Human rabies still continues to be a significant health problem in India and other developing countries where dogs are the major vectors of transmission. Rabies in humans can present in two clinical forms, i.e., furious and paralytic. While diagnosis of furious rabies can be made based on the typical symptoms and signs, paralytic rabies poses a diagnostic dilemma to the neurologists who may encounter these cases in their practice. Although there are certain clinical features that distinguish this disease from other forms of Guillain-Barre syndromes, confirmation of diagnosis may require laboratory assistance. Conventional techniques such as antigen detection, antibody assays and virus isolation have limited success. The recently introduced molecular techniques show more promise in confirming the cases of paralytic rabies. There has not been much success in the treatment of confirmed rabies cases and recovery from rabies is extremely rare. Therefore, preventive measures of this dreaded disease after an exposure become extremely important. The present article reviews the current status of human rabies with regard to antemortem diagnosis, disease management and post-exposure prophylaxis. Rabies - the oldest and most feared human disease known to man - causes an acute, progressive incurable encephalomyelitis caused by highly neurotropic ssRNA virus, taxonomically classified in the genus Lyssa virus and family Rhabdoviridae. Rabies in humans can present in two clinical forms, i.e., furious and paralytic. While the diagnosis of furious rabies can be made on distinctive symptoms and signs, paralytic rabies poses a diagnostic dilemma to the neurologists. Although there are certain clinical features that distinguish this disease from various forms of Guillain-Barre syndromes, confirmation of diagnosis may require extensive laboratory assistance. Neurologists in developing countries are likely to encounter cases of rabies encephalitis, particularly atypical and paralytic forms and a few with psychiatric manifestations for many years to come. An array of laboratory tests has been carried out in laboratories for the diagnosis of rabies, each having its own merits and de-merits. Conventional techniques such as antigen detection, antibody assays and virus isolation are time consuming and have limited success. In the present era, the antemortem diagnosis of rabies is gaining tremendous attention. For instance, the survival of patients presenting with hydrophobia are being reported from various geographical locations around the globe and in developing countries such as India.2 There iRabies virus is a negative sense single stranded RNA virus belonging to the genus Lyssavirus and family Rhabdoviridae. It is a bullet-shaped enveloped virus measuring 180 nm × 75 nm. The envelope is surrounded by numerous spikes made up of glycoprotein (G), which are necessary for viral attachment to receptors and is also a major protein for the induction of neutralizing antibodies. The other important proteins are the ribonucleoprotein (N), which is intimately associated with the helical RNA, the phosphoprotein (P) and a matrix protein (M) . The rabHuman infection by the rabies virus almost always occurs through the bite of an infected animal, dogs being the major vector of transmission. Direct transmission through the nervous system from the site of bite can occur in which case the incubation period tends to be short, sometimes as short as a week, if there are sufficient nerve endings exposed at the wound site. However, in majority of the cases, the virus undergoes a period of replication in the exposed muscles before entering the motor or sensory nerves supplying the muscle. NicotiniThe development of rabies encephalitis in an exposed individual depends on several factors viz. the severity of bite, site of bite, virus content in the saliva and probably some non-specific host immune factors. Transdermal bites on the head, neck and hands carry the highest risk and are usually associated with shorter incubation period. However, bites on the lower extremities are more common, and as revealed in the recent Indian survey, 80% of all human rabies cases had bites on the legs. It is also known that not every rabid bite results in clinical rabies. Rabies mortality varies from 35 to 57% in unvaccinated bite victims.[The incubation period for rabies is the most variable of all acute CNS infections. The average incubation period is around 1-3 months but may range from less than 7 days to 6 years. It is not still clear why there is such a variable and prolonged incubation period. The incubation period may depend on several factors including density of rabies virus receptors in the affected tissue, the degree of innervation in tissues, the quantity of virus inoculated and the properties of the rabies virus stain. It is asExcept for the local symptoms at the site of bite or bitten extremity, these are usually vague and nonspecific. There may be fever, malaise, generalized mayalgia and a sense of “not well-being.” In nearly 50% cases of paralytic rabies and 30% cases of furious rabies, local manifestation in the form of itching, pain or paresthesia at the site of bite may be the earliest symptom, which is often neglected by the patient and ignored by the physician. This symptom may later involve the entire bitten extremity. The sensory function is usually intact, and at this stage, there is no demonstrable weakness of the bitten extremity.Within hours or a few days after the prodrome, rabies patients enter an acute neurological phase. Two-thirds of patients suffer from an encephalitic or furious form and the remaining present with paralysis or a condition resembling Guillain-Barre syndrome (GBS). Patients with encephalitic form of illness usually die within 3-4 days; however, there may be a prolonged course of illness, sometimes up to 15 days in cases of paralytic rabies, especially if these patients are treated in intensive care units. A case of paralytic rabies at the neurological services of national institute of mental health and neurosciences (NIMHANS), Bangalore, India survived up to 45 days under these conditions.The earliest manifestation of furious rabies is nervousness and hyperactivity resembling an acute anxiety reaction, often associated with moderate to high-grade fever. Initially, mentation is preserved, but the attention span is shortened and within hours three typical features of furious rabies develop: phobic spasms, fluctuating consciousness and signs of autonomic dysfunction.Typical phobic spasms include hydrophobia and aerophobia. These are seen in almost all patients with furious rabies, although they may not be present in later stages of the disease when drowsiness and coma supervene. The term “hydrophobia” is derived form the Greek word meaning “fear of water.” This term is almost synonymous with rabies in humans. Aerophobia and hydrophobia can be demonstrated by blowing or fanning of air on the face or chest wall and by asking the patient to swallow water or mere offering a glass of water. Intense startling reaction results from spasms of the accessory respiratory muscles of the neck, pharyngeal muscles and diaphragm followed by extension of the neck and a feeling of dyspnoea. During these episodes, they are extremely aroused and exhibit fearful facial expressions. The pathophysiological mechanism of hydrophobia, which is only observed in humans and not in rabid animals, is still not clear. The mental status alternates between periods of agitation and apparent normal mental status. As the disease progresses, confusion becomes severe and patients can become wild and aggressive. The period of agitation is gradually followed by impaired consciousness and coma.The signs of autonomic dysfunction include hyper salivation, pupillary abnormalities such as constricted or dilated pupils, anisocoria, generalized piloerection, excessive sweating, priapism and rarely spontaneous ejaculations. Occasionally patients may present with typical features of mania, increased sexual arousal, attempts to rape, all of which can make the patients to land in psychiatric clinics.This form of rabies is seen in approximately 20% of patients, often with diagnostic problems. The major cardinal signs of furious rabies may never appear or appear very late in the disease and can be very mild. Weakness usually starts in the bitten extremity and then progressively involves all limbs and pharyngeal and laryngeal muscles. Facial weakness is a common feature. Some of the features that may differentiate paralytic rabies from Guillain Barre Syndrome are:Fever is almost always present in paralytic rabies but usually absent in cases of GBS once weakness develops, unless followed by complications such as aspiration pneumonia.Sensory function is intact in paralytic rabies, except for the initial paresthesia at the site of bite.Quadriparesis with the predominant involvement of proximal muscles and urinary incontinence are always found in the early course of paralytic rabies. In cases of GBS, urinary incontinence is rare. In GBS, especially in the early phase, both proximal and distal muscles are affected.Percussion myoedema may be present in both early and later stages of paralytic rabies. This is best elicited by the percussion of the chest, deltoid or thigh region and consists of mounding of a part of the muscle at the percussion site, which then flattens and disappears over a few seconds. It is not observed in patients with GBS, encephalitic form of rabies or in patients with neurological complications following Semple type of sheep brain rabies vaccines.Generalized or focal fasciculations are frequently present in paralytic rabies patients.Hydrophobia is unusual and can be terminal manifestation in the paralytic form of the disease. Survival is usually longer than in the furious form. Eventually, bulbar and respiratory muscles are paralyzed resulting in death due to cardio-respiratory arrest. Although the hallmark of paralytic rabies is ascending paralysis, sometimes the features of furious rabies such as anxiety, aerophobia, inspiratory spasms and altered sensorium may be observed - particularly in the terminal stages - thereby resulting in the overlap of symptoms between the two forms. These features, if present, provide a clue to the diagnosis of rabies rather than GBS.The pathogenetic basis for the two different clinical forms of rabies is not known. There is no difference in the virus strains that cause furious and paralytic forms of the disease and has no correlation with the incubation period or the site of bite. However, paralytic rabies is more frequently observed in patients who take partial course of either Semple or cell culture rabies vaccines. It is possible that paralytic rabies results from an immunopathologic attack on virus infected cells in the brain and spinal cord.Computed tomographic (CT) studies of the brain are usually normal in both forms of rabies, although hypodense lesions in cortex and basal ganglia have been described. On MagneThe electroencephalogram (EEG) may be normal or show nonspecific abnormalities in human rabies. Slow wave activities as well as periodic epileptic form activities have been observed. HematoloSerum, CSF, saliva and tissue such as skin, from highly innervated anatomical areas are the appropriate biological specimens for antemortem diagnosis and all these samples should be considered as potentially infectious see see . The apppost mortem to establish a definitive diagnosis [Viral isolates can be obtained by animal inoculation or cell culture passage of saliva or oral swabs, although of limited utility in clinical setting. These samples can be probed for viral nucleic acid. Viral antigen can be detected by Direct Fluorescent Antibody (DFA) test on brain biopsy material collected usually during iagnosis , cornealIntra vitam diagnosis of rabies by Fluorescent antibody test (FAT) in corneal impression was first described by Schneider in animals and by Cifuentes et al. in humans.[et al. showed that the reliability of corneal impressions for rabies diagnosis is limited, especially when sampling is performed under field conditions and a negative result could not rule out the diagnosis of rabies.[Rabies virus antigen can be detected by a simple FAT test on corneal epithelium during the terminal stages of the disease. n humans.19 The mef rabies.intra vitam diagnosis in animal and humans.[The examination of skin biopsy material was shown to be a valuable technique for d humans.22et al. found that 25-50% of patients showed immunofluorescence positive results for rabies viral antigen, and a proportion of positive results during the early phase of clinical illness increased as the disease progressed.[post mortem diagnosis in countries, where the opening of skull of the dead person is not accepted on cultural and religious grounds.Blenden ogressed. The testet al. have reported the use of hemi-nested RT-PCR for rapid ante mortem diagnosis within 36 h of sample submission in case of suspected rabies, where Fluorescent antibody test (FAT), Mouse inoculation test (MIT) and Rabies Tissue Culture Infection Test (RTCIT), have yielded a negative results. Smith et al. standardized hemi-nested RT-PCR, followed by automated sequencing and confirmed the presence of classical rabies virus (genotype1) in both saliva and skin specimens with in 36 h.[et al. evaluated the utility of conventional RT-PCR and SYBR Green Real time PCR for the ante mortem diagnosis of rabies using saliva samples. Real-time PCR assay was found to be more sensitive than conventional RT-PCR assay, highlighting the utility of molecular diagnostic tests in establishing ante mortem diagnosis of rabies using saliva samples within a few hours.[et al. conducted a study to find presence of rabies virus in saliva and cerebrospinal fluid (CSF) of suspected live rabid dogs at the time of quarantine by using a SYBR Green real-time RT-PCR based assay for the detection of rabies virus RNA. Positive CSF samples were found in 4 out of 15 dogs (27%), whose saliva samples were tested. The time interval from sample collection to result was less than 5 h. Their study suggested that because the virus may be absent or present at very low levels in clinical fluids, samples taken for ante-mortem diagnosis cannot definitively rule out rabies in the animal.[The demonstration of viral nucleic acid in saliva, CSF, corneal smear, skin biopsy by Polymerase Chain Reaction (PCR) appears to be quite promising for the antemortem diagnosis of human rabies . Both co in 36 h. Nagaraj ew hours. As the se animal. In 2001, 15 dogs %, whose et al. proposed the tissue culture technique (BHK 21 cells) as a routine method for the isolation of street strain of rabies virus.[intra vitam includes saliva samples, throat swabs, swabs of the nasal mucosa, corneal smears and cerebrospinal fluid.[Virus isolation from animals (or humans) is one of the most reliable methods for the diagnosis of rabies. Virus isolation from infected tissue can be carried out either in mice (mouse inoculation test - MIT) or in cell culture (rabies tissue culture isolation test-RTCIT). Rudd es virus. The specal fluid.Mouse inoculation test (MIT)The Swiss albino mouse is preferred for rabies diagnosis, but other strains can also be used since all are equally susceptible to intracerebral inoculation with street rabies virus. The Swiss albino mice are the most susceptible and common animals used for virus isolation. While weanling mice {21 to 30 days old, (weighing 9-15g)} are preferred, suckling mice less than 4 days are more susceptible. The homogenized brain tissue sample in buffered diluent containing protein stabilizer and antibiotics are intracerebrally inoculated (0.03 ml) into a minimum of six weanling mice for each specimen.The technical simplicity and high sensitivity are favored attributes of MIT. The main drawback of this test is the technical expertise, environment and ethical issues related to the usage of large number of animals.Rapid tissue culture infection test (RTCIT)in-vivo virus isolation is considerably reduced with the cell culture inoculation. Several cell lines may be used for the isolation such as BHK 21, the CER and mouse neuroblastoma.[2', the cells are fixed, stained with an antinucleocapsid antibody conjugated to fluorescein isothiocyanate (FITC) and observed under a fluorescent microscope.[The inoculation of the cell culture is a recognized method for the isolation of street virus for rabies diagnosis at present. The unpredictable and problematic delay with blastoma.31 The spcroscope. In many An indirect evidence for rabies infection is demonstrating a high titer of antibodies in CSF in nonvaccinated individuals. The following are the WHO -recommended tests based on this principle: Mouse Neutralization Test (NT) and Rapid Fluorescent Focus Inhibition Test (RFFIT).Mouse Neutralization Test (MNT)50', is determined by the Reed-Muench or Spearman-Karber methods. To each serum dilution from a suspected case of rabies, 32 to100 times the LD50 virus is added and the mixture is incubated for 90 min at 37°C and then inoculated intracerebrally into weanling mice (5-10 mice for each serum dilution). The mice are observed for 14 days, and the number of deaths occurring in each serum dilution is noted. The dilution of serum at which 50% of the mice are protected  is calculated by the Reed-Muench or Spearman-Karber methods. The precision of the assay is limited by the number of mice inoculated for each serum dilution and the increment between dilutions to be used. Tediousness and economics limit the numbers of mice, to be inoculated and dilutions to be evaluated. The individual resistance and nonspecific mortality associated with any animal test also adversely affects the precision of the test.[Webster and Atanasiu developed virus neutralization test in mice  in 1935.33 This ithe test.The adaptation of the “Challenge virus standard (CVS) strain” of rabies virus (attenuated virus) to grow in cell culture has led to the development of alternative assays in which the replication of non-neutralized virus in culture is detected by the observation of plaques, fluorescent antibody-stained infected cells or the colour developed with enzyme-labeled anti-rabies antibodyRapid Fluorescent Focus Inhibition Test (RFFIT)et al.[50  of virus and incubating the serum-virus mixture at 37°C. Subsequently, suspensions of BHK-21 cells are added. After a 20-h incubation period at 37°C in a 5% CO2 incubator, the cells are stained with an anti-rabies antibody conjugated to FITC. The antibody titer is defined as the reciprocal of the serum dilution, which reduces the challenge virus to 1FFD50. The titers obtained are approximately equal to those measured by the MNT. The rapidity with which the test can be carried out and the ease with which several samples may be tested at a time make it suitable for routine diagnosis. The demonstration of antibody in the serum in the absence of a history of vaccination for rabies or in CSF offers indirect evidence of rabies infection. The RFFIT has been shown to be slightly more sensitive than the MNT for detecting Virus Neutralizing antibodies (VNAs) in post-vaccinal sera.[The RFFIT is one of the most widely used substitutes to the Mouse Neutralization Test (MNT) and was developed by Smith et al. It is a et al.. The sernal sera.Fluorescence Antibody Virus Neutralization Test (FAVN)et al. in 1998.[50 live virus in cell line and each well is scored as having virus present or no virus after a 40-h incubation period. Results obtained with this test showed good agreement with the MNT and RFFIT. According to the authors, distinguishing negative sera from the positive with low titers of antibody is easier with the FAVN as compared to RFFIT. Hostnik has described a modification of this test in which the monoclonal anti-rabies antibodies and a peroxidase anti-mouse conjugate were used instead of a fluorescein-conjugated anti-rabies antibody.[This test, which is an adaptation of RFFIT, was developed by Cliquet  in 1998. In this antibody.The Indirect immunofluorescence assay (IFA)et al. and Gispen and Sathof reported the IFA to be more sensitive than NT, several other investigators found NT to be better.[et al., from South India, reported a sensitivity of 97.2% and specificity of 97.9% for IFA.