Recovering is about living my life, as it evolves: perspectives of stroke survivors in remote northwest Queensland.

PURPOSE: Recovering from stroke in remote Australia has rarely been considered, even though rehabilitation services are generally scarce. The primary purpose of this study was to explore stroke recovery, from the perspective of stroke survivors in remote northwest Queensland (NWQ), to explicate the lens through which they view recovering. The secondary purpose was to explore the role of technology to support stroke survivors in remote locations along their recovery journey. METHODS: A qualitative study was undertaken using elements of constructivist grounded theory for data collection and analysis. Semi-structured interviews were conducted with fifteen stroke survivors and two partners living, working or travelling in remote NWQ. RESULTS: From the participants' perspective, recovering in a remote area after stroke is about living my life, as it evolves by endeavouring to recover my way and navigating my recovery in my world. Technology was only considered helpful when it supported participants to recover their way in their world. CONCLUSION: Recovering from stroke from the perspective of stroke survivors in remote NWQ is about living their life, as they want it to be, and as it unfolds within their own context. Technology only has a place when it can support them to recover their way in their world. These findings reinforce the importance of health professionals listening, learning about, and enabling stroke survivors along their recovery journey, within their remote context and support network.Implications for RehabilitationRecovering from the perspective of stroke survivors is about living their life as it evolves.To support stroke survivors from remote areas, health professionals need to listen to and learn from each stroke survivor about what matters to them, what works for them, and about their world; including the challenges (e.g., switching between services) and enablers (e.g., community support) as the stroke survivor perceives them.Finding ways to utilise the strengths within and around them, may improve the recovery process for the stroke survivor in a remote area, ensuring they can access care that meets their needs in their world.Working together with stroke survivors, health professionals need to consider how technology could help them to live their life, while recovering their way and in their world.

Differential effects of phototherapy, adalimumab and betamethasone-calcipotriol on effector and regulatory T cells in psoriasis.

BACKGROUND: Psoriasis is a chronic T-cell-mediated skin disease with marked social and economic burdens. Current treatments are unsatisfactory, with unpredictable remission times and incompletely understood modes of action. Recent advances in our understanding of the pathogenesis of psoriasis have identified the imbalance between CD4+ T effector cells, particularly the T helper (Th)17 subset, and regulatory T cells (Tregs) as key to the development of psoriatic lesions, and therefore a novel therapeutic target. OBJECTIVES: To quantify in patients the effects of three commonly used psoriasis treatment modalities on the Th1, Th2, Th17 and Treg subsets, and to test whether any change correlates with clinical response. METHODS: Flow cytometry was used to enumerate Th1, Th2, Th17 and Treg subsets in blood and skin of patients with psoriasis before and after receiving any of the following treatments: narrowband ultraviolet B (NB-UVB), adalimumab and topical betamethasone-calcipotriol combination (Dovobet® ) RESULTS: All patients responded clinically to the treatments. NB-UVB significantly increased the numbers of circulating and skin Tregs, while, by contrast, adalimumab reduced Th17 cells in these compartments, and Dovobet had dual effects by both increasing Tregs and reducing Th17 cells. CONCLUSIONS: The differential effects reported here for the above-mentioned treatment modalities could be exploited to optimize or design therapeutic strategies to overcome the inflammatory drivers more effectively and restore the Th17-Treg balance in psoriasis.

Community participation for individuals with spinal cord injury living in Queensland, Australia.

STUDY DESIGN: Sequential mixed method design. OBJECTIVES: Determine factors associated with community participation for individuals with spinal cord injury (SCI). SETTING: Queensland, Australia. METHODS: Phase I consisted of a quantitative telephone survey of 270 people who had sustained a SCI within the past 50 years. To verify and interpret survey findings, Phase II involved a qualitative investigation. One focus group, one dyadic and one in-depth interview were conducted with a separate sample of eight people who had sustained a SCI within the past 50 years. RESULTS: In Phase I, employment, paid or unpaid, was the strongest independent factor associated with community participation, whereas time since injury, completeness of injury, secondary conditions and functional independence were also independently associated. In Phase II, participants expressed that survey findings were consistent with their lived experiences. They explained that overall, they needed a strong reason to participate so that benefits outweigh the effort required to participate. Once out in the community, they recognised that other opportunities for participation arise. CONCLUSION: Rehabilitation services need to support individuals with SCI to find meaningful employment and to engage in activities that provide them with a strong reason to participate.

