To assess the therapeutic validity and effectiveness of physiotherapeutic exercise interventions following total hip arthroplasty (THA) for osteoarthritis.The databases Embase, MEDLINE, Cochrane Library, CINAHL and AMED were searched from inception up to February 2017.Articles reporting results of randomized controlled trials in which physiotherapeutic exercise was compared with usual care or with a different type of physiotherapeutic exercise were included, with the applied interventions starting within six months after THA. Only articles written in English, German or Dutch were included.Therapeutic validity  and risk of bias  were assessed by two researchers independently. Characteristics of the physiotherapeutic exercise interventions and results about joint and muscle function, functional performance and self-reported outcomes were extracted.Of the 1124 unique records retrieved, twenty articles were included. Only one article was considered to be of high therapeutic validity. Description and adequacy of patient selection were the least reported items. The majority of the articles was considered as having potentially high risk of bias, according to both assessment tools. The level of therapeutic validity did not correspond with the risk of bias scores. Because of the wide variety in characteristics of the physiotherapeutic exercise and control interventions, follow-up length and outcome measures, limited evidence was found on the effectiveness of physiotherapeutic exercise following THA.The insufficient therapeutic validity and potentially high risk of bias in studies involving physiotherapeutic exercise interventions limit the ability to assess the effectiveness of these interventions following THA. Researchers are advised to take both quality scores into account when developing and reporting studies involving physiotherapeutic exercise. Uniformity in intervention characteristics and outcome measures is necessary to enhance the comparability of clinical outcomes between trials. Osteoarthritis (OA) is a common degenerative joint disorder, the hip being one of the most affected joints . PredomiAs part of the rehabilitation program following THA, patients are usually administered physiotherapeutic exercise ,10. PhysPhysiotherapeutic exercise can be considered as a complex intervention, as it can be administered in very different ways and settings. As a result, heterogeneity of effect may occur . HerbertSeveral systematic reviews have previously been conducted on the effectiveness of physiotherapeutic exercise following THA –23. ThesThe aim of our study was therefore to assess therapeutic validity in addition to effectiveness of physiotherapeutic exercise interventions in patients following THA for OA. To examine therapeutic validity and effectiveness of physiotherapeutic exercise, we reviewed randomized controlled trials (RCTs) comparing a physiotherapeutic exercise intervention with usual care or a different physiotherapeutic exercise intervention in patients who underwent unilateral primary THA because of OA. We hypothesized that studies of high therapeutic validity could demonstrate a positive effect on joint and muscle function, functional performance and self-reported outcomes in patients after THA.This systematic review was conducted following the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines .The following five databases were searched for relevant articles from inception up to 24 February 2017: Embase, MEDLINE, Cochrane Library, CINAHL and AMED. The search strategies for the different databases, which were optimized by a librarian, are shown in Articles describing the results of RCTs comparing postoperative physiotherapeutic exercise with usual care or comparing two different postoperative physiotherapeutic exercise interventions were included in this review. Articles were also included if the described trial met the following eligibility criteria: (1) the study included only patients who underwent unilateral primary THA (replacement of head and socket) because of OA; (2) the start of the intervention was within six months after THA; (3) the applied intervention consisted of land-based or water-based physiotherapeutic exercise (in both the inpatient and outpatient setting); (4) pre- and post-intervention measurements were conducted for both study groups; (5) outcomes from at least one of the following categories were reported: joint and muscle function ), functional performance  and self-reported outcomes ; and (6) the article was written in English, German or Dutch. Articles reporting trials that included patients who were undergoing partial hip replacement (head or socket), hip resurfacing or revision surgery were excluded. Other physiotherapeutic modalities such as manual therapy, osteopathy and electric stimulation therapy were not considered as physiotherapeutic exercise therapy according to the definition used in this study. Hence articles reporting trials in which these modalities were applied as intervention were excluded. Lastly, articles reporting the effect on outcome measures for the acute postoperative phase following THA  or for specific muscle properties  were not included in this systematic review.Two researchers (AW and SEB) independently assessed the eligibility of all identified articles. The first selection was made based on title, abstract and language. The full text of the remaining articles was subsequently retrieved to assess whether the article met the predefined inclusion criteria. Disagreements between the two researchers were solved in a consensus meeting.The following data were extracted from each included article by SEB: country and year of publication, sample size, participant characteristics (age and gender), characteristics of the physiotherapeutic exercise intervention , characteristics of the control intervention (frequency and intensity) and main results in each outcome category . Type of physiotherapeutic exercise was divided into the following three categories: strengthening exercise , aerobic exercise and functional exercise .The therapeutic validity of the physiotherapeutic exercise interventions was assessed by two researchers independently (SEB and GHS) using the CONTENT scale . The CONRisk of bias of the studies was assessed by two researchers independently (AW and SEB) using both the Physiotherapy Evidence Database (PEDro) scale and the Cochrane Collaboration’s tool. It was chosen to judge risk of bias twice to assess whether there are differences in the final judgment according to these assessment tools. The PEDro scale is an 11-item scale, which is found to be a reliable tool for use in systematic reviews of RCTs evaluating physiotherapeutic interventions . Each itDue to the heterogeneity of outcome measures and reported units of measurement, meta-analyses of data were not considered appropriate. Therefore, a narrative synthesis of data was used to evaluate the included studies and to give recommendations for future research. Furthermore, it was qualitatively assessed whether there seemed to be a match between the results of therapeutic validity assessments of physiotherapeutic exercise interventions and the risk of bias scores of the included studies.The aforementioned search strategy identified 1967 records, which contained 843 duplicates. Of the 1124 unique records, 1075 articles were excluded based on title, abstract or language. Twenty of the remaining 49 potentially relevant articles met the inclusion criteria and were therefore included in the systematic review. The list of excluded full-text articles with the reasons for exclusion is presented in The characteristics of the twenty included articles are shown in a priori intentions and hypotheses were described, while a rationale for the specific content and intensity of the therapeutic exercise was given in five articles (25%). The items description of patient eligibility and adequate patient eligibility achieved the lowest total scores. These items were reported in two articles (10%). It appears that the articles, which focus on strengthening exercises had higher scores on therapeutic validity than those involving other physiotherapeutic exercise interventions. In general, articles focusing on strengthening exercises seemed to score higher on the items setting and therapist, intensity, monitoring, and adherence.The assessment of the therapeutic validity using the CONTENT scale is shown in The results of the risk of bias assessment using the PEDro scale are shown in The assessment of risk of bias using the Cochrane Collaboration’s tool is shown in When only taking into account the final judgments on risk of bias shown in Three categories of outcome measures were predefined, based on the ICF model. Within these categories, different outcome measures and units of measurements were used. For joint and muscle function, hip muscle strength and hip ROM were the most evaluated outcomes. Hip muscle strength was measured in the following units of measurement: kilogram (kg) ,28,45, NIn the functional performance category, the 6-minute walk test (6MWT) ,40,41,43For self-reported outcomes, both disease-specific and generic questionnaires were used. The most commonly used disease-specific questionnaire was the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC): it was used in eight of the included articles to measure patient-reported pain, stiffness and/or physical function ,39,43,44In eleven of the included articles, the CG followed a usual care protocol . The other nine articles did not explicitly state whether the exercise program for the CG was usual care or if it was a protocol specifically developed for the trial. Nine of the included articles (45%) reported the frequency and intensity of the control intervention. The frequency varied from five to seven times a week. The intensity varied from 40 minutes to two hours or was reported as the number of repetitions of an exercise. Variety was also found in the setting of the control intervention (inpatient versus outpatient and land-based therapy versus a combination of land-based and aquatic therapy).Length of follow-up in the included articles varied from fifteen days to five years postoperatively. Some articles reported results of both short-term (immediately after the intervention period) and long-term follow-up (after a period in which the intervention was no longer applied). Different results for the physiotherapeutic exercise interventions in time were found. In the article of Husby et al., muscle strength of the operated leg increased significantly more in the IG compared to the CG . DirectlThe aims of this systematic review were to determine the therapeutic validity and to assess the effectiveness of physiotherapeutic exercise interventions for joint and muscle function, functional performance and self-reported outcomes in patients following THA for OA. It was found that the therapeutic validity of physiotherapeutic exercise interventions was insufficient: only one out of the twenty articles included could be considered to be of high therapeutic validity. In addition, a minority of the studies was considered to be of adequate quality according to the two risk of bias assessment tools used. The therapeutic validity scores did not correspond with the risk of bias scores that were found. Due to the heterogeneity in characteristics of the physiotherapeutic exercise and control interventions, the length of follow-up and the outcome measures used in the trials, no clear evidence was found for the effectiveness of physiotherapeutic exercise following THA. Our hypothesis that studies of high therapeutic validity might be able to elicit positive effects of physiotherapeutic exercise following THA has therefore not been confirmed yet.The insufficient therapeutic validity scores of the majority of the articles indicate that the potential effectiveness of the described physiotherapeutic exercise interventions is questionable. However, it cannot be stated whether the aspects of the CONTENT scale were not applied during the development of the intervention protocols or that these aspects were simply not reported in the articles. The lack of clear descriptions of the rationale and content of physiotherapeutic exercise interventions impedes an understanding of the focus and effect of such interventions. This