Remarkable spectator ligand effect on the rate constant of ligand substitution of (aqua)ruthenium(II) complexes.

The influence of two different di(1-pyrazolyl)alkane ligands on the rate constant of aqua ligand substitution of ruthenium(II) complexes with the formula [Ru(H2O)(L2)(tpmm)]2+ (L2 = di(1-pyrazolyl)methane (DPMet) or 2,2-di(1-pyrazolyl)propane (DPPro)) was investigated. A 9.4 x 10(5)-fold increase in the rate constant of ligand substitution at pH = 6.86 was observed when DPMet was replaced with DPPro. This remarkable increase was unexpected, considering that these bidentate ligands appear quite similar. To help lend insight into this dramatic spectator ligand effect, the activation parameters for the ligand substitution reactions were determined, and single-crystal X-ray data were collected on the structurally analogous (chloro)ruthenium(II) complexes, [Ru(Cl)(L2)(tpmm)]+. These results are discussed in the context of a heteroscorpionate effect exerted by the DPPro ligand.

The cytotoxicity of symmetrical and unsymmetrical bis(thiosemicarbazones) and their metal complexes in murine and human tumor cells.

A number of thiosemicarbazones have been tested previously and herein are included three bis(thiosemicarbazones) for comparison to the previous derivatives. In general the uncomplexed thiosemicarbazones were more potent in the cytotoxic screens than the bis(thiosemicarbazone) except in the murine L1210 and the human colon SW480 screens. Mode of action studies have only demonstrated slight differences in the effects of the two types of compounds on nucleic acid metabolism. The symmetrical and unsymmetrical bis(thiosemicarbazones) complexes of copper, nickel, zinc, and cadmium have been examined to compare them to the heterocyclic N(4)-substituted thiosemicarbazones metal complexes. These new derivatives demonstrated excellent activity against the growth of suspended lymphomas and leukemias although it should be pointed out that generally they were not as active as the copper complexes of N(4)-substituted thiosemicarbazones. Nevertheless, selected bis(thiosemicarbazones) complexes were active against the growth of human lung MB9812, KB nasopharynx, epidermoid A431, glioma UM-86, colon SW480, ovary 1-A9, breast MCK-7, and osteosarcoma Saos-2. In human HL-60 promyelocytic leukemia cells the complexes preferentially inhibited DNA and purine syntheses over 60 min. The regulatory enzyme of the de novo purine pathway, IMP dehydrogenase, appeared to be a major target of the complexes. However, minor inhibition of the activities of DNA polymerase alpha, PRPP-amido transferase, ribonucleotide reductase, and nucleoside kinases occurred over the same time period. No doubt these effects of the complexes on nucleic acid metabolism were additive since the d[NTP] pool levels were reduced after 60 min as was DNA synthesis. The symmetrical and unsymmetrical bis(thiosemicarbazones) and their metal complexes did not cause as severe DNA fragmentation as the heterocyclic N(4)-substituted thiosemicarbazone metal complexes; furthermore, their metabolic effects in the tumor cell were more focused on a single synthetic pathway.

Synthesis and evaluation of copper radiopharmaceuticals with mixed bis(thiosemicarbazone) ligands.

