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The increasing availability of personal genomic tests has led to discussions about the validity and utility of such tests and the balance of benefits and harms. A multidisciplinary workshop was convened by the National Institutes of Health and the Centers for Disease Control and Prevention to review the scientific foundation for using personal genomics in risk assessment and disease prevention and to develop recommendations for targeted research. The clinical validity and utility of personal genomics is a moving target with rapidly developing discoveries but little translation research to close the gap between discoveries and health impact. Workshop participants made recommendations in five domains: (1) developing and applying scientific standards for assessing personal genomic tests; (2) developing and applying a multidisciplinary research agenda, including observational studies and clinical trials to fill knowledge gaps in clinical validity and utility; (3) enhancing credible knowledge synthesis and information dissemination to clinicians and consumers; (4) linking scientific findings to evidence-based recommendations for use of personal genomics; and (5) assessing how the concept of personal utility can affect health benefits, costs, and risks by developing appropriate metrics for evaluation. To fulfill the promise of personal genomics, a rigorous multidisciplinary research agenda is needed.

Infantile spasms is a catastrophic childhood seizure disorder for which few animal models exist. Children with Down syndrome are highly susceptible to infantile spasms. The Ts65Dn mouse is a valid model for Down syndrome; therefore, we tested the hypothesis that the Ts65Dn mouse represents a substrate for an animal model of infantile spasms. The baseline of naïve Ts65Dn mice showed spontaneous spike-and-wave discharges, a pattern that worsened with baclofen and ?-butyrolactone, which induced acute epileptic extensor spasms (AEES) associated with epileptiform polyspike bursts and an electrodecremental response on the EEG. GABABR-agonist-induced AEES were significantly reduced with vigabatrin, rodent ACTH fragment, valproic acid, ethosuximide, and CGP 35348. Porcine ACTH had no effect. GABABR protein expression was significantly increased in the thalamus and medulla oblongata of Ts65D mice in comparison with wild-type controls. The GABABR agonist-treated Ts65Dn mouse shows the unique clinical, electrographic, and pharmacologic signature of infantile spasms and represents a valid, acute model of this disorder. GABABR-mediated mechanisms may contribute to the increased susceptibility of children with Down syndrome to infantile spasms.

NADPH-cytochrome P450 reductase (CPR) and cytochrome-b5(b5) together with NADH-b5reductase (b5R) play important roles in cytochrome P450 3A-mediated drug metabolism via electron transfer. However, it is not clear whether variability in expression of these accessory proteins contributes to the known interindividual variability in CYP3A activity. CPR and b5were measured in human liver microsomes (HLMs) by spectrophotometry and immunoblotting. HLMs from elderly (≥46 years) male donors (n = 11) averaged 27% (P = 0.034) and 41% (P = 0.011) lower CPR levels than young (≤45 years) male donors (n = 21) for spectrophotometric and immunoblot values, respectively. Similarly, HLMs from elderly male donors averaged 43% (P = 0.034) and 47% (P = 0.011) lower b5levels than young male donors for spectrophotometric and immunoblot values, respectively. α-Lipoic acid and 6-propyl-2-thiouracil were evaluated for selectivity of inhibition of CPR and b5R activities, respectively, using recombinant enzymes and HLMs, as well as for effects on CYP3A-mediated triazolam hydroxylation in HLMs with either NADH or β-NADPH. The results indicate that both compounds are relatively nonselective inhibitors of CPR and b5R activities. Finally, we used multivariate regression analysis and showed that variability in CPR or b5expression between HLMs does not contribute significantly to variability in CYP3A-mediated midazolam hydroxylation. Consequently, while aging is associated with decreased CPR and b5expression in human livers, this effect does not contribute to CYP3A variability.

In decentralised supply chains, lack of visibility, long delivery delays and complex transportation networks make it difficult to integrate inventory control with other logistics activities. However, because of the impact of stock turnover on just-in-time operations, inventory control has to be considered in the global optimisation of the supply chain. In the literature, transportation and inventory control decisions are seldom modelled together, because minimising transportation costs and increasing inventory turns are two contradictory objectives. This paper addresses this global optimisation problem. It presents a Decision Support System (DSS) that estimates logistics activities in a decentralised supply chain by integrating inventory control and transportation operations. Delivery frequencies and phases are the decision variables used to study the behaviour of the logistics system.

We have shown that cytochrome b5 (cyt b5), along with its reductase, NADH cytochrome b5 reductase (b5R), is capable of direct xenobiotic biotransformation. We hypothesized that functionally significant genetic variability in cyt b5 could be found in healthy individuals.

Radioiodine is considered the treatment of choice for hyperthyroidism, but in some situations, methimazole therapy is preferred, such as in cats with preexisting renal insufficiency. Unfavorable outcomes from methimazole are usually attributable to side effects, such as gastrointestinal upset, facial excoriation, thrombocytopenia, neutropenia, or liver enzyme elevations. Because restoration of euthyroidism can lead to a drop in glomerular filtration rate, all cats treated with methimazole should be monitored with blood urea nitrogen and creatinine levels in addition to serum thyroxine (T4) and a complete blood cell count. Transdermal methimazole is associated with fewer gastrointestinal side effects and can be used in cats with simple vomiting or inappetence from oral methimazole. Hypertension may not resolve immediately when serum T4is normalized, and moderate to severe hypertension should be treated concurrently with atenolol, amlodipine, or an angiotensin-converting enzyme inhibitor.

Background:Information is lacking on the prevalence and susceptibility patterns of bacterial isolates in dogs and cats with suspected hepatobiliary disease.

