[Emergency department utilization by HIV-positive adults in a Belgian setting]. / Etude des motifs d'admission au service des Urgences d'une cohorte de patients infectés par le VIH suivis au CHU de Liège.

The use of the emergency department (ED) by human immunodeficiency virus (HIV)-infected adults undergoes an evolution following the introduction of antiretroviral therapy (ART). Improving our knowledge about ED use characteristics will contribute to a correct diagnosis and therapeutic approach in this patient group, at the moment they are discharged from the ED. We conducted a one-year retrospective study on characteristics of ED use involving 1026 patients living with HIV. The majority of them was treated with antiretroviral therapy (95 %) and had a viral load lower than 50 copies (73.6 %). Among them, 117 patients (11.8 %) were admitted at least once to the ED. The most common ED discharge diagnoses were related to trauma (30 %). This study shows that the great majority of diagnoses were not related to infectious diseases (6.3 %, of which half were HIV-related). One hypothesis to explain these results would be that HIV-positive adults in this study had excellent antiretroviral coverage and were well controlled in terms of HIV.

L'utilisation du département des urgences (DU) par les adultes infectés par le virus de l'immunodéficience humaine (VIH) évolue suite à l'instauration des traitements antirétroviraux (TAR). Nous avons besoin d'améliorer nos connaissances à ce sujet et d'en savoir plus sur le diagnostic de ces patients lorsqu'ils quittent le service d'urgence. Nous avons réalisé une étude rétrospective sur une durée d'un an et qui s'intéresse aux caractéristiques de l'utilisation du DU par 1.026 patients vivant avec le VIH. La majorité d'entre eux était sous traitement anti-rétroviral (95 %) et avait une charge virale inférieure à 50 copies (73,6 %). Parmi eux, 117 (11,8 %) se sont présentés au moins une fois au DU. Les principaux motifs d'admission étaient d'ordre traumatologique (30 %). Cette étude montre que la grande majorité des motifs d'admission au DU des patients vivant avec le VIH n'était pas en rapport avec des pathologies infectieuses (seulement 6,3 %, dont la moitié directement liées au VIH). Une hypothèse pour expliquer ces résultats serait que les patients étudiés bénéficiaient d'une excellente couverture anti-rétrovirale et étaient bien contrôlés en termes de VIH.

[Hypercalcemia and acute renal failure: a case report of vitamin D intoxication]. / Le cas clinique du mois. Hypercalcémie et insuffisance rénale aiguë: un cas clinique d'intoxication à la vitamine D.

Vitamin D (VTD) deficiency has become a topical issue leading to screening with frequent supplementation. The latter can be dangerous and exceptionally causes overdoses. We report the case of a 20 year old patient with abdominal pain in the setting of hypercalcemia due to intoxication by VTD. This case offers the opportunity to describe the differential diagnosis of hypercalcemia and to brownse through the literature in search of clinical practice recommendations for VTD supplementation.

[Role of vitamin D in HIV infection]. / Rôle de la vitamine D dans l'infection par le VIH: revue des connaissances actuelles.

Besides its role in bone metabolism, vitamin D shows properties on autoimmune, oncological, cardiovascular, metabolic, or infectious diseases. In this article, we talk about interpellant relationships between vitamin D and HIV. This hormone plays an important role in HIV infection, as much at a skeletal level than in the course of the disease itself. First, we notice that a low vitamin D status is currently associated with HIV infection. Moreover, it is now known that low rate of 1,25-dihydroxyvitamin D in HIV patients is associated with advanced clinical HIV infection and increased mortality. Thus, vitamin D deficiency has to be considered as an important factor in HIV progression. Indeed, vitamin D increases macrophage activity, in some way through autophagy, and this process can inhibit HIV-1 infection. Then we consider the implications of antiretroviral therapies on vitamin D metabolism. We finally evaluate the benefits of a vitamin D supplementation in HIV + patients.

[Neurosurgical treatments for pain]. / Les traitements neurochirurgicaux de la douleur.

