'Odds Are: They Win': a disruptive messaging innovation for challenging harmful products and practices of the gambling industry.

OBJECTIVE: This paper presents an evidence informed rationale for focussing on harmful gambling products and industry practices in public health messaging through the example of a recent innovation called 'Odds Are: They Win'. METHODS: 'Odds Are: They Win' was initially developed through coproduction involving public health professionals and people with lived experience of gambling harms and implemented across a city-region area. A review of relevant evidence was undertaken, upon which the research team reflected to draw out the implications of 'Odds Are: They Win' for gambling harms messaging. RESULTS: Evidence is mounting that safer gambling campaigns framed in terms of individual responsibility are ineffective and can generate stigma. 'Odds Are: They Win' presents an alternative focus that is not anti-gambling but raises awareness of industry manipulation of the situational and structural context of gambling. This is in-keeping with historical lessons from the stop smoking field and emerging research in critical health literacy. The latter highlights the potential of education on the social and commercial determinants of health to stimulate behaviour change and collective action. CONCLUSION: 'Odds Are: They Win' is a potentially disruptive innovation for the gambling harms field. Research is required to robustly evaluate this intervention across diverse criteria, target audiences, and delivery settings.

Gender and health literacy: men's health beliefs and behaviour in Trinidad.

Gender variations in health literacy have implications for engagement in preventive behaviours and the uptake of health services, especially in areas such as the Caribbean where there are marked disparities in life expectancy and health service utilization. A self-reported questionnaire was used to examine men's concepts of health, their help-seeking behaviours and their functional and interactive health literacy. Two hundred and forty-eight men across the life course participated at three sites in Trinidad. Data were analysed using descriptive statistics, with free-text responses analysed thematically. Men were concerned about, and accepted responsibility for their own health but social norms concerning sickness and masculinity were barriers to accessing health services. Almost one-third (31.5%) sought advice from a healthcare service when they were last sick because they were prompted to do so by their wife/partner or family. Levels of functional and interactive health literacy were not high among older men, who were reliant on healthcare professionals to communicate health messages. There was an age divide in e-health literacy. There is little published evidence on men's health literacy, particularly from Caribbean countries such as Trinidad and Tobago. This study highlights the importance of the design and implementation of specific policies focusing on men's health. A major challenge is to engage with men who do not access health services.

RET-mediated autophagy suppression as targetable co-dependence in acute myeloid leukemia.

Many cases of AML are associated with mutational activation of receptor tyrosine kinases (RTKs) such as FLT3. However, RTK inhibitors have limited clinical efficacy as single agents, indicating that AML is driven by concomitant activation of different signaling molecules. We used a functional genomic approach to identify RET, encoding an RTK, as an essential gene in multiple subtypes of AML, and observed that AML cells show activation of RET signaling via ARTN/GFRA3 and NRTN/GFRA2 ligand/co-receptor complexes. Interrogation of downstream pathways identified mTORC1-mediated suppression of autophagy and subsequent stabilization of leukemogenic drivers such as mutant FLT3 as important RET effectors. Accordingly, genetic or pharmacologic RET inhibition impaired the growth of FLT3-dependent AML cell lines and was accompanied by upregulation of autophagy and FLT3 depletion. RET dependence was also evident in mouse models of AML and primary AML patient samples, and transcriptome and immunohistochemistry analyses identified elevated RET mRNA levels and co-expression of RET and FLT3 proteins in a substantial proportion of AML patients. Our results indicate that RET-mTORC1 signaling promotes AML through autophagy suppression, suggesting that targeting RET or, more broadly, depletion of leukemogenic drivers via autophagy induction provides a therapeutic opportunity in a relevant subset of AML patients.

Feline Respiratory Extramedullary Plasmacytoma with Lymph Node Metastasis and Intrahistiocytic Amyloid.

