Epidermal keratinocytes continuously proliferate and differentiate to form the mechanical and water permeability barrier that makes terrestrial life possible. In certain skin diseases, these processes become dysregulated, resulting in abnormal barrier formation. In particular, skin diseases such as psoriasis, actinic keratosis and basal and squamous cell carcinomas are characterized by hyperproliferation and aberrant or absent differentiation of epidermal keratinocytes. We previously demonstrated that 8-Cl-adenosine (8-Cl-Ado) can induce keratinocyte growth arrest without inducing differentiation. 3 [1,25(OH)2D3], a known keratinocyte differentiating agent and a clinical treatment for psoriasis, to inhibit keratinocyte growth. We found that low concentrations of 8-Cl-Ado and 1,25(OH)2D3 appeared to act additively to reduce proliferation of primary mouse epidermal keratinocytes. However, another agent (transforming growth factor-beta) that triggers growth arrest without inducing differentiation also coincidentally inhibits differentiation elicited by other agents; inhibition of differentiation is suboptimal for treating skin disorders, as differentiation is often already reduced. Thus, we determined whether 8-Cl-Ado also decreased keratinocyte differentiation induced by 1,25(OH)2D3, as measured using the early and late differentiation markers, keratin 1 protein levels and transglutaminase activity, respectively. 8-Cl-Ado did not affect 1,25(OH)2D3-stimulated keratin 1 protein expression or transglutaminase activity. To determine if this agent might be useful in treating hyperproliferative skin disorders, we investigated whether 8-Cl-Ado could enhance the ability of 1,25-dihydroxyvitamin DOur results suggest that 8-Cl-Ado might be useful in combination with differentiating agents for the treatment of hyperproliferative disorders of the skin. The epidermis of the skin serves as a mechanical and water permeability barrier essential for terrestrial life (reviewed in ) and is 3 [1,25(OH)2D3] is a known regulator of this process of keratinocyte growth and differentiation (reviewed in [In vitro, 1,25(OH)2D3 inhibits keratinocyte proliferation and stimulates the expression of numerous keratinocyte differentiation markers (reviewed in [In vivo a physiologic role for 1,25(OH)2D3 in regulating keratinocyte differentiation is suggested by several lines of evidence: (1) keratinocytes express both the 25-hydroxylase and the 1α-hydroxylase which converts inactive vitamin D3 to its active 1,25-dihydroxy metabolite . In viviewed in ); (2) rein vitro -11; and in vitro . Furtheriewed in ,14).8-Chloro-cyclic-adenosine monophosphate (8-Cl-cAMP) is known to inhibit growth and to induce apoptosis in a variety of cancer cells -18, suggPreviously, we demonstrated that 8-Cl-Ado arrests the growth of primary mouse epidermal keratinocytes without triggering differentiation . Thus, 82D3-induced inhibition of keratinocyte proliferation and stimulation of keratinocyte differentiation. We found that low concentrations of 8-Cl-Ado acted additively with 1,25(OH)2D3 to inhibit DNA synthesis, without affecting the ability of 1,25(OH)2D3 to enhance keratin 1 expression, a marker of early differentiation, or transglutaminase activity, a marker of late differentiation. Thus, our results suggest that a combination therapy with 1,25(OH)2D3 and 8-Cl-Ado could potentially be an effective treatment for hyperproliferative skin disorders including psoriasis, actinic keratosis and non-melanoma skin cancers.To determine whether 8-Cl-Ado, as a potent keratinocyte growth arrestor, could potentially be used to treat hyperproliferative skin diseases in combination with a current treatment, we investigated the effect of 8-Cl-Ado on 1,25(OH)2D3 to enhance its antiproliferative effect, we incubated primary epidermal keratinocytes for 24 hours with various concentrations of 8-Cl-Ado in the presence and absence of low concentrations of 1,25(OH)2D3 prior to assessing effects on de novo DNA synthesis as measured by [3H]thymidine incorporation into DNA. As shown in Figure 3H]thymidine incorporation at concentrations of 5–25 μM with an estimated half-maximal inhibitory concentration (IC50) of 5 μM. This value agrees well with our previously determined IC50 of 7.5 μM [2D3 also inhibited DNA synthesis at concentrations of 1 to 100 nM with an estimated IC50 of approximately 4 nM 2D3 yielded a greater inhibition than 8-Cl-Ado alone, and conversely, the combined effect of 5 and 10 μM 8-Cl-Ado with 1 nM 1,25(OH) 2D3 was significantly larger than 1 nM 1,25(OH)2D3 alone. Importantly, the combination of 10 nM 1,25(OH)2D3 with 10 μM 8-Cl-Ado produced an inhibition of [3H]thymidine incorporation that was significantly greater than that elicited by either agent alone. Indeed, the inhibition elicited by 10 μM 8-Cl-Ado and 10 nM 1,25(OH)2D3 was comparable to the inhibition produced by 100 nM 1,25(OH)2D3 alone 2D3, but, in fact, the two agents seem to act in an additive fashion to more effectively inhibit keratinocyte proliferation.To determine if 8-Cl-Ado could function with the growth inhibiting agent 1,25(OH)f 7.5 μM . In agref 7.5 μM ,34, 1,25M Figure . As show2D3 to induce the late differentiation marker, transglutaminase activity. For this experiment we chose the concentrations of 8-Cl-Ado (10 μM) and 1,25(OH)2D3 (10 nM) shown in Figure 2D3 significantly elevated transglutaminase activity by approximately 75%. The combination of 8-Cl-Ado and 1,25(OH)2D3was not significantly different from 1,25(OH)2D3 alone, with a significant approximate 60% increase relative to the control value. Thus, our results indicate that 8-Cl-Ado did not prevent the differentiative effect of 1,25(OH)2D3, suggesting that these two agents might be combined to treat keratinocyte hyperproliferative disorders, such as psoriasis.TGF-β, another agent that, like 8-Cl-Ado, induces growth arrest but not differentiation of keratinocytes ( and revi2D3 induced an approximate 45% increase in keratin 1 protein levels with the combination of 1,25(OH)2D3 and 8-Cl-Ado producing a comparable 46% increase . Western analysis demonstrated that 1,25(OH) results , in thes2D3 and its analogs has proven successful, although the possibility of toxicity as the result of 1,25(OH)2D3's ability to affect calcium metabolism has led to the search for topically effective analogs with little or no effect on serum calcium levels  required for treatment could be reduced, this decrease in dosage would presumably minimize systemic effects on calcium, which is the primary dose-limiting factor in the use of 1,25(OH)2D3 analogs in the treatment of psoriasis [2D3, a known keratinocyte differentiating agent and possible treatment for psoriasis [2D3 further supports the possible combined use of these two agents for treatment of hyperproliferative skin disorders.Most current treatments for psoriasis suffer from one or more disadvantages including lack of efficacy, contraindications due to deleterious side effects and/or aesthetic deficiencies ( and reviiewed in ). If thesoriasis . Thus, osoriasis , suggest0/G1 phase of the cell cycle with no increase in the sub-G0/G1 (apoptotic) population of cells [2D3-stimulated increase in transglutaminase activity . Howevell cycle . Clearly2D3 to inhibit keratinocyte proliferation without altering the ability of 1,25(OH)2D3 to induce differentiation. Thus, our results support the possibility of using 8-Cl-Ado alone or in combination with differentiating agents such as 1,25(OH)2D3 or its analogs to treat hyperproliferative keratinocyte disorders including psoriasis.In summary, our data show that 8-Cl-Ado functions with the keratinocyte-differentiating agent 1,25(OH)2D3 was a generous gift of Dr. Maurice Pechet (Research Institute for Medicine and Chemistry, Cambridge, MA). 8-Cl-Ado was obtained from Biolog (La Jolla, CA). [3H]Thymidine and [3H]putrescine were purchased from Dupont/NEN (Boston, MA). Dimethylated casein was obtained from Sigma (St. Louis, MO). All other reagents were from standard suppliers.Tissue culture reagents were obtained from standard suppliers as indicated in a previous publication . 1,252D3. Cultures were washed twice with phosphate-buffered saline without calcium or magnesium (PBS-) and macromolecules were precipitated using ice-cold 5% trichloroacetic acid (TCA). After additional washing with 5% TCA and distilled water, cells were solubilized in 0.3 M NaOH, and the amount of [3H]thymidine incorporated into DNA was determined by liquid scintillation counting.For measurement of [A, as in , near-co3H]putrescine radioactivity incorporated into casein after an overnight incubation at 37°C. Casein was precipitated with TCA, collected onto glass fiber filters and counted by liquid scintillation spectrometry. The cellular protein content of the samples was determined using the Bio-Rad DC protein assay system (Bio-Rad, Hercules, CA), with BSA as standard, and transglutaminase activity was expressed as cpm/μg protein.Transglutaminase activity was assessed essentially as described in . BrieflyKeratinocytes were treated and solubilized in sample buffer (31.2 mM Tris, pH 6.8, 1% SDS, 12.5% glycerol). Equal sample volumes were separated by SDS polyacrylamide gel electrophoresis on an 8% gel and transferred to Immobilon PVDF membrane (Millipore, Billerica, MA). Membranes were blocked with Odyssey blocking buffer (Licor Biosciences, Lincoln, NE), probed with a rabbit polyclonal anti-keratin 1 antibody (Covance, Princeton, NJ) and a mouse monoclonal anti-actin antibody (Sigma, St. Loius, MO). Immunoreactive proteins were visualized with IRDye800-coupled donkey anti-rabbit IgG  or IR Alexa Fluor 680-coupled goat anti-mouse IgG (Molecular Probes, Eugene, OR) on a Licor Odyssey Infrared Imaging System. Keratin-1 protein levels were corrected for background and normalized using background-corrected actin levels.Significance of differences was determined with the computer program InStat (Graphpad Software, San Diego, CA) using ANOVA with a Student-Newman-Keuls post-hoc test.2D3, 1,25-dihydroxyvitamin D3; 8-Cl-Ado, 8-chloro-adenosine; 8-Cl-cAMP, 8-chloro-cyclic-adenosine monophosphate; IC50, half-maximal inhibitory concentration; TGFβ, transforming growth factor-beta1,25(OH)WBB conceived of the study, planned the experiments, analyzed the data and drafted the manuscript; XZ and SJ planned, conducted and analyzed the keratin 1 expression experiments.


