Restoring endodontically treated teeth is one of the major treatments provided by the dental practitioner. Selection and proper use of restorative materials continues to be a source of frustration for many clinicians. There is controversy surrounding the most suitable choice of restorative material and the placement method that will result in the highest probability of successful treatment. This clinical study compares two different varieties of fiber posts and one cast post and core in terms of mobility of crown margin under finger pressure, recurrent caries detected at the crown margin, fracture of the restoration, fracture of the root and periapical and periodontal pathology requiring crown removal over the period of 12months as evaluated by clinical and radiographical examination.30 root canal treated, single rooted maxillary anterior teeth of 25 patients in the age range of 18–60 years where a post retained crown was indicated were selected for the study between January 2007 and August 2007; and prepared in a standard clinical manner. It was divided into 3 groups of 10 teeth in each group. After post space preparation, the Carbon fiber and Glass fiber reinforced posts were cemented with Scotch bond multipurpose plus bonding agent and RelyX adhesive resin cement in the first and second groups respectively. The Cast post and cores were cemented with Zinc Phosphate cement in the third group. Following post- cementation, the preparation was further refined and a rubber base impression was taken for metal-ceramic crowns which was cemented with Zinc Phosphate cement. A baseline periapical radiograph was taken once each crown was cemented. All patients were evaluated after one week (baseline), 3 months, 6 months and one year for following characteristics mobility of crown margin under finger pressure, recurrent caries detected at the crown margin, fracture of the restoration, fracture of the root and periapical and periodontal pathology.th month recall but all the cases of glass fiber post with composite core restorations did not show any signs of mobility of crown margin under finger pressure at all the recall periods on clinical and radiographical examination.Results after 12 months showed that none of the restorations among groups of cast post and core, carbon fiber reinforced post and glass fiber reinforced post with composite core restorations failed in terms of recurrent caries detected at the crown margin, fracture of the restoration, fracture of the root and periapical and periodontal pathology. One case of cast post and core and one case of carbon fiber reinforced post with composite core restorations showed slight mobility of crown margin under finger pressure at 12From this 12 months clinical evaluation of all the cases in the 3 groups comprising of cast post and core; carbon fiber reinforced post with composite core and glass fiber reinforced post with composite core restored with porcelain fused to metal crowns, it is concluded that glass fiber reinforced post with composite core when used in single rooted upper anterior teeth are associated with a higher success rate in restoration of endodontically treated teeth. Root-filled anterior teeth have traditionally been restored with cast or wrought metal posts and cores. Some researchers have suggested that as these metallic materials have much higher moduli than that of the supporting dentine, this mismatch in the moduli could lead to stress concentrating in the cement lute, leading to its failure. This has led to a search for a plastic-based material that has a modulus closer to that of dentine.Recently, several new types of post material have been introduced, including carbon fiber, glass fiber etc.Carbon fiber has certain properties that make it potentially useful in dentistry. It is biocompatible, corrosion-resistant, and strong. Most reports of the potential uses of carbon fiber in dentistry are limited to the reinforcement of existing restorative materials and as possible post material. The carbon fiber post is reported to have a modulus of elasticity that is nearly identical to that of dentine, so that it causes less tooth stress and hence, fewer root fractures. By comparison, the moduli of elasticity for stainless steel and titanium are roughly 20 and ten times greater than dentine's respectively. Posts with high moduli of elasticity do not flex with the tooth under loading, and are empirically believed to cause root fracture.[The use of carbon fiber posts, preformed metallic posts, and/or custom-cast metallic casts in the anterior region has been reported to result in unsatisfactory aesthetics. As a result, aesthetic fiber posts have become more popular. They are also well accepted because of their favorable physical properties and biocompatibility. Aesthetic fiber posts can be bonded within root canal spaces with polymer dentine-bonding agents and resin cements of similar flexibility. They effectively transmit stresses between the post and the root structure, thus reducing stress concentration and preventing fracture.Glass fiber-supported resin dowel systems were introduced in 1992. The dowels are composed of unidirectional glass fibers embedded in a resin matrix that strengthens the dowels without compromising the modulus of elasticity. Another advantage of glass fibers is that they distribute stress over a broad surface area, increasing the load threshold at which the dowel begins to show evidence of microfractures. Fiber-reinforced dowels are reported to reduce the risk of tooth fractures and display higher survival rates than teeth restored with Zirconia dowels.This study reports a prospective clinical trial comparing the success rate of carbon fiber-reinforced carbon (CFRC) endodontic posts and glass fiber-reinforced posts with cast posts and cores.Patients reporting to the Department of Conservative Dentistry and Endodontics for regular treatment in the Government Dental College and Research Institute, Bengaluru, were selected for the study. The study was conducted in accordance with all the local regulations for the ethical treatment of human subjects.The median age of the patients was 30.1 years, while the range was 18–60 years.The selection criteria for inclusion in the study were:Single-rooted maxillary anterior teeth where a post-retained crown was clinically indicated.All teeth should have adequate root filling with no evidence of any periapical pathology, perforation, or root fracture.The periodontium was examined using a Williams probe using four probing sites per tooth, and patients were only included in the trial when the periodontium was stable with no evidence of bleeding on probing and a minimum of 75% bone support.Teeth with pulpal and periapical pathosis and those that could be potential abutments for fixed or removable prostheses were excluded.Patients were excluded if there was a lack of adequate posterior support, defined as the absence of all molar teeth, or if there was any obvious occlusal interference or fremitus affecting the tooth to be restored.Twenty-five patients with the chief complaint of fractured maxillary anterior teeth were enrolled for this clinical study. Thirty root canal treated teeth in 25 patients were divided into three groups of ten teeth each:Group I consisted of ten cases restored with cast posts and cores.Group II consisted of ten cases restored with carbon fiber-reinforced posts and composite resin cores.Group III consisted of ten cases restored with glass fiber-reinforced posts and composite resin cores, followed by a full coverage restoration  from January 2007 to August 2007.Excess guttapercha was removed from the root canal using heated instruments and gates glidden drills. This was followed by space preparation by using increasing sizes of peeso reamers. A minimum apical seal of 5 mm of guttapercha filling was retained in the apical root portion. The teeth were prepared in a standard clinical manner with rotary instruments by a single operator. The root canal was then dried and lubricated with petroleum jelly. The wax pattern was fabricated for the post and core using inlay wax, and then forwarded to the laboratory for casting. The finished and polished cast post and core made of nickel-chromium alloy was then cemented into the canal using zinc phosphate cement. Following cementation of the post, the preparation was further refined and polyvinyl siloxane putty and light body impressions were taken for the laboratory construction of porcelein-fused to-metal crowns. The crown was cemented with zinc phosphate cement.The guttapercha was removed to maintain a 4–5 mm apical seal. The canal was accessed and irrigated with a solution of EDTA and sodium hypochlorite. The length of the post in the canal was determined and marked and the trimmed post was replaced in the canal to confirm its length. The prepared canal was etched with 37% phosphoric acid and after 15 seconds, the etchant was gently rinsed with water and dried with paper points. An adhesive primer and bonding agent (scotch bond multipurpose plus) was applied to the canal and an adhesive resin cement, Rely-X, was dispensed into the canal. The endodontic post was seated in the canal and the adhesive resin cement was light-cured for 60 seconds. The core was established with the successive addition of composite resin; the completed core build-up permitted prosthetic preparation. The core and the adjacent preparation were recorded in a rubber base impression material and the shade was selected, all of which were forwarded to the laboratory. Porcelain-fused-to-metal crowns were fabricated and the crowns were then cemented with zinc phosphate. An intraoral periapical radiograph was taken after each crown had been cemented. Patients were educated about oral hygiene and motivated to use proper brushing techniques.All patients were evaluated after one, three, and six months, and one year's interval. A periapical radiograph of each tooth was taken at each recall and an outline of clinical performance was recorded. Success or failure of the restorative tooth complex was evaluated clinically and radiographically, which was judged to have failed if each post crown satisfied one or more of the following criteria:Movement of the crown margin under finger pressureRecurrent caries detected at the crown marginFracture of the restorationFracture of the rootPeriapical or periodontal pathology requiring crown removalThe success rate of the restoration was then evaluated statistically.One cast post and core restoration showed signs of movement of the crown margin with the application of finger pressure at the one year recall point; the success rate was 90% . One of None of the restorations of cast posts and cores, carbon fiber-reinforced posts with composite cores, or glass fiber-reinforced posts with composite cores exhibited any recurrent caries at the various time intervals; thus, the success rate of 100% .None of the restorations of cast posts and cores, carbon fiber-reinforced posts with composite cores, or glass fiber-reinforced posts with composite cores exhibited any signs of fracture of the restoration on clinical and radiographic examinations at the various time intervals, thus, the success rate was 100% .None of the restorations of cast posts and cores, carbon fiber-reinforced posts with composite cores, or glass fiber-reinforced posts with composite cores exhibited any signs of fracture of the root on clinical and radiographic examinations at the various time intervals, thus, the success rate was 100% .None of the restorations of cast posts and cores, carbon fiber-reinforced posts with composite cores, or glass fiber-reinforced posts with composite cores exhibited any signs of periapical or periodontal pathology upon clinical and radiographic examinations at the various time intervals, thus, the success rate was 100% .The restoration of endodontically treated teeth with fiber-reinforced post systems has been drawing the attention of a growing number of clinicians. The progress in the technology of fiber-reinforced materials addressing the structure, shape, and optical properties of the posts has led to the development of materials that have overcome some of the limitations of metallic posts  concerning aesthetic appearance, mode of failure, and clinical performance.Restorations involving endodontic posts have been investigated in quite a few clinical studies in which the causes of failure have been recorded. From these studies, it appears that the main causes of failure were identified as: caries, loss of retention of the post, loss of retention of the crown, root fracture, post distortion, and post fracture.e.g., the design, length and thickness of the post, the ferrule effect, cementation, and the quantity of the remaining tooth substance. Many in vitro studies have shown that fiber-reinforced composite posts might possess some benefits over metal posts due their moduli of elasticity being closer to that of dentine. This phenomenon of 'modulus compensation of stress-induced root fractures' could have an impact on the post-core-crown restorations in the future. However, it should be noted that the modulus of the material is only one parameter influencing stress formation. Among others, the diameter of the post should also be taken into account.