A 14-year-old domestic longhaired cat presented with a 2-year history of nasal discharge and a recent onset of inappetence and submandibular lymphadenopathy. The cat was humanely destroyed after developing severe respiratory distress. Necropsy examination revealed thickened nasal turbinates and soft palate, and friable red-tan material within the frontal sinus, nasal cavity and nasopharynx. The lungs contained multifocal irregular friable tan nodules. Multiple lymph nodes were enlarged, friable and red-tan in colour. Histopathology revealed a mature type extramedullary plasmacytoma (EMP) within the frontal sinus, nasal cavity, soft palate, larynx, trachea, lungs and multiple lymph nodes. The lymph nodes and larynx also contained marked granulomatous inflammation with extensive intrahistiocytic (and lesser amounts of extracellular) lambda light chain amyloid, confirmed by electron microscopy and immunohistochemistry. Neoplastic cells expressed CD79a and MUM1. This is the first report of an infiltrative EMP of the feline respiratory tract with lymph node metastasis and predominantly intrahistiocytic amyloid.

JUN is a key transcriptional regulator of the unfolded protein response in acute myeloid leukemia.

The transcription factor JUN is frequently overexpressed in multiple genetic subtypes of acute myeloid leukemia (AML); however, the functional role of JUN in AML is not well defined. Here we report that short hairpin RNA (shRNA)-mediated inhibition of JUN decreases AML cell survival and propagation in vivo. By performing RNA sequencing analysis, we discovered that JUN inhibition reduces the transcriptional output of the unfolded protein response (UPR), an intracellular signaling transduction network activated by endoplasmic reticulum (ER) stress. Specifically, we found that JUN is activated by MEK signaling in response to ER stress, and that JUN binds to the promoters of several key UPR effectors, such as XBP1 and ATF4, to activate their transcription and allow AML cells to properly negotiate ER stress. In addition, we observed that shRNA-mediated inhibition of XBP1 or ATF4 induces AML cell apoptosis and significantly extends disease latency in vivo tying the reduced survival mediated by JUN inhibition to the loss of pro-survival UPR signaling. These data uncover a previously unrecognized role of JUN as a regulator of the UPR as well as provide key new insights into the how ER stress responses contribute to AML and identify JUN and the UPR as promising therapeutic targets in this disease.

PKCε as a novel promoter of skeletal muscle differentiation and regeneration.

INTRODUCTION: Satellite cells are muscle resident stem cells and are responsible for muscle regeneration. In this study we investigate the involvement of PKCε during muscle stem cell differentiation in vitro and in vivo. Here, we describe the identification of a previously unrecognized role for the PKCε-HMGA1 signaling axis in myoblast differentiation and regeneration processes. METHODS: PKCε expression was modulated in the C2C12 cell line and primary murine satellite cells in vitro, as well as in an in vivo model of muscle regeneration. Immunohistochemistry and immunofluorescence, RT-PCR and shRNA silencing techniques were used to determine the role of PKCε and HMGA1 in myogenic differentiation. RESULTS: PKCε expression increases and subsequently re-localizes to the nucleus during skeletal muscle cell differentiation. In the nucleus, PKCε blocks Hmga1 expression to promote Myogenin and Mrf4 accumulation and myoblast formation. Following in vivo muscle injury, PKCε accumulates in regenerating, centrally-nucleated myofibers. Pharmacological inhibition of PKCε impairs the expression of two crucial markers of muscle differentiation, namely MyoD and Myogenin, during injury induced muscle regeneration. CONCLUSION: This work identifies the PKCε-HMGA1 signaling axis as a positive regulator of skeletal muscle differentiation.

Fetal sex and the circulating renin-angiotensin system during early gestation in women who later develop preeclampsia or gestational hypertension.