There is no clear definition of osteogenesis imperfecta (OI). The most widely used classification of OI divides the disease in four types, although it has been suggested that there may be at least 12 forms of OI. These forms have been named with numbers, eponyms or descriptive names. Some of these syndromes can actually be considered congenital forms of brittle bones resembling OI (SROI).A review of different syndromes with congenital brittle bones published in the literature is presented. Syndromes are classified in "OI" (those secondary to mutations in the type I pro-collagen genes), and "syndromes resembling OI" (those secondary to mutations other that the type I pro-collagen genes, identified or not). A definition for OI is proposed as a syndrome of congenital brittle bones secondary to mutations in the genes codifying for pro-collagen genes (COL1A1 and COL1A2).A debate about the definition of OI and a possible clinical and prognostic classification are warranted. OI tarda has also been sub-divided in "gravis" and "levis" [Besides brittle bones, all other clinical characteristics of osteogenesis imperfecta (OI) are variable, and even different members of the same family may present with a dissimilar degree of severity . Severit "levis" . This cl "levis" . Some of "levis" ,6. The m "levis" ,8. In fa "levis" -11. Some "levis" -14, whil "levis" , Bruck s "levis" ), and ot "levis" , OI with "levis" , OI with "levis" , osteopo "levis" ,21. FollHere, syndromes with congenital brittle bones are divided in osteogenesis imperfecta (those secondary to mutations in the type I pro-collagen genes) and syndromes resembling OI (those secondary to mutations other than the type I pro-collagen genes, identified or not)The most common mutation causing OI type I causes a reduction in the production of otherwise normal type I collagen secondary to the effect of a null allele mutation. Patients often have normal stature, and a slightly low stature does not preclude the diagnosis of type I OI. "Type I OI" is not a synonymous of "mild OI". Individuals may have few or no fractures, mostly during the first years of life or even at birth , or numeThese individuals typically have short stature, bowing of long bones, and vertebral fractures. Scoliosis and joint laxity may be present. Patients with this form of OI are generally able to ambulate, but they may require aids for walking. Based in the presence of DI, moderate OI has been sub-divided in two forms, "a" and "b" . These pThese patients have triangular face, product of an enlarged head and under-development of the facial bones. They also have chest deformities, markedly short stature, and severe deformities of the long bones, vertebral fractures, and scoliosis. They are frequently wheelchair-bound, although some are able to walk with aids. Prenatal diagnosis is hard but sometimes possible using ultrasonography . Long boIn this form of OI, most newborns do not survive the perinatal period. Causes of death are malformations or hemorrhages of the central nervous system , extremeDescribed in one infant  who diedTwo boys  and a giFirst described by Bruck et al in 1897 in an adult patient , in thisThis form of SROI was first described in three families in 1972 . Other rTwo other forms of SROI with ocular involvement have been described: one variant with optic atrophy, retinopathy, and severe psychomotor retardation , anotherOriginally published as "type V OI" . PatientThese patients may also have calcification of the interosseous membrane between the radius and ulna, determining a clinical sign, as affected individuals are unable to pronate and supinate the forearm. The radial head may be dislocated. Patients with this syndrome have white sclera and no DI. Mutations in the pro-collagen genes could not be identified so far. Inheritance appears to be autosomal dominant, with variable penetrance.Undistinguishable from moderate to severe OI on a clinical basis, this rare form of SROI , has beeA particular form of SROI with short humerus and recessive inheritance was described in a First Nations community of Quebec, and published as "type VII OI" . The indA definition for osteogenesis imperfecta is proposed based on the presence of type I pro-collagen mutations. Inclusion of related syndromes with unidentified mutations should be considered as SROI until further defined. Different forms of syndromes with congenital brittle bones are reviewed. A debate about the definition of OI and a possible clinical and prognostic classification are warranted.OI Osteogenesis ImperfectaSROI syndromes resembling osteogenesis imperfectaDI Dentinogenesis imperfectaNone declared.The pre-publication history for this paper can be accessed here:


Theoretical and practical innovations are needed if we are to advance efforts to persuade and enable people to make healthy changes in their behavior. In this paper, I propose that progress in our understanding of and ability to promote health behavior change depends upon greater interdependence in the research activities undertaken by basic and applied behavioral scientists. In particular, both theorists and interventionists need to treat a theory as a dynamic entity whose form and value rests upon it being rigorously applied, tested and refined in both the laboratory and the field. To this end, greater advantage needs to be taken of the opportunities that interventions afford for theory-testing and, moreover, the data generated by these activities need to stimulate and inform efforts to revise, refine, or reject theoretical principles. Even with the dramatic advances in our understanding of the biological processes that determine health and illness, it has never been more clear that rates of disease morbidity and premature mortality reflect people's behavioral practices.  The beneAlthough there may be consensus in the professional community that there are considerable gaps in our understanding of health behavior change, critiques of the current state of affairs more often that not reflect the professional interests of the critic. Investigators who strive to specify the structural and psychological processes that regulate people's behavior lament the fact that too many interventions are not guided by a theoretical framework that specifies how they are supposed to elicit health behavior change. At the same time, investigators who design and implement health behavior interventions lament that the preponderance of theories of health behavior make it difficult to discern what factors are likely to be the most effective targets for intervention. Moreover, it is argued that theories are not sufficiently specified to determine when or how to modify factors that are to be targeted in an intervention.how theoretical principles are applied and, in doing so, have relied on the assumption that current theories of health behavior are useful and productive. Is this assumption valid? Could the often repeated plea for investigators to ground their intervention efforts in theory be a sign that there are significant limitations to the practical principles that can be derived from current theories of health behavior? If so, merely improving how people use theories will not be sufficient. What is needed is a shift in how we engage the interplay between theory and practice, with an emphasis placed on developing initiatives that target opportunities to develop, test, refine health behavior theory.Of course, concerns regarding the link between theory and practice are not new and efforts to address this problem have taken several forms. Considerable effort has been given to provide practitioners with a comprehensive and concise understanding of the array of theories that have been developed to address health behavior.  MoreoverIn this paper, I describe and advocate for a model of collaboration between basic and applied behavioral scientists. Although I recognize the value of improving the manner in which theoretical principles are matched to problems and methods, I propose that innovations in our understanding of and ability to promote health behavior change will not arise if theory is construed as a fixed entity that is delivered to interventionists for implementation. To date, although theories may fluctuate in their popularity, their properties have remained strikingly static over time. I believe greater attention must be paid to refining and, when necessary, rejecting theoretical principles. For this process to take shape, there needs to be an on-going series of exchanges between theorists and interventionists in which theory is treated as a dynamic entity whose value depends on it being not only applied and tested rigorously, but also refined based on the findings afforded by those tests.A fundamental implication of this perspective is that improvements in both health behavior theory and intervention methods depend on each other. If investigators are more receptive to the opportunities interventions afford for theory testing, there will be a dramatic increase in data that can reveal the adequacies and inadequacies of a given theory. These data will, in turn, enable theorists to improve the quality of the theoretical models available to guide subsequent intervention efforts.Interventions are designed to address important practical problems (e.g., obesity) and thus their value is inextricably linked to their ability to alleviate the targeted problem. Interventions need to provide a meaningful return on the time, money, and effort invested such that the outcomes afforded by a intervention strategy are proportional to the resources utilized. Of course, determining what is a sufficient return on an investment can be a challenge. Small effects may be impressive if the intervention is directed at a construct or behavior that is considered difficult to move.  In additWhat conditions are likely to facilitate a successful intervention? Broadly speaking, an intervention is most likely to be effective if it is appropriately grounded in the practical problem targeted.  For examHealth behavior theories provide an explicit statement of the structural and psychological processes that are hypothesized to regulate behavior (e.g., increasing the cost of high-fat foods will curtail consumption of these foods by making it more aversive or, perhaps, more difficult to purchase them). If theories describe the factors that guide people's behavior and justify how an intervention is designed and implemented, interventionists depend on the quality and predictive value of a theory. What determines a theory's value? From the perspective of a theoretician, a theory's value rests on its ability to provide an accurate account of the factors that regulate people's behavior.  Althoughand applicable; that specify not only the relation between two constructs, but also whether that relation does or does not change across contexts (e.g., does the impact of risk perceptions on behavior differ whether one is examining decisions to test for radon or to start smoking?). Given a set of a factors hypothesized to regulate people's behavior, interventionists need to be able to discern which of these factors are the most appropriate targets for intervention. In fact, a common complaint regarding theories is that they are not useful (See Jeffery, this issue). A theory may specify a host of factors that regulate a person's behavior, but in the absence of information regarding the relative importance of each factor leave an interventionist unsure as to where to direct her or his resources. For example, the Theory of Planned Behavior [a priori which set of constructs should be prioritized as a target for intervention. The interest interventionists have shown in stage-based models of health behavior may reflect the fact that the models attempt to specify the conditions under which specific constructs affect behavioral decisions. [From the perspective of an interventionist, the accuracy of the relations specified in a theory is an important but not sufficient determinant of its value. Interventionists need theories that are accurate Behavior  and TheoBehavior  propose cisions. Little guidance is also given as to how or even whether critical constructs can be manipulated. For example, my colleagues and I have proposed that satisfaction with the outcomes afforded by a pattern of behavior is a critical determinant of behavioral maintenance. ,21 ClaimIf the design and implementation of intervention strategies rely on assumptions regarding the factors that regulate people's behavior, why haven't current theories of health behavior evolved in ways that would enable them to more effectively guide intervention development? I believe the critical problem is that there has been a breakdown in the relation between basic and applied scientists who study health behavior.  