Influence of cocaine history on the behavioral effects of Dopamine D(3) receptor-selective compounds in monkeys.

Although dopamine D(3) receptors have been associated with cocaine abuse, little is known about the consequences of chronic cocaine on functional activity of D(3) receptor-preferring compounds. This study examined the behavioral effects of D(3) receptor-selective 4-phenylpiperazines with differing in vitro functional profiles in adult male rhesus monkeys with a history of cocaine self-administration and controls. In vitro assays found that PG 619 (N-(3-hydroxy-4-(4-(2-methoxyphenyl)piperazin-1-yl)butyl)-4-(pyridin-2-yl)benzamide HCl) was a potent D(3) antagonist in the mitogenesis assay, but a fully efficacious agonist in the adenylyl cyclase assay, NGB 2904 (N-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butyl)-9H-fluorene-2-carboxamide HCl) was a selective D(3) antagonist, whereas CJB 090 (N-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butyl)-4-(pyridin-2-yl)benzamide HCl) exhibited a partial agonist profile in both in vitro assays. In behavioral studies, the D(3) preferential agonist quinpirole (0.03-1.0 mg/kg, i.v.) dose-dependently elicited yawns in both groups of monkeys. PG 619 and CJB 090 elicited yawns only in monkeys with an extensive history of cocaine, whereas NGB 2904 did not elicit yawns, but did antagonize quinpirole and PG 619-elicited yawning in cocaine-history monkeys. In another experiment, doses of PG 619 that elicited yawns did not alter response rates in monkeys self-administering cocaine (0.03-0.3 mg/kg per injection). Following saline extinction, cocaine (0.1 mg/kg) and quinpirole (0.1 mg/kg), but not PG 619 (0.1 mg/kg), reinstated cocaine-seeking behavior. When given before a cocaine prime, PG 619 decreased cocaine-elicited reinstatement. These findings suggest that (1) an incongruence between in vitro and in vivo assays, and (2) a history of cocaine self-administration can affect in vivo efficacy of D(3) receptor-preferring compounds PG 619 and CJB 090, which appear to be dependent on the behavioral assay.

Combined dermal exposure to permethrin and cis-urocanic acid suppresses the contact hypersensitivity response in C57BL/6N mice in an additive manner.

Cutaneous exposure to the pyrethroid insecticide permethrin significantly suppresses contact hypersensitivity (CH) response to oxazolone in C57BL/6N mice. Additionally, cis-urocanic acid (cUCA), an endogenous cutaneous chromophore isomerized to its active form following exposure to ultraviolet radiation, modulates cell-mediated cutaneous immune responses. This study describes cutaneous immune alterations following combined topical permethrin and intradermal cUCA exposure. Female C57BL/6N mice were administered 5, 50 or 100 microg cUCA daily for 5 consecutive days. CH was then evaluated by the mouse ear swelling test (MEST) response to oxazolone. Decreased responses of 52.3%, 76.3% and 76.3%, respectively, as compared to controls were observed. Then, mice were co-exposed to 5 microg cUCA daily for 5 days and 1.5, 5, 15, or 25 microL permethrin, on either day 1, 3 or 5 of the cUCA treatment to evaluate combined immunomodulatory effects of the two chemicals, or cUCA daily for 5 days followed by permethrin on day 3, 5, or 7 after the last cUCA injection to demonstrate prolonged immunosuppressive effects. Two days after final treatment, mice were sensitized with oxazolone and MEST was performed. Mice receiving five cUCA injections and permethrin topically on cUCA injection day 1 showed up to 93.3% suppression of MEST compared to vehicle control. CH was suppressed by 87.5%, 86.6% and 74.2% in mice treated with 25 muL permethrin on days 3, 5 and 7 after cUCA, respectively, compared to vehicle control. Taken together, these data indicate co-exposure to cUCA and permethrin profoundly suppresses cell-mediated cutaneous immunity.

Molecular mechanisms of cis-urocanic acid and permethrin-induced alterations in cutaneous immunity.

