Search

In this work we study the distributed implementation of multicost routing in mobile ad hoc networks. In contrast to single-cost routing, where each path is characterized by a scalar, in multicost routing a vector of cost parameters is assigned to each link, from which the cost vectors of the paths are calculated. These parameters are combined according to an optimization function for selecting the optimal path. Up until now the performance of multicost routing in ad hoc networks has been evaluated either at a theoretical level or by assuming that nodes are static and have full knowledge of the network topology and nodes' state. In the present paper we assess the performance of multicost routing, based on energy-related parameters, in mobile ad hoc networks by embedding its logic in the Dynamic Source Routing (DSR) algorithm, which is a well-known distributed routing algorithm. We compare the performance of the multicost-DSR algorithm to that of the original DSR algorithm under various node mobility scenarios. The results confirm that the multicost-DSR algorithm improves the performance of the network in comparison to the original DSR, by reducing energy consumption overall in the network, spreading energy consumption more uniformly across the network, and reducing the packet drop probability and delivery delay.

In this work we study the combination of multicost routing and variable transmission power in wireless ad-hoc networks. In multicost routing, each link is assigned a cost vector consisting of several parameters. These parameters are treated separately and are combined at the end of the algorithm using various optimization functions, corresponding to different routing schemes, for selecting the optimal path. The cost parameters we use are the hop count, the interference caused, the node residual energies, and the node transmission powers. We assume that nodes can use power control to adjust their transmission power to the desired level. The experiments conducted show that the combination of multicost routing and adjustable transmission power can lead to reduced interference and energy consumption, improving network performance and lifetime.

In this work we study the dynamic one-to-one communication problem in energy- and capacity-constrained wireless ad-hoc networks. The performance of such networks is evaluated under random traffic generation and continuous energy recharging at the nodes over an infinite-time horizon. We are interested in the maximum throughput that can be sustained by the network with the node queues being finite and in the average packet delay for a given throughput. We propose a multicost energy-aware routing algorithm and compare its performance to that of minimum-hop routing. The results of our experiments show that generally the energy-aware algorithm achieves a higher maximum throughput than the minimum-hop algorithm. More specifically, when the network is mainly energy-constrained and for the 2-dimensional topology considered, the throughput of the proposed energy-aware routing algorithm is found to be almost twice that of the minimum-hop algorithm.

Inhibition of inosine monophosphate dehydrogenase by mycophenolate compounds results in potent immunosuppression, as demonstrated by the efficacy of the marketed prodrug mycophenolate mofetil (MMF) in clinical allotransplantation. Side effects are well-known and include bone marrow depression and gastrointestinal intolerability. Mycophenolate sodium (MPS) is in clinical development as an enteric-coated formulation to alleviate this gastrointestinal adverse effect. Accompanying this development, MPS and MMF were evaluated in a tolerability study in rats and in efficacy studies in rat allo- and xenotransplantation models. The compounds were given either singly or in combination with cyclosporine A and were efficacious in the prevention of allo- or xeno-graft rejection, but with a rather narrow window between optimal immunosuppression and adverse side effects. For instance, the minimal effective dose to prevent rejection of a kidney or heart allograft or a hamster heart xenograft is a daily dose of 10-20 mg/kg MPS, at which dose the first adverse side effects can be observed: the compound at 40 mg/kg is not tolerated. This window is even narrower for MMF than for MPS, and in most models, a minimal effective MMF dose could not be established. The window between optimal immunosuppression and adverse side effects is larger when the compounds are given in combination with cyclosporine A: in all models investigated combinations were established yielding long-term survival without histologic signs of rejection and without signs of side effects. Thus, the combination of an IMPDH inhibitor (MPS, MMF) and a calcineurin inhibitor (cyclosporine A) enables fine-tuning in achieving optimal immunosuppression avoiding drug side effects.

Mycophenolic acid sodium salt (ERL080) is currently in Phase III clinical trials for the prophylaxis of kidney transplant rejection upon coadministration with Neoral (cyclosporin A microemulsion). To assess the relative side effect profile of ERL080 and MMF as drug substances in Lewis rats, a rat strain commonly used in transplantation experiments, a comparative 4-week tolerability study was performed. Escalating doses of ERL080 and MMF were administered orally at 10–30 mg/kg/d (i.e., doses within or above the immunosuppressive range in rats), either in single compound treatment or in combination with cyclosporine (CsA) at a daily oral dose of 7.5 mg/kg. The compounds were well tolerated as documented by body weight monitoring, hematologic parameters, and weight and histology of organs. Major abnormalities observed were a dose-dependent reduction in thymus weight associated with immunosuppression, in some cases villous atrophy in the jejunum, a reduction in white blood cell counts and lymphocyte counts (mean value in distinct treatment groups not exceeding 40–50%), a decrease in red blood cell counts and hemoglobin concentration (at maximum 25–30%), and an increase in platelet counts (in some groups up to doubling). At a given dose, these adverse effects were slightly more pronounced for MMF than for ERL080, and for groups under CsA coadministration compared to both compounds given alone. No significant potentiation effect of CsA on the changes induced by ERL080 or MMF was observed. Moreover, there were no new toxic entities evident upon CsA microemulsion coadministration.

