Injuries in youth track and field are perceived to have multiple-level causes that call for ecological (holistic-developmental) interventions: A national sporting community perceptions and experiences.

Engaging in competitive sports as a youth can have many health benefits, but recent studies also report a high risk for injury. The long-term purpose of this Swedish research program is to develop a framework for safe track and field training for young athletes (aged 12-15 years). The aim of this study was to establish what is perceived to contribute and cause injuries in youth track and field by compiling the best available experiential knowledge about the underlying factors and use this knowledge to identify appropriate areas to handle these in practical ways. Nine focus group interviews with in total 74 participants and confirming interviews with five individuals were performed in seven Swedish regions. Qualitative research methods were used for data analysis. Injuries in youth athletes were not considered to be strictly the result of individual factors but rather the result of the interactions between factors at different levels. Three major factors emerged as follows: Insufficient knowledge for athletic development in daily practice; shortsighted communities of practice and sports policies not adjusted to youth; and societal health behaviors. The experiential knowledge in the national sporting community suggests that if effective and sustainable injury prevention processes are to be implemented for youth track and field, an ecological (holistic-developmental) approach to injury prevention is needed. Such an approach allows a longitudinal development-focused strategy for prevention that spans an athlete's entire career.

Predictive performance of telenursing complaints in influenza surveillance: a prospective cohort study in Sweden.

Syndromic data sources have been sought to improve the timely detection of increased influenza transmission. This study set out to examine the prospective performance of telenursing chief complaints in predicting influenza activity. Data from two influenza seasons (2007/08 and 2008/09) were collected in a Swedish county (population 427,000) to retrospectively determine which grouping of telenursing chief complaints had the largest correlation with influenza case rates. This grouping was prospectively evaluated in the three subsequent seasons. The best performing telenursing complaint grouping in the retrospective algorithm calibration was fever (child, adult) and syncope (r=0.66; p<0.001). In the prospective evaluation, the performance of 14-day predictions was acceptable for the part of the evaluation period including the 2009 influenza pandemic (area under the curve (AUC)=0.84; positive predictive value (PPV)=0.58), while it was strong (AUC=0.89; PPV=0.93) for the remaining evaluation period including only influenza winter seasons. We recommend the use of telenursing complaints for predicting winter influenza seasons. The method requires adjustments when used during pandemics.

How to avoid long-term sickness absence: the advice from women with personal experience.

OBJECTIVE: The aim of this study was to describe women's perceptions of what can be done to avoid extended sickness absence with following suffering and passivity. METHODS: Qualitative interviews were conducted with 82 women who had been on sickness absence (60 days or more) or were receiving disability pensions. The data were analysed using phenomenological methods. RESULTS: To be able to get back to work was found to be equivalent to breaking away from the prospect of isolation and loneliness. To support this, four parties were identified along with suggestions for their actions: the healthcare professionals, the woman who is on sick leave herself, the employer, and the social insurance official. Most interestingly, the family and close relatives were almost not mentioned at all. The results are connected to a theoretical model of distress in terms of enduring and suffering. CONCLUSIONS: It is necessary to look more carefully at how women on sickness absence use the resources in the world (like their families) to get well. More generally, the task is to understand why society deals insufficiently with women who need time off and cannot keep up with their duties because of illness.

RASONs: a novel antisense oligonucleotide therapeutic approach for asthma.