[The IFA is based on the interaction between antibody and viral antigen present in smears of infected mouse brain or cell cultures. The bound antibody is visualized using a fluorescein-labeled species-specific antiserum directed against one or more immunoglobulins classes. The slide is examined under a fluorescent microscope. The reaction is graded by the amount and brilliance of fluorescence. The IFA is reported to be more sensitive than the neutralization test (NT) in detecting antibody early in the immune response, making it valuable for diagnosis.40 The IFe better.–44 Madhu for IFA. A compar for IFA. The IFA Membrane staining is not easily observed in acetone-fixed preparations and it would be difficult to detect by the customary IFA technique. Relative insensitivity in detecting antiglycoprotein antibody may lead to an inaccurate estimate of the protection afforded by immunization, making the IFA unsuitable for vaccine efficacy trials.ante mortem diagnosis of rabies using clinical specimens may not be always successful, and negative tests do not rule out the possibility of rabies. In contrast to ante mortem diagnosis of rabies, post mortem diagnosis is more sensitive and specific. Negri bodies are present in more than 70% of infected human or animal brains [ante-mortem diagnosis. Rabies virus antigen could be detected by agglutination on a glass slide using latex particles coated with gamma globulin. Recently Kasempimolporn et al. developed a simple and inexpensive test based on latex agglutination (LA) for rabies virus antigen detection in the saliva of live dogs.[The attempts for l brains  Inset. Ml brains  The detel brains  or recenl brains 48 The del brains  Studies ive dogs.Human rabies is still considered as cent percent fatal, although some cases of recovery have been reported form time to time.–53 The mAlthough rabies is virtually 100% fatal once the symptoms develop, it can be effectively managed if appropriate post-exposure treatment is instituted immediately after exposure. The post-exposure prophylaxis consists of three important ingredients viz. local wound treatment, passive immunization with rabies immunoglobulins and active immunization with rabies vaccines. All these are equally important and treatment failures have occurred due to neglecting any of the procedures, particularly passive immunization.Local wound treatment should be instituted soon after the exposure. The bite wound(s) should be flushed with running tap water and washed with plenty of soap or detergent for at least 10 min. This removes the virus mechanically as well as inactivates the virus to a great extent. This should be followed with applying a local antiseptic such as Povidone Iodine. Suturing should be avoided as far as possible and if deemed necessary for surgical reasons, should be done only after infiltrating the wound with anti rabies immunoglobulin.www.apcri.org.The further management of the bite depends on the degree or severity of exposures and risk of developing rabies. The present categorization of exposures and the required treatment procedures that is universally followed is as per the national guideline, the details of which can be accessed from the web site of Association for Prevention and Control of rabies in India (APCRI): et al. assessed the safety of post-exposure rabies immunization and immunogenicity of purified vero cell rabies vaccine (PVRV) during pregnancy and found it to be safe and immunogenically efficacious. None of the women experienced any adverse side effects to the vaccine.[The manufacture and use of outdated nerve-tissue-derived Semple vaccine has been discontinued in India since January 2005. Highly potent and safe cell culture vaccines are available for post-exposure treatment for almost 3 decades. These are the Human Diploid Cell Vaccine (HDCV), Purified Chick Embryo Cell vaccine  and Purified Vero cell Rabies vaccine . Recently, a highly purified duck embryo vaccine  was introduced in India. Five doses of vaccine must be administered on day 0, 3, 7, 14 and 28 intramuscularly over the deltoid region. The dosage schedule is same for all age groups and there is no contraindication for rabies vaccination. Sudarshan  vaccine. As cell  vaccine. Recently vaccine.This is one aspect of post-exposure prophylaxis (PEP) that is often neglected by the medical practitioners. The presently available rabies vaccines induce protective levels of antibodies usually 10-14 days after initiating the course. Some cases of category III exposures may have very short incubation period and in such cases the mere administration of vaccine will not prevent rabies, as the virus would have reached CNS before the formation of sufficient quantities of neutralizing antibodies. Therefore, WHO advocates passive immunization with rabies immunoglobulin (RIG) in all category III exposures There are two types of RIGs presently available viz. highly purified and enzyme-refined equine rabies immunoglobulin (ERIG) and human rabies immunoglobulin (HRIG). The recommended dosage is 40 IU/kg body weight of ERIG and 20 IU/kg body weight of HRIG. The calculated dose should be infiltrated as much as possible locally into and around the wound and remaining if any should be administered IM in the gluteal region. The ERIGs should be administered only after a proper sensitivity test, although the incidence of anaphylactic reactions following the administration of present day ERIGs is very rare, (around 0.001%). Other adThis is recommended to people who are at continued risk of exposure to rabies such as veterinarians, laboratory workers handling rabies virus, dog catchers and forest rangers, medical and paramedical people treating rabies patients in ICU. Three doses of any modern rabies vaccine can be administered on days 0, 7 and 28. A booster dose is recommended to people at continued risk.et al. recommended the pre-immunization to travelers visiting areas where canine rabies is enzootic and access to appropriate medical care is limited.[As per the WHO recommendation, 2 doses of any modern vaccine is required on days 0 and 3 for people who are re-exposed to rabies and have taken a course of complete post-exposure treatment with any of the modern cell culture vaccine any time in the past. There is no need for administration of rabies immunoglobulin. Incorporation of intradermal vaccine into childhood immunization schedules has been proposed for developing countries. Hatz et  limited.The intramuscular route is recommended for rabies pre exposure vaccination if the antimalarial Chloroquine phosphate is being administered concurrently. This recommendation was made after a Peace Corps Volunteer died of rabies despite having completed a full intradermal (ID) pre-exposure series 6 months previously.In the era of wide international travel, neurologists, internists and medical practitioners in critical care management are confronted with cases of rabies masquerading as other neurological illness such as peripheral neuropathy. Similarly, in psychiatric practice, a case diagnosed as manic psychosis could in reality be one of the types of rabies. The knowledge of the technical modalities for antemortem diagnosis may assist in planning the hospital management and post-exposure prophylaxis of the treating medical team. Although the clinical outcome of rabies still remains grim, the pre-exposure and post-exposure vaccination in combination with passive immunization is likely to change the clinical outcome favorably.


Drug dependence is a major cause of morbidity and loss of productivity. Various theories ranging from economic to psychological have been invoked in an attempt to explain this condition. With the advent of research at the cellular and subcellular levels, perspectives on the etiology of drug dependence have also changed. Perhaps the greatest advance has been in the identification of specific receptors for each of the drugs, their target neurotransmitter systems and the intracellular changes produced by them. These receptors also provide potential targets for treatment strategies of drug dependence. This overview attempts to present the mechanisms in the development of dependence and the newer treatment strategies for the major drugs of abuse like alcohol, opioids, cannabis, nicotine and cocaine. Human addictions are chronically relapsing disorders characterized by compulsive drug use, an inability to limit the intake of drugs and the emergence of a withdrawal syndrome during cessation of drug use. Dependence has been defined as a cluster of behavioral, cognitive and physiological phenomena that develop after repeated substance use. It typically includes a strong desire to take the drug, difficulties in controlling its use, persisting in its use despite harmful consequences, a higher priority given to drug use than to other activities and obligations, increased tolerance and sometimes a physical withdrawal state -10).Cellular biology is defined as the study of the physiology and biochemistry of intracellular processes. Molecular biology is the branch of biology that seeks to explain all biological processes in terms of genes and genetic changes. With the advent of neuroscience as an indispensable branch of biomedical research, there has been explosive growth in the biological understanding of the process of addiction at the cellular and molecular levels. In this update, we have described recent research findings so as to increase awareness regarding these aspects of drug dependence syndromes.Drug addiction has been conceptualized as a complex and chronic disease process occurring in the brain, which is modulated by genetic, developmental and environmental factors. The most consistent and reproducible finding in drug addiction is that abused substances activate the mesolimbic dopamine system, which reinforces both pharmacological and natural rewards. The mesolimbic system consists of dopaminergic neurons in the ventral tegmental area (VTA) and their axonal projections to terminal fields in the nucleus accumbens (NAc) and the prefrontal cortex.Opioids, alcohol, nicotine, cannabinoids and psychostimulants all act on this system to increase synaptic levels of dopamine (DA). All these substances have specific receptors in