[Clinically, it is well established that the longevity of root-post-core-crown systems used to restore an endodontically treated tooth is affected by many factors,  account.	et al. carried out an in vitro comparison of carbon fiber with conventional cast posts and found that no root fractures were associated with carbon fiber posts, whereas with cast posts, 50% of the teeth had root fractures.[Dean ractures.In studies on the retention of carbon fiber-reinforced composite posts, luting procedures have been reported as the critical point, with failures occurring at the post-cement and post-core junctions. Moisture and water contact are problems to all resin-based systems, inducing hydrolysis and degradation of the organic matrix. As the matrix swells due to water or thermal changes, hydrothermal stresses are induced at the fiber/matrix interface that can result in debonding and/or matrix cracking, which facilitates further water absorption.A retrospective study of 236 patients evaluated the treatment outcome of teeth restored with the composipost system (carbon fiber-reinforced epoxy resin posts). Out of the 236 teeth restored with carbon fiber-reinforced epoxy resin posts, neither clinical nor radiographic examination revealed any dislodgement or root or post fractures. Promising results after 2–3 years of clinical service indicate that this system can be a viable alternative to conventional post-and-core systems.in vivo study, the patients were given oral hygiene instructions, which could have affected their motivation levels. This, in turn, would have had an effect on the absence of recurrent caries in all the three groups.Three factors influence the durability of restorations against recurrent caries: patients' caries activity, the quality of treatment provided, and the cariostatic effects of the restorative material. In the present clinical or in-vitro study by Arturo Martinez-Insua et al., who compared the fracture resistance of two types of restorations: teeth restored with prefabricated carbon-fiber posts and composite cores to cast dowel-core restored teeth, concluded that significantly higher fracture thresholds were recorded for the cast post and core group. Teeth restored with carbon-fiber posts and composite cores typically showed failure of the post/core interface before the fracture of the tooth occurred. This failure occurred in response to acceptably high loads. By contrast, teeth restored with cast posts and cores typically showed fracture of the tooth, albeit in response to loads that rarely occur in vivo.[According to the  in vivo.et al. compared the in vitro fracture strength of metallic and tooth-coloured posts and cores. Typical failure of the metal systems was marked by loosening of the bonding and pulling out of the posts in contrast to fracture of the ceramic posts. The study showed sufficient fracture strengths in all-ceramic systems and better fracture strength in posts with composite cores in comparison to gold post and core systems.Rosentritt Coronal microleakage is a major cause of endodontic failure. Saliva and organisms from the mouth migrate rapidly alongside poorly adapted restorations and even root fillings that appear well condensed. The periradicular tissues will be inflamed by such reinfection and the reactivation of micro-organisms lying dormant after initial treatment. A well sealing coronal restoration is therefore critical to endodontic success.In this one year, clinical evaluation of all the cases in the three groups comprising of cast posts and cores, carbon fiber-reinforced posts with composite cores, and glass fiber-reinforced posts with composite cores restored with porcelain-fused-to-metal crowns at one, three, and six months, and one year recall visits showed that glass fiber-reinforced posts with composite core restorations resulted in the highest success rate. The cast post and core restorations and carbon fiber-reinforced posts with composite core restorations showed 10% failure rates with relation to movement of the crown margin under finger pressure. With respect to recurrent caries detected at the crown margin, fracture of the restoration, fracture of the root, and periapical or periodontal pathology requiring crown removal, all the cases of cast posts and cores, carbon fiber-reinforced posts with composite cores, and glass fiber-reinforced posts with composite cores restored with porcelain-fused-to-metal crowns showed 100% success rate at all the recall visits up to 12 months.From this clinical evaluation over a period of one year of all the cases in the three groups comprising of cast posts and cores, carbon fiber-reinforced posts with composite cores, and glass fiber-reinforced posts with composite cores restored with porcelain-fused-to-metal crowns, it can be concluded that when used in single-rooted, upper anterior teeth, glass fiber-reinforced posts with composite core are associated with a higher success rate in the restoration of endodontically treated teeth.


Novel cardiovascular magnetic resonance (CMR) techniques and imaging biomarkers are often validated in small animal models or empirically in patients. Direct translation of small animal CMR protocols to humans is rarely possible, while validation in humans is often difficult, slow and occasionally not possible due to ethical considerations. The aim of this study is to overcome these limitations by introducing an MR-compatible, free beating, blood-perfused, isolated pig heart model for the development of novel CMR methodology.6 hearts were perfused outside of the MR environment to establish preparation stability. Coronary perfusion pressure (CPP), coronary blood flow (CBF), left ventricular pressure (LVP), arterial blood gas and electrolyte composition were monitored over 4 hours. Further hearts were perfused within 3T (n = 3) and 1.5T (n = 3) clinical MR scanners, and characterised using functional (CINE), perfusion and late gadolinium enhancement (LGE) imaging. Perfusion imaging was performed globally and selectively for the right (RCA) and left coronary artery (LCA). In one heart the RCA perfusion territory was determined and compared to infarct size after coronary occlusion.All physiological parameters measured remained stable and within normal ranges. The model proved amenable to CMR at both field strengths using typical clinical acquisitions. There was good agreement between the RCA perfusion territory measured by selective first pass perfusion and LGE after coronary occlusion (37% versus 36% of the LV respectively).This flexible model allows imaging of cardiac function in a controllable, beating, human-sized heart using clinical MR systems. It should aid further development, validation and clinical translation of novel CMR methodologies, and imaging sequences. Coronary artery disease (CAD) with subsequent myocardial infarction and heart failure constitutes a leading cause of death in the western world . MyocardCardiovascular magnetic resonance (CMR) is being used increasingly in the diagnosis and assessment of CAD as it has the unique capability of assessing myocardial function, viability and perfusion in one session . It alsoNovel CMR techniques and imaging biomarkers are often validated in small animal models or empirically in patients. Direct translation of small animal CMR imaging protocols to humans is rarely possible. On the other hand, validation of novel imaging techniques in humans, for example quantitative perfusion, novel sequences, optimized contrast agent injection schemes or responses to alterations of blood flow requires large patient populations and is occasionally not possible for ethical reasons.In order to observe cardiovascular physiology and pathophysiology in a controlled fashion, complex experimental models are necessary to mimic the human situation as closely as possible. The porcine heart closely resembles the human heart from the point of view of size, physiology and anatomy and consequently pigs are frequently used for in vivo cardiovascular research .Oscar Langendorff introduced a model of retrograde perfusion of mammalian hearts via the Aorta with Krebs Henseleit solution in 1895 -12.in situ physiological cardiac function ex vivo . Thi. Thi8]. Despite making the system MR compatible we were able to keep the short tubing and the small volume of the circuit. This is important as it allows the use of a mixture of autologous blood and crystalloid solution with near normal haematocrit and haemoglobin without the need for donor or support animals. Perfusion with blood leads to more stable function and less oedema compared to crystalloid solution perfusion .The main disadvantages of this model are the less physiological environment compared to in vivo experiments, the ischaemic period after heart removal and the high associated costs.For studies of myocardial perfusion rapid recirculation of contrast is prevented in the current model. This is an oversimplification of in vivo conditions but allows for repeated perfusion scans. In addition contrast arrival time was longer compared with in vivo as a consequence of distribution and dilution in the inflow-tubing. Whether this influences quantitative perfusion analysis with CMR needs to be investigated.As this was a feasibility study we did not perform metabolic assessment of the 6 hearts we perfused in the magnets. Therefore stable physiological function was assumed on the basis of the previously performed validation experiments. Future trials aiming to answer specific questions need to include metabolic measurements relevant to the nature of the hypothesis and to assure stable, robust and reproducible conditions for the specific scientific question.We performed a proof of concept study to demonstrate the feasibility of the model in the MR environment and thus we did not perform systematic statistical analysis.The current work demonstrates for the first time the feasibility of operating and imaging an isolated beating porcine heart preparation in a clinical MR scanner. The technical design of this isolated pig heart model allows ex vivo simulation and imaging of cardiac function. This novel system provides excellent control of physiological parameters and allows validation of novel techniques against gold standards and easy translation of the methods to patients using identical equipment and imaging sequences.Tobias Schaeffter served as a Consultant to Philips Healthcare. Eike Nagel received minor consultancy fees from GE and Philips Healthcare and minor speaker honoraria from GE, Philips Healthcare, and Bayer Schering Pharma. The other authors declare that they have no competing interests'.AS carried out the perfusion studies, designed and implemented the MR compatible model and drafted the manuscript. IG carried out the perfusion studies and substantially contributed to the design of the MR compatible model. AC carried out the perfusion studies, designed and implemented the MR compatible model. RS participated in the design of the MR compatible model and helped with the perfusion studies. MI helped with the perfusion studies, and participated in the study design. GH and NN helped with the perfusion studies. GM and DP participated in the study design and helped to draft the manuscript. TS participated in the sequence alignment and helped to draft the manuscript. EN designed and implemented the MR compatible model and drafted the manuscript. All authors read and approved the final manuscript.