T cell participation in autoreactivity to NC16a epitopes in bullous pemphigoid.

Bullous pemphigoid is a blistering skin disease characterized by autoantibodies against the NC16a domain of bullous pemphigoid 180. This study was performed to characterize and map the fine specificity of T cell responses to NC16a. Peripheral blood mononuclear cells (PBMC) from a total of 28 bullous pemphigoid patients and 14 matched controls were tested for proliferative and cytokine responses to recombinant NC16a and a complete panel of 21 overlapping peptides spanning this region of BP180. Proliferative responses to NC16A and the peptide panel in the patients with active disease were similar in frequency and magnitude to those in healthy donors, and included late responses typical of naive cells in approximately 60% of each group. Interleukin (IL)-4 responses were slightly stronger for six peptides, and significantly stronger for Nc16a, in patients than in controls. Factor analysis identified factors that separate responses to the peptide panel discretely into IL-4, T helper type 2 (Th2) pattern, interferon (IFN)-γ, Th1 pattern and IL-10 or transforming growth factor [TGF-ß, regulatory T cell (Treg )] pattern. Factors segregating IL-10 versus IFN-γ were predicted by active blistering or remission, and TGF-ß or IL-10 versus IFN-γ by age. Finally, we confirmed a significant up-regulation of IgE responses to BP180 in the patients with pemphigoid. This shows the complexity of T cell phenotype and fine autoreactive specificity in responses to NC16A, in patients and in normal controls. Important disease-associated factors determine the balance of cytokine responses. Of these, specific IL-4 and IgE responses show the strongest associations with pemphigoid, pointing to an important contribution by Th2 cytokines to pathogenesis.

Human interleukin-27: wide individual variation in plasma levels and complex inter-relationships with interleukin-17A.

Although it is widely believed that interleukin (IL)-27 is anti-inflammatory, its role in controlling human immune responses is not fully established. In particular, its interactions with T helper type 17 (Th)17 cytokines are unclear. Our aims were to establish the relationships between IL-27 and proinflammatory cytokines, including IL-17A, in human sera and cultures of peripheral blood mononuclear cells. Plasma IL-27 levels in 879 healthy humans from 163 families varied widely, but with relatively low heritability (19%). Despite IL-27 including a subunit encoded by Epstein-Barr virus-induced gene 3 (EBI3), there was no correlation of levels with serological evidence of infection with the virus. Although IL-27 has been reported to inhibit IL-17A production, we demonstrated a strong positive correlation in sera, but lower correlations of IL-27 with other proinflammatory cytokines. We verified that IL-27 inhibited IL-17A production by human peripheral blood T cells in vitro, but not that it stimulated IL-10 secretion. Importantly, addition of IL-17A decreased IL-27 production by stimulated T cells but had the opposite effect on resting T cells. Together, these data suggest a model whereby IL-27 and IL-17A exerts complex reciprocal effects to boost inflammatory responses, but restrain resting cells to prevent inappropriate activation.

Predominance of activated, clonally expanded T helper type 17 cells within the CD4+ T cell population in psoriatic lesions.

Recent evidence points to the T helper type 17 (Th17) subset as key in the pathogenesis of psoriasis, but cells of this type in lesions remain to be fully characterized. Here we isolated, enumerated, functionally tested and clonotyped the CD4(+) Th cell population ex vivo from lesional biopsies and paired peripheral blood samples from psoriasis patients. Th17 cells were over-represented dramatically in lesions from all patients, representing 49-93% of CD4(+) Th cells compared with 3-18% in blood. Most lesional Th17 cells produced interleukin (IL)-17A ex vivo without further stimulation and expressed the CD45RO(+) phenotype characteristic of activated or memory cells. There was no increase in 'natural' [CD25(hi) forkhead box protein 3 (FoxP3(+))] regulatory T cells in lesions versus peripheral blood, but there was enrichment of 'induced' IL-10(+) regulatory T cell numbers in biopsies from some patients. The lesional Th17 cells exhibited a bias in T cell receptor Vß chain usage, suggestive of specific expansion by antigen. The therapeutic challenge is to overcome the dominance of overwhelming numbers of such antigen-specific Th17 cells in psoriatic lesions.

