A randomised trial of the cool pad pillow topper versus standard care for sleep disturbance and hot flushes in women on endocrine therapy for breast cancer.

PURPOSE: Quality of life in women receiving adjuvant endocrine therapy for breast cancer (BC) may be impaired by hot flushes and night sweats. The cool pad pillow topper (CPPT) is a commercial product, promoted to improve quality of sleep disrupted by hot flushes. This study aimed to identify if the CPPT reduces severity of sleep disturbance by minimising effects of hot flushes. METHODS: This randomised phase II trial, recruited women with BC, on adjuvant endocrine therapy, experiencing hot flushes and insomnia. Participants were randomised (stratified by baseline sleep efficiency score (SES) and menopausal status) to the intervention arm (CPPT + standard care) or control arm (standard care). Participants completed Hospital Anxiety and Depression Scale and Functional Assessment of Cancer Therapy-Breast (FACT-B) questionnaires and fortnightly sleep/hot flush diaries (where responses were averaged over 2-week periods). The primary endpoint was change in average SES from -2 to 0 weeks to 2 to 4 weeks. RESULTS: Seventy-four pre- (68.9 %) and post-menopausal (31.1 %) women were recruited. Median age was 49.5 years. Endocrine therapies included tamoxifen (93.2 %). Median SES at weeks 2 to 4 improved in both arms but the increase on the intervention arm was almost twice that on the control arm (p = 0.024). There were significantly greater reductions in hot flushes and HADS depression in the intervention arm (p = 0.09 and p = 0.036, respectively). There were no significant differences in FACT-B or HADS anxiety. CONCLUSION: This study supports the use of the CPPT as an aid to reduce sleep disturbance and the frequency/severity of hot flushes.

Factors influencing student nurse decisions to report poor practice witnessed while on placement.

BACKGROUND: While it is commonly accepted that nursing care is generally of a good standard, it would be naïve to think that this is always the case. Over recent years, concern about aspects of the quality of some nursing care has grown. In tandem with this, there is recognition that nurses do not always report poor practice. As future registrants, student nurses have a role to play in changing this culture. We know, however, relatively little about the factors that influence student decisions on whether or not to report. In the absence of a more nuanced understanding of this issue, we run the risk of assuming students will speak out simply because we say they should. OBJECTIVES: To explore influences on student decisions about whether or not to report poor clinical practice, which is a result of deliberate action and which is witnessed while on placement. METHODS: Qualitative interviews were conducted with thirteen pre-registration nursing students from the UK. Participants included both adult and mental health nurses with an age range from 20 to 47. Data were analysed to identify key themes. Category integrity and fit with data were confirmed by a team member following initial analysis. RESULTS: Four themes. The first of these, 'I had no choice' described the personal and ethical drivers which influenced students to report. 'Consequences for self' and 'Living with ambiguity' provide an account of why some students struggle to report, while 'Being prepared' summarised arguments both for and against reporting concerns. CONCLUSION: While there is a drive to promote openness in health care settings and an expectation that staff will raise concerns the reality is that the decision to do this can be very difficult. This is the case for some student nurses. Our results suggest ways in which educationalists might intervene to support students who witness poor practice to report.

Hybridization and speciation.

Hybridization has many and varied impacts on the process of speciation. Hybridization may slow or reverse differentiation by allowing gene flow and recombination. It may accelerate speciation via adaptive introgression or cause near-instantaneous speciation by allopolyploidization. It may have multiple effects at different stages and in different spatial contexts within a single speciation event. We offer a perspective on the context and evolutionary significance of hybridization during speciation, highlighting issues of current interest and debate. In secondary contact zones, it is uncertain if barriers to gene flow will be strengthened or broken down due to recombination and gene flow. Theory and empirical evidence suggest the latter is more likely, except within and around strongly selected genomic regions. Hybridization may contribute to speciation through the formation of new hybrid taxa, whereas introgression of a few loci may promote adaptive divergence and so facilitate speciation. Gene regulatory networks, epigenetic effects and the evolution of selfish genetic material in the genome suggest that the Dobzhansky-Muller model of hybrid incompatibilities requires a broader interpretation. Finally, although the incidence of reinforcement remains uncertain, this and other interactions in areas of sympatry may have knock-on effects on speciation both within and outside regions of hybridization.