There are fetal sex-specific differences in the balance between angiotensin (Ang) II and Ang-(1-7) in the maternal circulation during pregnancy. To determine whether at 15 weeks' gestation plasma levels of Ang II and Ang-(1-7), as well as levels of prorenin and Ang-converting enzyme (ACE), predicted the development of gestational hypertension (GH) or preeclampsia (PreE) and were associated with estimates of fetal and maternal health, women who later developed GH (n=50) or PreE (n=50) were compared with body mass index-matched controls (n=100). Women who subsequently developed PreE or GH had increased Ang-(1-7) levels at 15 weeks' gestation compared with women with normal pregnancies. When separated by fetal sex, this difference was seen only in women carrying a female fetus. Prorenin and ACE concentrations were not useful biomarkers for the prediction of either PreE or GH at 15 weeks' gestation. Women with a male fetus who developed PreE and women who subsequently developed GH had increased blood pressures at 15 weeks' gestation compared with women with normal pregnancies, suggesting that these women were on an early trajectory for the development of hypertension. We propose that measurement of Ang-(1-7) during early gestation could be useful in predicting, those women who will go on to develop new-onset hypertension in pregnancy.

Staff and relatives' perspectives on the aggressive behaviour of older people with dementia in residential care: a qualitative study.

Staff and relative perspectives on patient aggression in dementia care units are seriously under researched in the U.K. Any work that has been conducted has relied upon quantitative studies. Qualitative research on aggression management in older peoples services are rare. In-depth views that can offer insights into causation and management strategies are therefore under represented in the literature. In order to investigate this issue further we interviewed a number of nursing staff and relatives in four U.K. care homes in the North West of England. Using a combined approach of one-to-one interviews (for staff) and focus groups (for relatives) we explored their views as to the reasons for and ways of responding to aggressive behaviour. This was part of a larger study reported upon elsewhere. Using thematic analysis we found similar results from both staff and relatives and as such their views were categorized into two broad areas: causation and management. In regards to causation we noted three sub-themes; internal, external and interpersonal factors which are further subdivided in the paper and for management two broad categories: the compassionate approach and 'don't go in strong'. The results indicated that staff in the participating units embraced a person-centred approach to aggression management. They predominantly respond to aggressive incidents with interpersonal strategies, such as distraction as opposed to medication or restraint. Overall they adopt a person centre approach to patient care. Relatives were clear in their perceptions of aggression as an interpersonal challenge, which is compounded or mediated by the illness of dementia. Consequently they were positive in their views of staff using non-coercive interventions. While the results of this and our earlier study are promising suggesting a less invasive approach to this aspect of dementia care, given the limitations of a small sample, more research of a similar nature is warranted. Findings from multidimensional studies can then provide a sounder basis for health and social care education, and person centred informed practice to reduce the incidence of aggression through preventative strategies.

The p53 family and programmed cell death.

The p53 tumor suppressor continues to hold distinction as the most frequently mutated gene in human cancer. The ability of p53 to induce programmed cell death, or apoptosis, of cells exposed to environmental or oncogenic stress constitutes a major pathway whereby p53 exerts its tumor suppressor function. In the past decade, we have discovered that p53 is not alone in its mission to destroy damaged or aberrantly proliferating cells: it has two homologs, p63 and p73, that in various cellular contexts and stresses contribute to this process. In this review, the mechanisms whereby p53, and in some cases p63 and p73, induce apoptosis are discussed. Other reviews have focused more extensively on the contribution of individual p53-regulated genes to apoptosis induction by this protein, whereas in this review, we focus more on those factors that mediate the decision between growth arrest and apoptosis by p53, p63 and p73, and on the post-translational modifications and protein-protein interactions that influence this decision.

Hereditary neuropathy with liability to pressure palsies: description of seven patients without known family history.

