Hydatid disease is common in many parts of the world, and causes considerable health and economic loss. This disease may develop in almost any part of the body.Bone involvement is often asymptomatic, and its diagnosis is primarily based on radiographic findings. A whole body bone scan is able to show the extent and distribution of lesions.We describe an unusual case of multifocal skeletal hydatosis and also explain the clinical and diagnostic points. We hope to stimulate a high index of suspicion among clinicians to facilitate early diagnosis and to consider this disease as a differential diagnosis in cases of multiple abnormal activity in bone scintigraphy especially among people in endemic areas. Echinococcosis is a zoonotic infection caused by adult or larval (metacestode) stages of cestodes belonging to the genus Echinococcus and the family Taeniidae. The adult Echinococcus lives in the small intestine of carnivores such as dogs, wolves, jackals and the excreted eggs of the worm are scattered through the stool of these animals . Echinococcus granulosus has a worldwide geographic distribution and occurs in all continents including circumpolar, temperate, subtropical and tropical zones [Hydatid disease may develop in almost any part of the body. Most hydatid cysts occur in the liver (59–75%), or in the lung 27%). Involvement of the kidney (3%) or brain (1–2%) is rare [7%. InvolBone localization is also rare comprising 0.5% to 2.5% of all human hydatidosis . The diaTherefore, plain radiography, CT scan, and MR imaging are helpful in diagnosing skeletal cystic echinococcosis . OsseousThe patient was a 53 year old man with a history of osseous hydatosis since the age of 30. He had had three surgical operations due to the disease. He had low back pain and radicular pain in both legs which had been aggravated over the past month. His past history for any other illnesses was negative. There wasn't a history of coughing or other respiratory symptoms. His general condition was good. On examination we detected low back tenderness in the lumbar area. He had a painful tumor-like mass in the right hemipelvis which was slightly warm without overlying erythema. Straight leg raising test (SLR) was positive in both legs. He had motor and sensory deficit, muscular atrophy and gate disturbance. No other abnormal findings were detected.Simple x-ray of the right femur showed advanced lytic bone destruction, centered in the proximal two thirds of the right femur. In addition there were the appearances of nailing due to previous surgery fig. . The plaEchinococcus granulosus tapeworm. This disease is common in many parts of the world and causes considerable health and economic loss [Hydatidosis is a common disease of both humans and animals resulting from infection with the larval stage of the mic loss .Liver and lungs are the most commonly involved organs and involvement of bone and muscles is uncommon . The preMen are involved more than women  and the Although the incidence of hydatid disease has decreased as a result of education and control measures, there are still foci of concern in South America and sporadic cases still occur in the United States, Europe, the Middle East, and Asia . HydatidA lucent expansile lesion with cortical thinning is the most frequent radiological pattern, and pathological fractures are common .As hydatid disease of bone remains asymptomatic over a long period, it is usually detected after a pathological fracture or secondary infection or following the onset of compressive myelopathy in the case of vertebral lesions .The differential diagnosis of skeletal cystic echinococcosis includes other infectious lesions (e.g. tuberculosis), fibrous dysplasia and tumors . Diagnosis is primarily based on findings of X-ray and CT scans ,7. WholeImmunodiagnostic procedures for serum antibody detection such as enzyme-linked immunosorbent assay (IgG-ELISA), the indirect hemagglutination antibody test (IHAT), the latex agglutination test (LAT), the immunofluorescence antibody test (IFAT), immunoelectrophoresis (IEP) and some other tests are used for the etiological confirmation of imaging structures suggestive for cystic echinococcosis or for diagnosis or differential diagnosis in cases of uncharacteristic imaging findings .The initial location of the lesion in long bones is metaphyseal or epiphyseal, later extending to the diaphysis. Potential complications include pathological fracture, infection, and fistulisation of the abscess .Surgery is the treatment of choice for hydatid bone lesions. Many authors have advocated wide resection of the involved bone along with the surrounding soft tissue as the only definitive treatment of the condition, with or without chemotherapy using albendazole or mebendazole .Growth in the direction of least resistance, in time, causes cortical destruction with extension of the cyst into surrounding soft tissues. This condition is rarely encountered in childhood . HydatidFinally, hydatid bone disease should be considered in the differential diagnosis of osteolytic lesions in radiological imaging as well as single or multiple abnormal uptakes in the whole body bone scan especially among people living in endemic areas.ELISA = enzyme-linked immunosorbent assay; IEP = immunoelectrophoresis; IFAT = immunofluorescence antibody test; IHAT = indirect hemagglutination antibody test; LAT = latex agglutination test; SLR = Straight leg raising test; WBBS = Whole body bone scintigraphy.The author(s) declare that they have no competing interests.AE revised the article for intellectual content details and helped to draft the manuscript .MA participated in writing of the manuscript and interpretation of the scintigraphic figures. MS, ME, AG, RG, SA, supervised the acquisition process and interpreted the scintigraphic and radiological images. All authors read and approved the final manuscript.Written informed consent was obtained from the patient for publication of this case report.


Almost any stage of inflammatory and immunological responses is affected by hormone actions. This provides the basis for the suggestion that hormones act as modulators of the host reaction against trauma and infection. Specific hormone receptors are detected in the reactive structures in inflamed areas and binding of hormone molecules to such receptors results in the generation of signals that influence cell functions relevant for the development of inflammatory responses. Diversity of hormonal functions accounts for recognized pro- and anti-inflammatory effects exerted by these substances. Most hormone systems are capable of influencing inflammatory events. Insulin and glucocorticoids, however, exert direct regulatory effects at concentrations usually found in plasma. Insulin is endowed with facilitatory actions on vascular reactivity to inflammatory mediators and inflammatory cell functions. Increased concentrations of circulating glucocorticoids at the early stages of inflammation results in downregulation of inflammatory responses. Oestrogens markedly reduce the response to injury in a variety of experimental models. Glucagon and thyroid hormones exert indirect anti-inflammatory effects mediated by the activity of the adrenal cortex. Accordingly, inflammation is not only merely a local response, but a hormone-controlled process.


Mitochondrial tRNAs have been the subject of study for structural biologists interested in their secondary structure characteristics, evolutionary biologists have researched patterns of compensatory and structural evolution and medical studies have been directed towards understanding the basis of human disease. However, an up to date, manually curated database of mitochondrially encoded tRNAs from higher animals is currently not available.We obtained the complete mitochondrial sequence for 277 tetrapod species from GenBank and re-annotated all of the tRNAs based on a multiple alignment of each tRNA gene and secondary structure prediction made independently for each tRNA. The mitochondrial (mt) tRNA sequences and the secondary structure based multiple alignments are freely available as Supplemental Information online.We compiled a manually curated database of mitochondrially encoded tRNAs from tetrapods with completely sequenced genomes. In the course of our work, we reannotated more than 10% of all tetrapod mt-tRNAs and subsequently predicted the secondary structures of 6060 mitochondrial tRNAs. This carefully constructed database can be utilized to enhance our knowledge in several different fields including the evolution of mt-tRNA secondary structure and prediction of pathogenic mt-tRNA mutations. In addition, researchers reporting novel mitochondrial genome sequences should check their tRNA gene annotations against our database to ensure a higher level of fidelity of their annotation. Mitochondrially encoded tRNAs (mt-tRNAs) are an excellent object of study for researchers in several fields for a variety of reasons. The primary reason is the wide variety of available completely sequenced mitochondrial genomes, which provides a large data sample from a broad phylogenetic background. Besides the obvious availability factor, mt-tRNAs show several unusual properties. mt-tRNAs are of particular interest to structural biologists, since the secondary structure of the mt-tRNAs is not as conserved as that of their nuclear encoded counterparts , and somThe evolution of secondary structure in mt-tRNAs is also coupled with rapid compensatory evolution that is aimed at the conservation of the secondary structure stability . Indeed,Although mt-tRNAs span only 10% of the entire mitochondrial genome, they appear to be "hotspots" of disease-causing mutations, such that 50% of all pathogenic mutations that have described for the mitochondria have been localized to one of the mt-tRNAs . In addiet al. [We obtained complete tetrapod mitochondrial genomes from GenBank  using thet al.  and two et al. ,14. Due Obvious errors in the sequence and the alignment were changed manually. Among large-scale errors annotation of the tRNA on the wrong strand was the most common (71 cases out of 6060 tRNAs) followed by labeling of the tRNA as transporting the wrong amino acid or complete omissions (20 cases out of 6060 tRNAs). However, most errors were more subtle, such as an omission or addition of several nucleotides in the flanks of the gene (690 cases out of 6060 tRNAs), that were corrected only through the analysis of secondary structure information coupled with the availability of a multiple alignment for the entire gene.Since mt-tRNAs are not as conserved in sequence and structure as nuclear tRNAs -3 a compSerAGY in all species [Cys [Empirically we observed the following constraints of tRNA secondary structure folding as performed by mfold: 1) minimum loop size was never less than 3 nucleotides and 2) WC and GU pairs were not formed if both of the neighbor nucleotides did not participate in pairing. A few mt-tRNA mfold secondary structures predictions that did not conform to the expected cloverleaf were manually rechecked and the alignment altered until the mfold prediction yielded a cloverleaf-like structure. In addition, some mt-tRNAs, including the mt-tRNALys [Phe  and five mammals did not have the sequence for tRNAPro . Thus, our database contains complete manually curated sequence and secondary structure information for 6060 mitochondrially encoded tRNA molecules.Most tetrapod mitochondrial genomes code for 22 different tRNAs with the exception of Metatherians that have lost the mt-tRNALys . In addiAsn gene form 3 WC pairs in the D-stem, while the classical tRNA structure supported by the alignment predicts 4 interacting nucleotides in this stem : Platform independent;Programming language: noneLicense: no restriction;Any restrictions to use by non-academics: no restriction.KYuP, LAM and FAK conceived the construction of the database, and participated in the construction of the initial and final alignments, corrected erroneously annotated tRNAs and were involved in secondary structure prediction. FAK drafted the paper, and all authors read and approved the final manuscript.


