Selective Targeting of Glucagon-Like Peptide-1 Signalling As a Novel Therapeutic Approach for Cardiovascular Disease in Diabetes

Glucagon-like peptide-1 (GLP-1) is an incretin hormone whose glucose-dependent insulinotropic actions have been harnessed as a novel therapy for glycaemic control in type 2 diabetes. Although it has been known for some time that the GLP-1 receptor is expressed in the cardiovascular system where it mediates important physiological actions, it is only recently that specific cardiovascular effects of GLP-1 in the setting of diabetes have been described. GLP-1 confers indirect benefits in cardiovascular disease (CVD) under both normal and hyperglycaemic conditions via reducing established risk factors, such as hypertension, dyslipidaemia and obesity, which are markedly increased in diabetes. Emerging evidence indicates that GLP-1 also exerts direct effects on specific aspects of diabetic CVD, such as endothelial dysfunction, inflammation, angiogenesis and adverse cardiac remodelling. However, the majority of studies have employed experimental models of diabetic CVD and information on the effects of GLP-1 in the clinical setting are limited although several large-scale trials are ongoing. It is clearly important to gain a detailed knowledge of the cardiovascular actions of GLP-1 in diabetes given the large number of patients currently receiving GLP-1 based therapies. This review will therefore discuss current understanding of the effects of GLP-1 on both cardiovascular risk factors in diabetes and direct actions on the heart and vasculature in this setting, and the evidence implicating specific targeting of GLP-1 as a novel therapy for CVD in diabetes.

Burkholderia pseudomallei:another emerging pathogen in cystic fibrosis

BACKGROUND: Burkholderia pseudomallei is an important cause of acute fulminant pneumonia and septicaemia in tropical regions of northern Australia and south east Asia. Subacute and chronic forms of the disease also occur. There have been three recent reports of adults with cystic fibrosis (CF) who presumably acquired B pseudomallei infection during extended vacations or residence in either Thailand or northern Australia.

METHODS: The clinical course, molecular characteristics, serology and response to treatment are described in four adult CF patients infected with B pseudomallei. Polymerase chain reaction (PCR) based methods were used to confirm B pseudomallei and exclude B cepacia complex. Genotyping was performed using randomly amplified polymorphic DNA (RAPD) PCR and pulsed field gel electrophoresis (PFGE).

RESULTS: Four patients are described with a mean duration of infection of 32 months. All but one patient lived in tropical Queensland. Two patients (with the longest duration of infection) deteriorated clinically and one subsequently died of respiratory failure. Both responded to intravenous treatment specifically targeting B pseudomallei. Another patient suffered two severe episodes of acute bronchopneumonia following acquisition of B pseudomallei. Eradication of the organism was not possible in any of the cases. PFGE of a sample isolate from each patient revealed the strains to be unique and RAPD analysis showed retention of the same strain within an individual over time.

CONCLUSIONS: These findings support a potential pathogenic role for B pseudomallei in CF lung disease, producing both chronic infection and possibly acute bronchopneumonia. Identical isolates are retained over time and are unique, consistent with likely environmental acquisition and not person to person spread. B pseudomallei is emerging as a significant pathogen for patients with CF residing and holidaying in the tropics.

Biosecurity and Emerging Plant Health Problems in Turf Production and Maintenance

Recent research has supported the view that the distributions of many pests and diseases have extended towards higher latitudes over the last 50 years. Probably driven by a combination of climate change and trade, this extension to the ranges of hundreds of plant pathogens may have serious implications not only for agriculture, horticulture and forestry, but also for turf production &maintenance. Here we review our data relating to the current status of three emerging pest and disease problems across North West Europe (rapid blight, Labyrinthula sp. , the root knot nematode, Meloidogyne minor and the pacific stem gall nematode, Anguina pacificae ) and discuss the factors which may be involved in their spread and increasing impact on the turf industry. With turf production and maintenance becoming an increasingly international business, we ask if biosecurity and the promotion of plant health in turf production fields and associated sport facilities should be a greater priority for the industry. We also examine if a lack of effective biosecurity measures in the materials supply chain has led to increased plant health problems.

