Patients with early age-related macular degeneration exhibit signs of macro- and micro-vascular disease and abnormal blood glutathione levels

Background: This pilot study aimed to investigate systemic and retinal vascular function and their relationship to circulatory markers of cardiovascular risk in early age-related macular degeneration (AMD) patients without any already diagnosed systemic vascular pathologies. Methods: Fourteen patients diagnosed with early AMD and 14 age- and gender-matched healthy controls underwent blood pressure, carotid intima-media thickness (C-IMT) and peripheral arterial stiffness measurements. Retinal vascular reactivity was assessed by means of dynamic retinal vessel analysis (DVA) using a modified protocol. Blood analyses were conducted for glutathione levels and plasma levels of total cholesterol (CHOL), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C) and triglycerides (TG). Results: The AMD patients showed significantly greater C-IMT (p = 0.029) and augmentation index (AIx) (p = 0.042) than the age-matched controls. In addition, they demonstrated a shallower retinal arterial dilation slope (Slope AD) (p = 0.005) and a longer retinal venous reaction time (RT) to flickering light (p = 0.026). Blood analyses also revealed that AMD patients exhibited higher oxidized glutathione (GSSG) (p = 0.024), lower redox index (p = 0.043) and higher LDL-C (p = 0.033) levels than the controls. Venous RT parameter correlated positively with blood GSSG levels (r = 0.58, p = 0.038) in AMD subjects, but not in the controls (p > 0.05). Conclusions: Patients diagnosed with early AMD exhibit signs of systemic and retinal vascular alterations that correlated with known risk markers for future cardiovascular morbidity. © 2013 Springer-Verlag Berlin Heidelberg.

Are transglutaminase 2 inhibitors able to reduce gliadin-induced toxicity related to celiac disease? A proof-of-concept study

Purpose Celiac disease is an autoimmune-mediated enteropathy characterized by adaptive and innate immune responses to dietary gluten in wheat, rye and barley in genetically susceptible individuals. Gluten-derived gliadin peptides are deamidated by transglutaminase 2 (TG2), leading to an immune response in the small-intestinal mucosa. TG2 inhibitors have therefore been suggested as putative drugs for celiac disease. In this proof-of-concept study we investigated whether two TG2 inhibitors, cell-impermeable R281 and cell-permeable R283, can prevent the toxic effects of gliadin in vitro and ex vivo. Methods Intestinal epithelial Caco-2 cells were treated with peptic-tryptic-digested gliadin (PT-gliadin) with or without TG2 inhibitors and thereafter direct toxic effects (transepithelial resistance, cytoskeletal rearrangement, junction protein expression and phoshorylation of extracellular-signal-regulated kinase 1/2) were determined. In an organ culture of celiacpatient- derived small-intestinal biopsies we measured secretion of TG2-autoantibodies into the culture medium and the densities of CD25- and interleukin (IL) 15-positive cells, forkhead box P3 (FOXP3)-positive regulatory Tcells (Tregs) and Ki-67- positive proliferating crypt cells. Results Both TG2 inhibitors evinced protective effects against gliadin-induced detrimental effects in Caco-2 cells but the cellimpermeableR281seemedslightlymorepotent. Inaddition,TG2 inhibitor R281 modified the gluten-induced increase in CD25- and IL15-positive cells,Tregs and crypt cell proliferation, but had no effect on antibody secretion in celiac-patient-derived biopsies. Conclusions Our results suggest that TG2 inhibitors are able to reduce certain gliadin-induced effects related to responses in vitro and ex vivo. © Springer Science+Business Media, LLC 2012.

Top-down lipidomics of low density lipoprotein reveal altered lipid profiles in advanced chronic kidney disease

This study compared the molecular lipidomic profi le of LDL in patients with nondiabetic advanced renal disease and no evidence of CVD to that of age-matched controls, with the hypothesis that it would reveal proatherogenic lipid alterations. LDL was isolated from 10 normocholesterolemic patients with stage 4/5 renal disease and 10 controls, and lipids were analyzed by accurate mass LC/MS. Top-down lipidomics analysis and manual examination of the data identifi ed 352 lipid species, and automated comparative analysis demonstrated alterations in lipid profi le in disease. The total lipid and cholesterol content was unchanged, but levels of triacylglycerides and N -acyltaurines were signifi cantly increased, while phosphatidylcholines, plasmenyl ethanolamines, sulfatides, ceramides, and cholesterol sulfate were signifi cantly decreased in chronic kidney disease (CKD) patients. Chemometric analysis of individual lipid species showed very good discrimination of control and disease sample despite the small cohorts and identifi ed individual unsaturated phospholipids and triglycerides mainly responsible for the discrimination. These fi ndings illustrate the point that although the clinical biochemistry parameters may not appear abnormal, there may be important underlying lipidomic changes that contribute to disease pathology. The lipidomic profi le of CKD LDL offers potential for new biomarkers and novel insights into lipid metabolism and cardiovascular risk in this disease. -Reis, A., A. Rudnitskaya, P. Chariyavilaskul, N. Dhaun, V. Melville, J. Goddard, D. J. Webb, A. R. Pitt, and C. M. Spickett. Topdown lipidomics of low density lipoprotein reveal altered lipid profi les in advanced chronic kidney disease. J. Lipid Res. 2015.