As scholnot tested in complex social settings such as those afforded by interventions to change health practices, the process by which theories develop is curtailed. Because the manner in which a theory is specified reflects, in part, the contexts in which it has been operationalized and tested, theories that are tested primarily in tightly controlled laboratory settings will likely be characterized by a rich description of the myriad of factors that could affect people's behavioral choices. The laboratory setting allows investigators to minimize noise and potential confounding or moderating factors and thus optimizes their ability to detect processes that can affect people's behavior without determining whether, in a more complex setting, they do affect behavior. [To the extent that behavioral theories are ehavior.  Thus, inInterventions afford an invaluable opportunity to discern the context dependence of causal relations that have been revealed in the laboratory. Some factors may be shown to always be critical, whereas others may be critical only under certain conditions.  For examThere are two sets of reasons why we must take better advantage of the opportunities interventions provide to implement and test theories of health behavior. One set focuses on what theory can do to improve the implementation and evaluation of an intervention, whereas the other set focuses on how interventions can be used to improve the accuracy and quality of prevailing health behavior theories. First, by grounding their work on theoretical principles regarding processes that regulate people's behavior, investigators can readily specify the critical assumptions that underlie their intervention protocol. These formal statements of cause and effect relations not only provide a clear justification for the proposed research activities (i.e., why an investigator believes a given intervention strategy will be effective), but also increase the likelihood that the proposed methodology will allow the investigator to detect whether and why the intervention had its intended effect. ,11a priori set of theoretical principles can provide an important conceptual and analytic framework for determining why an intervention was ineffective. In particular, it increases the likelihood that investigators have not only identified the constructs that may determine whether an intervention will prove effective, but also assessed them at the appropriate points in the decision process.When faced with unambiguous evidence of a successful intervention effect, investigators might be able to move forward without knowing why the intervention was effective. However, more often than not, investigators are faced with the task of determining why an intervention failed to produced the desired effect or why it worked under a limited set of conditions. An The second set of reasons why interventions should take advantage of opportunities to test theories of health behavior is that by providing a context in which some or all of the facets of a theory can be tested, interventionists are in a position to generate evidence that will enhance the accuracy and applicability of theory and thus, over time, improve the quality of the theories to which interventionists can turn. By systematically testing principles specified in health behavior theories, investigators are able to not only verify the accuracy of these predictions, but also develop a better understanding of their practical value. Across studies, evidence should accumulate that will allow investigators to differentiate between factors that should and should not be targeted for intervention. Because current theories of health behavior often provide a list of factors that may affect behavior, the set of potential mediating variables suggested by a theory may pose a daunting if not untenable measurement burden. However, the implementation of consistent and methodologically sound assessment of these factors should provide the empirical evidence needed to constrain and prioritize the variables on that list.The characteristics of intervention strategies that prove to be effective should also provide investigators with a better understanding of the determinants of a given construct. As was previously mentioned, theories may propose that a construct (e.g., satisfaction) is a critical determinant of decisions to maintain a new pattern of behavior, but provide limited guidance as to how to alter people's standing on that construct (e.g., how to help feel satisfied with the outcomes afforded by their new behavior).  An interTesting theoretical principles across a diverse array of settings and populations will also enable investigators to better specify the scope of a theory. Although interventions provide a wonderful opportunity to test theoretical principles in diverse samples and settings, formal and appropriately powered tests of moderators can put a considerable strain on sample size and resources. However, if investigators have appropriately assessed the critical constructs, systematic comparisons can be drawn across studies that taken together have tested a theoretical principle across a range of settings or people. The increase in public access to data sets should facilitate opportunities for this type of comparisons. With the information that is gleaned from these types of activities, it should be easier to determine which moderators are worth testing in a single, appropriately powered study design.are responsive to perceptions of the health benefits afforded by a balanced diet, but that other factors (e.g., control over access to food) preclude them from acting on those beliefs. The practical and theoretical conclusions that can be drawn from the identification of moderating factors are dramatically increased if investigators can identify the causal processes that underlie the observed impact of the moderator. In particular, can investigators discern whether the moderated effect was obtained because the moderator altered the ability of the intervention strategy to change the proposed mediating construct  or because it altered the effect the mediator has on the primary outcome measure ? Greater attention to the causal processes invoked by a moderator may also help investigators grapple with the daunting number of potential moderators. It is quite possible that moderators that differ at the level of description (e.g., gender, ethnicity) can be accounted for by the same underlying process.The identification of situational or personal factors that moderate the impact of a theoretical principal can be indicative of a number of different scenarios. For example, what might one conclude if an intervention that promoted the health benefits of eating a balanced diet altered the eating habits of college students but not those of high school students? It could indicate that health benefits do not affect what high school students choose to eat. Alternatively, it might be that high school students Finally, it is important to recognize that progress in theory development can arise from the failure to obtain evidence in support of a specific prediction. Empirical evidence that provides investigators with a better sense of the potential factors that do not affect health practices will allow them to reduce the number of constructs (and, in time, theories) invoked to predict and explain health behavior.If one assumes that there is interest in rendering interventions more receptive to theory-testing, what can be done to enhance an intervention's ability to assess principles derived from current health behavior theories? One issue is the appropriate evaluation of the critical manipulation(s) imbedded in the intervention. Any conclusions that can be drawn from the intervention, regardless of whether it reveals the predicted pattern of results, is predicated on the success with which the independent variable was manipulated. To this end, investigators need to at least consider assessing several constructs: the degree to which the intervention was implemented (e.g., did the interventionists consistently provide participants with the intervention exercises?), the degree to which participants correctly identified the emphasis of the intervention (e.g., did participants assigned to the optimistic outcome condition report their was a greater emphasis on favorable outcomes than did those assigned to the control condition?), and finally the degree to which the intervention altered the targeted set of opportunities, thoughts or feelings (e.g., did those assigned to the optimistic outcome condition develop more favorable expectations regarding the benefits afforded by behavior change than did those assigned to the control condition?).Although it is important that interventionists explicitly specify the constructs that determine the influence of the intervention on participant behavior, the quality of the evidence that can be gathered depends on the assessment procedures that are utilized. The persuasiveness of any claims regarding the importance (or lack of importance) of a particular construct is contingent on the use of measures that have been shown to be reliable and valid. Given that many of the constructs specified in theories of health behavior are conceptually similar, it is difficult to draw strong conclusions regarding the specific contributions of different variables in the absence of well-designed measures. ,27 In adAdequately testing basic principles also depends on a well-timed assessment schedule. Assessments are often too infrequent to detect meaningful changes on the construct. This is particularly true if the constructs of interest are psychological states that both affect and are affected by behavioral practices. However, specifying the optimal time to assess the primary constructs can be difficult. To the extent that one wants to determine whether an intervention strategy (e.g., a tailored message about dietary changes) alters the predicted mediating variable (e.g., willingness to modify one's diet), one might consider minimizing the length of time between the delivery of the intervention and the assessment of the mediator. However, at the same time, interest in the association between the hypothesized mediator and the outcome variable (e.g., change in diet) would also benefit from a shorter window of time between the two assessments. In many cases, the length of these two time windows are inversely related to each other and thus efforts to improve the chance of detecting one relation may hinder effects to detect the other. Of course, there are practical constraints on an investigator's ability to adequately assess constructs. What is needed is for investigators to take advantage of the measurement and testing opportunities when they do arise. Although what can be concluded from any single assessment effort may be limited, the cumulative impact of well designed tests of a theoretical principle can be substantial. If investigators consistently wait for another time or another investigator to conduct the relevant assessments, innovations in theory and practice will continue to be slow.As interventionists specify the degree to which a given study can test all or a facet of a given theory, they are more likely to articulate the contribution a proposed study could make to the empirical literature. This process not only makes the justification for the intervention clear, but also improves the likelihood that investigators will recognize when their and their colleagues' efforts have focused consistently on a single or limited aspect of a given theory. Research activities motivated by the Transtheoretical Model  provide The commitment of time and effort to using interventions to test theoretical principles will in the end be for naught, if there is not an equal commitment to the dissemination of the findings generated by these activities. In particular, investigators who are engaged in the development of health behavior theories must take advantage of the information afforded by intervention activities and demonstrate that they are responsive to this information as they refine and revise their theories. Enhanced communication should also provide an opportunity for basic and applied behavioral scientists to recognize the strengths and weakness of current theories of health behavior and thus help formulate a fuller understanding of what needs to be done to improve the quality of our theories.Although Lewin may have been right that there is "nothing more practical than a good theory" , his diNone declared.