Secondary hyperparathyroidism (sHPT) is common in patients with chronic renal failure. Despite the initiation of new therapeutic agents, several patients will require parathyroidectomy (PTX). Total PTX with autotransplantation of parathyroid tissue (TPTX+AT) and subtotal parathyroidectomy (SPTX) are currently considered as standard surgical procedures in the treatment of sHPT. Recurrencerates after TPTX+AT or SPTX are between 10% and 12% (median follow up: 36 months).Recent retrospective studies demonstrated a lower rate of recurrent sHPT of 0–4% after PTX without autotransplantation and thymectomy (TPTX) with no higher morbidity when compared to the standard procedures. The observed superiority of TPTX is flawed due to different definitions of outcomes, varying follow up periods and different surgical treatment strategies (with and without thymectomy).Patients with sHPT  on long term dialysis (>12 months) will be randomized either to TPTX or TPTX+AT and followed for 36 months. Outcome parameters are recurrence rates of sHPT, frequencies of reoperations due to refractory hypoparathyroidism or recurrent/persistent hyperparathyroidism, postoperative morbidity and mortality and quality of life. 50 patients per group will be randomized in order to obtain relevant frequencies of outcome parameters that will form the basis for a large scale confirmatory multicentred randomized controlled trial.sHPT is a disease with a high incidence in patients with chronic renal failure. Even a small difference in outcomes will be of clinical relevance. To assess sufficient data about the rate of recurrent sHPT after both methods, a multicentred, randomized controlled trial (MRCT) under standardized conditions is mandatory.Due to the existing uncertainties the calculated number of patients necessary in each treatment arm (n > 4000) makes it impossible to perform this study as a confirmatory trial. Therefore estimates of different outcomes are performed using a pilot MRCT comparing 50 versus 50 randomized patients in order to establish a hypothesis that can be tested thereafter.If TPTX proves to have a lower rate of recurrent sHPT, no relevant disadvantages and no higher morbidity than TPTX+AT, current surgical practice may be changed.International Standard Randomized Controlled Trial Number Registration (ISRCTN86202793) Secondary hyperparathyroidism (sHPT) is common in patients with chronic renal failure, affecting most of those who are receiving hemodialysis ,2. OveraRenal insufficiency leads to a reduced synthesis of 1,25-dihydroxy-Vitamin D secretion and a decrease in phosphate excretion resulting in hypocalcemia and hyperphospatemia. Consecutively, parathyroid hormone secretion and parathyroid cell hyperplasia increases. With time, sHPT is characterized by persistently elevated levels of intact parathyroid hormone (PTH) above the desired target range recommended by the Kidney Disease Outcomes Quality Initiative (KDOQI ) and comHowever, several reports indicate, that alterations in calcium and phosphorus metabolism, as a result of either sHPT or the therapeutic measures used to manage it, contribute to soft-tissue and vascular calcification, cardiovascular disease, and the risk of death -12.Episodes of hypercalcemia and hyperphosphatemia are often aggravated by the use of calcium as a phosphate-binding agent, particularly in combination with Vitamin D sterols, which increase the absorption of calcium and phosphorus -15. ReceDespite the advent of these new therapeutic agents, patients with long-standing sHPT often require parathyroidectomy. The indication for surgery depends on clinical symptoms of progressive renal osteopathy and impaired calcemic response following PTH secretion in the absence of Vitamin D deficiency: either if hypercalcemia develops (spontaneously or under treatment with Vitamin D), if the new therapeutic modalities fail to control sHPT or if medical therapy has to be adjourned because of adverse reactions. However, the rate of parathyroidectomies (PTX) did not change significantly between 1991 and 2001 despite the progression in medical therapy with phosphate binders and Vitamin D analogues .Overall PTX is required in about 20% of patients after 3–10 years of dialysis and up to 40% after 20 years ,25.Three different surgical procedures are reported in the literature following the first PTX for secondary HPT in 1960 : subtotaHowever, both procedures leave a fragment of activated, proliferated parathyroid tissue, though at different sites. Since the pathophysiological condition of chronic renal failure and maintenance dialysis continues, the growth stimulus persists and may cause recurrent sHPT at the site of the remnant. Although relapse of HPT has been observed at different intervals after initial surgery, it is quite clear that the incidence of recurrent disease increases with time ,38. A wiThe site of recurrence in patients after TPTX+AT is located in approximately 80% at the graft Figure  and in 2Graft-dependent recurrent sHPT after TPTX+AT can easily be cured by excision of the parathyroid autotransplant under local anaesthesia. If an operation is necessary for recurrent sHPT after subtotal PTX, reexploration of the neck is mandatory in all patients including the necessity of general anaesthesia and the increased risk of recurrent laryngeal nerve palsy . TherefoTotal parathyroidectomy without autotransplantation and without routinely performed thymectomy (TPTX) may provide an alternative strategy to the currently performed procedures mainly because of the reported lower rate of recurrent sHPT of 0–4% during long-term follow up ,36. PatiOne explanation for the absence of serious adverse events may be that thymectomy was not performed on a regular basis. The inferior parathyroid glands and the thymus derive together from the third pharyngeal pouch. Even in case of resection of all four parathyroid glands (TPTX) residual microscopic parathyroid tissue or supernumerary glands may be located in the thymus preventing the patients to develop hypoparathyroidism and its sequelae ,40,53-56The objective of this trial is to compare the different outcomes of two different surgical strategies (TPTX+AT+ versus TPTX) for secondary hyperparathyroidism over a three-year follow-up period.Reducing the risk for recurrent sHPT is an important factor for the patients and the health care system, as surgery for recurrent sHPT is associated with high costs for localization, a lesser cure-rate and a higher morbidity when compared to intial parathyroidectomy . All attFurther more, TPTX without parathyroid autotransplantation and without thymectomy is associated with a reduced operating time when compared to TPTX+AT thus leading to reduced costs when compared to TPTX+AT.To date, no prospective, randomized study exists comparing TPTX to the standard surgical procedures. The existing evidence of the potential superiority of TPTX regarding the recurrence rate is flawed due to mainly methodological problems of studies with different definitions of outcomes, varying follow up periods, different surgical treatment strategies (with and without thymectomy) and their retrospective design. Therefore bias and chance are not sufficiently controlled and the results of the present studies have to be interpreted with caution.The difference observed between the rates of recurrent sHPT of TPTX+AT and TPTX seems to be of clinical relevance. To assess the true rates of both methods, a multicentred, randomized controlled trial (MRCT) under standardized conditions is mandatory to achieve high internal as well as external validity.Due to the existing uncertainties the calculated number of patients necessary in each treatment arm (n > 4000) makes it impossible to perform this study as a confirmatory trial.Therefore estimates of different outcomes are performed using a pilot MRCT comparing 50 versus 50 randomized patients in order to establish a hypothesis that can be tested thereafter. This seems to be feasible and ethical.The objective of this study is to compare different outcomes of TPTX and TPTX+AT for sHPT over a three-year follow-up period. The information gained will be used for further clinical trials.The primary objective of this trial is to assess a better estimate of the rates of recurrence of both methods. This shall establish a hypothesis that can be tested thereafter.Secondary objectives are divided into those occurring intraoperative, postoperative until discharge and after discharge until 36 months postoperatively.Intraoperative categories comprise the duration of the surgical procedures, the expertise of the responsible surgeon, and complications and findings during surgery.Within the postoperative setting until discharge, the frequency of persistent hyperparathyroidism, the morbidity and the length of hospital stay are noted. During follow up, the frequency of persistent or recurrent sHPT, the frequency of subsequent parathyroid autotransplantation due to refractory hypoparathyroidism, the frequency of reexploration of the neck or the parathyroid autograft, the frequency of irreversible paralysis of the recurrent laryngeal nerve, the change of symptoms related to sHPT as well as the change in quality of life and finally the incidence of death are recorded.Patients on long-term (>12 months) dialysis with sHPT  either with hypercalcemia (developing spontaneously or under treatment with Vitamin D) or with normocalcemia in coincidence with renal osteopathy.Detailed inclusion and exclusion criteria are specified in table Patients are screened consecutively for eligibility in all participating centres after approval of the study protocol by the local ethics committee. A contract has been signed by the Study Centre of the German Surgical Society in Heidelberg (SDGC) and the participating hospitals for correct conduction of the trial according to Good Clinical Practice. All participating surgeons performing the interventions have been instructed by detailed manuals.Patients who are scheduled for parathyroidectomy because of sHPT will have a pretreatment visit to give informed consent. During this visit the patient will be screened and informed about the TOPAR PILOT trial. In this conversation with the patient the study procedures, risks, benefits and data management will be clarified in detail.Several appropriate methods are used in order to minimize random and systematic sources of bias.In order to achieve equal groups of patients free from systematic selection bias, an internet-based computer randomization is performed after informed consent at each centre. The main responsibility for the randomization process lies at the SDGC in Heidelberg.The internet-based computer randomization is performed using the Randomizer for Clinical Trials 1.6.0, developed at the Institute for Medical Informatics, Statistics and Documentation at Medical University of Graz, Austria. The randomization is stratified by centres and is done to generate equal treatment groups by minimizing selection bias. Stratification for the participating clinical sites reduces bias due to centre effects. The trial is only performed in high volume centres (defined as more than 15 parathyroidectomies per year for sHPT) minimizing bias due to learning effects. No additional surgical training has to be done as the neck exploration is the same in TPTX+AT as in the standard procedure and in TPTX.In order to obtain blinding in this trial a shame procedure would be mandatory in the TPTX group for fake autotransplantation which is in this case unethical due to the design of a non confirmatory study.Patients eligible to participate will be asked to give informed consent. Patients will be randomised into the following treatment groups thereafter.Consecutively, baseline data will be documented at screening visit, including past medical history, current specific medication and current symptoms of sHPT. A quality of life questionnaire (SF-36) will be handed out preoperatively.The responsible surgeon will document any particularities of the surgical intervention and the estimated number of similar operations he/she has performed so far. A standardized surgical approach to the parathyroids will be performed in both groups:With the patients under endotracheal anesthesia and with the neck hyperextended, a Kocher's incision is made, preferably in a skin crease. The incision line should be drawn preoperatively, two fingerbreadths above the suprasternal notch when the neck of the patient is extended. The subcutaneous layer and platysm muscle is cut with electric cautery. The upper flap is raised to the upper border of the thyroid cartilage. The lower flap is mobilized to the suprasternal notch. A retractor system is used to local standards. The cervical fascia is incised in the midline. The sternothyroid and sternohyoid muscles are