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Regulation of Extra-Pituitary Prolactin in Monocytes and MacrophagesBarrett, Richard 01 January 2018 (has links)
Recently it has been shown that leukocytes are capable of producing prolactin (PRL). Evidence of extra-pituitary PRL (ePRL) production is so far been limited to primates and is not shared across other mammal species such as mice and rats. While ePRL is characterized as an identical protein to traditional pituitary PRL, it is controlled under an alternative promoter and is thus regulated differently from pituitary PRL. Little is known about what regulates ePRL or its direct role in human physiology, but given that PRL has well over 300 described functions, it is likely that the autocrine and paracrine effects of this hormone could have far reaching implications in overall physiology. This work takes some of the first steps in understanding how leukocyte ePRL is regulated. Our results show that, adrenergic hormones are one key stimulus in ePRL expression in monocytes/macrophages. This is particularly intriguing considering the opposing role of these two signals in settings such as adipose tissue where adipose tissue macrophages are constantly exposed to pro-lipolytic adrenergic hormones that would in turn stimulate production of an anti-lipolytic hormone, PRL. Further, our work shows that the inflammatory phenotype of the leukocytes influences basal expression of PRL and overall ePRL expression increases significantly as monocytes differentiate into macrophages, as is a common occurrence in adipose tissue. The final portion of our work shows how monocytes/macrophages also respond to preadipocytes directly. These stem cell precursors to mature adipose cells release an unknown factor that stimulates ePRL production in monocytes/macrophages. Analysis of our gene array shows many of the genes stimulated by adipose stem cells alongside PRL are important genes in tissue regeneration and remodeling, a possible role that fits well with known effects of PRL. Understanding such primate specific interactions between the immune system and major metabolic tissues such as adipose fills vital gaps in knowledge that may explain why so many treatments fail when transitioning from mouse models to humans.
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An investigation of type 2 diabetes self-management in TaiwanWu, Hsiu-Li January 2009 (has links)
In Taiwan, as in other countries, type 2 diabetes is a major public health problem. Taiwanese nurses are being called upon to play an increasingly large role in diabetes care, but little is known about the factors that contribute to good or poor diabetes self-management in the Taiwanese context. This study is an exploratory investigation of Taiwanese women’s experiences of living with type 2 diabetes. Adopting an open-ended qualitative approach, the research aimed to discern personal characteristics, strategies, socio-cultural and health system factors that affected women’s ability to manage their condition effectively. Thirty-eight women were interviewed. These included twenty women who were nominated by health professionals as being effective at diabetes self-management and eithteen who were considered to have difficulties, in controlling their HbA1c. Five senior diabetes nurses were also interviewed. Data was analysed thematically. The study found that for many women, their diabetes diagnosis was marked by profound shock and change in their sense of self. Learning to live with diabetes was an ongoing ‘journey’ in which women engaged in a range of strategies to acquire information and support, to gain a sense of control over their condition and to find a health care provider they could trust. The findings challenge the prevailing medical model that defines ‘successful’ self-management on the basis of clinical outcomes alone. Rather, self-management was found to be highly contingent upon individual life circumstances. From women’s own perspectives, successful self-management involved coping with a context of severe social stigma and juggling their own self-care alongside maintenance of multiple social gender roles and financial responsibilities, often in the face of social or economic difficulties. The research points to a need for health professionals to adopt a non-judgemental, individualised and empowering philosophy in their approach to diabetes care whereby education and treatment is tailored to the specific and complex needs of individual patients.
