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To understand the interactions between the microtubule-based motor protein kinesin and intracellular components, we have expressed the kinesin heavy chain and its different domains in CV-1 monkey kidney epithelial cells and examined their distributions by immunofluorescence microscopy. For this study, we cloned and sequenced cDNAs encoding a kinesin heavy chain from a human placental library. The human kinesin heavy chain exhibits a high level of sequence identity to the previously cloned invertebrate kinesin heavy chains; homologies between the COOH-terminal domain of human and invertebrate kinesins and the nonmotor domain of the Aspergillus kinesin-like protein bimC were also found. The gene encoding the human kinesin heavy chain also contains a small upstream open reading frame in a G-C rich 5' untranslated region, features that are associated with translational regulation in certain mRNAs. After transient expression in CV-1 cells, the kinesin heavy chain showed both a diffuse distribution and a filamentous staining pattern that coaligned with microtubules but not vimentin intermediate filaments. Altering the number and distribution of microtubules with taxol or nocodazole produced corresponding changes in the localization of the expressed kinesin heavy chain. The expressed NH2-terminal motor and the COOH-terminal tail domains, but not the alpha-helical coiled coil rod domain, also colocalized with microtubules. The finding that both the kinesin motor and tail domains can interact with cytoplasmic microtubules raises the possibility that kinesin could crossbridge and induce sliding between microtubules under certain circumstances.

OBJECTIVE: Scientific evidence is lacking for the antiarthritic efficacy of turmeric dietary supplements that are being promoted for arthritis treatment. Therefore, we undertook studies to determine the antiarthritic efficacy and mechanism of action of a well-characterized turmeric extract using an animal model of rheumatoid arthritis (RA). METHODS: The composition of commercial turmeric dietary supplements was determined by high-performance liquid chromatography. A curcuminoid-containing turmeric extract similar in composition to these supplements was isolated and administered intraperitoneally to female Lewis rats prior to or after the onset of streptococcal cell wall-induced arthritis. Efficacy in preventing joint swelling and destruction was determined clinically, histologically, and by measurement of bone mineral density. Mechanism of action was elucidated by analysis of turmeric's effect on articular transcription factor activation, microarray analysis of articular gene expression, and verification of the physiologic effects of alterations in gene expression. RESULTS: A turmeric fraction depleted of essential oils profoundly inhibited joint inflammation and periarticular joint destruction in a dose-dependent manner. In vivo treatment prevented local activation of NF-kappaB and the subsequent expression of NF-kappaB-regulated genes mediating joint inflammation and destruction, including chemokines, cyclooxygenase 2, and RANKL. Consistent with these findings, inflammatory cell influx, joint levels of prostaglandin E(2), and periarticular osteoclast formation were inhibited by turmeric extract treatment. CONCLUSION: These translational studies demonstrate in vivo efficacy and identify a mechanism of action for a well-characterized turmeric extract that supports further clinical evaluation of turmeric dietary supplements in the treatment of RA. [ABSTRACT FROM AUTHOR]

Enactivism is a branch of embodied cognition theory that argues for a highly distributed model of cognition as a sense-making process involving brain, body, environment, and subjective experience. It is a theoretical framework with potential value for nursing since it offers an integrated framework for human sense-making that includes physiological and psychological factors as well as the primary experience of subjective perceptions. This paper presents an introduction to the background and main tenets of enactivist theory. These are discussed in relation to nursing, and mental health nursing to argue for the relevance of enactivism in nursing knowledge., (© 2024 The Author(s). Nursing Inquiry published by John Wiley & Sons Ltd.)

Problem: Aggressive behavior is common on psychiatric inpatient units. Seclusion and restraint interventions to manage patients' aggressive behavior may have the consequence of being traumatizing for patients. Pediatric psychiatric patients' perspective on the use of seclusion and restraint interventions is not present in the literature., Methods: This hermeneutic nursing research study asked the question, "How might we understand children's experiences of seclusion and restraints on an inpatient psychiatric unit?" Four past pediatric psychiatric inpatients shared their hospitalization experiences that occurred within the previous year when they were 10 years old. The texts of the research interviews were compared to Attachment Theory for a deeper understanding of the meaning of the message., Findings: Participants commonly described experiences with seclusion and restraints as feeling trapped and alone in a dark room. They recommended the nurses step into the room with them to help them heal. Interpretively, the rooms on inpatient units could be considered as actual and metaphorical spaces of possible harm or healing., Conclusion: The participant's voices expand understanding of nurse's use of discernment at the doorway of a patient room to ensure the most therapeutic care is provided to the patient in these spaces through a secure nurse-patient relationship., (© 2024 Wiley Periodicals LLC.)