issue has previously been reported by Bandholm & Kehlet, who state that a physiotherapeutic exercise intervention needs to be well described before the intervention can be implemented in clinical practice . To thisAdequate patient selection was one of the least reported items of the CONTENT scale in the included articles. One point is awarded for this item if the goals of the therapeutic exercise match the participants’ problems . Adequate patient selection is an important aspect in clinical trials, as it is established that there might be a difference in response to exercise therapies between patients. Several factors have been found to influence this response, such as level of physical functioning , age, anThree systematic reviews have previously been conducted in which the CONTENT scale was used to assess the therapeutic validity of physiotherapeutic exercise interventions in different patient populations –20. HoogSince the CONTENT scale was developed in a Delphi study conducted over four rounds in which five experts in the field of therapeutic exercise participated , it can The majority of the included studies was judged as having potentially high risk of bias, using both the PEDro scale and the Cochrane Collaboration’s tool. This is in line with the most recent systematic review on this topic . NonetheA review evaluating the Cochrane Collaboration’s tool found that it is often used in a non-recommended way . CorrectIn the current review, the levels of therapeutic validity did not correspond to the risk of bias scores. The only article considered as being of high therapeutic validity met the requirements of adequate quality according to the Cochrane Collaboration’s tool, but not according to the PEDro scale. The articles with insufficient therapeutic validity were mostly considered as being of insufficient quality according to the Cochrane Collaboration’s tool, but obtained varying scores according to the PEDro scale. Based on the current review, it is recommended that systematic reviews should not only assess risk of bias but also take the therapeutic validity of physiotherapeutic exercise interventions into account as both assess different aspects of the interventions.The diversity in characteristics of physiotherapeutic exercise interventions, control interventions and outcome measures prevents a clear answer to the question of the extent to which physiotherapeutic exercise can improve joint and muscle function, functional performance and self-reported outcomes following THA. Even within the defined intervention categories  there is a wide variety regarding setting, supervision, duration, frequency, intensity, start and follow-up length of the interventions. Only one trial (which was presented in two articles) was identified that investigated the effects of aerobic exercise ,35. GeneOverall it can be concluded that more thorough research is essential. The OARSI clinical trials guidelines would be useful to follow. In these guidelines it is stated that thorough description of interventions is needed so that others can replicate it including algorithms for treatment selection/progression, dosage , adherence strategies, home programs, training of treatment providers and treatment fidelity methods .Within the three different categories of outcome measures  there was a wide variety in used measurement instruments and reported units of measurement. In particular, hip muscle strength was expressed in different units of measurements across the articles. To conduct meta-analyses on muscle strength, uniformity of measurements is required. Differences in the scoring methods of the functional tests were found for functional performance. For example, chair rise performance assessed with the sit-to-stand test was rated as the maximal number of times patients were able to rise from a chair in 30 seconds in the study of Okoro et al. , while SThe earlier mentioned OARSI guidelines propose four categories of outcome measures: pain, patient-reported outcome measures, performance-based measures and patient global assessment. Regarding performance-based measures, a minimal core set is recommended to evaluate functional performance in hip and knee OA. This core set consists of three tests to evaluate performance of sit-to-stand (using the 30 seconds chair stand test), short walking distances  and stair negotiation tasks (using a timed stair task). The OARSI also developed a manual in which the protocols and psychometric properties of these tests are presented . MoreoveSome of the articles in our review assessed both joint and muscle function and functional performance ,36,40–43Due to limited information on the control interventions in the articles, there is limited evidence for the effectiveness of the physiotherapeutic exercise interventions. The majority of articles (55%) did not report on frequency and intensity of the control interventions. As a result, it is often not possible to assess whether a between-group difference is due to the exercise type or might be caused by a difference in exercise dose. To determine the effect of the exercise type, the interventions applied in both study groups should be as similar as possible in terms of the other characteristics , and these characteristics should be clearly described.The articles that did address the characteristics of the control intervention showed that there is variety in frequency and intensity between the different studies. The results also show that the “usual care” protocol may also vary considerably between countries and between clinical centers within countries. These differences in characteristics of control interventions between studies limit the ability to compare their results, so uniformity of control interventions across trials is desirable.Both short-term and long-term results were reported in some articles, with length of long-term follow-up ranging from six months to five years. Long-term follow-up is required to assess whether any significant improvements are lasting, even after ending the intervention. For hip muscle strength and functional performance there seem to be no between-group differences in the long term after a significant short-term effect in favor of the IG ,41. HoweTo our knowledge, this is the first systematic review to assess the therapeutic validity of physiotherapeutic exercise interventions following THA. In addition, we only included articles that focused on patients who underwent THA because of OA, and excluded articles that included patients with other conditions leading to THA .Several factors should be taken into account when interpreting the results of this systematic review. Although we searched five databases and included articles in three different languages, we might have missed articles relevant to our search. Furthermore, we did not contact the authors of the included articles for additional information when items from the therapeutic validity or risk of bias assessment tools were not reported in the article.When designing and describing studies in which a physiotherapeutic exercise intervention is applied, both therapeutic validity and risk of bias should be taken into account. The CONTENT scale should be used to describe the various aspects of therapeutic validity to increase the transparency of interventions applied in clinical trials. This review demonstrates that the potential effectiveness of physiotherapeutic exercise following THA is still questionable, due to potentially inadequate patient selection, the wide variation in characteristics of physiotherapeutic exercise interventions, control interventions and outcome measures. To gain complete insight into the effectiveness of physiotherapeutic exercise interventions, future studies should include a spectrum of outcome measures for example as proposed by OARSI  and apprDue to insufficient therapeutic validity of physiotherapeutic exercise interventions and potentially high risk of bias of the included studies, the effectiveness of physiotherapeutic exercise following THA for OA is unclear. Since the levels of therapeutic validity did not correspond to the risk of bias scores, both aspects should be taken into account when developing and reporting on protocols of clinical trials. In order to assess the effectiveness of physiotherapeutic exercise following THA, uniformity of characteristics of physiotherapeutic exercise interventions, control interventions, length of follow-up and outcome measures is necessary.S1 File(DOC)Click here for additional data file.S2 File(DOCX)Click here for additional data file.S3 File(DOCX)Click here for additional data file.S4 File(DOCX)Click here for additional data file.S1 Table(DOCX)Click here for additional data file.S2 Table(DOCX)Click here for additional data file.


Stem cells are the pluripotent cells that have the capacity to differentiate into other specialized cells. Recently, many experiments have been conducted to study the potentiality of stem cells in the tissue regeneration. We report two cases treated utilizing stem cells from human exfoliated deciduous teeth (SHED) in the management of periapical lesions in permanent teeth. Two normal human deciduous teeth from children, 7‒8 years of age, were collected to isolate stem cells. Two patients, one with periapical pathology alone and the other with periapical lesion along with an open apex in young permanent teeth, were selected for the study. After initial debridement of the root canals, homing of SHED was carried out and the access cavity was sealed using glass-ionomer cement. Clinical examination after 7 days, 30 days, 90 days, 180 days and 365 days revealed no symptoms. Closure of open apex and periapical tissue healing were observed radiographically at one-month review and maintained until 365-day review. Positive response to electric pulp testing was recorded for the treated teeth from the 3- to 12-month follow-ups. The treated cases demonstrated complete resolution of periapical radiolucency in a span of 30 days, which was faster than the conventional methods. SHED could be considred effective in treating the periapical lesions and open apex in permanent teeth. DPSCs obtained from human exfoliated decisuous teeth are known as SHED; these cells have the capacity to replicate and renew themselves. The lesions in the periapical area are the sequela of pulpal disease and are diagnosed during the routine radiographic examination.3 Various materials and techniques like pure calcium hydroxide, MTA, lesion sterilization and tissue repair, and periapical surgery have been advocated in the past. Traditional calcium hydroxide apexification procedure requires multiple visits and the barrier formed by calcium hydroxide apexification is porous and non-continuous, and makes the tooth brittle due to proteolytic and hygroscopic properties. MTA apexification technique provides non-porous and continuos barrier formation in one or two appointments but it has not been shown to reinforce teeth. Lesion sterilization and tissue repair (LSTR) technique is associated with discoloration of the treated tooth.4Recent advances in the stem cell research has created much interest in dental tissue regeneration, resulting in the emergence of tissue engineering in dentistry.5 Hence, this experiment was aimed to evaluate the effectiveness of stem cells from human exfoliated deciduous teeth (SHED) in the management of periapical lesions and open apex in permanent teeth. We here present two cases of periapical lesions that were successfully treated utilizing SHED.Recently, many studies are focussing on the use of stem cells in regenerative medicine.Two normal human deciduous teeth from children aged 7‒8 years were collected. Teeth with dental caries and pulpal, periapical and periodontal diseases were excluded.Enzymatic digestive method of the dental pulp tissue (DPSC-EZ) was used for the isolation of DPSCs.6 This technique involves sterile removel of dental pulp, digestion, characterization and screening by using specific markers. The preparation of culture media, sample collection, storage, handling, expansion, subculturing and characterization of stem cells were performed using the methods described by Vishwanath VR et al.7 The SHED was immediately transported from the laboratory to the department and utilized for the treatment on the same day  & 2.A