Pharmacology and therapeutic implications of current drugs for type 2 diabetes mellitus

Type 2 diabetes mellitus (T2DM) is a global epidemic that poses a major challenge to health-care systems. Improving metabolic control to approach normal glycaemia (where practical) greatly benefits long-term prognoses and justifies early, effective, sustained and safety-conscious intervention. Improvements in the understanding of the complex pathogenesis of T2DM have underpinned the development of glucose-lowering therapies with complementary mechanisms of action, which have expanded treatment options and facilitated individualized management strategies. Over the past decade, several new classes of glucose-lowering agents have been licensed, including glucagon-like peptide 1 receptor (GLP-1R) agonists, dipeptidyl peptidase 4 (DPP-4) inhibitors and sodium/glucose cotransporter 2 (SGLT2) inhibitors. These agents can be used individually or in combination with well-established treatments such as biguanides, sulfonylureas and thiazolidinediones. Although novel agents have potential advantages including low risk of hypoglycaemia and help with weight control, long-term safety has yet to be established. In this Review, we assess the pharmacokinetics, pharmacodynamics and safety profiles, including cardiovascular safety, of currently available therapies for management of hyperglycaemia in patients with T2DM within the context of disease pathogenesis and natural history. In addition, we briefly describe treatment algorithms for patients with T2DM and lessons from present therapies to inform the development of future therapies.

The Redox Potentials of n-type Colloidal Semiconductor Nanocrystals

Thesis (Ph.D.)--University of Washington, 2016-08

Neurorehabilitation of hand functions using brain computer interface

Introduction: Brain computer interface (BCI) is a promising new technology with possible application in neurorehabilitation after spinal cord injury. Movement imagination or attempted movement-based BCI coupled with functional electrical stimulation (FES) enables the simultaneous activation of the motor cortices and the muscles they control. When using the BCI- coupled with FES (known as BCI-FES), the subject activates the motor cortex using attempted movement or movement imagination of a limb. The BCI system detects the motor cortex activation and activates the FES attached to the muscles of the limb the subject is attempting or imaging to move. In this way the afferent and the efferent pathways of the nervous system are simultaneously activated. This simultaneous activation encourages Hebbian type learning which could be beneficial in functional rehabilitation after spinal cord injury (SCI). The FES is already in use in several SCI rehabilitation units but there is currently not enough clinical evidence to support the use of BCI-FES for rehabilitation. Aims: The main aim of this thesis is to assess outcomes in sub-acute tetraplegic patients using BCI-FES for functional hand rehabilitation. In addition, the thesis explores different methods for assessing neurological rehabilitation especially after BCI-FES therapy. The thesis also investigated mental rotation as a possible rehabilitation method in SCI. Methods: Following investigation into applicable methods that can be used to implement rehabilitative BCI, a BCI based on attempted movement was built. Further, the BCI was used to build a BCI-FES system. The BCI-FES system was used to deliver therapy to seven sub-acute tetraplegic patients who were scheduled to receive the therapy over a total period of 20 working days. These seven patients are in a 'BCI-FES' group. Five more patients were also recruited and offered equivalent FES quantity without the BCI. These further five patients are in a 'FES-only' group. Neurological and functional measures were investigated and used to assess both patient groups before and after therapy. Results: The results of the two groups of patients were compared. The patients in the BCI-FES group had better improvements. These improvements were found with outcome measures assessing neurological changes. The neurological changes following the use of the BCI-FES showed that during movement attempt, the activation of the motor cortex areas of the SCI patients became closer to the activation found in healthy individuals. The intensity of the activation and its spatial localisation both improved suggesting desirable cortical reorganisation. Furthermore, the responses of the somatosensory cortex during sensory stimulation were of clear evidence of better improvement in patients who used the BCI-FES. Missing somatosensory evoked potential peaks returned more for the BCI-FES group while there was no overall change in the FES-only group. Although the BCI-FES group had better neurological improvement, they did not show better functional improvement than the FES-only group. This was attributed mainly to the short duration of the study where therapies were only delivered for 20 working days. Conclusions: The results obtained from this study have shown that BCI-FES may induce cortical changes in the desired direction at least faster than FES alone. The observation of better improvement in the patients who used the BCI-FES is a good result in neurorehabilitation and it shows the potential of thought-controlled FES as a neurorehabilitation tool. These results back other studies that have shown the potential of BCI-FES in rehabilitation following neurological injuries that lead to movement impairment. Although the results are promising, further studies are necessary given the small number of subjects in the current study.

