Muscle-Type Nicotinic Receptor Blockade by Diethylamine, the Hydrophilic Moiety of Lidocaine

Lidocaine bears in its structure both an aromatic ring and a terminal amine, which can be protonated at physiological pH, linked by an amide group. Since lidocaine causes multiple inhibitory actions on nicotinic acetylcholine receptors (nAChRs), this work was aimed to determine the inhibitory effects of diethylamine (DEA), a small molecule resembling the hydrophilic moiety of lidocaine, on Torpedo marmorata nAChRs microtransplanted to Xenopus oocytes. Similarly to lidocaine, DEA reversibly blocked acetylcholine-elicited currents (IACh) in a dose-dependent manner (IC50 close to 70 μM), but unlike lidocaine, DEA did not affect IACh desensitization. IACh inhibition by DEA was more pronounced at negative potentials, suggesting an open-channel blockade of nAChRs, although roughly 30% inhibition persisted at positive potentials, indicating additional binding sites outside the pore. DEA block of nAChRs in the resting state (closed channel) was confirmed by the enhanced IACh inhibition when pre-applying DEA before its co-application with ACh, as compared with solely DEA and ACh co-application. Virtual docking assays provide a plausible explanation to the experimental observations in terms of the involvement of different sets of drug binding sites. So, at the nAChR transmembrane (TM) domain, DEA and lidocaine shared binding sites within the channel pore, giving support to their open-channel blockade; besides, lidocaine, but not DEA, interacted with residues at cavities among the M1, M2, M3, and M4 segments of each subunit and also at intersubunit crevices. At the extracellular (EC) domain, DEA and lidocaine binding sites were broadly distributed, which aids to explain the closed channel blockade observed. Interestingly, some DEA clusters were located at the α-γ interphase of the EC domain, in a cavity near the orthosteric binding site pocket; by contrast, lidocaine contacted with all α-subunit loops conforming the ACh binding site, both in α-γ and α-δ and interphases, likely because of its larger size. Together, these results indicate that DEA mimics some, but not all, inhibitory actions of lidocaine on nAChRs and that even this small polar molecule acts by different mechanisms on this receptor. The presented results contribute to a better understanding of the structural determinants of nAChR modulation.

On the behavior of the Pt(1 0 0) and vicinal surfaces in alkaline media

We address in this paper a voltammetric study of the charge transfer processes characteristic of Pt(1 0 0) and vicinal surfaces in alkaline media. The electrochemical behavior of a series of stepped surfaces of the type Pt(S)[n(1 0 0) × (1 1 1)] has been characterized using cyclic voltammetry at different pHs, charge displacement measurements and FTIR experiments for adsorbed CO. The results from these techniques allow assigning the different peaks appearing in the voltammogram to hydrogen and/or OH adsorption on the different sites of these surfaces, namely, terrace and step sites. Additionally, the potential of zero total charge (pztc) of the electrodes was determined. The resulting pztc values shift to more negative values when the step density increases on the surface up to n = 5. FTIR spectroscopy experiments have been used to monitor the adsorption of CO on the different surfaces as well as the consequent CO oxidation, accompanying a positive potential sweep. The oxidation of adsorbed CO on (1 0 0) terraces is catalyzed by the presence of the (1 1 1) steps. The FTIR spectra revealed that CO is mostly bonded in bridge configuration at low potentials interconverting to on-top when the electrode potential is increased.

Urinary albumin levels in the normal range determine arterial wall thickness in adults with Type 2 diabetes: a FIELD substudy

Aim Cardiovascular disease (CVD) rates are substantially higher among patients with Type 2 diabetes than in the general population. The objective of this study was to identify the determinants of carotid intima media thickness (IMT) in patients with Type 2 diabetes. Methods We measured the thickness of the intima media layer of the carotid artery, a strong predictor of the risk of future vascular events, in 397 Type 2 diabetic patients drawn from the Fenofibrate Intervention and Event Lowering in Diabetes study, prior to treatment allocation. Results The mean IMT was 0.78 mm [interquartile range (IQR) 0.23 mm], and the maximum IMT was 1.17 mm (IQR 0.36 mm). By multivariate analysis, age, sex, duration of diabetes, triglycerides, and total cholesterol were independently correlated with IMT, as was urine albumin-creatinine ratio (ACR) (P < 0.001). The effect of ACR on IMT was further examined by tertile. Clinically significant differences in IMT were associated with ACR > 0.65 mg/mmol, approximately one-fifth the standard clinical threshold for microalbuminuria (P < 0.01). Long-term diabetes, independent of other parameters, was associated with a 50% increase in age-related thickening. Conclusions IMT in people with Type 2 diabetes is independently and continuously related to urine albumin levels and to the duration of diabetes. These results support previous data linking urine albumin measurements within the normal range with increased ischaemic cardiac mortality in the setting of Type 2 diabetes, and strongly suggest that urine albumin levels within this range should trigger a formal evaluation for CVD.