To the Editor, Nasogastric tube (NGT) insertion is a procedure performed routinely in critical care settings. However, NGT placement often proves to be a daunting task, especially in the setting of anesthetized/uncooperative patients with anatomic distortion (i.e., patients with cervical spine instability and/or restricted neck movement) and an endotracheal tube (ETT) already in situ for airway protection and support of the respiratory system. In fact, serious complications secondary to NGT placement appear often in the literature. Therefore, NGT insertion may be a complex procedure that requires skill, experience, and the ability to improvise if it does not proceed smoothly. A 63-year-old male patient, who was sedated and mechanically ventilated in our intensive care unit, had a hard cervical collar in place after sustaining severe traumatic brain injury, cervical spine fracture, and multiple long bone fractures in a motor vehicle accident. The NGT was unintentionally removed during routine patient care, and despite many gentle and prolonged attempts, the on-call physicians’ efforts to re-insert the NGT were unsuccessful. The presence of the cervical collar created poor laryngoscopic views, even with the left molar approach, and the patient’s cervical spine injury did not allow maneuvres that could facilitate NGT insertion, such as neck flexion, turning the head laterally, lateral neck pressure, and forward displacement of the larynx. To this end, a number of techniques to advance the NGT were attempted without success, including blind insertion plus a combination of direct laryngoscopy and use of Magill forceps, placement of fingers in the posterior pharynx to guide the NGT tip downward, deflation of the ETT cuff, and use of a frozen NGT. Finally, a 9.5-mm internal diameter ETT (‘‘conduit’’ ETT) was placed in the oropharynx and—under direct laryngoscopy—was continually kept in contact with the posterior pharyngeal wall and behind the ETT already in place while simultaneously being advanced gently and as far as possible into the esophagus. A well-lubricated 14-Fr NGT was threaded into the ‘‘conduit’’ ETT and was advanced into the full length of the stomach without difficulty during the first attempt. Afterward, the ‘‘conduit’’ ETT was withdrawn and the NGT was pulled back, positioned at the appropriate length, and fastened in the usual way. It is worth noting that no change of head or neck position, no ETT cuff deflation, and no involvement of an assistant were necessary during this alternative mode of NGT insertion. The only technical requirement was to ensure that the ‘‘conduit’’ ETT diameter could accommodate the NGT, including its funnel-shaped proximal end. We did not determine fibreoptically the point where the NGT met resistance and was successfully bypassed by the ‘‘conduit’’ ETT. However, it has been previously shown that the most common sites of resistance at the laryngeal level are the piriform sinuses and the arytenoid cartilages. In conclusion, the use of an ETT as an introducer can facilitate NGT insertion in difficult settings. This alternative mode of NGT insertion is easy, inexpensive, and widely available in the operating room and the intensive care unit. In our view, it is worth considering this blind approach before the physician resorts to other techniques (i.e., videolaryngoscopy) that are either more expensive or that necessitate the involvement of additional equipment. P. Kopterides, MD (&) C. Papageorgiou, MD G. Dimopoulos, MD A. Armaganidis, MD 2nd Critical Care Department, ‘‘Attiko’’ University Hospital, 1 Rimini Str., Haidari, Athens, Greece e-mail: petkop@ath.forthnet.gr

A library of thioamide derivatives of leflunomide 1a and of its bioactive metabolite 1b has been synthesised on solid phase. Thus, para-substituted phenylacetic acids were coupled to TentaGel and were subsequently reacted with aromatic isothiocyanates. Treatment of the resulting enaminothioamides with hydroxylamine led to their simultaneous cyclisation and cleavage from the resin affording 2-25. Their in vitro profiling demonstrated that the amide-thioamide isologous substitution was detrimental of the biological activity.

