The safety of paediatric medications is paramount and contraindications provide clear pragmatic advice. Further advice may be accessed through Summaries of Product Characteristics (SPCs) and relevant national guidelines. The SPC can be considered the ultimate independent guideline and is regularly updated. In 2008, the authors undertook a systematic review of the SPC contraindications of medications licensed in the United Kingdom (UK) for the treatment of Attention Deficit Hyperactivity Disorder (ADHD). At that time, there were fewer contraindications reported in the SPC for atomoxetine than methylphenidate and the specific contraindications varied considerably amongst methylphenidate formulations. In 2009, the European Medicines Agency (EMA) mandated harmonisation of methylphenidate SPCs. Between September and November 2011, there were three changes to the atomoxetine SPC that resulted in revised prescribing information. In addition, Clinical Guidance has also been produced by the National Institute for Health and Clinical Excellence (NICE) (2008), the Scottish Intercollegiate Guidelines Network (SIGN) (2009) and the British National Formulary for Children (BNFC).An updated systematic review of the Contraindications sections of the SPCs of all medications currently licensed for treatment of ADHD in the UK was undertaken and independent statements regarding contraindications and relevant warnings and precautions were then compared with UK national guidance with the aim of assessing any disparity and potential areas of confusion for prescribers.As of November 2011, there were seven medications available in the UK for the treatment of ADHD. There are 15 contraindications for most formulations of methylphenidate, 14 for dexamfetamine and 5 for atomoxetine. Significant differences exist between the SPCs and national guidance part due to the ongoing reactive process of amending the former as new information becomes known. In addition, recommendations are made outside UK SPC licensed indications and a significant contraindication for methylphenidate  is missing from both the NICE and SIGN guidelines. Particular disparity exists relating to monitoring for suicidal and psychiatric side effects. The BNFC has not yet been updated in line with the European Union (EU) Directive on methylphenidate; it does not include any contraindications for atomoxetine but describes contraindications for methylphenidate that are no longer in the SPC.Clinicians seeking prescribing advice from critical independent sources of data, such as SPCs and national guidelines, may be confused by the disparity that exists. There are major differences between guidelines and SPCs and neither should be referred to in isolation. The SPC represents the most relevant source of safety data to aid prescribing of medications for ADHD as they present the most current safety data in line with increased exposure. National guidelines may need more regular updates. Attention Deficit Hyperactivity Disorder is a commonly diagnosed disorder affecting around 3-9% of school aged children and young people in the UK; the worldwide pooled prevalence rate of ADHD in the same population is estimated at 5.29% ,2 The nuAt the time of writing, there were eight medications licensed in the UK to treat ADHD. These medications were granted a marketing authorisation (license) by the UK regulatory agency, the Medicines and Healthcare products Regulatory Agency (MHRA) (formerly the Medicines Control Agency) following review of required efficacy and safety data. The MHRA is a government agency established in 2003 and is responsible for ensuring that medicines and medical devices are effective and are acceptably safe. Safety information is monitored from a variety of sources and, if required, risk benefit assessments are conducted. The MHRA initiated a risk: benefit assessment for atomoxetine in 2006.A draft SPC is submitted within the application for a product license and is then finalised in conjunction with the Marketing Authorisation Holder (MAH) and the regulatory agency with the purpose of enabling safe and appropriate prescribing. The totality of the data reviewed by the regulatory agency and which subsequently informs the SPC far exceeds that which is published in the peer-reviewed scientific literature. In summary, the SPC is the agreed statement of known facts about a given pharmaceutical compound at a particular point in time and it is critical that it is reviewed and amended regularly as new information emerges.Guidelines on the preparation and maintenance of SPCs are laid out by the European Commission (EC) and contraindications are defined as 'situations where the medicinal product must not be given for safety reasons' . StatemeThe conduct of pharmacovigilance for medicines for paediatric use requires special attention and reporting by multiple stakeholders of potential adverse events is of increasing importance . One sucBecause monitoring can and does lead to important safety changes the SPC can be regarded as the current and updated 'ultimate guideline' for safe and effective use of that compound. Other worldwide regulatory agencies have similar views. The US Food and Drug Administration (FDA) which is responsible for protecting the public health by assuring the safety, efficacy and security of drugs in the United States considers the communication of risks and benefits through its product labelling as "the cornerstone of risk management efforts for prescription drugs" . The SPCAlthough the entire SPC is important, the sections that relate to Contraindications (Section 4.3) and Special Warnings and Precautions for Use (Section 4.4) remain the most critical with respect to safety. Healthcare professionals, however, are not always fully aware of the content of SPCs, how it has been derived or how to access them.In April 2008, the authors presented a systematic review of the Contraindications sections of the eight medicines authorised in the UK at that time for the treatment of ADHD in children ) and a methodological study into the measurement of suicidality in paediatric clinical trials  ) .Suicidality is a key area of disparity between national guidance and SPCs. The SPC for atomoxetine specifically highlights the need for monitoring for the appearance or worsening of suicide-related behaviour and states that suicidal behaviours have occurred uncommonly in clinical trials. Suicide-related events are also listed as an uncommon Undesirable Effect on the SPC. The SPCs for methylphenidate list suicidal tendencies as a contraindication for usage, contain a warning relating to the emergence of suicidal behaviours and also list suicidal ideation as an uncommon Undesirable Effect. They also mandate monitoring for all psychiatric adverse events and this will include suicidal issues of all types. The dexamfetamine SPC states that any family history of suicide should be investigated prior to initiation of treatment as part of the screening for risk of bipolar disorder.In contrast to the SPC content, the NICE guidelines warn clinicians of "...suicidal problems and self harming behaviour with atomoxetine" and make no mention of the risks associated with other treatments. The SIGN Guidelines repeat this disparity by stating the need to closely monitor patients on atomoxetine in particular for agitation, irritability, suicidal thinking and self-harming behaviour.The atomoxetine suicidality data are derived from a retrospective analysis of atomoxetine usage in 14 paediatric trials which reported greater suicidal ideation with atomoxetine when compared with placebo (p = 0.016). In a cohort of 1,357 atomoxetine-treated subjects, there were five cases of suicidal ideation reported, no completed suicides and one suicidal attempt . The samSimilar inconsistencies arise with other sections of the SPCs. The NICE guidelines suggest using either atomoxetine or methylphenidate with co-morbid anxiety, but specifically recommend the need for observation for agitation or irritability only with atomoxetine despite a strong warning on the methylphenidate SPC relating to the need to clinically evaluate patients for agitation and irritability prior to the use of methylphenidate. The SPC also advises that patients should be regularly monitored for the emergence or worsening of these symptoms during treatment, at every adjustment of dose and then at least every 6 month or every visit. The atomoxetine SPC states that whilst treatment emergent agitation can be caused by atomoxetine at usual doses there are no specific monitoring recommendations around agitation and irritability. Methylphenidate is associated with the worsening of pre-existing anxiety, agitation or tension. Clinical evaluation for anxiety, agitation or tension should precede use of methylphenidate and patients should be regularly monitored for the emergence or worsening of these symptoms during treatment, at every adjustment of dose and then at least every 6 months or every visit. Recent changes to the atomoxetine SPC highlight that anxiety was not worsened in clinical trials but that patients being treated with atomoxetine should be monitored for the appearance or worsening of anxiety. The wording around the recommendations in the guidelines does not fully reflect the SPC content of either product.A similar disparity exists for usage of either agent when tics or Tourette's syndrome are present. Both NICE and SIGN recommend use of either methylphenidate or atomoxetine although the SPCs have differences. The atomoxetine SPC reports that there was no worsening of tics or Tourette's in a placebo-controlled trial, very rare post-marketing reports of tics have been received and that patients should be monitored for the appearance or worsening of tics. The methylphenidate SPC states that methylphenidate is associated with the onset of tics, that both tics and Tourette's may worsen with methylphenidate treatment and that clinical evaluation and examination should precede methylphenidate treatment.Other areas of debate include adverse events attributed to a drug. For example, in both National Guidelines, it is recommended that sexual dysfunction is monitored in atomoxetine patients (children and adults) but this requirement is not reflected in the SPC. The SPC contains no clinical trial data on sexual dysfunction specifically in children, only post-marketing surveillance data which includes children, adolescents and adults.®) since June 2011 [The disparity between these independent data sources may be complex for clinicians to interpret particularly when the NICE guidelines recommend use of methylphenidate in adults which has only been an approved indication for one form of methylphenidate , dysthymic disorder (13.5%) and Major Depressive Disorder (3%)  when usiAn important consideration is the balance of regulatory statements as contained in the SPC and the expertise of those routinely prescribing medications. Clinicians have had significant experience of using methylphenidate for many years in many children and as such have considerable expertise in weighing up potential tolerability and safety risks with the benefits of medication to individual patients. Relevant clinical publications, clinical expertise in using the medications and achieving positive results in cases that are contraindicated according to the SPC are highly influential in determining future drug use. There is experience of contraindicated medications being prescribed to patients with positive outcomes despite the potential risk of rare adverse events. The advantage of the regulatory statements is that they are based on cumulative case reports and as such reveal the rarer adverse events that would not otherwise be picked up in routine practice. As a consequence, appropriate levels of monitoring and precaution can be recommended for different products. These types of issue are evidenced by the level of debate in the scientific literature regarding the potential for methylphenidate to cause or worsen tics ,10,20.Clearly data are emerging rapidly in ADHD with the advent of new treatments and epidemiological research but national guidelines and SPCs cannot be updated as frequently as data emerge. For the period from January 2009 to April 2011, the search term "atomoxetine" in Pub Med generates 245 citations with at least 94 citations likely to contain clinical data, meta-analyses or reviews. The future safety of paediatric treatments are paramount and are likely to be advanced by the FDA and EMA regulations and the ability of large databases to address outcome measures of a more pragmatic kind. Some safety aspects may even be improved by drug treatment. Recent data on atomoxetine usage in a cohort of 13-16 year old children improving unhealthy dietary behaviours and physical activity as well as reducing behaviours contributing to unintentional injuries .To be able to make prescribing decisions based on sound evidence, clinicians need to be aware of, and be familiar with, the different sources of information available to them. The SPC, as an independent document reflecting current knowledge, may be the best way of achieving this.Clinicians seeking guidance regarding the use of medications for ADHD in UK will find significant disparity between relevant national guidance and SPCs; these differences extend to licensed indications, contraindications, warnings and precautions and monitoring schedules. The contraindications sections within the SPC provide clear categorical statements for which the relevant medications should not be prescribed.In view of the approval of the content of the SPC by the regulatory agency and the ongoing changes that take place to reflect current safety findings, many of which have been discussed in this manuscript, clinicians may be advised to consider the SPC as the ultimate guideline. The very recent decision by NICE not to update the current ADHD Guideline until 2014 may further increase the relevance of the respective SPCs.ADDUCE: ADHD Drugs Use Chronic Effects Programme; ADHD: Attention Deficit Hyperactivity Disorder; BNFC: British National Formulary for Children; CHMP: Committee for Medicinal Products for Human use; DSM-IV: Diagnostic and Statistical Manual of Mental Disorders Volume 4; EC: European Commission; EMA: European Medicines Agency; eMC: electronic Medicines Compendium; EU: European Union; FDA: Food and Drugs Administration; HKD: Hyperkinetic Disorder; MAH: Marketing Authorisation Holder; MHRA: Medicines and Healthcare products Regulatory Agency; NICE: National Institute for Health and Clinical Excellence; PSUR: Periodic Safety Update Report; SIGN: Scottish Intercollegiate Guidelines Network; SPC: Summary of Product Characteristics; STOP: Suicidality Treatment Occurring in Paediatrics; UK: United Kingdom.Nicola Savill and Chris Bushe are employees and shareholders of Eli Lilly and Company Ltd. Eli Lilly is the marketing authorisation holder and manufacturer of atomoxetine in the UK and has financed this manuscript.The paper has been written by NS and CB. The tables were compiled by NS and checked by CB. Both authors read and approved the final version of the manuscript.


