The World Federation of Occupational Therapists (WFOT) consists of 84 member organizations representing over 420,000 occupational therapists internationally . In 2014 The World Federation of Occupational Therapists (WFOT) aims to promote occupational therapy worldwide, foster international cooperation among occupational therapy associations, therapists, and other professional groups, advance the practice and standard of occupational therapy, promote ethical conduct, advance the interests of the profession, and facilitate the exchange of information . In 2014An Internet search identified two WFOT member organizations with existing telehealth position statements: the American Occupational Therapy Association (AOTA) and the Canadian Association of Occupational Therapists (CAOT). A broader Internet search of occupational therapy associations’ websites occurred; however, no additional telehealth position statements were located. The search was restricted to sites in native English and English translation, limiting results. Terminology  may be dependent on local interpretation and not fully capture the terms being utilized to describe the service delivery model. Also, many member organizations’ websites have content that is restricted to members only and therefore was inaccessible to researchers.Telehealth, a position paper wherein telehealth was defined as “the application of evaluative, consultative, preventative, and therapeutic services delivered through telecommunication and information technologies” (p. S69). This definition includes both synchronous, real-time telehealth applications  and asynchronous telehealth applications .The American Occupational Therapy Association’s (AOTA’s) concept of telehealth use for occupational therapy is broad and inclusive. In 2013, AOTA published In the United States, occupational therapy practitioners are using telehealth with many different populations in diverse settings, including early intervention, schools, pediatric and adult private practice, hospitals , the Veterans Administration (VA) healthcare system, community-based mental health settings, home health, and in the workplace . The AOTThe AOTA position paper on telehealth explicitly addresses the qualifications of the provider and ethical considerations when using telehealth technologies. Occupational therapy services provided via telehealth must be delivered by qualified professionals who abide by the same standards of care and ethical practices as for in-person delivery of occupational therapy services.The Canadian Association of Occupational Therapists (CAOT) updated its position statement on telehealth and electronic occupational therapy  in 2011 . The CAOThe CAOT is also engaged in initiatives to educate stakeholders and advance the use of telehealth within occupational therapy, facilitate professional development activities among occupational therapists in Canada, and increase access to telehealth research to promote evidence-based practice .In addition to reviewing existing telehealth position statements, the WFOT sent an email with a link to an online survey to all WFOT delegates in April 2014. In some cases, the WFOT delegate forwarded the survey link to the WFOT alternate or another individual within the member organization with knowledge of the topic. The survey consisted of 15 questions, including forced-choice and short answer responses . Forty-eChallenges and Strategies’ section of the WFOT Telehealth Position Statement. Themes that emerged included consideration for licensure/registration requirements, the cost of technology, privacy and security concerns, reimbursement requirements, and other issues including collaboration/transfer of knowledge, client selection, provider competencies, and standard of care.Qualitative data  were particularly beneficial in identifying important issues that impact the use of telehealth in the countries represented in the survey. These issues and factors informed the ‘Occupational therapy practitioners using telehealth technologies must abide by applicable licensure or registration requirements. To better understand licensure requirements within each represented country, survey participants were asked if occupational therapists were required to obtain a license, certificate, or registration to practice in their country. Participants were also asked to identify the body responsible for managing the license, certificate, or registration . Seventy-three percent of participants indicated that their country requires occupational therapists to obtain a license, certification, or registration in order to practice. The WFOT Telehealth Position Statement affirms that occupational therapy providers must adhere to licensure/registration requirements whether services are provided in-person or through telehealth technologies . A WFOT’The WFOT Telehealth Survey also asked participants to identify important factors that limit the use of telehealth within their country. Several response options were provided: no issues or factors; cost of the technology used in telehealth ; privacy and security concerns; reimbursement and payment models for telehealth; and a short answer response option for participants to identify issues and factors not listed. The most commonly cited factor impacting the use of telehealth was the cost of telehealth technologies. Seventy-five percent of participants indicated cost of the technology used in telehealth  was a limiting factor. While cost of technology is not specifically addressed in the document, the telehealth position statement does identify access to technology as a consideration of the client selection process.Thirty-three percent of participants cited privacy and security concerns as a limiting factor for telehealth adoption. One participant stated, “Careful consideration must be given to maintenance of client confidentiality with the technology tools that may be selected and used to provide telehealth services.” The WFOT Telehealth Position Statement addressed confidentiality: “Users of telehealth are obligated to employ mechanisms to ensure confidentiality for synchronous and stored client data in compliance with jurisdictional, institutional, and professional regulations and policies governing occupational therapy practice” (p. 3).Fifty-two percent of participants cited reimbursement and payment models for telehealth as a factor limiting the use of telehealth within their country. One participant stated:“Occupational therapy practitioners optimize exchange of electronic mail, video, voice calls, etc. with clients within private payment systems only…socioeconomic and political, government and non-government structures have yet to be established for reimbursement and payment systems for telehealth.”The WFOT Telehealth Position Statement requires therapists to “adhere to reimbursement requirements and accurately represent the services delivered through telehealth” (p. 3).Thirty-five percent of participants indicated that ‘other issues’ limited the use of telehealth in the countries they represented. These issues were clarified in short answer responses and included the need for collaboration with local occupational therapists to increase knowledge and skills, consideration of clients’ preferences and access to telehealth technologies, and provider competencies to maintain a high standard of care.Survey participants identified the need for collaboration to transfer knowledge and create sustainable occupational therapy services, particularly in under-resourced countries in terms of availability of occupational therapy practitioners. One participant commented:“I believe we need a statement to offer guidelines for useful and ethical use of telehealth internationally. My concerns are for guiding culturally appropriate, occupation centered, and low cost services that are directed toward growing OT in under-resourced countries. It offers tremendous opportunity for building expertise and a network of service providers and reduces the isolation and worries of some clinicians…Our great need for OT educators in under-resourced areas makes me hopeful that thoughtful use of telehealth could fill some gaps until we have in-country OT teachers to grow the profession. Another opportunity may be in the supervision of rehabilitation technician level providers.”This sentiment was shared by another participant who stated, “It will be good for countries that have no opportunities to have enough therapists to create a network to enhance the service and uplift skills and knowledge.” Another participant specified, “I am positive about the need [of telehealth]. We can learn from the best therapists worldwide.”The WFOT Telehealth Position Statement reaffirms the importance of collaboration, capacity building within countries, and the practice of authentic occupational therapy. To encourage collaboration with local occupational therapists, the WFOT Telehealth Position Statement advises providers to “seek opportunities to collaborate with and promote local occupational therapy providers, organizations, educational institutions, and/or associations in the interest of cohesive, relevant, and sustainable services” (p. 2). The official document further encourages authentic occupational therapy practice and “endorses practice that is client-centered and occupation-centered, and which portrays the breadth of the profession” (p. 3).Some of the most powerful comments related to client selection, including the clients’ perceptions of the delivery model and whether clients had access to telehealth technologies. One participant stated:“This is an extremely important area for us, but as OTs we must also reflect on the negative effects that the use of e-based OT might have. Many of our clients, especially those who are older and those with cognitive, intellectual or psychiatric disabilities, are in a weak position when it comes to the use of computers and internet. There is a risk that the development of e-based OT creates a digital alienation for these people. OTs must make sure that this is not happening.”Comments regarding client access and preference demonstrate the need for clinical reasoning to guide appropriate selection of clients for this service delivery model. One participant stated, “Most of the elderly population doesn’t have this kind of technology.” Another participant commented, “Consumers and providers prefer face-to-face [in-person] occupational therapy services.” Other participants echoed this sentiment, though they acknowledged potential benefits of the model within their country. For example, one participant from a country in the Middle East shared, “…current political situations make it difficult to move within the different regions of the country, however telehealth could break this barrier, but still very expensive technology and could have limited acceptance from the society.” A participant from another Middle Eastern country reported that the profession of occupational therapy is in its infancy in their country and added “at this stage we are still at the level of promoting occupational therapy services and do not think that it is appropriate to start with high technology level.”The WFOT Telehealth Position Statement includes a statement regarding client selection:“Therapists should use clinical reasoning to determine the appropriateness of telehealth use based on individual client situations . Telehealth should therefore not be used to avoid in-person services when indicated by client-specific needs, nor be used by therapists to avoid contact with clients on the basis of discrimination” (p. 2).The client’s ability to access telehealth technologies was identified as an important consideration. Additionally, the nature of the interventions to be provided should be considered to assure that services are client-centered and represent authentic occupational therapy . Alienation of clients, whether intentionally  or unintentionally  must be avoided.The WFOT has produced resources to support authentic, client-centered, culturally appropriate and ethical occupational therapy practice. These resources include the WFOT’s Other concerns expressed by participants related to provider competencies in the use of telehealth technology and reliability of the technology . One participant stated, “We should ensure that high standards are achieved with activities delivered through this media.” This participant further commented, “Communication through telehealth is more challenging than with in-person service delivery; we should train our practitioners to be great communicators and savvy users of technologies.” Another participant described the need for developing providers’ competencies around telehealth:“To engage occupational therapists fully in the implementation of telehealth, it is critical to thoroughly address concerns and reservations. Legitimate concerns, such as the unavailability of suitable devices, lapses in the reliability of technology and not being able to address the inevitable technical difficulties, frequently prevent staff from fully embracing telehealth. Therapists not only need training in how to use the technology, but also how to use it effectively to provide a successful service. They also require time to become familiar with the technologies and opportunities to practice and build their skill base. Since therapists are often called upon to support clients who encounter difficulties in using telehealth technologies, they benefit from having access to technical support, training and troubleshooting guides.”This participant then articulated some of the challenges and specific training needs associated with developing telehealth competencies:“The difficulties involved in translating face-to-face [in-person] services into a remote format should not be underestimated. Telehealth requires a different way of working, so therapists need opportunities to discuss concerns about maintaining the integrity and quality of services and develop protocols to guide service delivery. A good deal of contextual information is also lost when therapists are not physically present with the client. It is therefore important to develop additional skills and strategies to gather important information that is not readily accessible during a tele-consult. This type of training needs to be integrated into undergraduate training for training OTs and CPD [continuing professional development] for practicing OTs.”The WFOT Telehealth Position Statement asserts, “Therapists must maintain professional competency, acquire competency using