BACKGROUND/PURPOSE: Cutaneous cis-urocanic acid (cUCA) or ultraviolet B exposure has been shown to cause diminished cutaneous contact hypersensitivity (CH) and to induce systemic tolerance (increased regulatory T lymphocytes) in mice. Permethrin is also a known CH inhibitor, but the molecular mechanisms are currently poorly understood. In this study, CH was evaluated in four strains of mice: an immunosensitive strain (C57BL/6N), an immunoresistant strain (SvImJ), a strain developed from C57BL/6N mice but genetically altered at both the tumor necrosis factor-alpha receptors (TNFalphap55R and p75R), and a strain developed from C57BL/6N but genetically deleted at the interferon-gamma (IFNgamma) locus. METHODS: CH was evaluated in each group via oxazolone challenge following a 5-day exposure to intradermal (ID) cUCA or a single exposure to topical permethrin, or co-exposure to both chemicals in 5-week-old female C57BL/6N, SvImJ, and C57BL/6N mice genetically altered at the TNFalpha or IFNgamma locus. RESULTS: A 5-day exposure to ID cUCA or a single exposure to topical permethrin resulted in diminished CH response in C57BL/6N mice, and this effect was exacerbated with concurrent exposure to both chemicals. CH in SvImJ was both cUCA- and permethrin-resistant relative to C57BL/6N mice, as 5-day cUCA or a single exposure to permethrin did not diminish CH, nor did concurrent exposure to cUCA and permethrin. Mice deleted at both TNFalphaR loci displayed similar but somewhat blunted diminished CH responses to cUCA or permethrin. This trend became significant with combined chemical exposure. IFNgamma knockout mice displayed similar diminished CH responses to cUCA or permethrin alone. Unlike C57BL/6N mice, the IFNgamma knockout mice did not show a further reduction in CH with combined chemical exposure. CONCLUSIONS: These results suggest the following: (1)Mouse strains show variable susceptibility to permethrin- and cUCA-induced immunomodulation. (2)TNFalpha may be involved in the immunomodulatory effects of cUCA and permethrin. (3)IFNgamma may be required for the more than additive depression of CH caused by cUCA+permethrin.

Cis-urocanic acid increases immunotoxicity and lethality of dermally administered permethrin in C57BL/6N mice.

Immunomodulatory effects of a single topical permethrin exposure, 5-day exposure to cis-urocanic acid (cUCA), or a combination of the two chemicals were evaluated in 4- to 5-week-old female C57BL/6N mice. Permethrin alone decreased thymic weight and cellularity. Although cUCA alone did not affect thymic end points, coexposure to topical permethrin and cUCA exacerbated the thymolytic effects of permethrin. The single topical dose of permethrin also depressed several immune responses in isolated splenic leukocytes. This included splenic T-cell proliferative response to mitogen, splenic macrophage hydrogen peroxide production, and splenic B lymphocyte-specific antibody production. Unlike the effect of coexposure to these agents on thymic end points, cUCA did not exacerbate permethrin's adverse effect on any of the splenic end points examined. These results appear to suggest divergent mechanisms by which these compounds affect precursor and functionally mature T cells. At the doses used in this study, permethrin caused neurotoxic effects, including lethality, in a portion of the mice. For undetermined reasons, cUCA significantly increased the rate of lethality caused by permethrin. Although the permethrin doses used in this study exceed that typically used in human medicine, these results raise some concerns about the possibility that sunlight, via cUCA, may increase the risk of adverse central nervous system and immune effects caused by permethrin alone.

The mouse as a model for developmental immunotoxicology.

The laboratory mouse has been the most extensively used model system for demonstrating postnatal immune deficits following perinatal immunotoxicant exposure. Assays utilized have historically been those developed for adult mice. Clear gaps in the available database exist, however, regarding the predictive strength of adult mouse immune screens for detecting either transient or long-lasting postnatal immune suppression. Limited information is also available regarding postnatal ages when various immune assays can be first employed to detect developmental immunotoxicity in mice. Furthermore, difficulties and expense inherent with breeding of in-bred mice, as used for adult immunotoxicity studies, raise questions regarding the feasibility of an in-bred mouse model as a standard, widely available developmental immunotoxicity testing system. These and additional concerns will need to be addressed as a model system with utility for studying developmental immunotoxicants is produced.

Single-dose topical exposure to the pyrethroid insecticide, permethrin in C57BL/6N mice: effects on thymus and spleen.