We present a 25-year-old male patient with a diagnosis of multiple enchondromatosis, who developed chondrosarcoma on the proximal humerus of the right upper limb. The patient had the pre-existing lesions of Ollier’s disease discovered during his childhood. The patient underwent wide resection of the sarcoma with a prosthetic replacement of the proximal humerus. So far we have followed up the patient for 8 years with no evidence of local recurrence and/or metastasis. The therapeutic results have been satisfied with a good functional recovery of the treated limb, enabling the patient to return to the pre-disease daily living and occupational activities. The reconstructive procedures represent an effective surgical strategy for limb salvage in the treatment of large segmental defects after resection of humeral tumors, substantially solving the functional and esthetic problems due to such a wide resection, and significantly improving the quality of life for the patient. Ollier disease is a rare non-hereditary skeletal disorder characterized by the presence of multiple enchondromas (enchondromatosis), and these cartilaginous lesions can be limited to one limb, or localized to one half of the body , 2. The A 25-year-old male patient was admitted to our department, presenting progressive pain and numbness with a rapidly growing mass located in the upper part of the right arm for 2 months in 2005. At the time of the hospital admission, he had completely lost his occupational capacity of the arm (100% unable to work). Physical examination revealed a palpable mass on the upper part of his right arm with a size 13 × 12 cm. Radiographic examination demonstrated a large mass over 10 cm in diameter on the proximal humerus, with massive cortical erosion, extension of the tumor into soft tissues and indistinctness of the surface of the tumor . A diagnA limb-salvage strategy with treatment of the large segmental defects following resection of the tumor and a prosthetic replacement of the proximal humerus was designed for the patient. The informed consent was obtained from the patient prior to the operation. The tumor resection prosthesis was applied in the same session following the tumor resection . The tumDuring the 8-year follow-up, clinical and radiologic examinations were done at the periodic controls. There are no signs of local recurrence and/or remote metastasis so far. The therapeutic results have been satisfied with a good functional recovery of the treated limb, enabling the patient to return to the pre-disease daily living and occupational activities. The overall functional outcomes were assessed by the musculoskeletal tumor society (MSTS) scoring system. The patient had the overall score 24 in the last examinations of the follow-up, and the ranges of motion of the shoulder joint are shown in Proximal humerus tumors treated with amputation usually result in a complete loss of the hand/limb function. Limb-salvage procedures have been popularly put into clinical practice in spite of amputations in bone tumor surgery. However, the surgical procedures remain challenges for orthopedic surgeons toward simultaneous replacing the defects of bone/soft tissue and restoring the functions of the involved joints/limbs after tumor resection. Preservation of the functional capacities of the involved upper extremity along with a complete removal of the tumor is considered as the mostly important criteria in the surgical management of the bone tumor of the proximal humerus. Moreover, concerns also should be paid for preservation of length and cosmesis of the upper extremity toward supporting quality of life for the patients. The indications for the prosthetic replacement of the proximal humerus tumors as proposed by Ross et al  have beeIt is worth noting that good function of a treated upper limb with the procedures is largely based on the stability of the shoulder joint, while the stability of the shoulder joint can only be ensured by reliable reconstruction with minimizing the amount of resection of muscle and soft tissue within the complete removal of the tumor during surgery . Various


With the advent of whole genome sequencing made clinically available, the number of incidental findings is likely to rise. False positive incidental findings are of particular clinical concern, and they can usefully be classified into four categories. In order of increasing challenge, there is first, the substantial proportion of 'textbook cases' of mutations documented to cause human disease in a highly penetrant Mendelian fashion, which are incorrectly annotated in the databases. The second is the technical/measurement error rate in genome-scale sequencing. Third is the incorrect assignment of prior probabilities for much of our genetic and genomic knowledge. The fourth derives from testing multiple hypotheses across millions of variants. I will describe the nature of these components, provide rough estimates for the magnitude of the problem and point out existing approaches that will serve to control the growth of these aspects of the incidentalome.


This study explores potential data mining applications in the Casemix context, which is expected to yield effective and efficient health care services. The objective of work focuses on determining hidden relevant patterns which can’t be processed by human capabilities all alone. California Drug and Alcohol treatment Assessment (CALDATA) of administrative type database can be relevant study for the medical diagnosis in usage of alcohol and drugs for patients admitted and discharged during the stay in hospital to discover knowledge for recovery process.We utilized the observational study on cases registered to California Department of Alcohol and Drug Programs (ADP) to promote the initiative for increasing availability of abusive drug usage data for better drug recovery services among the California. The cases were diagnosed with Minitab diagnostic tool to access the Casemix databases for retrieval of hidden information using data mining tools. The K means clustering having used with dendrogram to determine the possibility of existence of patient admitted and discharged on the accountability for usage of abusive substance between the years 1991-1993. The classification of data is done among the educated and uneducated class for categorized race with correlation age at the time of admission to hospital. The analysis has been performed on the patients admitted due to abusive substance usage and treatment provided during the stay in hospital and discharge status for final medical diagnosis provided to patient those have suffered for long stay during hospitalization.There has been a tremendous increase in the incidence rate of admission cases in age group 45-49 years. The probability of over 40% cases acquiring maximum number of abusive substance exists in patients who have obtained post graduate education. The decline approximately 2.3% of criminal activities after proper diagnosis to patients with high level of alcohol dependency among the cases observed.The total number of cases evaluated to study was 1,826 in 1991-1993; total number of features selected was 1,205 for each case diagnosed. The cases were diagnosed on the basis of admission and discharge among the prevalence of abusive substance usage. The subject was classified for different subjects such as education, age, duration of stay in the hospital, estimated reduction on criminal cases, decrement of hospital cases while the treatment provided during the stay.We calculated the overall usage of abusive substance among the categorized race at time of admission with reference to the age. The results shows white were among the categorized age group of 17 and under has the maximum usage of abusive substance whereas native Americans are the one those who have minimum consumption of abusive substance usage. In diagnosis of longest time of stay during the treatment in hospital from day of admission to day of discharge due to abusive substance usage we have calculated the overall maximum number of prevalent cases during the year 1991- 1993, we have found that longest stay was observed for male/female aged below 17 years year and were correlated to marital status that is unmarried. The clusters in the dendrogram has been observed, where the largest cluster represents the maximum number of unmarried male/ female patients diagnosed for highest abusive substance usage, whereas the second cluster represents the second highest cases for divorced/ separated has the maximum usage of abusive substance, third cluster represent the single between the age group 21-24 years accounted for 48% cases for length of stay during hospitalization, fourth cluster represents the married cases those who were among age group 35-39 years, the minimum number of cases were studied for widowed.The integrated approach, K-means and Hierarchical Clustering technique using Minitab are well suited techniques to provide insight of health service databases. The probability of patients acquiring the abusive substance depends on several factors such as education, age, marital status and several other factors related to patients. The discharge status of these highly correlates to criminal activity and discharge status of hospitalization cases which have reduced down tremendously after providing treatment to admitted patients.


