Design, synthesis, antineoplastic activity, and chemical properties of bis(carbamate) derivatives of 4,5-bis(hydroxymethyl)imidazole.

A series of bis(carbamate) derivatives of 1,2-substituted 4,5-bis(hydroxymethyl)imidazoles were prepared and evaluated against murine P388 lymphocytic leukemia. Electron-withdrawing substituents at either N-1 or C-2 gave rise to inactive compounds. However, electron-donating substituents gave active compounds and the 2-(methylthio)-1-methyl derivative 2i (carmethizole), as the bis(N-methylcarbamate), was found to be very active. The derivative 2i, referred to by the name carmethizole, was also shown to be active against the MX-1 mammary xenograft, the human amelanotic melanoma cell line (LOX) xenograft, the M5076 sarcoma, and L1210 lymphocytic leukemia. The solution stability, water solubility, pKa, and log P of carmethizole are also reported.

Potential inhibitors of S-adenosylmethionine-dependent methyltransferases. 10. Base- and amino acid modified analogues of S-aristeromycinyl-L-homocysteine.

A series of base- and amino acid modified analogues of S-aristeromycinyl-L-homocysteine, a carbocyclic nucleoside, were synthesized and evaluated as inhibitors of S-adenosyl-L-methionine-dependent methyltransferases, including catechol O-methyltransferase, phenylethanolamine N-methyltransferase, and histamine N-methyltransferase. The base-modified analogues (8-azaadenine, 3-deazaadenine, and N6-methyladenine) were prepared by reaction of the corresponding carbocyclic 5'-chloro-5'-deoxynucleosides with the anion of homocysteine generated in situ either from L-homocystine or S-benzyl-L-homocysteine in Na/liquid NH3 or with DL-homocysteine thiolactone in alkaline solution. S-Aristeromycinyl-D-homocysteine was prepared with use of D-homocystine in the Na/liquid NH3 reaction. The sulfoxide and sulfone analogues were prepared by oxidation of S-aristeromycinyl-L-homocysteine. The various base- and amino acid modified analogues of S-aristeromycinyl-L-homocysteine were inactive as inhibitors of catechol O-methyltransferase. In contrast, the 3-deaza analogue was a good inhibitor (Ki = 20.5 +/- 1 microM) of phenylethanolamine N-methyltransferase whereas S-aristeromycinyl-D-homocysteine was an excellent inhibitor (Ki = 10.4 +/- 2.4 microM) of histamine N-methyltransferase. On the basis of these results, it would appear that the structural requirements for the binding S-aristeromycinyl-L-homocysteine are similar to those for binding S-adenosyl-L-homocysteine. Therefore, these carbocyclic analogues have the potential of being better inhibitors in vivo, because they should be more stable to metabolism than the ribosyl analogues.

Potential inhibitors of S-adenosylmethionine-dependent methyltransferases. 8. Molecular dissections of carbocyclic 3-deazaadenosine as inhibitors of S-adenosylhomocysteine hydrolase.

A series of 9-(hydroxyalkyl)-3-deazaadenines, which are analogues of the carbocyclic derivative of 3-deazaadenosine (3-deaza-C-Ado), were synthesized. The analogues were tested as inhibitors of bovine liver S-adenosyl-L-homocysteine (AdoHcy) hydrolase (EC 3.3.1.1) and as inhibitors of vaccinia virus (WR) replication in clone 929 mouse L cells and the results were compared to those observed for the parent compound, 3-deaza-C-Ado. 4-Amino-1-(2,3-dihydroxy-1-propyl)imidazo[4,5-c]pyridine (14), the analogue which included the 1'-, 2'-, and 3'-carbons of 3-deaza-C-Ado, was the most active inhibitor toward purified AdoHcy hydrolase. The inhibitory effect of 14 (Ki = 768 nM) on AdoHcy hydrolase was significantly less than that observed for 3-deaza-C-Ado (Ki = 4 nM). Analogue 14 also exhibited inhibitory activity against vaccinia virus replication, but the activity was less than that observed with 3-deaza-C-Ado. 4-Amino-1-(4-hydroxy-1-butyl)imidazo[4,5-c]pyridine (15) showed little or no inhibitory activity toward AdoHcy hydrolase, but it did exhibit antiviral effects comparable to 14. These results suggest that 3-deaza-C-Ado and analogue 14 may be producing their antiviral effects by altering a critical viral methylation (e.g., methylation of the 5'-cap of viral mRNA), whereas analogue 15 may be acting through an alternative mechanism.

