Cyclodextrins as Supramolecular Recognition Systems: Applications in the Fabrication of Electrochemical Sensors

Supramolecular chemistry, although focused mainly on noncovalent intermolecular and intramolecular interactions, which are considerably weaker than covalent interactions, can be employed to fabricate sensors with a remarkable affinity for a target analyte. In this review the development of cyclodextrin-based electrochemical sensors is described and discussed. Following a short introduction to the general properties of cyclodextrins and their ability to form inclusion complexes, the cyclodextrin-based sensors are introduced. This includes the combination of cyclodextrins with reduced graphene oxide, carbon nanotubes, conducting polymers, enzymes and aptamers, and electropolymerized cyclodextrin films. The applications of these materials as chiral recognition agents and biosensors and in the electrochemical detection of environmental contaminants, biomolecules and amino acids, drugs and flavonoids are reviewed and compared. Based on the papers reviewed, it is clear that cyclodextrins are promising molecular recognition agents in the creation of electrochemical sensors, chiral sensors, and biosensors. Moreover, they have been combined with a host of materials to enhance the detection of the target analytes. Nevertheless, challenges remain, including the development of more robust methods for the integration of cyclodextrins into the sensing unit.     

Abnormal deoxyuridine suppression test in congenital methylmalonic aciduria-homocystinuria without megaloblastic anemia: divergent biochemical and morphological bone marrow manifestations of disordered cobalamin metabolism in man

We studied two brothers (J.R. and M.R.) with the cobalamin D variant of congenital methylmalonic aciduria-homocystinuria, whose previously reported lack of megaloblastic anemia conflicted with current concepts of cobalamin's role in DNA synthesis and the "methyltetrahydrofolate (MTHF) trap" hypothesis. Both subjects were indeed hematologically normal, although J.R. had a mean corpuscular volume of 96 fl. However, both demonstrated abnormalities in the deoxyuridine suppression test. J.R. had an abnormal suppression value of 21.0% (normal less than 10%) that was correctable by adding hydroxocobalamin or folic acid in vitro but not MTHF. M.R. had normal suppression (8.9%), but demonstrated worsening (18.6%) when MTHF was added. J.R.'s classical deoxyuridine suppression pattern of cobalamin deficiency thus supports the trap hypothesis. However, his lack of comparable morphological changes suggests that impaired de novo thymidylate synthesis and the trap hypothesis, though valid, may not fully account for the megaloblastic maturation accompanying cobalamin deficiency. Equally noteworthy was the deleterious effect of MTHF on M.R.'s marrow, suggesting its potential usefulness as an in vitro "stress test" for latent cobalamin abnormality.     

Endogenous endothelin-1 limits exercise-induced vasodilation in hypertensive humans

Essential hypertension is a common disorder, associated with increased endothelin-1-mediated vasoconstrictor tone at rest. We hypothesized that increased vasoconstrictor activity of endothelin-1 might explain why the normal decrease in peripheral vascular resistance in response to exercise is attenuated in hypertensive patients. Therefore, we investigated the effect of endothelin A (ET(A)) receptor blockade on the vasodilator response to handgrip exercise. Forearm blood flow responses to handgrip exercise (15%, 30%, and 45% of maximum voluntary contraction) were assessed in hypertensive patients and matched normotensive subjects, before and after intra-arterial infusions of the ET(A) receptor antagonist BQ-123; a control dilator, hydralazine; and placebo (saline). Preinfusion (baseline) vasodilation in response to exercise was significantly attenuated at each workload in hypertensive patients compared with normotensive subjects. Intra-arterial infusions of hydralazine and saline did not increase the vasodilator response to exercise in either hypertensives or normotensives at any workload. The vasodilator response to exercise was markedly enhanced after BQ-123 at the 2 higher workloads in hypertensives (157+/-48%, P<0.01; 203+/-58%, P<0.01) but not in normotensives. This suggests that the impaired vasodilator response to exercise in hypertensive patients is, at least in part, a functional limitation caused by endogenous ET(A) receptor-mediated vasoconstriction. Treatment with endothelin receptor antagonists may, therefore, increase exercise capacity in essential hypertension.     