Brequinar is an immunosuppressant with the potential to be combined with cyclosporine in synergistic combination therapy. The drug tends to accumulate when given daily per os, and pharmacokinetic interaction with cyclosporine appears to enhance toxicity. Analogues with similar immunosuppressive activity have been identified at Du Pont Merck Pharmaceutical Co., that do not accumulate upon daily oral dosing in rats, and hence could have an improved potential in combination treatment with cyclosporine. We performed a toxicity study with brequinar and two brequinar analogues, administered orally once daily for 4 weeks, either alone or in combination with cyclosporine (Neoral, Novartis Pharma AG). In a first study relatively high doses were evaluated with cyclosporine at non-toxic doses of 5 and 10 mg/kg/d. The maximum tolerated dose of brequinar alone was estimated between 5 and 10 mg/kg/d; that of the analogues was estimated between 10 and 20 mg/kg/d, and above 20 mg/kg/d, respectively. In combination with cyclosporine at 5 and 10 mg/kg/d, approximately a 2-fold reduction in the maximum tolerated dose was observed. In a second study lower doses were evaluated in combination with cyclosporine at 2.5 and 5 mg/kg/d. Also this study revealed increased toxicity of brequinar (analogues) when given in combination with cyclosporine. The side effects observed were typical for drugs in the brequinar class and included leukocytopenia and thrombocytopenia, reduced body weight gain or body weight loss, thymic atrophy, cellular depletion of bone marrow and splenic white pulp, and villous atrophy in jejunum. Concentrations of brequinar (analogues) were determined in blood sampled 4 h after administration at day 1, 14 and 21-28 of the experiment. There was a tendency for drug accumulation in some groups treated with brequinar and cyclosporine. For one of the analogues at a low dose, higher concentrations were measured in groups treated with combinations of this compound and cyclosporine. We conclude that a potential synergism in immunosuppression using combinations of brequinar (analogues) and cyclosporine can be complicated by enhanced toxicity of the compounds. This indicates the need for a careful evaluation of the therapeutic window in a combined treatment together with detailed pharmacokinetics.

Analysis of the contact surface of the cyclophilin A (CypA)/cyclosporin A (CsA, 1) crystal structure delineates a unique cavity between both molecules in the vicinity of the Abu-2 side chain atoms of 1 (Abu pocket). Therefore, (5-hydroxynorvaline)-2-cyclosporin (2) was designed and prepared as a CsA derivative which could mediate additional interactions within the pocket. The X-ray crystal structure of the CypA/2 complex at 1.76 A resolution shows that 1 and 2 have identical backbone conformations and that the introduced hydroxypropyl chain makes indeed the expected supplemental interactions with CypA. However, 2 has 8-9-fold lower binding affinity than 1 for CypA. This results from a presumed unfavorable free energy change associated with the displacement of one of the tightly bound water molecules within the pocket and a change in prebinding equilibria. The role of the later was assessed by comparing the conformation distribution of 1 and 2 to that of norvaline-2-cyclosporin (3) and norvaline-2-(D-MeSer)-3-cyclosporin (4).

The title compound 1 was obtained in 10.3% overall yield via two acid-catalyzed rearrangements and pyrrolidine formation. Thus, bi-oxindole 6 afforded exclusively the thermodynamically stable cis-diazachrysene 7 which, after allylation, followed by aza-Claisen rearrangement gave alcohol 2. Pyrolytic ring closure of the latter yielded 1 in highly diastereoselective fashion.

The title compounds have been synthesized with 75% enantiomeric excess from Chiral p-tolylsulfoxides 1 and aldehydes, followed by thermal elimination of the sulfoxide.

In 7 steps, 6- or 9-hydroxylated or -methoxylated trans-octahydrobenzo [g] isoquinolines were efficiently synthesized starting from dimethoxynaphthalenes, as potential new selective ligands for serotonin receptors. The 6-substituted compounds had very little affinity to common neurotransmitter receptors, with the exception of adrenergic α 2 . The 9-substituted compounds, while showing interesting affinity for 5HT 1a receptors, had comparable affinities for adrenergic α 1 and α 2 , and in one case for dopamine D2 receptors

1-(2′-Deoxy-5′-O-dimethoxytrityl-′-D-ribofuranosyl)-1 H-benzimidazole 3′-[(p-chlorophenyl)(2-cyanoethyl) phosphate] (6) has been synthesized from 1-(β-D-ribofuranosyl)-1H-benzimidazole (3b) using regiospecific 2′-deoxygenation. The latter compound was obtained by glycosylation of benzimidazole with the D-ribose derivative 2 leading exclusively of the β-D-anomer.

Lewis acid catalyzed glycosylation of the 2′-tosyl ribofuranose derivative 5 leads exclusively to β-nucleosides in the uridine and adenosine series.

Both title compounds were obtained in four steps from 2R, 3R-dihydroxy-4R-valerolactone 5 readily available from D-ribonolactone.

Diphenylsuccinic acid (I) is cyclized in the presence of methanesulfonic acid, forming the tetrahydroindenoindenedione (II).

Diphenylsuccinic acid (I) is cyclized in the presence of methanesulfonic acid, forming the tetrahydroindenoindenedione (II).

The present study was undertaken to explore whether abortion in the 13th-16th week of gestation could be induced by a single extra-amniotic injection of prostaglandin. A long acting prostaglandin analogue 15(S)-15-Methyl-PGF 2α was utilized and different vehicles and injection techniques tried. The clinical results of the single injection method were compared with those using multiple injections of PGF 2α as has been described earlier. It was found that approximately 80% of the patients aborted following a single injection of 750 μg 15-me-PGF 2α and that the side-effect rate was acceptable from a clinical point of view. The method seems to be an attractive alternative usable during the “difficult” period for induction of abortion, i.e. when the uterus is too large for vacuum aspiration but too small for abdominal puncture of the amniotic sac.

Synthese a partir d'isopropylidene D-glyceraldehyde et de dimethylamino-3 propionate de methyle