Current evidence on integrated treatment for serious mental disorder and substance misuse

Substance misuse in people with serious mental disorders is common and has a wideranging negative impact. The multiplicity of problems suggests that this comorbidity is better conceptualized as a type of complex disorder than by ‘dual diagnosis’. Problems with sequential and parallel treatments have led to the development of integrated approaches, with one practitioner or team addressing both the substance use and mental disorder. These treatments are typically characterized by motivation enhancement, minimizing treatment-related stress, emphasizing harm reduction as well as abstinence, and assertive outreach. A review of published randomized trials demonstrates that superior effects to controls are rarely consistent across treatment foci and over time. While motivational interventions assist engagement, more intervention is usually required for integrated treatment programs to improve long-term outcomes more than control conditions. More intensive case management does not consistently improve impact, but extended cognitive-behavioral therapies have promise. Suggestions for maximizing treatment effects and improving research evidence are provided.

Improved image contrast of the bone-muscle interface with 3T MRI compared to 1.5T MRI [Abstract]

Virtual 3D models of long bones are increasingly being used for implant design and research applications. The current gold standard for the acquisition of such data is Computed Tomography (CT) scanning. Due to radiation exposure, CT is generally limited to the imaging of clinical cases and cadaver specimens. Magnetic Resonance Imaging (MRI) does not involve ionising radiation and therefore can be used to image selected healthy human volunteers for research purposes. The feasibility of MRI as alternative to CT for the acquisition of morphological bone data of the lower extremity has been demonstrated in recent studies [1, 2]. Some of the current limitations of MRI are long scanning times and difficulties with image segmentation in certain anatomical regions due to poor contrast between bone and surrounding muscle tissues. Higher field strength scanners promise to offer faster imaging times or better image quality. In this study image quality at 1.5T is quantitatively compared to images acquired at 3T. --------- The femora of five human volunteers were scanned using 1.5T and 3T MRI scanners from the same manufacturer (Siemens) with similar imaging protocols. A 3D flash sequence was used with TE = 4.66 ms, flip angle = 15° and voxel size = 0.5 × 0.5 × 1 mm. PA-Matrix and body matrix coils were used to cover the lower limb and pelvis respectively. Signal to noise ratio (SNR) [3] and contrast to noise ratio (CNR) [3] of the axial images from the proximal, shaft and distal regions were used to assess the quality of images from the 1.5T and 3T scanners. The SNR was calculated for the muscle and bone-marrow in the axial images. The CNR was calculated for the muscle to cortex and cortex to bone marrow interfaces, respectively. --------- Preliminary results (one volunteer) show that the SNR of muscle for the shaft and distal regions was higher in 3T images (11.65 and 17.60) than 1.5T images (8.12 and 8.11). For the proximal region the SNR of muscles was higher in 1.5T images (7.52) than 3T images (6.78). The SNR of bone marrow was slightly higher in 1.5T images for both proximal and shaft regions, while it was lower in the distal region compared to 3T images. The CNR between muscle and bone of all three regions was higher in 3T images (4.14, 6.55 and 12.99) than in 1.5T images (2.49, 3.25 and 9.89). The CNR between bone-marrow and bone was slightly higher in 1.5T images (4.87, 12.89 and 10.07) compared to 3T images (3.74, 10.83 and 10.15). These results show that the 3T images generated higher contrast between bone and the muscle tissue than the 1.5T images. It is expected that this improvement of image contrast will significantly reduce the time required for the mainly manual segmentation of the MR images. Future work will focus on optimizing the 3T imaging protocol for reducing chemical shift and susceptibility artifacts.