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Effect of hyperglycaemia on VEGF-A splice variants, junctional integrity and vascular leakage in human feto-placental vessels from normal and type 1 diabetic pregnanciesSciota, Flavia January 2012 (has links)
Hyperglycaemia is a main feature of diabetes, and this pathology is a main complication of pregnancy. Diabetic patients often require tighter glycaemic control in pregnancy, as glucose metabolism changes, and insulin dosages need to be adjusted. Throughout gestation, the placenta is therefore subjected to periods of hyperglycaemic insult. Thus, we wished to study how brief periods of hyperglycaemia affected the feto-placental vasculature, through study of important permeability molecules, pro-permeability VEGFa, anti-permeability VEGFb, and junctional stability molecule VE-cadherin. A 15mM concentration of glucose was chosen because it is a level seen postprandially in diabetic pregnancies. We explored this by explant and perfusion methods. We tested two chorionic villous explants methodologies to validate them for 4h and 24h duration studies, and found that a free-floating methodology which sought to replicate the in utero flow was not appropriate, as this resulted in high basal levels of endothelial VEGF and low junctional VE-cadherin, a feature that we hypothesised to be a wound healing response. Therefore, we chose the stationary explants methodology, with no simulation of flow, for our subsequent experiments. The stationary method, where chorionic villi were incubated with hyperglycaemia (15mM glucose) vs. euglycaemia (5mM glucose) for the two different durations (4h and 24h) revealed that 15mM glucose was affecting junctional stability and the pro-permeability molecule VEGF-A after a 24h hyperglycaemic insult, but that VEGF was not affected by 4h. Given that 4h is a physiologically important timepoint (representing a postprandial glucose peak seen in diabetic pregnancies), we continued with this timepoint in further experiments. Whilst we found no effect of 15mM glucose insult after a 4h incubation on total VEGF expression, we found that the recently discovered anti-permeability VEGFb splice variant was decreased in hyperglycaemia compared to euglycaemic explants. Furthermore, the there was a significant negative correlation between total VEGF and VEGFb levels, indicating that the ratio of the two molecules was changing in diabetic explants compared to normal explants. The diabetic explants showed no further down-regulation of VEGFb on 15mM glucose insult, indicating a tolerance of the diabetic placental vessels to hyperglycaemia. We then investigated whether total VEGF and/or VEGFb were important predictors of vascular dysfunction as measured by an increased in leakage to 76Mr dextran-TRITC tracer in a well established perfusion model. The vascular bed was perfused with 15mM glucose administered to the maternal circuit. After a 3h hyperglycaemic perfusion, we observed high total VEGF, low VEGFb, and a loss of VE-cadherin from the endothelial junctions. These changes corresponded to a mild increase in leakage to 76Mr dextran tracer measured by counting vessels showing 'hotspots' of tracer at perivascular regions (18% of vessels leakage in the hyperglycaemic perfusions vs. 10% leakage in the euglycaemic perfusions). The percentage of vessels exhibiting tracer leakage showed a significant negative correlation with VEGFb (Spearman r value -0.8857) but not total VEGF, indicating that the former may be an important predictor of vascular dysfunction. It would be clinically important to be able to predict placental vascular dysfunction in diabetic pregnancies. Further experiments are needed to see whether the VEGFa/VEGFb ratio can predict vascular leakage under hyperglycaemia and the other main feature of diabetic pregnancies, hyperinsulinaemic insult, and whether the hyperglycaemic insult resulting in the diabetic phenotype is reversible upon euglycaemic conditions being restored. Our studies so far have shown that the diabetic phenotype can be partly replicated, in terms of vascular leakage, with a single 15mM hyperglycaemic insult. Chronic insult may well prove to result in the fully leaky vessels observed in diabetic placentae. VEGFb might be an important predictor of this leakage, and may be clinically used for assessment of risks in diabetic pregnancies.
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Mechanisms underlying obesity-related insulin resistanceTewari, Nilanjana January 2016 (has links)
This thesis investigates the effect of body composition on insulin resistance and the impact of supplementation with nutritional support or carbohydrate treatment. Insulin resistance occurs as a response to a number of stressors, including surgery. However, the mechanism underlying the development of insulin resistance is as yet unclear. Adipose tissue distribution appears to play a role in the development of insulin resistance and obesity-related complications. In obese and non-obese patients undergoing open abdominal surgery who received preoperative carbohydrate or placebo, there was a significant fall in perioperative insulin sensitivity and changes in the expression of genes relating to carbohydrate and fat oxidation. There was no influence of perioperative carbohydrate or obesity on change in insulin sensitivity. Patients undergoing neoadjuvant chemotherapy for oesophageal cancer underwent pre and post chemotherapy assessment of insulin sensitivity and body composition. There was a significant reduction in insulin sensitivity despite minimal change in body composition and adequate nutritional intake. These studies have provided further information about the optimal methods for assessment of insulin sensitivity and body composition as well as an insight into mechanisms underlying the association between body composition and insulin sensitivity.