Potential inhibitors of S-adenosylmethionine-dependent methyltransferases. 9. 2',3'-Dialdehyde derivatives of carbocyclic purine nucleosides as inhibitors of S-adenosylhomocysteine hydrolase.

A series of purine (e.g., adenine, N6-methyladenine, 8-azaadenine, 3-deazaadenine) carbocyclic nucleosides, nucleoside 2',3'-dialdehydes, and nucleoside 2',3'-diols were synthesized as potential inhibitors of bovine liver S-adenosyl-L-homocysteine (AdoHcy) hydrolase (EC 3.3.1.1) and as potential inhibitors of vaccinia virus replication. The 2',3'-dialdehydes were prepared by periodate oxidation of the corresponding carbocyclic nucleosides. Reduction of the intermediate dialdehydes with sodium borohydride afforded the corresponding 2',3'-diols. Of the nucleosides tested, the most potent inhibitors of AdoHcy hydrolase were the adenine analogue (Ki = 110 +/- 38 nM) and the 3-deazaadenine analogue (Ki = 4 +/- 0.9 nM), which were reversible, competitive inhibitors. In contrast, the 2',3'-dialdehydes produced irreversible inhibition of AdoHcy hydrolase, resulting in incorporation of two to four molecules of the dialdehyde per molecule (tetramer) of the enzyme. On the basis of an Ackermann-Potter analysis, the following "apparent" Ki values were determined for the 2',3'-dialdehydes: adenine analogue, 61 nM; 8-azaadenine analogue, 57.5 nM; and 3-deazaadenine analogue, 32 nM. The nucleoside 2',3'-diols were substantially less effective as inhibitors of AdoHcy hydrolase, requiring millimolar concentrations to achieve significant inhibition. When tested for their ability to inhibit vaccinia virus replication, several carbocyclic nucleosides (e.g., adenine and 3-deazaadenine analogues) and several nucleoside 2',3'-dialdehydes (e.g., adenine, N6-methyladenine, 8-azaadenine, and 3-deazaadenine analogues) exhibited good antiviral effects. A good correlation existed between a compound's inhibitory effects on AdoHcy hydrolase and its antiviral effects, suggesting that the inhibition of viral replication is caused by inhibition of a critical methylation reaction, e.g., methylation of the 5'-cap of viral mRNA.

Synthesis, antitumor activity, and chemical properties of silaplatin and related platinum (II) and platinum (IV) complexes derived from beta-silyl amines.

Platinum (II) and platinum (IV) coordination complexes derived from beta-silyl-substituted amines were prepared. The solubility of selected complexes in water and physiological saline was measured, and the effect of the beta-silicon on the reactivity of the complex in aqueous solution was determined by HPLC. The stabilities of selected silyl complexes were compared to the carbon analogues. The cyclic complexes 2a ("silaplatin") and its Pt(IV) analogue, 2b, were very active against L1210 leukemia in vivo. Both the platinum (II) complex 2a and the platinum (IV) complex 2b produced a significant number of cures over the dose range 10-40 mg/kg. The platinum (II) complex 2a, silaplatin, was very active in vivo against an L1210 leukemia subline that was resistant to cisplatin; 2a was also active, when given ip, against ic implanted L1210. The cyclobutanedicarboxylic acid complex 3c was synthesized; this complex was active against both cisplatin sensitive and resistant L1210 leukemia but was less potent than the analogous dichloro compound 2a. The acyclic platinum (II) and platinum (IV) complexes 1a,b were synthesized and unexpectedly found to be inactive in vivo against L1210 leukemia. More lipophilic silaplatin analogues were prepared--Pt(II) complex 2c and Pt(IV) complex 2d have one additional methylene carbon compared to 2a,b, whereas Pt(II) complex 2e and Pt(IV) complex 2f have two additional methylene carbons. Cyclization of the alkyl groups attached to the silicon gave the spiro bicyclic Pt(II) complexes 10a and 11a and the Pt(IV) complexes 10b and 11b.