Colonisation with methicillin‐resistant Staphylococcus aureus prior to renal transplantation is associated with long‐term renal allograft failure

Renal transplant recipients are at an increased risk of developing Methicillin‐resistant Staphylococcus aureus due to their immunosuppressed status. Herein, we investigate the incidence of MRSA infection in patients undergoing renal transplantation and determine the effect of MRSA colonisation on renal allograft function and overall mortality. Between January 1st 2007 and December 31st 2012, 1499 consecutive kidney transplants performed in our transplant unit and a retrospective 1:2 matched case‐control study was performed on this patient cohort. The 1‐, 3‐ and 5‐year overall graft survival rates were 100%, 86% and 78%, respectively, in MRSA positive recipients compared with 100%, 100% and 93%, respectively, in the control group (P < 0.05). The 1‐, 3‐ and 5‐year overall patient survival rates were 100%, 97% and 79%, respectively, in MRSA positive recipients compared with 100%, 100% and 95%, respectively, in the control group (P = 0.1). In a multiple logistic regression analysis, colonisation with MRSA pre‐operatively was an independent predictor for renal allograft failure at 5 years (hazard ratio: 4.6, 95% confidence interval: 1–30.7, P = 0.048). These findings demonstrate that the incidence of long‐term renal allograft failure is significantly greater in this patient cohort compared with a matched control population.     

Music in the Park. An integrating metaphor for the emerging primary (health) care system

Background Metaphors are central to the human understanding of complex issues; through the immediate associations they evoke and frame problems and suggest solutions. Our suggestion of Music in the Park as a metaphor for health systems reform brings to the forefront the environmentally diverse but bounded spaces of health services that offer a variety of attractors within their confines, while pushing into the background organizational and economic concerns. Reflections Parks, like health services, are embedded in their local landscape, serving their communities, but most importantly parks are public spaces, publically funded, ideally offering universal access and equity and to be shared by all who want to go there. Music, like health, is tangible, technical and scientific, yet ultimately experiential and based on meaning. While it encompasses a wide range of styles and approaches, music making requires as its most important skill active listening which brings with it to be ‘in the moment’, to take personal risks and to draw energy and inspiration from the participants. Hence ‘audiences’ are equally active participants because music only has meaning if it internally resonates with the listener and only can exist in what is a co‐constructed experience. Conclusions Music in the Park is a metaphor for primary health care systems based on shared values of experts and unique local communities. Health professionals are players in this arena, who develop and practise the full range of their skills in response to individual and community needs and preferences. Their leadership works through inspiration and empowerment, making patients ‘co‐producers’ of their own health and ‘co‐shapers’ of their health services.     

The social construction of chronicity – a key to understanding chronic care transformations

Purpose The purpose of this paper is to argue the importance of contemporary analysis of the modern social construction of chronicity – encapsulating the world views of the chronically ill, and the medical and health system constructions of chronic disease, through the nature of care for chronic conditions. It is argued that chronic diseases are themselves, socially constructed, despite widely accepted disease classification systems. Thus, there is a need to examine how different ideas have permeated our clinical and health system developments and their social context and vice versa. Methods We examine historical ideas, theory and evidence about the tensions in social construction of chronic illness by those afflicted and the responses of society, the medical and health professions and increasingly the public and private institutions that shape health care. This is with the background of major differences in the two cultures that create knowledge: those based upon argument and intellectual logic – hermeneutic, and those based upon ‘objectivist’ empirical science, often called heuristic. Evidence‐based medicine (EBM) is the flagship of disease management, increasingly narrative‐based medicine and other similar genres are becoming the pragmatic face of social constructions, yet sit in juxtaposition without synthesis. A third culture has emerged of scientific intellectuals who straddle these cultures and in health care their public face is ‘mixed methods’. Findings Recent cases of modern ideas about improving chronic care were reviewed. We found that despite developments of social theory, the world view of the chronically ill exerts small influence in health system redesign, apparently dominated by chronic disease models. Confusion remains within health system reforms as to the social construction of chronicity – chronic disease, chronic condition or chronic illness and chronic care transformations. The role of Primary Care remains ambiguous straddling disease and illness. Radical redesign of health systems is taking place without an understanding and discourse about the nature of their construction. Ad hoc eclectism with unquestioning adoption of the dominant EBM paradigm is driving a new health culture based on disease‐based performance incentives, which is intrusive beyond the medical model and pays little attention to narratives of illness and even less to the whole social reconstruction of illness and wellness. Conclusions Health care systems cannot afford to avoid, and should actively embrace the critiques of social theory and analyses in the transformations of health systems to improve chronic care. Creative tensions between empirical and intellectual critique, and a synthetic middle ground are likely to lead to more realistic and innovative approaches spanning the nature of chronicity and the transformation of Primary Care.