The emerging roles of DNA methylation in the clinical management of prostate cancer

Aberrant DNA methylation is one of the hallmarks of carcinogenesis and has been recognized in cancer cells for more than 20 years. The role of DNA methylation in malignant transformation of the prostate has been intensely studied, from its contribution to the early stages of tumour development to the advanced stages of androgen independence. The most significant advances have involved the discovery of numerous targets such as GSTP1, Ras-association domain family 1A (RASSF1A) and retinoic acid receptor beta2 (RARbeta2) that become inactivated through promoter hypermethylation during the course of disease initiation and progression. This has provided the basis for translational research into methylation biomarkers for early detection and prognosis of prostate cancer. Investigations into the causes of these methylation events have yielded little definitive data. Aberrant hypomethylation and how it impacts upon prostate cancer has been less well studied. Herein we discuss the major developments in the fields of prostate cancer and DNA methylation, and how this epigenetic modification can be harnessed to address some of the key issues impeding the successful clinical management of prostate cancer.

Correlations between imatinib pharmacokinetics, pharmacodynamics, adherence, and clinical response in advanced metastatic gastrointestinal stromal tumor (GIST): An emerging role for drug blood level testing?

Imatinib is the standard of care for patients with advanced metastatic gastrointestinal stromal tumors (GIST), and is also approved for adjuvant treatment in patients at substantial risk of relapse. Studies have shown that maximizing benefit from imatinib depends on long-term administration at recommended doses. Pharmacokinetic (PK) and pharmacodynamic factors, adherence, and drug-drug interactions can affect exposure to imatinib and impact clinical outcomes. This article reviews the relevance of these factors to imatinib's clinical activity and response in the context of what has been demonstrated in chronic myelogenous leukemia (CML), and in light of new data correlating imatinib exposure to response in patients with GIST. Because of the wide inter-patient variability in drug exposure with imatinib in both CML and GIST, blood level testing (BLT) may play a role in investigating instances of suboptimal response, unusually severe toxicities, drug-drug interactions, and suspected non-adherence. Published clinical data in CML and in GIST were considered, including data from a PK substudy of the B2222 trial correlating imatinib blood levels with clinical responses in patients with GIST. Imatinib trough plasma levels <1100ng/mL were associated with lower rates of objective response and faster development of progressive disease in patients with GIST. These findings have been supported by other analyses correlating free imatinib (unbound) levels with response. These results suggest a future application for imatinib BLT in predicting and optimizing therapeutic response. Nevertheless, early estimates of threshold imatinib blood levels must be confirmed prospectively in future studies and elaborated for different patient subgroups.

Mechanisms of protein homeostasis in health, aging and disease.

When emerging from the ribosomes, new polypeptides need to fold properly, eventually translocate, and then assemble into stable, yet functionally flexible complexes. During their lifetime, native proteins are often exposed to stresses that can partially unfold and convert them into stably misfolded and aggregated species, which can in turn cause cellular damage and propagate to other cells. In animal cells, especially in aged neurons, toxic aggregates may accumulate, induce cell death and lead to tissue degeneration via different mechanisms, such as apoptosis as in Parkinson's and Alzheimer's diseases and aging in general. The main cellular mechanisms effectively controlling protein homeostasis in youth and healthy adulthood are: (1) the molecular chaperones, acting as aggregate unfolding and refolding enzymes, (2) the chaperone-gated proteases, acting as aggregate unfolding and degrading enzymes, (3) the aggresomes, acting as aggregate compacting machineries, and (4) the autophagosomes, acting as aggregate degrading organelles. For unclear reasons, these cellular defences become gradually incapacitated with age, leading to the onset of degenerative diseases. Understanding these mechanisms and the reasons for their incapacitation in late adulthood is key to the design of new therapies against the progression of aging, degenerative diseases and cancers.

Frailty, an Emerging Research and Clinical Paradigm: Issues and Controversies

Ne pas citer. Version pour diffusion uniquement. Citer l'article une fois publié. / Not to be cited. For distribution only. Cite article once published.

