Clinical and echocardiographic characteristics of cardioembolic stroke.

BACKGROUND AND PURPOSE: Ischaemic stroke frequently has a cardioembolic (CE) source. Clinical and echocardiographic parameters associated with CE stroke were evaluated. METHODS: In all, 93 consecutive ischaemic stroke patients who underwent a transthoracic echocardiogram were retrospectively analysed; strokes were classified by TOAST (Trial of Org 10172 in Acute Stroke Treatment) criteria. Echocardiographic parameters related to CE stroke, including left atrial volumes and function, were compared to 73 healthy controls. RESULTS: Of 93 patients (mean age 66.1 years, 56% male), nine (10%) had large artery atherosclerosis, 38 (41%) CE stroke, two (2%) small vessel disease, two (2%) other and 42 (45%) undetermined aetiology. Left atrial (LA) maximum volumes (LAVImax ) and minimum volumes (LAVImin ) were larger in the CE group than the non-CE group (45 vs. 32 ml/m2 , 32 vs. 13 ml/m2 , respectively, P < 0.001), whilst LA function indices including LA emptying fraction and LA function index (LAFI) were lower in the CE group (34% vs. 55%, and 0.12 vs. 0.35, respectively, P < 0.001). Adjusting for clinical characteristics, LAFI ≤0.3 was an independent predictor of CE stroke (adjusted odds ratio 5.3, P = 0.001). Additionally, LAVImax and LAVImin were larger (61 vs. 44 and 32 vs. 24 ml/m2 respectively, P < 0.01) and LAFI significantly lower (0.34 vs. 0.52, P < 0.001) in the undetermined aetiology group versus healthy controls. CONCLUSIONS: Left atrial enlargement with reduced LA function was associated with CE stroke and LAFI was the best independent predictor. LA parameters were also altered in the undetermined aetiology group, suggesting an underlying LA myopathy in this subset.

Effect of lifestyle focused text messaging on risk factor modification in patients with diabetes and coronary heart disease: A sub-analysis of the TEXT ME study.

AIMS: There is potential to provide public health interventions through text messaging for patients with Type 2 diabetes mellitus (T2DM). Our objective was to ascertain if lifestyle focused text messaging addressing cardiovascular risk factors in patients with coronary heart disease (CHD) and T2DM, was more effective than usual care. METHODS: This is a secondary analysis of the TEXT ME study, a randomised clinical trial of a 6-month text messaging intervention in patients with coronary heart disease. The measured outcomes include cholesterol, blood pressure (BP), body mass index (BMI), HbA1c, waist/hip circumference and smoking status. Our objective was to ascertain if lifestyle focused text messaging in patients with T2DM was more effective than usual care, and to determine if the intervention was more effective in patients with T2DM compared to those without. RESULTS: 229 participants in the TEXT ME study had T2DM (32%), 111 participants in the intervention group and 118 in the control group. At 6 months, the mean difference in systolic BP was -7.6 mmHg (95%CI -11.8, -3.37, p = 0.0003) and diastolic BP -3.7 mmHg (95%CI -6.12, -1.24, p = 0.0032). The mean difference in low density lipoprotein in the intervention arm, compared to the control arm, was -0.05 mmol/L (95%CI -0.27, 0.18, p = 0.813), and in triglycerides was -0.29 mmol/L (95%CI -0.59, 0.01, p = 0.035) respectively. The mean difference in BMI was -0.89 kg/m2 (95%CI -2.74, 0.95, p < 0.0001) in the intervention group, waist circumference -3.98 cm (95%CI -8.57, 0.61, p < 0.0001) and hip circumference -3.26 cm (95%CI -7.67, 1.16, p = 0.0006). Intervention subjects with diabetes were less likely to be smokers at 6 months. The mean difference in HbA1c between the control and intervention group was not significant (p = 0.126). The intervention was as effective in patients with diabetes, compared to those without. CONCLUSION: Among patients with coronary heart disease with T2DM, lifestyle-focused text messaging resulted in significant risk factor reduction.