Indoleamine 2,3 dioxygenase contributes to transferable tolerance in rat red blood cell inducible model of experimental autoimmune haemolytic anaemia.

Autoimmune haemolytic anaemia (AIHA) is caused by autoantibodies against red blood cell (RBC) surface antigens that render RBC susceptible to Fc-mediated phagocytosis and complement-mediated lysis. Experimental AIHA can be induced by injection of rat RBC to naive mice, but a lymphocyte-mediated regulatory mechanism eventually suppresses the production of autoantibodies specific for mouse RBC. Critically, this tolerogenic response can be transferred to naive mice by splenocytes from the rat RBC-immunized mouse. Here we investigate whether indoleamine 2,3 dioxygenase (IDO) or the initiators of IDO cascade, including the cytotoxic T lymphocyte antigen (CTLA)-4 receptor and its soluble isoform, contribute to this tolerogenic mechanism. Splenocytes from experimental AIHA mice were transferred adoptively to naive mice under the cover of anti-CTLA-4, anti-soluble CTLA-4 antibodies or IDO inhibitor 1-methyl tryptophan (1-MT). Recipient mice were immunized with rat RBC and levels of antibody against self-RBC and rat-RBC were monitored. Our results indicate that transfer of tolerance to naive recipients is dependent upon IDO-mediated immunosuppression, as mice receiving previously tolerized splenocytes under the cover of 1-MT were refractory to tolerance and developed haemolytic disease upon further challenge with rat RBC. Initiators of IDO activity, CTLA-4 or soluble CTLA-4 did not mediate this tolerogenic process but, on their blockade, boosted antigen-specific effector immune responses.

Contribution of Candida albicans cell wall components to recognition by and escape from murine macrophages.

The pathogenicity of the opportunistic human fungal pathogen Candida albicans depends on its ability to escape destruction by the host immune system. Using mutant strains that are defective in cell surface glycosylation, cell wall protein synthesis, and yeast-hypha morphogenesis, we have investigated three important aspects of C. albicans innate immune interactions: phagocytosis by primary macrophages and macrophage cell lines, hyphal formation within macrophage phagosomes, and the ability to escape from and kill macrophages. We show that cell wall glycosylation is critically important for the recognition and ingestion of C. albicans by macrophages. Phagocytosis was significantly reduced for mutants deficient in phosphomannan biosynthesis (mmn4Delta, pmr1Delta, and mnt3 mnt5Delta), whereas O- and N-linked mannan defects (mnt1Delta mnt2Delta and mns1Delta) were associated with increased ingestion, compared to the parent wild-type strains and genetically complemented controls. In contrast, macrophage uptake of mutants deficient in cell wall proteins such as adhesins (ece1Delta, hwp1Delta, and als3Delta) and yeast-locked mutants (clb2Delta, hgc1Delta, cph1Delta, efg1Delta, and efg1Delta cph1Delta), was similar to that observed for wild-type C. albicans. Killing of macrophages was abrogated in hypha-deficient strains, significantly reduced in all glycosylation mutants, and comparable to wild type in cell wall protein mutants. The diminished ability of glycosylation mutants to kill macrophages was not a consequence of impaired hyphal formation within macrophage phagosomes. Therefore, cell wall composition and the ability to undergo yeast-hypha morphogenesis are critical determinants of the macrophage's ability to ingest and process C. albicans.

The relationship between quality of life and disability across the lifespan for people with spinal cord injury.