telehealth technologies, ensure client safety, and adhere to ethical principles of practice” (p. 3). This assertion affirms that providers must acquire professional competency around the use of telehealth and maintain a high standard of care when providing occupational therapy services through telehealth technologies.Fifty-eight percent of participants reported knowledge of telehealth initiatives  in the country they represented. These initiatives were inclusive of occupational therapy practitioners, occupational therapy students, other professions, and interdisciplinary groups. Comments about these initiatives were associated with technology, training and information exchange, and improved access to OT services:“Applications for [electronic tablets] and smart phones are being developed, and research projects are ongoing with partnership between engineering and health,”A “non-government organization (NGO) in cooperation with information technology company is developing a service for persons with physical disabilities,”“There is a research [study]…to use telehealth for training parents of children with cerebral palsy in their home care,”“Clinical supervision and health based meetings are being provided by telecommunications across the country in some locations,”“Occupational therapists optimize exchange of electronic mails, video, voice calls, etc. with clients,”“Telehealth is being used by individual practitioners as well as by therapy companies who employ occupational therapy practitioners.”Many telehealth initiatives described in the survey aimed to improve access to occupational therapy services, particularly in rural areas. In some instances, telehealth technologies were used to facilitate communication with patients and their families or as a means to provide patient education. For example, one participant described the use of telehealth to support “communication between hospital and primary care/patient and relatives, typically on discharge from hospital.” The nature of these services included care coordination and patient/caregiver education on positioning, participation in activities of daily living, and correct use of adaptive equipment.In many of the countries represented, telehealth initiatives were primarily being used in medicine. One participant stated, “In OT, it is not yet common, but in some interdisciplinary groups it is. Especially in the practice of specialized medicine some initiatives and practices are developing.” Responses suggested that familiarity with telehealth and telehealth technologies in other healthcare disciplines and settings may lead to increased use of this service delivery model within OT. For example, one participant shared, “I think that there will be an increased demand for these kinds of services as our clients become more and more well informed. I do think that for many clients this could be a very good way of getting in contact with OTs.”Survey participants commented on the needs, current uses, and key considerations regarding use of telehealth to conduct occupational therapy evaluations in their respective countries. Many participants indicated that the use of telehealth for evaluation  would be beneficial to improve access to occupational therapy services, particularly for clients living in remote areas. Others alluded to the complexities of evaluation and potential limitations of telehealth technologies in this area. One participant stated:“OTs require access to the technologies and adequate Internet to use these technologies effectively. They also require training on how to use the technologies to achieve a good evaluation…There are complexities for OTs who use a holistic or PEO [Person-Environment-Occupation] approach to evaluation in getting all the information or understandings they require using telehealth/video-call technologies. A rich understanding of the home environment is difficult to ascertain through this medium. It is also difficult to engage with a number of people and read non-verbals. Clients are also unfamiliar with this technology and therefore experience some difficulties using it effectively.”Another important consideration for tele-evaluation is the need for further research to determine the reliability and validity of OT assessments administered remotely. This point was raised by one participant who noted, “the validity of standard evaluations when they are administered through telehealth technologies should be assessed.” The WFOT Telehealth Position Statement does not specifically address tele-evaluation or future research directions; however, the position statement does affirm that services provided through telehealth “should meet the same standards of care as services delivered in-person and comply with all jurisdictional, institutional, and professional regulations and policies governing the practice of occupational therapy (p. 1).”Survey participants were asked to comment on the needs, current uses, and key considerations for tele-consultation . Many participants indicated that remote consultation could improve knowledge and skills of providers in under-resourced or remote areas. One participant commented, “This would be extremely helpful for therapists working in remote areas who need to consult with an expert colleague regarding assessment of a particular client.” Other participants described ongoing tele-consultation initiatives including consultation with parents of children with disabilities via phone and videoconferencing, clients with multiple sclerosis in the areas of energy conservation and medication management, and between therapists for the purpose of sharing expertise. In reference to ongoing tele-consultation initiatives, one participant stated, “Telehealth works well for collaboration and consultation. Therapists in rural and remote areas use this well to get advice and support from other therapists.” This participant went on to describe other applications of tele-consultation including remote consultation with builders onsite during home modification evaluations.Convention on the Rights of Persons with Disabilities proclamation for States Parties to strengthen habilitation and rehabilitation services for persons with disabilities within their communities, the WFOT position statement states:The ability to share knowledge and expertise via tele-consultation is a significant benefit of telehealth and is incorporated in several sections of the WFOT Telehealth Position Statement. After citing the Telehealth may improve access to services within clients’ communities and ‘strengthen and extend comprehensive habilitation and rehabilitation services’ via the transfer of knowledge and skills from remote specialists to local health-care providers through consultation and mentoring relationships. (p. 1)World Report on Disability, which encouraged “sharing professional expertise between countries, as well as at critical times such as in the aftermath of a disaster”  quoted the co-produced World Health Organization and World Bank’s Survey participants described numerous examples of tele-intervention occurring within their respective countries. In one European country, a survey participant described how tele-intervention has resulted in improved access to OT services:“There are good examples in the northern part of [European country]. In this part of our country clients may have to travel more than 300 km to be able to meet an OT for face-to-face [in person] intervention. As far as I know most of these [tele-intervention] examples are given by OTs working with hand injuries. During these interventions the OT and client use videoconferencing.”Another participant from a country in the Middle East indicated that there were a few facilities providing tele-intervention, but stated “we need to develop this across the country.” Overall, participants’ responses validated the need for and potential benefits of tele-intervention. This perception was well articulated by one participant who commented, “Telehealth has the potential to increase equitable access at relatively low costs and efforts should be made to further implement these systems in practice.” However, concern for the potential impact of tele-intervention on the therapeutic relationship and limitations of a remote service delivery model were raised by some participants. One participant commented:“Interventions often require hands on [methods], use of equipment, or intimate engagement. A good deal of preparation and translation of face to face therapy events into a remote delivery format is required to do this effectively using telehealth.”The WFOT Telehealth Position Statement recognizes telehealth as an appropriate service delivery model for OT services, though clinical reasoning is needed to determine the best use of telehealth to achieve the same standards of care as services delivered in-person. The Position Statement reads:Telehealth is an appropriate delivery model for occupational therapy services when in-person services are not possible, practical, or optimal for delivering care and/or when service delivery via telehealth is mutually acceptable to the client and provider. Telehealth can also be part of a hybrid model wherein some occupational therapy services are delivered to a client in-person, and some occupational therapy services are delivered at a distance…Occupational therapy services via telehealth should be appropriate to the individuals, groups, and cultures served, and contextualized to the occupations and interests of clients. (p. 2)Participants commented on needs, current uses, and key considerations in the area of monitoring clients using telehealth (tele-monitoring). Participants were provided with the example of using technology to track a client’s behaviors or activity to clarify this model of care. Though the majority of participants reported no activity in the area of tele-monitoring in the country they represented, a few participants did describe ongoing tele-monitoring initiatives. One example involved the use of asynchronous data  to remotely monitor clients’ activities and observe progress over time. This same participant indicated that these videos are sometimes shared with other specialists on the rehabilitation team to improve communication, receive feedback, and monitor treatment outcomes. A participant from a country in the European Union (EU) stated, “There is a rehabilitation project within the EU using technology at home monitored by therapists in the rehabilitation centre.” Other participants described the use of tele-monitoring for clients with multiple sclerosis  and to support aging in place. Smart home technologies  were also described as part of a telehealth delivery model  to improve safety and occupational engagement; however, it is important to note that onsite use of these devices without the remote therapeutic component does not constitute a telehealth application. Overall, participants affirmed tele-monitoring to be a valuable telehealth application in occupational therapy. This sentiment was captured in the statement of one participant:“These technologies have some potential in assisting OTs in examining the impact and consequences of occupational engagement and assisting clients in modifying lifestyle in response to an acute or chronic health condition and promoting healthy ageing. The dedicated health monitoring devices as well as the mainstream fitness and smart devices provide opportunities to tracking and rewarding activity/occupational engagement and managing health conditions to optimise engagement.”In addition to the models of care outlined above, participants were asked to comment on the needs, current uses, and key considerations in the area of supervision (tele-supervision) via telehealth technologies. Many participants commented on the need, potential benefits, and important considerations associated with tele-supervision. One participant described that:“These technologies can assist novice and student therapists in accessing expert therapists and provide ongoing mentoring and supervision. It would reduce the travel time required to support students on placement. It would provide students and novice therapists with access to expert clinicians. The question is how best to set up a mentoring system that facilitates this.”Though most participants did not answer this question, presumably due to having no awareness or opinion on the use of tele-supervision or unfamiliarity with the term/translation, a few participants identified tele-supervision initiatives within the countries they represented. For example, one participant commented:“This is working very effectively in some areas but may not be the preferred choice for some occupational therapists who prefer physical face-to-face [contact] in the same environment. Having an initial face-to-face [in-person], and/or annual face-to-face [in-person] session may reduce this concern. This is an ideal form of supervision for those working in remote or isolated professional areas, or where supervision availability/skill range in local areas is limited. [Tele-supervision] relies on having the knowledge of how to use and availability of the technology.”Another participant described personal experience with tele-supervision, “This has been done for remote sites, and I personally have done this for consultation in international fieldwork (not as the primary supervisor during the time).” Participants identified important tele-consultation considerations including adherence to regulatory and reimbursement requirements and the need to assure high standards of care when providing supervision through telehealth technologies.The WFOT’s Telehealth Survey demonstrated that there was a need for an official document outlining the WFOT’s position on the use of telehealth in occupational therapy. Input from representatives of member organizations and review of existing occupational therapy telehealth position papers/statements informed the WFOT’s Position Statement on Telehealth, which addressed important practice considerations including licensure/registration requirements, need for collaboration/transfer of knowledge, client selection, provider competencies, and standard of care among other areas. Through the process of reviewing available occupational therapy telehealth position papers and statements and engaging WFOT member organizations, the WFOT created a valuable resource that will enhance the integration of telehealth in occupational therapy and established a process that may serve as a model for other international organizations.