The role of talker-specific information in word segmentation by infants.

Infants' representations of the sound patterns of words were explored by examining the effects of talker variability on the recognition of words in fluent speech. Infants were familiarized with isolated words (e.g., cup and dog) from 1 talker and then heard 4 passages produced by another talker, 2 of which included the familiarized words. At 7.5 months of age, infants attended longer to passages with the familiar words for materials produced by 2 female talkers or 2 male talkers but not for materials by a male and a female talker. These findings suggest a strong role for talker-voice similarity in infants' ability to generalize word tokens. By 10.5 months, infants could generalize different instances of the same word across talkers of the opposite sex. One implication of the present results is that infants' initial representations of the sound structure of words not only include phonetic information but also indexical properties relating to the vocal characteristics of particular talkers.

Cross-language word segmentation by 9-month-olds.

Dutch-learning and English-learning 9-month-olds were tested, using the Headturn Preference Procedure, for their ability to segment Dutch words with strong/weak stress patterns from fluent Dutch speech. This prosodic pattern is highly typical for words of both languages. The infants were familiarized with pairs of words and then tested on four passages, two that included the familiarized words and two that did not. Both the Dutch- and the English-learning infants gave evidence of segmenting the targets from the passages, to an equivalent degree. Thus, English-learning infants are able to extract words from fluent speech in a language that is phonetically different from English. We discuss the possibility that this cross-language segmentation ability is aided by the similarity of the typical rhythmic structure of Dutch and English words.

The relationship between cognitive failure and self-focused attention.

The Cognitive Failures Questionnaire and the Self-Consciousness Scale were administered to a sample of undergraduate students. The Private Self-Consciousness and Social Anxiety subscales were significantly correlated with CFQ, suggesting that dispositional self-focused attention may be one underlying cause of cognitive failure. Similarities in the relation between CFQ, SCS and task performance are discussed.

A morphometric study of the canine colon: comparison of control dogs and cases of colonic disease.

The microstructure of the canine colon was described morphometrically. The artifacts induced by administration of enemas and biopsy technique were studied by comparing biopsy specimens to tissues obtained at necropsy from 15 normal dogs. Biopsies from control dogs and clinical cases of colonic disease were then evaluated quantitatively, and histological abnormalities which might clarify mechanisms underlying large bowel dysfunction in the dog were sought. In control dogs, gland length and diameter, epithelial, goblet cell and mucosal mast cell numbers, and intraepithelial lymphocyte and mitotic indices were remarkably uniform throughout the colon. Minor variations were found in the proximal and distal regions of the colon. An apparent shortening of glands, and a reduction in mucous goblets and intraepithelial lymphocytes in biopsies were attributed to suboptimal orientation and irritation caused by enemas. The only significant difference from controls identified by morphometric analysis of biopsies from clinical cases was fewer epithelial cells lining longitudinal sections of glands. It was concluded that failure to identify morphometric variations in the colonic mucosa of clinical cases might reflect either a biased, homogeneously mild clinical syndrome in this group, or the possibility that in many of the clinical cases, a functional rather than physical abnormality was involved. The proprial inflammatory cell population was not examined quantitatively; further investigation of this component is merited.

Multifocal retinopathy of Great Pyrenees dogs.

Forty-four related Great Pyrenees dogs were examined ophthalmoscopically. Focal retinal elevations, multiple gray-tan-pink subretinal patches, and discrete areas of tapetal hyper-reflectivity were seen in 19 dogs, ranging from 13 weeks to 10 years of age. These lesions varied in size from focal spots that were barely visible with the indirect ophthalmoscope to areas that were larger than the optic disc. Complete blood cell counts, serum biochemical profiles, urinalyses, and blood pressure measurements were completed on four affected dogs and all were within normal reference ranges. Photopic and scotopic electroretinography was completed and the a-wave and b-wave amplitudes and latencies were similar for affected and age-matched nonaffected Great Pyrenees and other normal dogs. Electroretinograms that were examined twice during a 3-year period on three affected adult dogs did not reveal significant progressive deterioration of the a or b-wave parameters. Fluorescein angiography was completed on four affected dogs of ages 1 (n = 2), 5, and 6 years. These angiograms were repeated in three of these dogs 1 year later. The blood ocular barrier was intact in these dogs but there was blocked choroidal fluorescence. Postmortem examination, light microscopy, scanning and transmission electron microscopy were performed on three affected puppies and two affected adult dogs. These examinations revealed that the lesions in the puppies were limited to bilateral multiple areas of retinal pigment epithelial vacuolation, hypertrophy, and apparent separation from Bruch's membrane, and multiple serous retinal detachments. The affected adult dogs had focal retinal degeneration and retinal pigment epithelial hypertrophy, hyperplasia and pigmentation. Pedigree analysis and test mating confirm that this condition is inherited, probably as an autosomal recessive trait. This condition develops at approximately 13 weeks of age and the focal areas of retinal detachment and retinal pigment epithelial vacuolation progress to permanent and stable focal areas of retinal degeneration, and retinal pigment epithelial hypertrophy and pigmentation.

