Spasticity is a common impairment that follows stroke, and it results typically in functional loss. For this reason, accurate quantification of spasticity has both diagnostic and therapeutic significance. The most widely used clinical assessment of spasticity is the modified Ashworth scale (MAS), an ordinal scale, but its validity, reliability and sensitivity have often been challenged. The present study addresses this deficit by examining whether quantitative measures of neural and muscular components of spasticity are valid, and whether they are strongly correlated with the MAS.We applied abrupt small amplitude joint stretches and Pseudorandom Binary Sequence (PRBS) perturbations to both paretic and non-paretic elbow and ankle joints of stroke survivors. Using advanced system identification techniques, we quantified the dynamic stiffness of these joints, and separated its muscular (intrinsic) and reflex components. The correlations between these quantitative measures and the MAS were investigated.We showed that our system identification technique is valid in characterizing the intrinsic and reflex stiffness and predicting the overall net torque. Conversely, our results reveal that there is no significant correlation between muscular and reflex torque/stiffness and the MAS magnitude. We also demonstrate that the slope and intercept of reflex and intrinsic stiffnesses plotted against the joint angle are not correlated with the MAS.Lack of significant correlation between our quantitative measures of stroke effects on spastic joints and the clinical assessment of muscle tone, as reflected in the MAS suggests that the MAS does not provide reliable information about the origins of the torque change associated with spasticity, or about its contributing components. Spasticity, a complex phenomenon, is one of the major sources of disability in neurological impairment including stroke. Spasticity is routinely defined as a motor disorder characterized by velocity-dependent increase in tonic stretch reflexes (muscle tone) with exaggerated tendon jerks, resulting from hyper excitability of the stretch reflex as one component of the upper motor neuron syndrome .However, spasticity may involve complex changes in both neural and muscular systems, beyond a velocity dependent reflex resistance alone. Various alterations in musculo-tendinous structure such as alterations in muscle fiber size and fiber type distributions and probably fiber length, together with changes in mechanical and morphological properties of intra- and extra-cellular materials may also contribute to spasticity -5. In thAshworth scale:[; Modified Ashworth scale: [Ashworth scale:[; Modified Ashworth scale:[Despite spasticity being an important clinical problem, there is no universally accepted clinical measure of spasticity. Rating scales like the Ashworth scale (AS) and the Modified Ashworth scale (MAS) are the most commonly used clinical measures of spasticity but have clear limitations. For example, earlier studies have shown that these scales (Ashworth and Modified Ashworth) have a measurable but weak association with results from reflex-related EMG parameters . Butth scale:,16-23; Mth scale:). TherefOne potential problem of both the AS and the MAS is that these scales do not indicate if the resistance is due to a hyperactive stretch reflex, or whether it results from increased visco-elasticity of other tissues surrounding the joint. The Ashworth scales are unable to separate the contribution of different components of the neuromuscular system, or to determine which factors contribute under different functional conditions (such as different joint angles and different joint movement velocities). This differentiation is important, since it helps us to characterize the nature and origins of mechanical abnormalities associated with spasticity – these remain fundamental issues in our field. This information is also valuable for diagnosis and therapy, as these components arise from different physiological mechanisms.Recently, we have developed a novel system identification technique -35 that This investigation was part of a cohort study designed to investigate the nature and origins of neural and mechanical abnormalities following a hemispheric stroke.For our ankle study, twenty individuals with a single hemispheric stroke (59.2 ± 9.9 years) and for the elbow study, fourteen individuals with stroke (56 ± 12.7 years) with the similar inclusion criteria were recruited from the clinical outpatient department at the Rehabilitation Institute of Chicago (RIC). All the subjects gave informed consent to the experimental procedures, which had been reviewed and approved by the Institutional Review Board of Northwestern University. The experiments were performed on both the paretic and non-paretic side of a total number of 34 stroke survivors.The following inclusion criteria were applied: stable medical condition, absence of aphasia or significant cognitive impairment, absence of motor or sensory