Effects of ciliary muscle plasmid electrotransfer of TNF-alpha soluble receptor variants in experimental uveitis.

Intraocular inflammation has been recognized as a major factor leading to blindness. Because tumor necrosis factor-alpha (TNF-alpha) enhances intraocular cytotoxic events, systemic anti-TNF therapies have been introduced in the treatment of severe intraocular inflammation, but frequent re-injections are needed and are associated with severe side effects. We have devised a local intraocular nonviral gene therapy to deliver effective and sustained anti-TNF therapy in inflamed eyes. In this study, we show that transfection of the ciliary muscle by plasmids encoding for three different variants of the p55 TNF-alpha soluble receptor, using electrotransfer, resulted in sustained intraocular secretion of the encoded proteins, without any detection in the serum. In the eye, even the shorter monomeric variant resulted in efficient neutralization of TNF-alpha in a rat experimental model of endotoxin-induced uveitis, as long as 3 months after transfection. A subsequent downregulation of interleukin (IL)-6 and iNOS and upregulation of IL-10 expression was observed together with a decreased rolling of inflammatory cells in anterior segment vessels and reduced infiltration within the ocular tissues. Our results indicate that using a nonviral gene therapy strategy, the local self-production of monomeric TNF-alpha soluble receptors induces a local immunomodulation enabling the control of intraocular inflammation.

Address by Michea¡l Martin to the Conference - Legislating for Tobacco Free Society

