A qualitative exploration of South African men's perceived effects of Androgen Deprivation Therapy (ADT) as a treatment for advanced prostate cancer.

OBJECTIVE: We undertake qualitative research with men treated in a Pretoria, South Africa Oncology clinic to address men's self-reported experiences on androgen deprivation therapy (ADT). METHODS: Analyses rely upon 22 men's responses to open-ended questions during interviews. These men were 63-78 years of age, and almost all married (three widowed), had children and were no longer engaged in paid work. RESULTS: In addressing questions about the anticipated and experienced positive and broader side effects of ADT, men referred to its treatment for prostate cancer, with several generally specifying health or life. Patients also referred to a variety of more specific effects such as pain, nausea, difficulties urinating, gaining weight, low energy and sleep disruptions that appeared to reflect a mixture of influences of prostate cancer, ADT and oncological treatment. In addressing a question about the effects of ADT on romantic/sex life, 16 of 19 married men referred to deleterious impacts on their sex lives. With respect to perceived family, work or broader social life impacts, some men noted others' worries and social support. CONCLUSION: Findings are situated within discussions of existing research on ADT largely from North American or European samples, and broader views of testosterone and male social behavior.

Embedded research: a promising way to create evidence-informed impact in public health?

Background: Embedded research (ER) is recognized as one way to strengthen the integration of evidence into public health (PH) practice. In this paper, we outline a promising example of the co-production of research evidence between Fuse, the UKCRC Centre for Translational Research in Public Health and a local authority (LA) in north east England. Methods: We critically examine attempts to share and use research findings to influence decision-making in a LA setting, drawing on insights from PH practitioners, managers, commissioners and academic partners involved in this organizational case study. We highlight what can be achieved as a co-located embedded researcher. Results: The benefits and risks of ER are explored, alongside our reflections on the added value of this approach and the institutional prerequisites necessary for it to work. We argue that while this is not a new methodological approach, its application in PH as a way to facilitate evidence use is novel, and raises pragmatic and theoretical questions about the nature of impact and the extent to which it can be engineered. Conclusion: With increased situated understanding of organizational culture and norms and greater awareness of the socio-political realities of PH, ER enables new co-produced solutions to become possible.

Behaviour of 4- to 5-year-old nondisabled ELBW children: Outcomes following group-based physiotherapy intervention.

BACKGROUND: Extreme prematurity or extremely low birth weight (ELBW) can adversely affect behaviour. Nondisabled ELBW children are at risk of behavioural problems, which may become a particular concern after commencement of formal education. This study explored the frequency of behavioural and emotional problems amongst nondisabled ELBW children at 4 to 5 years of age and whether intervention had a positive influence on behaviour. The relationship between behaviour, gender, and other areas of performance at 5 years was explored. METHODS: Fifty 4-year-old children (born <28 weeks gestation or birth weight <1,000 g) with minimal/mild motor impairment were randomly allocated to intervention (n = 24) or standard care (n = 26). Intervention was 6 group-based physiotherapy weekly sessions and home programme. Standard care was best practice advice. The Child Behavior Checklist (CBCL) for preschool children was completed at baseline and at 1-year post-baseline. Other measures at follow-up included Movement Assessment Battery for Children Second Edition, Beery Visual-Motor Integration Test 5th Edition, and Peabody Picture Vocabulary Test 4th Edition. RESULTS: The whole cohort improved on CBCL total problems score between baseline (mean 50.0, SD 11.1) and 1-year follow-up (mean 45.2, SD 10.3), p = .004. There were no significant differences between groups over time on CBCL internalizing, externalizing, or total problems scores. The intervention group showed a mean difference in total problems score of -3.8 (CI [1.5, 9.1]) between times, with standard care group values being -4.4 (CI [1.6, 7.1]). Males had higher total problems scores than females (p = .026), although still performed within the "normal" range. CBCL scores did not correlate with other scores. CONCLUSIONS: The behaviour of nondisabled ELBW children was within the "normal" range at 4 to 5 years, and both intervention and standard care may have contributed to improved behavioural outcomes. Behaviour was not related to performance in other developmental domains.

A novel intronic splice site deletion of the IL-2 receptor common gamma chain results in expression of a dysfunctional protein and T-cell-positive X-linked Severe combined immunodeficiency.