the brain and the increase in dopamine levels in the mesolimbic system is the final effect that they produce. Receptor-mediated activity is the principal mechanism by which any chemical messenger acts. Chemical messengers are regulatory macromolecules, usually proteins. Receptors have two major functions of recognition and transduction. Correspondingly, each receptor has two domains, i.e., a ligand-binding and an effector domain. The ligand-binding domain has a hydrophilic and a lipophilic region and is usually heteropolymeric. The binding of the ligand causes a change in the quaternary structure of the receptor.Receptors have various effector mechanisms, which are broadly of four types:G protein-coupled receptors Receptors with intrinsic ion channelsEnzymatic receptorsReceptors regulating gene expressionOne of the most dramatic advances in drug abuse research has been the identification of the target of every major drug of abuse. This advance occurred with the advent of radioligand-binding techniques, the biochemical characterization of drug binding sites and ultimately, with the application of molecular biology to clone and isolate these structures. The various drugs of abuse and their respective receptor types are given in Drugs can upregulate or downregulate their receptors and their effector mechanisms . These cBoth the diversity of the receptor types and the cross-modality of drug-receptor interactions are becoming more and more significant. It was earlier thought that drug use caused changes in the specific binding sites, inactivation mechanisms or levels of endogenous ligand. The diversity of drug receptors now forces a consideration of changes in the actual structure of the receptor molecule or changes in the distribution of these molecules on the surface of the neuron. Drugs of abuse also have long-term effects resulting from the expression of genes activated as a consequence of the action of the drug.Several mechanisms have been proposed to explain opioid dependence.et al.[Opioid receptors act by decreasing the activity of adenylyl cyclase and thereby decreasing intracellular adenosine 3',5'-cyclic monophosphate (cAMP) levels. This was discovered by Sharma et al. when theet al. The mechet al.Activation of opioid receptors can affect membrane permeability to potassium ions. Activation of protein kinase C can attenuate opioid receptor activity and affect ion conductance.Chronic morphine use causes feedback inhibition of endogenous opioid synthesis, which further leads to opioid dependence and withdrawal. Opioid aThis occurs through antiopioid neurons such as neurons using nociceptin / orphaninFQ, glutamate, cholecystokinin or neuropeptide FF as neurotransmitters. A study demonstrated the loss of morphine analgesic tolerance in Nociceptin-orphanin (NOP) knockout mice. Naloxone-precipitated morphine withdrawal was markedly attenuated in NOP knockout mice.Expression of gill glutamate transporter, gamma interferon-inducible lysosomal thiol reductase (GILT-1) mRNA was found to be increased in the striatum and NAc of morphine-dependent rats and decreased in morphine-withdrawn rats. A glutamA (endothelin A) receptor was involved in the development of neonatal morphine tolerance.[In vitro opioid withdrawal induced an opioid-sensitive cation current mediated by the GABA transporter-1 (GAT-1). GAT-1 may be a target for therapy to reduce withdrawal symptoms.[ETolerance. In vitrosymptoms. Substancsymptoms.-) uptake into brain “microsacs”  were studied and it was found that alcohol increased Cl- uptake. Alcohol could thus enhance GABA-mediated inhibition of neurons.[Alcohol's effects on GABA-mediated chloride ion  as well as to decreased alpha1 protein levels.[A receptor numbers.Analyses in rats found that chronic alcohol treatment leads to reduced mRNA levels for one of the alpha subunits  have been associated with alcoholism especially with rapid onset, aggressiveness and severe impulsivity.–18 SpeciChronic alcohol intake was associated with decreased mesostriatal dopaminergic activity in rodents and decreased levels of dopamine and its metabolites in alcoholic patients. DecreaseChronic alcoholism causes a downregulation of CB1 receptors and their signal transduction system and increased the synthesis of the endogenous cannabinoids—arachidonylethanolamide and 2-arachidonylglycerol. Deletion29Glycine receptors (GlyR) in the NAc might act as targets for alcohol in its mesolimbic DA-activating effect. Glycine Peroxiredoxin, creatine kinase, fatty acid binding protein are some of the proteins that are upregulated in chronic alcoholic patients. Synuclein, tubulin and enolases are downregulated. These proteins are associated with the neurodegeneration in chronic alcoholism and some of these overlap with the changes in Alzheimer's disease.Nicotine acts on the nicotinic type of cholinergic receptors. Different combinations of alpha and beta subunits produce receptors with different responses to agonists and antagonists. Receptor sensitivities to agonists and antagonists are dependent upon the subunit composition of the receptor. The stimulation of nicotine receptors by nicotine shuts down the receptor by causing it to withdraw into a pit. Thus, dopaminergic stimulation of mesolimbic dopaminergic neurons stops soon after a low level of nicotine stimulation. Nicotine's effects are hence self-regulating and its effects on behaviour are less pronounced than cocaine. The number of binding sites changes with chronic exposure to nicotine.3334 Nico332-methyl-6-(phenylethynyl)-pyridine (MPEP), a metabotropic glutamate receptor subtype 5 (mGluR5) antagonist, decreased nicotine self-administration in rats. Hence, compounds increasing GABAergic transmission and mGluR5 antagonists have the potential to be used as antismoking medications.Nicotine withdrawal 24 h after nicotine cessation, caused a significant increase in preproenkephalin mRNA levels in the hippocampus and striatum. These effects were blocked by pretreating rats with mecamylamine. This suggests that brain opioid system(s) is / are involved in mediating nicotinic responses and its withdrawal.Cocaine is an inhibitor of monoamine transporters especially dopamine but also has minor effects at the serotonin and norepinephrine transporters. In a study by Hall in 2004, it was sThe cannabinoid agonist, HU210, provokes relapse to cocaine seeking after prolonged withdrawal. Cannabinoid receptor antagonists prevent relapse to cocaine use. The seleOverexpression of FosB increases sensitivity to the locomotor-activating and rewarding effects of cocaine and morphine, increases cocaine self-administration and increases incentive drive for cocaine.+ channels and activation of mitogen-activated protein kinase. Acute effects of cannabinoids as well as the development of tolerance are mediated by G protein-coupled cannabinoid receptors.Cannabis acts on the CB1  and CB2 (on immune cells) cannabinoid receptors. CB1 receptors mediate inhibition of adenylate cyclase and calcium channels, stimulation of KHepatic metabolism in tolerance to delta9tetrahydrocannabinol (delta9-THC) was tested by pretreating animals with SKF-525A  or phenobarbital . The data suggested (but did not demonstrate definitively) a metabolic mechanism of tolerance development. Lithium was found to prevent the cannabis withdrawal syndrome . The effects of lithium against the cannabinoid withdrawal syndrome were antagonized by systemic preapplication of an oxytocin antagonist.The discovery of molecular mechanisms of drug dependence has led to the identification of ligands that can be reliable treatment options 18-Methoxycoronaridine (18-MC) decreases drug self-administration in several animal models. Thus, it may be a potential treatment for multiple forms of drug abuse .The final common pathway of the action of drugs of abuse is through dopamine in the limbic system. Chronic administration of drugs leads to molecular changes in more than one neurotransmitter system and thus, various neurotransmitter systems are involved in the development of dependence on a single drug. Studying the neurobiological basis of addictive processes allows better understanding of current pharmacotherapy and will lead to the development of new and hopefully, more efficacious treatment strategies in the future.


Photodynamic therapy (PDT) for cancer in the oesophagus and bronchi with red (630 nm) light may occasionally lead to wall perforation and fistula. Therefore, we investigated the clinical use of a less penetrating wavelength (514 nm) for the curative treatment of nine superficial carcinomas in the oesophagus and bronchi after photosensitization with Photofrin II. Tumours without infiltration beyond the submucosa in the oesophagus and beyond the lamina propria in the bronchi were considered as superficial cancers. The outcome and complications were compared with those of 13 superficial cancers treated with PDT and 630 nm light. In addition, we evaluated histologically the extent of the long-term tissue damage and scarring following treatment of six oesophageal cancers with either green or red light. At first endoscopic control, 7-10 days after PDT, tissue necrosis simply matched the illuminated area, without evidence of selective tumour damage. Six of nine tumours treated with 514 nm light had a complete response compared with nine of 13 after 630 nm irradiation. No perforation or fistula occurred in either treatment group. However, severe chest pain and fever with or without pleural effusion, consistent with occult perforation, were observed in three patients after 630 nm illumination in the oesophagus. Histologically, fibrous scarring in the three distinct sites treated with green light was limited to the superficial layers of the oesophagus. After red light treatment, transmural fibrosis with marked thinning of the oesophageal wall was evident in two of the three specimens available for inspection. These results indicate that PDT with 514 nm light has the potential to cure superficial cancer in the oesophagus and bronchi with essentially the same probability of success as red light. In the oesophagus, green light prevents deep tissue damage, thus reducing the risk of perforation.