deficits in the non-paretic side, absence of severe muscle wasting or major sensory deficits in the paretic limb, and spasticity in the involved ankle or elbow muscles for duration of at least 1 year.All stroke subjects were evaluated clinically using the MAS to assess muscle spasticity (range 1 to 5)  prior toThe MAS was applied to the paretic joints of both the ankle and elbow.Ashworth and Modified Ashworth scores are generated by manually manipulating the joint through its available range of motion and clinically recording the resistance to passive movements. In other words, the examiner seeks to assess how joint stiffness changes with joint position and velocity.For the elbow study, subjects were seated on an adjustable, chair with their forearm attached to the beam of a stiff, position controlled motor by a custom fitted fiberglass cast Fig. . For theThe joint stretching motor device operated as a position control servo driving elbow or ankle position to follow a command input. Joint position was recorded with a precision potentiometer. Torque was recorded using a 6-degree of freedom load cell and velocity was recorded by a tachometer for both experiments.In ankle joint studies, displacements in the plantar-flexion direction were taken as negative and those in the dorsi-flexion direction as positive, while in elbow joint, displacements in the flexion direction were taken as negative and those in the extension direction as positive. Also, a 90° angle of the elbow and ankle joint was considered to be the neutral position (NP) and defined as zero.Electromyograms (EMGs) from tibialis anterior and lateral gastrocnemius for ankle joint and from biceps,  brachioradialis, and triceps for the elbow were recorded using bipolar surface electrodes . Position, torque, and EMGs were filtered at 230 Hz to prevent aliasing, and sampled at 1 kHz by a 16 bit A/D.Ankle and elbow passive Range of Motion (ROMs) were measured with the subjects attached to the motor, but with the motor turned off. Their ankle and elbow joints were manually taken through maximum range . The typical angular range was from 50° plantar-flexion to 20° dorsi-flexion for ankle joint and from 45° flexion to 75° extension for the elbow joint.To evaluate the stretch reflex response and to measure reflex torque magnitude, a series of 10 pulses was applied to the elbow/ankle joint with displacement amplitude of 5 deg and width of 40 ms. Pulses were applied with the joint placed in the neutral position and the responses ensembled-averaged.To identify overall stiffness properties and to separate the reflex and intrinsic components, we used Pseudorandom Binary Sequence (PRBS) inputs with amplitude of 0.03 rad and a switching interval of 150 ms. Our previously published results demonstrated that these perturbations are appropriate to characterize the joint dynamic stiffness at each functional condition and to separate its intrinsic and reflex components . Also, tTrials were conducted at different joint positions from full plantar-flexion to maximum tolerable dorsi-flexion, with 5 degree intervals for ankle joint and from full flexion to maximum extension, with 15 degree intervals for elbow joint. Each position was examined under passive conditions, where subjects were instructed to remain relaxed. Following each trial, the torque and EMG signals were examined for evidence of non-stationarities or co-activation of other muscles. If there was evidence of either, the data were discarded and the trial was repeated.We used a parallel cascade system identification technique to identify reflex and intrinsic contributions to elbow/ankle dynamic stiffness. This technique, described in detail in earlier publications ,38, is eIntrinsic stiffness (top pathway) was estimated in terms of a linear Impulse Response Function (IRF), which is a curve relating position and torque. The IRF characterizes the behavior of the system over its entire range of frequencies. The reflex pathway (bottom pathway) was modeled as a differentiator in series with a delay, a half-wave rectifier (indicating the direction of stretch), and a dynamic linear element. Reflex stiffness was estimated by determining the IRF between half-waved rectified velocity as the input and reflex torque as the output. The intrinsic and reflex stiffness IRFs were convolved with the experimental input to predict the intrinsic and reflex torque, respectively.IRFs were assessed in terms of the percentage of the output (torque) variance accounted for (%VAF), defined as:TQ: the observed torque, where, N: the number of points, Intrinsic and reflex stiffness gains were calculated by fitting linear models to their IRF curves.p values less than 0.05 were considered significant.Standard t-tests procedures were used to test for significant changes in intrinsic and reflex stiffness between paretic and non-paretic joints. Results with Spearman correlation coefficients were computed to test the relationship between the stroke effects on intrinsic and reflex stiffness