Investigating local policy drivers for alcohol harm prevention: a comparative case study of two local authorities in England

Background: The considerable challenges associated with implementing national level alcohol policies have encouraged a renewed focus on the prospects for local-level policies in the UK and elsewhere. We adopted a case study approach to identify the major characteristics and drivers of differences in the patterns of local alcohol policies and services in two contrasting local authority (LA) areas in England. Methods: Data were collected via thirteen semi-structured interviews with key informants (including public health, licensing and trading standards) and documentary analysis, including harm reduction strategies and statements of licensing policy. A two-stage thematic analysis was used to categorize all relevant statements into seven over-arching themes, by which document sources were then also analysed. Results: Three of the seven over-arching themes (drink environment, treatment services and barriers and facilitators), provided for the most explanatory detail informing the contrasting policy responses of the two LAs: LA1 pursued a risk-informed strategy via a specialist police team working proactively with problem premises and screening systematically to identify riskier drinking. LA2 adopted a more upstream regulatory approach around restrictions on availability with less emphasis on co-ordinated screening and treatment measures. Conclusion: New powers over alcohol policy for LAs in England can produce markedly different policies for reducing alcohol-related harm. These difference are rooted in economic, opportunistic, organisational and personnel factors particular to the LAs themselves and may lead to closely tailored solutions in some policy areas and poorer co-ordination and attention in others

Dual mechanism of daunorubicin-induced cell death in both sensitive and MDR-resistant HL-60 cells

Exposure of some acute myeloid leukaemia (AML) cells to daunorubicin leads to rapid cell death, whereas other AML cells show natural drug resistance. This has been attributed to expression of functional P-glycoprotein resulting in reduced drug accumulation. However, it has also been proposed that P-glycoprotein-expressing multidrug-resistant (MDR) cells are inherently defective for apoptosis. To distinguish between these different possibilities, we have compared the cell death process in a human AML cell line (HL-60) with a MDR subline (HL-60/Vinc) at doses that yield either similar intracellular daunorubicin concentrations or comparable cytotoxicity. Adjustment of the dose to obtain the same intracellular drug accumulation in the two cell lines did not result in equal cytotoxicity, suggesting the presence of additional resistance mechanisms in the P-glycoprotein-expressing HL-60/Vinc cells. However, at equitoxic doses, similar cell death pathways were observed. In HL-60 cells, daunorubicin induced rapid apoptosis at 0.5–1 μM and delayed mitotic cell death at 0.1 μM. These concentrations are within the clinical dose range. Similarly, HL-60/Vinc cells underwent apoptosis at 50–100 μM daunorubicin and mitotic cell death at 10 μM. These results show, for the first time, that anthracyclines can induce cell death by a dual mechanism in both sensitive and MDR cells. Our results also show that not only the cytotoxicity, but also the kinetics and mechanism of cell death, are dose dependent. Interestingly, regrowth was observed only in association with delayed cell death and the formation of enlarged, often polyploid, cells with micronucleation, suggesting that morphological criteria may be useful to evaluate treatment efficacy in patients with myeloid leukaemias. © 1999 Cancer Research Campaig

Promoter Methylation in Head and Neck Squamous Cell Carcinoma Cell Lines Is Significantly Different than Methylation in Primary Tumors and Xenografts

Studies designed to identify novel methylation events related to cancer often employ cancer cell lines in the discovery phase of the experiments and have a relatively low rate of discovery of cancer-related methylation events. An alternative algorithm for discovery of novel methylation in cancer uses primary tumor-derived xenografts instead of cell lines as the primary source of nucleic acid for evaluation. We evaluated DNA extracted from primary head and neck squamous cell carcinomas (HNSCC), xenografts grown from these primary tumors in nude mice, HNSCC-derived cell lines, normal oral mucosal samples, and minimally transformed oral keratinocyte-derived cell lines using Illumina Infinum Humanmethylation 27 genome-wide methylation microarrays. We found >2,200 statistically significant methylation differences between cancer cell lines and primary tumors and when comparing normal oral mucosa to keratinocyte cell lines. We found no statistically significant promoter methylation differences between primary tumor xenografts and primary tumors. This study demonstrates that tumor-derived xenografts are highly accurate representations of promoter methylation in primary tumors and that cancer derived cell lines have significant drawbacks for discovery of promoter methylation alterations in primary tumors. These findings also support use of primary tumor xenografts for the study of methylation in cancer, drug discovery, and the development of personalized cancer treatments

