Immune biomarkers in the spectrum of childhood noncommunicable diseases

A biomarker is an accurately and reproducibly quantifiable biological characteristic that provides an objective measure of health status or disease. Benefits of biomarkers include identification of therapeutic targets, monitoring of clinical interventions, and development of personalized (or precision) medicine. Challenges to the use of biomarkers include optimizing sample collection, processing and storage, validation, and often the need for sophisticated laboratory and bioinformatics approaches. Biomarkers offer better understanding of disease processes and should benefit the early detection, treatment, and management of multiple noncommunicable diseases (NCDs). This review will consider the utility of biomarkers in patients with allergic and other immune-mediated diseases in childhood. Typically, biomarkers are used currently to provide mechanistic insight or an objective measure of disease severity, with their future role in risk stratification/disease prediction speculative at best. There are many lessons to be learned from the biomarker strategies used for cancer in which biomarkers are in routine clinical use and industry-wide standardized approaches have been developed. Biomarker discovery and validation in children with disease lag behind those in adults; given the early onset and therefore potential lifelong effect of many NCDs, there should be more studies incorporating cohorts of children. Many pediatric biomarkers are at the discovery stage, with a long path to evaluation and clinical implementation. The ultimate challenge will be optimization of prevention strategies that can be implemented in children identified as being at risk of an NCD through the use of biomarkers.

The DALY, context and the determinants of the severity of disease: an exploratory comparison of paraplegia in Australia and Cameroon

This paper summarises the findings of an empirical investigation of some of the technical and social assumptions on which the disability adjusted life year (DALY) is based. The objectives of the study were to examine the notion that the burden of disease is broadly similar without regard to country, environment, gender or socio-economic status and to develop detailed descriptions of the experiences of the burden of disease as they related to these contextual factors. The study was a multi-factorial exploratory study employing qualitative and quantitative techniques to obtain data on the effects of country (development), environment (urban versus rural), gender and socio-economic status on people with paraplegia. The data provided an extensive and detailed compilation of context rich descriptions of living with paraplegia. Striking features of the data were the differences between countries with respect to the impact of the health conditions on functioning and highlight a context in which paraplegia of like clinical severity can be fatal in one environment and not in another. While there has been some focus on the control of social determinants of disease, there has been little work on the social determinants of the severity of disease. The underlying assumptions of the DALY, which ignore context in the assessment of the burden of disease, risk exacerbating inequalities by undervaluing the burden of disease in less-developed countries. There is a need to continue to subject the development of indicators to rigorous debate to determine a balance between the assumption of a global “average social milieu” and the treatment of each individual as belonging to their own context in the assessment of population health in order for indicators to be meaningful cross-culturally.

The VISA-A questionnaire: a valid and reliable index of the clinical severity of Achilles tendinoplasty

Background: There is no disease specific, reliable, and valid clinical measure of Achilles tendinopathy. Objective: To develop and test a questionnaire based instrument that would serve as an index of severity of Achilles tendinopathy. Methods: Item generation, item reduction, item scaling, and pretesting were used to develop a questionnaire to assess the severity of Achilles tendinopathy. The final version consisted of eight  questions that measured the domains of pain, function in daily living, and sporting activity. Results range from 0 to 100, where 100 represents the perfect score. Its validity and reliability were then tested in a population of non-surgical patients with Achilles tendinopathy (n = 45), presurgical patients with Achilles tendinopathy (n = 14), and two normal control populations (total n = 87). Results: The VISA-A questionnaire had good test-retest (r = 0.93), intrarater (three tests, r = 0.90), and interrater (r = 0.90) reliability as well as good stability when compared one week apart (r = 0.81). The mean (95% confidence interval) VISA-A score in the non-surgical patients was 64 (59–69), in presurgical patients 44 (28–60), and in control subjects it exceeded 96 (94–99). Thus the VISA-A score was higher in non-surgical than presurgical patients (p = 0.02) and higher in control subjects than in both patient populations (p<0.001). Conclusions: The VISA-A questionnaire is reliable and displayed construct validity when means were compared in patients with a range of severity of Achilles tendinopathy and control subjects. The continuous numerical result of the VISA-A questionnaire has the potential to provide utility in both the clinical setting and research. The test is not designed to be diagnostic. Further studies are needed to determine whether the VISA-A score predicts prognosis.

Bovine milk fat enriched in conjugated linoleic and vaccenic acids attenuates allergic airway disease in mice

Background: It has been argued that a reduction in the Western diet of anti-inflammatory unsaturated lipids, such as n-3 polyunsaturated fatty acids, has contributed to the increase in the frequency and severity of allergic diseases.

Objective: We investigated whether feeding milk fat enriched in conjugated linoleic acid and vaccenic acids (VAs) ('enriched' milk fat), produced by supplementing the diet of pasture-fed cows with fish and sunflower oil, will prevent development of allergic airway responses.