Introduction: Ethnic minorities experience disparities in prevention and treatment of burn injury. Research focused on burn injuries in Indigenous populations is limited. This review summarizes literature on burn injuries in Indigenous populations to be considered to inform new research., Methods: A search was conducted in CINAHL, Ovid MEDLINE, PSYCinfo and SocINDEX. for "burn OR scars OR scald OR deformity OR disfigurement" and "Aboriginal OR Indigenous OR First Nation OR American Indian OR Maori OR Native OR Torres Strait Islander OR Amerindian OR Inuit OR Metis OR Pacific Islander". Inclusion 1) peer reviewed studies of burns in Indigenous persons 2) in English. Exclusion 1) no data specific to Indigenous burns 2) not peer reviewed 3) not in full text 4) protocol publications., Results: The search identified 1091 studies with 51 for review. Sixteen were excluded. The 35 included publications were published between 1987 and 2022. Findings indicated higher incidence of injury and poorer outcomes amongst Indigenous people. Indigenous people suffered more flame and inhalation burns, had longer lengths of stay, and more complications including hypertrophic scarring. Australian Indigenous patients struggle with a lack of culturally safe communication and support for aftercare., Conclusion: Racial disparities exist in burn injury incidence and outcome for Indigenous persons. Qualitative research in this area will help providers better understand the experiences of Indigenous burn patients to develop more culturally competent care. We are currently developing a study using qualitative hermeneutic methodology to learn about the experiences of Indigenous burn survivors' injuries, recovery, and social reintegration., Competing Interests: Declaration of Competing Interest Authors have no conflicts of interest to declare. This manuscript, including related data, figures and tables has not previously been published. The manuscript is not under consideration elsewhere., (Copyright © 2024 Elsevier Ltd and ISBI. All rights reserved.)

The purpose of this paper is to explore the potential of dialectical pluralism (DP) for nursing knowledge development. Nursing scholars have discussed ways of developing nursing knowledge, exploring the fit and relevance of various worldviews for knowledge development and examining the dynamic and perpetual processes of knowledge development. Scholars have argued that knowledge development occurs under a certain worldview to which the researcher adheres. Many nurses employ various worldviews, which can give rise to ontological and epistemological conflicts. DP can help nurses appreciate the diversity of worldviews and recognize the importance of implicit worldviews to generate more practical nursing knowledge. DP as a philosophical approach can enable nurses to communicate between diverse worldviews, become tolerant of conflicting differences, and develop an array of nursing knowledge., Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: An enduring challenge remains about how to effectively implement programs, services, or practices. Too often, implementation does not achieve its intended effectiveness, fidelity, and sustainability, even when frameworks or theories determine implementation strategies and actions. A different approach is needed. This scoping review joined two markedly different bodies of literature: implementation and hermeneutics. Implementation is usually depicted as focused, direct, and somewhat linear, while hermeneutics attends to the messiness of everyday experience and human interaction. Both, however, are concerned with practical solutions to real-life problems. The purpose of the scoping review was to summarize existing knowledge on how a hermeneutic approach has informed the process of implementing health programs, services, or practices., Methods: We completed a scoping review by taking a Gadamerian hermeneutic approach to the JBI scoping review method. Following a pilot search, we searched eight health-related electronic databases using broadly stated terms such as implementation and hermeneutics. A diverse research team that included a patient and healthcare leader, working in pairs, independently screened titles/abstracts and full-text articles. Through the use of inclusion criteria and full-team dialogue, we selected the final articles and identified their characteristics, hermeneutic features, and implementation components., Results: Electronic searches resulted in 2871 unique studies. After full-text screening, we retained six articles that addressed both hermeneutics and implementing a program, service, or practice. The studies varied widely in location, topic, implementation strategies, and hermeneutic approach. All addressed assumptions underpinning implementation, the human dimensions of implementing, power differentials, and knowledge creation during implementation. All studies addressed issues foundational to implementing such as cross-cultural communication and surfacing and addressing tensions during processes of change. The studies showed how creating conceptual knowledge was a precursor to concrete, instrumental knowledge for action and behavioral change. Finally, each study demonstrated how the hermeneutic process of the fusion of horizons created new understandings needed for implementation., Conclusions: Hermeneutics and implementation have rarely been combined. The studies reveal important features that can contribute to implementation success. Implementers and implementation research may benefit from understanding, articulating, and communicating hermeneutic approaches that foster the relational and contextual foundations necessary for successful implementation., Trial Registration: The protocol was registered at the Centre for Open Science on September 10, 2019. MacLeod M, Snadden D, McCaffrey G, Zimmer L, Wilson E, Graham I, et al. A hermeneutic approach to advancing implementation science: a scoping review protocol 2019. Accessed at osf.io/eac37., (© 2023. The Author(s).)