Thank you Chairman I would like to extend a warm welcome to our keynote speakers, David Byrne of the European Commission, Derek Yach from the World Health Organisation, and Paul Quinn representing Congressman Marty Meehan who sends his apologies. When we include the speakers who will address later sessions, this is, undoubtedly, one of the strongest teams that have been assembled on tobacco control in Europe. The very strength of the team underlines what I see as a shift – a very necessary shift – in the way we perceive the tobacco issue. For the last twenty years, we have lived out a paradox. It isn´t a social side issue. I make no apology for the bluntness of what I´m saying, and will come back, a little later, to the radicalism I believe we need to bring – nationally – to this issue. For starters, though, I want to lay it on the line that what we´re talking about is an epidemic as deadly as any suffered by human kind throughout the centuries. Slower than some of those epidemics in its lethal action, perhaps. But an epidemic, nonetheless. According to the World Health Organisation tobacco accounted for just over 3 million annual deaths in 1990, rising to 4.023 million annual deaths in 1998. The numbers of deaths due to tobacco will rise to 8.4 million in 2020 and reach roughly 10 million annually by 2030. This is quite simply ghastly. Tobacco kills. It kills in many different ways. It kills increasing numbers of women. It does its damage directly and indirectly. For children, much of the damage comes from smoking by adults where children live, study, play and work. The very least we should be able to offer every child is breathable air. Air that doesn´t do them damage. We´re now seeing a global public health response to the tobacco epidemic. The Tobacco Free Initiative launched by the World Health Organisation was matched by significant tobacco control initiatives throughout the world. During this conference we will hear about the experiences our speakers had in driving these initiatives. This Tobacco Free Initiative poses unique challenges to our legal frameworks at both national and international levels; in particular it raises challenges about the legal context in which tobacco products are traded and asks questions about the impact of commercial speech especially on children, and the extent of the limitations that should be imposed on it. Politicians, supported by economists and lawyers as well as the medical profession, must continue to explore and develop this context to find innovative ways to wrap public health considerations around the trade in tobacco products – very tightly. We also have the right to demand a totally new paradigm from the tobacco industry. Bluntly, the tobacco industry plays the PR game at its cynical worst. The industry sells its products without regard to the harm these products cause. At the same time, to gain social acceptance, it gives donations, endowments and patronage to high profile events and people. Not good enough. This model of behaviour is no longer acceptable in a modern society. We need one where the industry integrates social responsibility and accountability into its day-to-day activities. We have waited for this change in behaviour from the tobacco industry for many decades. Unfortunately the documents disclosed during litigation in the USA and from other sources make very depressing reading; it is clear from them that any trust society placed in the tobacco industry in the past to address the health problems associated with its products was misplaced. This industry appears to lack the necessary leadership to guide it towards just and responsible action. Instead, it chooses evasion, deception and at times illegal activity to protect its profits at any price and to avoid its responsibilities to society and its customers. It has engaged in elaborate ´spin´ to generate political tolerance, scientific uncertainty and public acceptance of its products. Legislators must act now. I see no reason why the global community should continue to wait. Effective legal controls must be laid on this errant industry. We should also keep these controls under review at regular intervals and if they are failing to achieve the desired outcomes we should be prepared to amend them. In Ireland, as Minister for Health and Children, I launched a comprehensive tobacco control policy entitled “Towards a Tobacco Free Society“. OTT?Excessive?Unrealistic? On the contrary – I believe it to be imperative and inevitable. I honestly hold that, given the range of fatal diseases caused by tobacco use we have little alternative but to pursue the clear objective of creating a tobacco free society. Aiming at a tobacco free society means ensuring public and political opinion are properly informed. It requires help to be given to smokers to break the addiction. It demands that people are protected against environmental tobacco smoke and children are protected from any inducement to experiment with this product. Over the past year we have implemented a number of measures which will support these objectives; we have established an independent Office of Tobacco Control, we have introduced free nicotine replacement therapy for low-income earners, we have extended our existing prohibitions on tobacco advertising to the print media with some minor derogations for international publications. We have raised the legal age at which a person can be sold tobacco products to eighteen years. We have invested substantially more funds in health promotion activities and we have mounted sustained information campaigns. We have engaged in sponsorship arrangements, which are new and innovative for public bodies. I have provided health boards with additional resources to let them mount a sustained inspection and enforcement service. Health boards will engage new Directors of Tobacco Control responsible for coordinating each health board´s response and for liasing with the Tobacco Control Agency I set up earlier this year. Most recently, I have published a comprehensive Bill – The Public Health (Tobacco) Bill, 2001. This Bill will, among other things, end all forms of product display and in-store advertising and will require all retailers to register with the new Tobacco Control Agency. Ten packs of cigarettes will be banned and transparent and independent testing procedures of tobacco products will be introduced. Enforcement officers will be given all the necessary powers to ensure there is full compliance with the law. On smoking in public places we will extend the existing areas covered and it is proposed that I, as Minister for Health and Children, will have the powers to introduce further prohibitions in public places such as pubs and the work place. I will also provide for the establishment of a Tobacco Free Council to advise and assist on an ongoing basis. I believe the measures already introduced and those additional ones proposed in the Bill have widespread community support. In fact, you´re going to hear a detailed presentation from the MRBI which will amply illustrate the extent of this support. The great thing is that the support comes from smokers and non-smokers alike. Bottom line, Ladies and Gentlemen, is that we are at a watershed. As a society (if you´ll allow me to play with a popular phrase) we´ve realised it´s time to ´wake up and smell the cigarettes.´ Smell them. See them for what they are. And get real about destroying their hold on our people. The MRBI survey makes it clear that the single strongest weapon we have when it comes to preventing the habit among young people is price. Simple as that. Price. Up to now, the fear of inflation has been a real impediment to increasing taxes on tobacco. It sounds a serious, logical argument. Until you take it out and look at it a little more closely. Weigh it, as it were, in two hands. I believe – and I believe this with a great passion – that we must take cigarettes out of the equation we use when awarding wage increases. I am calling on IBEC and ICTU, on employers and trade unions alike, to move away from any kind of tolerance of a trade that is killing our citizens. At one point in industrial history, cigarettes were a staple of the workingman´s life. So it was legitimate to include them in the ´basket´ of goods that goes to make up the Consumer Price Index. It isn´t legitimate to include them any more. Today, I´m saying that society collectively must take the step to remove cigarettes from the basket of normality, from the list of elements which constitute necessary consumer spending. I´m saying: “We can no longer delude ourselves. We must exclude cigarettes from the considerations we address in central wage bargaining. We must price cigarettes out of the reach of the children those cigarettes will kill.” Right now, in the monthly Central Statistics Office reports on consumer spending, the figures include cigarettes. But – right down at the bottom of the page – there´s another figure. Calculated without including cigarettes. I believe that if we continue to use the first figure as our constant measure, it will be an indictment of us as legislators, as advocates for working people, as public health professionals. If, on the other hand, we move to the use of the second figure, we will be sending out a message of startling clarity to the nation. We will be saying “We don´t count an addictive, killer drug as part of normal consumer spending.” Taking cigarettes out of the basket used to determine the Consumer Price Index will take away the inflation argument. It will not be easy, in its implications for the social partners. But it is morally inescapable. We must do it. Because it will help us stop the killer that is tobacco. If we can do it, we will give so much extra strength to health educators and the new Tobacco Control Association. This new organisation of young people who already have branches in over fifteen counties, is represented here today. The young adults who make up its membership are well placed to advise children of the dangers of tobacco addiction in a way that older generations cannot. It would strengthen their hand if cigarettes move – in price terms – out of the easy reach of our children Finally, I would like to commend so many public health advocates who have shown professional and indeed personal courage in their commitment to this critical public health issue down through the years. We need you to continue to challenge and confront this grave public health problem and to repudiate the questionable science of the tobacco industry. The Research Institute for a Tobacco Free Society represents a new and dynamic form of partnership between government and civil society. It will provide an effective platform to engage and mobilise the many different professional and academic skills necessary to guide and challenge us. I wish the conference every success.

