Atomic resolution images of solid-liquid interfaces

A scanning tunneling microscope (STM) can provide atomic-resolution images of solids covered with a variety of liquids, including cryogenic fluids, both polar and nonpolar solvents, conductive aqueous solutions, oils, and even greases. This short overview includes images of solids covered with liquid nitrogen, liquid helium, paraffin oil, silicone oil, microscope immersion oil, silicone vacuum grease, fluorocarbon grease, glycerol, and salt water. These images show atoms, charge-density waves, grains in an evaporated metal film, and even corrosion processes as they occur in real time. The future includes not only basic research in surface science but also applied research in lithography, lubrication, catalysis, corrosion, electrochemistry, and perhaps even biology.     

Synthesis and biological evaluation of technetium-99m MAG3 as a hippuran replacement

A new technetium-chelating agent based on a triamide monomercaptide tetradentate set of donor groups, mercaptoacetylglycylglycylglycine (MAG3), was synthesized and evaluated. Chelation with 99mTc resulted in a single radiochemical product as expected. Studies in mice of [99mTc]MAG3 indicated excretion rates faster than omicron-iodohippurate (OIH) both in normal and in probenecid treated animals. Specificity for renal excretion was essentially complete. Clearance studies in rats resulted in 2.84 ml/min/100 g for [99mTc]MAG3, 2.17 for OIH, and 1.29 for [125I]iothalamate. Extraction efficiencies were 85% for [99mTc]MAG3, 69% for OIH and 39% for [125I]iothalamate. Probenicid depressed the clearance both of [99mTc]MAG3 and OIH at 25 and 50 mg/kg/hr, but to a greater extent with [99mTc]MAG3. The greater effect is offset, however, by the larger fraction secreted by the renal tubular cells. The animal results suggest that [99mTc]MAG3 may be a useful alternative to [131I]OIH.     

Arterial complications of total knee replacement. The Australian experience

Arterial complications occurring in association with knee replacement surgery are rare, even though most patients having this operation are elderly and therefore more likely to have peripheral vascular disease. We report a patient who developed an arterial complication during the course of a knee replacement operation, as well as the results of a survey of Fellows of the Australian Orthopaedic Association. Recommendations to minimise this serious complication are proposed.     

Cisplatin-5-fluorouracil chemotherapy for advanced inoperable squamous carcinoma of the head and neck

Patients with locally advanced, inoperable squamous cell carcinoma of the head and neck were offered three courses of cisplatin and 96-h 5-fluorouracil (5-FU) infusion. Subsequent therapy included surgery when feasible, irradiation therapy, and a maintenance program of methotrexate (MTX)-5-FU. Thirty-three patients were evaluated prospectively. Seven patients underwent a single course of chemotherapy. Five patients underwent two courses of chemotherapy. Twenty-one patients underwent three courses of adjuvant chemotherapy. The overall response rate was 48% (16 of 33). Fifteen of 21 patients (76%) receiving three courses of chemotherapy evidenced a response; this included three complete responses (CRs) (9%). No responses were seen in patients receiving only one or two courses of chemotherapy. Among responding patients, the initial favorable response to chemotherapy was apparent after the first course of chemotherapy. Patients who failed to demonstrate any response after two courses of chemotherapy did not respond after a third course. A significant group of patients fail to respond and should be offered participation in other investigational protocols as they become available.     

Distinct Pharmacologic Properties of Neuromuscular Blocking Agents on Human Neuronal Nicotinic Acetylcholine Receptors: A Possible Explanation for the Train-of-four Fade

Background: Nondepolarizing neuromuscular blocking agents (NMBAs) are extensively used in the practice of anesthesia and intensive care medicine. Their primary site of action is at the postsynaptic nicotinic acetylcholine receptor (nAChR) in the neuromuscular junction, but their action on neuronal nAChRs have not been fully evaluated. Furthermore, observed adverse effects of nondepolarizing NMBAs might originate from an interaction with neuronal nAChRs. The aim of this study was to examine the effect of clinically used nondepolarizing NMBAs on muscle and neuronal nAChR subtypes.

