Ultra-Violet Light Emission from HPV-G Cells Irradiated with Low Let Radiation From 90Y; Consequences for Radiation Induced Bystander Effects

In this study, we aimed to establish the emission of UV photons when HPV-G cells and associated materials (such as the cell substrate and cell growth media) are exposed to low LET radiation. The potential role of UV photons in the secondary triggering of biological processes led us to hypothesize that the emission and absorption of photons at this wavelength explain some radiation induced “bystander effects” that have previously been thought to be chemically mediated. Cells were plated in Petri-dishes of two different sizes, having different thicknesses of polystyrene (PS) substrate, and were exposed to β-radiation from ⁹⁰Y produced by the McMaster Nuclear Reactor. UV measurements were performed using a single photon counting system employing an interference-type filter for selection of a narrow wavelength range, 340±5 nm, of photons. Exposure of the cell substrates (which were made of polystyrene) determined that UV photons were being emitted as a consequence of β particle irradiation of the Petri-dishes. For a tightly collimated β-particle beam exposure, we observed 167 photons in the detector per unit μCi in the shielded source for a 1.76 mm thick substrate and 158 photons/μCi for a 0.878 mm thick substrate. A unit μCi source activity was equivalent to an exposure to the substrate of 18 β-particles/cm² in this case. The presence of cells and medium in a Petri-dish was found to significantly increase (up to a maximum of 250%) the measured number of photons in a narrow band of wavelengths of 340±5 nm (i.e. UVA) as compared to the signal from an empty control Petri-dish. When coloured growth medium was added to the cells, it reduced the measured count rate, while the addition of transparent medium in equal volume increased the count rate, compared to cells alone. We attribute this to the fact that emission, scattering and absorption of light by cells and media are all variables in the experiment. Under collimated irradiation conditions, it was observed that increasing cell density in medium of fixed volume resulted in a decrease in the observed light output. This followed a roughly exponential decline. We suggest that this may be due to increased scattering at the cell boundary and absorption of the UV in the cells. We conclude that we have measured UVA emitted by cells, cell medium and cell substrates as a consequence of their irradiation by low LET β-particle radiation. We suggest that these secondary UV photons could lead to effects in non-targetted cells. Some effects that had previously been attributed to a chemically mediated “bystander effect” may in fact be due to secondary UV emission. Some radiation bystander effect studies may require re-interpretation as this phenomenon of UV emission is further investigated.     

A survey of tobacco dependence treatment guidelines in 31 countries

Aims The Framework Convention on Tobacco Control (FCTC) asks countries to develop and disseminate comprehensive evidence‐based guidelines and promote adequate treatment for tobacco dependence, yet to date no summary of the content of existing guidelines exists. This paper describes the national tobacco dependence treatment guidelines of 31 countries. Design, setting, participants A questionnaire on tobacco dependence treatment guidelines was sent by e‐mail to a convenience sample of contacts working in tobacco control in 31 countries in 2007. Completed questionnaires were received from respondents in all 31 countries. During the course of these enquiries we also made contact with people in 14 countries that did not have treatment guidelines and sent them a short questionnaire asking about their plans to produce guidelines. Measurements The survey instrument was a 17‐item questionnaire asking the following key questions: do the guidelines recommend brief interventions, intensive behavioural support, medications; which medications; do the guidelines apply to the whole health‐care system and all professionals; do they refer explicitly to the Cochrane database; are they based on another country's guidelines; are they national or more local; are they endorsed formally by government; did they undergo peer review; who funded them; where were they published; do they include evidence on cost effectiveness of treatment? Findings According to respondents, all their countries' guidelines recommended brief advice, intensive behavioural support and nicotine replacement therapy (NRT); 84% recommended bupropion; 19% recommended varenicline; and 35% recommended telephone quitlines. Nearly half (48%) included cost‐effectiveness evidence. Seventy‐one per cent were supported formally by their government and 65% were supported financially by the government. Most (84%) used the Cochrane reviews as a source of evidence, 84% underwent a peer review process and 55% were based on the guidelines of other countries, most often the United States and England. Conclusion Overall, the guidelines reviewed followed the evidence base closely, recommending brief interventions, intensive behavioural support and NRT, and most recommended bupropion. Varenicline was not on the market in most of the countries in this survey when their guidelines were written, illustrating the need for guidelines to be updated periodically. None recommended interventions not proven to be effective, and some recommended explicitly against specific interventions (for lack of evidence). Most were peer‐reviewed, many through lengthy and rigorous procedures, and most were endorsed or supported formally by their governments. Some countries that did not have guidelines expressed a need for technical support, emphasizing the need for countries to share experience, something the FCTC process is well placed to support.     