Metformin in patients with type 2 diabetes and kidney disease:a systematic review

IMPORTANCE: Metformin is widely viewed as the best initial pharmacological option to lower glucose concentrations in patients with type 2 diabetes mellitus. However, the drug is contraindicated in many individuals with impaired kidney function because of concerns of lactic acidosis. OBJECTIVE: To assess the risk of lactic acidosis associated with metformin use in individuals with impaired kidney function. EVIDENCE ACQUISITION: In July 2014, we searched the MEDLINE and Cochrane databases for English-language articles pertaining tometformin, kidney disease, and lactic acidosis in humans between 1950 and June 2014.We excluded reviews, letters, editorials, case reports, small case series, and manuscripts that did not directly pertain to the topic area or that met other exclusion criteria. Of an original 818 articles, 65 were included in this review, including pharmacokinetic/metabolic studies, large case series, retrospective studies, meta-analyses, and a clinical trial. RESULTS: Although metformin is renally cleared, drug levels generally remain within the therapeutic range and lactate concentrations are not substantially increased when used in patients with mild to moderate chronic kidney disease (estimated glomerular filtration rates, 30-60 mL/min per 1.73m2). The overall incidence of lactic acidosis in metformin users varies across studies from approximately 3 per 100 000 person-years to 10 per 100 000 person-years and is generally indistinguishable from the background rate in the overall population with diabetes. Data suggesting an increased risk of lactic acidosis in metformin-treated patients with chronic kidney disease are limited, and no randomized controlled trials have been conducted to test the safety ofmetformin in patients with significantly impaired kidney function. Population-based studies demonstrate that metformin may be prescribed counter to prevailing guidelines suggesting a renal risk in up to 1 in 4 patients with type 2 diabetes mellitus-use which, in most reports, has not been associated with increased rates of lactic acidosis. Observational studies suggest a potential benefit from metformin on macrovascular outcomes, even in patients with prevalent renal contraindications for its use. CONCLUSIONS AND RELEVANCE: Available evidence supports cautious expansion of metformin use in patients with mild to moderate chronic kidney disease, as defined by estimated glomerular filtration rate, with appropriate dosage reductions and careful follow-up of kidney function.

Entropy Based Approach to Finding Interacting Genes Responsible for Complex Human Disease

2000 Mathematics Subject Classification: 62P10, 92D10, 92D30, 94A17, 62L10.

Retinal arteriolar diameter response to flicker light provocation - A useful marker for risk stratification in cardiovascular disease?

Purpose: To to evaluate the benefit of bilinear and linear fitting to characterize the retinal vessel dilation to flicker light stimulation for the purpose of risk stratification in cardiovascular disease. Methods: Forty-five patients (15 with coronary artery disease (CAD), 15 with Diabetes Mellitus (DM) and 15 with CAD and DM) all underwent contact tonometry, digital blood pressure measurement, fundus photography, retinal vessel oximetry, static retinal vessel analysis and continous retinal diameter assessment using the retinal vessel analyser (and flicker light provocation). In addition we measured blood glucose (HbA1c) and keratinin levels in DM patients. Results: With increased severity of cardiovascular disease a more linear reaction profile of retinal arteriolar diameter to flicker light provocation can be observed. Conclusion: Absolute values of vessel dilation provide only limited information on the state of retinal arteriolar dilatory response to flicker light. The approach of bilinear fitting takes into account the immediate response to flicker light provocation as well as the maintained dilatory capacity during prolonged stimulation. Individuals with cardiovascular disease however show a largely linear reaction profile indicating an impairment of the initial rapid dilatory response as usually observed in healty individuals

An examination of the UK community pharmacist's role in facilitating patient self-management of cardiovascular disease through lifestyle behaviours

