There is a growing body of evidence suggesting that nutritional status during treatment for cancer has a significant impact on treatment-related toxicities and outcomes among children and adolescents with cancer. The effects of nutritional status appear to extend into survivorship with a large proportion of survivors at risk for a variety of nutrition-related morbidities. The influence of dietary intake on overall treatment outcomes and long-term morbidities is largely unknown. In adults, evidence suggests that greater adherence to cancer prevention dietary guidelines improves long-term health outcomes among survivors of cancer. Surveys describing dietary intake among survivors of childhood cancer have found that most survivors are not meeting the recommended guidelines for many dietary nutrients and this may have an unfavorable effect on nutrition-related outcomes. However, more research is needed in this area so that well-designed clinical trials may be developed and tested. This review presents an overview of the existing literature describing dietary intake among survivors of childhood cancer, the clinical implications of reported dietary behaviors among survivors, and identifies areas for future research. In 1981, Doll and Peto published a landmark paper that estimated that nearly 70% of cancer risk is attributable to diet and exercise; 35% of cancer risk may be attributed to diet alone . This reet al. performed a meta-analysis of weight status among survivors of ALL and found that survivors’ mean BMI percentile is approximately 80%, a figure significantly higher than the general pediatric population [Success in the treatment of childhood cancer has led to estimates that 1 in every 250 adults are a survivor of a pediatric malignancy . While tpulation ,10.Independent of weight, unhealthy dietary behaviors have been associated with increased risk for chronic health conditions such as heart disease and diabetes among pediatric and adolescent populations. Considering the pre-existing risk factors facing survivors of childhood cancer, the effect of unhealthy dietary behaviors is likely to be more pronounced among this population. Thus, an understanding of existing dietary behaviors among survivors of childhood cancer becomes an essential first step in order to develop effective nutritional interventions.et al. reported that less than 30% of survivors met dietary intakes for bone-metabolizing nutrients, a finding lower than reported in the general population [et al. reported that 95% of Hispanic children and 97% of African-America were below the RDA for vitamin D and 31% and 38% were below the RDA for calcium, respectively [et al. reported that dietary intake of food sources rich in calcium was associated with readiness to change behavior, underscoring the importance of the inclusion of behavioral theories in nutritional interventions [A smaller number of studies have reported on select micronutrients, primarily vitamin D and calcium among survivors of ALL. Tylavsky pulation . For exaectively . Low intectively . Mays etventions . To dateventions ,22et al. conducted a cross-sectional survey in 118 survivors between the ages of 13–35 on reasons for low dietary intake of fruits and vegetables, whole-grains, and low-fat foods [It has been well-established that health behaviors are highly complex and embedded in larger psychosocial, environmental and economic contexts . The finat foods . Most coat foods . Other sat foods . Howeverat foods  thus nutet al. reported that with greater adherence to the Mediterranean Diet, the odds of developing metabolic syndrome fell by 31%  [The clinical implications of unhealthy diets on the risk of cancer among adolescents are limited and focus primarily on dietary intake during adolescence and risk of breast cancer . Most of= 0.019) , lending= 0.019) .One study explored the effect of supplementation with and without dietary counseling on the D in survivors of ALL . Particiet al. reported on health behaviors and late-effects after cancer treatment [Taken together, the limited data suggest that survivors of childhood cancer are not adhering to cancer prevention guidelines and are engaging in lifestyle behaviors that may further increase the risk for the development of nutrition-related chronic conditions. Effective dietary interventions may impact a large proportion of chronic conditions faced by survivors of childhood cancer, thus significantly altering the quality life after completion of cancer treatment. Phillips-Salimi reatment . Of the Clinical guidelines are an important component of optimizing the delivery of cancer care and have contributed to the advances in other aspects of supportive care within pediatric oncology ,37. DietIn pediatric oncology, most of the existing nutritional guidelines were developed by expert consensus and grounded in data collected among adults. Two of the most widely referred to guidelines designed for survivors of cancer are the American Cancer Society  and the With the developing evidence suggesting that dietary intake may alter the risk of nutrition-related chronic conditions and risk of cancer, it becomes essential to integrate dietary counseling into the clinical framework of survivorship care. Several priority areas may be identified from the existing literature to drive the development of high-quality clinical trials. First, more epidemiologic information is needed on the variability of dietary intake during and after treatment. It has been established that children who are overweight or obese experience reduced survival and are at increased risk of therapy-related toxicities ,43,44. SThe association of dietary intake and late effects is likely to vary by diagnosis and therapeutic regimen. Future epidemiologic studies may consider expanding outside the context of ALL so that nutritional interventions may be modified and designed based on diagnosis and treatment exposures. This may be especially relevant for pediatric malignancies that constitute the growing number of survivors including Hodgkin’s Disease, acute myelogenous leukemia, and medulloblastoma. The optimal timing for nutritional interventions, as well as, the development of nutritional interventions that are adaptable to a wide range of ages, ethnicities, and socioeconomic groups are most likely to be easily woven into the survivorship model. Consideration may be given to initiating dietary counseling prior to entering survivorship care. Approaching survivorship with prevention-based interventions, may anticipate treatment-related late effects and result in reduced morbidities, improved quality of life, and reduced burden on the health care system.Importantly, it is clear that education of clinicians providing care to survivors of childhood cancer is necessary to advance the provision of nutrition counseling to patients and their families. It is important that health messages be consistent and comprehensive . There iFinally, nutritional interventions must be comprehensive in their approach and multidisciplinary in nature. Nutritional interventions that encompass lifestyle-based approaches have been most effective in promoting long-term behavioral change in both the pediatric and adult populations . Adaptin


Calcitonin gene related peptide (CGRP) is a neuropeptide which play an important role in the trigeminal nociception. Previous studies have demonstrated that chronic paracetamol (APAP) treatment resulted in the enhancement of trigeminal nociception. However, the effect of chronic APAP treatment on the CGRP has never been explored.To investigate the effects of chronic APAP treatment (30 days) on the CSD–induced CGRP expression in the trigeminal ganglion.Rats were divided into control, CSD only, APAP treatment only and APAP treatment with CSD groups. Once-daily injection of APAP at a dose of 200 mg/kg body weight was intraperitoneally injected into the APAP-treated groups for 30 days. CSD was induced by topical application of potassium chloride on the parietal cortex. The expression of CGRP was monitored by immunohistochemistry and the CGRP mRNA level was investigated by RT-PCR.The induction of CSD caused an increase in the expression of CGRP in the trigeminal ganglion with a significantly higher in the number of CGRP-positive neuron than that observed in the control group. Interestingly, chronic APAP treatment in combination with or without CSD could significantly enhance the CGRP expression than that observed in CSD group. The results obtained from RT-PCR were in line with those obtained from immunohistochemical study. Chronic APAP treatment could significantly increase the CGRP mRNA level than that of control, especially in combination with CSD.Based on these results, it can be concluded that chronic APAP treatment can increase the CSD-induced CGRP expression in trigeminal ganglion.No conflict of interest.