X-linked severe combined immunodeficiency is caused by mutations in the IL-2 receptor common gamma chain and classically presents in the first 6 months of life with predisposition to bacterial, viral and fungal infections. In most instances, affected individuals are lymphopenic with near complete absence of T cells and NK cells. We report a boy who presented at 12 months of age with Pneumocystis jiroveci pneumonia and a family history consistent with X-linked recessive inheritance. He had a normal lymphocyte count including the presence of T cells and a broad T-cell-receptor diversity, as well as normal surface expression of the common gamma chain (CD132) protein. He however had profound hypogammaglobulinaemia, and IL-2-induced STAT5 phosphorylation was absent. Sequencing of IL-2RG demonstrated a 12-base pair intronic deletion close to the canonical splice site of exon 5, which resulted in a variety of truncated IL2RG mRNA species. A review of the literature identified 4 other patients with T-cell-positive X-SCID, with the current patient being the first associated with an mRNA splicing defect. This case raises the question of how a dysfunctional protein incapable of mediating STAT5 phosphorylation might nonetheless support T-cell development. Possible explanations are that STAT5-mediated signal transduction may be less relevant to IL7-receptor-mediated T-cell development than are other IL7R-induced intracellular transduction pathways or that a low level of STAT5 phosphorylation, undetectable in the laboratory, may be sufficient to support some T-cell development.

The Effect of Fish Oil, Vitamin D and Protein on URTI Incidence in Young Active People.

Upper respiratory tract infections (URTI) are a frequent illness among athletes. We investigated the effect of a multi-nutrient supplement (vitamin D, fish oil and protein) on the occurrence of URTI in young active people. 42 young recreational athletes were randomly assigned to receive either supplementation (550 mg DHA, 550 mg EPA, 10 µg vitamin D3 and 8 g whey protein) or placebo for 16 weeks. Unstimulated saliva samples were collected by passive drool. Samples were analysed for IgA (sIgA) concentration and the secretion rate extrapolated by multiplying concentration by saliva flow rate. Physical activity levels and URTI incidence were monitored by questionnaire. Training status was not different between the 2 groups. There were no differences in the incidence, severity and duration of URTI. However the number of symptom days was lower in the supplemented compared to the control group (1.72±1.67 vs. 2.79±1.76; P<0.05). sIgA concentration and secretion rate did not differ between groups. This study demonstrates that 16 weeks of supplementation with fish oil, vitamin D and protein did not modify the incidence, severity and duration of URTI, although the total number of symptom days was reduced, in a healthy active population.

Proton beam therapy and localised prostate cancer: current status and controversies.

Proton therapy is a promising, but costly, treatment for prostate cancer. Theoretical physical advantages exist; yet to date, it has been shown only to be comparably safe and effective when compared with the alternatives and not necessarily superior. If clinically meaningful benefits do exist for patients, more rigorous study will be needed to detect them and society will require this to justify the investment of time and money. New technical advances in proton beam delivery coupled with shortened overall treatment times and declining device costs have the potential to make this a more cost-effective therapy in the years ahead.

Presence of the metabolic syndrome is associated with shorter time to castration-resistant prostate cancer.

BACKGROUND: Metabolic syndrome (MS) is a set of risk factors that includes obesity and insulin resistance and has been implicated in the development of prostate cancer. Its impact on androgen deprivation therapy (ADT) efficacy has not been studied. PATIENTS AND METHODS: Retrospective study of prostate cancer patients seen from 1998 to 2005 in a medical oncology clinic. MS, as defined by modified Adult Treatment Panel III criteria, was assessed at the time of initiation of ADT. The study end points were time to prostate-specific antigen (PSA) progression and overall survival (OS) from time of starting ADT. RESULTS: Eighty-two patients treated with ADT and data to assess for presence of MS were identified. Median age in men with and without MS was 70 years and 49% of the patients evaluated met criteria for MS. Median time to PSA progression for patients with MS was 16 versus 36 months without MS (P=0.003). The median OS for patients with MS was 36.5 months after commencing ADT compared with 46.7 months for those patients without MS (P=0.061). CONCLUSIONS: This preliminary data suggest that MS is a risk factor for earlier development of castration-resistant prostate cancer and support the need for a prospective evaluation of this finding.

Unusual and severe lesions of proventricular dilatation disease in cockatiels (Nymphicus hollandicus) acting as healthy carriers of avian bornavirus (ABV) and subsequently infected with a virulent strain of ABV.