Shed cells or disrupted parts of the biofilm may enter the circulation causing serious and very hard to treat biofilm-associated infections. The activity of antimicrobial agents against the shed cells/disrupted biofilms is largely unknown.in vitro susceptibility of intact and disrupted biofilms of thirty clinical isolates of methicillin-resistant and methicillin–susceptible Staphylococcus aureus (MRSA and MSSA) and Staphylococcus epidermidis to vancomycin, quinupristin/dalfopristin, and linezolid and compared it to that of the suspended (planktonic) cells.We studied the P < 0.001) less resistant than those in the intact biofilms but more resistant than the planktonic cells. Quinupristin/dalfopristin showed the best activity against cells of the disrupted biofilms at concentrations above MICs and vancomycin, at 500 and 1,000 μg/ml, was significantly more active against the biofilms of MRSA and S. epidermidisBacteria in the disrupted biofilms were as resistant as those in the intact biofilms at the minimum inhibitory concentrations of the antibiotics. At higher concentrations, bacteria in the disrupted biofilms were significantly (The difficulty of treating biofilm-associated infections may be attributed not only to the difficulty of eradicating the biofilm focus but also to the lack of susceptibility of cells disrupted from the biofilm to antimicrobial agents. Staphylococcus aureus and Staphylococcus epidermidis are among the most frequent causes of both healthcare-associated and community-onset infections [Gram-positive infections have become a serious problem, especially in the nosocomialsetting, and treatment of these infections is complicated by the emergence of multidrug-resistant pathogens . Infectifections . Staphylfections -7.Staphylococcus epidermidis and Staphylococcus aureus where they are often found in biofilms upon removal of the devices [Biofilm-associated infections are becoming more common, and occur largely because of the increase in the use of indwelling medical devices. Central venous catheters (CVCs), for example, are inserted in more than 20 million hospitalized patients in the United States alone each year . The mor devices -12. Biof devices ,6,13. A  devices ,15, fail devices ,17, phys devices ,19. Othe devices -23, and  devices  also plain vitro susceptibility of intact and disrupted biofilms of MRSA, MSSA and S. epidermidis to vancomycin, quinupristin/dalfopristin, and linezolid and compared it to the susceptibility patterns of the same bacteria in suspension.Routinely, the diagnostic laboratories report the susceptibilities done on planktonic bacteria only. Although many studies have focused on the antimicrobial susceptibility of bacteria grown in biofilms -28, noneUnless otherwise indicated, all chemicals  were purchased from Sigma Chemical Co., St. Louis, Missouri, USA.Vancomycin (VAN) was purchased from Sigma Chemical Co., St. Louis, Missouri, USA. Quinupristin/dalfopristin (Q/D) was provided by Rhone-Poulenc Rorer, Collegeville, PA, USA and Linezolid (LNZ) was provided by Pharmacia & Upjohn, Kalamazoo, MI, USA.S. epidermidis were used in this study. The microorganisms are clinical isolates from patients with blood stream infections which were provided by the microbiology laboratories at St. John's Hospital, Springfield, Illinois. These isolates were screened for biofilm formation on polystyrene microliter plates as previously described [Ten isolates each of MRSA, MSSA, and escribed .90 and MBC90 obtained in susceptibility testing on planktonic bacteria were used in interpreting the results of the experiments with intact and disrupted biofilms.The minimum inhibitory concentrations (MICs) of the antibiotics were determined by using the broth microdilution technique as described by the National Committee for Clinical Laboratory Standards (NCCLS) . The min6 CFU/ml of the microorganisms were delivered to flat bottom 96 polystyrene plates . After 24 h incubation at 37°C, the supernatants were aspirated and the remaining biofilms were washed twice with distilled water. TSB with or without the antibiotics at MIC values or at 50,500, or 1,000 μg/ml was added to the wells. Biofilms in the plates used for disrupted wells were then dislodged by using sterile wooden sticks and all plates were incubated again for 24 h. Plates with disrupted biofilms were centrifuged at 3,000 rpm for 15 min. to sediment the biofilm particles and all plates were then cautiously aspirated. The intact biofilms and the sediments of the disrupted biofilms were then determined by using a modified colorimetric assay previously described by Roslev & King [To form biofilms, 100 μl portions of Tryptic Soy Broth (TSB) (Difco laboratories, Detroit, MI, USA) containing 1 × 106 CFU/ml of S. epidermidis isolate (SE6) were used to inoculate sterile plastic cover slips placed in a 4 well multidish (Nunc No. 176740, Roskilde, Denmark). After 24 h incubation at 37°C, the cover slips were moved to new plates and washed twice with distilled water. Fresh TSB (1 ml) with 500 μg/ml of vancomycin was added to the wells. Biofilms on cover slips designed to study the disrupted biofilms were then carefully dislodged. After incubation for another 24 h, the biofilms (intact and disrupted) were stained with LIVE/DEAD BacLight bacterial viability stain (Molecular Probes, Eugene, OR, USA) following manufacturer's instructions. The biofilms (intact and disrupted) were then examined by Olympus Fluoview CSLM (model IX 70, Olympus America Inc. NY, USA).One-milliliter portions of TSB containing 1 × 10In another set of experiments, the susceptibility of planktonic cells was examined by growing the bacteria in 1 ml portions of TSB. After 24 h, the bacterial suspensions were centrifuged at 10,000 rpm for 10 minutes, washed twice with sterile distilled water and finally dispersed in 1 ml portions of fresh TSB with the antibiotic. After another 24 h of incubation, the bacteria were stained and examined as previously mentioned.P < 0.05) to determine significance difference between means.The mean and S.D. were calculated from the results of 10 isolates of each of the Staphylococcal species. One-way analysis of variance (ANOVA) was used to determine the differences between various antibiotic treatments. Tukey's pair comparison test was used at the chosen level of probability . The ratios of viability of disrupted biofilms to that of intact biofilms were calculated for the isolates with each antibiotic concentration  are among the leading causes of nosocomial blood stream infections in the USA [S. aureus accounted for up to 13% of isolates recovered from patients with nosocomial infections from 1979 through 1995, and the percentage has increased in recent years [S. epidermidis is a common cause of blood stream infections associated with indwelling medical devices. S. aureus, in addition to causing blood stream infections, is a significant cause of tissue infections such as pneumonia and osteomyelitis [Coagulase-negative staphylococci and  the USA  with a c the USA . S. aurent years ,34. It hnt years . S. epidin vitro batch cultures are usually in nutrient-rich medium. Bacteria grown in biofilms differ greatly from the same organisms grown in suspensions by having different growth characteristics and taking up nutrients and drugs differently [Three phases of bacteria were used in this study; planktonic, biofilms and disrupted biofilms. Planktonic cells were used for determination of MICs and MBCs. This phase of bacteria has routinely been used as gold standard for determination of susceptibility of bacteria and prediction of clinical efficacy of antimicrobial agents. Planktonic cells grown in ferently ,37. Whenferently . These cferently ,35,39. BWe used 24 h incubation for interaction with antimicrobial agents in keeping with the procedures followed in diagnostic laboratories. Although it is possible that during this long incubation period the disrupted biofilm could have re-adhered to the polystyrene, we believe this was not the case. This is based on finding in our and other laboratories that antimicrobial agents are able to prevent the adherence of bacteria when exposed to them prior to formation of the biofilm -2790s were 4–8 times lower then the MBC90s for vancomycin and 16–32 times lower for quinupristin/dalfopristin. At higher concentrations, although the intact biofilms were significantly more resistant than the disrupted biofilms, the recalcitrance of the latter was clear. The antibiotic concentrations were 100–4,000 times the MIC90s for quinupristin/dalfopristin and 25–1,000 times the MIC90s for vancomycin and linezolid. None of these concentrations were able to kill 99.9 % of the microorganisms in the disrupted phase. This was further demonstrated by examining the viability of S. epidermidis cells in the three phases in the presence of vancomycin by using CSLM. The susceptibility of the disrupted biofilm lies between the highly resistant biofilm and the susceptible planktonic cells. This may be attributed to the fact that disrupted biofilms consist of fragments that may retain some features of the intact biofilms. It is obvious from the images that the disrupted biofilm consists of large clumps and aggregates compared to the typical clusters of planktonic cells. The semi quantitative assessment of viability by CSLM was similar to those obtained by the colorimetric assay.All isolates in suspension were susceptible to the antibiotics as determined by NCCLS guidelines. Vancomycin and quinupristin/dalfopristin were capable of killing 99.9 % of the bacteria in suspension at concentrations up to 16 μg/ml, while linezolid, a bacteriostatic antibiotic, did not show such effect even at the maximum concentration used. At the MICs, the antibiotics exerted little effect on the viability of the intact and disrupted biofilms. This was expected because even in suspension the MICS. epidermidis in the biofilm by quinupristin/dalfopristin was independent of antibiotic concentrations over the range of 20–200 times the MIC. This lack of dose response at high concentrations favors the hypothesis that the bacteria disrupted from the biofilm are more or less similar to those in the biofilm rather than the bacteria in suspension.Killing of the bacterial cells in intact or disrupted biofilms by quinupristin/dalfopristin and linezolid was independent of antibiotic concentrations over the range of 50–1000 μg/ml and over a higher range of vancomycin concentrations (500–1,000 μg/ml). Hamilton-Miller & Shah  found thS. aureus and S. epidermidis. It was also more active than vancomycin against biofilms of both S. aureus and S. epidermidis at 50 μg/ml. On the other hand, vancomycin at 500 and 1,000 μg/ml, was significantly more active against the biofilms of MRSA and S. epidermidis but not MSSA. It has been reported that vancomycin accumulates at high concentration in the biofilms of gram positive bacteria especially S. epidermidis compared to linezolid [For better comparison, the viability ratios of the disrupted to the intact biofilms were calculated at different concentrations of the antibiotics. Linezolid was less efficient in killing bacterial cells in intact or disrupted biofilms which explains its highest viability ratio. Quinupristin/dalfopristin, with the lowest viability ratio, was more active against the cells of the disrupted biofilms at concentrations above MICs for both inezolid . This maIn general, our data show that Quinupristin/dalfopristin is more active than vancomycin and linezolid against the disrupted biofilms and there was no difference between methicillin-susceptible and methicillin resistant staphylococci. We conclude that the difficulty in treating the infections related to indwelling medical devices may not be only due to lack of eradication of the cells in the biofilm phase, but also due to resistance of bacteria disrupted from the biofilm.ME did the biofilm work and participated with NK in the design of the study, review and interpretation of the data and discussion. SR and TK participated in the determination of MICs and MBCs of the antibiotics. All authors read and approved the final manuscript.


