Der Glucoseverbrauch des menschlichen Gehirns unter dem Einfluß intravenöser Infusionen von Glucose,Glucagon und Glucose-Insulin

Zusammenfassung 1. Bei Kranken mit cerebraler Arteriosklerose findet sich eine Verminderung der Hirndurchblutung sowie der cerebralen Sauerstoff-und Glucoseutilisation. Die Glucoseaufnahme ist besonders stark reduziert, der Quotient aus Glucoseverbrauch: O₂-Verbrauch sowie der cerebrale RQ sind statistisch signifikant vermindert. Daraus läßt sich ableiten, daß als Folge einer gestörten Glucosepermeation oder -utilisation im Gehirn vermehrt Nicht-Kohlenhydrate verbrannt werden.2. Es wurde geprüft, ob durch Erhöhung des arteriellen Blutzuckers eine Verbesserung der Glucoseaufnahme im Gehirn zu erreichen sei. Die Hirndurchblutung wurde mit der Stickoxydulmethode vonKety undSchmidt bestimmt. Gleichzeitig erfolgten Analysen des cerebralen O₂- und Glucoseverbrauchs sowie der Abgabe von CO₂, Lactat und Pyruvat. Enzymatische substratspezifische Meßmethoden kamen zur Anwendung.3. Intravenöse Glucoseinfusionen von 60 ml 50%-iger Glucose hatten trotz eines Blutzuckeranstiegs von 96 auf 265 mg-% keinen statistisch signifikanten Einfluß auf Hirndurchblutung und cerebralen Stoffwechsel.4. Auch nach intravenösen Glucagoninjektionen von 20/kg war trotz Hyperglykämie eine Änderung der Hirnzirkulation, sowie der O₂- und Glucoseutilisation nicht erkennbar.5. In 23 Untersuchungen wurden intravenöse Infusionen von 60 ml 50%iger Glucose mit 24 E Insulin verabfolgt. In neun Messungen mit normalen Ausgangswerten stieg die cerebrale Glucoseaufnahme um 47%, von 5,62 auf 8,29 mg/100 g·min an. Die Hirndurchblutung, der cerebrale O₂-Verbrauch und RQ sowie die Abgabe von Lactat und Pyruvat blieben unverändert normal.Bei 14 Kranken mit cerebraler Arteriosklerose und stark verminderten Hirnstoffwechselwerten nahm bei unveränderter Durchblutung und O₂-Verbrauch die Glucoseaufnahme im Hirn um 84% zu: Die arteriohirnvenöse Glucosedifferenz stieg von 6,8 auf 12,2mg-%, die Glucoseaufnahme von 2,80 auf 5,11 mg/100 g·min. Mit dieser Normalisierung der Glucoseutilisationswerte ging eine statistisch gesicherte Normalisierung auch des Quotienten aus Glucoseverbrauch: Sauerstoffverbrauch sowie des zuvor erniedrigten cerebralen RQ einher.6. Aus den Ergebnissen wird gefolgert, daß das Insulin einen fördernden Einfluß auf die Glucosepermeation in die Ganglienzellen hat. Die vermehrt aufgenommene Glucose kann einer gesteigerten Synthese von Hirnglykogen und Aminosäuren dienen, und bei pathologischen Ausgangswerten zu einer Normalisierung des cerebralen Glucosestoffwechsels führen, erkennbar am Anstieg des cerebralen RQ von 0,88 auf 0,99.7. Die Bedeutung dieser Befunde für die Therapie wird diskutiert.

