HLA-DRB1 associations with disease susceptibility and clinical course in Australians with multiple sclerosis

Human leucocyte antigen (HLA)-DRB1*1501 and other class II alleles influence susceptibility to multiple sclerosis (MS), but their contribution if any to the clinical course of MS remains uncertain. Here, we have investigated DRB1 alleles in a large sample of 1230 Australian MS cases, with some enrichment for subjects with primary progressive (PPMS) disease (n = 246) and 1210 healthy controls. Using logistic regression, we found that DRB1*1501 was strongly associated with risk (P = 7 x 10-45), as expected, and after adjusting for DRB1*1501, a predisposing effect was also observed for DRB1*03 (P = 5 x 10-7). Individuals homozygous for either DRB1*15 or DRB1*03 were considerably more at risk of MS than heterozygotes and non-carriers. Both the DRB1*04 and the DRB1*01/DRB1*15 genotype combination, respectively, protected against PPMS in comparison to subjects with relapsing disease. Together, these data provide further evidence of heterogeneity at the DRB1 locus and confirm the importance of HLA variants in the phenotypic expression of MS.

The health outcomes and costs of people attending an interdisciplinary chronic disease service in regional Australia : protocol for a longitudinal cohort investigation

Background Rates of chronic disease are escalating around the world. To date health service evaluations have focused on interventions for single chronic diseases. However, evaluations of the effectiveness of new intervention strategies that target single chronic diseases as well as multimorbidity are required, particularly in areas outside major metropolitan centres where access to services, such as specialist care, is difficult and where the retention and recruitment of health professionals affects service provision. Methods This study is a longitudinal investigation with a baseline and three follow-up assessments comparing the health and health costs of people with chronic disease before and after intervention at a chronic disease clinic, in regional Australia. The clinic is led by students under the supervision of health professionals. The study will provide preliminary evidence regarding the effectiveness of the intervention, and evaluate the influence of a range of factors on the health outcomes and costs of the patients attending the clinic. Patients will be evaluated at baseline (intake to the service), and at 3-, 6-, and 12-months after intake to the service. Health will be measured using the SF-36 and health costs will be measured using government and medical record sources. The intervention involves students and health professionals from multiple professions working together to treat patients with programs that include education and exercise therapy programs for back pain, and Healthy Lifestyle programs; as well as individual consultations involving single professions. Discussion Understanding the effect of a range of factors on the health state and health costs of people attending an interdisciplinary clinic will inform health service provision for this clinical group and will determine which factors need to be controlled for in future observational studies. Preliminary evidence regarding changes in health and health costs associated with the intervention will be a platform for future clinical trials of intervention effectiveness. The results will be of interest to teams investigating new chronic disease programs particularly for people with multimorbidity, and in areas outside major metropolitan centres.

“A politics of what” : A praxiography of renal disease in Indigenous renal patients

The morbidity and mortality rates of renal disease in Indigenous Australians are significantly higher than those of non-Indigenous Australians, and are increasing. The dominant discourses of renal disease currently predicate this as essentially a client problem, rather than (for example) a health care system problem. These discourses are indicative of the dominant “white” paradigm of health care, which fosters an expectation of assimilation by the marginalised “other.” In this paper, we draw upon a sociological methodology (the actor network approach) and a qualitative method (discourse analysis) to tease out these issues in Indigenous renal disease. Based on empirical data, we explore on the one hand the requirements of the discourses, technologies and practices that have been developed for a particular type of renal patient and health system in Australia. On the other, we examine the cultural and practical specificities entailed in the performance of these technologies and practices in the Indigenous Australian context. The meeting of the praxiographic orientation of the actor network approach—which has been called “the politics of what” (Mol 2002)—and the sociocultural concerns of discourse analysis does provide a useful guide as to “what to do” when confronted with issues in health care that currently seems unfathomable. Our praxiographic analysis of the discourse enabled us to understand the difficulties involved in translating renal health care networks across cultural contexts in Australia and to understand the dynamic and contested nature of these networks. The actor network approach has its limitations, however, particularly in the articulation of possible strategies to align two disparate systems in a way that would ensure better health care for Indigenous renal patients. In this paper we will discuss some of the problems we encountered in drawing on this methodology in our attempt to unearth practical solutions to the conundrums our data presented.