Four "mixed" bis(thiosemicarbazone) derivatives of pyruvaldehyde were synthesized that incorporate two dissimilar thiosemicarbazone functions. The corresponding [67Cu]copper(II) complexes were prepared and evaluated as possible copper radiopharmaceuticals. The pyruvaldehyde-based mixed bis(thiosemicarbazone) ligands, CH3C[=NNHC(S)NHMe]CH[=NNHC(S)NHEt] (1), CH3C[=NNHC(S)NHMe] CH[=NNHC(S)NEt2] (2), CH3C[=NNHC(S)NHMe]CH[=NNHC(S)-cyclo-N(CH2)5] (3), and CH3C [=NNHC(S)NHMe]CH[=NNHC(S)-cyclo-N(CH2)6] (4), were obtained by reaction of the appropriate thiosemicarbazide derivative with pyruvaldehyde-2-N4-methylthiosemicarbazone (CH3C[=NNHC(S) NHMe]CHO). The 67Cu-labeled copper(II) complexes of ligands 1-4 were prepared and screened in a rat model to assess the potential of each chelate as a 62Cu-radiopharmaceutical for imaging with positron emission tomography. The 67Cu-complexes of ligands 1-4 exhibit significant uptake into the brain and heart 1 min following intravenous administration to rats. For the 67Cu-complexes of ligands 2, 3, and 4, the cerebral and myocardial uptake of 67Cu is two-to-threefold lower at 2 h than at 1 min postinjection, due to significant biological clearance of these 67Cu-chelates. However, the 67Cu-complex of 1 affords cerebral and myocardial uptake and retention comparable to that of [67Cu]Cu-PTSM in this model. Although the kinetics of this new agent appear attractive, ultrafiltration studies using solutions of dog and human serum albumin reveal that the 67Cu-complex of ligand 1, like Cu-PTSM, interacts more strongly with human albumin than dog albumin. Thus, this new agent would appear to offer no advantage over Cu-PTSM as a 62Cu-labeled tracer for evaluation of regional tissue perfusion.

Carcinogenicity of N1-[tris(hydroxymethyl)]methyl-4-nitro-o-phenylenediamine fed to mated and non-mated Sprague-Dawley rats.

N1(-)[tris(hydroxymethyl)]methyl-4-nitro-o-phenylenediamine was fed in the diet to groups of 30 male and 55 female Sprague-Dawley rats at levels of 0.2, 0.6 and 2.0% for up to 6 months. One mid-dose and two high-dose females developed palpable mammary masses that were subsequently diagnosed as mammary adenocarcinomas at a 13-wk interim kill involving 10 rats/sex/group. After 14 wk, 25 females per group with no apparent masses were mated in a reproduction/teratology study. Mammary tumours developed in a dose-related fashion both in the pregnant rats and in the remaining 20 females/group that continued on treatment for 6 months. On gestation day 20 (wk 17-18) the final incidences of mammary adenocarcinomas in the low-, mid- and high-dose mated dose groups were 20, 60 and 84%, respectively, while the corresponding incidences in the non-mated females at 6 months were 5, 40 and 85%. Most mammary tumours were encapsulated but, at 6 months, lung metastases were noted in four rats, and four females also had Zymbal's gland tumours. Non-neoplastic changes in male and female rats considered to be related to treatment included increases in thyroid follicular cell size accompanied by an accumulation of golden-brown pigment, multifocal hepatic necrosis with non-suppurative inflammation, and renal tubular pigmentation. Increases in foetal variations in the mid- and high-dose groups were considered to be related non-specifically to retarded growth. Malformations observed in the high-dose group were found primarily in single foetuses and were not considered to be treatment related. Although the mean numbers of micronucleated polychromatic erythrocytes in bone marrow obtained from high-dose treated females after 13 wk slightly exceeded historical negative control values, the data were not considered indicative of a genotoxic effect because of the absence of either a dose relationship or a substantive increase in the frequency of micronucleated cells.

Who is treated using restrictive behavioral procedures? A population perspective.

Considerable controversy surrounds the continued use of restrictive behavioral procedures in the treatment of destructive behaviors, such as self-injury, aggression, and property damage, displayed by some people with mental retardation. This study reports on the extent that pharmacological and behavioral consequences occur in response to these behaviors within a population of 31,000 people in one state's developmental services system. Data on these individuals are analyzed to determine the degree to which intellectual level, residential setting type, type and extent of problem behaviors, and age are related to the prescriptive use of pharmacologic and behavioral consequences. These variables appear to bear a significant relationship on the extent to which consequences are applied as part of treatment. Furthermore, although pharmacologic and several behavior consequences are applied at similar rates, it was found that generally timeout, as a specific treatment procedure, was applied at rates considerably less than those for psychoactive medication in each population sub-group that was examined.

