Targeting oxidative stress in cancer

Importance of the field: Reactive oxygen species (ROS) occur as natural by-products of oxygen metabolism and have important cellular functions. Normally, the cell is able to maintain an adequate balance between the formation and removal of ROS either via anti-oxidants or through the use specific enzymatic pathways. However, if this balance is disturbed, oxidative stress may occur in the cell, a situation linked to the pathogenesis of many diseases, including cancer. Areas covered in this review: HDACs are important regulators of many oxidative stress pathways including those involved with both sensing and coordinating the cellular response to oxidative stress. In particular aberrant regulation of these pathways by histone deacetylases may play critical roles in cancer progression. What the reader will gain: In this review we discuss the notion that targeting HDACs may be a useful therapeutic avenue in the treatment of oxidative stress in cancer, using chronic obstructive pulmonary disease (COPD), NSCLC and hepatocellular carcinoma (HCC) as examples to illustrate this possibility. Take home message: Epigenetic mechanisms may be an important new therapeutic avenue for targeting oxidative stress in cancer. © 2010 Informa UK, Ltd.

The relationship between angiogenesis and the immune response in carcinogenesis and the progression of malignant disease

Recent studies have demonstrated that angiogenesis and suppressed cell- mediated immunity (CMI) play a central role in the pathogenesis of malignant disease facilitating tumour growth, invasion and metastasis. In the majority of tumours, the malignant process is preceded by a pathological condition or exposure to an irritant which itself is associated with the induction of angiogenesis and/or suppressed CMI. These include: cigarette smoking, chronic bronchitis and lung cancer; chronic oesophagitis and oesophageal cancer; chronic viral infections such as human papilloma virus and ano-genital cancers, chronic hepatitis B and C and hepatocellular carcinoma, and Epstein- Barr virus (EBV) and lymphomas; chronic inflammatory conditions such as Crohn's disease and ulcerative colitis and colorectal cancer; asbestos exposure and mesothelioma and excessive sunlight exposure/sunburn and malignant melanoma. Chronic exposure to growth factors (insulin-like growth factor-I in acromegaly), mutations in tumour suppressor genes (TP53 in Li Fraumeni syndrome) and long-term exposure to immunosuppressive agents (cyclosporin A) may also give rise to similar environments and are associated with the development of a range of solid tumours. The increased blood supply would facilitate the development and proliferation of an abnormal clone or clones of cells arising as the result of: (a) an inherited genetic abnormality; and/or (b) acquired somatic mutations, the latter due to local production and/or enhanced delivery of carcinogens and mutagenic growth factors. With progressive detrimental mutations and growth-induced tumour hypoxia, the transformed cell, to a lesser or greater extent, may amplify the angiogenic process and CMI suppression, thereby facilitating further tumour growth and metastasis. There is accumulating evidence that long-term treatment with cyclo-oxygenase inhibitors (aspirin and indomethacin), cytokines such as interferon-α, anti-oestrogens (tamoxifen and raloxifene) and captopril significantly reduces the incidence of solid tumours such as breast and colorectal cancer. These agents are anti-angiogenic and, in the case of aspirin, indomethacin and interferon-α have proven immunomodulatory effects. Collectively these observations indicate that angiogenesis and suppressed CMI play a central role in the development and progression of malignant disease. (C) 2000 Elsevier Science Ltd.

Evidence that human chlamydia pneumoniae was zoonotically acquired

Zoonotic infections are a growing threat to global health. Chlamydia pneumoniae is a major human pathogen that is widespread in human populations, causing acute respiratory disease, and has been associated with chronic disease. C. pneumoniae was first identified solely in human populations; however, its host range now includes other mammals, marsupials, amphibians, and reptiles. Australian koalas (Phascolarctos cinereus) are widely infected with two species of Chlamydia, C. pecorum and C. pneumoniae. Transmission of C. pneumoniae between animals and humans has not been reported; however, two other chlamydial species, C. psittaci and C. abortus, are known zoonotic pathogens. We have sequenced the 1,241,024-bp chromosome and a 7.5-kb cryptic chlamydial plasmid of the koala strain of C. pneumoniae (LPCoLN) using the whole-genome shotgun method. Comparative genomic analysis, including pseudogene and single-nucleotide polymorphism (SNP) distribution, and phylogenetic analysis of conserved genes and SNPs against the human isolates of C. pneumoniae show that the LPCoLN isolate is basal to human isolates. Thus, we propose based on compelling genomic and phylogenetic evidence that humans were originally infected zoonotically by an animal isolate(s) of C. pneumoniae which adapted to humans primarily through the processes of gene decay and plasmid loss, to the point where the animal reservoir is no longer required for transmission.