twelve-year-old male patient reported to the Department of Pedodontics and Preventive Dentistry, complaining of fractured lower anterior teeth. The patient gave a history of trauma six months back and on clinical examination, an Ellis class IV fracture was seen in teeth #31 and #41. Radiographic examination revealed periapical radiolucency involving both #31 and #41 . The teeA 12-year-old male patient reported to the Department of Pedodontics and Preventive Dentistry with a chief complaint of fractured upper front tooth. The patient had a history of trauma to tooth #11 two years back. Upon clinical examination, the patient was asymptomatic, and the tooth #11 with Ellis class IV fracture exhibited no response to thermal and electric pulp testing. Radiographically open apex in association with periapical lesion of approximately 2 mm in diameter was seen in #11 . To prom8 and when such treatments fail, other additional measures must be considered like the repetition of the nonsurgical treatment, surgery or simpler techniques such as marsupialization.Infection of the dental pulp is the major cause of periapical pathology leading to the loss of bone and appearance of radiolucency in the radiograph. The main rationale for management is to eradicate the root canal pathogens and substantially reduce the microbial overload. Numerous approaches have been reported in the literature, including non-surgical management, apical surgery and extraction. Initially, periapical lesions are treated with non-surgical conservative methods,9 suggested extension of instruments 1 mm beyond the apical foramen would eventually lead to the development of inflammatory reaction that destroys the cyst lining and thereby, converting the lesion into a granuloma. Upon elimination of the causative factors the granuloma heals spontaneously. Bender explained that penetration into the center of the radiolucency through the apical area helps establish drainage and relieve pressure, which helps in the resolution of the lesion.10 Much recently, the Cariology Research Unit of Niigata University advocated ‘Lesion sterilization and tissue repair (LSTR) therapy that involves the use of a combination of antibacterial drugs.' But the above-mentioned treatments require multiple visits and long-term evaluations to assess the clinical success.Bhaskar13PerioGlas®, a Bio-active ceramic, was used as a scaffold material in the present case report as it has the advantages of being osteostimulative, osteoconductive and resorbable and also facilitate application.14The potential role of scaffold as a delivery vehicle for cells has turned out to be progressively essential in a wide assortment of tissues and organs in cellular treatment for local repair. They assume a key role in the activation and attachment of cells in the favorable location. Because of the property of good osteoconductivity they play a major role in avoiding the formation of encapsulating tissue and furthermore helps in the induction of a strong bond between the scaffold and the host bone.6 The autografts which were placed resulted in the repair of the mandibular alveolar bony defects produced after extraction of impacted third molars, producing optimal qualitative and quantitative bone regeneration and bringing about an effective therapeutic strategy.15Literature review provides few promising in vivo investigations of bone repair using dental pulp stem cells (DPSCs). Papaccio’s group showed that autologous DPSCs, when seeded onto collagen sponge scaffolds, could be utilized to repair alveolar defects .16 analysed DPSCs from canine in an osseointegration study. DPSCs embedded with platelet-rich plasma were placed into bone defects in mandibular canine. Histological perceptions indicated mature, well formed bone, positive for osteocalcin and also signs of neovascularisation, showing the capability of DPSCs for bone regeneration in oral maxillofacial surgery.16Yamada et al17 Lee et al18 showed the utility of DPSCs to produce dentin/cementum, periodontal ligament and alveolar bone complex.In the present study, we used SHED for the treatment of periapical lesions and achieved success in a 30-day span in both the cases. Deciduous teeth are significantly different from permanent teeth in regard to their developmental process, tissue construction and functioning. Therefore the SHEDs have higher rate of proliferation, increased cell population doublings, sphere-like cell cluster formation and osteoinductive capacity factor inducing the host cells to form bone in vivo.19In our study, both teeth positively responded to cold test and electric pulp test, indicative of re-innervation of the pulp-like tissue within the canal. These findings might be indicative of the presence of pulp or pulp-like tissue within the root canal space after regenerative treatment. Histologic examination of the tissue formed within the root canal space of one case with continued development of root and positive response to electric pulp test at follow-ups revealed presence of a pulp-like tissue.The exact mechanism of healing of periapical lesions is not clearly known, but the possible mechanism of the healing was due to the SHED introduced into the canals reaching the periapical area and differentiating into osteoblast-like cells and thereby promoting adhesion, proliferation, finally leading to osseous regeneration. SHED may also have differentiated into fibroblasts that deposit collagen compressing the capillary network, thereby starving the epithelial cells which are later engulfed by macrophages.The present case studies were based on the clinical scenario that periapical pathologies are the most frequently encountered diseases in children, causing damage to the healthy pulp that eventually leads to the necrosis and incomplete apical closure. The treatment is often challenging to dentists, as they require long-term treatment periods. Hence, the following study was undertaken to minimize the treatment period.In the present cases, there were no complications after the homing of stem cells. The patient remained completely asymptomatic from postoperative period until the recent follow-up after 365 days. Although the present cases showed success of SHED in the treatment of periapical lesions and also immature apex, further clinical trials are required to assess the clinical efficiency of SHED.Based on the results, the allogeneic SHED as a new biologic alternative might be used for the successful treatment of periapical lesions and open apex in permanent teeth. With this extended knowledge of SHED’s therapeutic properties, further clinical investigations are warranted to assess the histological success. After stem cell banking, the next advance should be the availability of ready-for-use “allogeneic stem cell packs,” which will give dental specialists the capacity to deliver stem cell therapies.Authors would like to thank Fr. Nelli George, Fr. P. Bala , Dr. Sleeva Raju and staff of the Department of Pedodontics, St. Joseph Dental College, Eluru, Andhra Pradesh, India for their support through out the study.MGP and DN designed the study and extracted the stem cells from human exfoliated deciduous teeth (SHED). MGP and JRK performed the clinical procedures. MGP, JRK and DN drafted the manuscript. All the authors contributed to critical revision of the manuscript, and have read and approved the final manuscript.The authors declare that they have no competing interests with regards to authorship and/or publication of this paper.The authors report no funding for this article.The authors declare that the individuals, whose data were reported in this article, have given written consent to the authors and the Ethics Committee of St. Joseph Dental College, Eluru, Andhra Pradesh, India for the publication of this paper.


Accurate imaging of the thymus is essential in the diagnosis and surgical treatment of both neoplastic and nonneoplastic conditions. Imaging of the thymus is a rather complex task, which affects both initial diagnosis and further surgical treatment planning. Imaging techniques include a wide armamentary of possibilities, from the most frequently used computed tomography (CT) to 18-fluorodeoxyglucose positron emission tomography- (18-FDG-PET-) CT and chemical shift magnetic resonance imaging (CS-MRI). In cases where surgical treatment is involved diagnostic imaging is of pivotal importance, not only in distinguishing benign from malignant disease but also in making a way among subtypes of thymic conditions. The article presents a current review of the advantages and backdrops of different imaging techniques used in the diagnosis of benign and malignant thymic conditions, with emphasis on differential imaging of thymic hyperplasia (TH), ectopic thymic tissue (ETT), and thymic epithelial tumors (TETs), with special attention to the importance of MR imaging according to the new TNM classification of thymic epithelial tumors. Accurate diagnostic imaging is of great importance in the treatment management of thymic pathologies. Regarding thymectomy, there are three important topics which are significant during a discussion between a radiologist and a thoracic surgeon: (1) differentiating between thymic hyperplasia (TH) and thymoma (THA), (2) deciding whether a possible thymoma invades surrounding tissues, and (3) declaring the presence of ectopic thymic tissue (ETT) around the thymus. The answers given by the radiologist absolutely predict the decision of the thoracic surgeon. The diagnosis of THA alone is an absolute indication of thymectomy, though differing thymic abnormalities such as TH without myasthenia gravis (MG) should not be treated surgically. In cases of THA or thymic carcinoma (TC) treatment planning is based on imaging results. Thus dilemmas arise, whether it is possible to carry out a primary resection or neoadjuvant treatment should be the first step and how can the extent of resection be defined? In cases of MG it is very important to evaluate any lesion in the mediastinum which could raise the suspicion of ETT, because surgical removal of these lesions can highly improve the success rate of a thymectomy. Our article deals with the role of preoperative imaging and its effects on surgical decision making in the most relevant conditions of the thymus.The rate of unnecessary or nontherapeutic thymectomies carried out according to a previous CT diagnosis is 43.8% (of which 17.1% are thymic hyperplasia cases) which emphasizes the importance of accurate preoperative diagnosis of thymic lesions , 3.p = 0.048 versus 0.04), proving MRI to be more reliable [In recent years MRI has integrated two important sequences into its armamentary, namely, fat suppression and chemical shift imaging. Due to the presence of both fat and water, thymic tissue around the tumor will show signal intensity loss on opposed-phase imaging; hence chemical shift imaging can be useful in pointing out the tumor margin and rate of invasion. In older age thymic tissue has already almost completely been replaced by fat; therefore in older patients fat suppression imaging should be the method of choice to define exact tumor margins. With the use of fat suppression-MRI (FS-MRI) and chemical shift-MRI (CS-MRI), diagnosis can be more accurate. CS-MRI is able to differentiate TH from THA  and accoThallium 201 (201Tl) scintigraphy is also useful in the evaluation of thymic lesions. It represents cellular metabolic activity, regional blood flow, and the number of viable cells and is helpful in distinguishing between normal thymus (NT), TH, and THA in cases of MG. In cases of TH and THA a higher uptake was seen in different periods compared to the ones seen in case of the NT [f the NT . The disFDG-PET is more accurate in determining the metabolic and functional features than the morphologic characteristics of neoplasms with the possible recognition of residual or recurrent disease. In the study of El-Bawab et al., the role of FDG-PET was investigated among different thymic lesions . The ranges of standardized uptake value (SUV) were seen between 0.7–2.5 and 3.1–6.1 in TH and THA, respectively [In cases where the diagnosis of THA is obvious and an absolute indication for thymectomy is obtained, the most important factor for the surgeon is the radio-clinicopathological data concerning the THA. The following questions arise. (1) Is