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Summary 1. In patients suffering from cerebral arteriosclerosis cerebral blood flow and cerebral utilization of oxygen and glucose are decreased. There is a marked reduction in cerebral uptake of glucose, and the quotient Q of glucose-uptake: oxygen consumption and the cerebral RQ are diminished significantly. From these observations it may be concluded that the cerebral metabolism of Non-Carbohydrates is increased as a consequence of disturbed permeation or utilization of glucose.2. We investigated whether an improved cerebral uptake of glucose could be achieved by elevating the level of arterial glucose. The cerebral blood flow was measured by the nitrous oxide method ofKety andSchmidt. Simultaneously the consumption of oxygen and glucose and the delivery of CO₂, lactate and pyruvate were analysed. The determinations were performed by enzymatic substrate-specific methods.3. Intravenous infusions of 60 ml 50% glucose influenced neither cerebral blood flow nor cerebral metabolism significantly, in spite of an elevated blood sugar level from 96 to 265 mg-%.4. A hyperglycemia induced by the intravenous injection of glucagon (20/kg) did not change cerebral blood flow or cerebral metabolism essentially.5. In 23 investigations an infusion of 60 ml 50% glucose and 24 U insulin was given intravenously.In 9 patients showing normal control values the cerebral uptake of glucose increased significantly from 5,62 to 8,29 mg/100 g · min (= 47%). Cerebral blood flow, cerebral oxygen consumption, cerebral RQ and the delivery of lactate and pyruvate remained within normal limits.In 14 patients with cerebral arteriosclerosis and markedlyreduced reduced values of cerebral metabolism the glucose consumption increased significantly by 84%: The arteriovenous difference of glucose rose from 6,8 to 12,2 mg-%, the cerebral uptake of glucose from 2,80 to 5,11 mg/100 g · min. Together with the normalization of the values of glucose utilization the quotient Q of glucose-uptake/oxygen-consumption rose from the previously decreased value of 1,06 to 1,82, and the cerebral RQ became normalized by a significant increase from 0,88 to 0,99.6. It is concluded from theses results that insulin has an improving effect upon the permeation of glucose into the brain cells. The augmented uptake of glucose may serve to an increased synthesis of cerebral glycogen and amino acids and may under pathological conditions restore normal cerebral glucose metabolism.7. The therapeutic implications of these findings are discussed.Die Untersuchungen wurden mit Unterstützung der Deutschen Forschungsgemeinschaft durchgeführt.

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Herrn Prof. Dr. Drs. h. c.K. H. Bauer zum 75. Geburtstag.     

Reverse remodeling by net cardioplasty in a model of dilated cardiomyopathy: results of an animal study

AIM: End-stage heart failure is a growing clinical problem with only a few satisfactory therapeutical options. Dilated cardiomyopathy (DCM) is associated with a progressive decline in cardiac function. Our hypothesis was to arrest this worsening of cardiac function by mechanically containing the dilated heart with a special net. METHODS: In 16 pigs (50+/-7 kg) DCM congestive heart failure was initiated by rapid ventricular pacing (220 b/m). In series 1 (n=8) a polyester net was placed around both ventricles before pacing was induced, whereas in series 2 (n=8) ventricular wrapping was performed when DCM was established. RESULTS: Comparing hemodynamic data before re-operation of group 11-animals, the decrease of CO and dp/dt(max) was significantly lower in series 1 than in series 2 compared to the baseline values before pacing (CO: series 1:-22.6+/-3.3%, series 2:-52.4+/-6.4%, p<0.05; dp/dt: series 1: +16.4+/-2.8%, series 2: -51.5+/-5.9%, p<0.05). In series 2, after net implantation, we could furthermore show that deterioration of the animal stopped and hemodynamic data improved significantly in the following 2 weeks (CO: +62.9+/-10.5% and dp/dt +37.0+/-6.8%). CONCLUSION: Ventricular containment with a polyester net seems to be a therapeutic option in cardiac insuffiency caused by ventricular dilation. This cardioplasty induced a reverse remodeling of the dilated hearts with a significant improvement in diastolic and systolic ventricular function.     