The potential benefits of travelling across national borders to obtain medical treatment include improved care, decreased costs and reduced waiting times. However, medical travel involves additional risks, compared to obtaining treatment domestically. We review the publicly-available evidence on medical travel. We suggest that medical travel needs to be understood in terms of its potential risks and benefits so that it can be evaluated against alternatives by patients who are seeking care. We propose three domains –quality standards, informed decision-making, economic and legal protection – in which better evidence could support the development of medical travel policies. For the purposes of this paper, we define medical travel as including both essential and non-essential treatment. Although it is clear that cost, accessibility and quality are the main motivating factors for medical travel, data are largely limited to anecdotal projects from the perspective of a single country.,The potential benefits of medical travel include improved care, decreased costs and reduced waiting times.,,,Medical travel involves additional risks, compared to obtaining treatment domestically. If complications or adverse outcomes occur, additional expenses are likely, but insurance companies may not be willing to cover these costs.The growth in medical travel has implications for health service provision in destination countries. Access to health care for local residents might be adversely affected if local health professionals devote their time to treatment of foreigners rather than local communities. The ethical issues raised by medical travel are particularly acute in countries where access to basic medical care may be unaffordable for the local population. Here we review the scientific literature relevant to development of global policy on medical travel. Medical travel needs to be understood in terms of its potential risks and benefits so that it can be evaluated against alternatives.We carried out a non-systematic literature review. Articles were considered if they were found in any of six databases under the terms “medical tourism” or “medical travel” since the year 2000, with no language restrictions. The databases used were PubMed, EconLit, Google Scholar, the World Bank research database, Europe PubMed Central and EMBASE. We identified primary themes to be reviewed through common arguments used in higher quality sources as well as through common topics in low-quality or potentially very biased material. Papers were included if they provided specific data, policy or practice analyses, or substantial insight to key themes, regarding travel for necessary care. Where available, we extracted estimates of the numbers of medical travellers within the last 10 years.,,Most of the available data on medical travel is of poor quality. Sources are often not accessible or do not explain how estimated figures were calculated.The difference between high and low estimates of medical travellers increases if a wider range of timelines, methods and measures are included.,,,Clear parameters are needed for future work on medical travel, to develop an evidence base for policy development. The existing literature on medical travel emphasizes economic interests.,,While many different types of national quality-control measures exist, they are not applicable across international borders and this increases the risk of uninformed decision-making by potential medical travellers.,,More data on patient decision-making needs to be collected to ensure the practical value of any evidence generated on medical travel. Existing patient choice models indicate that there are a large number of considerations when deciding where to receive care and highly specified measures are needed to evaluate this at a global level.,,Knowledge of factors involved in patient choices about cross-border care is sparse.,To prevent harm, legal and economic frameworks for medical travel are needed.Legal frameworks need to clarify liabilities for adverse events and ensure equality of access for the local population. Access to health care has implications beyond individual care, including the perception of health-care system quality, which in turn influences individual well-being.There are considerable gaps in the current literature concerning the extent to which international health services are consumed and the needs of medical travellers are met. We suggest three key domains  for which scientific evidence would support the development of medical travel policies. There are challenges to obtaining such data, including barriers to accessing up-to-date information in governmental records, in health systems reviews, and in confidential databases kept by insurance firms. It is also difficult to find representative samples of patients who travel for care. There is currently a lack of consistent data on the specific procedures these patients seek, how many patients are involved and how much expenditure occurs. Effective research in medical travel as a global phenomenon requires consideration of all three domains, with the overall goal of improving access, quality of care, and health equity.


In the last decades four enigmatic medical conditions were described, all of which were characterized by an hyperactive immune response as well as similar clinical and laboratory manifestations. These conditions, namely siliconosis, the Gulf war syndrome (GWS), the macrophagic myofasciitis syndrome (MMF) and post vaccination phenomena represent environmental factors that may play a role in inducing or aggravating autoimmunity and auto-inflammation.Vaccines, administered to animal and humans, are clearly one of the best achievements of modern medicine and are commonly and safely inoculated to the vast majority of subjects. However in rare occasions vaccines may induce autoimmune or auto-inflammatory conditions both in animals and in humans. These conditions, either defined diseases such as Gullian Barre syndrome or enigmatic ones, have been reported following different vaccines and vaccination protocols. The susceptibility factors and the temporal association between vaccines and these rare immune mediated reactions are yet to be defined, however the similarities between vaccines and infections and the addition of an adjuvant  to almost every vaccine are considered major contributors to such adverse events. Perhaps the most evaluated condition is MMF, in which a cause was clearly delineated. MMF is a rare condition caused by deposition of alum, used to adjuvant different vaccines, which bring about an immune mediated muscles disease. Thus, in only a minority of genetically prone, i.e. HLA-DRB1*01 patients, alum may induce this syndrome.et a.l  showed that a group of 1546 patients with silicone breast implants had a statistically significant increase in 16 of 28 investigated symptoms when compared to a group of 2496 women who underwent reduction mammoplasties. Many of these symptoms satisfied several criteria for fibromyalgia and chronic fatigue syndrome, which is congruent with the FDA's finding that there is a statistically significant link between fibromyalgia and ruptured silicone gel implants.Another immune mediated phenomena leading to autoimmune diseases is exposure to silicones (i.e. breast implant). In a large study Fryzek A common denominator to each of these four syndromes as well as to various infectious agents is the trigger entailing adjuvant activity (7).Thus, herein we would like to suggest to include these four conditions under a common syndrome entitled the "Autoimmune (Auto-inflammatory) Syndrome induced by adjuvants" (ASIA). We propose several major and minor criteria that may aid in the diagnosis of this newly defined condition (ASIA).None declared.


