Ethanol consumption and behavioral impulsivity are increased in protein kinase Cgamma null mutant mice.

Etiological factors influencing the development of alcoholism are complex and, at a minimum, include an interaction between polygenic factors and personality and biological traits. Human and animal studies suggest that some genes may regulate both the traits associated with alcohol abuse, such as decreased sensitivity or anxiety, and vulnerability to alcoholism. The identification of these genes could elucidate neurochemical pathways that are important in the development of alcohol abuse. Results from the present study indicate that the gene encoding the neuronal-specific gamma subtype of protein kinase C (PKCgamma) influences both ethanol consumption and behavioral impulsivity, a personality characteristic associated with Type II alcoholics, in a pleiotropic manner. Mice lacking PKCgamma consume more ethanol in a two-bottle choice paradigm and also demonstrate increased behavioral impulsivity in an appetitive-signaled nosepoke task when compared with wild-type littermate control mice. Therefore, PKCgamma may be an important mechanism within the cell that mediates one or more neurochemical pathways relevant to an increased predisposition to alcoholism.

Isolation and sequence of a mouse brain cDNA coding for protein kinase C-gamma isozyme.

The regulatory enzyme, protein kinase C (PKC), is characterized by a family of related isozymes. Currently, nucleotide (nt) sequences for seven members of this family have been reported from the bovine, human and rat genomes. Only four of these seven PKC isoforms have been isolated in mouse: alpha, beta II, delta and epsilon. Here, we report the cDNA sequence encoding mouse PKC-gamma isolated from a C57BL/6 brain cDNA library. The mouse and rat PKC-gamma nt and deduced amino acid sequences share 97 and 100% identity, respectively.

Adrenalectomy and stress modulate GABAA receptor function in LS and SS mice.

The effects of manipulation of adrenal steroids by adrenalectomy (ADX) or stress on GABAA receptor function were characterized in long-sleep (LS) and short-sleep (SS) mice. 36Chloride flux was not altered in either line of mouse after ADX; however, exposure to a behavioral stressor resulted in a highly significant inhibition of ion channel activity measured in cortical membranes from both LS and SS mice. Adrenalectomy also had no effect on [3H]FNZ binding; whereas exposure to stress differentially altered benzodiazepine binding in LS and SS mice. In LS cortex both Bmax and Kd values increased, whereas in SS cerebellum, Bmax and Kd values were decreased after stress. In SS mice ADX did not affect GABA-enhancement of [3H]FNZ binding. In LS mice, however, ADX resulted in a potentiation of GABA-enhanced [3H]FNZ binding in cortex and an inhibition of enhancement in cerebellum. Corticosterone (CCS) replacement in ADX-LS mice returned enhancement values to those of sham-operated mice, indicating a role for basal levels of CCS in maintaining normal receptor coupling function in this line of mouse. These results suggest that GABAA receptor sensitivity is more labile under stressful conditions. Differential receptor responses to adrenal manipulation between LS and SS mice may be due to genetic variation in GABAA receptor subunit combinations in these lines of mice.

Biochemical and behavioral effects of steroids on GABAA receptor function in long- and short-sleep mice.

The in vitro and in vivo effects of alphaxalone, a steroid anesthetic, and two physiological steroids, tetrahydrodeoxycorticosterone (THDOC) and pregnenolone sulfate (PS), on GABAA receptor function were evaluated in long-sleep (LS) and short-sleep (SS) mice. In vitro, both alphaxalone and THDOC enhanced GABAergic inhibition as measured by [3H]FNZ binding and GABA-stimulated 36Cl- flux. However, with the exception of alphaxalone potentiation of [3H]FNZ binding, which was greater in SS brain regions, LS and SS mice did not differ in their degree of enhancement. Pregnenolone sulfate produced mixed agonistic and antagonistic effects on GABAergic function, dependent upon brain region, with few differences between the lines of mice. In vivo effects of these steroids on sleep time indicated that, like other anesthetic agents, THDOC and alphaxalone induced longer sleep times in LS mice. Antagonism by PS of ethanol-induced sleep time was observed in LS mice only; however, this effect was dependent upon the dose of ethanol used and on the vehicle used to prepare the steroid. Pentobarbital-induced sleep time was not reduced by PS treatment in either line of mouse. These results demonstrate that few differences in sensitivity of the GABAergic receptor to these steroids exist between LS and SS mice. Thus, unlike the differences between LS and SS mice in GABAergic mediation of responses to ethanol and benzodiazepines, there is little genetic variability in subtypes of GABAA receptors capable of modulation by steroids in these lines of mice.

Interaction of ethanol and stress with the GABA/BZ receptor in LS and SS mice.