Volumetric measurement of polyacrylamide hydrogel (PAHG) is useful for surgical planning. It is not only a significant factor in the preoperative evaluation of breast augmentation, but may also directly affect the postoperative shape of the breast. The objective of the present study was to evaluate whether magnetic resonance imaging (MRI) is able to provide precise calculations of injected PAHG volumes. MRI scans of ten randomly selected patients were imported to Mimics software. The volumes of PAHG were obtained following the reconstruction of the injected PAHG. In order to assess the precision and observer independency of the technique, the volumes of PAHG were estimated by three plastic surgeons using this method. No significant differences were identified among the PAHG injection volumes calculated by the three observers (P=0.173). The intra-observer correlation coefficient was 0.964, which indicates the precision and feasibility of this method for calculating the volume of PAHG. The use of MRI in combination with Mimics software to calculate PAHG volumes is likely to be of significant clinical benefit in preoperative surgical planning. Polyacrylamide hydrogel (PAHG) has been widely used for injection augmentation mammaplasty in Russia, China and Iran for more than two decades . AlthougSince April 2006, when the China State Food and Drug Administration announced that PAHG was prohibited from production and clinical application in plastic surgery, significant social concern was raised concerning the use of PAHG injections as soft tissue fillers. It was estimated that ~200,000 patients have received PAHG breast augmentation in the last decade . BetweenIt is vital to estimate the precise volume and depth of the PAHG injected for breast augmentation. It is not only a significant factor in the preoperative evaluation of breast augmentation, but may also directly affect the postoperative shape of the breast. Therefore, a reliable method for calculating the volume of the injected PAHG is required. Magnetic resonance imaging (MRI) scans are commonly used to analyze the position of the injected PAHG. Therefore, the development of a rapid and precise method of estimating the volume of PAHG on the basis of MRI scans would be of benefit. The purpose of the present study was to define a volume measurement method. In addition, the reliability and precision of the volume measurement method were monitored.Between 2005 and 2012, 407 patients underwent PAHG removal breast surgery in the Department of Aesthetic and Plastic Breast Surgery of the Plastic Surgery Hospital. Each patient underwent breast MRI pre-operatively. Ten patients that had never had breast surgery prior to the study were randomly selected and enrolled in the study. Clinical characteristics of the patients are shown in All patients were scanned prior to the operative procedures by MRI. A 1.5-T MRI scanner  with dedicated breast coils was used for the imaging. The standard protocol included axial T2-weighted images with and without fat depression and sagittal T1- and T2-weighted images with fat depression. The DICOM images of the MRI scans were imported into Mimics software . The axial T2-weighted images with fat suppression  were useThree plastic surgeons independently carried out the volumetric measurement. Each patient was measured ten times by three independent plastic surgeons. Calculated PAHG volume data are presented in PAHG was injected in different layers and distributed differently in different patients. In patient 8, PAHG was injected into the subglandular space and distributed regularly  and 2A. Calculated PAHG volume data are presented in et al considered the indications were as follows: Absence of breast neoplasm and infection; removal of >90% of the injected gel; no residual hydrogel in pectoral muscles and/or the subpectoral space; enough healthy mammary tissue and pectoral muscle present to cover the breast prostheses; inframammary folds are intact or are able to be reconstructed simultaneously; and no systemic or psychological problems (The purpose of the present study was to determine a method for precisely measuring the volumes of injected PAHG. The results demonstrate that the volume of the injected material may be precisely calculated, which is significant for the preoperative evaluation of patients prior to the removal of PAHG. Information concerning the distribution of the injected PAHG and the extent of the tissue infiltration was obtained. It was therefore possible to estimate the difficulty and the risks involved in the removal of the PAHG, as well as ensuring the feasibility of immediate breast augmentation and the postoperative shape of the breast. On the basis of the estimated volume, appropriately sized implants may be selected prior to breast augmentation, following the removal of the PAHG. However, there are specific restrictive indications for immediate breast shape repair. Luo The measurement method may also be used to calculate the volume of the residual hydrogel. The effectiveness of various approaches for the removal of PAHG from the breast may be evaluated on the basis of the estimated volume of residual hydrogel.et al have reported a method using a 3-D MRI reconstruction technique to determine the volume and distribution of the PAHG (There have been few studies analyzing volume measurement of PAHG. However, several studies have discussed the volume estimation of silicone gel-filled breast implants from MRI images –12. Prevthe PAHG . HoweverIn the present study, it was not possible to compare the calculated volumes of injected PAHG with the actual volumes, since information concerning the preoperatively injected PAHG volumes was not available. In addition, it was not possible to compare these volumes with the volume of the removed materials. Firstly, since PAHG is a hydrophilic filler material, some of the material may be easily aspirated following saline dilution. During the surgical procedure, the cavity was repeatedly irrigated with a large quantity of normal saline intraoperatively. Therefore, the amount of the removed PAHG may not be fully consistent with the estimated volume of PAHG. Secondly, the PAHG, as well as the degenerated tissue, were removed intraoperatively leading to the volume of all excised tissue being inconsistent with the estimated volume of PAHG. Thirdly, some of the PAHG may have been injected into another area, including the subcutaneous or intercostal muscles. In consideration of the intraoperative safety and the postoperative shape of the breast, it may not be possible to remove the PAHG completely. This also caused the volume of the materials removed to differ from the calculated volume of PAHG.In conclusion, MRI imaging offers a precise method for the volumetric measurement of injected PAHG. This is significant for pre- and post-operative evaluation and the selection of implants for immediate reconstruction.


During this last decade, nonlinear analyses have been used to characterize the irregularity that exists in the neuronal data stream of the basal ganglia. In comparison to linear parameters for disparity , nonlinear analyses focus on complex patterns that are composed of groups of interspike intervals with matching lengths but not necessarily contiguous in the data stream. In light of recent animal and clinical studies, we present a review and commentary on the basal ganglia neuronal entropy in the context of movement disorders. Characterization of the neuronal data stream of basal ganglia neurons has been the foundation of most of the functional models for movement disorders. The divergences (or complementarities) between these models mostly result from the analytical strategy used to characterize and to model the data stream of the basal ganglia (BG) neurons. The analysis of the firing rate has forged the “rate hypothesis” while the frequency analysis has forged the “oscillatory model.” Briefly, the rate hypothesis and oscillatory model suggest that increasing activity and/or beta oscillations in the output nuclei of the BG ) reduces motor selection and leads to hypokinesia in Parkinsonism.  Since this last decade, different groups have integrated new mathematical tools to characterize and/or model the activity of the BG neurons including nonlinear analyses which describe complex patterns in the neuronal data stream. After reviewing the recent findings from the nonlinear analysis of the BG neurons, we present a review on the avenues and hypotheses brought by these newly integrated mathematical tools and their possible impacts on the next generation of functional models of the basal ganglia.  The basal ganglia are part of corticocortical loops  –7 and ha The sequential and convergent arrangement of excitatory and inhibitory neurons in these nuclei has forged the concept that basal ganglia and, inherently, information processing rely on the summation of excitatory and inhibitory inputs and are therefore linear in nature. To compare neuronal activity in the basal ganglia to the model predictions, the measurements of the firing rate and other linear markers in the time domain have been examined in animal and clinical studies. Data from these studies have contributed to the “rate model” for movement disorders. This model is founded upon the assumption that the direct pathway (Str-GPi/SNr) is up-regulated by the D1 dopaminergic receptor and indirect pathway (Str-GPe-GPi/SNr) is down-regulated by the D2 dopaminergic receptor. The dynamic balance between these two pathways contributes in motor selection and motor inhibition, respectively . The “raIn addition to time domain analyses which are based on the probability distribution of interspike intervals (ISIs), other studies have characterized the firing activity of basal ganglia neurons in the frequency domain. In a majority of studies, differences in oscillatory activities have been identified between normal and pathological conditions –42. In PThe linear analyses used to characterize the basal ganglia activities in time and frequency domains measure the resultant linear combinations of independent patterns in the data stream. These analyses characterize the interspike interval (ISI) series by the summation of probability distributions for different durations of ISIs  or several frequencies (power spectrum). However, the irregularity in the neuronal firing activity is not linear –51 sinceThe clinical relevance of these nonlinear features in neuronal discharge is not yet clear. Specifically, it is unknown whether the nonlinear dynamics of basal ganglia neurons are affected by the conditions of parkinsonism or dystonia. In retrospective analyses of a database of PD and dystonia neurons with temporal organizations (as defined in ), SanghePharmacological studies in primate models for movement disorders are needed to further investigate this hypothesis as their basal ganglia neuronal activity exhibits similar patterns to those seen in patients . In addiSince anti-Parkinsonian treatments decrease entropy and hyperkinetic conditions are associated with lower entropy, it is time to include the basal ganglia neuronal entropy as a putative interfering factor in the current model for the selection and the inhibition of motor information in the basal ganglia circuitry. Through exploring the current data framework available, we present a primary hypothesis on the nature of the GPi neuronal entropy regarding abnormal movement production.From the data discussed above, we hypothesize that high entropy in the GPi neuronal data stream is associated to an increased motor inhibition  while reduced entropy in the GPi neuronal data stream is envisaged as a feature for increasing motor selection  see . This hyThe relation between the entropy theory and the functions of the basal ganglia can be substantiated by the intrinsic (and logarithmic) relation between entropy and the correlation dimension . Since tThe use of nonlinear domain analyses to describe the neuronal and network activities inside the basal ganglia may provide new qualitative and quantitative information regarding the nature of the sensory-motor processing as well as its distortion in pathological conditions. It is expected that the inclusion of key nonlinear features into silicone-based models of the basal ganglia could better reproduce complex and nonstationary signals recorded in normal and pathological conditions. To date, the “entropy hypothesis” may be useful to initiate a debate on nonlinear dynamics in basal ganglia activity and their roles in the selection and inhibition of motor programs. Most importantly, these nonlinear analyses may contribute to reduce the gap between the basal ganglia models and the theories on the processing of motor information.