The high prevalence of major depressive disorder in people with Parkinson’s disease (PD), its negative impact on health-related quality of life and the low response rate to conventional pharmacological therapies call to seek innovative treatments. Here, we review the new approaches for treating major depressive disorder in patients with PD within the framework of the network model of depression. According to this model, major depressive disorder reflects maladaptive neuronal plasticity. Non-invasive brain stimulation (NIBS) using high frequency repetitive transcranial magnetic stimulation (rTMS) over the prefrontal cortex has been proposed as a feasible and effective strategy with minimal risk. The neurobiological basis of its therapeutic effect may involve neuroplastic modifications in limbic and cognitive networks. However, the way this networks reorganize might be strongly influenced by the environment. To address this issue, we propose a combined strategy that includes NIBS together with cognitive and behavioral interventions. Major depressive disorder is a widely distributed chronic condition. While 1-year prevalence estimates of this entity round 5–10%, the lifetime prevalence reaches up to 15–20%. Moreover, major depressive disorder is characterized by high relapsing rates: 22–50% of patients suffer recurrent episodes within 6 months after recovery , a progressively debilitating neurological disorder affecting over 1 million individuals in the United States and approximately 6 millions worldwide. PD is considered as a movement disorder characterized by four cardinal motor symptoms: tremor, muscle rigidity, motor slowness and postural instability. However, most patients do also experience non-motor manifestations  has not been well established. The average prevalence of clinically significant depressive symptoms was calculated to be close to 35%  studies. Thus, although high-frequency electrical stimulation into the subthalamic nucleus (STN) is able to improve motor symptoms in advanced PD, it can also either improve or induce depressive symptoms , CBT and physical training Krystal, , 2.Electrical brain stimulation has a long history in the treatment of refractory depression. Electroconvulsive therapy (ECT) was introduced as a powerful therapeutic option for severe psychiatric disorders about 70 years ago. Since the early 50’s, ECT has been widely used with antidepressant purposes and is still considered as the most effective acute treatment for major depressive disorder  has been touted as a safe alternative to ECT. TMS is a non-invasive technique that uses electromagnetic induction to generate weak electric currents in the stimulated cortex, modifying cortical activity  stimulation during several daily sessions to achieve a long-lasting therapeutic effect. The rationale for the use of lateralized rTMS is based on the hypothesis that mood disorders may result from a relative imbalance between left and right frontal lobe activity  are able to improve motor functions, as measured by the Unified PD Rating Scale  after correction for publication bias  on brain plasticty in PD patients . An overall effect size of −0.80 (Hedges’ g) indicated that participants in the exercise treatment group had significantly lower depression scores than those receiving the control treatment or no-treatment (Rethorst et al., The indication of regular physical activity as a therapeutic strategy in PD-dep is mainly supported by the positive effects observed in depressed people without PD. A meta-analysis examined the effects of exercise on depression/depressive symptoms in 58 randomized controlled trials (Several hypotheses that involve biochemical, physiological, and psychosocial mechanisms have been offered to account for the effect of exercise on major depressive disorder. At a psychological level, physical exercise can increase perception and awareness of the body and physical self, with a positive impact on self-esteem and therefore fewer feelings of depression (Knapen et al., Emotion, movement and cognition are linked and are mediated through fronto-striatal loops. The prefrontal cortex is a central cerebral region that provides top-down regulation of attention, inhibition, motivation, and emotion through connections with subcortical structures (Tekin and Cummings, Although medications and CBT, alone or in combination, are considered effective treatments for major depressive disorder, up to 30% of patients show no improvement or only a partial response. Previous reports support the efficacy and good tolerability of rTMS in the treatment of major depressive disorder (Horvath et al., In summary, we reviewed here the importance of treating PD-dep because of its negative direct and indirect influence on quality of life and mobility. According to the network hypothesis of depression, we suggest a new type of combined therapy for treating PD-dep, focused on the optimization of activity-dependent plasticity in the prefrontal cortex, especially DLPFC rTMS and CBT Figure . This apKD did the literature search and wrote a first draft; GG corrected and revised the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Circadian rhythms act to optimise many aspects of our biology and thereby ensure that physiological processes are occurring at the most appropriate time. The importance of this temporal control is demonstrated by the strong associations between circadian disruption, morbidity and disease pathology. There is now a wealth of evidence linking the circadian timing system to metabolic physiology and nutrition. Relationships between these processes are often reciprocal, such that the circadian system drives temporal changes in metabolic pathways and changes in metabolic/nutritional status alter core molecular components of circadian rhythms. Examples of metabolic rhythms include daily changes in glucose homeostasis, insulin sensitivity and postprandial response. Time of day alters lipid and glucose profiles following individual meals whereas, over a longer time scale, meal timing regulates adiposity and body weight; these changes may occur via the ability of timed feeding to synchronise local circadian rhythms in metabolically active tissues. Much of the work in this research field has utilised animal and cellular model systems. Although these studies are highly informative and persuasive, there is a largely unmet need to translate basic biological data to humans. The results of such translational studies may open up possibilities for using timed dietary manipulations to help restore circadian synchrony and downstream physiology. Given the large number of individuals with disrupted rhythms due to, for example, shift work, jet-lag, sleep disorders and blindness, such dietary manipulations could provide widespread improvements in health and also economic performance. Possession of such rhythms enables organisms to anticipate predictable changes in the environment and thus adapt their physiology accordingly. Temporal control over metabolic processes also allows cells and organisms to separate opposing biochemical pathways, for example, redox reactions and anabolism v. catabolism. Moreover, in model species, it has been demonstrated that possession of circadian rhythms that synchronise to environmental changes confers a selective advantage.Circadian rhythms are cyclical endogenous processes that occur with a periodicity of approximately 24 h. They are found throughout the natural world, from simple unicellular organisms through to human beings1. PosA great deal of current research is being undertaken at the interface between the circadian timing system, metabolic physiology and nutritional science. Studying how these major biomedical areas inter-relate will not only increase our understanding of healthy metabolism, but may also guide the development of nutritional interventions for body-weight regulation, the management of obesity-related disease and the treatment of circadian disorders associated with shift work, jet-lag, abnormal sleep phase and blindness.. When the SCN are isolated from surrounding brain tissue in vivo, or maintained as tissue explants in vitro, their neurones maintain robust rhythmicity(–). Furthermore, if SCN tissue from one animal is transplanted to another animal that has had its SCN lesioned, the resulting behavioural rhythms reflect that of the donor animal, not the host. It is therefore clear that the SCN play a key role in the generation of mammalian circadian rhythms.It was recognised over 40 years ago that a small brain region within the anterior hypothalamus, the suprachiasmatic nuclei (SCN), is important for the expression of circadian rhythms in mammals,4. W. Following the cloning of genetic components of the mammalian clock came the discovery of rhythmic clock gene expression in peripheral tissues. Subsequent advances came from the use of transgenic animals in which reporter gene expression is driven by clock gene elements. Real-time imaging of tissue explants taken from these animals confirmed that many peripheral tissues possess an endogenous clock. Perhaps most surprisingly, circadian rhythms have also been identified in cultures of immortalised cells(–).Mammalian clocks outside the SCN, termed ‘peripheral clocks’, were first identified in tissues such as the retina, which exhibits rhythmic hormone secretion when maintained in culture9. Fol. For ethical and technical reasons, molecular analysis of human tissues is difficult and various strategies have been adopted to study human clock gene expression. However, clock gene rhythms have now successfully been observed in human leucocytes, fibroblasts and adipose tissue, with single time point analysis of clock gene expression in other tissues, including pancreatic islets.In animal models, rhythmic clock gene expression is known to occur in multiple tissues involved in metabolism and nutritional physiology, including the liver, pancreas, gastrointestinal tract, adipose tissue and skeletal muscle,18. . In normal circumstances, the clock in the SCN then synchronises rhythms elsewhere in the body through a variety of output pathways. A commonly used analogy to describe this organisation refers to the SCN as a conductor of an orchestra, with the peripheral tissues representing individual musicians; each of the ‘musicians’ is capable of generating its own time but requires the central ‘conductor’ to ensure that they all maintain correct time relative to each other and thus optimal overall output.The presence of rhythms throughout the body requires appropriate physiological mechanisms to keep tissues correctly synchronised to one another. The SCN receive photic information directly from the retina and are readily synchronised to the external light–dark cycle27. In. In addition, by influencing the timing of sleep–wake rhythms, the SCN also dictate the timing of certain behaviours, for example, feeding, which are thought to be critical to the rhythms in peripheral tissues as explained below.There are many ways through which the SCN can synchronise peripheral tissues. These include endocrine and neuronal pathways, such as the secretion of glucocorticoids and the tone of the autonomic nervous system28. In(–). Identification of the rhythmic transcripts revealed a large cluster of genes encoding proteins involved in metabolic pathways. Later proteomic analysis also suggested that up to 20 % of proteins in the mouse liver oscillate with a circadian rhythm, and many of these proteins are indeed involved in important metabolic functions. Technical advances have since permitted direct analysis of the daily metabolome in different tissues. Similar to the transcriptomic and proteomic data, both mouse(–) and human(–) studies estimate that up to 20 % of the metabolome is under 24 h regulation.Since the identification of clocks in peripheral tissues, a critical challenge has been to identify their physiological role. An early