Communication ethics in public health

As new diseases and medical conditions emerge, new community groups appear in the public health arena as consumer advocates or lobby groups seeking to affect policy or to represent ‘communities’ formed around these new diseases and conditions. The role of these groups in public health, their political status, and the extent to which they are actually representative are highly problematic for public health. These new constellations of social groups and activities challenge traditional ideas about public health decision-making and demand a rethinking of the constituency and limits of public health. Using discourse theory, symbolic interactionism, and ethological theory, the authors examine one case, exploring the perspectives of various communities on hepatitis C, and explore some issues that this raises for public health.

A "Candidate-Interactome" Aggregate Analysis of Genome-Wide Association Data in Multiple Sclerosis

Though difficult, the study of gene-environment interactions in multifactorial diseases is crucial for interpreting the relevance of non-heritable factors and prevents from overlooking genetic associations with small but measurable effects. We propose a "candidate interactome" (i.e. a group of genes whose products are known to physically interact with environmental factors that may be relevant for disease pathogenesis) analysis of genome-wide association data in multiple sclerosis. We looked for statistical enrichment of associations among interactomes that, at the current state of knowledge, may be representative of gene-environment interactions of potential, uncertain or unlikely relevance for multiple sclerosis pathogenesis: Epstein-Barr virus, human immunodeficiency virus, hepatitis B virus, hepatitis C virus, cytomegalovirus, HHV8-Kaposi sarcoma, H1N1-influenza, JC virus, human innate immunity interactome for type I interferon, autoimmune regulator, vitamin D receptor, aryl hydrocarbon receptor and a panel of proteins targeted by 70 innate immune-modulating viral open reading frames from 30 viral species. Interactomes were either obtained from the literature or were manually curated. The P values of all single nucleotide polymorphism mapping to a given interactome were obtained from the last genome-wide association study of the International Multiple Sclerosis Genetics Consortium & the Wellcome Trust Case Control Consortium, 2. The interaction between genotype and Epstein Barr virus emerges as relevant for multiple sclerosis etiology. However, in line with recent data on the coexistence of common and unique strategies used by viruses to perturb the human molecular system, also other viruses have a similar potential, though probably less relevant in epidemiological terms. © 2013 Mechelli et al.

Patterns of service utilisation within Australian hepatology clinics: High prevalence of advanced liver disease

Accepted Article Abstract Background: Liver diseases in Australia are estimated to affect 6 million people with a societal cost of $51 billion annually. Information about utilization of specialist hepatology care is critical in informing policy makers about the requirements for delivery of hepatology-related health care. Aims: This study examined etiology and severity of liver disease seen in a tertiary hospital hepatology clinic, as well as resource utilisation patterns. Methods: A longitudinal cohort study included consecutive patients booked in hepatology outpatient clinics during a 3 month period. Subsequent outpatient appointments for these patients over the following 12 months were then recorded. Results: During the initial 3 month period 1471 appointments were scheduled with a hepatologist, 1136 of which were attended. 21% of patients were “new cases”. Hepatitis B (HBV) was the most common disease etiology for new cases (37%). Advanced disease at presentation varied between etiology, with HBV (5%), Hepatitis C (HCV) (31%), non-alcoholic fatty liver disease (NAFLD) (46%) and alcoholic liver disease (ALD) (72%). Most patients (83%) attended multiple hepatology appointments, and a range of referrals patterns for procedures, investigations and other specialty assessments were observed. Conclusions: There is a high prevalence of HBV in new case referrals. Patients with HCV, NAFLD and ALD have a high prevalence of advanced liver disease at referral, requiring ongoing surveillance for development of decompensated liver disease and liver cancer. These findings that describe patterns of health service utilisation among patients with liver disease provide useful information for planning sustainable health service provision for this clinical population

Adenovirus species C is associated with chronic suppurative lung diseases in children

Background The role of human adenoviruses (HAdVs) in chronic respiratory disease pathogenesis is recognized. However, no studies have performed molecular sequencing of HAdVs from the lower airways of children with chronic endobronchial suppuration. We thus examined the major HAdV genotypes/species, and relationships to bacterial coinfection, in children with protracted bacterial bronchitis (PBB) and mild bronchiectasis (BE). Methods Bronchoalveolar lavage (BAL) samples of 245 children with PBB or mild (cylindrical) BE were included in this prospective cohort study. HAdVs were genotyped (when possible) in those whose BAL had HAdV detected (HAdV+). Presence of bacterial infection (defined as ≥104 colony-forming units/mL) was compared between BAL HAdV+ and HAdV negative (HAdV−) groups. Immune function tests were performed including blood lymphocyte subsets in a random subgroup. Results Species C HAdVs were identified in 23 of 24 (96%) HAdV+ children; 13 (57%) were HAdV-1 and 10 (43%) were HAdV-2. An HAdV+ BAL was significantly associated with bacterial coinfection with Haemophilus influenzae, Moraxella catarrhalis, or Streptococcus pneumoniae (odds ratio [OR], 3.27; 95% confidence interval, 1.38–7.75; P = .007) and negatively associated with Staphylococcus aureus infection (P = .03). Young age was related to increased rates of HAdV+. Blood CD16 and CD56 natural killer cells were significantly more likely to be elevated in those with HAdV (80%) compared with those without (56.1%) (P = .027). Conclusions HAdV-C is the major HAdV species detected in the lower airways of children with PBB and BE. Younger age appears to be an important risk factor for HAdV+ of the lower airways and influences the likelihood of bacterial coinfection