OBJECTIVES: Hereditary neuropathy with liability to pressure palsies (HNPP) is an inherited disorder resulting in a polyneuropathy with particular involvement at sites of entrapment, and is often underdiagnosed or misdiagnosed. We report findings on seven patients referred for evaluation of focal mononeuropathies or polyneuropathies of undetermined etiology, in whom we established a diagnosis of HNPP. MATERIALS AND METHODS: We retrospectively reviewed clinical, electrophysiological and laboratory data for patients diagnosed with HNPP over a 4-year period at our institution. RESULTS: All patients had transient or recurrent neurological symptoms, some with residual deficits. No patients had a family history of any neuropathy. Electrodiagnostic studies revealed abnormal conduction findings at symptomatic and asymptomatic sites. Testing for the Peripheral Myelin Protein (PMP22) deletion was positive in all patients. CONCLUSIONS: A high index of clinical suspicion and thorough electrodiagnostic evaluation can lead to correct diagnosis of HNPP, despite the absence of a positive family history.

Sequence analysis of a 101-kilobase plasmid required for agar degradation by a Microscilla isolate.

An agar-degrading marine bacterium identified as a Microscilla species was isolated from coastal California marine sediment. This organism harbored a single 101-kb circular DNA plasmid designated pSD15. The complete nucleotide sequence of pSD15 was obtained, and sequence analysis indicated a number of genes putatively encoding a variety of enzymes involved in polysaccharide utilization. The most striking feature was the occurrence of five putative agarase genes. Loss of the plasmid, which occurred at a surprisingly high frequency, was associated with loss of agarase activity, supporting the sequence analysis results.

Reducing nosocomial pressure ulcers in an acute care facility.

In 1996, a nursing committee at an acute care facility organized the first pressure ulcer point prevalence survey for that hospital. In 1996, hospital-acquired pressure ulcers were 90 percent of the predicted prevalence rate; in 1997, the rate dropped to 59 percent of the predicted prevalence and in 1998, to 53 percent of the predicted prevalence. The severity index decreased markedly from 291 (1996) to 98 (1997) then to 62 (1998). These improvements are attributed to the purposeful addition of multidimensional interventions, including best practices and research-based protocols, to prevent and treat nosocomial pressure ulcers.

The impact of maternal serum screening on the birth prevalence of Down's syndrome and the use of amniocentesis and chorionic villus sampling in South Australia.

OBJECTIVES: To describe the impact of maternal serum screening on the birth prevalence of Down's syndrome and on the use of amniocentesis and chorionic villus sampling in South Australia. DESIGN: A descriptive population-based study. SETTING: South Australia (population 1.48 million persons; approximately 20,000 births per year). PARTICIPANTS: Women who had births or terminations of pregnancy with Down's syndrome in 1982-1996, women who had maternal serum screening in 1991-1996, amniocentesis or chorionic villus sampling in 1986-1996. METHODS: Analysis of data from multiple sources on maternal serum screening, amniocentesis and chorionic villus sampling, births and terminations of pregnancy. MAIN OUTCOME MEASURES: Total prevalence and birth prevalence of Down's syndrome each year in 1982-1996; proportion of pregnant women using maternal serum screening in 1991-1996, and proportion using amniocentesis and chorionic villus sampling by indication in 1986-1996, by age group. RESULTS: Use of maternal serum screening for Down's syndrome increased from 17% when introduced in 1991 to 76% of women who gave birth in 1996. Between 1982 and 1986 and 1996, terminations of pregnancy for fetal Down's syndrome increased from 7.1 % to 75% and the birth prevalence of Down's syndrome fell by 60% from 1.05 to 0.42 per 1,000 births, against the background of an increase in total prevalence due to increasing maternal age. The use of amniocentesis increased from 5.8% in 1991 to 10.1% in 1996 mainly due to the increase among women younger than 35 years with maternal serum screening as the main reason. The increasing chorionic villus sampling rate among younger women stabilised at 0.4%, while the rate among older women decreased from 11.0% to 7.4%. CONCLUSIONS: The introduction of maternal serum screening in South Australia has resulted in increased use of any prenatal testing for Down's syndrome from about 7% (mainly older women having amniocentesis or chorionic villus sampling) to 84% of women (about 8% having direct amniocentesis or chorionic villus sampling and 76% having maternal serum screening first). This has resulted in a significant fall in the birth prevalence of Down's syndrome. maternal serum screening was the first indication of Down's syndrome for about half the terminations of pregnancy for Down's syndrome in 1993-1996, including three quarters of those in younger women.