Expert elicitation and its interface with technology : a review with a view to designing Elicitator

Expert knowledge is valuable in many modelling endeavours, particularly where data is not extensive or sufficiently robust. In Bayesian statistics, expert opinion may be formulated as informative priors, to provide an honest reflection of the current state of knowledge, before updating this with new information. Technology is increasingly being exploited to help support the process of eliciting such information. This paper reviews the benefits that have been gained from utilizing technology in this way. These benefits can be structured within a six-step elicitation design framework proposed recently (Low Choy et al., 2009). We assume that the purpose of elicitation is to formulate a Bayesian statistical prior, either to provide a standalone expert-defined model, or for updating new data within a Bayesian analysis. We also assume that the model has been pre-specified before selecting the software. In this case, technology has the most to offer to: targeting what experts know (E2), eliciting and encoding expert opinions (E4), whilst enhancing accuracy (E5), and providing an effective and efficient protocol (E6). Benefits include: -providing an environment with familiar nuances (to make the expert comfortable) where experts can explore their knowledge from various perspectives (E2); -automating tedious or repetitive tasks, thereby minimizing calculation errors, as well as encouraging interaction between elicitors and experts (E5); -cognitive gains by educating users, enabling instant feedback (E2, E4-E5), and providing alternative methods of communicating assessments and feedback information, since experts think and learn differently; and -ensuring a repeatable and transparent protocol is used (E6).

Grassland management activity data : current sources and future needs

Estimates of potential and actual C sequestration require areal information about various types of management activities. Forest surveys, land use data, and agricultural statistics contribute information enabling calculation of the impacts of current and historical land management on C sequestration in biomass (in forests) or in soil (in agricultural systems). Unfortunately little information exists on the distribution of various management activities that can impact soil C content in grassland systems. Limited information of this type restricts our ability to carry out bottom-up estimates of the current C balance of grasslands or to assess the potential for grasslands to act as C sinks with changes in management. Here we review currently available information about grassland management, how that information could be related to information about the impacts of management on soil C stocks, information that may be available in the future, and needs that remain to be filled before in-depth assessments may be carried out. We also evaluate constraints induced by variability in information sources within and between countries. It is readily apparent that activity data for grassland management is collected less frequently and on a coarser scale than data for forest or agricultural inventories and that grassland activity data cannot be directly translated into IPCC-type factors as is done for IPCC inventories of agricultural soils. However, those management data that are available can serve to delineate broad-scale differences in management activities within regions in which soil C is likely to change in response to changes in management. This, coupled with the distinct possibility of more intensive surveys planned in the future, may enable more accurate assessments of grassland C dynamics with higher resolution both spatially and in the number management activities.

Adapting to the work-life interface : the influence of individual differences, work and family on well-being, mental health and work engagement