Immunomodulatory effects of single topical exposure to permethrin were evaluated in 5-week-old female C57BL/6N mice. Mice exposed to 5-25 microl permethrin (equivalent to 220-1100 mg/kg body weight) on shaved interscapular skin were evaluated for altered body weight; splenic and thymic organ weight and cellularity; thymocyte cell surface expression, cellular apoptosis; splenic macrophage phagocytosis and hydrogen peroxide production; splenic B cell antibody production and T cell cytolytic activity; and mitogen-induced proliferation of splenocytes and thymocytes after in vivo or in vitro permethrin exposure. Topical permethrin application (25 microl) caused 32% inhibition of splenic T cell proliferation; in vitro exposure to permethrin also diminished splenocyte proliferation by 72% at 25 microM and 86% at 100 microM. permethrin did not appear to affect other leukocyte functional assays. Dose-related decreases in thymic cellularity of 52 and 80% were seen in mice exposed to 15 and 25 microl permethrin, respectively. Apoptosis was significantly increased in CD4(-)8(-) and CD4(-)8(+) thymocytes, and the CD4(+)CD8(+) thymocyte subpopulation was most severely diminished, suggesting possible chemical-induced apoptotic mechanism of thymic atrophy. Permethrin also caused splenic hypocellularity by 31% at 15 microl, and by 50% at 25 microl, an effect that may relate to inhibited proliferation or reduced seeding from the hypocellular thymus.

Suppression of the contact hypersensitivity response following topical exposure to 2-butoxyethanol in female BALB/c mice.

The effects of route of exposure, time of exposure and metabolism of 2-butoxyethanol (BE) on the contact hypersensitivity response (CHR) were evaluated in female BALB/c mice. Mice were either orally exposed to 50, 150 or 400 mg BE/kg or topically exposed to 0.25, 1.0, 4.0 or 16.0 mg BE on the ear and the oxazolone (OXA)-induced CHR evaluated by measuring ear thickness before and after OXA challenge. While no modulation was observed following oral exposure to BE, topical exposure resulted in a significant decrease in the CHR. Application of 4.0 mg BE in 4:1 acetone and olive oil (AOO) vehicle at the time of sensitization, challenge or both, decreased the CHR by 18%, 18% and 22%, respectively. A time course study of the effects of topical exposure to 4.0 mg BE/ear during the challenge phase of the CHR revealed that BE must be applied at the time of OXA challenge to significantly reduce the ear swelling response. In order to determine if metabolism of topically applied BE was required for suppression of the CHR, butoxyacetic acid (BAA), the primary metabolite of BE, was applied to the ear immediately following OXA challenge. No topical dose of BAA (2.0,4.0 and 8.0 mg BAA/ear) administered in this study altered the CHR. Blocking the metabolism of BE by oral administration of 4-methylpyrazole (MP), further reduced OXA-induced ear swelling when compared to mice exposed to BE without MP treatment. Taken together, these studies indicated that suppression of the CHR in mice following topical exposure to this glycol ether was due to the activity of BE itself and was not dependent on metabolic activation of the compound. Further studies were undertaken to identify a potential mechanism of BE-induced reduction of the CHR. Epidermal cells from untreated BALB/c mice were isolated and exposed to BE in vitro (10(-12), 10(-10), 10(-8), 10(-6) and l0(-4) M BE). In vitro exposure to BE at these concentrations did not significantly affect expression of MHC class II surface protein or protein synthesis in epidermal Langerhans cells, failing to provide in vitro evidence that BE-associated suppression of the CHR is associated with a reduction in MHC class II expression.

Topical permethrin exposure inhibits antibody production and macrophage function in C57Bl/6N mice.

Permethrin was applied to the shaved dorsal interscapular region of C57Bl/6N mice at doses of 0.5, 1.5 or 5.0 microl/day. These doses corresponded to approximately 22-220 mg/kg/day topical insecticide. Mice were exposed to permethrin in this manner daily for 10 or 30 consecutive days, or every other day for 7 or 14 exposures. The splenic macrophage chemiluminescent response was depressed in a dose-dependent manner at 2 and 10 days post-exposure to permethrin. Phagocytic ability of macrophages was not inhibited. Antibody production as shown by plaque-forming cell (PFC) assay decreased significantly after 10 consecutive days of exposure to permethrin. These data indicate that topical permethrin exposure may produce systemic immune effects.

Topical exposure to 2-butoxyethanol alters immune responses in female BALB/c mice.