Methods: Xenopus laevis oocytes were injected with messenger RNA encoding for the subunits included in the human [alpha]1[beta]1[varepsilon][delta], [alpha]3[beta]2, [alpha]3[beta]4, [alpha]4[beta]2, and [alpha]7 nAChR subtypes. The interactions between each of these nAChR subtypes and atracurium, cisatracurium, d-tubocurarine, mivacurium, pancuronium, rocuronium, and vecuronium were studied using an eight-channel two-electrode voltage clamp setup. Responses were measured as peak current and net charge.

Results: All nondepolarizing NMBAs inhibited both muscle and neuronal nAChRs. The neuronal nAChRs were reversibly and concentration-dependently inhibited in the low micromolar range. The mechanism (i.e., competitive vs. noncompetitive) of the block at the neuronal nAChRs was dependent both on subtype and the NMBA tested. The authors did not observe activation of the nAChR subtypes by any of the NMBAs tested.     

Behavioral, biochemical and neurotoxicological actions of the alpha-ethyl homologue of p-chloroamphetamine

The present set of experiments was designed to examine the effects of extension of the alpha-methyl of p-chloroamphetamine (PCA) to an alpha-ethyl. Therefore, the alpha-ethyl homologue of PCA, 1-(4-chlorophenyl)-2-aminobutane (CAB), was compared to PCA in a number of pharmacological assays. CAB was 2-fold less potent than PCA at inhibiting synaptosomal uptake of [3H]5-hydroxytryptamine ([3H]5-HT), and 5-fold less potent at inhibiting uptake of [3H]dopamine ([3H]DA). In drug discrimination assays, CAB was approximately 3-fold less potent than PCA in animals trained to discriminate 3,4-methylenedioxymethamphetamine (MDMA) or its alpha-ethyl homologue, S-(+)-N-methyl-1-(1,3-benzodioxol-5-yl)-2-butanamine (S-(+)-MBDB), from saline. Monitoring with in vivo microdialysis, 10 mg/kg of PCA caused a large increase in extracellular DA and a significant decrease in 3,4-dihydroxyphenylacetic acid (DOPAC) in the striatum. In contrast, 11 mg/kg CAB caused no increase and 22 mg/kg CAB caused only a slight increase in extracellular DA. Both doses of CAB caused a decrease in extracellular DOPAC. The potential 5-HT neurotoxicity of CAB was examined by measuring monoamine and metabolite levels and [3H]paroxetine binding at one week following acute doses. A 10 mg/kg dose of PCA caused an 80% decrease in cortical and hippocampal serotonergic markers, while an equimolar dose of CAB decreased only hippocampal 5-HT and 5-hydroxyindoleacetic acid (5-HIAA) levels. However, 22 mg/kg of CAB produced a 20-40% decrease in all serotonergic markers. Thus, extension of the alpha-alkyl significantly decreases the dopaminergic effects of PCA. The similar decrease in relative 5-HT neurotoxicity and the decreased ability to alter dopaminergic systems in vivo and in vitro supports the involvement of DA in the neurotoxicity of PCA.     

Evaluation of Tenidap (CP-66,248) on human neutrophil arachidonic acid metabolism, chemotactic potential and clinical efficacy in the treatment of rheumatoid arthritis

Ten patients with rheumatoid arthritis (RA) were evaluated in a placebo-controlled, double-blind study examining the clinical efficacy of a novel nonsteroidal anti-inflammatory agent: Tenidap (CP-66,248). RA patients receiving active drug therapy (n = 6) demonstrated clinically significant improvements in observer assessment of pain (p less than 0.025), painful joint count (p less than 0.010), and overall clinical assessment as based on a modified rheumatoid activity index, MRAI (p less than 0.025). In parallel laboratory assays, Tenidap was found to exhibit a significant in vitro dose-dependent inhibition of ionophore-stimulated neutrophil production of the 5-lipoxygenase product: [3H]leukotriene B4 (LTB4). Although more importantly, Tenidap was also found to exhibit an in vitro dose-dependent inhibition (IC50 20 microM) of the ionophore-stimulated release (deacylation) of the precursor [3H]arachidonic acid (AA) from membrane phospholipids. In further studies, Tenidap did not have any effect on fMLP-induced neutrophil chemotactic response. These results suggest that one of the possible mechanisms for the clinical effectiveness of this agent, may be through its effect at inhibiting the release of free AA from membrane phospholipids and therefore limiting its further metabolism into certain biologically-active inflammatory lipids.