PHA supports World No Tobacco Day

The Public Health Agency is taking the opportunity to highlight this year's World No Tobacco Day which takes place on Tuesday 31 May.In Northern Ireland, around 340,000 people aged 16 and over smoke. Smoking contributes not only to many cancers, heart disease, bronchitis and asthma, but to other illnesses, including stroke. In fact, smoking causes around 2,700 deaths per year here, all of them avoidable.The PHA is committed to saving lives by reducing the percentage of people who smoke. The PHA:works with councils to ensure smoking-related laws are enforced; funds a range of support to smokers who want to quit; educates young people to not start smoking, through programmes like 'Teenage Kicks' and 'Smokebusters'. In January this year, the PHA also launched its smoking campaign 'Things to do before you die' to encourage smokers, particularly those aged 20-49, to stop smoking.Health Minister Edwin Poots said:"Smoking is the greatest cause of preventable illness and premature death in Northern Ireland. While good progress has been made in the last number of years to reduce the number of people who smoke, more needs to be done."I would appeal to all smokers to use the wide range of support services available to make every effort to stop smoking - it is the single best step you can take to improve your health and quality of life."Mark Mc Bride, Health Improvement Manager, PHA, said "Smoking is the single greatest preventable cause of death in the world today. Across Northern Ireland there are over 600 support services for people who wish to stop smoking. These are based in GP surgeries, community pharmacies, hospitals, community centres and workplaces."From April 2010 to end March 2011 more than 1 in 10 of all adult smokers sought help from the support services and approximately half had quit after four weeks. This is a substantial - roughly 50% increase - on previous years and shows the benefit of the PHA campaigns and the dedication of the many specialists who help smokers quit."I would encourage everyone who is either thinking about quitting or ready to log on to our Want 2 Stop website www.want2stop.info or to contacting the Smokers' Helpline on 0808 812 8008 a Quit Kit free of charge."

Neuroendocrine characterization and anorexigenic effects of telmisartan in diet- and glitazone-induced weight gain.