Echinococcus vogeli, Echinococcus granulosus and Echinococcus multilucularis. Echinococcus granulosus is the most common cause of hydatid disease in humans. This disease occurs either through direct ingestion of parasite eggs from contact with infected dogs or indirectly from the ingestion of contaminated water or food.Hydatid disease is caused by the tapeworm Echinococcus. Genus Echinococcus has different species including Infestation of hydatid disease in humans most commonly occurs in the liver (55-70%), followed by the lungs (18-35%). Bone hydatidosis however is very rare (3%). We present herein a case of hydatid cyst of the fibula, which is an uncommon site for the occurrence of this disease. Hydatid disease is endemic in the Middle East, including Iran.34A 42-year-old shepherd presented with a two-week history of sudden pain and very mild swelling in the left lower leg. A tender swelling was noted at the upper to middle third of the left lateral aspect of leg. Radiographic findings revealed a multiple osteolytic lesion of the fibula with no reactive sclerosis . A cliniA direct lateral approach to the fibula after protection of the proneal nerve was used and surgical exposure was easily achieved. The osteotomy and resection of the bone cyst was done about 10 cm above and below its borders. After the resection of the bone cyst, the wall was opened by a curette and translucent cyst was seen.Echinococcus granulosus scattered amidst fragments of bone and bone marrow [Histopathology revealed the characteristic trilamellar hydatid cyst wall and scolices of e marrow  were seeAn ultrasound of the abdomen was later performed and did not reveal hydatid cyst in the lung or the liver. The patient was treated with albendazole for three cycles at a dose of 400mg twice a day for four weeks followed by a two- week rest without therapy.10The disease in the bone and joint begins once the blood-borne scolex settles there. It is a very slow process and therefore, bone cysts are seldom discovered in childhood, even though infestation probably occurs at this time.1314Disease should be suspected in cystic lesions affecting the bone, especially in endemic areas, as it may easily be misdiagnosed. It can mimic tuberculosis, simple bone cyst, sub-acute arthritis, giant cell tumors, malignant fibrous histiocytoma, myeloma and chondrosarcoma.16The purpose of this article is to alert orthopedic surgeons of this rare condition to emphasize the fact that this disease should be suspected in cystic lesions affecting any organ in the body, especially in endemic areas of the world and open and percutaneous needle biopsies should be avoided in such cases.


Correlate the anatomic features of atrioventricular septal defect with echocardiographic images.Sixty specimen hearts were studied by sequential segmental analysis. Echocardiograms were performed on 34 patients. Specimen hearts with findings equivalent to those of echocardiographic images were selected in order to establish an anatomo-echocardiographic correlation.Thirty-three specimen hearts were in situs solitus, 19 showed dextroisomerism, 6 were in situs inversus and 2 levoisomerism. Fifty-eight had a common atrioventricular valve and 2 had two atrioventricular valves. Rastelli types were determined in 21 hearts. Nine were type A, 2 intermediate between A and B, 1 mixed between A and B, 4 type B and 5 type C. Associated anomalies included pulmonary stenosis, pulmonary atresia atrial septal defect, patent ductus arteriosus and anomalous connection of pulmonary veins. Echocardiograms revealed dextroisomerism in 12 patients, situs solitus in 11, levoisomerism in 7 and situs inversus in 4. Thirty-one patients had common atrioventricular valves and three two atrioventricular valves. Rastelli types were established in all cases with common atrioventricular valves; 17 had type A canal defects, 10 type B, 3 intermediate between A and B, 1 mixed between A and B and 3 type C. Associated anomalies included regurgitation of the atrioventricular valve, pulmonary stenosis, anomalous connection of pulmonary veins, pulmonary hypertension and pulmonary atresia.Anatomo-echocardiographic correlation demonstrated a high degree of diagnostic precision with echocardiography. Atrioventricular septal defect is characterized by a lack of separation between the right atrium and the left ventricle, creating communication between the two sides of the heart with a variety of aberrations of the atrioventricular valves, ventricular geometry, the fibrous skeleton and the cardiac conduction system . This coEchocardiography has provided precise images of the anatomic findings of this congenital malformation with details of the atrioventricular septal defect, the common atrioventricular valve or two separate atrioventricular valves, the relationships between the leaflets of the valves in both forms, septal structures and their defects, disproportion between the left ventricular inflow and outflow tracts, unwedged aorta and the shunts that determine the clinical presentation ,5,6. ThiThis study presents an anatomo-echocardiographic correlation that compares the anatomic features of specimen hearts with atrioventricular septal defect to echocardiographic images of equivalent findings in patients with this congenital malformation. These comparisons should aid in diagnostic interpretation -12.Sixty specimen hearts from the Department of Embryology of the Instituto Nacional de Cardiología "Ignacio Chávez" with atrioventricular septal defect were examined. Each specimen was described following the guidelines of the segmental sequential system utilized in the diagnosis of congenital heart defects . Atrial Between May 2002 and December 2006 thirty-four adult patients from adult outpatient clinic with clinical suspicion of atrioventricular septal defect were studied. Fourteen were women and 20 men with an average age of 24.95 ± 6.94 years.All patients underwent complete clinical history and transthoracic and/or transesophageal echocardiograms. The echocardiographic study was performed using a Philips Sonos 5500 machine with an S3 electronic probe and multiplane transesophageal probe.Abdominal situs was determined from the subcostal plane, and the atrial situs on the basis of the morphology of the atrial appendages visualized in the apical 4-chamber view. Atrioventricular valve features and Rastelli type  were evaWhen the patient had a poor acoustic window and/or when diagnosis was in doubt transesophageal echocardiography was performed using a multiplane probe.Anatomo-echocardiographic correlation was demonstrated by establishing the correspondence between the anatomic feature of the specimen and the equivalent echocardiographic image from a patient with the same type of malformation.Atrial situs was solitus in 33 hearts, 19 had dextroisomerism, 6 had situs inversus and 2 had levoisomerism. All presented a common fibrous atrioventricular ring. Fifty-eight hearts had a common atrioventricular valve, and two had two separate valves. All had atrioventricular septal defects. Hearts with common atrioventricular valves had ventricular septal defects. In those with two atrioventricular valves this ventricular septal defect was obliterated by the insertion of the left atrioventricular septal anterior and posterior leaflets in the crest of the ventricular septum. Ostium primum was present in 58 hearts. In two the atrial septum was well developed and there was no ostium primum. The two types of atrioventricular septal defect manifested all hallmarks of the atrioventricular septal defect: excavation of the ventricular septum, disproportion of the left ventricular inflow tract and outflow tract, unwedged aorta, a common fibrous ring, absence of the membranous septum, atrioventricular valves on the same plane, and elongation of the left ventricular outflow tract. In two specimens's insertion of the chordae tendineae of the left antero-superior leaflet caused obstruction of the left ventricular outflow tract.Hearts with one valve had a five leaflet pattern: two (right and left) antero-superior leaflets, two (right and left) lateral leaflets and a common posterior leaflet. Hearts with two atrioventricular valves had a pattern of three leaflets.Rastelli types were established in twenty-one hearts. Nine were type A, two were intermediate between A and B, one was a mixture of types A and B, four were type B and five were type C. Rastelli types were not determined in thirty-nine hearts because 10 had double inlet to a single ventricle, nine a right ventricular double inlet and eight a left ventricular double inlet. Eleven were surgically altered and one had deterioration.Atrioventricular and ventriculo-arterial connections as well as associated anomalies are shown in Table Echocardiographic studies showed dextroisomerism in twelve patients, atrial situs solitus in eleven, levoisomerism in seven and situs inversus in four. Thirty-one patients had common atrioventricular valves and three had two separate valves.All of the patients had atrioventricular septal defects. Ventricular septal defects were found in the group with common atrioventricular valve; obliterated in the group with two atrioventricular valves by the insertion of the septal anterior and posterior leaflets of the left atrioventricular valve. Ostium primum was present in thirty-one hearts, while in three the atrial septum was well developed and no ostium primum was found.As in the anatomic