Auricular acupuncture has been utilized in the treatment of diseases for thousands of years. Dr. Paul Nogier firstly originated the concept of an inverted fetus map on the external ear. In the present study, the relationship between the auricular acupuncture and the vagal regulation has been reviewed. It has been shown that auricular acupuncture plays a role in vagal activity of autonomic functions of cardiovascular, respiratory, and gastrointestinal systems. Mechanism studies suggested that afferent projections from especially the auricular branch of the vagus nerve (ABVN) to the nucleus of the solitary tract (NTS) form the anatomical basis for the vagal regulation of auricular acupuncture. Therefore, we proposed the “auriculovagal afferent pathway” (AVAP): both the autonomic and the central nervous system could be modified by auricular vagal stimulation via projections from the ABVN to the NTS. Auricular acupuncture is also proposed to prevent neurodegenerative diseases via vagal regulation. There is a controversy on the specificity and the efficacy of auricular acupoints for treating diseases. More clinical RCT trials on auricular acupuncture and experimental studies on the mechanism of auricular acupuncture should be further investigated. Acupuncture is a part of traditional Chinese medicine (TCM). It has been accepted in China and has been used as one of the alternative and complementary treatments in western countries. Auricular acupuncture has been also used in the treatment of diseases for thousands of years. In the classic TCM text of Huang Di Nei Jing, which was compiled in around 500 B.C, the correlation between the auricle and the body had been described; all six Yang meridians were directly connected to the auricle, whereas the six Yin meridians were indirectly connected to the ear by their corresponding yang meridian, respectively . In HippNogier presented his discovery in several congresses and published it in an international circulation journal, which eventually led to the widespread acceptance of his approach. With some exceptions, the Chinese charts were very similar to Nogier's originals . The autonomic nervous system (ANS), which plays a crucial role in the maintenance of homeostasis, is mainly composed of two anatomically and functionally distinct divisions: the sympathetic system and the parasympathetic system. In terms of the influence of the parasympathetic system, the physiological significance of the vagus nerve is clearly illustrated by its widespread distribution . It conti6.7) point [Cardiac vagal postganglionic fiber endings release acetylcholine, which are bound with cholinergic M receptors on the myocardial cell membrane or vascular smooth muscle. Activation of the vagus nerve typically leads to a reduction in heart rate and blood pressure. Cardiovascular vagal regulations by auricular acupuncture have been investigated in clinical trials and animal experiments , 10–18. i) point . Acupunci) point .15) and cardiovascular regulation. In healthy volunteers, a significant decrease in heart rate and a significant increase in heart rate variability after manual ear acupressure at auricular acupoint CO15 have been shown [15 [15 produced marked short-term and long-term depressor effect as well as evident immediate effects on cardiac functional activities in grade II and grade III hypertension and marked effects on angiotensin II in grade III hypertension [Several investigations had focused on the relationship between auricular acupoint “Heart”  and a greater percentage change in normalized low frequency power of HRV, thus, it suggested that auricular acupuncture intervention led to more cardiac parasympathetic and less cardiac sympathetic activities, which contributed to the improvement of postmenopausal insomnia . 4 combined with other acupoints of Daimai (GB26), ST36, and Sanyinjiao (SP6) resulted in a net increase in vital capacity during the period of acupuncture analgesia which lasted for 3 to 4 hours after stimulation [In a controlled single-blind study, a significant decrease in the olfactory recognition threshold by auricular acupuncture at the auricular “Lung” point was found in 23 healthy volunteers . Bilatermulation . In fourmulation . Increase in intragastric pressure has been induced by auricular acupuncture in rats . By compThe auricle is innervated by cranial nerves and spinal nerves. Innervations of at least four nerves supply the anterior auricle: the auriculotemporal nerve, the auricular branch of the vagus nerve (ABVN), the lesser occipital nerve, and the greater auricular nerve. The auriculotemporal nerve is a mandibular branch of the trigeminal nerve, which mainly supplies the anterosuperior and anteromedial areas of the external ear. The auricular branch of the vagus nerve, which is the only peripheral branch of the vagus nerve, mainly supplies the auricular concha and most of the area around the auditory meatus. The lesser occipital nerve mainly innervates the skin of the upper and back parts of the auricular. The greater auricular nerve (GAN) from the cervical plexus supplies both surfaces of the lower parts of the auricle. The innervation of the auricle is characterized by a great deal of overlap between multiple nerves  see Fig. Both Chinese and Western researchers have recognized the relationship between the auricle and vagal regulation. Arnold's reflex was first described in 1832 by Friedrich Arnold, professor of anatomy at Heidelberg University in Germany. It is one of the somato-parasympathetic reflexes. Physical stimulation of the external acoustic meatus innervated by the ABVN elicits a cough much like the other cough reflexes induced by vagal tone. There were also clinic reports on vagal tone responses such as cardiac deceleration and even asystole and depressor response, induced by stimulations including cerumen cramming in auditory canal or auricular concha , 24. EngThe anatomical relationship between the ABVN and the nucleus of the solitary tract (NTS) has been investigated. After applying horseradish peroxidase (HRP) to the central cut end of the ABVN in the cat, some labeled neuronal terminals were seen in the interstitial, dorsal, dorsolateral, and commissural subnuclei of the NTS; some of these terminals may be connected monosynaptically with solitary nucleus neurons which send their axons to visceromotor centers in the brainstem . 15 activates the cardiac-related neurons in the NTS to evoke cardiovascular inhibition, whereas the inactivation of the NTS with local anesthetics decreased the cardiovascular inhibitory responses evoked by auricular acupuncture [The auricular concha is mainly innervated by the ABVN. The relationship between the acupuncture stimulation at auricular concha and the NTS has also been investigated. In an animal study, acupuncture stimulation at auricular concha induced the hypoglycemic effect by activating the firing activities of the neurons in NTS . It is apuncture . Recently, it is suggested to assess the function of the vagus nerve through transcutaneous electric stimulation of the ABVN innervating parts of the ear. The 8 mA stimulation was performed at five different electrode positions at the subject's right ear. A clear, reproducible vagus sensory evoked potential (VSEP) was recorded after stimulation at the inner side of the tragus of the right ear, instead of the other stimulation positions at the lobulus auriculae, the scapha, thecus antihelices superior, and the top of the helix. It is considered that cutaneous stimuli of this region are transported via the auricular nerve to the jugular ganglion and from there with the vagus nerve into the medulla oblongata and to the NTS . AlthougThe NTS in the brainstem carries and receives visceral primary afferent signals from a variety of visceral regions and organs. Neurons that synapse in the NTS participate into the autonomic reflexes, with a result to regulate the autonomic function. Outputs that go from the NTS are transferred to a large number of other regions of the brain including the paraventricular nucleus of the hypothalamus and the central nucleus of the amygdala as well as to other nuclei in the brainstem . Perhaps, extensive connections between the NTS with visceral organs and other brain structures  may elucTherefore, we proposed the “auriculovagal afferent pathway” (AVAP); both the autonomic and the central nervous system could be modified by auricular vagal stimulation via projections from the ABVN to the NTS see . The nuclei of the vagus nerve in the brainstem have been implicated as one of the earliest regions in the pathophysiological process of both Alzheimer's and Parkinson's diseases. Far-field potentials from brainstem after transcutaneous vagus nerve stimulation at the auricle have been utilized as a noninvasive method in the early diagnosis of neurodegenerative disorders –33. We sVagus nerve stimulation has been approved by FDA as an alternative treatment for neuropsychiatric diseases such as epilepsy and depression. In order to avoid the disadvantages of cervical vagus nerve stimulation, less invasive methods including transcutaneous vagus nerve stimulation –36 and e15, but not Stomach (CO4), produced depressor effect on vascular hypertension [Several studies investigated the specificity of auricular acupoints. Parts of the studies agree on the concept that specific areas of the ear are related to specific areas of the body. Acupuncture at COrtension , 42. Spertension , 44. There is still disagreement on the specificity of auricular acupoint. Similar patterns of cardiovascular and gastric responses could be evoked by stimulation at different areas of the auricle, which do not support the theory of a highly specific functional map in the ear . AuriculThere are inconsistent study results related to the treatment effects of auricular acupuncture, which may be related to trial designing, clinical observation measures, the set of sham acupuncture, and statistical analyses –48. In c


Memory T and B lymphocytes and long lived plasma cells represent a repository of the antigenic experience of an individual. By analyzing the specificity and function of these cells we can gain insights into the human immune response and identify mechanisms of protection and immunopathology. We have developed methods to dissect the functional heterogeneity and antigenic repertoire of human T cells, B cells and plasma cells. These methods are used: i) to identify subsets of effector and memory T cells with distinct roles in immune surveillance and protection in different tissues against different classes of pathogens, and ii) to dissect the relative role of plasma cells and memory B cells in the antibody response to pathogens and to isolate broadly neutralizing antibodies. A better understanding of the class and specificity of the human immune response will be instrumental to guide the design of effective vaccines.


