Effect of combined B1 and B2 kinin receptor blockade in porcine endotoxin shock.

In order to investigate the contribution of kinin receptor antagonism in the treatment of LPS-induced shock we conducted a randomized study with anaesthetized piglets. Before randomization the animals were stratified according to predetermined health criteria under baseline conditions. One group of control animals received LPS from S. abortus equi (2 micrograms/kg/h i.v. for 8 h) and saline (Group 1). Another group received LPS and the B2 antagonist CP-0127 (3 micrograms/kg/min), beginning 1 h after LPS (Group 2). Group 3 received LPS and the B2 antagonist in the aforementioned doses, and the B1 antagonist Leu9-des-Arg10-kallidin (3 micrograms/kg/min), also beginning 1 h after LPS. Overall survival figures after 8 h of LPS infusion were: Group 1, 10/22 (45%); Group 2, 10/17 (59%); Group 3, 10/28 (36%). Fifty percent (29/58) of animals that were healthy at baseline survived, but only 11% (1/9) of sick animals survived (Log Rank p = 0.0001). In the subset of healthy animals, survival rates for Groups 2 and 3 were 77% and 38%, respectively (p = 0.0519). It appears, therefore, that B2 blockade attenuates LPS-induced mortality whereas additional B1 blockade seems to reverse these beneficial effects. This suggests that in this animal model the B1 receptor does not serve the same purpose as the B2 receptor, and that up-regulation of B1 receptors during LPS shock may be an important mechanism of host defence.

[Role of serum adenosine deaminase as an immune parameter of tuberculosis]. / Die Rolle der Serum-Adenosindeaminase als Immunparameter der Tuberkulose.

We measured serum levels of adenosine-deaminase (ADA) in 44 tuberculosis patients, 70 patients with lung cancer pre treatment, and 130 normal blood donors. Increased ADA levels were found in 64.4% of the tuberculosis patients, in 95.2% in the case of bacillary tuberculosis, but only in 2.8% in the tumor patients. ADA serum levels were statistically significantly increased in tuberculosis patients when compared to lung cancer patients and controls and did not differ between controls and the tumor group. We conclude that serum ADA is a selective marker of immune stimulation in tuberculosis but not in lung cancer. Serum levels positively correlated to the disease extent in tuberculosis of immunocompetent patients. This marker deserves further investigation with respect to its clinical significance.

Multifunctional instrument for operative laparoscopy: technical, experimental and clinical results in gynaecology.

Whilst endoscopic surgical procedures are getting increasingly more complex, in the various surgical disciplines mono- and bifunctional instruments are only slowly being replaced by multifunctional ones. Therefore a complex, intelligent system was developed, the central part of which is a multifunctional instrument. All basic functions necessary for surgical laparoscopy are integrated and comprise: cutting electrodes (unipolar and bipolar) which can be advanced or retracted pneumatically; coagulation forceps with mechanical control; and irrigation and suction devices. All 5 mm instruments can be used and there is an option for others, such as laser or aqua-dissection. The various functions are controlled via the handle of the multifunctional instrument which is connected to the electronic control unit, the MULTILAP system, which supplies the energy, material, and information flow required. In vivo standardised experiments in pigs were first performed to test the new instrument. Operation time was reduced by more than 20% when compared with the same procedure performed conventionally, during which frequent changing of instruments was necessary. Clinical application, without complications in all 30 patients (uterus preserving procedures or reconstructive tubo-ovarian surgery) confirmed the advantages of a multifunctional device, with optimised cutting and coagulation of vessels more than 1-2 mm in diameter, and reduced duration of operation. Safety and ergonomics were improved. Thus, an electronically controlled instrument with multifunctional working channels for lasers, ultrasound appliances, or mechanical instruments is available for application in all domains of operative laparoscopy.

[Occurrence of beta-phenylethylamine and its derivatives in cocoa and cocoa products]. / Vorkommen von beta-Phenylethylamin und seinen Derivaten in Kakao und Kakaoerzeugnissen.

