Photodynamic therapy for the treatment of atherosclerotic plaque: Lost in translation?

Acute coronary syndrome is a life‐threatening condition of utmost clinical importance, which, despite recent progress in the field, is still associated with high morbidity and mortality. Acute coronary syndrome results from a rupture or erosion of vulnerable atherosclerotic plaque with secondary platelet activation and thrombus formation, which leads to partial or complete luminal obstruction of a coronary artery. During the last decade, scientific evidence demonstrated that when an acute coronary event occurs, several nonculprit plaques are in a “vulnerable” state. Among the promising approaches, several investigations provided evidence of photodynamic therapy (PDT)‐induced stabilization and regression of atherosclerotic plaque. Significant development of PDT strategies improved its therapeutic outcome. This review addresses PDT's pertinence and major problems/challenges toward its translation to a clinical reality.     

Anti-fibrotic therapy: lost in translation?

While preclinical development of potential anti-fibrotics is far advanced, with numerous pharmacological targets and promising agents, almost none has entered clinical validation. Reasons are manifold, including the usually slow progression of liver fibrosis, requiring high numbers of well-stratified patients undergoing long-term treatment when conventional liver biopsy based parameters or hard liver-related endpoints are used. Importantly, there is a notorious lack of sensitive and specific surrogate markers or imaging technologies for liver fibrosis progression or regression that would permit a rapid clinical screening for potential anti-fibrotics. Nonetheless, in view of an urgent need for anti-fibrotics that positively impact morbidity and mortality from chronic liver diseases, the field is now moving more quickly towards clinical translation. This development is driven by thoughtful preclinical validation, a better study design and improved surrogate readouts using currently available methodologies. Moreover, upcoming novel biomarkers and imaging technologies will soon permit a more exact and efficient assessment of fibrosis progression and regression.     

Cardiac remodelling and myocardial recovery: lost in translation?

The insight that decreases in left ventricular (LV) volume and mass occur secondary to the recovery of the myocardium at the cellular and molecular level has engendered a wider appreciation of the importance of LV remodelling as a mechanism for worsening heart failure. Despite these recent insights into the recognition of the importance of LV reverse remodelling in heart failure, many clinicians do not consider simple measurements of LV structure (i.e. LV volume) in their routine clinical decision‐making process, preferring instead to rely on measurements of LV function [e.g. ejection fraction (EF)] when making decisions about medical and surgical treatment options. Although there are probably multiple reasons of why the use of LV volumes has not gained wider acceptance in day‐to‐day clinical management of heart failure patients, the most likely reason is that clinicians remain extremely comfortable using the LVEF to assess their heart failure patients. Importantly, LV volumes predict outcome more reliably than does the EF. Moreover, knowledge regarding LV volumes is extremely useful in optimizing patient selection for surgical and device therapies. Based on the foregoing arguments, we suggest that it is time to begin developing individualized clinical strategies based upon a consideration of the important role that LV remodelling plays in the pathogenesis of heart failure, and that we begin to incorporate measurements of LV volume and mass into the clinical decision‐making process.     

Osteoarthritis: can anti-cytokine therapy play a role in treatment?

Osteoarthritis (OA) is the most common joint disorder worldwide, and it has an enormous socioeconomic impact both in the United States and throughout the world. The degree of articular inflammation is usually associated with the disease’s progression, indicating that this process could contribute to articular damage. IL-1 beta and anti-TNF alpha are the two major cytokines players in the physiopathology of OA. Hence, we aimed to review the current literature on the effects of IL-1 and TNF-alpha neutralization as a new OA therapy. In vitro and experimental models showed a reduction in cartilage destruction with IL-1 inhibition therapy by IL-1 receptor antagonists (IL-1Ra). Despite this favorable evidence in animal models, studies on the inhibition of IL-1R in humans are still scarce. Although there is clear evidence that TNF-alpha plays a role in the pathophysiology of OA, only a few experimental trials have investigated the efficacy of blocking this pro-inflammatory cytokine in the treatment of OA. So far, the few studies available in humans using anti-TNF-alpha and IL-1 receptor antagonist are not remarkable, suggesting that further investigation and new therapeutic approaches are needed.     

Whither diabetes research in India today?