Systematic review: Unmet supportive care needs in people diagnosed with chronic liver disease

Objective People with chronic liver disease, particularly those with decompensated cirrhosis, experience several potentially debilitating complications that can have a significant impact on activities of daily living and quality of life. These impairments combined with the associated complex treatment mean that they are faced with specific and high levels of supportive care needs. We aimed to review reported perspectives, experiences and concerns of people with chronic liver disease worldwide. This information is necessary to guide development of policies around supportive needs screening tools and to enable prioritisation of support services for these patients. Design Systematic searches of PubMed, MEDLINE, CINAHL and PsycINFO from the earliest records until 19 September 2014. Data were extracted using standardised forms. A qualitative, descriptive approach was utilised to analyse and synthesise data. Results The initial search yielded 2598 reports: 26 studies reporting supportive care needs among patients with chronic liver disease were included, but few of them were patient-reported needs, none used a validated liver disease-specific supportive care need assessment instrument, and only three included patients with cirrhosis. Five key domains of supportive care needs were identified: informational or educational (eg, educational material, educational sessions), practical (eg, daily living), physical (eg, controlling pruritus and fatigue), patient care and support (eg, support groups), and psychological (eg, anxiety, sadness). Conclusions While several key domains of supportive care needs were identified, most studies included hepatitis patients. There is a paucity of literature describing the supportive care needs of the chronic liver disease population likely to have the most needs—namely those with cirrhosis. Assessing the supportive care needs of people with chronic liver disease have potential utility in clinical practice for facilitating timely referrals to support services.

Resilience in chronic disease : the relationships among risk factors, protective factors, adaptive outcomes, and the level of resilience in adults with diabetes

Background: There are innumerable diabetes studies that have investigated associations between risk factors, protective factors, and health outcomes; however, these individual predictors are part of a complex network of interacting forces. Moreover, there is little awareness about resilience or its importance in chronic disease in adulthood, especially diabetes. Thus, this is the first study to: (1) extensively investigate the relationships among a host of predictors and multiple adaptive outcomes; and (2) conceptualise a resilience model among people with diabetes. Methods: This cross-sectional study was divided into two research studies. Study One was to translate two diabetes-specific instruments (Problem Areas In Diabetes, PAID; Diabetes Coping Measure, DCM) into a Chinese version and to examine their psychometric properties for use in Study Two in a convenience sample of 205 outpatients with type 2 diabetes. In Study Two, an integrated theoretical model is developed and evaluated using the structural equation modelling (SEM) technique. A self-administered questionnaire was completed by 345 people with type 2 diabetes from the endocrine outpatient departments of three hospitals in Taiwan. Results: Confirmatory factor analyses confirmed a one-factor structure of the PAID-C which was similar to the original version of the PAID. Strong content validity of the PAID-C was demonstrated. The PAID-C was associated with HbA1c and diabetes self-care behaviours, confirming satisfactory criterion validity. There was a moderate relationship between the PAID-C and the Perceived Stress Scale, supporting satisfactory convergent validity. The PAID-C also demonstrated satisfactory stability and high internal consistency. A four-factor structure and strong content validity of the DCM-C was confirmed. Criterion validity demonstrated that the DCM-C was significantly associated with HbA1c and diabetes self-care behaviours. There was a statistical correlation between the DCM-C and the Revised Ways of Coping Checklist, suggesting satisfactory convergent validity. Test-retest reliability demonstrated satisfactory stability of the DCM-C. The total scale of the DCM-C showed adequate internal consistency. Age, duration of diabetes, diabetes symptoms, diabetes distress, physical activity, coping strategies, and social support were the most consistent factors associated with adaptive outcomes in adults with diabetes. Resilience was positively associated with coping strategies, social support, health-related quality of life, and diabetes self-care behaviours. Results of the structural equation modelling revealed protective factors had a significant direct effect on adaptive outcomes; however, the construct of risk factors was not significantly related to adaptive outcomes. Moreover, resilience can moderate the relationships among protective factors and adaptive outcomes, but there were no interaction effects of risk factors and resilience on adaptive outcomes. Conclusion: This study contributes to an understanding of how risk factors and protective factors work together to influence adaptive outcomes in blood sugar control, health-related quality of life, and diabetes self-care behaviours. Additionally, resilience is a positive personality characteristic and may be importantly involved in the adjustment process among people living with type 2 diabetes.

