Tumor necrosis factor α in the pathogenesis of cerebral malaria

Physiologically in the brain, cytokines such as tumor necrosis factor-alpha (TN) are released by the immune system and can modulate neurological responses. Conversely, the central nervous system (CNS) is also able to modulate cytokine production. In the case of CNS disorders, cytokine release may be modified. Cerebral malaria (CM) is a complication of Plasmodium falciparum infection in humans and is characterized by a reversible encephalopathy with seizures and loss of consciousness. Central clinical signs are partly due to sequestration of parasitized red blood cells in the brain microvasculature due to interactions between parasite proteins and adhesion molecules. TNF is produced and released by host cells following exposure to various malarial antigens. The increase of TNF release is responsible for the overexpression of adhesion molecules. This article reviews the involvement of TNF in cerebral malaria and the relation with all the processes involved in this pathology. It shows that (i) TNF levels are increased in plasma and brain but with no clear correlation between TNF levels and occurrence and severity of CM; (ii) TNF is responsible for intercellular adhesion molecule-1 upregulation in CM, the relation being less clear for other adhesion molecules; (iii) TNF receptors are upregulated in CM, with TNF receptor 2 (TNFR2) showing a higher upregulation than TNFR1 in vivo; (iv) in murine CM, low doses of TNF seem to protect from CM, whereas excess TNF induces CM and anti-TNF therapies (antibodies, pentoxifylline) did not show any efficiency in protection from CM. Moreover, the involvement of lymphotoxin a, which shares with TNF the same receptors with similar affinity, appears to be an interesting target for further investigation.Received 4 December 2002; received after revision 7 February 2003; accepted 14 February 2003     

Axillary 5α-androst-16-en-3-one in men and women: Relationships with olfactory acuity to odorous 16-androstenes

Summary Axillary 5-androst-16-en-3-one (5-androstenone) levels were found to be significantly higher in men than in women but do not vary between left and right axillae, are not related to age, handedness or degree of hirsutism (in women) nor to anosmia to this steroid. In men (but not in women), levels are related linearly to axillary cholesterol concentrations but not to squalene. Olfactory thresholds for 5-androstenone varied widely, the lowest recorded being 0.2 ppb, but there was no difference in thresholds between men and women. Women (70%) found the smell repellant but anosmia did not differ greatly between men and women (9–20%). Anosmia to the smell of 5-androst-16-en-3-ol was most marked in women (90%) rather than in men (45%). Axillary 5-androstenone values were generally consistent with the musky or strong smells of male axillary extracts, compared with the sweet smell of those from female subjects.Supported by the Herbert Dunhill Trust.     

Metabolism in Porifera. IX. Studies on the biological conversion of cholesterol into 19-nor-cholestanol by the spongeAxinella polypoides

Summary The conversion of cholesterol into 19-nor-5-cholestan-3-ol by the spongeAxinella polypoides involves a partial loss (40%) of the 3-hydrogen atom; moreover administration to the sponge of [4-¹⁴C]cholesterol tritiated at C-4 and C-7 showed that the 4- and 7-hydrogen atoms are retained in this conversion. A competitive uptake experiment, [4-¹⁴C]cholesterol vs. [7-³H₂]5-cholestanol, showed that the sponge utilized exclusively cholesterol for the production of 19-nor-5-cholestan-3-ol.Part of this work has been presented at the Nato Conference on Marine Natural Products (Jersey, Great Britain, October, 1976).-This contribution is part of the Programma finalizzato Oceanografia e Fondi marini-sottoprogetto Risorse biologiche C.N.R. Italy.     

Retroaldol transformations in the westphalen diol series

Zusammenfassung Durch Behandlung mit Kalilauge erleidet 5-methyl-19-norcholestan-9, 10-diol-3, 6-dione eine Retroaldolisomerisierung unter Bildung des 10-Hydroxy-Isomers. Letzteres wurde als Hemiketalderivat isoliert. Bei drastischer Behandlung mit Alkali gehen beide Isomere in ein Anthrasteroid über.     

The molecular structure of the benzilic acid rearrangement product of 3α, 17β-diacetoxy-11-hydroxy-12-oxo-5β-androst-9(11)-ene

Zusammenfassung Die Struktur desp-Brombenzoates des Benzilsäureumlagerungsproduktes von 3, 17-Diacetoxy-11-hydroxy-12-oxo-5-9(11)-androsten wurde durch dreidimensionale Röntgenstrukturanalyse eines Einkristalls als 3-p-Brombenzoat des 11-Carboxy-3, 11, 17-trihydroxy-13-C-nor-5-androstan 11a, 17-Laktons erkannt.     