Becoming media literate? Media Education in Slovenia after Ten Years

The system of education in Slovenia includes pre-school education; primary education; secondary education (vocational education, technical education, general education [grammar schools]); higher education (university [undergraduate and postgraduate education] and professional type). In this course students develop the ability to analyze and evaluate media messages and to identify for themselves issues of concern, as well as... to discuss, understand, explain and with production through cooperation with student's media their own communication (ZaIa, age 34, media education professor at University of Maribor).

Diastolic dysfunction is a manifestation of ventricular-vascular interaction in patients with type 2 diabetes mellitus

Vascular disease is accelerated in patients with Type 2 diabetes mellitus (T2DM). Since the systemic vasculature plays a pivotal role in myocardial loading, this study aimed to determine the effect of arterial characteristics on left ventricular (LV) morphology and function in patients with T2DM. Conventional echocardiography and tissue Doppler imaging were performed in 172 T2DM patients (95 men; aged 55±11y) with preserved ejection fraction (62±5%). Patients were stratified into groups based on LV geometric pattern (normal [n = 79], concentric remodeling [n = 33], concentric hypertrophy [n = 29], eccentric hypertrophy [n = 31]). Total arterial compliance (TAC) was recorded by simultaneous radial tonometry and aortic outflow pulsed wave Doppler. Arterial (brachial and carotid) structure and function were determined by standard ultrasound methods. There were no significant differences between the LV geometric groups in demographic or clinical parameters. The concentric hypertrophy group had significantly increased carotid artery diameter (6.0±0.7mm versus 6.5±0.7mm; p < 0.05) and stiffness (1912±1203 dynes/cm2mm versus 2976±2695 dynes/cm2mm×10−6; p < 0.05) compared to those with normal geometry. However, TAC did not differ between groups. LV diastolic function, as determined by the ratio of diastolic mitral inflow velocity to mitral annulus tissue velocity (E/E_), was significantly associated with carotid artery relative wall thickness and intima media thickness (p < 0.05). Moreover, E/E_ was independently predicted by carotid artery relative wall thickness (β = 22.9; p = 0.007). We conclude that structural characteristics of the carotid artery are associated with abnormal LV structure and function in patients with T2DM. The LV functional irregularities may be a downstream consequence of amplified pressure wave reflections effecting sub-optimal ventricular-vascular interaction.

Ocular and systemic markers for vascular function in those at risk of type 2 diabetes mellitus and cardiovascular disease

