CAD have not been extensively investigated. Our review of the current data concludes that the bases of paraoxonases involvement in atherosclerosis are poorly understood and that this issue requires future comprehensive, multi-centered studies.Paraoxonases (PON) are three enzymes  that play a role in the organism’s antioxidant system; alterations in which are associated with diseases involving oxidative stress. In this review, we summarize the evidence of PON related to the pathogenesis of coronary artery disease (CAD) and atherosclerosis. We searched three electronic databases  with no date limit. All of the articles selected investigated PON enzymatic activity and/or PON gene polymorphisms. The selection focused on PON in relation to atherosclerosis, CAD and myocardial infarction. The exclusion criteria were a sample size <100 patients, non-human studies, editorials and systematic reviews without restrictions on the country of origin. With these criteria, we identified thirty-five prospective studies published between 1986 and 2014 with a total of 28,164 participants. The relationship between PON gene polymorphisms and CAD was not conclusive, but most studies support the concept that alterations in PON1 enzymatic activity levels do influence atheroma formation. Conversely, relationships between PON2 and PON3  The paraoxonases (PON) are enzymes involved in oxidative stress, in the atherosclerosis process and, consequently, in vascular disease. However, their specific role in these clinical derangements is still under debate, and we sought definitive conclusions by evaluating published studies.The PON family contains three enzymes: PON1, PON2 and PON3. Their genes are located adjacent to each other on chromosome 7q21-22 ,5. PON1 PON1 was initially described as an organophosphate hydrolase, and its role in insecticide poisoning has been extensively reported . SubsequPON2 and PON3 are also able to hydrolyze lactones similar to PON1, and they have also been implicated in the atherosclerosis process. Nevertheless, their modes of action have been shown not to be exactly equivalent to that of PON1, and further investigations are needed to fully clarify their roles. The antiatherogenic effect of PON2 could be attributed to the protection of mitochondria against oxidative stress, while PON3 has been shown to be a protective factor against obesity. As such, new and interesting lines of research are opened up. To summarize, the three members of the PON family are related genetically, possess lactonase activity and are involved in the atherosclerosis process .PON gene polymorphisms, their enzymatic activities and their correlation with atherosclerosis.The aim of this systematic review is to update and clarify the scientific evidence available on PON enzymes and their roles in cardiovascular disease. We provide, here, a novel approach integrating The search was performed in three electronic databases: PubMed, Scopus and Cochrane. Article selection was performed in July 2014, and no date limit was applied to articles selected. Studies included were restricted to those on humans and to English-language journals. Search terms were combined using Boolean operations. The search terms included: (“Paraoxonases” OR “PON”) AND . Initially, the referenced articles were manually screened independently by two investigators of the team. The first screening selection was based on the article’s title and a second screening on the abstract. All duplicate publications were omitted.All of the articles involved in PON enzymatic activity and/or PON gene polymorphisms were selected. The selection focused on the PON relationship with atherosclerosis, coronary artery disease (CAD) and myocardial infarction (MI). Other diseases and comorbidities were excluded.The exclusion criteria were a sample size of <100 patients, non-human studies, editorials and systematic reviews. No country distinctions were applied.Data were extracted and pooled and included: year of publication, sample size, type of study, disease observed and the polymorphisms studied. Because serum PON1 possesses a wide catalytic versatility and is able to hydrolyze a variety of substrates , the mean = 215) and with 201 contributions considered irrelevant based on the titles and 37 on the abstract, the selection was reduced to 49 full-text articles. Subsequently, studies (n = 14) with missing data or without compliance with inclusion or exclusion criteria were discarded. Finally, 35 manuscripts were included in this systematic review [The initial electronic search of the above-mentioned databases identified 502 articles . After edies n =  with misc review ,45,46,47The overall study characteristics are displayed in vs. the disease. The strongest association was found with PON1 Q192R polymorphism, specifically reporting a protective role of the 192Q allele and a deleterious effect of the 192R allele [We found that the influence of the several PON genetic polymorphisms on CAD was not generally substantiated. Several studies ,34,42,44R allele ,24,42,44R allele ,34 in whR allele ,33,34. OR allele  suggesteR allele ,33 stateR allele ,33,34,42R allele ,43,45,46R allele ,41,43,45R allele ,40 note vs. white Americans [vs. Chinese populations [vs. no association or positive association vs. negative association , the current use of synthetic substrates limits the interpretation of the data, since it is not clear whether these measured activities reflect the real endogenous physiological activity of the enzyme. Experimental evidence suggests that, essentially, the lactonase assay measures PON1 that is tightly bound to HDL particles, while the esterase assay measures the tightly-, as well as the loosely-, bound enzyme . The difper se or to coincidental differences in allelic frequencies between cases and controls. This is especially true when the reported sample sizes are small, i.e., gene-association studies should be performed with a large sample size involving at least several hundred participants. The extent of the genetic contribution to complex diseases is difficult to ascertain, and the individual contribution of each gene is likely to be modest. Thus, taking into account that the analysis of allele frequencies uses a simple χ2 test, the observed associations between a given polymorphism and a particular disease may be merely coincidental. Since a p-value of 0.05 is accepted as confirmation of statistical significance, by definition, there is a 5% possibility that a positive result is obtained by chance alone. Increasing the sample size minimizes this risk [Further confusions arise from serum PON1 activity being strongly determined by the enzyme genotype ,52. Henchis risk .Of note is that we found a higher rate of association between PON1 gene polymorphisms and CAD in the articles from 2004 onward, compared to the earlier studies. Of the articles published in the last 10 years, 64% showed an association between PON1 gene polymorphisms and CAD, in contrast to 42% of the articles published before 2004. This observation may be related, perhaps, to changes in the methodology and/or design, and changes in these results may be expected in future investigations.There is a lack of consensus on the definitions of the outcomes studied, including oxidative stress, arteriosclerosis, artery wall thickness and CAD. Some articles used, as inclusion criteria, the risk factors for arteriosclerosis and previous atherothrombotic events , while ovs. cardiovascular disease. This is relevant, since experimental studies in animals and in cultured cells suggest that these two enzymes play an important role in the protection against oxidative stress [i.e., their contributions to atherosclerosis and CAD need elucidation. Further, PON1, PON2 and PON3 genes are in genetic disequilibrium. This may imply that the three enzymes influence each other in complex, but as yet unknown, ways [We could find no conclusive relationship between PON1 polymorphisms and CAD or MI. However, there is a consensus on polymorphisms influencing PON1 enzymatic activity, both in the healthy population and in CAD patients. Further, most studies support the concept that alterations in PON1 enzymatic activity levels are associated with oxidative stress, a higher degree of atheromatous plaque formation and poorer clinical outcomes. Nevertheless, there appears to be a step missing that precludes us relating the PON1 genetic polymorphisms with outcomes (CAD or MI). Indeed, variable expressions of PON1, PON2 and PON3 have been detected in macrophages and smooth muscle cells of human atheroma plaques ,55. Howee stress ,58,59,60wn, ways . Alteratwn, ways .This systematic review has sought to highlight the gaps in our knowledge of the role(s) that PON enzymes play in the pathogenesis of CAD. We propose the implementation of international, multicenter, multiethnic studies with larger sample sizes to analyze PON1, PON2 and PON3 genetic polymorphisms, the circulating enzyme concentrations and activities and relating these findings in the peripheral blood to changes occurring in tissue during the atherosclerosis process.