Pain represents the most frequent symptom faced by general practitioners and is associated with 60% of neurological troubles. Pain consists in a conscious, subjective, unpleasant and protective sensory experience transmitted by thermoalgic pathways in the central nervous system (nociceptive pain). Lesioning of peripheral or central sensory pathways can also generate pain associated with hypoesthesia (phantom or neuropathic pain). Since the 1920's, neurosurgeons have attempted to alleviate nociceptive and neuropathic chronic pain by interrupting (irreversible interruptive techniques) thermoalgic fibers (neurotomies, rhizotomies, cordotomies, tractotomies, thalamotomies, cingulotomies). Some of them (neurotomies, rhizotomies) are still used today when all medications have failed. They can provide immediate and tremendous pain relief like in trigeminal neuralgia. However, the technique, when not sufficiently selective, can generate a neuropathic pain and then a short-lating pain relief. Increasing knowledge on pathophysiological mechanisms of pain allowed surgery to interfere with the functioning of the sensory circuits without lesioning and to modulate neuronal activity in order to reduce pain (neuromodulation). Non-lesioning modulating techniques (then reversible) appeared (deep brain stimulation, epidural spinal cord or motor cortex stimulation, intrathecal infusion, radiosurgery) and are currently applied to efficiently alleviate neuropathic pain.

Inhibitory effect of curcuminoids and tetrahydrocurcuminoids on equine activated neutrophils and myeloperoxidase activity.

In the horse, the inflammation response to various pathologies (intestinal strangulations, laminitis, etc.) involves an excessive stimulation of the polymorphonuclear neutrophils releasing reactive oxygen species (ROS) and myeloperoxidase (MPO). The aim of the present work was to study the effect of natural polyphenols, curcuminoids and tetrahydrocurcuminoids (THC) on isolated stimulated equine neutrophils and on the activity of purified MPO. The ROS production and the release of MPO by activated neutrophils were measured by chemiluminescence and ELISA techniques, respectively. The activity of purified MPO was measured by studying its nitration, chlorination or oxidation capacity and by using an original method called SIEFED allowing the study of drug interaction with the enzyme without interferences of the medium. Curcuminoids and THC had dose-dependent inhibitory effects on ROS production and MPO release by activated neutrophils and on purified MPO activity. We suggest that the higher efficacy of curcuminoids versus THC could be explained, at least partially, by its chemical structure: the conjugated double bounds and the plane structure of curcuminoids made easier the neutralization of the radical species generated by activated neutrophils and the interaction of the drug with the active site of MPO. These inhibitory effects of curcuminoids on the oxidant activity of equine neutrophils and on MPO activity open therapeutic perspectives in equine pathologies with excessive inflammatory reactions.

Anatomical and physiological basis, clinical and surgical considerations, mechanisms underlying efficacy and future prospects of cortical stimulation for pain.

The analgesic efficacy of cortical stimulation on refractory neuropathic pain has been established. Although it offers pain relief to 45-75% of the patients, this technique remains under evaluation and the definitive protocol for its application has not been established yet. The mechanisms underlying the analgesic efficacy of cortical stimulation are still largely unknown. Successive technical adaptations have been proposed and tried in order to reduce the number of non-responding patients. In this chapter, we summarize the limited amount of crucial information that has been acquired so far on pain processing in the central nervous system, on the functional pathophysiology of neuropathic pain and on the mechanisms underlying the efficacy of cortical stimulation. We also discuss key issues that could help to increase the success rate and enhance the future prospects of the technique.

Endovascular treatment of intracranial aneurysms with a branch arising from the sac.