indication that peripheral clocks had a strong influence on metabolism came from transcriptomic analyses. Depending on the analytical methods used, these studies estimated that up to 20 % of the transcriptome in peripheral tissues exhibits 24 h variation–33. , the precise nature of metabolic abnormality in transgenic animals depends upon their genetic background. Nonetheless the dysregulation of key metabolic processes, including glucose and lipid homeostasis, following disruption of key genes involved in circadian biology reveals fundamental links between circadian genetics and metabolism(–). Consistent with these animal data, a number of groups have now reported correlations between aspects of human metabolism and clock gene polymorphisms(–).Genetic evidence for a role of circadian clocks in key metabolic processes is now substantial. As discussed previously41, thLox recombinase system to disrupt the Bmal1 (brain and muscle arnt-like protein-1) gene in a tissue-specific manner, circadian rhythms in the liver, pancreas and white adipose tissue have been selectively ‘knocked out’ allowing the in vivo role of their clocks to be investigated. Mice bearing a liver-specific clock disruption exhibit increased glucose clearance following acute challenge, fasting hypoglycaemia and other features suggesting that the hepatic clock regulates glucose export into the blood. By contrast, disruption of the pancreatic clock results in hyperglycaemia, reduced glucose tolerance and impaired insulin secretion. Finally, knock-out of Bmal1 in white adipose tissue induces obesity; a contributory mechanism to this phenotype is the temporal modification of PUFA signalling from adipocytes to appetite-regulatory regions of the hypothalamus, leading to increased feeding during the resting phase of the day. Thus, circadian dysfunction in individual tissues can lead to major changes in whole-body energy metabolism.One limitation of studies involving individuals with ‘whole body’ genetic changes is that they do not clearly indicate the contribution of individual tissue rhythms to whole-organism physiology. Using the Cre-the blood54. By. Such temporal restriction induces a bout of activity in advance of food availability, termed ‘food anticipatory activity’ (FAA). This phenomenon was originally observed in rats, but has since been reported in multiple vertebrate and invertebrate species. More detailed analysis in rodents reveals that this FAA is also accompanied by physiological changes including increased core body temperature and serum glucocorticoid concentration.Restriction of food availability to a narrow time window each day results in profound reorganisation of behaviour and physiology,59. .Interestingly, FAA exhibits properties that are consistent with it being controlled by endogenous circadian clock(s), rather than being merely a food-driven phenomenon. For example, if the temporal window of food availability is abruptly delayed, the onset of FAA takes multiple 24 h cycles to resynchronise to the new feeding time. Moreover, if an animal is completely food deprived, FAA persists at approximately the same time every 24 h for as long as the food deprivation can be maintained,59., these mice do retain the ability to display FAA. It is therefore believed that the genetic control of the FEO differs from other circadian processes. In keeping with this idea, food anticipatory responses persist in SCN-lesioned animals, indicating that the FEO resides in tissue(s) outside of the SCN, the master circadian clock. Some studies have suggested that the FEO may be closely linked to the dorsomedial hypothalamic nuclei, a brain region known to be involved in the homeostatic regulation of feeding. Other work has highlighted the potential role of extra-hypothalamic brain regions in FAA. The anatomical localisation of the FEO remains a controversial topic, however(–). Indeed the FEO may lie outside of the brain or require the interplay between multiple tissues.The underlying circadian basis of FAA has led to the postulation that animals contain a food-entrainable oscillator (FEO). Although there are reported differences in FAA in mice lacking genetic components of the circadian clock60, thOne potential mechanism underlying food-entrainable rhythmicity is the effect of feeding time on peripheral tissue clocks. In normal physiological conditions, the timing of behavioural rhythms, such as feeding, is driven by the SCN and thus represents a mechanism through which the SCN can synchronise rhythms in the periphery. The powerful nature of timed feeding as a circadian signal becomes apparent when food availability is divorced from SCN rhythms.. Full entrainment of the liver rhythms appears to occur within 2–3 d, whereas the other peripheral tissues may require up to 1 week before they exhibit the maximal phase shift. A later mouse study involved removal of food access for the first 6 h of the dark period of a light–dark cycle, with mild energy restriction. After 4 d in this protocol, mice exhibited delayed rhythms of hepatic and plasma TAG concentration, together with delayed rhythms of lipogenic and clock gene expression in both liver and adipose tissue. When animals are able to eat ad libitum quantities of food during temporal restriction paradigms, SCN rhythms remain locked to the light–dark cycle. However, the combination of temporal food restriction and hypoenergetic food availability does induce reorganisation of rodent SCN rhythms. Indeed, hypoenergetic feeding of nocturnal rodents without restricting food availability to the light period alters the phase of SCN-driven rhythms as well as gene expression in peripheral tissues. Thus the overall effect of feeding on circadian organisation appears to involve an interaction between both the timing and the quantity of food intake . To date there are no comparable molecular data from human studies. One rare investigation of timed feeding on human circadian physiology is an experiment in which subjects were fed a single daily carbohydrate-rich meal for 3 d; morning consumption of this meal advanced core body temperature and heart rate, but not melatonin, rhythms compared with evening meal timing. Furthermore, a delay in the timing of three daily meals within a fixed light–dark cycle is known to delay the phase of plasma leptin rhythms, which may be at least partially due to changes in adipose tissue clocks.An important caveat when extrapolating the studies described above to human society is the relevance to standard human meal patterns. A common theme in human society is a feeding pattern of three meals per d. In contrast, most animal studies to date have utilised prolonged ree meals78. Co. Interestingly, however, ingestion of 100 % glucose, sucrose or maize starch is insufficient to alter the phase of liver rhythms, indicating that mixed macronutrient content may be necessary for food entrainment in the liver. At the physiological level, temporal food restriction more rapidly resynchronises peripheral clock gene rhythms in mice that have been adrenalectomised, compared with sham-operated controls. This finding suggests that glucocorticoid signalling, which is believed to be an endocrine link between the SCN and peripheral clocks, may inhibit or delay the impact of temporal food availability. At the molecular level, it has been demonstrated that rhythmic phosphorylation of key transcription factors CREB and Akt (cAMP response element-binding protein and protein kinase B) in the mouse liver is driven by temporal feeding patterns. In keeping with this result, the expression of multiple genes targeted by molecular nutrient and stress sensors was similarly dependent on feeding time. Finally, mice deficient for the gene Parp1 (poly [ADP-ribose] polymerase 1) or the neurone-specific γ form of protein kinase C (PKCγ) exhibit impaired synchronisation to timed feeding. Despite these advances, the mechanisms that mediate the effects of food on the circadian system are poorly understood and will doubtless be the subject of multiple further studies.Although redundancy of signalling pathways providing input to the relevant tissues hinders elucidation of mechanistic insight into food entrainment, some progress has been made. At the nutritional level, phase shifting of the liver clock seems greater when the starch component of a mixed diet provides a large postprandial glucose concentration82. Inper se. As a result, they are not considered to be truly circadian.Diurnal rhythmicity refers to 24 h changes that occur in individuals kept in a varying environment, for example, a 24 h light–dark cycle. Although such rhythms are often relevant to a real-life scenario, there is the possibility that they are driven by environmental fluctuations rather than endogenous processes . Sensitivity to elevated glucose concentration is greatest in the early morning and then declines over the course of the day, leading to a phenomenon that has been termed ‘afternoon diabetes’. This daily change is not dependent upon changes in gastrointestinal function, but instead appears to be the result of altered glucose utilisation and insulin sensitivity, with maximal insulin sensitivity occurring in the early morning and decreasing throughout the day.Arguably the best-characterised daily metabolic rhythms in humans relate to changes in glucose homeostasis. Diurnal changes in glucose tolerance have been recognised in human subjects for many years89. Se. A study of postprandial responses to breakfast and lunch reported approximately 50 % less change in plasma TAG concentration following lunch than breakfast, despite the plasma TAG fraction showing no differences in concentration of [13C]palmitic acid that was included in each meal. The physiological basis for temporal differences in postprandial TAG response may therefore be independent of absorption or mobilisation of meal-derived lipids from the gut.In addition to glucose homeostasis, the regulation of plasma lipids is also subject to daily variation. Not only are basal concentrations of TAG elevated at night, but also there are diurnal changes in the postprandial TAG response. Ingestion of a meal at night results in increased plasma TAG that remains elevated for longer than the response to the same meal given during the day90. A . Diurnal rhythms have been reported for many of these hormones, including leptin, adiponectin, chemerin, lipocalin and visfatin(–). Although the secretion of these hormones is likely to be governed by multiple factors such as feeding and sleep, detailed analyses of leptin secretion suggest that there is likely to be an underlying circadian component to adipokine rhythmicity. Furthermore, given the functional roles of adipokines, their rhythmic secretion may make important contributions towards the daily changes in glucose and lipid homeostasis described above.A number of groups have studied temporal variation of adipokines, which are adipose-derived hormones that regulate metabolic physiology in the brain and multiple peripheral tissues,93. . In a constant routine, subjects are kept awake in a supine posture in constant dim light, with identical regular  snacks. Although this protocol effectively removes environmental rhythms, it does result in the development of sleep debt due to the necessity to keep subjects awake. One solution to this problem is to allow subjects to sleep during the dark phase of a light–dark cycle that is sufficiently different from 24 h to permit entrainment of subjects' circadian rhythms; this is the basis of a forced desynchrony protocol. For example, a commonly used variant of this protocol employs a 28 h light–dark cycle that therefore allows subjects to sleep every 28 h, while their circadian rhythms occur (‘free run’) with a frequency of approximately 24 h.In order to unmask truly endogenous circadian rhythms from temporal changes in the environment, a number of different laboratory protocols have been