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GlyCon : glycaemic control of stress hyperglycaemia in intensive care unitsFernández Méndez, Rocío January 2017 (has links)
Background and aims Untreated stress-induced hyperglycaemia in critically ill patients has been associated with harmful effects, which can even be fatal. Current evidence about the optimal glycaemic targets, and the most effective and safest methods of glycaemic control (GC) in intensive care units (ICU), is contradictory. GlyCon study aimed to investigate the effectiveness, efficiency and safety of the monitoring and insulin treatment methods for GC implemented in the seven ICUs of an NHS ICU network in the UK. In addition, GlyCon study also aimed to explore the contents of the local protocols for GC of these ICUs, as well as the views of ICU professionals about several aspects of GC. Methodology A multi-method study was undertaken, comprising three sub‑studies: (1) a document review of the protocols for GC designed by and implemented at each of the participating ICUs, using techniques of inductive content analysis and descriptive statistics; (2) an online survey to ICU medical and nursing staff, on their opinion about effective GC, and deviations from protocol instructions, which was analysed using descriptive statistics and logistic regression; (3) A retrospective study about the methods and outcomes of GC, based on a review of electronic and manual medical records of a stratified random sample of 146 patients admitted to the seven participating ICUs during 2012 and 2013. The main analyses of association between the exposures and the primary outcome measure (percentage of time with glycaemic levels of 4‑10mmol/L, or TIR, which was transformed into the odds of being within that range at any time, or odds of IR), were mainly based on generalised estimating equations using the logit link, and autoregressive correlation structure. Secondary outcome measures of time‑efficiency and safety were also investigated, and analysed using univariate statistics and multiple log‑linear regression. Results The protocols for GC implemented in the seven ICUs differed greatly in their target patients, target glycaemic levels, recommended methods for monitoring, and insulin titration algorithms, among others. Most of the 40 respondents to the survey agreed that TIR≥75% constitutes good GC and TIR < 50% constitutes poor GC. Opinions were divided on intermediate levels of TIR, with professionals having more experience in intensive care tending to rate such intermediate TIR as poor GC more often than their less experienced colleagues. Most of the proposed protocol deviations were considered as major by at least two thirds of the respondents. Professionals’ role (nurse vs. physician) and their number of years of experience were significantly associated with different views. The blood glucose (BG) monitoring frequencies and insulin hourly dosages, at each glycaemic status, differed by ICU, and between patients with and without diabetes. Non‑adherence to protocol instructions regarding BG monitoring and insulin infusion rates occurred more often than not. The median (IQR) TIR was 91% (81‑96%) and 56% (34‑71%) among patients without and with diabetes, respectively. A number of time-dependent and time-constant factors were associated with higher odds of IR at any time. Time-constant protective factors included: having spent more than 20% of admission time receiving insulin during hyperglycaemia, certain ICU protocols, and lower levels of severity on admission. Time-dependent protective factors were: the number of hours from admission, and the dobutamine and insulin hourly dosages. Time-dependent detrimental factors were: non‑adherence to protocol insulin instructions, the hourly nutritional energy administered, and the hourly dosage of certain drugs, including adrenaline and hydrocortisone. Conclusions Protocols for GC, practice of GC, and outcomes of GC, all differed significantly across hospitals. Some protocols seemed more effective, time‑efficient or safe than others, but there was a high incidence of non‑adherence to protocol instructions in all ICUs. This contrasts with professionals rating deviations from protocols as major, more often than not. Certain monitoring and insulin treatment methods for GC were more effective, and some were more time‑efficient than others, particularly among patients without diabetes. There is a clear need for protocols to include different recommendations for patients with diabetes, as well as to formally emphasise the importance of GC also in patients without diabetes. ICU multidisciplinary teams should be involved in the development of these protocols, and their views should be accounted for in research studies about the effectiveness of GC in the ICU.