Aim: A discussion of the philosophy of pragmatism and how it can underpin and integrate nursing education, practice, research and policy across the nursing profession., Background: Although the concepts of plurality, truth, fallibilism, subjectivity and meliorism have been discussed across foundational philosophical literature, the relation of these concepts across various facets of the nursing profession have not been thoroughly articulated in the nursing literature., Design: Critical theoretical reflection., Data Sources: In this article, we draw from literature written on the philosophy of pragmatism from 1907 through to 2021., Implications for Nursing: We propose an integrative approach for the nursing profession where education, practice, research and policy speak and contribute to each other through a lens of pragmatism. In this approach, education has a relationship with practice and practice has a direct line to research where nurses on the front lines can engage with pragmatic inquiry. Researchers in return can inform frontline nurses and policymakers of evidence emerging in areas pertinent to practice. These relationships are made possible through integrated knowledge translation by including all stakeholders at every point of knowledge generation. Each facet of the nursing profession is filled with stakeholders of nursing knowledge, who are invested in its utility. Although it requires focused effort to integrate knowledge across the profession, pragmatism calls for action in the face of challenges in hope for a stronger body of nursing knowledge and ultimately profession., Conclusion: Pragmatism is an apt philosophy to underpin and integrate nursing education, practice, research and policy across the nursing profession., (© 2022 John Wiley & Sons Ltd.)

Epistemological pluralism is a recognized feature of nursing knowledge, which embraces both objective, scientific knowledge and situated knowledge that include subjective experience, values and affect, and is encountered in relationship. While there is a lively literature about describing and validating the need for pluralism in nursing's knowledge base, there has been less discussion of how to work with and across different kinds of knowing that are used in practice. In this paper, I describe Kasulis' heuristic framework for understanding more clearly what is entailed in different kinds of knowledge, and what some of their advantages and disadvantages might be. The framework was created by Thomas Kasulis, an American scholar of Japanese philosophy who identified broad orientations in Asian and Western philosophies that he characterized as 'intimacy' and 'integrity', respectively. Kasulis emphasized that his framework is a heuristic, a tool for making distinctions more clearly between different styles of thinking, that can manifest not only between cultural traditions from different parts of the world, but also between subcultures within one of the dominant orientations. He breaks his two orientations down by five distinguishing categories of objectivity, relating, affect, embodiment and transparency. In this paper, each category is described and discussed in relation to aspects of nursing knowledge. Looking at different epistemological viewpoints in this way helps to clarify their differences, and to explain the difficulty of reading across them, when they entail basic assumptions that are not commensurable with each other. Kasulis' framework offers a new way of reading across viewpoints commonly seen in the epistemological pluralism of nursing. It is a tool that can sharpen critical discernment about what is at stake, what can be gained, and what might get missed while operating in either the intimacy or integrity orientation., (© 2020 John Wiley & Sons Ltd.)

The majority of healthcare professionals regularly witness fragility, suffering, pain and death in their professional lives. Such experiences may increase the risk of burnout and compassion fatigue, especially if they are without self-awareness and a healthy work environment. Acquiring a deeper understanding of vulnerability inherent to their professional work will be of crucial importance to face these risks. From a relational ethics perspective, the role of the team is critical in the development of professional values which can help to cope with the inherent vulnerability of healthcare professionals. The focus of this paper is the role of Communities of Practice as a source of resilience, since they can create a reflective space for recognising and sharing their experiences of vulnerability that arises as part of their work. This shared knowledge can be a source of strength while simultaneously increasing the confidence and resilience of the healthcare team., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Humanism has appeared intermittently in the nursing literature as a concept that can be used in understanding nursing. I return to the concept in response to noticing the term appearing in the context of health humanities, where it is loosely associated both with humanities and being humane. I review the usage and critiques of humanism in both nursing and medical literature and then re-evaluate what the idea of humanism might hold for nursing, trying to avoid the traps of an over-determination of the human subject, or dichotomizing nursing as art or science, technology or caring. I draw on writings on humanism primarily from Emmanuel Levinas and Edward Said to emphasize strands in humanism of obligation towards others and of critical discernment within history and culture directed towards democratic practices. I discuss in passing the strong association in the UK particularly between humanism and scientism as a note of caution about the plurality of the term humanism. I conclude that humanism is a tradition that does offer productive ways of thinking about nursing with the proviso that it ought to be treated carefully as a problematic tradition and not as a new essence for nursing., (© 2019 John Wiley & Sons Ltd.)

