Effect of aldosterone antagonism on myocardial dysfunction in hypertensive patients with diastolic heart failure

Background - Specific treatments targeting the pathophysiology of hypertensive heart disease are lacking. As aldosterone has been implicated in the genesis of myocardial fibrosis, hypertrophy, and dysfunction, we sought to determine the effects of aldosterone antagonism on myocardial function in hypertensive patients with suspected diastolic heart failure by using sensitive quantitative echocardiographic techniques in a randomized, double-blinded, placebo-controlled study. Methods and Results - Thirty medically treated ambulatory hypertensive patients (19 women, age 62 +/- 6 years) with exertional dyspnea, ejection fraction >50%, and diastolic dysfunction (E/A 250m/sec) and without ischemia were randomized to spironolactone 25 mg/d or placebo for 6 months. Patients were overweight (31 +/- 5 kg/m(2)) with reduced treadmill exercise capacity (6.7 +/- 2.1 METS). Long-axis strain rate (SR), peak systolic strain, and cyclic variation of integrated backscatter (CVIB) were averaged from 6 walls in 3 standard apical views. Mean 24-hour ambulatory blood pressure at baseline (133 +/- 17/80 +/- 7mm Hg) did not change in either group. Values for SR, peak systolic strain, and CVIB were similar between groups at baseline and remained unchanged with placebo. Spironolactone therapy was associated with increases in SR (baseline: -1.57 +/- 0.46 s(-1) versus 6-months: -1.91 +/- 0.36 s(-1), P < 0.01), peak systolic strain (-20.3 &PLUSMN; 5.0% versus -26.9 &PLUSMN; 4.3%, P < 0.001), and CVIB (7.4 +/- 1.7dB versus 8.6 +/- 1.7 dB, P = 0.08). Each parameter was significantly greater in the spironolactone group compared with placebo at 6 months (P = 0.05, P = 0.02, and P = 0.02, respectively), and the increases remained significant after adjusting for baseline differences. The increase in strain was independent of changes in blood pressure with intervention. The spironolactone group also exhibited reduction in posterior wall thickness (P = 0.04) and a trend to reduced left atrial area (P = 0.09). Conclusions - Aldosterone antagonism improves myocardial function in hypertensive heart disease.

Evaluation of random plasma cortisol and the low dose corticotropin test as indicators of adrenal secretory capacity in critically ill patients: A prospective study

It is unclear whether a random plasma cortisol measurement and the corticotropin (ACTH) test adequately reflect glucocorticoid secretory capacity in critical illness. This study aimed to determine whether these tests provide information representative of the 24 hour period. Plasma cortisol was measured hourly for 24 hours in 21 critically ill septic patients followed by a corticotropin test with 1 μ g dose administered intravenously. Serum and urine were analysed for ACTH and free cortisol respectively. Marked hourly variability in plasma cortisol was evident (coefficient of variation 8-30%) with no demonstrable circadian rhythm. The individual mean plasma cortisol concentrations ranged from 286 59 nmol/l to 796 &PLUSMN; 83 nmol/l. The 24 hour mean plasma cortisol was strongly correlated with both random plasma cortisol (r(2) 0.9, P< 0.0001) and the cortisol response to corticotropin (r(2) 0.72, P< 0.001). Only nine percent of patients increased their plasma cortisol by 250 nmol/l after corticotropin (euadrenal response). However, 35% of non-responders had spontaneous hourly rises > 250 nmol/l thus highlighting the limitations of a single point corticotropin test. Urinary free cortisol was elevated (865&PLUSMN; 937 nmol) in both corticotropin responders and non-responders suggesting elevated plasma free cortisol. No significant relationship was demonstrable between plasma cortisol and ACTH. We conclude that although random cortisol measurements and the low dose corticotropin tests reliably reflect the 24 hour mean cortisol in critical illness, they do not take into account the pulsatile nature of cortisol secretion. Consequently, there is the potential for erroneous conclusions about adrenal function based on a single measurement. We suggest that caution be exercised when drawing conclusions on the adequacy of adrenal function based on a single random plasma cortisol or the corticotropin test.