the THA resectable, (2) does it infiltrate surrounding tissues so that neoadjuvant therapy should come first, (3) what is the rate of regression after neoadjuvant treatment, and (4) should the resection be extended? These questions can be answered after an extended and more meticulous imaging process with the adaptation of the newly proposed TNM classification. Relationship to surrounding tissues or organs (mainly great vessels and myocardium), the presence or lack of lymph node metastases , and involvement of pleural/pericardial sites should be investigated and mentioned.The diagnosis and classification of thymic epithelial tumors (TET) have been a topic of argument for many years. TETs have been uniformly classified by the WHO in 1999, with emphasis on both clinical and functional aspects . Type A The recent uniform staging classification system was processed by the Thymic Domain of the Staging and Prognostic Factors Committee (TD-SPFC) in collaboration with IASLC and ITMIG . The mosPreoperative imaging should point out the exact borders and presence or lack of invasion of THA concerning the above-mentioned tissues or organs. In resectable cases primary thymectomy is indicated, while in case of an unresectable tumor, neoadjuvant treatment should be applied.An additional useful and important change is the verification of regional thymic lymph node levels. The N1 level involves the anterior nodes, while the N2 level is limited to the deep intrathoracic or cervical nodes , 11. LymIn the diagnostic imaging of thymic epithelial tumors (TETs) and in the differentiation between various WHO subtypes, CT imaging plays a key role , 13. In In the study conducted by Zhu et al. which focuses on surgical outcomes, the rate of neoadjuvant treatment was 6% in case of THAs (B2-B3-TC) with a 15% rate of incomplete resection . The stuMRI can be helpful in differentiating among THA subtypes and can predict the aggressivity of the disease. The presence of a septum within the tumor is highly suggestive of THA. On MR imaging, the tumors showing smooth contour, almost complete capsule, septum within the tumor, and homogenous enhancement are more likely to be low-risk, than high-risk THAs or TCs. Sadohara's study states that MRI is more accurate in detecting a capsule, septum, or a haemorrhage than CT .It has been declared that diffusion weighted imaging (DWI) with the measurement of the apparent diffusion coefficient (ADC) can be helpful to distinguish between benign and malignant thymic lesions . In addiThe thymus is definitely involved in the pathogenesis of MG. The incidence of thymic pathologies occurring among MG patients is roughly 75% , 23: witPrinciples of surgical treatment of MG include complete removal of the thymus with perithymic fat and possible ETT. In MG cases usually two questions arise in terms of surgical treatment. (1) Does the patient have THA? If the answer is yes, it is an absolute indication for thymectomy. (2) Is there any amount of ETT or “abnormal fat” around the thymus or in the mediastinum? In case ETT remains in the mediastinum or on the neck, the postoperative improvement of MG is significantly worse.During its development, thymic primordia arise from the third and fourth pharyngeal pouches, become cylindrical, form the thymopharyngeal ducts, and descend into the anterior mediastinum. On the 8th gestational week, the thymic primordia fuse at their lower poles and on the 14th to 16th weeks, the thymus further differentiates into cortical and medullary components .ETT may be found in various locations according to the path of descent  and anywAll THAs are considered malignant, due to their invasive and metastatic potential, and thus should be surgically resected in every case. In terms of surgical or nonsurgical treatment planning, precise staging is one of the most important factors. Preoperative imaging should mention T, N, and M status of the THA with special attention to perithymic invasion. Performing a complete resection of not only the gland itself but also surrounding tissues containing thymic cells and lymph nodes is of utmost importance. Incomplete resection is associated with a high-recurrence rate and poor prognosis. Throughout the years several surgical methods have been described for the resection of THAs. The traditional approach is the median sternotomy. The MIA  for resection of THAs has gained widespread popularity in recent years. These techniques include VATS thymectomy from both sides, cervical thymectomy, subxiphoidal thymectomy, uniportal thymectomy, and robotic resection. VATS thymectomy is a radical and expansively used minimally invasive technique in the successful removal of not only the gland but also surrounding thymic tissue . In advaImaging evaluation of the thymus comprises many obstacles, mainly due to the fact that there are changes in size, shape, consistency, and amount of fat with age to the organ. Precise diagnosis and differentiation between each thymic condition through imaging are essential for ideal surgical treatment planning and avoiding overtreatment. While CT remains the cornerstone of thymic imaging, MRI evolves as a useful problem-solving modality for evaluation of various thymic conditions and may remarkably support CT in everyday clinical practice, especially in cases accompanied by MG in combination with different types of the THAs or TC. CT combined with PET imaging can be effectively used in the diagnosis of advanced THAs or TC, with control of regression after neoadjuvant treatment, thus facilitating the rate of surgical success. MRI is superior to CT in distinguishing normal and hyperplastic thymus from THA. With the adding of chemical shift sequence, MRI maintains a higher accuracy in distinguishing THAs from TH which is essential in the algorithm of treatment planning and deciding whether surgery is needed. In terms of neoplastic conditions, MRI proved to be an accurate modality in differentiating high- and low-risk thymomas and can be helpful in separating THA from TC. Distinguishing among various thymoma subtypes on imaging is fundamental for further treatment planning  and achieving total remission. It would be beneficial if the new proposed TNM and regional N-stage classification for TETs could be more accurately described by preoperative imaging similarly to the current N-stage system for lung cancer, thus contributing to more precise clinical classification. Treating patients with MG is one of the mainstays of thymic surgery. Total removal of the thymus and the resection of ETT in typical locations  are of paramount importance in banishing MG. Preoperative imaging could be extremely helpful in discovering possible ectopic thymic foci.


Human bone allografts present a better alternative to autografts in terms of minimization of the harvesting procedure complications. Prior to the use in clinical applications, they require sterilization which aims to reduce bioburden. This often comes at the expense of their biological properties as carriers of cells. In this study, we evaluated the cytocompatibility of human bone allografts processed and sterilized by three different methods with mesenchymal stromal cells. Bone morphology, biological and biochemical properties of the extracted bone-conditioned medium and viability of cells were assessed. We found that chemical sterilization had a strong negative effect on cell viability, whereas thermal sterilization and washing with subsequent γ-irradiation both resulted in a bone graft compatible with the progenitor cells. Moreover, washing of the bone prior to sterilization allowed solid removal of cell debris and other bone marrow components. Taken together, our findings demonstrate the importance of a proper choice of the bone graft processing method for the production of the biomaterial suitable for tissue engineering. Grafting of the human bone is extensively employed in orthopedics and maxillofacial surgery to promote the repair of bone tissue. This includes the treatment of non-union fractures, augmentation of large bone defects and restoration of the bone stock in revision surgery for periprosthetic osteolysis . Dependiin vitro conditions, these cells can also differentiate toward at least three lineages: osteogenic, chondrogenic and adipogenic .Conflict of interest statement. None declared.


Fracture dislocations are common around the elbow joint. However, closed fracture of the distal radius with ipsilateral elbow dislocation is an uncommon injury pattern. We discuss the case of a middle-aged woman presenting with posterolateral elbow dislocation with concomitant ipsilateral closed intra-articular fracture of the distal radius. It was treated with closed reduction for the elbow dislocation first followed by closed reduction for the distal radius fracture. Even with conservative management, the patient had a good functional outcome at one year. The importance and incidence of such a rare injury pattern and the possible mechanism of injury has been discussed. Distal radius fractures are one of the most commonly encountered trauma cases in any orthopaedic casualty . The eneA 45-year-old housewife presented to the emergency department with complaints of pain and swelling in the right wrist and right elbow. She gave a history of fall from a bike on the outstretched hand in a high-velocity road traffic accident. There was no history of head injury or injury to any other part of the body. On examination, there was swelling and deformity in the right wrist as well as the right elbow. The right wrist joint was tender and the range of movement was painful. Similarly, there was tenderness in the right elbow and range of movement could not be assessed due to the pain. Crepitus could be felt at the right wrist joint suggesting a fracture, whereas there was no crepitation in the elbow. The distal neurovascular status was normal. Plain radiographs revealed severely-comminuted distal radius fracture with dorsal angulation with intra-articular extension, along with concomitant ipsilateral postero-lateral elbow dislocation Figure .Closed reduction of the right elbow was done first in the emergency room under sedation with longitudinal traction and flexion of the elbow. The distal radius fracture was then reduced by giving longitudinal traction followed by initial dorsal tilt to dis-impact the fracture and then volar and ulnar tilt. The distal neurovascular status was again checked immediately after closed reduction and was found to be intact. The check films showed a congruent reduction of the elbow joint along with an acceptable reduction of the distal radius fracture Figure .However, the patient was counselled for pinning of distal radius fracture in view of severe comminution and intra-articular extension to prevent a longitudinal collapse of the distal fragment. Due to financial constraints, the patient refused any operative intervention and hence was managed with an above-elbow posterior slab for one week followed by an above-elbow cast for three weeks. She was given a below-elbow cast for further two weeks. Active elbow and wrist range-of-motion exercises were started after six weeks of trauma. At the follow-up of one year, she had a good functional outcome with painless, full extension and flexion movements of the wrist and the elbow joint as well as full range of pronation and supination. She could resume her household work without any functional deficit.Fracture dislocations are common around the elbow joint in skeletally mature population. However, the usual fractures involved are those of proximal ulna or radius . Elbow dThe mechanism of injury probably involved longitudinal compressive force with an extension  component as the fracture had dorsal angulation. Therefore, the reduction should logically be attempted in flexion of the wrist as well as the elbow joint with longitudinal traction. In the previously reported case, the elbow dislocation was reduced in extension whereas, in our case, it was reduced in flexion . The redThe above case underscores the importance of thorough assessment of the wrist using clinical examination and if required, plain radiographs in cases of elbow dislocation, particularly in high energy trauma. This case report will increase awareness about the possibility of such a combination and will help in preventing missed injuries.