Objective: To identify factors predictive of pregnancy-related anxiety (PRA) among women in Mwanza, Tanzania., Design: A cross-sectional study was used to explore the relationship between psychosocial health and preterm birth., Setting: Antenatal clinics in the Ilemela and Nyamagana districts of Mwanza, Tanzania., Participants: Pregnant women less than or equal to 32 weeks' gestational age (n=212) attending the two antenatal clinics., Measures: PRA was measured using a revised version of the 10-item PRA Questionnaire (PRA-Q). Predictive factors included social support (Multidimensional Scale of Perceived Social Support), stress (Perceived Stress Scale), depression (Edinburg Postpartum Depression Scale) and sociodemographic data. Bivariate analysis permitted variable selection while multiple linear regression analysis enabled identification of predictive factors of PRA., Results: Twenty-five per cent of women in our sample scored 13 or higher (out of a possible 30) on the PRA-Q. Perceived stress, active depression and number of people living in the home were the only statistically significant predictors of PRA in our sample., Conclusions: Our findings were contrary to most current literature which notes socioeconomic status and social support as significant factors in PRA. A greater understanding of the experience of PRA and its predictive factors is needed within the social cultural context of low/middle-income countries to support the development of PRA prevention strategies specific to low/middle income countries., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Background : Chronic pain affects one in five Canadians. People with chronic pain frequently experience loss in their lives related to work, relationships, and their independence. They may be referred to a chronic pain program, which aims to strengthen coping through medical intervention and self-management skills. Data suggest that, even when individuals begin their pain program, many feel overwhelmed and do not continue. Aims : The aim of this study was to conduct a needs assessment to explore the acceptability and feasibility of developing a psychosocial intervention, narrative therapy (NT), to address loss for chronic pain patients on the wait list of a chronic pain program. Methods : Two focus groups were conducted with ten patients who had experienced being on a wait list for a provincial chronic pain management program (CPMP). Transcribed interviews were subjected to thematic and interpretive analysis. Results : Two major themes emerged from the analysis: loss of identity and sharing a story of chronic pain. All patients were enthusiastic toward an NT intervention, although individual preferences differed regarding mode of delivery. Conclusions : Loss is a significant part of the chronic pain experience. NT seems to be an acceptable intervention to address loss for patients on the wait list for a chronic pain program., (© 2017 Eloise C. J. Carr, Graham McCaffrey, and Mia Maris Ortiz. Published with license by Taylor & Francis Group, LLC.)

Novels are one humanities resource available to educators in health disciplines to support student reflection on their own professional practice and therapeutic relationships with patients. An interdisciplinary team, including nurses, a physician, and an English instructor, carried out an interpretive study of the use of a novel by clinical nursing instructors in an undergraduate practicum course. Students placed in assisted living or long term care facilities for the elderly were expected to read a contemporary work, Exit Lines, by Joan Barfoot, which is set in a comparable facility. The objective was to increase understanding of the meanings that participants ascribed to the novel reading exercise in relation to their development as student nurses. By using a hermeneutic approach, we used dialogue throughout the study to elicit perspectives among participants and the interdisciplinary research team. Major themes that emerged included the students' tacit awareness of epistemological plurality in nursing, and the consequent importance of cultivating a capacity to move thoughtfully between different points of view and ways of knowing., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

This article is the third part of a hermeneutic research study examining the impact of childhood cancer experiences on the parental relationship. In Part 1, we offered an exploration of the phenomenon with background literature; a description of the research question, method, and design; and finally a discussion of relationships that survived, thrived, or demised, with an emphasis on the notions of difference and trading. In Part 2, we furthered the interpretations to look at the complexities of issues such as teams, roles, focus, protection, intimacy, grieving, putting relationships on hold, and reclaiming them. In this article, we discuss the advice that the participants offered us and how that advice might have implications for other parents in similar situations and health care professionals working with families experiencing childhood cancer., (© The Author(s) 2016.)

In this Part 2 of a three-part research paper, we further our interpretations from our hermeneutic study examining how having a child who has experienced cancer had an impact on the relationship between the parents. In Part 1, we identified the focus of the study and provided background to the topic. We also described the research question, method, and design before offering an interpretive analysis of couples whose relationships survived, thrived, or demised. In this article, we extend the interpretations under an overarching theme of "taking one for the team." Here, we discuss issues of changes in focus and roles, and the notions of tag teaming, protection, intimacy, and grieving. We examine the phenomenon of putting relationships on hold, then finding reclamation later. In Part 3, we offer implications of these findings for other parents in similar situations and for health care professionals working with these families., (© The Author(s) 2016.)

