While many drug discovery research programs aim to develop highly selective clinical candidates, their clinical success is limited because of the complex non-linear interactions of human brain neuronal circuits. Therefore, a rational approach for identifying appropriate synergistic multipharmacology and validating optimal target combinations is desperately needed. A mechanism-based Quantitative Systems Pharmacology (QSP) computer-based modeling platform that combines biophysically realistic preclinical neurophysiology and neuropharmacology with clinical information is a possible solution. This paper reports the application of such a model for Cognitive Impairment In Schizophrenia (CIAS), where the cholinomimetics galantamine and donepezil are combined with memantine and with different antipsychotics and smoking in a virtual human patient experiment. The results suggest that cholinomimetics added to antipsychotics have a modest effect on cognition in CIAS in non-smoking patients with haloperidol and risperidone and to a lesser extent with olanzapine and aripiprazole. Smoking reduces the effect of cholinomimetics with aripiprazole and olanzapine, but enhances the effect in haloperidol and risperidone. Adding memantine to antipsychotics improves cognition except with quetiapine, an effect enhanced with smoking. Combining cholinomimetics, antipsychotics and memantine in general shows an additive effect, except for a negative interaction with aripiprazole and quetiapine and a synergistic effect with olanzapine and haloperidol in non-smokers and haloperidol in smokers. The complex interaction of cholinomimetics with memantine, antipsychotics and smoking can be quantitatively studied using mechanism-based advanced computer modeling. QSP modeling of virtual human patients can possibly generate useful insights on the non-linear interactions of multipharmacology drugs and support complex CNS R&D projects in cognition in search of synergistic polypharmacy. While polypharmacy is more of a rule than an exception in real-life clinical treatment, preclinical animal models are ill-equipped to address the issue of comedication because of fundamental species-specific differences in drug metabolism, the impact of human-specific genotypes, the different pharmacology of the drugs for human vs. rodent targets and incomplete pathology  is a major unmet medical need for this patient population; while psychosis can be readily managed by the current antipsychotic drug armentarium, cognitive and negative symptoms are hampering patients to return to a more normal professional life  with allosteric potentiating effects on nicotinic receptors (nAChR) currently approved for Alzheimer's Disease  platform, a mechanism-based computer model of the relevant humanized cortical networks that has been developed for clinical readouts in psychiatry and neurology, and calibrated with group average clinical data. Such an approach is similar to Physiology-Based PharmacoDynamic (PBPD) Modeling in line with new terminology around Physiology-Based Pharmacokinetic Modeling (PBPK) and is gaining traction in pharmaceutical research and development. The platform has been able to blindly, prospectively and correctly predict an unexpected clinical outcome in schizophrenia and Alzheimer's disease (AD)  and has been described in detail elsewhere , with T0 being the half-life in untreated patients. The AchE is one of the fastest enzymes in the human body   nAChR is further determined by the galantamine or donepezil mediated AChE inhibition in addition to inhibition of the presynaptic M2 mAchR autoreceptor by specific antipsychotics, such as olanzapine. In our model, this is illustrated by the fact that binding of ACh to α4β2 nAChR ranges from 24%  to 62% .As a disproportionally large fraction of schizophrenia patients smoke   and in the presence of risperidone, haloperidol and aripiprazole (donepezil only). For instance the fraction of correct responses went up from 66 to 71% for risperidone with 24 mg galantamine. However, smoking also tended to diminish the cognitive response when augmented with quetiapine and olanzapine. When aripiprazole is augmented with galantamine, smoking shifted the peak response of the inverse U-shaped curve.This section deals with the simulation of combination therapy of memantine with cholinomimetics on cognitive outcomes. Note that we simulate the outcome of up to five agents in the same patient, i.e., the parent molecule and active metabolite of an antipsychotic, an AChE-I such as donepezil and galantamine, memantine and nicotine. This is a situation that is often encountered in clinical practice.From the data a complex picture emerges, ranging from a negative effect (adding AChE-I lowers the effect of memantine) with quetiapine and aripiprazole, to an additive effect with risperidone  doses into a negative interaction, i.e., cognitive performance drops with increasing memantine dose. The negative interaction decreases slightly as the quetiapine dose increases. This is likely because adding AchE-I to quetiapine substantially improves cognition; so that further block of the NMDA receptors with memantine reduces GABA tone and drives the network to fire at a very high frequency determined only by the refractory period of the pyramidal neurons, reducing the variability of the interspike distribution and the information bandwidth.In smoking conditions, the slope of cognitive improvement with memantine without AchE-I is much smaller for all quetiapine doses, because the baseline performance of smoking and quetiapine is already higher than in the non-smoking condition. Adding AchE-I in the smoking condition to quetiapine and memantine has a relative smaller negative effect than in the non-smoking condition, although the absolute values of the slopes are similar. This illustrates the complex non-linear pharmacodynamic interactions between different comedications.Table This study addresses the question of a suggested synergistic interaction between AChE-I such as donepezil and galantamine and memantine on cognitive readouts in schizophrenia  has a disproportionately larger impact given the affinity of ACh for the M2 mAChR (which is in the 300 nM range). Blocking the presynaptic autoreceptor could further increase the release of Ach beyond the added effect of AChE inhibition which would then drive the postsynaptic nAChR into desensitization. The level of free ACh in schizophrenia patients is relatively normal, in contrast to the reduced free ACh in Alzheimer's patients, suggesting that the nAChR work on a very different baseline.The combination of AChE-I with antipsychotics shows a number of interesting and unexpected outcomes. The 24 mg galantamine has a higher response than any of the two doses of donepezil for risperidone and haloperidol, an effect that is sustained in smokers. Interestingly galantamine shows an inverse U-shape dose-response with olanzapine in non-smokers; the lowest dose of 8 mg had a higher effect than the highest dose. Smoking also drives the responses of both donepezil and galantamine into an inverse dose-response when combined with aripiprazole or olanzapine. One could argue that the interaction of olanzapine with the presynaptic M1A agonism and lack the inhibition of the presynaptic 5-HT1BR that is a hallmark of risperidone; these two properties might account for a relatively good baseline performance as compared to risperidone. The 5-HT1A pathway has been documented to play a role in antipsychotic response , almost all smokers with an average risperidone dose of 5.4 mg  where anticholinergics were excluded and showed a clear clinical and statistical benefit in delayed memory and attention on the RBANS scale. The negative Lindenmayer trial was a 52-week study of long-acting injection Risperidone (25 and 50 mg) in 32 patients in which galantamine was titrated up to 24 mg; no data on smoking were available. Anticholinergics were allowed for treatment of EPS side-effects, but no data are available on the frequency of this comedication.Two trials with galantamine  and the somewhat lower dose of 25 mg Ris Consta in the Lindenmayer study as compared to 6 mg oral risperidone. Sensitivity analyses in the model show that lower risperidone doses tend to perform better in the cognitive model, leaving somewhat less dynamic range for additional effect of pro-cognitive enhancers; this is partially explained by the anti-cognitive effect of the dose-dependent presynaptic 5-HTIn general, however, the information available from peer-reviewed articles usually does not have the granularity needed to identify the different comedications for individual patients in the different treatment arms. Exploration of other databases such as ADNI, where the comedications are given at the level of individual subjects or the database from electronic health records from the South London and Maudsley National Health Systems registry  NMDA-antagonist. Memantine's interaction under When adding AChE-inhibitors to antipsychotics and memantine, the effect greatly depends upon both the nature of the antipsychotic and the smoking condition. Overall, the effect is additive, with the exception of aripiprazole and quetiapine for both smokers and non-smokers and for olanzapine in the smoking condition, where addition of AChE-I decreases the effect of memantine.A synergistic effect is observed for olanzapine in the non-smoking condition and for haloperidol in both conditions. The observation that adding AChE-I to memantine can improve cognitive readouts is in line with clinical data in Alzheimer's patients . Finally, variability might be a consequence of different genotypes, for instance the COMTVal158Met and the 5-HTTLPR s/l that all can affect cognitive outcomes. In principle, the QSP platform is able to simulate virtual individual patients complete with PK/PK interactions, different individual doses of the different drugs and any combination of the common genotypes. As an example, we have implemented the COMTVal158Met genotype in the QSP platform using human imaging studies in unmedicated healthy volunteers as a different half-life of dopamine and norepinephrine in cortical synapses (Spiros and Geerts, 2R occupancy, although very handy and appealing because of its simplicity, might need a substantial correction.The major message from this simulation exercise is the unexpected impact of different antipsychotics each with their own fingerprint of pharmacological activity on the dose-response of the same drug-drug combination and/or combined with smoking. The non-linear interactions of drug pharmacodynamics plays an important role in real-life drug treatment, as polypharmacy is more the rule than the exception. This is particularly important when considering the design of clinical trials; careful consideration of inclusion/exclusion of comedications can substantially reduce the patient variability in the different treatment arms and increase the probability that a clinical signal can be detected. Failure to take these differential interactions into account might lead to reduction of the clinical signal as treatment arms become inadvertently populated with drugs that do not work or work adversely. We suspect that this might be one of the causes of clinical trial failures of drugs tested with augmentation therapy in Cognitive Impairment with Schizophrenia. Obviously other processes contribute to the variability in clinical trial outcomes such as different genotypes, different pathological baselines and PK variability. In this regard, we would argue that the concept of chlorpromazine equivalents (Beckmann and Laux, 2R occupancy and that this can significantly impact clinical outcome.An additional collorary is that new drugs with a specific selective pharmacology aimed at augmentation therapy could only be combined with specific antipsychotics, because of negative pharmacodynamic interaction of other antipsychotics with specific drug pharmacology of the new investigative compound. In addition, smoking through its effect on nicotinic receptors can significantly affect cognitive outcome. The results of this paper suggest that the complex poly-pharmacy profile of marketed antipsychotics can lead to non-linear pharmacodynamics interactions beyond their simple DThe 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.


