Restoration of active transport of solutes and oxidative phosphorylation by naphthoquinones in irradiated membrane vesicles from Mycobacterium phlei

Irradiation of the inverted membrane vesicles of Mycobacterium phlei with light at 360 nm inactivated the natural menaquinone [MK₉(II-H)] and resulted in a loss of substrate oxidation, pH gradient, membrane potential, active transport of proline or calcium ions, and oxidative phosphorylation. Restoration of the protonmotive force and active transport occurred on addition of naphthoquinones such as vitamin K₁, menadione, or lapachol to the irradiated membrane vesicles. However, coupled phosphorylation was restored only by vitamin K₁. Menadione and lapachol did not act as uncoupling agents. The magnitude of the pH gradient and membrane potential in the quinone-restored system was a reflection of the rate of oxidation and was correlated with the rate of uptake of proline or Ca²⁺. These results are consistent with the chemosmotic hypothesis proposed for the energy transducing mechanism for active transport and further demonstrate that the complete respiratory chain is not required to drive active transport. In contrast, the data suggest that in addition to the driving force (protonmotive force) necessary to establish oxidative phosphorylation, a specific spatial orientation of the respiratory components, such as the naphthaquinones, is essential for the utilization of the proton gradient or membrane potential or both. Bypass of electrons from the respiratory chain with menadione may explain the inability of this quinone to restore oxidative phosphorylation; however, lapachol restores oxidation by the same electron transport pathway as the natural menaquinone but fails to restore phosphorylation. Because all three quinones restore the protonmotive force, other factors that are discussed must be considered in understanding the mechanism of oxidative phosphorylation.     

Angiotomographic study of the normal cerebral circulation II. The vertebrobasilar system

Summary Simultaneous tomography applied to normal vertebral angiography has, by the dissociation of the vascular planes, made a selective and spatial study of the vertebrobasilar circulation possible, and therefore the identification of the vessels which are partly or totally hidden by other vascular structures. This technique has also led to a better delimitation and sometimes a direct observation and spatial localization of some anatomical structures above and below the tentorium.

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Angiotomographisches Studium des normalen zerebralen Kreislaufs. Vertebrobasilares System

Zusammenfassung Die simultane an der Vertebralangiographie angewandte Tomographie hat durch die Dissoziation der Gefäßebenen eine selektive und räumliche Untersuchung der Gefäße des vertebrobasilaren Kreislaufs und folglich der Gefäße ermöglicht, die zum Teil oder vollständig durch andere vaskularen Strukturen versteckt werden.Diese Methode hat auch eine bessere Abgrenzung und manchmal eine direkte Beobachtung, sowie eine räumliche Bestimmung einiger anatomischer Strukturen über und unter dem Tentorium erlaubt.

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Etude angiotomographique de la circulation cérébrale normale. Système vertébro-basilaire

Résumé La tomographic simultanée, appliquée à l'angiographie vertébrale, a permis, par la dissociation des plans vasculaires, une étude sélective et spatiale des vaisseaux de la circulation vertébrobasilaire et donc l'identification des vaisseaux qui sont partiellement ou totalement cachés par d'autres structures vasculaires. Cette technique a permis aussi une meilleure délimitation et parfois une observation directe et une localisation spatiale de certaines structures anatomiques au-dessus et au-dessous de la tente.

     

Cryosurgery of major and minor salivary gland: a light microscopic evaluation in the Rhesus monkey.

The minor salivary glands in the hard palate and the submandibular gland of the Rhesus monkey were subjected to a liquid nitrogen, direct-spray, one-cycle freeze. A 4-min freeze in the temperature range of -40 degrees C to -60 degrees C was used. The extent of tissue destruction was determined at intervals up to 1 year. Clinically relevant findings resulted and form the basis for subsequent studies by this group of investigators.     

Valproic acid and plasma levels of phenytoin.

Eight patients were treated concurrently with a constant dose of phenytoin and valproic acid for 1 year. During initial therapy with valproic acid, total plasma phenytoin levels decreased. The interaction was transient and was not observed at the end of 1 year. Total plasma phenytoin levels returned to pre-valproic-acid levels in seven patients.     

Transgenic mice overexpressing the wild-type form of the HMGA1 gene develop mixed growth hormone/prolactin cell pituitary adenomas and natural killer cell lymphomas

Overexpression of HMGA1 proteins is a constant feature of human carcinomas. Moreover, rearrangements of this gene have been detected in several human benign tumors of mesenchymal origin. To define the role of these proteins in cell transformation in vivo, we have generated transgenic mice overexpressing ubiquitously the HMGA1 gene. These mice developed mixed growth hormone/prolactin cell pituitary adenomas and natural killer (NK)-T/NK cell lymphomas. The HMGA1-induced expression of IL-2 and IL-15 proteins and their receptors may account for the onset of these lymphomas. At odds with mice overexpressing a wild-type or a truncated HMGA2 protein, adrenal medullar hyperplasia and pancreatic islet cell hyperplasia frequently occurred and no increase in body size and weight was observed in HMGA1 mice. Taken together, these data indicate an oncogenic role of the HMGA1 gene also in vivo.     

The role of disturbed pH dynamics and the Na+/H+ exchanger in metastasis

Recent research has highlighted the fundamental role of the tumour's extracellular metabolic microenvironment in malignant invasion. This microenvironment is acidified primarily by the tumour-cell Na(+)/H(+) exchanger NHE1 and the H(+)/lactate cotransporter, which are activated in cancer cells. NHE1 also regulates formation of invadopodia - cell structures that mediate tumour cell migration and invasion. How do these alterations of the metabolic microenvironment and cell invasiveness contribute to tumour formation and progression?     