This article is the first of a three-part report of a research study that used hermeneutic inquiry to examine the effects of childhood cancer on the relationship between the parents of the child. In Part 1, we identity the topic of investigation and the relevant literature; describe the research question, method, and design; and begin our interpretations of the data with a focus on the couples who remained together and those who experienced relationship demise. In this analysis, we discovered that issues of difference and trading played a strong role in how the couples fared in their relationships. In Part 2 of this series, we focus on further interpretations, and in Part 3, we discuss the implications of the study for other parents and for health care professionals., (© The Author(s) 2016.)

Aims and Objectives: To provide a critical review of nursing literature about compassion, identifying major themes, questions arising and directions for future investigation of the topic., Background: Compassion has emerged as a topic of broad social concern in recent years and is particularly pertinent to nurses., Design: Critical review was selected as the most appropriate way of analysing literature from both qualitative research studies and conceptual articles., Methods: An electronic database search was conducted, discovering articles published between 1952 and 2013. The search was then limited to publications since 2000 to capture recent development of the concept. The search was limited to peer-reviewed literature, excluding a large body of editorial material, resulting in 20 relevant articles. Two books were also added that contributed important perspective to the analysis. Critical analysis of the resulting material was undertaken to identify themes, tensions and implications in the literature., Results: Major themes were compassion as practice and compassion as a moral virtue, holding implications for how nurses can demonstrate compassion in relation to contemporary healthcare values. A third major theme was the influence of institutional environments in facilitating or limiting the expression of compassion., Conclusions: Compassion is a human experience of deep significance to nursing and needs understanding in the context of healthcare environments dominated by discourses of efficiency and rationalisation. There is an emergent literature about how compassion may be understood, taught and sustained among nurses but it is a topic that requires continued attention., Relevance to Clinical Practice: More precise understanding of compassion will support nurses in advocating for compassionate care, participating in interdisciplinary dialogue, and contributing to the design of healthcare environments that are conducive to compassionate care., (© 2015 John Wiley & Sons Ltd.)

The number of patients suffering from postoperative pain due to orthopedic surgery and bone fracture is projected to dramatically increase because the human life span, weight, and involvement in high-activity sports continue to rise worldwide. Joint replacement or bone fracture frequently results in skeletal pain that needs to be adequately controlled for the patient to fully participate in needed physical rehabilitation. Currently, the 2 major therapies used to control skeletal pain are nonsteroidal anti-inflammatory drugs and opiates, both of which have significant unwanted side effects. To assess the efficacy of novel therapies, mouse models of orthopedic and fracture pain were developed and evaluated here. These models, orthopedic surgery pain and bone fracture pain, resulted in skeletal pain-related behaviors that lasted 3 weeks and 8 to 10 weeks, respectively. These skeletal pain behaviors included spontaneous and palpation-induced nocifensive behaviors, dynamic weight bearing, limb use, and voluntary mechanical loading of the injured hind limb. Administration of anti-nerve growth factor before orthopedic surgery or after bone fracture attenuated skeletal pain behaviors by 40% to 70% depending on the end point being assessed. These data suggest that nerve growth factor is involved in driving pain due to orthopedic surgery or bone fracture. These animal models may be useful in developing an understanding of the mechanisms that drive postoperative orthopedic and bone fracture pain and the development of novel therapies to treat these skeletal pains.

Studies in animals and humans show that blockade of nerve growth factor (NGF) attenuates both malignant and nonmalignant skeletal pain. While reduction of pain is important, a largely unanswered question is what other benefits NGF blockade might confer in patients with bone cancer. Using a mouse graft model of bone sarcoma, we demonstrate that early treatment with an NGF antibody reduced tumor-induced bone destruction, delayed time to bone fracture, and increased the use of the tumor-bearing limb. Consistent with animal studies in osteoarthritis and head and neck cancer, early blockade of NGF reduced weight loss in mice with bone sarcoma. In terms of the extent and time course of pain relief, NGF blockade also reduced pain 40% to 70%, depending on the metric assessed. Importantly, this analgesic effect was maintained even in animals with late-stage disease. Our results suggest that NGF blockade immediately upon detection of tumor metastasis to bone may help preserve the integrity and use, delay the time to tumor-induced bone fracture, and maintain body weight., (©2014 American Association for Cancer Research.)