Multi-electrode recordings allow the recording of the activity of a neural population of tens to hundred cells over periods of hours. Two examples are given by the recording of the activity of ganglion cells in the retina -3,6 , anIn the present work we propose a new and efficient algorithm to infer fields and pairwise couplings of an Ising model from the data. Our procedure considerably improves over the algorithm presented in  and is bij inferred from Dark and Flicker. We have found that most of the couplings are conserved under the two stimuli but some pairs of neurons with large interactions in Flicker have weak couplings in Dark. We have used the inferred couplings to draw retinal maps in the receptive fields plane of the cells. For Dark, the largest coupling map define a planar graph with short range  connections. For flicker the strong non conserved couplings pointed out in the previous paragraph often are long-range interactions.Our procedure has been validated on synthetic data sets, and used to re-analyze multi-electrode recordings of neural cells of the activity of salamander ganglion cells previously published in ,6 and ofWe will discuss some important aspects of the Ising model such as: How do couplings change with the removal of cells from the recording? What temporal correlations are neglected in the Ising model (dependence on the bin size Dt)? How do couplings inferred with a dynamical model (Integrate and Fire) compare with Ising couplings ?


Low-dimensional attractive manifolds with flows prescribing the evolution of state variables are commonly used to capture the lawful behavior of behavioral and cognitive variables. Neural network dynamics underlie many of the mechanistic explanations of function and demonstrate the existence of such low-dimensional attractive manifolds. In this study, we focus on exploring the network mechanisms due to asymmetric couplings giving rise to the emergence of arbitrary flows in low dimensional spaces. Here we use a spiking neural network model, specifically the theta neuron model and simple synaptic dynamics, to show how a qualitatively identical set of basic behaviors arises from different combinations of couplings with broken symmetry, in fluctuations of both firing rate and spike timing. We further demonstrate how such network dynamics can be combined to create more complex processes. These results suggest that 1) asymmetric coupling is not always a variance to be averaged over, 2) different networks may produce the same dynamics by different dynamical routes and 3) complex dynamics may be formed by simpler dynamics through a combination of couplings. The mechanistic explanations employed in behavioral, cognitive and neural sciences often take the form of network models and their dynamics. Various signatures of nonlinear dynamical phenomena are ubiquitous in these disciplines, e.g. phase transitions, pattern formation and time-scale separation. Yet, in the literature, one does not find a systematic account of the relationship between the emergence of the dynamics of behavioral and cognitive processes and the dynamics of the underlying neural networks and their structural properties. We argue here that such an account of the structure-function relationship begins by understanding the different ways the structure of a neural network leads to its collective dynamics. In particular, we focus on the contributions of network connectivity as a means to control the emergence of arbitrary low-dimensional dynamics.The nonlinear nature of human perception and action dynamics is well documented, with the early example of the Necker cube. In general, hysteresis and autonomous switching in cases of perceptual ambiguity have been modeled in terms of a bistable system Recent examples from neuroscience are available on the temporally extended neural processes underlying such behaviors. For examples, Graziano and colleagues stimulate a local ), which themselves can be dynamically complex, nonlinear, multistable and display all the features of behavior known from cognitive sciences. Perdikis and colleagues proposed such SFMs as building blocks for cognitive architectures Two important forms of degeneracy are present in the network models in this work: First, for any given process a network may generate, the mapping of the generating dynamical mechanism onto a connectivity matrix may be achieved by many different structural configurations. This degeneracy is systematic and reflected mathematically by the adjoint mapping of To account for the structure of more complex behaviors, it becomes necessary to understand how basic processes or primitives may be constituents of complex behaviors. In nonlinear or non-modular systems, compositionality is a nontrivial problem. The presupposition of timescale hierarchy allows for the decomposition of complex dynamics into simpler dynamics on multiple temporal scales. Such decomposition may either occur in parallel, which will give rise to two mutually coupled subsystems forming a hierarchy; alternatively the decomposition may occur sequentially (such as in the coexistence of slow and fast manifolds in the system dynamics), which will give rise to serial behaviors on different timescales (fast-slow). We showed the effectiveness of the former in the last simulation where control signals on a slow timescale reshape the effective phase space of the network; this reshaping produces produces transitions in the qualitative dynamics produced by the network that can then be identified by examining the changes in principal components over time. When applied in combination with sequential dynamics, phase space reshaping of SFMs may rapidly yield complex articulated processes, suggestive of how such processses may be structured in behavior.Recent work Another formulation of how behavioral dynamics are embedded in neural networks has been extensively developed by Schöner and colleagues The more general framework of liquid state computing, recently outlined in This has been clearly identified in the work of At the macroscopic level of the brain, lines of research have developed that coincide theoretically with the results presented here. In particular, the theory of neurocognitive networks As an illustrative example of a functionally meaningful process in behavioral neuroscience, we examine the production of simple movements, where it has been suggested that multistability, limit cycle and monostability form a fundamental set of classes of behaviors We derive different possible implementations of the basic dynamics discussed above in terms of the firing rate and spike timing patterns, and connectivity. We begin with a spiking state variable Such phase models are obtained using standard techniques in nonlinear oscillator theory In Putting the neuron in a network context, we introduce an additional term in the coefficient of In order to analyze the rate dynamics of We will also consider a reduction of the network relevant to short timescales based on the assumption To derive the phase locking attractors in a network, we use the set of conditions that for any pair of neurons In general, the existence conditions yield simple stability results whose structure does not depend on the details of the phase response curve. In order to apply such results to In order to obtain a phase response curve, we start with the definition of the perturbed period Figure S13D network dynamics: Analogously with A fixed point, B limit cycle, C bistability, and D monostability.(TIFF)Click here for additional data file.Figure S2Excitator flows: The behavior of an Excitator system is shown here for bistable, limit cycle and monostable dynamics  in the phase space (top) and the time series (bottom). Red lines in the phase space are the nullclines of the system, while black lines show how the phase flows with time on example trajectories.(TIFF)Click here for additional data file.Figure S3Theta neuron dynamics:A Firing rate as a function of input for the theta neuron described in the text. Two circles give the input and rate for the two sample simulations shown on the right. B, C Time series from simulations of (TIFF)Click here for additional data file.Figure S4Rate reduction approximation The assumption of the rate reduction in the text is that the mean firing rate captures the relevant information in a spike train. Here we show in A and B, respectively, cases of low and high firing rates. Upper panels show in blue, red and green curves the omega dynamics time series under a mean firing rate, equal interspike interval (ISI) spike train and Poissonian spike train. Bottom plots show the log sum squared error of the mean firing rate time series with respect to that of equal ISI and Poissonian spike trains in green and blue.(TIFF)Click here for additional data file.Figure S5Phase response curves:A The phase response curve is found by perturbing the post synaptic neuron with a single presynaptic spike which produces a jump in the phase of the post synaptic oscillator. The black traces show the pre and post synaptic neurons B and C corresponding to positive and negative coupling values, respectively. Both are bimodal, however for both the stronger knee reflects the sign of coupling. The gray lines show the same response curve assuming the phase is linear with time.(TIFF)Click here for additional data file.


After publication of this work , we haveThe University of Georgia has filed a United States provisional patent on this technology.YY and RJ conceived the study. RJ performed the experiments under the guidance of YY. An equal contribution by YY and RJ was made for literature review and drafting of the manuscript. Both authors read and approved the final manuscript.