A flock of 14 apparently healthy cockatiels, purchased from a single aviary, was tested for the presence of avian bornavirus (ABV). Twelve birds were found to be intermittently shedding ABV, predominantly genotype 4. Four of the cockatiels known to be shedding ABV4 were subsequently challenged with the tissue culture derived, virulent M24 strain of ABV4. The challenged birds remained in apparent good health until day 92 when one was found dead. The remaining three birds began to exhibit severe neurologic signs, ataxia and convulsions on day 110 and were euthanized. On necropsy, all four birds showed mild proventricular enlargement. In contrast, histopathological examination showed unusually severe and widespread tissue lesions. These included massive lymphocytic infiltration and lymphoid nodule formation within and around the ganglia throughout the gastrointestinal tract. There were similar lesions in the medullary cords of the adrenal gland, heart, spleen, liver, kidney, lungs, pancreas, testes and ovary. Immunohistochemistry demonstrated ABV P antigen not only in the cells of the central and autonomic nervous systems, but also within the mononuclear cells infiltrating the various organs. Two healthy cockatiels, one of which was a known ABV carrier, were inoculated with uninfected tissue culture cells and euthanized on day 150. These birds showed no gross lesions of proventricular dilatation disease but had a mild lymphocytic infiltration in their liver, spleen, and kidneys. Prior infection with ABV did not therefore confer significant immunity on these birds, and may have resulted in increased disease severity following challenge.

Is Roifman syndrome an X-linked ciliopathy with humoral immunodeficiency? Evidence from 2 new cases.

Roifman syndrome is a rare syndrome of bone dysplasia, growth retardation, retinal dystrophy and humeral immunodeficiency. Six cases have been reported to date, all of whom are male. We report a boy with clinical features of Roifman syndrome, whose older sister has skewed X-inactivation and a milder phenotype of the same disorder, supporting the hypothesis that this is an X-linked recessive condition. Both children had previously had a provisional diagnosis of Jeune dysplasia, and the boy had neonatal hip X-rays which demonstrated 'acetabular spurs' which are seen in a number of diseases thought to be caused by dysfunction of nonmotile cilia, including Jeune asphyxiating thoracic dystrophy. This finding in combination with other features such as retinal dystrophy, hepatic and renal disease suggests that the gene which is affected in Roifman syndrome may be involved with the function of nonmotile cilia and that Roifman syndrome may be the first example of a ciliopathy with associated immunodeficiency.

Evidence for a gamma-interferon receptor that regulates macrophage tumoricidal activity.

Gamma-interferon (IFN-gamma) is the macrophage-activating factor (MAF) produced by normal murine splenic cells and the murine T cell hybridoma 24/G1 that induces nonspecific tumoricidal activity in macrophages. Incubation of 24/G1 supernatants diluted to 8.3 IRU IFN-gamma/ml with 6 X 10(6) elicited peritoneal macrophages or bone marrow-derived macrophages for 4 h at 37 degrees C, resulted in removal of 80% of the MAF activity from the lymphokine preparation. Loss of activity appeared to result from absorption and not consumption because (a) 40% of the activity was removed after exposure to macrophage for 30 min at 4 degrees C, (b) no reduction of MAF activity was detected when the 24/G1 supernatant was incubated with macrophage culture supernatants, and (c) macrophage-treated supernatants showed a selective loss of MAF activity but not interleukin 2 (IL-2) activity. Absorption was dependent on the input of either IFN-gamma or macrophages and was time dependent at 37 degrees C but not at 4 degrees C. With four rodent species tested, absorption of murine IFN-gamma displayed species specificity. However, cultured human peripheral blood monocytes and the human histiocytic lymphoma cell line U937 were able to absorb the murine lymphokine. Although the majority of murine cell lines tested absorbed 24/G1 MAF activity, two murine macrophage cell lines, P388D1 and J774, were identified which absorbed significantly reduced amounts of natural IFN-gamma. Purified murine recombinant IFN-gamma was absorbed by elicited macrophages but not by P388D1. Normal macrophages but not P388D1 bound fluoresceinated microspheres coated with recombinant IFN-gamma and binding was inhibited by pretreatment of the normal cells with 24/G1 supernatants. Scatchard plot analysis showed that 12,000 molecules of soluble 125I-recombinant IFN-gamma bound per bone marrow macrophage with a Ka of 0.9 X 10(8) M-1. Binding was quantitatively inhibitable by natural IFN-gamma but not by murine IFN alpha. IFN-beta competed only weakly. Monoclonal antibodies against IFN-gamma either inhibited or enhanced MAF activity by blocking or increasing IFN-gamma binding to macrophages, respectively. These results indicate that IFN-gamma reacts with a receptor on macrophage in a specific and saturable manner and this interaction initiates macrophage activation.