The progression of cardiovascular disease (CVD) is largely modifiable through lifestyle behaviours. UK pharmacists are contractually obliged to facilitate patient self-management of chronic conditions such as CVD. Pharmacists are easily accessible health professionals who are well placed to identify “at risk” patients through medication regimes. Research has identified varying attitudes towards and levels of involvement in pharmacist-led health promotion activity. Given the diverse and exploratory nature of the work, a pragmatic, mixed methods approach was used to explore community pharmacists’ role in facilitating patient self-management of CVD. The thesis presents four studies: a qualitative study with pharmacists; a cross sectional questionnaire of community pharmacists; a systematic review and a qualitative study with patients with CVD. The qualitative study with pharmacists gave an insight into pharmacists’ experiences of giving patients with CVD lifestyle advice and the factors underpinning commonly cited barriers to providing public health services. This informed the development of the cross-sectional questionnaire which identified the predictors of pharmacists’ intentions to give two different types of advice to facilitate patient self-management. The systematic review identified a small number of interventions to prepare pharmacists to facilitate patient lifestyle behaviour change and evaluated the theories and behaviour change techniques used in successful interventions; however due to poor study quality and poor reporting of the interventions limited conclusions about the efficacy of the interventions could reliably be drawn. Finally, the qualitative study gave an insight into the experiences of patients with CVD using community pharmacy services and their expectations of the service they receive from community pharmacists. Recommendations about changes to pharmacy policy and practice in order to support pharmacists’ provision of CVD self-management advice are made.

The relationship of systemic markers of renal function and vascular function with retinal blood vessel responses

Purpose: To test the hypothesis of a significant relationship between systemic markers of renal and vascular function (processes linked to cardiovascular disease and its development) and retinal microvascular function in diabetes and/or cardiovascular disease.Methods: Ocular microcirculatory function was measured in 116 patients with diabetes and/or cardiovascular disease using static and continuous retinal vessel responses to three cycles of flickering light. Endothelial function was evaluated by von Willebrand factor (vWf), endothelial microparticles and soluble E selectin, renal function by serum creatinine, creatinine clearance and estimated glomerular filtration rate (eGFR). HbA1c was used as a control index.Results: Central retinal vein equivalence and venous maximum dilation to flicker were linked to HbA1c (both p<0.05). Arterial reaction time was linked to serum creatinine (p=0.036) and eGFR (p=0.039), venous reaction time was linked to creatinine clearance (p=0.018). Creatinine clearance and eGFR were linked to arterial maximum dilatation (p<0.001 and p=0.003 respectively) and the dilatation amplitude (p=0.038 and p=0.048 respectively) responses in the third flicker cycle. Of venous responses to the first flicker cycle, HbA1c was linked to the maximum dilation response (p=0.004) and dilatation amplitude (p=0.017), vWf was linked to the maximum constriction response (p=0.016), and creatinine clearance to the baseline diameter fluctuation (p=0.029). In the second flicker cycle, dilatation amplitude was linked to serum creatinine (p=0.022). Conclusions: Several retinal blood vessel responses to flickering light are linked to glycaemia and renal function, but only one index is linked to endothelial function. Renal function must be considered when interpreting retinal vessel responses.

Application of mint and cinamon against Fusarium disease of winter wheat

In our study the application of mint species (spearmint, peppermint ‘Mitcham’ and peppermint ‘Mexian’) and cinnamon was investigated against Fusarium head blight of winter wheat in vitro and in vivo. The effect of crude drugs and the aqueous extract of mint, and the effect of essential oils of mint and cinnamon on mycelial growth were evaluated in lab. On artificial media the crude drug showed higher inhibition than aqueous plant extracts. Cinnamon and spearmint oils e.ectively inhibited mycelia growth. In field trial artificially inoculated winter wheat was treated with the in vitro effective oils under small-plot conditions. The disease incidence was most inhibited by cinnamon oil, applied curative. According to our results the essential oil of cinnamon can be an appropriate candidate for the research of alternative disease control.