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Corticosteroid toxicity in childrenAljebab, Fahad January 2017 (has links)
Corticosteroid medicines have anti-inflammatory and immunosuppressant effects. Corticosteroids are prescribed for a wide range of conditions in children. The duration of treatment ranges from a few days (short course) to long term. They are usually given orally in the different dosage form of tablets, syrup or soluble tablets. There are a wide range of adverse drug reactions (ADRs) associated with corticosteroids. This thesis initially evaluates the incidence of each individual ADR in children using systematic reviews. Prospective studies of palatability and pharmacoepidemiology using different methods are also used to evaluate aspects of using corticosteroids in children in Saudi Arabia and the UK. A systematic review of the toxicity of short-course oral corticosteroids in children was conducted. Six electronic databases were searched for articles that evaluated the toxicity of oral corticosteroids in children for up to and including 14 days of treatment. Thirty eight articles including 22 randomised controlled trials (RCTs). The review found that the three most frequent ADRs were vomiting, behavioural changes and sleep disturbance, with incidence rates of 4.3 – 5.4% of patients. Infection was one of the most serious ADRs. A systematic review of the toxicity of long-course oral corticosteroids in children was conducted. One hundred studies including 33 prospective cohort studies and 21 RCTs met the inclusion criteria. The review found that the three most frequent ADRs were weight gain, growth retardation and Cushingoid features, with incidence rates of 18.1 – 21.1% of patients. Infection was one of the most serious ADRs, with twenty one deaths. Hypothalamic-pituitary-adrenal (HPA) axis suppression was detected in 249 of 429 patients in whom it was measured. Based on the findings that were highlighted from the systematic review, a prospective observational/interview study was performed. This study evaluated the tolerability and palatability of oral prednisolone and dexamethasone in children in Saudi Arabia and the UK. Palatability was evaluated by asking patient/parent’s opinions of the taste and acceptability of the medication. Tolerability in particular nausea, vomiting and abdominal pain was evaluated by direct questioning of the patient/parents after each administration. Dexamethasone sodium phosphate solution was the most palatable preparation. Prednisolone base tablets were rated the least palatable and were also the least well tolerated. Palatability scores seemed to improve with second doses. A prospective pharmacoepidemiological study of corticosteroids use in Saudi Arabian children was conducted. This study aimed to evaluate the prescribing pattern of corticosteroids for children in the Emergency, outpatient clinics and paediatric wards in the Gurayat General Hospital (GGH) in Saudi Arabia. A total of 1000 patients were approached for the study. Most of whom were asthmatic, eczema, bronchiolitis, and croup patients. A total of 1209 prescriptions were prescribed from different departments. The three most frequently prescribed corticosteroids medications were hydrocortisone ampoules (24.4%), prednisolone tablets (16.4%) and mometasone furoate ointment (9%). This research has contributed to the field of corticosteroids in children by providing more information about the most common and serious ADRs and determining their relative risk levels.
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Pulmonary neuroendocrinology in health and disease : an immunocytochemical and radioimmunoassay studyMcCann, John Patrick January 1986 (has links)
No description available.
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Diabetic retinopathy : in vitro and clinical studies of mechanisms and pharmacological treatmentsSaker, Saker January 2016 (has links)
Diabetic retinopathy (DR) is the leading cause of visual impairment in the working-age population in developed countries and thus is one of the major ocular health problems worldwide. Diabetes seems to have paradoxical effects on the microvasculature in different tissues. The concentration of glucose in the cellular microenvironment determines the cells ability to proliferate, as well as its permeability, and react to different cytokines. The main cause of visual loss in diabetic eye disease is caused by an increase in microvascular endothelial permeability which leads to vessel leakage and fluid build-up, diabetic macular oedema (DMO). Endothelial cell permeability is influenced by multiple factors which have not been fully elucidated, particularly in human models. In addition, the gene and protein expression between retinal and choroidal endothelial cells, even in humans, has been shown to be affected differently by diabetes. Current treatments for DMO include steroid such as dexamethasone (DEX) and anti-vascular endothelial growth factor (VEGF) drugs (e.g. ranibizumab, Novartis). These target reducing vascular leakage in the macula once it has occurred, but do not attempt to treat the underlying pathology and evidence suggests treatment does not result in a completely dry macula in most cases. The ideal treatment for DMO should improve vision and improve morphological changes in the macula. With the introduction of microperimetry, we are able to determine macular sensitivity and to correlate it with a precise location of oedema. The aim of this project was to investigate, in vitro, the role of hyperglycaemia in the pathogenesis of DR through effects on the proliferation, vascular permeability and/or alteration in adhesion molecule expression of the human ocular micro-vascular endothelial cells (EC). This was supplemented with clinical studies on pharmacological treatments for DMO. The main conclusions made were that high glucose increased retinal EC (REC) permeability in vitro and that this increase was likely caused by a decrease in selective tight junction protein expression. The levels of the angiogenic stimulator VEGF-A in the REC were not altered by high glucose, despite increased expression of the related gene hypoxia inducible factor (HIF)-1a levels. DEX both reduced permeability and restored tight junction expression and a combination of DEX and ranibizumab reduced REC permeability more than either agent alone in vitro. Fixation stability is dependent on foveal cone function. Eyes with good visual acuity normally have excellent fixation stability. However, eyes with poor visual acuity may have reduced fixation. Clinically, this study has shown that DMO eyes with good fixation stability related to good central cone function, normally demonstrate good visual acuity. Where fixation stability is impaired, VA may be reduced. VA changes following treatment of DMO correlated better with fixation stability parameters than with morphological changes on OCT. Fixation stability may, therefore, be a new important parameter in quantifying and predict the functional impact of DMO, and may be, other macular disorders.