Gastroaortic fistula formation is a very rare complication following oesophageal resection and, in most cases, leads to sudden death. We report the case of a 65-year-old male with an adenocarcinoma of the oesophagus who underwent neoadjuvant chemoradiation followed by a minimally invasive transthoracic oesophagectomy with gastric tube reconstruction and intrathoracic anastomosis. After an uneventful postoperative course and hospital discharge, the patient reported blood regurgitation on postoperative day 23. Endoscopy revealed an adherent blood clot on the oesophageal wall, which after dislocation caused exsanguination. Autopsy determined the cause of death being massive haemorrhage due to a gastroaortic fistula. The sudden onset of haemorrhage makes this condition particularly difficult to treat. Recognition of warning signs such as thoracic or epigastric pain, regurgitation of blood, or the passing of bloody stools or melena is crucial in the early detection of fistula and may improve patient outcome. The development of an aortic fistula after oesophagectomy is a life threatening condition mostly due to its lethal nature even when diagnosed at an early stage. This rare complication generally occurs 2-3 weeks after oesophagectomy  and ofteWe report a case in which there was in fact a small sentinel or herald bleed, as a prelude to massive exsanguination. Early recognition of a sentinel bleed may be essential to improve patient outcome.A 65-year-old male presented to our outpatient clinic with a three-week history of dysphagia and weight loss. Workup revealed an eT3N3M0 adenocarcinoma of the lower third of the oesophagus. The patient was treated with neoadjuvant chemoradiation, consisting of a five-week course of carboplatin/paclitaxel combined with radiotherapy consisting of 23 fractions of 1.8 Gy, 41.4 Gy in total. Following neoadjuvant therapy a minimally invasive transthoracic oesophagectomy was performed with gastric tube reconstruction with an intrathoracic end-to-side circular stapled anastomosis according to the Ivor-Lewis technique. The postoperative course was uneventful and a postoperative contrast swallow on postoperative day 7 showed no sign of anastomotic leak. The patient was discharged in good condition on the 13th postoperative day.Histological examination of the resection specimen showed a significant response to the neoadjuvant chemoradiation (tumor regression grade 2 according to Mandard) with a small residual adenocarcinoma invading the submucosa and 11 negative lymph nodes (ypT1N0).Ten days after hospital discharge, the patient reported regurgitation of small amounts of blood and mild dysphagia. Dietary intake was reduced to fluids only and the patient was scheduled for endoscopy the following day.Endoscopy of the upper oesophagus and gastric tube showed an intact anastomosis with an adherent blood clot. Dislocation of the clot revealed an uncontrollable massive arterial bleeding and caused severe haemorrhagic shock. Despite endoscopic attempts to control the bleeding and administered advanced life support, the patient succumbed due to exsanguination in the endoscopy suite.Postmortem examination revealed a 1.5 centimetre diameter dehiscence at the level of the intrathoracic anastomosis with a closely adherent aortic wall, revealing a gastroaortic fistula at the level of the intrathoracic anastomosis without signs of aneurysmal widening of the aortic diameter. The gastrointestinal tract was full of blood, supporting the cause of death being exsanguination due to the gastroaortic fistula. No signs of residual malignancy were found during examination.Formation of fistulae between the aorta and the gastric tube after oesophagectomy is a very rare phenomenon. The first report of the occurrence of an aortoesophageal fistula was by Dubrueil  in 1818,Our case describes a fistula secondary to oesophageal surgery, but in general, aetiology of secondary fistula is diverse, including foreign body perforation, peptic ulceration of the gastric tube, and anastomotic leakage . Most coPrevious reports have suggested that the degree and method of dissection might predispose for aortic erosion . HoweverAnother possibility is the presence of continuous contact pressure between the linear staples at the level of the anastomosis and the aortic wall causing an erosion of the aorta and eventually resulting in gastroaortic fistula. This mechanism has been previously described as being responsible for formation of tracheogastric fistulae . Thus faThe contribution of neoadjuvant therapy to the formation of fistula is to be considered. Our patient was treated with a five-week course of carboplatin/paclitaxel combined with radiation therapy consisting of 23 fractions of 1.8 Gy . As shown in Although this phenomenon is mostly observed six months to five years after radiation therapy , it is pThe sudden onset of haemorrhage makes this condition particularly difficult to treat. Recognition of warning signs such as thoracic or epigastric pain, regurgitation of blood, or passing of bloody stools or melena is crucial in the early detection of fistula and may improve patient outcome.Our patient reported dysphagia and regurgitation of blood, in retrospect being the first sign of the underlying pathology. This type of sentinel bleeding has been reported in other types of gastrointestinal surgery, such as pylorus preserving pancreaticoduodenectomy and classic Whipple surgery . SentineAlthough early recognition of this sequence of events seems essential in order to maximize the survival, there is no apparent consensus on the optimal diagnostic strategy. Endoscopy of the upper gastrointestinal tract might aid in the detection of fistula. Endoscopic findings may be directly due to visualization of pulsatile blood into the oesophagus or a pulsatile adherent blood clot. More subtle findings during endoscopy might point in direction of a fistula, such as submucosal hematoma shown as a blue-gray discoloration of the oesophageal wall . HoweverThe literature reports twenty-three cases of gastroaortic fistula following oesophageal surgery, all but three reporting a fatal outcome despite surgical efforts . The maiPatients reporting regurgitation of blood or hematemesis following an oesophagectomy should raise suspicion of a gastroaortic fistula. This sentinel or herald bleed should prompt us to actively “seek the leak.” It is essential to recognise the lucid interval between the sentinel bleed and the massive hematemesis and utilize it to rapidly confirm diagnosis and create a treatment plan. Depending on the extent of the bleeding, we would advise to start with a computed tomography scan with arterial contrast to visualise the origin of the bleeding and determine the best surgical approach, either endovascular, endoscopic, or invasive salvage surgery. In case of an inconclusive scan, a subsequent endoscopy of the upper gastrointestinal tract might confirm the suspicion. However, despite early diagnosis and extensive surgical effort, reported patient outcome is poor.


Rapidly destructive coxarthrosis (RDC) is rare and develops unusual clinical course. Recent studies suggest multiple possible mechanisms of the development of RDC. However the exact mechanism of RDC is still not clear. The difficulty of the study on RDC is attributed to its rareness and the fact that the data before the onset of RDC is normally unavailable. In this report, we presented the patient having the radiographic data before the onset who had rapid osteoarthritis (OA) development after contralateral THA, which meets the current criteria of RDC. We thought that the increased posterior tilt of the pelvis after THA reinforced the stress concentration at pre-existed anterior acetabular cyst, thereby the destruction of the cyst was occurred. As a result the rapid OA was developed. We think that there is the case of rapid osteoarthritis developing due to alternating load concentration by posterior pelvic tilt on preexisting anterior acetabular cyst such as our patient among the cases diagnosed as RDC without any identifiable etiology. The recognition of sagittal alignment changes and anterior acetabular cyst may play important role in prediction and prevention of the rapid hip osteoarthritis development similar to RDC. Rapidly destructive coxarthrosis (RDC) was firstly described by Postel and Kerboull in 1970 , 3 and sAn 80-year-old female had a total hip arthroplasty (THA) on her right hip due to chronic osteoarthritis of the hip for 7 years. At the time of right THA, she had no symptoms on her left hip. However, 2 months after right THA, she started to have left hip pain without any trauma. Gradually left hip pain was deteriorated, as a result left THA was performed 10 months after right THA. After right THA, the patient had no minor trauma such as falls or standing firmly. There were no clinical signs and results of blood test indicating the systematic autoimmune disorder and the infection.Concerning the radiographic evaluation, standard X-ray of the hip and CT scan were obtained. At the time of right THA, left hip was showing enough joint space with aectabular cyst at anterior part Figures . CT scanFor sagittal alignment assessment, full-length standing lateral radiograph was used; in brief the subject stood in a relaxed position, with the arms folded across the chest to minimize variation due to the effects of trunk posture on the lumbosacral junction . The pelLeft THA was performed under general anesthesia. The intra-articular joint fluid was sent for the microorganisms examination . After left THA, no complication was observed.Postel and Kerboull firstly described RDC in English literature in 1970 [Recent studies suggest multiple possible mechanism of the development of RDC. Yamamoto and Bullough reported that SIF of the femoral head occurs in elderly women with osteopenia, and they speculated that insufficiency fracture resulting from osteopenia might lead to rapid breakdown of the hip joint . The terIn this report, we presented the patient who had rapid OA development, which meets the current criteria of RDC after contralateral THA. We thought that the increased posterior tilt of the pelvis after THA reinforced the stress concentration at pre-existed anterior acetabular cyst, thereby the destruction of the cyst was occurred. As a result the rapid OA was developed .In general, pelvic posterior tilt increases according to the ages due to the decrease of the lumbar lordosis and back muscle weakness , 12. By Concerning the bone cyst, even though many studies have been performed on the mechanism of development of the bone cyst, the exact mechanism is still not clear. There is the hydrodynamic theory , namely,We think that there is the case of rapid osteoarthritis developing due to alternating load concentration by posterior pelvic tilt on preexisting anterior acetabular cyst such as our patient among the cases diagnosed as RDC without any identifiable etiology. The recognition of sagittal alignment changes and anterior acetabular cyst may play important role in prediction and prevention of the rapid hip osteoarthritis development similar to RDC.


The mean age of acute dengue has undergone a shift towards older ages. This fact points towards the relevance of assessing the influence of age-related comorbidities, such as diabetes, on the clinical presentation of dengue episodes. Identification of factors associated with a severe presentation is of high relevance, because timely treatment is the most important intervention to avert complications and death. This review summarizes and evaluates the published evidence on the association between diabetes and the risk of a severe clinical presentation of dengue.A systematic literature review was conducted using the MEDLINE database to access any relevant association between dengue and diabetes. Five case-control studies  compared the prevalence of diabetes  of persons with dengue  and patients with severe clinical manifestations. All except one study were conducted before 2009 and all studies collected information towards WHO 1997 classification system. The reported odds ratios were formally summarized by random-effects meta-analyses. A diagnosis of diabetes was associated with an increased risk for a severe clinical presentation of dengue .Large prospective studies that systematically and objectively obtain relevant signs and symptoms of dengue fever episodes as well as of hyperglycemia in the past, and at the time of dengue diagnosis, are needed to properly address the effect of diabetes on the clinical presentation of an acute dengue fever episode. The currently available epidemiological evidence is very limited and only suggestive. The increasing global prevalence of both dengue and diabetes justifies further studies. At this point, confirmation of dengue infection as early as possible in diabetes patients with fever if living in dengue endemic regions seems justified. The presence of this co-morbidity may warrant closer observation for glycemic control and adapted fluid management to diminish the risk for a severe clinical presentation of dengue. Both dengue and diabetes have reached epidemic dimensions and pose a joint threat to a large proportion of populations in low- and middle-income countries. Dengue is no longer a disease primarily affecting children. Therefore the influence of non-communicable diseases such as diabetes, which are increasingly prevalent in adults, on the clinical presentation of a dengue episode becomes a public health priority. We conducted a systematic literature review to assess the available evidence on the effect of diabetes mellitus (DM) on the clinical presentation of dengue. The meta-analysis of published evidence combined with supporting biological evidence point to an increased risk for potentially life threatening symptoms of dengue among patients with diabetes. The current evidence is limited by statistical power and other study limitations and does not allow conclusions about a causal effect