The metaphor of host and guest has value for exploring the practice and role identity of nurses on inpatient mental health units. Two complementary texts, one from the ancient Zen record of Lin-chi, and the other from the contemporary hermeneutic philosopher Richard Kearney, are used to elaborate meanings of host and guest that can be applied to the situation of mental health nurses. In a doctoral study with a hermeneutic design, I addressed the topic of nurse-patient relationship using an interpretive framework that included sources from Buddhist thought. The positions of host and guest emerged from interviews with nurses as one interpretive theme to open up new understanding of the topic. The two texts, originally distant in era and culture, both employ the host and guest metaphor. They are applied to extracts from interviews to open up discussions of hierarchy, status, patients' perspectives, otherness and resistances as features of nurses' complex experience. These provide insights into understanding practice and suggest implications for how institutional environments shape practice. An intercultural reading of texts can provide a source of new understanding of nurse-patient relationships., (© 2014 John Wiley & Sons Ltd.)

The blood-brain barrier (BBB) is a physical and metabolic barrier that separates the central nervous system from the peripheral circulation. Central nervous system drug delivery across the BBB is challenging, primarily because of the physical restriction of paracellular diffusion between the endothelial cells that comprise the microvessels of the BBB and the activity of efflux transporters that quickly expel back into the capillary lumen a wide variety of xenobiotics. Therapeutic manipulation of protein trafficking is emerging as a novel means of modulating protein function, and in this minireview, the targeting of the trafficking of 2 key BBB proteins, P-glycoprotein and occludin, is presented as a novel, reversible means of optimizing central nervous system drug delivery.

P-glycoprotein (ABCB1/MDR1, EC 3.6.3.44), the major efflux transporter at the blood-brain barrier (BBB), is a formidable obstacle to CNS pharmacotherapy. Understanding the mechanism(s) for increased P-glycoprotein activity at the BBB during peripheral inflammatory pain is critical in the development of novel strategies to overcome the significant decreases in CNS analgesic drug delivery. In this study, we employed the λ-carrageenan pain model (using female Sprague-Dawley rats), combined with confocal microscopy and subcellular fractionation of cerebral microvessels, to determine if increased P-glycoprotein function, following the onset of peripheral inflammatory pain, is associated with a change in P-glycoprotein trafficking which leads to pain-induced effects on analgesic drug delivery. Injection of λ-carrageenan into the rat hind paw induced a localized, inflammatory pain (hyperalgesia) and simultaneously, at the BBB, a rapid change in colocalization of P-glycoprotein with caveolin-1, a key scaffolding/trafficking protein. Subcellular fractionation of isolated cerebral microvessels revealed that the bulk of P-glycoprotein constitutively traffics to membrane domains containing high molecular weight, disulfide-bonded P-glycoprotein-containing structures that cofractionate with membrane domains enriched with monomeric and high molecular weight, disulfide-bonded, caveolin-1-containing structures. Peripheral inflammatory pain promoted a dynamic redistribution between membrane domains of P-glycoprotein and caveolin-1. Disassembly of high molecular weight P-glycoprotein-containing structures within microvascular endothelial luminal membrane domains was accompanied by an increase in ATPase activity, suggesting a potential for functionally active P-glycoprotein. These results are the first observation that peripheral inflammatory pain leads to specific structural changes in P-glycoprotein responsible for controlling analgesic drug delivery to the CNS., (© 2012 The Authors. Journal of Neurochemistry © 2012 International Society for Neurochemistry.)

In this study, the authors examined the experiences of grandparents who have had, or have, a grandchild with childhood cancer. Sixteen grandparents were interviewed using unstructured interviews, and the data were analyzed according to a hermeneutic-phenomenological tradition, as guided by the philosophical hermeneutics of Hans-Georg Gadamer. In Part 1 of this report, interpretive findings around worry, burden, silence, the nature of having one's universe shaken, of having lives put on hold, and a sense of helplessness were addressed. In Part 2, the authors discuss interpretations related to the notions of support, burden, protection, energy, standing by, buffering, financial shouldering, and relationship. The study concludes with implications that the grandparents in the study bring to pediatric nurses in their practices with families in pediatric oncology.

In this study, the authors examined the experiences of grandparents who have had, or have, a grandchild with childhood cancer. Sixteen grandparents were interviewed using unstructured interviews, and the data were analyzed according to hermeneutic-phenomenological tradition, as guided by the philosophical hermeneutics of Hans-Georg Gadamer. Interpretive findings indicate that grandparents suffer and worry in many complex ways that include a doubled worry for their own children as well as their grandchildren. According to the grandparents in this study, this worry was, at times, silenced in efforts to protect the parents of the grandchild from the burden of concern for the grandparent. Other interpretations include the nature of having one's universe shaken, of having lives put on hold, and a sense of helplessness. The grandparents in this study offer advice to other grandparents as well as to the health care system regarding what kinds of things might have been more helpful to them as one level of the family system, who, like other subsystems of the family, are also profoundly affected by the event of childhood cancer.