A mathematical model for the maneuvering simulation of a propelled SPAR vessel

To predict the maneuvering performance of a propelled SPAR vessel, a mathematical model was established as a path simulator. A system-based mathematical model was chosen as it offers advantages in cost and time over full Computational Fluid Dynamics (CFD) simulations. The model is intended to provide a means of optimizing the maneuvering performance of this new vessel type. In this study the hydrodynamic forces and control forces are investigated as individual components, combined in a vectorial setting, and transferred to a body-fixed basis. SPAR vessels are known to be very sensitive to large amplitude motions during maneuvers due to the relatively small hydrostatic restoring forces. Previous model tests of SPAR vessels have shown significant roll and pitch amplitudes, especially during course change maneuvers. Thus, a full 6 DOF equation of motion was employed in the current numerical model. The mathematical model employed in this study was a combination of the model introduced by the Maneuvering Modeling Group (MMG) and the Abkowitz (1964) model. The new model represents the forces applied to the ship hull, the propeller forces and the rudder forces independently, as proposed by the MMG, but uses a 6DOF equation of motion introduced by Abkowitz to describe the motion of a maneuvering ship. The mathematical model was used to simulate the trajectory and motions of the propelled SPAR vessel in 10˚/10˚, 20˚/20˚ and 30˚/30˚ standard zig-zag maneuvers, as well as turning circle tests at rudder angles of 20˚ and 30˚. The simulation results were used to determine the maneuverability parameters (e.g. advance, transfer and tactical diameter) of the vessel. The final model provides the means of predicting and assessing the performance of the vessel type and can be easily adapted to specific vessel configurations based on the generic SPAR-type vessel used in this study.

Historical cohort study examining comparative effectiveness of albuterol inhalers with and without integrated dose counter for patients with asthma or chronic obstructive pulmonary disease

This study was supported financially by an unrestricted grant from Teva Pharmaceuticals, Frazer, PA, USA. The authors thank Jenny Fanstone of Fanstone Medical Communications Ltd., UK, and Elizabeth V Hillyer for medical writing support, funded by Research in Real-Life. We acknowledge with gratitude Dr Ruchir Parikh for his review of and contributions to the manuscript.

Retinal microvascular dysfunction occurs similarly in Alzheimer's disease and primary open angle glaucoma patients

Purpose: The exact nature of the relationship between Alzheimer’s disease (AD) and primary open angle glaucoma (POAG) is still the subject of debate. One factor attributed to the aetiology of both conditions is vascular dysfunction. This study aimed to investigate the similarities and differences in retinal microvascular function between mild AD patients, early stage POAG patients and healthy controls Methods: Retinal vessel reactivity to flickering light was assessed in 10 AD, 19 POAG and 22 healthy age matched control patients by means of dynamic retinal vessel analysis (DVA, IMEDOS, GmbH, Jena, Germany) according to an established protocol. All patients additionally underwent BP measurements and blood analysis for glucose and lipid metabolism markers Results: AD and POAG patients demonstrated comparable alterations in retinal artery reactivity, in the form of an increased arterial reaction time (RT) to flicker light on the final flicker cycle (p=0.014), which was not replicated in the healthy age and cardiovascular risk matched controls (p>0.05). Furthermore, the sequential changes in RT on progressing from flicker one to flicker three were found to differ between healthy controls and the two disease groups (p=0.001) Conclusions: AD and POAG patients demonstrate comparable signs of vascular dysfunction in their retinal arteries at the early stages of their disease process. These comparable signs may reflect similarities in the pathophysiological processes that occur in the development of both conditions

Guideline-based decision support has a small, non-sustained effect on transthoracic echocardiography ordering frequency.

BACKGROUND: Guidance for appropriate utilisation of transthoracic echocardiograms (TTEs) can be incorporated into ordering prompts, potentially affecting the number of requests. METHODS: We incorporated data from the 2011 Appropriate Use Criteria for Echocardiography, the 2010 National Institute for Clinical Excellence Guideline on Chronic Heart Failure, and American College of Cardiology Choosing Wisely list on TTE use for dyspnoea, oedema and valvular disease into electronic ordering systems at Durham Veterans Affairs Medical Center. Our primary outcome was TTE orders per month. Secondary outcomes included rates of outpatient TTE ordering per 100 visits and frequency of brain natriuretic peptide (BNP) ordering prior to TTE. Outcomes were measured for 20 months before and 12 months after the intervention. RESULTS: The number of TTEs ordered did not decrease (338±32 TTEs/month prior vs 320±33 afterwards, p=0.12). Rates of outpatient TTE ordering decreased minimally post intervention (2.28 per 100 primary care/cardiology visits prior vs 1.99 afterwards, p<0.01). Effects on TTE ordering and ordering rate significantly interacted with time from intervention (p<0.02 for both), as the small initial effects waned after 6 months. The percentage of TTE orders with preceding BNP increased (36.5% prior vs 42.2% after for inpatients, p=0.01; 10.8% prior vs 14.5% after for outpatients, p<0.01). CONCLUSIONS: Ordering prompts for TTEs initially minimally reduced the number of TTEs ordered and increased BNP measurement at a single institution, but the effect on TTEs ordered was likely insignificant from a utilisation standpoint and decayed over time.

Mitochondrial DNA damage induced autophagy, cell death, and disease.