Heterocyclic and aromatic amine carcinogens are thought to lead to tumor initiation via the formation of DNA adducts, and bioactivation to arylhydroxylamine metabolites is necessary for reactivity with DNA. Carcinogenic arylhydroxylamine metabolites are cleared by a microsomal, NADH-dependent, oxygen-insensitive reduction pathway in humans, which may be a source of interindividual variability in response to aromatic amine carcinogens. The purpose of this study was to characterize the identity of this reduction pathway in human liver. On the basis of our findings with structurally similar arylhydroxylamine metabolites of therapeutic drugs, we hypothesized that the reductive detoxification of arylhydroxylamine carcinogens was catalyzed by NADH cytochrome b5reductase (b5R) and cytochrome b5(cyt b5). We found that reduction of the carcinogenic hydroxylamines of the aromatic amine 4-aminobiphenyl (4-ABP; found in cigarette smoke) and the heterocyclic amine 2-amino-1-methyl-6-phenylimidazo 4,5-b pyridine (PhIP; found in grilled meats) was indeed catalyzed by a purified system containing only human b5R and cyt b5. Specific activities were 56−346-fold higher in the purified system as compared to human liver microsomes (HLM), with similar Michaelis−Menten constants (Kmvalues) in both systems. The stoichiometry for b5R and cyt b5 that yielded the highest activity in the purified system was also similar to that found in native HLM (∼1:8 to 1:10). Polyclonal antisera to either b5R or cyt b5 significantly inhibited N-hydroxy-4-aminobiphenyl (NHOH-4-ABP) reduction by 95 and 89%, respectively, and immunoreactive cyt b5 protein content in individual HLM was significantly correlated with individual reduction of both NHOH-4-ABP and N-hydroxy-PhIP (NHOH-PhIP). Finally, titration of HLM into the purified b5R/cyt b5 system did not enhance the efficiency of reduction activity. We conclude that b5R and cyt b5 are together solely capable of the reduction of arylhydroxylamine carcinogens, and we further hypothesize that this pathway may be a source of individual variability with respect to cancer susceptibility following 4-ABP or PhIP exposure.

Purpose: Pelizaeus-Merzbacher disease and spastic paraplegia type 2 are allelic X-linked disorders that principally affect males and are caused by mutations in the proteolipid protein 1 gene. Neurologic symptoms are occasionally observed in carrier females, and anecdotal evidence suggests that these clinical signs are more likely in families with affected males. We analyze 40 pedigrees to determine whether such a link exists.Methods: From a chart review of patients from Wayne State University, we categorize patients according to disease severity and type of genetic lesion within the proteolipid protein 1 gene. We then analyze the clinical data using nonparametric t tests and analyses of variance.Results: Our analyses formally demonstrate the link between mild disease in males and symptoms in carrier female relatives. Conversely, mutations causing severe disease in males rarely cause clinical signs in carrier females. The greatest risk of disease in females is found for nonsense/indel or null mutations. Missense mutations carry moderate risk. The lowest risk, which represents the bulk of families with Pelizaeus-Merzbacher disease, is associated with proteolipid protein 1 gene duplications.Conclusions: Effective genetic counseling of Pelizaeus-Merzbacher disease and spastic paraplegia carrier females must include an assessment of disease severity in affected male relatives.

The hepatitis C virus (HCV) is the cause of a silent pandemic that, due to the chronic nature of the disease and the absence of curative therapy, continues to claim an ever-increasing number of lives. Current antiviral regimens have proven largely unsatisfactory for patients with HCV drug-resistant genotypes. It is therefore important to explore alternative therapeutic stratagems whose mode of action allows them to bypass viral resistance. Antisense oligonucleotides, ribozymes, small interfering RNAs, aptamers and deoxyribozymes constitute classes of oligonucleotide-based compounds designed to target highly conserved or functionally crucial regions contained within the HCV genome. The therapeutic expectation for such compounds is the elimination of HCV from infected individuals. Progress in oligonucleotide-based HCV antivirals towards clinical application depends on development of nucleotide designs that bolster efficacy while minimizing toxicity, improvement in liver-targeting delivery systems, and refinement of small-animal models for preclinical testing.

Furamidine is an effective antimicrobial agent; however, oral potency of furamidine is poor. A prodrug of furamidine, 2,5-bis(4-amidinophenyl)furan-bis-O-methylamidoxime (DB289), has greatly improved oral potency. DB289 is transformed to furamidine via O-demethylation, and N-dehydroxylation reactions with four intermediate metabolites formed. The O-demethylation reactions have been shown to be catalyzed by cytochrome P450. The enzymes catalyzing the reductive N-dehydroxylation reactions have not been determined. The objective of this study was to identify the enzymes that catalyze N-dehydroxylation of metabolites M1, a monoamidoxime, and M2, a diamidoxime, formed during generation of furamidine. M1 and M2 metabolism was investigated using human liver microsomes and human soluble cytochrome b5and NAD cytochrome b5reductase, expressed in Escherichia coli. Kinetics of M1 and M2 reduction by human liver microsomes exhibited high affinity and moderate capacity. Metabolism was significantly inhibited by antibodies to cytochrome b5and b5reductase and by chemical inhibitors of b5reductase. The amidoximes were efficiently metabolized by liver mitochondria, which contain cytochrome b5/b5reductase, but not by liver cytosol, which contains minimal amounts of these proteins. Expressed cytochrome b5/b5reductase, in the absence of any other proteins, efficiently catalyzed reduction of both amidoximes. Kmvalues were similar to those for microsomes, and Vmaxvalues were 33- to 36-fold higher in the recombinant system compared with microsomes. Minimal activity was seen with cytochrome b5or b5reductase alone or with cytochrome P450 reductase alone or with cytochrome b5. These results indicate that cytochrome b5and b5reductase play a direct role in metabolic activation of DB289 to furamidine.

Furamidine is an effective antimicrobial agent; however, oral potency of furamidine is poor. A prodrug of furamidine, 2,5-bis(4-amidinophenyl)furan-bis-O-methylamidoxime (DB289), has greatly improved oral potency. DB289 is transformed to furamidine via O-demethylation, and N-dehydroxylation reactions with four intermediate metabolites formed. The O-demethylation reactions have been shown to be catalyzed by cytochrome P450. The enzymes catalyzing the reductive N-dehydroxylation reactions have not been determined. The objective of this study was to identify the enzymes that catalyze N-dehydroxylation of metabolites M1, a monoamidoxime, and M2, a diamidoxime, formed during generation of furamidine. M1 and M2 metabolism was investigated using human liver microsomes and human soluble cytochrome b5 and NAD cytochrome b5 reductase, expressed in Escherichia coli. Kinetics of M1 and M2 reduction by human liver microsomes exhibited high affinity and moderate capacity. Metabolism was significantly inhibited by antibodies to cytochrome b5 and b5 reductase and by chemical inhibitors of b5 reductase. The amidoximes were efficiently metabolized by liver mitochondria, which contain cytochrome b5/b5 reductase, but not by liver cytosol, which contains minimal amounts of these proteins. Expressed cytochrome b5/b5 reductase, in the absence of any other proteins, efficiently catalyzed reduction of both amidoximes. Km values were similar to those for microsomes, and Vmax values were 33- to 36-fold higher in the recombinant system compared with microsomes. Minimal activity was seen with cytochrome b5 or b5 reductase alone or with cytochrome P450 reductase alone or with cytochrome b5. These results indicate that cytochrome b5 and b5 reductase play a direct role in metabolic activation of DB289 to furamidine.