The increasing use and complexity of imaging techniques have not been matched by increasing awareness and knowledge by prescribers and practitioners. Imaging examinations that expose to ionizing radiation provide immense benefits when appropriate, yet they may result in an increased incidence of radiation-induced cancer in the long-term. The radiation issue is relevant not only for the individual patient but also for the community because small individual risks multiplied by millions of examinations become a significant population risk. As recently highlighted by recent European and American Guidelines, the long-term risk associated with radiation exposure should be considered in the risk-benefit assessment behind appropriate prescription of diagnostic testing. The fast and strong development of medical imaging represents an exceptional success in the history of medicine. Imaging tests are now the mainstay of our diagnostic approach in many diseases: they allow detection of anatomical and physiological abnormalities often unmasking clinically silent conditions, they are crucial to guide treatment and they can be life-saving. Nevertheless, the widespread use of imaging techniques poses some relevant concerns about the unsustainable society costs and the non-negligible health risks of an inappropriate use -3.γ-rays are well-known proven carcinogens, according to the classification of the World Health Organization’s International Agency for Research on Cancer [stochastic effects that are due to radiation-induced mutations and deterministic effects (i.e. tissue reactions) due to radiation-induced cell death. Deterministic effects only occur above a threshold level of radiation, which is generally higher than levels occurring from a single non-invasive imaging procedure. The risk of developing cancer deriving from radiation exposure is mainly stochastic, which means that it may occur without a specific threshold level, although the magnitude of this risk remains unclear, particularly at very low doses. The risk is also cumulative.Medical radiation from X-rays and nuclear medicine is the largest man-made source of radiation exposure in Western countries . Ionizinn Cancer . RadiatiAccording to the risk estimates released in the Seventh Report of the Committee to Assess Health Risks from Exposure to Low Levels of Ionizing Radiation, the attributable risk of cancer is 1/750 for 15 mSv exposure . RadiatiFor each dose, the risk varies greatly depending on the age (lower in the elderly) and gender  . ChildreImage Gently, Step Lightly Campaign, focused on the risks of unnecessary and excessive medical radiation exposure from interventional radiology administered to paediatric patients [The issue of radiological responsibility in children was recently addressed in the US with the patients . The Eurpatients .Many data clearly show that both patients and doctors - including radiologists, cardiologists, paediatricians, and nuclear cardiologists - have until recently been largely unaware of the long-term risk of the imaging studies they commonly use ,11. PatiThe number of CT scans of all types performed in the USA has quadrupled since 1993, and the same increasing trend has also been observed in Europe . The incThe radioprotection issue is intrinsically linked also to the appropriateness issue. Some recent studies have shown significant percentages of partially or totally inappropriate radiological examinations, even in top-level academic medical centres ,17. ExamBedside point-of-care ultrasonography is emerging as a crucial bedside tool that allows timely decision-making, especially in critically ill patients. Besides conventional ultrasonography, point-of-care echo is a new diagnostic approach to help the attending physicians answer specific questions that are clinically focused and need rapid response.This new way of using the probe as an extension of the examining hand and ear is gaining consensus especially in intensive care units and emergency departments but also for the management of more stable patients. CT definitively remains the gold standard imaging tool for most conditions, but the implications of transferring a critically ill patient out of ICU have stimulated the scientific community and physicians to approve this innovative and revolutionary approach to ultrasound . AccordiIt is crucial that the new generations of physicians and health care providers are no longer unaware of the basics of radioprotection. The White Paper itself suggests a profound remodelling of radioprotection teaching. It is advised that ‘education of future referring physicians on radiation exposure to patient during diagnostic imaging should begin during medical school. The goal is to develop the awareness of radiation exposure in students during training. Any clinician should be steered toward an imaging regimen that minimizes radiation.’  The two Underlining the importance of radiological awareness does not translate in an underestimation of the crucial, irreplaceable role of some imaging techniques and examinations that can be life-saving and have dramatically changed the management of some serious illness. The risks of a test should always be weighed against the risks if a disease remains undetected, detected at a later stage, incorrectly prognosticated or suboptimally treated . It is h


Scholars underline the pivotal role of tobacco cigarette smoking in carcinogenesis process for blood tumors. A controversial debate is represented by the diffusion of tobacco use in young cancer survivors that had a previous diagnosis of blood tumor during the childhood. Compared with their peers, scientific evidence highlights that pediatric survivors have more difficult to give-up cigarette smoking. Furthermore, tobacco-smoking is frequently linked with others risk behaviors as drinking or substance abuse. In reviewing the main knowledge on this topic, authors affirm the need for increasing research on blood cancer survivors in order to depict psychological characteristics of pediatric blood cancer survivors. Improving health decision-making skills in young survivors could reduce the risk to adopt un-healthy behaviors and increase psychological wellbeing. Furthermore, authors propose tailored antismoking interventions based on the knowledge of the psychological and cognitive factors that support smoking during the transition toward emerging-adulthood. Tobacco cigarette smoking has a pivotal role in carcinogenesis process for blood tumors, as well in surveillance for health related quality of life in survivors , blood tumors patients, have more troubles understanding, and managing health information and health behavior  on them should be implemented considering the different age of participants.Third connected to the previous points, the-long term follow-ups provide the opportunity for the oncologists to support and educate young survivors to adopt no-smoking behaviors. These goals might be achieved only promoting the implementation of tailored antismoking interventions based on the knowledge of the psychological and cognitive factors that support smoking during the transition toward emerging-adulthood. This kind of intervention is coherent with the personalized medicine model suggested in previous researches on cancer patients (Kondylakis et al., The review was conceived by MM and SR. Data extraction was carried out by MM, SR, and CF with support from GP. Reporting of findings was led by MM with support from SR and CF. All authors contributed to manuscript preparation and approved the final version.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.


Point-of Care analysis is increasingly being applied in the prehospital scene. Arterial blood gas analysis is one of many new initiatives adding to the diagnostic tools of the prehospital physician. In this paper we present a study on the feasibility of the Radiometer ABL-90 in a ground-based Mobile Emergency Care Unit and report on some clinical situations in which the apparatus has proven beneficial. Point-of-Care analysis and treatment is increasingly being applied in the prehospital setting. Obtaining an electrocardiogram and initiating thrombolysis is by now an established part of the prehospital treatment in coronary occlusion . IncreasHowever, full blood gas analysis in prehospital services requires a more extensive set-up than previously described. Within the hospital, the ABL-90  blood gas analyzer has proven fast and reliable. The ABL-90 is portable and data can be sent to the patient data management systems. An internal battery provides back-up when disconnected from the inverter. The apparatus thus would appear suitable for prehospital use.We report a study on the feasibility of the ABL-90 implemented in the anaesthesiologist staffed Mobile Emergency Care Unit (MECU) in Odense, Denmark.Initially, the vehicle was equipped with an inverter capable of supplying the ABL-90 with 90 Watts and 230 Volts alternating current. Following that, the susceptibility of the ABL-90 towards vibrations and gravitational forces was assessed. A dummy with dimensions and weight identical to the ABL-90 was constructed and mounted in the vehicle. An accelerometer was placed on the dummy, measuring g-forces during several emergency MECU runs. Furthermore, the shock response spectrum of the unit was calculated. The extent of g-forces exerted and the shock response spectrum measured confirmed the possible functionality of the ABL-90 following the physical impact endured during the emergency runs, and further testing was carried out.Although g-forces exerted were rather low , initial findings demonstrated that the ABL-90 was unreliable. An inlet of the apparatus proved to be responsible for failure, disconnecting the inlet from the calibration system. A re-designed cradle with added cushioning and a newly constructed sample inlet, designed to minimize the risk of a discontinued connection between the sample inlet and solution pack corrected this issue enabling the ABL-90 to function flawlessly. In order to ensure correct results, validation of the blood sample analyses was performed by the Department of Clinical Biochemistry at Odense University Hospital. A maintenance program was also established ensuring that a supplementary ABL-90 is always accessible should maintenance or replacement of solution packs require the unit to be disassembled.For a period of 18 months the ABL-90 has been functioning in the MECU in Odense, Denmark Fig The ability to perform rapid, accurate arterial blood gas analysis at the scene has significantly improved the diagnostic possibilities of the MECU, as the diagnosis of several conditions in which a fast diagnosis and subsequent therapy is vital, thus has been made possible.Among many clinical scenarios where arterial blood gas analyses are performed at the scene, some of the special conditions where the results have proven relevant have been:In patients with presumed septic shock or septicaemia, analysis of lactate and pH in many cases has enabled the MECU to establish the diagnosis prehospitally, to obtain blood cultures and to initiate antibiotic therapy at the scene.In several cases, patients suspected of exposure to Carbon monoxide poisoning have been released at the scene thus obviating admission to hospital once blood gas analysis has rejected the presence of Carboxyhemoglobin.In other related cases, patients exposed to indoor fires with potential for cyanide formation have been diagnosed as the shift to anaerobic metabolism caused by cyanide has been detected by lactic acidosis.In patients with exacerbation of chronic obstructive pulmonary disease, rapid blood gas analysis has helped the physician at the scene to better direct patient therapy.2-level should be targeted within rather narrower limits than interpretation of end-tidal CO2 measurement allows.Also, the blood gas analyser is helpful in adjusting the level of respiratory support in intubated patients with elevated intracranial pressure, in which the COAs the apparatus has the potential of transmitting prehospital results to intra-hospital patient data management systems it facilitates improved diagnostic and treatment possibilities, both prehospitally and in preparing emergency departments for patients before their arrival at the departments. Transmission of data to the receiving emergency department enables these departments to increase their levels of preparedness and thereby initiate the correct treatment faster.The direct costs associated with the technology are acquisition of the apparatus. The retail price is EUR 15.000 per unit, while indirect costs  amount to EUR 11.500 per year. Implementation is relatively straightforward. Only minute changes have been made in the MECU to make the ABL-90 suitable for the unit.We have successfully introduced the possibility of acquiring full blood gas analyses prehospitally in a mobile emergency care unit.