Telmisartan is an angiotensin II receptor blocker with peroxisome proliferator-activated receptor-gamma agonistic properties. Telmisartan prevents weight gain and decreases food intake in models of obesity and in glitazone-treated rodents. This study further investigates the influence of telmisartan and pioglitazone and their association on weight gain and body composition by examining their influence on neuroendocrine mediators involved in food intake. Male C57/Black 6 mice were fed a high-fat diet, weight matched, and randomized in 4 treatment groups: vehicle, pioglitazone, telmisartan, and pioglitazone-telmisartan. Weight gain, food and water intake, body composition, plasma leptin levels, and the hypothalamic expression of neuroendocrine mediators were analyzed. Additional studies were performed with irbesartan and in angiotensin II 1(A) receptor-knockout mice. Telmisartan abolished weight and fat gain in vehicle- and pioglitazone-treated mice while decreasing food intake, the hypothalamic expression of the agouti-related protein, and plasma leptin levels. Modifications in neuropeptide Y and proopiomelanocortin were not consistent with changes in food intake. The effects on weight gain and expression of the agouti-related protein were intermediate with irbesartan. The effects of telmisartan on weight gain were even more pronounced in angiotensin II 1(A) receptor-knockout mice. This study confirms the anorexigenic effects of telmisartan in mice fed a high-fat diet and suggests for the first time a functional role of telmisartan on hypothalamic orexigenic agouti-related protein regulation. These anorexigenic properties abolish both weight gain and body composition modifications in fat-fed and glitazone-treated mice. The anorexigenic properties are independent from the angiotensin II 1(A) receptor.

A one-year monitoring of nicotine use in sport: frontier between potential performance enhancement and addiction issues

Tobacco consumption is a global epidemic responsible for a vast burden of disease. With pharmacological properties sought-after by consumers and responsible for addiction issues, nicotine is the main reason of this phenomenon. Accordingly, smokeless tobacco products are of growing popularity in sport owing to potential performance enhancing properties and absence of adverse effects on the respiratory system. Nevertheless, nicotine does not appear on the 2011 World Anti-Doping Agency (WADA) Prohibited List or Monitoring Program by lack of a comprehensive large-scale prevalence survey. Thus, this work describes a one-year monitoring study on urine specimens from professional athletes of different disciplines covering 2010 and 2011. A method for the detection and quantification of nicotine, its major metabolites (cotinine, trans-3-hydroxycotinine, nicotine-N′-oxide and cotinine-N-oxide) and minor tobacco alkaloids (anabasine, anatabine and nornicotine) was developed, relying on ultra-high pressure liquid chromatography coupled to triple quadrupole mass spectrometry (UHPLC-TQ-MS/MS). A simple and fast dilute-and-shoot sample treatment was performed, followed by hydrophilic interaction chromatography-tandem mass spectrometry (HILIC-MS/MS) operated in positive electrospray ionization (ESI) mode with multiple reaction monitoring (MRM) data acquisition. After method validation, assessing the prevalence of nicotine consumption in sport involved analysis of 2185 urine samples, accounting for 43 different sports. Concentrations distribution of major nicotine metabolites, minor nicotine metabolites and tobacco alkaloids ranged from 10 (LLOQ) to 32,223, 6670 and 538 ng/mL, respectively. Compounds of interest were detected in trace levels in 23.0% of urine specimens, with concentration levels corresponding to an exposure within the last three days for 18.3% of samples. Likewise, hypothesizing conservative concentration limits for active nicotine consumption prior and/or during sport practice (50 ng/mL for nicotine, cotinine and trans-3-hydroxycotinine and 25 ng/mL for nicotine-N′-oxide, cotinine-N-oxide, anabasine, anatabine and nornicotine) revealed a prevalence of 15.3% amongst athletes. While this number may appear lower than the worldwide smoking prevalence of around 25%, focusing the study on selected sports highlighted more alarming findings. Indeed, active nicotine consumption in ice hockey, skiing, biathlon, bobsleigh, skating, football, basketball, volleyball, rugby, American football, wrestling and gymnastics was found to range between 19.0 and 55.6%. Therefore, considering the adverse effects of smoking on the respiratory tract and numerous health threats detrimental to sport practice at top level, likelihood of smokeless tobacco consumption for performance enhancement is greatly supported.