retracted or divided. On both sides, thyroid lobes are rotated medially, and the middle thyroid veins are divided. The lobes are retracted medially one after another and the inferior thyroid arteries and recurrent laryngeal nerves are identified.After mobilization of the thyroid gland, the parathyroid glands have to be identified within the cricothyroid space or in the thyrothymic tongue. Resection of all four (or more) parathyroid glands is performed, carefully avoiding any damage to the parathyroid capsules. The surgeon must change gloves to avoid seeding of parathyroid cells after preserving a part of each gland for pathology. Thymectomy on one side is only performed, if only one gland is found in the respective side or if palpation reveals a suspicious mass within the thymus.Performance of TPTX, supplemented by bilateral routine cervical thymectomy as complete as possible.3 in size, 20 of these pieces are placed in single muscle pockets each of the brachioradial muscle which are closed by clips thereafter.Autotransplantation (AT): a small incision is made over the brachioradial muscle of the non-shunt-bearing forearm . After cutting approximately 50 mg of the most normal appearing, e.g. smallest, preferably nonnodular parathyroid gland into pieces of 1 mmA small part of each gland has to be sent to pathology for frozen section in order to confirm organ diagnosis. The remaining parathyroid tissue will be placed in cold sterile saline solution for later cryopreservation. Cryopreservation is performed by placing cut pieces of the selected parathyroid gland into a vial containing a solution of 80% culture media, 10% patient serum and 10% dimethyl sulfoxide. The vial is then cooled to 70°C at a rate of 1°C per minute.At day of discharge from hospital, the laboratory parameters and current specific medication are documented again. Patients are asked to fill out another quality of life questionnaire (SF-36). Assessment of vocal cord function has to be documented.After discharge a follow up visits at 6, 12, 24 and 36 months postoperatively are performed. Follow-up visits consist of a telephone call, a written questionnaire ) to the patient, who is asked to complete it with the help of their general practitioner or nephrologists. The follow up is under the responsibility of the centres under supervision of the SDGC.Figure This trial is designed on the basis of a critical appraisal of the existing evidence. The observed difference between the recurrence rates of TPTX+AT and TPTX is of clinical relevance. To assess both methods a multicentred randomized controlled trial is mandatory.A pilot study design was chosen for the following reasons: In the context of a noninferiority design with a binary primary endpoint using the confidence interval approach for the odds ratio a sample size of 2 × 656 = 1310 patients would be needed to detect non-inferiority with δ = 1588 based on equal risks of recurrence in both groups (or lower in TPTX) with a power of 80% and a significance level of 5% (Monte-Carlo simulation using logistic regression). Incorporating a rate of drop-outs of 15%, 2 × 770 = 1540 patients would be needed. In case of slight differences between the centres the power will not change significantly. Assuming that a risk of 12,5% in the TPTX+AT group is not inferior based on the risk rate of 10% in the TPTX group (difference of 0.025 or an odds ratio of 1.286) would lead to a sample size of more than 4000 and is therefore far from feasibility. The latter margin is the same as usually used for bioequivalence trials (change of 80% or 125%). Therefore better estimates are needed and a pilot multicentred randomized controlled trial comparing 50 versus 50 randomized patients seems feasible and ethical to assess the recurrence rate of both methods after three years in specialized centres.Sites are selected according to their experience in parathyroid surgery and willingness to adhere to the clinical trial protocol. The surgical expertise of each participating surgeon is documented and taken into account during the analysis of the trial data.A small part of each gland is sent to pathology for frozen section in order to confirm organ diagnosis. The success of the intervention is assessed by perioperative monitoring of PTH and calcium recorded in the CRF. All participating centres guarantee cryopreservation of parathyroid tissue from each patient to enable possible subsequent parathyroid autotransplantation, if necessary. If postoperative persistent hypoparathyroidism refractory to medical treatment occurs, reimplantation is performed. The necessity of reimplantation is discussed and defined in each individual case by a medical clinical expert board. Therefore, clinical symptoms (e.g. repeated episodes of paraesthesia and seizures or others), the necessity and amount of medication to achieve normocalcemia and laboratory data  will be taken into consideration.All serious adverse events (SAE) have to be reported to the principal investigator and the leading ethic committee. For the safety analysis the incidence of adverse events (AE) and SAE are analyzed. Patients may be withdrawn from the study at any time either at their own request or at the request of the principal investigator.Safety evaluation will be done. The adverse events of both treatment groups will be demonstrated in comparison considering severity and causality. Safety interim analyses are planned each year and the independent data and safety board will follow the progress of the trial to control the safety.Statistical methods are used to assess the quality of data, homogeneity of treatment groups, endpoints and safety of the TPTX versus TPTX+AT technique. The analysis is performed on the basis of an intention to treat (ITT) population and with respect to ITT principles. A patient belongs to the ITT population, when the patient was found to be suitable for the study, signed the informed consent form and was randomized thereafter.Baseline characteristics as well as efficacy and safety endpoints will be analyzed with descriptive methods. The description of continuous variables includes at least: number of observations, mean, standard deviation, median, minimum and maximum in the trial population. The description of nominal variables includes at least the number and percentage of patients belonging to the relevant categories in the trial population as well as in each treatment group. In order to improve the presentation of the observed data, graphical methods will be applied.TOPAR PILOT was designed at the Department for Visceral, Thoracic and Vascular Surgery, Philipps-University, Marburg in cooperation with the Study Centre of the German Surgical Society (SDGC), Heidelberg and the Institute of Medical Biometrics and Informatics (IMBI) at the University of Heidelberg.Quality assurance will be done in cooperation with the Network of Coordinating Centres for Clinical Trials (KKS).The trial is monitored by an independent monitor of the KKS in Heidelberg. The trial is performed according to the Declaration of Helsinki in its current German version and the Good Clinical Practice (GCP). Before the start of the trial the independent ethics committee of the Philipps-University, Marburg gave a positive vote on August 21th 2006. The trial was registered on August 22d in 2006 at the International Standard Randomized Controlled Trial Number Registration (ISRCTN86202793).This trial is funded by the German Federal Ministry of Education and Research  and the German Surgical Society [Deutsche Gesellschaft für Chirurgie (DGCH)]. Additional industrial funding for the infrastructure of the SDGC is received from Ethicon GmbH, Norderstedt, Germany, and Tyco Healthcare Deutschland GmbH, Neustadt, Germany.Up to now, 2 centres are initiated. The first patient was randomized on January 24th 2007. The expected recruitment period will last 18 months.TOPAR PILOT is a randomized controlled multicentred pilot trial to generate high quality evidence comparing the outcomes of TPTX+AT vs. TPTX. Since secondary hyperparathyroidism is a very common disease in patients with chronic kidney failure, even a small difference in outcomes will be of clinical relevance. If TPTX proves to have no relevant disadvantages and a smaller rate of recurrent sHPT, a large scale confirmatory study will be launched to establish this approach.Recent reports comparing TPTX+AT to TPTX were retrospective, underpowered or not designed as RCT's. No unique definition for recurrent sHPT was used to calculate the rate of recurrent sHPT. The follow up periods of former studies have often been too short and were not standardized table . TherefoThe evaluation of optimal surgical options and procedures should be performed according to the best current knowledge. Due to the principles of Evidence-based Medicine (EbM), the randomized controlled trial is assumed to be the "Gold Standard" in evaluating different medical methods and procedures. Even in RCT's, the risk of bias should not be underestimated. In surgical trials a double blinded trial design is difficult to establish. In this study, even a patient-blinded trial design would necessitate a shame procedure at the forearm for fake autotransplantation in the TPTX-group which is in this case unethical due to the design of a non confirmatory study.However, the patient selection, power, randomization, surgeon's skill, data assessment and documentation of outcome measures and statistical analysis are important design issues and susceptible to the different forms of bias. Hence, all these issues are specified in the trial protocol a priori.To minimize selection bias all patients scheduled for parathyroidectomy because of sHPT are screened consecutively in all participation sites. Moreover, neither patient age nor the amount of PTH-secretion is an exclusion criterion. Screening lists and case report files are monitored by independent investigators from the SDGC to ensure correct patient recruitment and meticulous documentation.Randomization is done using in an internet-based computer randomization. The randomization will be stratified by centres and will be done to generate equal treatment groups by minimizing selection bias. Stratification for the participating clinical sites will reduce bias due to centre effects.In this study, stratification for surgeon's skill is made and measured data will be analyzed by analysis of variance in regard to surgeon's skill and centre. Due to this analysis of variance, bias of centre effects and surgeon's skill should be reduced.The trial will only be performed in high volume centres (defined as more than 15 parathyroidectomies per year for sHPT) minimizing bias due to learning effects. No additional surgical training has to be done as the neck exploration is the same in TPTX as in the standard procedure of TPTX+AT.In conclusion, this is the first randomized controlled multicentred trial comparing different surgical techniques in parathyroid surgery for sHPT. If significant, the results will be revised by a large scale confirmatory study. The results may change the current surgical practice thereafter.CAEK - Chirurgische Arbeitsgemeinschaft Endokrinologie (Study Group of Endocrine Surgeons);KKS - Koordinierungszentrum für Klinische Studien ;MRCT - multi-centre randomized controlled trial;PTX - Parathyroidectomy;SDGC - Studienzentrum der Deutschen Gesellschaft für Chirurgie ;sHPT - secondary hyperparathyroidism;SPTX - subtotal parathyroidectomy;TPTX+AT - Total parathyroidectomy with autotransplantation and with routinely performed thymectomy;TPTX - Total parathyroidectomy without autotransplantation and without routinely performed thymectomy;PTH - Intact parathyroid hormone.The author(s) declare that they have no competing interests.KS conceived of the study, made substantial contributions to conception and design as well as to the acquisition and interpretation of data. Moreover, she has been essentially involved in drafting the manuscript.JAV participated in the sequence alignment and partly drafted the manuscript.SW participated in the design of the study and performed the statistical analysis.ED participated in the sequence alignment and helped to draft the manuscript.NV participated in the design of the study and was mainly involved in the analysis and interpretation of data as well as in the performance of the statistical analysis.HPK participated in the design of the study and its coordination and helped to draft the manuscript.CMS made substantial contributions to conception and design, has been involved in drafting the manuscript and revised it critically for important intellectual content.MR conceived of the study, has been involved in drafting and revising the manuscript and gave final approval of the version to be published.All authors read and approved the final manuscript.