Does character displacement initiate speciation? Evidence of reduced gene flow between populations experiencing divergent selection.

Character displacement - trait evolution stemming from selection to lessen resource competition or reproductive interactions between species - has long been regarded as important in finalizing speciation. By contrast, its role in initiating speciation has received less attention. Yet because selection for character displacement should act only where species co-occur, individuals in sympatry will experience a different pattern of selection than conspecifics in allopatry. Such divergent selection might favour reduced gene flow between conspecific populations that have undergone character displacement and those that have not, thereby potentially triggering speciation. Here, we explore these ideas empirically by focusing on spadefoot toads, Spea multiplicata, which have undergone character displacement, and for which character displacement appears to cause post-mating isolation between populations that are in sympatry with a heterospecific and those that are in allopatry. Using mitochondrial sequence data and nuclear microsatellite genotypes, we specifically asked whether gene flow is reduced between populations in different selective environments relative to that between populations in the same selective environment. We found a slight, but statistically significant, reduction in gene flow between selective environments, suggesting that reproductive isolation, and potentially ecological speciation, might indeed evolve as an indirect consequence of character displacement. Generally, character displacement may play a largely under appreciated role in instigating speciation.

Analysis of range expansion in two species undergoing character displacement: why might invaders generally 'win' during character displacement?

Ecological character displacement occurs when interacting species diverge in resource use and associated traits in response to selection to minimize resource competition between them. Yet, when resource quality is asymmetric, the species that monopolizes the more profitable resource following character displacement may have higher fitness and therefore be deemed the 'winner'. Here, we ask: does the winner tend to be the resident species (i.e. the earlier inhabitant of the geographic region where character displacement occurred) or the invader (i.e. the subsequent inhabitant of the region)? We focus on two spadefoot toad species that have undergone character displacement. Previous studies revealed that Spea bombifrons gains the higher quality resource following character displacement; consequently, Spea multiplicata must use the lower quality resource, and as a result, experiences negative fitness consequences. Where the two species have undergone character displacement, three lines of evidence implicate S. bombifrons as the invader: S. bombifrons possess lower haplotype and nucleotide diversity; they do not exhibit isolation by distance (in contrast to S. multiplicata); and they display much higher population growth rates. We hypothesize that historical patterns of selection in its ancestral range pre-adapted S. bombifrons to evolve phenotypes capable of monopolizing the superior resource. Generally, because superior competitive abilities may facilitate successful invasions, invaders may be well positioned to win during character displacement.

Development and characterization of nine polymorphic microsatellite markers for Mexican spadefoot toads (Spea multiplicata) with cross-amplification in Plains spadefoot toads (S. bombifrons).

We developed nine polymorphic microsatellite markers for the Mexican spadefoot toad, Spea multiplicata. Allele numbers range from five to 12, with observed heterozygosities from 0.48 to 0.87. Because two loci are in linkage disequilibrium, these nine loci provide eight independent markers. Three loci exhibit departure from Hardy-Weinberg equilibrium, possibly resulting from null alleles or population admixture. These markers will be useful for assessing population structure and relatedness in S. multiplicata. Based on our success at cross-amplification in the Plains spadefoot toad (Spea bombifrons), these loci also may be useful in this species with additional optimization.

Character displacement: in situ evolution of novel phenotypes or sorting of pre-existing variation?

Character displacement - the divergence of traits between species in response to competition for resources or mates - has long been viewed as a major cause of adaptive diversification and species coexistence. Yet, we lack answers to basic questions concerning the causes and consequences of character displacement, not the least of which is why some species are more prone than others to undergo character displacement. Here, we address these questions by describing how character displacement can proceed through two nonexclusive routes that differ in the source of phenotypic variation, and, hence, in the ease with which character displacement may unfold. During in situ evolution of novel phenotypes, new traits that are divergent from a heterospecific competitor are generated and spread in sympatry. During sorting of pre-existing variation, such traits are initially favoured in allopatry before the two species encounter one another. Later, when they come into contact, character displacement transpires when these pre-existing divergent phenotypes increase in frequency in sympatry relative to allopatry. Because such sorting of pre-existing variation should unfold relatively rapidly, we suggest that species that express resource or mating polymorphism prior to interactions with heterospecifics may be more prone to undergo character displacement. We discuss the key differences between these two routes, review possible examples of each, and describe how the distinction between them provides unique insights into the evolutionary consequences of species interactions, the origins of diversity, and the factors that govern species coexistence.