Effects on immune parameters following topical exposure to 2-butoxyethanol (BE) in mice are reported in the present study. The objective was to determine whether subacute topical exposure to BE can modulate functional immune responses and/or nonspecific immune parameters such as lymphoid organ weight and cellularity. Female BALB/c mice were topically exposed to vehicle or BE at concentrations of 100, 500, 1,000, and 1,500 mg BE/kg/day for 4 consecutive days. Assessment of immune parameters began 24 hours after the final dose. No effects were observed at any of the BE concentrations on thymus cellularity or thymus to body weight ratio. A significant increase in spleen cellularity and spleen to body weight ratio was observed at 1,500 mg BE/kg/day. Topical BE exposure significantly reduced the splenic T cell proliferative response to concanavalin A (Con A) and the mixed lymphocyte response (MLR) to allogeneic antigen. No significant effect was observed in the splenic B cell proliferative response to lipopolysaccharide (LPS), nor was there an effect on the in vitro primary antibody response to sheep red blood cells (SRBCs). No significant alteration occurred in either splenocyte cytotoxic T lymphocyte (CTL) activity or natural killer (NK) cell activity following topical BE exposure. This study suggests that topical exposure to BE may suppress some aspects of T cell immunity but does not affect B cell immunity.

Nonspecific stimulation of the maternal immune system. I. Effects On teratogen-induced fetal malformations.

BACKGROUND: Maternal immune stimulation has reported, but unconfirmed, efficacy for reducing chemical-induced morphologic defects in mice. METHODS: Teratogenic chemicals (2,3,7, 8-tetrachlorodibenzo-p-dioxin [TCDD], ethyl carbamate [urethane], methylnitrosourea [MNU], or valproic acid [VA]) were given to pregnant mice to induce cleft palate (TCDD, urethane), digital defects (urethane, MNU), or exencephaly (VA). Before teratogen administration, the immune system of female mice was stimulated by intraperitoneal (IP) administration of pyran copolymer or attenuated bacillus Calmette Guérin (BCG), or by footpad injection with Freund's complete adjuvant (FCA). RESULTS: Fetal defects caused by all four chemicals studied were reduced by maternal immunostimulation, sometimes dramatically. In addition to reducing VA-induced exencephaly, immunostimulation with FCA resulted in fetal mice displaying anury (absence of tails). Activated maternal immune cells could not be detected in fetal circulation using flow cytometry and a fluorescent cell-tracking probe. CONCLUSIONS: For the chemicals tested, maternal immune stimulation has efficacy in reducing fetal defects. Immune protection against teratogenesis may be an indirect effect of maternal immune cell activation.

Environmental contamination and assessment of doses from radiation releases in the Southern Urals.

The Southern Urals in Russia was contaminated by radioactive discharges into the Techa River (1949-1956), the Kyshtym accident (1957), and the current releases and discharges from the Mayak Nuclear Materials Production Complex. In this paper, the consequences of radioactive contamination of the Ural region are analyzed. The current content of 90Sr in the components of food chains is as follows (Bq kg(-1) wet weight): potatoes, 0.2-6.7; grain, 0.5-12.6; milk, 0.2-6.3; beef, 0.2-1.7; lake water, 0.12-1.0; river water, 0.2-8.5; fish, 7-480; mushrooms, 400-1,100; and berries, 700-16,000. The content of 137Cs is as follows: potatoes, 0.5-3.8; grain, 0.3-2.9; milk, 0.2-4.5; beef, 0.3-2.6; lake and river water, 0.002-0.019; fish, 2-32; mushrooms, 110-1,600; and berries, 150. A major fraction of the dose to humans comes from the consumption of local food products, including natural ones, which have higher contamination levels than agricultural products. The average annual dose rates in contaminated areas are (0.5-4) x 10(-4) Sv y(-1), which is lower by a factor of 10(2)-10(4) than in the periods of "acute" exposure (1950-1951 and 1957-1958). Natural organisms received very high doses up to 200-800 Gy resulting from radioactive discharges into the Techa River and the radiation accident in 1957. In all cases, including the "acute" exposure followed by the chronic irradiation, the doses to biota were by a factor of 10-10(3) higher than those to humans.

Comparative study of risk factors for skin breakdown with cervical orthotic devices: Philadelphia and Aspen.

PURPOSE: To compare risk factors for skin breakdown between Philadelphia and Aspen cervical collars. METHODS: Crossover design. Twenty healthy volunteers wore Philadelphia and Aspen cervical collars in random order. Occipital pressure, relative skin humidity, and skin temperature measured at 0 and 30 minutes. Paired t-tests compared changes between collars from 0 to 30 minutes. FINDINGS: Occipital pressure and skin temperature were not statistically different between collars. Relative skin humidity increased more in Philadelphia (29% +/- 17%) than Aspen (8% +/- 9%), p < 0.001. CONCLUSIONS: Aspen resulted in lower relative skin humidity.

Trauma multidisciplinary QI project: evaluation of cervical spine clearance, collar selection, and skin care.