Fascin,an actin-bundling protein,modulates colonic epithelial cell invasiveness and differentiation in vitro

In epithelial tissue, cell-matrix and cell-cell adhesive interactions have important roles in the normal organization and stabilization of the cell layer. The malignant conversion of epithelial cells involves alterations in the expression and function of these adhesion systems that enable a switch to a migratory phenotype in tumor invasion and metastasis. Fascin is an actin-crosslinking protein that is found in the core actin bundles of cell-surface spikes and projections that are implicated in cell motility. We demonstrate that fascin is not detectable in normal colonic epithelium, but is dramatically up-regulated in colorectal adenocarcinoma. To test the hypothesis that fascin could participate in tumor invasive behavior, we developed a cell culture model to examine the effect of fascin expression on the adhesive interactions, invasiveness, and differentiation of colonic epithelial cells. We report marked effects on the organization of cell-surface protrusions, actin cytoskeleton, and focal adhesions in the absence of alterations in the protein levels of the major components of these structures. These effects correlate with alterations in cell movements on two-dimensional matrix, and increased invasiveness in three-dimensional matrix. The cells also show increased proliferation and decreased capacity for normal glandular differentiation in collagen gels. We propose that up-regulation of fascin, by promoting the formation of protrusive, actin-based, cell-motility structures, could be a significant component in the acquisition of invasive phenotype in colonic carcinoma.     

Haptoglobin genotypic distribution (including Hp0 allele) and associated serum haptoglobin concentrations in Koreans

BACKGROUND: Haptoglobin polymorphism is associated with the prevalence of infections, autoimmune diseases, cardiovascular diseases, and other disorders. Congenital haptoglobin deficiency is associated with anaphylactic transfusion reactions in anhaptoglobinaemic patients with antihaptoglobin antibody. AIMS: To investigate haptoglobin genotypic distribution (including the Hp(0) allele) and associated serum haptoglobin concentrations in Koreans. METHODS: Five hundred and nine healthy Korean adults were randomly selected. Two methods were used: haptoglobin genotyping based on a polymerase chain reaction (PCR) system that exploited the structural difference of the Hp(1) and Hp(2 )alleles, and another PCR method that detected haptoglobin gene deletion by amplification of the junctional region of the Hp(0) allele. Serum haptoglobin concentrations were measured by nephelometry. RESULTS: The haptoglobin genotypes of 509 subjects were as follows: Hp(1)Hp(1), 7.1%; Hp(2)Hp(1), 37.7%; Hp(2)Hp(2), 49.3%; Hp(0)Hp(1), 2.2%; Hp(0)Hp(2), 3.5%; Hp(0)Hp(0), 0.2%. The gene frequency of Hp(0) in Koreans was calculated to be 0.031. Significant differences were seen among the concentrations of each haptoglobin genotype (Kruskal-Wallis test). Hp(0)Hp(2), but not Hp(0)Hp(1), was associated with hypohaptoglobinaemia. CONCLUSIONS: PCR methods for differentiating between haptoglobin genotypes, including the Hp(0) allele, may be useful in a broad spectrum of basic studies and clinical examinations.     

Early diagnosis of typhoid fever by the detection of salivary IgA

BACKGROUND:/AIMS: Current diagnostic methods for typhoid fever have low sensitivity and specificity. This study aimed to develop an enzyme linked immunosorbent assay (ELISA) with greater sensitivity and specificity. METHODS: The ELISA was developed and evaluated on patients with acute typhoid infection, febrile controls, and healthy controls. A sequential study on patients with culture confirmed typhoid was also carried out to determine the time period of maximum sensitivity. RESULTS: The ELISA detected anti-Salmonella typhi lipopolysaccharide (LPS) salivary IgA antibodies. A six month follow up study of patients with culture confirmed typhoid fever showed that the test shows maximum efficiency during the second and third weeks of fever and enables detection of the acute infection during the early phase. CONCLUSIONS: This ELISA can detect typhoid fever during the early phase of infection and is most efficient during the second and third weeks of fever, the time at which patients normally present for treatment. Because the sensitivity of the assay is subsequently greatly reduced, it will be useful for the diagnosis of acute infection.     