Although not empirically proven, the limbic system is a functional concept which may be employed to explain various brain functions.le grand lobe limbique’ or the great limbic lobe and applied the term “limbic” (from the Latin limbus for border) to the curved rim of the cortex which incudes the cingulate and the parahippocampal gyri. However, its putative role in emotion was elaborated by the American physician, James Papez in 1937 in the seminal paper titled ‘A proposed mechanism of emotion’. This anatomical model is referred to as the Papez circuit.5]James Papez's delineation of a circuit after injecting rabies virus into a cat's hippocampus and monitoring its progression through the brain, unraveled the basis of cortical control of emotion. Further elaboration of the circuit has included the prefrontal cortex (PFC), amygdala and septum among other areas .12]212]The major input to the hippocampal formation arises from neurons in layers II and III of the entorhinal cortex. In addition, some septal and hypothalamic fibres reach the hippocampal formation via the fornix. A few fibres also arrive from the contralateral hippocampal formation via the hippocampal commissure.The intrinsic connections of the hippocampus involve fibers from the entorhinal area, dentate gyrus, Ammon's horn and the subiculum. The three primary pathways of this area are called the perforant pathway, mossy fibers and Schaffer collaterals. The existence of a fourth pathway, the alvear path from the entorhinal area to Ammon's horn through the alveus, has been questioned.The perforant path is considered the main afferent pathway to the hippocampus, where glutamatergic fibers from the entorhinal area “perforate” the subiculum and reach the dentate gyrus (granule cell layer), traversing the fused hippocampal fissure. Investigators debate whether some perforant fibers reach Ammon's horn. The glutamatergic mossy fibers then extend from the dentate gyrus to CA3 , although some efferent fibers from CA3 project to the fimbria. Many axons of CA3, however, give off the Schaffer collaterals that reach the dendrites of CA1. CA1 is considered the main output of the hippocampus with fibers extending to the alveus, fimbria and then fornix. A supplementary linkage with the subiculum also is believed to be present .10]10]The efferent fibers from the hippocampal region form three groups: precommissural fornix, postcommissural fornix and nonfornical fibers. The precommissural fibers of the fornix may originate from the cornu ammonis or the subiculum. These fibers travel within the fimbria, crura and body of the fornix. The cornu ammonis fibers terminate exclusively in the lateral septal nucleus, whereas the subicular fibers are distributed to nucleus accumbens, anterior olfactory nucleus, lateral septal nucleus, precommissural hippocampus, medial frontal cortex and gyrus rectus. The postcommissural fibers mostly terminate in the mamillary body, although some fibers also project to the anterior thalamic nucleus, bed nucleus of the stria terminalis and ventromedial hypothalamic nucleus. The nonfornical fibers project directly from the hippocampus to the entorhinal area as well as to the posterior cingulate and retrosplenial cortices and the amygdala .10]10]Amygdala serves to integrate information processing between prefrontal / temporal association cortices and the hypothalamus. The amygdala has two major output pathways:Dorsal route via stria terminalis projects to the septal area and hypothalamus.Ventral route via the ventral amygdalofugal pathway terminates in the septal area, hypothalamus and the medial dorsal thalamic nucleus .Figure The amygdala has also got connections with the basal ganglia circuit via its projections to the ventral pallidum and ventral striatum, which is relayed back to the cortex via the dorsomedial nucleus of the thalamus .This circuit is relayed via the basolateral amygdala. This circuit consists of the orbitofrontal and anterior temporal cortex, amygdala  and magnocellular division of the dorsomedial nucleus of the thalamus , which relays back to the orbitofrontal cortex. This cirThe functions of the various structures of limbic system are outlined below .The limbic structures are closely related to the olfactory cortex and have a role in the processing of olfactory sensation. Amygdala is involved in the emotional response to smell while another limbic structure—the entorhinal cortex, is concerned with olfactory memories .13]13]Amygdala plays a role in food choice and emotional modulation of food intake. The lateral nucleus of the hypothalamus is the center for control of feeding whereas the ventromedial nucleus functions as the satiety center.Positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) have shown that the limbic system is one of the most active brain areas during the process of dreaming. The limbic system probably interweaves unconscious primal emotions with our conscious cognitive thoughts and perceptions and thereby ties together emotions and memory during rapid eye movement (REM) sleep to form the content of dreams. The suprachiasmatic nucleus of hypothalamus is the circadian rhythm generator controlling the sleep-wake cycle. The ventFear responses are produced by the stimulation of the hypothalamus and amygdala. Amygdalar destruction abolishes fear and its autonomic and endocrine responses. Amygdala is also involved in fear learning, which is blocked when long-term potentiation (LTP) is disrupted in pathways to the amygdala. Imaging studies have shown that viewing fearful faces activates the left amygdala.17Rage responses to minor stimuli are observed after removal of the neocortex. The destruction of the ventromedial hypothalamic nuclei and septal nuclei in animals with intact cerebral cortices may induce rage. Rage may also be generated by the stimulation of an area extending back through the lateral hypothalamus to the central gray matter of the midbrain. Bilateral destruction of the amygdala results in placidity. However, when the ventromedian nucleus is destroyed after the destruction of the amygdala, the placidity generated is converted to rage.Limbic stimulation causes changes in respiration and blood pressure. The stimulation of the cingulate gyrus and hypothalamus can elicit autonomic responses. There is however little evidence for localization of autonomic responses in limbic circuitry. HypothalThe medial preoptic area of the hypothalamus is a key structure in the central control of male sexual behavior. Chemosensory efferents from the main and accessory olfactory systems project to the medial amygdala (MeA). MeA sends direct and indirect innervations  to the medial preoptic area (MPOA). MPOA and MeA receive genitosensory input from the spinal cord through the central tegmental field (CTF). The parvocellular portion of the CTF called the subparafascicular nucleus (SPFp) seems to be especially important for stimuli related to ejaculation. The MPOA sends efferents to the paraventricular nucleus of the hypothalamus (PVN), the ventral tegmental area, the nucleus paragigantocellularis and other autonomic and somatomotor areas .19]19]The parvocellular part of the paraventricular nucleus (PVN) of the hypothalamus contains neurons that send direct oxytocinergic and vasopressinergic projections to the lumbosacral cord. Dopamine can trigger penile erection by acting on oxytocinergic neurons located in the paraventricular nucleus of the hypothalamus. Activation of oxytocinergic neurons originating in the PVN and projecting to extrahypothalamic brain areas, by dopamine and its agonists—excitatory amino acids (N-methyl-D-aspartic acid) or oxytocin itself or by electrical stimulation leads to penile erection. The inhibition of these neurons on the other hand, by GABA and its agonists or by opioid peptides and opiate-like drugs, inhibits this sexual response. The activation of these neurons is secondary to the activation of nitric oxide synthase (NOS), which produces nitric oxide. At least some of the glutamatergic inputs to the MPOA are from the medial amygdala (MeA) and bed nucleus of the stria terminalis (BNST), which mediate the female-stimulated increase in dopamine, which in turn, enhances copulatory ability. Extracellular glutamate in the MPOA increases during copulation, especially during ejaculation and increased glutamate facilitates copulation and genital reflexes.The reward circuitry underlying addictive behavior includes amygdala and nucleus accumbens. The amygdala plays a central role in cue-induced relapse. Relapse associated with cues, stress and a single dose of a drug of abuse (Comment: which one? What kind?) results in release of excitatory neurotransmitters in brain areas like hippocampus and amygdala. The pathway of motivated behavior involves the prefrontal cortex, the ventral tegmental area (VTA), the amygdala especially the basolateral amygdala and extended amygdala, the nucleus accumbens core and the ventral pallidum. This pathway is involved in the motivation to take drugs of abuse (drug-seeking) and the compulsive nature of drug-taking .21]21]Emotion has powerful influence on learning and memory. Amygdala, in conjunction with prefrontal cortex and medial temporal lobe, is involved in consolidation and retrieval of emotional memories. Amygdala, prefrontal cortex and hippocampus are also involved in the acquisition, extinction and recovery of fears to cues and contexts. Hippocampus is critical for long-term, declarative memory storage.The components include the hippocampus and adjacent cortex, the parahippocampal regions (PHG) and the entorhinal and perirhinal regions. This memory system is involved in the storage of new memories.The diencephalic memory circuit consists of the hypothalamus, mammillary body and the dorsomedial nucleus of thalamus. This circuit is important for the storage of recent memory; a dysfunction of this circuit results in Korsakoff's syndrome.Social cognition refers to thought processes involved in understanding and dealing with other people. Social cognition involves regions that mediate face perception, emotional processing; theory of mind (TOM); self-reference and working memory. Together, the functioning of these regions would support the complex behaviors necessary for social interactions. Limbic structures involved are the cingulate gyrus and amygdala.Temporal lobe epilepsy is the most common epilepsy in adults and is most often caused by hippocampal sclerosis. Hippocampal sclerosis with additional involvement of the amygdala and parahippocampal gyrus is termed mesial temporal sclerosis (MTS). CA1 or the Sommer sector, is the region most vulnerable to hypoxia. CA4, sometimes described as the endfolium, has intermediate vulnerability to insults, whereas CA3, which enters the concavity of the gyrus dentate, is only slightly vulnerable. CA2 is the most resistant and well-preserved sector. The frequency and widespread distribution of these cerebral abnormalities suggest that MTS is not limited to the medial temporal lobe but instead, represents a limbic system disorder.Limbic