gains and Ashworth scores in the spastic, paretic elbow and ankles.Figure There are two distinct components to the torque response; a torque increase correlated with ankle position and its derivatives, beginning with no delay attributed to intrinsic mechanics, and a transient component associated with dorsiflexion displacements only, likely representing the contribution of stretch reflex mechanisms. The colored area reflects the integral of the torque response elicited by the rising edge of the pulse perturbation-it's a good (if indirect) estimate of reflex gain. Unexpectedly, both peak-reflex torque and reflex gain were larger in the subject with MAS score of 1 than in the subject with the MAS score of 3.K) and reflex stiffness (GR)at the neutral positions (the joint angle of 90°) around which elbow flexor reflexes, and ankle plantarflexor reflexes are expected to have their maximum relative contributions to overall stiffness [Beginning a short time after measuring the MAS, we quantified intrinsic stiffness  were then estimated as the difference in each property between the paretic and non-paretic joints.The stroke effects on each neuromuscular property  and on K (left row) versus the values of MAS for the elbow (left column) and ankle (right column). The scatter of the points and the low values of the correlation coefficient (r2 < 0.23) indicate that there was no significant relation between our objective quantitative measures of stroke effects on joint neuromuscular properties and the clinical assessment of muscle tone (via the MAS).Figure To further explore the possible correlation between our neuromuscular measures and the MAS, we also investigated the overall position-dependency of stroke effects; i.e. the differences between paretic and non-paretic sides as the starting joint angle were changed systematically.To ensure that the amplitudes of the reflex EMG and torque responses did not change with time, or as a result of the perturbation stimuli, pulse trials were injected before and after PRBS trials and the responses were compared. Torque and EMGs were recorded and ensemble-averaged. Changes in reflex torque of more than 20% before and after trials were taken as evidence of a change in the subject's state, due to fatigue or other factors, and trial was discarded. This occurred rarely and in most experiments no trials were discarded.GR and K as a function of elbow position over the ROM for both paretic and non-paretic limbs. GR was significantly larger in the paretic than non-paretic elbow at most positions (p < 0.0001) and the difference increased as the elbow was extended . K was strongly position dependent although this dependency was different for both sides. K increased sharply in the paretic limb as the elbow was moved from mid-flexion to full extension, whereas it decreased slowly and remained invariant in the contralateral limb.Similar to GR and K is well described by a first-order model as indicated by the superimposed solid lines . The stroke effects on reflex and intrinsic mechanical properties were estimated using the difference between the slope/intercepts of the paretic and the slope/intercepts of the non-paretic side. Since abnormalities in the GR and K of the ankle joint in people with stroke were basically similar to those of the elbow joint [The position-dependency of both ow joint , the strWe examined the position-dependent data for each of reflex and intrinsic mechanisms at each elbow and ankle joint separately. To correlate our results with this scale, we estimated the stroke effect on these joint mechanical properties  and K (right column) versus the values of MAS for the elbow  indicate that there was no significant relation between these variables, and consequently between our quantitative measures of stroke effects on joint mechanics and the MAS.Figures bow Fig.  and anklbow Fig. , respectIn our earlier studies, we demonstrated that the parallel-cascade model is valid and reliable for both upper and lower extremity and for normal and spastic subjects including SCI and stroke subjects -35,37. HTo further assess validity we convolved the intrinsic and reflex stiffness IRFs  with the PRBS input of trial 2 Fig.  to estimOur earlier studies demonstrated that both neural and muscular systems are altered in spastic limbs, but the changes were complex and depended on multiple factors. In the current study, we compared the changes in intrinsic and reflex stiffness at different joint angles in both upper and lower extremities with a standard clinical manual assessment of spasticity (Modified Ashworth). Our main result was that there was no significant relation between our quantitative measures of stroke effects on spastic joints and the clinical assessment of muscle tone, as reflected in the Ashworth scores.Although the Ashworth scales have often been used clinically, the question of its utility as a prognostic measure has not been fully addressed. This issue is important when these assessments are used to choose the