Human macrophage-derived chemokine (MDC), a novel chemoattractant for monocytes, monocyte-derived dendritic cells, and natural killer cells.

A cDNA encoding a novel human chemokine was isolated by random sequencing of cDNA clones from human monocyte-derived macrophages. This protein has been termed macrophage-derived chemokine (MDC) because it appears to be synthesized specifically by cells of the macrophage lineage. MDC has the four-cysteine motif and other highly conserved residues characteristic of CC chemokines, but it shares <35% identity with any of the known chemokines. Recombinant MDC was expressed in Chinese hamster ovary cells and purified by heparin-Sepharose chromatography. NH2-terminal sequencing and mass spectrophotometry were used to verify the NH2 terminus and molecular mass of recombinant MDC (8,081 dalton). In microchamber migration assays, monocyte-derived dendritic cells and IL-2-activated natural killer cells migrated to MDC in a dose-dependent manner, with a maximal chemotactic response at 1 ng/ml. Freshly isolated monocytes also migrated toward MDC, but with a peak response at 100 ng/ml MDC. Northern analyses indicated MDC is highly expressed in macrophages and in monocyte-derived dendritic cells, but not in monocytes, natural killer cells, or several cell lines of epithelial, endothelial, or fibroblast origin. High expression was also detected in normal thymus and less expression in lung and spleen. Unlike most other CC chemokines, MDC is encoded on human chromosome 16. MDC is thus a unique member of the CC chemokine family that may play a fundamental role in the function of dendritic cells, natural killer cells, and monocytes.

Human immune interferon gene is located on chromosome 12.

A cDNA clone for human immune interferon (IFN-gamma) gene sequences, plasmid p69, was used to chromosomally map the IFN-gamma gene by detecting human IFN-gamma gene sequences in DNA isolated from human-rodent somatic cell hybrids. We were able to map the IFN-gamma gene by correlating the human chromosomes present in these hybrids with the human specific 8.8 and 2.0 kilobase pair fragments produced by EcoRI digestion of genomic DNA. Southern blot analysis of 37 hybrid cell lines indicated that the gene for IFN-gamma was on human chromosome 12. A hybrid containing a portion of chromosome 12 localized the IFN-gamma gene to the p1205 leads to qter region.

Differential expression of chemokine receptors and chemotactic responsiveness of type 1 T helper cells (Th1s) and Th2s.

T helper cells type 1 (Th1s) that produce interferon-gamma predominantly mediate cellular immune responses and are involved in the development of chronic inflammatory conditions, whereas Th2s which produce large amounts of IL-4 and IL-5 upregulate IgE production and are prominent in the pathogenesis of allergic diseases. The precise factors determining whether Th1- or Th2-mediated immune responses preferentially occur at a peripheral site of antigen exposure are largely unknown. Chemokines, a superfamily of polypeptide mediators, are a key component of the leukocyte recruitment process. Here we report that among four CXC (CXCR1-4) and five CC (CCR1-5) chemokine receptors analyzed, CXCR3 and CCR5 are preferentially expressed in human Th1s. In contrast, Th2s preferentially express CCR4 and, to a lesser extent, CCR3. In agreement with the differential chemokine receptor expression, Th1s and Th2s selectively migrate in response to the corresponding chemokines. The differential expression of chemokine receptors may dictate, to a large extent, the migration and tissue homing of Th1s and Th2s. It may also determine different susceptibility of Th1s and Th2s to human immunodeficiency virus strains using different fusion coreceptors.

Pathological effects of cortical architecture on working memory in schizophrenia.