The proposed method evaluates the changes in the collection of activated or suppressed signaling pathways involved in aging and longevity, termed signaling pathway cloud, constructed using the gene expression data and epigenetic profiles of young and old patients' tissues. The possible interventions are selected and rated according to their ability to regulate age-related changes and minimize differences in the signaling pathway cloud. While many algorithmic solutions to simulating the induction of the old into young metabolic profiles in silico are possible, this flexible and scalable approach may potentially be used to predict the efficacy of the many drugs that may extend human longevity before conducting pre-clinical work and expensive clinical trials.The major challenges of aging research include absence of the comprehensive set of aging biomarkers, the time it takes to evaluate the effects of various interventions on longevity in humans and the difficulty extrapolating the results from model organisms to humans. To address these challenges we propose the  The increasing burden of the aging on the economies of the developed countries is turning the quest to increase healthy life spans from an altruistic cause into a pressing economic priority required to maintain the current standards of living and facilitate economic growth , provided clues that transcription profiles of cancer cells mapped onto the signaling pathways may be used to screen for and rate the targeted drugs that regulate pathways directly and indirectly related to aging and longevity. Instead of focusing on individual network elements, this approach involves creating the signaling pathway cloud, a collection of signaling pathways involved in aging and longevity each comprised of multiple network elements and evaluating the individual pathway activation strength. Despite significant advances in aging research, the knowledge of the aging processes is still poor, and combining all available factors involved in cellular aging, aging of the organisms, age-related diseases, stress-resistance, and stress-response along the many other factors into a comprehensive signaling pathway cloud may be more beneficial than focusing on the narrow collection of elements. The creation of the pathway cloud may allow for the annotated databases of molecules and other factors to be screened for effectiveness of individual compounds in replicating the “young” signaling activation profiles in silico.Our prior work with gene expression and epigenetics of various solid tumors  and naked mole rat  that senesce at a slower rate than members of the same order show less transcriptome changes with age  from 10 to 200%. We converted the obtained gene lists from different models to the general list of human orthologs where it is possible. 226 genes of 315 from our set were subjected to over-representation pathway analysis in , general metabolism , RNA transport, cell cycle and meiosis, gap junction, peroxisome, cyrcadian rhythm, different synapse types , gastric acid secretion as well as age-related diseases pathways , Hepatitis B, HTLV-I infection and cancer pathways . We considered obtained such a way pathways as probably associated with the human longevity. Human genes known as key activators/repressors of these pathways may be used in provided further mathematical model.SPCD) is proportional to the following estimator function,AGEL]i and [RGEL]j are gene expression levels of an activator i and repressor j, respectively. To obtain an additive rather than multiplicative value, it is enough just turn from the absolute values of the expression levels to their logarithms, arriving at the pathway activation strength (PAS) value for each pathway -to-Young ratio, YORn, one just has to divide the expression levels for a gene n in the sample taken for the senescent person by the same average value for the normalized young group. The discrete value of ARR (activator/repressor role) equals to the following numbers:The methods that may be applied for the possible analysis of geroprotector efficiency by pathways regulation have been arisen from our research experience of cell signaling pathways. As far as we have seen before  equals to zero when the OYR value lies within the tolerance limit, and to one when otherwise. During the current study, we have admitted that the OYR lies beyond the tolerance limit if it satisfies simultaneously the two criteria. First, it either higher than 3/2 or lower than 2/3, and, second, the expression level for a corresponding gene from an old patient of an individual patient differs by more than two standard deviations from the average expression level for the same gene from a set of analogous young tissue/organ samples.The Boolean flag of in vivo and in vitro may be expanded to identify and predict the efficacy of personalized aging-suppressive intervention regimens for individual patients based on the transcriptome information from various tissue biopsies and blood samples.We propose a new computational approach for identifying and rating the variety of factors including small molecules, peptides, stress factors and conditions with the known effects on the transcriptomes at different ages of one or more cell or tissue types or known targets Figure . The appPAS values for the general set of the pathways as close to zero as possible. Since many of the drugs approved for use in humans have known molecular targets and some have been screened for the impact on longevity in model organisms  for each individual pathway Figure  and consin silico screening and ranking of drugs and other factors that act on many signaling pathways implicated in aging processes by calculating their ability to minimize the difference between signaling pathway activation patterns in cells of young and old patients and confirming the results using in vivo and in vitro studies.Longevity studies of aging-suppressive drug efficiency in higher mammals take several years and decades and may cost millions of dollars. An intelligent process for predicting the activity and ranking the geroprotective activity of various factors and strengthening the prediction in rapid and cost-effective studies on cell cultures and model organisms may help increase the longevity dividend of these studies. In this paper we propose a method for 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.


A number of new data were obtained concerning the relationship of nitrogen oxide metabolism and C-reactive protein formation, clinical course of rheumatoid arthritis. For the first time a complex approach was suggested for the pathogenic justification of simvastatin use in the scheme of conventional treatment to increase the therapy efficiency, to achieve stable early remission in patients with rheumatoid arthritis. It was proved that an important mechanism of increasing the therapeutic efficiency of simvastatin was its action on the system of endothelial function in blood and joint fluid. It was suggested that one should include assessment of blood and joint fluid for nitrogen oxide, nitrate diaphorase and nitrate reductase in the algorithm of investigation and dynamic observation, choice of tactics and therapy efficiency assessment.Obtained new data are necessary for increasing the pharmacotherapy efficacy in patients with rheumatoid arthritis taking into account the metabolic activity of NO-synthetase mechanism in blood and synovial fluid. An algorithm was suggested for screening observation and differentiated management of patients with rheumatoid arthritis taking account of severity of nitrogen oxide metabolism disorders. A differentiated approach was worked out and justified of simvastatin prescription both to increase the efficacy of treatment taking into account the clinical activity of the disease and to correct metabolic disorders in patients with rheumatoid arthritis.


Freezing of gait (FOG) is a disabling symptom of advanced Parkinson's disease (PD) that leads to an increased risk of falls and nursing home placement. Interestingly, multiple lines of evidence suggest that the manifestation of FOG is related to specific deficits in cognition, such as set shifting and the ability to process conflict-related signals. These findings are consistent with the specific patterns of abnormal cortical processing seen during functional neuroimaging experiments of FOG, implicating increased neural activation within cortical structures underlying cognition, such as the Cognitive Control Network. In addition, these studies show that freezing episodes are associated with abnormalities in the BOLD response within key structures of the basal ganglia, such as the striatum and the subthalamic nucleus. In this article, we discuss the implications of these findings on current models of freezing behavior and propose an updated model of basal ganglia impairment during FOG episodes that integrates the neural substrates of freezing from the cortex and the basal ganglia to the cognitive dysfunctions inherent in the condition. Freezing of Gait (FOG) is a common disabling symptom of Parkinson's disease (PD) that typically manifests itself as a sudden inability to walk, despite the intention to move forward , the STN and the MLR  and the bilateral ventral striatum , the STN is able to bypass the striatum and directly drive an increase in inhibitory GABAergic output from the output structures of the basal ganglia, such as the internal segment of the GPi. Increased activity in the GPi, which is a member of the direct pathway of the basal ganglia, leads to an increase in the rate of inhibitory output onto the brainstem and thalamic structures that control the output of effective motor behaviors Frank,  see Fig. Given iGiven the specific patterns of connectivity within the basal ganglia circuitry, the likely sequelae of impaired striatal activity is that the output structures (the GPi internus and the substantia nigra pars reticularis) will enter into low-energy oscillatory states, coupling with structures such as the STN (Buzsáki and Draguhn, These proposed roles of the STN are well supported by behavioral (Aron and Poldrack, The oscillating inhibitory state of the basal ganglia nuclei may also explain the poorly understood phenomenon of “trembling in place,” which refers to lower limb oscillatory activity in the 5–7 Hz range commonly observed during episodes of FOG (Moore et al., One of the major implications of this model is that freezing is best conceptualized as a functional disorder that only manifests once certain circumstances have occurred. This raises an interesting question regarding the likely location of pathology in the brains of patients with PD and freezing behavior. Based on the model, any pathological process that impaired the capacity of the brain to deal with information processing, and thus, to manifest increased conflict signaling would lead to an increase in freezing behavior.Although there are many regions of the brain in which pathology would lead to increased global conflict, the most likely candidates are the ascending neurotransmitter projection systems of the brainstem, such as the ventral tegmental area, the locus coeruleus, and or the dorsal raphe nucleus. Each of these nuclei sends modulatory neurotransmitters to large portions of the brain, including both cortical and subcortical sites involved in walking and executive function. Indeed, these regions are often the target of Lewy body pathology (Rye and DeLong, Another possible candidate region is the PPN (Mazzone et al., It is also possible that the proposed increase in STN oscillatory activity is due to a dysfunctional process within the pSMA (see Figure Although the separate predictions of these different hypotheses may be difficult to dissociate with fMRI, measures with higher temporal resolution may help to clarify the precise role of each structure in the spatiotemporal evolution of a freezing episode. As such, future studies should now be constructed to test the different aspects of this model using an array of neuroscientific techniques. Firstly, activity within the STN and PPN could potentially be recorded directly during DBS surgery, allowing for the analysis of the time course of activation and deactivation patterns within the different nuclei with respect to freezing behavior. Future neuroimaging experiments should explore the presence or absence of impairments in functional and effective connectivity associated with the predictions of the model, with a particular emphasis on the dynamic connectivity between cortical and subcortical structures. Finally, computational modeling experiments could be designed in order to probe the dynamic elements of the model, focusing on whether abnormal conflict processing through the STN can predict the specific behavioral patterns displayed on different neuropsychological and motor-based tasks by patients with freezing. Together, the results of these studies will help to inform the next generation of therapeutic advances for freezing behavior in PD, including the utilization of targeted closed-loop DBS (Rosin et al., 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.


Breast cancer is a major health problem among women in the world. The successful treatment of this disease is limited by the fact that essentially all breast cancers become resistant to chemotherapy. Therefore, there is a need to design new chemotherapeutic agents able not only to target breast cancer but also to display increased efficacy and overall decreased systemic toxicity. Platinum (II) complexes are widely used in cancer chemotherapy. The most important platinum-based drugs are cisplatin, carboplatin, the first platinum (II) derivatives entering the market, and more recently oxaliplatin, nedaplatin, iobaplatin, heptaplatin and picoplatin The computer-aided calculations are commonly applied to rational design of many pharmacological group of drugs. Platinum based cytostatics are one of the exceptions. The correlation between antiproliferative activity and molecular descriptors of Pt-drug analogues of clinically used complexes are present in this work. The main goal of this study was to show the relations between hydrophobicity and biological activity in the series of neutral platinum (II) and platinum(IV) complexes. The object of the study is several groups of analogues of oxaliplatin and picoplatin complexes, with N-donors ligands . The influence of the type and the positions of the substituents on the conformational energies and thermodynamic stabilities of a series of platinum (II) and platinum (IV) complexes has been studied by molecular mechanics. The calculations were carried out for the ligand conformations. The obtained energies and thermodynamic stabilities are in agreement with experimental data on the reactivity and antitumor activity of the compounds.