Differences in adaptive functioning among people with autism or mental retardation.

This report describes differences in motoric and instrumental activity of daily living skills (MADLs and IADLs) between 1,442 people with autism and 24,048 people with mental retardation, using data from an adaptive behavior measure. Comparisons were made using groups defined by age (5-12, 13-21, and 21-35 years) and intellectual level. Diagnoses of record were confirmed through group analyses of rates of problem behaviors consistent with autism and comparison to an independent data base. Findings suggest that at ages 5-12 the skills of children with autism are more developed than those of children with mental retardation matched by age and intellectual level. However, in the older groups these differences diminish, and with increasing age (21-35 years) more developed instrumental skills are observed for people with mental retardation.

A 90-day toxicity study of the effects of petroleum middle distillates on the skin of C3H mice.

Petroleum middle distillates (PMDs) elicit skin tumors in mouse epidermal carcinogenesis studies. The response is characterized by a long latency with only a small percentage of animals developing tumors. Although the carcinogenic activity of certain other petroleum hydrocarbons largely depends upon the presence of polycyclic aromatic hydrocarbons (PAHs), many PMDs contain relatively low concentrations of PAHs. PMDs are also irritating to mouse skin, and chronic irritation may be involved in the development of skin tumors. This study was conducted to investigate the patterns of cutaneous irritation elicited by topical application of PMDs having compositional differences. The three PMDs selected for study were a steam cracked gas oil (SCGO), a lightly refined paraffinic oil (LRPO), and a jet fuel (JF). Male C3H/HeNCr1BR mice (25/group) were treated topically (37.5 microliters 2x/week for 13 weeks) with 10%, 50% or 100% (undiluted) concentrations of each PMD. Catalytically cracked clarified oil (CCCO, 10%), a potent carcinogen to mouse skin, was also tested. The vehicle was a noncarcinogenic mineral oil with a viscosity of 90 SUS. Cutaneous changes were evaluated by gross observations and light microscopy. Cutaneous irritation was the only significant toxic response in this study. Neither the vehicle nor any of the 10% PMD concentrations produced significant cutaneous irritation. The 10% CCCO and 50% PMD treatments all elicited slight to moderate proliferative and inflammatory changes in mouse skin. Ulcers were also observed microscopically in mice treated with 10% CCCO and 50% SCGO. The 100% SCGO treatment produced evidence of necrosis on Days 1-7 but not later in the study despite continued treatment. In contrast, the irritating effects of 100% LRPO were not evident until 2-3 weeks of study, and at study completion were characterized by moderately severe inflammatory and proliferative changes. The effects of 100% JF were qualitatively similar to 100% LRPO but less marked. Thus, the SCGO caused a different pattern of cutaneous responses than either LRPO or JF. The possible relationships of these cutaneous changes to epidermal carcinogenesis are being studied further.

Psychological services for persons with mental retardation and psychiatric impairments.

Key informant characterizations of services provided by psychologists to persons with mental retardation and psychiatric impairments were described. Responses indicate that informants relied most heavily upon clinical history, observation and behavior checklists, and clinical signs in rendering diagnostic judgments. Therapeutic efforts were directed to a diversity of aspects of interpersonal and social adjustment, with benefit considered to be greater for persons with mild or moderate mental retardation.

Pemphigus and pemphigoid in domestic animals: an overview.

Pemphigus and pemphigoid are uncommon dermatological entities in domestic animals and of a presumed autoimmune nature. In one form or another, they have been reported in the dog, cat, horse and goat. Although these diseases are considered to be bullous dermatoses, the clinical presentation may vary from ulcerative to exfoliative to proliferative depending on the individual condition. Currently, four variants of pemphigus are recognized (vulgaris, vegetans, foliaceus, erythematosus) and two of pemphigoid (bullous, cicatricial) although cicatricial pemphigoid has not yet been conclusively demonstrated in animals. Diagnosis is based on history, clinical signs, histopathology and immunopathology. Therapy must be immunosuppressive to be effective and is palliative rather than curative.