appropriate treatment or as outcome measures following intervention, both clinically and for research.GR) was significantly larger in paretic than in the non-paretic side at most positions. However the position-dependence of reflex stiffness was broadly similar in both groups. Although the rate of change was a distinguishable feature between paretic and non-paretic sides, it was significantly greater in the paretic than in the non-paretic limb.Our findings in people with chronic hemiparetic stroke demonstrate that both reflex and intrinsic stiffnesses in elbow and ankle joints are strongly dependent on position, similar to our previous findings in SCI subjects . FurtherGiven these observations, the question arises as to how an ordinal scale like MAS can distinguish the rate of changes at different joint positions. While Ashworth scales give us one ordinal score to define joint spasticity, they certainly can't represent the joint dynamic stiffness and position- and velocity dependency of both intrinsic and reflex components.In our present study, we have investigated the biomechanical parameters of stretch reflex responses and their correlation with available spasticity scales. The Ashworth Scale produces a global assessment of the resistance to passive movement of an extremity, not just stretch-reflex hyperexcitability. Specifically, the Ashworth score is likely to be influenced by non-contractile soft-tissue properties, by persistent muscle activity (dystonia), by intrinsic joint stiffness, and by stretch reflex responses . Our resOthers have reported different results in broadly similar studies. Starsky et al. (2005) showed that biomechanical parameters, especially peak reflex torque at the highest speed, had a strong correlation with the AS. They suggested that the Ashworth measurements of spastic hypertonia are influenced strongly by stretch reflex hyperexcitability . The difGiven the known velocity dependence of the spastic reflex response, the control of the stretching velocity for the MAS in clinical practice is another controversial problem. Indeed, different investigators recommend different velocities to determine MAS or AS score but there is not consistency in these recommendations to date. To overcome this problem, recently, it has been suggested that other clinical scales like the Tardieu Scale which involves the use of two speeds of passive movement  could be superior than MAS in identifying the neural component of spasticity .A groundwork study of upper-limb reflex responses performed by Wolf et al. (1996) suggested that the reflex response onset threshold might also depend on speed. They demonstrated that the most consistent reflex responses were obtained at the faster speeds (1.0 radian/s) when starting at the more flexed position (90 degree) . The speWhile the position dependence of stretch reflex is one of the defining characteristics of spastic hypertonia, the question about which angular range should be used to distinguish the reflex effects from intrinsic effects has not been identified. With our approach, we were unable to detect a correlation between spasticity measures and MAS scores. Taken together we strongly believe that the MAS score doesn't give us any information about spasticity producing factors or contributing components.Our findings revealed that there was no significant correlation between the quantitative measures of neural and muscular components of joint dynamic stiffness and MAS scores, for either the upper extremity or the lower extremity. These findings indicate that Modified Ashworth scores are quite inconsistent with more objective measures of spasticity. Consequently, although the MAS seems to be a quick and easy clinical test to assess spasticity, and it remains widely accepted, it neither can characterize the contributions of neuromuscular components to spasticity nor their modulation with position and velocity of the joint stretch.If the purpose of a clinical assessment is to measure response to an intervention, it is important to distinguish the mechanical and neurogenic components of spasticity. Accordingly, the MAS might be used as a clinical measurement of muscle tone alongside other precise measures but it is not sufficient alone for monitoring the development of spasticity or progress of treatment.R: Reflex stiffness gain; K: Intrinsic stiffness gain; NP: Neutral Position.ROM: Range of Motion; MAS: Modified Ashworth Scale; EMGs: Electormygrams; PRBS: Pseudorandom Binary Sequence; IRF: Impulse Response Function; VAF: Variance Accounted for; GThe authors declare that they have no competing interests.LA participated in performing the experiments, interpreting data and writing the paper. WZR participated in interpreting data and writing the manuscript, RLH participated in interpreting data and writing the manuscript, and MMM designed the study, supervised data collection and analysis, and participated in interpreting and writing the manuscript. All authors read and approved the final manuscript.


