The challenge of acquiring a satisfactory EBSD result of CWSR Zircaloy-4 cladding tube.

This work presents a methodology combining SEM, EDS, conventional EBSD, and transmission-EBSD to analyse a recrystallised Zircaloy-4 sheet and cold-worked stress-relieved (CWSR) Zircaloy-4 cladding in unprecedented detail. Second-phase precipitates (SPPs) in Zircaloy-4 specimens were revealed after chemical polishing using a solution containing hydrofluoric acid (HF). Pitting corrosion of Zircaloy-4 specimens was revealed after electropolishing using an electrolyte containing HClO4 . A zirconium coupon without SPPs was used to confirm the chemical response of SPPs on surface morphology. Intrinsic features of cold-worked Zircaloy-4 such as relatively small grain sizes, high dislocation density, and complex microstructure make it significantly more difficult to collect excellent EBSD results compared to recrystallised Zircaloy-4. The fine hydride structure of as-hydrided CWSR Zircaloy-4 cladding further increases the level of challenge on EBSD analysis. LAY DESCRIPTION: We present a methodology combining multiple microscopic methods to analyse a recrystallised Zircaloy-4 sheet and cold-worked stress-relieved (CWSR) Zircaloy-4 cladding, important alloys of structural materials widely used in nuclear application, and emphasis on the challenge of acquiring a satisfactory electron backscatter diffraction (EBSD) result of CWSR Zircaloy-4 cladding material in great details. EBSD is a powerful technique to characterise the crystallographic distribution and lattice type of conductive crystalline materials, especially for a highly textured material like CWSR Zircaloy-4 alloy. However, zirconium alloys are known to be one of the most difficult materials to prepare for EBSD characterisation. We point out that the configuration of the microstructure of the specimen cause the challenge in the EBSD sample preparations. Moreover, the occurrence of tiny zirconium hydride precipitates in Zircaloy-4 increases the difficulty. We believe that the information of the EBSD sample preparation related results in this paper can provide researchers and scientists in this community a useful reference to speed up the EBSD sample preparation of CWSR Zircaloy-4 cladding material and to expect the corresponding EBSD results.

A preliminary investigation of mesoionic xanthine analogues as inhibitors of platelet aggregation.

A series of mesoionic xanthines (e.g. mesoionic thiazolopyrimidines, 3, and thiadiazolopyrimidines, 5) and related analogues were examined as inhibitors of human platelet aggregation. Appropriately substituted compounds were found to fully inhibit platelet aggregation, and anhydro-(6-ethyl-8-isopentyl-7-oxo-5-hydroxy-1,3,4-thiadiazolo[3,2 -a]pyrimidinium hydroxide) (5b) was 40 times more potent than the structurally related xanthine theophylline (1). Gel filtration studies suggest that compound 5b irreversibly inhibits aggregation and this might be due to its ability to act as a latent acylation agent.

Anticonvulsant activity of caramiphen analogs.

Caramiphen potently blocks maximal electroshock (MES)-induced seizures in mice and rats. The anticonvulsant mechanism has been hypothesized to be due to high-affinity binding to sigma recognition sites in brain. To study the structure-activity relationship for anticonvulsant activity of caramiphen we evaluated 8 analogs in MES-induced seizures in rats and also determined whether a correlation exists between anticonvulsant potency and sigma binding affinity. Some of the analogs potently inhibited sigma binding but were devoid of anticonvulsant activity. Aminocaramiphen 2 (ED50 = 3.4 mg/kg) and N-methyl-4-piperidinyl 1-phenylcyclopentanecarboxylate 9 (ED50 = 4.8 mg/kg) showed anticonvulsant activity comparable to caramiphen (ED50 = 3.1 mg/kg), although in sigma binding assays the affinities were 3-and 30-fold less than caramiphen, respectively. In the presence of 250 microM of phenytoin, caramiphen and p-aminocaramiphen showed 3- to 5-fold increases in affinity for [3H](+)pentazocine binding, whereas piodocaramiphen, which was inactive as an anticonvulsant, showed no change in affinity for sigma binding. These results indicate that anticonvulsant activity of the caramiphen analogs is not due to interaction with sigma binding sites.

Caramiphen, iodocaramiphen and nitrocaramiphen are potent, competitive, muscarinic M1 receptor-selective agents.