More than fifty parameters were evaluated before and after irradiation at several time points up to 200 days. A partial least square discriminant analysis showed a good distinction of TBI from PBI situations that were equivalent to 5 Gy. Furthermore, all the animals were pooled in two groups, TBI (n = 6) and PBI (n = 12), for comparison using a logistic regression and a non parametric statistical test. Nine plasmatic biochemical markers and most of hematological parameters turned out to discriminate between TBI and PBI animals during the prodromal phase and the manifest illness phase. The most significant biomarkers were aspartate aminotransferase, creatine kinase, lactico dehydrogenase, urea, Flt3-ligand, iron, C-reactive protein, absolute neutrophil count and neutrophil-to-lymphocyte ratio for the early period, and Flt3-ligand, iron, platelet count, hemoglobin, monocyte count, absolute neutrophil count and neutrophil-to-lymphocyte ratio for the ARS phase. These results suggest that heterogeneity could be distinguished within a range of 2.5 to 5 Gy TBI.In case of a mass casualty radiation event, there is a need to distinguish total-body irradiation (TBI) and partial-body irradiation (PBI) to concentrate overwhelmed medical resources to the individuals that would develop an acute radiation syndrome (ARS) and need hematologic support . To improve the identification and medical care of TBI versus PBI individuals, reliable biomarkers of exposure could be very useful. To investigate this issue, pairs of baboons (n = 18) were exposed to different situations of TBI and PBI corresponding to an equivalent of either 5 Gy  Exposure to a nuclear or radiological (NR) event would lead to a heterogeneous population, with different radiation doses and degrees of shielding. The effectiveness of the medical care that follows depends on early triage and diagnosis of the victims to separate the “worried well” from the irradiated victims, especially in case of a large scale event. Moreover, the discrimination between TBI and PBI patients is of vital importance as they will have a different clinical outcome. Medical management relies on physical, clinical and biological dosimetry. In accidental or malevolent situations, physical dosimeters would not be worn. Clinical signs and symptoms would therefore be the main tools for early triage . Thus, tThe dicentric chromosome assay (DIC) is the gold standard for radiation dose estimate which is based on the scoring of these unstable aberrations in peripheral blood lymphocytes. In addition to the dicentric frequency, the distribution per cell can also be used to identify heterogeneous exposures. However, there is no linear relationship between the respective volumes of peripheral blood lymphocytes and bone marrow exposed. Moreover, DIC cannot account for radiation-induced tissue functional effects depending on the dose delivered to a given organ, the irradiated volume and the dose distribution. Indeed there are regional variations in clinical consequences for each organ . FurtherHere, we assessed the feasibility of using several biomarkers to identify PBI versus TBI at different time windows after exposure. The baboon model was chosen for its genetic and physiological proximity to humans and its size, which allowed us to take in consideration the impact of corpulence in dose distribution . Moreove9/L with obvious signs of petechiae or the hematocrit less than 20%. Ampicillin (50 mg/kg/day) and gentamycin (1.5 mg/kg/day) were provided during neutropenia (ANC lower than 0.5 x 109/L) and cefalexin (1 mg/kg/ day for 3 days) during prolonged febrile periods above 39°C.The twenty-one adult male baboons weighing 23.2 ±5.3 kg used in this work were housed in the nonhuman primate facility of the French Army Biomedical Research Institute (IRBA), as described in previous works –9. The e60Co source [The animals were anesthetized and then exposed to a o source –9. Two bTime to onset, severity and duration of 7 clinical signs were recorded: vomiting, erythema, diarrhea, petechiae, hair loss, fever, and body weight loss. Each symptom was quantified  depending on presence and severity. Measurements were made at 22 different time points: before irradiation and at 1hour (h), 6h, 12h, 1day (d), 2d, 3d, 4d, 5d, 7d, 10d, 14d, 17d, 21d, 24d, 28d, 35d, 42d, 60d, 90d, 120d and 200d after irradiation.Nine hematological parameters were performed on a Pentra 120 analyzer  and using May-Grünwald Giemsa stain : ANC, ALC, MONO, red blood cells (RBC), PLT, Hb level, hematocrite and mean corpuscular volume (MCV). Additionally, the neutrophil-to-lymphocyte ratio (NLR) was calculated and also used as a parameter. Measurements were made at the same 22 time points used for clinical dosimetry.The following 7 coagulation and fibrinolysis factors were evaluated: activated partial thromboplastin time, prothrombin time, thrombin time, fibrinogen level, factor V, Fibrin d-dimer and monomer . Furthermore, the following 26 plasmatic biomarkers: albumine, total protein, chloride, sodium, potassium, lactate, alanine aminotransferase (ALT), AST, amylase, CK, LDH, alkaline phosphatise (ALP), cholesterol, triglycerides, urea, creatinine, glucose, citrullin, EPO, Flt-3 Ligand, Iron, C3c, C-reactive protein, haptoglobin, orosomucoid, transferring were measured using Hitachi 912 Analyzer . Citrulline was assessed by high-performance liquid chromatography . EPO (Erythropoietin) and Flt-3 Ligand were assessed using enzyme linked immunoassay . Most coagulation, fibrinolysis factors and plasmatic biomarkers were measured at 17 different time points: before irradiation and at 1d, 2d, 3d, 4d, 5d, 7d, 10d, 14d, 21d, 24d, 28d, 42d, 60d, 90d, 120d and 200d after irradiation.Additionally, hematopoietic bone marrow (BM) colony-forming units from exposed and shielded humerus were evaluated before irradiation and at 1d, 42d and 200d after TBI and PBI (as described in ). These in vitro exposure  of blood from two animals.The anubis baboon has a diploid chromosome number of 42 with a minute akrocentric Y chromosome. Dicentrics frequency and distribution per cell were evaluated (2 parameters) before exposure and at 1h, 6h, 1d, 28d and 200d after irradiation (6 time points). Dicentric frequency was determined for at least 250 lymphocytes (or 100 dicentrics) per sample. The u-value of the dicentric distribution was calculated to determine if the exposure was inhomogeneous (PBI) and the Dolphin method  was usedThe analysis was based on three independent statistical approaches. A first general analysis method was carried out on all the data of all 5 Gy equivalent baboons to validate the model. In the following approaches, the analysis of each biomarker was done by comparing the combined PBI data with the combined TBI data.A soft independent modelling of class analogy using a non-linear iterative partial least square discriminant analysis (PLSDA) using SIMCA Version11.5  was carried out on 11331 (of the 12950 expected) individual values from fourteen TBI and PBI baboons equivalent to a 5 Gy global exposure. The expected values are the product of 51 biological and clinical markers multiplied by their experimental times (925 variables), multiplied by 14 baboons. The 1619 missing values correspond to data that could not be recovered for technical or logistical reasons that led to insufficient quality or quantity of sample. This first general analysis method allows the classification of individuals based on a great number of samples and was used to validate the experimental radiation model.As a second approach, all the animals were pooled in two groups, TBI (n = 6) and PBI (n = 12) for comparison employing univariate logistic regression analysis . This regression was performed to assess odds-ratio (OR) which quantify the association probability between a dichotomic variable (TBI vs PBI exposure) and each of the independent clinical or biological factors susceptible to influence it . Corresponding 95% confidence intervals, p-values (chisq) were generated. We also calculated the area under a ROC (receiver-operator characteristic) curve providing a reasonable indication of overall diagnostic accuracy. ROC areas of 1.0 indicate complete agreement between the predictive model and known exposure status and thus a clear distinction between partial and total body irradiation. Statistical significant frequency differences in e.g. vomiting or diarrhea were calculated using chi-square statistics. All calculations were performed using SAS .Thirdly the Mann-Whitney non parametric rank test was carried out on all data to analyse the potential of each clinical or biological parameter to discriminate between the combined TBI data and the combined PBI results for a given time independently of pre-irradiation values.The comparison of pairs of animals with the same exposure was only preformed for the DIC assay as this marker is already the reference for the classification of exposure victims.Body dosimetry showed an average gradient of dose distribution front-to-back equal to 2.9 for both TBI and the exposed side of PBI. For PBI, the dose delivered to shielded areas was roughly 6% of that delivered to exposed areas.With respect to clinical parameters, petechiae were observed around 15d for TBI baboons only. Furthermore, regarding animals for which cutaneous areas were exposed to doses equal to or higher than 7.5 Gy (whatever TBI or PBI situation) erythema was observed at 2d to 6d and hair loss from 21d.PLSDA applied to the 14 baboons exposed to an equivalent of 5 Gy showed a very good validation of the model  and a clUsing a univariate logistic regression on data of pooled animals , 23 variables (out of 925) were assessed as either significantly associated with the exposure or representing complete separation of the TBI from the PBI data set at certain time points after irradiation . VariablConcerning the Mann-Whitney test, the same parameters were identified for longer time windows. More precisely the comparison of mean values from 9 plasmatic biochemical markers and most of hematological parameters appeared significantly different between groups of baboons that received either a PBI or a TBI during the prodromal phase (0.25d–7d) and the manifest illness phase (10d–28d). The most significant biomarkers of exposure for the early period were AST, CK, LDH, urea, EPO and coagulation factor V . The mosFor the DIC assay specifically the results were analysed per pair of animals as this marker is currently the reference for the classification of exposure victims. The u-values were most effective at classifying partial irradiations 1d after exposure: 92%. The average estimations for this time are shown in The numbers of BM cells capable of dividing  in the exposed areas showed a dose-dependent decrease 1d after exposure. A start of recovery could be seen at 42d .To assess the impact of frequent blood sampling on hematologic status, a group of three age-matched baboons was used as sham-irradiated individuals. Twenty-one days after sham-irradiation, red blood cells and haemoglobin levels were in average 96% and 99% respectively those of base line values.Predicting the damage undergone by individuals externally exposed to ionizing radiation following an unexpected nuclear or radiological event is a complex issue. An event like this would lead to a diverse injured population, with different radiation doses and degrees of bone marrow shielding. This diversity was reproduced here by the inclusion of pairs of baboons with different dose-equivalent exposures in two groups, TBI and PBI, which are compared. The baboon model was chosen for its genetic and physiological proximity to humans and its size, which allowed us to take in consideration the impact of corpulence in dose distribution.Radiation injury might not be an emergency in comparison with blast, but haemorrhage and trauma, exposure to severe radiation doses and/or combined injuries still require rapid clinical evaluation with estimation of both radiation dose and heterogeneity . Indeed,The goal was to identify biomarkers of exposure that could contribute to patients’ diagnosis and prognosis using deployable biodosimetry tools. We therefore evaluated in baboons the capacity of a few biomarkers to discriminate between different situations of TBI and PBI equivalent to a global exposure in the range of 2.5 Gy to 5 Gy which accounts for documented radiation accidents. Indeed baboons exposed to TBI from 2 Gy develop a classical acute radiation syndrome  close toThe analysis was based on three independent statistical approaches. A first general analysis method was PLSDA and it was carried out on all the data of all 5 Gy equivalent baboons. The fact that TBI baboons results were similar (plotted together) and well separated from PBI validated a model that intended to discriminate partial from