Reaction of [RhOs(CO)4(μ-CH2)(dppm)2][CF3SO3] (1) with PMe3, PEt3, PMePh2, and P(OMe)3 occurs by substitution of a carbonyl to yield the products [RhOsL(CO)3(μ-CH2)(dppm)2][CF3SO3], in which the phosphine or phosphite ligand (L) is bound to Rh adjacent to the bridging methylene group. Identical products are obtained by the reaction of these ligands with the related tricarbonyl species [RhOs(CO)3(μ-CH2)(dppm)2][CF3SO3] (2). The P(OMe)3 adduct slowly isomerizes to a product in which the Rh-bound carbonyl and phosphite ligands have exchanged positions, such that the phosphite ligand is opposite the Rh−CH2 bond. Although P(OPh)3 does not react with 1, it does react with 2 to yield a product analogous to the second P(OMe)3 isomer. Protonation of the three phosphine adducts generates methyl complexes in which this group is σ-bound to Os but has a bridged agostic interaction with Rh. In these three products the phosphine ligands are coordinated to Rh. The PMe3 compound isomerizes to the thermodynamic product in which migration of the PMe3 group to Os is accompanied by migration of a carbonyl to Rh, whereas the products containing the PEt3 and PMePh2 ligands dissociate these phosphines, generating [RhOs(CH3)(OSO2CF3)(CO)3(dppm)2][CF3SO3], in which the methyl group is terminally bound to Rh. Protonation of the first P(OMe)3 isomer yields a methyl-bridged product analogous to those noted above for the phosphine adducts. This product slowly isomerizes to one having the methyl ligand terminally bound to Rh and the phosphite ligand bound to Os. Protonation of the second P(OMe)3 isomer yields two products; the first is that noted above having the methyl group on Rh, while the second has the opposite arrangement of methyl and phosphite ligands, with the methyl group on Os and the phosphite on Rh. This latter product slowly isomerizes to the former. Protonation of the methylene-bridged triphenyl phosphite adduct yields a product in which the phosphite ligand is coordinated to Rh while the methyl group is terminally bound to Os. The X-ray crystal structures of a number of species are reported, and a rationalization for the products observed and the rearrangements occurring is presented.

This case report describes sulphonamide‐induced nephrotic syndrome in a young dobermann dog. The clinical signs and laboratory abnormalities resolved shortly after discontinuation of the sulphonamide antibiotic and with generalised supportive care. Since nephrotic syndrome typically carries a guarded prognosis in veterinary medicine and is poorly responsive to therapy, a thorough drug history should be an important part of the investigation of any animal with a protein‐losing nephropathy.

Hydroxylamine metabolites, implicated in dose-dependent and idiosyncratic toxicity from arylamine drugs, and amidoximes, used as pro-drugs, are metabolized by an as yet incompletely characterized NADH-dependent microsomal reductase system. We hypothesized that NADH cytochrome b5 reductase and cytochrome b5 were responsible for this enzymatic activity in humans. Purified human soluble NADH cytochrome b5 reductase and cytochrome b5, expressed in Escherichia coli, efficiently catalyzed the reduction of sulfamethoxazole hydroxylamine, dapsone hydroxylamine, and benzamidoxime, with apparent Km values similar to those found in human liver microsomes and specific activities (Vmax) 74 to 235 times higher than in microsomes. Minimal activity was seen with either protein alone, and microsomal protein did not enhance activity other than additively. All three reduction activities were significantly correlated with immunoreactivity for cytochrome b5 in individual human liver microsomes. In addition, polyclonal antibodies to both NADH cytochrome b5 reductase and cytochrome b5 significantly inhibited reduction activity for sulfamethoxazole hydroxylamine. Finally, fibroblasts from a patient with type II hereditary methemoglobinemia (deficient in NADH cytochrome b5 reductase) showed virtually no activity for hydroxylamine reduction, compared with normal fibroblasts. These results indicate a novel direct role for NADH cytochrome b5 reductase and cytochrome b5 in xenobiotic metabolism and suggest that pharmacogenetic variability in either of these proteins may effect drug reduction capacity.

The reactions of allene, methylallene, and 1,1-dimethylallene with [RhM(CO)4(μ-CH2)(dppm)2][X] (M = Os, X = BF4 (1); M = Ru, X = CF3SO3 (3); dppm = μ-Ph2PCH2PPh2) in the presence of 1 equiv of trimethylamine oxide yield a variety of products. Under these conditions compounds 1 and 3 react with allene to yield the trimethylenemethane-bridged products [RhM(CO)2(μ-η³:η¹-C(CH2)3)(dppm)2][X] (M = Os (5), Ru (6)), in which the trimethylenemethane fragment is η¹-bound to the group 8 metal by one methylene group and η³-bound to Rh by the rest of the fragment. These compounds react with CO and PMe3 to yield [RhM(CO)2L(μ-η³:η¹-C(CH2)3)(dppm)2][X] (L = CO, PMe3), in which L is coordinated to Rh and the η³:η¹-binding mode of trimethylenemethane is retained. Although attack of L occurs at Rh for the Rh/Ru species, carbonyl attack in the Rh/Os compound initially occurs at Os with subsequent scrambling throughout the three carbonyl sites; attack of PMe3 on the Rh/Os compound occurs at Rh. Methylallene reacts with 1 and Me3NO to give a species analogous to 5 and 6, having the methyl substituent on one of the terminal carbons of the allylic functionality. This methyl group is involved in an agostic interaction with Rh, which can be displaced by CO. The tricarbonyl complex [RhOs(CO)3(μ-CH2)(dppm)2][CF3SO3] (2) reacts with 1,1-dimethylallene at −10°C to give [RhOs(CO)3(μ-η¹:η¹-(CH3)2CCCH2CH2)(dppm)2][CF3SO3], in which the dimethylvinyl group is adjacent to Rh, exo to the RhCCH2CH2Os dimetallacycle. At ambient temperature this species decomposes to give 1,1-dimethyl-1,3-butadiene. Compound 3 reacts with 1,1-dimethylallene in the presence of Me3NO to yield [RhRu(CO)2((CH3)2CCCH2CH2CO)(dppm)2][CF3SO3] (14), in which [2+1+1] coupling of the allene, the bridging methylene group, and a coordinated carbonyl has occurred. The dative bond from the bridging acyl moiety of 14 to Ru is displaced in reactions with H2 and CO to give [RhRu(CO)2(C(O)CH2CH2C(&dbd;C(CH3)2))(μ-H)2(dppm)2][CF3SO3] and [RhRu(CO)3(C(O)CH2CH2C(&dbd;C(CH3)2))(dppm)2][CF3SO3], respectively. A rationalization of this chemistry is presented.

