Project description:At one level, obesity is clearly a problem of simple physics, a result of eating too much and not expending enough energy. The more complex question, however, is why do some people eat more than others? Studies of human and mouse genetics over the past two decades have uncovered a number of pathways within the brain that play a key role in the control of food intake. A prime example is the leptin-melanocortin pathway, which we now know greatly contributes to mammalian appetitive behaviour. However, genetic disruption of this pathway remains rare and does not represent the major burden of the disease that is carried by those of us with 'common obesity'. In recent years, genome-wide association studies have revealed more than 100 different candidate genes linked to BMI, with most (including many components of the melanocortin pathway) acting in the central nervous system and influencing food intake. So while severe disruption of the melanocortin pathway results in severe obesity, subtle variations in these genes influence where you might sit in the normal distribution of BMI. As we now enter this 'post-genomics' world, can this new information influence our treatment and management of obese patients?
Project description:Methotrexate (MTX) is the first line drug for the treatment of a number of rheumatic and non-rheumatic disorders. It is currently used as an anchor disease, modifying anti-rheumatic drug in the treatment of rheumatoid arthritis (RA). Despite the development of numerous new targeted therapies, MTX remains the backbone of RA therapy due to its potent efficacy and tolerability. There has been also a growing interest in the use of MTX in the treatment of chronic viral mediated arthritis. Many viruses-including old world alphaviruses, Parvovirus B19, hepatitis B/C virus, and human immunodeficiency virus-have been associated with arthritogenic diseases and reminiscent of RA. MTX may provide benefits although with the potential risk of attenuating patients' immune surveillance capacities. In this review, we describe the emerging mechanisms of action of MTX as an anti-inflammatory drug and complementing its well-established immunomodulatory activity. The mechanisms involve adenosine signaling modulation, alteration of cytokine networks, generation of reactive oxygen species and HMGB1 alarmin suppression. We also provide a comprehensive understanding of the mechanisms of MTX toxic effects. Lastly, we discussed the efficacy, as well as the safety, of MTX used in the management of viral-related rheumatic syndromes.
Project description:Despite recent efforts to characterize innovative individuals within a species, we still know very little about the ontogeny of innovation ability. A number of studies have found that innovation rates are correlated with personality traits, such as neophilia and exploration. Juvenile birds are frequently more neophilic and explorative, yet few studies have found evidence of age-related differences in innovative problem-solving success. Here, we show consistently higher innovation efficiency in juveniles of a wild, omnivorous parrot species across a variety of tasks and contexts. We tested 104 kaka (Nestor meridionalis), ranging in age from four months to 13 years. Twenty-four individuals participated in all three of our problem-solving tasks, two of which involved a familiar feeder and one an entirely novel apparatus. Juveniles were the most efficient problem-solvers in all three tasks. By contrast, the adults' success was context dependent and limited to the novel apparatus, which did not require modification of a pre-learned behavioural response. This suggests greater behavioural flexibility in the juvenile birds, who also showed higher persistence and exploratory diversity than adults. These traits may enable young kaka to discover efficient foraging techniques, which are then maintained throughout adulthood.
Project description:Severe sepsis is a major challenge for clinicians caring for acutely ill patients. For many years, several biomarkers have been tested and proposed to improve the ability not only to diagnose but also to anticipate clinical response to antibiotics. Despite the availability of many sophisticated and novel biomarkers, current evidence demonstrates that C-reactive protein (CRP), a well-known and relatively inexpensive biomarker, is useful in the clinical setting. The sequential evaluation of plasma CRP concentrations in patients with severe sepsis and the interpretation of its patterns may allow assessments of individual prognosis and response to treatment.
Project description:Understanding the mechanism by which streptomycin binds to the small subunit of the mitoribosome may help researchers design less toxic derivatives of this antibiotic.
Project description:: Duchenne muscular dystrophy (DMD) is one of the most severe forms of inherited muscular dystrophies. The disease is caused by the lack of dystrophin, a structurally essential protein; hence, a definitive cure would necessarily have to pass through some form of gene and/or cell therapy. Cell- and genetic-based therapeutics for DMD have been explored since the 1990s and recently, two of the latter have been approved for clinical use, but their efficacy is still very low. In parallel, there have been great ongoing efforts aimed at targeting the downstream pathogenic effects of dystrophin deficiency using classical pharmacological approaches, with synthetic or biological molecules. However, as it is always the case with rare diseases, R&D costs for new drugs can represent a major hurdle for researchers and patients alike. This problem can be greatly alleviated by experimenting the use of molecules that had originally been developed for different conditions, a process known as drug repurposing or drug repositioning. In this review, we will describe the state of the art of such an approach for DMD, both in the context of clinical trials and pre-clinical studies.
Project description:Radiation therapy is a major treatment modality for management of non-small cell lung cancer. Radiation pneumonitis is a dose limiting toxicity of radiotherapy, affecting its therapeutic ratio. This review presents patient and treatment related factors associated with the development of radiation pneumonitis. Research focusing on reducing the incidence of radiation pneumonitis by using information about lung ventilation, imaging-based biomarkers as well as normal tissue complication models is discussed. Recent advances in our understanding of molecular mechanisms underlying lung injury has led to the development of several targeted interventions, which are also explored in this review.
Project description:Although older adults rarely outperform young adults on learning tasks, in the study reported here they surpassed their younger counterparts not only by answering more semantic-memory general-information questions correctly, but also by better correcting their mistakes. While both young and older adults exhibited a hypercorrection effect, correcting their high-confidence errors more than their low-confidence errors, the effect was larger for young adults. Whereas older adults corrected high-confidence errors to the same extent as did young adults, they outdid the young in also correcting their low-confidence errors. Their event-related potentials point to an attentional explanation: Both groups showed a strong attention-related P3a in conjunction with high-confidence-error feedback, but the older adults also showed strong P3as to low-confidence-error feedback. Indeed, the older adults were able to rally their attentional resources to learn the true answers regardless of their original confidence in the errors and regardless of their familiarity with the answers.
Project description:Jahchan and colleagues report the use of a biostatistical analysis to identify effective therapeutics for small cell lung cancer (SCLC). Their results reveal a new use for the tricyclic antidepressant imipramine in SCLC and shed light on the therapeutic potential of drug repositioning in cancer and other diseases.