total exposures. In the second (univariate logistic regression) and third (Mann-Whitney) approaches, the analysis of each biomarker was done by comparing the combined PBI data with the combined TBI data.Here, two baboons required irradiated blood cell transfusions, one animal exposed to 5 Gy TBI and the other to 7.5 Gy / 2.5 Gy TBI. The latter was euthanized on day 25 because of an irreversible bone marrow aplasia. Thus, the course of exploration in this study covered not only the period of diagnosis but also the manifest illness phase when patients’ clinical review could be required for treatment decision making. Furthermore, the assessment of two different equivalent doses was aimed at testing the robustness of the identified biomarkers to distinguish TBI and PBI.Although a relevant early bio-indicator of exposure for TBI –6, CRP dNot surprisingly hematologic parameters were able to make the difference between our models of TBI and PBI, as the latter were mostly designed in terms of percentage of BM sparing. Thus ANC, ALC, Hb, MONO, PLT and more especially Flt3-ligand as an early predictor , were stIron level is also related to hematopoietic tissue response and the TBI group showed from 5d to 21d a durable increase that may be linked to intravascular hemolysis. Hb level decreased by 8% on average in both groups between 2d and 5d which is a common feature of radiation-induced silent hemolysis. Moreover, preliminary data suggested that EPO plasmatic levels could be a usable biomarker from 7d or even more 10d after irradiation, the greater the volume of exposed body the higher the EPO level.Different enzymes such as AST, LDH and CK, known markers of tissue injury, rose greatly early after exposure with higher levels following TBI. AST increased whereas ALT did not which may account for general visceral injury affecting the heart, the liver, skeletal muscle and kidneys. The great content of LDH in RBC could account for hemolysis, preceding iron increase. CK exhibited the strongest increase very probably in connection with skeletal muscle disorder in inflammatory context. Urea increased in both irradiation situations but greater after TBI reflecting a transient kidney dysfunction justifying a mechanistic study.Additional parameters that would be easy to deploy  such as the PB and reticulocyte count  could beThis study strongly suggests that among the numerous parameters investigated in baboons irradiated within the range of 2.5 to 5 Gy, several bio-markers are capable of distinguishing the type of exposure at least within the dose range studied.In practice, in case of a large size NR event, a consensus radiation categorization such as METREPOL  would be employed as it provides early diagnosis and clinical re-evaluation of irradiated patients based on clinical signs and symptoms, and lymphocyte count kinetics . The par


Background. Short-lasting unilateral neuralgiform headache with conjunctival injection and tearing (SUNCT) syndrome is an unusual cause of headache, mainly described in older adults, and is rare in children. Pain attacks may be severe, frequent, and prolonged. The therapeutic benefits of many drugs are disappointing. Patient and Methods. A 12-year-old boy suffered severe headache and toothache for 20 days. As treatment with nonsteroidal anti-inflammatory drugs, anticonvulsants, and steroids proved ineffective, he was treated with ipsilateral multisite subcutaneous injections of botulinum toxin A 70 U around the orbit, the temporal area, and the upper gum. Results. The pain had reduced in frequency and severity by the fourth day after treatment and had completely disappeared after 7 days. There were no side effects or recurrence during a subsequent 17-month follow-up period. Conclusion. Botulinum toxin A can be used to treat the first episode of SUNCT in children over the age of 12 years.  Short-lasting unilateral neuralgiform headache with conjunctival injection and tearing (SUNCT) syndrome is an unusual cause of headache and is mainly found in middle aged or older patients. It is rare in children. The clinical features of SUNCT syndrome are a transient onset of severe unilateral orbital pain, accompanied by ipsilateral conjunctival injection and tearing. It is classified, along with cluster headache and paroxysmal hemicranias, as a trigeminal autonomic cephalalgia (TAC). SUNCT syndrome may be difficult to diagnose and challenging to treat. Recently, gabapentin, lamotrigine, oxcarbazepine, and topiramate have been reported to have some therapeutic effects, but the extent of the therapeutic benefits of anticonvulsants and nonsteroidal anti-inflammatory drugs (NSAIDs) is unsatisfactory in many cases. Here, we describe the successful use of botulinum toxin A in the treatment of SUNCT syndrome in a 12-year-old boy, in whom a number of standard drug treatments had proved ineffective.The patient, a 12-year-old boy, was admitted to the Pediatric Department of our hospital in April 2013 with a 20-day history of severe paroxysmal unilateral headache and toothache. The weight of the patient is 50 kg. He complained of spontaneous pain in the left orbital and temporal areas, accompanied by severe pain in the left upper tooth . He experienced 10 pain attacks each day that resolved spontaneously after about 1 minute, which mainly occurred during daytime and were accompanied by redness and tearing of the ipsilateral eye, a running nose, and left-sided facial flushing. Clinical examination revealed left facial hyperalgesia but no other abnormality. Cranial magnetic resonance imaging (MRI), angiography, and venography were normal. Lumbar puncture revealed normal cerebrospinal fluid pressure and biochemical and cytological profiles. Routine blood tests were normal, as were the serum C-reactive protein concentration, erythrocyte sedimentation rate, and an autoimmune screen.Oral carbamazepine 200 mg three times a day was commenced, but there was no change in the severity or frequency of pain attacks. The patient had allergic reaction after four-day use. Allergic symptoms include sample urticaria rash on his face and both legs. The rash was itchy and faded when pressed. Thus, carbamazepine was discontinued immediately. After transfer to our department, gabapentin 100 mg was administered orally three times a day (the reason to use the low dose was to prevent side effects), without relief. Similarly, pregabalin (75 mg twice daily), indomethacin (25 mg three times daily), flunarizine (5 mg at night), ibuprofen (300 mg four times daily), topiramate , and methylprednisolone (80 mg intravenously once daily) were used, 7–10 L/min of pure oxygen was used for 10–20 min per day, and 2% of lidocaine 2 mL nasal drops (once daily) was trialed for 4 days, without obvious improvement. The drugs were changed in a short time because they could not relieve the pain and the patient's parents urged us to change drugs. In this situation, we considered trying botulinum toxin A treatment. We had given a clear and comprehensive description of the indication, the usage, and the risks of the botulinum toxin type A to the child and his parents prior to medication. And the parents signed the informed consent. With the agreement of his parents, botulinum toxin A treatment was given. Botulinum toxin A  was injected subcutaneously in the ipsilateral upper gum, temporal area, orbit, and cheek, at a dose of 2.5–5 U at each site, separated by 1.5 cm. After 4 days, the pain began to improve and attacks became less frequent. After 7 days, the pain had completely resolved and the patient was discharged, having stopped all medication. Seventeen months after the initial episode, there has been no recurrence of symptoms.SUNCT syndrome is an unusual form of headache typified by severe, transient, unilateral, orbital pain attacks, accompanied by ipsilateral conjunctival injection and tearing. Sjaastad and colleagues reported in 1989 . It is mThe cause of SUNCT syndrome is usually not identified: the pathogenesis and pathophysiology are unclear. Functional MRI has identified active metabolism and increased perfusion in the hypothalamus , suggestSUNCT presents with pain in and around the orbit, often radiating to the ipsilateral forehead, temporal area, nose, cheek, or upper mandible. The pain is severe and unbearable and may be burning, sharp, or pulsatile in nature. It begins quickly, peaking within 2-3 s, persists for several seconds to minutes, and has no signs. The second edition of the International Headache Society classification . In contThe treatment of SUNCT syndrome is challenging; drugs tend to be the first choice. As SUNCT is characteristic of neuropathic pain, anticonvulsants are often used; however, the evidence for their use is not underpinned by any randomized controlled trials. Favoni and colleagues also summarized the drugs used successfully in their cohort of patients: lamotrigine 400 mg per day was effective in 52 out of 81 patients (64.2%), gabapentin 3,600 mg per day in 24 out of 71 (33.8%), topiramate in 14 out of 43 (32.6%), carbamazepine 200–1,200 mg per day in 25 out of 119 (21%), local nerve block with lidocaine in nine out of 11 (81.8%), and intravenous lidocaine in 22 out of 26 patients (84.6%) . OxcarbaFor patients for whom drug therapy has proved ineffective, more invasive techniques such as microvascular decompression, local nerve block, glycerol, gamma knife or radiofrequency ablation, percutaneous balloon compression, and nerve stimulation may be employed. In one study, 75% of the patients (12 out of 16) undergoing microvascular decompression for SUNCT had achieved complete relief from symptoms within 32 months of surgery , 15. ThrOur patient's symptoms met the diagnostic criteria of the International Headache Society , but sho


The most typical and well known inhibitory action in the cortical microcircuit is a strong inhibition on the target neuron by axo-somatic synapses. However, it has become clear that synaptic inhibition in the cortex is much more diverse and complicated. Firstly, at least ten or more inhibitory non-pyramidal cell subtypes engage in diverse inhibitory functions to produce the elaborate activity characteristic of the different cortical states. Each distinct non-pyramidal cell subtype has its own independent inhibitory function. Secondly, the inhibitory synapses innervate different neuronal domains, such as axons, spines, dendrites and soma, and their inhibitory postsynaptic potential (IPSP) size is not uniform. Thus, cortical inhibition is highly complex, with a wide variety of anatomical and physiological modes. Moreover, the functional significance of the various inhibitory synapse innervation styles and their unique structural dynamic behaviors differ from those of excitatory synapses. In this review, we summarize our current understanding of the inhibitory mechanisms of the cortical microcircuit. The microcircuit of the neocortex is a very complex, composed of excitatory neurons , inhibitory non-pyramidal interneurons Jones, , glutama3A receptor  measured by a paired recording study of the FS basket cell and the L5 CCS pyramidal cell combined with 3D reconstruction of the synaptic junction from serial electron micrographs and simulation analysis  and protein kinase A (PKA), and by suppressing transmitter glutamate release by inhibition of presynaptic voltage-sensitive Ca2+ channels and/or by activation of K+ channels  distribution in the axon initial segment of the target pyramidal cells  values obtained with local uncaging of GABA on axon initial segment, soma and dendrite of the dentate gyrus cells of hippocampus using gramicidin-perforated patch-clamp method were −59.4 ± 1.5 mV, −65.8 ± 1.2 mV, and −70.9 ± 1.5 mV, respectively, and the intracellular levels of Cl− [Cli] calculated on the basis of the EGABA values were 11, 7.9 and 6.0 mM, respectively  and the intracellular membrane potential at each domain, and how hyperpolarization and shunting inhibitions are used within individual domains  with reference number 15A091. All surgery was performed under ketamine and xylazine, or isoflurane anesthesia, and every effort was made to minimize suffering.YK: conception and design, acquisition of data or micrographs, analysis and interpretation of data, making figure panels, drafting or revising the article. FK: making figure panels, drafting or revising the article. MN: acquisition of simulation data. YK: conception and design, drafting or revising the article.This work was supported by a Grant-in-Aid for Scientific Research , , (15K14324) and on Innovative Areas “Adaptive circuit shift (No. 3603)”  and “Prediction and decision making (No. 4303)” (26120730) of The Ministry of Education, Culture, Sports, Science, and Technology, Japan, The NOVARTIS Foundation (Japan) for the Promotion of Science.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.