Carcinogenic and toxicologic effects of inhaled ethylene oxide and propylene oxide in F344 rats.

The chronic inhalation toxicity and carcinogenicity of ethylene oxide (EO) and propylene oxide (PO) were evaluated in a 2-year inhalation bioassay. Five groups of male weanling Fischer 344 rats, 80 per group, were exposed at 0 ppm (shared control; filtered air), 50 ppm EO, 100 ppm EO, 100 ppm PO, or 300 ppm PO (7 hr/day, 5 days/week) for 104 weeks. Body weights from rats exposed to EO and PO at all exposure concentrations were significantly reduced compared to controls. A statistically significant increase in mortality was observed in all groups of exposed rats compared to controls. Skeletal muscle atrophy in the absence of any sciatic nerve neuropathology was found in rats exposed at 100 ppm EO and 300 ppm PO. Statistically significant associations between EO exposure and an increased incidence of the following rat neoplasms were observed: mononuclear cell leukemia, peritoneal mesothelioma, and mixed cell brain glioma. Among rats exposed to PO there was a dose-dependent increase in the incidence of complex epithelial hyperplasia in the nasal passages, and two adenomas were detected in the nasal passages of rats exposed at 300 ppm PO. The incidence of adrenal pheochromocytomas was elevated in both PO exposure groups, but not in a dose-related manner. All rat groups were affected by an outbreak of Mycoplasma pulmonis infection which occurred about 16 months into the study. This infection alone and in combination with the epoxide exposures affected the survival of rats in this study, and influenced the development of the proliferative lesions in the nasal mucosa of the PO-exposed rats. No treatment-related changes in any clinical chemistry or urinalysis indices were detected. PO exposure did not increase the incidence of the three neoplasms associated with EO exposure; however, adrenal pheochromocytomas and proliferative lesions of the nasal cavity were increased in rats exposed to PO.

Thyroid adenocarcinoma in a dog.

A 13-year-old male German Shepherd had polydipsia, polyuria, polyphagia, weight loss, listlessness, elevated serum T, and gamma globulin levels, and a palpable thyroid mass. Examination of the resected mass revealed an adenocarcinoma. The dog recovered without further treatment.

Age-related neoplastic and degenerative lesions in aging male virgin and ex-breeder ACI/segHapBR rats.

A variety of neoplastic and degenerative lesions were observed in 216 aged male breeder (to 24 months of age) and virgin ACI/segHapBR rats sacrificed from 24 to 40 months of age. The most common neoplasms were pheochromocytomas, pituitary tumors, interstitial cell tumors of the testis, and tumors of the skin and subcutis. Many rats had multiple endocrine tumors. Age-related prostate hyperplasias and tumors were reported previously in these rats. Most of these tumors increased in incidence with advancing age, with few differences between virgins and ex-breeders. Testicular atrophy and tumors were more common in younger ex-breeder rats than in young virgin rats, but tumors reached a similar incidence in older virgin rats. Focal hyperplastic lesions appeared to represent the earliest stages of neoplasia in pituitary and adrenal glands, thyroid, prostate, testis, and liver. Common age-related nonneoplastic degenerative lesions were found in various tissues.

Enzootic and epizootic Venezuelan equine encephalomyelitis virus in horses infected by peripheral and intrathecal routes.

Forty-five horses were infected peripherally or intrathecally with enzootic or epizootic strains of Venezuelan equine encephalomyelitis (VEE) virus. Low titers of virus appeared in cerebrospinal fluid (CSF) after peripheral inoculation of enzootic or epizootic VEE virus strains. Intrathecal infection with either epizootic or enzootic VEE virus produced higher titers of virus in CSF than did peripheral infection. In contrast to peripheral infections with enzootic strains, intrathecal infections with these strains caused death. The animals that died had widespread histopathologic changes and large amounts of virus in brain tissue. The attenuated VEE virus vaccine strain, TC-83, also multiplied in the brain of horses inoculated intrathecally but caused no clinical disease and little histopathologic damage.