The objective of this study was to determine whether transdermal methimazole was as safe and effective as oral methimazole for the control of hyperthyroidism in cats. Forty‐seven cats with newly diagnosed hyperthyroidism were randomized to receive either transdermal methimazole in pluronic lecithin organogel (PLO; applied to the inner pinna), or oral methimazole (2.5 mg q12h for either route). Cats were evaluated at weeks 0, 2, and 4 with a physical exam, body weight determination, CBC, biochemical panel, urinalysis, measurement of total levothyroxine (T4) concentration, indirect Doppler blood pressure determinaiton, and completion of an owner questionnaire. Data between the 2 groups and over time were compared by nonparametric methods. Forty‐four cats followed the protocol (17 oral and 27 transdermal). Significantly more cats treated with oral methimazole had serum T4concentrations within the reference range after 2 weeks (14 of 16 cats) compared to those treated by the transdermal route (14 of 25; P =.027). This difference was no longer significant by 4 weeks of treatment (9 of 11 for oral versus 14 of 21 for transdermal), possibly because of inadequate numbers evaluated by 4 weeks. Cats treated with oral methimazole had a higher incidence of gastrointestinal (GI) adverse effects (4 of 17 cats) compared to the cats treated with transdermal methimazole (1 of 27; P =.04), but no differences were found between groups in the incidence of neutropenia, hepatotoxicity, or facial excoriations. Although the overall efficacy of transdermal methimazole is not as high as that of oral methimazole at 2 weeks of treatment, it is associated with fewer GI adverse effects compared to the oral route.

Thiopurine methyltransferase (TPMT) is an important enzyme in the metabolism of thiopurine medications such as azathioprine. In humans, activity varies widely among individuals, primarily because of genetic polymorphisms. Low TPMT activity increases the risk of myelosuppression from azathioprine and 6‐mercaptopurine, whereas high TPMT activity is associated with poor drug efficacy. The purpose of this study was to determine whether dogs also show a wide range of TPMT activity. Heparinized blood samples were obtained from 177 dogs associated with a veterinary teaching hospital. Red blood cell (RBC) TPMT activity was measured by means of a modification of a radiochemical method as established for use in people. TPMT activity varied across a 9‐fold range (7.9–71.8 U of RBC per milliliter; median, 21.7). Variation in TPMT activity was not associated with age, sex, or neutering status. Giant Schnauzers had much lower TPMT activity (7.9–20 U of RBC per milliliter; median, 13.1; P< .001) than did other breeds, and Alaskan Malamutes had much higher TPMT activity (22.7–71.8 U of RBC per milliliter; median, 36.0; P< .001) than did other breeds. Such variations in TPMT activity in the canine population and within groups of related dogs could affect thiopurine drug toxicity and efficacy in canine patients.

A common genetic polymorphism for thiopurine S-methyltransferase (TPMT) is a major factor responsible for individual variation in the toxicity and therapeutic efficacy of thiopurine drugs in humans. We set out to determine whether inheritance might also influence the level of TPMT activity in the domestic cat, Felis domesticus. As a first step, red blood cell (RBC) TPMT activity was measured in blood samples from 104 cats. The average level of cat RBC TPMT activity was lower than that observed in humans and was not related to either age or sex of the animal. We then cloned and characterized the F. domesticus TPMT cDNA and gene. Genotype-phenotype correlation analysis was performed by resequencing the cat TPMT gene using DNA samples from 12 animals with high and 12 with low levels of RBC TPMT activity. Thirty-one single nucleotide polymorphisms (SNPs) were observed in these 24 DNA samples, including five that altered the encoded amino acid, resulting in nine allozymes (six observed and three inferred). Twelve of the 31 feline TPMT SNPs were associated, collectively, with 56% of the variation in level of RBC TPMT activity in these 24 animals. When those 12 SNPs were assayed in all 89 cats for which DNA was available, 30% of the variation in level of RBC TPMT activity was associated with these 12 polymorphisms. After expression in COS-1 cells, five of the eight variant cat allozymes displayed decreased levels of both TPMT activity and immunoreactive protein compared with the wild-type allozyme. These observations are compatible with the conclusion that inheritance is an important factor responsible for variation in levels of RBC TPMT activity in the cat. They also represent a step toward the application of pharmacogenetic principles to companion animal thiopurine drug therapy.

The purpose of this study was to summarize the clinical findings in 40 dogs with systemic hypersensitivity reactions associated with the administration of potentiated sulfonamides. Dogs ranged from 6 months to 14 years of age, with a mean of 5.7 ± 3.2 years. Spayed female dogs were overrepresented (24 of 40, or 60% of the dogs), as were Samoyeds (3 of 40; 8%) and Miniature Schnauzers (5 of 40; 13%). Mean dosages of potentiated sulfonamides were 47.0 ± 14.9 mg/kg/d (range, 23.4–81.4 mg/kg/d). The time from the 1st administration of the drug to the onset of the clinical signs of hypersensitivity ranged from 5 to 36 days, with a mean of 12.1 ± 5.9 days. There was no relationship between either the dosage or type of sulfonamide given and the time to the onset of the clinical signs. Fever was the most common clinical sign observed (55% of the dogs); thrombocytopenia was 2nd (54%), and hepatopathy (28%) was 3rd. Neutropenia, keratoconjunctivitis sicca (KCS), hemolytic anemia, arthropathy, uveitis, skin and mucocutaneous lesions, proteinuria, facial palsy, suspected meningitis, hypothyroidism, pancreatitis, facial edema, and pneumonitis were also observed in some patients. Of 39 dogs with adequate follow‐up, 30 (77%) recovered, whereas 8 (21%) either died or were euthanized, and 1 recovered clinically but had persistent increases in alanine aminotransferase (ALT) activity. Dogs with hepatopathy generally had a poorer prognosis (46% recovery) than dogs without hepatopathy (89% recovery; P =.0035). Sixty‐three percent of the dogs with thrombocytopenia recovered, compared to 90% of the dogs without thrombocytopenia (P= .042). Recovery was not associated with sex, age, breed, or type of sulfonamide administered.

