Implication of Complement System and its Regulators in Alzheimer’s Disease

Alzheimer’s disease (AD) is an age-related neurodegenerative disease that affects approximately 24 million people worldwide. A number of different risk factors have been implicated in AD, however, neuritic (amyloid) plaques are considered as one of the defining risk factors and pathological hallmarks of the disease. Complement proteins are integral components of amyloid plaques and cerebral vascular amyloid in Alzheimer brains. They can be found at the earliest stages of amyloid deposition and their activation coincides with the clinical expression of Alzheimer's dementia. This review emphasizes on the dual key roles of complement system and complement regulators (CRegs) in disease pathology and progression. The particular focus of this review is on currently evolving strategies for design of complement inhibitors that might aid therapy by restoring the fine balance between activated components of complement system, thus improving the cognitive performance of patients. This review discusses these issues with a view to inspiring the development of new agents that could be useful for the treatment of AD

Heart Rate Variability Measurement and Clinical Depression in Acute Coronary Syndrome Patients: Narrative Review of Recent Literature

Aim: We aimed to explore links between heart rate variability (HRV) and clinical depression in patients with acute coronary syndrome (ACS), through a review of recent clinical research literature. Background: Patients with ACS are at risk for both cardiac autonomic dysfunction and clinical depression. Both conditions can negatively impact the ability to recover from an acute physiological insult, such as unstable angina or myocardial infarction, increasing the risk for adverse cardiovascular outcomes. HRV is recognized as a reflection of autonomic function. Methods: A narrative review was undertaken to evaluate state-of-the-art clinical research, using the PubMed database, January 2013. The search terms “heart rate variability” and “depression” were used in conjunction with “acute coronary syndrome”, “unstable angina”, or “myocardial infarction” to find clinical studies published within the past 10 years related to HRV and clinical depression, in patients with an ACS episode. Studies were included if HRV measurement and depression screening were undertaken during an ACS hospitalization or within 2 months of hospital discharge. Results: Nine clinical studies met the inclusion criteria. The studies’ results indicate that there may be a relationship between abnormal HRV and clinical depression when assessed early after an ACS event, offering the possibility that these risk factors play a modest role in patient outcomes. Conclusion: While a definitive conclusion about the relevance of HRV and clinical depression measurement in ACS patients would be premature, the literature suggests that these measures may provide additional information in risk assessment. Potential avenues for further research are proposed

Extracting the barbs from complement assays: Identification and optimisation of a safe substitute for traditional buffers

Complement assays have for many years utilised buffers based on barbitone (veronal) despite the well-recognised toxicity of this agent and the tight regulations on its use in most countries. The use of barbitone in complement assay buffers is steeped in history, from a time when no other suitable buffers were available. This is no longer the case, encouraging us to explore alternatives to barbitone for complement assays. We compared a simple, non-toxic HEPES buffer with commercially sourced complement fixation test diluent (CFD), the “gold standard” barbitone buffer, in several clinically relevant complement activity assays and across species. In classical pathway haemolysis assays in human and non-human serum, there was no difference in haemolytic curves or calculated haemolytic activity (CH50) between CFD and an optimised HEPES buffer (HBS) supplemented with cations. Alternative pathway haemolysis assays in human serum were also identical in the two buffers. In a complement fixation test for anti-erythrocyte antibodies, complement consumption was identical for the two buffer systems. The data demonstrate that barbitone-based buffers are unnecessary for assays of complement activity and can readily be replaced with safe and simple alternatives

Omega-3-Fatty Acids Hold Therapeutic Potential for the Prevention and Treatment of Diabetic Neuropathy