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The role of nurses in diabetes care and the impact of the different approaches of nurses' role on patients percieved quality of nursing care : two case studies from the UK and KuwaitAlshammari, Muna A. B. J. M. January 2018 (has links)
Type 2 diabetes (T2D) is considered as a global major health problem, which requires healthcare systems to find solutions to meet the needs of the great numbers of people with T2D. One key to these solutions is nurses who undertake the provision of diabetes care. Nursing care in T2D varies across countries as a result of differences in healthcare systems, the way in which they are organised and other factors relating to nursing practice. The UK and Kuwait are two countries which have high incidences of T2D but differing health care delivery models, which has raised the need to understand the different roles of nurses in providing T2D care in these two countries’ healthcare systems. Key aims of this research were: (1) to investigate the actual roles undertaken by nurses in T2D care; (2) to investigate the extent to which these different roles affect perceived quality of nursing care; (3) to investigate the guidelines of diabetes care in the UK and Kuwait; and (4) to evaluate if nurses are delivering care based on these guidelines. This study investigated two cases in the UK and Kuwait regarding nursing roles in T2D care and how they affect the perceived quality of nursing care. In order to understand the phenomenon, a multiple case study design was employed involving multiple sources of information including documents review, non-participant observations, and semi-structured interviews with nurses and their patients with T2D. The diabetes clinic sites for this study were Nottingham University Hospitals (NUH) Trust in the UK and the Ministry of Health (MoH) hospitals in Kuwait. A thematic approach was utilised as a framework for the within-case and cross-case analyses. The findings of the study showed that nurses are motivated and competent to provide optimum care to achieve patient satisfaction, which is a significant sign of quality of nursing care. The nurse-led system in the UK and the physician-led system in Kuwait indicate different approaches in T2D care. In the UK, the nurse’s part in T2D care has been extended and advanced, making the role comparable to a physician's role. For instance, the status of 'nurse consultant' and 'nurse prescriber', allows the nurse to coordinate and lead diabetes care. In Kuwait, nurses contribute significantly to T2D diabetes care; however, their role is not officially recognised as they are not titled ‘diabetes nurse’ despite the fact they follow physician-established guidelines. Findings from this research further showed that the role of a diabetes nurse in Kuwait lacks clarity, as evidenced by the lack of any published statements specifying their roles according to their specialisation, experience and qualifications. This absence of what nurses are supposed to be doing or a lack of a statement relating to the guideline-informed role of nurses has therefore resulted in an undervaluation and lack of support for this role in Kuwait. The results of this study enhanced understanding of the roles nurses play within T2D care in both the UK and Kuwait. The information gathered also provides better understanding about nurses’ guideline-informed roles and their actual roles in T2D care and therefore that data determines how the differences in the roles of nurses might impact on patients' perceived quality of nursing care.