The interaction of stress and ethanol with the GABA/BZ receptor system was evaluated in LS and SS mice. The effects of two separate in vivo treatments, a 2.5 g/kg injection of ethanol or a behavioral stressor, on GABA-enhanced [3H]-FNZ binding were nearly identical in both lines of mice. A 2.5 g/kg ethanol- or stress-pretreatment resulted in increased enhancement in SS cortex, but not LS. In cerebellum, treatment effects were demonstrated in both SS and LS mice. Intraperitoneal injections of increasing doses of ethanol produced biphasic stimulation of GABA-enhanced [3H]-FNZ binding in LS brain regions, but not SS. Adrenalectomies performed one week prior to ethanol administration produced a loss of ethanol enhancement in cerebellum of both lines. However, in cortex, removal of the adrenals had no effect. The in vitro addition of 30 mM ethanol to brain preparations incubated at 37 degrees C from stressed and unstressed animals resulted in greater enhancement of binding in cortex, but not cerebellum of stressed mice. Differences in the degree of enhancement between the lines of mice were lost if the animals were stressed prior to sacrifice or if membrane preparations were incubated at 4 degrees C. The results of this study suggest that the interaction between ethanol and stress is mediated by the GABAergic system, but responses vary dependent on brain region, dose of ethanol, and degree of ethanol sensitivity.

Adrenalectomy increases bicuculline-induced seizure sensitivity in long-sleep and short-sleep mice.

Susceptibility to bicuculline-induced seizure onset and tonus was increased in LS and SS mice after adrenalectomy (ADX). Replacement with 10% corticosterone (CCS) in ADX animals resulted in a return to seizure latencies equal to those of sham-operated (SHAM) mice. In SS mice, dexamethasone (DEX) and cholesterol-control replacement was as effective as 10% CCS in returning seizure thresholds to SHAM values. In LS mice, DEX was only effective at a low bicuculline dose. Within the sham-operated group SS mice were more susceptible to bicuculline-induced seizure onset than LS mice; however, after ADX latencies did not differ between the two lines. These results suggest that seizure thresholds are regulated to some extent by the hypothalamic-pituitary-adrenal (HPA) axis. The effects of ADX on GABA-related seizure activity may also be influenced by genotype, such that genetic differences in GABAA receptor function and adrenocortical responses in LS and SS mice may be responsible for the differential seizure latencies observed in sham-operated mice.

Differential sensitivity to the anxiolytic effects of ethanol and flunitrazepam in PKCgamma null mutant mice.

Tests of ethanol effects in PKCgamma null mutant mice have indicated that PKCgamma plays a role in initial sensitivity to ethanol-induced sedation, hypothermia, and GABA(A) receptor function and impacts neurochemical pathways mediating anxiety. The present study was undertaken to evaluate whether the decreased sensitivity to ethanol previously observed in these mice generalized to the anxiolytic effects of ethanol. PKCgamma null mutant mice and wild-type controls were tested in the elevated-plus maze, the black/white box, and the mirrored chamber after ethanol (0, 1.0, 1.25, 1.5 g/kg) or flunitrazepam (FNZ) (0, 0.015, 0.03, 0.06 mg/kg). Results indicated that although both genotypes exhibited anxiolytic responses to ethanol in the elevated plus-maze, null mutant mice were less sensitive than wild-type control mice; however, in the black/white box, PKCgamma null mutants were more sensitive than controls to the anxiolytic effects of FNZ. Neither ethanol nor FNZ produced anxiolytic responses in the mirrored chamber for either genotype. These results suggest that PKCgamma differentially mediates anxiolytic responses to ethanol and FNZ and that this relationship interacts with each drug's efficacy in reducing anxiety-related behaviors specific to each of the three mazes.

Care-as-service, care-as-relating, care-as-comfort: understanding nursing home residents' definitions of quality.

PURPOSE: This study explored how nursing home residents define quality of care. DESIGN AND METHODS: Data were collected through in-depth interviews and were analyzed using grounded dimensional analysis. RESULTS: Residents defined quality in three ways: (a) Care-as-service residents focused on instrumental aspects of care. They assessed quality using the parameters of efficiency, competence, and value. (b) Care-as-relating residents emphasized the affective aspects of care, defining quality as care that demonstrated friendship and allowed them to show reciprocity with their caregivers. (c) Care-as-comfort residents defined quality as care that allowed them to maintain their physical comfort, a state that required minute and often repetitive adjustments in response to their bodily cues. IMPLICATIONS: Residents' perceptions of care quality have implications for long-term care practice. The integration of these perceptions into quality assurance instruments could improve the usefulness of tools designed to obtain resident input.