Diabetic neuropathy is a debilitating complication of diabetes, affecting over 50% of diabetic patients. Overweight humans display manifestations of diabetic neuropathy before developing overt diabetes and mice fed a high fat diet exhibit signs of neuropathy including mechanical hindpaw hypersensitivity and neuronal inflammation, suggesting fat diet-induced inflammation may play a role in the development of neuropathy. Omega-3 (n-3) fatty acids have anti-inflammatory properties and may hold therapeutic potential as a preventative treatment for prediabetic and diabetic patients at risk for neuropathy. PURPOSE: Investigate the impact of diet composition on signs of neuropathy. We hypothesized that a diet rich in n-3 fatty acids would attenuate hindpaw hypersensitivity during prolonged feeding of a high fat diet. METHODS: C57BL/6 mice were randomized into four diet groups (n = 12/group) for 32 weeks: 10% low fat-fish oil (LFFO), 41% high fat-fish oil (HFFO), 10% low fat-lard (LFL), or 41% high fat-lard (HFL). Neuropathy was characterized at baseline and every other week thereafter using the von Frey behavioral test for hindpaw mechanical sensitivity. A glucose tolerance test was performed at end study, and total area under the curve (AUC) was calculated using the trapezoidal method. RESULTS: At end study, body weight was greater in HFL compared to all other groups. Body weight was also greater in HFFO compared to LFFO. Fasting glucose and glucose AUC were higher in HFL compared to LFFO and HFFO. Following the same pattern as body weight, fasting glucose was higher in HFFO compared to LFFO. Although percent paw withdrawal was greater in HFL compared to HFFO and LFFO, there were no significant differences for LF vs. HF for fish oil or lard. CONCLUSION: A HFL diet induced signs of neuropathy including hindpaw hypersensitivity, whereas a fish oil diet was protective against hindpaw hypersensitivity. Moreover, omega-3-fatty acids may hold therapeutic potential for neuropathy prevention in nondiabetic and diabetic patients

Dynamic virtual ecosystems as a tool for detecting large-scale responses of biodiversity to environmental and land-use change

In the face of biodiversity loss, we rely upon measures of diversity to describe the health of ecosystems and to direct policymakers and conservation efforts. However, there are many complexities in natural systems that can easily confound biodiversity measures, giving misleading interpretations of the system status and, as a result, there is yet to be a consistent framework by which to measure this biodiversity loss. Ecosystems are governed by dynamic processes, such as reproduction, dispersal and competition for resources, that both shape their biodiversity and how the system responds to change. Here, we incorporate these processes into simulations of habitat and environmental change, in order to understand how well we can identify signals of biodiversity loss against the background inherent variability these processes introduce. We developed a tool for Ecosystem Simulation through Integrated Species Trait-Environment Modelling (EcoSISTEM), which models on the species-level for several sizes of ecosystem, from small islands and patches through to entire regions, and several different types of habitat. We tested a suite of traditionally-used and new biodiversity measures on simulated ecosystems against a range of different scenarios of population decline, invasion and habitat loss. We found that the response of biodiversity measures was generally stronger in larger, more heterogeneous habitats than in smaller or homogeneous habitats. We were also able to detect signals of increasing homogenisation in climate change scenarios, which contradicted the signal of increased heterogeneity and distinctiveness through habitat loss

Compendium of current complement therapeutics

The complement system is well known for its role in innate immunity and in maintenance of tissue homeostasis, providing a first line of defence against infection and playing a key role in flagging apoptotic cells and debris for disposal. Unfortunately, complement also contributes to pathogenesis of many diseases, in some cases driving pathology, and in others amplifying or exacerbating the inflammatory and damaging impact of non-complement disease triggers. The driving role of complement in a single disease, paroxysmal nocturnal hemoglobinuria (PNH), provoked the development and eventual FDA (US Food and Drug Administration) approval of eculizumab (Soliris™), an anti-C5 antibody, for therapy. Although PNH is very rare, eculizumab provided clinical validation and demonstrated that inhibiting the complement system was not only well-tolerated, but also provided rapid therapy and saved lives. This clinical validation, together with advances in genetic analyses that demonstrated strong associations between complement and common diseases, drove new drug discovery programmes in both academic laboratories and large pharmaceutical companies. Numerous drugs have entered clinical development and several are in phase 3 trials; however, many have fallen by the wayside. Despite this high attrition rate, crucial lessons have been learnt and hurdles to development have become clear. These insights have driven development of next generation anti-complement drugs designed to avoid pitfalls and facilitate patient access. In this article, we do not set out to provide a text-heavy review of complement therapeutics but instead will simply highlight the targets, modalities and current status of the plethora of drugs approved or in clinical development. With such a fast-moving drug development landscape, such a compendium will inevitably become out-dated; however, we provide a snapshot of the current field and illustrate the increased choice that clinicians might enjoy in the future in selecting the best drug for their application, decisions based not only on efficacy but also cost, mechanistic target, modality and route of delivery