A hundred and five years ago, Albert Calmette and Camille Guérin began a daunting task, which is unmatched even today, that led to the most widely used vaccine in human history. Despite a century of scientific advances, BCG  remains the only vaccine for prevention of tuberculosis. Due to the fact that the use of BCG vaccines will continue, either as a stand-alone or as a prime vaccine in prime-boost immunization strategies, the World Health Organization (WHO) has underlined the necessity for further work toward better characterization, evaluation and quality control of the BCG vaccine, taking into account recent advances in genetics and molecular biology. The potential benefit of such improved characterization could be addressed to better and easier differentiation between sub-strains used by different manufacturers. It may help to ensure consistency of production in terms of genetic stability and it may also help the clinical evaluation of new antituberculosis vaccines. Last but not least, the state-of-the-art technologies could facilitate the quality control performed by the manufacturers and by National Control Authorities as well. The BCG  live, attenuated vaccine is the only vaccine used for immunoprophylaxis of tuberculosis since 1921 till now. BCG is the most widely administered vaccine in the world, with 91.7% global coverage in 2012.[A number of unresolved issues in the quality assessment of BCG vaccine have been identified  and stilDue to the fact that the use of BCG vaccines will continue, either as a stand-alone or as a prime vaccine in prime-boost immunization strategies, the necessity for further work in better characterization of the BCG vaccines and of the production strains has been underlined. The impoThe World Health Organization (WHO) has recognized the need to improve both characterization of this vaccine and the assays used for its control, taking into consideration recent advances in genetic and molecular biology. The potential benefit of such improved characterization could be addressed to better and easier differentiation between sub-strains used by different manufacturers; it may help to ensure consistency of production in terms of genetic stability and also this may help the clinical evaluation of BCG vaccines in the future.A better understanding of vaccine characteristics relevant to production and control as well as to the safety and efficacy in humans should lead to improved control tests. For this purpose relevant and effective vaccine evaluation using state-of-the-art technologies is of fundamental importance for testing BCG immunogenicity, BCG safety, BCG identity and potency and last but not least – in searching of immune correlates in clinical trials (for new vaccines).The following quality control tests could be a subject to improvement and could be potentially replaced by new and more perfect models in agreement with current scientific achievements.Mycobacterium bovis. The viability of organisms is essential for the stimulation of a protective immune response and monitoring viable counts is an integral part of quality control. Although measurement of viable cells is not in itself an assay of potency, it has been used as a surrogate of BCG immunogenicity and efficacy.[The BCG vaccine is based on a live attenuated strain of efficacy.However, the cultural viable count assay, often known as colony-forming unit (CFU) test, is problematic and very time consuming, as mycobacteria are very slow growing microorganisms.,9 Due toSince adenosine triphosphate (ATP) is a major metabolite of living cells which is rapidly lost in dead cells, measuring ATP content can provide reliable estimates of the number of living cells. The determination of ATP based on bioluminescence is one of the alternative methods for rapid detection of the viability of the BCG vaccine. BioluminA modified ATP bioluminescence assay has been developed by Statens Serum Institute (SSI) as an alternative rapid assay for viable count of BCG vaccine. This ATPThe modified ATP assay is simple and easy to perform. The test is rapid and time saving; the time to obtain results is reduced from five weeks to three days. The method is by far more reproducible than the cultural method. The sensitivity of the bioluminescent method is much higher than the one of traditional methods such as spectrophotometric and fluorometric assays. There is a high range of linearity between the values of the registered signal and the concentration of the evaluated substance. Other advantages of this method are that small amounts of the examined sample are used, and also simple and not expensive equipment.However, future studies should be carried out on the modified ATP assay in order to establish the reproducibility and suitability of this method. These investigations should be advanced by further examinations of the correlation between the cultural viable counts and ATP content of different BCG vaccines produced. It is important for each individual laboratory to establish this correlation by experimental tests for each BCG product.The number of sub-strains used for BCG vaccine production has effectively been reduced to five: Russian BCG-I, Tokyo 172-1, Danish 1331, Moreau RDJ and Pasteur 1173-P2. These five sub-strains account for more than 90% of the BCG production worldwide. Since the current identity test for BCG vaccine using acid-fast staining and colony morphology lacks specificity, it is essential to develop a robust, routine assay for manufacturers and regulatory laboratories to identify different sub-strains of BCG. This will also ensure genetic consistency in production, from master seed lot through working seed lot and to final product. Different approaches such us DNA microarray to look for single nucleotide polymorphisms (SNPs), deletions and duplications can provide a better insight into the molecular characterization of different BCG sub-strains. Although these techniques are not intended for routine use during the production, they can identify regions of interest and importance for further studies. For the purpose of the last revision of WHO recommendations for BCG production and control, the imprM. bovis BCG from other bacteria in the Mycobacterium tuberculosis complex, most of which are virulent. This main disadvantage calls for searching for more reliable methods which can differentiate BCG sub-strains themselves as well as distinguish BCG sub-strains from pathogenic mycobacteria. Now, the monograph for BCG in European Pharmacopoeia has stated that molecular techniques may be used as alternatives for identification.The current required identity test for BCG vaccine is acid-fast staining together with a characteristic appearance of colonies grown on solid medium. These microbiological techniques for testing BCG identity cannot distinguish M. tuberculosis H37Rv. Some deletions vary between BCG sub-strains.[M. tuberculosis, and for phosphate-dependent gene expression) has also been identified as a successful target site for use in identifying BCG sub-strains.[M. tuberculosis.[One of the alternatives for BCG identity testing is the multiplex PCR (mPCR) assay, which was developed in the National Institute for Biological Standards and Control (NIBSC), UK. As a res-strains. As summa-strains., RD1 was-strains. The mPCR-strains. It has brculosis. The assaThe method is suitable not only for comparing and identification of BCG sub-strains in manufacture and control , but also for specific identification of BCG isolates from a variety of clinical situations including both immunosuppressed children and adults undergoing therapy for bladder cancer.Once standardized within a control laboratory, the novel mPCR could be very effective for determining the identity of BCG vaccines.in vitro assay has been developed [esat-6 and the cfp-10 gene. PCR targeting these two genes allowed discrimination between BCG and pathogenic mycobacteria and thus – detection of contamination. The sensitivity of this assay ranged from 1 genome  for cfp-10 primers and 1000 genomes for esat-6 primers when using purified DNA preparations.In the 2004 WHO consultation report, guinea pigs are reported to be currently used for routine monitoring of the presence of virulent mycobacteria in BCG vaccine.[eveloped  which caM. tuberculosis contamination in BCG vaccines. Applying this new method will not only reduce the time required for testing absence of virulent mycobacteria in BCG products, but also significantly reduce the use of animals and therefore, a lot of ethical considerations can be solved.Further work is required, as pointed out in the 2004 WHO report,[M. tuberculosis.[M. tuberculosis but also differences among BCG vaccines. This fact reveals ongoing evolution of BCG strains after 1921. Each sub-strain has its own signature molecular profile and differs from other sub-strains. These differences can be used to characterize any sample of BCG vaccine.[A recent advance that permits a more rigorous analysis of BCG strains has been the sequencing of the entire genome of rculosis. The asserculosis. demonstr vaccine.Current BCG sub-strains are genomically different from one another. Apart from deletion of genomic regions (RDs), tandem duplications DU1, DU2) and SNPs have also been observed in different sub-strains. In addition, variability in gene expression profiles and at transcriptomic level among sub-trains is also under investigation.[ and SNPsThe most appropriate schedule for genetic typing of BCG suggested in the 2005 WHO report is based on variable number tandem repeat (VNTR) number at MIRU 4, RD pattern and number and location of tandem duplications.[In parallel, it is important to know how genetic differences are expressed in the final product. Identification of differences in protein expression offer a way towards this, as there is accumulating knowledge about proteins relevant to the protective response to tuberculosis. Using the proteomic technique, it is possible to identify the different protein profiles of different vaccine strains. This is particular important to identify any changes in protein profiles from working seed, different passage levels to final lot preparation of the product.M. bovis BCG were published.[Currently, as a part of the BCG vaccine characterization programme, extensive molecular genetic characterization studies have been undertaken. As a result, the data about whole sequencing and deciphering the genome of ublished.The results about comparative genome and transcriptome analysis revealed extensive variations in gene expression between early BCG strains  and late BCG strains . The variations result from increased gene dosage or from altered activity of pleiotropic regulators leading to over- or under-production of certain proteins, including virulence factors and enzymes. Brosch eM. bovis BCG, sub-strain Sofia SL222, gave an insight to the specific genetic properties of the Bulgarian BCG vaccine.[M. bovis BCG, sub-strain Sofia, has two copies of IS 6110. The second copy is inserted into the promotor region of the gene phoP which increase the gene expression and induce the higher level of virulence. One of the main characteristics of the strain is the presence of RD2 region, which is typical only for the ‘early’ BCG sub-strains . RD2 encompasses the region Rv1979c-Rv1989c ; including gene mpt64 coding the high-immunogenicity protein МРТ64. Another specificity of the strain is a rearrangement in the genome – a DU2 type I duplication in the region Rv3299-Rv3316 encoding enzymes of the citric acid cycle. This duplication generates genome plasticity, which indicates that the genome is still dynamic. A novel 1.6 kb deletion was identified that affects the genes Rv3697c and Rv3698, related to membrane proteins in the cell wall structure. This region is also deleted in the genome of BCG Russia but not in any other strain. This deletion therefore must have occurred prior to the in vitro cultivation of BCG Sofia.Molecular typing and genome sequencing of  vaccine. The geneM. bovis AF 2122/97 and M. tuberculosis H37Rv. The genome of BCG Sofia SL222 was shown to be closer to that of Tokyo 172 (99.68% similarity), rather than to Pasteur 1173-P2. The size of the genome of M. bovis BCG Sofia SL222 is 4 369 629 bp and contains 4317 genes functionally distributed into 309 sub-systems.The genome of BCG Sofia SL222 was compared to those of sub-strains Tokyo 172, Pasteur 1173P2, M. bovis BCG Sofia it is now clear that the strain harbours genetic properties which pertain only to the strains closest to the original one of Calmette and Guérin. The genome of BCG Sofia  appears to be most conservative among the genomes of other ‘early’ BCG sub-strains, which contributes to its genetic stability. Thus, one of the most powerful enabling technologies of the post-genomic era proved the genetic identity, provenance and stability of the Bulgarian BCG vaccine for a period longer than 30 years.As a result of the genetic characterization of The genotyping of BCG vaccines has an important value in standardization and differentiation of sub-strains used in vaccine manufacture. It can prove the consistency of production regarding its genetic stability. In addition, last but not least, the molecular characterization of BCG sub-strains unfolds an opportunity for finding reliable correlates in clinical assessment of protective efficacy and safety of the BCG vaccine in humans, which is particularly important in the development of new antituberculosis vaccines or immunization strategies.