developed. The most widely used of these are the constant routine and forced desynchrony protocols,102.. Consistent with this finding, analysis of postprandial responses during a forced desynchrony of 27-h days revealed effects of both circadian time and length of prior wakefulness on glucose and TAG concentration. By contrast, postprandial insulin responses were regulated by circadian time, but not length of wakefulness. A more recent forced desynchrony protocol kept volunteers on 28-h days, each of which contained four meals: breakfast, lunch, dinner and a snack shortly before bedtime. It was found that the times during which subjects were awake and eating during their biological night resulted in multiple cardiometabolic changes, including decreased plasma leptin concentration and increased concentrations of both plasma glucose and insulin. In fact, the postprandial responses of some of these healthy subjects during the biological night were equivalent to the responses of a pre-diabetic individual. In a separate cross-over study using forced desynchrony, volunteers had daily metabolic profiles assessed after both three 21-h days and also three 27-h days. Although there were some differences in response to the 21-h v. 27-h days, both schedules disrupted glucose–insulin metabolism, increased carbohydrate oxidation and reduced protein oxidation, but had little or no effect on appetite or energy balance. The human circadian system therefore exerts clear influence over key aspects of metabolic physiology.Various research groups have utilised the above protocols to investigate the contribution of the endogenous circadian system to daily rhythms of glucose and lipid metabolism. One study in which 4-hourly meals were administered over a constant routine revealed elevation of both postprandial glucose and TAG during the biological night, especially after high-fat meal intervention over the week preceding the constant routine103. CThe data discussed above describe the interaction between clocks and metabolism on a relatively short-term time frame. Of importance to health is the longer-term relationship between circadian rhythms, metabolic status and body weight. Indeed, many studies in the literature have reported altered daily rhythms in association with factors including altered body weight, presence of metabolic disease and long-term changes in nutrient intake.. However, not all studies have been able to replicate this finding. The reasons for discrepancies are not clear, but may include varied pre-laboratory controls, sex of subjects, extent of obesity (i.e. BMI of 30–35 v. 40+ kg/m2) and distribution of fat within the obese subjects recruited.Following the demonstration of daily rhythms of plasma leptin in human subjects, it was reported that the percentage amplitude of these rhythms declined in obese individuals,,. How has been supported by recent data reporting elevated amplitude melatonin rhythms in obese non-diabetic men, although blunted melatonin rhythms are present in weight-matched men with type 2 diabetes. In addition, nocturnal melatonin concentration correlates with aspects of the metabolic syndrome in women. The functional relevance of these endocrine data is supported by molecular and genetic evidence for a role of melatonin signalling in metabolic physiology and type 2 diabetes mellitus. Common polymorphisms of the human MT2 melatonin receptor have been associated with impaired glucose homeostasis and type 2 diabetes in multiple populations(–). Although the calculated risk of developing type 2 diabetes is small for these polymorphisms, subsequent work identified additional rare MT2 variants that confer a much higher risk of diabetes and also disrupt melatonin signalling in cell culture experiments. Evidence from animal models further supports the existence of a physiological link between melatonin, insulin secretion and insulin sensitivity. When comparing rodent and human data, it should be recognised that elevated melatonin secretion occurs at night in all species, irrespective of whether they are active at night or during the day; therefore direct translation of data relating melatonin to glucose homeostasis from rodents to humans is difficult. Despite this, there is now evidence to support linking low nocturnal melatonin levels in humans, estimated from morning urinary metabolite concentration, with the risk of developing type 2 diabetes and also insulin resistance in non-diabetic subjects.Another hormone that appears to demonstrate correlation between rhythm amplitude, body weight and metabolic health is melatonin. An early report that nocturnal melatonin concentration positively correlates with BMI in insulin-sensitive human subjects111 ha, liver and brain stem of obese and diabetic mice. However, interpretation of these data is sometimes hampered by the use of different genetic strains in the lean and obese groups. We have recently compared daily profiles of clock gene expression in subcutaneous adipose biopsies taken from lean and obese human subjects and failed to observe any effects of body weight on these molecular rhythms. Although it is possible that differences would have been observed if we had been able to serially sample other  adipose depots, the data nonetheless indicate that obesity per se does not impair clock gene rhythms in all metabolically active tissues.Comparison of molecular rhythms in lean and obese individuals has also been addressed by a number of research groups. Reduced amplitude rhythms have been reported in tissues such as adipose,124,. In another experiment, mice were fed for 7 weeks with either a high- or low-fat diet, fasted for 24 h and killed in constant darkness. Comparison of clock gene expression in the liver of these animals revealed a phase delay of approximately 3 h with no consistent reduction in rhythm amplitude in the animals fed on a high-fat diet. Analysis of two daytime time points in mice maintained on high- or low-fat diets for 11 months also revealed altered liver and kidney clock gene expression. In contrast to the above studies, which all used male mice, few significant differences were observed in liver and adipose clock gene rhythms from female mice fed high- or low-fat diets for 8 weeks.A small number of animal studies have compared lean and obese groups generated by manipulation of dietary intake, rather than examining the effects of altered body weight due to genetic differences. In most cases, dietary obesity results in clear changes in aspects of the circadian system, but the available results are not entirely consistent. In one study, 6 weeks of high-fat diet altered behavioural and endocrine rhythms, together with changes in gene expression profiles that included reduced amplitude clock gene rhythms in adipose and liver127. I, adiposity and nocturnal postprandial response (described below) have been reported. Furthermore, the extreme changes in dietary intake utilised in animal experiments may not accurately represent typical human diets. It is therefore clear that more research is required in this area before the translational consequences are fully understood.The differences in type and magnitude of response observed in mice chronically fed a high-fat diet probably reflect details of experimental design such as sex of the animal, dietary composition and environmental conditions used during the protocol. Sex is an issue of note in regard to human physiology, where sex differences in circadian rhythms131, aAs would be expected for an emerging research field, the available literature mostly derives from controlled laboratory experiments. However, the biological principles described have far-reaching implications for many people living in contemporary society.. This body-weight effect becomes statistically significant within 2 weeks and despite trends towards increased energy intake and reduced activity in the light-fed animals, there were no statistically significant changes in these parameters. In a refinement of the protocol, mice were fed a high- or low-fat diet that was available either ad libitum throughout the day, or during a 4 h period in the middle of the light phase. Remarkably, temporal food restriction resulted in reduced body weight on both high- and low-fat diets, to the extent that mice on a restricted high-fat diet weighed less than those provided with a low-fat diet ad libitum. This occurred despite no difference in energy consumption (as expressed relative to body weight) between the restricted high-fat-diet group and the two low-fat-diet groups, although mice under restricted feeding did exhibit elevated total daily activity compared with ad libitum controls. Comparing these two studies, it seems that the duration of restricted food availability has profound effects on body-weight regulation, but the mechanisms underlying this phenomenon are not yet clear.Evidence is rapidly accumulating to support an important role of meal times in the long-term regulation of body weight. Proof-of-concept studies in animal models have utilised different timed feeding paradigms. Mice housed in a light–dark cycle and fed a high-fat diet gain more weight when the food is available only throughout the light phase, when they would usually be resting, than when it is provided throughout the dark phase133. Tper se on metabolism and body weight. Work in this area has understandably focused to a large degree on meals taken at the start and end of the day, for instance the study of breakfast consumption and individuals with night eating disorders. Evidence suggests a role for regular breakfast consumption in the maintenance of healthy body weight, although the issue has rarely been approached from a chronobiological perspective and questions remain about the causative mechanisms involved. Night eating syndrome has recently been included in the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5). It is broadly characterised by recurrent episodes of nocturnal eating that cannot be better accounted for by other behavioural and psychiatric disorders, and is discussed in detail elsewhere. The relationship between night eating syndrome and body weight is complex, with some variable findings reported in the literature. Despite this, the overall evidence provides compelling associations between night eating and obesity, with a consistent finding that night eating syndrome is more prevalent in overweight and obese groups. The importance of evening meals is further highlighted in studies of subjects without night eating disorder. For example, energy consumption after 20.00 hours has been associated with BMI independently of age, sleep timing and sleep duration. This group later reported that protein intake within 4 h of sleep onset is associated with elevated BMI after controlling for age, sex, sleep timing and sleep duration.In humans, there is an increasing interest in the effects of meal timing  involved,136.. In a separate experiment, obese/overweight women consumed energy-restricted diets that differed in the proportion of energy distributed between breakfast and dinner. The women eating more energy at breakfast than dinner not only lost more weight but also exhibited an improved metabolic profile in insulin sensitivity and TAG concentration. Together these data support the hypothesis that the timing of food intake is important for body-weight regulation.The link between food timing and body weight is also apparent in dietary weight-loss studies. A group of 420 individuals undergoing a 20-week weight-loss programme were categorised according to the time at which they ate lunch, which was their main daily meal. Those in the late group lost less weight and at a slower rate than the early group, with no difference in energy intake, energy expenditure, dietary composition or sleep duration141. I. This clearly indicates that a large section of the population experiences regular misalignment of their behaviour with