specimen hearts, patients with a common atrioventricular valve had a five leaflet pattern: two (right and left) antero-superior leaflets, two (right and left) lateral leaflets and a common posterior leaflet. Hearts with two atrioventricular valves had a pattern of three leaflets.Rastelli types were determined in all cases with common atrioventricular valves. Seventeen had type A, ten type B, three intermediate between A and B, three type C and one a mixture of types A and B.Atrioventricular and ventriculo-arterial connections and associated anomalies are shown in Table A comparison of the anatomic features of the atrioventricular canal with corresponding images obtained from patients with the same condition showed strong correlation.In the common valve type the chambers open into a wide canal with ostium primum, atrioventricular septal defect and ventricular septal defect. In Rastelli type A the chordae tendineae of the anterior leaflets insert in the crest of the ventricular septum Fig. . The apiIn the atrioventricular septal defect with two separate valve orifices these are contained within the common atrioventricular junction. The wide septal defect includes the ostium primum and the atrioventricular septal defect. The septal leaflets of the left atrioventricular valve insert in a continuous manner in the crest of the ventricular septum, obliterating the ventricular septal defect Fig. . The apiThe view of the atrioventricular septal defect with two valve orifices from the right chambers shows a well-developed atrial septum. The fusion of the septal leaflets of the left atrioventricular valve on the crest of the ventricular septum and the commissure that separates these septal leaflets, as well as the broad commissure between the septal and anterior leaflets of the right atrioventricular valve can be seen through the wide septal defect Fig. . The 4-cThe two-dimensional echocardiographic apical 4-chamber image with color Doppler of an atrioventricular septal defect with two valve orifices makes it possible to observe the atrial shunt above the atrioventricular valves  and in the papillary muscle adjacent to the ventricular septum  to the papillary muscle tethered to the apical portion of the ventricular septum Fig. . In the In a view from the right chambers of a Rastelli type C atrioventricular septal defect the left anterior leaflet can be seen to pass over the ventricular septum and insert in the papillary muscle in the right ventricular free wall Fig. . The 4-cFigure The Rastelli type C insertion of anterior leaflets and ventricular septal defect are shown in an atrioventricular septal defect with common atrioventricular valve in situs inversus Fig. . Color DIn atrioventricular septal defect with common atrioventricular valve the "scooped out" appearance of the ventricular septum can be seen, as well as the interchordal spaces forming the ventricular septal defect Fig. . The 4-cA comparison of the left ventricles in atrioventricular septal defect with common atrioventricular valve and with two separate valves shows the similarity of the insertions of left anterior leaflets in the two types. In the former there are interchordal spaces and in the latter continuous insertion and obliterated ventricular septal defect. In both types the atrioventricular septal defect shows a similarity in the shortening of the inlet and elongation of the outlet Fig . The echObstruction of the left ventricular outflow tract by encroachment of the left anterior leaflet of the left atrioventricular valve can be observed in an atrioventricular canal with two valve orifices Fig. . The parIn an atrioventricular septal defect with common atrioventricular valve dilatation of the valve ring produces unwedging of the aortic valve and the fibrous continuity between this valve and the left anterior leaflet of the common atrioventricular valve Fig. . The parAs this anatomic specimen shows, atrioventricular septal defect with common valve can be associated with right ventricular double outlet and Fallot's tetralogy. A Rastelli type C insertion of the left anterior leaflet, pulmonary stenosis and infundibular septum separating the two outflow tracts can be observed Fig. . The echThe atrioventricular septal defect can have a common atrioventricular valve that has equal connections to the two ventricles Fig. . The echLeft dominance is evident in an atrioventricular septal defect with common atrioventricular valve in dextroisomerism. Note that in the postero-superior view both atria have anatomically right characteristics, the valve ring is displaced toward the left ventricle and there is an atrial septal band that is typical of this atrial situs Fig. . The twoAn atrioventricular septal defect can also have right dominance in dextroisomerism. The internal view of the right ventricle reveals the predominant connection of the common atrioventricular valve with this chamber Fig. . The samThe atrioventricular septal defect occurs as a consequence of detained growth and development of the postero-inferior and antero-superior mesenchymal endocardial cushions of the atrioventricular canal. Thus, their fusion, which in the normal heart constitutes the atrioventricular septum separating the right atrium from the left ventricle, does not occur. Instead, a large septal defect is established that includes components at the atrioventricular and ventricular levels and in many cases at the atrial level (ostium primum) ,3.This congenital heart defect can be found in any position (situs) of the heart: situs solitus, situs inversus or in the isomeric positions of dextroisomerism or levoisomerism Fig. , 21. In It is noteworthy that the pathological stigmata of the two anatomic forms of atrioventricular septal defect are practically identical. When the atrioventricular leaflets are removed from the atrioventricular ring in the basal portion of the ventricular mass there is no way to determine whether the patient to whom the heart pertained had a so called "partial" or "complete" type of atrioventricular canal . This clIt is the relationships among the leaflets within the common atrioventricular junction that determine the number of atrioventricular orifices, while the relationships between the leaflets and the septal structures dictate the possible shunts that can be established between the two sides of the heart ,19-22.Other anatomic characteristics that can be determined by ultrasound involve the septal structures and their defects. Classic cases manifest a lack of separation between the left ventricle and the right atrium, as the term atrioventricular septal defect suggests. The absence of the membranous septum and an incomplete muscular ventricular septum create a large perimembranous and inflow tract ventricular septal defect in cases of atrioventricular septal defect with common atrioventricular valve that is obliterated when there are two atrioventricular valves. Finally, failure of closure of the ostium primum originates a large atrial septal defect, although in some cases the ostium primum is absent and the septum is complete . The conIn cases of atrioventricular septal defect with a common atrioventricular valve and a ventricular septal defect the mode of insertion of the right and left anterior leaflets determines the Rastelli type, a classification with significance for surgical correction. In fact, Rastelli types A, B and C constitute the most frequent sites of insertion in a spectrum of possibilities. In this study intermediate insertions between types A and B and mixed A and B insertions in the same heart are shown.As far as the dominance of the left Fig.  or rightOther key characteristics of this cardiac anomaly that are present in types with one and two valve orifices are the unwedged aorta with respect to the atrioventricular valves with a "goose neck" deformity of the left ventricular out flow tract. This is caused by displacement of the common atrioventricular fibrous ring and elongation and displacement of the distance between the apex and the aortic valve. With the echocardiographic 5-chamber apical image it is easy to identify the decrease in the ventricular inlet that reflects a disproportion between it and the elongated outlet: the greater shortening of the inlet greater the elongation of the outlet. This swan's neck shape constitutes a potential postoperative risk of obstruction ,23. On oThe problems of clinical diagnosis can be solved by cross-sectional echocardiography that shows the classic anatomic features of the atrioventricular defect ,19,24.In conclusion, this group of lesions is unified by the anatomical hallmarks of a common atrioventricular junction and deficient atrioventricular septation. An understanding of the anatomy of this congenital malformation is mandatory for clinical diagnosis by imaging. The anatomo-echocardiographic correlation between specimen hearts and echocardiograms of patients with equivalent findings demonstrates the high degree of precision that can be achieved with echocardiographic diagnosis. Validation by anatomic specimens is the defining reference for the imaging that is indispensable for diagnosis, treatment and follow-up of these patients.LMC and NEZ participated to the written manuscript, MKN made the photographs of the heart specimens and helped to draft the manuscript and CK helped to draft the manuscript and made the translation from Spanish into English. All the authors read and approved the final manuscript.