Methods: C57BL/6 mice were fed a control diet containing soybean oil and diets supplemented with milk lipids. They were sensitized by intraperitoneal injection of ovalbumin (OVA) on days 14 and 28, and challenged intranasally with OVA on day 42. Bronchoalveolar lavage fluid, lung tissues and serum samples were collected 6 days after the intranasal challenge.

Results: Feeding of enriched milk fat led to marked suppression of airway inflammation as evidenced by reductions in eosinophilia and lymphocytosis in the airways, compared with feeding of normal milk fat and control diet. Enriched milk fat significantly reduced circulating allergen-specific IgE and IgG1 levels, together with reductions in bronchoalveolar lavage fluid of IL-5 and CCL11. Treatment significantly inhibited changes in the airway including airway epithelial cell hypertrophy, goblet cell metaplasia and mucus hypersecretion. The two major components of enriched milk fat, cis-9, trans-11 conjugated linoleic acid and VA, inhibited airway inflammation when fed together to mice, whereas alone they were not effective.

Conclusion: Milk fat enriched in conjugated linoleic and VAs suppresses inflammation and changes to the airways in an animal model of allergic airway disease.

The health-related quality of life burden of co-morbid cardiovascular disease and major depressive disorder in Australia : findings from a population-based, cross-sectional study

Purpose Health-related quality of life (HRQOL) can be significantly impaired by the presence of chronic conditions such as cardiovascular disease (CVD) and major depressive disorder (MDD). The aim of this paper was to (1) identify differences in HRQOL between individuals with CVD, MDD, or both, compared to a healthy reference group, (2) establish whether the influence of co-morbid MDD and CVD on HRQOL is additive or synergistic and (3) determine the way in which depression severity interacts with CVD to influence overall HRQOL.

Methods Population-based data from the 2007 Australian National Survey of Mental Health and Well-being (NSMHWB) (n = 8841) were used to compare HRQOL of individuals with MDD and CVD, MDD but not CVD, CVD but not MDD, with a healthy reference group. HRQOL was measured using the Assessment of Quality of Life (AQOL). MDD was identified using the Composite International Diagnostic Interview (CIDI 3.0).

Results Of all four groups, individuals with co-morbid CVD and depression reported the greatest deficits in AQOL utility scores (Coef: −0.32, 95% CI: −0.40, −0.23), after adjusting for covariates. Those with MDD only (Coef: −0.27, 95% CI: −0.30, −0.24) and CVD only (Coef: −0.08, 95% CI: −0.11, −0.05) also reported reduced AQOL utility scores. Second, the influence of MDD and CVD on HRQOL was shown to be additive, rather than synergistic. Third, a significant dose–response relationship was observed between depression severity and HRQOL. However, CVD and depression severity appeared to act independently of each other in impacting HRQOL.

Conclusions HRQOL is greatly impaired in individuals with co-morbid MDD and CVD; these conditions appear to influence HRQOL in an additive fashion. HRQOL alters with depression severity, therefore treating depression and improving HRQOL is of clinical importance.

Lower whole blood glutathione peroxidase (GPX) activity in depression, but not in myalgic encephalomyelitis / chronic fatigue syndrome: another pathway that may be associated with coronary artery disease and neuroprogression in depression

BAKGROUND: Major depression and myalgic encephalomyelitis / chronic fatigue syndrome (ME/CFS) are two disorders accompanied by an upregulation of the inflammatory and oxidative and nitrosative (IO&NS) pathways and a decreased antioxidant status. Moreover, depression is accompanied by disorders in inflammatory and neuroprogressive (IN-PRO) pathways.

METHODS: This study examines whole blood glutathione peroxidase (GPX) in depression and in ME/CFS; GPX is an enzyme that reduces hydroperoxides by oxidizing glutathione and consequently protects the cells from oxidative damage. Blood was sampled in 39 patients with depression, 40 patients with ME/CFS and 24 normal volunteers. Whole blood was analysed for GPX activity using the Ransel assay (Randox). Severity of illness was measured by means of the Hamilton Depression Rating Scale (HDRS) and the Fibromyalgia and Chronic Fatigue Syndrome Rating Scale (FF scale).

RESULTS: We found that whole blood GPX activity was significantly (p=0.001) lower in depressed patients than in normal controls and that there were no significant differences between ME/CFS and controls. In depression and ME/CFS, there were significant and inverse relationships between GPX activity and the FF items, depressed mood and autonomic symptoms. In depression, there were significant and negative correlations between whole blood GPX and the HDRS score and autonomic symptoms.