of diabetes. Yet, based on the currently available evidence, diabetes patients with fever and living in a dengue endemic region should seek confirmation of dengue infection as early as possible. Diabetes should be considered in the triage of patients for close observation and early intervention, which are challenges, particularly during dengue outbreaks. Timeliness of intervention is the most important factor averting serious complications and death in patients with acute dengue. Today there are 347 million people worldwide who have DM  OR "dengue"[All Fields]) AND ("diabetes mellitus"[MeSH Terms] OR ("diabetes"[All Fields] AND "mellitus"[All Fields]) OR "diabetes mellitus"[All Fields] OR "diabetes"[All Fields]”.We included articles in all languages; articles which reported on epidemiology, clinical signs, and laboratory parameters for dengue-infected patients, or on severity assessment. There was no restriction in publication dates, place of study, study design or age of research participants. As a validity assessment, the PRISMA criteria were used ,26.For meta-analyses, we included studies that compared the prevalence of DM between persons affected by different dengue stages (case-control studies), reporting estimates of association and their 95% confidence intervals, or enough information to derive this.We extracted the year during which dengue cases were diagnosed (year during which the study was conducted), year of the publication, country of the study, study design, study definitions of dengue infection and diabetes, and confounder adjustments. We extracted data on the sample size of enrolled persons and number of cases and controls and on the estimates (unadjusted and adjusted models) of the association  between diabetes and severe dengue. The transition of the patients data from clinical or hospital records to this review was based on published non-individual and non-identifying data. Data were extracted from the published papers independently by two reviewers and disagreements were resolved by discussion.The studies included in this review mostly included dengue diagnosed before 2009 and applied the WHO 1997 dengue classification criteria . A 2009 In the reviewed publications, laboratory diagnosis methods to confirm dengue virus infection as the cause of disease varied across studies and involved detection of virus, viral nucleic acid, antigens or antibodies, or a combination of these techniques . The detIn studies included in this review, the diagnosis of DM was mostly ascertained by self-reported diagnosis in the context of in-person interviews or DM diagnosis listed in clinical records. The DM diagnosis was further verified by requesting the prescription and/or medication package during the in-person interview in the only population-based case-control study . An oral2 metric and Tau2 to describe the between study heterogeneity and variance respectively.We used random-effects models for meta-analyses of the association between DM and a severe clinical presentation of dengue . They taWe conducted sensitivity analyses by using a fixed effect model and excluding a study, which was based on non-matched random controls and that only reported unadjusted estimates . We perfOur literature search resulted in 32 hits . After eEpidemiological studies included in the meta-analysis compared the prevalence of DM and other co-morbidities between patients suffering from acute dengue with a severe presentation and controls with acute or past dengue without severe clinical manifestations . In the The only population-based case-control study  identifiA hospital-based study including persons aged 15 to 65 in Pakistan  comparedIn Singapore, a hospital-based study was conducted in the nation’s largest clinic. It included all admitted patients with acute dengue without age restriction . InformaIn 2002 in Taiwan, all patients with confirmed acute DF treated at the Kaoshiung Medical University Hospital during a large outbreak occurring in the southern Taiwan were categorized into groups of DF and DHF/DSS by strictly adhering to clinical WHO 1997 criteria and laboratory confirmation under the auspices of the Taiwanese Centre of Disease Control . ClinicaA hospital-based study in Southern India  obtainedWe included the results of five above mentioned studies in a meta-analysis. One of these studies reported two separate estimates from two independent cross-sectional assessments; hence, we considered them as separate studies. The meta-analysis showed that the presence of a severe clinical presentation of dengue was positively associated with the presence of DM.A diagnosis of DM was associated with an increased risk for severe clinical manifestations of dengue by 75%  compared to non-DM patients . This ORWe additionally identified five case series reporting dengue-related hospitalizations and the prevalence of DM in these cases. They are listed in The few published studies specifically addressing the role of DM as a risk factor for a severe clinical presentation of dengue provide suggestive evidence for an adverse effect. This result merits further investigation in the context of study designs that overcome the weaknesses of currently available publications as addressed below.Assigning causality to the modifying effect of diabetes on the clinical presentation of dengue is premature. First, the case-control studies conducted to date and summarized above are mostly retrospective in nature. The clinical and laboratory diagnostic criteria applied in different studies vary broadly, as does the definition for the control group. Second, the WHO 1997 dengue classification used in the studies reviewed, has itself a number of limitations. For example, the development of this classification was based on disease patterns of children in Thailand, potentially limiting its generalizability to other geographical regions and to older age groups. Furthermore, clinical assessments such as the Tourniquet test do not differentiate between DF, DHF and other febrile illness ,39. It aBiological evidence exists to support the hypothesis for a high DHF: DF ratio in diabetes. One example for a line of reasoning is that the cytokine overload related to a Th1 to Th2 shift and a severe manifestation of dengue superimposed by the cytokine overload of a diabetic state may be particularly detrimental to the endothelium and for subsequent vascular leakage –43. The Currently available epidemiological studies on the DM/DHF, DSS association do not provide sufficient clinical details to specifically address this “cytokine overload” hypothesis. For example, the Brazilian study explicitly stated that it did not look into ascites or pleural effusion, as these were very rarely recorded . The othThe potential role of altered innate immunity in mediating the association between DM and a severe clinical presentation of dengue obtains indirect support by observations that the latter may also have a higher prevalence of asthma and allergies. Patients with asthma and allergy also exhibit altered Th1 and Th2 responses ,31. But Understanding factors increasing the likelihood of dengue patients with severe clinical symptoms would help the physician to decide in a timely fashion on the need for close observation, adequate treatment, or hospitalization. The available evidence points to DM as a potentially important co-factor. Additional prospective studies among DM and non-DM patients are needed to assess the impact of pre-existing DM as well as of hyperglycemia at the time of dengue diagnosis on the risk of a severe clinical presentation of dengue and of related deaths. Even in the absence of causal inference, it seems justified that fever episodes in patients with DM and living in a dengue endemic region are confirmed for dengue as soon as possible and that they remain under close surveillance if an acute dengue infection is confirmed. Future studies need to also address whether better control of glycemia level in dengue patients with DM can improve the outcome of the patient and decrease the risk of a severe clinical presentation. As the fluid management in diabetic patients with a severe clinical presentation of dengue poses a particular challenge, this issue should be taken into consideration by these studies. Diabetic patients in dengue endemic regions should consistently receive recommendations to protect against dengue infection by taking preventive measures against indoor mosquito breeding and against mosquito bites.S1 Table(PDF)Click here for additional data file.


Review of literature reveals that in Idiopathic Scoliosis (IS) children, the post-operative rib hump (RH) correction using full transpedicular screw construct has never been compared to hybrid constructs, applying the Rib-Index (RI) method. Therefore the aim of this report is to study which of the above two constructs offers better postoperative Rib Hump Deformity (RHD) correction.Twenty five patients with Adolescent Idiopathic Scoliosis (AIS) were operated using full pedicle screw construct or hybrid construct. Sixteen underwent full screw instrumentation (group A) and nine an hybrid one (group B). The median age for group A was 15 years and for group B 17.2 years. The RHD was assessed on the lateral spinal radiographs using the RI. The RI was calculated by the ratio of spine distances d1/d2, where d1 is the distance between the most extended point of the most extending rib contour and the posterior margin of the corresponding vertebra on the lateral scoliosis films and d2 is the distance from the least projected rib contour and the posterior margin of the same vertebra. Moreover the amount of RI correction was calculated by subtracting the post-operative RI from the pre-operative RI.Although within group A the RI correction was statistical significant  and similarly in group B , between group A and B the post-operative RI correction mean values were found to be no statistically significant, (p=0.803).Although the pre- and post-operative RI correction was statistically significant within each group, this did not happen post-operatively between the two groups. It appears that the RHD correction is not different, no matter what the spinal construct type was used. Provided that the full screw construct is powerful, the post-operative derotation and RHD correction was expected to be better than when an hybrid construct is applied, which is not the case in this study. It is therefore implied that the RHD results more likely from the asymmetric rib growth rather than from vertebral rotation, as it has been widely believed up to now. In 2013 Lykissas et al, reported that costoplasty combined with pedicle screws and vertebral derotation significantly improved RH deformity as opposed to pedicle screws and vertebral derotation alone. Another interesting implication is that the spinal deformity is the result of the thoracic asymmetry, implication in line with the late Prof. John Sevastikoglou’s (Sevastik’s) thoracospinal concept. Idiopathic scoliosis is a 3D deformity of the trunk with detectable bony asymmetries and deformities, not only of the spine - the central axis - but also of the rib cage and other parts of the body. The thorax, like any other part of the skeleton, displays variations in dimensions and proportions . The bonThe aim of this report is to study whether there is a difference of the post-operative RHD correction between these two constructs.Sixteen patients with Adolescent Idiopathic Scoliosis (AIS) were operated using a full pedicle screw construct (group A) Figure , while nIn group A the mean pre-operative RI was 1.93 and the post-operative 1.37 (p<0.001) Figure . HoweverThe scoliosis surgery techniques evolved from the Harrington era and the advent of new technologies proved to be promising. A challenging question is what type of surgical instrumentation offers better rib-hump correction: a full screw or an hybrid construct? The full screw construct is more powerful and therefore frequently used. However this study reveals that whatever the type of instrumentation used, there was no statistically significant post-operative difference in correction between the two groups, in terms of RHD. The RHD more likely seems to result from the asymmetric rib growth than from vertebral rotation.There are certain limitations in this study that is its retrospective nature, the limited number of patients involved and the relative heterogeneity of the curve types.Although the pre- and post-operative RI correction was significant within the two studied groups of patients, none of the two constructs used offered better RHD correction. Provided that the full screw construct is powerful, the post-operative derotation and the RHD correction should have been better corrected than with an hybrid construct, yet this was not the case in this study. This discordance between the ribcage and the spine behavior after surgery could be attributed to a different scoliogenic course and this could have potential aetiological implications. It seems likely that the thoracic deformity contributes to RHD more than the potential vertebral rotation.This is the extended abstract of IRSSD 2014 program book .The ethical & scientific committee of "ATTIKON" Hospital has approved the use of patients data and imaging respecting their privacy, for the purpose of the retrospective clinical study titled <Rib hump deformity assessment using the rib index in adolescent idiopathic scoliotics treated with full screw or hybrid constructs: aetiological implications>. Patients were informed prior medical services or admission to the University Hospital "ATTIKON" that imaging and other medical data could be used in teaching and academic purposes.There no competing interests to disclose.TBG: Conceived the idea of RI, drafted the text and searched the literature. NAS: Drafted the text, searched the literature. KCS: Reviewed the paper. All authors contributed their professional skills to the inclusions of the text. All authors have read and approved the final manuscript.