To date, there is no report in the international literature of an oligodendroglioma of the ciliary body, nor is there an analysis of the possible origins of this lesion.Here we report on a 52-year-old man admitted to our hospital with a ciliary body tumor revealed by clinical examination and ultrasound, computed tomography and magnetic resonance imaging studies. Following enucleation, pathological and immunohistochemical analyses were performed. Postoperative histopathological staining results included OLIGO-2(+) and GFAP(-), leading to a pathological diagnosis of oligodendroglioma of the ciliary body in the right eye (WHO grade II).Since malignant gliomas derive from transformed neural stem cells, the presence of oligodendroglioma in the ciliary body supports the hypothesis that gliomas can occur wherever neural stem cells exist. Tumors of the ciliary body derived from oligodendrocytes are difficult to diagnose; pathological analyses are essential. The list of most commonly occurring primary brain tumors includes gliomas, and the vast majority of these are astrocytomas or oligodendrogliomas. The latter usually originate from oligodendrocytes in the brain parenchyma, especially in adult patients. To our knowledge,the oligodendroglioma of the retina ,2 and thThe patient is a 52-year-old man who presented to our division after six months of deteriorating vision associated with metamorphopsia. On physical examination, visual acuity of the left eye was found to be 20/20, whereas vision in the right eye was limited to detection of horizontal motion of the examiner's hand. The anterior and posterior segments of the left eye were normal. The movement of the right eye was smooth, and the anterior segment was normal, but an irregularly shaped solid mass was found in the anterior temporal vitreous cavity, coupled with a localized concave surface in the adjacent retina. B-mode ultrasound examination revealed a mass-like echo of medium intensity roughly distributed within the echo representing the right anterior vitreous cavity. The posterior portion of the vitreous produced a "v"-shaped echo with its cutting-edge connecting to that of the optic disk Figure . Color DOligodendrogliomas, which originate in oligodendrocytes, are relatively rare neuroepithelial tumors, accounting for about 3% of all intracranial tumors and 20% of gliomas . They arThe pathogenesis of oligodendrogliomas of the ciliary body should be consistent with that for intracranial gliomas, which originate from neural stem cells. Neural stem cells are a group of cells that differentiate into neurons, glial cells and oligodendrocytes . They arOur case provides further confirmation that gliomas might occur wherever neural stem cells exist. Malignant gliomas derive from transformed neural stem cells. Oligodendrogliomas and astrocytomas of the ciliary body originate from oligodendrocytes and astrocytes that have differentiated from retinal stem cells. Ciliary retinal stem cells have the same properties of mobility and pluripotentiality as neural stem cells. When stimulated by carcinogenic factors, retinal stem cells can give rise to tumors of a variety of cell types. It is possible for stem cells derived from retinal ciliary epithelium to be well-differentiated and mature enough to replace dead retinal neurons when surgically transplanted-15. FurtDefinitive diagnosis of oligodendroglioma of the ciliary body can be made only after results of pathological and immunohistochemical analyses are known. Although extremely rare, preoperatively oligodendroglioma should be included in the differential diagnosis of ciliary body tumors.The authors declare that they have no competing interests.QG, SBS and QY are the main authors. SPX, GDC and QLG have been involved in drafting the manuscript and revising it for intellectual content.JH provided figures.All Authors have given approval to the final version of the work.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2407/10/579/prepub


This issue covers a broad territory of PAG function: neuropharmacology, functional organization, and PAG plasticity in adaptive behavior, emotion, anxiety, and the less-studiedplasticity of the PAG function infemales.Interest in the involvement of PAG in defensive behavior has a long history. Thinking about this area wasradically changed by the seminal contributions of Bandler and DePaulis indefining functional columns arranged in both coronal and saggital planes of thePAG. Most papers in this sectionrespect the importance of those functional columns while adding to ourunderstanding how they might contribute to panic, anxiety, defensive responseto natural threats, as well as aversive learning.Del-Ben and Graeffin the paper entitled “Panic disorder: Is the PAG involved?” review preclinical as well as human imaging research in thecontribution of PAG dysfunction topanic anxiety disorder. Others have shown how preclinical models ofposttraumatic stress disorder (PTSD) and using brief exposure to predators(predator stress) have helped to advance our understanding of the neuralsubstrates of stress-induced lasting sensitization of rodent anxiety includingpotentiation of startle response. Adamec et al. contribution in the paperentitled “Viral Vector Induction of CREB Expression in the Periaqueductal Gray Induces a Predator Stress-Like Pattern ofChanges in pCREB Expression, Neuroplasticity and Anxiety in Rodents” extendsinitial findings implicating pCREB expression in the lateral column of the PAG in neuroplastic changes in amygdala-PAG communication as mediators of predator stress-enhancedstartle and anxiety. Using viral vector enhancement of CREB expression in the PAG, the authorsprovide support for the idea that stress-precipitated increases in pCREB in thePAG are sufficient to potentiatecentral amygdala to PAG neuraltransmission, to increase anxiety in the elevated plus maze, and to potentiate startleresponse. In a related vein, exposure to stressful stimuli increases endocannabinoid(eCB) levels in the PAG and localadministration of cannabinoid receptor 1 (CB1) agonists or drugs thatfacilitate eCB-mediated neurotransmission produce antinociceptive andantiaversive effects. Stimulated by these findings, Moreira et al. in “Anti-aversiveeffects of cannabinoids: is the periaqueductal gray involved?” explore the anxiolytic potential of PAG injection of CB1 agonists and cannabidiol in avariety of tests of anxiety as well as in contextual fear conditioning. Theyprovide evidence that dorsal lateral PAG is a site of antiaversive actions of cannabinoids. Other PAG columnar function  inantinociception is explored by Morganet al. in “Behavioral Consequences of Delta Opioid ReceptorActivation in the Periaqueductal Gray of Morphine Tolerant Rats”. It is known that chronicmorphine administration shifts delta-opioid receptors (DOR)from the cytoplasm to the plasma membrane. Moreover, microinjection of morphineinto the VlPAG produces antinociception. In light of these findings, it washypothesized that movement of DORs to the membrane would induce antinociceptionto the DOR agonist deltorphin IIas a way to compensate for morphine tolerance. Their findings suggest thatchronic morphine administration alters DORs in the vlPAG with little evidenceof compensation for the decrease in antinociception caused by morphinetolerance.PAG Function in Females. Until very recently, research on thePAG along with most other brain areas was conducted almost exclusivelyin males with the implicit assumption that the anatomy and physiology were the same in females. Three articles in this issue showthat this is not the case. Not only are there significant differences inthe organization of the PAG between the sexes but the circuitry of the female PAG also exhibits considerable plasticity in response to changes in its hormonalmilieu.A receptor in the PAG. One of the functional consequences is adecrease in ongoing GABAergic tone and an increase in neural excitabilitywithin PAG circuits. These changesmay underlie the increased susceptibility to the development of stress-inducedhyperalgesia that was shown to occur during late dioestrus and may also berelevant to Lloyd and Murphy's reports of a reduction in morphine's efficacy infemale rats duringdioestrus. Mota-Ortiz et al. in the paper entitled “Afferent Connectionsto the Rostrolateral Part of the Periaqueductal Gray: a Critical Region Influencingthe Motivation Drive to Hunt and Forage” examine afferent inputs to the rostrolateral PAG (rlPAG ) in female rats. In nursing females, morphine treatment induces a behavioral “switch” from maternal to foraging behavior which ismediated via the rostrolateral PAG (rlPAG ). The authors report that the rlPAG receives inputs from medialprefrontal cortical areas involved in controlling attention-related anddecision-making processes. Other afferents from different amygdalar,hypothalamic, and brainstem sites provide information to PAG related to feeding, drinking, or huntingbehaviors. It is suggested that this unique combination of afferent connectionspositions the rlPAG to influence the decision whether hunting/foraging or otherbehaviors would be the most appropriate adaptive response for females,particularly in the presence of their young.Lloyd and Murphy in the paper entitled “TheRole of the Periaqueductal Gray in the Modulation of Pain in Males and Females:Is the Anatomy and Physiology Really That Different?” show that descending projections from the PAG, which are believed to modulate spinalprocessing of nociceptive input, are more numerous in female rats than inmales. Paradoxically morphine, which exerts much of its antinociceptive effectsby activating these projections, excited a much smaller proportion of theneurones in females compared to males, a finding that may explain the clinicalfinding of reduced efficacy of the analgesic effects of morphine in women comparedto men. Lovick and Devall in the paper entitled “TheRole of the Periaqueductal Gray in the Modulation of Pain in Males and Females: Is the Anatomy and Physiology Really That Different?” show how the fall in production of progesteroneduring the late dioestrus phase of the oestrous cycle leads to upregulation ofcertain subunits of the GABAThesepapers are by no means exhaustive of the interest and breadth of work in the PAG field. Nevertheless, together they reflect therich functional diversity of activities of the PAG. Moreover, they make apparent the importance of paying attention to sex and particularcolumnar areas when studying this fascinating structure, whose activity is offundamental importance for survival of the individual in a challenging andconstantly changing environment.T. A. LovickT. A. LovickRobert AdamecRobert Adamec