Orally administered melatonin stimulates the 3α/β-hydroxysteroid oxidoreductase but not the 5α-reductase in the ventral prostate and seminal vesicles of pinealectomized rats

Summary Pinealectomized rats were treated orally with melatonin (MEL) for 14 days. Prostates and seminal vesicles were investigated for the activity of the 4-3-ketosteroid-5-oxidoreductase (5-R) and of the 3/-hydroxysteroid-oxidoreductase (3-HSO). The activity of the 3a-HSO was significantly stimulated (p<0.01, Friedman test) when compared to controls. The activity of the 5-R did not change significantly.This work was supported by the Deutsche Forschungsgemeinschaft, Sonderforschungsbereich 34 (Endokrinologie).     

Singlet oxygen reactivity of bilirubin and related tetrapyrroles

Summary The rates of chemical reactivity (k_R) and physical quenching (k_Q) of singlet oxygen by bilirubin IX, mesobilirubin IX, bilirubin IX dimethyl ester, aetiobilirubin IV, biliverdin IX, biliverdin IX dimethyl ester, aetiobiliverdin IV and an oxodipyrromethene have been determined. The k_R and k_Q values approach the diffusion threshold for the bilirubin-like substrates, but k_RQ by about a factor of 10³ for the verdins. A reaction mechanism involving superoxide ion is suggested. Bilirubin appears to quench singlet oxygen by an electron-transfer mechanism.The authors wish to thank the National Science Foundation (CHE 74-20877) and the National Institute of Child Health (HD 09026) for generous support of this work.     

Deuterium isotope effects in the ninhydrin reaction of primary amines

Summary The rate of development of Ruhemann's purple in the ninhydrin reaction of two deuterated primary amines, -d₂-p-tyramine and -d₂--phenylethylamine, is significantly reduced It appears to be a primary isotope effect and indicates that the cleavage of the carbon-hydrogen bond at the -position is involved in the rate-determining step of the color reaction.Acknowledgements. We thank Dr A.A. Boulton for his advice and encouragement and the Canadian Medical Research Councel and Saskatchewan Health for their continuing financial support.     

Testosterone metabolism by mouse placenta in vitro

Zusammenfassung 4-C¹⁴-Testosteron wurde durch Mäuseplazenta in vitro zu Steroiden umgesetzt: 3-Hydroxy-5-androstan-3, 17-dion, 3-Hydroxy-5-androstan-3, 17-dion, 4-Androsten-3, 17-dion und 5-Androstan-3, 17-dion. Eine Umsetzung von Testosteron zu Östrogenen wurde nicht nachgewiesen.     

A new partial synthesis of holaphyllamine

Résumé L'holaphyllamine peut être aisément préparée à partir du 3, 6-ditosyloxy-5-pregnan-20-one par réaction avec NaN₃.     

Identification of 3α, 17α, 21-trihydroxy-5α-pregnane (allotetrahydro-17α-hydroxy-cortexone) and 3α,21-dihydroxy-5α-pregnane (allo-tetrahydro-cortexone) in human urine

Résumé Le 3, 17, 21-trihydroxy 5-pregnane (allo-tétrahydro-17-hydroxy-cortexone) et le 3,21-dihydroxy 5-prégane (allo-tétrahydro-cortexone) ont été identifiés dans l'urine humaine. Ces composés avaient les mêmes migrations chromatographiques avant ou après acétylation ou oxydation que les respectifs stéroïdes de synthèse.     

Interdependence between locomotor activity and duration of wakefulness in humans during isolation

Summary Locomotor activity was recorded in 14 subjects who lived singly in an isolation unit for 16 to 88 days. Their free-running circadian rhythms had a mean period of 25.9 h, with individual means in the duration of wakefulness () ranging from 12.1 to 22.9 h. Intraindividually, the hourly means of activity were negatively correlated with to such a degree that the total amount of activity per day remained constant irrespective of large variations in .     

Age- and sex-related differences in the content of prothymosinα in rat tissues

Differences in the tissue content of prothymosin during the early postnatal development of male and female rats are reported. Thymus and spleen have been found to contain significantly higher amounts of prothymosin in the newborn and prepubertal animals, as compared to adults, whereas liver has been found to contain low levels of prothymosin throughout development. These findings indicate a functional association of prothymosin with the proliferating lymphoid tissues of the young rat.     