Cable-stayed bridges are one of the most popular types of long-span bridges. The structural behaviour of cable-stayed bridges is sensitive to the load distribution between the girder, pylons, and cables. The determination of pretensioning cable stresses is critical in the cable-stayed bridge design procedure. By finding the optimum stresses in cables, the load and moment distribution of the bridge can be improved. In recent years, different research works have studied iterative and modern methods to find optimum stresses of cables. However, most of the proposed methods have limitations in optimising the structural performance of cable-stayed bridges. This paper presents a multiconstraint optimisation method to specify the optimum cable forces in cable-stayed bridges. The proposed optimisation method produces less bending moments and stresses in the bridge members and requires shorter simulation time than other proposed methods. The results of comparative study show that the proposed method is more successful in restricting the deck and pylon displacements and providing uniform deck moment distribution than unit load method (ULM). The final design of cable-stayed bridges can be optimised considerably through proposed multiconstraint optimisation method. The construction of cable-stayed bridges is rapidly increasing all over the world. The structural behaviour of cable-stayed bridges is significantly sensitive to the load distribution between the girder, pylons, and cables. Cables are one of the main parts of a cable-stayed bridge. They transfer the dead load and traffic load of the girders to the pylons. They are also sensitive to dynamic loads such as wind loads, which make their health monitoring a serious issue –4. DeterThe structural complexity of cable-stayed bridges makes their design process a serious engineering concern. Lazar et al.  and ToriChen et al.  proposedMoreover, in recent years, variety of research works have applied modern methods for finding the cable forces in cable-stayed bridges –19. A scIn cable-stayed bridges, as the number of stay cables is significant, the number of design variables could be quite large and this can lead to potential numerical problems. The modern complex models with a large number of variables do not furnish an applicable method to find cable forces for engineering simulations and there is a need to introduce a more simplified accurate model to find the optimised cable forces for cable-stayed bridges.Certain numbers of the recent proposed optimisation methods use an iterative process to determine the economical solution. Most of the proposed optimisation approaches have limitations in determining the optimal pretensioning forces. Among proposed iterative optimization strategies, the ULM method seems to be a prominent fundamental method for optimising the cable forces considering its easy extensibility and applicability to real construction engineering problems. The main advantage of ULM is that it can provide a tensioning strategy during the individual construction stages by taking time-dependent effects and geometrically nonlinear behaviour into account. Lee et al.  proposedThe main purpose of this paper is to present an effective multiconstraint optimisation strategy for cable-stayed bridges based on the application of an inverse problem through ULM method resulting in reduced stresses and shorter simulation times than the other proposed approaches. Adjusting local optimum values of cable stresses is also possible through the proposed optimization technique.The design data of Japan's Tatara bridge is considered in this analytical study through ANSYS (12) .A new multiconstraint optimisation method to obtain posttensioning cable forces for cable-stayed bridges is employed in this research work. The main objectives of this study are to determine the optimum posttensioning cable forces for cable-stayed bridges through multiconstraint optimisation method under the action of dead load and to compare the posttensioning cable forces from the ULM method and the proposed multiconstraint method.A multiconstraint optimisation method is proposed in this study for finding the cable stresses in long-span cable-stayed bridges. Under the combination of the dead load and cable forces, the first estimation of pretensioning cable forces is taken based on the ULM because the computations are less difficult to converge compared to the other iterative methods. Multiconstraints are applied to make the moment distribution along the deck uniform and minimise the member stresses and also deflections.To better understand the applied method for optimising cable forces, the scheme of ULM method is presented in Mj) for j points along the main girder as the sum of the moments created under the action of dead load (MDLj) and also unit cable forces (MTij), which is multiplied by an unknown factor (Xi). The structure will be analysed by adjusting constraints to achieve the pretensioning forces (Ti) in the cables. The constraints used by Janjic et al. [there should be no out-of-plane displacement at the top of pylons;there should be no vertical displacement of the deck under dead load.The ULM defines the moment distribution in the structure .The pylon should be kept straight vertically, which means that the resultant horizontal components of the cable forces will reach equilibrium with almost no out-of-plane displacement produced at the top point of the pylons. To avoid convergence problems in the iterative procedure, the upper and lower bound of 2 × 10−2 m are also considered to satisfy this constraint . This constraint should be satisfied in each control point (j) along the main girder. It is predictable that the middle of the main span would be one of the critical locations for satisfying this criterion.The vertical displacement of the girder should be kept at approximately zero because the initial configuration of the bridge should be maintained after pretensioning and before applying the live load. To avoid convergence problems in the iterative procedure, the upper and lower bound of 2 × 10To produce optimal cable tensions, the following constraints are additionally proposed in this study through an iterative method.(3)N = 0).There should be no axial force in the middle of the main span, meaning that the cable forces should not produce extra forces in the girder ((4)Ti ≤ Tallowable).Relaxation is significantly accelerated in steel cables when the permanent stress is greater than 50% of the tensile strength. Therefore, the stresses from permanent loads should not exceed 0.45 of the tensile strength . Each ob(5)Mmin ≤ Mj ≤ Mmax). This constraint introduces a local optimisation in which the corresponding cable force (Ti) causing the moment of the girder to fall out of the acceptable range can be changed directly.For the girders, the difference between the maximum positive and maximum negative moments should be limited to an acceptable range  . The BEAM4 elements from the ANSYS element library are used to model the central spine. Stress-stiffening and large deflection capabilities are included in the model. The MPC184 elements are applied to model the rigid links, and MASS21 elements are used to include the mass of the equilibrium blocks, parapet, and anchors that are nonstructural members. The steel pylons, heads, and struts of the pylons are modelled as three-dimensional (3D) elastic BEAM4 elements. The general arrangement of the two pylons of the bridge is shown in The cables of the bridge are parallel stranded cables with a tensile strength of 1,569 MPa. The cables are modelled in ANSYS by employing 3D nonlinear tension-only truss elements LINK10) and utilising the stress-stiffening capability to consider the sag effect, which occurs because the cables do not have any bending stiffness . The cab and util (x) and two translational degrees-of-freedom at each abutment are fixed. Elastic bearings were used for the pylon-to-deck connections. Thus, the spring constant about 3.92 × 106 (N/m) is adopted to limit the girder displacement in the direction of the bridge axis based on design information about the bridge. The boundary conditions at the piers, at the base of the pylons, and at the connection of each abutment are simulated in the FE model. The pylon bases are considered as being fixed in all degrees-of-freedom. The end connections permit the end of the deck to rotate freely about the vertical and transverse axes. Rotation about the longitudinal axis−2 m are considered to satisfy these constraints. However, the ULM does not produce well-distributed cable forces and girder moments in long-span cable-stayed bridges, as mentioned previously. The bending moments of the PC girders due to the dead load are extremely large compared with those of the steel girders, and the adjustment of these bending moments by cable prestressing alone is unrealistic. Furthermore, the effect of CWs on the final profile is not significant. Therefore, the weight of PC girders is excluded in the cable prestress determination.The iterative multiconstraint method is applied in this study to find the pretensioning cable forces of simulated bridge. The cable forces of the bridge are preestimated by the ULM, utilising the deflection constraints (constraints (1) and (2) as mentioned in Three more constraints are applied in the optimisation procedure in addition to the ULM deflection constraints to produce the optimum cable forces. The constraints are applied in 2 more steps  as mentioned in 7 N.m is considered for optimising bending moments in iterative process based on engineering judgement. However, the bending moment in PC girders and deck-to-pylon connections exceeds the considered range which is excluded from the iterative process manually to provide a uniform moment distribution in each span of the deck. The bending moments of the deck are checked for uniformity (constraint (5) as mentioned in The analytical study shows that the optimization process may get locked in some local minimums. The solution for this problem is explained in Asgari et al. .A comparative study is conducted in this paper to compare the structural responses of the optimised cable-stayed bridge by multiconstraint method with responses derived from ULM. The comparison of the bending moment distributions in the simulated cable-stayed bridge  shows thThe static and dynamic responses of the optimised cable-stayed bridge by multiconstraint method are also compared with the responses of ULM-optimised cable-stayed bridge to investigate the effect of pretensioning cable forces on the bridge responses. The results of static analysis shown in The prestressed modal analysis is conducted after the static analysis to investigate the effect of the cable pretensions on the dynamic behaviour of the bridge. The modal analysis of the FE model starts from deformed equilibrium configuration of the bridge, which means prestressed modal analysis is conducted following the static analysis under the dead load and cable tensions to achieve the initial equilibrium configuration. The determination of pretensioning cable forces is critical in the cable-stayed bridges design procedure. The results of investigations show that ULM method is a prominent method for optimizing the cable forces considering its easy extensibility, fast process, and applicability to real construction engineering problems. However, the cable forces optimised by ULM can be further improved because it does not produce well-distributed cable forces and girder moments in long-span cable-stayed bridges.A new multiconstraint iterative algorithm is presented in this study to determine the cable pretensions of a long-span cable-stayed bridge, overcoming the limitations of previously proposed methods. The iterative procedure introduces three more constraints in addition to the conventional displacement constraints of the ULM. The additional constrains are assigned through 2 more iterative steps. As the proposed method follows ULM procedure in optimising cable forces, the time-dependent effects such as creep, shrinkage, or relaxations of pretensioning forces as well as geometrical nonlinearities can be considered. Furthermore, the proposed process can be used in the construction process of cable-stayed bridges.The results of comparative study show that the proposed method further decreases the pylon base and main girder bending moments up to 53% and 39%, respectively, comparing to ULM. The maximum displacement at top point of the pylons and along girder also decreased which results in a safe design. Moreover, the multiconstraint method produces more uniform pretensioning forces in cables and also more uniform bending moment distribution along the deck, resulting in more economical design of the bridge. However, there is no significant difference between the dynamic characteristics of cable-stayed bridge optimised by ULM and multiconstraint method.