Rheumatic diseases are characterized by high prevalence and functional disability of patients. Right diagnosis in the onset of disease, early aggressive therapy with antirheumatic drugs including biologics improve the prognosis and prevent disability of patients. Only high qualified pediatric rheumatologists can do it.To analyze system of pediatric rheumatologists training in Russian Federation (RF).Description of medical education in pediatric rheumatology in RF.Training of pediatricians is performed at a pre-degree stage at Pediatric Faculties of State Universities. Graduates get a degree of a pediatrician.There is no medical specialization of "Pediatric Rheumatologist" in the list of medical professions in RF. In 2012 a position of rheumatologist was included into the staff schedule of children's polyclinic. In children's hospitals Pediatric Rheumatology Departments are provided, and position of rheumatologist was included into the staff schedule of pediatric hospitals. A graduate of Pediatric Faculty or of General Medicine Faculty  serves internship in pediatrics either in the form of 1 year-internship training or in the form of 2 year-residency training. After that the graduates get a certificate of a medical specialist (pediatrician) and a right for clinical practice. Further residency training in rheumatology is required (2 years) or professional development training in rheumatology of at least 500 hour- duration. After completion the graduate receives a certificate of rheumatologist. Further training is performed in the form of advanced medical training in postgraduate stage. A rheumatologist undergoes thematic advanced training in pediatric rheumatology in the volume of 144 hours and gets a certificate. Further professional training is obtained within the system of continuous medical education.In 2003 at the I.M. Sechenov First Moscow State Medical University a Pediatrics and Pediatric Rheumatology Chair was established, first in RF. The key area of activity is to improve qualification of pediatricians in the fields of diagnostics, treatment and rehabilitation of children with rheumatic disorders. Within 10 years 28 advanced training programs have been performed. For remote regions online programs using videoconference calls are organized. Advanced training is performed at training schools within annual Meetings of the Union of Pediatricians of RF. The School of Pediatric Rheumatologist was founded in 2006. 1,464 pediatricians took part in the School since 2006. Since 2011 precongress master classes in pediatric rheumatology have been organized within the Congress of Pediatricians of RF with participation of European and American pediatric rheumatologists. A total of 2,742 pediatricians have underwent advanced training in pediatric rheumatology in 10 years. Once in 5 years a rheumatologist should undergo training to confirm the certificate.Training of pediatricians in pediatric rheumatology is very important for suspicion of rheumatic disease at onset. Training of pediatric rheumatologists is very important for early diagnostics and adequate treatment of rheumatic diseases.None declared.


Intra articular Coronal fracture of the femoral condyle (Hoffa) is rare-especially that of medial condyle. We report the case of a patient who had a bilateral Hoffa fracture of the medial condyles  occurred as a result of an accident at work (worker mover). Lesions were treated with the functional and orthopaedic approach. At follow- up of 8-month functional score was excellent with normal flexion, an absence of laxity, an absence of pain and an unlimited market. Through a review of the literature the mechanism, the diagnostic methods and therapeutic will be analysed. Coronary, isolated from the dorsal portion of the femoral condyle fracture was first described by Friedrich Busch 1844-1916) and not as always assumed by Albert Hoffa in 1904 [844-1916 It was Mr. B P. Age from 44 years, admitted to the Emergency Department for injuries knees following an accident at work. It is a moving worker who allegedly received while working on his knees, a cab office heavy mode of injury has a direct impact on the knees at 20 degrees of flexion. Review painful swelling of the knees with a patellar shock at the level of the knees (hemarthrosis), more intense pain sitting at the level of the internal compartments of the knee. No there was no vasculonervous, but important lesions of varying degrees of complications . These sAccording to AO classification  the lesiPartial articular, coronal plane fractures of the posterior part of femoral condyles are rare and account for less than 1% of distal femoral fractures. Generally results from trauma secondary to motor vehicle accidents or a fall from a height . High veBilateral Hoffa fracture  or unicoIn these cases the contribution of the CT scan is undeniable: confirms diagnosis, enjoys travel, detect comminution, and research associated injuries. Associated lesions have been described in literature , 9–11 buConservative treatment of Hoffa fracture has some risk: secondary displacement, prolonged immobilization give rise to myoatrophy and joint stiffness. In our case we realized an orthopaedic treatment due to septic risk due to skin lesions and the absence of displacement. This treatment is binding but can lead good functional results. The non-bloody treatment must be mainly reserved for displaced and stable fractures.In conclusion, we describe a case of a bilateral unicondylar medial Hoffa fracture treated successfully with orthopedic method. Peculiarity of our case is: the scarcity of its localization, unusually, let wasn't result of motor vehicular accidents, it is a closed injury. CT scan allowed diagnosis and associated injuries.


A recent systematic review of the duration of migraine aura reported that aura symptoms may last longer than one hour in a significant proportion of patients. Here wead hoc aura diary that included the time of onset and the end of each aura symptom and the headache. We also collected demographic and clinical variables of each patient including age, gender, presence of headache associated with aura, frequency of migraine with aura attacks, age at onset of migraine with aura, duration of illness, co-occurrence of migraine without aura or tension-type headache, age of migraine without aura onset, use of a migraine preventive therapy, family history for migraine with aura and white matter lesions at MRI in the analysis. We performed an analysis to evaluate if there was any demographic or clinical variable associated with having suffered from at least one PA out of three attacks.We recruited 176 consecutive patients affected by migraine with aura at the Headache Centres of Pavia and Trondheim. The study received approval by the local Ethics Committees. All patients signed an informed consent form. Fifty-four patients completed the study recording prospectively the characteristics of three consecutive attacks in an Fifty-four patients completed the study recording in a diary the characteristics of three consecutive auras n=162 auras). Fourteen out of 54 patients (26%) had at least one PA, while 30 patients (74%) had three TA. In univariate analyses, none of the clinical or demographic parameters was significantly associated with the fact of having experienced a PA .None.


People with eating disorders (EDs) are reported to have set-shifting difficulties, strengths in local or detailed information processing and weak central coherence or global processing. This study aimed to explore the validity of a novel, brief, global, neurocognitive task which has not previously been utilised in an ED population, the Navon Figures Task (NFT). The NFT is substantially quicker to administer than traditional neurocognitive tasks. Twenty women with anorexia nervosa (AN) and 20 healthy control women completed the Rey-Osterrieth Complex Figures Task (RCFT) to measure global/local processing strategies and completed the Wisconsin Card Sorting Test (WCT) to measure of set-shifting ability. The NFT was used as a measure of both set-shifting ability and central coherence. Consistent with previous findings, women with AN showed a tendency towards poorer performance on the RCFT and WCT than healthy control women. Scores on the NFT and RCFT were significantly, positively and strongly correlated in both the AN and healthy control samples, as were scores on the NFT and WCT. This indicates that the NFT has good concurrent validity with the other measures. These preliminary findings support the use of the NFT as a sensitive and practical measure in assessing central coherence and set-shifting abilities in EDs. Using measures like the NFT may potentially enhance our understanding of neurocognitive traits in AN and may help guide our treatment approaches to AN in the future.Assessment stream of the 2014 ANZAED Conference.This abstract was presented in the