Ivermectin toxicosis in a dog.

Ivermectin, a broad-spectrum antiparasitic agent, was believed responsible for signs of CNS dysfunction in a dog. Within 2 hours of oral administration of ivermectin, the dog had hind limb ataxia. Neurologic signs progressed rapidly until the dog was in a semicomatose state at admission 20 hours later. The dog improved gradually under supportive care. The ivermectin had been given for suspected endoparasitism. Clinical signs were similar to those reported in dogs with clinical and experimental exposure to ivermectin.

Hyperferritinemia associated with malignant histiocytosis in a dog.

A 3.5-year-old male Golden Retriever with lethargy, generalized lymphadenopathy, and hepatosplenomegaly was determined to have malignant histiocytosis, based on the morphologic appearance of neoplastic cells by light and electron microscopic examination, evidence of erythrophagocytosis, the presence of diffuse nonspecific esterase activity, and immunohistochemical demonstration of vimentin intermediate filaments. Because of the appearance of abundant iron stores in the bone marrow, serum was obtained for determination of iron, total iron binding capacity, and ferritin values. Serum ferritin concentrations were markedly increased. Measurement of serum ferritin concentrations may be useful in supporting a diagnosis of malignant histiocytosis, and the monitoring of serum ferritin concentrations may be useful for assessing treatment and regression of the disease.

Risk factors associated with parvovirus enteritis in dogs: 283 cases (1982-1991).

OBJECTIVE: To determine breed, sex, and seasonal predisposition for development of canine parvovirus (CPV) enteritis in dogs. DESIGN: Retrospective case-control study. SAMPLE POPULATION: Medical records from 283 dogs with confirmed CPV enteritis and from 834 age-matched control dogs that were healthy or had been admitted with nonenteric illness. PROCEDURE: Effects of season, breed, sex, and neutering on the risk of developing CPV enteritis were examined by calculation of unadjusted odds ratios and performance of multivariate analysis. Stratified and contingency table analyses were performed to identify interactions and confounding among variables. RESULTS: Rottweilers, American Pit Bull Terriers, Doberman Pinschers, and German Shepherd Dogs were at increased risk and Toy Poodles and Cocker Spaniels were at decreased risk for developing CPV enteritis, compared with that for mixed-breed dogs. For dogs more than 6 months old, sexually intact males were twice as likely as intact females to develop CPV enteritis. Dogs were 3 times more likely to be admitted with CPV enteritis in July, August, and September, compared with the rest of the year. Dogs were 12.7 times more likely to be admitted with CPV enteritis if they had not been currently vaccinated. CLINICAL IMPLICATIONS: Lack of vaccination is a significant risk factor for development of CPV enteritis. Seasonal, sex, and breed predispositions for the development of CPV enteritis also exist.

Cutaneous T-cell lymphoma in a cat.

An 8-year-old castrated male cat was examined because of a chronic, nonhealing, ulcerative lesion on the left hind limb. Cutaneous lymphoma was diagnosed on the basis of the morphologic appearance of malignant cells and Pautrier's microabscesses on light and electron microscopic examination. The tumor was found to be of T-cell origin by use of a polyclonal antibody recognizing T-cell antigen. Results of serum ELISA for FeLV were negative. The gp70 antigen of FeLV was not detected immunohistochemically in tumor tissue sections, using polyclonal goat antisera and avidin/biotin/peroxidase complex technique. Presence of FeLV was demonstrated by the polymerase chain reaction procedure, involving amplification of a 166-base pair region of FeLV DNA. Although FeLV is reported to be the cause of most types of lymphoma in cats, cats with epitheliotropic cutaneous lymphoma have consistently negative test results for circulating FeLV antigen. In such cases, using the polymerase chain reaction method, tumor DNA may be assessed for integrated FeLV provirus and the presence of FeLV can be confirmed.