Caramiphen, iodocaramiphen and nitrocaramiphen were examined for affinity at the muscarinic M1, M2 and M3 receptor subtypes in radioligand binding assays. Caramiphen binds with high affinity at the M1 site labeled by [3H]pirenzepine in rat cortex (Ki = 1.2 nM) and displays a 27-fold greater preference for the M1 than the M2 site labeled by [3H](-)-quinuclidinyl benzilate in rat heart, and a 6-fold greater preference for the M1 than the M3 site labeled by [3H]N-methylscopolamine in rat submaxillary gland. Iodocaramiphen binds with high affinity (Ki = 2.1 nM) and selectivity (59-fold) for the M1 vs. M2 subtype, and is 4-fold more selective for the M1 vs. M3 site. Nitrocaramiphen binds with high affinity for M1 sites (Ki = 5.5 nM) and with a 71-fold selectivity over M2, and a 10-fold selectivity for the M1 over the M3 subtype. All three compounds interacted with the M1 binding site in a competitive manner. Nitrocaramiphen and iodocaramiphen are as potent and showed a comparable selectivity for binding to the M1 over the M2 site than the prototypical agent pirenzepine (M1; Ki = 5.2 nM, 51-fold selectivity). Additionally, nitrocaramiphen demonstrates at least a 10-fold selectivity for the M1 over the M3 site. These ester-type antimuscarinics may be better ligands for the study of M1 receptors in brain than the hydrophilic agent pirenzepine.

Muscarinic receptor binding profile of para-substituted caramiphen analogues.

Para-substituted analogues of the antimuscarinic agent caramiphen were synthesized and evaluated for their ability to bind to the M1 and M2 subtypes of the muscarinic receptor. The purpose of the set was to look for a possible relationship in binding affinity or receptor subtype selectivity with aromatic substituent parameters such as Hammett's sigma or Hansch's pi values. It is felt this could be determined initially with only four properly chosen substituents. In this approach, substituents were chosen which have an extreme value for sigma and for pi, in a positive and negative direction, in all combinations. The substituents chosen for examination were amino (-sigma, -pi); 1-pyrrolidinyl (-sigma, +pi); 1-tetrazolyl (+sigma, -pi), and iodo (+sigma, +pi). It was determined in this research that caramiphen binds with high affinity (Ki = 1.2 nM) and is selective for the M1 over M2 muscarinic receptor subtype (26-fold). An examination of para-substitution reveals that compounds with electron-withdrawing (+sigma) substituents showed M1 selectivity, while the derivatives with electron-donating groups (-sigma) were nonselective in the binding assays. On the basis of this finding, the nitro and cyano derivatives were prepared and found to be M1 selective. The + sigma derivatives showed a decrease in M2 affinity while the p-nitro and p-iodo derivatives retained approximately equal affinity as caramiphen for the M1 site. The nitro- and iodocaramiphen derivatives were as potent (M1, Ki = 5.52 and 2.11 nM, respectively) and showed a greater selectivity of M1 over M2 binding than the M1 prototypical agent pirenzepine (M1, Ki = 5.21 nM).

Inhibition of platelet aggregation by an irreversible local anesthetic.

Three known local anesthetic agents were examined for their ability to inhibit platelet aggregation induced by adenosine diphosphate or epinephrine. Drug-treated platelet-rich plasma samples were filtered through agarose gel to remove free drug, and the ability of the platelets to aggregate was again determined. One of the local anesthetics contained a "one-armed" nitrogen mustard structure and appeared to produce an irreversible inhibition of aggregation. The other two agents gave a block of aggregation that was reversed upon gel filtration.

Pretreatment with phencyclidine, an N-methyl-D-aspartate antagonist, attenuates long-term behavioral deficits in the rat produced by traumatic brain injury.