Increasing studies suggest the importance of including prospective memory measures in clinical evaluation of dementia due to its sensitivity and functional relevance. The Prospective and Retrospective Memory Questionnaire (PRQM) is originally a self-rated memory inventory that offers a direct comparison between prospective and episodic memory. However, the informant's report has been recognized as a more valid source of cognitive complaints. We thus aimed to examine the validity of the informant-rated form of the PRMQ in assessing memory function of the patients and in detecting individuals with early dementia. The informants of 140 neurological outpatients with memory complaints completed the Taiwan version of the PRMQ. Tests of prospective memory, short-term memory, and general cognitive ability were also administered to non-demented participants and patients with early stages of Alzheimer's disease (AD). Results showed significant relationships between the PRMQ ratings and objective cognitive measures, and showed that higher ratings on the PRMQ were associated with increasing odds of greater dementia severity. Receiver operative characteristic (ROC) curves showed an adequate ability of the PRMQ to identify patients with dementia (93% sensitivity and 84% specificity). Hierarchical regression revealed that the PRMQ has additional explanatory power for dementia status after controlling for age, education and objective memory test results, and that the prospective memory subscale owns predictive value for dementia beyond the retrospective memory subscale. The present study demonstrated the external validity and diagnostic value of informants' evaluation of their respective patients' prospective and retrospective memory functioning, and highlighted the important role of prospective memory in early dementia detection. The proxy-version of the PRMQ is a useful tool that captures prospective and episodic memory problems in patients with early AD, in combination with standardized cognitive testing. Alzheimer's disease (AD) is the leading cause of dementia syndromes. Early detection is an important task, considering the nature of progressive course and possible disease-modifying therapies Prospective memory refers to the memory of an action to be performed at a future time Nonetheless, assessment of prospective memory is time-consuming, preventing it from being adopted into clinical routine. Therefore, development of a more efficient tool would be beneficial. The Prospective and Retrospective Memory Questionnaire (PRMQ) However, the source of reports may have a great impact on the reliability of a questionnaire. Self-reported data of the patients with AD who manifest anosognosia or decreased awareness of their memory loss The objective of the present study was to examine the clinical utility of the informant's report of the patient's memory impairments on the PRMQ, given its convenience, time-saving, and real-life relevance. We aimed to confirm four assumptions: First, there are correlations between informant-ratings on the PRMQ and objective cognitive measures. Second, there are differences between informants' ratings for patients at different stages of dementia. Third, the informant-rated PRMQ yields acceptable sensitivity and specificity in detecting dementia, as reflected by Receiver Operative (ROC) curves. Fourth, there is an incremental explanatory power of the informant-rated PRMQ for detecting dementia after controlling for age, education, and objective memory test.One hundred and forty neurological outpatients and their informants who completed the PRMQ were enrolled in the present study according to inclusion and exclusion criteria. These patients visited the memory clinic of the department of neurology at a regional general hospital in Taiwan from June to December 2013. Patients with memory complaints who received a cognitive evaluation were included. Exclusion criteria included: age younger than 45; history of stroke; head injury with loss of consciousness for more than 30 minutes; neurological diseases; and psychiatric disorders .Information from clinical interviews performed by neurologists and clinical neuropsychologists, cognitive tests, laboratory results, and brain imaging findings (28 patients had magnetic resonance imaging and 75 patients had computerized tomography results) was collected. Medical history was obtained by family interviews. Participants were classified into three stages according to the Clinical Dementia Rating Scale (CDR) All patients received the Mini-Mental Status Examination (MMSE) The single-trial prospective memory tasks included an event-based task and a time-based task. Each task was scored by a combination of the prospective component score and the retrospective component score. The former assessed whether the participant remembered that an action was to be accomplished and the latter assessed the content of the action. The Envelope Test is an event-based prospective memory task adapted from previous studies The Telephone Test is a time-based prospective memory measure we modified from the prompt card task α to test the reliability of the scales was also calculated.Demographic and cognitive variables of each group were illustrated by descriptive statistics and compared by analysis of variance (ANOVA). Wilcoxon signed-rank tests were employed to examine the difference between mean ratings of the prospective and retrospective memory subscales within each severity group. Zero-order correlations were performed by Spearman sign-rank correlations to examine the relationships between age, education, cognitive performance, and ratings on questionnaires. Cronbach's We conducted multinomial logistic regression to examine dementia severity as a function of the PRMQ ratings, while covarying for age and education. We coded our dependent variable  as an ordinal outcome . In this multinomial logistic regression model, exponentiated coefficients are calculated as ratios of relative probabilities, thus can be called conditional odds ratios (COR).Receiver operating characteristic (ROC) curves were created to test the clinical utility of informant-reported PRMQ, and to set the cut-off score. Optimum cut-off scores for the PRMQ were determined at the maximum Youden index (J =  sensitivity + specificity −1) level SD), and p<0.05 indicated statistical significance.The hierarchical regression model was used to examine the incremental power of the PRMQ ratings after accounting for the influence of demographic variables and objective short-term memory measure. The incremental power of the prospective memory subscale was also examined, controlling for the influence of age and the retrospective memory subscale. Many of these variables had skewed distributions; however, the distributions of the regression residuals were normally distributed, and this analytic approach was deemed appropriate. All statistical tests were performed by using SPSS version 19. Values are presented as mean and standard deviation  and education  between the groups. Wilcoxon signed-rank tests revealed significantly higher mean ratings for the prospective memory subscale than for the retrospective memory subscale in each group, but to a greater extent in the very mild dementia group  as compared with the no-dementia group  and the mild dementia group .Demographic data and the summary of measurement results are shown in ρ = 0.30 ∼ 0.38; p<0.001), but not with education . Significant associations were also shown between the PRMQ ratings and the MMSE , short-term memory , and prospective memory tasks . Cronbach's α was 0.97 for the total scale, 0.94 for the prospective memory subscale, and 0.93 for the retrospective memory subscale, yielding appropriate internal consistency. As can be seen in By using ROC analysis for the prospective memory subscale, retrospective memory subscale, and the PRMQ total scale, the calculated AUC values were 0.94, 0.93, and 0.94, respectively . Therefop<0.001; ΔR2 = 0.327). In addition, when controlling for age and ratings on the retrospective memory subscale .Hierarchical linear regression conducted to predict dementia status see  showed asubscale , ratingsThe current study aimed to examine the validity and diagnostic value of the informant-rated PRMQ in clinical settings. Results confirmed our previous assumptions. First, the informants' ratings on the PRMQ were significantly associated with objective measures of short-term memory, prospective memory, and general cognitive ability. Second, higher frequency of memory failures, as reflected by the PRMQ, was associated with higher odds of greater dementia severity. Third, the informants' ratings on the PRMQ displayed good sensitivity and specificity in identifying dementia patients. Fourth, the informant-rated PRMQ demonstrated incremental validity over demographics and objective memory test in detecting dementia. Our findings confirmed that informants' ratings of patients' prospective and retrospective memory problems can accurately reflect their impairments, and supported the utility of the informant's evaluation on the PRMQ as an alternative memory measure for clinical practice Our study supported the view that prospective memory measure is sensitive to the early stages of dementia There have been several well-established memory questionnaires that assess the patients' memory function or the informants' report of the patients' function in real life, such as the Everyday Memory Questionnaire (EMQ) Some proxy-rated questionnaires have been shown to be effective in detecting patients with dementia or mild cognitive impairment, such as the AD8 An informant-rated memory questionnaire is a reliable dementia-screening tool with several merits in clinical settings. First, studies consistently showed correlations between the objective test performance and the informant's reports of memory There are several limitations in the current study. First, the educational level of our sample was relatively low. This may compromise the representativeness and limit the generalization of the current results. However, analysis showed that there is little influence of patients' educational level on the informant's ratings of the memory questionnaire. In fact, the high occurrence of illiterate patients in our hospital has restricted the use of several neuropsychological test tools. One of the advantages of the PRMQ is that the patient's prior academic attainment is not requisite. Second, the items covered in the prospective memory subscale describe more of the general rather than specific performance of the patient's prospective memory in daily life, and provide little information about which process problem is responsible for performance failure. The subscale thus merely provides an overall index serving as a screening tool for further assessment. Third, patients in the non-dementia group were those with subjective memory complaints but showed normal cognitive function on objective cognitive testing. These patients may be in an early stage of memory deterioration. However, our study demonstrated that informant-rated PRMQ is capable of reflecting the patient's memory impairment and may be used to indicate dementia status.In sum, the current study demonstrated the external validity and diagnostic value of informants' evaluation of their respective patients' prospective and retrospective memory functioning, and highlighted the important role of prospective memory in early dementia detection. The proxy-version of the PRMQ is a useful tool that captures prospective and episodic memory problems in patients with early AD, in collaboration with standardized cognitive testing.