Perineuriomas have been defined as tumorous lesions of the peripheral nerves which derive from perineurial cell proliferation and may be associated with abnormalities on chromosome 22.Three years after a painful cubital vein procaine injection, a 33 year-old man developed a median nerve lesion, initially diagnosed as carpal tunnel syndrome. Symptoms progressed despite appropriate surgery. Clinical and electrophysiological re-evaluation revealed a fusiform mass at the distal upper arm, confirmed by MRI. Immunohistochemical studies classified the tumor as a mixed perineurioma and neuroma.Perineurioma mixed with neuroma may potentially caused by the previous trauma or cytotoxic effects of procaine. In the past years, there has been much confusion concerning the definition of the entity of rare focal lesions of the peripheral nerves since terms such as perineurioma, localized hypertrophic neuropathy, or hypertrophic neuritis have been used as synonyms -5. AccorIn contrast, localized hypertrophic neuropathy has been defined as a distinct entity which is comprised of Schwann cell-onion-bulb formations, immunohistochemically stains strongly for protein S100, and is epithelial membrane antigen negative -11. Locand and 3rd fingers. Electromyography of the right biceps brachii muscle was normal. In the fibrillations, an increased duration and amplitude of motor unit potentials and reduced recruitment pattern were found in the right abductor pollicis brevis muscle. Forearm muscles were not investigated. A carpal tunnel syndrome was diagnosed and treated by surgery.Three years after a cubital procaine-HCL 0.05% injection had caused acute severe local pain radiating to his forearm and wrist, a 33-year old man complained about pain in his right hand. Two months later, he also suffered from numbness in the distribution of the right median nerve and wasting of thenar muscles. Furthermore a muscular atrophy in his right forearm was noted. Nerve conduction studies showed an increased distal latency in the median nerve, a very low thenar compound muscle action potential on median nerve stimulation, a reduced sensory conduction velocity of 39 m/s in the median nerve on thumb stimulation and no sensory nerve action potential on stimulation of the 2rd finger. Somatosensory evoked potentials of the left median and right radial and ulnar nerve were normal. No potential was recorded at Erb's point in the supraclavicular fossa, at the sixth and second cervical vertebra and the contralateral cortex on median nerve stimulation on the right.Ten months later the patient was admitted to our department because of persistence of his symptoms. Nerve conduction studies showed no response over the thenar muscle on median nerve stimulation at the wrist and elbow. Fibrillations and sparse motor unit potentials with increased duration and amplitude (up to 10 mV) were found in flexor digitorum superficialis muscle, in contrast to the normal Electromyography-findings of the right flexor carpi ulnaris. On median nerve stimulation at the elbow a low compound muscle action potential with an increased distal latency was recorded over flexor digitorum superficialis muscle in the right side (right: amplitude 1 mV, latency 9.0 ms, left: amplitude 7 mV, latency 3.2 ms). No sensory nerve action potential was recorded at the wrist on stimulation of the 1st, 2nd or 3Proximal median nerve lesion was suggested. Palpation along the median nerve revealed a fusiform mass at the distal third of the right upper arm, which could be confirmed by MRI  declared that they have no competing interests.The pre-publication history for this paper can be accessed here:


Yellowfin and skipjack tuna are globally distributed in the world's tropical and sub-tropical oceans. Since little, if any, migration of these fishes occurs between the Atlantic and Indo-Pacific Oceans, one might expect to see genetic differences between sub-populations in these ocean basins. However, yellowfin and skipjack tuna have extremely large population sizes. Thus, the rate of genetic drift should be slower than that observed for other tunas.Low levels of genetic differentiation were observed between Atlantic and Pacific samples of yellowfin tuna. In contrast, no genetic differentiation was observed between Atlantic and Pacific samples of skipjack tuna.Much lower levels of genetic differentiation were found among sub-populations of yellowfin tuna compared to those observed for other large tunas, probably due to the large population size of yellowfin tuna. Since skipjack tuna appear to have even larger population sizes, it is not surprising that no genetic differentiation was detected between Atlantic and Pacific samples of these fish. Thunnus albacares, has a global distribution in tropical and sub-tropical oceans. Annual catches of yellowfin tuna have averaged 1.2 million metric tons since 1998 with sizes ranging from 5 to 20 kg [The yellowfin tuna, Thunnus albacares) from the Atlantic (n = 20) and Pacific Oceans (n = 100) using an RFLP analysis of whole mitochondrial DNA (mtDNA). Subsequently, Ward et al. [In an earlier study, Scoles and Graves  were unad et al.  found sid et al. ,5.Katsuwonus pelamis) are found in tropical and warm temperate waters of the world's oceans. They are present in the three major oceans in large numbers and comprise approximately 40% of the annual catch of the world's tunas. Annual catches are on the order of 2 million metric tons or approximately 670 million individuals per year [Thunnus. Tagging studies have demonstrated limited seasonal movements, but not much transoceanic movement. Thus, they probably do not spawn at discrete locations [Skipjack tuna  were estimated for both species, which may explain the observed levels of inter-oceanic genetic partitioning.To measure the degree of genetic differentiation between the Atlantic and Pacific sub-populations of either yellowfin or skipjack tuna, we examined the hypervariable control region I (CR-I) and a segment of a coding region gene of the respective mitochondrial DNAs. Genetic differences were observed between the Atlantic and Pacific yellowfin tuna samples with PCR-RFLP data of the ATCO gene region, but not with CR-I sequence data. In contrast, no differences between the Atlantic and Pacific skipjack tuna samples were detected with either type of data. Information contained in the CR-I reveals very different demographic histories for yellowfin tuna and skipjack tuna. However, very large long-term female effective population sizes (Nh = 0.997) and a nucleotide diversity (π) of 3.5%. Diversity indices for each locality sampled were also high, although values of π and h were slightly lower for the NW Atlantic yellowfin sample where five haplotypes were repeated twice. For skipjack tuna, a total of 394 bp was determined for 115 individuals (Table h = 0.999). Nucleotide diversity (π = 8.4%) was more than twice as high in skipjack tuna as in yellowfin tuna. All of the sampling localities of skipjack tuna had very high diversity values . For both species, the high haplotypic diversity values are consistent with the observed large census population sizes (Nc). Phylogenetic analyses resulted in very different trees for each species. The CR-I gene-tree topology of skipjack tuna is much larger and better structured than the yellowfin tuna phylogeny, and contains multiple branches with high bootstrap proportion support  control region was determined for 148 yellowfin tuna  gene by Terol et al. [cytB gene for each DNA in the Atlantic and Pacific skipjack tuna samples. Little additional variation was observed, and allele frequencies were similar in the two samples  whereas the effective number of yellowfin tuna females prior to expansion was small (Ne0 = 823). However, the values of θ1 suggest large long-term numbers of effective female breeders (Ne1) of about 98 million for skipjack tuna and about 10 million for yellowfin tuna.The unimodal mismatch distribution for the pooled sample of yellowfin tuna Figure  and a sist Table  both sugst Table  and the st Table , suggestCompared to other scombroid species with cosmopolitan distributions, we found substantially less genetic differentiation between Atlantic and Pacific sub-populations of yellowfin tuna and no inter-oceanic genetic differentiation of skipjack tuna. For instance, in bigeye tuna, there are two highly divergent mtDNA clades, one is cosmopolitan and the other is endemic to the Atlantic ,13. ThisAn alternative explanation to account for the lack of inter-oceanic differentiation in skipjack tuna and yellowfin tuna, is that the time since population expansion began has not been sufficient to allow for the populations to become differentiated. Assuming the very conservative mutation rate for CR-I of 4.9% per million years, a generation time 3.5 years, and the tau value 8.52, expansion of yellowfin tuna occurred about 522 Ky ago. By comparison, the estimated time for genetic differentiation of the Atlantic and Pacific populations of swordfish and of the Atlantic and Pacific bluefin tunas, using the same mutation rate, is very similar (450–470 Ky), and an even shorter time (170 Ky) is sufficient to explain the substantial genetic differentiation between the Atlantic and Mediterranean swordfish populations . Thus, te estimates are 900,000 for bluefin tuna and 800,000 for swordfish [ef values. The observed correspondence does not take into consideration dramatic changes in abundance of some of these species over the last 20 years, nor sex ratio differences, or the age distribution of the catch . However, the comparison supports the hypothesis that skipjack tuna and yellowfin tuna, which are the two most abundant species, also have the largest effective population sizes, and the lowest amounts of genetic partitioning compared to other scombroid fishes.Among large pelagic species, the female effective population size can be estimated from the demographic estimates obtained from the CR-I sequences of Atlantic bluefin tuna and swordfish. Assuming a mutation rate of 4.9% per million years and a generation time of 6 years, the female Nwordfish . Effectiwordfish ,31, suggBigeye tuna, and bluefin tuna have much greater levels of genetic differentiation between Atlantic and Pacific subpopulations when mitochondrial DNA control region sequences are compared ,31. HoweOne exception to the patterns described above is albacore tuna. The distribution of albacore tuna mitochondrial DNAs does not appear to fit the patterns described above for the other temperate tuna species. Albacore abundance is similar to that of bigeye tuna and both species have two mtDNA clades. However, in albacore the two clades are not as well differentiated nor do they display the phylogeographic association observed for the bigeye tuna clades . InsteadMuch lower levels of genetic differentiation were found among sub-populations of yellowfin tuna compared to those observed for other large tunas, probably due to the large population size of yellowfin tuna. Since skipjack tuna appear to have even larger population sizes than yellowfin tuna, it is not surprising that no genetic differentiation was observed between Atlantic and Pacific samples of these fish.Samples of yellowfin tuna were obtained from the eastern Pacific Ocean , the Indian Ocean (n = 63), the Gulf of Mexico and the East Coast of Florida n = 38) and the Gulf of Guinea (n = 100). Samples of skipjack tuna were obtained from the Northwest Atlantic (n = 31), off the coast of Brazil (n = 19), the eastern Pacific Ocean (n = 43), and the south Pacific near the Solomon Islands n = 37). DNA isolation, mitochondrial DNA D-loop region amplification, and nucleotide sequence analyses have been described previously ,32. The . DNA iso and the 0 and θ1 and their probabilities [The demographic history contained in the mtDNA CR-I sequence data was inferred using two approaches. First, the null hypothesis of neutrality may be rejected when a population has experienced population expansion . Accordibilities  were estbilities .DdeI or HpyCH4III and the digestion products were resolved by electrophoresis in a 1.2% agarose gel.For the analysis of the mitochondrial cytochrome b gene, a 650 bp fragment of the skipjack tuna cytochrome b gene was amplified using primers CB3 (GGCAAATAGGAARTATCATTC) and GLUDG (TGACTTGAARAACCAYCGTTG) . The ampBE, JV, and JAB conceived the study, supervised the genetic studies, analyzed the data and wrote the manuscript. JAB, AL, and ET performed the DNA sequence analyses. BE, DB, ET, LL, and KC performed the DNA amplifications and RFLP analyses.