The devastating impact of Type 2 Diabetes Mellitus (T2DM) -related morbidity and mortality on global healthcare is escalating with higher prevalences of obesity, poor diet, and sedentary lifestyles. Therefore, the clinical need for early diagnosis and prevention in groups of high-risk individuals is necessary. The purpose of this thesis was to investigate the use of surrogate markers, namely retinal vascular function, to determine future vascular endothelial dysfunction, atherosclerosis, large vessel disease and cardiovascular risk in certain groups. This namely covered normoglycaemic and normotensive South Asians (SAs), those with Impaired-Glucose Tolerance (IGT) and individuals with a familial history (FH) of T2DM. Additionally the effect of overweight and obesity was studied. The techniques and modified protocols adopted for this thesis involved the investigation of endothelial function by means of vascular reactivity at the ocular and systemic level. Furthermore, the relationships between retinal and systemic function with circulating markers for endothelial cell function and cardiovascular risk markers were explored. The principal studies and findings of the research were: Vascular Function in Normoglycaemic Individuals with and without a FH of T2DM WE FH individuals exhibited higher levels of total cholesterol levels that correlated well with the retinal arterial dilation amplitude to flicker light stimulus. However this did not extend to noticeable differences in markers for endothelial cell damage and impaired retinal and systemic function. Vascular Function in Normoglycaemic South-Asians vs. White-Europeans without a FH and Vascular Disturbances Compared to healthy WEs (normo -glycaemic and -tensive), SA participants exhibited levels of dyslipidaemia and a state of oxidative stress that extended to impaired vascular function as detected by reduced brachial artery flow-mediated dilation, slower retinal arterial vessel dilation reaction times (Appendix 3) and steeper constriction profiles. Furthermore, gender sub-group analysis presented in a sub-chapter shows that SA males demonstrated 24-hour systemic blood pressure (BP) and heart rate variability (HRV) abnormalities and heightened cardiovascular disease (CVD) risk. Vascular Function in Individuals Newly Diagnosed with IGT as compared to Normoglycaemic Healthy Controls Newly-diagnosed WE and SA IGT patients showed a greater risk for CVD and T2DM progression by means of 24-hour BP abnormalities, dyslipidaemia, increased carotid artery intimal-media thickness (c-IMT), Framingham scores and cholesterol ratios. Additionally, pre-clinical markers for oxidative stress and endothelial dysfunction, as evident by significantly lower levels of plasma glutathione and increased levels of von-Willebrand factor in IGT individuals, extended to impaired vascular systemic and retinal function compared to normal controls. This originally shows retinal, systemic and biochemical disturbances in newly-diagnosed IGT not previously reported before. Vascular Function in Normal, Overweight and Obese Individuals of SA and WE Ethnicity In addition to the intended study chapters, the thesis also investigated the influence of obesity and overweight on vascular function. Most importantly, it was found for the first time that compared to lean individuals it was overweight and not obese individuals that exhibited signs of vascular systemic and ocular dysfunction that was evident alongside markers of atherosclerosis, CVD risk and endothelial damage.

Factors affecting the durability of 5.25 inch floppy diskette media and its mechanisms of wear

This project is targeted towards establishing the durability and mechanisms of wear involved in the use of 5.25 inch magnetic floppy diskettes with particular reference to the media manufactured by the Minnesota Mining and Manufacturing Company, 3M Center, St. Paul, Minnesota, USA. In the present work most stress has been laid on the presentation of the conclusions drawn from the results obtained using samples produced specifically for this project. These samples were produced on the pilot plant at 3MTM, St. Paul, USA and are identified by the code 58759-4 with sample numbers SR1 to SR4 each with different lubrication conditions. All of the categories have been produced with four different surface roughnesses by varying the degree of burnishing. It has been found that the mechanisms of wear are related to a fatigue process. Some surprises have been noted in respect of the value of burnishing compared to the observations made elsewhere. Good reasons for these observed differences have been noted, however, and it will be shown that these are merely superficial and not concerned with wear of any real type. The present work reports the effects of the changes in the media's lubrication status and its surface topography as well as presenting evidence for the suggested wear mechanisms.

An assessment of the industry cluster approach as a tool for local economic development:the case of the new media industry in Birmingham

Industry cluster policies are a current trend in local economic development programmes and represent a major shift from traditional approaches. This trend has been coupled by an increasing interest in new media industry as a significant focus for regional development strategies. In England clusters and new media industry have therefore come to be seen as important tools in promoting local and regional economic development. This study aimed to ascertain the success of these policies. In order to achieve the aims of the study, the Birmingham new media industry was chosen for the study. In addition to an extensive review of the literature, semi-structured interviews were conducted with new media firms and Business Support Agencies (BSAs) offering programmes to promote the development of the new media industry cluster. The key findings of the thesis are that the concerns of new media industry when choosing their location do not conform to the industry cluster theory. Moreover, close proximity in geographical location of the industries does not mean there is collaboration and any costs saved as a result of close proximity to similar firms are at present seen as irrelevant because of the type of products they offer. Building trust between firms is the key in developing the new media industry cluster and the BSAs can act as a broker and provide neutral ground to develop it. The key policy recommendations are that new media industry is continually changing and research must continuously track and analyse cluster dynamics in order to be aware of emerging trends and future developments that can positively and negatively affect the cluster. Policy makers need to keep in mind that there is no uniform tool kit to foster the different sectors in cluster development. It is also important for them to be winning support and trust of new media firms since this is key in the success of the cluster. When cluster programs are introduced they must explain their benefits to industries more effectively in order to encourage them to participate in programmes. The general conclusions of the thesis are that clusters are a potentially important tool in local economic development policy and that the new media industry has a considerable growth potential. The kinds of relationships which cluster theory suggests develop between do not, as yet, appear to exist within the new media cluster. There are however, steps that the BSAs can take to encourage their development. Thus, the BSAs need to ensure that they establish an environment that enables growth of the industry.