DC preparations for therapy.

This review describes and compares the different DC preparations currently under laboratory and clinical investigation as vehicles for cancer immunotherapy.

Oncology health care professionals' attitudes to cancer: a professional concern.

BACKGROUND: Despite the known benefits of screening, early detection and advances in treatment modalities, negative attitudes to cancer persist among health care professionals, and cancer remains the most feared disease in modern society. Attitudes to cancer may create a barrier to communication between patients and health care professionals, hinder early detection, treatment and rehabilitation, and may influence decision making about referral to specialist services and the selection of appropriate treatments. DESIGN: A descriptive survey was conducted, within a Regional Cancer Centre, to evaluate oncology health care professionals' attitudes towards cancer. Attitudes were measured using the Burns' Cancer Belief Scales. RESULTS: Regardless of gender, profession and clinical experience, all health care professionals displayed persistently negative attitudes towards cancer. No statistically significant difference was detected between gender, profession, clinical experience or specialist education, and although small in number, no major differences were found between group means. CONCLUSIONS: Oncology health care professionals hold negative attitudes towards cancer and changing these attitudes presents a significant challenge. Educational programmes and supportive strategies may alleviate fears and promote a more positive image of cancer. However, such strategies must be based on an understanding of current attitudes towards this phenomenon.

Inhibition of 20 S and 26 S proteasome activity by lithium chloride: impact on the differentiation of leukemia cells by all-trans retinoic acid.

Lithium affects several enzymatic activities, however, the molecular mechanisms of lithium actions are not fully understood. We previously showed that LiCl interacts synergistically with all-trans-retinoic acid to promote terminal differentiation of WEHI-3B D(+) cells, a phenomenon accompanied by the recovery of the retinoid-induced loss of retinoic acid receptor alpha protein pools. Here, we demonstrate the effects of LiCl on proteasome-dependent degradation of retinoic acid receptor alpha proteins. LiCl alone, or in combination with all-trans-retinoic acid, increased cellular levels of ubiquitinated retinoic acid receptor alpha and markedly reduced chymotryptic-like activity of WEHI-3B D(+) 20 S and 26 S proteasome enzymes. Neither KCl nor all-trans-retinoic acid affected enzyme activity, whereas NaCl produced a modest reduction at relatively high concentrations. In addition, LiCl inhibited 20 S proteasome chymotryptic-like activity from rabbits but had no effect on tryptic-like activity of the 26 S proteasome. This effect has significant consequences in stabilizing the retinoic acid receptor alpha protein levels that are necessary to promote continued differentiation of leukemia cells in response to all-trans-retinoic acid. In support of this concept, combination of proteasome inhibitors beta-clastolactacystin or benzyloxycarbonyl-Leu-Leu-Phe with all-trans-retinoic acid increased differentiation of WEHI-3B D(+) cells in a manner that was analogous to the combination of LiCl and all-trans-retinoic acid.

Prolonged ex vivo culture of cord blood CD34(+) cells facilitates myeloid and megakaryocytic engraftment in the non-obese diabetic severe combined immunodeficient mouse model.

A clinical goal for ex vivo expansion of cord blood (CB) CD34(+) cells is to shorten the period of neutropenia and thrombocytopenia following myeloablative therapy and transplantation. Prolongation of cytokine expansion leads to the production of greater numbers of cells, and should have an impact on neutrophil and platelet recovery. Furthermore, expansion of CD34(+) cells should support the continued production of neutrophils and platelets in the 6-week period following transplantation. We tested these hypotheses by characterization of the kinetics (human CD45(+) cells in the blood) and phenotype (CD45, CD34, CD61, CD33, CD19 and CD3) of human engraftment in the non-obese diabetic severe combined immunodeficient mouse (NOD-SCID) following 7 or 14 d of ex vivo expansion of CB CD34(+) cells. Mice transplanted with 14 d cells showed greater percentages of human CD45(+) cells in the blood, bone marrow and spleen than mice transplanted with unexpanded cells or 7 d cells. Prolonging cytokine exposure of CD34(+) cells and transplantation with increasing numbers of input cells facilitated the production of absolute numbers of CD34(+), CD33(+), CD61(+) and CD19(+) cells in vivo. Furthermore, analysis of SCID engrafting potential showed that prolongation of culture duration facilitates in vivo expansion of CD45(+), CD34(+) and CD19(+) cells after transplantation. It is anticipated that prolonged (2 weeks) ex vivo culture of CB will have a beneficial clinical effect.