During this rather short time, he together with Emil von Behring discovered the causative pathogens of tetanus and diphtheria and contributed substantially to our basic understanding of the interaction of the immune system and invading pathogenic microorganisms In keeping with the tradition of Kitasato, a major theme of the symposium will be the translation of basic science principles into understanding human disease. The keynote lecture of the 2011 Kitasato symposium will be delivered by Antonio Lanzevecchia (Belinzona/Switzerland) who has contributed many novel insights into understanding of immune regulation and host defense. His lecture is entitled "Dissecting the human immune response to pathogens".After successful meetings in 2009 and 2010, an international faculty of largely immunologists and rheumatologists will gather in Potsdam on September 22This year's Kitasato Symposium will be a joint meeting with the Research Collaborative Consortium (Sonderforschungsbereich) 650 "Cellular approaches to the suppression of unwanted immune reactions - from bench to bedside". As in previous years, the Kitasato symposium will focus on mechanisms of autoimmunity and tolerance emphasizing the role of cytokines. A deeper understanding of these aspects and adapyive and innate immunity has paved the way to innovative therapies for autoimmune disease within the last decade, especially in rheumatoid arthritis  and very recently in systemic lupus erythematosus (BAFF/BLyS blockade).In specific sessions, the role of tolerance in autoimmunity as well as transplantation, signaling pathways in cytokine stimulation, the analysis of new cytokine targets, and the translational of cytokine biology into human disease will be discussed. The Symposium will especially focus on novel developments within the last few years with the promise of yielding new targets for therapy. In addition, insights on disease biology developing from the clinical use of biologis will be highlighted.It is the promise of the meeting to provide new perspectives of basic, translational and clinical research in the field serving the ultimate goal of improving the treatment of patients. The collection of the individual contributions is summarized in the following abstract supplement.


With the gradual development of intelligence, human got curious to know his origin and evolutionary background. Historical statements and anthropological findings were his primary tool for solving the puzzles of his own origin, until came the golden era of molecular markers which took no time to prove it’s excellence in unveiling answers to the questions regarding the migration pattern of human across different geographical regions. As a bonus these markers proved very much beneficial in solving criminal offenses and in understanding the etiology of many dreaded diseases and to design their prevention. In this review, we have aimed to throw light on some of the promising molecular markers which are very much in application now-a-days for not only understanding the evolutionary background and ancient migratory routes of humans but also in the field of forensics and human health. Since the origin, spread of mankind across the world has always been an emerging area of interest for modern biologists. Humans migrated “out of Africa” to other geographical locations around the world and eventually diversified into distinct human races populating distinct geographical regions. Human diversity did not only remain restricted to their socio-cultural and linguistic domains but also have penetrated deep inside their genetic root. The wealth of genetic/allelic diversity is not only an excellent resource for human diversity studies but also is highly informative for the study of human genetic predisposition of various diseases . Thus thSince human genome varies from individual to individual, no two individuals are alike genetically or phenotypically. With the development of various molecular techniques the application of genetics to the study of human evolution gave rise to the fields of molecular evolution and molecular anthropology. Various informative and polymorphic genetic markers were discovered and the gene frequency data emerging out from their analyses largely contributed to the successful study of evolution and diversity of human races worldwide. The use of a good number of uniparental and biparental markers for genetic diversity studies is a recent trend in which Y-haplogroup, mitochondrial DNA (mtDNA), human leukocyte antigen (HLA) and killer-cell immunoglobulin-like receptor (KIR) are the promising ones. The inheritance pattern emerging out from the analyses of these markers stirred a debate on the validity of two distinct models of human dispersals since their inception more than 25 years ago .Homo sapiens, distributed throughout the Old World and all regional populations were connected by gene flow as they are today. Some skeletal features developed and persisted for varying periods in the different geographical regions justifying the development of recognizable regional morphologies in the continents of Africa, Europe, and Asia. On the other side, the “recent out of Africa” model  which according to The application of mtDNA to trace the evolutionary pattern and the migration events in human is based on the fact that certain haplotypes are observed in peoples of certain geographical regions of the World  on the Y chromosome. There is now extensive knowledge regarding the geographic origins of Y-SNPs based on studies of global populations . BecauseY haplogroup diversity has been carried out by Earlier studies indicated that Y-chromosome polymorphisms were geographically restricted and that FST values for the NRY were higher than those for mtDNA . Hammer Additionally, Y-chromosome microsatellites find extensive application in forensic researches whereby databases of population haplotype frequencies are established for Europe, the United States and for Asia. Y microsatellite analysis provides assailant specific profile during diagnosis of the rape case when the rapist is mainly azoospermic . PaterniThe major histocompatibility complex (MHC)/HLA is unique in that it is the most polymorphic genetic system in the human genome and the only system to display functional polymorphism . Due to Human leukocyte antigen polymorphism study has been carried out in many of the ethnic populations of India including the primitive tribal group Toto . DebnathApart from being an invaluable tool for population genetic studies, MHC polymorphism has important role in organ transplantation and human disease associations. HLA associations have also helped in defining syndromes of disease categories having common/shared pathogenic mechanism like ankylosing spondylitis and related spondylo-arthropathies that are presumed to be associated with HLA-B27. HLA association studies in infectious and autoimmune diseases show the presence of susceptibility and protective alleles in populations of different ethinic origins . HLA assHuman leukocyte antigen associations with diseases vary in different populations. Disease predisposing genes and their molecular subtypes could help to determine and predict the incidence of the diseases in some populations. It is therefore important to have a population based database of HLA alleles and their frequencies of prevalence in healthy individuals so that disease predisposing influence of a particular phenotype could effectively be assessed in the populations.Being a functionally a polymorphic system, investigations into the distribution of MHC alleles in world populations are very important in this regard since the MHC genetic makeup of each of these populations would reflect interplay of both the basic genetic origin and effects of natural phenomenon such as founder effect and environmental selection. Differences in the prevalence of HLA alleles in different populations in varied environmental conditions could be utilized to assess the role of each of these alleles in conferring survival advantage to human populations.Killer-cell immunoglobulin-like receptors were first described by Immunogenetic studies based on KIR genes in different ethnic populations around the world show significant differences in the distribution of group A and B haplotypes. Whereas in the Japanese population group A genotypes  were found at frequencies well above 50%, only a single individual out of 67 exhibited a group A genotype in a survey among Australian Aborigines ,b.The KIR frequencies of many of the ethnic populations were analyzed worldwide. In one such work, KIR gene profile was studied for the Rajbanshi population, an essential caste population of Sub-himalayan part of north-eastern India . It was Figure 3 (adopted from The frequencies of the inhibitory KIR genes in most of the world population groups are very high except those on the B haplotypes, i.e., KIR2DL2, KIR2DL5A, and KIR2DL5B. Detailed analysis revealed that indigenous populations such as aborigines and Amerindians have outlying frequencies of the KIR genes. Obviously there is a close inverted correspondence between the frequencies of KIR3DL1 and KIR3DS1 genes in an individual population. Based on KIR haplotype B genes In humans, KIRs recognize HLA class I proteins leading to the inhibition or activation of cytotoxic cell activity and cytokine production by T and NK cells thus focusing on the role of these receptors in immunological responses of NK cells . The intHuman have developed their interest in unveiling the mysteries of human migratory pattern and evolutionary trends since his origin. These above mentioned markers are serving the scientific world to trail back through time to understand the dispersal pattern of humans. To add to their importance, these markers are also responsible for understanding the underlying etiology of certain disease pathogenesis. Application of these markers especially Y-SNPs in forensics has been an interesting achievement in the past decade. Apart from these markers, a group of recently emerging markers which are gaining the attention of the researchers all over the world are the toll-like receptors TLRs; . In addiThe authors declare that the research was conducted in the absence of any commercialor financial relationships that could be construed as a potential conflict of interest.