Use of tranexamic acid (TXA) in trauma has been the subject of growing interest by researchers and health professionals. However, there are still several open questions regarding its use. In some aspects medical literature is controversial. The points of disagreement among experts include questions such as: Which patients should receive TXA in trauma? Should treatment be performed in the pre-hospital environment? Is there any need for laboratory parameters before starting TXA treatment? What is the drug safety profile? The main issue on which there is still no basis in literature is: What is the indication for treatment within massive transfusion protocols?  Answer the questions proposed based on critical evaluation of the evidence gathered so far and carry out a study of cost-effectiveness of TXA use in trauma adapted to the Brazilian reality.  A literature review was performed through searching Pubmed.com, Embase and Cab Abstract by headings "tranexamic AND trauma", in all languages, yielding 426 articles. Manuscripts reporting on TXA utilization for elective procedures were excluded, remaining 79 articles. Fifty-five articles were selected, and critically evaluated in order to answer study questions. The evaluation of cost effectiveness was performed using CRASH-2 trial data and Brazilian official population data.  TXA is effective and efficient, and should be administered to a wide range of patients, including those with indication evaluated in research protocols and current indication criteria for TXA should be expanded. As for the cost-effectiveness, the TXA proved to be cost-effective with an average cost of R$ 61.35 (currently US$16) per year of life saved.  The use of TXA in trauma setting seems to be effective, efficient and cost-effective in the various groups of polytrauma patients. Its use in massive transfusion protocols should be the subject of further investigations. Tranexamic acid (TXA) is a synthetic analogue of the amino acid lysine, discovered in the laboratory in 1962. TXA has low commercial cost, which has favored its routine use for patients presenting with metrorrhagia and for bleeding prevention in patients with hereditary bleeding disorders submitted to dental extractionTXA acts by reversibly binding to lysine receptor sites on plasminogen, thus preventing it to bind to the tissue plasminogen activator (tPA). Once this binding is prevented, plasmin will not be formed, avoiding fibrinolysis,,,Randomized controlled trials, cohort studies and meta-analyzes were performed to evaluate and measure the potential effects of TXA utilization in trauma patientsBecause of the universal distribution of trauma and its concentration in low and middle per capita income countries, it becomes important to evaluate cost-effectiveness of TXA in this scenario. Studies evaluating cost-effectiveness of TXA in different Countries have been published. However there are no prior studies evaluating the Brazilian reality with its peculiarities that hinder its comparison to other countries of lower income per capitaThis study aimed to review the accumulated knowledge in the use of TXA and respond to issues that are relevant to clinical practice. In addition it is intended to make an analysis of the cost effectiveness of TXA use specifically to Brazilian reality.Search strategy: PubMed, Medline, Embase and Cab Abstract by the terms "tranexamic AND trauma" in all languages, resulting in 426 articles. Those related to elective surgery were excluded, remaining 79 articles. After excluding those with irrelevant content for the purpose of this study, 55 articles have remained. Among these, there were seven original articles reporting on intervention studies, two Cochrane meta-analysis, an one cost-effectiveness study, six review articles and six subgroup analyzes from previous studies.Evaluation of cost effectiveness of TXA was performed by calculating the incremental cost of treatment divided by the number of years of life gained with the intervention. The determination of the incremental cost of treatment, i.e., the extra amount to be spent on the implementation of the treatment compared to standard treatment (without use of TXA) was performed taking into account the estimated costs for the treatment of patients with TXA in the dose recommended by the study "Effects of tranexamic acid in death", vascular occlusive events, and blood transfusion in trauma Patients with significant hemorrhage (CRASH-2)As for calculating the number of years of life gained with the treatment the following equation was utilized:Number of years of life gained = (average Brazilian life expectancy - mean age of the CRASH-2 patients) / (NNT from CRASH-2)In this equation, NNT is the number of patients to be treated to prevent one death in CRASH-2 study. In other words, NNT is the inverse of the absolute risk reduction. Having the number of life years gained and average incremental cost of treatment, we can directly estimate the cost-effectiveness using the formula below:Cost-effectiveness = (average price of treatment) / number of years life gained)in which the cost-effectiveness is given in R$ (Brazilian currency) per life year gained.This formula was utilized instead of a parametric function Gompertz used in other cost-effectiveness study published on the subjectAccording to meta-analysis there is no statistically significant relationship between use of TXA and mortality reduction in elective surgeries. However, the low prevalence of death secondary to bleeding in elective surgeries may have contributed to make the magnitude of a possible benefit not possible to estimate due to the statistical power of the studies,An additional meta-analysis in the context of antifibrinolytic use in trauma was conducted. Furthermore, there are no specific data specifically evaluating subgroups of patients suffering from penetrating or blunt injury. The mechanism by which this drug acts in trauma, especially with regard to its anti-inflammatory effect remains uncertainThere remain many questions to be answered about the use of TXA in the trauma setting. No information is available on the efficacy and effectiveness of the association of TXA and blood products or its use in massive transfusion protocols. There is no evidence from controlled studies of the possible synergistic effect observed between TXA and cryoprecipitate evaluated by the MATTERs study; there is no data on the use of TXA in patients undergoing damage control surgery,,,The largest benefit in mortality prevention with the use of TXA is observed in patients with established coagulopathy and severe traumaAlthough the CRASH-2 study did not report statistically significant differences with regards to thromboembolic events in the intervention and controlOnly one study was designed with the main objective to assess thromboembolic events in trauma patients treated with TXA. This is an observational study that evaluated 115 patients at high risk for such events. This study found no difference in the occurrence of thromboembolic events among patients receiving TXA vs. those not receiving the drug (p=0.788),Both the CRASH-2 study and the MATTERs study utilized clinical parameters to indicate the treatment or inclusion in the studyThere are no studies directly evaluating the use of TXA in massive transfusion protocols. The only data available related to the subject comes from subgroup analysis of the MATTERs study,A recent study in the prehospital care with medical evacuation by helicopter was published in 2013,A cohort reporting the use of TXA in the prehospital environment by Israeli defense forces also was publishedFrom the data of both studies, which together totalized 53 patients, it can be concluded that, although the published experience is still modest, it seems safe to use TXA in the prehospital environment. Note also that the average use time of the trauma was 65 min in the first study (no data concerning this second study), that is, the upper limit of subgroup analysis showed greater benefit in the CRASH-2. Similarly, recently published study reports on a series of 20 consecutive patients receiving TXA during prehospital aeromedical transports with no adverse effectsThe potential of avoiding a large number of deaths using the TXA has been identified by various researchers. Estimates based on CRASH-2 data and epidemiological information from the World Health Organization (WHO) come to point out the possibility of avoiding 128,000 of the 400,000 annual deaths that occur in bleeding trauma patients around the worldIn order to clarify some of these questions, this study aims to make a cost-effectiveness evaluation of TXA use in trauma in Brazil.To evaluate the price of TXA, a survey of prices of TXA provided by different laboratories, Pfizer (reference product) Nikkho (similar), Hipolabor (generic) and EMS (generic) was conducted. Evaluation of official data published online trading days from January 2013 to December 2014, for vials of 250 mg of TXA. Costs related to the other materials required for the administration of TXA described above were estimated through evaluating the results of official electronic auctions published between January 2013 and December 2014. For the study purposes only winning proposals for each one of the sessions were considered, as they represent the actual value paid in acquisitions made by Brazilian public hospitals responsible for the care of most trauma patients in Brazilian public healthcare system. The calculated values are shown in The 2014 official data estimates the Brazilian life expectancy at 74.9 years. Using the data above, the information of the CRASH-2 study and the formula presented in the section above, the following value were obtained: R$ 54.65 per life year gained using the lower available prices, and R$ 116.63 using If the higher available prices resulting in an average of R$ 85.64. It is still possible to infer that the incremental cost of treatment with TXA to save a life ranges from R$ 2,202.29 to R$ 4,700.05, with an average of R$ 3,451.17. For comparison purposes, a study calculated the cost per year of life gained for $ 48  in Tanzania, $ 66 in India and $ 64 in the United Kingdom,,,,The effectiveness of TXA in trauma seems well established (level of evidence A)This study concluded that the use of TXA is highly cost-effective, and the average cost for each year of life saved is estimated at R$ 61.35. This data highly justifies the adoption of TXA treatment for polytrauma protocols, following the prescription model used by the CRASH-2 teams, and entails conducting studies to assess the cost-effectiveness of protocols with even more comprehensive indication criteria for this drug.