Role of inducible nitric oxide synthase in induction of RhoA expression in hearts from diabetic rats

AIMS: Recent studies from our laboratory demonstrated that increased expression of the small GTP-binding protein RhoA and activation of the RhoA/rho kinase (ROCK) pathway play an important role in the contractile dysfunction associated with diabetic cardiomyopathy in hearts from streptozotocin (STZ)-induced diabetic rats. Nitric oxide (NO) has been reported to be a positive regulator of RhoA expression in vascular smooth muscle, and we have previously found that the expression of inducible NO synthase (iNOS) is increased in hearts from STZ-diabetic rats. Therefore, in this study, we investigated the hypothesis that induction of iNOS positively regulates RhoA expression in diabetic rat hearts. METHODS AND RESULTS: To determine whether NO and iNOS could increase RhoA expression in the heart, cardiomyocytes from non-diabetic rats were cultured in the presence of the NO donor sodium nitroprusside (SNP) or lipopolysaccharide (LPS) in the absence and presence of the selective iNOS inhibitor, N(6)-(1-iminoethyl)-l-lysine dihydrochloride (L-NIL). In a second study, 1 week after induction of diabetes with STZ, rats were treated with L-NIL (3 mg/kg/day) for 8 more weeks to determine the effect of iNOS inhibition in vivo on RhoA expression and cardiac contractile function. Expression of iNOS was elevated in cardiomyocytes isolated from diabetic rat hearts. Both SNP and LPS increased RhoA expression in non-diabetic cardiomyocytes. The LPS-induced elevation in RhoA expression was accompanied by an increase in iNOS expression and prevented by L-NIL. Treatment of diabetic rats with L-NIL led to a significant improvement in left ventricular developed pressure and rates of contraction and relaxation concomitant with normalization of total cardiac nitrite levels, RhoA expression, and phosphorylation of the ROCK targets LIM (Lin-11, Isl-1, Mec-3) kinase and ezrin/radixin/moesin. CONCLUSION: These data suggest that iNOS is involved in the increased expression of RhoA in diabetic hearts and that one of the mechanisms by which iNOS inhibition improves cardiac function is by preventing the upregulation of RhoA and its availability for activation.     

Is blood pressure during the night more predictive of cardiovascular outcome than during the day?

The objective of this study was to investigate the prognostic significance of the ambulatory blood pressure (BP) during night and day and of the night-to-day BP ratio (NDR). We studied 7458 participants (mean age 56.8 years; 45.8% women) enrolled in the International Database on Ambulatory BP in relation to Cardiovascular Outcome. Using Cox models, we calculated hazard ratios (HR) adjusted for cohort and cardiovascular risk factors. Over 9.6 years (median), 983 deaths and 943 cardiovascular events occurred. Nighttime BP predicted mortality outcomes (HR, 1.18-1.24; P<0.01) independent of daytime BP. Conversely, daytime systolic (HR, 0.84; P<0.01) and diastolic BP (HR, 0.88; P<0.05) predicted only noncardiovascular mortality after adjustment for nighttime BP. Both daytime BP and nighttime BP consistently predicted all cardiovascular events (HR, 1.11-1.33; P<0.05) and stroke (HR, 1.21-1.47; P<0.01). Daytime BP lost its prognostic significance for cardiovascular events in patients on antihypertensive treatment. Adjusted for the 24-h BP, NDR predicted mortality (P<0.05), but not fatal combined with nonfatal events. Participants with systolic NDR of at least 1 compared with participants with normal NDR (> or = 0.80 to <0.90) were older, at higher risk of death, but died at higher age. The predictive accuracy of the daytime and nighttime BP and the NDR depended on the disease outcome under study. The increased mortality in patients with higher NDR probably indicates reverse causality. Our findings support recording the ambulatory BP during the whole day.     