Type-2 TOPSIS:a group decision problem when ideal values are not extreme endpoints

In the traditional TOPSIS, the ideal solutions are assumed to be located at the endpoints of the data interval. However, not all performance attributes possess ideal values at the endpoints. We termed performance attributes that have ideal values at extreme points as Type-1 attributes. Type-2 attributes however possess ideal values somewhere within the data interval instead of being at the extreme end points. This provides a preference ranking problem when all attributes are computed and assumed to be of the Type-1 nature. To overcome this issue, we propose a new Fuzzy DEA method for computing the ideal values and distance function of Type-2 attributes in a TOPSIS methodology. Our method allows Type-1 and Type-2 attributes to be included in an evaluation system without compromising the ranking quality. The efficacy of the proposed model is illustrated with a vendor evaluation case for a high-tech investment decision making exercise. A comparison analysis with the traditional TOPSIS is also presented. © 2012 Springer Science+Business Media B.V.

Crisis communication and social media : the changing environment for natural disaster response

Over the past two years there have been several large-scale disasters (Haitian earthquake, Australian floods, UK riots, and the Japanese earthquake) that have seen wide use of social media for disaster response, often in innovative ways. This paper provides an analysis of the ways in which social media has been used in public-to-public communication and public-to-government organisation communication. It discusses four ways in which disaster response has been changed by social media: 1. Social media appears to be displacing the traditional media as a means of communication with the public during a crisis. In particular social media influences the way traditional media communication is received and distributed. 2. We propose that user-generated content may provide a new source of information for emergency management agencies during a disaster, but there is uncertainty with regards to the reliability and usefulness of this information. 3. There are also indications that social media provides a means for the public to self-organise in ways that were not previously possible. However, the type and usefulness of self-organisation sometimes works against efforts to mitigate the outcome of the disaster. 4. Social media seems to influence information flow during a disaster. In the past most information flowed in a single direction from government organisation to public, but social media negates this model. The public can diffuse information with ease, but also expect interaction with Government Organisations rather than a simple one-way information flow. These changes have implications for the way government organisations communicate with the public during a disaster. The predominant model for explaining this form of communication, the Crisis and Emergency Risk Communication (CERC), was developed in 2005 before social media achieved widespread popularity. We will present a modified form of the CERC model that integrates social media into the disaster communication cycle, and addresses the ways in which social media has changed communication between the public and government organisations during disasters.

Crisis communication and social media:the changing environment for natural disaster response

Over the past two years there have been several large-scale disasters (Haitian earthquake, Australian floods, UK riots, and the Japanese earthquake) that have seen wide use of social media for disaster response, often in innovative ways. This paper provides an analysis of the ways in which social media has been used in public-to-public communication and public-to-government organisation communication. It discusses four ways in which disaster response has been changed by social media: 1. Social media appears to be displacing the traditional media as a means of communication with the public during a crisis. In particular social media influences the way traditional media communication is received and distributed. 2. We propose that user-generated content may provide a new source of information for emergency management agencies during a disaster, but there is uncertainty with regards to the reliability and usefulness of this information. 3. There are also indications that social media provides a means for the public to self-organise in ways that were not previously possible. However, the type and usefulness of self-organisation sometimes works against efforts to mitigate the outcome of the disaster. 4. Social media seems to influence information flow during a disaster. In the past most information flowed in a single direction from government organisation to public, but social media negates this model. The public can diffuse information with ease, but also expect interaction with Government Organisations rather than a simple one-way information flow. These changes have implications for the way government organisations communicate with the public during a disaster. The predominant model for explaining this form of communication, the Crisis and Emergency Risk Communication (CERC), was developed in 2005 before social media achieved widespread popularity. We will present a modified form of the CERC model that integrates social media into the disaster communication cycle, and addresses the ways in which social media has changed communication between the public and government organisations during disasters.

Metformin:effects on micro and macrovascular complications in type 2 diabetes

Introduction: The antihyperglycaemic agent metformin is widely used in the treatment of type 2 diabetes. Data from the UK Prospective Diabetes Study and retrospective analyses of large healthcare databases concur that metformin reduces the incidence of myocardial infarction and increases survival in these patients. This apparently vasoprotective effect appears to be independent of the blood glucose-lowering efficacy. Effects of metformin: Metformin has long been known to reduce the development of atherosclerotic lesions in animal models, and clinical studies have shown the drug to reduce surrogate measures such as carotid intima-media thickness. The anti-atherogenic effects of metformin include reductions in insulin resistance, hyperinsulinaemia and obesity. There may be modest favourable effects against dyslipidaemia, reductions in pro-inflammatory cytokines and monocyte adhesion molecules, and improved glycation status, benefiting endothelial function in the macro- and micro-vasculature. Additionally metformin exerts anti-thrombotic effects, contributing to overall reductions in athero-thrombotic risk in type 2 diabetic patients. © 2008 Springer Science+Business Media, LLC.