Dysfunction of the Sacroiliac Joint (SIJ) is one of the key sources of low back pain. For prolonged pain relief, some patients undergo fluoroscopic guided radio-frequency (RF) ablation of SIJ, during which a number of RF probes are inserted to create thermal lesions that disrupt the posterior sacral nerve supply. This procedure is minimally invasive, laborious, time-consuming and costly. To study if High Intensity Focused Ultrasound (HIFU) ablation is a feasible alternative approach to SIJ pain treatment, we performed experiments using HIFU to ablate SIJ in the swine model.Three female Yorkshire swine  underwent bilateral Magnetic Resonance guided HIFU (MRgHIFU) ablation of the SIJs. Treatment assessment was performed using contrast-enhanced imaging, histopathology and evaluation of pain and changes in ambulation and gait.Contiguous lesions along the right and left SIJs were achieved in all animals. In one out of three animals, excessive heating of the muscle and skin tissue in the near-field resulted in unwanted muscle necrosis. No changes in animal behavior, ambulation or gait were detected.The initial experiments with MRgHIFU ablation of SIJs in sub-acute swine model show promise for this ablation modality as a non invasive and more precise alternative to the currently used fluoroscopically - guided RF ablations and injections. Dysfunction of the Sacroiliac Joint (SIJ) is a source of pain in approximately 15 to 30% of patients who suffer from low back pain , a condiThe SIJ and the posterior sacroiliac ligament are reported to be innervated by the dorsal ramus of L5 and the lateral branches of S1 to S4 nerve roots . These bThe evidence for the therapeutic effectiveness of RFA outweighs that of intra-articular injections , 14. HowMagnetic Resonance Imaging guided High Intensity Focused Ultrasound (MRgHIFU) is a unique ablation modality that can noninvasively create thermal lesions of any shape deep inside the body under a real-time temperature monitoring. In recent years, MRgHIFU has been found to be clinically effective for pain palliation of bone metastasis, osteoarthritis, osteoid osteoma and facet arthritis –21. In pThe challenges of MRgHIFU ablation of the SIJ are the potential risk of damaging thermal exposure of the adjacent untargeted sacral nerves, sacral bone, adjacent muscle and skin. The ventral nerve roots may be harmed if ultrasound of sufficient intensity reaches directly through the posterior sacral foramina or heats the adjacent sacral bone, which in turn conducts the heat to the nerve roots. Proximity of skin to the targeted SIJ may expose the skin and adjacent muscle tissue to the pre-focal portion of the ultrasound beam, potentially causing unwanted heating. To study if HIFU ablation of the SIJ may be a feasible clinical procedure, we performed preliminary experiments using MRgHIFU to ablate the SIJ in three swine.Unlike lumbar spine, where swine is considered a suitable animal model, the appropriateness of swine as an animal model for studying sacral ablation is not discussed in the literature. Hence, the first section of this study presents qualitative description of the selected swine animal model as it relates to the human sacral anatomy. The subsequent sections of the study present our experimental approach and the effects of the HIFU ablation as they appear on follow-up imaging, histology and behavioral assessment.All animal procedures received approval from the Institutional Animal Care and Use Committee. Appropriate handling and care was provided by trained staff in accordance with the principles of laboratory animal care and guidelines from the United States Department of Agriculture.To evaluate if the swine model can approximate human sacral anatomy, veterinary anatomy literature was surveyed. The computerized tomography (CT) images of swine available in our laboratory were reviewed to observe the bony anatomy of porcine sacrum. Appearance of the porcine sacral nerves was described based on the histology images prepared as described in Treatment Assessment section.Animal protocol used in this study is described in detail in . BrieflyA clinical HIFU system  installed in a 3 Tesla MRI scanner  was used. The animals were placed on the MRgHIFU table in a supine, feet-first position. A polyacrylamide gel pad was used between the tissue and HIFU transducer bath to provide acoustic coupling Fig. . PlanninThe central frequency of focused ultrasound was increased to 1.35 MHz to minimize ultrasound penetration into bone tissue . The focThe contrast-enhanced MRI (CE-MRI) was performed immediately following the procedure, using intravenous gadopentetate dimeglumine MRI contrast agent , 0.2 ml/kg (0.1 mmol/kg) and T1-weighted fast spoiled gradient-recalled echo imaging. Forty-eight hours after treatment, the animals were imaged on a Computerized Tomography (CT) scanner  using iohexol contrast medium . On CE-MRI and CT images, the extent of thermal necrosis was inferred from the regions lacking contrast uptake. Twice a day, the veterinary staff visually inspected the skin for potential burns and observed the animals for altered gait, abnormal posture, changes and asymmetry in movement. Pain assessment was performed via observation and palpation, both superficial and deep .Histopathological analysis of treated tissue was performed per the following steps. First, the whole sacrum, including the sacroiliac joints and muscle attached to the bone, were fixed by immersion in 10% neutral buffered formalin for approximately six weeks until complete fixation was achieved. Second, the specimen was placed into decalcifying solution Surgipath Decalcifier I  for eight to ten weeks. Upon complete decalcification, the sample was sectioned transversely into 5 mm thick slices and each slice was inspected for any visible tissue changes. Then the areas of interest in each slice were excised en bloc with adjacent muscle and bone. For each study respectively, thirty five, fourteen and sixteen histological samples  were processed routinely in alcohol and xylene, embedded in paraffin, sectioned at 5-micron thickness, and stained with hematoxylin and eosin (H&E). Each histological sample was analyzed for changes in muscle, bone and neural tissue using a microscope (Olympus BX45) with objectives ranging from 1.25X to 60X. The histology slides from the second and third experiment were also scanned with a digital scanner , using 20×/0.8NA objective. The digital scans of the slides were then analyzed using dedicated software . The dimensions of the nerves, vessels and the distances between various structures were measured using the software measuring tool. Based on the noted tissue changes, the region of ablation was delineated in several samples to compare to the apparent ablation zone as visible on gross pathology and imaging. Additionally, these histological samples were used to describe the innervation of the SIJ.Sacral anatomy of swine was found similar to human. Some differences between the two are as follows. Compared to human sacrum, consisting of five vertebral bodies, in swine, sacrum consists of four vertebrae Fig. , b. TheyThe spinal cord, that normally terminates at the lumbar vertebrae level in humans, extends to the S2–S3 level in pigs . No repoHistologic analysis of the sections of L6-S1, S2 and S3 vertebral bodies Fig. -b, e-f aContrast-enhanced MR and CT imaging, gross pathology and histology showed that contiguous lesions along the right and left SIJs were achieved in all animals Fig. . In the In the subsequent two experiments, the number of sonications was reduced and the cooling time between the sonications was increased Table . In thesAn example of ablation zone contour as determined from the histological analysis is shown on low magnification in Fig. Neither changes in animal behavior and function (ambulation and gait) nor signs of superficial or deep pain were detected during the post-procedural 48-h period.This work evaluated the potential of MRgHIFU for noninvasive denervation of the SIJ for the first time. The preliminary study presented here demonstrates that MRgHIFU can create contiguous elongated lesions along the SIJ and thermal necrosis of the lateral branch nerves without causing unwanted neurological damage and with minimal thermal damage to the adjacent muscle tissue and bone.Utilizing swine model for preliminary study of safety and feasibility of HIFU ablation of SIJ is justified by anatomic similarities between porcine and human sacra. The main disadvantage of this model is the smaller size of the lower sacral vertebral bodies compared to those in humans, which makes it challenging to delineate the anatomical landmarks and target the space between the foramina and the SIJ. Nearly nonexistent spinous process in swine enables HIFU beam to be directed at a broad range of angles to reach the target. A more pronounced spinous process bone in humans may limit the angles at which the target can be approached by HIFU.Oblique orientation of the sacral foramina passages and the small diameter of the posterior foramina compared to that in humans limit direct access to the ventral nerve roots, thus minimizing the risk of any unwanted heating of these critical structures. In humans, the sacrum is flatter and wider leaving more space to position the HIFU lesions between the SIJs and the foramina. At the same time, in human, the larger diameter of the foramina and their orientation toward midline potentially can make the nerve roots more exposed. And while the dorsal nerve root has been directly targeted during RF ablation to treat SIJ pain in the past , damage Thus, studying the porcine sacral anatomy illustrates the modifications needed for technique regardless of species, and more importantly inter-human variations. It is expected that variations in human anatomy will alter the sonication direction, time, and intensity for appropriate lesioning of the innervation of the SIJ. Understanding the flexibility of MRgHIFU systems will allow a clinician to make appropriate adjustments patient to patient.Contiguity of the thermal lesions, which is typically challenging to verify during the fluoroscopy-guided RFA, was achieved in all of the experiments as was demonstrated on follow-up contrast-enhanced imaging and histo-pathological analysis. The extent of the lesion in muscle was greater using the focal targeting approach compared to near-field approach. Histology showed thermal damage of the nerves, muscle and bone contained in the targeted area. Histological changes in ablated nerves were consistent with previous work on HIFU ablation of the sciatic nerve in acute rabbit and swine models , 27, 36.Unplanned ablation of the muscle region between the sacrum and skin which occurred in the first experiment can be explained by accumulation of the residual heat following each ablation. Thermometry imaging which was performed in axial plane for the most part of treatment on the left side was not capturing the heating during many sonications as was realized upon switching from axial to sagittal thermometry imaging plane. Curvilinear surface of sacrum in cranio-caudal direction led to the heat deposition not necessarily at the position of the planned focal spot, thus single-slice axial plane was not imaging the area being heated during a sonication. Due to this not-immediately realized phenomenon, and high confidence in ablation of a target not previously attempted, a large number of sonications were performed in the first experiment, and the default cooling time was insufficient to ensure the muscle tissue in the near field does not accumulate excessive thermal dose. Furthermore, MR thermometry implemented of the system used here computes the temperature increase during a sonication relative to the temperature reference in the beginning of each sonication, which may lead to underestimation of thermal dose .Measures taken in the other two experiments, i.e. reduction of the number of sonications, increase of the cooling time and frequent use of sagittal MR thermometry plane, showed that SIJs can be safely ablated without excessive near-field heating. Fortunately, newer version of the clinical MRgHIFU systems offer multi-slice thermometry capability, which will enable capturing the highest temperatures during sonications even when it is not positioned at the expected location. Additionally, long-term MR thermometry, proposed by R. Bitton in , should While the initial results presented in this article show promise for MRgHIFU in non-invasive and efficient treatment of SIJ, further studies are needed to optimize this procedure. Focusing approach, the number of sonications and the energy range explored here were effective in creating thermal lesions, however, they can be further refined to reduce the procedure time and to minimize thermal damage in bone and muscle. While pre-focal targeting approach, which was applied to the right SIJs in this study, can help reduce the procedure time owing to the larger ablated surface per sonication, the opening of the dorsal foramina needs to be carefully avoided affecting the area that can be safely treated in one sonication. Proximity of skin to the SIJ needs to be taken into account to avoid unwanted heating of the skin and adjacent muscle tissue. Cooling time between the subsequent sonications is the parameter that will need to be optimized in order to provide sufficient time for the skin to cool off while keeping the treatment time minimal. As accurate MR thermometry is challenging in the bone, in this study, we monitored the changes in muscle temperature during each sonication.One of the limitations of this study is the lack of measurements of nerve conduction, which could confirm whether HIFU ablation indeed denervated the SIJs. Unfortunately due to location of the targeted nerves, deep inside the muscle tissue immediately adjacent to the bone and their relatively small size, nerve conduction studies were not feasible. Therefore, disruption of the nerves in this study is currently implied from the presence of the thermal lesions encompassing the nerves and the thermal changes of the nerve.This preliminary study of MRgHIFU ablation of SIJs in sub-acute swine model shows promise for this ablation modality as a non-invasive potentially more precise alternative to the currently used fluoroscopic-guided RFA and injections. This current research is a proof of concept for the use of HIFU for denervation of the SIJ in the human population. This preliminary proof-of-concept experiment offers initial guidance to subsequent animal, cadaver and clinical studies. Further study is warranted to determine appropriate treatment protocol for MRgHIFU of the lateral branches in the human population.