This study examined the effects of pretreatment with phencyclidine (PCP), a selective N-methyl-D-aspartate (NMDA) antagonist, on behavioral and physiologic responses of the rat to experimental traumatic brain injury (TBI). For the behavioral experiments, rats were administered either saline or PCP (1.0, 2.0, or 4.0 mg/kg, intrapentoneally [IP] 15 min before TBI. Rats were ventilated as necessary following injury. The duration of acute suppression of several reflexes (pinna, corneal, righting, and flexion) and responses (escape, head support, and spontaneous locomotion) was recorded for up to 70 min after trauma. Longer-term behavioral assessments (beam walking, beam balance, inclined plane, ambulatory activity, and body weight) were made for up to 10 days after trauma. PCP did not significantly alter the duration of acute behavioral suppression. At a dosage of 1.0 mg/kg, PCP significantly attenuated all long-term deficits except beam walking. Maximal protection against beam walking deficits was provided by the 4.0 mg/kg dosage of PCP. Sixty-three percent of saline-treated animals died within 10 days after injury. For rats pretreated with 1.0, 2.0, and 4.0 mg/kg of PCP, 40%, 23%, and 33% died, respectively. In physiologic experiments, pretreatment with 4.0 mg/kg of PCP (IP) 15 min before injury did not significantly affect systemic cardiovascular responses, plasma glucose levels, or blood gas levels observed within 30 min after injury. While the possibility of effects mediated by other neurotransmitter systems cannot be excluded, these data suggest that NMDA agonist-receptor interactions contribute to the pathophysiology of brain injury. In addition, neural mechanisms that mediate transient unconsciousness following moderate levels of head injury may differ from mechanisms that mediate more persistent neurologic deficits.

Acute manic psychosis following the dermal application of N,N-diethyl-m-toluamide (DEET) in an adult.

Extensive animal testing and 30 years of human experience have established the general safety of DEET when applied episodically to skin or bedclothes. Local and systemic toxic and allergic reactions to DEET have been observed in man. Three weeks prior to admission, for the purpose of self-medication, a 30 year old man began daily applications of the insect repellant, DEET followed by a 1-2 hour period in a light-bulb heated box. Sedation and incoherence were noted for short periods following each application session. Aggressiveness and psychotic ideation led to hospital admission where he displayed psychomotor hyperactivity, rapid and pressured speech, tangentiality, flight of ideas, and grandiose delusions. Treatment was begun with haloperidol. Clinical improvement was complete within 6 days, atypical for classic endogenous mania. Drug and metabolites were identified in the urine more than 2 weeks after the last drug application.

1-(4-Aminobenzyl)-and 1-(4-aminophenyl)isoquinoline derivatives: synthesis and evaluation as potential irreversible cyclic nucleotide phosphodiesterase inhibitors.

In an effort to increase the specificity of the potent phosphodiesterase inhibitor papaverine, we synthesized two series of novel 1-(4-aminobenzyl)- and 1-(4-aminophenyl)isoquinoline derivatives, incorporating alkylating moieties on the amine substituents. These compounds were evaluated for their inhibitory action on phosphodiesterase preparations from bovine heart and rat cerebral cortex. Studies were also conducted to determine whether these compounds were reacting with the enzymes in an irreversible manner. The compounds were potent inhibitors of the phosphodiesterases; however, no evidence was found for an irreversible inhibition.

Synthesis and anticancer activity of asparagine analogs.

A series of 11 asparagines substituted on N4 was prepared and evaluated for their ability to inhibit the growth of L5178Y leukemia cell cultures. These cells require an exogenous source of L-asparagine and should be sensitive to an asparagine antimetabolite. The compounds were prepared by reaction of phthalylaspartic anhydride with a primary or secondary amine, followed by removal of the phthalyl group with hydrazine. One compound, N,N-dibenzylasparagine, showed significant activity. Additional study of asparagine derivatives bearing large, lipophilic groups at N4 is warranted.

Antimuscarinic agents: furan analogs of benzilate esters.

The methiodide and ethiodide salts of 5-(dimethylaminomethyl)- and 5-(diethylaminomethyl)-alpha, alpha-diphenylfurfuryl alcohol were prepared, These compounds may be considered as furan analogs of dialkylaminoethyl benzilate alkiodides. The pA2 values of these compounds as antagonists of acetylcholine were determined on rat jejunum preparation. All four compounds were significantly less potent than the analogous ester antimuscarinic lachesine. The furan ring cannot be substituted for the ester moiety of typical antimuscarinics. Possible modes of binding by antagonists to the receptor proposed previously are considered that might account for this less-than-expected antimuscarinic activity.

Interactions of acetylcholine mustard with acetylcholinesterase.

The hydrolysis of acetylcholine and acetylcholine mustard by acetylcholinesterase was compared over a substrate concentration range of 1-10 mM. Reactions were allowed to proceed for 2 min at 25 degrees. Results of these experiments reveal that the substrates have similar affinities for the enzyme, whereas the maximum velocity for the hydrolysis of acetylcholine mustard was significantly lower than for acetylcholine. These findings suggest that acetylcholine mustard has the ability to inactive acetycholinesterase.