Inhalation based approaches enable the local delivery of antisense oligonucleotides (ASONs) to the respiratory tract and thus facilitate the ability of ASONs to target and modulate the activity of discordantly expressed respiratory disease genes. Studies involving EPI-2010, a respirable antisense oligonucleotide (RASON), targeting the adenosine A(1) receptor, a G-protein-coupled-receptor (GPCR) that plays an important role in the aetiology of asthma, demonstrate that ASON therapeutics can be delivered directly to the lung as an aerosol. EPI-2010 has been shown to inhibit adenosine A(1) receptor expression and significantly improve allergen-induced airway obstruction and bronchial hyper-responsiveness in animal models of human asthma. Absorption, tissue distribution, metabolism and excretion (ADME) and safety studies of aerosolised EPI-2010 suggest that phosphorothioate RASONs can be delivered to target respiratory tissues in low, safe, efficacious and long-acting doses. This supports the concept that RASONs offer the potential to address a variety of respiratory targets including those for which approaches employing systemic distribution and systemic bioavailability of the therapeutic agent may be undesirable. In addition, our studies with EPI-2010 indicate that the RASON approach may represent a technology that is uniquely positioned to address the challenges of the post-genome era in respiratory drug discovery, since it enables simultaneous in vivo target validation and antisense therapeutic discovery in an accelerated timeframe.

Respirable antisense oligonucleotides: a new drug class for respiratory disease.

Respirable antisense oligonucleotides (RASONs), which attenuate specific disease-associated mRNAs, represent a new class of respiratory therapeutics with considerable potential. RASONs overcome previous obstacles that have impeded the development of antisense therapeutics targeting diseases in other organ systems. RASONs are delivered directly to the target tissue via inhalation; their uptake seems to be enhanced by cationic properties inherent in pulmonary surfactant, and, because of the markedly different target properties of mRNA and proteins, they can have very long durations of effect compared with traditional drugs targeting the protein of the same gene. RASONs contain chemical modifications that decrease their degradation by cellular nucleases. However, total insensitivity to nucleases is probably not an optimal design criterion for RASONs, because moderate nuclease sensitivity can prevent their systemic delivery, decreasing the potential for systemic toxicity. EPI-2010 is a 21-mer phosphorothioate RASON that attenuates bronchoconstriction, inflammation and surfactant depletion in preclinical models of human asthma, has a duration of effect of seven days, and seems to undergo minimal systemic delivery.

Absorption, distribution, metabolism, and excretion of a respirable antisense oligonucleotide for asthma.

EPI-2010 is a respirable antisense oligonucleotide (RASON), which selectively attenuates discordantly overexpressed adenosine A(1) receptors in allergic lung (Nature 1997;385:721). In the present study, aerosolized [(35)S]-labeled EPI-2010 (5 mg exposure; specific activity 0.055 Ci/mmol) was administered to normal rabbits by endotracheal tube to assess biodistribution, route of elimination, and potential cardiovascular toxicity. The animals were killed at 0, 6, 24, 48, and 72 h after inhalation of EPI-2010. Duplicate aliquots from different tissues and samples were solubilized and assessed for radioactivity. Approximately 1.4% of the total aerosolized EPI-2010 was deposited into the lung. The concentration of the drug in the lung at 0, 6, 24, 48, and 72 h was 64.0 +/- 1.5, 67.0 +/- 4.4, 32.0 +/- 3.7, 23.4 +/- 1.4, and 2.1 +/- 0.5 microg equivalents, respectively. Only a small amount of the radioactivity was detected in extrapulmonary tissues. By 72 h, 67.5% of the administered dose was excreted in the urine, which represented the major pathway of elimination. In postlabeling studies, intact full-length EPI-2010 could only be detected in the lung. Autoradiographic analysis after inhalation of [(35)S]-labeled EPI-2010 showed a relatively uniform deposition of drug throughout the lung. The aerosolized EPI-2010 did not have any significant systemic effects on the cardiovascular system as determined by Cardiomax-II analysis. This pattern of distribution and the lack of effect on cardiovascular function support the concept that RASONs offer the potential to safely address respiratory targets for which systemic distribution and systemic bioavailability may be contraindicated.

Autoradiographic evidence that intrastriatal administration of adenosine A(1) receptor antisense oligodeoxynucleotide decreases adenosine A(1) receptors in the rat striatum and cortex.