Malaria in the Asia-Pacific region has been targeted for elimination by the year 2030. This article asks the question, “by what means?” in the context of proven technical strategies and tools against key challenges imposed by the distinct character of the Asia-Pacific malaria problem. The misperception of malaria in the Asia-Pacific region as a less serious but otherwise essentially similar problem to African malaria lulls us into rote application of the same tools and strategies. Those now mitigating the harm done by malaria in Africa will not suffice to eliminate malaria in the Asia-Pacific region – these tasks and the problems are fundamentally distinct. This article describes the singular characteristics of Asia-Pacific malaria and the bearing of those upon the technical strategy of malaria elimination. Most of the tools needed for that endeavour do not yet exist and spirited calls for elimination within the next 14 years may discourage the patience and investments needed to conceive, optimise and validate them. The technical strategies for doing so now implemented there came with compelling bodies of scientific evidence demonstrating positive impacts. Indeed, recent estimates of morbidity and mortality across Africa point to profound progress having been achieved in the past decade .In 2007 Bill and Melinda Gates implored the malaria community to adopt a strategy of eliminating malaria rather than learning to live with it in perpetuity by mitigation of harm alone . The Wor2This Latin phrase asks, “by what means?” The meaning of that question in the context of this article does not refer to the social and political assets needed to rally human energies and fiscal resources to the cause of eliminating malaria in the Asia-Pacific region. Instead, it is a technical question referring to the tangible tools, tactics and strategies aimed at specific biological problems to be engaged in that enterprise. If the important task of rallying support for elimination is successful, how will those mobilised resources be translated into significant gains against malaria in the Asia-Pacific region? What tools will be brought to bear and how? This article addresses these questions in the context of crucially important differences between the malaria problem of Africa and that of the Asia-Pacific region. In brief, the tools that have successfully mitigated harm in Africa  are poorly suited to the task of eliminating malaria in the Asia-Pacific region. Malaria here imposes obstacles to elimination not shared with African malaria and few tools yet exist to cope with those.The elimination agenda must recognise and acknowledge important biological distinctions between the African and Asian-Pacific malaria problems. The means of eliminating malaria from the Asia-Pacific region will necessarily be fundamentally distinct from those of mitigating harm done by the relatively heavy burdens of malaria in much of Africa. What are those distinctions and by what means will humanity drive the plasmodia to extinction in the Asia-Pacific region? These questions will also be relevant across the very long and wide fringes of the heavily malarious heart of Africa – areas where there is relatively low and more diverse ecologies of transmission.3The perception of malaria in the Asia-Pacific region as an essentially similar but less serious problem than African malaria oversimplifies it to an extraordinary degree. The two problems are wholly distinct in biological, clinical, epidemiological and social dimensions. Few commonalities link them beyond the role of anopheline mosquitoes in conveying the plasmodia amongst humans. A lay view of that limited commonality imposes the dangerous risk of rote adoption of African strategies and tools in driving an Asian-Pacific malaria problem to elimination. Understanding specific features of Asia-Pacific malaria that distinguish it from the dominant high burden African malaria is key to formulating a rational elimination strategy.The singular nature of Asia-Pacific malaria is its enormous diversity and range relative to African malaria in terms of species of parasites, their mosquito vectors, epidemiology, ecology of transmission, parasite resistance to drugs, human genetics and awareness of malaria as a serious problem. The following summarise these distinctions.3.1Endemic malaria transmission occurs in almost all nations of the Asia-Pacific region, excepting only Japan, Australia, New Zealand and Singapore , and SriA study of malaria-attributable mortality in India illustrates the uncertainties . SystemaThe relatively low levels of transmission in the Asia-Pacific region should not lull us into believing or hoping that absolute morbidity and mortality burdens are also relatively low – the enormous numbers of people composing denominators of risk for illness or death may conceal very substantial numbers of people composing the numerators, the ill and dead.3.2The task of bringing low transmission to zero is far more challenging than reducing high levels of transmission. A number of key factors help explain this. High prevalence of microscopically- or RDT-patent infection of blood is the rule in high transmission settings. Meta-analyses consistently reveal an inverse correlation between the proportion of sub-patent to patent parasitemias and prevalence of infection . As prevPlasmodium vivax . Vigorous efforts to contain or eliminate this problem have not been successful. ACT treatment failures now commonly occur in Thailand, Cambodia, Laos and Vietnam  successfully infected humans who then infected mosquitoes that became infective to both humans and monkeys  How widespread is the problem? (ii) Are asymptomatic carriers present? (iii) Are other species involved? (iv) Is human-to-human transmission of these species occurring? In clinical studies done during the 1950s and 1960s, experimental infections of humans with not only  monkeys . These p monkeys . Biologi monkeys . Human-tP. cynomolgi  occur in highly endemic Africa, several dozen confirmed vector species (many of them zoophilic and exophilic) flourish across the Asia Pacific region in an enormous variety of habitats and ecological settings , including domestic migration. In India up to 100 million people may be mobile and migrant within borders, most of them urban poor seeking seasonal work in agriculture. Such movement, from a densely populated area of limited economic opportunity to relatively unsettled frontiers with endemic malaria transmission, may be typical of most seasonal migrations.The relatively high density of human populations throughout much of the Asia-Pacific region drives people to seek economic opportunity away from their homes. That is, they are mobile and migrant, and the region has a tradition of this lifestyle reaching back centuries   . There iAn. sundaicus drove transmission , 57% of them living in rural settings (http://www.unescap.org/stat/data/syb2011/I-People/Urbanization.asp). Although urban malaria transmission occurs in India, the responsible vector, Anopheles stephensi, is largely absent from the rest of region. No other anopheline species in the region tolerate urban environments. Asia-Pacific malaria is thus overwhelmingly a disease of those living in relatively isolated and impoverished rural areas. The demographic example of the Indonesian archipelago of 13,500 islands highlights this important fact (The Asia-Pacific region was home to 4.3 billion people in 2013 (ant fact , where 1ant fact  confirmeThe absence of robust estimates of malaria morbidity and mortality across most of the Asia-Pacific region lulls us dangerously to accept it as evidence of relatively light absolute burdens amongst the two billion people living at risk. The widely disregarded study of malaria mortality in India  warns us4Eliminating malaria from the Asia-Pacific region requires specific technical strategies and tools for coping with all of the unique features of the problem summarised here. Unfortunately, most of these strategies or tools have not yet been conceived and none have been optimised and validated. The danger in spirited advocacy for elimination of Asia-Pacific malaria by 2030 is the arrest of the hard work of developing the very tools needed to achieve it. Young scientists in the region may steer clear of what is perceived as a vanishing health problem. Funding agencies may find investment in long-term development of tools unattractive or irrational – a new class of hypnozoitocides, for example, may take a decade or more of relatively very expensive work, only to emerge when presumably no longer needed. If the year 2030 arrives and the plasmodia have yet to be eliminated from the region, we may find deferred investments in people and technical progress will have ensured the inability to be rid of this problem.Malaria is a formidable foe, especially in the Asia-Pacific region. A vision of eliminating the plasmodia that excludes the technical means of doing so should be acknowledged as dangerous hubris. These parasites will not surrender to human will alone, but to human ingenuity aimed at highly specific technologically defined points of deliberate and sustained biological attack on them. Conceiving those strategies and tools, optimising and validating them, and finally aggressively implementing them should be the focus of the earnest will to drive the plasmodia to extinction in the Asia-Pacific region.