G-protein signaling: back to the future

Heterotrimeric G-proteins are intracellular partners of G-protein-coupled receptors (GPCRs). GPCRs act on inactive G·GDP/G heterotrimers to promote GDP release and GTP binding, resulting in liberation of G from G. G·GTP and G target effectors including adenylyl cyclases, phospholipases and ion channels. Signaling is terminated by intrinsic GTPase activity of G and heterotrimer reformation – a cycle accelerated by regulators of G-protein signaling (RGS proteins). Recent studies have identified several unconventional G-protein signaling pathways that diverge from this standard model. Whereas phospholipase C (PLC) is activated by G_q and G, novel PLC isoforms are regulated by both heterotrimeric and Ras-superfamily G-proteins. An Arabidopsis protein has been discovered containing both GPCR and RGS domains within the same protein. Most surprisingly, a receptor-independent G nucleotide cycle that regulates cell division has been delineated in both Caenorhabditis elegans and Drosophila melanogaster. Here, we revisit classical heterotrimeric G-protein signaling and explore these new, non-canonical G-protein signaling pathways.Received 21 October 2004; received after revision 20 November 2004; accepted 30 November 2004     

Lack of tolerance development to tumor necrosis factor α inside the central nervous system

Tumor necrosis factor (TNF) was repeatedly microinfused into the lateral ventricle of guinea pig brains at a dose of 200 ng, 4 times within 150 min, at intervals of 3 days. In comparison to guinea pigs infused with solvent according to the same time schedule, the animals responded to TNF with pronounced fevers. The quantity of the fever response was the same after each of the 4 microinfusions of TNF. Three days after the last infusion of TNF or solvent all animals received an intramuscular injection of bacterial lipopolysaccharide (LPS). The fever in response to LPS was the same in both groups. Thus, the reported development of tolerance to repeated systemic administration of TNF^1–3 does not develop inside the blood-brain barrier. Also, the febrile response to LPS is not influenced by repeated central pre-treatment with TNF, whereas repeated peripheral treatment does have an effect.     

Synthese von 22,26-Imino-cholestan-Derivaten

Summary 3, 16-diacetoxy-5-pregnane-20-one and the analogue pregn-5-ene derivative have been converted into (22R, 25R)-22, 26-imino-5-cholestane-3, 16-diol. The configuration at C-22 and C-25 was determined by transformation into the known (22R, 25R)-5-solanidane-3-one. Application of the Ruschig method led to (25R)-22,26-imino-5-cholest-22(N)-ene-3, 16-diol.

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Solanum-Alkaloide. XVI. Mitteilung. — XV. Mitteilung:K. Schreiber undH. Ripperger, Tetrahedron Letters Nr.27, 9 (1960).     

Exchange of tritium from randomly tritiated taurocholate by microbial bile salt oxidoreductases

Summary Tritium distribution on randomly labelled taurocholate (TC) was estimated at 28%, 4%, 1% and <0.5% on the hydrogens opposite the 3-, 7- and 12-OH groups and taurine moiety respectively. Anomalously,C. perfringens 3-hydroxysteroid dehydrogenase (3-HSDH) catalyzed tritium loss of 36% on formation of 7-, 12-dihydroxy-3-keto-5-cholanoate, implying additional losses of tritium at other sites by this enzyme.This work is supported by the National Cancer Institute.     

Über die Konfiguration des Rifamycins B und verwandter Rifamycine

Summary The relative configurations of rifamycin B and related rifamycins have been determined by X-ray analysis and in part by NMR spectroscopy. The absolute configuration has been derived from the configuration of a degradation product, the dextrorotatory ,-dimethyl pimelic acid.     

Wirkung von 6β-Methoxy-9β,10α-pregna-4,6-dien-3,20-dion

Summary 6-Methoxy-9,10 -pregna-4,6-diene-3,20-dione inhibites the ⁴-3-oxosteroid-5-reduction in microsomes and the ⁴-3-oxosteroid-5-reduction in the soluble fraction of male rat liver. The 3- and 3-hydroxysteroid dehydrogenase are not inhibited by this substance.

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Diese Arbeit wurde von der Firma Hoffmann-La Roche, Basel, unterstützt.