Treatment of a patient by vaccination with autologous dendritic cells pulsed with allogeneic major histocompatibility complex class I-matched tumor peptides. Case Report.

Dendritic cells (DCs) are antigen-presenting cells that play a central role in the initiation and modulation of antitumor immune responses. In this pilot study, we investigated the ability of autologous DCs pulsed ex vivo with allogeneic major histocompatibility complex class I-matched glioblastoma peptides to stimulate host antitumor immune responses when injected as a vaccine. A patient with recurrent brainstem glioblastoma multiforme (GBM) received a series of three intradermal immunizations of antigen-pulsed DCs on an outpatient basis following surgical debulking of her posterior fossa tumor. Dendritic cell vaccination was well tolerated, and no clinical signs of autoimmunity or experimental allergic encephalomyelitis were detected. She developed a measurable cellular immune response against the allogeneic glioblastoma peptides used in her vaccine preparation, as demonstrated by in vitro T-cell proliferation assays. In addition, increased T-cell infiltration was noted within the intracranial tumor site in the biopsy sample obtained following DC vaccination. An objective clinical response, however, was not evident, and this patient eventually died 21 months after her disease was diagnosed. To our knowledge, this is the first patient with brain cancer ever to be treated with DC-based immunotherapy. This case illustrates that vaccination with DCs pulsed with acid-eluted glioblastoma peptides is feasible and can induce systemic antigen-specific immunity in a patient with recurrent GBM. Additional studies are necessary to determine the optimum DC doses and antigen loading conditions that may translate into clinical effectiveness and survival benefit for patients with brain tumors. Phase I trials for malignant glioma are currently underway.

Medullary lateral tegmental field: an important synaptic relay in the baroreceptor reflex pathway of the cat.

This study was designed to test the hypothesis that the medullary lateral tegmental field (LTF) is an important synaptic relay in the baroreceptor reflex pathway controlling sympathetic nerve discharge (SND) of urethan-anesthetized cats. We determined the effects of blockade of excitatory amino acid-mediated neurotransmission in the LTF on three indexes of baroreceptor reflex function: cardiac-related power in SND, strength of linear correlation (coherence value) of SND to the arterial pulse (AP), and inhibition of SND during increased arterial pressure produced by abrupt obstruction of the abdominal aorta. Bilateral microinjection of D-(-)-2-amino-5-phosphonopentanoic acid, an N-methyl-D-aspartate (NMDA) receptor antagonist, abolished cardiac-related power and coherence of SND to the AP, and it prevented inhibition of SND during aortic obstruction. These data support the view that NMDA receptor-mediated neurotransmission in the LTF is critical for baroreceptor reflex control of SND. Bilateral microinjection of 1,2, 3,4-tetrahydro-6-nitro-2,3-dioxobenzo-[f]-quinoxaline-7-sulfonamid e, a non-NMDA receptor antagonist, decreased cardiac-related power and total power in the 0- to 6-Hz band of SND; however, the AP-SND coherence value remained high, and inhibition of SND during aortic obstruction was preserved. These data imply that non-NMDA receptor-mediated neurotransmission in the LTF is involved in setting the level of excitatory drive to sympathetic nerves.

Haemophilus influenzae associated scleritis.