encephalitis is a paraneoplastic syndrome that has been reported with carcinoma of the lung, breast and some other primaries. The mechanism of disease is not known but it manifests as encephalitis that primarily involves the hippocampus, amygdala, cingulate gyrus, insula and orbital-frontal cortex. Afflicted patients develop subacute onset of memory loss, dementia, involuntary movements and ataxia.Degenerative changes in the limbic system likely have a role in the genesis of neurodegenerative diseases, particularly Pick's disease and Alzheimer's disease. Marked atrophy is found in the limbic system, most notably the dentate gyrus and hippocampus. In Alzheimer's disease, senile plaques and neurofibrillary tangles are dispersed throughout the cerebral cortex and basal ganglia, but the hippocampus and amygdala are often severely involved.Anxiety disorders may be the result of a failure of the anterior cingulate and hippocampus to modulate the activity of the amygdala (top-down regulation). A fear circuitry, involving the amygdala, prefrontal and anterior cingulate has been described (bottoms-up regulation).Studies have shown reduced limbic volumes in schizophrenia. The Papez circuit is probably involved in schizophrenia. The evidence for this is the distortion of cortical neuronal organization of layer II of the ERC, decreased size of hippocampus and the reduced number of GABAergic cells in the cingulate and anterior thalamus with resultant glutamatergic excitotoxicity. The other circuit involved is the basolateral circuit which mediates the social cognition deficits in schizophrenia.Studies have shown variation in the volumes of the frontal lobes, basal ganglia, amygdala and hippocampus in affective disorders. Functional studies have revealed decreased prefrontal and anterior cingulate activity in affective disorders. The anterior cingulate is the center for integration of attentional and emotional output and helps effortful control of emotional arousal. RecentlyLimbic structures have been implicated in the genesis of attention deficit / hyperactivity disorder (ADHD). The enlarged hippocampus in children and adolescents with ADHD may represent a compensatory response to the presence of disturbances in the perception of time, temporal processing and stimulus-seeking associated with ADHD. Disrupted connections between the amygdala and orbitofrontal cortex may contribute to behavioral disinhibition seen in individuals with ADHD.Kluver-Bucy syndrome results due to a bilateral destruction of the amygdaloid body and inferior temporal cortex. It is characterized by visual agnosia, placidity, hypermetamorphosis, hyperorality and hypersexuality. This disorder may be caused by many conditions including cerebral trauma; infections including herpes and other encephalitides; Alzheimer's disease and other dementias; Niemann-Pick disease and cerebrovascular disease.Korsakoff's psychosis is caused by damage to mammillary bodies, dorsomedial nucleus of thalamus and hypothalamus . It is a syndrome associated with chronic prominent impairment of recent and remote memory. Recent memory is characteristically more disturbed than remote memory. Immediate recall is usually preserved. Confabulation may be marked but is not invariably present.Autism and Asperger's syndrome involve the disproportionate impairment in specific aspects of social cognition. Limbic structures involved include the cingulate gyrus and amygdala, which mediate cognitive and affective processing. The basolateral circuit integral for social cognition is disrupted in autism spectrum disorders.The limbic system plays a pivotal role in behavior. The intricate functional neuroanatomy of limbic system with its diverse circuits may explain some of the manifestations of neuropsychiatric disorders. Relentless research has identified the role of the amygdala in various anxiety disorders and emotional memory. The monitoring role of anterior cingulate, the trisynaptic hippocampal circuitry underlying cognitive functioning and the significance of hypothalamus in various neurovegetative functions suggest the integral role of the limbic system in understanding human behavior and its aberrations.


Development of neural network models for the prediction of glucose levels in critically ill patients through the application of continuous glucose monitoring may provide enhanced patient outcomes. Here we demonstrate the utilization of a predictive model in real-time bedside monitoring. Such modeling may provide intelligent/directed therapy recommendations, guidance, and ultimately automation, in the near future as a means of providing optimal patient safety and care in the provision of insulin drips to prevent hyperglycemia and hypoglycemia. Following severe trauma, approximately 25% of patients experience hyperglycemia . SustainThe standard method for management of glycemic control in critical care patients is adjustment of a variable infusion of insulin on the basis of discrete point of care (POC) blood glucose monitoring via handheld glucose meters . This PO®) and concurrent medical records data from a 38 year old trauma patient (who had an intensive care stay of 16 days). The model was configured for prediction of glucose by implementing a prediction horizon of 75 minutes. Additionally, a general feed forward neural network was developed/trained using 515.7 hours  of CGM and medical records data from 5 critical care patients and configured with the same 75 minute prediction horizon.After institutional review board approval a patient specific neural network model was developed/trained using 243.6 hours  of continuous glucose monitoring (CGM) , and units of insulin delivered as input variables for prediction. The second or hidden layer of the neural network was designed to limit the range of neural network model inputs to between -1 and 1. This enables data within the neural network to be more easily processed and for trends in data to be identified more effectively. Figure A computer program implementing the neural network model for real-time prediction of glucose was developed. Data from the trauma patient not utilized for initial model development/training  was used to test the performance of the patient specific and general neural network models. Clarke Error Grid Analysis (CEGA) was completed to assess clinical acceptability of real-time predictions. Overall error (mean absolute difference percent [MAD%]) was calculated for real-time predictions.clinically acceptable. Region C contains points that lead to unnecessary treatments, and Region D contains points indicating a potentially dangerous failure to detect hypoglycemia. Region E contains predicted values that would confuse treatment of hypoglycemia for hyperglycemia and vice-versa. A successful predictive model and system would thus need a majority of predicted CGM values to fall with regions A and B in the Clarke Error Grid. If a majority of predicted values fall within regions A and B of the Clark Error Grid, any therapeutic interventions made using the NNM predictive results would not lead to any adverse or unwanted glycemic excursions.CEGA was established in 1987 and was originally utilized to assess patient estimates of blood glucose compared to those obtained using a "gold-standard" reference glucose meter . The accIn addition to performance analysis of the neural network model, the utility of CGM in the trauma patient was analyzed. This was accomplished by determining the percentage of hypoglycemic (≤70 mg/dl) and hyperglycemic ≥150 mg/dl) events that were detected by CGM and not by conventional POC glucose monitoring. In this analysis we locate hypoglycemic and hyperglycemic CGM values and search for POC monitoring values within a defined time window. A time window of 60 minutes is defined as 30 minutes before and 30 minutes after the detected extreme. If there is a POC value within the time window it is defined as a successful detection of hypoglycemia/hyperglycemia via POC monitoring. Table 50 mg/dl Throughout the patient's length of stay in the ICU, CGM detected a total of 642 hyperglycemic and 124 hypoglycemic occurrences. The patient was on an insulin drip throughout their length of stay in intensive care and POC glucose monitoring was completed intensively. Table Figure Figure clinically acceptable with no predicted values falling within regions C, D, or E of the error grid. CEGA also revealed that the patient specific model generated predictions with a high degree of accuracy as 95.1% of the values fell within region A of the error grid and had values within 20% of the reference glucose concentration.Figure The real-time application of a neural network model for glycemic prediction in critical care patients will provide significant insight to glycemic excursions at points in time where POC glucose values are not obtained. The ability to predict glucose concentration during these time domains would provide caregivers a means of modifying insulin dosages and therapy for optimization of glycemic control. The optimization of glycemic control in critical care trauma patients could reduce morbidity, and mortality in these patients -5. This CEGA was developed in 1987 for use in the quantification and assessment of patient's estimates of their blood glucose levels compared with the value obtained by a meter . It was The utilization of this predictive model in real-time bedside monitoring for intelligent/directed therapy recommendation, guidance, and ultimately automation, will provide caregivers a means of enhancing patient safety and care. Furthermore, CGM identifies hypoglycemic and hyperglycemic excursions where conventional POC glucose values are not obtained, and results of this investigation demonstrate the utility of CGM in the critical care trauma setting. For the patients with an extended length of stay in the ICU, the results of this investigation substantiate the position that a patient specific neural network model (generated and trained with data from a single patient) may provide increased clinical performance and safety at the bedside. Further clinical trials will need to be pursued.Utilization of CGM in this patient population is clinically useful. Further investigation regarding the development and optimization of the real-time implementation of the neural network for prediction of glucose is ongoing and warranted based on this preliminary report.Written informed consent was obtained from the patient for publication of this report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief.The authors declare that they have no competing interests.SMP and BDC conceived and wrote the mathematical algorithm. TJP, SMP, BDC, and RJB were involved in conception and design. JDL, DS, TS, TJP, MJB, SMP, and AC were involved in data acquisition. TJP and MJB cared for the patient. All authors were involved in interpretation of the data. TJP, MJB, SMP, AC, and BDC were involved in drafting the manuscript or revising it for critically important intellectual content. All authors have given final approval of the version to be published.