Strain-specific restriction of the antiphagocytic property of group A streptococcal M proteins

Group A streptococcal M proteins are type-specific virulence factors that inhibit phagocytosis. We used two M proteins, M5 and Emm22, to analyze the influence of genetic background on the properties of M proteins. Mutant strains, engineered to lack these M proteins, were complemented with genes encoding the homologous or heterologous M protein, and the complemented strains were analyzed for phagocytosis resistance. Neither the M5 nor the Emm22 protein conferred phagocytosis resistance in the heterologous background, but they did do so in the homologous background. This was not due to lack of surface expression in the heterologous background. Moreover, the M5 and Emm22 proteins expressed in heterologous background appeared to have normal structure, since they were not affected in their ability to bind different human plasma proteins. In particular, M5 or Emm22 had normal ability to bind human complement inhibitors, a property that has been implicated in phagocytosis resistance. Results similar to those obtained with M5 and Emm22 were obtained in experiments with the M6 and Emm4 proteins. Together, these data suggest that the surface expression of M protein alone may not be sufficient to confer phagocytosis resistance and consequently that strain-specific factors other than M and Emm proteins may contribute to the ability of group A streptococci to resist phagocytosis.     

Are house dust mite allergen levels influenced by cold winter weather?

BACKGROUND: Moisture is vitally important for house dust mites and they cannot survive in cold or hot-dry climates. AIMS OF THE STUDY: To investigate the influence of two extraordinarily cold and dry winters in 1995/1996 and 1996/1997 on house dust mite levels in German homes. METHODS: Dust samples were collected between June 1995 and December 2001 on the mattresses of 655 adults and 454 schoolchildren living in five different areas of Germany. We compared house dust mite allergen Dermatophagoides pteronyssinus (Der p 1) levels before and during the winters of 1995/1996 and 1996/1997 with levels after these winters. RESULTS: D. pteronyssinus (Der p 1) levels in samples taken after the cold winters of 1995/1996 and 1996/1997 were approximately two times lower than Der p 1 levels in dust samples collected before or during these respective winters (Geometric means: Erfurt 89 vs 33 ng/g; Hamburg 333 vs 219 ng/g; Bitterfeld, Hettstedt, and Zerbst 296 vs 180 ng/g). Except for Hamburg, the decrease in Der p 1 levels was statistically significant. D. pteronyssinus levels measured in dust samples collected in 2001 (i.e. 3 years after the two cold winters) show a statistically non-significant increase (Geometric means: Erfurt 33 vs 39 ng/g; Hamburg 219 vs 317 ng/g), suggesting that it may take a long time for mite allergen levels to increase again after a sudden decrease. CONCLUSION: We conclude that Der p 1 levels in German mattress dust samples have been approximately reduced by a factor of three to four by the two consecutive cold winters of 1995/1996 and 1996/1997.     

Female sex hormones decrease constitutive endothelin-1 release via endothelial sigma-1/cocaine receptors: an action independent of the steroid hormone receptors.

Cardiovascular disease is rare in premenopausal women compared to men. The authors investigate sex hormone-induced endothelin-1 (ET-1) release and the involvement of classic sex hormone receptors as well as the ability of sigma-1/cocaine receptors to respond to sex hormones. ET-1 release was measured in the supernatant of endothelial cells after treatment with beta-estradiol, progesterone, testosterone, or combined with their antagonists, and with the sigma-1 receptor ligand ditolylguanidine (DTG), or haloperidol, a sigma-1 receptor antagonist. Binding assays were performed using 2.5 x 10(-8) M [3H]DTG. Female sex hormones decreased ET-1 release whereas testosterone increased it, sex hormone antagonists only slightly attenuated or had no effect on the respective hormone's effect. DTG totally blocked the female sex hormone-induced inhibition on ET-1 release, whereas testosterone-induced stimulation was not affected. However, haloperidol blocked both. [3H]DTG binding was displaced by beta -estradiol but not by testosterone. DTG-binding sites account for 513 +/- 114 per cell, KD 8.79 nM. These data suggest that besides classic steroid hormone receptors, sigma-1/cocaine receptors mediate the effects of female sex hormones on ET-1 release, an up to now unknown signalling pathway. Results also suggest that female and male sex hormones may bind to different sites on sigma-1 receptors, exerting opposite pharmacological effects.     

On the Orientation of the HL-A Region and the PGM3 Locus in the Chromosome

A study of four families with a cross-over within the HL—A region and in which the crossover parent is heterozygous at PGM₃ indicates with a probability of about 95% that the chromosomal orientation of the three linked loci is LA · FOUR · PGM₃.