Plantar ulceration is the commonest disability in leprosy and occurs in about 10 to 20% of leprosy patients. Various loco-regional flaps have been described for reconstruction of trophic ulcers; however, very large defects are not amenable to local flaps and free flaps form one of the important treatment options. We present a case of a post Hansen's trophic ulcer over the forefoot managed using a radial artery forearm free flap. Debridement of the osteomyelitic bone, removal of the bony prominences, coverage by a well-vascularised tissue, end-to-side arterial anastomosis, use of anterior tibial as the recipient vessel and good postoperative compliance in foot care on the part of the patient gave us good results. The term ‘plantar’ ulcer was introduced by Price in 1959. Various A middle-aged male, farmer by occupation, presented to us with recurrent trophic ulcer over the forefoot since the past four years. He had completed multi-drug therapy ten years back and was free of active disease. He was managed by various modalities including walking cast, regular dressings, skin grafting and fillet flap from the great toe and second toe at various centres including ours, but had developed a recurrence. He presented to us with a large trophic ulcer over the first, second and third metatarsal head region Figures  and b. TThe vein was tortuous in nature and was comparatively thin-walled as compared to non-leprosy patients.The intima of the arterial wall was greatly thickened.After suture removal, the patient was mobilized by gradual weight-bearing from Day 14 after providing protective footwear. The flap was firmly adhered to the undersurface with no difficulty in ambulation. The donor forearm had patchy raw areas, which healed with dressings. The patient was discharged with advice regarding foot care and ambulation, intermittent rest between long stretches of walks and regular use of footwear. After nine months of follow-up there was no recurrence of the ulcer and the flap was well settled Figures  and 4.Trophic ulcer is the most common complication seen in patients of leprosy, and all the treatment modalities have significant recurrence rates. Plantar ulcers in leprosy are not just defects of tissues like traumatic ulcers. It is a pathological process with loss of tissue, underlying osteomyelitis, loss of or decreased sensation, and decreased blood supply.Patients managed with rest and dressings have some foci of residual inflammation, and recur soon after the patient is mobilized. For smalLarger defects over the forefoot sole region have no availability of local tissue. Cross leg flaps cause increased morbidity in the form of stiffness of joints and potential for formation of bedsore. A Chopart or a Lisfranc amputation can be aFree tissue transfer can provide ample amount of vascularised tissue to the defect. Innervated microvascular flaps are generally not done in leprosy because the recipient nerve is also likely to be involved in the disease process and the flaps have very less chance of even getting protective sensations. Use of eWe preferred anterior tibial over the posterior tibial as the recipient vessel because:Posterior tibial is the more dominant vessel of the leg.Anastomosis to the posterior tibial artery would lead to a scar over the weight-bearing region and pressure over the pedicle on early ambulation.The patient is an integral part of the team, and meticulous, dedicated and lifelong care of the foot on his part is important for good post operative outcome.Debridement of the osteomyelitic bone, removal of the bony prominences, coverage by a well-vascularised tissue, end-to-side arterial anastomosis, use of anterior tibial vessels as recipient and good postoperative compliance in foot care on the part of the patient gave us good results.


A recently published systematic review indicated superiority of duodenum-preserving techniques when compared with pancreatoduodenectomy, for the treatment of patients with chronic pancreatitis in the head of the gland. A multicentre randomised trial to confirm these results is needed.ChroPac aims to investigate differences in quality of life, mortality and morbidity during 24 months after surgery (duodenum-preserving pancreatic head resection versus pancreatoduodenectomy) in patients with chronic pancreatitis of the pancreatic head.ChroPac is a randomised, controlled, observer and patient blinded multicentre surgical trial with two parallel comparison groups. The primary outcome measure will be the average quality of life during 24 months after surgery. Statistical analysis is based on the intention-to-treat population. Analysis of covariance will be applied for the intervention group comparison adjusting for age, centre and quality of life before surgery. Level of significance is set at 5% (two-sided) and sample size (n = 100 per group) is determined to assure a power of 90%.The ChroPac trial will explore important outcomes from different perspectives . Its pragmatic approach promises high external validity allowing a comprehensive evaluation of the surgical strategy for treatment of patients with chronic pancreatitis.Controlled-trials.com ISRCTN38973832 Chronic pancreatitis (CP) is defined as a continuous inflammatory process causing permanent structural damage ultimately resulting in impairment of the gland's exocrine and endocrine function ,2. The mA recently published randomised trial demonstrated superiority of surgical treatment (i. e. pancreaticojejunostomy) as compared with endoscopic drainage in patients with chronic pancreatitis and a distal pancreatic duct obstruction without an inflammatory mass, respectively . MoreoveChroPac aims to investigate differences in QoL during 24 months after surgery of DPPHR versus PD and mortality as well as