Smoke Free Spaces: Progress in reducing exposure to second-hand smoke in Northern Ireland incorporating the five year review of smoke-free legislation

This report provides an overview of progress in reducing Second Hand Smoke (SHS) exposure in Northern Ireland that incorporates the five year review of smoke-free legislation, but also extends to a consideration of SHS exposure in non-work environments.  The report considers aspects of inequalities in SHS exposure in particular according to social disadvantage and with a focus on vulnerable subgroups of the population.

Effects of a whey protein supplementation on intrahepatocellular lipids in obese female patients.

Background & aims: High protein diets have been shown to improve hepatic steatosis in rodent models and in high-fat fed humans. We therefore evaluated the effects of a protein supplementation on intrahepatocellular lipids (IHCL), and fasting plasma triglycerides in obese non diabetic women.Methods: Eleven obese women received a 60 g/day whey protein supplement (WPS) for 4-weeks, while otherwise nourished on a spontaneous diet, IHCL concentrations, visceral body fat, total liver volume (MR), fasting total-triglyceride and cholesterol concentrations, glucose tolerance (standard 75 g OGTT), insulin sensitivity (HOMA IS index), creatinine clearance, blood pressure and body composition (bio-impedance analysis) were assessed before and after 4-week WPS.Results: IHCL were positively correlated with visceral fat and total liver volume at inclusion. WPS decreased significantly IHCL by 20.8 +/- 7.7%, fasting total TG by 15 +/- 6.9%, and total cholesterol by 7.3 +/- 2.7%. WPS slightly increased fat free mass from 54.8 +/- 2.2 kg to 56.7 +/- 2.5 kg, p = 0.005). Visceral fat, total liver volume, glucose tolerance, creatinine clearance and insulin sensitivity were not changed.Conclusions: WPS improves hepatic steatosis and plasma lipid profiles in obese non diabetic patients, without adverse effects on glucose tolerance or creatinine clearance. Trial Number: NCT00870077, ClinicalTrials.gov (C) 2011 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.

Acute respiratory and cardiovascular admissions after a public smoking ban in geneva, Switzerland.

BACKGROUND: Many countries have introduced legislations for public smoking bans to reduce the harmful effects of exposure to tobacco smoke. Smoking bans cause significant reductions in admissions for acute coronary syndromes but their impact on respiratory diseases is unclear. In Geneva, Switzerland, two popular votes led to a stepwise implementation of a state smoking ban in public places, with a temporary suspension. This study evaluated the effect of this smoking ban on hospitalisations for acute respiratory and cardiovascular diseases. METHODS: This before and after intervention study was conducted at the University Hospitals of Geneva, Switzerland, across 4 periods with different smoking legislations. It included 5,345 patients with a first hospitalisation for acute coronary syndrome, ischemic stroke, acute exacerbation of chronic obstructive pulmonary disease, pneumonia and acute asthma. The main outcomes were the incidence rate ratios (IRR) of admissions for each diagnosis after the final ban compared to the pre-ban period and adjusted for age, gender, season, influenza epidemic and secular trend. RESULTS: Hospitalisations for acute exacerbation of chronic obstructive pulmonary disease significantly decreased over the 4 periods and were lowest after the final ban (IRR = 0.54 [95%CI: 0.42-0.68]). We observed a trend in reduced admissions for acute coronary syndromes (IRR = 0.90 [95%CI: 0.80-1.00]). Admissions for ischemic stroke, asthma and pneumonia did not significantly change. CONCLUSIONS: A legislative smoking ban was followed by a strong decrease in hospitalisations for acute exacerbation of chronic obstructive pulmonary disease and a trend for reduced admissions for acute coronary syndrome. Smoking bans are likely to be very beneficial for patients with chronic obstructive pulmonary disease.