Factors associated with alcohol reduction in harmful and hazardous drinkers following alcohol brief intervention in Scotland: a qualitative enquiry

Background: Alcohol Brief Intervention (ABI) uses a motivational counselling approach to support individuals to reduce excessive alcohol consumption. There is growing evidence on ABI’s use within various health care settings, although how they work and which components enhance success is largely unknown. This paper reports on the qualitative part of a mixed methods study. It explores enablers and barriers associated with alcohol reduction following an ABI. It focuses on alcohol’s place within participants’ lives and their personal perspectives on reducing consumption. There are a number of randomised controlled trials in this field though few ABI studies have addressed the experiences of hazardous/harmful drinkers. This study examines factors associated with alcohol reduction in harmful/hazardous drinkers following ABI. Methods: This qualitative study was underpinned by a realist evaluation approach and involved semistructured interviews with ten harmful or hazardous alcohol drinkers. Participants (n = 10) were from the intervention arm of a randomised controlled trial (n = 124). All had received ABI, a 20 min motivational counselling interview, six months previously, and had reduced their alcohol consumption. Interviews were recorded, transcribed verbatim and thematically analysed. Results: Participants described their views on alcohol, its’ place in their lives, their personal perspectives on reducing their consumption and future aspirations. Conclusions: The findings provide an insight into participants’ views on alcohol, ABI, and the barriers and enablers to change. Participants described a cost benefit analysis, with some conscious consideration of the advantages and disadvantages of reducing intake or abstaining from alcohol. Findings suggest that, whilst hospital admission can act as a catalyst, encouraging individuals to reflect on their alcohol consumption through ABI may consolidate this, turning this reflective moment into action. Sustainability may be enhanced by the presence of a ‘significant other’ who encourages and experiences benefit. In addition having a purpose or structure with activities linked to employment and/or social and leisure pursuits offers the potential to enhance and sustain reduced alcohol consumption. Trial registration: Trial registration number TRN NCT00982306 September 22nd 200

Phase I Clinical Trials in Acute Myeloid Leukemia: 23-Year Experience From Cancer Therapy Evaluation Program of the National Cancer Institute

Therapy for acute myeloid leukemia (AML) has largely remained unchanged, and outcomes are unsatisfactory. We sought to analyze outcomes of AML patients enrolled in phase I studies to determine whether overall response rates (ORR) and mortality rates have changed over time

Predicting Responses of Geo-ecological Carbonate Reef Systems to Climate Change: A Conceptual Model and Review

Coral reefs provide critical ecological and geomorphic (e.g. sediment production for reef-fronted shoreline maintenance) services, which interact in complex and dynamic ways. These services are under threat from climate change, requiring dynamic modelling approaches that predict how reef systems will respond to different future climate scenarios. Carbonate budgets, which estimate net reef calcium carbonate production, provide a comprehensive ‘snap-shot’ assessment of reef accretionary potential and reef stability. These budgets, however, were not intended to account for the full suite of processes that maintain coral reef services or to provide predictive capacity on longer timescales (decadal to centennial). To respond to the dual challenges of enhancing carbonate budget assessments and advancing their predictive capacity, we applied a novel model elicitation and review method to create a qualitative geo-ecological carbonate reef system model that links geomorphic, ecological and physical processes. Our approach conceptualizes relationships between net carbonate production, sediment transport and landform stability, and rates knowledge confidence to reveal major knowledge gaps and critical future research pathways. The model provides a blueprint for future coral reef research that aims to quantify net carbonate production and sediment dynamics, improving our capacity to predict responses of reefs and reef-fronted shorelines to future climate change