Characterization of thymic atrophy and the mechanism of thymocyte depletion after in vivo exposure to a mixture of herbicides

3,4-Dichloropropionanilide (propanil) and 2,4-dichlorophenoxyacetic acid (2,4-D) are two commonly used herbicides that are marketed as a chemical mixture. It was hypothesized that the interaction between these two herbicides, when administered as a mixture, would result in a greater effect on the immune system than the individual components of the mixture. The present study demonstrates in a murine model that a mixture of propanil and 2,4-D, when compared to single herbicide exposures, exacerbates decreases in thymocyte populations 2 d postexposure and inhibits the repopulation of T-cells in the thymus 7 d postexposure. Exposure to 150 mg herbicide/kg body weight of propanil or 2,4-D alone had no effect on thymus weight. In contrast, decreases in the ratio of thymus weight to body weight (TW:BW) occurred 2 d after treatment with the mixture of 150 mg propanil/kg body weight + 150 mg 2,4-D/kg body weight (150/150). Thymic atrophy was associated with a decrease in the double-positive thymocyte population (CD4+CD8+) and correlated with sera corticosterone levels from 600 to 1000 pg/ml. Therefore, the hypothesis was tested that glucocorticoids, induced after exposure to herbicides, were responsible for the thymic atrophy and depletion of thymocytes. However, similar levels of corticosterone were induced after exposure to 50, 100, or 150 mg propanil/kg body weight, and 50/50 or 100/100 mixture treatments, doses that did not produce thymic atrophy or cell loss. In addition, RU 486, a glucocorticoid receptor blocker, only partially abrogated the thymic atrophy in mice exposed to the 150/150 mixture of herbicides. These results suggest that glucocorticoids are only partially responsible for herbicide-induced thymic atrophy. This study demonstrates that the effects of exposure to a mixture of chemicals cannot always be predicted based on single exposure data and emphasizes the importance of mixture-based studies.     

Involvement of 5-HT2 receptors in the antinociceptive effect of Uncaria tomentosa

Uncaria tomentosa (Willd.) DC (Rubiaceae) is a vine that grows in the Amazon rainforest. Its bark decoctions are used by Peruvian Indians to treat several diseases. Chemically, it consists mainly of oxindole alkaloids. An industrial fraction of U. tomentosa (UT fraction), containing 95% oxindole alkaloids, was used in this study in order to characterize its antinociceptive activity in chemical (acetic acid-induced abdominal writhing, formalin and capsaicin tests) and thermal (tail-flick and hot-plate tests) models of nociception in mice. UT fraction given by the i.p. route dose-dependently suppressed the behavioural response to the chemical stimuli in the models indicated and increased latencies in the thermal stimuli models. The antinociception caused by UT fraction in the formalin test was significantly attenuated by i.p. treatment of mice with ketanserin (5-HT2 receptor antagonist), but was not affected by naltrexone (opioid receptor antagonist), atropine (a nonselective muscarinic antagonist), l-arginine (precursor of nitric oxide), prazosin (alpha1-adrenoceptor antagonist), yohimbine (alpha2-adrenoceptor antagonist), and reserpine (a monoamine depleter). Together, these results indicate that UT fraction produces dose-related antinociception in several models of chemical and thermal pain through mechanisms that involve an interaction with 5-HT2 receptors.     

Antinociceptive effect of proanthocyanidins from Croton celtidifolius bark

The chemical composition of the chromatography 63 subfraction (63SF) from the ethyl acetate soluble fraction of the crude extract of Croton celtidifolius bark presented a high content of total proanthocyanidins (75.0+/-2.3%). HPLC analysis of 63SF revealed a dimeric profile (e.g.catechin-(4alpha-->8)-catechin and gallocatechin-(4alpha-->8)-catechin) and polymeric proanthocyanidins. In pharmacological investigations, 63SF administered intraperitoneally exhibited dose-dependent antinociceptive activity against several chemical stimuli, including the intraperitoneal injection of acetic acid (ID50 (the dose of 63SF which was able to reduce the nociceptive response by 50% relative to the control value)=0.9 (0.5-1.6)) and the intraplantar injection of capsaicin (ID50=13.0 (10.0-17.0)), glutamate (ID50=4.0 (2.0-7.0)) and formalin (ID50 first phase=36.0 (24.0-53.0) and late phase=11.0 (8.0-14.0)). 63SF administered orally exhibited an antinociceptive effect in the formalin test (ID50 first phase=125.0 (89.0-177.0) and late phase=65.0 (33.0-95.0)). In the same test, 63SF was effective when given soon after the first phase, as well as exhibiting therapeutic activity. Furthermore, 63SF was effective in models of thermal nociception including tail-flick and hot-plate tests. When the mice were treated in the neonatal period with capsaicin, the antinociceptive effect of 63SF in the first phase of the formalin test was abolished, but pretreatment with naltrexone did not change the antinociceptive effect of 63SF. Together, these results provide evidence that 63SF exerted a pronounced systemic antinociception against chemical (acetic acid, formalin, glutamate and capsaicin tests) and thermal (hot-plate and tail-flick tests) nociceptive models of pain in mice at a dose that did not interfere with the locomotor activity. The mechanism by which this sub-fraction produced antinociception remains unclear, but it is unlikely to involve the activation of the opioid system. However, unmyelinated C-fibres sensitive to treatment with capsaicin are likely to participate in antinociception caused by 63SF.