Post-inhibitory rebound is taken into account. The model includes a reciprocally innervated circuit of neurons projecting to pairs of agonist and antagonist muscles. A set of four burst neurons has been simulated: inhibitory agonist, inhibitory antagonist, excitatory agonist, and excitatory antagonist. The model fits well with the known anatomical organization of neural circuits for limb movements in premotor/motor areas, and, interestingly, this model does not require any structural modification in the anatomical organization or connectivity of the constituent neurons. The authors simulate essential tremor when Ih is increased. Membrane excitability is augmented by up-regulating Ih and It. A high level of congruence with the recordings made in patients exhibiting essential tremor is reached. These simulations support the hypothesis that increased membrane excitability in potentially unsteady circuits generate oscillations mimicking tremor disorders encountered in daily practice. This new approach opens new perspectives for both the understanding and the treatment of neurological tremor. It provides the rationale for decreasing membrane excitability by acting on a normal ion channel in a context of impaired external inhibition.Neural circuits controlling fast movements are inherently unsteady as a result of their reciprocal innervation. This instability is enhanced by increased membrane excitability. Recent studies indicate that the loss of external inhibition is an important factor in the pathogenesis of several tremor disorders such as essential tremor, cerebellar kinetic tremor or parkinsonian tremor. Shaikh and colleagues propose a new conceptual scheme to analyze tremor disorders. Oscillations are simulated by changing the intrinsic membrane properties of burst neurons. The authors use a model neuron of Hodgkin-Huxley type with added hyperpolarization activated cation current (I Tremor is defined as a rapid oscillation of a body part . Tremor Current theories suggest that tremor is driven by complex combinations of mechanical reflex and central neurogenic oscillations. These oscillations are superimposed on a background of irregular fluctuations in muscle force and limb displacements . In tremSeveral brain areas play a key-role in tremorgenesis Figure . These r-the loop between motor cortex and basal ganglia-the loop between the cerebellum and the brainstem, especially the Guillain-Mollaret triangle, which links dentate nucleus of the cerebellum with the contralateral red nucleus and the inferior olive -the loop between the cerebellum, the thalamic nuclei and the motor cortex -the peripheral loops, including the afferences from the muscle spindles to the alpha-motoneurons  and from the peripheral sensors to the motor cortex . The stretch reflex depends on monosynaptic connections between primary afferent fibers and motor neurons. Spindles also inhibit motor neurons to antagonist muscles through Ia inhibitory interneurons. Afferent fibers from Golgi tendon organs provide a negative feedback for regulating tension via Ib inhibitory interneurons.Pathological Tremor is usually rhythmic. However, tremor is a non linear and non stationary phenomenon . These lIt is currently assumed that most kinds of tremor are associated with an overexcitability of neurons, rendering the neurons prone to discharge in a rhythmic way. Therefore the initial events leading to an increase of excitability deserve attention. Several drugs reducing neuronal membrane excitability improve tremor. This is typically the case with propranolol, GABA-mimetic inhibitory agents such as gabapentin or topiramate, or ethanol. These drugs affect the balance between GABA and glutamate.h, related to HCN1–HCN4) or the low threshold calcium current  [h and It, they could simulate the range of frequencies of tremor recorded from patients. The increase in these currents resulted in alternating bursts of action potentials in the neurons innervating the sets of agonist and antagonist muscles. The frequency of the simulated tremor was very close to the actual tremor frequency recorded in human.In this issue, Shaikh and colleagues propose a new conceptual scheme to analyze tremor disorders . They prhannels) ,15, or aOne of the consequences of this model is the following: interfering with the function of a normal ion channel to decrease membrane excitability in case of impaired external inhibition might reduce the oscillatory behaviour. This might have a special interest for circuits in the thalamus, inferior olive, cerebrum and cerebellum, given their electrophysiological properties and their patterns of innervation. Indeed, these structures are particularly prone to spontaneous or triggered oscillations. Thalamo-cortical firing patterns vary with their membrane potential, and thalamic neurons might behave as oscillators or even resonators . The intTremor is attracting the attention of scientists from various disciplines, because of the high prevalence of neurological disorders associated with tremor and thanks to the progress made these last years in terms of better characterization of neurological disorders, mainly with brain imaging  and molecular biology techniques. The model presented here brings new insights into mechanisms of tremor disorders and also opens direct and short-term perspectives in terms of treatment evaluation. The similarities with the recordings made in patients are outstanding. Furthermore, this model might serve in the future for the deciphering of motor commands and neural representations of movement, the so-called 'internal models' which now encompass not only motor but also cognitive operations . In this


The anti-inflammatory agent sodium aurothiomalate appears to act upon mononuclear phagocytes, inhibiting their lysosomal enzyme activity. Evidence is presented that gold salts can increase the number of lung tumour nodules that develop following intravenous injection of tumour cells and pretreatment can enhance the take of a subcutaneous tumour inoculum. In contrast, they do not affect the later growth of tumour. Gold salts can also suppress the action of systemically administered C. parvum in inhibiting the growth of subcutaneous tumours. These results are taken as supporting the evidence in favour of a fast acting nonspecific anti-tumour mechanism, probably macrophage mediated, that can be inhibited by gold salts and enhanced by C. parvum. The effect of gold salts upon other biological changes induced by C. parvum is examined, including its adjuvant action, and the results are discussed in the context of the mechanisms underlying the immunotherapeutic action of this organism.


The medical cost associated with back pain in the United States is considerable and growing. Although the differential diagnosis of back pain is broad, epidemiological studies suggest a correlation between adult and adolescent complaints. Injury of the pars interarticularis is one of the most common identifiable causes of ongoing low back pain in adolescent athletes. It constitutes a spectrum of disease ranging from bone stress to spondylolysis and spondylolisthesis. Bone stress may be the earliest sign of disease. Repetitive bone stress causes bone remodeling and may result in spondylolysis, a non-displaced fracture of the pars interarticularis. A fracture of the pars interarticularis may ultimately become unstable leading to spondylolisthesis. Results in the literature support the use of bone scintigraphy to diagnose bone stress in patients with suspected spondylolysis. Single photon emission computed tomography (SPECT) provides more contrast than planar bone scintigraphy, increases the sensitivity and improves anatomic localization of skeletal lesions without exposing the patient to additional radiation. It also provides an opportunity for better correlation with other imaging modalities, when necessary. As such, the addition of SPECT to standard planar bone scintigraphy can result in a more accurate diagnosis and a better chance for efficient patient care. It is our expectation that by improving our ability to correctly diagnose bone stress in patients with suspected injury of the posterior elements, the long-term cost of managing this condition will be lowered. The economic burden of back pain is estimated to be more than $90 billion per year in the United States ,2. CostsThe differential diagnosis for back pain is broad and includes degenerative disease, infection, inflammation, tumors and trauma -7. InjurAthletes comprise the majority of patients presenting with spondylolysis -12. SporThe medical history should include duration of symptoms, modifying and alleviating factors, level and intensity of sport participation as well as changes in muscle, bowel and bladder function. Physical examination involves inspection and palpation of the spine as well as examination of range of motion . InspectRadiographs of the spine have limited sensitivity compared with other imaging modalities in detecting bone stress and acute spondylolysis. Furthermore, radiographic defects of the pars interarticularis may not be symptomatic ,18. FiguBone scintigraphy is very sensitive for the detection of bone stress. Repetitive stress causes local bone remodeling and abnormal uptake of scintigraphic tracer. Single photon emission computed tomography (SPECT) has 10-20 times more contrast than planar bone scintigraphy and is more sensitive than radiography and planar bone scans. Furthermore, scintigraphic abnormalities have been found to correlate with painful lesions of the pars interarticularis -21. The CT demonstrates detailed osseous morphology, is more specific than bone scintigraphy and may predict the probability of ultimate bone healing ,23. HoweMRI is not as sensitive as SPECT for identifying bone stress of the pars interarticularis and does not delineate bony detail to the same extent as CT ,25. MRI In general, when bone stress or spondylolysis is suspected, bone scintigraphy with SPECT is recommended. If SPECT demonstrates a pars lesion, a thin-cut CT  through the area of abnormality on SPECT, is recommended to confirm the diagnosis and stage the lesion. If SPECT is negative, pars stress is unlikely to be the cause of the low back pain and MRI may be helpful in identifying other causes of back pain ,26.Complete bony union offers the best long term prognosis. Some patients attain a fibrous union and are consequently able to return to prior activity, with favorable short-term prognoses. Treatment often includes rest from aggravating activities, non steroidal anti-inflammatory medication, bracing and physical therapy emphasizing hamstring stretching and core strengthening. The length of activity restriction, use of bracing and type of rehabilitation programs varies, reflecting a lack of consensus among practitioners. In recalcitrant cases, electrical stimulation may be added ,27,28. PStudies have consistently demonstrated that SPECT is more sensitive than planar bone scintigraphy to identify skeletal lesions -33. CollWe conducted an internal review of all patients with low back pain or suspected spondylolysis referred to the Division of Nuclear Medicine at Children's Hospital, Boston for skeletal scintigraphy between October 2005 and September 2006. Of 115 identified patients undergoing skeletal SPECT and planar scintigraphy, SPECT identified an abnormal focus of increased tracer uptake in the pars interarticularis in 42 patients (37%). All abnormalities detected on planar bone scintigraphy were also detected with SPECT. Planar bone scintigraphy identified an abnormal focus of tracer uptake in the pars interarticularis in 19 patients (17%). SPECT identified additional sites of pars stress in 5 of the 19 patients with pars stress suggested on planar bone scintigraphy (26%).In general, SPECT increases contrast and improves anatomic localization in comparison to planar scintigraphy . In SPECThe economic burden of back pain is significant and growing. Epidemiological studies suggest a correlation between adult and adolescent complaints. Pars interarticularis injury, a spectrum of disease ranging from bone stress to spondylolysis and spondylolisthesis, is the most common identifiable cause of ongoing low back pain in adolescent athletes.In the current era of multi-modality imaging, radiographs, skeletal scintigraphy, CT and MRI all play an important role in imaging patients with back pain. Planar bone scintigraphy has a long history in the diagnosis of patients with suspected injury of the pars interarticularis because it is more sensitive than radiographs for localizing the site of bone stress and because CT of the spine is associated with significant ionizing radiation. The addition of SPECT to planar skeletal scintigraphy increases sensitivity and improves disease localization without exposing the patient to additional radiation. SPECT can also identify early pars stress prior to the development of osseous change detectable with CT. As such, incorporation of SPECT into the standard planar bone scintigraphy routine should lead to a more accurate initial diagnosis. It is our hypothesis that by improving our ability to promptly diagnose patients with suspected injury of the pars interarticularis, the patients will be better served and the long-term cost of management can be lowered.SPECT: Single photon emission computed tomography; CT: Computed tomography; MRI: Magnetic resonance imaging.The authors declare that they have no competing interests.Katherine Zukotynski is an Instructor in Radiology at Harvard Medical School and Christine Curtis is Team Leader in Clinical Research at the Children's Hospital Boston. Frederick D Grant is an Instructor in Radiology  at Harvard Medical School. Lyle Micheli is a Professor of Orthopedic Surgery at Harvard Medical School. Ted Treves is a Professor of Radiology at Harvard Medical School.  All of the authors have read and approved the final manuscript.