Preclinical efficacy of azacitidine and venetoclax for infant KMT2A-rearranged acute lymphoblastic leukemia reveals a new therapeutic strategy

Infants with KMT2A-rearranged B-cell acute lymphoblastic leukemia (ALL) have a dismal prognosis. Survival outcomes have remained static in recent decades despite treatment intensification and novel therapies are urgently required. KMT2A-rearranged infant ALL cells are characterized by an abundance of promoter hypermethylation and exhibit high BCL-2 expression, highlighting potential for therapeutic targeting. Here, we show that hypomethylating agents exhibit in vitro additivity when combined with most conventional chemotherapeutic agents. However, in a subset of samples an antagonistic effect was seen between several agents. This was most evident when hypomethylating agents were combined with methotrexate, with upregulation of ATP-binding cassette transporters identified as a potential mechanism. Single agent treatment with azacitidine and decitabine significantly prolonged in vivo survival in KMT2A-rearranged infant ALL xenografts. Treatment of KMT2A-rearranged infant ALL cell lines with azacitidine and decitabine led to differential genome-wide DNA methylation, changes in gene expression and thermal proteome profiling revealed the target protein-binding landscape of these agents. The selective BCL-2 inhibitor, venetoclax, exhibited in vitro additivity in combination with hypomethylating or conventional chemotherapeutic agents. The addition of venetoclax to azacitidine resulted in a significant in vivo survival advantage indicating the therapeutic potential of this combination to improve outcome for infants with KMT2A-rearranged ALL

Impact Factor: outdated artefact or stepping-stone to journal certification?

A review of Garfield's journal impact factor and its specific implementation as the Thomson Reuters Impact Factor reveals several weaknesses in this commonly-used indicator of journal standing. Key limitations include the mismatch between citing and cited documents, the deceptive display of three decimals that belies the real precision, and the absence of confidence intervals. These are minor issues that are easily amended and should be corrected, but more substantive improvements are needed. There are indications that the scientific community seeks and needs better certification of journal procedures to improve the quality of published science. Comprehensive certification of editorial and review procedures could help ensure adequate procedures to detect duplicate and fraudulent submissions.Comment: 25 pages, 12 figures, 6 table

Spectra of Heliumlike Krypton From Tokamak Fusion Test Reactor Plasmas

Krypton has been injected into ohmically-heated TFTR plasmas with peak electron temperatures of 6 key to study the effects of krypton on the plasma performance and to investigate the emitted krypton line radiation, which is of interest for future-generation tokamaks such as ITER, both as a diagnostic of the central ion temperature and for the control of energy release from the plasma by radiative cooling. The emitted radiation was monitored with a bolometer array, an X-ray pulse height analysis system, and a high-resolution Johann-type crystal spectrometer; and it was found to depend very sensitively on the electron temperature profile. Satellite spectra of heliumlike krypton, KrXXXV, near 0.95 [Angstrom] including lithiumlike, berylliumlike and boronlike features were recorded in second order Bragg reflection. Radiative cooling and reduced particle recycling at the plasma edge region were observed as a result of the krypton injection for all investigated discharges. The observations are in reasonable agreement with modeling calculations of the krypton ion charge state distribution including radial transport

‘Maintaining balance and harmony’: Javanese perceptions of health and cardiovascular disease