Hypertension is associated with narrower retinal arteriolar calibre in persons with and without coronary artery disease.

The aims of this study were to investigate independent associations between hypertension and retinal vessel calibre in a high cardiovascular risk cohort and to determine whether these associations also exist in patients without coronary artery disease (CAD). The Australian Heart Eye Study is an observational study that surveyed 1680 participants presenting to a tertiary referral hospital for the evaluation of potential CAD by coronary angiography. Hypertension was defined as systolic >140 mm Hg, diastolic >90 mm Hg or treated (use of antihypertensive medications). Retinal arteriolar and venular calibres were measured from retinal photographs. CAD was quantified using severity (Gensini) and extent scores. Subanalyses were performed for people with and without CAD and for men and women. A total of 1114 participants had complete data on hypertension, coronary vessel evaluation and retinal vessel measurements and were included in cross-sectional analyses. Among persons with CAD, those with hypertension (compared with without) had narrower retinal arteriolar calibre (mean arteriolar calibre difference 2.1 µm, P=0.02), adjusting for age, sex, ethnicity, body mass index, smoking status and fellow vessel calibre. This association was also present among persons without CAD (mean difference 5.0 µm, P=0.04). Stratification by sex indicated that women with hypertension had marginally narrower retinal arterioles compared with normotensive women (multivariable-adjusted P=0.04). No significant association between hypertension and retinal arteriolar calibre was observed in men (P=0.13). No significant differences in retinal venular calibre were observed (P>0.05). In conclusion, in both subjects with and without CAD, hypertension was independently associated with narrower retinal arterioles.

Perfusion redistribution after a pulmonary-embolism-like event with contrast enhanced EIT.

Recent studies showed that regional pulmonary perfusion can be reliably estimated using electrical impedance tomography (EIT) with the aid of hypertonic saline based contrast enhancement. Building on these successful studies, we studied contrast EIT for pulmonary perfusion defect caused by an artificially induced pulmonary embolism (PE) in a large ovine model (N = 8, 78 ± 7.8 kg). Furthermore, the efficacy of a less invasive contrast bolus of 0.77 ml kg(-1) of NaCl 3% was compared with a more concentrated bolus of 0.13 ml kg(-1) of NaCl 20%. Prior to the injection of each contrast bolus injection, ventilation was turned off to provide a total of 40 to 45 s of apnoea. Each bolus of impedance contrast was injected through a catheter into the right atrium. Pulmonary embolisation was performed by balloon occlusion of part of the right branch of the pulmonary trunk. Four parameters representing the kinetics of the contrast dilution in the lung were evaluated for statistical differences between baseline and PE, including peak value, maximum uptake, maximum washout and area under the curve of the averaged contrast dilution curve in each lung. Furthermore, the right lung to left lung (R2L) ratio of each the aforementioned parameters were assessed. While all of the R2L ratios yielded significantly different means between baseline and PE, it can be concluded that the R2L ratios of area under the curve and peak value of the averaged contrast dilution curve are the most promising and reliable in assessing PE. It was also found that the efficacy of the two types of impedance contrasts were not significantly different in distinguishing PE from baseline in our model.

Development of a set of mobile phone text messages designed for prevention of recurrent cardiovascular events.