Bronfenbrenner.s Bioecological Model, expressed as the developmental equation, D f PPCT, is the theoretical framework for two studies that bring together diverse strands of psychology to study the work-life interface of working adults. Occupational and organizational psychology is focused on the demands and resources of work and family, without emphasising the individual in detail. Health and personality psychology examine the individual but without emphasis on the individual.s work and family roles. The current research used Bronfenbrenner.s theoretical framework to combine individual differences, work and family to understand how these factors influence the working adult.s psychological functioning. Competent development has been defined as high well-being (measured as life satisfaction and psychological well-being) and high work engagement (as work vigour, work dedication and absorption in work) and as the absence of mental illness (as depression, anxiety and stress) and the absence of burnout (as emotional exhaustion, cynicism and professional efficacy). Study 1 and 2 were linked, with Study 1 as a cross-sectional survey and Study 2, a prospective panel study that followed on from the data used in Study1. Participants were recruited from a university and from a large public hospital to take part in a 3-wave, online study where they completed identical surveys at 3-4 month intervals (N = 470 at Time 1 and N = 198 at Time 3). In Study 1, hierarchical multiple regressions were used to assess the effects of individual differences (Block 1, e.g. dispositional optimism, coping self-efficacy, perceived control of time, humour), work and family variables (Block 2, e.g. affective commitment, skill discretion, work hours, children, marital status, family demands) and the work-life interface (Block 3, e.g. direction and quality of spillover between roles, work-life balance) on the outcomes. There were a mosaic of predictors of the outcomes with a group of seven that were the most frequent significant predictors and which represented the individual (dispositional optimism and coping self-efficacy), the workplace (skill discretion, affective commitment and job autonomy) and the work-life interface (negative work-to-family spillover and negative family-to-work spillover). Interestingly, gender and working hours were not important predictors. The effects of job social support, generally and for work-life issues, perceived control of time and egalitarian gender roles on the outcomes were mediated by negative work-to-family spillover, particularly for emotional exhaustion. Further, the effect of negative spillover on depression, anxiety and work engagement was moderated by the individual.s personal and workplace resources. Study 2 modelled the longitudinal relationships between the group of the seven most frequent predictors and the outcomes. Using a set of non-nested models, the relative influences of concurrent functioning, stability and change over time were assessed. The modelling began with models at Time 1, which formed the basis for confirmatory factor analysis (CFA) to establish the underlying relationships between the variables and calculate the composite variables for the longitudinal models. The CFAs were well fitting with few modifications to ensure good fit. However, using burnout and work engagement together required additional analyses to resolve poor fit, with one factor (representing a continuum from burnout to work engagement) being the only acceptable solution. Five different longitudinal models were investigated as the Well-Being, Mental Distress, Well-Being-Mental Health, Work Engagement and Integrated models using differing combinations of the outcomes. The best fitting model for each was a reciprocal model that was trimmed of trivial paths. The strongest paths were the synchronous correlations and the paths within variables over time. The reciprocal paths were more variable with weak to mild effects. There was evidence of gain and loss spirals between the variables over time, with a slight net gain in resources that may provide the mechanism for the accumulation of psychological advantage over a lifetime. The longitudinal models also showed that there are leverage points at which personal, psychological and managerial interventions can be targeted to bolster the individual and provide supportive workplace conditions that also minimise negative spillover. Bronfenbrenner.s developmental equation has been a useful framework for the current research, showing the importance of the person as central to the individual.s experience of the work-life interface. By taking control of their own life, the individual can craft a life path that is most suited to their own needs. Competent developmental outcomes were most likely where the person was optimistic and had high self-efficacy, worked in a job that they were attached to and which allowed them to use their talents and without too much negative spillover between their work and family domains. In this way, individuals had greater well-being, better mental health and greater work engagement at any one time and across time.

Cognitive behaviour therapy (CBT) for the treatment of co-occurring depression and substance use : current evidence and directions for future research

Issues and Approach: The high rates of co-occurring depression and substance use, and the negative impact of this on illness course and outcomes have been well established. Despite this, few clinical trials have examined the efficacy of cognitive behaviour therapy (CBT). This paper systematically reviews these clinical trials, with an aim of providing recommendations for how future research can develop a more robust evidence base for the treatment of these common comorbidities. Leading electronic databases, including PubMed (ISI) and PsychINFO (CSA), were searched for peer-reviewed journal articles using CBT for the treatment of co-occurring depression and substance use. Of the 55 articles identified, 12 met inclusion criteria and were included in the review. ---------- Key Findings: There is only a limited evidence for the effectiveness of CBT either alone or in combination with antidepressant medication for the treatment of co-occurring depression and substance use. While there is support for the efficacy of CBT over no treatment control conditions, there is little evidence that CBT is more efficacious than other psychotherapies. There is, however, consistent evidence of improvements in both depression and substance use outcomes, regardless of the type of treatment provided and there is growing evidence that that the effects of CBT are durable and increase over time during follow up. ---------- Conclusions. Rather than declaring the ‘dodo bird verdict’ that CBT and all other psychotherapies are equally efficacious, it would be more beneficial to develop more potent forms of CBT by identifying variables that mediate treatment outcomes.