STUDY DESIGN: Prospective cross-sectional survey. OBJECTIVES: To compare quality of life (QOL) for people with spinal cord injury (SCI) and their able-bodied peers and to investigate the relationship between QOL and disability (impairments, activity limitations and participation restrictions) across the lifespan, for people with SCI. SETTING: A community outreach service for people with SCI in Queensland, Australia. METHODS: A random sample of 270 individuals who sustained SCI during the past 60 years was surveyed using a guided telephone interview format. The sample was drawn from the archival records of a statewide rehabilitation service. QOL was measured using the World Health Organization Quality of Life Assessment Instrument-Bref, impairment was measured according to the American Spinal Injury Association classification and the Secondary Condition Surveillance Instrument, activity limitations using the motor subscale of the Functional Independence Measure and participation restrictions using the Community Integration Measure. Lifespan was considered in terms of age and time since injury. Correlation and regression analyses were employed to determine the relationship between QOL and components of disability across the lifespan. RESULTS: QOL was significantly poorer for people with SCI compared to the Australian norm. It was found to be associated with secondary impairments, activity limitations and participation restrictions but not with neurological level, age or time since injury. The single most important predictor of QOL was secondary impairments whereas the second most important predictor was participation. CONCLUSION: To optimize QOL across the lifespan, rehabilitation services must maintain their focus on functional attainment and minimizing secondary conditions, although at the same time enabling participation.

Immunomodulation against leukemias and lymphomas: a realistic future treatment?

Immunotherapy offers the potential for cure of malignancy without the side effects too commonly seen with conventional chemotherapy. The efficacy of allogenic transplantation and monoclonal antibodies in hematological malignancies illustrate this principle and are now part of routine care. Newer cell based and molecular approaches aimed at stimulating cytotoxic activity against host derived tumor associated antigens are able to 'boost' anti-tumor immunity as judged by immunological assays in vitro. Although clinically meaningful responses were originally less evident, more promising results are now being reported. Our growing understanding of tumor immunology provide rationales for further improvements in the field.

Upper limb recovery after stroke: the stroke survivors' perspective.

PURPOSE: This study investigated stroke survivors' perspective of upper limb recovery after stroke. The aim was to determine factors other than medical diagnosis and co-morbidities that contribute to recovery. The objectives were to explore how stroke survivors define recovery, identify factors they believe influence recovery and determine strategies used to maximize upper limb recovery. METHOD: A qualitative study consisting of three focus groups and two in-depth interviews was conducted with stroke survivors (n = 19) and spouses (n = 9) in metropolitan, regional and rural Queensland, Australia. Data were analysed using principles of grounded theory. RESULTS: Stroke survivors maximize upper limb recovery by 'keeping the door open' a process of continuing to hope for and work towards improvement amidst adjusting to life with stroke. They achieve this by 'hanging in there', 'drawing on support from others', 'getting going and keeping going with exercise', and 'finding out how to keep moving ahead'. CONCLUSIONS: This study provides valuable insight into the personal experience of upper limb recovery after stroke. It highlights the need to develop training strategies that match the needs and aspirations of stroke survivors and that place no time limits on recovery. It reinforces the benefits of stroke support groups and advocates their incorporation into stroke recovery services. These findings can be used to guide both the development and evaluation of stroke survivor centred upper limb training programmes.

IL-4 and IL-10 modulate autoimmune haemolytic anaemia in NZB mice.

New Zealand Black (NZB) mice spontaneously develop autoimmune haemolytic anaemia (AIHA). Here the effect of injecting NZB mice with plasmids encoding IL-4 (pIL-4) or IL-10 (pIL-10) on NZB disease was tested. Both constructs delayed the development of anaemia as judged by increased haematocrit values as compared with controls, but neither altered the IgG1 to IgG2 red blood cell (RBC) bound autoantibody levels. The increased haematocrit value was associated temporally with increased RBC bound IgG in NZB mice treated with pIL-10, but not pIL-4. By contrast, up-regulation of splenic macrophage FcgammaRIIb2 mRNA was associated temporally with increased haematocrit values in NZB mice given pIL-4. However, no such increase occurred in NZB mice that inhaled a peptide containing a dominant T-cell epitope, although this treatment is known to bias the autoimmune response towards Th2 and to reduce the severity of anaemia. It is considered that IL-4 treatment, in part, ameliorates NZB anaemia by increasing the expression of the inhibitory FcgammaRIIb2 and thereby reducing the capacity of splenic macrophages to phagocytose autoantibody coated RBC, but that this mechanism does not explain the beneficial effects of the inhaled peptide.