BACKGROUND AND PURPOSE: The endovascular treatment (EVT) of intracranial aneurysms is no more limited by the presence of a branch at the neck or by the neck width. Saccular aneurysms with a branch arising from the sac, however, are mostly candidates for surgery rather than embolization. We prospectively evaluated the feasibility and safety of the EVT in such cases. METHODS: Between May and November 2004, 9 consecutive patients with a saccular aneurysm that presents a branch arising from the sac were treated by embolization. There were 7 women and 2 men (mean age, 58 years). Six patients presented with a subarachnoid hemorrhage (SAH), and 3 were asymptomatic. All patients were treated by selective coiling with (n = 6) or without (n = 3) the remodeling technique. Clinical outcome was assessed with a modified Glasgow Outcome Scale at 3 months. RESULTS: EVT was successfully performed in all patients and resulted in 7 excellent outcomes and 2 deaths related to SAH complications. The arterial branch could be preserved in 7 cases and intentionally occluded in 2. Neither embolic nor ischemic complication occurred in the vascular territory of the involved branch. Angiographic results showed 5 neck remnants, 2 incomplete occlusions, and 2 complete occlusions. No rebleeding occurred. CONCLUSION: Our study, though limited by its small patient population, suggests that saccular intracranial aneurysms with a branch arising from the sac may be treated by endovascular approach with excellent clinical results; however, larger series with long-term follow-up are mandatory to confirm these preliminary results mostly in terms of anatomic stability.

Curative potential of herpes simplex virus thymidine kinase gene transfer in rats with 9L gliosarcoma.

The transfer of the gene coding for the thymidine kinase of the herpes simplex virus (HSV-tk), followed by ganciclovir (GCV) administration, has been described for the treatment of several types of cancer, especially brain tumors. We further studied the efficacy of this approach by using the 9L rat gliosarcoma model, and cells producing 5 x 10(3), 9 x 10(4), 3 x 10(5) HSV-tk retroviral particles per milliliter. Their stereotactic injection in 9L brain tumors and GCV treatment did not result in any increase of survival. To study a model of optimal in vivo transduction, we examined the survival of rats with tumors growing from 9L cells that had been previously transduced in vitro with the HSV-tk vectors (9LTk cells). We observed that GCV administration cured 26% (n = 42) of the animals with 9LTk brain tumors, with most of the relapsing tumors remaining HSV-tk positive. The increase of either the dose or the duration of GCV treatment did not improve the survival rate. But the cerebral localization of the tumor played an important role, because this survival rate reached 67% (n = 12) when similar tumors were growing subcutaneously. No or only marginal antitumoral responses were induced by the presence of a selectable marker gene in the HSV-tk vectors. These results demonstrate that in vitro HSV-tk gene transfer in 9L tumor cells, but not in vivo gene transfer, followed by GCV treatment, is able to cure rats at a rate that is higher for subcutaneous than for intracerebral tumors.

Recent advances in the chemistry of cholecystokinin receptor ligands (agonists and antagonists).

During the last few years, cholecystokinin (CCK) has emerged as an important hormone. This polypeptide has been located either in peripheral tissues such as the gastro-intestinal tract and the pancreas as well as in the central nervous system. High affinity CCK receptors are divided in two main subtypes: the CCK-A (A for (A for "alimentary") and the CCK-B (B for "brain") receptors. The latters are currently associated with the gastrin receptors. Since CCK is involved in many different biological processes such as gut function, digestive processes, control of feeding behaviour and neurotransmitter release, the therapeutical potential of cholecystokinin receptor ligands seems to be extremely broad and promising. Several families of CCK receptor ligands (peptides, peptidomimetics, peptoids or non-peptides) were prepared during the last twenty years. The main goal of these researches was to improve agonistic or antagonistic potency but also to find selective compounds for a specific CCK receptor subtype. This review presents the recent developments (since 1995) in the chemistry of CCK receptor ligands.

New trends in the design of drugs against Alzheimer's disease.

First described by Alois Alzheimer in 1907, Alzheimer's disease (AD) is the most common dementia type, affecting approximately 20 million people worldwide. As the population is getting older, AD is a growing health problem. AD is currently treated by symptomatic drugs, the acetylcholinesterase inhibitors, based on the cholinergic hypothesis (1976). During the past decade, advances in neurobiology have conducted to the identification of new targets. Although some of these innovative approaches tend to delay onset of AD, others are still symptomatic. In this review, we present an overview of the several strategies and new classes of compounds against AD.