Gloomy but smarter: the academic consequences of attributional style.

The social psychological literature concerning the relationship between attribution and performance has documented the detrimental effects of particular types of attributional pattern on performance, expectancies and mood. The present paper reports three studies in which there was a consistent relationship between attributional style and actual performance. Undergraduate students who tended to attribute achievement-orientated failure to stable, and to some extent global, causes actually performed well on subsequent academic and ability tasks. These findings are new and constitute a challenge to the prevailing assumptions in the literature.

Vulnerability to depressive mood reactions: retesting the hopelessness model of depression.

A replication of Metalsky, Halberstadt & Abramson's (1987) test of the revised hopelessness model of depression was conducted. Depressive mood response to examination outcome was assessed in undergraduate students across two periods of examination. In phase 1, consistent with Metalsky et al. (1987), examination outcome was the sole predictor of depressive mood response on receipt of exam results. There was no evidence for a delayed mood response five days later. In phase 2, the interaction between attributional style and exam outcome was predictive of depressive mood response on receipt of exam results. Taken together, the results provide support for the diathesis-stress and specific vulnerability components of the model with respect to immediate mood response. No support was found for the causal mediation component. Differences between recently published studies are reported and implications for the model discussed.

Unusual case of foreign body-induced struvite urolithiasis in a dog.

A 6-year-old, castrated male dog was presented because of inappropriate urination and hematuria. Radiographs indicated a bladder stone with a sewing needle at its center. The urolith was removed and diagnosed as predominantly struvite, most likely a result of the foreign body and a urinary tract infection.

Injuries suffered by dogs from riding in the back of open pickup trucks: a retrospective review of seventy cases.

Case records of 70 dogs injured while riding in the back of open pickup trucks during the period January 1, 1982, to May 1, 1993, were reviewed. Most dogs were young (mean age 2.4 y) and of medium to large size (average weight 22.6 kg). Sixty-five dogs (93%) were injured during the months of April through October. Forty-nine dogs (70%) had single injuries and 21 dogs (30%) sustained multiple injuries. Fractures were the most frequent injury incurred, with fractures of the femur the most common. Surgical repair was recommended in all but 2 cases.

Spatial and temporal clustering of calcium oxalate and magnesium ammonium phosphate uroliths in dogs living in Ontario, Canada between 1998 and 2006.

Using the spatial scan statistic with a Bernoulli model, in a comparison of the two most common canine uroliths, calcium oxalate (CaOx) and magnesium ammonium phosphate (struvite) we determined whether there was evidence of spatial and/or temporal clustering of each urolith type based on canine submissions from Ontario to the Canadian Veterinary Urolith Centre (CVUC) between 1998 and 2006. During this period, there were 10,478 canine submissions, excluding cases that were identified as recurrent. We were able to georeference approximately 93% of these incident cases. After adjusting for spatial and temporal distributions of dogs based on the demographic risk factors of age, sex, and breed-type, statistically significant spatial and temporal clusters were present for both CaOx and struvite urolith types. A purely temporal struvite cluster occurred between February 10, 1998 and December 20, 2001, whereas, a purely temporal CaOx cluster occurred between September 2, 2005 and December 21, 2006. Hypotheses to explain the spatial clustering of uroliths include variation in the spatial distribution of water hardness, diet-type, access to veterinary care, and the use of surgical versus medical therapies to treat these uroliths. Based on the cluster locations, water hardness was unlikely to explain the spatial difference between the two cluster types whereas variables related to human population density were more consistent with our findings; the CaOx cluster occurred in the highest population density area of Ontario, and the struvite cluster occurred in the lowest population density area of southern Ontario. The temporal struvite cluster at the beginning and CaOx cluster at the end of the study period reflect a similar trend away from struvite towards CaOx urolithiasis among both canines and humans in the developed countries of North America and Europe.