In this study, the effect of a phosphorothioated A(1) adenosine receptor antisense oligodeoxynucleotide on A(1) receptor density and mRNA in the striatum and cortex of rats was determined. Receptor autoradiography and in situ hybridization revealed a reduction in striatal and cortical A(1) receptor density and cortical A(1) receptor mRNA, respectively, in antisense-treated brains but not in those treated with a mismatch oligonucleotide. There was no change in A(2) receptor binding. These data imply that the corticostriatal pathway synthesizes A(1) receptors and transports them to its terminals.

Oligonucleotide therapy of allergic asthma.

The recent increase in the prevalence of and mortality from asthma has inspired several new molecular techniques to improve treatment. Because asthma is a disease of gene polymorphism, gene therapy is unlikely to be effective. Alternative methods use oligonucleotides (ODNs) in the form of (1) DNA vaccination expressing CpG motifs that mimic bacterial DNA or (2) antisense ODNs inhaled and locally deposited into pulmonary airways to specifically modulate receptors for inflammatory mediators. DNA vaccination, a form of "molecular immune surveillance," attenuates a TH2 predominance. Antisense directed against the adenosine A(1 ) receptor abrogates A(1 ) sensitivity, improves allergen-induced immediate airway obstruction, and inhibits the expected increase in histamine responsiveness in allergic rabbits. Adenosine receptor inhibition lasts for an average of 7 days and the majority of the antisense remains in the lung. ODN therapy for asthma seem unlimited, but confirmation awaits the extension from animal models to human studies.

Insight into adenosine receptor function using antisense and gene-knockout approaches.

The extensive role of adenosine in discriminating input from the extracellular environment is effected through a series of cell membrane-spanning proteins--the adenosine A1, A2A, A2B and A3 receptors. New genetic and epigenetic tools have emerged that facilitate the elucidation of the function of these receptors with greater specificity than is generally possible with traditional antagonist drugs. These tools include antisense oligonucleotides (epigenetic) and gene 'knockin' and 'knockout' mice (genetic) and are discussed in this article by Jonathan Nyce.

Respirable antisense oligonucleotide (RASON) therapy for allergic asthma.

A new technology for treating respiratory disease, respirable antisense oligonucleotides (RASONs), has recently been developed by our group. RASONs are short, single-stranded nucleic acids, generally modified to reduce degradation. They differ from traditional drugs, which usually antagonise preformed proteins already functioning in a disease process. Instead, RASONs can attenuate the expression of disease-associated genes by targeting the messenger RNA (mRNA). Delivered directly to the target tissue, the lung, they avoid the problems of ineffective delivery encountered by other routes of administration. When an adenosine A(1) antisense oligonucleotide was delivered to the lungs of allergic rabbits with up-regulated A(1) adenosine receptors, desensitisation to the bronchoconstrictor effects of adenosine, histamine and a common aeroallergen (dust mite) occurred. The effect on A(1) receptors persisted on average for nearly 7 days. RASON (the phosphorothioate antisense oligonucleotide EPI-2010) administered in low dosage was evenly distributed throughout the lung (with no detectable systemic active metabolites), and was excreted primarily in urine. These results demonstrate that RASONs can be efficiently and effectively delivered to the peripheral lung. They potently and selectively attenuate the expression of disease-associated genes, an approach to therapy which is now being extended to other potentially important mediators of bronchial asthma.

Intrastriatal adenosine A1 receptor antisense oligodeoxynucleotide blocks ethanol-induced motor incoordination.

Intrastriatal administration of a 21-mer phosphorothioate antisense oligodeoxynucleotide targeting the adenosine A1 receptor blocked ethanol-induced motor incoordination in the rat and reduced striatal adenosine A1 receptor content, as judged by specific binding of the A1-specific ligand 8-cyclopentyl-1,3-dipropylxanthine (Bmax = 0.350 +/- 0.07, Kd = 1.87 +/- 0.50 nM). No effect upon striatal adenosine A2 receptor content was observed (Bmax = 0.415 +/- 0.04, Kd = 13.13 +/- 1.25 nM) with the A2-specific ligand 2-p-(2-carboxyethyl)phenethylamino-5'-N-ethylcarboxamidoadenosine. A mismatched control oligodeoxynucleotide of identical G-C base composition and general sequence structure was without effect on adenosine A1 receptor (Bmax = 0.666 +/- 0.11, Kd = 1.32 +/- 0.27 nM) or adenosine A2 receptor content (Bmax = 0.501 +/- 0.08; Kd = 14.65 +/- 1.82 nM) or ethanol-induced motor incoordination. These results confirm an important role of the striatal adenosine A1 receptor in mediating certain motor-related physiological effects of ethanol.