This article is an historical case study of the effects of consolidating surgical services in Alberta's Capital Health Authority from 1994 to 2001. The consolidation resulted in the region's two largest hospitals offering primarily high intensity inpatient surgical care, while three other hospitals offered low-intensity day surgery and short-stay procedures only. Over time, refinements of the initial model were required. Lessons learned from the initiative are also presented.

Protonation of the methylene-bridged complex [RhOs(CO)3(μ-CH2)(μ-CO)(dppm)2][CF3SO3] with triflic acid at −80 °C yields the methyl complex [RhOs(CO)4(μ-CH3)(dppm)2][CF3SO3]2 (1) in which the methyl group is primarily bound to Os while involved in an agostic interaction with Rh. Warming this species to −20 °C results in methyl migration to a terminal site on Rh, yielding [RhOs(CH3)(CO)2(μ-CO)2(dppm)2][CF3SO3]2 (2), and subsequent warming to ambient temperature results in migratory insertion to yield the acetyl-bridged [RhOs(CF3SO3)(CO)2(μ-C(CH3)O)(μ-CO)(dppm)2][CF3SO3] (3). Replacement of the coordinated triflate anion in 3 by CO and PMe3 occurs at low temperature to give [RhOs(L)(CO)2(μ-C(CH3)O)(μ-CO)(dppm)2][CF3SO3]2 (L = CO (4), PMe3 (5a)). Warming the PMe3 adduct results in transformation of the acetyl group, which is C-bound to Rh in 5a, to a group that is C-bound to Os in 5b. One carbonyl in 3 is labile and is readily lost, yielding [RhOs(CF3SO3)(CO)2(μ-C(CH3)O)(dppm)2][CF3SO3] (6). Attempts to obtain the above methyl or acetyl species by reaction of the hydride-bridged species [RhOs(X)(CO)3(μ-H)(μ-CO)(dppm)2][X] (X = CF3SO3 (7a), BF4 (7b)) with diazomethane were unsuccessful.

Thiopurine S-methyltransferase (TPMT) plays an important role in the metabolism of thiopurine drugs. In humans, a common genetic polymorphism for TPMT is a major factor responsible for individual variation in the toxicity and therapeutic efficacy of these drugs. Dogs (Canis familiaris) are also treated with thiopurine drugs and, similar to humans, they display large individual variations in thiopurine toxicity and efficacy. We set out to determine whether dogs might also display genetically determined variation in TPMT activity. As a first step, we observed that canine red blood cell (RBC) TPMT activity in samples from 145 dogs varied over a nine-fold range. That variation was not associated with either the age or sex of the animal. Subsequently, we cloned the canine TPMT cDNA and gene. The canine cDNA encoded a protein that was 81.2% identical to the enzyme encoded by the most common TPMTallele in humans. A genotype–phenotype correlation analysis was performed by resequencing the canine TPMTgene using DNA samples from 39 animals selected for high, low or intermediate levels of RBC TPMT activity. We observed nine polymorphisms in these 39 DNA samples, including three insertion/deletion events and six single nucleotide polymorphisms (SNPs), one of which was a nonsynonymous cSNP (Arg97Gln). However, when the variant allozyme at codon 97 was expressed in COS-1 cells, it did not display significant differences in either basal levels of TPMT activity or in substrate kinetics compared with the wild-type allozyme. Six of the nine canine TPMTpolymorphisms were associated with 67% of the variation in level of RBC TPMT activity in these 39 blood samples. When those six SNPs were assayed using DNA from all 145 animals studied, 40% of the phenotypic variance in the entire population sample could be explained by these polymorphisms. Therefore, inheritance is a major factor involved in the regulation of variation in RBC TPMT in the dog, just as it is in humans. These observations represent a step towards the application of pharmacogenetic and pharmacogenomic principles to companion animal drug therapy.

OBJECTIVE: To examine the efficacy and toxicity of ISA(TX)247, a novel calcineurin inhibitor, in comparison to cyclosporine (cyclosporin A, CSA) and placebo in established collagen induced arthritis. ISA(TX)247 has up to 3-fold greater potency than CSA in an in vitro whole blood calcineurin inhibition assay and in in vivo solid organ and cell transplantation models. Phase I clinical trials show no discernible nephrotoxicity. METHODS: Type II collagen immunized DBA/Lac J mice with established arthritis were randomized to treatment with ISA(TX)247 (125/250/500 microg/mouse), CSA (250/500 microg/mouse), or drug vehicle, by daily intraperitoneal injection for 10 days from the onset of clinical arthritis. RESULTS: A significant dose dependent reduction in clinical severity was observed in ISA(TX)247 treated but not in CSA treated animals 10 days after the onset of established arthritis, and when examined by area under the curve analysis during the treatment period. Significant improvement in paw swelling (p < 0.001), synovial histology (p < 0.001), and articular cartilage damage scores (p = 0.002) was also noted in ISA(TX)247 treated animals, even in the 125 pg dose group (p = 0.03 for paw swelling and synovial histology). By comparison, CSA had no significant effect on either synovial inflammation or articular cartilage damage. ISA(TX)247 (500 microg dose group) was the only treatment to significantly decrease the development of proximal interphalangeal joint erosions (p < 0.05). A significant reduction in Type II collagen antibody titer was noted in ISA(TX)247 animals in both 250 microg (p = 0.02) and 500 microg (p = 0.004) dosage groups, but only in the 500 microg group for CSA (p = 0.004). Treatment was well tolerated, with no significant toxicity in ISA(TX)247 groups. CONCLUSION: ISA(TX)247 demonstrates efficacy and safety in the treatment of established collagen induced arthritis. Together with its improved potency and nephrotoxicity profile in comparison to CSA, this agent warrants further clinical investigation in autoimmune disease. Phase II studies in rheumatoid arthritis have been initiated.

The cationic heterobinuclear complex [RhRu(CO)3(μ-H)2(dppm)2][X] (1) is prepared by protonation of the monohydride species [RhRu(CO)3(μ-H)(dppm)2] (dppm = μ-Ph2PCH2PPh2; X^- = BF4^-, CF3SO3^-). Treatment of 1 with carbon monoxide affords the tetracarbonyl complex ion [RhRu(CO)4(dppm)2][X] (2), which yields the methylene-bridged product [RhRu(CO)4(μ-CH)2(dppm)2][X] (3), upon treatment with excess diazomethane at −78 °C. Reaction of 3 with trimethylamine-N-oxide results in CO removal, affording the methylene-bridged tricarbonyl species [RhRu(CO)3(μ-CH)2(dppm)2][X] (4). Although compound 3 is unreactive toward further treatment with CH2N2, compound 4 reacts readily with diazomethane, yielding a mixture of uncharacterized products. Compounds 3 and 4 react with PMe3 to yield [RhRu(PMe3)(CO)3(μ-CH)2(dppm)2][X] (5), in which coordination of PMe3 at the unsaturated Rh center occurs. The structures of compounds 2, 3, and 5 have been determined by X-ray methods. Comparisons of the reactivity of compound 3 with that of the analogous Ir/Ru and Rh/Os complexes toward diazomethane are presented.