2-Phenylethylamine was extracted from cocoa nibs and chocolates and analysed by coupled gas chromatography-mass spectroscopy. The amine concentration increases in fermentation of cocoa and decreased during roasting and alkalization. Its concentration in chocolates is dependent on non-fat cocoa contents. Previously unreported aldimines were found in cocoa powders, which arise from the condensation of phenylethylamine and aldehydes. The main component of these products is N-phenylmethyl-N-phenylmethylene amine (CAS 3240-95-7).

Microbial transformations of some monoterpenoids and sesquiterpenoids.

The absolute configurations of fragrances, flavours and drugs are often important for their special properties. The growing interest of organic chemists in chiral synthons has stimulated work on biotransformations, for which readily available and inexpensive compounds can be used as substrates. Microbial transformations of 1-menthenes like gamma-terpinene, alpha-terpinene, limonene and alpha-phellandrene give the corresponding 1,2-trans-diols with high stereospecificity. Because of the volatility and toxicity of these substrates, and their low solubility in aqueous solutions, a special fermentation technique has been developed in which the terpenes are fed continuously to extended cultures of Corynespora cassiicola or Diplodia gossypina. (4R)-Limonene is transformed by Gibberella cyanea to (1S,2S,4R)-p-menth-8-en-1,2-diol, but 3,3,5,5-tetramethyl-limonene yields a 6-monohydroxylated product and a 6,10-dihydroxylated product with a 6-hydroxy-8,10-epoxy structure as the main metabolite. Vicinal diols are also formed from aliphatic terpenes, by reaction at the terminal isoprenoid groups. Some oxirane structures are found as intermediates. Acyclic sesquiterpenes often form complex mixtures when they are metabolized further. The products of the transformation of trans-nerolidol by several fungi are given as examples. Cyclic sesquiterpenes, with less flexible structures, are oxidized more specifically. Whereas longifolene is a very poor substrate for Corynespora cassiicola, isolongifolene is always hydroxylated at one of the methyl groups attached to C-7. The 14- or 15-hydroxy compounds are further oxidized, very fast, in the 3 position or 4 position.

Glycosylated hemoglobins and their relation to the control of juvenile diabetes mellitus.

Patients with juvenile diabetes mellitus were studied over a period of six months. During this time their metabolic control was classified and the relation between the blood concentration of the glycosylated hemoglobins Hb A1a + b + c and the degree of diabetic control was established. 12 out of 37 diabetic children were under good control, whereas 6 patients were poorly controlled. Well controlled children had low concentrations of glycosylated hemoglobins, within the range of non-diabetic subjects. Those under poor control showed an almost twofold increase of the concentration of these minor hemoglobins. Hb A1a + b + c levels of 8 newly diagnosed diabetics were also extremely elevated. Since the hemoglobin-sugar linkage is irreversible, these components remains much longer elevated than the blood glucose itself. It is concluded that the determination of Hb A1a + b + c levels is a valuable tool for the evaluation of the efficiency of diabetic therapy in addition to blood and urinary glucose measurements.

Cri-du-chat syndrome in a child with a 5/15 translocation and interstitial centromeric heterochromatin.

A child is described with most of the typical clinical features of the cri-du-chat syndrome. G- and C-banding studies revealed the karyotype 45,XX, -5, -15, +tdic (5;15) with the loss of short arm material from chromosome 5. Centromeric heterochromatin of the translocated No. 15 is still present in the translocation chromosome. However, no silver precipitation after AgNO3-staining was observed on the translocation chromosome, thus indicating a loss or genetic inactivation of the NOR-region of the translocated No. 15. These cytogenetic results and their possible relationship to the cri-du-chat phenotype are discussed.

Inhibition of gluconeogenesis in isolated rat kidney tubules by branched chain alpha-ketoacids.

