Queensland Alcohol-related violence and Night-time Economy Monitoring (QUANTEM): Rationale and overview

This commentary introduces the special section on the outcomes of the Queensland Alcohol-related violence and Night-time Economy Monitoring project and outlines the political and policy context of the interventions put in place under the Queensland government's Tackling Alcohol-Fuelled Violence strategy. The development of the strategy was informed by alcohol policy initiatives trialled in other major Australian cities over the past two decades. The articles in this special section examine the impact of the Tackling Alcohol-Fuelled Violence policy stages on alcohol-related harms and local economies across selected entertainment precincts (Safe Night Precincts). A rich array of data were utilised, including administrative health and justice data, data reflective of nightlife trading (i.e. foot traffic data, ID scanner data and live music performances) and street surveys. Findings have implications for research, policy and practice and demonstrate the need for comprehensive evaluations that can accommodate the complexities of modern alcohol policy in Australia.     

Chronic BMY7378 treatment alters behavioral circadian rhythms

The mammalian circadian clock is synchronized to the day : night cycle by light. Serotonin modulates the circadian effects of light, with agonists inhibiting response to light and antagonists enhancing responses to light. A special class of serotonergic compounds, the mixed 5‐HT_1A agonist/antagonists, potentiates light‐induced phase advances by up to 400% when administered acutely. In this study, we examine the effects of one of these mixed 5‐HT_1A agonist/antagonists, BMY7378, when administered chronically. Thirty adult male hamsters were administered either vehicle or BMY7378 via surgically implanted osmotic mini pumps over a period of 28 days. In a light : dark cycle, chronic BMY7378 advanced the phase angle of entrainment, prolonged the duration of the active phase and attenuated the amplitude of the wheel‐running rhythm during the early night. In constant darkness, chronic treatment with BMY7378 significantly attenuated light‐induced phase advances, but had no significant effect on light‐induced phase delays. Non‐photic phase shifts to daytime administration of a 5‐HT_1A/7 agonist were also attenuated by chronic BMY7378 treatment. qRT‐PCR analysis revealed that chronic BMY7378 treatment upregulated mRNA for 5‐HT_1A and 5‐HT_1B receptors in the hypothalamus and downregulated mRNA for 5‐HT_1A and monoamine oxidase‐A in the brainstem. These results highlight adaptive changes of serotonin receptors in the brain to chronic treatment with BMY7378 and link such up‐ and downregulation to changes in important circadian parameters. Such long‐term changes to the circadian system should be considered when patients are treated chronically with drugs that alter serotonergic function.     

Neurotoxic injury pathways in differentiated mouse motor neuron-neuroblastoma hybrid (NSC-34D) cells in vitro--limited effect of riluzole on thapsigargin, but not staurosporine, hydrogen peroxide and homocysteine neurotoxicity

The neuroblastoma-spinal motor neuron fusion cell line, NSC-34, in its differentiated form, NSC-34D, permits examining the effects of riluzole, a proven treatment for amyotrophic lateral sclerosis (ALS) on cell death induction by staurosporine (STS), thapsigargin (Thaps), hydrogen peroxide (H₂O₂) and homocysteine (HCy). These neurotoxins, applied exogenously, have mechanisms of action related to the various proposed molecular pathogenetic pathways in ALS and are differentiated from endogenous cell death that is associated with cytoplasmic aggregate formation in motor neurons. Nuclear morphology, caspase-3/7 activation and high content imaging were used to assess toxicity of these neurotoxins with and without co-treatment with riluzole, a benzothiazole compound with multiple pharmacological actions. STS was the most potent neurotoxin at killing NSC-34D cells with a toxic concentration at which 50% of maximal cell death is achieved (TC₅₀ = 0.01 μM), followed by Thaps (TC₅₀ = 0.9 μM) and H₂O₂ (TC₅₀ = 15 μM) with HCy requiring higher concentrations to kill at the same level (TC₅₀ = 2200 μM). Riluzole provided neurorescue with a 20% absolute reduction (47.6% relative reduction) in apoptotic cell death against Thaps-induced NSC-34D cell (p ≤ 0.05), but had no effect on STS-, H₂O₂- and HCy-induced NSC-34D cell death. This effect of riluzole on Thaps induction of cell death was independent of caspase-3/7 activation. Riluzole mitigated a toxin that can cause intracellular calcium dysregulation associated with endoplasmic reticulum (ER) stress but not toxins associated with other cell death mechanisms.     