Prior cryopreservation of ex vivo-expanded cord blood cells is not detrimental to engraftment as measured in the NOD-SCID mouse model.

Cytokine-mediated expansion has been proposed and successfully used to facilitate engraftment post transplantation. This study examined whether cryopreservation following expansion has a detrimental effect on the ability of cells to engraft, using the NOD-SCID mouse model. Cord blood (CB) CD34(+) cells were incubated for 7 days with stem cell factor (SCF), flt-3 ligand (FL), and megakaryocyte growth and development factor (MGDF). Expanded CD34(+) cells were transplanted into NOD-SCID mice either fresh or following cryopreservation and thawing. After thawing, recovery of nucleated cells was 94%, of CD34 cells was 63%, and of day-14 progenitors was 17%. The loss of day-14 progenitor cells among the thawed expanded cells did not influence the kinetics of human engraftment in the mouse. Bone marrow (BM) of mice transplanted with thawed expanded CD34(+) cells (14 +/- 3.9%) showed significantly higher levels of human engraftment than mice transplanted with fresh expanded CD34(+) cells (1.5 +/- 0.5%, p = 0.0064). Thawed expanded CD34(+) cells had significantly higher SCID Engrafting Potential (SEP) than freshly expanded CD34(+) cells (p < 0.001). Results suggest that prior cryopreservation does not prevent expanded cells engrafting in NOD-SCID mice.

Regulation of leptin release and lipolysis by PGE2 in rat adipose tissue.

The role of eicosanoids formed by adipose tissue from rats was examined in the presence of the specific cyclooxygenase-2 inhibitor NS-398. This agent totally blocked the release of prostaglandin E2 (PGE2) by rat adipose tissue over a 24-h incubation in primary culture. The final concentration of PGE2 after 24 h was 12 nM, and half-maximal inhibition of PGE2 formation required 35 nM NS-398. While inhibition of PGE2 formation by NS-398 had no effect on basal leptin release or lipolysis, it enhanced the lipolytic action of 10 nM isoproterenol by 36%. The in vivo administration of PGE2 doubled serum leptin. PGE2 also directly stimulated leptin release by rat adipose tissue incubated in the presence of 25 nM dexamethasone, which inhibited endogenous PGE2 formation by 94%. The inhibition of lipolysis as well as the stimulation of leptin release by PGE2 were mimicked by N6-cyclopentyladenosine (CPA). These data indicate that exogenous PGE2 can stimulate leptin release by adipose tissue when the basal formation of PGE2 is blocked by dexamethasone. However, while the endogenous formation of PGE2 does not appear to regulate basal lipolysis or leptin release, it may play a role in the activation of lipolysis by catecholamines.

A1 adenosine receptor activation increases adipocyte leptin secretion.

A1 adenosine receptors (A1ARs) are heavily expressed in adipocytes and influence fat cell metabolism. Because increasing evidence suggests a role for leptin in mediating appetite and fat cell metabolism, we tested whether ALARs regulate leptin production. Rats were treated with the A1AR agonist N6-cyclopentyladenosine (CPA), and changes in circulating levels of leptin and leptin gene expression were examined. Serum leptin levels rose 2- to 10-fold, with peak increases seen 8-16 h after injection of CPA (P < 0.05). In contrast, CPA did not alter steady state levels of adipose tissue leptin mRNA. To assess the influence of endogenous adenosine on circulating leptin levels, rats were also injected with dipyridamole (DPY), an adenosine reuptake blocker. DPY induced 80% increases in serum levels at 8 h after injections (P < 0.05). Supporting the idea that stimulation of leptin production is A1AR mediated, pretreatment with the A1AR antagonist 8-cyclopentyl-1,3-dipropylxanthine completely blocked increases in leptin levels after DPY treatment. To complement in vivo studies, the effect of A1AR activation on leptin secretion was also studied in epididymal fat pad cultures. In cultures, CPA treatment increased leptin secretion by 37% (P < 0.05). Collectively, these data show that the adenosinergic system can increase leptin secretion by directly activating A1ARs in fat tissue.