The heterobinuclear complexes [IrRu(CO)3(μ-H)(dppm)2] (1) and [IrRuH(CO)3(μ-CO)(dppm)2] (2) are prepared from the reactions of [PPN][HRu(CO)4] with [IrCl(dppm)2] and [Ir(CO)(dppm)2][Cl], respectively (PPN = (Ph3P)2N; dppm = Ph2PCH2PPh2). Protonation of both monohydride species yields the dihydride [IrRu(CO)3(μ-H)2(dppm)2][BF4] (3), which under an atmosphere of carbon monoxide gives [IrRu(CO)4(dppm)2][BF4] (4). The methylene-bridged complex [IrRu(CO)3(μ-CH2)(μ-CO)(dppm)2][BF4] (5) is obtained by the reaction of compound 4 with diazomethane at ambient temperature. Although 5 does not react further with diazomethane under these conditions, carbonyl abstraction using trimethylamine oxide in the presence of CH2N2 yields the methylene-bridged ethylene adduct [IrRu(C2H4)(CO)3(μ-CH2)(dppm)2][BF4] (6). Labeling studies indicate that the majority of the ¹³C-labeled methylene group of 5 remains in the bridging site, with approximately 10% of the label incorporated into the ethylene formed. Compound 6 can also be prepared from 5 and ethylene in the presence of Me3NO. The compounds [IrRuL(CO)3(μ-CH2)(dppm)2][BF4] (L = NCMe, PMe3, CH2CHCN) can also be prepared from 5 in the presence of Me3NO or by ethylene displacement from 6. Although the PMe3 adduct has this group bound to Ir, as for the ethylene ligand in 6, the acrylonitrile and acetonitrile groups are bound to Ru. Furthermore, the acrylonitrile ligand is N-bound through the cyano group, analogous to the acetonitrile ligand. The structures of [IrRuH(CO)3(μ-CO)(dppm)2] (2), [IrRu(CO)3(μ-CH2)(μ-CO)(dppm)2][BF4] (5), and [IrRu(PMe3)(CO)3(μ-CH2)(dppm)2][BF4] (7) have been determined by X-ray methods. Compounds 2 and 7 have comparable edge-shared bioctahedral structures in which the geometries at the different metals in each structure are similar. The bridging carbonyl in 2 is replaced by a methylene group in 7, and the Ir-bound hydride is replaced by PMe3. Compound 5 has bridging CO and CH2 groups on opposite faces of the IrRuP4 framework with two terminal carbonyls on Ru and one on Ir.

Nickeltitanium NiTi alloy derives its biocompatibility and good corrosion resistance from a homogeneous oxide layer mainly composed of TiO2, with a very low concentration of nickel. In this article, we described the corrosion behavior of NiTi alloys after mechanical polishing, electropolishing, and sterilization processes using cyclic polarization and atomic absorption. As a preparative surface treatment, electropolishing decreased the amount of nickel on the surface and remarkably improved the corrosion behavior of the alloy by increasing the mean breakdown potential value and the reproducibility of the results 0.99 ± 0.05 VSCE vs. 0.53 ± 0.42. Ethylene oxide and Sterrad® sterilization techniques did not modify the corrosion resistance of electropolished NiTi, whereas a steam autoclave and, to a lesser extent, peracetic acid sterilization produced scattered breakdown potential. In comparing the corrosion resistance of common biomaterials, NiTi ranked between 316L stainless steel and Ti6A14V even after sterilization. Electropolished NiTi and 316L stainlesssteel alloys released similar amounts of nickel after a few days of immersion in Hanks solution. Measurements by atomic absorption have shown that the amount of released nickel from passive dissolution was below the expected toxic level in the human body. Auger electron spectroscopy analyses indicated surface contamination by Ca and P on NiTi during immersion, but no significant modification in oxide thickness was observed. © 2000 John Wiley & Sons, Inc. J Biomed Mater Res, 51, 685–693, 2000.

The following article has been excerpted from “Fetal Heartz ate Auscultation”, one of the newest monographs in the AWHONN Symposia Series.

Current models of basal ganglia anatomy posit the existence of multiple parallel, anatomically segregated circuits. Anatomical data from non-human primates suggest that the circuits subserving motor functions are segregated from those subserving cognitive functions. Here we present data that demonstrate that, in humans, motor and cognitive frontosubcortical circuits are segregated. We studied a group of patients with Parkinson's disease undergoing surgical lesioning of the globus pallidus internus for relief of their symptoms. Lesion location along an anteromedial-to-posterolateral axis was found to be related to postsurgical outcome on both cognitive and motor measures. Performance on several neuropsychological measures, including the generation of category exemplars and continuous mental addition, was linearly related to distance along this axis, with anteromedial lesions leading to postsurgical impairment, intermediate lesions having little effect and posterolateral lesions leading to an improvement on several measures. The same relationship was found between memory performance under conditions of proactive interference and lesion location within the globus pallidus internus. In contrast, bradykinesia, assessed as the speed of finger-tapping, had a non-linear relationship to lesion location, intermediate lesions leading to greater postsurgical improvement than lesions in more extreme anteromedial or posterolateral locations. These data demonstrate that the cognitive effects of pallidotomy can be dissociated from the motor effects. These effects depend upon the placement of the lesions within the globus pallidus internus, supporting the segregation of functionally distinct circuits in the human pallidum.