Adenosquamous carcinoma of the pancreas is a rare variant of pancreatic exocrine carcinoma. We report a case of 70 year old man who came to our hospital with abdominal pain, anorexia and jaundice. Imaging of the abdomen showed a mass in the region of the head of the pancreas. Histological evaluation of the pancreatic tumor showed an adenosquamous carcinoma which was extensively infiltrative with perineural invasion, involvement of peripancreatic lymph nodes and all the thickness of the duodenum wall. The tumor exhibited a biphasic malignant growth identified as well to moderate differentiated adenocarcinoma and well to poorly differentiated squamous cell carcinoma. Adenosquamous carcinoma of the pancreas is a rare aggressive subtype of pancreatic ductal adenocarcinoma and accounts for 1-4% of all exorcine malignancies of the pancreas.Also referred to as mucoepidermoid carcinoma and adenoacanthoma in older literature, pancreatic adenosquamous carcinoma is characterized by adenomatous cell population mixed with varying amounts of keratinized squamous cell elements -3 The prA 70 year old man from Greece having Hellenic Nationality, came to the emergency department of our hospital with abdominal pain, anorexia and jaundice. The duration of symptoms prior to presentation was four weeks. Physical examination revealed moderate tenderness on palpation of the hypogastrium. His past medical history included essential hypertension and hyperlipidemia. There was no family history of gastrointestinal diseases. Laboratory studies showed elevated bilirubin and alkaline phosphatase levels and moderately elevated serum carbohydrate antigen 19-9 (Ca 19-9) of 380 U/ml . Abdominal ultrasound and computerized tomography scan showed a mass in the head of the pancreas measuring 4.5 cm in size and curative pancreaticoduodenectomy was performed. Histological evaluation of the pancreatic tumor showed an adenosquamous carcinoma which was extensively infiltrative with perineural invasion, involvement of peripancreatic lymph nodes and all the thickness of the duodenum wall. The tumor elicited an intense desmoplastic stromal reaction and areas of necrosis Figure . The adePancreatic adenosquamous carcinoma is a rare aggressive subtype of ductal adenocarcinoma and accounts for 1-4% of all exocrine malignancies of the pancreas. Also referred to as mucoepidermoid carcinoma and adenoacanthoma in older literature, adenosquamous carcinoma demonstrates both malignant squamous cell and glandular differentiation . SquamouWritten informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journalThe authors declare that they have no competing interests.ES drafted the article. XG contributed to the writing and revising of the manuscript. CG performed the histological examination. DZ analyzed and interpreted the patient data. NP analyzed and interpreted the patient data. EK and NF participated in its design. TV supervised the preparation of the article and helped in final manuscript. All authors read and approved the final manuscript.


Matrix metalloproteinases (MMPs) are proteolytic enzymes that may contribute to tissue destruction in Sjögren's syndrome (SS). Low-dose doxycycline (LDD) inhibits MMPs. We evaluated the efficacy of LDD for the subjective symptoms in primary SS patients.This was a randomized, double blind, placebo controlled cross-over study. 22 patients were randomly assigned to receive either 20 mg LDD or matching placebo twice a day for 10 weeks. The first medication period was followed by 10-week washout period, after which the patient received either LDD or placebo, depending on the first drug received, followed by the second washout period. Stimulated saliva flow rates and pH were measured before and after one and ten weeks of each medication and after washout periods. VAS scale was used to assess the effect of LDD and placebo on following six subjective symptoms: xerostomia; xerophtalmia; difficulty of swallowing; myalgia; arthralgia; and fatigue. The effect was evaluated for each medication and washout period separately.Overall, the effects of medications on subjective symptoms were minor. Wilcoxon test demonstrated increased fatigue with LDD during medication (p < 0.05). The differences may, however, reflect normal fluctuation of symptoms in SS patients.LDD may not be useful in reducing the primary SS symptoms. Sjögren syndrome (SS) is a slowly progressing autoimmune rheumatic disease with unknown etiology . It is aMatrix metalloproteinases (MMPs) constitute a family of zinc-containing endoproteinases with 23 members. The principal function of MMPs is the proteolytic degradation of connective tissue matrix proteins, and in concert they can degrade practically all extracellular matrix proteins . MMPs paThe effect of medication targeting the potential factors behind the pathogenesis of SS on subjective symptoms has recently been a focus of interest in several studies ,17, but Tetracyclines are antimicrobial agents, inhibiting also MMPs with a mechanism which is independent from their antimicrobial effect . DoxycycBased on the earlier studies a hypothesis was formed that through its MMP-inhibitory action, LDD could be effective in treatment of SS by decreasing the tissue damage and therefore also the subjective symptoms of the patients. The aim of this study was to evaluate the effectiveness of LDD on clinical symptoms of SS in a randomized, double-blinded, placebo-controlled clinical cross-over trial.Seventeen subjects out of 22 patients included at the onset of the study (77%) completed the study and provided the VAS score data after each medication and washout period. The stimulated salivary flow rates and pH were low compared to normal reference values  Figure . No statIn Figure Comparison of the VAS scores between the pre-medication and seven-week medication demonstrated statistically significantly higher values for myalgia after seven weeks of both LDD and placebo Figure . CompariFor the post-experimental telephone interview, 16 patients were reached. Five patients had experienced significant alleviation of symptoms during one of the medication periods. Three patients had felt the benefits during the LDD medication and two had felt the benefits during placebo medication.In spite of tissue destructive nature of primary SS, the subjective symptoms are the most significant handicap. Therefore development of palliative treatment strategies has long been an object of interest. Local treatments, such as artificial saliva or lozenges, are insufficient and provide only temporary relief ,23. PiloThe low salivary flow rate and low saliva pH were expected, as values of this kind are normally found in SS patients with established disease. Measuring the unstimulated salivary flow rate proved impossible due to practically zero unstimulated saliva secretion in most patients. The findings indicate the severe condition of SS in the subjects involved in the study.th week of Periostat medication the finding may be a coincidence. This is supported by the post-experimental interview, which clearly indicated that there was no overall effect on subjective symptoms by LDD. On the other hand, taking into consideration the multi-dimensional subjective symptomology of SS patients, with mostly unknown pathology behind the symptoms, it is possible that MMP inhibition might in some way increase the subjective feeling of myalgia. The lack of clinically significant findings in this study may also be affected by the low numer of patients (22 patients) involved, even though all the patients in the patient records of Northern Ostrobothnia Hospital District  with SS diagnosis were included into screening. Another study with larger patient population, requiring multi-center study, would be needed for the final conclusion in this matter. However, since the positive effects of LDD medication on SS subjective symptoms seem to be minor, larger-scale studies with SS patients, at least the patients with established disease as in this study, do not seem justified.Overall, the changes in the subjective symptoms within the LDD or placebo medication or washout periods were small and most likely reflect the usual fluctuation of symptoms rather than true differences caused by medication. Considering the subjective symptoms that exhibited statistically significant differences within specific medication or washout, only the increase in fatigue with LDD medication seems possibly clinically significant Figure . Muscle MMP inhibition with LDD was not effective in alleviating the subjective symptoms of primary SS patients with already established disease. The finding is concurrent with the other studies aiming at the reduction of symptoms by directing the systemic medication against potential pathogenetic factors ,17, withDetailed description of the patient inclusion and exclusion criteria has been presented previously . BrieflyThis was a randomized, double blind, placebo-controlled clinical trial, and the patients were randomized at the baseline. Randomization was performed by use of a computer-generated list, and the drug and placebo were indistinguishable in appearance, smell and taste. Neither the person in charge of clinical protocol of the study nor the patients were aware of the treatment assignments.®; further referred as LDD) or matching placebo  twice a day for a period of 10 weeks  were used to describe the intensity of the following symptoms: xerostomia; xerophtalmia; difficulty of swallowing; myalgia; arthralgia; and fatigue. The patients were instructed to provide a VAS rating every week at the same time of the week for each of the six symptoms, using a range from 0 for the total absence of symptom to 100 for worst imaginable symptom. After each medication and washout period the VAS score sheets were collected Figure  and new Six months after the experiment the patients were contacted by telephone and asked for their subjective opinion whether the drug provided any help in general for their subjective symptoms or not  Figure .SPSS for Windows Release 11.5.1  was used for the statistical analysis. Since the number of the marked scores decreased towards the end of each medication and washout period (because of apparent reduction of co-operation towards the end of each period), the statistical analysis was only extended to the 7th week of each period. Wilcoxon signed ranks test for two related variables was used to analyse the differences between the pre-medication and 7-week medication samples within both medication regimens, and between the values after 7-week LDD and 7-week placebo medications, to evaluate the possible effect of LDD on subjective symptoms. The same test was also used to examine the differences between the pre-medication levels, to exclude the effect of possible differences at the starting point of the medication regimens.LDD: Low-dose doxicycline;SS: Sjögren's Syndrome;MMP: Matrix metalloproteinases.The author(s) declare that they have no competing interests.HS was responsible for the handling of the subjects and collection of the samples, participated into data analysis and writing of the manuscript. RKN participated in the design of the study, collection of the patient material and drafting of the manuscript. MM-G participated in the handling of the collection and analysis of the samples. TV participated in the design of the study. LT participated in preliminary data analysis, performed the statistical analysis and drafting of the manuscript. TS conceived of the study, participated in its design, coordination, funding, data-analysis and drafting of the manuscript. All authors read and approved the final manuscript.