Facilitating needs based cancer care for people with a chronic disease : evaluation of an intervention using a multi-centre interrupted time series design

Background: Palliative care should be provided according to the individual needs of the patient, caregiver and family, so that the type and level of care provided, as well as the setting in which it is delivered, are dependent on the complexity and severity of individual needs, rather than prognosis or diagnosis. This paper presents a study designed to assess the feasibility and efficacy of an intervention to assist in the allocation of palliative care resources according to need, within the context of a population of people with advanced cancer. ---------- Methods/design: People with advanced cancer and their caregivers completed bi-monthly telephone interviews over a period of up to 18 months to assess unmet needs, anxiety and depression, quality of life, satisfaction with care and service utilisation. The intervention, introduced after at least two baseline phone interviews, involved a) training medical, nursing and allied health professionals at each recruitment site on the use of the Palliative Care Needs Assessment Guidelines and the Needs Assessment Tool: Progressive Disease - Cancer (NAT: PD-C); b) health professionals completing the NAT: PD-C with participating patients approximately monthly for the rest of the study period. Changes in outcomes will be compared pre-and post-intervention.---------- Discussion: The study will determine whether the routine, systematic and regular use of the Guidelines and NAT: PD-C in a range of clinical settings is a feasible and effective strategy for facilitating the timely provision of needs based care.

Telemonitoring or Structured Telephone Support Programmes for Patients with Chronic Heart Failure: Systematic Review and Meta-Analysis

Objective: To determine whether remote monitoring (structured telephone support or telemonitoring) without regular clinic or home visits improves outcomes for patients with chronic heart failure. Data sources: 15 electronic databases, hand searches of previous studies, and contact with authors and experts. Data extraction: Two investigators independently screened the results. Review methods: Published randomised controlled trials comparing remote monitoring programmes with usual care in patients with chronic heart failure managed within the community. Results: 14 randomised controlled trials (4264 patients) of remote monitoring met the inclusion criteria: four evaluated telemonitoring, nine evaluated structured telephone support, and one evaluated both. Remote monitoring programmes reduced the rates of admission to hospital for chronic heart failure by 21% (95% confidence interval 11% to 31%) and all cause mortality by 20% (8% to 31%); of the six trials evaluating health related quality of life three reported significant benefits with remote monitoring, and of the four studies examining healthcare costs with structured telephone support three reported reduced cost and one no effect. Conclusion: Programmes for chronic heart failure that include remote monitoring have a positive effect on clinical outcomes in community dwelling patients with chronic heart failure.

Ureaplasma parvum serovar 3 multiple banded antigen size variation after chronic intra-amniotic infection/colonization

Ureaplasma species are the microorganisms most frequently associated with adverse pregnancy outcomes. The multiple banded antigen (MBA), a surface-exposed lipoprotein, is a key virulence factor of ureaplasmas. The MBA demonstrates size variation, which we have shown previously to be correlated with the severity of chorioamnion inflammation. We aimed to investigate U. parvum serovar 3 pathogenesis in vivo, using a sheep model, by investigating: MBA variation after long term (chronic) and short term (acute) durations of in utero ureaplasma infections, and the severity of chorioamnionitis and inflammation in other fetal tissues. Inocula of 2x107 colony-forming-units (CFU) of U. parvum serovar 3 (Up) or media controls (C) were injected intra-amniotically into pregnant ewes at one of three time points: day 55 (69d Up, n=8; C69, n=4); day 117 (7d Up, n=8; C7, n=2); and day 121 (3d Up, n=8; C3, n=2) of gestation (term=145-150d). At day 124, preterm fetuses were delivered surgically. Samples of chorioamnion, fetal lung, and umbilical cord were: (i) snap frozen for subsequent ureaplasma culture, and (ii) fixed, embedded, sectioned and stained by haematoxylin and eosin stain for histological analysis. Selected fetal lung clinical ureaplasma isolates were cloned and filtered to obtain cultures from a single CFU. Passage 1 and clone 2 ureaplasma cultures were tested by western blot to demonstrate MBA variation. In acute durations of ureaplasma infection no MBA variants (3d Up) or very few MBA variants (7d Up) were present when compared to the original inoculum. However, numerous MBA size variants were generated in vivo (alike within contiguous tissues, amniotic fluid and fetal lung, but different variants were present within chorioamnion), during chronic, 69d exposure to ureaplasma infection. For the first time we have shown that the degree of ureaplasma MBA variation in vivo increased with the duration of gestation.