Recent developments in the chemistry of potassium channel activators: the cromakalim analogs.

Potassium channels play a crucial role in controlling the cell membrane potential. Among the different varieties of K(+) channels, the ATP-sensitive potassium channels (K(ATP) channels) have been characterized in numerous cell types, such as skeletal and smooth muscle cells, endocrine cells, cardiac cells and central neurons. Several molecules are known to activate K(ATP) channels and have been named "potassium channel openers" (PCOs). Such compounds may have a wide therapeutic potential and a few drugs are currently used as antihypertensive agents. Different chemical series of PCOs have been explored. This heterogeneous group of organic compounds comprises the benzopyran series including potent vasorelaxant drugs, such as cromakalim. The latter compound, a typical example of potassium channel opener, exerts its biological effect by activating K(ATP) channels. This review presents recent developments in the chemistry of cromakalim analoges and reports chemical aspects governing their potency and tissue selectivity.

Recent advances in inducible cyclooxygenase (COX-2) inhibition.

Cyclooxygenase is the key enzyme in the biosynthesis of prostanoids, biologically active substances that are involved in several physiological processes but also in pathological conditions such as inflammation. Since ten years now, it is well known that this enzyme exists under two forms: a constitutive (COX-1) and an inducible form (COX-2). Both enzymes are sensitive to inhibition by conventional nonsteroidal anti-inflammatory drugs (NSAIDs). Observations that COX-1, involved in several homeostatic processes, played a housekeeping role while COX-2 expression was associated with inflammation and other pathologies such as cancer proliferation have led to the development of COX-2 selective inhibitors in order to reduce the classical side-effects, of which gastric irritation is the most common, associated with the use of conventional NSAIDs.

6-Substituted 2-oxo-2H-1-benzopyran-3-carboxylic acid as a core structure for specific inhibitors of human leukocyte elastase.

Pyridyl esters of 6-substituted 2-oxo-2H-1-benzopyran-3-carboxylic acid were designed as mechanism-based inhibitors of human leukocyte elastase. Compounds of series 4 specifically inhibited this enzyme. Several of the tested compounds (series 2 and 3) acted as powerful time-dependent inhibitors of both human leukocyte elastase and alpha-chymotrypsin; some compounds of these series inhibited thrombin. Trypsin was not inhibited. A transient inactivation was observed for human leukocyte elastase (k(i)/K(I) = 107 000 M(-1). s(-1) for 4c) and thrombin (k(i)/K(I) = 7 200 M(-1).s(-1) for 3b) as demonstrated by spontaneous or hydroxylamine-accelerated reactivation, irrespective of the nature of the substituent at the 6-position. Conversely, alpha-chymotrypsin was irreversibly inhibited by 6-chloromethyl derivatives (k(i)/K(I) = 107 400 M(-1). s(-1) for 3b). The presence of a latent alkylating function at the 6-position (chloromethyl group) was required for leading to this inactivation. In the absence of such an alkylating function (series 4), human leukocyte elastase was specifically inhibited suggesting that this new series of human leukocyte elastase inhibitors may be of potential therapeutic interest in degradative and degenerative processes involving this enzyme.

Esters and amides of 6-(chloromethyl)-2-oxo-2H-1-benzopyran-3-carboxylic acid as inhibitors of alpha-chymotrypsin: significance of the "aromatic" nature of the novel ester-type coumarin for strong inhibitory activity.