Synchronous or metachronous occurrence of gastrointestinal stromal tumors (GISTs) and other primary gastrointestinal neoplasms has previously been reported. However, to the best of our knowledge, there are few studies regarding metachronous multiple GISTs and adenocarcinoma of the colon. The current case of an 80-year-old male patient who underwent a laparoscopic right hemicolectomy for colonic adenocarcinoma, located in the ascending colon, is presented. Twenty-one months after receiving the laparoscopic right hemicolectomy, two new disc-like bulge lesions in the descending colon and rectosigmoid were identified during an endoscopic follow-up examination, and a segmental bowel resection was performed. The final diagnosis of multiple colonic GISTs was established as a result of histopathological examination and immunohistochemistry. Gastrointestinal stromal tumors (GISTs) are a common mesenchymal tumor of the gastrointestinal tract. GISTs were mistaken for leiomyosarcoma and other mesenchymal sarcomas prior to 1983 and have an incidence of ~1–2/100,000 worldwide . The majPreviously, the synchronous occurrence of GISTs and other primary gastrointestinal malignancies has been reported in the literature –7. HowevIn June 2008, an 80-year-old male patient was admitted to the Department of Colorectal Surgery at The Liaoning Provincial Tumor Hospital  complaining of anemia and increasing paroxysmal abdominal pain during the previous month prior to admission. The patient’s medical history was unremarkable. On physical examination, the patient’s abdomen was flat and soft without tenderness and no mass was palpated. A blood count test revealed anemia, while the levels of carcinoembryonic antigen (CEA) and carbohydrate antigen (CA)19-9 were 14.14 ng/ml and 28.9 U/l, respectively. The chest X-ray was unremarkable and an abdominal computed tomography (CT)-scan, conducted to establish the tumor staging, demonstrated that there were no sites of distant metastasis. A fiberoptic colonoscopy showed an irregular bulging mass in the ascending colon, which occupied half of the intestinal lumen, however, no other abnormalities were detected in the remaining regions of the colon and rectum. Histological examination of the biopsy specimen revealed a well-differentiated adenocarcinoma.®; F. Hoffmann-La Roche, Basel, Switzerland) as adjuvant chemotherapy at a dose of 1,250 mg/m2 twice daily, administered on days 1–14 every 21 days over 24 weeks.A laparoscopy assisted right hemicolectomy was subsequently performed. During surgery, a tumor mass, measuring 3×2 cm, which was invading the serous membrane was detected in the ascending colon; there was no evidence of lymph node metastasis . HistoloA regular follow-up regime included a complete physical examination, basic serum chemistry, a chest X-ray, an abdominal ultrasound or CT-scan, and assessments of CEA and CA19-9 levels; this regime was performed every three months for two years. A fiberoptic colonoscopy was performed annually following treatment. In April 2010, two disc-like bulging lesions were identified in the descending colon and rectosigmoid during the follow-up colonoscopy. This included one lesion, which was a distance of 40 cm from the anus at the descending colon and measured 1.5×1.5 cm. The other lesion was located at the rectosigmoid and measured 1.2×1.2 cm . An explPrevious studies have demonstrated that ~20% of patients with GISTs develop other types of cancer, with the predominant GIST-associated cancers being gastrointestinal 47%), lymphoma/leukemia (7%), prostate (9%) and breast (7%) –7. Howev%, lymphoDespite recent progress regarding the diagnosis and treatment of GISTs, little is currently known concerning the rare case of synchronous or metachronous GISTs along with tumors of different histogenesis. The majority of previous case reports describe small GISTs that were discovered during surgical procedures for another primary malignancy . In the As a result of postoperative pathological examination and immunohistochemical analysis of the relevant factors, including CD117, the diagnosis was finally determined to be colonic multiple GISTs. Based on the location, size and number of mitotic figures, and according to the improved National Institute of Health risk classification , the patAs the natural history of GISTs is unknown, the method for the effective management of GISTs that are <2 cm in size remains elusive. However, the present case indicates that a resection may be essential for a colonic cancer patient, when the endoscopic diagnosis of new lesions in the colon, during an endoscopic follow-up, is complicated.In conclusion, metachronous GISTs and adenocarcinoma in the colon are rare. However, it is important to carefully investigate and differentiate between potential lesions during a routine postoperative colonoscopy following colorectal cancer surgery, as the patient may present with rare GISTs, which may be confused with the recurrence of colorectal cancer. In addition, a surgical resection may be necessary, when the diagnosis of new neoplastic lesions during the follow-up colonoscopy of a colonic cancer patient is in doubt.


Ananteris Thorell, 1891, but few details were revealed. Based on observations in the field and laboratory, examination of material in museum collections, and scanning electron microscopy, we document autotomy of the metasoma  in fourteen species of Ananteris. Autotomy is more common in males than females, and has not been observed in juveniles. When the scorpion is held by the metasoma, it is voluntarily severed at the joints between metasomal segments I and II, II and III, or III and IV, allowing the scorpion to escape. After detachment, the severed metasoma moves (twitches) automatically, much like the severed tail of a lizard or the severed leg of a spider, and reacts to contact, even attempting to sting. The severed surface heals rapidly, scar tissue forming in five days. The lost metasomal segments and telson cannot be regenerated. Autotomy of the metasoma and telson results in permanent loss of the posterior part of the scorpion’s digestive system  and the ability to inject venom by stinging. After autotomy, scorpions do not defecate and can only capture small prey items. However, males can survive and mate successfully for up to eight months in the laboratory. In spite of diminished predation ability after autotomy, survival allows males to reproduce. Autotomy in Ananteris therefore appears to be an effective, adaptive, anti-predation escape mechanism.Autotomy, the voluntary shedding or detachment of a body part at a determined cleavage plane, is a common anti-predation defense mechanism in several animal taxa, including arthropods. Among arachnids, autotomy has been observed in harvestmen, mites, and spiders, always involving the loss of legs. Autotomy of the opisthosoma (abdomen) was recently reported in a single species of the Neotropical buthid scorpion genus  Autotomy is the process by which some animals voluntarily shed or detach a body part, usually as an anti-predator defense mechanism. In order to be considered autotomy, the process of shedding or detachment must be provoked by external stimuli, achieved by an intrinsic mechanism, and mediated by the nervous system –3.Autotomy occurs along permanent sites of weakness, cleavage planes that permit a clean break when a body part is detached, with anatomical features that minimize trauma and promote rapid sealing of the fluid compartment, leading to swift closure and healing of the wound , 4.Among invertebrates, autotomy is characterized by limited loss of hemolymph from either the stump or discarded appendage . The sepThe detached body part, e.g., the tail of lizards or the legs of arthropods , 8, may Ananteris Thorell, 1891 [Autotomy of a body part is an effective anti-predator defense mechanism that evolved independently in various taxa . The phell, 1891 –18, whicll, 1891 –26. ThesAnanteris is provoked by external stimuli, achieved by an intrinsic mechanism, and mediated by the nervous system; (2) to confirm that cleavage planes are present in the metasoma of Ananteris; (3) to assess whether the incidence of autotomy differs between the sexes; and (4) to provide data about post-autotomy behavior which may illuminate the functional significance of metasomal autotomy.Based on observations in the field and laboratory, examination of material in museum collections, and scanning electron microscopy, we document autotomy of the metasoma in fourteen species of the genus, and provide behavioral observations with the following objectives: (1) to verify that metasomal autotomy in Collecting permits were issued by the following agencies: Brazil, Ministério do Meio Ambiente, Instituto Chico Mendes de Conservação da Biodiversidade (ICMBio #17974-3), and Instituto Brasileiro do Meio Ambiente e dos Recursos Naturais Renováveis (IBAMA #10148-1); Bolivia, Ministerio de Medio Ambiente y Agua (MMAyA VMA-DGBAP #1319); Perú, Direccion General de Forestal y Fauna Silvestre (#002-2008-INRENA-IFFS-DCB); Ecuador, Ministerio de Ambiente (scientific research authorization #007-14 IC-FAU-DNB/MA); Argentina, Secretaría de Ambiente de la Provincia de Córdoba (#SECA01-524433053-908). Specimens from Colombia belong to registered biological collections and did not require of specific permissions for this study. Specimens from Venezuela are part of old collections for which no permissions could be traced. This study did not involve any endangered or protected species.Ananteris specimens were collected in Argentina, Bolivia, Brazil, Colombia, Peru and Venezuela . The species, sex, age, site of detachment, and presence of a scar, were noted for each specimen. The incidence of autotomy, i.e., the percentage of scorpions with part of the metasoma (including telson) missing and a scar present at the severed stump, in a single population was calculated for those species with more than ten specimens from a single collection locality. The results for different populations of the same species were not combined because it was assumed that the incidence of autotomy could vary among localities due to ecological factors . Differences among sexes and stages  were analyzed as 2×3 contingency tables with Fisher’s exact test in R v. 3.1.1 statistical package [The scorpion collections of several museums were searched for  package .Ananteris solimariae Botero-Trujillo & Flórez, 2011 were collected for experimentation from a population at Girón, Santander Department, Colombia. One of the females, gravid when captured, gave birth, and two second instar juveniles from her litter were also used in the experiments.Twenty-five adult males and five adult females of Gryllodes sigillatus Walker, 1869. After 7 to 10 days of acclimation, each adult scorpion was placed separately in a plastic container with a rough surface (humid cotton), and subjected to the following treatment, designed to demonstrate if detachment was provoked by external stimuli and achieved by an intrinsic mechanism. The metasoma was held with forceps on segments III, IV or V and gently pulled backwards to simulate capture by a predator, for no more than 30 seconds (sufficiently short duration to categorize the phenomenon as autotomy). The time to detachment of the metasomal segments was noted, if applicable. In order to avoid damaging the small second instar juveniles with the forceps, the posterior part of the metasoma was instead attached to sticky tape, which was pulled backwards with the forceps. Ten adult males were subjected to the same treatment, but using glass Petri dishes as a substrate, and the same specimens were held in the air for 30 seconds, without being allowed to contact any substrate. Experiments were filmed with a SONY Cyber-shot DSC-W35 camera and photographs taken with a Canon EOS Rebel T2i camera fitted with a 50 mm macro lens. The healing process of the wound was also documented, by photographing the development of scars on the severed stump of the metasoma during successive time intervals. The effect of anesthesia on autotomy was also investigated, to confirm whether autotomy is mediated by the nervous system, by placing another five adult male individuals of A. solimariae in a styrofoam box with ice, prior to manipulation of the metasoma. Differences between the experiments  were analyzed as 2×2 contingency tables with Fisher’s exact test in R v. 3.1.1 [Scorpions were housed separately in plastic containers  with moistened cotton as water