Human atrial beta1L-adrenoceptor but not beta3-adrenoceptor activation increases force and Ca2+ current at physiological temperature

BACKGROUND AND PURPOSE It has been proposed that BRL37344, SR58611 and CGP12177 activate b3-adrenoceptors in human atrium to increase contractility and L-type Ca2+ current (ICa-L). b3-adrenoceptor agonists are potentially beneficial for the treatment of a variety of diseases but concomitant cardiostimulation would be potentially harmful. It has also been proposed that (-)-CGP12177 activates the low affinity binding site of the b1-adrenoceptor in human atrium. We therefore used BRL37344, SR58611 and (-)-CGP12177 with selective b-adrenoceptor subtype antagonists to clarify cardiostimulant b-adrenoceptor subtypes in human atrium. EXPERIMENTAL APPROACH Human right atrium was obtained from patients without heart failure undergoing coronary artery bypass or valve surgery. Cardiomyocytes were prepared to test BRL37344, SR58611 and CGP12177 effects on ICa-L. Contractile effects were determined on right atrial trabeculae. KEY RESULTS BRL37344 increased force which was antagonized by blockade of b1- and b2-adrenoceptors but not by blockade of b3-adrenoceptors with b3-adrenoceptor-selective L-748,337 (1 mM). The b3-adrenoceptor agonist SR58611 (1 nM–10 mM) did not affect atrial force. BRL37344 and SR58611 did not increase ICa-L at 37°C, but did at 24°C which was prevented by L-748,337. (-)-CGP12177 increased force and ICa-L at both 24°C and 37°C which was prevented by (-)-bupranolol (1–10 mM), but not L-748,337. CONCLUSIONS AND IMPLICATIONS We conclude that the inotropic responses to BRL37344 are mediated through b1- and b2-adrenoceptors. The inotropic and ICa-L responses to (-)-CGP12177 are mediated through the low affinity site b1L-adrenoceptor of the b1-adrenoceptor. b3-adrenoceptor-mediated increases in ICa-L are restricted to low temperatures. Human atrial b3-adrenoceptors do not change contractility and ICa-L at physiological temperature.

Randomised controlled trial of an automated, interactive telephone intervention to improve type 2 diabetes self-management (Telephone-Linked Care Diabetes Project) : study protocol

Background: An estimated 285 million people worldwide have diabetes and its prevalence is predicted to increase to 439 million by 2030. For the year 2010, it is estimated that 3.96 million excess deaths in the age group 20-79 years are attributable to diabetes around the world. Self-management is recognised as an integral part of diabetes care. This paper describes the protocol of a randomised controlled trial of an automated interactive telephone system aiming to improve the uptake and maintenance of essential diabetes self-management behaviours. ---------- Methods/Design: A total of 340 individuals with type 2 diabetes will be randomised, either to the routine care arm, or to the intervention arm in which participants receive the Telephone-Linked Care (TLC) Diabetes program in addition to their routine care. The intervention requires the participants to telephone the TLC Diabetes phone system weekly for 6 months. They receive the study handbook and a glucose meter linked to a data uploading device. The TLC system consists of a computer with software designed to provide monitoring, tailored feedback and education on key aspects of diabetes self-management, based on answers voiced or entered during the current or previous conversations. Data collection is conducted at baseline (Time 1), 6-month follow-up (Time 2), and 12-month follow-up (Time 3). The primary outcomes are glycaemic control (HbA1c) and quality of life (Short Form-36 Health Survey version 2). Secondary outcomes include anthropometric measures, blood pressure, blood lipid profile, psychosocial measures as well as measures of diet, physical activity, blood glucose monitoring, foot care and medication taking. Information on utilisation of healthcare services including hospital admissions, medication use and costs is collected. An economic evaluation is also planned.---------- Discussion: Outcomes will provide evidence concerning the efficacy of a telephone-linked care intervention for self-management of diabetes. Furthermore, the study will provide insight into the potential for more widespread uptake of automated telehealth interventions, globally.