the solar day. A second common cause of abrupt circadian misalignment is jet-lag, the rapid travel across time zones. Although this experience is a rare and transient phenomenon for most people, it nonetheless affects a substantial number of individuals and in some cases  can be a regular event. A related phenomenon that is common in society is a weekly change between widely differing sleep times on work and free days. This has been termed ‘social jet-lag’ and is associated with elevated BMI.Since industrialisation, humans have gained the ability to regulate environmental conditions and subsequently alter temporal patterns of behaviour. Indeed the phrase ‘24/7 society’ is now in common usage to describe the constant presence of industrial and social activity. In order to cope with the demands of this modern aspect of society, varied work schedules are now commonplace, with approximately 20 % of the European workforce engaged in night shifts143. T. Understanding the aetiology of shift work-related morbidity is complex due to diverse contributory factors such as sleep disturbance, altered social pressure and patterns of food intake. For example, although shift workers often report normal total energy intake, there is commonly an altered temporal distribution of feeding characterised by more irregular eating times, more snacking and fewer substantial meals. Alongside these lifestyle changes it is likely that disrupted circadian physiology is a major contributor to the pathophysiological consequences of shift work. Indeed it is generally recognised that many shift workers in temperate regions poorly adapt circadian rhythms to their work conditions. As a result, these individuals experience prolonged durations of misalignment between their circadian biology and behavioural patterns.Multiple health problems are associated with shift work, including increased risk of cardiovascular and metabolic disease146. U rather than a high-fat pre-meal. Furthermore, there are reported sex differences in postprandial response, with a more pronounced elevation of TAG in the first night of a simulated night shift in men than in women.As described previously, postprandial profiles of glucose and TAG concentration vary over the day. Such studies clearly imply that shift workers eat a substantial proportion of their meals during the time of suboptimal glucose and lipid tolerance. This prediction is strengthened by studies of simulated shift work where subjects are subjected to an abrupt shift of typically 6–10 h in their daily routine. Interestingly, the postprandial response in such protocols is altered by the preceding diet. In comparable experiments, the exaggerated postprandial response following a test meal in shifted subjects was reduced for glucose and insulin but increased for TAG following a low-fat pre-meal150 ra. Given the large number of individuals undertaking shift work in modern society, there is a clear need to improve circadian alignment in these individuals. One possible intervention is the manipulation of light, which is able to reset circadian rhythms and also directly improve alertness even following short exposure times. However, timed food may also be a powerful method for resetting rhythms to a new phase. Of particular interest is the ability of timed food to reset peripheral tissue rhythms.In real shift workers, there are also postprandial data describing the relative insulin resistance and lipid intolerance following abrupt shift changes152. G. Similar findings have been reported in rats exposed to an artificial shift work protocol, although the body-weight increase and metabolic disturbances experienced were attenuated when food availability was restricted to the normal activity phase. Further development of these animal models will permit detailed molecular analysis to complement human studies of shift work and its adverse effects.Animal models support the idea that timed food intake could be a valuable intervention to minimise adverse effects of shift work. Mice subjected to an artificial shift work-like environmental schedule exhibit circadian desynchrony and metabolic disturbance155. SA wealth of data from varied experimental approaches provides us with clear links between circadian, metabolic and nutritional biology. These findings provide a strong foundation upon which to model mechanisms underlying the temporal differences in response to food intake. One limitation of the field is that little translational research has yet been performed in human subjects. Understanding the circadian regulation of human metabolism will have profound implications for nutritional science and explain how time of day is important for postprandial physiology. Furthermore, it will also reveal how timed dietary intake can be used as a means to alleviate some of the deleterious effects of circadian misalignment that are experienced by large numbers of people within modern society.


Synaptotagmin II (syt2), in the PFC in a chronic pain model is associated with long-term changes in DNA methylation. The challenges of understanding the contributions of epigenetic mechanisms such as DNA methylation within the PFC to pain chronicity and their therapeutic implications are discussed.Chronic pain is accompanied with long-term sensory, affective and cognitive disturbances. What are the mechanisms that mediate the long-term consequences of painful experiences and embed them in the genome? We hypothesize that alterations in DNA methylation, an enzymatic covalent modification of cytosine bases in DNA, serve as a “genomic” memory of pain in the adult cortex. DNA methylation is an epigenetic mechanism for long-term regulation of gene expression. Neuronal plasticity at the neuroanatomical, functional, morphological, physiological and molecular levels has been demonstrated throughout the neuroaxis in response to persistent pain, including in the adult prefrontal cortex (PFC). We have previously reported widespread changes in gene expression and DNA methylation in the PFC many months following peripheral nerve injury. In support of this hypothesis, we show here that up-regulation of a gene involved with synaptic function,  Chronic pain is associated with a multitude of co-morbidities, including depression, anxiety, cognitive impairment, memory deficits and loss of motivation both in humans  can be reversed with effective pain management . These data offers additional insight into the function of previously uncharacterized transcripts that do not code for protein. Thus, non-coding RNAs within the PFC may also play a role in neuropathic pain. Our transcriptome analysis also revealed enrichment of non-annotated transcripts derived from within and outside of gene bodies (non-annotated in mm9 genome assembly)  [GenBank: AL596207.10] as our test case. Syt2, a known regulator of synaptic function, belongs to a family of membrane-trafficking proteins, is involved in synaptic vesicle docking and fusion, and acts as a calcium sensor for fast neurotransmitter release. Since syt2 was previously shown to be upregulated in the PFC of neuropathic mice 6 months after injury . In order to directly determine whether methylation of CG sites in this syt2 regulatory region affects the ability of this region to activate transcription, the region was subcloned into a CpG-deficient luciferase reporter; the same region was subcloned in the antisense direction as a negative control. The promoter was then methylated in vitro using Sss1 DNA methyltransferase or mock methylation was performed in absence of enzyme as a negative control. Since the vector does not contain CG sites, only CG sites in the inserted syt2 region could be methylated in vitro. The mock methylated and methylated syt2 luciferase reporters were transiently transfected into HEK293 cells. The luciferase assay results demonstrated that this syt2 region directs transcriptional activity that is inhibited by the same methylation of CG sites that are differentially methylated in vivo in response to nerve injury . Interestingly, we observe changes in DNA methylation in a very limited area in the promoter. This is consistent with the hypothesis that DNA methylation silences promoter activity through interference with binding of factors discussed above. For example, we have shown previously that epigenetic programming by maternal care of the Glucocorticoid receptor gene involves site specific changes in one CG which is also the binding site for the transcription factor NGFI-A  in our transcriptomic screen of the PFC. Is this because massive dysregulation of hypermethylation/hypomethylation through the DMNTs occurs early after injury but by 6 months has reached a new steady state? Given the chronicity of pain and its co-morbidities, we believe that the processes underlying neuroplasticity are part of the etiology of the disease and exist in a continuum of cause and effect. For example, while co-morbidities of chronic pain may not manifest themselves early following injury, the emergence of co-morbidities may initiate a cascade of transcriptional changes in the brain that program long-term changes. This cascade, modulated by DNA methylation and other epigenetic processes over the course of months to years, may feed into the pathology of chronic pain, thus increasing the burden of the disease. Would that imply that pain-related changes in methylation are more difficult to reverse months vs. days after injury? All of these questions merit further exploration. However, it should be noted that DNA methylation states of genes are regulated by many factors in addition to global levels of enzyme such as local presence of transcription factors and chromatin states of genomic loci, these rather than global changes in enzyme levels might be the determining causal agents of changes in DNA methylation in chronic pain.Interpretation of changes of DNA methylation in the brain, as compared to other tissues, is complicated by cell heterogeneity. In the brain, it is difficult to attribute altered patterns of methylation to specific cell types. In Lister et al., mapping of the brain methylome, cell sorting enabled distinction between neurons compared to astrocytes (Lister et al., It is important to note that epigenetic changes are not independent of one another. A great deal of crosstalk between DNA methylation has been reported (D’Alessio et al., Finally, while this manuscript uses the example of syn2 to illustrate the main hypothesis, the role of individual genes or gene families is virtually unexplored. While some differentially methylated sites may be critically important in pain-related neuroplasticity, it is likely that many are not. Understanding epigenetic regulation at both the genome-wide and the gene-specific levels will provide insights into how chronic pain changes the brain and how to reverse it.One fundamental difference between epigenetic regulation and genetic polymorphisms is the potential of the former to be modulated by pharmacological manipulations Szyf, , 2009. ITo date, most pharmacological interventions directly targeting epigenetic mechanisms have been used to provide evidence of epigenetic involvement rather than to explore viable treatment options. However, with the increased emphasis on pain epigenetics, it is plausible that more targeted approaches could be applied to the treatment of pain and its related comorbidities at the peripheral, spinal, and supraspinal levels. Currently, small molecule drugs targeting epigenetic machinery function globally, modifying the genome across multiple cells and tissues. Appropriate targeting of epigenetic therapeutics is needed to enhance specificity and reduce systemic side-effects. This targeting can be tissue-, cell- or gene-specific. Although this statement reflects common wisdom that good agents should be “magic bullets” it isn’t clear that “dirty” drugs will not have a therapeutic value. It is possible that general DNA methylation inhibitors such as RG108 (Machnes et al., in vitro (Maeder et al., Although gene-targeting DNA methylation modifiers are still only a hypothetical approach, of potential therapeutic value might be gene-specific epigenetic targeting through recently developed genome editing technology. For example, TET-TALE fusion proteins have been shown to effectively target and demethylate individual genes The therapeutic interventions currently thought to offer some benefits through DNA methylation exist include nutritional inputs such as folate and other methyl donor intermediates. Relevant to neuropathy, folate has been shown to aide axonal regeneration in a dose-dependent manner through DNA methylation machinery and folate metabolism (Iskandar et al., Despite its high prevalence, little is known about the brain mechanisms underlying chronic pain and its associated co-morbidities. This hypothesis paper builds upon previous publications where we propose that DNA methylation contributes to the chronic changes in behavior and gene expression in neuropathic mice. Furthermore, it provides proof of principle evidence for linking peripheral injury-triggered central changes in DNA methylation and transcriptional regulation. Finally, we propose that long-term alterations in DNA methylation could provide a molecular substrate for chronic pain-related changes in the CNS, forming a “memory trace” for pain in the brain.