Nitinol is a very attractive material for manufacturing minimally-invasive therapy devices and tools because of its unique superelasticity and shape-memory properties. While several studies have shown it to possess good biocompatibility, its high nickel content and possible dissolution during corrosion still remain a concern. However, passivation and electropolishing can significantly decrease nickel dissolution from Nitinol by forming a corrosion-resistant titanium oxide surface layer. In general, passivated and electropolished Nitinol exhibits equivalent, if not better, static corrosion behaviour and ability to resist and repassivate (repair) surface damage when compared with 316L stainless steel (SS). Combining Nitinol with SS, titanium and tantalum does not significantly affect its corrosion behaviour. However, combining Nitinol with gold, platinum and platinum-iridium alloy can result in an order of magnitude increase in corrosion rate. Nickel release from Nitinol decreases from well below dietary levels to nearly non-detectable levels in the first few days following immersion in a physiological medium. Finally, in vivo studies indicate minimal corrosion of Nitinol during implantation, with released nickel concentration in surrounding tissues or organs being equivalent to that released by 316LSS.

Sirolimus (rapamycin, Rapamune) is a potent immunosuppressive drug that received marketing approval from the US Food and Drug Administration on September 15, 1999. Research into defining its pharmacokinetic (PK) behavior, interaction with other agents, and metabolism is ongoing. It has been established that oral doses of both liquid and solid formulation are rapidly, though incompletely and variably, absorbed. Metabolism by the intestinal and hepatic CYP3A family of enzymes likely contributes to variability in absorption and low bioavailability. Sirolimus has a long terminal half-life, the AUC correlates well with trough and peak concentrations, and it exhibits a moderate degree of dose proportionality. There is significant interpatient variability in PK parameters of sirolimus, though it exhibits predictable PK behavior when used with prednisone and cyclosporine neoral. There is a decreased rejection risk with higher doses and target level attainment. Several species of sirolimus metabolites have been characterized, and are measurable in whole blood and tissue specimens. Many more species of sirolimus metabolites are detectable, but they are not quantifiable at this time. The total concentration of metabolites appears to be less than that of the parent drug when examined through the PK profile. A reference method for the quantitation of metabolites remains elusive because of a lack of proper standardization. The clinical significance of sirolimus metabolites remains to be proven.

While North Atlantic tropical cyclone (TC) forecasts are numerous, the number of Gulf of Mexico (GOM) storms is normally left ambiguous. Motivated by the 2020 GOM hurricane season, this study introduces two methods of anticipating upcoming GOM TC frequency on June 1 of each year: (a) statistically transforming Climate Forecast System (CFS)‐predicted June–November GOM 500‐hPa temperature (T500); and (b) applying a 0.284 multiplier, the climatological proportion of GOM versus North Atlantic TCs, to a representative, widely circulated North Atlantic‐wide forecast. Both methods perform skillfully, especially given their simplicity. Though warm T500normally inhibits deep convection and is not generally considered among statistical TC forecasts, it is comparatively well represented by modeling systems. Additionally, T500is well correlated with traditional, yet less accurately resolved, TC environmental parameters. While unfavorable to individual TCs, T500generally (though indirectly) indicates several difficult‐to‐model physical aspects of more favorable GOM TC environments. Seasonal forecasts of North Atlantic tropical cyclone (TC) activity have become quite common in recent years. Unfortunately, the number of Gulf of Mexico (GOM) storms is not often stated among North Atlantic‐wide forecasts. Consequently, this study introduces two methods of anticipating upcoming GOM TC frequency at the first day of hurricane season. The first is based solely on June–November midlevel temperatures over the GOM predicted by the Climate Forecast System (CFS), version 2. The second applies a 0.284 multiplier, the climatological proportion of GOM TCs within the North Atlantic, to a widely circulated North Atlantic‐wide forecast. Both methods perform skillfully, especially given their simplicity. Though warm midlevel temperature is not generally considered among statistical TC forecasts, we show that it is comparatively well modeled by the reanalysis/forecast systems, and is correlated to other TC‐related variables that are less accurately resolved. Midlevel temperature provided the greatest gain in performance over the scaling factor for the most active GOM hurricane seasons. The Gulf of Mexico (GOM) encounters 28.4% of all North Atlantic tropical cyclonesGOM named storm counts are significantly positively correlated with 500‐hPa temperatureClimate Forecast System (CFS) predictions of GOM 500‐hPa temperature were accurate, skillful indications of subsequent named storm activity The Gulf of Mexico (GOM) encounters 28.4% of all North Atlantic tropical cyclones GOM named storm counts are significantly positively correlated with 500‐hPa temperature Climate Forecast System (CFS) predictions of GOM 500‐hPa temperature were accurate, skillful indications of subsequent named storm activity

The terrestrial gamma‐ray flash (TGF) and Energetic Thunderstorm Rooftop Array (TETRA‐II) detected 22 X‐ray/gamma‐ray flash events associated with lightning between October 2015 and March 2019 across three ground‐based detector locations in subtropical and tropical climates in Louisiana, Puerto Rico, and Panama. Each detector array consists of a set of bismuth germanate scintillators that record X‐ray and gamma‐ray bursts over the energy range 50 keV–6 MeV (million electron volts). TETRA‐II events have characteristics similar to both X‐ray bursts associated with lightning leaders and TGFs: sub‐millisecond duration, photons up to MeV energies, and association with nearby lightning (typically within 3 km). About 20 of the 22 events are geolocated to individual lightning strokes via spatiotemporally coincident sferics. An examination of radar reflectivity and derived products related to events located within the Next Generation Weather Radar (NEXRAD) monitoring region indicates that events occur within mature cells of severe and non‐severe multicellular and squall line thunderstorms, with core echo tops which are at or nearing peak altitude. Events occur in both high lightning frequency thunderstorm cells and low lightning frequency cells. Events associated with high frequency cells occur within 5 min of significant lightning jumps. Among NEXRAD‐monitored events, hail is present within 8 km and 5 min of all except a single low‐altitude cold weather thunderstorm. An association is seen with maximum thunderstorm development, lightning jumps, and hail cells, indicating that the TETRA‐II X‐ray/gamma‐ray events are associated with the peak storm electrification and development of electric fields necessary for the acceleration of electrons to high energies. Ground‐level TETRA‐II events occur near maxima in lightning rates, hail, echo top heights, and vertically integrated liquid densityEvents occur in both high and low lightning frequency storms and close to maximum updraft developmentEvents occur in association with multi‐cell and squall line thunderstorms, but not single‐cell storms Ground‐level TETRA‐II events occur near maxima in lightning rates, hail, echo top heights, and vertically integrated liquid density Events occur in both high and low lightning frequency storms and close to maximum updraft development Events occur in association with multi‐cell and squall line thunderstorms, but not single‐cell storms

Nurses working in intrapartum settings have many responsibilities to ensure a safe and satisfying birth experience for the families in their care. Paperwork, while essential, often takes time away from providing supportive care for laboring women and their families. In striking a balance between responsibilities and obligations, nurses must play an active role in designing a charting system that allows essential and important data to be recorded in the least amount of time.

