'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.

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.

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.

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.

Damage to the monkey retina by broad-spectrum fluorescent light.

Adult rhesus and pigtail monkeys were exposed to a uniform field of light from daylight fluorescent lamps to determine the initial site and characteristics of structural retinal damage induced by continuous exposure and the threshold intensity required to produce the effects. Electron microscopic examination revealed that the initial site of damage is the photoreceptor outer segments. Damage remained restricted to the outer segments at intensities as high as 24,700 lux and with 12 hr exposure periods repeated for up to 4 days. Rods were swollen at the distal tip and showed disc membrane separation. Come outer segments were affected at the proximal end with vesiculation and membrane rearrangement. The threshold intensity for morphological changes to comes in the macula for a single 12 hr exposure was between 195 and 361 mu W/cm2 at the retina (400 to 700 mm; uncorrected for ocular transmittance), whereas the threshold for changes in rods was higher, at between 361 and 615 mu W/cm2. These levels correspond to between 5900 and 10,800 lux (550 to 1000 ft-cd) for comes and 10,800 to 19,400 lux (1000 to 1800 ft-cd) for rods of monkeys with fully dilated pupils. The paramacular areas of the retina were less sensitive to damage than macular areas of the same animal. No paramacular changes were observed in animals exposed to 10,800 lux or less. The patched (control) eyes of each monkey remained structurally normal in both the macula and paramacula at all exposure levels. These results demonstrate the sensitivity of the adult primate retina to damage by relatively moderate levels of light.

Evidence for preferential stimulation of gastric inhibitory polypeptide secretion in the rat by actively transported carbohydrates and their analogues.

A rat intestinal perfusion technique has been used to assess the ability of a number of monosaccharides, monosaccharide analogues and disaccharides to stimulate intestinal release of immunoreactive gastric inhibitory polypeptide (GIP). Perfusates containing glucose, sucrose, galactose, maltose, 3-O-methylglucose or alpha- or beta- methylglucoside at concentrations of 100 mmol/l in Krebs-Ringer phosphate buffer (KRP) produced significant stimulation of GIP release compared with the control perfusions with KRP alone (P less than 0.02). Mannose, 6-deoxygalactose, 2-deoxyglucose, myoinositol, fructose or lactose (100 mmol/l of each) did not stimulate GIP release compared with controls. There was no significant difference in the ability of sucrose, maltose or beta-methylglucoside (100 mmol/l of ach) to release GIP compared with 100 mmol glucose/l, but galactose, 3-O-methylglucose and alpha-methylglucoside (100 mmol/l of each) produced significantly lower GIP responses than did glucose (P less than 0.02). Addition of 5 mmol phloridzin/l to a perfusate containing 50 mmol glucose/l prevented intestinal absorption of glucose and abolished the GIP response. The molecular configuration of monosaccharides which have the ability to stimulate GIP release agreed well with the structural requirements for active transport by the sodium-dependent hexose pathway.

Evidence for a dose-dependent inflammatory response to quartz in the rat lung and its significance in early changes in collagen metabolism.

The response of the rat lung to a range of doses of quartz at 50 and 100 days after its administration by intratracheal instillation has been assessed by bronchopulmonary lavage. The effects on the number of polymorphonuclear leukocytes (PMN), lymphocytes and macrophages are described. In addition the concentrations of soluble protein and hydroxyproline and the activities of lactate dehydrogenase, PZ peptidase and collagenase in lavage fluid supernatants were measured and an assessment of the hydroxyproline content of recovered cells was made. Finally PZ peptidase and collagenase were assayed in PMN-enriched cell fractions and in samples obtained from short-term culture of recovered macrophages. There was a dose-dependent increase in the recovery of all three cell types, and in the amounts of lactate dehydrogenase, protein and hydroxyproline in lavage fluids, which showed no signs of resolution over the 100-day period studied. Measurements of PZ peptidase and collagenase suggested that the PMN, not the macrophages, are the major source of these degradative enzymes. The relevance of these findings with regard to the importance of PMN in quartz-induced fibrosis is discussed.

The advantages and limitations of an in vivo test system for investigating the cytotoxicity and fibrogenicity of fibrous dusts.

The acute response of the rat lung to a range of fibrous materials has been investigated by bronchopulmonary lavage, at dose levels of 0.5 and 1.0 mg, 1 and 7 days after their administration by intratracheal instillation. The materials chosen for study included UICC chrysotile A, amosite, crocidolite and anthophyllite, and samples of S. African "long" amosite and glass fiber. In addition, the subacute response to 1, 2 and 3 mg of chrysotile and amosite has been studied at 50 and 100 days after instillation. In the acute phase at 1 day after instillation, the response to chrysotile was greater than that to any of the other materials, but by 7 days there was no gradation in the response to different dusts. In the subacute phase, cell recoveries were low, and it was not possible to assess the long-term cytotoxic or fibrogenic effects of amosite and chrysotile by analyses of lung washes, even though biochemical and histological methods indicated gross changes in lung pathology.

Detecting recurrent choroidal neovascularization. Comparison of clinical examination with and without fluorescein angiography.