Neural connectivity of the prefrontal cortex is essential to working memory. Reduction of prefrontal connectivity and abnormal prefrontal dopamine modulation are common characteristics associated with schizophrenia. Two experiments separately modeled the effects of exaggerated pruning and of synaptic depression to imitate schizophrenic performance in a prefrontal neural network. In the first model, effects of cortical pruning were simulated with a set of scale-free networks of neurons and compared with empirical results from the Sternberg working memory task. The second set of simulations were based on the synaptic theory of working memory. Simulations of this model measured memory duration in relation to synaptic facilitation and depression constants and in relation to the level of neural connectivity. In the first set of simulations, modulating levels of cortical pruning resulted in a gain or loss in accuracy and speed of memory recollection. In the second set of simulations, increased facilitation time constants and decreased inhibitory time constants resulting in longer memory durations, and overly connected networks resulted in very low memory durations. In the first model, the decline in memory performance can be attributed to the emergence of pathological memory behavior brought about by the warping of the basins of attraction. Collectively, the simulations demonstrate that a reduction of prefrontal cortical hubs can lead to schizophrenia like performance in neural networks, and may account for pathological working memory in the disorder.

Compression garment wear and sensory variables after burn: a single-site study.

OBJECTIVE: Compression garments are well accepted as routine practice for scar management after burn. In a recent systematic review, six main reasons for compression garment non-adherence were identified including sensory disturbances. To further understand the impact of sensory issues, the aim of the present study is to investigate associations between sensory variables and compression garment wear. METHOD: Adults (N = 117) attending a quaternary adult burns outpatient clinic completed: The Adolescent/Adult Sensory Profile; a custom-designed compression garment wear questionnaire; and three quantitative sensory testing procedures (Two-Point Discrimination, Mechanical Detection Threshold and Pressure Pain Threshold). RESULTS: Patients who reported lower Pressure Pain Threshold or Mechanical Detection Threshold, higher acuity for Two Point Discrimination, and higher than average sensory avoiding and sensory sensitivity patterns were less adherent with garment wear. CONCLUSIONS: Overall, sensory factors assessed using both self-report and quantitative sensory testing were associated with compression garment adherence. This knowledge suggests the value in developing and evaluating sensory-informed treatment strategies to improve compression garment wear.

Non-adherence with compression garment wear in adult burns patients: A systematic review and meta-ethnography.

OBJECTIVE: Up to 40% of adult burn-injured patients are non-adherent with prescribed compression garment wear. The aim of this paper is to systematically review the literature to understand barriers to adherence with compression garment wear. METHOD: Papers were included if they: investigated adults who required compression garment wear for the management of burns scars; focussed on reasons for non-adherence to compression garment wear; and were available in English. The process of meta-ethnography was then followed to synthesise the findings. RESULTS: The factors impacting adherence to compression garment wear were grouped into six themes: sensory factors, psychological state, the impact of the garment on the patient's function, the availability of social support, the degree of choice, and the education provided to patients by their therapists. A model of compression garment adherence was developed detailing how these factors fit within the continuum of treatment for a burn-injured patient. CONCLUSIONS: Adherence to compression garment wear post-burn injury is a complex, dynamic phenomenon impacted by a range of factors. Findings from this review may inform approaches to support more consistent and/or extended garment wear, potentially improving scar outcomes and quality-of-life. Further research is recommended to investigate how each of the six identified themes impact adherence.

Antiproliferative activity of a hybrid protein between interferon-gamma and tumor necrosis factor-beta.

A hybrid protein between interferon-gamma and tumor necrosis factor-beta was made by ligating the respective genes and expressing the fused genes under the control of the trp promoter in Escherichia coli. The antiproliferative activity of the hybrid protein in vitro was greatly increased compared with either interferon-gamma or tumor necrosis factor-beta alone, and both antiviral activity and cytotoxic effect were retained in the hybrid protein. The hybrid protein may have potential clinical application.

Modulation of respiratory frequency by peptidergic input to rhythmogenic neurons in the preBötzinger complex.

Neurokinin-1 receptor (NK1R) and mu-opioid receptor (muOR) agonists affected respiratory rhythm when injected directly into the preBötzinger Complex (preBötC), the hypothesized site for respiratory rhythmogenesis in mammals. These effects were mediated by actions on preBötC rhythmogenic neurons. The distribution of NK1R+ neurons anatomically defined the preBötC. Type 1 neurons in the preBötC, which have rhythmogenic properties, expressed both NK1Rs and muORs, whereas type 2 neurons expressed only NK1Rs. These findings suggest that the preBötC is a definable anatomic structure with unique physiological function and that a subpopulation of neurons expressing both NK1Rs and muORs generate respiratory rhythm and modulate respiratory frequency.