general and pancreas-associated postoperative morbidity.ChroPac will be performed in thirteen trial sites with expertise for pancreatic surgery. Most of the participants were involved in a former multicentre-trial surgical trial for pancreatic left resection  carried out by the Study Centre of the German Surgical Society (SDGC). Thus the ChroPac trial group consists of international pancreatic surgeons at high-volume centres who also have expertise in trial conduction.All patients scheduled for primary elective surgery for chronic head-pancreatitis will be eligible, assuming their ability to understand the character and individual consequences of participation as well as written informed consent. Patients participating in another interventional trial with potential interference of intervention  and outcome  will be excluded.A total of 200 patients will be randomised and included in the analysis.Randomised, controlled, observer and patient blinded multicentre surgical trial with two parallel comparison groups.13 centres with high-level expertise for pancreatic surgery will contribute to recruitment of study patients. The duration of the trial for each participant is expected to be about 2 years. The duration of the overall trial is expected to be 5 years, including prearrangement and analysis. Recruitment of participants started in April 2009. The process of the trial conduct is illustrated in Figure http://www.randomizer.at. Block randomisation will be performed for each centre to achieve equal group sizes per centre.In order to achieve comparable intervention-groups, patients will be allocated concealed by preoperative randomisation at the day of surgery using a centralised web based tool Patients and outcome assessors will be blinded for the trial intervention.Any surgical technique that removes inflamed pancreatic tissue of the head without resection of the duodenum .PPW or CW.The procedures in both groups can be chosen according to preference of the surgeon which is based on his/her personal knowledge, skills and mainly the anatomical situation of the patient, since ChroPac aims to compare general surgical strategies rather than to compare certain modifications of the surgical procedure. Each participating centre performs the procedure according to local standards and according to the anatomical situation.The schedule of trial interventions is presented in Table No additional risks for study patients are awaited, since all surgical procedures carried out within ChroPac represent clinically established standard methods of treatment of chronic pancreatitis.The primary outcome measure of this trial is the average QoL during 24 months after surgery, measured 6, 12 and 24 months after surgery by the EORTC QLQ-C30 scale „physical functioning“ (PF-2). Secondary outcomes of: mortality, general  and pancreas-associated postoperative morbidity , operation time, intraoperative blood loss, initial postoperative hospital stay, reoperation, hospital stay related due to chronic pancreatitis within 24 months after randomisation, weight gain, development of exocrine insufficiency and new onset of diabetes mellitus will be assessed , outcome  and causality . The assessment is based on surgical findings and the clinical course of the patient. It needs to be done by the investigators in the participating trial centres. They will be furnished with written recommendations on how to assess causality with trial intervention within the ChroPac trial.Serious adverse events have to be reported by the attending physician to the principal investigator within 24 hours after the SAE becomes known.The sample size calculation is based on the primary outcome and the primary analysis for the intention-to-treat population. The prior assumption based on the evaluation of 2 clinical trials is a mean intervention group difference of 10% for the EORTC QLQ-C30 scale "physical functioning" (range 0 to 100) with an estimated standard deviation of 20% 24 months after the surgical intervention ,15.With a two-sided level of significance α = 5% and a power of 1-β = 90%, a sample size of 86 patients per intervention group is required to detect this difference with a two-sided Student's t-test. It is assumed that an application of an analysis of covariance in the evaluation will lead to a reduction of the standard deviation. Furthermore, using the average of the EORTC QLQ-C30 scale "physical functioning" measured after 6,12 and 24 months instead of the value 24 months after the surgical intervention will presumably sharpen and stabilize the extent of the intervention group difference as also differences between the intervention groups that occur earlier after the surgery are taken into account. It can therefore be expected that this will increase the actual power of the trial as compared with the power calculated on the basis of the above-mentioned assumptions.To compensate a potential loss in power caused by withdrawals, the sample size is increased by 15% and hence a total of 200 patients will be randomised.The confirmatory analysis is performed for the intention-to-treat (ITT) population.The two-sided null-hypothesis for the primary outcome measure states that both surgical interventions lead to the same expected average QoL scores during 24 months after surgery. This null-hypothesis will be tested by application of an analysis of covariance that adjusts for age, centre and EORTC QLQ-C30 scale „physical functioning“ before surgery. Missing values will be replaced by multiple imputation .Methods of descriptive data analysis will be used for the secondary outcome measures. Descriptive statistics will be calculated according to the scale level of the variables. Further analyses include the time course of the primary and secondary outcome