Thecause of the disruption is thought to be the multifollicular development achieved duringovarian stimulation which results in supraphysiological concentrations of steroids se-creted by a high number of corpora lutea during the early luteal phase. This will directlyinhibit luteinizing hormone (LH) secretion by the pituitary via negative feedback at thelevel of the hypothalamic-pituitary axis, leading to a luteal phase defect. With the intro-duction of the gonadotropin-releasing hormone (GnRH) antagonist protocol, it becamefeasible to trigger final oocyte maturation and ovulation with a single bolus of GnRHagonist (GnRHa) as an alternative to human chorionic gonadotropin (hCG). GnRHa trig-gering presents several advantages, including the reduction in or even elimination ofovarian hyperstimulation syndrome. Despite the potential advantages of GnRHa trig-gering, previous randomized controlled trials reported a poor clinical outcome with highrates of early pregnancy losses, despite supplementation with a standard LPS in the formof progesterone and estradiol. Following these disappointing results, several studies nowreport a luteal phase rescue after modifications of the LPS, resulting in a reproductiveoutcome comparable to that seen after hCG triggering. We herein review luteal phase dif-ferences between the natural cycle, hCG trigger and GnRHa trigger and present the mostrecent data on handling the luteal phase after GnRHa triggering.The luteal phase of all stimulated  In the natural cycle ovulation is induced by amid-cycle surge of luteinizing hormone (LH) andfollicle-stimulating hormone (FSH) from the pituitaryelicited by a rise in the late follicular phaselevel of estradiol and progesterone. Ovulationmarks the transition from follicular phase to lutealphase, characterized by the formation of a corpusluteum which releases steroid hormones, includingprogesterone and estradiol. Importantly, the steroidproduction is totally dependent on the pulsatile secretionof LH by the pituitary , 2.Apart from securing the function of the corpusluteum, LH plays a crucial role during the lutealphase by up-regulating growth factors like vascularendothelial growth factor A (VEGFA) andfibroblast growth factor 2 (FGF2). In addition,cytokines are up-regulated and extragonadal LHreceptorsare activated in the endometrium. Allthese factors are thought to enhance and supportimplantation and early neo-vascularization , 3.The role of the previously described mid-cycleFSH surge during the natural cycle is not fully understood;however, FSH seems to promote oocytenuclear maturation, i.e. resumption of meiosis and cumulus expansion. Furthermore, FSH has been shown to induce LH receptor formation in the luteinizing granulosa cells, thus optimizing the function of the corpus luteum , 3.Following implantation, the embryo gradually begins to secrete human chorionic gonadotropin (hCG) into circulation, structurally and biochemically similar to LH . The funApart from progesterone, the corpus luteum produces other steroid hormones, including estradiol. Estradiol has a modulatory effect on the secretory endometrial progesterone receptor concentration and may serve to replenish and maintain a sufficient level of endometrial receptors to secure an adequate response to progesterone .Controlled ovarian stimulation (COS) is a key component of modern IVF treatment, as the availability of multiple oocytes for fertilization increases the chance of pregnancy .in vitro fertilization/intra-cytoplasmic sperm injection (IVF/ICSI) cycle, the luteal phase is physiologically abnormal. The most plausible reason for this is the multifollicular development achieved during the follicular phase, leading to a high number of corpora lutea. The collective steroid production of the corpora lutea will result in supraphysiological concentrations of progesterone and estradiol which directly inhibit the LH secretion by the pituitary via negative feedback actions at the level of the hypothalamic-pituitary-gonadal-axis . This life threatening condition, characterized by massive enlargement of the ovaries and an increased vascular permeability, among others, is a iatrogenic complication following COS , 6. The The best strategy to prevent OHSS has previously been to indentify high-risk patients before ovarian stimulation, followed by the use of an appropriate COS protocol .With the introduction of the GnRH antagonist protocol for the prevention of a premature LH surge, it became possible to trigger ovulation with GnRHa. The GnRH antagonist occupies the GnRH receptor without causing down-regulation, and by injecting a single bolus of GnRHa, the antagonist is displaced from the receptor. This activates the receptor, inducing a flare-up of gonadotrophins (LH and FSH), which effectively stimulate the final oocyte maturation and ovulation. However, important differences exist regarding the profile and duration of the LH surge after triggering with GnRHa compared to that of the natural cycle. In the natural cycle, the LH surge is characterized by three phases with a total duration of ~48 hours. After GnRHa triggering, the surge consist of two phases, only, with a duration of ~24-36 hours leading to a significantly reduced amount of LH released .Apart from an LH surge, GnRHa triggering also induces an initial secretion of FSH resembling that of the natural cycle. This more natural surge of gonadotrophins after triggering with GnRHa may explain why some authors reported retrieval of an increased amount of mature oocytes compared to hCG triggering , 3.The induced surge of gondotrophins results in an initial rise in the levels of progesterone and estradiol followed by a decrease during the next 24 hours prior to oocyte pick-up (OPU). Subsequently a second rise in the level of progesterone takes place as ovarian steroidogenesis shifts from follicular to luteal phase. In contrast, the estradiol level continues to fall .After GnRHa trigger the circulating levels of progesterone and estradiol are significantly lower throughout the luteal phase as compared to those obtained after hCG triggering due to the shorter half-life of LH (~60 minutes) compared to that of hCG (>24 hours) .The important clinical advantage of GnRHa triggering, however, is the reported significant reduction in or even elimination of OHSS , 3 causeAs previously mentioned, the luteal phase after COS is defect due to supraphysiological steroid hormone concentrations inhibiting the LH secretion via negative feedback at the level of the hypothalamic-pituitary-gonadal-axis. As seen above the LH activity will be further compromised after GnRHa triggering due to the shorter duration of the endogenous induced LH surge and a potential weaker activation of the LH/hCG receptor. The result of this is a significant reduction in LH activity throughout the early/mid luteal phase leading to premature luteolysis and implantation failure .In contrast, after hCG triggering, the luteal actions of LH will be covered by the bolus of hCG injected and then gradually by the hCG produced by the implanting embryo. Thus, supplementation with progesterone is sufficient to secure the reproductive outcome. However, after GnRHa triggering the lack of endogenous LH activity necessitates a modification of the standard luteal phase supplementation currently used after hCG triggering , 3.The initial randomized controlled trials (RCTs) reported a poor clinical outcome with an extremely high early pregnancy loss rate (EPL) when GnRHa was used to trigger final ovulation, despite the use of standard LPS with vaginal progesterone and oral estrogen -11. The After the first disappointing results, trials were performed to explore the possibility of correcting the luteal phase by injecting a small bolus of LH activity in the form of hCG. HCG in standard doses would increase the risk of OHSS, but by supplementing with a reduced dose, the treatment was thought to be safe, even for the OHSS high risk patient. Therefore, trials were conducted to explore the hypothesis that a small hCG bolus could rescue the luteal phase without increasing the risk of OHSS , 12-15.Humaidan et al.  conducteFollowing this study, the question to ask was: does GnRHa triggering followed by a bolus of 1500 IU hCG in a group of patients at risk of OHSS reduce the OHSS incidence compared with hCG trigger? This question was explored in a more recent study by Humaidan et al. , includiNo OHSS cases were seen in the group at risk of OHSS after GnRHa triggering despite supplementation with 1500 IU hCG, compared to an incidence of 3.4% in the group at risk of OHSS triggered with hCG. In contrast, two late-onset moderate OHSS cases were seen in the OHSS low-risk group triggered with GnRHa followed by two boluses of 1500 IU hCG, versus no cases of OHSS after hCG triggering. The authors concluded that future trials should focus on the minimal hCG activity needed for LPS in the low risk group to secure the reproductive outcome without increasing the risk of OHSS. The safety of the LPS protocol was previously tested among 12 hyper responders (Using the same protocol, Radesic et al.  retrospeThese results were further corroborated by the conclusions of a recent international multicentre retrospective study. In this study Iliodromiti et al.  includedIn another effort to find the optimal dose of hCG necessary during the luteal phase after GnRHa triggering, Castillo et al.  reportedIn another retrospective analysis, Shapiro et al.  reportedFinally, Kol et al.  exploredIn conclusion, supplementation with hCG rescues the luteal phase after ovulation induction with GnRHa, resulting in reproductive outcomes similar to that of hCG. However, it still needs to be determined whether "dual-trigger", a single bolus of hCG or repeated low-doses of hCG is the best option. Regardless of the chosen protocol, it is crucial to individualize the luteal phase treatment with hCG according to the ovarian response to stimulation in an effort to reduce the risk of OHSS.An alternative way of increasing the LH activity during the insufficient luteal phase after GnRHa triggering would be to administer repeated doses of recombinant LH.This concept was explored in a proof-of-concept study performed by Papanikolaou et al. . The stuThe authors in this small group of normo-responder patients concluded that rLH effectively secures a good reproductive outcome after triggering with GnRHa without any OHSS development. The study was the first to assess the concept of applying repeated doses of rLH as LPS to overcome the luteal phase insufficiency after GnRHa triggering and the results seem promising. However, larger RCTs are necessary to draw conclusions about the safety and efficacy of this protocol. Furthermore, an obvious limiting factor for the use of rLH for LPS is the high cost of this preparation.As the standard LPS regimens turned out to be insufficient after GnRHa trigger , 11, US The first report was by Engmann et al.  who randThis protocol resulted in DR and EPL rates comparable to those of hCG triggering. Furthermore, the study reported a total elimination of OHSS after GnRHa triggering despite the fact that PCOS patients were included, many of which were at high-risk of developing OHSS after ovarian stimulation.An important question that needs to be explored is whether this protocol applies to normo-gonadotrophic patients. LH levels are significantly higher in PCOS patients during the follicular and luteal phases, due to a higher frequency and amplitude of the LH pulse. Further, in PCOS patients the hypothalamus has a reduced sensitivity to negative feedback from the ovarian steroid hormone concentrations, in particular progesterone . This leIn accordance with the results from Engmann et al.  and ShapAlthough the results seem promising in terms of the reproductive outcome and the total elimination of OHSS among OHSS high-risk patients, the study by Shapiro et al.  is obvioMoreover, there are some potential biases in the study by Engmann et al. . Thus, aImportantly, the abovementioned encouraging results are contrasted by others. In a previous study performed by Babayof et al.  28 PCO pThese findings are further supported by Orvieto  who repoAn alternative approach to encounter the luteal phase insufficiency seen after GnRHa triggering is to segmentate the IVF cycle, i.e. to stimulate in one cycle, trigger with GnRHa and transfer in subsequent frozen-thaw cycles. This seems to be a very safe approach for patients at risk of OHSS and recent trials suggest similar pregnancy rates between fresh and frozen-thawed embryos -22.The concept was recently explored in a RCT by Shapiro et al. including 177 patients . A blastTo extend the indication, Shapiro et al.  conducteIn summary, a freeze-all strategy further reduces the risk of OHSS and may be the best current option for patients with a very high risk of OHSS . HoweverMany recent publications indicate that the time has come for a paradigm shift in the triggering policy of ART. HCG has been the gold standard for ovulation induction, however, after the introduction of the GnRH antagonist protocol for the prevention of a premature LH rise, triggering of final oocyte maturation and ovulation with a single bolus of GnRHa is definitely an alternative.GnRHa triggering possesses important advantages over hCG triggering, mainly in terms of a significant reduction in-if not total elimination of OHSS. Following the initial disappointing clinical reports several subsequent studies implemented a modified luteal support in terms of supplementation with either LH activity or luteal steroids. Using the modified LPS, the reproductive outcome increased remarkably and is now comparable to that seen after hCG triggering. Although the modified LPS has had a significant positive effect on the reproductive outcome after GnRHa triggering without increasing the risk of OHSS, the most optimal LPS still has to be investigated.Until the optimal luteal supplementation protocol has been defined an alternative option in patients with an extreme ovarian response or with a significant comorbidity is a freeze all strategy and transfer in a subsequent natural or stimulated cycle.