Laparoscopic greater curvature plication in morbidly obese women with type 2 diabetes:effects on glucose homeostasis, postprandial triglyceridemia and selected gut hormones

Background: Laparoscopic greater curvature plication (LGCP) is an emerging bariatric procedure that reduces the gastric volume without implantable devices or gastrectomy. The aim of this study was to explore changes in glucose homeostasis, postprandial triglyceridemia, and meal-stimulated secretion of selected gut hormones [glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-1 (GLP-1), ghrelin, and obestatin] in patients with type 2 diabetes mellitus (T2DM) at 1 and 6 months after the procedure. Methods: Thirteen morbidly obese T2DM women (mean age, 53.2 ± 8.76 years; body mass index, 40.1 ± 4.59 kg/m2) were prospectively investigated before the LGCP and at 1- and 6-month follow-up. At these time points, all study patients underwent a standardized liquid mixed-meal test, and blood was sampled for assessment of plasma levels of glucose, insulin, C-peptide, triglycerides, GIP, GLP-1, ghrelin, and obestatin. Results: All patients had significant weight loss both at 1 and 6 months after the LGCP (p≤0.002), with mean percent excess weight loss (%EWL) reaching 29.7 ;plusmn2.9 % at the 6-month follow-up. Fasting hyperglycemia and hyperinsulinemia improved significantly at 6 months after the LGCP (p<0.05), with parallel improvement in insulin sensitivity and HbA1c levels (p<0.0001). Meal-induced glucose plasma levels were significantly lower at 6 months after the LGCP (p<0.0001), and postprandial triglyceridemia was also ameliorated at the 6-month follow-up (p<0.001). Postprandial GIP plasma levels were significantly increased both at 1 and 6 months after the LGCP (p<0.0001), whereas the overall meal-induced GLP-1 response was not significantly changed after the procedure (p ;gt0.05). Postprandial ghrelin plasma levels decreased at 1 and 6 months after the LGCP (p<0.0001) with no significant changes in circulating obestatin levels. Conclusion: During the initial 6-month postoperative period, LGCP induces significant weight loss and improves the metabolic profile of morbidly obese T2DM patients, while it also decreases circulating postprandial ghrelin levels and increases the meal-induced GIP response. © 2013 Springer Science+Business Media New York.

Facile synthesis and proposed mechanism of α,ω‐oxetanyl-telechelic poly(3-nitratomethyl-3-methyl oxetane) by an SN2(i) nitrato displacement method in basic media

The synthesis of a novel heterocyclic–telechelic polymer, α,ω-oxetanyl-telechelic poly(3-nitratomethyl-3-methyl oxetane), is described. Infrared spectroscopy (IR), gel permeation chromatography (GPC), and nuclear magnetic resonance (NMR) spectroscopy have been used to confirm the successful synthesis, demonstrating the presence of the telechelic-oxetanyl moieties. Synthesis of the terminal functionalities has been achieved via displacement of nitrato groups, in a manner similar to that employed with other leaving groups such as azido, bromo, and nitro, initiated by nucleophiles. In the present case, displacement occurs on the ends of a nitrato-functionalized polymer driven by the formation of sodium nitrate, which is supported by the polar aprotic solvent N,N-dimethyl formamide. The formation of an alkoxide at the polymer chain ends is favored and allows internal back-biting to the nearest carbon bearing the nitrato group, intrinsically in an SN2(i) reaction, leading to α,ω-oxetanyl functionalization. The telechelic-oxetanyl moieties have the potential to be cross-linked by chemical (e.g., acidic) or radiative (e.g., ultraviolet) curing methods without the use of high temperatures, usually below 100°C. This type of material was designed for future use as a contraband simulant, whereby it would form the predominant constituent of elastomeric composites comprising rubbery polymer with small quantities of solids, typically crystals of contraband substances, such as explosives or narcotics. This method also provides an alternative approach to ring closure and synthesis of heterocycles.