Characterization of Anti-Salmonella enterica Serotype Typhi Antibody Responses in Bacteremic Bangladeshi Patients by an Immunoaffinity Proteomics-Based Technology

Salmonella enterica serotype Typhi is the cause of typhoid fever and a human-restricted pathogen. Currently available typhoid vaccines provide 50 to 90% protection for 2 to 5 years, and available practical diagnostic assays to identify individuals with typhoid fever lack sensitivity and/or specificity. Identifying immunogenic S. Typhi antigens expressed during human infection could lead to improved diagnostic assays and vaccines. Here we describe a platform immunoaffinity proteomics-based technology (IPT) that involves the use of columns charged with IgG, IgM, or IgA antibody fractions recovered from humans bacteremic with S. Typhi to capture S. Typhi proteins that were subsequently identified by mass spectrometry. This screening tool identifies immunogenic proteins recognized by antibodies from infected hosts. Using this technology and the plasma of patients with S. Typhi bacteremia in Bangladesh, we identified 57 proteins of S. Typhi, including proteins known to be immunogenic (PagC, HlyE, OmpA, and GroEL) and a number of proteins present in the human-restricted serotypes S. Typhi and S. Paratyphi A but rarely found in broader-host-range Salmonella spp. (HlyE, CdtB, PltA, and STY1364). We categorized identified proteins into a number of major groupings, including those involved in energy metabolism, protein synthesis, iron homeostasis, and biosynthetic and metabolic functions and those predicted to localize to the outer membrane. We assessed systemic and mucosal anti-HlyE responses in S. Typhi-infected patients and detected anti-HlyE responses at the time of clinical presentation in patients but not in controls. These findings could assist in the development of improved diagnostic assays.Salmonella enterica serotype Typhi is a human-restricted pathogen that is the primary cause of enteric fever. It is estimated that S. Typhi infects over 20 million individuals and kills approximately 200,000 people globally each year (4). Currently, commercially available typhoid vaccines provide approximately 50 to 75% protection for 2 to 5 years (21), although an anti-typhoid Vi conjugate vaccine demonstrated 90% protection in 2- to 5-year-old children in a large field trial (23). Available and practical diagnostic tests for typhoid fever lack sensitivity and/or specificity (28). Identifying immunogenic S. Typhi antigens expressed during human infection could lead to improved diagnostic assays and vaccines.Infection with S. Typhi begins with the ingestion of contaminated water or food. The bacteria invade the gastrointestinal mucosa, translocate to the lymphoid follicles, where they survive and replicate within macrophages, and then disseminate via the bloodstream to the liver, spleen, and intestinal lymph nodes (14). The incubation period is typically 8 to 14 days (22), and symptoms include fever, abdominal pain, anorexia, weakness, potential complications of intestinal perforation, encephalopathy, and gastrointestinal bleeding (14, 34). Clinical studies demonstrate that S. Typhi infection stimulates both an intestinal mucosal and systemic humoral and cellular immune response (14, 34). S. Typhi is a facultative intracellular pathogen of macrophages, and both cellular and antibody-mediated immune responses are known to play roles in controlling and clearing S. Typhi infection (37). Despite this, there are limited data on antigen-specific cellular responses during wild-type S. Typhi infection in humans. Analyses of cellular immune responses during S. Typhi infection have largely used whole-cell preparations or flagellar antigens and have focused predominately on measuring immune responses in recipients of oral live attenuated typhoid vaccines, not in individuals with wild-type disease (24, 25, 40-42, 49).Antibody responses during wild-type infection have been better studied but have focused largely on a relatively small number of antigens, including O antigen (lipopolysaccharide [LPS]), H antigen (flagellar component), polysaccharide capsular antigen (Vi antigen), heat shock proteins such as GroEL, and outer membrane proteins such as OmpC and -F (13, 34). In addition, gut-derived IgA antibody-secreting cells that recognize LPS, a membrane preparation, or whole-killed S. Typhi organisms can be detected in the peripheral blood following natural S. Typhi infection or oral typhoid vaccination (16, 43, 50, 54). These cells eventually return home to the gastrointestinal mucosa, where they secrete secretory IgA antibody (36, 43).A number of immunoaffinity-based techniques that screen protein libraries of pathogens to identify immunogenic antigens have been developed (12, 17, 38), and we have previously reported using one such approach, in vivo-induced-antigen technology (IVIAT), to identify immunogenic S. Typhi antigens expressed during human infection (12). Another previously described technique, proteomics-based expression library screening (PELS), involves using antibody-charged columns to capture antigens produced by an Escherichia coli-based expression system containing an inducible library of a pathogen of interest, with subsequent elution and identification of bound proteins using mass spectrometric analysis (17). Here we describe using a modification of this approach that we have termed immunoaffinity proteomics-based technology (IPT). IPT involves directly screening the pathogen of interest using columns charged with IgG, IgM, or IgA antibody fractions recovered from the blood of infected humans. We applied IPT to S. Typhi to gain further insights into immunogenic antigens expressed in patients bacteremic with S. Typhi in Bangladesh.     