To motivate individuals to adhere to a regular physical activity regime, guidelines must be supplemented with persuasive messages that are disseminated widely. While substantial research has examined effective strategies for disseminating physical activity messages, there has been no systematic effort to examine optimal message content. This paper reviews studies that evaluate the effectiveness of three approaches for constructing physical activity messages including tailoring messages to suit individual characteristics of message recipients (message tailoring), framing messages in terms of gains versus losses (message framing), and targeting messages to affect change in self-efficacy .We searched the MEDLINE, PsycINFO, EMBASE and CINAHL databases up to July 2008. Relevant reference lists also were searched. We included intervention trials, field experiments, and laboratory-based studies that aimed to test the efficacy or effectiveness of tailored messages, framed messages and self-efficacy change messages among healthy adults. We used a descriptive approach to analyze emerging patterns in research findings. Based on this evidence we made recommendations for practice and future research.Twenty-two studies were identified. Twelve studies evaluated message tailoring. In 10 of these studies, tailored messages resulted in greater physical activity than a control message. Six studies evaluated framed messages. Five of these studies demonstrated that gain-framed messages lead to stronger intentions to be active compared to a control message. Moreover, a gain-frame advantage was evident in three of the four studies that assessed physical activity. Four studies evaluated self-efficacy change messages. The two studies that used an experimental design provide a clear indication that individuals' beliefs can be affected by messages that incorporate types of information known to be determinants of self-efficacy. Overall, strong evidence to support definitive recommendations for optimal message content and structure was lacking.Additional research testing the optimal content of messages used to supplement physical activity guidelines is needed. Tailored messages, gain-framed messages, and self-efficacy change messages hold promise as strategies for constructing physical activity messages and should be a focus of future research. However, in order to obtain the dose-response benefit, individuals must adhere to being regularly active over weeks, months and years of life. Thus, to motivate individuals to adhere, guidelines must be supplemented with messages that convey why and how to achieve the recommended activity level. It is through the process of messaging that the guidelines and supporting messages are disseminated to the target audience [Physical activity guidelines for healthy adults offer evidence-based recommendations about how much physical activity it takes to reduce the risk of morbidity and mortality and/or to obtain health benefits. Guidelines are not made with the idea that they will motivate individuals to adhere to being active. Rather, they provide a general goal for telling people audience .process of physically getting the message to the population flowing through a medium or media  that the target audience is most apt to use. It is also the process of moving the message through people to which the audience is more apt to relate, in situations that offer opportunities for action in which the audience is more apt to engage.Messages and messaging are identified as critical yet distinct elements essential to the process of translating physical activity guidelines into a format appropriate for use by Canadians . Messageall have potential as strategies for communicating physical activity messages. However, the impact of these strategies vary, some directly affect behavior while others are more likely to impact proximal outcomes such as individual awareness and message recall.In the physical activity domain, the process of messaging has received the most research attention. Research examining the optimal mode  and the appropriate context  for message dissemination has been summarized and evaluated in a series of literature and systematic reviews -6. From Another key finding from these reviews is that the likelihood of creating more enduring behavior change is maximized when messages are delivered as part of a comprehensive and multi-level behavior change intervention . The VERhow we should tell people about the guidelines than we know about what we should tell them [While the existing reviews of messaging provide direction for disseminating physical activity guidelines and messages, they provide little insight into the optimal content of these messages. In essence, we know more about the process of ell them . It is iell them ,11. TherAccording to Brawley and Latimer , messageFirst, we reviewed evidence from studies examining the impact of message tailoring on physical activity behavior. Message tailoring involves presenting information in a manner that suits the individual characteristics of the message recipient. Tailoring increases message salience  and the Second, we reviewed evidence from studies testing the impact of message framing on physical activity behavior and intentions. Message framing is the emphasis a message has on the benefits of adopting (gain-framed) or the costs of failing to adopt (loss-framed) a target behavior. In the physical activity domain, loss-framed messages emphasize the costs of being inactive  whereas gain-framed messages emphasize the benefits of being active . Appropriately framing health messages can enhance message persuasiveness . AccordiFinally, we reviewed strategies for constructing messages that target influential determinants of physical activity behavior. Following from the review by Rhodes and Pfaeffi in this issue , we opteIn summary, substantial research has examined effective strategies for disseminating physical activity messages. However, there has been no systematic effort to examine the optimal content of these messages. Thus, the aim of this paper was to review studies that evaluate the efficacy or effectiveness of three approaches to constructing physical activity messages including tailoring messages, gain-framing messages, and targeting messages to affect change in self-efficacy.The general inclusion criteria for studies reviewed were: (a) the messages were communicated using minimal contact dissemination methods  in which messages were delivered directly to study participants , (b) the primary messages encouraged physical activity only, (c) the study included a post-test message evaluation at minimum, (d) the paper was the primary report of a trial or experiment (d) the paper was written in English, (e) the study participants were healthy adults between 18-65 years of age, and (f) the outcome measures included an assessment of physical activity and/or a theoretical determinant of physical activity participation .Bauman and colleagues  emphasizAdditional inclusion criteria were applied for each research question. To examine the effects of tailored messages, we included studies that used messages that were tailored to at least one characteristic of the message recipient. Because this area of research was adequately developed in that there was multiple, large randomized controlled trials, only studies with a control group were included. To examine the effects of message framing, we included studies that ascribed to the Rothman and Salovey  framing The MEDLINE , PsycINFO , EMBASE (1980 - 2008 Week 30), and CINAHL (1982 - 2008 July Week 3) databases were searched. The search terms used are included in Table Screening was conducted in three phases. In Phase 1, citations and abstracts were screened by a trained research assistant under the supervision of a reviewer. Papers unrelated to physical activity or that described an intervention targeting children were excluded immediately. In Phase 2, using the full set of inclusion criteria, the remaining citations and abstracts were screened by a trained research assistant and verified by a reviewer. In Phase 3, the full text of potentially relevant articles was obtained and reviewed independently by two reviewers. Discrepancies were discussed and resolved by the reviewers. The database of studies included and excluded from the review with reasons for exclusion listed is available from the first author AEL.Two research assistants abstracted data from the articles using a standard form. Abstracted data included: sample size, baseline participant characteristics, study design, guiding theoretical framework, message characteristics , outcome assessment tools, and outcome data. All abstracted data were verified independently by two reviewers.A trained research assistant and a reviewer independently evaluated the methodological quality of each study. The evaluation captured elements of study and intervention design. The five criteria for assessing study design quality were based on the systematic review guidelines from the Cochrane Collaboration Back Review Group  and haveWe used a descriptive approach to analyze the research findings. For the message tailoring and framing studies, there was adequate data and methodological consistency to examine patterns of findings across studies. Studies that demonstrated a significant advantage for the intervention group  versus the control group at any one assessment time point were considered to have a positive effect. Studies that demonstrated a non-significant pattern of findings that favored the intervention group were classified as having a positive trend. Due to differences in study design, the self-efficacy studies were critiqued and analyzed on an individual basis.We formulated practice recommendations for each message construction approach. The recommendations were devised and graded based on the pre-specified process described by Tremblay and colleagues . This sThe results of the literature search are depicted in Figure We identified 12 -33studieAll of the studies tailored messages to individuals' stage of change. Stages of change algorithms classify individuals into one of five stages of motivational readiness: precontemplation , contemplation , preparation , action , or maintenance . According to the transtheoretical model , within In nine of the studies, messages were delivered using print media ,31,33. Tn = 6 [n = 3 [n = 8 [Self-reported physical activity behavior was the primary outcome in each of the 12 studies. In all cases behavior was evaluated using a valid and reliable assessment tool. The type of activity reported varied from leisure time physical activity  t3 [n = 8 ,31,33).For the most part, participants in these studies were middle- aged adult volunteers recruited from workplaces and through media advertisements. In 11 of the studies -25,27-33Eleven studies -31,33useThe methodological quality of the studies varied. Seven of the studies met between 2 to 3 of the evaluation criteria. Common methodological limitations of these studies included lack of intent-to-treat analysis, failure to control for baseline activity levels in the analysis of the final outcome measure and minimal or no description of allocation concealment. While studies were clear in indicating that participants were randomized to experimental conditions, little detail regarding the method used to generate the randomization lists was given. The remaining five studies met between 4 to 7 of the criteria. Generally these studies were well-designed but had minor limitations. For example, none of the studies conducted a manipulation check to evaluate whether participants perceived that the tailored information was well-suited to their needs.A summary of tailoring effects is provided in Table It is important to consider these findings within the context of certain study design features including the type of control group and messaging strategies used. By study design, a consistent