A series of esters and amides of 6-(chloromethyl)-2-oxo-2H-1-benzopyran-3-carboxylic acid were synthesized and evaluated in vitro for their inhibitory activity toward bovine alpha-chymotrypsin and human leukocyte elastase. Both series behaved as time-dependent inhibitors of alpha-chymotrypsin, but ester-type coumarins were clearly more efficient than the corresponding amides in inactivating the serine proteinase. The best inactivations were observed with "aromatic" esters, in particular with meta-substituted phenyl esters such as m-chlorophenyl 6-(chloromethyl)-2-oxo-2H-1-benzopyran-3-carboxylate, which appears to be one of the most powerful inactivators of alpha-chymotrypsin yet reported (kinact/KI = 760,000 M-1 S-1 at pH 7.5 and 25 degrees C). Usually, the coumarin derivatives failed to inhibit significantly human leukocyte elastase. As a result, the reported series of aromatic coumarinic esters behaves as a new chemical family of selective alpha-chymotrypsin inhibitors.

4H-1,2,4-Pyridothiadiazine 1,1-dioxides and 2,3-dihydro-4H-1,2, 4-pyridothiadiazine 1,1-dioxides chemically related to diazoxide and cyclothiazide as powerful positive allosteric modulators of (R/S)-2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic acid receptors: design, synthesis, pharmacology, and structure-activity relationships.

A series of 4H-1,2,4-pyridothiadiazine 1,1-dioxides and 2, 3-dihydro-4H-1,2,4-pyridothiadiazine 1,1-dioxides bearing various alkyl and aryl substituents on the 2-, 3-, and 4-positions was synthesized and tested as possible positive allosteric modulators of the (R/S)-2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic acid (AMPA) receptors. Many compounds were found to be more potent than the reference compounds diazoxide and aniracetam as potentiators of the AMPA current in rat cortex mRNA-injected Xenopus oocytes. The most active compound, 4-ethyl-2,3-dihydro-4H-pyrido[3,2-e]-1,2, 4-thiadiazine 1,1-dioxide (31b), revealed an in vitro activity on Xenopus oocytes not far from that of cyclothiazide, the most potent allosteric modulator of AMPA receptors reported to date. Moreover, 31b, but not cyclothiazide, was found to potentiate the duration and the amplitude of the excitatory postsynaptic field potentials induced by electric stimulation in rat hippocampal slices. Such an effect could indicate, for 31b, but not for cyclothiazide, a possible interaction with postsynaptic AMPA receptor binding sites located on hippocampal CA1 neurons. Structure-activity relationships indicated that the structural requirements responsible for a biological activity on AMPA receptors are different from those responsible for an inhibitory activity on the insulin releasing process (putative ATP-sensitive K+-channel openers). For instance, 31b and other related dihydropyridothiadiazines were found to be ineffective as inhibitors of insulin release from rat pancreatic B-cells, in contrast to diazoxide and known pyridothiadiazines reported as ATP-sensitive K+-channel openers. Conversely, the pyridothiadiazines active on B-cells were found to be ineffective as potentiators of the AMPA currents in Xenopus oocytes. Thus, 31b appeared to be more specific than diazoxide as an AMPA receptor modulator. This compound may be considered as a new pharmacological tool, different from diazoxide and cyclothiazide, for studying AMPA receptors. Moreover, 31b can also constitute a new therapeutic agent for the treatment of cognitive disorders.

3-Alkylamino-4H-pyrido[2,3-e]-1,2,4-thiadiazine 1,1-dioxides structurally related to diazoxide and pinacidil as potassium channel openers acting on vascular smooth muscle cells: design, synthesis, and pharmacological evaluation.