supply and fed every two weeks with crickets, v. 3.1.1 .A. solimariae, were conducted with 92 live individuals  of ten other scorpion species in seven genera and three families: Bothriuridae Simon, 1880: Bothriurus cordubensis Acosta, 1995: 3 adult males, 2 adult females; Bothriurus flavidus Kraepelin, 1911: 2 adult males, 1 adult female, 3 immatures; Brachistosternus ferrugineus Thorell, 1876: 4 adult males, 5 adult females, 5 immatures; Timogenes elegans Mello-Leitão, 1931: 4 adult males, 1 adult female; Timogenes dorbignyi Guérin Méneville, 1843: 3 adult males, 1 adult female; Urophonius brachycentrus Thorell, 1876: 2 adult males, 4 adult females, 3 immatures; Buthidae C.L. Koch, 1837: Tityus trivittatus Kraepelin, 1898: 5 adult females; Zabius fuscus Thorell, 1876: 8 adult males, 6 adult females, 4 immatures; Zabius birabeni Mello-Leitão 1938: 4 adult males, 2 adult females; Hormuridae Laurie, 1896: Opisthacanthus elatus Gervais, 1844: 2 adult males, 5 adult females, 13 immatures. The bothriurid and buthid specimens were collected at several localities in Córdoba Province, Argentina, whereas the O. elatus specimens were collected in Santander Department, Colombia, in 2012.Additional experiments, identical to those performed on Ananteris balzani Thorell, 1891, Tityus uruguayensis Borelli, 1901 and Z. fuscus, the last two species included for comparison with A. balzani, were manipulated with forceps to induce detachment of the metasoma between segments II and III, and III and IV. Scanning electron micrographs (SEM) were taken of the sites of detachment in these specimens, as well as of the scarred, post-autotomy metasomal segments of two A. solimariae specimens, with a Philips XL30 TMP SEM. Samples for SEM were dehydrated and coated with gold-palladium in a Thermo VG Scientific SC 7620 sputter coater.In order to determine whether a defined cleavage plane exists in the metasoma, six ethanol-preserved specimens of three buthid species (two adult specimens per species), A. solimariae specimens post-autotomy was recorded in the laboratory and, when possible, compared with the behavior of intact  specimens. In order to assess the effect of losing part of the metasoma on male mating success, four mating trials were conducted with two adult females and four adult males, two with the metasoma intact and two without the last three metasomal segments. Each pair was placed in a mating arena (20 × 40 × 30 cm) with a substrate comprising soil, stones and pieces of tree bark from the collection locality. Mating behavior was observed and filmed under a 40 W red lamp. Two mating trials were conducted per female. The first two trials, involving males with an intact metasoma, were conducted when the females were gravid. The second and third trials, involving post-autotomy males, were conducted several months later, after both females had given birth and the juveniles had left their mothers.The behavior of Ananteris . Other defense behaviors exhibited by some species at the time of collection included fleeing and tanatosis.Evidence of autotomy was found in fourteen species of nanteris . In seven = 23). The phenomenon was observed in only six adult females and not in immatures. The metasoma detached most frequently between segments III and IV (n = 33), less often between II and III (n = 15), and only twice between I and II , but the difference was not significant within each species (p > 0.05). Autotomy affected 8.33 to 14.29% of the adult males in the population.Incidence of autotomy in the field for five populations of four species was low, from 5.26 to 8.33% . Only adA. solimariae shed part of the metasoma after being held with forceps for 30 seconds or less, whereas three adult males, four adult females and both immatures did not. The frequency of autotomy was significantly greater among adult males than adult females .Under laboratory conditions, 22 of 25 adult males and one of five adult females of n = 10), when held in the air (n = 10), or when anesthetized with ice prior to manipulation (n = 5). The frequency of autotomy was significantly greater among adult males on rough surfaces (22 out of 25) than adult males on Petri dishes (0 of 10), adult males held in the air (0 of 10) and anesthetized adult males (0 of 5) .Autotomy only occurred when scorpions were in contact with a rough substrate with their pedipalps and/or legs. Autotomy did not occur when scorpions were in contact with smooth, slippery surfaces  (n = 4), and rarely between I and II (n = 2). Cleavage occurred between metasomal segments III and IV if the specimen was held with the forceps on segments IV, V, or on the telson, between segments II and III if held on segments III or IV  , less ofr IV see , and betr IV see . Autotomr IV see .The detached metasoma of some individuals carried part of the digestive tract of the preceding metasomal segments along with it (see Movies n = 19) of cases . If touched, the telson reacted to stimuli, attempting to sting in 47% (n = 22) was dead by day 25. The remainder survived up to 8 months in the laboratory. No evidence of autotomy was observed in the other scorpion taxa tested.Post-autotomy survival rate was high. All individuals were alive three weeks afterward and only one male  using the pedipalps and chelicerae to grab and consume them alive  or the ked away ).A. balzani revealed a cleavage plane between segments II and III and between segments III and IV , the entire proctodeum , and the anus, which opens at the posteroventral end of segment V, in the intersegmental membrane preceding the telson [There are several costs associated with autotomy in e telson . The onle telson , may perLoss of the telson, which bears the venom gland and aculeus (sting), negatively affects the scorpion’s ability to catch larger prey or to sting potential predators, and considerably reduces its defense capabilities, but post-autotomy scorpions can still capture and feed successfully on smaller prey. A similar observation has been reported in crabs with autotomy of the chelipedes .Ananteris has not yet been determined, however.Another possible cost of autotomy could be the loss of metasomal photoreceptors, which have been identified in a few scorpion species to date , 34. TheAnanteris scorpions are able to survive and mate successfully. A complete sequence of courtship behavior has not yet been described in any species of Ananteris, hence is impossible to know whether male Ananteris perform ‘clubbing’  or the ked away ). NevertAlthough we have data for few species and populations, the incidence of autotomy in the field was low  and restricted to adult males. The higher incidence of autotomy in adult males may be explained by the difference in breeding behavior between the sexes. Male scorpions are more vagile, wandering in search of females during the breeding season, placing them at greater risk of predation . The difAnanteris mauryi Lourenço, 1982 [Ananteris exhibit autotomy, which may prove to be synapomorphic for the genus, but further observations on the remaining species and/or a phylogenetic hypothesis confirming their monophyly are needed to confirm this hypothesis. Research into the costs and benefits of metasomal autotomy in Ananteris are also needed, to explore how trade-offs may have influenced its evolution, and the occurrence of autotomy should be investigated in other scorpion taxa.Including ço, 1982 , at leasS1 Appendix(DOC)Click here for additional data file.S1 MovieThe metasoma (“tail”) was held with forceps and gently pulled backwards to simulate capture by a predator. After autotomy, the detached metasoma writhed vigorously, and the telson  reacted to stimuli when touched.(AVI)Click here for additional data file.S2 Movie(AVI)Click here for additional data file.S3 Movie(AVI)Click here for additional data file.S4 MovieDetached metasoma writhed vigorously post-autotomy, but the telson  did not react to stimuli when touched.(AVI)Click here for additional data file.S5 MovieSperm transfer occurred successfully and an empty spermatophore is evident at the end of the sequence.(AVI)Click here for additional data file.


We determined the optimal cutoff titers in admission and convalescent-phase samples for scrub typhus indirect immunofluorescence assay using Bayesian latent class models. Cutoff titers of ≥1:3,200 in an admission sample or of a ≥4-fold rise to ≥1:3,200 in a convalescent-phase sample provided the highest accuracy . Orientia tsutsugamushi  , 1:100, 1:200, and at a 2-fold dilution series up to a maximum of ≥1:25,600  were used as previously described . In brieA total of 161 patients were included in the study. The median age was 41 years , and 63% (99/158) were male. The median duration of fever before admission to hospital was 5 days , and 138 patients (85.7%) had convalescent-phase samples available. The median duration between the admission sample and convalescent-phase sample was 12 days . Culture, a combination of PCR assays, IgM ICT, and the presence of eschar were positive in 9, 27, 31, and 17 patients, respectively. Overall, 62 patients were considered IFA IgM positive based on the conventional cutoff titers (42 had an admission IFA IgM of ≥1:400), and 46 patients were considered IFA IgM positive based on STIC .First, we used the unbiased ROC curves to evaluate the performance of admission IFA IgM in an admission sample alone  and showAs we found that a criterion of a ≥4-fold rise to ≥1:200 in a convalescent-phase sample led to the low specificities of conventional and STIC cutoff titers of IFA IgM, we validated this finding by evaluating the results of IFA IgM in those who had alternative diagnoses in our data set as previously described . We founIn this study, we used an unbiased Bayesian LCM approach and defined optimal cutoff titers for IFA IgM as either ≥1:3,200 in an admission samples or as a ≥4-fold rise to ≥1:3,200 in a convalescent-phase sample. With these new cutoff titers, the sensitivity and specificity of the IFA IgM is 81.6% and 100%, respectively, indicating that they can be used to diagnose scrub typhus with high confidence in clinical and research settings. The low specificity caused by the low cutoff titers of IFA IgM could be due to cross-reactivity of the IFA IgM with infections caused by other organisms in our setting, and this is also likely to occur in other tropical countries . AlthougThe biased selection of cutoff titers is a common problem affecting many serological tests for tropical infectious diseases because the reference tests are rarely, if ever, perfect . In addi


Pestivirus genus of the family Flaviviridae, was determined here. The virus, originally isolated from a pronghorn antelope, has a genome of 12,273 nucleotides, with a single open reading frame of 11,694 bases encoding 3,897 amino acids.The complete genome sequence of pronghorn virus, a member of the  Pestivirus genus of the family Flaviviridae is composed of a group of agriculturally important viruses. The recognized species of the genus include bovine viral diarrhea virus 1 (BVDV-1), BVDV-2, classical swine fever virus, and border disease virus (pro), the hallmark of the pestiviruses. The pronghorn isolate belongs to the noncytopathic biotype and grows in both ovine- and bovine-derived cell lines. Pronghorn virus was considered the most divergent pestivirus until the isolation and sequencing of Bungowannah virus  individual sequences, with an average depth of coverage of 712.6×. Illumina sequencing provided 4,340,978 reads with 700,290 pestivirus sequence reads. The pestiviral sequences were assembled in one single contig, with a median coverage of 4,290.5×. Following assembly of the complete genomic RNA using data from both platforms, the genome length was determined to be 12,273 bases, with a single ORF of 11,694 bases . The 5′ and 3′ untranslated regions (UTR) comprise 369 and 210 nucleotides, respectively. These are similar in length to those reported for other pestiviruses. There are seven nucleotide differences between the sequences determined by the two methods  that most likely resulted from subculturing of the virus. In addition, two nucleotide residues within the 3′ UTR (A12257 and T12260) were absent in the genomic sequence determined by Illumina sequencing, which most likely resulted from subculturing of the virus. In the earlier report describing pronghorn virus, the nucleotide sequences of NAY781152.The complete genomic sequence of pronghorn virus has been deposited in GenBank under the accession no.