Chlamydomonas , Scenedesmus , and Stigeoclonium  revealed tremendous variability in their architecture, the retention of only few ancestral gene clusters, and derived clusters shared by Chlamydomonas and Scenedesmus. Unexpectedly, our recent phylogenies inferred from these cpDNAs and the partial sequences of three other chlorophycean cpDNAs disclosed two major clades, one uniting the Chlamydomonadales and Sphaeropleales (CS clade) and the other uniting the Oedogoniales, Chaetophorales and Chaetopeltidales (OCC clade). Although molecular signatures provided strong support for this dichotomy and for the branching of the Oedogoniales as the earliest-diverging lineage of the OCC clade, more data are required to validate these phylogenies. We describe here the complete cpDNA sequence of Oedogonium cardiacum .To gain insight into the branching order of the five main lineages currently recognized in the green algal class Chlorophyceae and to expand our understanding of chloroplast genome evolution, we have undertaken the sequencing of chloroplast DNA (cpDNA) from representative taxa. The complete cpDNA sequences previously reported for Oedogonium chloroplast genome displays a distinctive architecture. This genome is one of the most compact among photosynthetic chlorophytes. It has an atypical quadripartite structure, is intron-rich (17 group I and 4 group II introns), and displays 99 different conserved genes and four long open reading frames (ORFs), three of which are clustered in the spacious inverted repeat of 35,493 bp. Intriguingly, two of these ORFs (int and dpoB) revealed high similarities to genes not usually found in cpDNA. At the gene content and gene order levels, the Oedogonium genome most closely resembles its Stigeoclonium counterpart. Characters shared by these chlorophyceans but missing in members of the CS clade include the retention of psaM, rpl32 and trnL(caa), the loss of petA, the disruption of three ancestral clusters and the presence of five derived gene clusters.Like its three chlorophycean homologues, the 196,547-bp Oedogonium chloroplast genome disclosed additional characters that bolster the evidence for a close alliance between the Oedogoniales and Chaetophorales. Our unprecedented finding of int and dpoB in this cpDNA provides a clear example that novel genes were acquired by the chloroplast genome through horizontal transfers, possibly from a mitochondrial genome donor.The  The Chlorophyceae (sensu Mattox and Stewart) is a morphologically diverse class of green algae, which together with three other green algal classes  form the Chlorophyta . The ChlScenedesmus obliquus   and the absence of trnS(gga) in the former alga ] and lack petA. These members of the OCC clade also differ from those of the CS clade in exhibiting insertions of more 2,500 codons  immediately before the 3'conserved region of rps4. The sequences of these insertions are extremely divergent, thereby precluding us from decrypting their nature. Intriguingly, the corresponding 3' regions of the Chlamydomonas and Scenedesmus rps4 genes are missing not only a large insertion but also the highly conserved sequence corresponding to the last 40 codons . T. Torf538element; ) revealeorf485-encoded protein disclosed limited similarity  with the conserved domain of the septation ring formation regulator ErzA (pfam06160), a protein that modulates the frequency and position of FtsZ ring formation during the bacterial cell cycle. Because the detected similarity is marginal and restricted to a portion of the ErzA domain, the orf485 product is unlikely to function as an ErzA protein.BlastP searches with the orf1252 product revealed sequence similarity with the maturase domain of reverse transcriptases encoded by bacterial group II introns and also with the maturase domain of the protein predicted from the free-standing orf932 in Scenedesmus cpDNA , have not been found in other chlorophycean genomes. Like Chlamydomonas and Scenedesmus cpDNAs, it displays an IR; however, the patterns observed for the partitioning of genes among the two SC regions are distinctly different in these three genomes , indicating that the degree of gene packaging has no influence on the size of intron populations observed in chlorophycean genomes. Although members of the group I intron family are predominant in both genomes, introns sharing similar structures and identical insertion positions are found at only five genomic sites . The Oeus tauri  and the dium sp. , two gentes Fig. .Oedogonium chloroplast genome revealed shared derived characters (i.e. synapomorphies) at the levels of gene content and gene organization that reinforce our recent study based on comparative analyses of chloroplast gene sequences and gene structural features in supporting the idea that the five recognized lineages of the Chlorophyceae fall within two major clades, the CS and OCC clades .medium C  under 12medium C . This DNmedium C . After hmedium C . SequencGenes and ORFs were identified by Blast homology searches  against Forward and palindromic repeats larger than 20 bp were identified with the Comparative Repeat Analysis program . Number s or propensity of adjacent genes to occur on the same DNA strand was determined as described by Cui et al. [s = (n-nSB)/(n-1), where nSB is the number of sided blocks, i.e. the number of blocks including adjacent genes on the same strand of the genome, and n is the total number of genes. The set of genes used for this analysis did not include the orf485, orf512/int, orf538/dpoB and orf1252. Conserved gene pairs or gene clusters exhibiting identical gene polarities in selected green algal cpDNAs were identified using a custom-built program.The sidedness index Ci et al.  using thJ–SB participated in the conception of this study, performed most of the sequence analyses, generated the tables and figures and drafted the manuscript. CO performed the sequencing and contributed to the assembly and annotation of the genome sequence. CL and MT conceived and supervised the study, contributed to the analysis and interpretation of the data and prepared the manuscript. All authors read and approved the final manuscript.


We evaluate the role of nerve growth factor (NGF) eye drops to treat a herpetic corneal ulcer resistant to systemic and local acyclovir treatment in an HIV-positive patient.A 68 year old HIV-positive male presented with a herpetic corneal ulcer which was treated unsuccessfully with acyclovir. Acyclovir sensitivity of herpes simplex virus was tested with a dye uptake assay and we found that the herpes simplex virus isolated was resistant to acyclovir. We started eye drop therapy with NGF and the corneal herpetic ulcer healed in 23 treatment days.The case presented here is the first described in the literature in which a herpetic corneal ulcer was successfully treated with NGF. We recommend that trials of NGF therapy in herpetic keratitis should be carried out on a larger number of acyclovir resistant cases. Herpes simplex virus HSV-1) infections of the eye, and in particular keratitis, are quite frequent in people with acquired immunodeficiency syndrome  infectio due to t3. Furthermore he was not on Highly Active Anti-Retroviral Treatment (HAART). We treated the patient with oral acyclovir, 800 mg five times daily, and topical acyclovir ointment four times daily. After 10 days of treatment no clinical improvement was observed .We administered NGF eye drops  every two hours in the inferior conjunctival fornix until the ulcer was healed, which occurred after 23 days of treatment , neurotrophin 4/5 (NT-4) and brain-derived neurotrophic factor (BDNF). Neurotrophins exert their biological functions by binding to high affinity transmembranous receptors belonging to the trk family of receptor tyrosin kinase including trkA, trkB and trkC and p75 .TrkA is the receptor of NGF and consists of a 140 KD molecule, which modulates not just neuronal survival but also the migration and proliferation of other cell lines .NGF is a polypeptide that is essential for the survival and growth of sympathetic and sensorial system neurons and for CNS neuronal differentiation . The proIn vitro and in vivo studies  have shoThe case presented here is the first described in the medical literature in which a corneal herpetic ulcer, resistant to antiviral therapy, was treated with NGF. Although the use of NGF for the treatment of this type of disorder is still under debate, we believe that its use in selected cases of herpetic keratitis resistant to acyclovir therapy must be investigated on a larger number of cases to confirm our result.The author(s) declare that they have no competing interests.Mauro Cellini, MD recruited the patient from the Cornea Disease Service of the S. Orsola-Malpighi Hospital; he drafted the manuscript and reviewed the literature. Prof. Emilio Campos examined the patient in the time. Pietro Leonetti reviewed the manuscript.Mauro Cellini, MD  examined the patient and received the informed written consent from the patientfor publication of the manuscript and any accompanying images.


Pigmented villonodular synovitis is a benign proliferative disease involving the synovium. Pigmented villonodular synovitis is rare after replacement arthroplasty and has not been recognised and reported as a cause of failure of unicompartmental knee replacement in the literature. Pigmented villonodular synovitis (PVNS) is a proliferative disease affecting the synovial joints resulting in villous or nodular changes in the synovial tissue, large effusions and bony erosions . PVNS afA 69-year-old retired Caucasian gentleman with a BMI of 30, presented with one year history of activity related anteromedial knee pain without any mechanical symptoms. He previously underwent medial unicompartmental knee replacement 4 years ago and was asymptomatic till his symptoms started insidiously a year ago. He suffers from hypertension and does not have any other co-morbidities. He is a non-smoker and drinks alcohol occasionally.Clinically he had a well healed surgical scar over the anteromedial aspect of the knee, moderate effusion, mild tenderness over the medial tibial plateau, and no signs of instability with the last 10 degrees of flexion restricted. Radiographs showed good alignment of the medial unicompartmental prosthesis with no evidence of loosening (Figure He underwent arthroscopy of the knee which showed evidence of pigmented proliferation with villous appearance of the synovial tissue suggestive of PVNS Figure . ArthrosPVNS is a benign proliferative disorder of the synovium of unknown etiology . It can PVNS may be intra- or extraarticular and can present in the diffuse or nodular form with a tendency to bleed and erode bone . Joint eThe suggested treatment for PVNS depends on the severity of joint involvement and age of the patient. The options are synovectomy, radiotherapy, arthrodesis and arthroplasty ,9,10. OuThe main reasons for failure of unicompartmental knee replacement are infection, aseptic loosening, mal-alignment, other compartment degeneration, polyethylene wear and instability . In our This case highlights an unusual case of PVNS as a cause of failure of unicompartmental knee replacement. Although rare, we suggest considering PVNS in the differential diagnosis of patients presenting with knee pain after unicompartmental knee arthroplasty.The authors declare that they have no competing interests.Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journalPM, DP and SJ have been involved in the treatment of the patient, literature search and manuscript preparation. All authors have read and approved the final manuscript.