Measuring the burden of disease in Shandong province : an adoption of the disability-adjusted life year [应用伤残调整寿命年测量山东省居民疾病负担]

Objective To estimate the burden of diseases in Shandong province by the means of DALY (Disability- adjusted life year) thus to investigate the key public health problems referencing for health policy making. Methods DALYs were calculated following the procedures developed for the Global Burden of Disease (GBD) study to ensure comparability. We measured YLLs using the mortality data of 19 Disease Surveillance Points (DSPs) in Shandong Province during 2000 and 2005. YLDs were estimated based on data for WPRO in the 2002 GBD study published by WHO. Results During this period, the average DALYs loss by all causes for the residents of DSPs in Shandong was 149.74 per thousand persons each year. Noncommunicable diseases accounted for 76.63% of the disability adjusted life years, communicable diseases and other disorders represented 14.13%, and injuries 9.24%. Nearly half of the DALYs (45%) happened among the elderly (60+). Malignant neoplasm was the number one cause of DALYs loss in the male, followed by neuropsychiatric disorder, injury, cerebrovascular disease, heart disease，etc. However, neuropsychiatric disorder possessed the largest single contributor to DALY in the female and followed by heart disease, malignant neoplasm, cerebrovascular disease and respiratory disease. Conclusion Non-communicable diseases such as circulatory diseases, neuropsychiatric disorders and malignant neoplasms were the main causes of disease burden in Shandong province. The importance of neuropsychiatric disorders was more striking and should be recognized properly. The lack of morbidity data is the main limitation of this study. Abstract in Chinese 目的 应用伤残调整寿命年测量山东省居民疾病负担,提出该地区主要卫生问题,为卫生决策提供科学依据. 方法 以山东省2000-2005年19个疾病监测点的死因监测资料为基础,利用世界卫生组织(WHO)提供的方法计算不同疾病在不同性别年龄人群所造成的伤残调整寿命年(DALYs),其中,YIJDs根据WHO公布的亚太区2002年疾病负担数据进行估算. 结果 2000-2005年山东省疾病监测系统居民因为早死和残疾年平均损失149.74个DALYs/千人,其中,76.6%的DALYs损失因慢性非传染性疾病所致,14.1%由传染性疾病等引起,9.2%因为意外伤害造成;接近1/2(45%)的DALYs损失发生在60岁以上人群;恶性肿瘤为造成男性居民DALYs损失的首位原因,其次为精神行为疾患、意外伤害、脑血管病和心脏病等,女性居民则以精神行为疾患为DALYs首位原因,其次为心脏病、恶性肿瘤、脑血管病和呼吸系统疾病. 结论 以循环系统疾病、精神行为疾惠和恶性肿瘤为首的慢性非传染性疾病为造成山东省疾病负担DALYs损失的主要原因.对于精神行为疾患的重要性的认识有待于进一步提高,研究的主要局限性在于发病率资料的缺乏.

Does a 10-valent pneumococcal-Haemophilus influenzae protein D conjugate vaccine prevent respiratory exacerbations in children with recurrent protracted bacterial bronchitis, chronic suppurative lung disease and bronchiectasis : protocol for a randomised controlled trial