Busy saying nothing new: Live silence in TV reporting of 9/11

News of the attacks on New York and Washington on September 11th 2001 spread fast, mainly through dramatic images of the events broadcast via a global television media, particularly 24-hour news channels such as BBC News 24 and CNN. Following the initial report many news channels moved to dedicated live coverage of the story. This move, to what Liebes (1998) describes as a 'disaster marathon', entails shifting from the routine, regular news agenda to one where the event and its aftermath become the main story and reference for all other news. In this paper, we draw upon recordings from the BBC News 24 channel on September 11th 2001 during the immediate aftermath of the attacks on the World Trade Centre and Pentagon to argue that the coverage of this event, and other similar types of events, may be characterised as news permeated with strategic and emergent silences. Identifying silence as both concrete and metaphorical, we suggest that there are a number of types of silence found in the coverage and that these not only act to cover for lack of new news, or give emphasis or gravitas, but also that the vacuum created by a lack of news creates an emotional space in which collective shock, grieving or wonder are managed through news presented as phatic communion.

Online counselling: The motives and experiences of young people who choose the internet instead of face to face or telephone counselling

This study used a Consensual Qualitative Research methodology to explore the motivations and experiences of young people who utilize the Internet for counselling over other counselling media. Semi-structured online group interviews (focus groups) were conducted with 39 participants from the Kids Help Line, a 24-hour national telephone and counselling service located in Australia. Analysis revealed five domains relevant to the adolescents' motives and experiences and the frequency of categories within and across cases were analyzed to generate and understand themes and patterns. Specific motivators and barriers are identified and discussed, as are implications for practice and continued research.

Relationships of activity and sugar drink intake on fat mass development in youths

Purpose: To determine whether a significant relationship exists between fat mass (FM) development and physical activity (PA) and/or sugar-sweetened drink (SD) consumption in healthy boys and girls aged 8-19 yr. Methods: A total of 105 males and 103 females were assessed during childhood and adolescence for a maximum of 7 yr and a median of 5 yr. Height was measured biannually. Fat-free mass (FFM) and FM were assessed annually by dual x-ray absorptiometry (DXA). PA was evaluated two to three times annually using the PAQ-C/A. Energy intake and SD were assessed using a 24-h dietary intake questionnaire also completed two to three times per year. Years from peak height velocity were used as a biological maturity age indicator. Multilevel random effects models were used to test the relationship. Results: When controlling for maturation, FFM, and energy intake adjusted for SD, PA level was negatively related to FM development in males (P < 0.05) but not in females (P > 0.05). In contrast, there was no relationship between SD and FM development of males or females (P > 0.05). There was also no interaction effect between SD and PA (P > 0.05) with FM development. Conclusion: This finding tends support to the idea that increasing PA in male youths aids in the control of FM development. Models employed showed no relationship between SD and FM in either gender.

Use of a GnRH agonist and hCG to obtain an index of testosterone secretory capacity in the koala (Phascolarctos cinereus)

Testosterone secretion in mammals typically occurs in random pulses such that a single blood sample provides limited information on reproductive endocrine status. However, it has been shown in several species that an index of the prevailing testosterone biosynthetic capacity of the testes can be obtained by measuring the increase in circulating testosterone after injection of a GnRH agonist or human chorionic gonadotrophin (hCG). Hence, the aims of the present study were to examine fluctuations in testosterone secretion in the koala (n = 6) over a 24-hour period and then characterise testosterone secretion after injection of the GnRH agonist buserelin (4 mu g) or hCG (1000 IU). The latter was used to establish an index of the prevailing testosterone biosynthetic capacity of the koala testis. Individual koalas showed major changes in blood testosterone concentrations over 24 hours, but there was no apparent diurnal pattern of testosterone secretion (P >.05). Injection of buserelin and hCG resulted in an increase (P

Evaluation of the effectiveness of enrichment for a group of captive squirrel monkeys (Saimiri sciureus) using time-lapse recording and instantaneous scan sampling