advantage (6/6) for tailored messages emerged compared to no message control group ,29-31,33By messaging approach, we consider tailoring effects in the context of mode of dissemination and dose of information on tailoring effects. In the studies reviewed, while significant tailoring effects were demonstrated using print material, these effects also were consistently demonstrated using online tools. In the one study directly comparing print and web delivery of tailored materials, it was determined that both were adequate modes of delivering a tailored message .The general pattern of findings also suggests that more frequent doses of information may enhance the effects of tailored messages. Tailoring effects were reported more consistently in studies where participants received repeated exposures to tailored information than those that provided a single exposure.Overall, there is insufficient evidence to support definitive recommendations for the use of tailoring to construct messages that support physical activity guidelines (Evidence Level 2). Thus, based on the existing evidence, we suggest that it is not essential to tailor the messages that accompany physical activity guidelines. However, given that the pattern of findings indicates that tailoring messages may have some advantage over generic messages, we recommend that when the messages can be tailored easily and with little additional financial cost , tailoring should be considered. If tailoring is used, multiple exposures seem beneficial and the transtheoretical model's stages of change seem to be appropriate targets for tailoring (Grade B).More definitively, we recommend using messages, tailored or not, to accompany physical activity guidelines. In the studies reviewed, participants who received a physical activity message consistently reported engaging in more physical activity than participants who did not receive a message or who received a general health message.Six studies -39 examiAs per the study inclusion criteria, all of the studies applied Rothman and Salovey  guidelinn = 3; [n = 1; [All of the identified studies measured participants' intentions to be active. Four studies also assessed physical activity behavior using valid and reliable self-report measures ).n = 4 studies) or community dwelling adults (n = 2 studies). Two of the studies only included participants who were sedentary. The other studies did not pre-screen participants' activity level. Thus both active and inactive participants likely were included in these studies.Across five of the six studies, the majority of participants were female. Participants were either undergraduate students  than messages attributed to low credible sources. This pattern of findings is wholly consistent with evidence from communications research on a variety of topics that has repeatedly demonstrated the importance of delivering messages through a credible source .The pattern of main and moderated effects of framed messages on physical activity behavior and intentions seems sufficiently consistent (Evidence Level 2) to cautiously recommend the use of gain-framed messages rather than loss-framed messages for creating messages to accompany physical activity guidelines (Grade B). Some research has begun to examine the utility of mixed-framed messages. The findings have been equivocal. Until further evidence is available, it seems prudent to use strictly gain-framed messages to encourage physical activity participation (Grade B).We identified two proof-of principle-type experiments, a field experiment, and a randomized controlled trial that met the inclusion criteria for this review. Our overview of these four studies addresses issues related to the study outcomes and design first because these matters provide conceptual background for discussing all other aspects of the study. These studies are described in the tables included in Additional File different theories but are considered to be conceptually similar by some researchers, conceptual definitions are important to understand in order to orient the reader.In each study the outcomes on which we focused for this review were combined measures of perceived behavioral control and self-efficacy. Given that perceived behavioral control and self-efficacy are two constructs that are part of Perceived behavioral control (PBC) is defined as individuals' expectancy that performance of physical activity and related behavior is within their control. Behavioral control can be broadly described as ranging from easily performed behaviors to behavioral goals needing specialized skills, opportunities, and human and physical resources. Judgments of perceived behavioral control are assumed to take into account both an individual's internal personal resources and external influences that would affect execution of a behavior .Self-efficacy is defined as individuals' beliefs about their abilities to coordinate those skills and abilities to secure the goals they want in specific circumstances or domains . Bandura  also empand individuals' perception of whether performance of the behavior is actually up to them . The latter, self-efficacy, focuses on individuals' beliefs about taking courses of action  that bring about their specific goals .Although some theorists argue that these constructs are similar, there is sufficient evidence to suggest that, depending on measurement, perceived behavioral control is different from self-efficacy . The forAs per the operational definitions described above, the three experimental studies targeted change in perceived behavioral control/self-efficacy as one of their outcome variables. The randomized controlled trial used change in self-efficacy as an outcome measure.The study design features varied. The two proof of principle-type experiments ,43 used These studies exposed participants to messages containing information that concerned the self-management of physical activity. The two proof of principles experiments and the randomized controlled trial delivered their messages in print form. The field experiment delivered the message in DVD format. All studies only delivered the message for one exposure. In the three experiments, message content was guided primarily by the protection motivation theory (PMT ). The frParticipants in the experimental investigation by Stanley and Maddux  read a dUsing a similar experimental paradigm as Stanley and Maddux , the stuIn the field experiment, the experimental video concerned colon cancer and exercise. Self-efficacy/perceived behavioral control information focused upon the how-to-do aspects of planning and incorporating physical activity and exercise into lifestyle in order to accumulate 30 minutes of moderate to vigorous physical activity daily. In the randomized controlled trial, the print materials focused on physical activity benefits and ways to overcome barriers to physical activity. The overcoming barriers portion of the print materials targeted information that participants presumably could use to adapt to barriers that interfered with being regularly active.The two experimental studies used young healthy university undergraduates as their participants. The field experiment that used the DVD format for message delivery used middle-aged school employees. The randomized controlled trial used women with young children. Two of the three experimental investigations reported samples of greater than 70 percent females. The randomized controlled trial was exclusively female.All four studies used a randomized design. The first two experiments satisfied 4 of the 9 quality criteria. These studies were conducted as proof-of-principle experiments and not designed to meet quality criteria for randomized controlled intervention trials. Thus, some quality criteria were either not applicable or because of information not being provided, evaluation of the criterion was uncertain. The field experiment and randomized controlled trial exposed participants to multi-component messages and thus sacrificed testing "pure " message effects on any one theoretical component in favor of an overall theory effect or combined multiple component effect. These latter two studies assessed the individual self-efficacy variable in their evaluation but any change would have to be attributed to the overall message versus the self-efficacy message content alone. These studies contrast with the experiments in that regard. Although participants in the experiments read all messages based upon components of the PMT, these messages were read separately and their effects analyzed for independent influence. While it could be argued that the reading of all messages could have overlapping influence and thus no pure effects of one PMT variable could be detected, this influence was not like the influence of the completely blended messages in the field experiment and RCT. The two experiments were able to consider the main effects analysis of each variable in the overall experiment. Where the analysis detected a main effect of the self-efficacy/perceived behavioral control variable, there was no interaction effect of the other PMT variables. Thus the evidence for the influence of the persuasive message was strongest in the two proof-of-principles experiments.The two experimental studies provide a clear indication that when individuals read structured messages that incorporate types of information known to be determinants of self-efficacy/perceived behavioral control, study participants' beliefs can be affected. In the study by Stanley and Maddux  perceiveCompared to the two experimental studies, the findings from the field experiment and the randomized controlled trial provide less indication of how message content influences efficacy-related beliefs. In the field experiment by Graham and colleagues , the mesThe findings of the 4 studies using messages to change self-efficacy/perceived behavioral control are mixed. There is insufficient evidence to confirm a reliable systematic effect (Level 3). However, a closer look reveals that when the messages are theory-based, carefully controlled and the content is targeted to specifically influence the dependent variable using determinants or conditions known to alter beliefs about efficacy and perceived control, the results are somewhat more promising. The first two studies we reported in this section used this specifically-targeted approach. The caveats related to the results of these two experiments is that they are limited to educated, undergraduate university students and the actual influence of altering these control beliefs on actions related to physical activity behavior  is unknown (Grade C).not conclude that there was strong evidence to support definitive recommendations for optimal message content. Rather, findings from this review point to several promising practices as summarized in Table The purpose of this systematic review was to examine the evidence testing the utility of three message construction approaches  that could be used to inform the content of messages that accompany physical activity guidelines. Twenty-two studies were reviewed. Overall, we could In our review of message tailoring research, a pattern of findings emerged that favored tailored messages compared to generic messages or no message whatsoever. Tailoring effects tended to emerge more consistently with multiple message exposure. The findings from our review align with message tailoring research in the broader health domain. For example, a meta-analysis  of 57 str = .11, CI: -.056, .270) and approached, but did not reach standard levels of significance. This analysis was underpowered and differed from our review in two ways. First, our review did not include all of the same studies as the meta-analysis. We included two additional, recently published studies with large sample sizes, multiple message exposure, and results favoring gain-framed messages. We also considered moderated framing effects. This