Background genotype modulates the effects of γ-PKC on the development of rapid tolerance to ethanol-induced hypothermia.

The role of γ-PKC in initial sensitivity and in the development of rapid tolerance to the hypothermic effects of ethanol were investigated in γ-PKC null mutant mice. Effects of the single gene mutation were evaluated on three different genetic backgrounds. Null mutants from a C57BL/6J X 129/SvJ mixed genetic background failed to develop rapid tolerance after 4 days of i.p. ethanol injections. However, when the null mutation was introgressed onto a C57BL/6J background for six generations to create a congenic line, the expression of rapid tolerance unexpectedly reoccurred in the null mutant mice. Subsequent outcrossing of the γ-PKC null mutation to a C57BL/6J X 129/SvEvTac mixed background did not restore the no tolerance phenotype. These observations, taken together with similar results reported previously concerning the development of chronic tolerance to ethanol in these same genotypes, ¹ indicate that the gene coding for gamma-PKC has pleiotropic effects in the expression of both rapid and chronic tolerance to ethanol-induced hypothermia. However, the impact of γ-PKC is modulated by the background genotype. These results stress the necessity of understanding interactions with genetic background when interpreting the effects of single gene mutations on complex behavioral traits.

The effects of ethanol and Ro 15-4513 on elevated plus-maze and rotarod performance in long-sleep and short-sleep mice.

The effects of ethanol and diazepam were examined in long-sleep (LS) and short-sleep (SS) mice using the elevated plus-maze. Ethanol had more pronounced effects in SS mice than in LS mice. In contrast, LS mice were more sensitive to the effects of diazepam on the elevated plus-maze. The ataxic effects of ethanol were measured by rotarod performance. SS mice were more resistant to the ataxic effects of a 2.0 g/kg dose of ethanol than LS mice. Ro 15-4513 reversed ethanol's ataxic effects when administered after ethanol in both LS mice and SS mice. Pentobarbital-induced ataxia was unaffected by treatment with Ro 15-4513. Studies of competition of Ro 15-4513 on 3H-flunitrazepam binding indicated that LS and SS mice did not differ in this measure in cortex, cerebellum or hippocampus.

The use of recombinant inbred strains to study mechanisms of drug action.

Long-sleep (LS) and short-sleep (SS) mice which were selectively bred for sensitivity to the sedative-hypnotic effects of ethanol have been used extensively in the examination of sensitivity to ethanol as well as to other CNS depressants. Understanding the relationship between sensitivity to ethanol and other depressants using LS and SS mice has been limited to a two mouse line comparison because these mice do not exist as replicate lines. To circumvent this problem, DeFries et al. have bred LSXSS recombinant inbred strains (LSXSS RIs) from a cross of LS and SS mice. These mice are being characterized on their responses to a variety of CNS depressants and agents that interact with the GABAergic system. Preliminary results are presented here on the sensitivity of these LSXSS RIs to pentobarbital, phenobarbital, and flurazepam as measured by sleep times. Additionally, analyses of seizure susceptibility to the GABAergic antagonist, bicuculline, in 24 LSXSS RIs indicate that there is no significant relationship between this measure of GABAergic function and sensitivity to ethanol as measured by the sleep-time response. These results are presented in the context of questions that can be resolved using RIs in drug-abuse research.

Intergenerational caregiving: adult caregivers and their aging parents.

Theory-generating methodologies can be used to add to our knowledge in areas that are already well researched in addition to areas that have not been extensively studied. The study presented here demonstrates how the grounded-theory method was used to generate a new theory of intergenerational caregiving. Analysis revealed five conceptually distinct, overlapping categories of caregiving. Only one of these includes what is generally considered to be caregiving, that is, hands-on caregiving behaviors or tasks. The other four types are not observable behaviors but are processes crucial to intergenerational caregiving and to an understanding of the experience of intergenerational caregiving.

Implementation of writing-to-learn in a program of nursing.

Writing-to-learn (WTL) is a paradigm for coordinating the learning of content with the development of cognitive skills needed to contextualize knowledge. The authors describe the place of writing assignments in existing courses, give examples of how assignments were revised to satisfy the intent of WTL as an instructional strategy, and describe the resources and support needed to facilitate its implementation in the curriculum.

Applications of transgenic and knockout mice in alcohol research.

Multiple genetic and environmental factors contribute to the development of alcoholism. Researchers attempting to elucidate the roles of specific genes in alcoholism risk have benefited from advances in genetic engineering. Two important tools used by researchers include transgenic mice, in which a foreign gene is integrated into an animal's genetic material, and knockout/knock-in mice, in which targeted genes either are rendered nonfunctional or are altered. Both of these animal models are currently used in alcohol research to determine how genes may influence the development of alcoholism in humans.