Many ecosystem services provided by forests are important for the livelihoods of indigenous people. Sacred forests are used for traditional practices by the ethnic minorities in northern Thailand and they protect these forests that are important for their culture and daily life. Swidden fallow fields are a dominant feature of the agricultural farming landscapes in the region. In this study we evaluate and compare the importance of swidden fallow fields and sacred forests as providers of medicinal plants among the Karen and Lawa ethnic minorities in northern Thailand.We made plant inventories in swidden fallow fields of three different ages  and in sacred forests around two villages using a replicated stratified design of vegetation plots. Subsequently we interviewed the villagers, using semi-structured questionnaires, to assess the medicinal use of the species encountered in the vegetation survey.We registered a total of 365 species in 244 genera and 82 families. Of these 72(19%) species in 60(24%) genera and 32(39%) families had medicinal uses. Although the sacred forest overall housed more species than the swidden fallow fields, about equal numbers of medicinal plants were derived from the forest and the fallows. This in turn means that a higher proportion (48% and 34%) of the species in the relatively species poor fallows were used for medicinal purposes than the proportion of medicinal plants from the sacred forest which accounted for 17–22%. Of the 32 medicinal plant families Euphorbiaceae and Lauraceae had most used species in the Karen and Lawa villages respectively.Sacred forest are important for providing medicinal plant species to the Karen and Lawa communities in northern Thailand, but the swidden fallows around the villages are equally important in terms of absolute numbers of medicinal plant species, and more important if counted as proportion of the total number of species in a habitat. This points to the importance of secondary vegetation as provider of medicinal plants around rural villages as seen elsewhere in the tropics. Ecosystem services and goods have received much attention in recent years. Typically services and goods include 1) supply of valuable commodities and materials such as agricultural-, forest-, mineral-, and pharmaceutical products, 2) support and regulation of environmental conditions through flood control, water purification, pollination, and a number of other similar processes and 3) provision of cultural and aesthetic benefits that may also be the basis for ecotourism [As in many tropical regions, shifting cultivation is a major land use system in northern Thailand and it is a major driver of deforestation in the upland areas ,3. AboutSacred forests are segments of the landscape that represents old traditions of preserving climax forest patches based on local culture and religious beliefs and they are found throughout the world. A sacred forest represents a functional link between cultural life and the forest management system of a region. Sacred forests have been studied in many parts of the world including Africa, , China , and espSimplistic views of ethnoecological relationships between ethnic groups and their surrounding ecosystems often view the untouched virgin species rich forests as the main provider of useful plants, whereas secondary vegetation is often seen as degraded and useless. A growing body of evidence however points to these secondary recovering ecosystems as important providers of useful plants. Examples of how secondary vegetation make important contributions to the provision of useful plants come from the Amazon and the Atlantic forests in South America -26 and fThe study area is in Mae Cheam watershed in northern Thailand approximately 75 km southwest of the city of Chiang Mai. This watershed is important for its biodiversity and its varied forest types and vegetation and in addition it is inhabited by several ethnic minority groups . Our stuWe established sampling plots around both villages in 2009 and 2010 in the sacred forest and swidden fallow fields of various ages . Three plots (20 × 40 m) were laid out parallel to contour lines and these three plots were replicated in each habitat. In the 24 plots  all plant species were collected and later identified at the Queen Sirikit Botanic Garden Herbarium (QSBG) with the help of taxonomic specialists J. F. Maxwell and M. Norsaengsri. Voucher specimens are deposited at the herbaria of the Department of Biology, Chiang Mai University and at Queen Sirikit Botanic Garden Herbarium (QSBG), Chiang Mai, Thailand. Based on species lists derived from the vegetation surveys of each habitat type, ethnobotanical data were gathered between August, 2011 and February, 2012 using semi-structured interviews. Our informants were villagers who were born and had always lived in the communities and their ages ranged from 15–84 years. Photographs of plants and freshly collected material from the swidden fallow fields and sacred forest were shown to the informants following established interview techniques ,36. The Jaccard’s Index (JI) was used to determine the similarity of medicinal plants species , which ia is the number of species unique to area A and b is the number of species unique to area B, and c is the number of species found in both areas.Where Use Value was calculated to determine the most important medicinal plant species in each habitat ,Ui is the number of use-reports cited by each informant for a given species in each habitat and N is the total number of informants.Where Linear regression was done to account for correlated responses between the age of fallow fields and total number of medicinal plants in each sampling sites. Chi-square test was used to analyze differences between habitat and number of medicinal plants species in the two villages and to analyze if the sources of medicinal plants depend on the habitat. All analyses were done with the SPSS 16.0 software package for Windows.In total we registered 365 species, 245 in the Karen village and 240 in the Lawa village. The highest species richness was found in the sacred forests of both villages and the lowest number of species was found in the youngest (1–2 years old) fallow fields  nor when the villages were tested separately . Linear regression test in both villages showed that the age of the fallow fields was a weak factor and had negatively significant effect on the total number of medicinal plants  and also negative effect in each village but without significant differences . This explains that the age of fallow did not affect the total number of medicinal plants. So although the sacred forest is much older and richer in species than the fallow fields, they do not provide higher number of medicinal plant species  also when the village were tested separately .Because the four habitat types provide roughly similar numbers of medicinal plants even if their overall species richness is significantly different, the proportion of the species that is used medicinally of a given habitat is greatly different. The young 1–2 years) fallow fields have few species but 48% and 34% of them are used medicinally by the Karen and the Lawa, respectively. In the species rich sacred forests, in contrast, only 22% and 17% of the species are used medicinally (Figure –2 years etc. It is interesting that the most recently abandoned field, i.e., the swidden fallows that are 1–2 years old, have the highest proportion of their species being used medicinally. This preference for using secondary vegetation as a source of medicinal plants has previously been demonstrated in the Atlantic Forest of Brazil [The swidden fallow fields of different ages of regeneration and the sacred forests provided about equal numbers of medicinal plant species to the two villages. This is surprising when seen in the light of the much higher overall species richness of the sacred forest compared to the surrounding swidden fallow fields. The more intense use of the secondary vegetation of the fallows may be because they are closer to where the villagers have their houses. Another possible explanation may be discouragement coming from the village council’s desire to conserve the sacred forest. The fallow fields, in contrast, are part of the productive land surrounding the villages and the swidden fallows belong to individual villagers which eliminates any problem related to ownership, f Brazil  and alsof Brazil , in dry f Brazil  and in Vf Brazil . It appeSacred forest and their surrounding fallow fields of different age of regeneration provided approximately the same number of medicinal plant species to both villages. Because the fallow fields were less species rich, the proportion of their species with medicinal uses was consequently higher. Sacred forests are conserved as community forest and they make up a network of protected forest in northern Thailand . NeverthThe authors declare that they have no competing interests.The article was initiated by AJ, who recorded and analysis data and prepared the first write-up of the manuscript. HB has critically edited and shaped subsequent versions. AI, AJ, PW have read and approved the final version of the manuscript. All authors read and approved the final manuscript.AJ is a PhD student at the University of Chiang Mai, Thailand, under supervision of associate professor PW and co-supervision of AI and AJ, assistant professors at University of Chiang Mai and members of the Ethnobotany research group. HB is professor at Aarhus University, Bioscience, and functions as external supervisor to AJ and as host to her long term visit to Aarhus University.


The structure of the cerebral cortex results from the orderly migration of two major types of neurons, the glutamatergic projection neurons and the GABAergic interneurons. Most GABAergic neurons originate from the ganglionic eminences. They first migrate tangentially toward the pallium and then migrate radially through the developing brain cortex. The disruption of the VZ and SVZ of the palium and subpalium has been shown to occur at key developmental periods in the hydrocephalic mutant mouse hyh. The aim of the present investigation was to study whether such a disruption of the VZ and SVZ results in abnormalities of the GABAergic neurons populating the brain cortex.The brain of non-hydrocephalic and hydrocephalic hyh mice at postnatal day 7 (n=20) were processed for immunocytochemistry and immunofluorescence using antibodies against GABA and the marker of neuronal nuclei NeuN. Sections processed for double immunofluorescence were inspected with an epifluorescence microscope provided with the multidimensional acquisition software AxioVision Rel. Single and overlay images were used for quantitative analyses of the whole populations of cortical neurons (NeuE-reactive) and that of GABAergic neurons. Absolute and relative cell density and intracortical distribution were recorded for the GABAergic neurons.The mutant hyh mice were characterized by (i) a marked reduction in the width of the cerebral cortex; (ii) a reduction in the total number of GABAergic neurons; (iii) a reduction in the relative number of GABAergic neurons with respect to the total population of neurons (GABA/NeuE); (iv) an abnormal distribution of GABAergic neurons in the cortex layers, with a significant reduction in layers II and III and an increase in layer IV y V. The hyh mutation is associated with: (i) a decreased number of GABAergic neurons migrating from the ganglionic eminences; (ii) abnormal migration of GABAergic neurons through the developing brain cortex; (iii) in hyh mice disruption of the VZ and SVZ is associated to the onset of hydrocephalus and abnormal corticogenesis.


Research suggests that selenium may influence the behavior of the cancer risk in two ways. As an antioxidant, selenium helps to protect the body against free radicals. Selenium may also prevent or slow tumor growth, as some breakdown products of selenium can inhibit tumor growth by enhancing immune cell activity and inhibition of tumor blood vessel development.The aim of this study was to determine the level of selenium in blood serum as a potential marker of risk for cancers of the colon, stomach or pancreas.The research material was a total of 94 samples of blood serum from people with cancer, diagnosed and confirmed in one of the organs: colon (55 cases), pancreas (30 cases) or stomach (9 cases) and 94 samples of blood serum derived from healthy individuals which paired control group. The criteria adopted for pairing included: gender, year of birth (+/- 3 years), history of the occurrence of cancers in the family among first degree relatives and smoking status expressed in pack-years.Selenium concentration in blood plasma was determined using graphite furnace atomic absorption spectrometry (GFAAS). The measurement accuracy was +/- 5% µg Se/l.Association between Se concentration and frequency of cancers in quartiles are presented in table The obtained results suggest that low levels of selenium in the body may correlate with an increased risk of pancreatic cancer, colon or stomach, and thus constitute one of the markers of risk for cancers of such sites. Research requires the extension to a larger number of samples including tumor size, and performance analysis for selenoprotein genes.Prospective studies can elucidate:a) the use of selenium measurements as markers of risk of above cancers;b) possibility of lowering risk of the cancers of the colon, pancreas and stomach by supplementation of diet with selenium.


This work takes part in the European DebugIT project which goal is to build a technical and semantic information technology platform able to share heterogeneous clinical data sets from different hospitals for the monitoring and the control of infectious diseases and antimicrobial resistances in Europe. The aim of the study is to compare the incidence rates of antimicrobial resistance at the HEGP hospital obtained in real-time by the DebugIT platform to those established by the yearly-performed analysis processed by the microbiologists of the HEGP hospital.The INSERM database covers seven years of anonymized microbiology data and represents an image of the HEGP EHR data. To be able to semantically integrate the data with other European peers, we went through several steps of data normalisation and quality works. These tasks led to the setup of semantic data providers  that were integrated at a European level. We built a common view of our domain knowledge upon which we aligned our semantic data providers. We compared the incidence rates of antimicrobial resistance produced by the DebugIT platform at the HEGP hospital to a gold standard produced yearly by the experts.Despite different data processing methods (e.g only microbiologists de-duplicate data in case of repetitive antibiograms on different isolates), the results were highly similar .This study shows the adequacy of the control capabilities of the DebugIT platform and the maturity of the semantic integration methods developed by the project consortium for the setup of a pan-European surveillance network.None declared.