Allogeneic red blood cell transfusion is associated with increased morbidity and mortality in adult trauma patients. Although studies have suggested that the adoption of a more restrictive transfusion strategy may be safely applied to critically ill adult and all-cause critically ill pediatric patients, recent developments in our understanding of the negative consequences of red blood cell transfusion have focused almost entirely on adult populations, while the applicability of these findings to the pediatric population remains poorly defined. The object of this study was to evaluate the effect of red blood cell transfusion within the first 24 hours following admission on mortality in pediatric trauma patients treated at our institution.Age, race, and mechanism of injury did not differ between transfused and non-transfused groups, although there were significantly more female patients in the transfusion group . Shock index (pulse/systolic blood pressure), injury severity score, and new injury severity score were all significantly higher in the transfused group . Patients who received a red blood cell transfusion experienced a higher mortality compared to the non-transfused group . When attempting to control for injury severity, goodness-of-fit analysis revealed a poor fit for the statistical model preventing reliable conclusions about the contribution of red blood cell transfusion as an independent predictor of mortality.Red blood cell transfusion within the first 24 hours following admission is associated with an increase in mortality in pediatric trauma patients. The potential contribution of red blood cell transfusion as an independent predictor of hospital mortality could not be assessed from our single-institution trauma registry. A review of state-wide or national trauma databases may be necessary to obtain adequate statistical confidence. Nonoperative management of blunt traumatic injury is now a widely accepted practice in hemodynamically stable patients,2. The tRecent developments in our understanding of the negative consequences of PRBC transfusion have focused almost entirely on adult populations, while the applicability of these findings to the pediatric population remains poorly defined. The purpose of this study was to examine the effect of blood transfusion within the first 24 hours of admission on hospital mortality in the pediatric trauma patient population.Over the 8-year study period, 1639 pediatric trauma patients were admitted to our trauma center of which 106 (6.5%) received at least one PRBC transfusion within the first 24 hours of admission. Patient characteristics of the overall cohort, as well as transfused and non-transfused groups are presented in Table Physiologic and anatomic measures of injury severity of transfused and non-transfused groups are presented in Table Patients who received a PRBC transfusion experienced a longer mean intensive care unit (ICU) length of stay and were significantly more likely to stay in the ICU > 1 day. Table  AdditionFollowing trauma, cause of death varies according to the time after the initial insult. In a study looking at the etiologies of traumatic deaths, Sauaia et al, found thIn the acute setting PRBC transfusion can be lifesaving; however, consequences of transfusion may paradoxically result in an increased loss of life from organ failure. PRBC transfusion is often used to attenuate hemoglobin reduction from injury-associated blood loss, but evidence has been accumulating that suggests PRBC transfusion is an independent predictor of post-injury infection and MSOFAlthough the hospital mortality rate was significantly higher in our transfused group, patients within this group were more severely injured as measured by physiologic (SI) and anatomic (ISS) measures of injury severity. Over the 8-year study period, only 106 pediatric trauma patients who received a PRBC transfusion within the first 24 hours of admission were identified. Additionally, the removal of patients missing SI or ISS values further reduced the number of observation in this group by approximately 20% (n = 85 patients). All patients having SI and ISS values were included in the final analysis regardless of injury score in order to try to evaluate the effect of transfusion on the entire pediatric trauma population, because we were also interested in outcomes involving lesser injured patients . However, the small sample size in the transfused group statistically limited our ability to evaluate the independent effects of PRBC transfusion on mortality, as goodness-of-fit analysis on statistical models incorporating SI and/or ISS demonstrated that these models were unreliable. Therefore, a review of state-wide or national trauma databases may be necessary to obtain adequate statistical confidence to determine the independent effects of PRBC on mortality in the pediatric trauma patient population.Our study suffered from a number of limitations. As a tertiary referral center, many of the patients in this study arrived as transfers from referring institutions. Incomplete transfer records limited our ability to quantify the volume of blood transfused, as well as determine the age of the blood products received. Furthermore the study period also bridged our transition over to exclusively using leukocyte-depleted packed red cells. Age of transfused blood correlates with a higher risk of MOF in trauma patients and alsoRed blood cell transfusion in the first 24 hours following admission is associated with an increase in mortality in pediatric trauma patients. The potential contribution of red blood cell transfusion as an independent predictor of hospital mortality could not be assessed from our single-institution trauma registry. A review of state-wide or national trauma databases may be necessary to obtain adequate statistical confidence. Future research is needed to discover the mechanisms underlying poor transfusion outcomes in both the adult and pediatric populations.The study was approved by the Institutional Review Board of the University of North Carolina. Over an eight-year period (1998–2006), trauma patient admissions were retrospectively reviewed from an established and verified trauma registry. All pediatric patients (≤ 16 years of age) sustaining blunt or penetrating trauma were included in the analysis and classified into transfused , and non-transfused groups.Retrospectively acquired data from the trauma registry included age, gender, race, mechanism of injury (MOI), admission systolic blood pressure (SBP), heart rate (HR), and respiratory rate (RR). The shock index (SI) was calculated using the admission HR and SBP (SI = HR/SBP) and reprNo specific transfusion protocol was present during the time of this study. Nonoperative management and PRBC transfusion were performed at the discretion of the attending trauma surgeon initially evaluating the patient or the attending intensivist once the patient was transferred to the ICU. In general, hemodynamic instability, failure to respond to resuscitation, and ongoing blood loss were common indications for transfusion.t test was used for continuous variables. Data are expressed as mean ± standard deviation and comparison between groups is referred to as being statistically significant if p ≤ 0.05. Multivariate logistic regression was used to model the independent effect of blood transfusion on overall hospital mortality. Statistical methods and results were reviewed by an independent statistician.Univariate analysis was used to identify variables that were associated with blood transfusion, ICU length of stay, hospital length of stay, and hospital mortality. Chi-squared test was used to compare population proportions and two-tailed p values are reported. Student's The authors declare that they have no competing interests.TS collected data, participated in the statistical analysis, and drafted the manuscript. PR collected data, participated in the design of the study, performed the statistical analysis, and helped draft the manuscript. AC conceived of the study and participated in its design and coordination, and helped to draft the manuscript. All authors read and approved the final manuscript.


Previous reports suggest an as yet unidentifiable subset of patients with plasmacytoma will progress to myeloma. The current study sought to establish the risk of developing myeloma and determine the prognostic factors affecting the progression of disease.Patients with plasmacytoma diagnosed between 1973 and 2005 were identified in the SEER database(1164 patients). Patient demographics and clinical characteristics, treatment(s), cause of death, and survival were extracted. Kaplan-Meier, log-rank, and Cox regression were used to analyze prognostic factors.The five year survival among patients initially diagnosed with plasmacytoma that later progressed to multiple myeloma and those initially diagnosed with multiple myeloma were almost identical . Five year survival for patients with plasmacytoma that did not progress to multiple myeloma was significantly better (72%). Age > 60 years was the only factor that correlated with progression of disease (p = 0.027).Plasmacytoma consists of two cohorts of patients with different overall survival; those patients that do not progress to systemic disease and those that develop myeloma. Age > 60 years is associated with disease progression. Identifying patients with systemic disease early in the treatment will permit aggressive and novel treatment strategies to be implemented. Plasmacytoma results from clonal proliferation of plasma cells that are identical to plasma cells of myeloma on both the cyotologic and immunophenotypic levels. Plasmacytoma can be subclassified as osseous disease or extraosseous tumor -7. The cLocal radiotherapy and alternatively surgery are treatment options yielding adequate local control ,10. DespThe current manuscript attempts to ascertain the impact of local treatment on disease progression in patients with skeletal plasmacytoma. Specifically, the study sought to establish the incidence of development of myeloma and the treatment outcomes of patients initially diagnosed with plasmacytoma. Furthermore, the study seeks to compare clinical parameters in cases of plasmacytoma not progressing to systemic disease with those developing into myeloma to identify prognostic factors. In order to answer these questions, the SEER Database was utilized as a source of patient data. Previously the population based SEER database has been used to describe the outcomes for breast, colorectal, prostate, lung, ovarian, sarcomas and neuroectodermal cancers and has been validated as to the accuracy -21. The The Surveillance, Epidemiology, and End-Results (SEER) Program of the National Cancer Institute (NCI) was established as a direct result of the National Cancer Act 1971. Currently SEER collects data from 17 population based registries covering approximately 26% of the US population. It is the only comprehensive source of population based data in the U.S. that includes the stage of cancer at the time of diagnosis and follow-up of all patients for survival data. In addition, each registry collects data on patient demographics, primary tumor site and morphology, and first course of treatment (occurring within 4 months of diagnosis) -34. The rd Edition (ICD-O-3) [The SEER database was used to identify all cases of skeletal plasmacytoma diagnosed from 1973-2005 using International Classification of Disease for Oncology, 3ICD-O-3) . We usedPatients' age was converted to a categorical variable  for