Testosterone, dominance signalling and immunosuppression in the house sparrow, Passer domesticus

The immunocompetence handicap hypothesis (ICHH) suggests that dominance signals are costly because their development is controlled by testosterone, which is immunosuppressive. Signal control therefore links an increased disease risk with a high quality signal. The chest bib of the house sparrow, Passer domesticus, is a signal known to be related to dominance and under control of testosterone levels. We experimentally manipulated testosterone in male sparrows during the breeding season and again independently during the post-breeding period to test whether variation in levels of testosterone could cause variation in levels of immunocompetence. There was no effect of testosterone manipulation on the cell-mediated response of birds to phytohaemagglutinin injection, nor did testosterone levels appear to affect either white blood cell ratios or red blood cell counts. In contrast, both breeding season and post-breeding season testosterone levels had significant effects upon the humoral response of the birds to sheep red blood cell injections. However, whilst testosterone during the breeding season appeared to act immunosuppressively, the role of post-breeding levels is less clear. In concordance with a previous study, there was an indication that corticosterone is involved in mediating the immunosuppressive effects of testosterone. The strength of the secondary humoral response and the cell-mediated response were negatively related suggesting the possibility of a trade-off between the different arms of the immune system. These results provide some support for the ICHH as a mechanism promoting the evolution of costly badges of status, although the results question whether the immunosuppressive cost can be mediated by testosterone at the time of badge development.

Review of the role of emergency nurses in management of chemotherapy-related complications

Aims and objectives : To examine the role of emergency nurses in caring for patients who receive chemotherapy in ambulatory oncology settings. Reasons for emergency department presentations are examined, specific sources of clinical risk for patients receiving chemotherapy who require emergency care are discussed and cost implications of emergency department presentations related to chemotherapy are analysed.

Background : Given the increased administration of chemotherapy in ambulatory settings, emergency nurses play an important role in the management of patients undergoing adjuvant chemotherapy. Emergency departments are the major entry point for acute inpatient hospital care of complications arising from chemotherapy.

Design : Systematic review.

Results : Chemotherapy-related emergency department presentations have considerable clinical and cost implications for patients and the healthcare system. Strategies to improve emergency department management of chemotherapy complications and reduction in preventable emergency department presentations has significant implications for improving cancer patients' quality of life and reducing the cost of cancer care.

Conclusions : Nurses are well placed to play a pivotal role in chemotherapy management and lead interventions such as a specialist oncology nursing roles that provide information and support to guide patients through their chemotherapy cycles. These interventions may prevent emergency department presentations for patients receiving chemotherapy in ambulatory settings.

Relevance to clinical practice : Patients receiving chemotherapy require access to specialised care to manage distressing symptoms, as they are at significant clinical risk because of immunosuppression and may not exhibit the usual signs of critical illness. A team approach both within and across nursing specialities may improve care for patients receiving chemotherapy and increase effective use of healthcare resources.

'Iron-saturated' lactoferrin is a potent natural adjuvant for augmenting cancer chemotherapy