In this paper I lay out the ground for a creative dialogue between Buddhist thought and contemporary nursing. I start from the observation that in tracing an arc from the existential human experience of suffering to finding compassionate responses to suffering in everyday practice Buddhist thought already appears to present significant affinities with nursing as a practice discipline. I discuss some of the complexities of entering into a cross-cultural dialogue, which is already well under way in the working out of Western forms of Buddhism, and which is beginning to be reflected in nursing literature. I introduce philosophical hermeneutics as a useful framework for elaborating an open and constructive exchange. I then discuss key Mahayana Buddhist concepts of emptiness and two truths that lead to a dynamic and open way of understanding reality and responding in the world. I turn to examples of original texts to give a flavour of the varied and distinctive forms of literature in the Buddhist tradition. This is intended partly to keep the reader alert to cultural difference (from a Western standpoint, that is) while exploring the creative potential of Buddhist thought. Hermeneutics again provides a framework for interpretation. This paper establishes a philosophical ground for a critical and creative dialogue between Buddhist thought and nursing., (© 2012 Blackwell Publishing Ltd.)

Our laboratory has shown that λ-carrageenan-induced peripheral inflammatory pain (CIP) can alter tight junction (TJ) protein expression and/or assembly leading to changes in blood-brain barrier xenobiotic permeability. However, the role of reactive oxygen species (ROS) and subsequent oxidative stress during CIP is unknown. ROS (i.e., superoxide) are known to cause cellular damage in response to pain/inflammation. Therefore, we examined oxidative stress-associated effects at the blood-brain barrier (BBB) in CIP rats. During CIP, increased staining of nitrosylated proteins was detected in hind paw tissue and enhanced presence of protein adducts containing 3-nitrotyrosine occurred at two molecular weights (i.e., 85 and 44 kDa) in brain microvessels. Tempol, a pharmacological ROS scavenger, attenuated formation of 3-nitrotyrosine-containing proteins in both the hind paw and in brain microvessels when administered 10 min before footpad injection of λ-carrageenan. Similarly, CIP increased 4-hydroxynoneal staining in brain microvessels and this effect was reduced by tempol. Brain permeability to [(14)C]sucrose and [(3)H]codeine was increased, and oligomeric assemblies of occludin, a critical TJ protein, were altered after 3 h CIP. Tempol attenuated both [(14)C]sucrose and [(3)H]codeine brain uptake as well as protected occludin oligomers from disruption in CIP animals, suggesting that ROS production/oxidative stress is involved in modulating BBB functional integrity during pain/inflammation. Interestingly, tempol administration reduced codeine analgesia in CIP animals, indicating that oxidative stress during pain/inflammation may affect opioid delivery to the brain and subsequent efficacy. Taken together, our data show for the first time that ROS pharmacological scavenging is a viable approach for maintaining BBB integrity and controlling central nervous system drug delivery during acute inflammatory pain.

Membrane protein sorting is mediated by interactions between proteins and lipids. One mechanism that contributes to sorting involves patches of lipids, termed lipid rafts, which are different from their surroundings in lipid and protein composition. Although the nerve growth factor (NGF) receptors, TrkA and p75(NTR) collaborate with each other at the plasma membrane to bind NGF, these two receptors are endocytosed separately and activate different cellular responses. We hypothesized that receptor localization in membrane rafts may play a role in endocytic sorting. TrkA and p75(NTR) both reside in detergent-resistant membranes (DRMs), yet they responded differently to a variety of conditions. The ganglioside, GM1, caused increased association of NGF, TrkA, and microtubules with DRMs, but a decrease in p75(NTR). When microtubules were induced to polymerize and attach to DRMs by in vitro reactions, TrkA, but not p75(NTR), was bound to microtubules in DRMs and in a detergent-resistant endosomal fraction. NGF enhanced the interaction between TrkA and microtubules in DRMs, yet tyrosine phosphorylated TrkA was entirely absent in DRMs under conditions where activated TrkA was detected in detergent-sensitive membranes and endosomes. These data indicate that TrkA and p75(NTR) partition into membrane rafts by different mechanisms, and that the fraction of TrkA that associates with DRMs is internalized but does not directly form signaling endosomes. Rather, by attracting microtubules to lipid rafts, TrkA may mediate other processes such as axon guidance.