Comparison of adverse events following immunization with pandemic influenza A (H1N1)pdm09 vaccine with or without adjuvant among health professionals in Rio de Janeiro, Brazil

A vaccination campaign against pandemic influenza A (H1N1)pdm09 was held in Brazil in March 2010, using two types of monovalent split virus vaccines: an AS03-adjuvanted vaccine and a non-adjuvanted vaccine. We compared the reactogenicity of the vaccines in health professionals from a Clinical Research Institute in Rio de Janeiro, Brazil and there were no serious adverse events following immunization (AEFI) among the 494 subjects evaluated. The prevalence of any AEFI was higher in the AS03-adjuvanted vaccine at 2 h and 24 h post-vaccination [preva-lence ratio (PR): 2.05, confidence interval (CI) 95%: 1.55-2.71, PR: 3.42, CI 95%: 2.62-4.48, respectively]; however, there was no difference between the vaccines in the assessments conducted at seven and 21 days post-vaccination. The group receiving the AS03 post-adjuvanted vaccine had a higher frequency of local reactions at 2 h (PR: 3.01, CI 95%: 2.12-4.29), 24 h (PR: 4.57, CI 95%: 3.29-6.37) and seven days (PR: 6.05, CI 95%: 2.98-12.28) post-vaccination. We concluded that the two types of vaccines caused no serious AEFI in the studied population and the adjuvanted vaccine was more reactogenic, particularly in the 24 h following vaccination. This behaviour must be confirmed and better characterised by longitudinal studies in the general population.

Integrating human indoor air pollutant exposure within Life Cycle Impact Assessment.

Neglecting health effects from indoor pollutant emissions and exposure, as currently done in Life Cycle Assessment (LCA), may result in product or process optimizations at the expense of workers' or consumers' health. To close this gap, methods for considering indoor exposure to chemicals are needed to complement the methods for outdoor human exposure assessment already in use. This paper summarizes the work of an international expert group on the integration of human indoor and outdoor exposure in LCA, within the UNEP/ SETAC Life Cycle Initiative. A new methodological framework is proposed for a general procedure to include human-health effects from indoor exposure in LCA. Exposure models from occupational hygiene and household indoor air quality studies and practices are critically reviewed and recommendations are provided on the appropriateness of various model alternatives in the context of LCA. A single-compartment box model is recommended for use as a default in LCA, enabling one to screen occupational and household exposures consistent with the existing models to assess outdoor emission in a multimedia environment. An initial set of model parameter values was collected. The comparison between indoor and outdoor human exposure per unit of emission shows that for many pollutants, intake per unit of indoor emission may be several orders of magnitude higher than for outdoor emissions. It is concluded that indoor exposure should be routinely addressed within LCA.

Real-life versus package insert: a post-marketing study on adverse-event rates of the virosomal hepatitis A vaccine Epaxal® in healthy travellers.

There are various methods to collect adverse events (AEs) in clinical trials. The methods how AEs are collected in vaccine trials is of special interest: solicited reporting can lead to over-reporting events that have little or no biological relationship to the vaccine. We assessed the rate of AEs listed in the package insert for the virosomal hepatitis A vaccine Epaxal(®), comparing data collected by solicited or unsolicited self-reporting. In an open, multi-centre post-marketing study, 2675 healthy travellers received single doses of vaccine administered intramuscularly. AEs were recorded based on solicited and unsolicited questioning during a four-day period after vaccination. A total of 2541 questionnaires could be evaluated (95.0% return rate). Solicited self-reporting resulted in significantly higher (p<0.0001) rates of subjects with AEs than unsolicited reporting, both at baseline (18.9% solicited versus 2.1% unsolicited systemic AEs) and following immunization (29.6% versus 19.3% local AEs; 33.8% versus 18.2% systemic AEs). This could indicate that actual reporting rates of AEs with Epaxal(®) may be substantially lower than described in the package insert. The distribution of AEs differed significantly between the applied methods of collecting AEs. The most common AEs listed in the package insert were reported almost exclusively with solicited questioning. The reporting of local AEs was more likely than that of systemic AEs to be influenced by subjects' sex, age and study centre. Women reported higher rates of AEs than men. The results highlight the need for detailing the methods how vaccine tolerability was reported and assessed.