Bovine lactoferrin (bLf), an iron-containing natural defence protein found in bodily secretions, has been reported to inhibit carcinogenesis and the growth of tumours. Here, we investigated whether natural bLf and iron-saturated forms of bLf differ in their ability to augment cancer chemotherapy. bLf was supplemented into the diet of C57BL/6 mice that were subsequently challenged subcutaneously with tumour cells, and treated by chemotherapy. Chemotherapy eradicated large (0.6 cm diameter) EL-4 lymphomas in mice that had been fed iron-saturated bLf (here designated Lf(+)) for 6 weeks prior to chemotherapy, but surprisingly not in mice that were fed lesser iron-saturated forms of bLf, including apo-bLf (4% iron saturated), natural bLf (approximately 15% iron saturated) and 50% iron-saturated bLf. Lf(+)-fed mice bearing either EL-4, Lewis lung carcinoma or B16 melanoma tumours completely rejected their tumours within 3 weeks following a single injection of either paclitaxel, doxorubicin, epirubicin or fluorouracil, whereas mice fed the control diet were resistant to chemotherapy. Lf(+) had to be fed to mice for more than 2 weeks prior to chemotherapy to be wholly effective in eradicating tumours from all mice, suggesting that it acts as a competence factor. It significantly reduced tumour vascularity and blood flow, and increased antitumour cytotoxicity, tumour apoptosis and the infiltration of tumours by leukocytes. Lf(+) bound to the intestinal epithelium and was preferentially taken up within Peyer's patches. It increased the production of Th1 and Th2 cytokines within the intestine and tumour, including TNF, IFN-gamma, as well as nitric oxide that have been reported to sensitize tumours to chemotherapy. Importantly, it restored both red and white peripheral blood cell numbers depleted by chemotherapy, potentially fortifying the mice against cancer. In summary, bLf is a potent natural adjuvant and fortifying agent for augmenting cancer chemotherapy, but needs to be saturated with iron to be effective.

Testing the immunocompetence handicap hypothesis : a review of the evidence

The immunocompetence handicap hypothesis was formulated 12 years ago in an attempt to offer a proximate mechanism by which female choice of males could be explained by endocrine control of honest signalling. The hypothesis suggested that testosterone has a dual effect in males of controlling the development of sexual signals while causing immunosuppression. Our purpose in this review is to examine the empirical evidence to date that has attempted to test the hypothesis, and to conduct a meta-analysis on two of the assumptions of the hypothesis, that testosterone reduces immunocompetence and increases parasitism, to ascertain any statistical trend in the data. There is some evidence to suggest that testosterone is responsible for the magnitude of trait expression or development of sexual traits, but this is by no means conclusive. The results of many studies attempting to find evidence for the supposed immunosuppressive qualities of testosterone are difficult to interpret since they are observational rather than experimental. Of the experimental studies, the data obtained are ambiguous, and this is reflected in the result of the meta-analysis. Overall, the meta-analysis found a significant suppressive effect of testosterone on immunity, in support of the hypothesis, but this effect disappeared when we controlled for multiple studies on the same species. There was no effect of testosterone on direct measures of immunity, but it did increase ectoparasite abundance in several studies, in particular in reptiles. A funnel analysis indicated that the results were robust to a publication bias. Alternative substances that interact with testosterone, such as glucocorticoids, may be important. Ultimately, a greater understanding is required of the complex relationships that exist both within and between the endocrine and immune systems and their consequences for mate choice decision making.

Frequency-dependent physiological trade-offs between competing colour morphs

Evolutionary theory suggests that alternative colour morphs (i.e. genetically controlled phenotypes) may derive similar fitness under frequency-dependent selection. Here we experimentally demonstrate opposing effects of frequency-dependent social environments on plasma hormone levels (testosterone and corticosterone) and immune function between red- and black-headed male morphs of the Gouldian finch (Erythrura gouldiae). Red-headed males are highly sensitive to changes in the social environment, especially towards the relative density of their own aggressive morph, exhibiting high stress responses and immunosuppression in socially competitive environments. In contrast, the non-aggressive black-headed males follow a more passive strategy that appears to buffer them against social stresses. The differential effect of hormones on aggressive behaviour and immune performance reinforces the contrasting behavioural strategies employed by these colour morphs, and highlights the importance of the social environment in determining the individual basis of behavioural and physiological responses.

Requirements for ICAM-1 immunogene therapy of lymphoma.