Effects of immediate versus delayed antihypertensive therapy on outcome in the Systolic Hypertension in Europe Trial

BACKGROUND: To assess the impact of immediate versus delayed antihypertensive treatment on the outcome of older patients with isolated systolic hypertension, we extended the double-blind placebo-controlled Systolic Hypertension in Europe (Syst-Eur) trial by an open-label follow-up study lasting 4 years. METHODS: The Syst-Eur trial included 4695 randomized patients with minimum age of 60 years and an untreated blood pressure of 160-219 mmHg systolic and below 95 mmHg diastolic. The double-blind trial ended after a median follow-up of 2.0 years (range 1-97 months). Of 4409 patients still alive, 3517 received open-label treatment consisting of nitrendipine (10-40 mg daily) with the possible addition of enalapril (5-20 mg daily), hydrochlorothiazide (12.5-25 mg daily), or both add-on drugs. Non-participants (n = 892) were also followed up. RESULTS: Median follow-up increased to 6.1 years. Systolic pressure decreased to below 150 mmHg (target level) in 2628 participants (75.0%). During the 4-year open-label follow-up, stroke and cardiovascular complications occurred at similar frequencies in patients formerly randomized to placebo and those continuing active treatment. These rates were similar to those previously observed in the active-treatment group during the double-blind trial. Considering the total follow-up of 4695 randomized patients, immediate compared with delayed antihypertensive treatment reduced the occurrence of stroke and cardiovascular complications by 28% (P = 0.01) and 15% (P = 0.03), respectively, with a similar tendency for total mortality (13%, P = 0.09). In 492 diabetic patients, the corresponding estimates of long-term benefit (P < 0.02) were 60, 51 and 38%, respectively. CONCLUSIONS: Antihypertensive treatment can achieve blood pressure control in most older patients with isolated systolic hypertension. Immediate compared with delayed treatment prevented 17 strokes or 25 major cardiovascular events per 1000 patients followed up for 6 years. These findings underscore the necessity of early treatment of isolated systolic hypertension.     

Detection of left ventricular dysfunction after acute myocardial infarction: comparison of clinical, echocardiographic, and neurohormonal methods.

OBJECTIVE--The SAVE study showed that captopril improves mortality in patients with left ventricular dysfunction after myocardial infarction and that this benefit occurred even in patients with no clinically overt heart failure. On the basis of this, it seems important to identify correctly which patients have left ventricular dysfunction after a myocardial infarction. The objective was to compare various methods of identifying patients with left ventricular dysfunction (left ventricular ejection fraction, LVEF, < or = 40%) after acute myocardial infarction. The methods compared were echocardiography (quantitative and qualitative visual assessment), clinical evaluation (subjective assessment and three clinical score methods), and measurement of plasma concentrations of cardiac natriuretic peptide hormones (atrial and brain natriuretic peptides, ANP and BNP). DESIGN--Cross sectional study of left ventricular function in patients two to eight days after acute myocardial infarction. SETTING--Coronary care unit of a teaching hospital. PATIENTS--75 survivors of a recent myocardial infarction aged 40 to 88 with no history of cardiac failure and without cardiogenic shock at the time of entry to the study. MAIN OUTCOME MEASURES--Sensitivities and specificities of the various methods of detecting left ventricular dysfunction were calculated by comparing them with a cross sectional echocardiographic algorithm for LVEF. RESULTS--Clinical impression was poor at identifying LVEF < 40% (sensitivity 46%). Clinical scoring improved this figure somewhat (modified Peel index sensitivity 64%). Qualitative visual assessment echocardiography was a more sensitive method (sensitivity 82%) for detecting LVEF < 40%. Plasma BNP concentration was also a sensitive measure for detecting left ventricular dysfunction (sensitivity 84%) but plasma ANP concentration was much poorer (sensitivity 64%). CONCLUSION--Left ventricular dysfunction is easily and reliably detected by echocardiographic measurement of LVEF and also by a quick qualitative echocardiographic assessment but is likely to be missed by clinical assessment alone. High concentrations of plasma BNP maybe another useful indicator of left ventricular dysfunction, particularly in hospitals where not all patients can be screened by echocardiography or radionuclide ventriculography after myocardial infarction.