T-cell specificity in murine autoimmune haemolytic anaemia induced by rat red blood cells.

Autoimmune haemolytic anaemia (AIHA) can be induced in mice by repeated injections with rat red blood cells (RBC). Here we describe the identification of rat and murine RBC antigens recognized by T-cells from mice with this disease. Splenic T-cells from mice with AIHA proliferated in response to multiple murine RBC membrane components, each of which is recognized by rat RBC induced autoantibodies. Thus, there were responses to murine autoantigen fractions that correspond in apparent molecular mass with the anion channel Band 3, with spectrin from the membrane skeleton and with the high and low molecular mass glycophorins, and the equivalent fractions from rat RBC also stimulated proliferation by T-cells. It was confirmed that purified Band 3 from murine and rat RBC also elicited responses. In contrast with the results in AIHA, T-cells from healthy control mice failed to respond to the antigens from either species, with the exception of proliferation induced by murine spectrin in one experiment and weak responses elicited by rat Band 3. It is suggested that T-cells activated by multiple cross-reactions between rat and murine RBC proteins, and by epitope spreading, are necessary to drive autoantibody production in this model of AIHA.

Coincidence of immune-mediated diseases driven by Th1 and Th2 subsets suggests a common aetiology. A population-based study using computerized general practice data.

BACKGROUND: The recent rise in the prevalence of immune-mediated diseases has been attributed to environmental factors such as a lack of microbial challenge, or dietary change, that deviate the overall balance between mutually antagonistic subsets of T helper (Th) cells. OBJECTIVE: An alternative proposal is that recent environmental changes have resulted in an immune system that is more likely to produce both Th1 and Th2 responses against benign antigens. The prediction of this hypothesis, that Th1 and Th2-mediated diseases are not mutually exclusive, and may be positively associated, is tested here in a whole population. METHODS: Data from General Practices participating in the Scottish Continuous Morbidity Recording (CMR) project were used to determine the coincidence of the major Th2-mediated atopic diseases; asthma, eczema and allergic rhinitis, with the Th1-mediated autoimmune conditions; type I diabetes, rheumatoid arthritis and psoriasis. We also identified the prescription rates of inhaled therapy for asthma in patients with Th1-mediated disease. RESULTS: There was a significant increase in the risk of presenting with a Th1-mediated autoimmune condition in patients with a history of allergic disease (standardized prevalence ratio (95% confidence interval) 1.28 (1.18-1.37)). Likewise, the standardized prevalence ratios of presenting with either eczema (1.67 (1.48-1.87)) or allergic rhinitis (1.22 (1.02-1.44)) were significantly increased in subjects with a history of Th1-mediated disease. There was a particularly strong association between current psoriasis and current eczema (standardized prevalence ratio ofpsoriasis in subjects with eczema 2.88, 95% confidence interval (CI) 2.38-3.45). There was also a significant increase in prescriptions for inhaled asthma therapy in patients with Th1 disease. CONCLUSION: It is concluded that Th1- and Th2-mediated diseases are significantly associated in a large General Practice population. This finding supports the proposal that autoimmune and atopic diseases share risk factors that increase the propensity of the immune system to generate both Th1- and Th2-mediated inappropriate responses to non-pathological antigens.

Antenatal determinants of neonatal immune responses to allergens.

BACKGROUND: The environmental factors responsible for recent increases in the prevalence of asthma and atopic disease have been assumed to act after birth. Their possible effects on fetal immune development in utero have not been investigated systematically, although sensitization to allergens may occur before birth. OBJECTIVE: This prospective study determined whether the risk factors for asthma and atopic disease, namely family history of atopic disease, maternal smoking, birth order, or maternal dietary intake of antioxidant vitamins, exert antenatal effects on the fetal immune system that may predispose to childhood atopy. METHODS: The T helper (Th) cell proliferative responses of cord blood mononuclear cells (CBMC) from a sample of 223 neonates, representative of children born to a cohort of 2000 pregnant women, were measured and related to family, maternal and environmental factors associated with the pregnancy. RESULTS: The magnitude of CBMC-proliferative responses to allergens increased significantly in association with a family history of atopic disease or maternal smoking, and decreased significantly with increasing birth order and high maternal dietary intake of vitamin E. The epidemiological association between birth order and atopy may therefore be a consequence of antenatal influences rather than of protective effects of childhood infections. The association between maternal intake of vitamin E and CBMC responsiveness suggests that diet during pregnancy may influence the fetal immune system in such a way as to modulate the risk of childhood atopy. CONCLUSION: These results provide a new insight into the aetiology of atopic disease by demonstrating that the maternal environmental risk factors for atopy, diet, birth order and smoking, influence the development of the fetal immune system. This raises the prospect of preventative public health interventions during pregnancy.