BACKGROUND: Supporting lifestyle change is an effective way of preventing recurrent events in people with cardiovascular disease (CVD). However, there is a need to develop innovative strategies that increase access to programmes for individuals at high risk of CVD. This study aimed to develop a bank of text messages designed to provide advice, motivation, and support for decreasing cardiovascular risk. DESIGN: Iterative development process with mixed methods METHODS: An initial bank of 120 text messages was drafted based on behaviour change techniques, guidelines, and input from clinicians and public health experts. A questionnaire was then administered to participants (n = 53) for evaluation of message content, usefulness, and language. To test the process of delivery, a pilot study was conducted using a specifically designed computer programme that delivered messages to multiple mobile phones according to a pre-specified schedule. Data were collected regarding message timing, delivery, and usefulness. RESULTS: In the qualitative questionnaire, 92% of participants found the messages easy to understand and 86% found the messages contained useful information. Positive feedback was also obtained from the pilot study. Based on these results, together with suggestions provided, several messages were reworded and an additional 44 were written. The need for semi-personalization was also identified and a random set of 103 individualized messages was created. CONCLUSIONS: A final bank of 137 mobile telephone text messages designed to support behaviour change and decrease cardiovascular risk have been developed through a multistep iterative process. This provides a scientific approach for future developers of health-related text messages.

Towards true unipolar ECG recording without the Wilson central terminal (preliminary results).

We present an innovative bio-potential front-end capable of recording true unipolar ECG leads for the first time without making use of the Wilson central terminal. In addition to the convenience in applications such as continuous monitoring and rapid diagnosis, the information in unipolar recordings may yield unique diagnostic information as it avoids the need to essentially subtract data or make use of the averaging effect imposed from the Wilson central terminal. The system also allows direct, real-time software calculation of signals corresponding to standard ECG leads which achieve correlations in excess of 92% with a gold standard ECG during a parallel in vivo recording. In addition, the implemented circuit is wideband (0.05-1000 Hz), compatible with standard (Ag/AgCl) bio-potential electrodes, and dry (paste-less) textile electrodes. The circuit is also low power, requiring less than 50 mW (when powered at 12 V) per standard ECG lead (two channels required). It is therefore well suited for wearable, long-term applications.

Evaluation of different stimulation and measurement patterns based on internal electrode: application in cardiac impedance tomography.

The conductivity distribution around the thorax is altered during the cardiac cycle due to the blood perfusion, heart contraction and lung inflation. Previous studies showed that these bio-impedance changes are appropriate for non-invasive cardiac function imaging using Electrical Impedance Tomography (EIT) techniques. However, the spatial resolution is presently low. One of the main obstacles in cardiac imaging at the heart location is the large impedance variation of the lungs by respiration and muscles on the dorsal and posterior side of the body. In critical care units there is a potential to insert an internal electrode inside the esophagus directly behind the heart in the same plane of the external electrodes. The aim of the present study is to evaluate different current stimulation and measurement patterns with both external and internal electrodes. Analysis is performed with planar arrangement of 16 electrodes for a simulated 3D cylindrical tank and pig thorax model. In our study we evaluated current injection patterns consisting of adjacent, diagonal, trigonometric, and radial to the internal electrode. The performance of these arrangements was assessed using quantitative methods based on distinguishability, sensitivity and GREIT (Graz consensus Reconstruction algorithm for Electrical Impedance Tomography). Our evaluation shows that an internal electrode configuration based on the trigonometric injection patterns has better performance and improves pixel intensity of the small conductivity changes related to heart near 1.7 times in reconstructed images and also shows more stability with different levels of added noise. For the internal electrode, when we combined radial or adjacent injection with trigonometric injection pattern, we found an improvement in amplitude response. However, the combination of diagonal with trigonometric injection pattern deteriorated the shape deformation (correlation coefficient r=0.344) more than combination of radial and trigonometric injection (correlation coefficient r=0.836) for the perturbations in the area close to the center of the cylinder. We also find that trigonometric stimulation pattern performance is degraded in a realistic thorax model with anatomical asymmetry. For that reason we recommend using internal electrodes only for voltage measurements and as a reference electrode during trigonometric stimulation patterns in practical measurements.

A review on electrical impedance tomography for pulmonary perfusion imaging.