Intercellular cell adhesion molecule-1 (ICAM-1) is a cell-surface glycoprotein capable of eliciting bidirectional signals that activate signalling pathways in leukocytes, endothelial, and smooth muscle cells. Gene transfer of xenogeneic ICAM-1 into EL-4 lymphomas causes complete tumor rejection; however, it is unknown whether the mechanism responsible involves the "foreignness" of the ICAM-1 transgene, bidirectional signalling events, ICAM-1-receptor interaction, or a combination of the latter. To begin to address this question, we constructed four different therapeutic expression vectors encoding full-length ICAM-1, and forms in which the N-terminal ligand-binding domains and cytoplasmic tail had been deleted. Mouse EL-4 tumors (0.5 cm in diameter), which actively suppress the immune response, were significantly inhibited in their growth following injection of expression plasmids encoding either full-length xenogenic (human) ICAM-1, or a functional cytoplasmic domain-deficient form that retains ligand-binding activity. Efficacy of ICAM-1-mediated antitumor immunity was significantly augmented by administration of the antivascular drug 5,6-dimethylxanthenone-4-acetic acid (DMXAA), which suppressed blood supply to the tumor, leading to enhanced leukocyte infiltration, and complete tumor eradication in a gene dosage and CD8(+) T cell and NK cell-dependent fashion. Generation of potent cytotoxic T cell (CTL)-mediated antitumor immunity was reflected by ICAM-1-facilitated apoptosis of tumor cells in situ. In contrast, nonfunctional ICAM-1 lacking the N-terminal ligand-binding Ig domain failed to generate antitumor immunity, even in the presence of DMXAA. These studies demonstrate that ICAM-1-stimulated antitumor immunity can overcome tumor-mediated immunosuppression, particularly when employed in combination with an attack on the tumor vasculature. The ligand-binding domain of ICAM-1 is essential for generating antitumor immunity, whereas the cytoplasmic domain and bidirectional activation of tumor signalling pathways are not essential.

Systemic activation of dendritic cells by toll-like receptor ligands or malaria infection impairs cross-presentation and antiviral immunity

The mechanisms responsible for the immunosuppression associated with sepsis or some chronic blood infections remain poorly understood. Here we show that infection with a malaria parasite (Plasmodium berghei) or simple systemic exposure to bacterial or viral Toll-like receptor ligands inhibited cross-priming. Reduced cross-priming was a consequence of downregulation of cross-presentation by activated dendritic cells due to systemic activation that did not otherwise globally inhibit T cell proliferation. Although activated dendritic cells retained their capacity to present viral antigens via the endogenous major histocompatibility complex class I processing pathway, antiviral responses were greatly impaired in mice exposed to Toll-like receptor ligands. This is consistent with a key function for cross-presentation in antiviral immunity and helps explain the immunosuppressive effects of systemic infection. Moreover, inhibition of cross-presentation was overcome by injection of dendritic cells bearing antigen, which provides a new strategy for generating immunity during immunosuppressive blood infections.

The effects of testosterone on immune function in quail selected for divergent plasma corticosterone response

The immunocompetence handicap hypothesis (ICHH) suggests that the male sex hormone testosterone has a dual effect; it controls the development and expression of male sexually selected signals, and it suppresses the immune system. Therefore only high quality males are able to fully express secondary sexual traits because only they can tolerate the immunosuppressive qualities of testosterone. A modified version of the ICHH suggests that testosterone causes immunosuppression indirectly by increasing the stress hormone corticosterone (CORT). Lines of Japanese quail (Coturnix japonica) selected for divergent responses in levels of plasma CORT were used to test these hypotheses. Within each CORT response line (as well as in a control stock) we manipulated levels of testosterone in castrated quail by treatment with zero (sham), low or high testosterone implants, before testing the birdsʼ humoral immunity and phytohaemagglutinin (PHA)-induced immune response, as well as body condition. The PHA-induced response was not significantly affected by CORT selected line, testosterone treatment or their interaction. There was, however, a significant effect of CORT line on humoral immunity in that the control birds exhibited the greatest antibody production, but there was no significant effect of testosterone manipulation on humoral immunity. The males in the sham implant treatment group had significantly greater mass than the males in the high testosterone group, suggesting a negative effect of high testosterone on general body condition. We discuss these results in the context of current hypotheses in the field of sexual selection.