Mesenchymal stem cells in osteoarthritis therapy : current status of theory, technology, and applications

Osteoarthritis (OA) is a chronic, non-inflammatory type of arthritis, which usually affects the movable and weight bearing joints of the body. It is the most common joint disease in human beings and common in elderly people. Till date, there are no safe and effective diseases modifying OA drugs (DMOADs) to treat the millions of patients suffering from this serious and debilitating disease. However, recent studies provide strong evidence for the use of mesenchymal stem cell (MSC) therapy in curing cartilage related disorders. Due to their natural differentiation properties, MSCs can serve as vehicles for the delivery of effective, targeted treatment to damaged cartilage in OA disease. In vitro, MSCs can readily be tailored with transgenes with anti-catabolic or pro-anabolic effects to create cartilage-friendly therapeutic vehicles. On the other hand, tissue engineering constructs with scaffolds and biomaterials holds promising biological cartilage therapy. Many of these strategies have been validated in a wide range of in vitro and in vivo studies assessing treatment feasibility or efficacy. In this review, we provide an outline of the rationale and status of stem-cell-based treatments for OA cartilage, and we discuss prospects for clinical implementation and the factors crucial for maintaining the drive towards this goal.

Heterogeneous photocatalytic degradation of phenols in wastewater : a review on current status and developments

In recent years, there has been an enormous amount of research and development in the area of heterogeneous photocatalytic water purification process due to its effectiveness in degrading and mineralising the recalcitrant organic compounds as well as the possibility of utilising the solar UV and visible spectrum. One hundred and twenty recently published papers are reviewed and summarised here with the focus being on the photocatalytic oxidation of phenols and their derivatives, predominant in waste water effluent. In this review, the effects of various operating parameters on the photocatalytic degradation of phenols and substituted phenols are presented. Recent findings suggested that different parameters, such as type of photocatalyst and composition, light intensity, initial substrate concentration, amount of catalyst, pH of the reaction medium, ionic components in water, solvent types, oxidising agents/electron acceptors, mode of catalyst application, and calcination temperatures can play an important role on the photocatalytic degradation of phenolic compounds in wastewater. Extensive research has focused on the enhancement of photocatalysis by modification of TiO2 employing metal, non-metal and ion doping. Recent developments in TiO2 photocatalysis for the degradation of various phenols and substituted phenols are also reviewed.

Neural interface systems : a new legal frontier?

In an age where digital innovation knows no boundaries, research in the area of brain-computer interface and other neural interface devices go where none have gone before. The possibilities are endless and as dreams become reality, the implications of these amazing developments should be considered. Some of these new devices have been created to correct or minimise the effects of disease or injury so the paper discusses some of the current research and development in the area, including neuroprosthetics. To assist researchers and academics in identifying some of the legal and ethical issues that might arise as a result of research and development of neural interface devices, using both non-invasive techniques and invasive procedures, the paper discusses a number of recent observations of authors in the field. The issue of enhancing human attributes by incorporating these new devices is also considered. Such enhancement may be regarded as freeing the mind from the constraints of the body, but there are legal and moral issues that researchers and academics would be well advised to contemplate as these new devices are developed and used. While different fact situation surround each of these new devices, and those that are yet to come, consideration of the legal and ethical landscape may assist researchers and academics in dealing effectively with matters that arise in these times of transition. Lawyers could seek to facilitate the resolution of the legal disputes that arise in this area of research and development within the existing judicial and legislative frameworks. Whether these frameworks will suffice, or will need to change in order to enable effective resolution, is a broader question to be explored.