AIMS: To describe the clinical course and treatment of Haemophilus influenzae associated scleritis. METHODS: Retrospective case series. RESULTS: Three patients developed scleritis associated with ocular H influenzae infection. Past medical history, review of systems, and laboratory testing for underlying collagen vascular disorders were negative in two patients. One patient had arthritis associated with an antinuclear antibody titre of 1:160 and a Westergren erythrocyte sedimentation rate of 83 mm in the first hour. Each patient had ocular surgery more than 6 months before developing scleritis. Two had cataract extraction and one had strabismus surgery. Nodular abscesses associated with areas of scleral necrosis were present in each case. Culture of these abscesses revealed H influenzae in all patients. Treatments included topical, subconjunctival, and systemic antibiotics. Scleral inflammation resolved and visual acuity improved in each case. CONCLUSION: H influenzae infection may be associated with scleritis. Accurate diagnosis and treatment may preserve ocular integrity and good visual acuity.

Treatment of intracranial gliomas with bone marrow-derived dendritic cells pulsed with tumor antigens.

OBJECT: An approach toward the treatment of intracranial gliomas was developed in a rat experimental model. The authors investigated the ability of "professional" antigen-presenting cells (dendritic cells) to enhance host antitumor immune responses when injected as a vaccine into tumor-bearing animals. METHODS: Dendritic cells, the most potent antigen-presenting cells in the body, were isolated from rat bone marrow precursors stimulated in vitro with granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-4. Cultured cell populations were confirmed to be functional antigen-presenting cells on the basis of expressed major histocompatibility molecules, as analyzed by fluorescence-activated cell sorter cytofluorography. These dendritic cells were then pulsed (cocultured) ex vivo with acid-eluted tumor antigens from 9L glioma cells. Thirty-eight adult female Fischer 344 rats harboring 7-day-old intracranial 9L tumors were treated with three weekly subcutaneous injections of either control media (10 animals), unpulsed dendritic cells (six animals), dendritic cells pulsed with peptides extracted from normal rat astrocytes (10 animals), or 9L tumor antigen-pulsed dendritic cells (12 animals). The animals were followed for survival. At necropsy, the rat brains were removed and examined histologically, and spleens were harvested for cell-mediated cytotoxicity assays. The results indicate that tumor peptide-pulsed dendritic cell therapy led to prolonged survival in rats with established intracranial 9L tumors implanted 7 days prior to the initiation of vaccine therapy in vivo. Immunohistochemical analyses were used to document a significantly increased perilesional and intratumoral infiltration of CD8+ and CD4+ T cells in the groups treated with tumor antigen-pulsed dendritic cells compared with the control groups. In addition, the results of in vitro cytotoxicity assays suggest that vaccination with these peptide-pulsed dendritic cells can induce specific cytotoxic T lymphocytes against 9L tumor cells. CONCLUSIONS: Based on these results, dendritic antigen-presenting cells pulsed with acid-eluted peptides derived from autologous tumors represent a promising approach to the immunotherapy of established intracranial gliomas. which may serve as a basis for designing clinical trials in patients with brain tumors.

Cystoid macular edema associated with cytomegalovirus retinitis in patients with the acquired immunodeficiency syndrome.

PURPOSE: To describe the clinical and fluorescein angiographic appearance of cystoid macular edema associated with cytomegalovirus retinitis in patients with the acquired immunodeficiency syndrome (AIDS). METHODS: We retrospectively examined the clinical and photographic records of four patients with AIDS and cytomegalovirus retinitis who developed cystoid macular edema. RESULTS: Seven eyes of four patients with AIDS and cytomegalovirus retinitis experienced decreased vision associated with cystoid macular edema. Vitreous inflammation was mild in each patient. In all eyes, the retinitis involved zone 1, and in all but one eye, the cytomegalovirus retinitis was inactive. In one eye, the cystoid macular edema was worsened by formation of a dense juxtafoveal epiretinal membrane. CONCLUSIONS: Although infrequently recognized, cystoid macular edema can cause visual loss in patients with AIDS and cytomegalovirus retinitis. Fluorescein angiography should be considered in any patient with cytomegalovirus retinitis and unexplained visual loss.