One aim of providing enrichment to captive animals is to promote the expression of behavioural patterns similar to their wild conspecifics. We evaluated the effectiveness of four types of simple feeding enrichment, using surveillance cameras to record the behaviour of 11 captive squirrel monkeys housed in a single enclosure at Alma Park Zoo in Brisbane, Australia. The enrichment involved differences in presentation (whole/chopped) and distribution (localised/scattered) of fruit and vegetables that were part of the normal diet of these animals. Distinguishing between individual squirrel monkeys was not possible from the videos, so Instantaneous Scan Sampling was used to record the numbers of animals performing particular behaviours every 15 minutes over the 24 hour period as well as every 5 minutes for the hour following provision of enrichment. This provided an estimation of the percentage of time spent by the group in various activities. As a result of the enrichment, the activity budget of the group more closely approximated that of wild squirrel monkeys. However on a number of occasions where the enrichment required the squirrel monkeys to work to obtain their food (whole fruit and vegetables), a number of individuals became aggressive towards the zookeepers. This result highlights the variation in responses of individual animals towards enrichment and indicates that in enclosures with large numbers of animals, the response of each individual should be evaluated in addition to the overall benefit of the enrichment for the group. Furthermore, this variation also suggests that it may be beneficial to provide the animals with choices of enrichment as opposed to providing single forms of enrichment that may only be effective for a proportion of the animals in the enclosure, and may even result in undesirable responses from some individuals.

Feel it and deal with it: mental health practitioners' experiences of exposure to the trauma of survivor clients

Empathic engagement by the trauma therapist with another person's traumatic experiences is believed to create risks for the helping professional. Much attention has been focused upon the mental health professional experiencing symptoms of distress as a result of their exposure to the material of clients who survive traumatic incidents. This thesis contains the findings of a qualitative study that centres on a group of male mental health professionals and their experiences of exposure to the trauma material of survivor clients. The participants of the study practise within an internal Employee Assistance Program that provides, among other duties, a 24 hour, 7 day response to critical incidents to a heavy transport industry. Using semi-structured, in-depth interviews, the effects on the trauma therapists are explored by analysing their reactions to their survivor clients' accounts, the impact of these experiences upon their psychological schema, the organisational culture in which they practise and its influence upon their experiences and the methods participants use to cope with the psychological effects of exposure to trauma material. Participants' experiences are closely examined for critical comparisons with vicarious traumatization. Therapists' responses reveal their continued ability and motivation to empathically engage with the trauma material of survivor clients despite the potential risks.

Attitudes of young people with diabetes to an Internet-based virtual clinic

We assessed the feasibility of developing a virtual diabetes clinic for young people, using the Internet. The proposed content of the site would be based on self-efficacy theory, aiming to develop confidence in self-management of diabetes. A questionnaire about the proposed Website was delivered to 72 patients who attended a young person’s outpatient clinic in a district hospital. Thirty-nine replies were received, a response rate of 54%. The mean age of the respondents was 13 years. A positive attitude to the potential clinic was reported by 95% of respondents. The items rated as most useful were: quick and easy access to up-todate information about diabetes; the opportunity to ask an expert; good graphics; easy navigation; interactivity. Responses to open questions indicated that 24-hour access and anonymity in asking questions were also valued. A virtual clinic appears to be a possible method of health-care delivery to young people with diabetes.

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.

Neurophysiologic assessment of esophageal sensory processing in noncardiac chest pain

Background & Aims: Esophageal hypersensitivity is thought to be important in the generation and maintenance of symptoms in noncardiac chest pain (NCCP). In this study, we explored the neurophysiologic basis of esophageal hypersensitivity in a cohort of NCCP patients. Methods: We studied 12 healthy controls (9 women; mean age, 37.1 ± 8.7 y) and 32 NCCP patients (23 women; mean age, 47.2 ± 10 y). All had esophageal manometry, esophageal evoked potentials to electrical stimulation, and NCCP patients had 24-hour ambulatory pH testing. Results: The NCCP patients had reduced pain thresholds (PT) (72.1 ± 19.4 vs 54.2 ± 23.6, P = .02) and increased P1 latencies (P1 = 105.5 ± 11.1 vs 118.1 ± 23.4, P = .02). Subanalysis showed that the NCCP group could be divided into 3 distinct phenotypic classifications. Group 1 had reduced pain thresholds in conjunction with normal/reduced latency P1 latencies (n = 9). Group 2 had reduced pain thresholds in conjunction with increased (>2.5 SD) P1 latencies (n = 7), and group 3 had normal pain thresholds in conjunction with either normal (n = 10) or increased (>2.5 SD, n = 3) P1 latencies. Conclusions: Normal esophageal evoked potential latencies with reduced PT, as seen in group 1 patients, is indicative of enhanced afferent transmission and therefore increased esophageal afferent pathway sensitivity. Increased esophageal evoked potential latencies with reduced PT in group 2 patients implies normal afferent transmission to the cortex but heightened secondary cortical processing of this information, most likely owing to psychologic factors such as hypervigilance. This study shows that NCCP patients with esophageal hypersensitivity may be subclassified into distinct phenotypic subclasses based on sensory responsiveness and objective neurophysiologic profiles. © 2006 by the American Gastroenterological Association.