measures. Additionally, sensitivity analyses will be conducted using different patient populations (per-protocol population excluding patients with relevant protocol violations), different imputation techniques for missing values, and different statistical methods for taking into account covariates. Graphical methods including scatter plots and boxplots will be used to visualize the findings of the trial.The safety analysis includes calculation of frequencies and rates of complications and serious adverse events reported in the two intervention groups. All analyses will be done using SAS Version 9.1. or higher.Patients are free to withdraw trial participation at their own request at any time and without giving reasons for their decision. Moreover, the primary investigator can withdraw study patients, if continuation of the trial would be detrimental to the patient's well being.Withdrawals will be documented in the CRF and in the patient's medical records and all ongoing serious adverse events have to be followed up.In case of any irregularities for example concerning the frequency or type of serious adverse events reported the principal investigator will inform the members of the independent DSMB without delay. At least once every 12 months, the DSMB will receive a written safety report. The result of the risk/benefit assessment will be reported to the principal investigator including recommendations concerning the continuation of the trial .No interim analysis is planned for ChroPac. The trial can be prematurely closed by the coordinating investigator in consultation with the steering committee, the Data Safety Monitoring Board and the responsible biometrician for the following reasons:• The incidence or severity of serious adverse events/morbidity in this trial indicates a potential health hazard caused by the trial treatment.• It appears that patients' enrolment is unsatisfactory with respect to quality and/or quantity or data recording is severely inaccurate and/or incomplete.• External evidence demanding a termination of the trial.In case of premature closure, the ethics committee has to be informed.ChroPac is funded by the DFG (Deutsche Forschungsgemeinschaft/project funding reference number SE 1682/2-1).Clinical Monitoring will be performed by an independent institution already experienced due to the tasks in some other surgical trials  . Monitorth 2009. Ethics approval was reviewed on April 20th 2009 and finally issued on May 19th 2009.Before the start of the trial, the trial protocol, informed consent document and any other trial documents were submitted to the independent ethics committee on January 30The procedures set out in this trial protocol, pertaining to the conduct, evaluation and documentation of this trial, are designed to ensure that all persons involved in the trial abide by Good Clinical Practice and the ethical principles described in the current revision of the Declaration of Helsinki. The trial will be carried out in keeping with local legal and regulatory requirements.http://www.controlled-trials.com and was given a unique number for a world-wide identification of this trial (ISRCTN38973832).The trial protocol was registered The basic and clinical research aims to identify parameters which influence the clinical outcome and may be useful for prognostic or therapeutical decision making in future with main focus on differences between the two surgical techniques (DPPHR vs. PPW). Serum parameters (20 ml blood) are investigated and pancreatic tissue is analysed by histology, as well as biochemical and molecular biological techniques in a standardised fashion. The molecular alterations are analysed in detail and assessed for its clinical implications. Important parameters of pancreatic tissue in chronic pancreatitis include inflammation and fibrosis and the correlation to pain and pain relief: standardised histological reporting of the degree of inflammation and fibrosis, identification and quantification of expression of pancreatic enzyme activation (e.g. trypsin), cytokines, chemokines, growth factors , stellate cells and its mediators, collagens are performed.Since pain is the most frequent indication for pancreatic surgery, a main focus is the investigation of pancreatic and peripancreatic nerves, neurotransmitter, nerve growth factors, and the correlation of pain, chronic inflammation and its relief by pancreatic resection. Potential markers include substance P, NK-1R, CGRP, VIP, NPY, PACAP, bradykinine, eicosanoids. Diabetes mellitus (endocrine insufficiency) has major impact on the long-term outcome of patients with chronic pancreatitis. The correlation of endocrine insufficiency and reduction of endocrine cells and products  in chronic pancreatitis are investigated. Chronic pancreatitis is a known risk factor for pancreatic cancer and premalignant lesions can be detected in inflammatory disease. Serum and tissue markers of carcinogenesis including K-ras, p-53 will be investigated and correlated with histology, clinical outcome, and surgical techniques used. All investigations will be performed centralised and all data stored in a separate database. This will be linked to the clinical database to answer the above-mentioned questions.Surgical treatment of chronic pancreatitis is indicated in the case of pancreatic head enlargement with local complications , suspicion of malignancy, and most commonly intractable pain ,4. Even The preferred surgical treatment of chronic pancreatitis has been a focus of studies and debate for decades. Several modifications of DPPHR were developed in the last years in order to reduce surgical trauma and compared with PD and PPW in four single centre RCTs for safety and efficacy. The results have been pooled in a systematic review and