Background Recurrent protracted bacterial bronchitis (PBB), chronic suppurative lung disease (CSLD) and bronchiectasis are characterised by a chronic wet cough and are important causes of childhood respiratory morbidity globally. Haemophilus influenzae and Streptococcus pneumoniae are the most commonly associated pathogens. As respiratory exacerbations impair quality of life and may be associated with disease progression, we will determine if the novel 10-valent pneumococcal-Haemophilus influenzae protein D conjugate vaccine (PHiD-CV) reduces exacerbations in these children. Methods A multi-centre, parallel group, double-blind, randomised controlled trial in tertiary paediatric centres from three Australian cities is planned. Two hundred six children aged 18 months to 14 years with recurrent PBB, CSLD or bronchiectasis will be randomised to receive either two doses of PHiD-CV or control meningococcal (ACYW(135)) conjugate vaccine 2 months apart and followed for 12 months after the second vaccine dose. Randomisation will be stratified by site, age (<6 years and >= 6 years) and aetiology (recurrent PBB or CSLD/bronchiectasis). Clinical histories, respiratory status (including spirometry in children aged >= 6 years), nasopharyngeal and saliva swabs, and serum will be collected at baseline and at 2, 3, 8 and 14 months post-enrolment. Local and systemic reactions will be recorded on daily diaries for 7 and 30 days, respectively, following each vaccine dose and serious adverse events monitored throughout the trial. Fortnightly, parental contact will help record respiratory exacerbations. The primary outcome is the incidence of respiratory exacerbations in the 12 months following the second vaccine dose. Secondary outcomes include: nasopharyngeal carriage of H. influenzae and S. pneumoniae vaccine and vaccine-related serotypes; systemic and mucosal immune responses to H. influenzae proteins and S. pneumoniae vaccine and vaccine-related serotypes; impact upon lung function in children aged >= 6 years; and vaccine safety. Discussion As H. influenzae is the most common bacterial pathogen associated with these chronic respiratory diseases in children, a novel pneumococcal conjugate vaccine that also impacts upon H. influenzae and helps prevent respiratory exacerbations would assist clinical management with potential short- and long-term health benefits. Our study will be the first to assess vaccine efficacy targeting H. influenzae in children with recurrent PBB, CSLD and bronchiectasis.

The epidemiology of invasive group A streptococcal disease in Victoria, Australia

Objective To estimate the incidence and severity of invasive group A streptococcal infection in Victoria, Australia. Design Prospective active surveillance study. Setting Public and private laboratories, hospitals and general practitioners throughout Victoria. Patients eople in Victoria diagnosed with group A streptococcal disease notified to the surveillance system between 1 March 2002 and 31 August 2004. Main outcome measure Confirmed invasive group A streptococcal disease. Results We identified 333 confirmed cases: an average annualised incidence rate of 2.7 (95% CI, 2.3-3.2) per 100000 population per year. Rates were highest in people aged 65 years and older and those younger than 5 years. The case-fatality rate was 7.8%. Streptococcal toxic shock syndrome occurred in 48 patients (14.4%), with a case-fatality rate of 23%. Thirty cases of necrotising fasciitis were reported; five (17%) of these patients died. Type 1 (23%) was the most frequently identified emm sequence type in all, age groups. All tested isolates were susceptible to penicillin and clindamycin. Two isolates (4%) were resistant to erythromycin. Conclusion The incidence of invasive group A streptococcal disease in temperate Australia is greater than previously appreciated and warrants greater public health attention, including its designation as a notifiable disease.

Meningococcal disease - 2 NT cases in August 1997 - The view from CDC

On 1 August 1997, the Friday afternoon of the start of a three day weekend (NT Picnic Day Monday 4 August) a case of suspected meningococcal disease was notified to CDC Katherine by an experienced, long serving, local GP...

Death of a five year old from meningococcal disease in Darwin : a case of unprecedented public alarm

On Saturday, 25 October 1997 a five year old boy died in the Intensive Care Unit (ICU) of Royal Darwin Hospital (RDH) from meningococcal disease. While disease is expected throughout Australia during the late winter and early spring months, and deaths occur, this case was remarkable in the Northern Territory with respect to the unprecedented public response to media reports of the death.

Reduced Thrombospondin-1 at presentation predicts disease progression in superficial bladder cancer

Objectives: Superficial bladder cancer (SBC) presents a difficult clinical dilemma at diagnosis as only a small subgroup of patients will subsequently develop invasive disease. Study of cancer biology has found that angiogenesis is central to growth and spread. This study examines the relationship between the angiogenic inhibitory factor Thrombospondin-1 (TSP-1) at initial presentation and subsequent progression of SBC. Methods: Using immunohistochemistry, 220 cases of SBC were examined for pattern and extent of expression of TSP-1 at initial presentation. Results: TSP-1 was detected in perivascular tissue, at the epithelial-stromal junction, in the stroma and in tumour cells and reduced perivascular TSP-1 staining at presentation was an independent predictive factor for the subsequent development of muscle invasive or metastatic disease. Conclusion: This adds further weight to the theory that TSP-1 plays a major part in the biology of bladder cancer possibly through the control of angiogenesis. © 2002 Elsevier Science B.V. All rights reserved.