OBJECTIVE/DESIGN: To evaluate prospectively the ability of three retina specialists to detect recurrent choroidal neovascularization (CNV) after clinical examination alone and then with fluorescein angiography at 3 and 6 weeks and at 3, 6, 9, and 12 months after laser photocoagulation. SETTING: Single tertiary retinal referral center. PATIENTS: All patients who had laser treatment for CNV within 14 months of their study visit. One hundred thirty-seven eyes of 134 patients were evaluated during 401 visits. MAIN OUTCOME MEASURES: Sensitivity, specificity, positive predictive value, and negative predictive value of clinical examination with biomicroscopy to detect recurrent CNV when defined as leakage on the periphery of the laser-treated area on the fluorescein angiogram. RESULTS: Ninety-seven definite or probable recurrences in 56 eyes were identified on the fluorescein angiogram. Clinical examination had a sensitivity of 59%, specificity of 94%, positive predictive value of 76%, and negative predictive value of 88%. These figures varied somewhat by underlying cause, age, time since treatment, and lesion location. Using either a reported or measured loss of vision with the results of biomicroscopy as an indication of recurrence increased the sensitivity to 77% but reduced the specificity to 81%. CONCLUSIONS: Clinical examination probably cannot replace fluorescein angiography in detecting all recurrent CNV after laser treatment. However, for follow-up visits in which recurrent CNV was not suspected on biomicroscopy, definite or questionable recurrent CNV was identified on the fluorescein angiogram only 12% of the time, while the absence of recurrent CNV using this method was confirmed 88% of the time.

Exogenous control of the cycle simplifies thawed embryo transfer and results in a pregnancy rate similar to that for natural cycles.

To determine if a satisfactory PR could be achieved in thawed ET using a simplified protocol, standard monitoring in the natural cycle was compared with a controlled preparation of the endometrium with exogenous E2 and P without hormonal or ultrasonographic monitoring. All patients had normal ovarian function, and no GnRH-a were administered. Pregnancy rates, ongoing PRs, and embryo implantation rates were similar in the two groups. The use of exogenous E2 and P without GnRH-a suppression to control the cycle for thaw ET is safe, convenient, and results in PRs at least as good as in the natural cycle. It may be of particular value in patients with an irregular cycle or in those for whom prolonged monitoring is undesirable.

Factors predicting outcome in 215 consecutive thawed embryo replacements.

This retrospective study was undertaken to determine which factors were associated with outcome in thawed embryo replacement cycles. The number of embryos replaced and the response to exogenous ovarian stimulation in the original IVF cycle were significantly associated with the conception rate.

Multimeric analysis of von Willebrand factor by molecular sieving electrophoresis in sodium dodecyl sulphate agarose gel.

We report the development and optimisation of an agarose gel electrophoretic method for the separation and detection of von Willebrand Factor (vWF) multimers. The method has been specifically developed for use in the clinical evaluation and classification of patients with von Willebrand's Disease (vWD) and clearly shows structural multimer abnormalities associated with the bleeding diathesis of this inherited bleeding disorder.

von Willebrand factor characterization of a severe dry-heat treated factor VIII concentrate, AHF (high purity).

Eight batches of a severe dry-heat treated (80 degrees C for 72 hours) Factor VIII concentrate manufactured by the Commonwealth Serum Laboratories (CSL Ltd.) were analysed for the following von Willebrand factor-related (vWf) activities: ristocetin cofactor activity (vWf:RCof), collagen binding activity (CBA), vWf antigen levels (vWf:Ag), vWf multimeric analysis and 2-stage FVIII clotting activity (VIII:C). The average potency per vial of vWf:Ag was 440 +/- 80 units, vWf:RCof 500 +/- 60 units, CBA 350 +/- 50 units and VIII:C 242 +/- 36 International Units. Multimeric analysis indicated the presence of high molecular weight multimers and a triplet structure slightly different to normal plasma. Viral inactivation studies using a marker virus, Sindbis, demonstrated that the terminal severe dry- heating step reduced the viral load in the product by greater than 6 log10TCID50/ml. This CSL Ltd. FVIII concentrate may thus provide a safer, purer and more convenient source of vWf than cryoprecipitate. Clinical studies to establish product efficacy in patients with von Willebrand's disease are underway.

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.

Electroradioimmunoassay: a sensitive method for the quantitation of alpha-fetoprotein.

A sensitive technique, electroradioimmunoassay has been adapted for the estimation of alpha1-fetoprotein in normal adult human plasma and serum. Commercially available antisera were used and a 10-fold increase in sensitivity was obtained in comparison with two conventional radioimmunoassays. Plasma alpha 1-fetoprotein levels of 2.6 +/- 1.2 microgram/1 (mean and standard deviation) were found in a normal population as compared with levels of 4.1 +/- 2.6 microgram/l in a group of 49 patients with alcoholic liver disease.

Photoaging effects on spectral transmittance of plastic filters.

We examined the effects of ultraviolet (UV) radiation in combination with high levels of infrared (IR) radiation on the spectral transmittance of plastic filters. The biological action spectrum for damage to the human eye and skin changes dramatically in the 300-400 nm wavelength range. Cut-off filters used in this region to shape the spectrum of exposure sources are thus critical to the design of experiments which use broadband light sources. The changes in transmittance of three types of plastic filters were observed over an exposure period of 1000 h. One set of three filters was exposed mainly to UV radiation, while the other set was exposed to UV radiation plus IR radiation. Filters exposed to both UV and IR radiation showed spectral changes in their transmittance, while the filters exposed to UV only showed no measurable changes.

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.