Multiple lipid scoring system for prediction of coronary heart disease risk: application to African Americans

BACKGROUND: Clinicians often obtain a panel of lipids but then only use low-density-lipoprotein (LDL) cholesterol to make clinical decisions. We previously described the multiple lipid measure, a strategy that integrates information about seven lipid measures. Our current inquiry uses the multiple lipid measure to create a scoring system and validates that system in a second cohort. METHODS AND RESULTS: A scoring system that uses total cholesterol, high-density lipoprotein (HDL) cholesterol, LDL cholesterol and triglycerides was developed and tested. African-American participants of the Atherosclerosis Risk in Communities (ARIC) Study were used to validate the multiple lipid measure score. For nonsmokers, scores > or = 2 had a hazard ratio of 4.25 (95% CI 1.92-9.40) compared to reference scores of < or = -3 in adjusted survival analysis predicting incident coronary heart disease risk in the ARIC. The best conventional single lipid measure for nonsmokers was LDL cholesterol. Compared to LDL cholesterol <100 mg/dl, those with LDL cholesterol > or = 160 mg/dl had a hazard ratio of 2.31 (95% CI 1.13-4.75). For current smokers, the best conventional lipid measure was the total cholesterol/HDL cholesterol ratio, which was similar in predictive ability to the multiple lipid measure score. However, the multiple lipid measure score predicted an additional 10% of the cohort at risk compared to the total cholesterol/HDL cholesterol ratio. CONCLUSIONS: The use of the multiple lipid scoring system improves the assessment of incident coronary heart disease risk and may have utility for clinicians in integrating lipid values.     

Monitoring the delivery of cancer care: Commission on Cancer and National Cancer Data Base

The primary objective of the Commission on Cancer (CoC) is to ensure the delivery of comprehensive, high-quality care that improves survival while maintaining quality of life for patients with cancer. This article examines the initiatives of the CoC toward achieving this goal, utilizing data from the National Cancer Data Base (NCDB) to monitor treatment patterns and outcomes, to develop quality measures, and to benchmark hospital performance. The article also highlights how these initiatives align with the Institute of Medicine's recommendations for improving the quality of cancer care and briefly explores future projects of the CoC and NCDB.