Targeting histone deacetylases for the treatment of disease : Epigenetics Review Series

The 'histone code' is a well-established hypothesis describing the idea that specific patterns of post-translational modifications to histones act like a molecular 'code' recognized and used by non-histone proteins to regulate specific chromatin functions. One modification, which has received significant attention, is that of histone acetylation. The enzymes that regulate this modification are described as lysine acetyltransferases or KATs, and histone deacetylases or HDACs. Due to their conserved catalytic domain HDACs have been actively targeted as a therapeutic target. The pro-inflammatory environment is increasingly being recognized as a critical element for both degenerative diseases and cancer. The present review will discuss the current knowledge surrounding the clinical potential and current development of histone deacetylases for the treatment of diseases for which a pro-inflammatory environment plays important roles, and the molecular mechanisms by which such inhibitors may play important functions in modulating the pro-inflammatory environment. © 2009 Foundation for Cellular and Molecular Medicine/Blackwell Publishing 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.

A metastatic neuroendocrine anaplastic small cell tumor in a patient with multiple endocrine neoplasia type 1 syndrome : assessment of disease status and response to doxorubicin, cyclophosphamide, etoposide chemotherapy through scintigraphic imaging with 111In-pentetreotide

Extrapulmonary small cell and small cell neuroendocrine tumors of unknown primary site are, in general, aggressive neoplasms with a short median survival. Like small cell lung cancer (SCLC), they often are responsive to chemotherapy and radiotherapy. Small cell lung cancer and well differentiated neuroendocrine carcinomas of the gastrointestinal tract and pancreas tend to express somatostatin receptors. These tumors may be localized in patients by scintigraphic imaging using radiolabeled somatostatin analogues. A patient with an anaplastic neuroendocrine small cell tumor arising on a background of multiple endocrine neoplasia type 1 syndrome is reported. The patient had a known large pancreatic gastrinoma and previously treated parathyroid adenopathy. At presentation, there was small cell cancer throughout the liver and skeleton. Imaging with a radiolabeled somatostatin analogue, 111In- pentetreotide (Mallinckrodt Medical B. V., Petten, Holland), revealed all sites of disease detected by routine biochemical and radiologic methods. After six cycles of chemotherapy with doxorubicin, cyclophosphamide, and etoposide, there was almost complete clearance of the metastatic disease. 111In-pentetreotide scintigraphy revealed uptake consistent with small areas of residual disease in the liver, the abdomen (in mesenteric lymph nodes), and posterior thorax (in a rib). The primary gastrinoma present before the onset of the anaplastic small cell cancer showed no evidence of response to the treatment. The patient remained well for 1 year and then relapsed with brain, lung, liver, and skeletal metastases. Despite an initial response to salvage radiotherapy and chemotherapy with carboplatin and dacarbazine, the patient died 6 months later.

InterLACE : a new international collaboration for a Life course approach to women's reproductive health and chronic disease events.

Evidence from population-based studies of women increasingly points to the inter-related nature of reproductive health, lifestyle, and chronic disease risk. This paper describes the recently established International Collaboration for a Life Course Approach to Reproductive Health and Chronic Disease. InterLACE aims to advance the evidence base for women's health policy beyond associations from disparate studies by means of systematic and culturally sensitive synthesis of longitudinal data. Currently InterLACE draws on individual level data for reproductive health and chronic disease among 200,000 women from over thirteen studies of women's health in seven countries. The rationale for this multi-study research programme is set out in terms of a life course perspective to reproductive health. The research programme will build a comprehensive picture of reproductive health through life in relation to chronic disease risk. Although combining multiple international studies poses methodological challenges, InterLACE represents an invaluable opportunity to strength evidence to guide the development of timely and tailored preventive health strategies.