Effects of ubiquinone and mevalonic acid on hepatic peroxisomal enzymes induced by dehydroepiandrosterone.

The adrenal steroid, dehydroepiandrosterone (DHEA) has been identified as a peroxisome proliferator. We examined the effects of the cellular antioxidant ubiquinone and its precursor mevalonic acid on the induction of enzymes associated with DHEA-mediated peroxisome proliferation in male F-344 rats. Upon treatment with DHEA (300 mg/kg orally for 14 days), there was a significant increase in hepatic activities of peroxisomal beta-oxidation (3 fold), 3-ketoacyl-CoA thiolase (4 fold) and catalase (1.8 fold). Co-administration of either mevalonic acid (100 mg/kg intraperitoneally) or ubiquinone (50 mg/kg orally) with DHEA significantly attenuated the DHEA-mediated induction of these enzymes. However, neither ubiquinone nor mevalonic acid alone significantly altered peroxisomal enzyme activities in rat liver. These data suggest that exogenous administration of ubiquinone or mevalonic acid can modulate the induction of the enzymes involved in peroxisome proliferation.

DNA antisense therapy for asthma in an animal model.

Asthma is an inflammatory disease characterized by bronchial hyper-responsiveness that can proceed to life-threatening airway obstruction. It is one of the most common diseases in industrialized countries, and in the United States accounts for about 1% of all healthcare costs. Asthma prevalence and mortality have increased dramatically over the past decade, and occupational asthma is predicted to be the pre-eminent occupational lung disease in the next decade. Increasing evidence suggests that adenosine, an endogenous purine that is involved in normal physiological processes, may be an important mediator of bronchial asthma. In contrast to normal individuals, asthmatic individuals respond to adenosine challenge with marked airway obstruction, and concentrations of adenosine are elevated in the bronchoalveolar lavage fluid of asthma patients. We performed a randomized crossover study using the dust mite-conditioned allergic rabbit model of human asthma. Administration of an aerosolized phosphorothioate antisense oligodeoxynucleotide targeting the adenosine A1 receptor desensitized the animals to subsequent challenge with either adenosine or dust-mite allergen.

Induction of peroxisomal enzymes in rat liver by dehydroepiandrosterone sulfate.

Male F-344 rats, when treated with either 150 mg/kg or 300 mg/kg body weight of DHEAS for 14 days, produced a dose-dependent increase in liver weight and peroxisomal beta-oxidation activity, characteristic of peroxisomal proliferation. Contrary to previous observations in vitro, we also found a significant increase in catalase activity in rat liver with the higher dose of the steroid. Furthermore, the in vivo induction of peroxisomal beta-oxidation by DHEAS observed in our study was significantly less than reported in vitro, and also unlike previously reported in vitro results, was approximately equivalent to DHEA administered in vivo.

Respirable antisense oligonucleotides as novel therapeutic agents for asthma and other pulmonary diseases.

Respirable antisense oligonucleotides (rAsONs) targeting discordantly expressed mediators of inflammation and/or bronchoconstriction and delivered to the lung via inhalation represent a new class of epigenetic-based therapeutics for asthma and other pulmonary diseases. The properties of these agents (solubility, chemical stability, rapid design based on primary DNA sequence information) combine synergistically with characteristics of the lung (non-invasive route of administration directly to the target organ, presence of uptake-modifying surfactant) to enhance the therapeutic potential of these oligonucleotide-based drugs. Their potential is further increased by the possibility of engineering antisense oligonucleotides whose effects are limited to the lung, reducing or avoiding the possibility of systemic toxicity.