DISCUSSION: The results show that lowered whole blood GPX activity contributes to the lowered antioxidant status in depression. Since GPX activity is a predictor of neuroprogression and coronary artery disease (CAD), lowered GPX activity in depression contributes to the IN-PRO pathways and the comorbidity between depression and CAD. Our results suggest that patients with depression would benefit from Ebselen or a supplementation with glutathione, N-Acetyl-l-Cysteine and selenium.

More rapid and severe disease outbreaks for aquaculture at the tropics : implications for food security

1. Aquaculture is replacing capture fisheries in supplying the world with dietary protein. Although disease is a major threat to aquaculture production, the underlying global epidemiological patterns are unknown. 2. We analysed disease outbreak severity across different latitudes in a diverse range of aquaculture systems. 3. Disease at lower latitudes progresses more rapidly and results in higher cumulative mortality, in particular at early stages of development and in shellfish. 4. Tropical countries suffer proportionally greater losses in aquaculture during disease outbreaks and have less time to mitigate losses. 5. Synthesis and applications. Disease can present a major problem for food production and security in equatorial regions where fish and shellfish provide a major source of dietary protein. As the incidences of some infectious diseases may increase with climate change, adaptation strategies must consider global patterns in disease vulnerability of aquaculture and develop options to minimize impacts on food production.

Disease burden evaluation of fall-related events in the elderly due to hypoglycemia and other diabetic complications: a clinical review

A hypoglycemia-induced fall is common in older persons with diabetes. The etiology of falls in this population is usually multifactorial, and includes microvascular and macrovascular complications and age-related comorbidities, with hypoglycemia being one of the major precipitating causes. In this review, we systematically searched the literature that was available up to March 31, 2014 from MEDLINE/PubMed, Embase, and Google Scholar using the following terms: hypoglycemia; insulin; diabetic complications; and falls in elderly. Hypoglycemia, defined as blood glucose <4.0 mmol/L (70 mg/dL) requiring external assistance, occurs in one-third of elderly diabetics on glucose-lowering therapies. It represents a major barrier to the treatment of diabetes, particularly in the elderly population. Patients who experience hypoglycemia are at a high risk for adverse outcomes, including falls leading to bone fracture, seizures, cognitive dysfunction, and prolonged hospital stays. An increase in mortality has been observed in patients who experience any one of these events. Paradoxically, rational insulin therapy, dosed according to a patient's clinical status and the results of home blood glucose monitoring, so as to achieve and maintain recommended glycemic goals, can be an effective method for the prevention of hypoglycemia and falls in the elderly. Contingencies, such as clinician-directed hypoglycemia treatment protocols that guide the immediate treatment of hypoglycemia, help to limit both the duration and severity of the event. Older diabetic patients with or without underlying renal insufficiency or other severe illnesses represent groups that are at high risk for hypoglycemia-induced falls and, therefore, require lower insulin dosages. In this review, the risk factors of falls associated with hypoglycemia in elderly diabetics were highlighted and management plans were suggested. A target hemoglobin A1c level between 7% and 8% seems to be more appropriate for this population. In addition, the first-choice drugs should have good safety profiles and have the lowest probability of causing hypoglycemia - such as metformin (in the absence of significant renal impairment) and incretin enhancers - while other therapies that may cause more frequent hypoglycemia should be avoided.

The health profile of people living with Parkinson's Disease managed in a comprehensive care setting

Background: Globally there are few reports of the impairments, disabilities and medications used in people living with idiopathic Parkinson’s disease. Caregiver characteristics and caregiver burden have seldom been reported. We examined the health status in a large cohort of people living with Parkinson’s disease and their caregivers managed in a comprehensive health care setting.

Methods/Design: A prospective, cross sectional analysis of impairments, disabilities and Parkinson’s disease medication use was conducted in a sample of 100 people with Parkinson’s disease rated I-IV on the modified Hoehn & Yahr scale. Participants were recruited from the Victorian Comprehensive Parkinson Program in Melbourne, Australia. Their caregivers were invited to provide their views on the burden of care, services provided and support received.

Results: The severity of impairments and disabilities was strongly associated with disease duration (mean of 5.5 years). Those with long standing disease or more severe disease also used more Parkinson’s disease medications and participated in fewer social roles than people who were newly diagnosed or mildly affected. The severity of impairments was strongly correlated with limitations in performing activities of daily living. Limitations in performing daily activities were also found to be a significant contributing factor for health-related quality of life (PDQ-39 SI β=0.55, p=0.000; EQ-5D SI β=0.43, p=0.001). People with Parkinson’s disease lived at home with relatives. The average caregiver was a spouse or child providing approximately 3.5 hours of care per day, with the capacity to provide 9.4 hours per day and had provided care for four years. Additional support was high (63%) for 2.5 hours per day.

Conclusion: The comprehensive care setting of this cohort describes a relatively benign condition despite a wide range of disease duration and severity. This report provides a baseline with which to compare other delivery models.