Antigen presentation by macrophages is enhanced by the uptake of necrotic, but not apoptotic, cells.

The aim of this study was to determine whether phagocytosis of necrotic or apoptotic cells affects antigen presentation by murine bone marrow-derived macrophages. After uptake of necrotic neutrophils, macrophages were able to stimulate significantly higher T cell proliferation in vitro against both the recall antigen albumin and the mitogen concanavalin A. No such effect was seen following phagocytosis of apoptotic neutrophils. Flow cytometry revealed that, within 4h of ingestion, macrophages that had taken up the necrotic cells expressed higher levels of CD40 than those that had phagocytosed apoptotic cells. Macrophage cultures pulsed with apoptotic, but not necrotic, neutrophils contained higher levels of transforming growth factor beta1, but lower concentrations of tumour necrosis factor alpha, compared to untreated controls. Our interpretation of these results is that macrophages that have taken up necrotic neutrophils co-stimulate T cells with greater efficiency due to rapid CD40 up-regulation, whereas those that have ingested apoptotic cells are not only ineffective in co-stimulation, but also secrete inhibitory cytokine.

In utero priming of allergen-specific helper T cells.

BACKGROUND: Allergic diseases are major health problems in developed countries. Cord blood mononuclear cells (CBMC) at birth can proliferate after stimulation with allergen and this has led to the widespread view that the sensitization of the fetal immune system by allergens is a key determinant in establishing immunological bias towards allergy. However, the notion that the immune system can be primed by allergen in utero remains unproven. Determination of the CD45 isoform of responding T helper cells is an established method of determining the activation status of responding T helper cells because unsensitized cells express CD45RAhigh and previously sensitized cells CD45ROhigh. OBJECTIVE: To determine if sensitization of allergen-specific T helper cells can occur in utero by determining the CD45 isoform of CBMC proliferating in response to allergen. METHODS: CBMC proliferative responses were measured after stimulation in culture with a panel of allergens, mitogen and control antigen. To ascertain whether any responding T helper cells had been primed in utero, depletion experiments established whether they carried the CD45ROhigh marker of previous activation or the CD45RAhigh marker of unstimulated T cells. RESULTS: CBMC from a high proportion of 223 randomly selected neonates were stimulated to proliferate in vitro by allergens, with 76% responding to timothy grass pollen. In 50% of such responses to timothy grass, the CD45 isoform of the T cells that proliferate indicated that they had been previously activated. However, the remaining 50% of responses to timothy grass were mediated by previously unstimulated T cells. Proliferative responses mediated by CBMC sensitized in utero tended to be greater in magnitude than those mediated by unsensitized cells (P = 0.08). Seventy-five per cent of CBMC samples proliferated after stimulation with mycobacterial PPD and, as in BCG-vaccinated adults, all such CBMC proliferative responses at birth were predominately mediated by sensitized cells. CONCLUSION: Allergen- and antigen-specific Th cells can be primed in utero.

Helper T cells in antibody-mediated, organ-specific autoimmunity.

The production of pathogenic autoantibodies in organ-specific autoimmune diseases is largely T cell dependent. For many of these diseases, the precise specificities and cytokine profiles of the T cells that respond to the corresponding autoantigens have now been identified. This knowledge has been exploited to treat some models of antibody-mediated autoimmunity using peptides corresponding to the dominant helper epitopes, giving impetus to the development of a similar approach in the equivalent human diseases.