The blood-brain barrier (BBB) has a critical role in central nervous system homeostasis. Intercellular tight junction (TJ) protein complexes of the brain microvasculature limit paracellular diffusion of substances from the blood into the brain. Hypoxia and reoxygenation (HR) is a central component to numerous disease states and pathologic conditions. We have previously shown that HR can influence the permeability of the BBB as well as the critical TJ protein occludin. During HR, free radicals are produced, which may lead to oxidative stress. Using the free radical scavenger tempol (200 mg/kg, intraperitoneal), we show that oxidative stress produced during HR (6% O(2) for 1 h, followed by room air for 20 min) mediates an increase in BBB permeability in vivo using in situ brain perfusion. We also show that these changes are associated with alterations in the structure and localization of occludin. Our data indicate that oxidative stress is associated with movement of occludin away from the TJ. Furthermore, subcellular fractionation of cerebral microvessels reveals alterations in occludin oligomeric assemblies in TJ associated with plasma membrane lipid rafts. Our data suggest that pharmacological inhibition of disease states with an HR component may help preserve BBB functional integrity.

Hypoxic (low oxygen) and reperfusion (post-hypoxic reoxygenation) phases of stroke promote an increase in microvascular permeability at tight junctions (TJs) of the blood-brain barrier (BBB) that may lead to cerebral edema. To investigate the effect of hypoxia (Hx) and reoxygenation on oligomeric assemblies of the transmembrane TJ protein occludin, rats were subjected to either normoxia (Nx, 21% O(2), 60 min), Hx (6% O(2), 60 min), or hypoxia/reoxygenation (H/R, 6% O(2), 60 min followed by 21% O(2), 10 min). After treatment, cerebral microvessels were isolated, fractionated by detergent-free density gradient centrifugation, and occludin oligomeric assemblies associated with plasma membrane lipid rafts were solubilized by perfluoro-octanoic acid (PFO) exclusively as high molecular weight protein complexes. Analysis by non-reducing and reducing sodium dodecyl sulfate (SDS)-polyacrylamide gel electrophoresis/western blot of PFO-solubilized occludin revealed that occludin oligomeric assemblies co-localizing with 'TJ-associated' raft domains contained a high molecular weight 'structural core' that was resistant to disassembly by either SDS or a hydrophilic reducing agent ex vivo, and by Hx and H/R conditions in vivo. However, exposure of PFO-solubilized occludin oligomeric assemblies to SDS ex vivo revealed the non-covalent association of a significant amount of dimeric and monomeric occludin isoforms to the disulfide-bonded inner core, and dispersal of these non-covalently attached occludin subunits to lipid rafts of higher density in vivo was differentially promoted by Hx and H/R. Our data suggest a model of isoform interaction within occludin oligomeric assemblies at the BBB that enables occludin to simultaneously perform a structural role in inhibiting paracellular diffusion, and a signaling role involving interactions of dimeric and monomeric occludin isoforms with a variety of regulatory molecules within different plasma membrane lipid raft domains.

Receptor endocytosis is regulated by ligand binding, and receptors may signal after endocytosis in signaling endosomes. We hypothesized that signaling endosomes containing different types of receptors may be distinct from one another and have different physical characteristics. To test this hypothesis, we developed a high-resolution organelle fractionation method based on mass and density, optimized to resolve endosomes from other organelles. Three different types of receptors undergoing ligand-induced endocytosis were localized predominately in endosomes that were resolved from one another using this method. Endosomes containing activated receptor tyrosine kinases (RTKs), TrkA and EGFR, were similar to one another. Endosomes containing p75(NTR) (in the tumor necrosis receptor superfamily) and PAC1 (a G-protein-coupled receptor) were distinct from each other and from RTK endosomes. Receptor-specific endosomes may direct the intracellular location and duration of signal transduction pathways to dictate response to signals and determine cell fate.

Tight junctions (TJs) at the blood-brain barrier (BBB) dynamically alter paracellular diffusion of blood-borne substances from the peripheral circulation to the CNS in response to external stressors, such as pain, inflammation, and hypoxia. In this study, we investigated the effect of lambda-carrageenan-induced peripheral inflammatory pain (i.e., hyperalgesia) on the oligomeric assembly of the key TJ transmembrane protein, occludin. Oligomerization of integral membrane proteins is a critical step in TJ complex assembly that enables the generation of tightly packed, large multiprotein complexes capable of physically obliterating the interendothelial space to inhibit paracellular diffusion. Intact microvessels isolated from rat brains were fractionated by detergent-free density gradient centrifugation, and gradient fractions were analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis/ Western blot. Injection of lambda-carrageenan into the rat hind paw produced after 3 h a marked change in the relative amounts of oligomeric, dimeric, and monomeric occludin isoforms associated with different plasma membrane lipid raft domains and intracellular compartments in endothelial cells at the BBB. Our findings suggest that increased BBB permeability (i.e., leak) associated with lambda-carrageenan-induced peripheral inflammatory pain is promoted by the disruption of disulfide-bonded occludin oligomeric assemblies, which renders them incapable of forming an impermeant physical barrier to paracellular transport.