the enzyme system showed strong cooperativity with Hill coefficients of 2.9 (LDH-M4-specific) and 2.4 (LDH-H4-specific). Mathematical modelling of the reassociation and reactivation of lactate dehydrogenase and its specific inhibition by the peptides led to the conclusion that the peptides react with monomers, dimers or a transition state during the tetramerisation process. kappa 1 for the dimerisation step of M4 = 2.0 X 10(5) M-1 . S-1 and of H4 = 8.2 X 10(4) M-1 . S-1; kappa 2 for the tetramerisation step of M4 = 2.8 X 10(5) M-1 . S-1 and of H4 = 1.2 X 10(5) . M-1 S-1, were calculated, the second step still being the faster one (Rudolf, R. and Jaenicke, R. (1976) Eur. J Biochem. 63, 409--417).

A peptide that induces slow-wave (delta) and spindles electroencephalogram enhancement after intraventricular (brain) infusion has been isolated from rabbits and given the name delta-sleep-inducing peptide (DSIP). Amino acid seqeunce: Trp-Ala-Gly-Gly-Asp-Ala-Ser-Gly-Glu. This compound, five possible metabolic products (containing residues 1--8, 2--9, 2--8, 1--4, and 5--9), two nonapeptide analogues with two amino acids exchanged, and a related tripeptide (Trp-Ser-Glu) were synthesized. All nine synthetic peptides were infused intraventricularly in rabbits under double-blind conditions. A total of 58 rabbits including controls were evaluated. The electroencephalogram leads from the neocortex and the archicortex were directly fast-Fourier transformed and analyzed by a Univac 1108 computer system. Only the delta-sleep-inducing peptide (snythetic) showed significant and specific enhancement/induction of delta and spindle electroencephalogram patterns.

The synthetic delta sleep inducing peptide (DSIP) passes the blood-brain barrier, since i.v. injection in free moving rabbits (30 nmoles/kg) significantly increases the cortical delta activity and decreases the motor activity during 5 h.

Previously reported experiments with animals suggested that reduced renal arterial flow might be the actual cause for the pathogenicity of nephroptosis. Clinical studies now give evidence that measurements of urinary LDH may be a criterion equal to the isotope nephrogram (ING) in considering this disease. Patients with a "mobile" kidney verified by i.v. pyelography were examined by an ING and a 1-day test for urinary LDH. In accordance with periodic kidney displacement total urinary LDH activities were measured in a 8-h urine volume in the supine position and a 8-h urine volume in the erect position of the patients. Evaluations were all expressed as percentage increase of LDH activity of the patient in the erect versus supine position and correlated with his ING-pattern. Among 45 nephroptotic individuals 34 showed, in accordance with a pathological ING, a mean LDH increase of more than a 100%. Eleven individuals had normal INGs and less than 20% increase equal to a group of 16 normal controls. We postulated a 30% increase as the upper limit between normal and pathological urinary LDH. The percentage distribution of isoenzymes was also altered within the pathological LDH range: LDH-I, which increases in normal controls, now decreased in nephroptotic patients. LDH-IV and V, which decrease in controls, now increased. Homomeric isoenzymes obviously show reciprocal behavior. The degree of kidney descent in cm does not correlate with percentage increase of urinary LDH, i.e. it is not a criterion for pathogenicity. Biopsies taken during nephropexy revealed that from an anamnestic duration of 50 weeks onwards the kidney is significantly affected and tissue damages become evident. If patients were re-investigated after nephropexy they showed normal i.v. pyelograms and normal LDH and no longer had clinical symptoms.