Although electrical impedance tomography (EIT) for ventilation monitoring is on the verge of clinical trials, pulmonary perfusion imaging with EIT remains a challenge, especially in spontaneously breathing subjects. In anticipation of more research on this subject, we believe a thorough review is called for. In this paper, findings related to the physiological origins and electrical characteristics of this signal are summarized, highlighting properties that are particularly relevant to EIT. The perfusion impedance change signal is significantly smaller in amplitude compared with the changes due to ventilation. Therefore, the hardware used for this purpose must be more sensitive and more resilient to noise. In previous works, some signal- or image-processing methods have been required to separate these two signals. Three different techniques are reviewed in this paper, including the ECG-gating method, frequency-domain-filtering-based methods and a principal-component-analysis-based method. In addition, we review a number of experimental studies on both human and animal subjects that employed EIT for perfusion imaging, with promising results in the diagnosis of pulmonary embolism (PE) and pulmonary arterial hypertension as well as other potential applications. In our opinion, PE is most likely to become the main focus for perfusion EIT in the future, especially for heavily instrumented patients in the intensive care unit (ICU).

Design and rationale of the tobacco, exercise and diet messages (TEXT ME) trial of a text message-based intervention for ongoing prevention of cardiovascular disease in people with coronary disease: a randomised controlled trial protocol.

Background Although supporting lifestyle change is an effective way of preventing further events in people with cardiovascular disease, providing access to such interventions is a major challenge. This study aims to investigate whether simple reminders about behaviour change sent via mobile phone text message decrease cardiovascular risk. Methods and analysis Randomised controlled trial with 6 months of follow-up to evaluate the feasibility, acceptability and effect on cardiovascular risk of repeated lifestyle reminders sent via mobile phone text messages compared to usual care. A total of 720 patients with coronary artery disease will be randomised to either standard care or the TEXT ME intervention. The intervention group will receive multiple weekly text messages that provide information, motivation, support to quit smoking (if relevant) and recommendations for healthy diets and exercise. The primary end point is a change in plasma low-density lipoprotein cholesterol at 6 months. Secondary end points include a change in systolic blood pressure, smoking status, quality of life, medication adherence, waist circumference, physical activity levels, nutritional status and mood at 6 months. Process outcomes related to acceptability and feasibility of TEXT ME will also be collected. Ethics and dissemination Primary ethics approval was received from Western Sydney Local Health Network Human Research Ethics Committee-Westmead. Results will be disseminated via the usual scientific forums including peer-reviewed publications and presentations at international conferences. Clinical trials registration number ACTRN12611000161921.

Reactive oxygen species are critical for the growth and differentiation of medullary thyroid carcinoma cells.

Reactive oxygen species have recently been demonstrated to play a role in numerous cellular signal transduction pathways. Here we investigate the involvement of H2O2 in Raf-1-mediated differentiation in the human medullary thyroid carcinoma (MTC) cell line TT:deltaRaf-1:ER. Catalase, but not Cu/Zn superoxide dismutase, completely inhibited Raf-1-induced differentiation of beta-estradiol-treated TT: deltaRaf-1:ER. In addition, catalase treatment down-regulated RET expression at both the mRNA and protein levels and induced apoptosis in the parental TT cell line and uninduced TT:deltaRaf-1:ER human MTC cells. These results implicate H2O2 as a downstream mediator of c-Raf-1-induced differentiation and as a survival factor in MTC cells.

Cloning and chromosomal localization of the human BARX2 homeobox protein gene.

The human BARX2 gene encodes a homeodomain-containing protein of 254 amino acids, which binds optimally to the DNA consensus sequence YYTAATGRTTTTY. BARX2 is highly expressed in adult salivary gland and is expressed at lower levels in other tissues, including mammary gland, kidney, and placenta. The BARX2 gene consists of four exons, and is located on human chromosome 11q25. This chromosomal location is within the minimal deletion region for Jacobsen syndrome, a syndrome including craniosynostosis and other developmental abnormalities. This chromosomal location, along with the reported expression of murine barx2 in craniofacial development, suggests that BARX2 may be causally involved in the craniofacial abnormalities in Jacobsen syndrome.