Hodgkin’s lymphoma (HL) is one of the most curable malignant diseases in adults. However, HL patients have a higher risk of developing second malignancies compared with the general population. The population of adult cancer survivors is growing, thus, the long-term effects of cancer treatment, including secondary cancer development, have become an increasingly important concern in the field of oncology. The current study presents the case of a female HL survivor who developed two secondary malignancies within 29 years of follow-up. Furthermore, a review of the literature was conducted, which focused on secondary breast and gastrointestinal cancers in HL survivors. Hodgkin’s lymphoma (HL), which predominantly occurs in young and middle-aged individuals, is one of the most curable malignant diseases in adults. Modern treatments have increased the number of malignant disease survivors, for example therapeutic advances over the past few decades have resulted in a significant improvement in the HL five-year survival rate ,2. Howev2 on day 1; vincristine, 2 mg on day 1; procarbazin, 100 mg/m2 on days 1–7; doxorubicin, 35 mg/m2 on day 8; bleomycin, 10 mg/m2 on day 8; vinblastine, 6 mg/m2 on day 8; prednisolone, 40 mg/m2 on days 1–14). After completion of the chemotherapy regimen, the patient was irradiated in the supradiaphragmatic and paraaortic lymph node areas, and achieved complete remission.In June 1985, a 43-year-old, previously healthy female presented at the Regional Oncological Center of Copernicus Memorial Hospital  with a two-week history of a painless enlargement of the left supraclavicular lymph nodes. No fever, pruritus, night sweats or weight loss were noted. Physical examination revealed hard, immovable, ~4 cm in diameter lymph nodes in the left supraclavicular area. Furthermore, bilateral hilar enlargement was identified upon chest X-ray. An excisional biopsy of the enlarged lymph node was performed and a diagnosis of HL  was established. Additionally, a bone marrow biopsy and exploratory laparotomy were performed. The disease was staged at IIA according to the Ann Arbor staging system  with clusters of microcalcifications and a Breast Imaging, Reporting and Data System ; hemoglobin, 10.2 g/dl ; mean cell volume, 76.3 fl  and a high platelet count of 549 K/μl . The patient was referred for a colonoscopy, which identified a mass in the left colic flexure. A pathology report of the biopsied mass indicated adenocarcinoma, and chest and abdomen computed tomography (CT) scans revealed no distant metastasis. The patient subsequently underwent a left hemicolectomy. The pathology report determined moderately differentiated pT3 adenocarcinoma, according to TNM staging system . The patient underwent a videothoracoscopy with a radical wedge resection. The pathology report indicated grade two metastatic tubular adenocarcinoma, which possibly corresponded to colorectal cancer metastasis; however, a positron emission tomography-CT scan did not reveal any other metastatic lesions. Following surgery the patient received no systemic treatment and remains under surveillance.Secondary malignancies are serious adverse effects of systemic therapy. According to the Surveillance, Epidemiology and End Results Program, secondary malignancies account for 16% of all cancer ,8. Subseet al  of developing breast cancer .The incidence of secondary breast cancer depends on the dose and volume of irradiation, chemotherapy regimen used and the age at the time of treatment. The greatest risk of developing secondary breast cancer is reported in females who are <30 years old during HL treatment and in females administered with a treatment strategy of radiotherapy alone. The cumulative lifetime incidence in these females is almost 30% . Mantle et al  assessedet al . Furthermore, the HL survivors exhibited a similar absolute risk of colorectal cancer at 35–40 years compared with the general population at the age of 50–54 years old. Youn et al  were colorectal cancer. Combined-modality treated patients exhibited a significantly increased risk of developing colorectal cancer  in comparison with chemotherapy alone, which was not associated with significant risk . However, chemotherapy alone significantly increased the risk of developing lung cancer, leukemia and non-HL (Breast cancer in HL survivors with a history of radiation occurs at younger age compared with the general population. The breast cancer is typically bilateral and appears to be independent to other risk factors, such as obesity, smoking or the use of oral contraceptives –28. Secoet al  identifiun et al  assessedIn conclusion, it is necessary to assess the potential risks and long-term complications of anticancer therapy among cancer survivors. Future efforts should be focused on developing novel screening strategies for individuals who have survived cancer, educating patients and introducing effective prevention strategies. Secondary malignancies appear at a younger age in cancer survivors compared with the general population, however, younger individuals are not recommended for routine screening. Thus, patients should be informed of the likelihood of developing secondary malignancies and preventative strategies among cancer survivors should be promoted.


AbstractTrichophoromyiaruifreitasisp. n. is described as a new species of sand fly from the genus Trichophoromyia Barretto. This description is supported with illustrations and photographs that detail the morphological characteristics of male specimens collected in the municipality of Assis Brasil, Acre State, Brazilian Amazon. This species is similar to Trichophoromyiaauraensis (Mangabeira), but the two species can be easily differentiated by the distribution of setae on their parameres, and by the presence of a dorsal lobe in the parameres of the new species. Leishmania Ross, a protozoan that causes leishmaniases  lainsoni Silveira, Shaw, Braga and Ishikawa, and Leishmania (Viannia) braziliensis Vianna (The genus s Vianna . To dates Vianna . Most deTrichophoromyiaauraensis (Mangabeira) is a known vector in that area , and some paratypes are deposited at the Leônidas and Maria Deane Institute.Holotype male and 7 paratype males collected using CDC light traps in Assis Brasil, São Francisco road, Trichophoromyia due the male characters, the fifth palpomere slightly longer to the third, genitalia longer than or equal to the thorax, gonostyli with four spines  Holotype  small, measuring approximately 2040  from thorax to the end of the gonostylus. Head, thorax and abdomen brown, contrasting markedly with lower pleura and femora; paratergite, upper anepisternum, anepimeron and metepisternon pale.Head length 340  from post-occiput to clypeus apex, and maximum width 325 . Eyes measuring 190  long by 100  wide, with incomplete interocular suture. Interocular distance 120  and ommatidia with a diameter of 18 ; interocular distance six times greater than the diameter of the ommatidia  from anterior margin of pronotum to posterior margin of metanotum. Ventrocervical sensillae absent. Anepisternum with upper bristles 10  long, and lower bristles 5  long. Wing ; tibiae = 1400 ; basitarsi = 800 ; tarsomeres: I = 300 , II = 200 , III = 160 , IV = 100 . Hind femora without spines.ing Fig. : length Abdomen length 2010  from first tergite to gonostylus apex. Genitalia  wide, simple, subtriangular, proximal half part with a convex dorsal lobe, that is recovered with 28–30 long setae recurved at the apex; some setae running along the dorsal margin narrow at the rounded end of paramere, approximately ten (10) setae; apical margin with 4–5 much thicker setae. Proximal portion of paramere with a discrete translucid ventral lobe. Aedeagus conical PageBreakand pigmented. Lateral lobe 350  long, cylindrical, not inflated, with a group of long slender setae that run along the back of the apex and spread throughout the distal half. Genital pump 180  long, and genital piston 150  long  has a paramere with a very pronounced dorsal lobe in the tip, with setae present solely within the apical region.ere Figs  and 3b tTrichophoromyia species have recently been described in the Amazon basin: Trichophoromyianautaensis in Loreto State, Peru, described by Fernandez, Lopez, Roldan and Requena; and, Trichophoromyiaadelsonsouzai in Pará State, described by Santos, Silva, Barata, Andrade and Galati. Both species have parameres with dorsal lobes; however, in Trichophoromyianautaensis the lobe is located in the median part of the paramere, while in Trichophoromyiaadelsonsouzai the paramere has a relatively broad hump, exhibiting dorsal curvature in the apical region (Two new l region .Trichophoromyia, the parameres of the new species, Trichophoromyianapoensis and Trichophoromyia sp.1 of Araracuara are similar. The digital area after the dorsal proximal lobe is approximately twice as long as it is broad in the new species compared with the other two species. However, Trichophoromyianapoensis is distinct from the others in that it possesses 2-3 long recurved setae at paramere apex, and a tuft of setae concentrated at the tip of dorsal lobe (Trichophoromyiaruifreitasi and Trichophoromyia sp.1 of Araracuara are covered by setae. Trichophoromyia sp.1 of Araracuara species possesses 4-6 long setae near its lateral ventral margin of the paramere apex (Trichophoromyia sp.1 of Araracuara also possesses other setae that are smaller than the width of the dorsal lobe, while Trichophoromyiaruifreitasi possess long setae that are distributed in the dorsal lobe. Trichophoromyia, and described Trichophoromyiaadelsonsouzai, differentiating between the majority of species in the genus, except by the Trichophoromyianapoensis and Trichophoromyia sp.1 of Araracuara, not included in their analysis, and more closely related with the paramere of Trichophoromyiaruifreitasi. The new species described here raises the number of Trichophoromyia species worldwide to 42, and 21 in Brazil.In comparison with other known species from the genus sal lobe . The parere apex . AdditioPageBreak