PURPOSE: To evaluate data regarding cervical collars and develop guidelines related to product selection, cervical spine clearance, and skin care. METHODS: Production selection and skin care were evaluated by multidisciplinary teams review of QI data. RESULTS: The multidisciplinary teams identified a c-spine clearance algorithm, a methodology for continuous skin evaluation, and a new policy for skin care under the c-collar. CONCLUSIONS: Focused attention to problems surrounding cervical spine immobilization can decrease patient complications.

Solving the problem of pressure ulcers resulting from cervical collars.

Cervical orthotic devices (cervical collars) are integral to the treatment of patients with suspected or confirmed fracture of the cervical spine. Pressure ulcers can develop under the cervical collar on the occipital protuberance and on the chin due to both prolonged immobilization and the collar construction. A multidisciplinary team at a Northwest Ohio trauma center led an investigation of this problem when a one day study of pressure ulcer prevalence revealed that of 4% of nosocomial pressure ulcers, 2% were attributed to cervical collars. To solve this problem, the team visualized risk factors using a fishbone diagram, investigated by calling manufacturers and other institutions and by searching the literature, developed educational programs on skin care and correct collar fitting, conducted a product trial on a new collar, and continuously monitored the results. The conclusions of the team were that the pressure ulcers were the result of the construction of the previous cervical collars used. The product trial resulted in zero skin breakdown for the 20 patients involved. Changes implemented as a result were an improved skin care regimen, education on proper fitting and appropriate choice of collars, and implementation of the new collar for trauma patients.

Case management: a new practice model for ET nurses.

An examination of wound, ostomy, and continence nursing practice provides ideas for improving patient care and for role development of the ET nurse. During this period of rapid health care reform, opportunities to expand ET nursing practice must be explored. For many ET nurses, care of the patient with an ostomy remains a primary focus. The fitting of prosthetic equipment and patient education concerning ostomy care may not, however, be enough to demonstrate the impact of ET nursing care on the outcome of patients with an ostomy. Caring for the patient undergoing gastrointestinal surgery by means of a case management model is a new option for ET nurses. Nurse case managers focus on the patient and the impact of illness from admission until discharge. They are accountable for coordinating the multidisciplinary team who cares for the patient and for the evaluation of outcomes. ET nurses must evaluate the outcomes of their care to demonstrate the continued need for our specialty practice. This article describes the efforts of ET nurses at a tertiary care center in the Midwest to develop a case management system for patients undergoing gastrointestinal surgery within their practice. The process of developing a critical pathway, or care map, is also described.

A study of risk factors in patients placed on specialty beds.

Air-fluidized and low-air loss beds have become common throughout the United States. Many studies have demonstrated the efficacy of these beds in the prevention and treatment of pressure ulcers. Determining which patients truly need this therapy and which could have positive outcomes with other pressure-relieving or pressure-reducing devices can be difficult. The purpose of this research was to examine medical diagnoses, total Braden Scale scores, Braden Scale subscores (sensory perception, moisture, activity, mobility, nutrition, and friction/shear), nutritional levels, and comorbid conditions among patients placed on specialty beds for prevention and treatment of pressure ulcers. A retrospective chart review of 47 patients who used specialty beds during an 18-month period was used to determine factors that were clinically significant.

Topical exposure to chlordane reduces the contact hypersensitivity response to oxazolone in BALB/c mice.

Previous studies have shown that prenatal exposure to the organochlorine pesticide chlordane significantly decreases the ear swelling response to the contact allergen oxazolone in BALB/c mice. Alterations of macrophage function in the efferent arm of the contact hypersensitivity response have also been reported. In the current study, chlordane was applied topically and the effects of oxazolone-induced contact hypersensitivity were determined. Initially, the reduction in oxazolone-induced ear swelling in topically-exposed female BALB/c mice was compared to 30-day-old BALB/c female mice exposed prenatally to chlordane. Prenatal chlordane exposure induced a 36% reduction in ear swelling compared to a 60% reduction following topical treatment at the challenge phase. Topically-applied chlordane also reduced the oxazolone-induced ear swelling by 40% when applied at sensitization. When applied at both sensitization and challenge, ear swelling was reduced by 71%. In a time-course study, it was determined that chlordane must be applied at the time of sensitization, challenge or both or within 1 h post-challenge to significantly reduce ear swelling. A dose-response study showed that the lowest concentration of chlordane resulting in a significantly reduced ear swelling response was 20 micrograms per ear.