Finally, we will summarize the progress made in the development of genetically engineered mouse models of DIPG. Cooperation of studies incorporating all of these modeling systems to both investigate the unique mechanisms of gliomagenesis in the brainstem and to test potential novel therapeutic agents in a preclinical setting will result in improvement in treatments for DIPG patients.Diffuse intrinsic pontine glioma (DIPG) is a rare and incurable brain tumor that arises in the brainstem of children predominantly between the ages of 6 and 8. Its intricate morphology and involvement of normal pons tissue precludes surgical resection, and the standard of care today remains fractionated radiation alone. In the past 30 years, there have been no significant advances made in the treatment of DIPG. This is largely because we lack good models of DIPG and therefore have little biological basis for treatment. In recent years, however, due to increased biopsy and acquisition of autopsy specimens, research is beginning to unravel the genetic and epigenetic drivers of DIPG. Insight gleaned from these studies has led to improvements in approaches to both model these tumors in the lab and to potentially treat them in the clinic. This review will detail the initial strides toward modeling DIPG in animals, which included allograft and xenograft rodent models using non-DIPG glioma cells. Important advances in the field came with the development of  Diffuse intrinsic pontine glioma (DIPG) arises in the pons of mostly children and is incurable. Of the 200–300 new cases of DIPG per year in the United States, the median age at diagnosis is 7 years of age, and the median survival is <1 year from diagnosis. Surgery is not an option, radiation provides only temporary relief, and no small molecule or chemotherapeutic agent has been demonstrated to prolong survival in this disease , Nestin, GFAP, Vimentin, Sox2, Olig2, and CD133, suggesting a primitive neural precursor cell type  via convection-enhanced delivery (CED), showing that this delivery method may represent an effective drug delivery alternative for DIPG patients, bypassing the restrictive blood–brain barrier . One cavin vitro  provide the advantage of studying tumors that arise in their natural microenvironment in immune-proficient animals. The first GEMMs of DIPG were generated using the RCAS /tumor virus A (TVA) modeling system and genetic alterations commonly found in the human disease Figure  43–45).–45.43–45in vitro, and re-introduced into the murine pons as an ex vivo approach although the in vitro culture conditions will alter the cells.Early work with the RCAS system used germline Ink4a-ARF loss and PDGFB overexpression targeted to Nestin-expressing cells of the neonatal mouse pons , the likBecher et al.  was the in vitro data and found the drug concentration levels in treated mice were well below the known IC-50 for BMS-754807. The aggressiveness of this most recent BSG GEMM parallels the clinical disease and represents a good tool for pre-clinical therapeutic trials.RCAS-based GEMMs have evolved by utilizing the increasing understanding of DIPG genetic alterations, incorporating the three most highly recurring genetic alterations: PDGF signaling overexpression, p53 loss, and the H3.3K27M mutation . Cells pin vivo setting, which may help to uncover novel characteristics of the human disease. In this regard, using the RCAS model described above, comparison of gene expression profiles of BSGs versus those initiated in the cerebral cortex revealed that those in the brainstem harbored high levels of the transcription factor Pax3  or electroporation  could lPre-clinical models of DIPG are continuing to improve as our knowledge of DIPG etiology expands. The current models each have advantages to their use and have all contributed invaluable insight into DIPG biology and treatment Table . Human cXenografts of human cells into immunocompromised mice also retain the advantage of using patient-derived cells. However, full recapitulation of human tumor development is compromised by the alteration of tumor microenvironment and absence of an immune system. Therefore, GEMMs are an important complement to human xenograft models, and while they have shown much promise, they remain underdeveloped. The next generation of GEMMs should incorporate the knock-in of common DIPG mutations, such as H3.3K27M, into the endogenous loci in order to better simulate the expression level and localization of the mutated gene products. Additionally, while current GEMMs use overexpression of PDGFB ligand as an oncogenic driver, amplification of the wild-type PDGFRα receptor is most common in patients . TherefoThe increased development and availability of cell models, xenografts, and GEMMs of DIPG represent great promise to improve the treatment of this deadly disease. While the path from development of genetically faithful animal models to generation of efficacious therapies can be long and arduous, continuing to improve the models as more information about the human disease is uncovered is necessary. Using the available tools to identify novel therapeutic agents and causes of therapy resistance will be paramount in developing effective treatment strategies. Cooperation between researches utilizing all of the available pre-clinical models discussed here will be the key to advancement in this field. These models represent valuable tools, which will aid in testing future therapeutic agents and lend further insight into the biological mechanisms of DIPG.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.


Pancreatoduodenectomy (PD) is an extensive surgery, and its complications are grave. Acute ischemia of the jejunal loop due to thrombosis of the superior mesenteric vein (SMV) and its branches is one of the most dangerous complications that, although rare, if left untreated leads to abdominal sepsis and death of a patient.A 77-year-old man underwent PD for pancreatic cancer. On postoperative day 2, the patient developed a severe anemia with hypotension. The computed tomography showed acute ischemia of the jejunal loop due to thrombosis. The emergent surgery was performed. The removal of the ischemic intestine and re-anastomoses of the biliary and pancreatic ducts could be performed all at once because necrosis and inflammation were still very mild in early stage.If suspicion for thrombosis of the SMV and its branches is raised, re-laparotomy should be considered. Early re-operation can lead to removal of the ischemic intestine and re-anastomoses in one-step surgery. Pancreatic cancer is one of the most lethal malignancies and is associated with a very poor overall survival, and surgery remains the only option for the possibility of cure for patients with localized pancreatic cancer . PancreaThe most common complications of PD can be divided into four groups: postoperative seromas and abscesses, delayed gastric emptying, hemorrhage (early vascular bleeding), and anastomotic leakage . NeverthWe herein report a case of a male patient who had been diagnosed with acute ischemia of the jejunal loop due to thrombosis of the SMV branches 2 days after PD for pancreatic cancer and was performed the removal of the ischemic intestine and re-anastomoses of the biliary and pancreatic ducts in one-step surgery because necrosis and inflammation were still very mild in early stage.The patient was a 77-year-old man who was diagnosed with pancreatic head cancer with asymptomatic worsening of diabetes mellitus and admitted to our department for elective surgery. The patient’s past history had no obvious problems. Subtotal stomach-preserving PD with lymph node dissection was performed. There was no tumor involvement of the PV and SMV; therefore, no venous reconstruction was performed. Reconstruction was performed by the Roux-en-Y method. The jejunal loop was pulled out through the transverse mesocolon, and then pancreaticojejunostomy and hepaticojejunostomy were performed by retrocolic anastomoses. The pancreatic duct was anastomosed to a small opening on the jejunal wall using eight interrupted 6-0 monofilament absorbable sutures. The pancreatic tube was inserted and secured at the posterior wall of the anastomosis as an external drainage. The biliary duct was anastomosed to the jejunum using 16 interrupted 5-0 monofilament absorbable sutures with a lost tube. Gastrojejunostomy was performed using linear stapling devices by an antecolic anastomosis, and then Braun anastomosis was added. There was no abnormal finding on the reconstructed jejunal loop intraoperatively. After the surgery, the patient was admitted to the intensive care unit under stable condition.On postoperative day (POD) 1, there was a little amount of bleeding from the nasogastric tube. However, no signs of elevated levels of amylase in exudate fluid from the drains and no clinical abdominal tenderness with peritoneal signs were found. On POD 2, the abdomen was without peritoneal signs, audibly with peristaltic movement, and the drains showed no signs of pancreatic fistula and intraabdominal bleeding. However, the patient developed a severe anemia with hypotension. The enhanced abdominal computed tomography (CT) showed acute ischemia of the jejunal loop with a thickened wall Fig. . AlthougIntraoperative findings showed severe venous congestion of the jejunal loop. The intestine appeared to be ischemic but not necrotic Fig. . HoweverHis postoperative course was uneventful except for delayed gastric emptying. The patient was released from the hospital under no anticoagulant therapy on POD 35 after the secondary operation.As surgical and oncologic treatment for pancreatic cancer has been improved during recent years, the indication for PD has been expanded. In the past days, the only truly resectable tumors were those without involvement of the superior mesenteric artery (SMA), celiac artery, hepatic artery (HA), PV, and SMV. However, the past few years have seen the development of a new category of borderline resectable tumors, including tumors that involve <180° of the circumference of the SMA, abut or encase the HA for a short segment, or narrow (or occlude) the PV or SMV for a short segment with surgical options for reconstruction . As a reHowever, identification of the thrombosis of the SMV and its branches after PD in early postoperative course is of great difficulty by fact that clinical symptoms are non-specific and covered by postoperative paralysis of the gastrointestinal tract and modified pain reaction by the administration of the analgesic medications. Furthermore, specific biomarkers for intestinal ischemia have yet to be determined. It has been reported that D-dimer is in part useful to assess acute thromboembolic occlusion of the SMV; however, the use of D-dimer as a marker for ischemia has high sensitivity, but low specificity, and could be used for exclusion of diagnosis at best , 11.Treatment of thrombosis of the SMV and its branches is divided into conservative, interventional, and surgical treatments. The initial treatment goal is cessation of thrombotisation and enabling of the body’s fibrinolytic activity for destruction of the thrombus. Administration of the therapeutic dosage of heparin provides immediate effect. Another possibility is thrombolysis administrated locally using interventional therapy –7. HowevAlthough there are a few reports of acute SMV thrombosis after PD, they are composed of either case reports or very small series of patients with heterogeneous clinical conditions. Therefore, the true cause of acute SMV thrombosis remains unknown . In thisAfter PD, early postoperative thrombosis of the SMV and its branches is a real and potentially catastrophic complication leading to acute bowel ischemia. Awareness of the potential for acute ischemia of the jejunal loop due to thrombosis of the SMV and its branches will allow for early detection and one-step surgery with the removal of the ischemic intestine and re-anastomoses of the biliary and pancreatic ducts all at once because necrosis and inflammation were still very mild in early stage.Written informed consent was obtained from the patient for publication of this Case Report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.


A 60-year-old white woman presented with a 1-year history of melanonychia of the left small fingernail, which she hid with nail polish. There were multiple hyperpigmented bands longitudinally oriented. Of note, the patient had a history of skin cancer and a family history of melanoma.What is the epidemiology of melanonychia?What is the pathophysiology of melanonychia?What evaluation options are available for the diagnosis of melanonychia?What are the treatment options for melanonychia?Melanonychia is characterized as a brown or black hyperpigmentation of the nail. The band usually presents lengthwise along the nail unit and is also known as longitudinal melanonychia (LM) or melanonychia striata . It is i2There are many causes of melanonychia, and the presence of LM can indicate both local and systemic diseases. The major pathophysiological pathways include melanocytic activation, hyperplasia, or the invasion of the nail matrix by a melanin-producing pathogen. Melanocytic activation occurs when melanocytes found within the nail matrix are stimulated to produce pigment, or melanin, without an increase in the total number of cells.5The proper evaluation and testing of melanonychia are important to quickly rule out dangerous pathologies. Clinical guidelines to assess LM were created following the ABCDEF pneumonic. A stands for age and race, B stands for brown or black band or breadth in the nail bed, C stands for change in band morphology, D stands for digit(s) involved, E stands for extension (Hutchinson's sign), and F stands for family history of melanoma.Treatment of melanonychia depends on the underlying pathology. Treating the underlying systemic disease, removing an offending drug, or using antibiotic or antifungal treatments may cause the hyperpigmentation to regress. In the majority of cases, benign causes do not necessitate treatment. In the cases of subungual melanoma , wide local excision, amputation, and sentinel lymph node mapping/biopsy may be indicated.8Although the majority of melanonychia cases have benign causes, it is crucial for clinicians to quickly identify the underlying cause to rule out malignancy. In the case of our patient, a nail bed biopsy and fingernail specimen showed fibrovascular tissue with chronic inflammation and scattered foreign body giant cells. A Grocott's methenamine silver stain showed scattered fungal elements consistent with an onychomycosis. The patient was treated with antifungals and the melanonychia resolved.