Reports about standardized and repeatable experimental procedures investigating supraspinal activation in patients with gait disorders are scarce in current neuro-imaging literature. Well-designed and executed tasks are important to gain insight into the effects of gait-rehabilitation on sensorimotor centers of the brain. The present study aims to demonstrate the feasibility of a novel imaging paradigm, combining the magnetic resonance (MR)-compatible stepping robot (MARCOS) with sparse sampling functional magnetic resonance imaging (fMRI) to measure task-related BOLD signal changes and to delineate the supraspinal contribution specific to active and passive stepping. Twenty-four healthy participants underwent fMRI during active and passive, periodic, bilateral, multi-joint, lower limb flexion and extension akin to human gait. Active and passive stepping engaged several cortical and subcortical areas of the sensorimotor network, with higher relative activation of those areas during active movement. Our results indicate that the combination of MARCOS and sparse sampling fMRI is feasible for the detection of lower limb motor related supraspinal activation. Activation of the anterior cingulate and medial frontal areas suggests motor response inhibition during passive movement in healthy participants. Our results are of relevance for understanding the neural mechanisms underlying gait in the healthy. Sequentially coordinated periodic extension and flexion movements of the hips, knees, and ankles are common to a number of human locomotor movements, such as ground level walking, running or stair climbing. It is believed that the required sensorimotor control enabling these periodic movements is achieved by the interaction of proprioceptive feedback, the central pattern generators at the spinal level, and higher-level control signals from cortical and subcortical supraspinal centers  study reported significant signal increases in medial primary sensorimotor regions (M1/S1) and the supplementary motor area (SMA)  for investigating the supraspinal involvement in the control of upright gait. The results reported by the experiments in the erect posture using radiotracers, fNIRS or EEG are in strong agreement with the supraspinal activations found in fMRI experiments of the lower limbs, despite the absence of vestibular stimulation and body-balance in fMRI experiments due supine position of subjects during scanning. The accordance of findings across lower limb motor control experiments using different body postures and imaging modalities implies that supine fMRI experiments of the lower limbs provide information representative of gait-related brain activation. Using fMRI, active  or passive  single-joint movements of the ankle or the knee -compatible robot MARCOS enables such highly repetitive and controlled delivery of standardized active and passive, periodic, bilateral, multi-joint lower limb stepping movements that resemble human gait  to demonstrate the feasibility of a novel imaging paradigm, combining the MR-compatible stepper MARCOS with a sparse temporal sampling fMRI protocol and (b) to delineate the supraspinal contribution specific to active and passive bilateral, periodic, multi-joint, lower limb motor control in healthy participants. This should provide a framework for comparison for future studies involving neurologic patients with lower limb deficits.We hypothesize that the sparse sampling imaging protocol allows the detection of sensorimotor related cortical and sub-cortical activity in the brain, and that active control of bilateral periodic multi-joint lower limb movement elicits stronger activation of the sensorimotor network of the brain than does passive execution of the same movements.This study was approved by the Ethics Committee of the Canton of Zurich  and was conducted in accordance with the standards for research involving human participants defined by the Declaration of Helsinki. Before inclusion of participants it was ensured that they did not meet any of the following exclusion criteria: (1) neurological, musculoskeletal or cardiac dysfunction, (2) cardiac pacemaker, neuro-stimulator, or hearing aid, and (3) drug-abuse. All participants were informed about the aims and the course of the study and gave written consent for their participation. All data collection took place on the same scanner at the University Hospital of Zurich, Switzerland.SD 4 years). Further demographic information about the study sample can be found in Table Twenty-four healthy, right-handed and—footed  at ETH Zurich and is built from materials of low magnetic susceptibility . It is a one-degree-of-freedom robotic device actuated by two pneumatic cylinders per leg allowing predefined flexion and extension movements of each leg individually in the sagittal plane. The resulting movement resembles “marching on the spot” including rotation about the hip, knee and ankle joints. Proper function of the robot is continuously monitored by several redundant mechanisms to ensure subject safety. MR-compatibility of the system was established by Hollnagel et al. (www.pearltec.ch) around the head, were combined to firmly, yet comfortably, fixate the upper body and head of each participant  = 3.025 s]. The duration between the onsets of two imaging clusters was hence 19.075 s. Ninety three volumes in 31 clusters of 3 volumes were acquired, using a whole brain T2*-weighted, single-shot, echo planar imaging (EPI) sequence . Thirty five interleaved, angulated, transversal slices covering the whole brain were acquired in each volume .Imaging data were acquired on a whole body 1.5 Tesla Philips Achieva system  using an 8-channel SENSE . For each trial the mean stepping amplitude , mean stepping frequency, and the mean peak robot-participant interaction force at the knee (KF) and foot (FF) were computed. Trial means were averaged across the left and the right side since stepping of the left and the right leg was not significantly different . Then, trial means were averaged within each condition per participant. Each performance parameter characterizing active and passive stepping was then entered into a two-way analyses of variance (ANOVA) with the factors “trial” and “condition” to test for between-trial and between-condition effects. In addition, the root mean squared error (RMSE) for each parameter in each condition was calculated. For 95% of the measurements, the absolute deviation between a single measurement and its true value is expected to be less than the RMSE multiplied by 1.96  and force data, using custom routines written in Matlab 2012b  running on Matlab 2012b . For each run, the three volumes prior to the first “MOVE” block were discarded. The remaining 90 images were realigned to the mean image and unwarped to account for residual head motion related variance and image distortions along air-tissue boundaries ]   . The cluster threshold method was applied to control for the overall type I error. Anatomical correlates of clusters of activation were determined with the help of probabilistic cytoarchitectonic maps implemented in the Anatomy toolbox . Parameter estimates  and percent signal change were extracted from the following ROIs using the MarsBaR toolbox  were built from the functional activations of a conjunction analysis .p-values > 0.1). There was only a significant main effect of condition for maximal knee force  and maximal foot force  but not for movement amplitude and stepping frequency. RMSE values for all performance metrics were up to 5 times higher during active as compared to passive . This set of regions comprised an extended cluster of activated voxels covering the paracentral lobules, composed of bilateral medial M1/S1 areas .The correlation analysis between the ROI β-weights and the performance metrics did not yield any statistically significant correlations between the degree of brain activation and participant performance  Figure , Table 3The aims of the present study were (a) to demonstrate the feasibility of a novel imaging paradigm combining the MR-compatible stepper MARCOS with a sparse temporal sampling fMRI protocol, and (b) to delineate the supraspinal contribution specific to active and passive, bilateral, periodic, multi-joint, lower limb motor control in healthy participants. Our data revealed significant, task-correlated neural activation in a congruent set of regions in the sensorimotor network during active and passive stepping. The ROI-analysis demonstrated higher activation  of these regions for active than for passive stepping. No significant correlations between the degree of brain activation and participant performance were found.The present study yielded significant activation in cortical and sub-cortical bilateral sensorimotor areas including medial M1/S1, SMA proper, CMA, S2, cerebellar vermis and putamen associated with rhythmic, reciprocal active and passive stepping akin to human locomotion.Substantial overlap of neural activations in these areas between active and passive movements of the lower limbs has been reported in the past, both for unilateral ankle movements . Eight of the ROIs were defined using a conjunction of the contrasts active vs. baseline and passive vs. baseline  we cannot offer a concise physiological explanation. We suspect it to be produced by residual head movement , and thus, it occurred as the result of the spatial proximity of the olfactory cortex to the base of the skull, an area which is known to be susceptible to movement artifacts.Since EMG was not measured during task execution in the present study, it cannot be completely ruled out that some of the neural activity observed during passive movement is caused in part by involuntary muscle activation. However, a recent study by our group demonstrated that healthy participants are very well able to remain passive while MARCOS is moving their legs along the predefined trajectory . Additionally, it must be considered that the knee