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Background: Robust evidence supports the effectiveness of screening and brief alcohol interventions in primary healthcare. However, lack of understanding about their “active ingredients” and concerns over the extent to which current approaches remain faithful to their original theoretical roots has led some to demand a cautious approach to future roll-out pending further research. Against this background, this paper provides a timely overview of the development of the brief alcohol intervention evidence base to assess the extent to which it has achieved the four key levels of intervention research: efficacy, effectiveness, implementation, and demonstration.Methods: Narrative overview based on (1) the results of a review of systematic reviews and meta-analyses of the effectiveness of brief alcohol intervention in primary healthcare and (2) synthesis of the findings of key additional primary studies on the improvement and evaluation of brief alcohol intervention implementation in routine primary healthcare.Results: The brief intervention field seems to constitute an almost perfect example of the evaluation of a complex intervention. Early evaluations of screening and brief intervention approaches included more tightly controlled efficacy trials and have been followed by more pragmatic trials of effectiveness in routine clinical practice. Most recently, attention has shifted to dissemination, implementation, and wider-scale roll-out. However, delivery in routine primary health remains inconsistent, with an identified knowledge gap around how to successfully embed brief alcohol intervention approaches in mainstream care, and as yet unanswered questions concerning what specific intervention component prompt the positive changes in alcohol consumption.Conclusion: Both the efficacy and effectiveness of brief alcohol interventions have been comprehensively demonstrated, and intervention effects seem replicable and stable over time, and across different study contexts. Thus, while unanswered questions remain, given the positive evidence amassed to date, research efforts should maintain a continued focus on promoting sustained implementation of screening and brief alcohol intervention approaches in primary care to ensure that those who might benefit from screening and brief alcohol interventions actually receive such support. Brief interventions for alcohol provide a clinically effective and cost-effective means of identifying and addressing alcohol-related problems when delivered in primary healthcare settings –4. OrigiFeedback, Responsibility, Advice, Menu, Empathy, and Self-efficacy) principles . There are also concerns as to whether current brief intervention approaches remain faithful to their theoretical roots. It has therefore been suggested that poor delivery of brief interventions coupled with potential content drift, should result in a cautious approach to future roll-out, whilst additional research is carried out to establish the efficacy of individual intervention components more conclusively  , 34, whiFirst, the paper draws on the results of a recent overview of systematic reviews and meta-analyses of the effectiveness of brief alcohol intervention in this setting . This ovFor the purposes of this paper, primary healthcare has been operationalized to include all immediately accessible general healthcare facilities but not emergency settings. Brief intervention comprises a single session and/or up to a maximum of five sessions of engagement with a patient, and the provision of information and advice designed to achieve a reduction in risky alcohol consumption or alcohol-related problems. Heavy drinking is defined as drinking in excess of 60 g of alcohol per day for men and 40 g for women . HazardoAn efficacy trial is designed to evaluate what an intervention achieves under optimum conditions . It provper se. Despite this challenge, an attempt has been made to disaggregate the component parts of brief alcohol intervention in trial-based evaluations  to assess the extent to which trial-based evaluations show features of uniformity and standardization (efficacy) or not  or not . The con) or not  and more) or not .“an intervention will be effective only if an efficacious treatment/program is delivered/implemented in such a way as to be made available to an appropriate target audients in a manner acceptable to them ”  when delivered in optimum conditions; effectiveness trials determine whether those benefits continue to be realized in more real-world settings. Sufficient replicability and stability of effects are important aspects of this work especially in “typical” conditions of delivery where availability, compliance or acceptance, and measurement factor may vary . As Flayere to)” .A recent review of reviews identified at least 56 separate randomized controlled trials of screening and brief alcohol interventions in primary health care, which consistently reported that brief alcohol interventions are effective at reducing hazardous and harmful drinking in primary healthcare, with weekly alcohol consumption the most commonly reported outcome . A key iThis said, while the overall evidence base seems to show that brief alcohol interventions are both efficacious and effective when delivered in primary care settings, some individual large scale pragmatic trials have reported null findings. For example, a recent large UK trial (SIPS) reported no significant differences in hazardous and harmful drinking status in patients receiving simple feedback after screening plus a patient information leaflet (the control condition), those receiving 5 min of structured advice, and those receiving a further 20 min brief lifestyle counseling . This fiWhilst there have been successive attempts to encourage the routine delivery of brief alcohol interventions in day-to-day practice, most efforts have demonstrated limited success –60, and Implementation studies may take a number of forms, exploring the many influences on patient, healthcare professional, and organizational behavior in either healthcare or population settings . In the In addition, previous research also points toward a series of structural and organizational factors that influence alcohol intervention delivery. Lack of training or suitable intervention materials , 72, inaInternet applications for screening and brief interventions for alcohol in primary care settings – implementation and sustainability by Wallace and Bendtsen in this issue for more on this subject).Alongside research to identify notable barriers to the routine delivery of screening and brief alcohol intervention in primary care, there have also been studies exploring facilitating factors. For example, Screening, Brief Intervention, and Referral to Treatment (SBIRT) is US-based program to promote the use of evidence-based practice to identify, reduce, and prevent problematic use, abuse, and dependence on alcohol and illicit drugs –86. One per se and multi-component support programes were more effective (Regarding work that actively promotes uptake and adoption of brief interventions in practice, the largest study conducted to date was part of a World Health Organisation Collaborative project. This study found that active dissemination strategies were needed to ensure that practitioners were aware of the evidence on brief interventions, whilet both training and support were needed to convert this knowledge into action . Moreoveffective  than focA key limitation of earlier implementation research, however, is that changes in practitioner behavior tend to be limited to the time-frame of each individual study that attempts to promote screening and brief alcohol intervention. When the research work ends, the focus on screening and brief alcohol intervention also tends to stop. A significant challenge is to find ways of embedding this activity in mainstream clinical work to achieve sustained delivery , and alsThe development of national alcohol strategies, specific guidance for practitioners on when and how to deliver screening and brief interventions, and national payment programs for ASBI has recently been introduced in the UK to promote their wider roll-out , 92. KhaThis paper demonstrates that overall, there is a plentiful outcome evaluation literature, which consistently reports positive effects of screening and brief alcohol intervention when delivered in primary care. Much of this literature is of a moderate to high quality, and the outcome effects persist even when the less well designed studies are discounted from the assessment. As such, we have surely long passed the point of needing to ask the question “do these interventions work?,” or even “do they work in the real world of primary care?.” Both efficacy and effectiveness have been comprehensively demonstrated through this substantial body of evidence, and intervention effects seem replicable and indeed stable over time, and across different study contexts. Indeed, with the benefit of hindsight, the brief intervention field seems to constitute an almost perfect example of the evaluation of a complex intervention . Early eNo field of research work is perfect however, and especially one that has been evolving over a 30 year period. Consequently, it is not surprising that a considerable degree of heterogeneity exists within the screening and brief intervention literature or that there can often seem to be a re-treading over previously covered ground. There is also a genuinely interesting and as yet unanswered question concerning what specific factors prompt the positive changes in alcohol consumption that occur after brief alcohol intervention that undoubtedly needs further examination. However, the search for these “active ingredients” should not delay progress in rolling out these interventions into health systems for patient benefit. Many people do not fully understand how their car actually works, yet most still successfully drive them each day. Given the positive evidence amassed to date, research efforts should maintain a continued focus on promoting sustained implementation of screening and brief alcohol intervention approaches in primary care.Moreover, frontline practitioners responsible for the implementation of any policy or health program may make adaptations based on the availability of resources, compatibility with organizational or professional values, expertise, and knowledge , resultiThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.