Community intervention programmes to reduce cardiovascular disease (CVD) risk factors within urban communities in developing countries are rare. One possible explanation is the difficulty of designing an intervention that corresponds to the local context and culture

"I should live and finish it": A qualitative inquiry into Turkish women's menopause experience

<p>Abstract</p> <p>Background</p> <p>While bio-medically, menopause could be treated as an illness, from a psychosocial and cultural perspective it could be seen as a "natural" process without requiring medication unless severe symptoms are present.</p> <p>Our objective is to explore the perceptions of Turkish women regarding menopause and Hormone Therapy (HT) to provide health care workers with an insight into the needs and expectations of postmenopausal women.</p> <p>Methods</p> <p>A qualitative inquiry through semi-structured, in-depth interviews was used to explore the study questions. We used a purposive sampling and included an equal number of participants who complained about the climacteric symptoms and those who visited the outpatient department for a problem other than climacteric symptoms but when asked declared that they had been experiencing climacteric symptoms. The interview questions focused on two areas; 1) knowledge, experiences, attitudes and beliefs about menopause and; 2) menopause-related experiences and ways to cope with menopause and perception of HT.</p> <p>Results</p> <p>Most of the participants defined menopause as a natural transition process that one should go through. Cleanliness, maturity, comfort of not having a period and positive changes in health behaviour were the concepts positively attributed to menopause, whereas hot flushes, getting old and difficulties in relationships were the negatives. Osteoporosis was an important concern for most of the participants. To deal with the symptoms, the non-pharmacological options were mostly favoured.</p> <p>Conclusion</p> <p>To our knowledge, this is the first qualitative study which focuses on Turkish women's menopausal experiences. Menopause was thought to be a natural process which was characterised by positive and negative features. Understanding these features and their implications in these women's lives may assist healthcare workers in helping their clients with menopause.</p

SIV Nef Proteins Recruit the AP-2 Complex to Antagonize Tetherin and Facilitate Virion Release

Lentiviral Nef proteins have multiple functions and are important for viral pathogenesis. Recently, Nef proteins from many simian immunodefiency viruses were shown to antagonize a cellular antiviral protein, named Tetherin, that blocks release of viral particles from the cell surface. However, the mechanism by which Nef antagonizes Tetherin is unknown. Here, using related Nef proteins that differ in their ability to antagonize Tetherin, we identify three amino-acids in the C-terminal domain of Nef that are critical specifically for its ability to antagonize Tetherin. Additionally, divergent Nef proteins bind to the AP-2 clathrin adaptor complex, and we show that residues important for this interaction are required for Tetherin antagonism, downregulation of Tetherin from the cell surface and removal of Tetherin from sites of particle assembly. Accordingly, depletion of AP-2 using RNA interference impairs the ability of Nef to antagonize Tetherin, demonstrating that AP-2 recruitment is required for Nef proteins to counteract this antiviral protein

Emerging Synergisms Between Drugs and Physiologically-Patterned Weak Magnetic Fields: Implications for Neuropharmacology and the Human Population in the Twenty-First Century

Synergisms between pharmacological agents and endogenous neurotransmitters are familiar and frequent. The present review describes the experimental evidence for interactions between neuropharmacological compounds and the classes of weak magnetic fields that might be encountered in our daily environments. Whereas drugs mediate their effects through specific spatial (molecular) structures, magnetic fields mediate their effects through specific temporal patterns. Very weak (microT range) physiologically-patterned magnetic fields synergistically interact with drugs to strongly potentiate effects that have classically involved opiate, cholinergic, dopaminergic, serotonergic, and nitric oxide pathways. The combinations of the appropriately patterned magnetic fields and specific drugs can evoke changes that are several times larger than those evoked by the drugs alone. These novel synergisms provide a challenge for a future within an electromagnetic, technological world. They may also reveal fundamental, common physical mechanisms by which magnetic fields and chemical reactions affect the organism from the level of fundamental particles to the entire living system