There is evidence for an adaptive role of the omega -3 fatty acid, docosahexaenoic acid (DHA) during stress. Mechanisms of action may involve regulation of stress mediators, such as the catecholamines and proinflammatory cytokines. Prevention of stress-induced aggression and hostility were demonstrated in a series of clinical trials. This study investigates whether perceived stress is ameliorated by DHA in stressed university staff.Subjects that scored ≥ 17 on the Perceived Stress Scale were randomised into a 6-week pilot intervention study. The diet reactive group was supplemented with 6 g of fish oil containing 1.5 g per day DHA, while the placebo group was supplemented with 6 g a day of olive oil. The groups were compared with each other and a wider cross sectional study population that did not receive either active or placebo intervention.p < 0.05). However, there was not a significant between-group difference between the fish oil and the placebo group, nor the placebo group and the control group.There was a significant reduction in perceived stress in both the fish oil and the placebo group from baseline. There was also a significant between-group difference between the fish oil group and the no-treatment controls in the rate of stress reduction  in the fish oil group compared with no-treatment controls. This effect was not demonstrated in the placebo group. As a pilot study, it was not sufficiently powered to find the difference between the fish oil group and the placebo group significant. Further work needs to be undertaken to conclusively demonstrate these data trends. However, the findings from this research support the literature in finding a protective or 'adaptogenic' role for omega-3 fatty acids in stress.There were significant differences ( There was no difference in aggression in the DHA group [A research group in Japan have shown a protective effect of DHA during stress. A multi-centred randomised, placebo-controlled, double blind study involving 53 medical students and 3 months supplementation with 1.5 g/d was timed to coincide with a period of intense stress. They found that aggression towards others was significantly increased in the control group by 8.9% from baseline (The second study was modelled on the previous study with the major difference being timing . A similp < 0.01). There were highly significant between-group differences (p < 0.002). The same researchers demonstrated that hostility levels significantly decreased in a population of university staff taking DHA supplementation compared with no change in hostility levels in subjects taking the placebo [Hostility was also found to increase significantly during psychological stress. In a ra placebo . DHA appet al [p < 0.03). This reduction corresponded with a 78% increase in the ratio of epinephrine (E) to NE in the DHA group (p < 0.02). The higher E:NE ratios were interpreted as a favourable adaptive response to stress. This claim was substantiated by citations of studies which reported a failure to normalise the E:NE ratio during psychological stress observed in patients with duodenal ulcer. This ratio is believed to be protective as it has been associated with lower death rates in 412 older men. Thus, the authors concluded, a possible adaptive mechanism for DHA during stress may be to regulate the E:NE ratio.Sawazaki and Hamazaki et al  investiget al [ex vivo. Subjects with low serum omega-3 fatty acid levels had significantly higher stimulated production of interleukin-6 at baseline compared with the subjects with high serum levels (p = 0.026) and a trend towards a significant difference during academic stress (p = 0.1). Stimulated production of interferon-γ and tumour necrosis factor-α was significantly greater in subjects with low serum omega-3 fatty acids (p = 0.02). The higher serum omega 3 levels were believed to be protective in academic stress because they were associated with lower levels of pro-inflammatory cytokinesAnother possible mechanism whereby omega-3 fatty acids may be protective in stress is by modulation of proinflammatory cytokines. Maes and Christophe et al  found thThe primary aim of the present study is to investigate whether manipulation of dietary fats has an effect on perceived stress, as measured by the Perceived Stress Scale (PSS). The hypothesis is that DHA will ameliorate stress in moderate to highly stressed university staff.A small intervention study was nested within a larger prospective cross sectional study. Figure Moderately stressed subjects were randomised into a 6-week intervention study. The nutritional intervention study was designed as a double blind randomised placebo-controlled clinical trial (pilot), involving three groups. The three groups were (1) active (1.5 g/d DHA from fish oil); (2) placebo (olive oil); and (3) control (no treatment). The supplementation period was 6-weeks.All procedures and processes were subject to the prior approval of the Human Research Ethics Committee at Southern Cross University.A power calculation was conducted using the variability data on the PSS . The α aAll staff members of Southern Cross University were invited via intra-staff email to participate in the study on the effects of dietary fats in stress. Staff that responded to the initial recruitment email had the questionnaire personally delivered. They were instructed to complete the questionnaire and return it via internal mail. Staff members were contacted by phone and invited to participate in the nutritional intervention study if the score on the PSS was greater than or equal to 17.Recruitment for the intervention study commenced in June 2002 and was conducted over a 4-week period. Scores from the PSS at Time 1 formed the screening for the intervention study. The PSS was re-administered at baseline. The supplementation period commenced at the end of June and was completed by mid July 2002. Time 2 questionnaires were then sent out to all subjects that had participated at Time 1. Questionnaires were returned and scored in September 2002.Subjects were included if they were 18–60 years, had not taken a course of fish oil in the past three months, refrained from taking other nutritional supplements and/or aspirin and from radically changing their diet for the duration of the trial, and had a normal physical examination. Subjects were excluded for medical history of coronary heart disease, any type of clotting disorder, clinically diagnosed depression, psychiatric history, diabetes mellitus, or in female subjects, pregnancy or lactation. Suitable candidates undertook a brief clinical assessment.Subjects gave informed consent for the study and were subsequently randomised into two groups. A computer program was used to generate the stratified randomisation schedule. The investigators involved with the study had no knowledge of the details or results of randomisation, the study participants had no knowledge of the group to which they had been allocated, all investigators and statisticians associated with the research were blinded regarding ongoing results.Each capsule contains 1000 mg tuna oil, with 10 mg d-alpha-Tocopherol (vitamin E). The tuna oil was standardised to contain docosahexaenoic acid (DHA) 252 mg per 1000 mg, and eicosapentaenoic acid (EPA) 60 mg per 1000 mg oil. The placebo capsules contained 1000 mg olive oil, consisting predominantly of monounsaturated fatty acids. The placebo capsules were identical to the DHA capsules in every way, including size, shape, colour and smell.There was a 2-week wash out period prior to the commencement of the supplementation period that applied to subjects taking any form of natural or complementary medicine. All subjects were instructed to take 3 capsules with breakfast and 3 for dinner for 6 weeks.Compliance was measured by collecting the bottles with any remaining supplements at the completion of the study. The number of remaining supplements was divided by the total number of supplements dispensed. Less than 85% compliance resulted in the withdrawal of subject data from analysis.The primary outcome was the differences between groups in changes over time in perceived stress, as measured by the Perceived Stress Scale (PSS) . The PSSA two-level structure was used, where level-one units were measurement occasions, consisting of Time 1 and Time 2. Level-two units were the treatment groups, consisting of T1 =the group of subjects that did not go into the intervention study; T2 = the placebo (olive oil) group and T3 = the active (fish oil) group.Response rate to the recruitment email was 13.6% of full-time equivalent university staff. The response rate for the return of personally delivered questionnaires was 85%. The flow of participants through the intervention study is given in figure A further 11 potential subjects were excluded as a result of the interview process; 9 because they did not want to cease other complementary medicines for the duration of the trial, 1 because of positive findings in the clinical assessment and 1 was a female subject still occasionally lactating.A high percentage (30%) of subjects that began the intervention study were withdrawn; 3 subjects were lost to follow-up and 6 discontinued intervention; 5 due to illness related reasons and 1 because taking the supplements caused discomfort with swallowing. This resulted in 70% (n = 21) of subjects that commenced the trial participated until completion of the trial.Multilevel analysis uniquely allows the use of unbalanced data sets. The variance component model using restricted maximum likelihood estimation was used in the hierarchical model building strategy. Absent data were assumed to be 'missing at random', implying that the reason for the missing data is not relevant to the phenomena being investigated .The success of randomisation was verified by dividing the subjects into groups to assess whether the distribution of group characteristics was evenly balanced. The group was divided by age, gender, BMI and gender and is given in table These frequencies and distributions are not outside the range of expected results from the randomisation process. The main concern is that the numbers are very low in some groups. For instance, 3 male subjects in the placebo group and 4 academic staff in the placebo group may not be enough to be sensitive to significant effects, increasing the risk of a Type II error. However, the results of multivariate analysis of variance found that gender and occupational status did not have any effects on perceived stress. Therefore, the unbalanced distribution of group characteristics was not relevant.p < 0.05) and there was no significant difference between group means on paired-samples t-tests. Therefore all subsequent analysis treated Time 1 PSS as baseline scores. Preliminary analysis involved testing for any main effects of occupation level, gender and age on the various stress measures. A two-way between-groups multivariate analysis of variance was used to test for significant interactions between the active (fish oil) and placebo (olive oil) groups over time. Age, gender and occupation levels were all added to the model with no significant effects. Therefore all models were reduced to test for the two main effects of treatment and time on perceived stress.Correlations between PSS scores at Time 1 and baseline were high (0.9, When the fish oil group was compared with the placebo group (olive oil), variance components analysis found no difference. No treatment effect was found but there was a trend towards an effect for the fish oil group . There was a main effect for time in both groups.Because of the very small numbers of subjects on the study, results of the comparison between the fish oil and the placebo groups were then compared with the group of subjects that did not participate in the intervention study. Means and standard deviations for the three groups on the PSS are given in table The effects of time were significantly greater for subjects on the intervention study. There was a significant effect of treatment in the respective active and the placebo groups. Once the effects of time were accounted for, only the fish oil group estimated means were significantly different. The changes in the group means over time are provided in table The change over time in PSS means were not the same for the two groups in the intervention study. Inclusion in the fish oil group predicted a larger reduction in estimates of perceived stress than the placebo group. Estimated means at Time 2 on the PSS were 17.4 for the fish oil group, where those for the placebo group were 20.6.p < 0.05). The change over time in the placebo group was not significantly different from those in the no-treatment group. Changes in the placebo group over time were also not significantly