Isolated rat kidney tubules served as a model to investigate the direct effects of branched chain aminoacids, their alpha-ketoderivatives, and of the homolog straight chain aliphatic alpha-ketoacids on renal gluconeogenesis. It is demonstrated that the alpha-ketoderivatives, rather than the branched chain aminoacids themselves, are potent inhibitors of renal gluconeogenesis from precursors, entering the glucogenic pathway on all levels below and above triose phosphate. This inhibitory action is not specific for the branched chain alpha-ketoacids, since it is also observed in the presence of the homolog straight chain aliphatic alpha-ketoacids. The suppression of renal gluconeogenesis by alpha-ketoacids can not be explained by a direct inhibition of gluconeogenic reactions, by inhibition of cellular respiration, or by interference with the stimulatory action of Ca++, cAMP, and L-lysine on renal gluconeogenesis. Although the point of inhibitory attack of alpha-ketoacids in renal gluconeogenesis could not be localized, an impairment of the kidney to respond to metabolic acidosis with an increase of gluconeogenesis was observed, since the pH optimum of renal gluconeogenesis was shifted from pH 6.8 to pH 7.7 in the presence of alpha-ketoisovaleric acid.

Gluconeogenesis in kidney cortex slices of the guinea pig. Its relation to acidosis and to calcium.

In contrast to rat kidney cortex the glucogenic capacity of kidney cortex slices from normally treated guinea pigs was very low. Reduction of the pH of the incubation medium by either lowering the HCO3-concentration or by increasing the pCO2 resulted only in varying stimulatory effects on glucose production from endogeneous or exogeneous sources. Considerable rates of net synthesis of glucose from lactate, pyruvate, malate, 2-oxoglutarate, glutamate, and glycerol--but not from glutamine--were only observed in kidneys from animals with prolonged metabolic acidosis. Neither in experiments with normally treated animals nor in those with acidotic guinea pigs the glucose production decreased, when calcium was omitted from the incubation medium. Though glutamine was not converted into glucose, it served as a substrate for ammoniagenesis. On the basis of the presented results it is concluded that species differences exist in the regulation of renal gluconeogenesis.

The influence of branched chain aminoacids and their ketoderivatives on renal gluconeogenesis.

Isolated kidney tubules served as a model to investigate the direct effect of branched chain aminoacids and their ketoderivatives on gluconeogenesis. The data presented in this paper demonstrate that the ketoderivatives rather than the branched chain aminoacids themselves inhibit renal glucosesynthesis from various precursors entering the glucogenic pathway at different levels. Though the point of the inhibitory attack of ketoacids could not be localized, an impairement of the kidney cortex to respond to metabolic acidosis with an increase of gluconeogenesis is evident from the present data. The relevance of the presented data concerning the production of hypoglycemia and metabolic acidosis in leucine induced hypoglycemia and maple syrup urine disease is discussed.

Regulation of phosphoenolpyruvate carboxykinase by glutamine and ATP as possible control mechanisms of renal gluconeogenesis.

In different metabolic states renal phosphoenolpyruvate carboxykinase (PEP-CK) activities are closely correlated with in vitro glucogenic rates, suggesting a limitation of the glucogenic capacity of kidney by this enzyme. Stimulation of renal gluconeogenesis from pyruvate, lactate, and succinate by lysine and glutamine was therefore associated with a regulatory attack of these amino acids at the level of PEP-carboxykinase. This postulate was confirmed by the failure of lysine to stimulate glucose synthesis from fructose. Experimental support for an interference of glutamine and PEP-carboxykinase was obtained by a study on the inactivation of this enzyme in kidney cortex homogenates: A rapid inactivation of enzyme activity within 40-50 min could be slowed down by glutamine. In addition the inactivation was counteracted by ATP. At suboptimal concentrations of the trinucleotide its effect was potentiated by c-AMP and c-GMP. Studies on the effect of ATP on PEP-carboxykinase in kidney cortex homogenates from rats in different metabolic states revealed: In homogenates from carbohydrate fed animals extreme low activities of PEP-CK were not altered by ATP, whereas elevated enzyme activities after a protein rich diet could be further raised by a factor of 2 or 3 by ATP. GTP and ITP could substitute for ATP. An extension of these studies on hepatic enzymes showed a similar inactivation of tyrosine aminotransferase (TAT) and a protective effect of ATP. The data obtained from these experiments favour an interconversion of PEP-carboxykinase and tyrosine aminotransferase into different forms as possible mechanism for their regulation.