Mechanical neck disorder is a widespread and non-neurological musculoskeletal condition resulting from modern lifestyles. Presently, the fundamental electrophysiological properties of the motor units of the sternocleidomastoid muscles and the characteristics of the short-term synchronization of the motor unit in patients with neck pain are ambiguous. This study therefore aims to clarify the fundamental electrophysiological properties of the motor units of the sternocleidomastoid muscles in patients with mechanical neck disorder and in asymptomatic individuals. We further investigated whether alterations in the degree of motor unit short-term synchronization occur. The surface electrophysiological signals of the bilateral sternal heads of the sternocleidomastoid muscles of twelve patients with mechanical neck disorder and asymptomatic individuals were detected at 25% of the maximum voluntary contraction during cervical isometric flexion and then decomposed into individual motor unit action potential trains. We found that the patients with mechanical neck disorder showed significantly higher initial and mean firing rates of the sternocleidomastoid muscles and displayed substantially lower motor unit short-term synchronization values compared with the asymptomatic subjects. Consequently, these convincing findings support the assertion that patients with mechanical neck disorder display altered neuromuscular control strategies, such as the reinforcement of motor unit recruitment firing rates in the sternocleidomastoid muscles. The motor units of these patients also revealed neural recruitment strategies with relatively poor efficiency when executing the required motor tasks. Mechanical neck disorder (MND) is commonly considered a widespread and unnerved musculoskeletal condition. Its threats to general health are becoming increasingly severe as technology advances in many industries. MND is defined as generalized neck pain and disability without any abnormal anatomical structures or identifiable orthopedic and neurological problems, such as spinal vertebral fracture, exceptional spinal lordosis, spinal spondylosis, spinal osteoarthritis and so on . ClinicaA number of studies have investigated the association between neck pain and the neuromuscular control strategies of neck muscles. Generally speaking, neck pain is associated with increased activation and greater fatigability of the superficial cervical flexor muscles and the upper trapezius , 16 and Because motor units are the fundamental functional units of the neuromuscular systems, the recruitment and derecruitment of the motor units or the pattern of the discharge rates of activated motor units have been proven to manipulate the forced production of the neuromuscular systems . AdditioAlong with these basic myoelectric properties, the motor unit short-term synchronization describes an above-chance tendency for near-simultaneous discharges between pairs of motor units. It is believed that the phenomenon of motor unit synchronization is a deliberate neuromuscular strategy originated from shared synaptic inputs from the branching of last-order neurons , 32 and However, investigations exploring the fundamental electrophysiological properties of the motor units of the sternocleidomastoid muscles in patients with MND are still rare. Additionally, no prior reports have described the features of the motor unit short-term synchronization of the sternocleidomastoid muscles. Therefore, the objectives of the current work are to clarify the fundamental electrophysiological properties of the motor units of the sternocleidomastoid muscles and to determine whether differences in the degree of motor unit short-term synchronization exist among patients with MND and asymptomatic individuals during cervical isometric flexion.Two groups of volunteers were recruited to participate in the present investigation. Twelve patients with physician-diagnosed MND  who had sought medical treatment within the past 6 weeks participated voluntarily in the present study. The second group consisted of twelve asymptomatic individuals . None had any history of cervical surgery, cervical trauma, cervical pain or neuromuscular problems. Additional demographic details were initially recorded for each participant and are summarized in All participants clearly understood the major aims of the study and signed consent forms prior to participating in the investigations. All the experimental procedures of the present investigation were approved by the Institutional Review Board of Kaohsiung Medical University Chung-Ho Memorial Hospital (No. KMUH-IRB-20120078).TM system . The accuracy of this system has been certified to be 92.5% on average. The dEMGTM sensor consists of five pin electrodes; four of five electrodes are arranged in a 5-mm square, and the fifth pin electrode is located in the center of the square. This arrangement enables four channels of surface differential electrophysiological signals to be recorded simultaneously. To measure voluntary isometric contraction force during cervical flexion, a custom-designed force-measuring device with a tension/compression minibean load cell was made and anchored to an examination couch.The surface electrophysiological signals were detected from the sternal head of the sternocleidomastoid muscles bilaterally using the non-invasive dEMGTM sensors were then placed over the belly of the sternal head of the sternocleidomastoid muscles bilaterally and fixed with adhesive tape. The ground electrode was attached over the sternal end of the clavicle, and a load cell was affixed to the custom-designed force-measuring device, which was attached firmly to the forehead of each participant  to 1750 Hz (24 dB/octave), digitized with 16-bit resolution at a sampling rate of 20 kHz and stored on a personal computer for decomposition processing. In addition, the raw EMG signals had to successfully pass the certification of the Delsys Signal Quality Check, with the signal to noise ratio of > 2, baseline noise < 4.8 μV root mean square, and line interference < 1.0 to be acceptable for decomposition processing, according to the user’s guide. Next, the Precision Decomposition III algorithm was utilized to decompose the resulting digital electrophysiological signals into their constituent motor unit action potential trains , 44.After successfully decomposing the raw surface electrophysiological signals into constituent motor unit action potential trains, all the firing rate curves of the identified motor units were smoothed using a Hanning filter with a 2-s duration, and a self-developed code in the M Matlab programming language  was used for further analysis. Subsequently, three characteristic parameters were extracted to describe the recruitment electrophysiological properties of each identified motor units of the sternocleidomastoid muscles. Except for the recruitment threshold, which is defined as the relative force level (% MVC) at which the initial firing instance begins to discharge, the initial firing rate indicates the representative firing rate at which the initial firing instance occurs and the mean firing rate is defined as the average number of pulses per second (pps) during the duration of the constant force (10 s) when performing the prescribed motor task  for the demographic data. The relative strength of the relationships between the initial and mean firing rates and the recruitment threshold of each identified motor unit in asymptomatic individuals and in patients with MND were verified using Pearson’s correlation analysis. Moreover, the correlation between the short-term synchronization and mean recruitment threshold was assessed using grouped data with class intervals of 5% MVC for all motor unit pairs. Furthermore, a parametric independent samples P < 0.05 and r = -0.652, P < 0.05) and in patients with MND . Figs P < 0.05) except for those exhibiting motor units with recruitment thresholds corresponding to 15~20% MVC. The detailed motor unit firing behavior of the sternocleidomastoid muscles for the asymptomatic individuals and the patients with MND is summarized in the In total, 479 motor units from asymptomatic individuals and 612 motor units from patients with MND were successfully decomposed into constituent motor unit action potential trains. Undoubtedly, there were stronger inverse relationships between the initial, mean firing rates and the recruitment thresholds for the sternocleidomastoid muscles in asymptomatic individuals (r = -0.633, Moreover, the degrees of short-term synchronization of all possible motor unit pairs from the sternocleidomastoid muscles were determined to characterize the neuromuscular control strategies in asymptomatic individuals and in patients with MND. Existing evidence has substantiated the hierarchical control of motor units during voluntary isometric contraction in various neuromuscular systems, such as the vastus lateralis, vastus medialis, first dorsal interosseous and tibialis anterior muscles , 46–48, When considering the electrophysiological properties of motor units, the higher values of initial and mean firing rates in the patients with MND shown here were not identical to the findings of Falla et al., who reported reduced modulation of the discharge rates of the identified motor units in the sternocleidomastoid muscles of women with chronic neck pain . The conAnother important issue should be worthy of discussing. As we know, the excitability of the motoneurone was gradually suppressed during sub-maximal fatiguing contractions  and the Regarding motor unit short-term synchronization, significant dependence of short-term synchronization on the mean recruitment threshold in each identified motor unit pair was documented in asymptomatic individuals. These results agree with previous observations of stronger short-term synchronization of the motor unit pairs with high-mean recruitment thresholds than with low-mean recruitment thresholds , 45, 58.Finally, some experimental limitations of the current work should be mentioned. Firstly, the sternocleidomastoid and anterior scalene muscles actually are major superficial cervical muscles and are believed to contribute for the voluntary cervical flexion . TheoretIn summary, the present study showed that the identified motor units of the sternocleidomastoid muscles displayed significantly higher initial and mean firing rates in patients with MND than in asymptomatic individuals, except for the identified motor units with recruitment thresholds corresponding to 15~20% MVC. Simultaneously, the patients with MND displayed lower motor unit short-term synchronization values of the sternocleidomastoid muscles compared with asymptomatic individuals. These convincing findings suggest that patients with MND used altered neuromuscular control strategies, such as the reinforcement of motor unit recruitment firing rates in the sternocleidomastoid muscles, to achieve the target force while performing cervical isometric flexion. Furthermore, the motor units of the MND patients also exhibited less efficient neural recruitment strategies than asymptomatic individuals when executing the required motor tasks.


It is important to learn the early signs of retinoblastoma. Early detection, diagnosis and treatment depends on it.Something white in the eye, often first noticed by parents. Confirm by conducting a red reflex test (see p. 23)Squint: one eye turns in or out (not as common).The most common early signs see  of retinForward displacement of the eye (proptosis)A visible tumour (fungating mass) involving just the globe, or extending to the orbit and/or the face.Signs of more advanced retinoblastoma include:Poor vision, whether noticed by the parents or a health workerNystagmus (constant eye movements)Hyphaema (bleeding into the anterior chamber)Pseudohypopyon Periocular inflammationPhthisis bulbi (shrinkage of the globe)Raised pressure in the eye (glaucoma)Enlargement of the globeChange in iris colour (heterochromia).Less common signs of retinoblastoma include:germline retinoblastoma are usually present in both eyes within the first few months of life (or even at birth in some instances). They include:Carers saying the eyes are not normalA white reflex in the pupil Occasionally nystagmus  in both eyes).Signs of non-germline retinoblastoma usually present later, often at the age of 2–3 years. The most common presenting features in patients with non-germline retinoblastoma are leucocoria  and squint (less common).Children with Note: If a child presents with unilateral retinoblastoma in the first year of life, it may be germline (p. 7). The child has a greater risk of developing more tumours in the same or the other eye. Careful screening of the fellow eye, throughout childhood, is essential for all children suspected of having germline disease.In high-income countries, children with retinoblastoma may present with reduced vision, an acute red eye or orbital inflammation.In low resource settings advanced cases with proptosis (forward displacement of the eye) or fungating orbital masses are seen more commonly due to late presentation.Digital flash photography, often from a mobile phone, can show the white reflex in the pupil in some cases and lead to earlier detection; however, squint, refractive errors, and photographs taken from an angle can also produce the appearance of a white reflex, with only a minority of cases having retinoblastoma.So, although most causes of an absent red pupil reflex on a photograph are not retinoblastoma it is still a useful public education tool. In Honduras, it was associated with a reduction in the proportion of children with retinoblastoma presenting with advanced disease.