Background and aimsIndia has the second largest number of patients with diabetes, and research to contain it and limit its complications is needed.MethodsA literature search was done using Pubmed and Google Scholar search engines to prepare a narrative review on this topic.ResultsIndia’s contribution to research on diabetes remains inadequate, both quantitatively and qualitatively. Most of the work thus far has been done by a limited number of organisations and individuals, and has been confined to certain limited areas of interest. Nearly 40% of the publications on diabetes in India between 2000 and 2009 originated from just 20 institutions. Many important aspects of diabetes in India remain uninvestigated. In this review we make an attempt to evaluate the current status of diabetes research in India and to understand the hurdles dissuading a large proportion of healthcare professionals in India from embarking on a career in research. We also suggest solutions for overcoming these hurdles.ConclusionsConsidering the major health and economic problems posed by the unrestrained diabetes epidemic in India, research in this area remains highly inadequate.     

Overall mortality in diabetes mellitus: where do we stand today?

Life expectancy for a patient with type 2 diabetes remains substantially shorter than an equivalent individual without diabetes, largely because of a greater risk of cardiovascular disease. Diabetes is also associated with an increased incidence of many types of cancer, suggesting that malignancy may also contribute to higher rates of mortality. Hyperglycemia is one of the key risk factors for diabetes-associated macro- and microvascular disease, and as such, intensive glycemic control is associated with improved outcomes for patients, including a reduction in this risk of death from any cause, when initiated early in the disease course. Recent trials in patients with more advanced disease have failed to demonstrate a mortality benefit with intensive glycemic control, although this may reflect their short observation period. Intensive multifactorial therapy, including lifestyle intervention and control of hyperglycemia, hypertension, lipids, thrombosis, and microalbuminuria, is likely to be the best strategy against diabetes-associated macrovascular mortality. However, analysis of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial indicates that there may be a subpopulation of patients who are unable to achieve glycemic targets with intensive therapy and that aggressive intensification of treatment in this group may increase mortality risk. It remains to be determined whether the relationship between diabetes and malignancy is causal or whether they share common risk factors. Current recommendations for a healthy lifestyle based on good diet, physical exercise, and weight management in order to control diabetes-related complications are likely to apply in reducing the risk of many forms of cancer and should be advocated for all patients.     

The mold conundrum in chronic rhinosinusitis: Where do we stand today?

Chronic rhinosinusitis (CRS) is an inflammatory disorder affecting the nose and paranasal sinuses. Although bacteria have long been implicated as pathogens in most forms of CRS, fungi may be responsible for some forms. Several recent studies demonstrated that, under optimal conditions, fungi can be identified in the nose and paranasal sinuses of nearly every individual (including all CRS patients). An aberrant immune response to these ubiquitous fungi has been suggested to explain the development of CRS in some individuals. Several mechanisms requiring additional research, including adequate controls, have been proposed and are reviewed in this article. Although preliminary trials suggested that CRS signs and symptoms improve upon treatment with topical and oral antifungal agents, several double-blind, placebo-controlled trials demonstrated the contrary. In the absence of convincing immunologic data and evidence of clinical improvement upon therapy with antifungal agents, the case against fungi remains unproven.     

Current targets: where are we today?

Implementation of the National Service Framework (NSF) for coronary heart disease has particular workload implications for primary care. Studies conducted in general practices known to be representative of practices across the country suggest that, in order to meet current targets, the average general practitioner with a 2000 patient list would need to address 444 disease control measures in 210 patients. These relate primarily to smoking cessation and control of blood pressure, cholesterol, and blood sugar. Despite the enormous scale of cardiovascular disease, a considerable degree of recording and activity is going on within primary care in response to the NSF. However, some areas of cardiovascular care appear to need particular improvement. For example, with respect to lipid management, many high risk patients have not had their lipids measured, while many of those on lipid lowering drugs are not achieving current targets.     

Osteoarthritis: a problem of growth not decay?

The traditional view of OA is that it is primarily a disease of articular cartilage that results, by altering the biomechanics of the joint, in secondary changes to the subchondral bone and, through secondary inflammation, other joint tissues. This focus on cartilage tends to ignore other musculoskeletal changes reported, especially those remote from affected joints. It has been proposed instead that generalized OA is a systemic musculoskeletal disorder with a metabolic component. Evidence for this position will be presented by summarizing changes identified in all the major musculoskeletal tissues. This will endeavour to show the links between these tissues, most of which have a common mesenchymal origin. Dysregulated tissue turnover, with the balance in favour of growth, will be seen to be a common thread underlying many of the changes described. It is proposed that the production of new tissue in the midst of existing tissue, in the wrong place and at the wrong time, could result in the changes observed and that reversion of cellular behaviour to an earlier, developmental-like, phenotype may provide a mechanism that could drive the disease process. New therapies may arise both from recognizing this whole musculoskeletal disease phenotype and by exploring what might be the factors underlying this cellular reversion.