Giant cell tumors (GCTs) of bone are aggressive benign tumors. Wide resection is reserved for a small subset of patients with biologically more aggressive, recurrent, and extensive tumors. Wide resection and mobile joint reconstruction are preferable for treating tumors around the knee. In certain situations, resection arthrodesis or an amputation is suggested. In this prospective study we report the outcome of 8 patients of aggressive GCT of lower end of femur treated with resection arthrodesis.et al.Eight patients with mean age of 37.25 years (range 30–45 years) with Campanacci Grade III (Enneking stage III) giant cell tumors at the distal femur were treated with wide resection and arthrodesis using dual free fibular graft and locked intramedullary nail from January 2003 to January 2008. There were four males and four females patients. The mean follow-up was 48.75 months (range 30–60 months). The functional evaluation was done using the standard system of musculoskeletal tumor society with its modification developed by Enneking At the final follow up the functional score ranged from 20 to 27 out of total score of 30. Graft union was achieved in all cases in a duration mean of 14.5 months (range 12-20 months).One case required secondary bone graft due to delayed union, and one case had superficial wound infection which healed on systemic antibiotics. At final followup, all the patients were disease free.Wide resection and arthrodesis in aggressive GCTs of the distal femur with involvement of all muscle compartments is a good treatment option. Resection arthrodesis offers a biological reconstruction alternative to amputation in a special group of patients when extensive resection precludes mobile joint reconstruction. Giant cell tumor (GCT) is a benign aggressive tumor of bone.34The available surgical options range from curettage to wide resection with suitable reconstruction.6The ideal reconstruction of the defect created after en block resection of the tumor is still a subject of debate. Endoprosthetic replacement incurs a high cost, requires adequate motor reconstruction and repeated surgeries. Massive allografts are widely used in many centers. However, it requires substantial time and money, and for a variety of reasons, it is not available in many countries.8In this prospective case series, we report the outcome in eight patients with aggressive GCT of the lower end of femur, treated with wide resection and arthrodesis of the knee, and report the radiological and functional outcome at a mean follow-up of 4 years.This prospective study included eight patients with aggressive giant cell tumor of the distal femur, who were operated between January 2003 and May 2005. All participating surgeons used the same technique of wide resection and reconstruction. There were four male and four female patients. Ages ranged from 30 to 45 years (mean of 37.25 years). The mean follow-up was 48.75 months  . One casAll patients underwent staging studies that included plain radiography, computed tomography (CT), magnetic resonance imaging (MRI), and chest CT. The aim of these studies was to determine the extent of the soft tissue component, its relation with the neurovascular bundle, breach of the articular surface, the intramedullary extent of the disease, and planning a precise resection length.Campanacci's staging system for giant cell tumor of boneIf the clinical presentation and the imaging studies were compatible with diagnosis of a classic benign giant cell tumor of bone, the biopsy (frozen section) and surgery were performed during the same session (six cases). In case of atypical clinical or radiologic presentation, either CT-guided core needle (one case) or open incisional biopsy was performed, and surgery was delayed until histopathologic evaluation had been completed (one case).A long medial incision that begins in the mid-thigh, crossing the knee joint along the medial parapatellar area and distal to the tibial tubercle, extending gently posterior to the inferior border of the pes muscles was made. The biopsy site was included, with a 1-cm margin in all directions. Fasciocutaneous flaps were developed. The popliteal space was approached by detaching or retracting the medial hamstrings. The superficial femoral artery was identified within the sartorial canal. The length of the resection was measured from the medial joint line to the correct area on the femur and then marked. All the remaining soft tissue at the level of transection was cleared. The tumor was resected with all involved muscles. Extraarticular resection was done in all cases followed by knee preparation for fusion. The resulting defect ranged from 14 to 17 cm with a mean of 15.87 . ReconstIn case 2, the patient presented with intramedullary nail used for fixation of undiagnosed pathological fracture. The nail had to be removed through a separate proximal lateral incision, and the entire medulla was irrigated with phenol .et al (1997) for assessment of graft union both proximally and distally which require unequivocal radiographic evidence of bone healing of graft and osteotomy sites including uninterrupted external bony borders between the fibular graft and the recipient bone, obscured or absent osteotomy lines at both junctions, and clinical resumption of normal function and weight –bearing without discomfort.Postoperatively, the patients were examined every week for the first month for the detection of early complications as infection and then monthly for the first year for early detection of any local or systemic recurrence and progression of graft incorporation. We used the system of Hsu At the end of the follow-up, all patients were alive and were free from any signs of local or systemic recurrence. The functional evaluation was performed using a modified system of the Musculoskeletal Tumor Society.et al.Radiological union of the reimplanted segment proximally and distally was assessed according to the method proposed by Hsu Giant cell tumor is an infrequent and unpredictable lesion.21215The principal treatment modality of this locally aggressive benign tumor is surgery.166The defects resulting from tumor resection can be reconstructed using various approaches.23Several methods of resection arthrodesis were described. Yadav advocates the use dual fibular graft to bridge the intercalary defect after en bloc resection.et al described limb reconstruction with the callus distraction method in seven cases of tumors of the distal femur. The defect after tumor resection ranged from 8 to 20 cm.et al described the use of the Ilizarov technique for management of subarticular defects after en bloc resection or curettage and phenol cauterization in GCT of the proximal tibia in five patients. The mean length of bone defect was 5.7 cm, and the mean duration of external fixation was 233 days. The advantages of this method include the lack of graft rejection, the reattachment of ligaments and tendon to the bone, the prevention of articular collapse, early movement of the knee, and ankle joint and early weight-bearing. Disadvantages include the long duration of external fixator application, pin tract infection, wire breakage, and frustration of patients due to the long duration of treatment.26Kapukaya In our prospective clinical study, eight patients with Campanacci grade III giant cell tumor of the distal femur were treated using resection arthrodesis by dual nonvascularized fibular graft and knee fusion nail. At a mean follow-up of 4 years, all the patients were alive and free from any signs of local or systemic recurrence, with the graft united proximally and distally in all patients. Similar rates of union (100%) following resection arthrodesis of the knee in various tumors have been reported by other workers.et al,Direct comparison of the results of resection arthrodesis with endoprosthetic reconstruction in our series is not appropriate due to the differences in the disease processes and indications. However, all our patients achieved good functional results, which is comparable to that of endoprosthetic patients (78.3%). This result confirms the study conducted by Harris Wide resection is indicated in aggressive GCT of the distal femur with extensive soft tissue involvement. Resection of all involved muscle compartments is essential to obtain proper safety margin. This will make motor reconstruction of mobile endoprosthesis impossible, and consequently, arthrodesis will be a viable option. Arthrodesis can be achieved by the use of fibular grafts and intramedullary knee fusion nail with good to excellent results. An immovable knee in good alignment and functional position is considered to be an appropriate sacrifice to achieve a stable, pain-free limb.


Body weight is regulated by several mechanisms including genetic, physiologic, and behavioural factors. In obesity, an imbalance occurs between food intake and energy expenditure, which leads to an excess fat accumulation and negative health consequences. One of the major contributing factors to the increase of obesity worldwide is the inappropriate dietary intake and energy density of the diet, together with lower physical activity levels . Given tThis special issue focuses on recent research findings describing the effect of dietary and nutritional factors on the control of body weight and how would these findings be utilized towards the prevention and management of overweight and obesity.Nutritional experience in the beginning of development can lead to epigenetic changes in the genome that influence the risk of obesity in later life. This epigenetic memory that persists into adulthood may have a role in the development of obesity and could be a potential reason for metabolic diseases later in life .From epidemiological point of view, nutritional research in the area of obesity faces some challenges. These include choosing the optimal dietary assessment method, obtaining accurate and reproducible data, performing the proper data analysis, and drawing accurate conclusions. Dietary assessment relies on the ability of individuals to recall a complex collection of exposures and hence is associated with measurement error . To overDietary approaches for improving overweight and obesity are the focus of X. Guo et al. who report the result of a 12-week randomized controlled intervention study in a Chinese population with overweight and obesity. By studying the effects of a meal replacement with 388 kcal in total energy at dinner time, the authors report improvement of body composition and metabolic parameters in the study subjects. Interestingly, the glucose and blood pressure reduction demonstrated in the study subjects is gender-specific, leading the authors to emphasize on the importance of gender stratification when a nutritional intervention study is designed for improvement of health.The current issue's themes of “nutrients content and energy density in foods and beverages” and of “the dietary assessment methods in clinical studies” are investigated by H. Takase et al. who are describing their development of a dietary factor assessment tool for evaluating associations between visceral fat accumulation and major nutrients in Japanese adults. Their reported “tool” overcomes the need to actually measure the visceral fat mass which would not be feasible in large-population studies. By conducting dietary surveys and visceral fat measurement and analyzing the obtained data, the authors present the effect of appetite on visceral fat accumulation and on energy intake mainly from carbohydrate. In addition, they report the healthy food choice relation to visceral fat accumulation and to the dietary protein/fat ratio, dietary fiber/carbohydrate ratio, and N-3 fatty acid/fat ratio. Albeit being a large-population study, the authors propose its applicability at an individual level. Under the same theme, but conducting a different type of “cross-sectional” study, Charvet A. and F. G. Huffman describe their study entitled “Beverage intake and its effect on body weight status among WIC preschool-age children.” The intake of sugar-sweetened beverages is positively correlated with both the intakes of 100% fruit juice and milk, whereas water intake is negatively correlated. This study emphasizes on the need to limit 100% fruit juice intake and encourage water intake, which is important in order to reduce the risk for overweight and obesity in preschool-age children.Investigating the cultural base underlying mothers' choice for their children milk is another article in this special issue and is submitted by L. P. Kim and N. Mallo. By combining and interpreting phone surveys and one-on-one interviews, the researchers are able to examine the association between maternal perceptions of self-weight and child-weight status and milk consumption behavior. The researchers report that perceiving the child to be overweight by his/her mother will guide her to make a healthier food choice for the family, namely, choosing reduced-fat milk instead of whole milk. The study emphasizes on the importance of considering the mothers' culturally driven perceptions and the pediatrician's influence when designing obesity prevention strategies for Hispanic families.A further interesting article assessing different dietary and lifestyle factors as predictors of successful weight loss maintenance after follow-up for an 18-month period postbariatric surgery is presented by Masood A. and colleagues. The authors demonstrate that the patients' poor compliance to healthy dietary and behavioural lifestyle practices is the main cause for weight regain in this critical postbariatric period. This has led the authors to recommend more emphasis on the follow-ups and nutritional counseling sessions provided to the postbariatric patients to ensure maintaining the achieved beneficial weight loss after the surgery.