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Cardiovascular and metabolic outcomes associated with insulin use in type 2 diabetes : evidence from insulin users in the UK primary careAnyanwagu, Uchenna Chidi January 2017 (has links)
In clinical use, insulin improves glycaemic control at the cost, typically, of weight gain and more hypoglycaemia – both being risk factors for cardiovascular (CV) disease mortality. The issue of the effect of exogenous insulin on CV disease meanwhile has been debated for a long time. Data on the CV outcomes associated with insulin-treated diabetes in both randomised trials and observational studies have largely been inconsistent. Thus, a balance of the positives and the negatives of insulin therapy needs to be taken into account when prescribing insulin in routine clinical practice, particularly in the context of the progressive nature of diabetes, its requirement for combination glucose-lowering therapy and the availability of novel glucose lowering agents. So, in a cohort of only insulin-users in ‘real-world’ condition, this thesis aims to explore the association between insulin use and CV and metabolic outcomes. Firstly, a systematic review and meta-analysis of clinical trials that compared only insulin vs other non-insulin glucose-lowering therapies (GLTs) within the past decade was performed and the risk of CV events and important metabolic outcomes were compared between both treatment groups. Then, data from RCTs were compared with ‘real-world’ data (using the UK Primary Care database – The Health improvement Network (THIN)) in terms of clinical outcomes between insulin regimens. Thirdly, using THIN database, retrospective cohort studies were conducted to explore the CV outcomes associated with insulin as regards to the use of newer GLTs, concurrent use of other medications, target HbA1c outcome levels and baseline metabolic profile of insulin-users. Logistic, linear, and Cox regression models; and propensity-score matching models were fitted to explore these associations. Finally, a comparative cross-sectional study was conducted to explore clinical outcomes between the insulin users in a representative UK population database (THIN) vs the local Derbyshire integrated Diabetes service database. A meta-analysis of RCTs first provided insight that allayed fears on the CV concerns on insulin use. It showed no difference in the risk of death and adverse CV events between insulin and non-insulin GLTs. Although insulin was associated with better glycaemic control, similar proportions of both insulin and non-insulin users attained their target HbA1c. The increase in the risks of hypoglycaemia and weight-gain seen in insulin users did not translate to adverse CV events. Furthermore, although RCTs provide superior evidence from which clinical guidelines are built, they do not mirror what happens in ‘real-world’. The discrepancies in glycaemic control (which is lower in real-world) and weight (higher in RCTs) were highlighted. Thus, caution is needed in the extrapolation of RCT-derived estimates of clinical outcomes when formulating guidelines for routine clinical practice. Given the observed discrepancies between weight and HbA1c outcomes between real world and RCT, I investigated the CV and metabolic effects of insulin therapy in the context of baseline weight and insulin-induced weight gain. I observed that in a background of obesity, the use of insulin did not lead to poorer glycaemic control beyond 24 months, instead, patients who were obese experienced a significant reduction in weight and BMI. In the morbidly obese, the risk of composite adverse CV outcomes was, however, increased by 30%. Also, insulin-induced weight-gain was associated with significant reductions in HbA1c and no adverse CV outcomes and mortality. When compared with newer GLTs like the glucagon-like peptide receptor agonists (GLP-1RA), insulin was associated with greater weight-gain and a higher risk of composite CV events and mortality; but in combination with GLP1-RA, it showed both a decrease in the risk of CV event and a reduction in weight. In the elderly insulin users with multiple comorbidities and longer duration of diabetes, extreme HbA1c targets were associated with increased mortality – representing a U-shaped relationship between mortality and HbA1c targets. Furthermore, background statin use among insulin users did not worsen glycaemic control in the long term, but was associated with reduction in composite adverse CV events and mortality independent of the statin type. Finally, the Derby model of integrated diabetes service appeared to confer better clinical outcomes compared with the UK population in terms of the achievement of the combined National Institute for Health and Care Excellence (NICE) targets of HbA1c (< 7.5%), blood pressure (< 140/80) and total cholesterol (< 4mmol/L). This research highlights the important central role insulin plays in the management of T2D; and adds to the growing evidence on its safety and benefits among the high risk groups – the elderly, obese and those with longer duration of diabetes. It also highlights the benefits of the combination of insulin with newer novel GLTs; and concomitant use of other medications which modify CV risk factors. Above all, it recommends individualised treatment approach with full consideration of individual’s metabolic profile and other social factors. Further trials focusing on insulin therapy combinations with newer GLTs will be invaluable in providing more water-tight evidence in insulin use.
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