Patient-reported outcomes following islet cell or pancreas transplantation (alone or after kidney) in type 1 diabetes: a systematic review

Aims For selected individuals with complex Type 1 diabetes, pancreatic islet transplantation (IT) offers the potential of excellent glycaemic controlwithout significant hypoglycaemia, balanced by the need for ongoing systemic immunosuppression. Increasingly, patient-reported outcomes (PROs) are considered alongside biomedical outcomes as a measure of transplant success. PROs in IT have not previously been compared directlywith the closest alternate treatment option, pancreas transplant alone (PTA) or pancreas after kidney (PAK).

Methods We used a Population, Intervention, Comparisons, Outcomes (PICO) strategy to search Scopus and screened 314 references for inclusion.

Results Twelve studies [including PRO assessment of PAK, PTA, islet-after kidney (IAK) and islet transplant alone (ITA); n = 7–205] used a total of nine specified and two unspecified PRO measures. Results were mixed but identified some benefits which remained apparent up to 36 months post-transplant, including improvements in fear of hypoglycaemia, as well as some aspects of diabetes-specific quality of life (QoL) and general health status. Negative outcomes included short-term pain associated with the procedure, immunosuppressant side effects and depressed mood associated with loss of graft function.

Conclusions The mixed resultsmay be attributable to limited sample sizes. Also, some PROmeasures may lack sensitivity to detect actual changes, as they exclude issues and domains of life likely to be important forQoL post-transplantation and when patients may no longer perceive themselves to have diabetes. Thus, the full impact of islet ⁄ pancreas transplantation (alone or after kidney) on QoL is unknown. Furthermore, no studies have assessed patient satisfaction, which may highlight further advantages and disadvantages of transplantation.

The role of testosterone in bib size determination in the male house sparrow Passer domesticus, is age dependent

Secondary sexual signals are thought to indicate individual quality. In order to understand the evolutionary pressures that give rise to such traits it is important to understand the physiological mechanisms underlying their production. The black bib of the house sparrow Passer domesticus is known to function as a badge of social status in males. Past studies have found that the size of the bib in older males is determined, at least partly, by the androgen testosterone. The immunocompetence handicap hypothesis suggests that testosterone has a key role in maintaining honest signalling – it is both involved in the development or expression of sexual signals and is immunosuppressive. In this paper we test experimentally two hypo theses relating to bib size development, whether 1) testosterone is only immunosuppressive in conditions where the natural feedback loop from the testes has been removed, and 2) testosterone is, in addition to influencing the bib size of older males, responsible for the size of the bib in juvenile sparrows. In the first experiment we found that exogenous testosterone administered to intact males during the winter (when LH and FSH levels are very low and were not artificially increased by castration) caused significant immunosuppression, albeit in interaction with the stress hormone corticosterone. Second, we found that exogenous testosterone administration in castrated fledgling male house sparrows had no effect on subsequent post-juvenile moult bib size relative to controls. Our results suggest that in some circumstances testosterone can be immunosuppressive, but that its role in bib size determination is age-dependent.

Chicken anemia virus : an understanding of the in-vitro host response over time

Chicken anemia virus (CAV) is an economically important virus affecting the chicken meat and egg industry. CAV is characterized by anemia, lymphoid depletion, and immunosuppression. Microarrays were used to investigate the response of MDCC-MSB1 cells (MSB1) to infection with CAV at 24 and 48 h post-infection (hpi). The major genes responding to CAV infection include genes involved in inflammation, apoptosis, and antiviral activity. Several cytokines were differentially regulated at either 24 or 48 hpi, including interleukin 2 (IL-2), interleukin receptors IL-1R, IL-22R, IL-18R, and IL-7R, and interferon-α (IFN-α). While there were many genes differentially regulated in this experiment, only two genes were common to both time points, suggesting a dramatic change in gene expression over the two time points studied. The present study is the first microarray experiment to investigate CAV, and we identified a number of key pathways involved in viral infection. Overall, there were more genes upregulated at 24 hpi than at 48 hpi, including genes involved in cytokine signaling, apoptosis, and antiviral activity. The two time points were vastly different in their gene expression patterns, in that at 24 hpi there were many genes involved in the response to infection, whereas at 48 hpi there were many genes associated with apoptosis and immunosuppression.