Sexuality in cancer and palliative care 2: Exploring the issues.

The first article in this series discussed the effects of cancer and its treatment of sexual function. However, impaired sexual function may also occur in the absence of any specific physiological change. As well as the patients' perceptions of their disease, the attitudes of society and health care professionals and the environment and culture within health care may contribute to sexual dysfunction in patients with cancer. This article will explore some of the wider issues surrounding sexuality and examine some of the reasons why this subject is so often poorly addressed.

Conditions that enable human hematopoietic stem cell engraftment in all NOD-SCID mice.

BACKGROUND: Transplantation of human hematopoietic stem cells is the only true test of their long-term repopulation potential. Models are readily available to evaluate murine hematopoietic stem cells, but few exist that allow reliable quantification of human stem cells. The non-obese diabetic-severe combined immunodeficient (NOD-SCID) mouse model enables quantification of human hematopoietic stem cells, but the conditions that permit human engraftment in all animals have yet to be defined. The aims of the project were, therefore, to describe the variables that allow human engraftment in the NOD-SCID mouse model and the techniques that accurately quantify this engraftment. METHODS: NOD-SCID mice that had or had not received 250, 325, or 400 cGy irradiation received cord blood (CB) mononuclear or CD34+ cells i.v. or i.p. Mice were killed 6 weeks after transplantation, and the bone marrow, spleen, and thymus were harvested. Four-color flow cytometric analysis, semi-quantitative PCR, myeloid and erythroid progenitor, and stem cell assays were used to monitor human engraftment. RESULTS: A 250 or 325 cGy and i.v. injection of CB mononuclear or CD34+ cells is required to detect multilineage human engraftment in the bone marrow, spleen, or thymus of NOD-SCID mice. Four-color flow cytometric analysis and semi-quantitative PCR enable accurate detection of 0.1% human cells. Progenitor and stem cell assays provide functional information about the engrafted cells. CONCLUSIONS: Successful development of the NOD-SCID mouse model and techniques to assess human engraftment now allow it to be used reliably to analyze the effects of short-term cytokine exposure on the long-term repopulating capacity of CB stem cells.

Etidronate therapy for hypercalcemia in subcutaneous fat necrosis of the newborn.

Subcutaneous fat necrosis of the newborn (SCFN) is characterized by indurated violet skin nodules and, occasionally, life-threatening hypercalcemia. Current treatments of patients with SCFN-related hypercalcemia are often only partially successful and may be associated with prolonged hypercalcemia. We now report the use of etidronate, a bisphosphonate, to control hypercalcemia in an infant with SCFN.

Cytokine-mediated expansion does not deplete cord blood cells with stem cell characteristics.

Cord blood (CB) has been successfully used to regenerate the hematopoietic system after myeloablative therapy. We investigated whether cytokine mediated expansion depletes CB of cells with stem cell characteristics. CB mononuclear cells (MNC) were enriched for quiescent (primitive) stem cells by incubation with 25 micrograms/ml 5-Fluorouracil (5-FU) and control CB MNC were incubated with media alone. Cells were then incubated for 7 days with Interleukin-1 (IL1)+IL3+Stem Cell Factor (SCF) and progenitor content, cell cycle status, nucleated cell count, immunophenotype and resistance to 25 micrograms/ml 5-FU (primitive stem cells) were evaluated before and after cytokine exposure. Incubation with IL1+IL3+SCF caused an increase (fold expansion) in committed (28.6 +/- 8.1), immature (5.8 +/- 1.8), and primitive progenitors (4.1 +/- 0.8) among control CB MNC compared to a decrease in committed progenitors (0 +/- 0) but an increase in both immature (8.4 +/- 4.8) and primitive progenitors (7 +/- 2.9) among 5-FU resistant CB MNC. An increase in the proportion of CD34+ cells occurred in both fractions. Expanded control CB MNC showed a significant increase in numbers of 5-FU resistant committed (p = 0.024), immature (p = 0.014) and primitive progenitors (p = 0.01) as compared with fresh CB MNC. Re-exposure of 5-FU resistant expanded CB MNC to 5-FU shows growth of some immature and primitive progenitors. Cytokine-mediated expansion of untreated and quiescent CB cells is possible and cytokine-mediated expansion does not deplete CB cells with stem cell characteristics.