the purpose of analysis. The appendicular skeleton included long and short bones of limbs and associated joints, and the scapula. Axial skeleton included vertebra, ribs, sternum, clavicle and associated joints, bones of skull, face and associated joints, mandible, and pelvic bones. Staging categories of local, regional, and distant were described in SEER according to AJCC staging system . Since, Incidence rates were age adjusted and normalized using the 2000 US Standard population . StatistA total of 1164 cases of plasmacytoma are included in the SEER Data-base from 1973-2005. Nearly three quarter of the cases (74.7%) were diagnosed during the most recent decade, 1996-2005 reflecting the geographic expansion of the data collection effort during these years. The demographic and clinical characteristics of the entire patient cohort are summarized in Table The overall incidence for plasmacytoma was 0.3462/100,000 in 2005; similar to what has been reported by Dores et al . Afro-AmPatients diagnosed at age < 60 years Figure  had a siPatients undergoing surgery fared no better than patients without resection . In contrast, administration of radiation therapy was associated with an improvement in survival . Further analysis revealed that use of any local disease control modality, either surgery or radiation therapy was associated with better outcomes as compared to the absence of any local disease control . We found that there was no significant difference in 5 year survival among patients initially diagnosed with multiple myeloma and those initially labeled as plasmacytoma who subsequently later progressed to multiple myeloma . In contrast, 5 year survival for patients with plasmacytoma who did not progress to multiple myeloma was significantly better with , Figure Analysis of statistically significant factors on multivariate analysis did not reveal any prognostic factors significantly associated with progression of plasmacytoma into a systemic disease other than age Table . AssociaIn order to assess the potential ascertainment bias: the potential bias of falsely diagnosing patients with myeloma as plasmacytoma patients, a cross-tabulation was performed between cause of death and different treatment groups. Our analysis reveals 27 of 60 patients with no attempt at local control, died of myeloma. This ratio of progression to myeloma was similar in other treatment groups (dns) with chi-square not revealing any statistical significance.The current study is the first to demonstrate the impact of local treatment on skeletal plasmacytoma using a population based registry. It further demonstrates the differences in treatment related outcomes among patients diagnosed with plasmacytoma not progressing to myeloma, those that progressed to myeloma. Epidemiological studies comparing SEER areas to non-SEER areas in the U.S. conclude that their age and sex distributions are comparable except that SEER areas tended to be more affluent and more urban than non-SEER areas . When coAlso, the 5 year survival for patients diagnosed with multiple myeloma and those diagnosed as plasmacytoma initially but who subsequently developed myeloma later on, were almost identical Figure . This maAnother controversy highlighted in literature involves the fate of patients with plasmacytoma in regards to disease progression. While some have demonstrated a significant portion of patients free of disease after 5 and 10 years, others believe in the inevitability of progression for all patients ,43,46,47Surgery alone has been proposed as the best treatment option for extramedullary plasmacytomas , but conLimitations of the current study include lack of any information on specific chemotherapy regimens or any other adjuvant therapy in the SEER Database. Thus we are unable to comment directly on survival benefit conferred upon by the use of chemotherapy or efficacy of a particular regimen in a particular subset of patients. Similarly, no information regarding any medical history, radiological studies or serological work up is provided in the database limiting our analysis on diagnostic accuracy of MRI, and prognostic significance of absence of myeloma protein, anemia, hypercalcemia, renal insufficiency and stability of M-protein. Accuracy of staging information can be a potential pitfall in all studies based on database. Another issue associated with the reported data in SEER is the potential bias of falsely labeling myeloma patients as plasmacytoma patients. The results of bone marrow aspirate are not reported in SEER, and in clinical practice treatment decisions are usually made based on this parameter. This raises the suspicion of marrow involvement >30% among those not receiving the local therapy. Our analysis reveals no correlation between any treatment groups and 'cause of death'. We also attempted to address the controversy regarding progression to myeloma. In clinical practice, the evaluation regarding progression to myeloma is carried out after a specified time interval. SEER does not report the time for evaluation regarding progression; we assessed the outcome using 'cause of death' information. The time to progression cannot be assessed.Despite the above mentioned limitations such as retrospective nature of data, lack of information about chemotherapy or serological or radiological investigations; the current study addresses some of the controversies in disease progression and impact of local treatment for plasmacytoma using a large populations based well validated national database. The current study also reiterates the need of better understanding of the disease process of plasma cell neoplasm and the inclusion of molecular markers in the database.The authors declare that they have no competing interests.MUJ carried out analysis and wrote the manuscript.SPS conceived the idea and was the senior author in preparation of manuscript.Both authors have read and approve the manuscript.


Arboviruses are transmitted in nature exclusively or to a major extend by arthropods. They belong to the most important viruses invading new areas in the world and their occurrence is strongly influenced by climatic changes due to the life cycle of the transmitting vectors. Several arboviruses have emerged in new regions of the world during the last years, like West Nile virus (WNV) in the Americas, Usutu virus (USUV) in Central Europe, or Rift Valley fever virus (RVFV) in the Arabian Peninsula. In most instances the ways of introduction of arboviruses into new regions are not known. Infections acquired during stays in the tropics and subtropics are diagnosed with increasing frequency in travellers returning from tropical countries, but interestingly no attention is paid on accompanying pet animals or the hematophagous ectoparasites that may still be attached to them. Here we outline the known ecology of the mosquito-borne equine encephalitis viruses , WNV, USUV, RVFV, and Japanese Encephalitis virus, as well as Tick-Borne Encephalitis virus and its North American counterpart Powassan virus, and will discuss the most likely mode that these viruses could expand their respective geographical range. All these viruses have a different epidemiology as different vector species, reservoir hosts and virus types have adapted to promiscuous and robust or rather very fine-balanced transmission cycles. Consequently, these viruses will behave differently with regard to the requirements needed to establish new endemic foci outside their original geographical ranges. Hence, emphasis is given on animal trade and suitable ecologic conditions, including competent vectors and vertebrate hosts. During the last decades the appearance of new infectious diseases and an increasing invasion of diseases into new areas created a new category of pathogens: emerging and re-emerging pathogens. Most of the emerging viruses are zoonotic which means they can infect both animals and humans . As outlAedes albopictus, Aedes japonicus), is well-known and, in several countries, is under close observation, the risk and the importance of animal trade for the importation of arboviruses has not been studied extensively . More than 150 of these are known to cause human and/or animal diseases. For many of those viruses, only limited information is available regarding their vector and host spectrum. Hence, we have chosen some prominent examples of important arboviruses causing human and animal diseases, which belong to the genera alphaviruses (family Togaviridae), flaviviruses (family Flaviviridae), and phleboviruses (family Bunyaviridae) to discuss the animal aspect in virus dispersal.The last International Catalogue of Arboviruses listed more than 500 arboviruses and related viruses [; http://Culex tarsalis [[Aedes and six species of the genus Culex [Aedes and vertebrate hosts including rice rats (Oryzomys spp.), rabbits and introduced European hares (Lepus europaeus) [Western Equine Encephalomyelitis (WEE) is caused by the Western equine encephalomyelitis virus (WEEV) which belongs to the genus Alphavirus in the family Togaviridae . The virarsalis [, Figure arsalis [. Howeverus Culex . In Soutropaeus) -26. Humaropaeus) . Therefohttp://diseasemaps.usgs.gov/; as of December 8th 2009). Less land irritation and consequently less breading opportunities for vector mosquito species have been claimed for the fading of the virus. To some extent the use of vaccines, which are available for equines but not for humans, might have attributed to this situation. Nevertheless, WEEV has been used to develop chimeric vaccines in combination with other alphaviruses such as Sindbis or eastern equine encephalitis viruses [[In humans, WEEV causes severe encephalitis with higher manifestation rates in children and in elderly persons. Fatality rates may be up to 5% . WEEV isviruses [; see belAedes eggs  may be possible means of importation [Culex pipiens and from Aedes vexans. Both mosquito species form a major part of the Central European mosquito fauna. For a natural transmission cycle, WEEV is dependent on passerine birds and possibly also on small wild mammals. Both groups of animals are abundant in Europe and although no data are available on the potential of European species to serve as natural maintenance or amplifying hosts, there are no obvious reasons to argue against a potential for transmission in European species. Hence, the risk of the introduction of WEEV into Europe seems to be low, although the required components for a natural transmission cycle of WEEV seem to be available  is caused by eastern equine encephalomyelitis virus (EEEV) which is also a member of the genus Alphavirus in the family Togaviridae. EEEV causes severe disease in humans, in horses and in some game animals . In humaCuliseta melanura and passerine and wading birds of different species . The results of studies of transovarial transmission of EEEV in mosquitoes are conflicting. Probably EEEV is not transmitted via infection of eggs to the next mosquito generation while for Coquilletidia perturbans transovarial transmission could be proved [EEEV occurs in North and South America. While the natural transmission cycle(s) in South America are not well understood, transmission in Eastern North America is mainly dependent on ornithophilic mosquitoes of the species s Figure . The cycAedes vexans and Culex pipens are among the most abundant mosquito species in Europe. However, at least in North America, Culiseta melanura seems to be the main vector for EEEV. The genus Culiseta is a rather species poor genus (five species worldwide), which has been