Biology and characterisation of polyalanine as an emerging pathological marker

Dix-huit maladies humaines graves ont jusqu'ici été associées avec des expansions de trinucléotides répétés (TNR) codant soit pour des polyalanines (codées par des codons GCN répétés) soit pour des polyglutamines (codées par des codons CAG répétés) dans des protéines spécifiques. Parmi eux, la dystrophie musculaire oculopharyngée (DMOP), l’Ataxie spinocérébelleuse de type 3 (SCA3) et la maladie de Huntington (MH) sont des troubles à transmission autosomale dominante et à apparition tardive, caractérisés par la présence d'inclusions intranucléaires (IIN). Nous avons déjà identifié la mutation responsable de la DMOP comme étant une petite expansion (2 à 7 répétitions supplémentaires) du codon GCG répété du gène PABPN1. En outre, nous-mêmes ainsi que d’autres chercheurs avons identifié la présence d’événements de décalage du cadre de lecture ribosomique de -1 au niveau des codons répétés CAG des gènes ATXN3 (SCA3) et HTT (MH), entraînant ainsi la traduction de codons répétés hybrides CAG/GCA et la production d'un peptide contenant des polyalanines. Or, les données observées dans la DMOP suggèrent que la toxicité induite par les polyalanines est très sensible à leur quantité et leur longueur. Pour valider notre hypothèse de décalage du cadre de lecture dans le gène ATXN3 dans des modèles animaux, nous avons essayé de reproduire nos constatations chez la drosophile et dans des neurones de mammifères. Nos résultats montrent que l'expression transgénique de codons répétés CAG élargis dans l’ADNc de ATXN3 conduit aux événements de décalage du cadre de lecture -1, et que ces événements sont néfastes. À l'inverse, l'expression transgénique de codons répétés CAA (codant pour les polyglutamines) élargis dans l’ADNc de ATXN3 ne conduit pas aux événements de décalage du cadre de lecture -1, et n’est pas toxique. Par ailleurs, l’ARNm des codons répétés CAG élargis dans ATXN3 ne contribue pas à la toxicité observée dans nos modèles. Ces observations indiquent que l’expansion de polyglutamines dans nos modèles drosophile et de neurones de mammifères pour SCA3 ne suffit pas au développement d'un phénotype. Par conséquent, nous proposons que le décalage du cadre de lecture ribosomique -1 contribue à la toxicité associée aux répétitions CAG dans le gène ATXN3. Pour étudier le décalage du cadre de lecture -1 dans les maladies à expansion de trinucléotides CAG en général, nous avons voulu créer un anticorps capable de détecter le produit présentant ce décalage. Nous rapportons ici la caractérisation d’un anticorps polyclonal qui reconnaît sélectivement les expansions pathologiques de polyalanines dans la protéine PABPN1 impliquée dans la DMOP. En outre, notre anticorps détecte également la présence de protéines contenant des alanines dans les inclusions intranucléaires (IIN) des échantillons de patients SCA3 et MD.

Understanding the alphaviruses: Recent research on important emerging pathogens and progress towards their control

The alphaviruses were amongst the first arboviruses to be isolated, characterized and assigned a taxonomic status. They are globally very widespread, infecting a large variety of terrestrial animals, insects and even fish, and circulate both in the sylvatic and urban/peri-urban environment, causing considerable human morbidity and mortality. Nevertheless, despite their obvious importance as pathogens, there are currently no effective antiviral drugs with which to treat humans or animals infected by any of these viruses. The EU-supported project—VIZIER (Comparative Structural Genomics of Viral Enzymes Involved in Replication, FP6 Project: 2004-511960) was instigated with an ultimate view of contributing to the development of antiviral therapies for RNA viruses, including the alphaviruses [Coutard, B., Gorbalenya, A.E., Snijder, E.J., Leontovich, A.M., Poupon, A., De Lamballerie, X., Charrel, R., Gould, E.A., Gunther, S., Norder, H., Klempa, B., Bourhy, H., Rohayemj, J., L’hermite, E., Nordlund, P., Stuart, D.I., Owens, R.J., Grimes, J.M., Tuckerm, P.A., Bolognesi, M., Mattevi, A., Coll, M., Jones, T.A., Åqvist, J., Unger, T., Hilgenfeld, R., Bricogne, G., Neyts, J., La Colla, P., Puerstinger, G., Gonzalez, J.P., Leroy, E., Cambillau, C., Romette, J.L., Canard, B., 2008. The VIZIER project: preparedness against pathogenic RNA viruses. Antiviral Res. 78, 37–46]. This review highlights some of the major features of alphaviruses that have been investigated during recent years. After describing their classification, epidemiology and evolutionary history and the expanding geographic distribution of Chikungunya virus, we review progress in understanding the structure and function of alphavirus replicative enzymes achieved under the VIZIER programme and the development of new disease control strategies.