Raf-1 causes growth suppression and alteration of neuroendocrine markers in DMS53 human small-cell lung cancer cells.

Ras mutations are common in lung adenocarcinomas and squamous-cell cancers, which are non-small-cell lung cancers (NSCLCs). However, small-cell lung cancers (SCLCs) rarely have ras mutations, suggesting that ras activation may not confer a growth advantage in these cells. In one SCLC cell line DMS53, activated ras expression induced increased neuroendocrine differentiation and decreased cell proliferation. We show here that DMS53 cells undergo differentiation and G1-specific growth arrest in response to ras/raf/ mitogen-activated protein kinase kinase (MEK)/mitogen-activated protein kinase (MAPK) pathway activation. To assess the consequences of activating the raf/MEK/MAPK pathway downstream of ras, we transfected a DMS53 cell line with DeltaRaf-1:ER, an activatable form of c-raf-1. DeltaRaf-1:ER activation suppressed cell proliferation and cloning on soft agar by 90% without evidence of apoptosis. Cell cycle analysis showed a reduced proportion of cells in S phase, and was associated with induction of the cyclin-dependent kinase (cdk) inhibitor p16(INK4). Expression of the cell cycle-specific proteins pRb, Rb2/p130, p107, cyclin A, cdc-2, and E2F-1 was decreased after DeltaRaf-1:ER activation in DMS53 cells. The activity cdk4 and cdk2 was also reduced, as consistent with cell cycle arrest in cells with activated DeltaRaf-1:ER cells. In addition, DeltaRaf-1:ER reduced the expression of neuroendocrine markers, gastrin releasing peptide, and ret gene in DMS53:DeltaRaf-1:ER cells. These results provide further evidence that activation of the raf/MEK/ MAPK signaling pathway, which is associated with transformation in many circumstances, can reduce the growth of SCLC cells, and suggest that activation of this pathway might be clinically efficacious in some settings.

The identification of a cis-element and a trans-acting factor involved in the response to polyamines and polyamine analogues in the regulation of the human spermidine/spermine N1-acetyltransferase gene transcription.

The superinduction of spermidine/spermine N1-acetyltransferase (SSAT) gene has been associated with a cytotoxic response to a new class of antineoplastic polyamine analogues. The initial mechanism of SSAT superinduction is an increase in transcription in response to analogue exposure. This increased transcription appears to be modulated through the association between a nuclear protein factor and a cis-element described here as the polyamine-responsive element (PRE). The PRE was identified as a 9-base pair sequence, 5'-TATGACTAA-3', in the context of a 31-base pair stretch from -1522 to -1492 base pairs with respect to the SSAT transcriptional start site. This element binds a nuclear factor from polyamine analogue-responsive cells, but not from polyamine analogue-insensitive cells. The labeled PRE was used to clone and identify the transcription factor, Nrf-2, that binds constitutively to the PRE sequence. Although the PRE sequence shares homology to the originally identified Nrf-2 recognition sequence, the two sequences are not identical. The Nrf-2 transcription factor appears only to be present in cell types that are capable of expressing high amounts of SSAT. The results of these studies suggest that Nrf-2, bound to the PRE, plays an important regulatory role of expression of the human SSAT gene.

Audit of service to a minority client group: male to female transsexuals.

Male to female transsexual clients are a group of clients for whom there are few dedicated services in New Zealand. To examine service utilization in Wellington, New Zealand, 70 male to female transsexual clients were identified and their medical records audited for selected aspects of sexual health service delivery. Audit revealed that sexual health history is recorded incompletely and behavioural risk factors are not fully explored, sexual health examination and testing is incomplete. We conclude opportunities to expose relevant behavioural factors and to educate for sexual safety and health promotion are lost with this infrequently attending minority client group.

Tissue-specific expression of human achaete-scute homologue-1 in neuroendocrine tumors: transcriptional regulation by dual inhibitory regions.