NPY-Y1 receptor antisense injected centrally in rats causes hyperthermia and feeding.

The central actions of neuropeptide Y antisense oligodeoxynucleotide (aNPY) and NPY-Y1 receptor antisense (aNPY-Y1) on body temperature (Tb), feeding and body weight of unrestrained rats were determined by the repeated intracerebroventricular (i.c.v.) injection of 0.5 microgram doses. aNPY-Y1 caused intense phasic rises in Tb, lowered body weight and caused transient feeding. aNPY increased food intake paradoxically, accompanied by a gain in body weight but did not affect Tb. Circadian activity was unaffected by either antisense oligodeoxynucleotide, and the mismatched NPY (mNPY) was without effect. These results show that NPY-Y1 receptors underlie the central thermolytic action of NPY, since aNPY-Y1 induces hyperthermic responses. Overall, the functional reduction in NPY activity by aNPY might cause a compensatory de novo synthesis of NPY in structures remote from the ventricles to augment feeding behavior.

Antisense to NPY-Y1 demonstrates that Y1 receptors in the hypothalamus underlie NPY hypothermia and feeding in rats.

Neuropeptide Y (NPY) is a highly potent endogenous peptide which when injected into the medial hypothalamus causes spontaneous eating behaviour and an intense fall in body temperature (Tb). This study used antisense oligodeoxynucleotides (ODNs) to determine whether the Y1 subtype of NPY receptor could underlie these remarkable physiological responses. In the unrestrained rat, the ventromedial hypothalamus (VMH) which is highly reactive to NPY was injected with antisense for NPY (aNPY), Y1 receptors (aNPY-Y1) and mismatched controls (mNPY; mNPY-Y1). After cannulae were implanted bilaterally in the brain of 19 rats, 0.4 or 0.8 microgram per 0.8 microliter of the phosphorothioate synthesised ODNs were delivered to the VMH of the rats at 12 h intervals over 2 d. Only the lower dose of aNPY-Y1, but not aNPY, evoked an intense phasic rise in the Tb following each micro-injection. Simultaneously, 0.4 microgram per 0.8 microliter of aNPY-Y1, but not aNPY, suppressed feeding behaviour after a sequence of micro-injections and on the following day. Body weights and locomotor activity of the rats likewise declined concomitantly with the hyperthermia and hypophagia caused by the Y1 receptor antisense. Neither of the control ODNs for NPY or Y1 receptors injected similarly in the VMH of the rats exerted any effects on these measures. These results clearly provide convincing evidence that in the VMH the Y1 subtype of NPY receptor mediates, in part, the neuronal mechanisms responsible for spontaneous feeding and hypothermia produced by native NPY when applied directly to this structure. The concurrent decline in body weight and activity caused by aNPY-Y1 could be caused by the episodes of hyperthermia.

Intravenous NPY (27-36)-D decreases cardiac output in conscious Sprague-Dawley rats.

Intravenous (IV) administration of NPY (27-36)-D, a substituted carboxyterminal fragment of neuropeptide Y (NPY), decreases mean arterial pressure (MAP) in normo-and hypertensive rats by a mechanism partially involving histamine receptors. The purpose of this study is to further characterize the cardiovascular effects of NPY (27-36)-D. NPY (27-36)-D dose-dependently decreased MAP, cardiac output, and stroke volume without significantly altering peripheral resistance. Myocardial contractility diminished by 151.2 +/- 31.8, 529.6 +/- 182.5, and 495.4 +/- 66.7 mmHg/s2 in rats treated with 300, 500, and 750 nmol/kg NPY (27-36)-D, respectively. Therefore, NPY (27-36)-D modifies MAP, in part, by a reversible negative inotropic effect on the heart.