Risk factors for recurrent Mycobacterium ulcerans disease after exclusive surgical treatment in an Australian cohort

Objective: To describe risk factors for recurrence after exclusive surgical treatment of Mycobacterium ulcerans infection. Design, setting and participants: Prospective observational cohort study of all M. ulcerans cases managed with surgery alone at Barwon Health, a tertiary referral hospital, from 1 January 1998 to 31 December 2011. A random-effects Poisson regression model was used to assess rates and associations of treatment failure. Main outcome measures: Rates of treatment failure and rate ratios (RRs) for factors associated with treatment failure. Results: Of 192 patients with M. ulcerans infection, 50 (26%) had exclusive surgical treatment. Median age was 65.0 years (interquartile range [IQR], 45.5-77.7 years), and median duration of symptoms was 46 days (IQR, 26-90 days). There were 20 recurrences in 16 patients. For first lesions, the recurrence incidence rate was 41.8 (95% CI, 25.6-68.2) per 100 person-years, and median time to recurrence was 50 days (IQR, 30-171 days). Recurrence occurred ≤ 3 cm from the original lesion in 13 cases, and >3 cm in nine. On univariable analysis, age ≥60 years (RR 13.84; 95% CI, 2.21-86.68; P< 0.01), distal lesions (RR, 20.43; 95% CI, 1.97-212.22; P<0.01), positive histological margins (RR, 21.02; 95% CI, 5.51-80.26; P< 0.001), immunosuppression (RR, 17.97; 95% CI, 4.17-77.47; P <0.01) and duration of symptoms >75 days (RR, 10.13; 95% CI, 1.76-58.23; P =0.02) were associated with treatment failure. On multivariable analysis, positive margins (RR, 7.72; 95% CI, 2.71-22.01; P<0.001) and immunosuppression (RR, 6.45; 95% CI, 2.42-17.20; P =0.01) remained associated with treatment failure. Conclusions: Recurrence rates after exclusive surgical treatment of M. ulcerans disease in an Australian cohort are high, with increased rates associated with immunosuppression or positive histological margins.

Preoperative immunonutrition and its effect on postoperative outcomes in well-nourished and malnourished gastrointestinal surgery patients: a randomised controlled trial

Background/Objectives:
Invasive procedures such as surgery cause immunosuppression, leading to increased risk of complications, infections and extended hospital stay. Emerging research around immune-enhancing nutrition supplements and their ability to reduce postoperative complications and reduce treatment costs is promising. This randomised controlled trial aims to examine the effect of preoperative immunonutrition supplementation on length of hospital stay (LOS), complications and treatment costs in both well-nourished and malnourished gastrointestinal surgery patients.

Subjects/Methods:
Ninety-five patients undergoing elective upper and lower gastrointestinal surgery were recruited. The treatment group (n=46) received a commercial immuno-enhancing supplement 5 days preoperatively. The control group (n=49) received no supplements. The primary outcome measure was LOS, and secondary outcome measures included complications and cost.

Results:
A nonsignificant trend towards a shorter LOS within the treatment group was observed (7.1±4.1 compared with 8.8±6.5 days; P=0.11). For malnourished patients, this trend was greater with hospital stay reduced by 4 days (8.3±3.5 vs 12.3±9.5 days; P=0.21). Complications and unplanned intensive care admission rates were very low in both the groups. The average admission cost was reduced by AUD1576 in the treatment group compared with the control group (P=0.37).

Conclusions:
Preoperative immunonutrition therapy in gastrointestinal surgery has the potential to reduce the LOS and cost, with greater treatment benefit seen in malnourished patients; however, there is a need for additional research with greater patient numbers.