different from changes in the fish oil group over time.The within-group changes over time are given in table p < 0.05). The stress reduction for the fish oil group was significantly different from the no-treatment controls (p < 0.05). The stress reduction in the placebo group was not significantly different from the no-treatment controls. The fish oil group had more substantial stress reductions than the olive oil group, but the differences between the fish oil and the placebo groups did not reach statistical significance.There were significant reductions in stress for both the fish oil and the placebo (olive oil) groups from baseline (both p < 0.05). Arguably, the key factor influencing these results is 'regression to the mean', an effect that may have been exaggerated by methodological limitations such as timing, a large placebo effect, and the possibility that the placebo was not a true placebo. These issues are discussed in the following sections.All subjects taking the nutritional intervention reported significantly less perceived stress at Time 2 . Therefore, this group was considered a potential control group for the intervention study.The time course of the study may have noticeably influenced the regression to the mean. The academic year at Southern Cross University consists of two semesters. This study commenced mid-way through the first semester (Time 1). Questionnaires were reissued at the beginning of the second semester (Time 2), immediately after the mid-year break. Staff may generally have been more relaxed and less stressed after the break. The variation of stress levels associated with time may have been minimised if Time 2 had been at mid-semester 2, a time that corresponds more closely with Time 1.Evidence of a treatment effect beyond statistical regression will be demonstrated in the between-group differences. The only such difference was between the fish oil group and the no-treatment controls. This evidence supports the hypothesis that fish oil ameliorates chronic stress.The present study has several important limitations, including (1) selection bias (2) unsuccessful blinding (3) inadequate power and (4) the possibility of an active effect from the 'placebo'.Invariably, recruitment involving self-selection entails some degree of selection bias . In thisWhile the results demonstrated a strong trend towards a difference between the fish oil and the olive oil groups, this difference failed to reach statistical significance with the current sample size. Post-hoc power calculations were conducted using the PSS means and standard deviations. The study had 90% power to find a 20% difference between the fish oil and the placebo groups, and only 40% power to find a difference of 10% significant. The study was underpowered to find the difference between the groups statistically significant.Although the capsules appeared in every way identical, there was one distinct difference. The fish oil capsules were often accompanied by very mild gastrointestinal disturbances in the form of a slight after taste in the mouth, which was unmistakably fishy. All the subjects taking the fish oil suspected as much because they had the taste of fish in their mouth after ingestion of the capsules.Interestingly, half (50%) the subjects taking the placebo during this study also believed they were taking the active because they 'felt better'. The placebo group did actually report significantly less stress levels. This effect may be due regression to the mean, as previously discussed. Other factors that must be considered are the 'placebo effect' and the possibility of an active effect from the placebos.Half (50%) of the subjects taking the placebo believed themselves to be taking the active. If these subjects believed in the treatment and expected to benefit from it, then it is likely they reported the improvements, which may have influenced the mean of the group. If half the group were reporting an exaggerated stress reduction, then the mean of the group would show a trend towards a treatment effect. Indeed, this was observed: The placebo group demonstrated significant stress reduction; however, the change over time was not significantly different from reductions observed in the no-treatment controls.p < 0.05), where the change over time for the no-treatment controls was not significant. This apparent placebo effect, however, may have been inflated by statistical regression or an active effect from the placebo.Perhaps the most unbiased way to estimate true placebo effects is to observe the difference between a placebo group and a group of no-treatment controls in a three-arm clinical study . In the cis-9,10-octadecenoamide (oleamide), an analogue of 9-octadecenoic acid (oleic acid) [cis-9,10-octadecenoamide (oleamide) by conversion into oleic acid [The use of olive oil as a placebo is not uncommon in essential fatty acid research . Howeveric acid) . Oleamidic acid) . Cell meic acid) . In addieic acid . UnderstThe issue of a correct choice of placebo for essential fatty acid research is difficult. Most studies use omega-6 rich oil, such as corn oil, soy oil, or safflower seed oil. However, this practice is not completely unbiased as the omega-6 oil competes with omega-3 fatty acids for metabolism. Given in high enough doses, the omega-6 oils will overwhelm delta-6 desaturase and inhibit the metabolism of the omega-3 fatty acids.This methodology results in a systematic measurement error, where the omega-3 metabolism in the placebo group may be suppressed. Further, the placebo is not a true placebo if it has a specific effect on the measurement outcome. Between-group differences in these studies may be enhanced. Alternatively, soy oil has been shown to increase omega-3 levels in omega-3 deficiency. As the regulation of the end products of n-3:n-6 blood levels is complex and not fully understood, it is probably best to avoid using these fatty acids as a placebo. This practice may increase the variance in the measurement error to an unknown extent. The monounsaturated fatty acid found in olive oil was chosen here to avoid further imbalances between the essential fatty acids.p < 0.05). Furthermore, the difference was significant compared with no-treatment controls (p < 0.05). The placebo group also demonstrated significant reductions in perceived stress compared to baseline levels (p < 0.05). However, when compared with the no-treatment control group, the differences in perceived stress were not significant for the placebo group.Perceived stress was significantly reduced from baseline after 6 weeks supplementation with 1.5 g/d DHA from fish oil (The study may have demonstrated an exaggerated regression to the mean due to its timing, a strong placebo effect or the placebo itself may have had an active effect. The question that olive oil may have a subtle but protective effect in stress has nevertheless been raised. Perhaps 6 g per day of olive oil was not sufficient dietary intake to find a difference between the placebo and no-treatment controls significant, especially with such a small sample.This research has provided preliminary findings suggesting that DHA ameliorates perceived stress. Future research is required to conclusively substantiate the ameliorating effects of DHA in stress, and further investigate the role of olive oil and/or other dietary fats in stress reduction.This research was purely academic research and has no commercial interest. However, Blackmores Ltd, a company that sells fish oil capsules, also employs one of the authors, Chris Oliver.


Health for All by the Year 2000 (HFA2000) into national contexts by using the changes in the public health policies of Finland and Portugal from the 1970's onward and the relationship of these changes to WHO policy development as test cases. Finland and Portugal were chosen to be compared as they represent different welfare state types and as the paradigmatic transition from the old to new public health is assumed to be related to the wider welfare state development.This article explores the transfer of World Health Organization's (WHO) policy initiative The policy transfer approach is used as a conceptual tool to analyze the possible policy changes related to the adaptation of HFA into the national context. To be able to analyze not only the content but also the contextual conditions of policy transfer Kingdon's analytical framework of policy analysis is applied.Our analysis suggests that no significant change of health promotion policy resulted from the launch of HFA program neither in Finland nor in Portugal. Instead the changes that occurred in both countries were of incremental nature, in accordance with the earlier policy choices, and the adaptation of HFA program was mainly applied to the areas where there were national traditions. The World Health Organization (WHO) launched a policy framework called Health for All by the Year 2000 (HFA2000), in 1978, and has since then been advocating this framework for health policy making to all its member states [Policy transfer is a theoretical perspective that has been used to describe the spread of policy ideas from one political setting to another . Most stIn order to analyze the transfer of HFA policy it is necessary to recognize that HFA policy is not a totally coherent health strategy that can be defined in one compact and consensual manner. The ambiguous nature of HFA policy stems from fact that it is constructed in various policy documents drawn up in temporally and contextually different situations. We refer to the following four central documents and the ideal model of public health policy they construct when we speak of HFA policy: the Declaration of Alma-Ata 1978) [978 [1], While a few studies have addressed the spreading of the HFA policy to the member states -11, thisIn the policy transfer literature past policies, present policy complexity and the question of policy feasibility are seen as possible policy constraints. Likewise factors such as identical past policies or similar ideology can be seen to facilitate the transfer . LocatinWhat was transferred?) but also the contextual conditions (How/why did this happen?) of policy transfer we use Kingdon's (1986) analytical framework of policy analysis [To be able to analyze not only the content  was to advocate such a policy under the concept of medical care. Many health policy makers thought that HFA does not apply to OECD countries. Others argued that the idea of a comprehensive social and intersectoral health policy under the banner of primary health care also challenged the OECD countries. According to this understanding, Europe, too, was to develop its own HFA policy [In most OECD countries there already was some organizational form of primary A policy .Seven years after Alma-Ata, in 1985, the WHO Regional Committee for Europe adopted its own HFA policy. It advocated a comprehensive, intersectoral and participatory health policy aiming at health gain and equity in health . The conThe concept of HFA was accompanied by the introduction of two other challenging concepts: health promotion  and new Each of these three concepts had their own history and points of reference. For example, health promotion was mainly developed from a critical assessment of the health education of the 1970's . New pubThe Ottawa Charter on Health Promotion mentions peace, shelter, education, food, income, a stable ecosystem, sustainable resources, social justice and equity as basic prerequisites for health . In addiThe European version of HFA may also be read from a welfare state reform advocacy perspective. The European HFA strongly advocates a broad health policy managed by objectives . The strFor the purposes of this study, we may conclude that there are three related concepts, health for all, health promotion and new public health that have a lot in common in their critique of the hospital focused and biomedically oriented health policy paradigms. They all advocate a broader socio-political orientation for health policy. However, they do not have a common idea of what this broader orientation is. We find it helpful to distinguish at least three different orientations. The first is the broad social and economic development context where the Alma-Ata Declaration located the radical local development program under the concept of primary health care. The second is the managerialistic welfare state reform context where the European HFA located the proposed health policy guided by HFA targets. A third orientation has been developed under the banner of the Ottawa Charter. This third variant may also be located in a welfare state reform context, but in a different idea of reform emphasizing community development.Finland experienced an extremely rapid urbanization phase in the 1960's and