In 1988, a cardiovascular prevention program which combined an individual and a population-based strategy was launched within primary health-care in Sollentuna, a municipality in Stockholm County. The aim of this study was to investigate time trends in the incidence of and mortality from acute myocardial infarction and all-cause mortality in Sollentuna compared with the rest of Stockholm County during a period of two decades following the implementation of a cardiovascular prevention program.The average population in Sollentuna was 56,589 (49% men) and in Stockholm County (Sollentuna included) 1,795,504 (49% men) during the study period of 1987–2010. Cases of hospitalized acute myocardial infarction and death were obtained for the population of Sollentuna and the rest of Stockholm County using national registries of hospital discharges and deaths. Acute myocardial infarction incidence and mortality were estimated using the average population of Sollentuna and Stockholm in 1987–2010.During the observation period, the incidence of acute myocardial infarction decreased more in Sollentuna compared with the rest of Stockholm County in women . There was a trend towards a greater decline in Sollentuna compared to the rest of Stockholm County in the incidence of acute myocardial infarction (in men), acute myocardial mortality, and all-cause mortality but the differences were not significant.During a period of steep decline in acute myocardial infarction incidence and mortality in Stockholm County the municipality of Sollentuna showed a stronger trend in women possibly compatible with favorable influence of a cardiovascular prevention program.NCT02212145ClinicalTrials.gov  The prevention of cardiovascular disease (CVD) is a matter of great concern, even though coronary heart disease (CHD) has declined substantially in most industrialized countries during the last few decades . The leaA few CVD prevention programs in primary care have been performed in Sweden –16. MostThe aim of this study was to investigate time trends in the incidence of and mortality from acute myocardial infarction and all-cause mortality in Sollentuna compared with the rest of Stockholm County during a period of two decades following the implementation of a cardiovascular prevention program.All individuals living in Stockholm County on January 1, 1987 to December 31, 2010 were included in this retrospective, observational register study. Separate analyses were performed for the population of Sollentuna Municipality (Sollentuna) and Stockholm County excluding Sollentuna (Stockholm). The average population per year was 56,589 (49% men) in Sollentuna and 1,795,504 (49% men) in Stockholm County (including Sollentuna).There were some differences in characteristics between the populations of Sollentuna and Stockholm County in 1990 and 2010. In Sollentuna compared with Stockholm County, the employment rate was higher, a larger proportion were married, a lower proportion were foreign born, and education and wages were generally higher among men and women in both 1990 and 2010 .Aggregated outcome data were obtained from the Cause of Death Register, and the Swedish National Hospital Discharge Register, which contains more than 99% of all somatic and psychiatric hospital discharges in Sweden from 1987 and onwards . Data frAll-cause and AMI mortality as well as hospitalizations for AMI (ICD-9 code (1987–1996) 410 and ICD-10 code (1997-) I21 and I22), were obtained for the population of Sollentuna and Stockholm, using national registers .2, smoking, diastolic blood pressure ≥90 mmHg, s-cholesterol ≥5.2 mmol/l, and s-triglycerides ≥2.3 mmol/l. Values of s-cholesterol between 5.2 mmol/l and 6.4 mmol/l were regarded as borderline hypercholesterolemia and these patients received only general advice and no follow-up, while s-cholesterol levels of ≥6.5 mmol/l were regarded as a risk factor which required advice, treatment and follow-up. These patients were also given the opportunity to participate in groups which focused on weight reduction, smoking cessation and physical exercise. Co-operation with a local sports club in Sollentuna was initiated, and physical activity on prescription was started. Within a few years, more than 25 different custom exercise groups had been initiated [In 1988, three health-care centers started an individual and population-oriented cardiovascular prevention program in Sollentuna . Between August 8, 1988 and December 10, 1993, persons  who visited the health-care centers, with or without appointments, regardless of reason for contact, were offered a health check with the emphasis on lifestyle and cardiovascular risk factors. The participants aged between 15 and 86 years, and with an average age of 45.5 years (men 46.2 years and women 45.1 years) answered a questionnaire on life-style and cardiovascular risk factors. Height, weight, waist and hip circumference, blood pressure, fasting blood lipids and blood glucose were measured. Those with one or more cardiovascular risk factor, according to established Swedish guidelines at that time, were offered individual counselling with the emphasis on lifestyle changes by a physician and/or a nurse [nitiated ,19. FurtIn parallel with the individualized work conducted during the first eight years, comprehensive population-oriented work was undertaken. On about 70 different occasions, key people from grocery stores, nurseries, schools, the municipality, public dental care and different associations in the municipality were invited to educational meetings on how to improve lifestyle and prevent cardiovascular disease. Several collaborative projects were initiated.All data were delivered from registers in aggregated form, and no individual patient consent was required. Within the project it was not possible to provide individual information and obtain individual informed consent from the whole study population of Stockholm County. The Regional Ethical Review Board in Stockholm approved the project (reference number: 2012/1172-31/1 and 2013/1329-32).www.clincaltrials.gov. The authors confirm that all ongoing and related studies are registered.The study is registered at Incidence and mortality rates were calculated by calendar year, gender and age, using the mean population as the denominator. The data were divided into five calender-year groups . Rates were expressed per 100,000 person years and were age standardized using direct standardization andthe population of Sweden in 2000 as standard population. To test for differences in trend, an interaction term between groups (Sollentuna vs Stockholm) and time was included. All effects were evaluated with the F-test. No tests for competing risk were taken into consideration.In presentation of the background data differences between Sollentuna and Stockholm were tested using chi-square tests  and Student´s t-test (continuous variables).The observed numbers of prevented or postponed deaths were calculated by subtracting the number of all-cause deaths per 100,000 people in Sollentuna and Stockholm in 1987–1989 from those in 2005–2010. Statistical analyses were performed using SPSS version 19.During the observation period, the numbers of AMI cases registered were 3,207 (60% men) in Sollentuna, and 135,958 (58% men) in Stockholm. AMI deaths occurred in 1,011 persons (58% men) living in Sollentuna and 50,365 persons (55% men) living in Stockholm. All-cause death was registered in 8,504 persons (50% men) in Sollentuna and 370,295 persons (48% men) in Stockholm.The AMI incidence, AMI mortality, and all-cause mortality declined substantially in Sollentuna as well as in Stockholm during the observation period Figs –3. In woBetween 1987–1989 and 2005–2010, the AMI mortality decreased in Sollentuna men , in Stockholm men from 392 to 181 per 100,000, in Sollentuna women from 161 to 70 per 100,000 and in Stockholm women from 178 to 93 per 100,000. The all-cause mortality rate decreased more in both men and women from Sollentuna men from 2,046 to 1,268, and women 1,251 to 909 per 100,000 compared with Stockholm men from 2,168 to 1,469, and women 1,325 to 1,015 per 100,000. In Sollentuna compared with Stockholm, 79 fewer men and 32 fewer women per 100,000 died between 1987–1989 and 2005–2010.The decline in all-cause mortality between 1987–1989 and 2005–2010, resulted in a large number of prevented or postponed deaths in Sollentuna and Stockholm respectively .This study covering more than 20 years follow-up shows that the incidence of AMI decreased more in women living in Sollentuna compared with women living in Stockholm in 1987–2010. The AMI incidence in men, as well as AMI and all-cause mortality for both men and women, declined and there were trends towards a greater decline (n.s.) in Sollentuna Municipality compared with the rest of Stockholm County.The average life expectancy has increased continuously during the last few decades in Sweden. In 2011, the life expectancy was 79.8 years for men and 83.7 years for women in Sweden . The maiFew studies which have evaluated the long-term effects of CVD prevention programs have been published. Studies from the USA  failed to show any differences in trends for CVD morbidity and mortality between the intervention and control group , 30. HowAlmost all the risk factors for MI, such as hypercholesterolemia, hypertension, type 2 diabetes mellitus, and abdominal obesity, as well as an unhealthy diet, low physical activity, high alcohol consumption, smoking and psychosocial factors can be modified , 35. GuiMisclassification of CHD deaths may occur in particular among deaths occuring outside hospital . HoweverIn Western Europe, including Sweden the data have shown a more rapid decline of CVD in mortality in higher socioeconomic groups . Low comWe studied six municipalities (including Sollentuna) in Stockholm County with the largest proportions of people with a high education level in 1990 and used education as a socioeconomic indicator. The increase in the proportion of men and women with high education level between 1990 and 2010 was similar to Sollentuna or higher in the other municipalities  Figs. ThOther small-scale local prevention initiatives have been ongoing in Stockholm County, and this may have influenced the result .The decline in AMI and all-cause mortality was fairly similar in both men and women from Sollentuna and Stockholm during the study period. However, consistent trends towards a larger decline, especially in Sollentuna, were found in all the studied outcomes for both genders. There were fairly large differences in the decline in the incidence of AMI, AMI mortality, and all-cause mortality between the municipalities in Stockholm County . It is pThe strengths of our study were that the entire populations of the county and municipality were included and that registries of hospital discharges and deaths had a high level of completeness.The decline in AMI incidence and mortality and all-cause mortality was pronounced, in both men and women from Sollentuna and the rest of Stockholm, during this long-term follow-up of a cardiovascular prevention program. The AMI incidence declined significantly more in women from Sollentuna, which may indicate a positive effect of the individual and population-oriented cardiovascular prevention program.S1 Fig(TIF)Click here for additional data file.S2 Fig(TIF)Click here for additional data file.S3 Fig(TIF)Click here for additional data file.S4 Fig(TIF)Click here for additional data file.S5 Fig(TIF)Click here for additional data file.S6 Fig(TIF)Click here for additional data file.S7 Fig(TIF)Click here for additional data file.S8 Fig(TIF)Click here for additional data file.S9 Fig(TIF)Click here for additional data file.S10 Fig(TIF)Click here for additional data file.S1 Text(PDF)Click here for additional data file.S2 Text(PDF)Click here for additional data file.S3 Text(PDF)Click here for additional data file.