and the foot of each leg are mechanically coupled when participants are secured to the robot MARCOS. The target movement (flexion and extension of the whole leg) could theoretically be achieved through different strategies. The same movement can be realized with either emphasizing hip flexion/extension, and the activation of related muscles or alternatively by accentuating knee flexion/extension. This may have hence influenced the individual and group peak activations.The two-way repeated measures ANOVA of task performance  as recorded by the position and force sensors of the robot did not reveal a significant main effect of “trial” for any of the performance metrics in both movement conditions. It is therefore a valid claim that the motor paradigm presented in the current study enables repeatability within active and passive movement conditions. For the passive condition this was expected, since the movements of the lower limbs were brought about by the robotic device. As for the active condition the applied measures to limit knee movement amplitude and movement frequency have proofed to be feasible means to reach high between-trial repeatability.KF and foot FF) between active and passive stepping movements. From studies in the upper limbs it is known that the degree of brain activation may depend on the exerted force and movement amplitude  and a significant main effect of condition in movement dynamics  in the lower limbs, it would have been more intuitive to normalize knee movement amplitudes to individual leg segment lengths across participants. It can be assumed that joint angles rather than end effector positions in space are the variables controlled by and influencing the activity of the human motor system  as the device drove their knees up and down when producing the stepping pattern, while producing forces in the opposite direction when performing active stepping movements. Accordingly, higher mean FF were measured during active than during passive stepping (Δ = 16 N). There are currently only two studies investigating the influence of external axial loads to the lower limbs on supraspinal activation . Secondly, the T1-decay along the consecutive volumes may alter the contrast of EPI images potentially affecting the accuracy of the fMRI data preprocessing steps that depend on tissue contrast (Perrachione and Ghosh, Although our study investigated healthy participants, our findings may have direct implications for the management of gait impaired patients, for the development and application of robotic rehabilitative devices in the clinical setting, and for the monitoring of brain reorganization using standardized and repeatable experimental procedures over time.The activation of the sensorimotor network during passive movement of the participants' legs indicates that the ascending proprioceptive feedback from passive movement alone suffices to stimulate the same supraspinal cortical and sub-cortical sensorimotor areas as active movements, although to a lesser degree. The peripheral sensory cues produced by passive movement might be a suitable rehabilitation strategy for severely motor-impaired patients with very limited, or absent voluntary activation of their lower limb muscles, firing up the processes of brain reorganization and maintaining brain function in de-efferented patients. Furthermore, repeated passive movement allows the investigation of motor control related brain areas in these patients who cannot move their limbs. A possible issue with passive movement in gait rehabilitation however is, that patients with some residual voluntary activity might soon rely completely on the robot and lose their self-motivation for, and attention to the task if not challenged appropriately (Wolbrecht et al., We conclude that the combination of a clustered sparse temporal fMRI protocol with the MR-compatible stepper MARCOS is a feasible instrument for the standardized and repeatable investigation and detection of the neural correlates of active and passive, bilateral, lower limb stepping movements akin to human locomotion. Significantly higher activation of the sensorimotor network during active than during passive bilateral lower limb motor control may represent more than the mere monitoring of afferent proprioceptive input.Although our study investigated healthy participants, the presented paradigm should enable future work with neurologic gait-impaired patients in cross-sectional and longitudinal studies. Clinical rehabilitation studies combining gait training with standardized and repeatable neuro-imaging experiments of gait-like stepping may yield more accurate knowledge about effects of specific training strategies on supraspinal activation patterns and thereby support the development and application of novel approaches to motor rehabilitation.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Alzheimer’s disease (AD), which has emerged as one of the most common brain disorders, begins in the hippocampal formation and gradually spreads to the remaining brain at its most advanced stages, and is characterized partly by deposition of amyloid plaques in the brain tissue but also in the blood vessels themselves. Our studies have dealt with both the delivery of neurotrophic factors through the FUS-induced blood-brain barrier (BBB) opening to the hippocampus in both the presence and absence of disease in AD mouse models. The Brain-Derived Neurotrophic Factor (BDNF) is widely and abundantly expressed in the CNS and is available to some peripheral nervous system neurons that uptake the neurotrophin produced by peripheral tissues. BDNF can modulate neuronal synaptic strength and has been implicated in hippocampal mechanisms of learning and memory. As BDNF has been proven to serve as a neuroprotective agent, delivery of exogenous BDNF is a good candidate for therapeutic treatment of several CNS disorders.FUS at 1.5 MHz with in-house microbubbles of an average diameter of 4-5 mm was performed in transgenic AD mice. Two transgenic mouse models, the PS/APP and J20, were used, which are characterized by amyloid plaques and cognitive deficits, respectively.BDNF was injected following BBB opening. The BDNF bioactivity was assessed quantitatively by immunohistochemical detection of the pTrkB receptor and activated pAkt, pMAPK, and pCREB in the hippocampal neurons.BBB opening using FUS and microbubbles was found to have similar characteristics and follows similar timelines in AD mouse models as in wildtype mice. BDNF was found to trigger molecular pathways with the pTrkB, pMAPK and pCREB showing significant enhancement compared to the contralateral hemisphere (no FUS).Current efforts include demonstration of therapeutic efficacy of BDNF delivery in AD mouse models. Targeting of the hippocampus in non-human primates will also be shown.


Ni - Nickel; Cd - Cadmium; TL - Thallium; As - Arsenic; DEHP - Di-(2-ethylhexyl) phthalates; DBP - Di-n-butyl phthalates; AMF - Arbuscular mycorrhizal fungi; MHB - Mycorrhizal helping bacteria; PGPR - Plant growth promoting rhizobacteria; ↑ - Increased; ↓ - Reduced Pollution of water and soil with heavy metals highlights one of the most important public health threats. Soil and plants are polluted with heavy metals like nickel (Ni), cadmium (Cd), thallium (Tl) and arsenic (As) which mostly comes from the irrigation system, chemical industry, agrochemicals, and pesticides in the environment. The plant root signifies the first barrier to the selective accumulation of ions and heavy metals present in the soil. Kinetic data, uptake for nutrient ions and chemically related nonnutrient analogs suggest that metabolic processes associated with root absorption of nutrients regulate both rate of absorption and the affinity of specific nonnutrient ions. Differnet detailed kinetic studies of Ni, Cd, and Tl uptake by intact plants demonstrate multiphasic root absorption processes over a wide range of concentration . For exMicrobes present in the rhizoshperes region of soil play an important role in the phytoremediation of the metals . MostlyHowever, high concentration of heavy metals adversely effects the plant growth. As there are different role of heavy metals in the plant including their role as electron carrier, catalyzing enzymatic activities, in the redox reactions, and their presence in the structure of DNA and RNA. In addition, heavy metals also influence the functionality of enzymes as well as protein. The functionality, activity and permeability of plasma membrane of the plants are effected by heavy metals. The oxidative stress of heavy metals also influences the plants growth by production of reactive oxygen species .To overcome such problems, using different mechanisms that plants must be able to keep ions hemostasis in their tissue by detoxifying the adverse effects of heavy metals. The different strategies for the remediation of heavy metals and other trace elements are shown in Figure 1Oryza Sativa) field in California by Bais . UD1023ais (2006). Arseni14. UD102ais . This work is under study and the researchers want to determine the mechanisms involved in the slowdown of arsenic movement into the roots and also to the edible portion of the plants by the UD1023. Our idea about this bacterium is related to scientists achievement in future, when they will successfully find the mechanism, how it mobilize iron and diminish the uptake of not only arsenic but also other noxious heavy metals. Other need of the hour is that scientists should successfully modify the roots of the rice and other plants as well as the soil with this bacterium. Then it will be helpful in practical application in agriculture. Coating seeds with this bacterium will have great importance if we utilize the low cost approaches and easy implementation to take a negligible level of arsenic in the human food chain. And we are of the opinion that this approach might be helpful in confining the uptake of other metals like cadmium, lead and mercury.