Arteriovenous malformation (AVM) of the pancreas is uncommon in the gastrointestinal tract. We present a case of AVM of the pancreatic head in a 59-year-old male. He was admitted to a hospital with hematemesis and tarry stool and referred to our hospital in March 2014 on the diagnosis of pancreatic artery pseudoaneurysm. A computed tomography scan showed the presence of irregular dilated and/or stenotic vessels with meandering in the pancreatic head. Magnetic resonance imaging showed strong enhancement of the conglomeration in the pancreatic head. Selective angiography showed the proliferation of a vascular network in the pancreatic head and an early visualization of the portal vein at the arterial phase. The patient qualified for surgery with a preoperative diagnosis of AVM of the pancreatic head. We performed pylorus-preserving pancreaticoduodenectomy. The histological results confirmed the presence of irregular dilated tortuous arteries and veins in the pancreatic head. Surgical treatment may represent definitive management of symptomatic AVM. An arteriovenous malformation (AVM) is a complex tangle of abnormal arteries and veins linked by one or more direct connections called a fistula or shunt. The number of reported cases of AVM in digestive organs has increased in recent years because of the widespread use of imaging modalities such as angiography, computed tomography (CT), magnetic resonance imaging, and color Doppler ultrasonography. However, the incidence of pancreatic AVM remains extremely low, with fewer than 200 cases reported in the literature since Halpern described the first case in 1968 [A definitive diagnosis is established using angiographic evaluation. Surgery is regarded as the definitive treatment for pancreatic AVM. Here, we summarize the clinical course and radiological findings of a patient with pancreatic AVM and include a review of the associated literature.A 59-year-old male was admitted to another hospital in March 2014 with symptoms of hematemesis and tarry stool. He had a history of hypertension, cardiac infarction, and aortic regurgitation. Laboratory data collected on admission revealed anemia , and he received a transfusion of four units of packed red blood cells. A CT scan showed the presence of irregular dilated arteries in the pancreatic head, and he was diagnosed with pancreatic artery pseudoaneurysm presenting with multiple arterial feeder vessels.The patient was referred to our hospital for treatment. On admission, a CT scan showed the presence of meandering irregular dilated vessels in the pancreatic head Fig.  and an eThe intraoperative examination revealed that there were no abnormal vessels and/or collateral vessels on the surface or around the pancreas except dilated drainage veins at the top of the pancreatic head Fig. . But, seVarious hypotheses have been proposed to explain the origin of AVM. Lande et al.  speculatIn an AVM case series reported by Song et al. , the medMechanisms of gastrointestinal bleeding can be classified into four types: (1) bleeding from a duodenal ulcer due to ischemic injury of the duodenal mucosa by local infarction, resulting in abnormal vessels of pancreatic AVM; (2) bleeding from the pancreatic duct and/or the bile duct through the orifice of the ampulla of Vater; (3) bleeding from eroded vessels in the wall of the gastrointestinal tract by pancreatic AVM; and (4) bleeding from gastroesophageal varices because of portal hypertension due to pancreatic AVM. In our case, no ulcers or varices of the esophagus or stomach were found during the preoperative endoscopy, and no abnormalities were found in the intestine during the operation. Furthermore, no abnormalities were found in the bile duct of the resected specimen. Macroscopically, the exact point of bleeding could not be identified. But, histological examination revealed that dissections were found in the outer media of the arteries in the pancreatic head Fig. . TherefoDiagnosis is usually confirmed by imaging because the symptoms are nonspecific and the incidence of this entity is very low. Angiography is useful for the diagnosis of pancreatic AVM, with the findings of pancreatic AVM characterized by dilated and tortuous feeding arteries, a racemose intrapancreatic vascular network followed by a transient dense pancreatic stain, early venous filling into the portal vein, and early disappearance of the pancreatic stain . Recent In an AVM case series reported by Song et al. , pancreaThe patient presented here underwent pylorus-preserving pancreaticoduodenectomy and had a favorable outcome.In patients with symptomatic pancreatic AVM, surgical resection of the affected pancreas may be the only definitive treatment. Patients with portal hypertension are generally followed carefully because of the potential for the recurrence of gastrointestinal bleeding or rupture of esophageal varices.Written informed consent was obtained from the patient for the publication of this case report and any accompanying images. A copy of the written consent form is available for review of the Editor-in-Chief of this journal.


Objective: A significant subset of patients with migraine headaches has pain relief after neuroplasty/muscular decompression of select cranial and cervical nerves. In the majority of cases, compression occurs secondary to compression of the nerves by adjacent muscles. Previous studies have shown that both surgical decompression and chemical denervation  provide relief of migraine headaches; however, controversy remains. If some migraine headaches are caused by muscular compression, then paresis of the compressing muscles by underlying myopathic/metabolic disease should result in migraine relief in some patients. Methods: We report a case of mitochondrial myopathy causing weakness primarily of the muscles of facial expression and the neck in the context of chronic migraine headaches (>20-year history). Muscle biopsy was obtained to confirm the myopathic diagnosis. Results: There was complete resolution of the patient's migraine headaches that occurred simultaneously with the onset of symptomatic paresis of the muscles of facial expression and the neck. The relief has persisted for more than 10 months. Neurologic evaluation and muscle biopsy confirmed a diagnosis of mitochondrial myopathy. Conclusions: Pathologic paresis/paralysis of facial and/or cervical muscles can result in persistent resolution of migraine headache pain, giving further evidence to the concept that peripheral and/or cranial nerve compression causes migraine headache pain in a subset of patients with a diagnosis of migraine. There is a growing body of evidence that cranial and peripheral nerve compression causes headache pain in a subset of patients with a diagnosis of migraine.A 46-year-old woman with a history of migraine headaches, closed head injury, and temporomandibular joint dysfunction after jaw dislocation presented with progressive weakness, particularly in the face, head, neck, and proximal upper extremities. The weakness was first noted 10 months earlier. The weakness was initially noted in the right upper eyelid (ptosis) and the right face. The facial weakness then progressed to bilateral facial weakness. There was no history of botulinum toxin treatment.Physical examination revealed cranial motor weakness, including brow ptosis, eyelid ptosis, and the absence of corrugator or procerus function bilaterally. Jaw strength was normal.Further inquiry into her neurologic history revealed that her migraine headaches primarily initiated with pain in the supraorbital areas bilaterally with tenderness over the supraorbital notches. The patient reported frequent migraine headaches that began in her third decade of life. She reported at least 2 disabling migraines per month. The migraines worsened in intensity in her fourth and fifth decades. Contemporaneously, with the development of symptomatic facial and cervical weakness , the patient's migraines ceased. This resolution has persisted over the following 10 months.Initially, myasthenia gravis was considered, but testing was negative. A deltoid muscle biopsy was performed. Biopsy results were consistent with mitochondrial myopathy.Compression of cranial and cervical nerves occurring in the context of migraine headaches and the relief of migraine headaches by chemical or surgical decompression of these nerves have been a subject of significant study over the past few years. Decompression/neuroplasty of compressed nerves can provide objective headache relief in 80% to 90% of select patients and has been demonstrated in prospective, placebo controlled trials of the supraorbital and supratrochlear nerves , the zygomaticotemporal nerve , and the greater occipital nerve (C2 subdivision).In the overwhelming majority of cases with a compressive neuropathy mechanism, the compression is caused by muscle , but to a lesser extent there are other causes including bony and cartilaginous impingement .3Nevertheless and despite these data, controversy exists over the role and adequacy of these trials and reports.This case report approaches this controversy from a different perspective: namely, a patient with established migraine headaches that resolved after development of craniofacial and cervical muscle weakness due to muscle biopsy–proven mitochondrial myopathy.This case is the first case to our knowledge that reports migraine resolution in the context of the development of myopathic disease. It generates questions for further research such as what is the frequency of migraine resolution/improvement in other cases of nontraumatic pathologic facial/cervical weakness.


