Inducible nitric oxide synthase activity of cloned murine microglial cells

Nitric oxide (NO) is a short-lived diffusable molecule now believed to participate in multiple physiologic functions in the CNS including neurotransmission and the maintenance of vascular tone. Previously, we reported that cell lines obtained by retroviral immortalization of tissue macrophages (M?;) could be induced to synthesize nitrite (NO), a stable end product of the NO synthetic pathway. We have further characterized the induction and activity of this pathway in a panel of seven microglial clones derived from primary embryonic mouse brain cultures. Like M?;, these clones were found to release high levels of NO_-² in response to recombinant interferon-γ (rIFN-γ) as a priming signal together with either bacterial lipopolysaccharide (LPS) or exogenous recombinant tumor necrosis factor-α (rTNF-α). As previously demonstrated for M?;, phagocytosis of zymosan particles during induction of enzyme activity enhanced subsequent NO production, which is of interest in light of the postulated phagocytic role of microglia within the CNS. Biochemical characterization of enzyme activity in intact microglial clones and in isolated cytosolic fractions indicates that the microglial NO synthase present in these murine cell clones represents the M?;-like isotype. These findings suggest that microglial cells could represent a major source of NO within the CNS.     

First experience in healthy volunteers with technetium-99m l,l-ethylenedicysteine,a new renal imaging agent

Animal studies have indicated that technetium-99m l,l-ethylenedicysteine (^99mTc-l,l-EC) may be a promising tracer agent for renal function studies. We have performed a paired study with ^99mTc-mercaptoacetyltriglycine (^99mTc-MAG₃) and ^99mTc-l,l-EC in six male volunteers. In both cases, iodine-131-labelled o-iodohippurate was co-injected as an internal biological standard. The analog images between 0 and 30 min p.i. were of identical diagnostic value for both tracer agents. The two renograms were similar in all volunteers. The mean 1-h plasma clearance for ^99mTc-MAG₃ and 99 mTc-l,l-EC was significantly different, respectively 382.9 ± 17.1 ml/min per 1.73 m² versus 460.2 ± 47.7 ml/min per 1.73 m² (P<0.003). The urinary excretion after 30 min p.i. was 69.4% ± 5.6% of the injected dose for ^99mTc-MAG₃ versus 66.5% ± 2.5% for ^99mTc-l,l-EC (P>0.05) and after 60 min p.i. respectively 83.1% ± 3.9% versus 79.8 % ± 4.3 % (P > 0.05). ^99mTc-l,l-EC has a very low plasma protein binding (31% ± 6.8%) as compared to ^99mTc-MAG₃ (88% ± 5.2%) and a larger volume of distribution. Although the exact mechanism responsible for the high plasma clearance of ^99mTc-l,l-EC is not yet fully known, we conclude that this new agent merits further clinical evaluation in patients to establish its value as a renal radiopharmaceutical. Correspondence to: A. Verbruggen     

Common carotid haemodynamic and metabolic effects of acutely administered nifedipine in human subarachnoid haemorrhage

Although the drugs known as "calcium antagonists" exert inhibitory actions on vascular smooth muscle, there are no quantitative data concerning the clinical use of these vasodilator agents in human subarachnoid haemorrhage. In the present clinical study, we have measured the effects of nifedipine (20 mg tablet) on common carotid artery diameter (D) blood flow velocity (V) common carotid blood flow (CCBF) as an index of cerebral blood flow, systolic (Qs) and diastolic (Qd) blood flow fractions using a pulsed Doppler apparatus and on carotid arterial pressure (CAP), heart rate (HR) and oxygen consumption (VO2). Eight patients with subarachnoid haemorrhage were studied during anaesthesia for cerebral angiography. Thirty minutes after sublingual nifedipine, diameter (P less than 0.05), blood flow velocity (P less than 0.001), CCBF (P less than 0.001), Qs (P less than 0.05), and Qd (P less than 0.05) increased with a decrease in Qs/Qd ratio (P less than 0.05). carotid vascular resistance (CVR) fell (P less than 0.02) and oxygen consumption of the brain increased (P less than 0.01). Systolic, diastolic, and mean carotid blood pressure, heart rate, and arteriovenous difference in oxygen were unchanged. The increase in CCBF was closely correlated with the vascular resistance in the control state (r = 0.928, P less than 0.001) and with oxygen consumption (r = 0.869, P less than 0.001). We conclude that in vivo, nifedipine exerts a preferential action on cerebral vessels, vasodilating large arteries and arterioles. This action is more powerful if the vessels are already vasoconstricted. Thus, the use of nifedipine could be fruitful in cerebral ischaemia that is secondary to subarachnoid haemorrhage.     