The development of filamentous fungi in submerged culture

During the 24 hour period following inoculation, aggregation of spores and sporelings can have an important effect on the subsequent growth of filamentous fungi in submerged culture. This early phase of growth does not appear to have received much attention, and it was for this reason that the author's research was started. The aggregation, germination and early growth of the filamentous fungus Aspergillus niger have been followed in aerated tower fermenters, by microscopic examination. By studying many individual sporelings it has been possible to estimate the specific growth rate and germination times, and then to assess the branching characteristics of the fungus over a period of from 1 to 10 hours after germination. The results have been incorporated into computer models to simulate the development of the physical structure of individual and aggregated sporelings. Following germination, and an initial rapid growth phase, fungi were found to grow exponentially: in the case of A.niger the mean germination time was about 5 hours and the doubling time was as short as 1.5 hours. Branching also followed an exponential pattern and appeared to be related to hyphal length. Using a simple hypothesis for growth along with empirical parameters, typical fungal structures were generated using the computer models : these compared well with actual sporelings observed under the microscope. Preliminary work suggested that the techniques used in this research could be successfully applied to a range of filamentous fungi.

Ceramide and reactive oxygen species (ROS) as signal transduction molecules in inflammation

Reactive oxygen species (ROS) and the sphingolipid ceramide are each partly responsible for the intracellular signal transduction of a variety of physiological, pharmacological or environmental agents. Furthermore, the enhanced production of many of these agents, that utilise ROS and ceramide as signalling intermediates, is associated with the aetiologies of several vascular diseases (e.g. atherosclerosis) or disorders of inflammatory origin (e.g. rheumatoid arthritis; RA). Excessive monocyte recruitment and uncontrolled T cell activation are both strongly implicated in the chronic inflammatory responses that are associated with these pathologies. Therefore the aims of this thesis are (1) to further elucidate the cellular responses to modulations in intracellular ceramide/ROS levels in monocytes and T cells, in order to help resolve the mechanisms of progression of these diseases and (2) to examine both existing agents (methotrexate) and novel targets for possible therapeutic manipulation. Utilising synthetic, short chain ceramide to mimic the cellular responses to fluctuations in natural endogenous ceramide or, stimulation of CD95 to induce ceramide formation, it is described here that ceramide targets and manipulates two discrete sites responsible for ROS generation, preceding the cellular responses of growth arrest in U937 monocytes and apoptosis in Jurkat T-cells. In both cell types, transient elevations in mitochondrial ROS generation were observed. However, the prominent redox altering effects appear to be the ceramide-mediated reduction in cytosolic peroxide, the magnitude of which dictates in part the cellular response in U937 monocytes, Jurkat T-cells and primary human peripheral blood resting or PHA-activated T-cells in vitro. The application of synthetic ceramides to U937 monocytes for short (2 hours) or long (16 hours) treatment periods reduced the membrane expression of proteins associated with cell-cell interaction. Furthermore, ceramide treated U937 monocytes demonstrated reduced adhesion to 5 or 24 hour LPS activated human umbilical vein endothelial cells (HUVEC) but not resting HUVEC. Consequently it is hypothesised that the targeted treatment of monocytes from patients with cardiovascular diseases with short chain synthetic ceramide may reduce disease progression. Herein, the anti-inflammatory and immunosuppressant drug, methotrexate, is described to require ROS production for the induction of cytostasis or cytotoxicity in U937 monocytes and Jurkat T-cells respectively. Further, ROS are critical for methotrexate to abrogate monocyte interaction with activated HUVEC in vitro. The histological feature of RA of enhanced infiltration, survivability and hyporesponsiveness of T-cells within the diseased synovium has been suggested to arise from aberrant signalling. No difference in the concentrations of endogenous T-cell ceramide, the related lipid diacylglycerol (DAG) and cytosolic peroxide ex vivo was observed. TCR activation following PHA exposure in vitro for 72 hours did not induced maintained perturbations in DAG or ceramide in T-cells from RA patients or healthy individuals. However, T-cells from RA patients failed to upregulate cytosolic peroxide in response to PHA, unlike those from normals, despite expressing identical levels of the activation marker CD25. This inability to upregulate cytosolic peroxide may contribute to the T-cell pathology associated with RA by affecting the signalling capacity of redox sensitive biomolecules. These data highlight the importance of two distinctive cellular pools of ROS in mediating complex biological events associated with inflammatory disease and suggest that modulation of cellular ceramides represents a novel therapeutic strategy to minimise monocyte recruitment.