the 1970's. A large part of the population moved from the rural areas to industrial and service workplaces in the urban centers. The proportion of working people earning their main income from agriculture decreased from 26% to 10% in 1950–1980 . A signiIn the late 1960's and the early 1970's, the challenge of the Finnish health policy was often articulated by asking: "Why does a country with Europe's healthiest children have the sickest middle-aged male population?" International comparative statistics had indicated that the country was at the European top in terms of low child mortality, but the adult population, particularly males, was dying younger than most other West European adult populations. The positive health status of children was understood as an outcome of a universal, strong and preventive maternal, child and school health system. The health system for the adult population was criticized for being too hospital centered ,33. The The Primary Health Care Act of 1971 started the building of multi-professional and multi-functional local health centers to carry forward the idea of "people's health work" at the local level . It tookGiven this background, the WHO concept of Primary Health Care as expressed in the Alma-Ata Declaration (1978) was not foreign to Finnish health policy experts. Rather, many of them felt that Finns were pioneers significantly contributing to the development of the WHO policy and demonstrating its applicability also in the Northern hemisphere ,37.However, transforming into practice the radical idea of the local health center carrying out "people's health work" was not a simple task. Since the initial expansion phase, the developmental activities and reforms of the health centers have mostly focused on improving the medical cure and care functions . AccordiThe North Carelia project was and continues to be the best known Finnish example of community action for public health. However, the evaluators of Finnish health promotion policy have repeatedly expressed critical assessment of the leadership and implementation of community action at the local level ,20. It hFinland also used to be a dissident in resisting the managerialistic idea advocated by the WHO Regional Office for Europe to manage health promotion policy by setting the policy aims in the form of numerical health improvement targets .At the beginning of the 2000s, reference to the role and responsibility of local actors and local community is an essential part of health policy rhetoric . The latOne aspect of the rapid expansion of the Finnish welfare state in the early 1970s was the idea of improving people's health through a comprehensive planning system of all public sectors. Health indicators were to be used to provide feedback on the health impact of developments in the various public sectors and policies in these sectors should be adjusted accordingly . AlcoholThe Finnish record on developing policies outside the health sector to promote health has been referred to in placing the country among the forerunners of the Health for All policy in Europe ,20. In aThe Carnation Revolution in 1974 ended a long period of authoritarian rule in Portugal and opened the door to the democratization of the country. As in the other Southern European countries, the democratic Constitution was of a progressive nature while conferring wide economic, social and cultural rights and duties on the citizens . The ConThe Southern European welfare state is a relatively recent addition to the conceptual map of European welfare state models. Many southern countries' present day characteristics are related to the legacy of authoritarianism, as well as to the historically strong presence of the Catholic Church . Leibfrisemi-institutionalization and catching up-effect conceptualize the Southern European welfare state on the one hand as a developing (vs. mature) welfare state and on the other hand as following a different path than the more northern European welfare states [See [crisis before maturation, welfare state has remained to some extent a semi- institutionalized promise until the present day.The notions of tes See ,52]. The. Thesemites [See . Due to th century until 1971 was dominated by preventive public health policies. Through general preventive measures, such as sanitary education, environmental sanitation, hygiene, mental hygiene and sickness prevention "sanitary police" (polícia sanitária) aimed at governing the health of the nation. Preventive policies were directed towards the collectivity and they benefited the individual citizen only indirectly. Publicly provided health care services were tied to the clientele of social assistance and were only available to poor people until 1971, when the right to health care was legally defined to be the right of every citizen [Reforma de Saúde e Assistência) established in 1971 marked the beginning of the second phase of health policies [Sistema Nacional de Saúde) law in 1979 [The development of Portuguese health policy can be broadly divided into two historical phases that are linked to the general welfare state development. The first period from the beginning of the 18 citizen . The refpolicies . The con in 1979  signifie in 1979 .Maternal and child health were already part of health policy during the authoritarian era, and women's and children's health was also included into the primary health care concept established with the Reform of Health and Assistance . HoweverThe reform of Health and Assistance aimed at creating a nationwide network of local level health centers that were supposed to provide primary health care services for the entire population . AlthougA right to health care has been an essential part of the democratization process, strengthening social citizenship. Nevertheless the democratization of health care has not been linear; health was politicized following the creation of the public NHS. The critical welfare state philosophy of the liberal political cycle (1985–1995) affected the content of health policies by favoring privatizations of health care during the term of office of the Social Democrats (centre-right party) ,64. Due Revista Portuguesa de Saúde Pública) published a special issue dedicated to HFA in 1988. In the Editorial of the journal it is suggested that HFA2000 should in Portugal have as an objective rather "adequate health care for all" than "health for all" [The Portuguese Journal of Public Health  private institutions of social solidarity  and non-governmental organizations (Organizações Não-governamentais) are recognized as the main representative categories of community. Strengthening partnerships with these organizations is seen as indispensable for achieving the goals set. Although these organizations are also identified as doing health promotion work, they are mainly actors in curing and caring. The second community level actor identified as relevant for health promotion activity is the local level of public administration. Direct citizen participation (e.g. user/consumer/patients' associations) and the need to cooperate with syndicates and health professionals are also mentioned in the strategy. However, they are not given any significant role in the program implementation. All these community categories identifiable in the health strategy seem to match the current categorizations of community actors and their partners in the social sector [See ].The fourth category of community action for health promotion manifest in the form of setting-based projects of Healthy Cities (WHO), the Health Promoting Schools- network (WHO & EU) and Healthy Workplaces (EU). The first Healthy City was established in 1995 and now there are 9 cities belonging to the national network of Healthy Cities . The HeaThe Ottawa Charter emphasizes the role of policy as a factor promoting healthy choices. In other words, this means that health should be taken into consideration in all public policies. When analyzing the Portuguese development in relation to intersectoral policies, there is action in conventional intersectoral issues, such as tobacco, alcohol and nutrition, but it does not seem that any major development has happened in these policy domains. The project of Healthy Schools and the overall health education campaigns are based on interministerial cooperation and pacts between the Ministry of Health and the Ministry of Education. Intersectoral work is also carried out in the field of drug addiction ,15. In tPortuguese public health indicators have shown remarkable improvements during the last three decades. The fact that public health indicators have been improving side by side with general socio- economic indicators has led researchers to conclude that although the creation of NHS and the improved access to health care have influenced the positive evolution of the health status of the Portuguese population, these improvements are greatly connected to general improvements in economic and social conditions, such as education, income and living standard, housing, sanitation, hygiene, and transport infrastructures ,73,54. Tsaneamento basico) has been a priority in Portuguese post- authoritarian development policy, however in the government programs (1976–2002) basic sanitation is not recognized as a priority of health policy. Although in some programs environmental conditions and habitation are seen to influence public health and the welfare of the population, basic sanitation is not explicitly considered either as a health policy problem, or as a goal or means. Basic sanitation is not conceptualized as an issue of health policy, it is not explicitly on the government's health policy agenda, neither is health used as an argument to improve it in other sectors. Only in the XIII Government Program (1995–1999) are water quality and the intersectoral action needed to reach it mentioned in the section dealing with health policy. Apart from this, the issue of basic sanitation has become conceptualized as an issue of renovation of infrastructure, and this discourse has constituted it as a policy of infrastructure and renovation. In the Regional Development Plan (2nd Community Support Framework 1994–1999) basic sanitation is conceptualized as an issue of environment and no reference is made to health [Basic sanitation  calls a semi-institutional welfare state. This may be a good explanation for the continuity of health promotion policy in Finland, in contrast to the discontinuity in Portugal which also is reflected in the concept "semi-institutional".Both HFA and the two countries examined have also been influenced by the end of the "Golden Age of the Welfare State" . The difThe development of health promotion policy in the two countries has also been related to changes in politics, particularly to changes in the political composition and orientation of the national governments. In this regard, the Portuguese development has been stormier with a radical regime shift in the Carnation Revolution, starting a new regime inspired by socialist visions, followed by a turn to liberal conservative governments ten years later. The Socialist Party's victory in the elections of 1995 after ten years in opposition signified a change in social policy orientation once again ,81. HoweOur analysis does not give a clear picture of the significance of politics in the adoption of HFA in the two countries. We may assume that the continuity in the Finnish politics has contributed to the continuity in the Finland-WHO dialogue and interaction as expressed, e.g., in the reviews of WHO-teams of Finnish health policy development ,20. The In Kingdonian (1995) terms, we may sum up that the health policy problem of both Finland and Portugal, being European laggards in the 1970's, caused them to be open to transfer of policies from abroad. Thus, the "problem stream" was ready for policy transfer. The "policy stream" seems also to have been ready for a certain kind of transfer, but only for those versions or elements of HFA that could be fitted into the specific policy contexts of the countries. HFA as such was not a dynamo of policy change in either country. The "politics stream" changed in both countries so that the window for radical policy changes was closed fairly soon. After that, if any political window was open, it was only for incremental changes in line with the post-expansive welfare state reform agenda.This study is a part of a research project called "Finnish National Health Promotion Policy from an International Comparative Perspective", which has been financed by the Academy of Finland.JL acted as a scientist in WHO Centre for Health Policy, Brussels, in 1999.JL is responsible for the analysis of Finnish policy while LTG has done the analysis on Portugal and drafted the other parts of the article.