A series of 3-alkylamino-4H-pyrido[2,3-e]-1,2,4-thiadiazine 1, 1-dioxides structurally related to diazoxide and pinacidil were synthesized and tested as possible K(ATP) channel openers on isolated pancreatic endocrine tissue as well as on isolated vascular, intestinal, and uterine smooth muscle. In contrast to previously described 3-alkylamino-4H-pyrido[4,3-e]-1,2,4-thiadiazine 1, 1-dioxides, most of the new compounds were found to be poorly active on B-cells but exhibited clear vasorelaxant properties. 3-(3, 3-Dimethyl-2-butylamino)-4H-pyrido[2,3-e]-1,2,4-thiadiazine 1, 1-dioxide (4d) and 7-chloro-3-(3, 3-dimethyl-2-butylamino)-4H-pyrido[2,3-e]-1,2,4-thiadiazine 1, 1-dioxide (5d), two compounds bearing the alkyl side chain of pinacidil, were found to be the most active representatives of their respective series on rat aorta rings. 3-Cycloalkylalkylamino- and 3-aralkylamino-7-chloro-4H-pyrido[2,3-e]-1,2,4-thiadiazine 1, 1-dioxides also expressed myorelaxant activity on electrically stimulated guinea pig ileum and on oxytocin-induced contractions of the rat uterus. Further biological investigations ((86)Rb efflux measurements, vasodilator potency on 30 and 80 mM KCl-induced contractions in the absence and presence of glibenclamide) revealed that compounds 4d and 5d, but not compound 5f, expressed the pharmacological profile of classical K(ATP) channel openers. In conclusion, by changing the position of the nitrogen atom in the pyridine ring, we now have obtained a family of drugs expressing an opposite tissue selectivity. Taken as a whole, the present findings also suggest that 3-alkylamino-4H-pyrido[2,3-e]-1,2,4-thiadiazine 1, 1-dioxides such as 4c, 4d, 5c, and 5d may be considered as new examples of K(ATP) channel openers expressing a pharmacological profile similar to that of pinacidil and diazoxide.

3-and 4-substituted 4H-pyrido[4,3-e]-1,2,4-thiadiazine 1,1-dioxides as potassium channel openers: synthesis, pharmacological evaluation, and structure-activity relationships.

4-N-Substituted and -unsubstituted 3-alkyl- and 3-(alkylamino)-4H-pyrido[4,3-e]-1,2,4-thiadiazine 1,1-dioxides were synthesized and tested vs diazoxide and selected 3-alykl- and 3-(alkylamino)-7-chloro-4H-1,2,4-benzothiadiazine 1,1-dioxides as potassium channel openers on pancreatic and vascular tissues. Several 4-N-unsubstituted 3-(alkylamino)pyridothiadiazines and some 3-(alkylamino)-7-chlorobenzothiadiazines were found to be more potent than diazoxide for the inhibition of the insulin-releasing process. Moreover, the 3-(alkylamino)pyridothiadiazines appeared to be more selective for the pancreatic than for the vascular tissue. By means of the pharmacological results obtained on pancreatic B-cells, structure--activity relationships were deduced and a pharmacophoric model for the interaction of these drugs with their receptor site associated to the pancreatic K(ATP) channel was proposed. According to their selectivity for the B-cell (endocrine tissue) vs the vascular (smooth muscle tissue) ionic channel, selected 3-(alkylamino)-4H-pyrido[4,3-e]-1,2,4,-thiadiazine 1,1-dioxides may serve as pharmacological tools in studying the K(ATP) channels ("pancreatic-like" K(ATP) channels) in other tissues.

Original 2-alkylamino-6-halogenoquinazolin-4(3H)-ones and K(ATP) channel activity.

A series of 6-substituted 2-alkylaminoquinazolin-4(3H)-ones structurally related to 3-alkylamino-4H-pyrido[4,3-e]-1,2,4-thiadiazine 1,1-dioxides were synthesized and tested as putative K(ATP) channel openers on isolated pancreatic endocrine tissue as well as on isolated vascular, intestinal, and uterine smooth muscle. Most of the 6-halogeno-2-alkylaminoquinazolin-4(3H)-ones were found to inhibit insulin release from pancreatic B-cells and to exhibit vasorelaxant properties. In contrast to their pyridothiadiazine dioxide isosteres previously described as more active on the endocrine than on the smooth muscle tissue, quinazolinones cannot be considered as tissue selective compounds. Biological investigations, including measurements of (86)Rb, (45)Ca efflux from pancreatic islet cells and measurements of vasodilator potency in rat aortic rings exposed to 30 or 80 mM KCl in the presence or the absence of glibenclamide, were carried out with 6-chloro- and 6-iodo-3-isopropylaminoquinazolin-4(3H)-ones. Such experiments showed that, depending on the tissue, these new compounds did not always express the pharmacological profile of pure K(ATP) channel openers. Analyzed by X-ray crystallography, one example of quinazolinones appeared to adopt a double conformation. This only suggests a partial analogy between the 2-alkylaminoquinazolin-4(3H)-ones and the 3-alkylamino-4H-pyrido[4,3-e]-1,2,4-thiadiazine 1,1-dioxides. In conclusion, the newly synthesized quinazolinones interfere with insulin secretion and smooth muscle contractile activity. Most of the compounds lack tissue selectivity, and further investigations are required to fully elucidate their mechanism(s) of action.