Evaluation of intensification and maintenance programs in the treatment of acute lymphoblastic leukemia.

This cooperative prospective study was designed to answer the following questions in cases with acute lymphoblastic leukemia induced to achieve complete remission with the combination of vincristine and prednisone (if by day 29 the bone marrow was not M1, daunorubicin was added to the former regimen) and who received preventive CNS therapy with 2400 rad of cobalt-60 to craniocervical region and simultaneously intrathecal methotrexate and dexamethasone: 1) Is a short intensification with cytosine-arabinoside and cyclophosphamide immediately after complete remission useful? 2) Does the use of weekly doses of 6-mercaptopurine and methotrexate have the same maintenance effect as daily 6-mercaptopurine and twice weekly methotrexate? and 3) Do further 3 month-doses of intrathecal methotrexate and dexamethasone help to decrease still more the incidence of meningeal leukemia? From October 1972 to December 1975, 473 previously untreated patients entered this study and 465 (390 children and 75 adults) are evaluated in this paper. Of them, 373 (80%) achieved complete remission (children 84% and adults 61%). Out of 109 "high risk" children (one or more of the following characteristics at diagnosis: marked organomegaly, mediastinal widening, leukocytosis above 50000/mm3 and CNS involvement) 83 (76%) and out of 281 "standard risk" children (all the others) 244 (87%) achieved complete remission. The median duration of complete remission according to different prognostic factors was as follows: "high risk" children 10 months, adults 24 months and "standard risk" children 25 months. Duration of complete remission of the "standard risk" children in relation to with or without intensification, daily or weekly maintenance and additional intrathecal therapy or none, showed no significant difference; however, those who received intensification, daily maintenance and further intrathecal therapy behaved slightly better. Median survival for all the cases of this study was as follows: adults 10 months, "high risk" children 12 months and "standard risk" children 26 months. At 36 months, 13% of "high risk" children, 25% of adults and 39% of "standard risk" children are still alive. We conclude that the variables studied in this protocol did not show significant extension of complete remission, however the sum of them seems to offer some advantage. Moreover, what appears clear is the importance of prognostic factors which must be taken into account in future studies.     

Het identificeren van benzodiazepinen en het aantonen van ontledings-produkten met behulp van een en hetzelfde DLC-systeem

Samenvatting Een systeem voor dunnelaagchromatografie wordt beschreven met behulp waarvan twaalf verschillende benzodiazepinen kunnen worden geïdentificeerd en waarmee tevens eventuele ontledingsprodukten kunnen worden aangetoond. Er wordt gebruik gemaakt vanhptlc Silica Gel 60 F₂₅₄ plaatjes en als loopvloeistof wordt tolueen-methanol (96 + 6) gebruikt.De vlekjes kunnen direct onderuv-licht worden waargenomen; ze kunnen nader worden geïdentificeerd na bespuiten met zwavelzuur en/of het reagens van Bratton Marshall. Van enkele benzodiazepinen kan de identiteit echter pas worden vastgesteld nadat ze zijn gehydrolyseerd.     