Aware of the diffusion capacity of bleaching in the dental tissues, many orthodontists are subjecting their patients to dental bleaching during orthodontic treatment for esthetic purposes or to anticipate the exchange of esthetic restorations after the orthodontic treatment. For this purpose specific products have been developed in pre-loaded whitening trays designed to fit over and around brackets and wires, with clinical efficacy proven. Objective: The objective of this study was to evaluate, through spectrophotometric reflectance, the effectiveness of dental bleaching under orthodontic bracket. Material and Methods: Thirty-two bovine incisors crown blocks of 8 mm x 8 mm height lengths were used. Staining of tooth blocks with black tea was performed for six days. They were distributed randomly into 4 groups . The color evaluation was performed (CIE L * a * b *) using color reflectance spectrophotometer. Metal brackets were bonded in groups 1 and 3. The groups 1 and 2 samples were subjected to the carbamide peroxide at 15%, 4 hours daily for 21 days. Groups 3 and 4 were subjected to 3 in-office bleaching treatment sessions, hydrogen peroxide 38%. After removal of the brackets, the second color evaluation was performed in tooth block, difference between the area under the bracket and around it, and after 7 days to verified color stability. Data analysis was performed using the paired t-test and two-way variance analysis and Tukey’s. Results: The home bleaching technique proved to be more effective compared to the office bleaching. There was a significant difference between the margin and center color values of the specimens that were subjected to bracket bonding. Conclusions: The bracket bond presence affected the effectiveness of both the home and office bleaching treatments. Key words:Tooth bleaching, spectrophotometry, orthodontics. In a literature review, Joiner 2006]  describe  describBovine incisor physical-chemical characteristics do not differ considerably from human dentin. The bovine dentin tubule diameter is 3-5µm with 20,000 tubules/mm2, and human dentin, in the outer layers near the enamel, is 0.5-1.2 µm with 10,000-25,000 tubules/mm2 . This isConcerning color coordinates, Trakyali, Özdemir, Arun [2009]  and KarpThis study revealed that, besides the significant change of lightness [L*] in the enamel and dentin, it was verified that there was a reduction of red, reaching more neutral colors [white and gray] for the home treatment [a*] and a reduction of yellow that was more significant in groups without brackets [b*].In relation to color stability after 7 days, this work demonstrated that the home bleaching treatment was less stable, showing changes in enamel and dentin; however, the office treatment showed greater stability and even bleaching continuation for 7 days after the final treatment, observed by the increase of the coordinate L value. The high concentration of hydrogen peroxide inside the tooth structure after in-office bleaching makes it continue to act after the treatment, giving a false impression of stability. These results corroborate those Wiegand, Vollmer, Foitzik, Attin, Attin [2005]  that conAlso, regarding color stability, substrate dentin proved to be more stable compared to enamel because of coordinate a*. In this study, there was discoloration in the enamel but not in the dentin, which contradicts Wiegand, Vollmer, Foitzik, Attin, Attin [2005] , who conIt was evident that the bracket bond presence negatively affected the effectiveness of both the home and in-office bleaching treatments.


Background: Hairy cell leukemia (HCL) is a chronic B-cell lymphoid leukemia characterized by pancytopenia, splenomegaly, myelofibrosis and the presence in peripheral blood, bone marrow and spleen of atypical lymphoid cells with a hairy aspect. The study aims to evaluate a group of patients with hairy cell leukemia, hospitalized in the Clinic of Hematology and Oncology, Kermanshah, Iran, on a period of 15 years and affect of between cladribine therapy and IFN therapy on the patients with HCL.Methods: This is a retrospective analysis of 11 patients in the Clinic of Hematology and Oncology, Kermanshah, Iran, between 2004 and 2013. Clinical features at diagnosis, differential count  types of therapy, survival rate and BRAF mutation have been monitored. As a result, cladribine therapy is the best treatment option for patients.Results: The mean age of patients was 50 years with 100% of men. Approximately 45% of them had splenomegaly at diagnosis. 100% of patients had pancytopenia at diagnosis.9% of patients had mutation of BRAF V600E. Before of treatment, there were fatigue, weight loss, vomiting, fever, night sweat and itching in all of the patients.Conclusion: There is presence of hairy cells in peripheral blood and bone marrow and was associated with pancytopenia, splenomegaly, myelofibrosis in HCL patients. Also, cladribine therapy is best option for treatment of patients and it is better than IFN. The prevalence of the disease is unknown, although HCL accounts for 2% of all leukemias, the incidence of HCL increases annually.2 Hairy cell leukemia (HCL) is a chronic B-cell lymphoid leukemia characterized by pancytopenia, splenomegaly, myelofibrosis and the presence in peripheral blood, bone marrow and spleen of atypical lymphoid cells with a hairy aspect.3 .4The presence of the BRAF V600E mutation has recently been described in hairy cell leukemia (HCL) but not in other common lymphomas5 and immunomodulatory activities of interferon (IFN) can improve or even normalize peripheral blood counts in patients with HCL.6Cladribine is a well-known purine nucleoside analog with activities against lymphoproliferative disorders such as HCL,7Currently, flow cytometric analysis (FC) and frozen section immunohistochemistry (IHC) represent the only available methods for diagnosis of hairy cell leukemia (HCL).6Despite the fact that more effective chemotherapeutics are available in the treatment of HCL today, splenectomy still remains a valid treatment option in certain cases. HCL with massive splenomegaly  but low bone marrow involvement can be an indication for splenectomy as first-line treatment. 8 CD11c+, CD19+, CD20+, CD22+9 and CD5 in HCL, while CD10- and CD23- are expressed in some cases.10Flow cytometric analysis shows the expression of CD103+,1,11 but in the rest of cases abdominal pain and the laboratory features such as anemia, monocytopenia and neutropenia were commonly more.12The clinical presentations included splenomegaly, hepatomegaly, fatigue, pallor, weight loss, infections, rarely lymphadenopathy, In 10% of cases, the disease is asymptomaticThe study aims to evaluate the efficacy of treatment with cladribine and IFN in a group of 11 patients with hairy cell leukemia hospitalized at the Clinic of Hematology and Oncology, Kermanshah, Iran, over a period of 15 years. This is a retrospective analysis of 11 patients at the Clinic of Hematology and Oncology, Kermanshah, Iran, between 2004 and 2013. Clinical features including splenomegaly (n=6), fatigue, weight loss, vomiting, fever, pallor, lymphadenopathy were identified in all patients at initial diagnosis. We determined differential count, types of therapy, survival rate and BRAF mutation in all patients. Complete response (CR) to multiple different drug types (consisted of cladribine and/or interferon) was defined as the disappearance of all clinical features, normal spleen size, WBC, hemoglobin and platelet. Partial response (PR) to drugs required the existence of at least clinical features and abnormality in WBC, hemoglobin and platelet. Statistical AnalysisSurvival was determined from date of first administration of cladribine and/or interferon to death. Kaplan-Meier survival  curves  were mad-1 and 56100 /µL, respectively  received interferon alpha, 2 of whom had a PR and 1 had a CR. seven patients  received cladribine, 6 of whom had a CR and 1 achieved PR. one patient (No.4) who had received cladribine and interferon showed CR. Before treatment, fatigue, weight loss, vomiting, fever, night sweat and itching were reported in all patients. Of the 11 patients, one (No.7) died after 115 months of treatment with interferon. The mean survival time after first administration of cladribine and/or interferon was 56.9 months. The survival rate among patients was 90%.1 Bone marrow, spleen and liver are characteristically infiltrated by leukemic B cells showing abundant cytoplasm with “hairy” projections and unique immunophenotypic features.13 Diagnosis of HCL was based on the presence of hairy cells in peripheral blood and bone marrow and was associated with pancytopenia, splenomegaly, myelofibrosis.In this study, all patients were associated with pancytopenia and splenomegaly, and bone marrow and spleen were infiltrated hairy cells.14In this study, all patients were associated with pancytopenia and splenomegaly, and bone marrow and spleen were infiltrated hairy cells. While little is known about the biological role of 4/5 affected genes, BRAF represents the most frequently mutated gene encoding a protein kinase in human cancers.15,16 Moreover, dysregulation of the mitogen-activated protein kinase (MAPK) pathways, of which BRAF is a component, was previously implicated in HCL pathogenesis.17 In conclusion, BRAF V600E mutation seems to have an important role in the pathogenesis of HCL if it is not even the disease-defining genetic event.6 9% of patients had BRAF mutation (n=1). The presence of BRAF mutation in most individuals with HCL and the response of these patients have suggested that BRAF mutations are an oncogenic driver in this disease,17 but in this study BRAF V600E mutation appeared not to have very important role in HCL pathogenesis. Hence, in order to achieve a reasonable outcome, it is recommended to recruit more participants from other parts of Iran. Interestingly, the same amino acid change (V600E) identified in our patient represents a mutational hotspot in melanomas and papillary thyroid cancers, where its oncogenic activity has been extensively documented.10 and in another study on 39 HCL patients, the median age of patients was 52 years with a high frequency in men.1 This study included only male participants with a median age 50 years. According to these studies, In a study on 28 cases of HCL, the median age of patients was 47 years with male predominance (M: F=6:1),According to 4 earlier studies, men have greater risk of HCL and patients with HCL are usually middle-aged men. 18 and it induces protracted remissions in patients with hairy cell leukemia. The results indicate that HCL is potentially curable after cladribine treatment.19 HCL can be well-controlled with Cladribine: overall complete response rates ranged from 76 to 98%, median disease-free survival of 16 years, normal lifespan and rare HCL-related deaths.10 The response of hairy cell leukemia (HCL) to IFN-α is one of the most dramatic and specific effects in the whole of clinical oncology, but the mechanism of action of IFN-α in HCL remains unclear.20 Although IFN-α is highly active in HCL, IFN-α is not curative in this disease.21 Poor response to alpha-IFN-α treatment could likely be related to a peculiar immunological phenotype of the hairy cell.22Cladribine has been identified as a lymphocyte-specific agent23 Therefore, IFN therapy cannot be deemed effective in all HCL patients, but cladribine is effective for treatment of patients, and induces high CR rates like the study conducted by Davies et al.15In this study, 6 of 7 patients treated with cladribine had CR, but among patients (n=3) treated with IFN–α, 1 achieved CR and 1 died after 115 months. The results of a study by Damasio et al on 169 patients showed that the majority of patients (n=169) treated with IFN had PR. Diagnosis of HCL is sometimes difficult, but WBC<3000, hemoglobin<10, platelet<100000 and also fatigue, weight loss, vomiting, fever, night sweat and itching in patient are signs of HCL. The presence of hairy cells in peripheral blood and bone marrow was associated with pancytopenia, splenomegaly and myelofibrosis in HCL patients. Moreover, our results have shown that cladribine therapy is the best option for treatment of HCL.