Regional methionine and glucose uptake in high-grade gliomas: a comparative study on PET-guided stereotactic biopsy.

UNLABELLED: Gliomas are regionally heterogeneous tumors. The local relationship between histologic features and radiotracer uptake evaluated by PET should therefore influence analysis and interpretation of PET results on gliomas. This study explored this local relationship as a result of PET guidance of stereotactic biopsies. METHODS: Local histology was confronted to the regional uptake of 18F-2-fluoro-2-deoxy-D-glucose (18F-FDG) and 11C-methionine (11C-MET) in 14 patients with high-grade glioma diagnosed during a procedure of PET-guided stereotactic biopsies. We analyzed the uptake of both tracers in regions of interest centered on the stereotactic coordinates of 93 biopsy samples. RESULTS: A semiquantitative analysis revealed a significant regional correlation between 11C-MET and 18F-FDG uptakes. Uptake of both tracers was significantly higher on the site of tumor samples showing anaplastic changes than in the rest of the tumor. Presence of necrosis in anaplastic areas of the tumor significantly reduced the uptake of 11C-MET. CONCLUSION: PET with 11C-MET and 18F-FDG may help to evaluate, in vivo, the metabolic heterogeneity of human gliomas. Anaplasia is a factor of increased uptake of both tracers, but microscopic necrosis in anaplastic areas influences their uptake differently. This finding probably relates to the differences in tracer uptake by non-neoplastic components of necrotic tumors. These results underline the complementary role of 18F-FDG and 11C-MET for the study of brain tumors and favors their use for stereotactic PET guidance of diagnostic or therapeutic procedures.

Synthesis and characterization of a quinolinonic compound activating ATP-sensitive K(+) channels in endocrine and smooth muscle tissues.

Original quinolinone derivatives structurally related to diazoxide were synthesized and their effects on insulin secretion from rat pancreatic islets and the contractile activity of rat aortic rings determined. A concentration-dependent decrease of insulin release was induced by 6-chloro-2-methylquinolin-4(1H)-one (HEI 713). The average IC(50) values were 16.9+/-0.8 microM for HEI 713 and 18.4+/-2.2 microM for diazoxide. HEI 713 increased the rate of (86)Rb outflow from perifused pancreatic islets. This effect persisted in the absence of external Ca(2+) but was inhibited by glibenclamide, a K(ATP) channel blocker. Inside-out patch-clamp experiments revealed that HEI 713 increased K(ATP) channel openings. HEI 713 decreased (45)Ca outflow, insulin output and cytosolic free Ca(2+) concentration in pancreatic islets and islet cells incubated in the presence of 16.7 or 20 mM glucose and extracellular Ca(2+). The drug did not affect the K(+)(50 mM)-induced increase in (45)Ca outflow. In aortic rings, the vasorelaxant effects of HEI 713, less potent than diazoxide, were sensitive to glibenclamide and to the extracellular K(+) concentration. The drug elicited a glibenclamide-sensitive increase in (86)Rb outflow from perifused rat aortic rings. Our data describe an original compound which inhibits insulin release with a similar potency to diazoxide but which has fewer vasorelaxant effects. Our results suggest that, in both aortic rings and islet tissue, the biological effects of HEI 713 mainly result from activation of K(ATP) channels ultimately leading to a decrease in Ca(2+) inflow.