Interaction between polycyclic aromatic hydrocarbons, crude oil and oil dispersants in the Salmonella mutagenesis assay

Mutagenicity assays were carried out in the Salmonella/microsometest, using five S. typhimurium his strains (TA1535, TA1537,TA1538, TA98 and TA100), both in the presence and absence ofpost-mitochondrial preparations from Aroclor-induced rat liversand suitable co-factors. Seven oil dispersants showed a widerange of toxicity towards the bacterial strains, without elicitingany mutagenic response at sub-lethal concentrations. One sampleof crude oil and its dimethylsulphoxide (DMSO) extract werealso negative, and no mutagenic effect could be detected bychecking mixtures of crude oil with each of the seven dispersantstested. Two polycyclic aromatic hydrocarbons, benzo(a)pyrene(BP) and benz(a) anthracene (BA), which are generally consideredto be the most documented carcinogenic components of crude oil,were mutagenic with a frameshift mechanism, requiring metabolicactivation. BP mutagenicity was not affected by oil dispersantsnor by seawater. Conversely, the mutagenicity of BP DMSO-solutionswas abolished in the presence either of whole crude oil, ofits DMSO extract, or of crude oil/dispersant mixtures. Theselosses of mutagenicity could be mainly ascribed to a mechanicaltrapping of BP by oil components.     

Randomized trial of two beta-mimetic drugs (ritodrine and fenoterol) in acute intra-partum tocolysis

Summary The uterine inhibitory effect and potential maternal and fetal side effects of two -mimetic compounds, ritodrine hydrochloride and fenoterol hydrobromide, were compared in a randomized trial. The drugs were administered by intravenous infusion to 24 healthy term nulliparous women during effective first-stage labour; each of them received fenoterol (1, 2, or 4 µg/min) or ritodrine (100, 200, or 400 µg/min). There was no difference between the drugs in the intensity of the uterine inhibition. However, for a similar inhibitory effect, the duration of tocolysis was longer after ritodrine. During the intrapartum and neonatal periods, neither compound induced any change in the fetal parameters investigated, and their effects on maternal parameters were comparable.     

Development and inhibition of the target phenomenon in tenotomized rat muscle

Summary The sequence of development of the target phenomenon in tenotomized gastrocnemius muscle was studied: the presence of target fibres was preceded by the occurrence of contraction bands and of moth eaten appearance of the fibres. This phenomenon was far more pronounced and occurred earlier in type II than in type I fibres.This target phenomenon and the contraction artefacts could be inhibited in the tenotomized muscles by simultaneous neurotomy or immobilization of the muscle with a plaster cast. Delayed denervation inhibited also the target phenomenon, if performed less than 5 days after the tenotomy. These series of experiments seem to indicate that the target phenomenon occurs in more irritable muscle fibres and that muscular activity is needed for its development.     

Effect of bronchodilation on regional lung function measured by 133Xe and gamma camera

Using ¹³³Xe, a gamma camera and off-line data handling the effect of inhaled Salbutamol on regional lung function was measured in six patients with chronic obstructive lung disease and associated bronchospasm.After bronchodilation only minor changes were obtained in regional ventilation or in the arterial hypoxemia, although the overall airways obstruction improved markedly. These findings suggest that the bronchodilating agent had an effect mainly on the larger airways and almost did not influence the function of the more peripheral lung units responsible for gas exchange. Also, a slight but direct effect on the perfusion was demonstrated. The effect on the ¹³³Xe ventilation-perfusion ratio was not correlated with that on the hypoxemia, indicating that the first is not a good representation of the latter.Supported by a grant from the Fonds voor Geneeskundig Wetenschappelijk Onderzoek     

Synthesis,physical properties and microbiological activities of more water soluble silver sulfadiazine derivatives

In this study the preparation of five hydrophilic derivatives of sulfadiazine is reported. The common structural element in the compounds is the 2-sulfonamidopyrimidine moiety. Three of these compounds are suitable for the preparation of a photostable 1∶1 silver compound. These silver compounds are five to ten times more water soluble than silver sulfadiazine. TheIr,¹H- and¹³C-Nmr data point to a similar co-ordination of silver in these compounds as with silver sulfadiazine. The microbiological activity of these silver compounds againstSt. aureus is slightly lower.