Use of transgenics, null mutants, and antisense approaches to study ethanol's actions.

Behavioral and biochemical responses mediating ethanol's actions have been difficult to study in humans and animals because of their complex polygenic nature. Recent progress in the creation of new animal models using recombinant DNA technology has provided a set of genetic tools by which the role of specific candidate genes in ethanol's actions can be examined. These techniques include the creation of transgenic and null mutant mice, as well as manipulation of protein synthesis with antisense treatments. These techniques are reviewed, and their potential applications to alcohol research are discussed.

Working toward consensus: providers' strategies to shift patients from curative to palliative treatment choices.

End-of-life decision making is a complex phenomenon and providers, patients, and families often have different views about the appropriateness of treatment choices. The results presented here are part of a larger grounded-theory study of reconciling decisions near the end of life. In particular, we examined how providers (N = 15) worked near the end of patients' lives toward changing the treatment decisions of patients and families from those decisions that providers described as unrealistic (i.e., curative) to those that providers described as more realistic (i.e., palliative). According to providers, shifting patients' and families' choices from curative to palliative was usually accomplished by changing patients' and families' understanding of the patient's overall "big picture" to one that was consistent with the providers' understanding. Until patients and families shifted their understanding of the patient's condition-the big picture-they continued to make what providers judged as unrealistic treatment choices based on an inaccurate understanding of what was really going on. These unrealistic choices often precluded possibilities for a "good death." According to providers, the purpose of attempting to shift the patient or proxy's goals was that realistic goals lead to realistic palliative treatment choices that providers associated with a good death. In this article we review strategies used by providers when they believed a patient's death was imminent to attempt to shift patients' and families' understandings of the big picture, thus ultimately shifting their treatment decisions.

Expanding conceptualizations of culturally competent care.

AIM: The aim of the study was to gain an understanding of cultural competence from the perspectives of non-mainstream nurse educators, specifically those of Latin heritage. BACKGROUND/RATIONALE: Although the theoretical concepts of 'cultural diversity' and 'culturally competent care' have been supported and promoted by the largest professional nursing organizations, the practical application of these concepts has often created difficulties for nurse researchers, educators, and clinicians. The lack of progress in teaching and evaluating cultural competence suggested the need to 'center the margins' and explore cultural competence from the margins of one particular non-mainstream nursing group, Latina nurse educators. DESIGN/METHODS: A grounded theory research design was employed. A group of 10 doctoral, prepared, self-identified, Latina nurse educators participated in face- to-face audiotaped interviews. Data collection, analysis, and theoretical sampling decisions occurred concurrently, strengthening theory generation. Institutional review board approval was received for all steps of the study. The major limitation of the study was the omission of student voices. RESULTS/FINDINGS: The analysis suggests that the Latina participants shared the common purpose of teaching students how to think about difference. The teaching practices of this group of Latina educators was based on a belief that 'difference' is not solely about specific cultural groups. For example, content about 'Hmongs' or 'Latinos'. Rather, Latina faculty focused on teaching students how to directly connect with anyone perceived as different from oneself. CONCLUSION: Latina faculty did not distinguish between competent care and culturally competent care; for them, competence necessarily includes cultural competence. They conceptualize the provision of competent care to all persons who are perceived as different, rather than focusing only on those who are perceived as 'culturally' different. These conceptualizations have the potential to shed new light on how nurses and nurse educators think about, develop, and integrate cultural competence into nursing education, practice, and research.

Patient-centered care: understanding its interpretation and implementation in health care.

Providing patient-centered care (PCC) has been the focus of recent organizational restructuring and quality improvement efforts in health care. Much has been written about PCC in the past 5 years; however, there are multiple perspectives about the interpretation and implementation of this concept. Descriptions of PCC in the health care literature generally, in some way, refer to meeting patients' needs. Literature describing PCC falls into two categories. The first category interprets PCC as the reorganization of services around patients' needs. The second defines PCC as understanding patient-perceived needs, priorities, and expectations for health care. PCC, however, is still most often implemented from a traditional provider-centered, disease-focused framework that often results in patient care and outcomes that are not congruent with patients' preferences. Shifting to a model of care in which patients define their needs and priorities creates some unique issues in health care. Nursing, with its long-standing commitment to being patient focused, needs to lead the research effort to develop patient-centered models of care that consider and incorporate patients' preferences. Nurses must be mindful, however, of their socialization in the traditional model of care and the resulting underlying attitudes and assumptions they bring to their research and work with patients.