Microvascular disease after renal transplantation

Background/Aims: Individuals who reach end-stage kidney disease (CKD5) have a high risk of vascular events that persists even after renal transplantation. This study compared the prevalence and severity of microvascular disease in transplant recipients and patients with CKD5. Methods: Individuals with a renal transplant or CKD5 were recruited consecutively from renal clinics, and underwent bilateral retinal photography (Canon CR5-45, Canon). Their retinal images were deidentified and reviewed for hypertensive/microvascular signs by an ophthalmologist and a trained grader (Wong and Mitchell classification), and for vessel caliber at a grading centre using a computer-assisted method and Knudtson’s modification of the Parr-Hubbard formula. Results: Ninety-two transplant recipients (median duration 6.4 years, range 0.8 to 28.8) and 70 subjects with CKD5 were studied. Transplant recipients were younger (p<0.001), with a higher eGFR (p< 0.001), but were just as likely to have a moderate-severe hypertensive/microvascular retinopathy (46/92, 50%) as subjects with CKD5 (38/70, 54%; OR 0.84, CI 0.45 to 1.57, p=0.64), and had similar mean arteriole and venular calibres (135.1 ± 7.5 μm and 137.9 ± 14.9 μm, p=0.12; and 199.1 ± 17.8 μm and 202.4 ± 27.8 μm, p=0.36, respectively). Arteriole and venular caliber were not different in nine patients examined before and after transplantation (p=0.62 and p=0.11, respectively). Conclusions: Hypertensive/microvascular disease occurred just as often and was generally as severe in transplant recipients and subjects with CKD5. Microvascular disease potentially contributes to increased cardiac events post- transplantation.

High adult mortality in disease-challenged frog populations increases vulnerability to drought

Pathogen emergence can drive major changes in host population demography, with implications for population dynamics and sensitivity to environmental fluctuations. The amphibian disease chytridiomycosis, caused by infection with the fungal pathogen Batrachochytrium dendrobatidis (Bd), is implicated in the severe decline of over 200 amphibian species. In species that have declined but not become extinct, Bd persists and can cause substantial ongoing mortality. High rates of mortality associated with Bd may drive major changes in host demography, but this process is poorly understood. Here, we compared population age structure of Bd-infected populations, Bd-free populations, and museum specimens collected prior to Bd emergence for the endangered Australian frog, Litoria verreauxii alpina (alpine tree frog). We then used population simulations to investigate how pathogen-associated demographic shifts affect the ability of populations to persist in stochastic environments. We found that Bd-infected populations have a severely truncated age structure associated with very high rates of annual adult mortality. Near-complete annual adult turnover in Bd-infected populations means that individuals breed once, compared with Bd-free populations where adults may breed across multiple years. Our simulations showed that truncated age structure erodes the capacity of populations to withstand periodic recruitment failure; a common challenge for species reproducing in uncertain environments. We document previously undescribed demographic shifts associated with a globally emerging pathogen and demonstrate how these shifts alter host ecology. Truncation of age structure associated with Bd effectively reduces host niche width, and can help explain the contraction of L. v. alpina to perennial waterbodies where the risk of drought-induced recruitment failure is low. Reduced capacity to tolerate other sources of mortality may explain variation in decline severity among other chytridiomycosis-challenged species and highlights the potential to mitigate disease impacts through minimising other sources of mortality.

Highly specific changes in antioxidant levels and lipid peroxidation in Parkinson's disease and its progression : disease and staging biomarkers and new drug targets.

There is evidence that immune-inflammatory, stress of reactive oxygen and nitrogen species (IO&NS) processes play a role in the neurodegenerative processes observed in Parkinson's disease (PD). The aim of the present study was to investigate peripheral IO&NS biomarkers in PD. We included 56 healthy individuals and 56 PD patients divided in two groups: early PD stage and late PD stage. Plasma lipid hydroperoxides (LOOH), malondialdehyde (MDA), nitric oxide metabolites (NOx), sulfhydryl (SH) groups, catalase (CAT) activity, superoxide dismutase (SOD) activity, paraoxonase (PON)1 activity, total radical trapping antioxidant parameter (TRAP) and C-reactive protein (CRP) were measured. PD is characterized by increased LOOH, MDA and SOD activity and lowered CAT activity. A combination of five O&NS biomarkers highly significantly predicts PD with a sensitivity of 94.5% and a specificity of 86.8% (i.e., MDA, SOD activity, TRAP, SH-groups and CAT activity). The single best biomarker of PD is MDA, while LOOH and SOD activity are significantly associated with late PD stage, but not early PD stage. Antiparkinson drugs did not affect O&NS biomarkers, but levodopa+carbidopa significantly increased CRP. It is suggested that MDA may serve as a disease biomarker, while LOOH and SOD activity are associated with late PD stage characteristic. New treatments for PD should not only target dopamine but also lipid peroxidation.