The T2★of hexainethylenetetramine, C6H12N4, and sodium nitrite, NaNO2, at 297°K and 77°K, and of 4-methoxy analine, C5H9NO, at 297°K are reported. Two different nitrogen super-regenerative N.Q.R. spectrometers were used. Two different techniques for obtaining T2★were used: one measured the shift in signal detection threshold quench frequency with changing sample mass; the other measured the change in signal intensity for a small change of quench frequency near threshold. The importance of quench frequency studies and spectrometer construction for signal detection are discussed.

This research examined the creative writing responses of 140 third- and sixth-grade boy and girl writers to story characters cast in either stereotypic (male mechanic and female nurse) or nonstereotypic (female mechanic and male nurse) occupational roles. The 560 stories were examined for maintenance of character in assigned occupational role, development of character along gender-stereotypic and -nonstereotypic lines, and evidence of gender change in the lead character. Results suggested that development of character was consistent with gender expectations for the lead character in the stereotypic stories and in the nonstereotypic female mechanic story. For the nonstereotypic male nurse story, the development of character was consistent with the author's gender. Further evidence of stereotypic thinking occurred in those nonstereotypic stories where the lead character's gender was changed to be consistent with the stereotype of the occupational role. These findings support previous research on gender differences and gender perceptions

The purpose of this study was to determine the molecular basis for a relative deficiency in the cat of cytosolic arylamine N-acetyltransferase (NAT), an enzyme family that is important in the metabolism of xenobiotics and that normally consists of at least two related enzymes, NAT1 and NAT2. N-acetyltransferase in feline liver showed high affinity (mean Km= 2.1 μM) for p-aminobenzoic acid, an NAT1 selective substrate in humans and rabbits, but showed a very poor affinity (mean Km> 10 mM) for sulfamethazine, an NAT2 selective substrate in humans and rabbits. Immunoreactive N-acetyltransferase was detected in feline liver, bladder and colon using an NAT1-specific antipeptide antibody, but was not detected in any tissues using an NAT2-specific antibody. Southern blot analysis of genomic DNA demonstrated a single band in domestic cats using each of six restriction digests; single bands were also found on Southern blot analysis of six wild felids. The deduced amino acid sequence of the central portion of feline N-acetyltransferase, obtained by polymerase chain reaction amplification in both domestic cats and seven wild felids (lion, tiger, lynx, snow leopard, bobcat, Asian leopard cat and cheetah), contained three residues, Phe125, Arg127, and Tyr129, which determine NAT1-like substrate specificity in humans. These results support the conclusion that cytosolic arylamine N-acetylation activity is low in the cat because of the presence of a single N-acetyltransferase that has substrate specificity, immuno-genicity and sequence characteristics similar to human NAT1, and that the unusual presence of only a single N-acetyltransferase gene appears to be a family wide trait shared by other felids.

The Société de Transport de la Communauté Urbaine de Montréal (STCUM; Montreal Urban Community Transit Corporation) has recently undertaken the task of computerizing its phone information center, called AUT-OBUS. AUT-OBUS provides callers with optimal route choices within the STCUM transit network. An original system based on geographic and operations data bases combined with interactive path calculation and data processing software has already been implemented. A special geographic information system was developed to process the origins and destinations on the basis of the client's specifications. Multiple forms of spatial referencing are provided: street addresses, trip generators and attractors, monuments, special activities, street intersections, transit references (subway and rail stations, bus routes, terminals, etc.). The best path calculation is carried out by using interactively calibrated impedance functions (walking, in-vehicle, waiting, transfers, fares, and mode restriction). An added challenge was the necessary consideration of the network geometry, commercial speed, day type, trip time, and headway and the validation of the computed paths with existing schedules. For a transit network the size of Montreal's, consisting of 16,000 bus stops, 230 bus routes, and a pedestrian network of 80,000 links and 28,000 nodes, the calculation of the optimal path for a given origin–destination pair is less than 2 sec with a typical personal computer with a Pentium processor.

The reactions of AlMe3with di(2-pyridylmethyl)amine have been investigated. Two new complexes, AlMe2[N(CH2-2-Py)2] (1) and Al2Me4[2,3,5,6-tetra(2-pyridyl)piperazyl] (3), were obtained as the major and the minor product, respectively, from the reaction of AlMe3with di(2-pyridylmethyl)amine in a 1:1 ratio in toluene at 23 °C. The reaction of AlMe3with di(2-pyridylmethyl)amine in a 2:1 ratio yielded a dinuclear complex Al2Me5[N(CH2-2-Py)2] (2). These complexes were fully characterized by NMR, and elemental and single-crystal X-ray diffraction analyses. Crystal data: 1, C14H18N3Al, monoclinic, P21/m, a = 7.568(2), b = 7.340(1), c = 13.120(8) Å, β = 104.17(3)°, V = 706.6(4) Å3, Z = 2; 2, C14H27N3Al2, triclinic, , a = 8.422(1), b = 16.711(6), c = 7.659(1) Å, α = 91.94(2)°, β = 113.08(1)°, γ = 85.17(2)°, V = 988.2(4) Å3, Z = 2; 3, C28H32N6Al2, monoclinic, P21/c, a = 7.522(8), b = 15.841(8), c = 11.584(4) Å, β = 98.53(5)°, V = 1365(1) Å3, Z = 2. Compound 1is a mononuclear complex with the aluminum atom in an approximately trigonal bipyramidal geometry and the amido nitrogen atom in a trigonal planar geometry. Compound 2contains two aluminum centers bridged by an amido nitrogen atom where one of the aluminum atoms has a tetrahedral geometry while the other has a trigonal bipyramidal geometry. The dinuclear compound 3can be described as the result of two unusual C—C bonds coupling between the methylene carbon atoms of two molecules of 1. The aluminum coordination environment in 3is similar to that of 1. Keywords: aluminum, amide, pyridyl, 2,3,5,6-tetra(2-pyridyl)piperazine, structure.

The objectives of this study were to determine the concentration of itraconazole achieved in corneal tissue and aqueous humour after topical application of a 1% itraconazole ointment; to determine the effect of including dimethyl sulphoxide (DMSO) in the ointment on achievable ocular tissue itraconazole concentrations; and to assess if any gross or histopathologic ocular toxicity results from the topical application of 1% itraconazole with or without the addition of DMSO.