Malignancies with neuroendocrine (NE) features such as medullary thyroid cancer (MTC) and small cell lung cancer (SCLC) are prototypic neoplasms arising from peripheral endocrine cells. The mechanisms that regulate the NE phenotype in these tumors and their cellular precursors are not well understood. However, a basic helix-loop-helix transcription factor that is homologous to Drosophila neural fate determination proteins may have a central role. Human achaete-scute homologue-1 (hASH1), a human homologue of the Drosophila achaete-scute complex, is highly expressed in MTC, SCLC, and pheochromocytomas. To determine what mechanisms allow constitutive expression of hASH1 in NE tumors, we cloned human genomic DNA fragments containing the hASH1 gene and characterized its promoter region. We show that hASH1 expression is restricted to NE cell lines by a transcriptionally regulated mechanism. Dual promoters initiate hASH1 transcription, with the predominant site being an evolutionarily conserved initiator (INR) element. Transient transfection studies provide evidence for a generalized enhancer region that has high activity in all cell lines tested. Restriction of hASH1 expression to NE tumor cells depends on two tissue-specific repressor regions, present in the proximal and distal (> 13.5 kb) 5'-flanking region. Understanding the mechanisms of tissue-specific control of hASH1 gene expression provides a useful model to explore regulatory cascades influencing both normal nervous system development and the NE phenotype of tumors such as MTC and SCLC.

Conservation of the Drosophila lateral inhibition pathway in human lung cancer: a hairy-related protein (HES-1) directly represses achaete-scute homolog-1 expression.

The achaete-scute genes encode essential transcription factors in normal Drosophila and vertebrate nervous system development. Human achaete-scute homolog-1 (hASH1) is constitutively expressed in a human lung cancer with neuroendocrine (NE) features, small cell lung cancer (SCLC), and is essential for development of the normal pulmonary NE cells that most resemble this neoplasm. Mechanisms regulating achaete-scute homolog expression outside of Drosophila are presently unclear, either in the context of the developing nervous system or in normal or neoplastic cells with NE features. We now provide evidence that the protein hairy-enhancer-of-split-1 (HES-1) acts in a similar manner as its Drosophila homolog, hairy, to transcriptionally repress achaete-scute expression. HES-1 protein is detected at abundant levels in most non-NE human lung cancer cell lines which lack hASH1 but is virtually absent in hASH1-expressing lung cancer cells. Moreover, induction of HES-1 in a SCLC cell line down-regulates endogenous hASH1 gene expression. The repressive effect of HES-1 is directly mediated by binding of the protein to a class C site in the hASH1 promoter. Thus, a key part of the process that determines neural fate in Drosophila is conserved in human lung cancer cells. Furthermore, modulation of this pathway may underlie the constitutive hASH1 expression seen in NE tumors such as SCLC, the most virulent human lung cancer.

RREB-1, a novel zinc finger protein, is involved in the differentiation response to Ras in human medullary thyroid carcinomas.

An activated ras oncogene induces a program of differentiation in the human medullary thyroid cancer cell line TT. This differentiation process is accompanied by a marked increase in the transcription of the human calcitonin (CT) gene. We have localized a unique Ras-responsive transcriptional element (RRE) in the CT gene promoter. DNase I protection indicates two domains of protein-DNA interaction, and each domain separately can confer Ras-mediated transcriptional inducibility. This bipartite RRE was also found to be Raf responsive. By affinity screening, we have cloned a cDNA coding for a zinc finger transcription factor (RREB-1) that binds to the distal RRE. The consensus binding site for this factor is CCCCAAACCACCCC. RREB-1 is expressed ubiquitously in human tissues outside the adult brain. Overexpression of RREB-1 protein in TT cells confers the ability to mediate increased transactivation of the CT gene promoter-reporter construct during Ras- or Raf-induced differentiation. These data suggest that RREB-1 may play a role in Ras and Raf signal transduction in medullary thyroid cancer and other cells.