The role of REST in transcriptional and epigenetic dysregulation in Huntington's disease

Huntington's disease (HD) is a devastating disorder that affects approximately 1 in 10,000 people and is accompanied by neuronal dysfunction and neurodegeneration. HD manifests as a progressive chorea, a decline in mental abilities accompanied by behavioural, emotional and psychiatric problems followed by, dementia, and ultimately, death. The molecular pathology of HD is complex but includes widespread transcriptional dysregulation. Although many transcriptional regulatory molecules have been implicated in the pathogenesis of HD, a growing body of evidence points to the pivotal role of RE1 Silencing Transcription Factor (REST). In HD, REST, translocates from the cytoplasm to the nucleus in neurons resulting in repression of key target genes such as BDNF. Since these original observations, several thousand direct target genes of REST have been identified, including numerous non-coding RNAs including both microRNAs and long non-coding RNAs, several of which are dysregulated in HD. More recently, evidence is emerging that hints at epigenetic abnormalities in HD brain. This in turn, promotes the notion that targeting the epigenetic machinery may be a useful strategy for treatment of some aspects of HD. REST also recruits a host of histone and chromatin modifying activities that can regulate the local epigenetic signature at REST target genes. Collectively, these observations present REST as a hub that coordinates transcriptional, posttranscriptional and epigenetic programmes, many of which are disrupted in HD. We identify several spokes emanating from this REST hub that may represent useful sites to redress REST dysfunction in HD.

Unhealthy landscapes: policy recommendations on land use change and infectious disease emergence

Anthropogenic land use changes drive a range of infectious disease outbreaks and emergence events and modify the transmission of endemic infections. These drivers include agricultural encroachment, deforestation, road construction, dam building, irrigation, wetland modification, mining, the concentration or expansion of urban environments, coastal zone degradation, and other activities. These changes in turn cause a cascade of factors that exacerbate infectious disease emergence, such as forest fragmentation, disease introduction, pollution, poverty, and human migration. The Working Group on Land Use Change and Disease Emergence grew out of a special colloquium that convened international experts in infectious diseases, ecology, and environmental health to assess the current state of knowledge and to develop recommendations for addressing these environmental health challenges. The group established a systems model approach and priority lists of infectious diseases affected by ecologic degradation. Policy-relevant levels of the model include specific health risk factors, landscape or habitat change, and institutional (economic and behavioral) levels. The group recommended creating Centers of Excellence in Ecology and Health Research and Training, based at regional universities and/or research institutes with close links to the surrounding communities. The centers' objectives would be 3-fold: a) to provide information to local communities about the links between environmental change and public health ; b) to facilitate fully interdisciplinary research from a variety of natural, social, and health sciences and train professionals who can conduct interdisciplinary research ; and c) to engage in science-based communication and assessment for policy making toward sustainable health and ecosystems.

Real-time early infectious outbreak detection systems using emerging technologies

The use of emerging technologies ( such as RFID - Radio Frequency Identification and remote sensing) can be employed to reduce health care costs and also to facilitate the automatic streamlining of infectious disease outbreak detection and monitoring processes in local health departments. It can assist medical practitioners with fast and accurate diagnosis and treatments. In this paper we outline the design and application of a real-time RFID and sensor-base Early Infectious (e.g., cholera) Outbreak Detection and Monitoring (IODM) system for health care.

Oxidative stress : emerging mitochondrial and cellular themes and variations in neuronal injury

Oxidative stress plays a central role in neuronal injury and cell death in acute and chronic pathological conditions. The cellular responses to oxidative stress embrace changes in mitochondria and other organelles, notably endoplasmic reticulum, and can lead to a number of cell death paradigms, which cover a spectrum from apoptosis to necrosis and include autophagy. In Alzheimer's disease, and other pathologies including Parkinson's disease, protein aggregation provides further cellular stresses that can initiate or feed into the pathways to cell death engendered by oxidative stress. Specific attention is paid here to mitochondrial dysfunction and programmed cell death, and the diverse modes of cell death mediated by mitochondria under oxidative stress. Novel insights into cellular responses to neuronal oxidative stress from a range of different stressors can be gained by detailed transcriptomics analyses. Such studies at the cellular level provide the key for understanding the molecular and cellular pathways whereby neurons respond to oxidative stress and undergo injury and death. These considerations underpin the development of detailed knowledge in more complex integrated systems, up to the intact human bearing the neuropathology, facilitating therapeutic advances.