approach of examining moderators is consistent with an emerging research direction that is aiming to specify more precisely when gain-framed messages will be most effective [Our review of the message-framing research, also recommends that message framing is a sufficient and promising practice, but not essential. The pattern of findings for behavioral and social-cognitive outcomes in the studies we reviewed was consistent with the theory-based hypothesis that gain-framed would be more persuasive than loss- or mixed-frame messages. Our suggestion that framing physical activity messages has potential to enhance message effectiveness differs from the conclusion drawn from a meta-analysis  of 93 stffective . Given tOur review of messages meeting our criteria for selection and targeting change in self-efficacy beliefs as one outcome yielded only four studies; two proof-of-principles experiments, one field experiment and one complex intervention. The lack of systematic research testing physical activity messages that target theoretical determinants such as self-efficacy is disappointing. In 1987, Olson and Zanna  suggesteGiven the evidence gaps in this research area, our recommendation for including information known to affect recipients' self-efficacy beliefs is really only a suggestion for constructing future messages associated with physical activity guidelines. There is insufficient evidence to make a definitive recommendation. Researchers and message designers would be wise to consider research from the counselling-based intervention literature in both symptomatic and asymptomatic populations that have proven effective in altering self-efficacy and other theoretical determinants of physical activity behavior . ConsidOur cautious suggestions for the use of tailored, framed, and self-efficacy change messages were due in part to the limited quality of the evidence. In a standard assessment of methodological quality based on criteria for randomized controlled intervention trials, the message framing and tailoring studies fared poorly. The self-efficacy studies also were subject to several design limitations. These gaps in methodology are reflective of the relatively immature state of the research area. For example, the application of message tailoring and message framing principles to physical activity promotion has only slowly emerged over the last decade. As the field has matured, the methodological rigour in the most recent studies has increased steadily . However, it should also be recognized that identified methodological gaps are partly reflective of the differing approaches to experimental design across multiple fields  rather than gaps that might normally be associated with a single field and one design paradigm. The judgment of insufficient evidence to make definitive recommendations is appropriate when the standard of evaluation is the randomized clinical trial. However, a number of the effects we identified were observed in experimental studies and we have confidence that these studies met quality standards at a level commensurate with peer-reviewed proof-of-principle studies for their respective fields. Thus, we have made suggestions for the future rather than recommendations per se.Two notable limitations of the majority of studies in the review were the sole reliance on self-report measures to assess physical activity and the predominance of women in the study samples. Although the studies reviewed used valid and reliable measures of physical activity, the measures were constructed primarily for use in much larger cohort studies and as result tend to lack sensitivity to small changes in behavior . Also, tThe second limitation, the large proportion of women in the reviewed studies, limits the external validity and any generalizability of findings to the population at large. Health promotion research in general lacks evidence of effective strategies for changing men's behavior  and futuIn addition to these general limitations, a specific limitation of the tailoring studies was the narrow scope of tailoring approaches used. All studies tailored messages using the stages of change. Research related to other health behaviors  has demonstrated the utility of tailoring to a variety of demographic  and persOur systematic review had several limitations. A database search strategy different than what we used is needed for future systematic reviews. The small yield from our database search in part is a reflection of the field being underdeveloped. As a result, there are relatively few studies to be included in the review regardless of the search strategy. Also, the investigators who conduct message evaluation research are from a variety of fields. For example, psychologists, physical activity scientists, and communication experts differ in what they mean by the term social marketing. Keywords from these fields and literatures vary widely thereby limiting their systematic application in a database search.An additional limitation was our exclusion of studies conducted among clinical populations . The common mandate for the evidence-based reviews for physical activity guidelines in this issue, including our review, was a focus on research concerning healthy adult participants. Although there is a need to promote healthy lifestyle practices in clinical populations, and there is promising research identifying characteristics of effective messages and strategies for these individuals, this was necessarily excluded from our review.Finally, our review focused primarily on intermediate  and distal outcomes . This specific focus was necessary given the nature of the research included in the review - few studies included proximal outcomes . Among the studies that assessed proximal outcomes the measurement approach varied across studies precluding meaningful comparisons. Although proximal outcomes were not considered in the current review, they should be included in future studies evaluating message effectiveness. These outcomes are important indicators of message and campaign success .We were unable to make definitive recommendations for practice given that there was insufficient evidence. The small amount of systematic research examining the appropriate content for physical activity messages unquestionably highlights the need for additional research in this area. However, we can make general recommendations for future research examining optimal message content for constructing persuasive messages for physical activity. These pertain to the three approaches we reviewed and are as follows:• More controlled experimental research is needed to isolate effective message characteristics and examine the generalizability of study findings. These studies should be carefully designed to minimize confounders such as the mode of message delivery. Specifically, we do not know whether presentation by a combination of modalities enhances or detracts from individuals' attention. Thus, it is important to reliably determine the effects of the content of the messages before advancing to more complex multi-method modes of message presentation.• Research also should examine the optimal dose of information required to maximize message effectiveness.Our recommendations for future investigation specific to each of the message construction approaches are as follows:and generic physical activity messages in the same study. This study design provides a rigorous test of tailored messages  comparing tailored messages to mismatched messages lleagues ).stable dispositional characteristics. Thus, for example, the need for repeated assessments in stage of change studies of messages tailored to dynamic message recipient characteristics is eliminated.• Research should begin to test the impact of messages that are tailored to characteristics other than message recipients' stages of change . Several studies in the broader realm of health promotion have begun to establish the effectiveness of messages tailored to psychological constructs that differentiate people on the basis of how they process incoming health information . A prac• Additional large, multi-message randomized controlled trials targeting inactive adults are needed to strengthen the evidence-base regarding use of gain-framed messages to promote physical activity participation.when gain- and loss-framed messages will be most effective [• Researchers should continue to investigate factors that moderate framing effects. This research helps to refine and advance current message framing postulates by specifying more precisely ffective .• Conduct more randomized control experiments to demonstrate the effectiveness of altering sources of efficacy-relevant information in targeted messages to change efficacy beliefs and behavior.are not necessarily immediate and regular types of activity participation, but rather, immediate, motivated actions such as getting further information; developing plans; and enrolling in an activity.• Researchers must carefully select outcome measures appropriate to the goal of the message. To gauge message effectiveness accurately, the measurement of self-efficacy/perceived control beliefs should correspond to the message content. Appropriate indicators  of behaviors to be changed must also be reconsidered. Probable behaviors most likely to be affected by a persuasive message relate to behavioral "first steps" toward physical activity. Examples of these behavioral steps what individuals should do but also why and how they should do it. Research examining the optimal content of messages encouraging physical activity is an emerging field. To date, there is insufficient evidence from the three message construction approaches we reviewed to lead to definitive, practical recommendations for persuasive messages that would support the dissemination of physical activity guidelines. We suggest that the effects of message tailoring, message framing, and targeting sources of self-efficacy enhancing information show promise but more research systematically isolating effective message characteristics is required.To motivate individuals in a behavioral direction that may lead to future adherence to regular physical activity, guidelines must be supplemented with messages that convey not only Note. Most abbreviations appear in the tables included in the Additional Files. PA: physical activity; SE: self-efficacy; RE: Response Efficacy; PV: Perceived Vulnerability; PS: Perceived Severity; PMT: Protection Motivation Theory.This work was funded by the Public Health Agency of Canada (PHAC) and the authors received an honorarium from PHAC for completing the systematic review. AEL and LRB have also received honoraria and speaker fees from several other non-for profit organizations that have an interest in physical activity and health.AEL directed and was involved in all aspects of this systematic review including conceptualization, data abstraction, and manuscript preparation. LRB participated in the design of the research questions and manuscript preparation. RLB contributed to the development of the research questions and the literature review and data abstraction process. RLB also helped to draft the manuscript. All authors read and approved the final manuscript.Message tailoring - Quality assessment and study summary tables. The tables summarize the results of the assessment of study quality and describe the research methods and the results of the message tailoring studies.Click here for fileMessage framing - Quality assessment and study summary tables. The tables summarize the results of the assessment of study quality and describe the research methods and the results of the message framing studies.Click here for fileSelf-efficacy change messages - Quality assessment and study summary tables. The tables summarize the results of the assessment of study quality and describe the research methods and the results of the studies evaluating self-efficacy change messages.Click here for file