Anti-neuronal autoimmune encephalitis (AIE) comprises a recently characterized group of immune-mediated disorders that result in limbic, multifocal, or diffuse encephalitis due to direct interaction of autoantibodies with neuronal surface or synaptic proteins. The pathological effects of the autoantibodies vary according to the target antigen but when they are removed, neuronal dysfunction is commonly reversed. Ongoing research on AIE constantly increases the number of novel autoantibodies and expands the spectrum of neurological syndromes that are important in the differential diagnosis of psychiatric illness, dementia, or viral encephalitis. This review summarizes recent advances in AIE, focusing on pathogenetic mechanisms and novel associations with other CNS disorders such as neurodegeneration, relapsing symptoms post-herpes simplex virus encephalitis, and demyelinating diseases. In addition, an algorithmic approach to detect and characterize neuronal cell surface autoantibodies is proposed. Antibody-associated neuronal autoimmune disorders are a heterogenous group of syndromes that result from an autoimmune reaction to neuronal antigens. These disorders can broadly be divided into two main groups: classic paraneoplastic neurological syndromes (PNS) that associate with autoantibodies to intracellular neuronal antigens  and autoimmune encephalitis (AIE) that associate with autoantibodies to neuronal surface or synaptic antigens . The PNSMost data on pathogenetic mechanisms associated with the neuronal cell surface autoantibodies focus on the NMDAR-antibodies found in patients with anti-NMDAR encephalitis. These autoantibodies recognize an extracellular, conformation-dependent epitope region close to aminoacid 369 of the GluN1 subunit of the NMDAR. The autoantibodies crosslink and internalize the NMDAR, which reduces the receptor density on the neuronal surface resulting in neuronal dysfunction . This prEach of the currently known neuronal cell surface or synaptic autoantibodies associates with a specific syndrome or limited set of symptoms Table . Anti-NMAn intriguing relation between autoimmunity and neurodegeneration has recently been discovered with the characterization of the IgLON5-antibody. These autoantibodies were detected in patients with prominent rapid-eye movement (REM) and non-REM-sleep dysfunction with abnormal behavior and movements, and brainstem symptoms with a chronic (or less frequently subacute) progressive disease course. Autopsy of two patients revealed deposits of tau that mainly affected neurons of the hypothalamus, thalamus, and brainstem. Although these findings suggest a link between IgLON5-antibodies and tau aggregation, it remains to be elucidated whether the autoantibodies are pathogenic or only an epiphenomenon . With thDifferent techniques are available for the diagnosis of neuronal cell surface antibodies: tissue-based assays , cell-based assay , primary cultures of neurons (in-house), and immunoprecipitation . In the TBA, rat or mouse brains are stained with CSF or serum of patients with an indirect immunhistochemistry or immunofluorescence technique. Anti-neuronal antibodies attach to their receptor or synaptic antigen in the rodent brain, resulting in a neuropil staining pattern in the hippocampus. In the CBA, cells  are transfected with the respective surface receptor or synaptic antigen and stained with CSF or serum of the patients with an indirect immunofluorescence technique. Autoantibodies against the specifically expressed receptor result in a membrane staining of the cells. Primary cultures of hippocampal neurons are stained with CSF or serum of patients with an indirect immunofluorescence technique and the autoantibodies are visualized as surface staining of neurons. In the IP, autoantibodies that are present in serum of patients bind to a specific antigen, the antigen–antibody complex is precipitated out of solution and measured.Most laboratories use the CBA for the diagnosis of neuronal cell surface autoantibodies, which is a highly sensitive and specific assay but bears the disadvantage that new autoantibodies are not detected. The TBA provides an excellent screening method, which detects most of the currently known neuronal cell surface autoantibodies (with some limitations for the GlyR- and D2R-antibodies) and can reveal new autoantibodies. To reach a maximum of sensitivity and specificity, a combination of TBA as screening method and CBA as confirmatory test may be considered Figure A. StainiThe sensitivity and specificity of serum and CSF testing has only been investigated in a few AIE, mainly anti-NMDAR encephalitis. While at the time of diagnosis of this disease autoantibodies are always present in CSF, the serum can be negative in up to 14% of patients, suggesting that serum examination alone may be insufficient to exclude AIE . On the Consecutive dilution steps of serum or CSF in TBA or CBA can be used to determine autoantibody titers (the endpoint where staining is still visible is indicated as the respective titer). The relation between autoantibody titers, relapses, and outcome was extensively investigated for anti-NMDAR encephalitis . For exaA recent study characterized CXCL13 as a potential biomarker for anti-NMDAR encephalitis. The CXCL13 is a cytokine produced by plasma cells and monocytes/macrophages. Seventy percent of patients with new onset of anti-NMDAR encephalitis had elevated CXCL13 levels in the CSF. Prolonged elevation of CSF CXCL13 (4–6 weeks) was an indicator of limited response to therapy suggesting that these patients could be candidates for more aggressive immunotherapy .The CNS is an immune-privileged organ, protected by the blood–brain barrier. Recognition of a specific antigen during immune surveillance results in the activation of inflammatory cells and release of inflammatory cytokines and chemokines that alter tissue barrier and initiate inflammation. Antigens such as neuronal membrane antigens do not activate the immune system under physiological conditions, but if activation is induced elsewhere, they can become targets for an autoimmune attack. A number of mechanisms were identified that could account for breaking immune tolerance in AIE Table .One possible trigger factor of AIE is the presence of a systemic tumor that expresses the neuronal antigen and studies have identified the expression of the targeted receptor subunit in the tumors of patients with anti-NMDAR, AMPAR, and GABA(B)R encephalitis , 5, 7. TAround 20% of patients with herpes simplex virus encephalitis (HSVE) have relapsing symptoms without evidence for viral reactivation . These episodes often manifest as choreic-like movements  accompanied by behavioral changes and were considered as immune-mediated. Recent studies found autoantibodies to the NMDAR, D2R, and other cell surface or synaptic proteins (antigens still unknown) in some of these patients, suggesting that HSVE may be a trigger for AIE . The preIn a considerable percentage of patients with AIE, the triggering factor remains unknown. Studies on different AIE established a marked predominance in females, suggesting a hormonal component of the disease although this may relate more to the known increased rate of autoimmunity in women. Genetic determinants likely contribute to susceptibility to autoimmunity. For example, specific alleles of HLA-DQB1 and HLA-DRB1 were preferentially found in patients with IgLON5-antibodies . PatientRecent neuroimmunological studies have provided fundamental insights into disease pathogenesis of AIE and explanations for the wide spectrum of syndromes. The mechanisms by which autoantibodies interfere with synaptic transmission are diverse but all share the potential reversibility of the dysfunction, explaining in part the good recovery of many patients after immunotherapy. These disorders result in different clinical phenotypes and their description has led to novel associations with other CNS diseases  making these patients an interdisciplinary challenge for treating physicians. Neuronal cell surface autoantibodies when tested appropriately are highly sensitive and specific diagnostic markers for AIE and have important implications for treatment decision and long-term patient management. Recognition of the specific AIE is important as these disorders may have different co-morbidities or associated tumors that need to be considered in the overall management of the patients.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Monoclonal Antibodies (mAbs) comprise a class of therapeutic biologics that has been increasingly used over the last decades. The concept of using antibodies to selectively target tumors was proposed by Paul Ehrlich over a century ago . The devAntibodies can trigger direct effects on tumor growth causing apoptosis or inhibition of proliferation, they can also mediate immune effector functions. The first antibodies used in the clinic were of murine origin. Due to their immunogenicity in humans and poor ability to induce human immune effector responses, they exhibited limited clinical applicability. Chimeric, humanized and fully human monoclonal antibodies have now been developed to address these problems. Chimeric antibodies are encoded by genes from more than one species, usually with antigen-binding regions from mouse genes and constant regions from human genes, while humanized antibodies are genetically engineered mouse antibody in which the protein sequence has been modified to mimic that of human antibodies . AntibodCancer cells express various cell surface receptors that activate intracellular pathways leading to growth. Amongst these, EGFR or ErbB1, ErbB2 or HER-2/Neu, HER-3 and HER-4 are of the same family and are overexpressed in epithelial malignancies originating from the colon, breast, lung and head and neck resulting in rapidly proliferating disease and increased metastatic potential. Anti-EGFR antibodies bind to the receptor domain of the EGFR receptor inhibiting the downstream activation of the receptor and increasing receptor internalization. These antibodies can inhibit the cancer cell cycle leading to apoptosis. In addition, the combination of antibodies with chemotherapy enhances the activity of chemotherapy. AntiHER-2 antibodies promote receptor internalization and cell cycle arrest. Anti-HER2 antibodies can also block heterodimer formation between HER-2 and HER-3 or HER-4 providing an additional mode of action [in vivo antitumor effects of certain monoclonal antibodies in murine models and clinical trials. The antitumor activities of trastuzumab and rituximab have been shown to be lower in FcgR -deficient mice than wild-type mice, for example [This mechanism results in the immune-mediated destruction of the cancer cells that are coated by antibodies. The effector cells in the antibody-dependent cytotoxicity include macrophages, NK cells and neutrophils. ADCC depends on the Fc portion of the antibody that binds a Fc gamma receptor (FcgR) on the effector cells. ADCC occurs when the Fab and Fc portions of the mAb engage both tumor cell antigen and an activating FcgR, respectively, thus creating a bridge from the tumour cell to the effector cell. Target cell recognition is then coupled to a lytic attack on the target cell mounted by effector cells. Several studies have established the importance of FcgR interactions for the  example . The rol example .CDC results from a cytolytic cascade mediated by a series of complement proteins, resulting in lysis of the antibody-bound cell . AntibodAntibodies can bind to circulating proteins and interfere with their ability to find their targets to help facilitate growth of the tumors. One important example of this mechanism is bevacizumab which is a fully humanized monoclonal antibody against VEGF-A. Bevacizumab binds and inactivates the biological activity of VEGF-A, inhibiting angiogenesis and thus, tumor growth and proliferation . SiltuxiCytotoxic agents can be linked to tumor targeted monoclonal antibodies with the aim of delivering them specifically to the tumors cells . This apSeveral antibodies have been approved by the FDA for the treatment of a variety of solid tumors and hematological malignancies Table . TherapeThere are multiple therapeutic and diagnostic antibodies that are currently under testing or development . The curThe number of monoclonal antibodies that have been approved or are in development for cancer treatment has been steadily increasing over the last years. Because of their high target specificity, generally low toxicity and the ability to activate the immune system, the use of therapeutic antibodies for cancer treatment is very promising. They currently provide clinical benefit to patients with cancer and have been established as 'standard of care' agents for several tumor types. Advances in the identification and validation of new targets, manipulation of tumor-host microenvironment interactions, and optimization of antibody structure to promote anti-tumor immune responses will generate many new treatments for cancer over the next decade.