claimed to be the reason for higher levels of genetic identity in viruses transmitted by Culiseta mosquitoes than in viruses that mainly use Culex or Aedes vector species [The risk of an importation of EEEV into Europe or other areas outside of the American continent seems to be low. Basically, an importation seems possible via infected mosquitoes, infected birds  and also via infected reptiles and amphibians. As already mentioned for WEEV, no frequent migration of birds between the Americas and Europe exists. Therefore an introduction seems only possible as a result of human activities . Although no studies on the vector competence of European mosquito species for EEEV are available,  species . In contCulex (Melanoconion) and rodents  [[Venezuelan equine encephalomyelitis is caused by a complex of viruses  which belongs to the genus Alphavirus in the family Togaviridae. The complex includes seven different virus species and a number of subtypes and varieties . VEEV ocntomys) [, Figure ntomys) [. Howeverntomys) [. Other wntomys) [,39.Aedes and Psorophora which have a peridomestic/peri-agricultural behaviour and may transmit VEEV to equines, donkeys and mules. Equids develop high virus titres and therefore may serve as amplifying hosts for VEEV. An equine-mosquito-cycle may induce an extensive virus circulation with a spill-over to humans and cause epidemic VEE  and replicate to higher titres in this mosquito species than in mosquitoes involved in endemic transmission (Melanoconion) [Culex and Aedes in Europe are competent for VEEV has not been studied so far. However, American strains of Aedes albopictus were found to be capable of transmitting VEEV [The epidemic occurrence of VEEV during the last two decades shows that it is highly variable in nature and that single amino acid changes in the viral genome may cause major changes in vector competence of mosquitoes or in the pathogenicity in equids -43. Studoconion) . The inting VEEV ,46. TherWest Nile virus (WNV) is a member of the Japanese encephalitis group of the genus Flavivirus in the family Flaviviridae. The evolutionary origin of WNV seems to be in Central Africa, from where it spread over various parts of the world and locally new genotypes emerged . ActuallCulex [Aedes, Anopheles, Aedomyia, Mansonia, Coquilletidia) and of hard and soft ticks  for the endemic and epidemic transmission cycles remains to be determined [Rana ridibunda) was found to be viremic and was able to transmit the virus to blood-sucking Culex pipiens [Like other members of the Japanese encephalitis serogroup, WNV in nature is maintained in a bird-mosquito cycle Figure . WNV wasCulex . The imptermined . Varioustermined ,55. WNV  pipiens . TherefoWNV is an often cited example of a dispersing arbovirus since it invaded into North America in 1999 . From thCulex pipiens), climate warming, and perhaps also the decline of infections with the closely related St. Louis encephalitis virus, an indigenous virus of the Japanese encephalitis serogroup in the Americas [The exact way of introduction of WNV into North America is still unclear. Several additional factors are discussed which improved the establishment and transmission of WNV in this new environment Table . Among tAmericas . HoweverAmericas ,59. In aAmericas . The intAmericas ,61,62.Flavivirus of the family Flaviviridae. JEV is transmitted in a natural transmission cycle involving mosquitoes of the genus Culex and water birds (mainly egrets and herons) [Japanese encephalitis virus (JEV) is a member of the similarly named serogroup in the genus  herons) . Actuall herons) . Current herons) . Up to 3 herons) . JEV inf herons) .Culex. The primary vector is Culex tritaeniorhynchus, which is associated with rice paddies and irrigated crop fields in whole Southeast Asia. Culex tritaeniorhynchus feeds on water birds and on larger mammals, also on pigs and therefore transmits JEV to this important amplifying host, and also to equids and to humans. Other Culex species, like Culex pipens, Culex vishnui and Culex bitaeniorhynchus may play a local role for the transmission of JEV  and the Asian cattle egret (Bubulcus ibis coromandus) [Culex tritaeniorhynchus. Therefore, an enzootic or an epizootic cycle may be initiated from mosquitoes directly after diapause. The invasion of JEV in new areas in Southeast Asia during the last decades has been mainly associated with the increase of human populations and, consequently, in increasing areas of rice paddies and pig farming [The natural transmission cycle mainly involves mosquitoes of the genus V Figure . The natomandus) . There i farming . JEV rec farming ,70.Japanese encephalitis virus shows a clear tendency of expansion. One mechanism of spread involves the air transport of infected mosquitoes. This method of spread was shown by the introduction of JEV into Pacific islands like Guam or Saipan ,72. A reRift Valley fever (RVF) is a disease which was first described as an entity during an epizootic outbreak in 1930 - 1931 in Kenya . There, Phlebovirus of the family Bunyaviridae. It is transmitted in an enzootic cycle among wildlife and mosquitoes [Aedes, Ochlerotatus, Stegomyia, Anopheles, Culex, Neomelaniconion, Eretmapodites and others) as vectors [[Aedes. Aedes macintoshi seems to play a major role in Eastern Africa [Aedes macintoshi lays infected eggs into the ground and these eggs need one or more severe flooding to hatch. Therefore an inter-epidemic period  and an epidemic period  can be distinguished. The occurrence of epidemic periods is clearly associated with heavy rains which are closely linked to warming of the Indian Ocean during the El Nino Southern Oscillations  can be infected and develop systemic infection. However, only Aedes vexans and Culex erraticus developed virus titres which were high enough to transmit the virus to laboratory animals [These examples show that RVFV, without any doubt, is one of the most aggressive migrating arbovirus. The routes of dispersal detected so far seem to be in parallel with the great migration routes of camels. Therefore, there is some good evidence that viremic, but non-symptomatic infected camels transported the virus to Egypt and possibly also to the Arabian Peninsula . As also animals ,90. TherFlavivirus in the family Flaviviridae [Culex in South Africa in 1959. Since that time the virus was isolated several times from mosquitoes, rodents and birds throughout Sub-Saharan Africa [Turdus merula) and some other bird species. USUV could be detected the following years and its area of distribution extended into south-east (Hungary), south , west (Switzerland), and north  of the original location of emergence where it also caused mortality in birds [Usutu virus (USUV) belongs to the Japanese encephalitis serogroup within the mosquito-borne cluster of the genus iviridae . It was n Africa . There hn Africa . In 2001in birds ,94,95. Iin birds ,97. USUVCulex, Coquillettidia and Mansonia are thought to be the main vectors. In Austria, Culex spp. may play a major role, although USUV so far has not been isolated from mosquitoes but has been detected in overwintering Culex pipiens pools by real time RT-PCR (our own unpublished results). There seems to be a mode of adaptation of the virus to the new bird species and/or to the new mosquito species in Europe. After high mortality rates in blackbirds during the first two years of emergence of USUV, in the following years increasing rates of seropositive birds were detected in Austria which gave evidence for a continuing circulation of USUV with a somewhat lower pathogenicity, inducing an herd immunity in the bird populations [USUV is thought to be maintained in nature in a mosquito-bird transmission cycle. In Africa ornithophilic mosquitoes of the genera ulations .USUV appears as an impressive example for the introduction and permanent establishment of a so-called "tropical" arbovirus in moderate climates. In a recent study, it was argued that USUV is mainly maintained in a natural cycle in areas of Austria with a minimum of at least ten hot days (> 30°C) . In thisFlavivirus in the family Flaviviridae [Ixodes ricinus and Ixodes persulcatus). The natural vertebrate hosts of TBE virus are small rodents of the genera Myodes and Apodemus, although other Rodentia or Eulipotyphla (formerly: Insectivora) may contribute to the natural transmission cycle [[Ixodes ricinus in Europe, larvae become active above 10°C while nymphs start searching for suitable hosts at 7°C. This means, among many other factors, that a fast warming in spring will be beneficial for co-feeding and in turn will result in higher numbers of TBEV-positive ticks [So far, only the invasive potential of mosquito-borne arboviruses has been discussed. The example of tick-borne encephalitis virus (TBEV) shows that also tick-transmitted arboviruses may be able to invade new areas. TBEV is a flavivirus of the tick-borne group of the genus iviridae . It is dn cycle [; see Fign cycle [. In contn cycle [. The skin cycle [. Adults ve ticks ,103.Ixodes ricinus) on every 30th bird which migrated in autumn from Northern Europe towards the South. About one out of 2200 migrating birds carried a TBEV-infected tick [TBEV is the most important tick-transmitted arbovirus of human pathogenicity in Europe and Asia ,105. An ted tick . These dted tick . At leasted tick . The antth [Ixodes cookie and woodchucks and mustelids; Ixodes marxi and squirrels; Ixodes scapularis and white-footed mice [Dermacentor ticks, namely D. andersoni and D. variablis but the corresponding enzootic cycle has not ben explored in further detail. Vertical transmission of POWV was observed in Ixodes scapularis [Powassan virus (POWV) is the sole member of the tick-borne encephalitis serological complex of flaviviruses in North America. It received its name after the town Powassan in Ontario, Canada, were it was isolated from the brain of a child deceased after encephalitis in the late 1950th  and a coth . The latth -118. Morted mice . POWV haapularis . The curapularis . One wayapularis . So thisIt is interesting that for other tick-borne arboviruses, similar results on the importance of human activities for the spread into new, non-endemic areas are evolving. Kyasanur Forest virus, a virus related to TBEV is limited to some regions (Karnataka) in India . HoweverArboviruses are maintained in nature in complex transmission cycles between arthropods and vertebrates. They have developed strategies of adaptation and evolution to spread into new areas and eventually become established. Several recent examples show, that tropical arboviruses are capable to spread to countries with moderate climates. While bird-associated mosquito-borne viruses seem to be transported mainly by migrating birds, human activities  play a major role for arboviruses where humans play a role as natural vertebrate hosts. Also for tick-borne arboviruses, mainly human activities seem to contribute to the spread over long distances and the establishment in new ecosystems changed by human activities. In most cases of newly emerging zoonotic arboviruses, the ways of introduction remain obscure. Future research should aim at exploring the circumstances of these events. A better understanding of how arboviruses travel and why they become established in other geographic areas will be of great benefit for human and veterinary public health, because it may help to prevent devastating outbreaks of arboviral diseases in humans and animals.The authors declare that they have no competing interests.Both authors contributed equally to this work.