Montivipera raddei species complex (MRC) that contains rare and endangered viper species limited to Iran, Turkey and Armenia. We also investigated the current distribution of MRC to locate unidentified isolated populations as well as to evaluate the effectiveness of the current network of protected areas for their conservation. Present distribution of MRC was modeled based on ecological variables and model performance was evaluated by field visits. Some individuals at the newly identified populations showed uncommon morphological characteristics. The distribution map of MRC derived through modeling was then compared with the distribution of protected areas in the region. We estimated the effectiveness of the current protected area network to be 10%, which would be sufficient for conserving this group of species, provided adequate management policies and practices are employed. We further modeled the distribution of MRC in the past  and under two scenarios in the future (to 2070). These models indicated that climatic changes probably have been responsible for an upward shift in suitable habitats of MRC since the Last Glacial Maximum, leading to isolation of allopatric populations. Distribution will probably become much more restricted in the future as a result of the current rate of global warming. We conclude that climate change most likely played a major role in determining the distribution pattern of MRC, restricting allopatric populations to mountaintops due to habitat alterations. This long-term isolation has facilitated unique local adaptations among MRC populations, which requires further investigation. The suitable habitat patches identified through modeling constitute optimized solutions for inclusion in the network of protected areas in the region.We determined the effects of past and future climate changes on the distribution of the  Global climate change is responsible for large-scale alterations in geographic distributions of animal and plant species worldwide ,2. The mIn general, current geographic distributions of taxa can be explained by the patterns of past climate changes, especially relative to glacial periods ,8. The iMontivipera raddei species complex (MRC) contains rare species with small allopatric populations [Montivipera kuhrangica [M. latifii [M. raddei raddei [M. raddei albicornuta [M. kuhrangica, M. r. albicornuta, and M. latifii, which are endemic to Iran and exceptionally rare [M. r. albicornuta and M. latifii- for antivenin production [The ulations –13 that ulations . Followihrangica , M. lati latifii , M. raddi raddei , and M. icornuta . The whoicornuta ,12,18. Hlly rare ,19. Illeoduction  is also M. kuhrangica, as the most southern distribution among this complex in Zagros Mountains [The distribution of MRC has not been thoroughly investigated and factors limiting its distribution are not understood. It is known however, that MRC populations appear in small isolated patches ,12,21. Tountains  indicateEcological Niche Models (ENMs) are fundamental tools for conservation and management of species ,23, espeThe global climate has become considerably warmer since the Last Glacial Maximum 21 kyr BP  . We therExplanatory variables were prepared for two modeling approaches; a general model to predict the current potential distribution of MRC, and climate-only models to evaluate possible changes on bioclimatic niche under climate change scenarios. For the general model, we used three categories of eco-geographic factors, including climate, topography and land-cover  that havr < 0.8) variables. Using the Shuttle Radar Topography Mission (SRTM) elevation model, three topographic explanatory variables were compiled: elevation and slope as the most important factors describing topographic context, as well as Solar Radiation Index (SRI), calculated for a period between April to June to depict total amount of incoming solar insolation (WH/m2 year). We considered SRI because the regarded period coincides with MRC post-hibernation, when receiving thermal energy is an important factor affecting these species. SRI was calculated in ArcGIS 9.3 Spatial Analyst Tools using the Digital Elevation Model (DEM) of the study area. For land-cover data we used cover types from Globcover v. 2.1 map [Because of the high autocorrelation between climatic variables, we extracted values for these variables from occurrence points of the species and screened them to low-correlated  (∼ 21 kyr BP), present and future (average for 2061–2080). Herein, we developed an ENM for the present climate conditions by using 2.5 arc-second variables and subsequently projected it onto the past and future conditions. The bioclimatic data for the LGM were developed and mapped by Paleoclimate Modeling Intercomparison Project Phase II (PMIP2) based on two different global circulation models, GCM: the Community Climate System Model (CCSM), ), and thBecause of the cryptic nature of the species concerned and shortage of information on their ecology and distribution range, a set of occurrence data from 46 point localities for MRC was compiled based on data obtained from Herp-Net database as well as field surveys conducted by the authors in several years within Iran. Our fieldwork included searching suitable habitats for vipers and recording any observations. Point localities that we obtained cover the entire natural distribution area of the MRC along highland territories of Iran, Turkey and Armenia. Ecological niche modeling was performed using maximum entropy (Maxent) algorithm . We seleThe training area of an ENM preferably comprises environmental conditions that are accessible for the target species . In thisTo make better use of the small sample size, we applied the cross-validation method in Maxent 3.3.3, where the occurrence data was randomly split into 10 equal-sized folds, and training models were created by eliminating each fold in turn. The eliminated folds were then considered to test the performance of the training models using receiver operating characteristic (ROC) plots. We used ROC as a measure of discrimination capacity to represent the models’ ability to predict species presence and absence locations by plotting sensitivity (true positive) against 1 –specificity  ,44 and uWe also generated 1000 random points within the baseline climatic niche, extracted annual mean temperature of climate change scenarios for each point, and averaged this parameter through random points. Doing so helped us get a better understanding of the changes in temperature throughout the years.http://protectedplanet.net.Evaluating the level of conservation achieved by protection areas can be done by considering species occurrence data –48 or usResults of ecological niche modeling showed that suitable habitats of MRC are patchily distributed in higher elevations of the Zagros, Alborz, and Kopet Dagh mountains within Iran, and in Ararat and lesser Caucasus in Turkey and Armenia.Interestingly, the general model with all eco-geographic variables showed that presence of MRC is predicted in areas where no previous records of occurrence exist. Reinforcing our hypothesis, during production of our paper we confirmed new localities for MRC in suitable patches in Alvand mountain in the west and Bozgoush area in the northwest of Iran  that werThe ROC plots indicated high average AUCs and low SD of AUC and omission error, reflecting the high predictive performance of our ENMs. Average AUCs for cross-validated general model and baseline climate change model was 0.969 and 0.981, respectively, where the low SD of AUCs and average omission error of the models reflected high precision .An overlay of the distribution map resulted from general modeling with the map of national protected areas of Iran, Turkey and Armenia indicated that 7.74% of suitable areas (with a probability of 0.33–0.66) and 2.19% of highly suitable areas (with a probability of 0.66–1) are protected by the existing protected area network.Based on results from the general model, distribution of the threatened MRC is largely determined by bioclimatic variables rather than biophysical variables. The jackknife analysis revealed that, based on the difference between regularized gains of variables, annual mean temperature, minimum and mean temperature of past hibernation period (May), minimum temperature of coldest month and distance to mosaic grassland (50–70%) / shrubland or forest were the most informative explanatory variables affecting the distribution of MRC in highland territories of the study area. However, the relative contributions of the eco-geographical variables to the general model  indicateThe importance of bioclimatic variables under climate change scenarios indicated that thermal tolerance is more limiting for MRC distribution than humidity. We found that annual mean temperature was the most important climatic variable followed by minimum temperature of the coldest month, annual precipitation and maximum temperature of the warmest month.According to the results of the climate change models, the predicted past, current and future ranges of habitat of MRC are likely to be negatively affected by climate change scenarios . We founAfter confirming changes in the bioclimatic niche of MRC, we tested our hypothesis of upward altitudinal shift by tracing the changes of average altitude within probability classes of climatic niche models. As we expected, our results revealed that average altitude within probability classes is higher for future scenarios in comparison with past and current conditions . By compMontivipera species across the Zagros, Alborz and Kopet Dagh Mountains in Iran and Ararat and lesser Caucasus mountains in Turkey and Armenia. Currently, Lar National Park in central Alborz, home to Montivipera latifii [Allopatric populations of the MRC are mostly located within a matrix of presumably unsuitable habitat, indicating characteristics of relict and highly threatened populations . As we h latifii , is the  latifii . HoweverAs expected, historical biogeography of MRC plays a major role in defining the current distribution of this species complex, with altitude identified as the variable that best explains the patchy distribution pattern. In general, apart from topographic and climatic variables, vegetation-related factors contributed substantially to explaining the current distribution of MRC. Vegetation preferred by MRC is mostly monotonous vegetation of pastures above tree-line and artificial forests in mountains  as indicMontivipera raddei species complex has faced continuous habitat contractions throughout its biogeographic history starting from thousands of years ago and continuing well into the future. Modeling the distribution of MRC in the past suggested that the gradual rise in temperature in most of the Iranian plateau after the last Maximal Glacial period [et al. who stated “evolution of tolerances of terrestrial organisms to cold temperature should be more frequent than the evolution of high temperatures” [l period  forced tratures” .The upwaMacrovipera lebetina that occupy lower elevations within the distribution range of MRC. It has been proposed that the presence of this species may have led to upward movement of MRC species [Macrovipera and Montivipera in much of their range, but locally, as in parts of Armenia and eastern Turkey, Macrovipera lebetina and MRC are sympatric from 1200 m up to 2000 m asl. [Although our results clearly indicate that the present distribution of MRC can be related to the response of these species to climate change in the last 21000 years and that alterations in their niche is a response to the general trend of climate change, other factors could have contributed to the movement of these species from lowlands to high elevations. A possible alternative explanation for the upward shift from warmer to colder habitats is competition with other species such as  species . Evidenc0 m asl. .A second alternative explanation concerns anthropogenic activities in the lowland that could have caused local extinctions in MRC populations, leading the remaining populations to move to higher elevations, consequently causing their climatic niche to become colder than the past. However, not all lowland habitats at the distribution range of MRC have experienced alterations by human activities such as agriculture, ruling out this explanation as a prevalent cause of shift in MRC habitat suitability. Some important regions in distribution of MRC with unaltered lowland habitats include Amir-Abad (Takab), Lar National Park and Makoo in Iran and Khosrov and Shikahokh forest reserves in Armenia. The most important anthropogenic effects on MRC are in fact taking a toll on the species today. Illegal collection and overgrazing in the current distribution range takes place in the high elevations and can threaten long-term survival of these species.Lacerta schreiberi.Our models for the future distribution of MRC predicted a further upward shift in distribution of suitable habitats until 2070, leading to significant habitat loss due to global climate warming. Spatial fingerprints of climate change are usually associated with changes in the distribution of species at latitudinal or altitudinal extremes (see Results in –56). SucIntegrating molecular studies with ecological niche modeling allows for better understanding the evolutionary scenarios and responses of these species to climate change . We suggOverlapping the distribution map for MRC with the network of protected areas in the region showed that 10% of suitable habitats are being protected. This seems to be an acceptable coverage of the distribution range for these species. It must be noted that due to the cryptic nature of MRC, their presence in many of the protected areas in the region is not yet known. Communicating our results with the managers of such protected areas will play an important role in the conservation of these species. After confirming the presence of MRC populations within their managed areas, protected area managers will then be able to consider the critical habitats of these species within their management planning.Iranolacerta genus [It is of paramount importance for the conservation of MRC to adopt an adaptive approach to reconsider the network of protected areas in the region. Establishing additional reserves based on suitable habitats identified in our models can considerably increase the effectiveness of MRC conservation. Moreover, according to the distribution pattern of reptiles in the mountainous zones of the Iranian plateau, the suitable habitats that we identified overlap with the distribution of syntopic species such as ta genus  which arEstablishment of new protected areas, although necessary, will not ensure the viability of MRC populations, unless effective management would be practiced. The vegetative structure of MRC habitats makes them attractive to nomadic herders, exposing these valuable habitats to overgrazing . Such huS1 Table(DOCX)Click here for additional data file.