Mammalian mitochondria contain multiple small genomes. While these organelles have efficient base excision removal of oxidative DNA lesions and alkylation damage, many DNA repair systems that work on nuclear DNA damage are not active in mitochondria. What is the fate of DNA damage in the mitochondria that cannot be repaired or that overwhelms the repair system? Some forms of mitochondrial DNA damage can apparently trigger mitochondrial DNA destruction, either via direct degradation or through specific forms of autophagy, such as mitophagy. However, accumulation of certain types of mitochondrial damage, in the absence of DNA ligase III (Lig3) or exonuclease G (EXOG), can directly trigger cell death. This review examines the cellular effects of persistent damage to mitochondrial genomes and discusses the very different cell fates that occur in response to different kinds of damage.

Non-Pharmacological Approaches for Pain Management in Sickle Cell Disease: Development of a Mindfulness-Based Intervention

Background: Sickle Cell Disease (SCD) is a genetic hematological disorder that affects more than 7 million people globally (NHLBI, 2009). It is estimated that 50% of adults with SCD experience pain on most days, with 1/3 experiencing chronic pain daily (Smith et al., 2008). Persons with SCD also experience higher levels of pain catastrophizing (feelings of helplessness, pain rumination and magnification) than other chronic pain conditions, which is associated with increases in pain intensity, pain behavior, analgesic consumption, frequency and duration of hospital visits, and with reduced daily activities (Sullivan, Bishop, & Pivik, 1995; Keefe et al., 2000; Gil et al., 1992 & 1993). Therefore effective interventions are needed that can successfully be used manage pain and pain-related outcomes (e.g., pain catastrophizing) in persons with SCD. A review of the literature demonstrated limited information regarding the feasibility and efficacy of non-pharmacological approaches for pain in persons with SCD, finding an average effect size of .33 on pain reduction across measurable non-pharmacological studies. Second, a prospective study on persons with SCD that received care for a vaso-occlusive crisis (VOC; N = 95) found: (1) high levels of patient reported depression (29%) and anxiety (34%), and (2) that unemployment was significantly associated with increased frequency of acute care encounters and hospital admissions per person. Research suggests that one promising category of non-pharmacological interventions for managing both physical and affective components of pain are Mindfulness-based Interventions (MBIs; Thompson et al., 2010; Cox et al., 2013). The primary goal of this dissertation was thus to develop and test the feasibility, acceptability, and efficacy of a telephonic MBI for pain catastrophizing in persons with SCD and chronic pain.

Methods: First, a telephonic MBI was developed through an informal process that involved iterative feedback from patients, clinical experts in SCD and pain management, social workers, psychologists, and mindfulness clinicians. Through this process, relevant topics and skills were selected to adapt in each MBI session. Second, a pilot randomized controlled trial was conducted to test the feasibility, acceptability, and efficacy of the telephonic MBI for pain catastrophizing in persons with SCD and chronic pain. Acceptability and feasibility were determined by assessment of recruitment, attrition, dropout, and refusal rates (including refusal reasons), along with semi-structured interviews with nine randomly selected patients at the end of study. Participants completed assessments at baseline, Week 1, 3, and 6 to assess efficacy of the intervention on decreasing pain catastrophizing and other pain-related outcomes.

Results: A telephonic MBI is feasible and acceptable for persons with SCD and chronic pain. Seventy-eight patients with SCD and chronic pain were approached, and 76% (N = 60) were enrolled and randomized. The MBI attendance rate, approximately 57% of participants completing at least four mindfulness sessions, was deemed acceptable, and participants that received the telephonic MBI described it as acceptable, easy to access, and consume in post-intervention interviews. The amount of missing data was undesirable (MBI condition, 40%; control condition, 25%), but fell within the range of expected missing outcome data for a RCT with multiple follow-up assessments. Efficacy of the MBI on pain catastrophizing could not be determined due to small sample size and degree of missing data, but trajectory analyses conducted for the MBI condition only trended in the right direction and pain catastrophizing approached statistically significance.

Conclusion: Overall results showed that at telephonic group-based MBI is acceptable and feasible for persons with SCD and chronic pain. Though the study was not able to determine treatment efficacy nor powered to detect a statistically significant difference between conditions, participants (1) described the intervention as acceptable, and (2) the observed effect sizes for the MBI condition demonstrated large effects of the MBI on pain catastrophizing, mental health, and physical health. Replication of this MBI study with a larger sample size, active control group, and additional assessments at the end of each week (e.g., Week 1 through Week 6) is needed to determine treatment efficacy. Many lessons were learned that will guide the development of future studies including which MBI strategies were most helpful, methods to encourage continued participation, and how to improve data capture.