The impact of diabetes on the pathogenesis of sepsis

Diabetes is associated with an increased susceptibility to infection and sepsis. Conflicting data exist on whether the mortality of patients with sepsis is influenced by the presence of diabetes, fuelling the ongoing debate on the benefit of tight glucose regulation in patients with sepsis. The main reason for which diabetes predisposes to infection appears to be abnormalities of the host response, particularly in neutrophil chemotaxis, adhesion and intracellular killing, defects that have been attributed to the effect of hyperglycaemia. There is also evidence for defects in humoral immunity, and this may play a larger role than previously recognised. We review the literature on the immune response in diabetes and its potential contribution to the pathogenesis of sepsis. In addition, the effect of diabetes treatment on the immune response is discussed, with specific reference to insulin, metformin, sulphonylureas and thiazolidinediones

25th RCOphth Congress, President's Session paper:25 years of progress in medical retina

The quarter century since the foundation of the Royal College of Ophthalmologists has coincided with immense change in the subspecialty of medical retina, which has moved from being the province of a few dedicated enthusiasts to being an integral, core part of ophthalmology in every eye department. In age-related macular degeneration, there has been a move away from targeted, destructive laser therapy, dependent on fluorescein angiography to intravitreal injection therapy of anti-growth factor agents, largely guided by optical coherence tomography. As a result of these changes, ophthalmologists have witnessed a marked improvement in visual outcomes for their patients with wet age-related macular degeneration (AMD), while at the same time developing and enacting entirely novel ways of delivering care. In the field of diabetic retinopathy, this period also saw advances in laser technology and a move away from highly destructive laser photocoagulation treatment to gentler retinal laser treatments. The introduction of intravitreal therapies, both steroids and anti-growth factor agents, has further advanced the treatment of diabetic macular oedema. This era has also seen in the United Kingdom the introduction of a coordinated national diabetic retinopathy screening programme, which offers an increasing hope that the burden of blindness from diabetic eye disease can be lessened. Exciting future advances in retinal imaging, genetics, and pharmacology will allow us to further improve outcomes for our patients and for ophthalmologists specialising in medical retina, the future looks very exciting but increasingly busy

Immunoregulatory dysfunctions in type I diabetes: Natural and antibody-dependent cellular cytotoxic activities

Peripheral blood lymphocytes from 13 patients with established insulin-dependent diabetes mellitus (IDDM) and 2 prediabetic patients were examined for natural killer (NK) and antibody-dependent cellular cytotoxic activities (ADCC), lectin-dependent cellular cytotoxicity (LDCC), interferon- and interleukin-2-induced cytotoxicity, and concanavalin A-induced suppressor-cell activities in comparison with age-matched normal controls. IDDM patients demonstrated normal levels of NK and ADCC activities against K562 and antibody-coated SB target cells, respectively, compared to controls. IDDM patients showed normal levels of LDCC activity. Notable deviations from control values were, however, observed with diabetic lymphocytes in the following systems. Interferon-and interleukin-2-induced NK activities were significantly higher with IDDM lymphocytes than with control cells. IDDM lymphocytes precultured with concanavalin A demonstrated lower NK and ADCC activities than control cells and manifested decreased suppressor effects on the NK activity of normal allogeneic lymphocytes. Lymphocytes from one of two prediabetic patients showed increased NK, ADCC, and LDCC activities in comparison to controls. The increased interferon- and interleukin-2-induced enhancement of NK activity and reduced suppressor activity of lymphocytes from IDDM patients may be involved in the pathogenesis of the disease.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/44848/1/10875_2004_Article_BF00915375.pd

Increasing frailty is associated with higher prevalence and reduced recognition of delirium in older hospitalised inpatients: results of a multi-centre study

Purpose Delirium is a neuropsychiatric disorder delineated by an acute change in cognition, attention, and consciousness. It is common, particularly in older adults, but poorly recognised. Frailty is the accumulation of deficits conferring an increased risk of adverse outcomes. We set out to determine how severity of frailty, as measured using the CFS, affected delirium rates, and recognition in hospitalised older people in the United Kingdom. Methods Adults over 65 years were included in an observational multi-centre audit across UK hospitals, two prospective rounds, and one retrospective note review. Clinical Frailty Scale (CFS), delirium status, and 30-day outcomes were recorded. Results The overall prevalence of delirium was 16.3% (483). Patients with delirium were more frail than patients without delirium (median CFS 6 vs 4). The risk of delirium was greater with increasing frailty [OR 2.9 (1.8–4.6) in CFS 4 vs 1–3; OR 12.4 (6.2–24.5) in CFS 8 vs 1–3]. Higher CFS was associated with reduced recognition of delirium (OR of 0.7 (0.3–1.9) in CFS 4 compared to 0.2 (0.1–0.7) in CFS 8). These risks were both independent of age and dementia. Conclusion We have demonstrated an incremental increase in risk of delirium with increasing frailty. This has important clinical implications, suggesting that frailty may provide a more nuanced measure of vulnerability to delirium and poor outcomes. However, the most frail patients are least likely to have their delirium diagnosed and there is a significant lack of research into the underlying pathophysiology of both of these common geriatric syndromes

Investigation of the Use of Spectral Clustering for the Analysis of Molecular Data

Abstract Image Spectral clustering involves placing objects into clusters based on the eigenvectors and eigenvalues of an associated matrix. The technique was first applied to molecular data by Brewer [J. Chem. Inf. Model. 2007, 47, 1727–1733] who demonstrated its use on a very small dataset of 125 COX-2 inhibitors. We have determined suitable parameters for spectral clustering using a wide variety of molecular descriptors and several datasets of a few thousand compounds and compared the results of clustering using a nonoverlapping version of Brewer’s use of Sarker and Boyer’s algorithm with that of Ward’s and k-means clustering. We then replaced the exact eigendecomposition method with two different approximate methods and concluded that Singular Value Decomposition is the most appropriate method for clustering larger compound collections of up to 100 000 compounds. We have also used spectral clustering with the Tversky coefficient to generate two sets of clusters linked by a common set of eigenvalues and have used this novel approach to cluster sets of fragments such as those used in fragment-based drug design