Abnormal retinal vascular reactivity in individuals with impaired glucose tolerance:a preliminary study

To investigate the relationship between vascular function parameters measured at the retinal and systemic level and known markers for cardiovascular risk in patients with impaired glucose tolerance (IGT). Sixty age- and gender- matched White-European adults (30 IGT and 30 normal glucose tolerance -NGT) were recruited for the study. Fasting plasma glucose, lipids and 24-hour blood pressure (BP) was measured in all subjects. Systemic vascular and endothelial function was assessed using carotid-artery intimal media thickness (cIMT) and flow mediated dilation (FMD). Retinal vascular reactivity was assessed by the Dynamic Retinal Vessel Analyser (DVA). Additionally, blood glutathione (GSH, GSSG and tGSH) and plasma von-Willebrand (vWF) factor levels were also measured. Individuals with IGT demonstrated higher BP values (p<0.001), fasting TG and TG:HDL ratios (p<0.001) than NGT subjects. Furthermore, Total:HDL-C ratios and Framingham scores were raised (p=0.010 and p<0.001 respectively). Blood glutathione levels (GSH, GSSG and tGSH) were lower (p<0.001, p=0.039 and p<0.001 respectively) while plasma vWF was increased (p=0.014) in IGT subjects compared to controls. IGT individuals also demonstrated higher IMT in right and left carotid arteries (p=0.017 and p=0.005, respectively) alongside larger brachial artery diameter (p=0.015), lower FMD% (p=0.026) and GTN induced dilation (GID) (p=0.012) than healthy controls. At the retinal arterial level, the IGT subjects showed higher baseline fluctuations (BDF) (p=0.026), longer reaction time (RT) (p=0.032) and reduced baseline-corrected flicker response (bFR) (p=0.045). In IGT subjects retinal BDF correlated with and Total:HDL (p= 0.003) and HDL-C (p= 0.004). Arterial RT also correlated with FMD (p=0.017) in IGT but not NGT subjects. In IGT individuals there is a relationship between macro- and microvascular function, as well as a direct correlation between the observed retinal microcirculatory changes and established plasma markers for CVD. Multifactorial preventive interventions to decrease vascular risk in these individuals should be considered.

Primary open-angle glaucoma vs normal-tension glaucoma:the vascular perspective

Objective: To compare and contrast the presence of ocular and systemic vascular function in newly diagnosed and previously untreated primary open angle glaucoma (POAG) and normal tension glaucoma (NTG) patients with comparable, early stage, functional loss. Methods: The systemic vascular function of 19 POAG patients, 19 NTG patients and 20 healthy controls was assessed by means of 24 hour ambulatory blood pressure (ABPM), peripheral pulse wave analysis (PWA) and carotid intima-media thickness (IMT). Retinal vascular reactivity to flicker light was assessed using dynamic retinal vessel analysis (DVA,IMEDOS, GmbH, Jena, Germany). Results: When compared to normal controls, both POAG and NTG patients exhibited similarly increased nocturnal systemic blood pressure variability (p=0.011); peripheral arterial stiffness (p=0.015), carotid IMT (p=0.040) and reduced ocular perfusion pressure (OPP) (p<0.001). Furthermore, on DVA analysis, both groups of glaucoma patients also exhibited steeper retinal arterial constriction slopes (slope AC) following cessation of flicker (p=0.007) and a similarly increased fluctuation in arterial and venous baseline diameter (p=0.008 and p=0.009 respectively) in comparison to controls. Conclusion: POAG and NTG patients exhibit similar alterations in both ocular and systemic circulation at the early stages of their disease process. This highlights not only the importance of considering vascular risk factors in both conditions, but also raises questions about the current separation of the two conditions into completely distinct clinical entities.