meta-analysis demonstrating a superiority of DPPHR in terms of QoL, exocrine insufficiency, length of hospital stay, weight gain and occupational rehabilitation .Although DPPHR is technically demanding these techniques seem to be promising due to lesser operative trauma and the gastrointestinal and metabolic integrity by preservation of the duodenum . TherefoThe research question of ChroPac is based on sufficient pilot data and since further single centre studies would not be able to strength the external validity, only a multicentre trial can demonstrate the superiority of DPPHR compared with PD in a setting close to daily practice. The Study Centre of the German Surgical Society (SDGC) as the coordinating organisation is experienced and has a proven track record in performing multicentre surgical trials, which highlight the SDGC's central role in trial design and administration and only go to strengthen the feasibility of the proposed trial . An inveHowever, the design of ChroPac raised some discussion during the design phase:"quality of life" was debated amongst surgeons, clinical investigators and methodological specialists. As a consequence, QoL will be evaluated by the EORTC QLQ-C30 subscore "physical functioning", which was validated and used in prior RCTs. Besides pain, several other aspects are summarized in this score and assessed from the patients' point of view, which justifies the validity of our primary outcome measure. As a secondary outcome all data of the full EORTC QLQ questionnaire will be collected in order to assess all dimensions of impairments and QoL.Firstly, the choice of the primary efficacy outcome measure Secondly, the specific trial design was a matter of debate. Since RCTs can be performed as efficacy (or explanatory) as well as effectiveness (or pragmatic) trials, the question to focus on internal validity  or on external validity  was of major importance. Thus, performing an efficacy trial promises distinct evaluation of two surgical procedures rather than surgical strategies. ChroPac as an efficacy trial would have required explicitly defined surgical procedures (e.g. Frey versus PPW) and study patients. However, patients' compliance and generalisability is known to be low in these study designs and four single RCTs are already available ,20. As aFirstly, the available systematic review showed that the comparison of duodenum-preserving techniques versus pancreatoduodenectomy is currently hampered by the methodological weakness of only small available RCTs. Secondly, focussing on a sufficient sample size and optimal data quality the pragmatic approach with compact trial data acquisition and reduced study visits accounts for the compliance of both the investigators and the participating study patients. Thirdly, even a pragmatic approach allows a translational research part for further investigations of nature and mechanisms of chronic pancreatitis. Moreover, ChroPac evaluates a complex intervention and has to consider the expertise of different surgeons, peri-operative treatment regimens and concomitant interventions. Since these varying components reflect the current state-of-the-art treatment of chronic pancreatitis in centres of excellence for pancreatic surgery, ChroPac provides the most efficient evaluation of the present standard.In summary, the ChroPac-Trial was designed to identify the best surgical strategy for treatment of chronic pancreatitis-either duodenum-preserving head resection or pancreatoduodenectomy. Focussing on a comparison of a general surgical strategy implies that the ChroPac-Trial will not be able to identify the best specific surgical technique in terms of available modifications of either PD or DPPHR. The aim of the ChroPac-Trial was therefore to maximize external validity while sustaining acceptable internal validity, which was accomplished by its pragmatic approach .The authors declare that they have no competing interests.MKD, TB, MWB and CMS designed and planned the ChroPac Trial. PC, CH, MG, HJS, JM and JW gave scientific input for the trials background, rationale and conduct. MK supervised the statistical background of the ChroPac Trial. JW conceived the translational research part. All authors read and approved the final manuscript.


Hernia of Morgagni occurs through an anterior defect in the diaphragm. Symptoms of these hernias are attributable to the herniated viscera. In our case, there was partial obstruction due to herniation of the distal stomach and pylorus into the right hemithorax that was reduced surgically through a right thoracolapaorotomy. Of special emphasis are the various modalities used to diagnose this condition in our case. Hernia through the foramen of Morgagni (HM) is uncommon in adults, accounting for only 3% of all treated diaphragmatic hernias. Hernia oA 72-year-old woman presented to emergency with recurrent abdominal pain and vomiting from 4 months and acute abdomen for 1 week. She complained of non-bilious, non-projectile vomiting containing food particles. Visible peristalsis was appreciated, which appeared aggravated after taking food. She did not complain of any history of trauma or breathlessness. On clinical examination, her vitals were stable as she had been resuscitated in emergency and she was evaluated with radiographs, endoscopy and computed tomographic (CT) examinations. Plain radiograph performed on the day of admission, 1 week from the onset of acute symptoms, showed opacification of the entire lower part of the right hemithorax with significant air lucency within . The opaDiaphragmatic hernia of Morgagni-Larrey is a rare entity that usually presents on the right side. These hernias occur in the anterior midline/paramedian location through the sternocostal hiatus of the diaphragm called the foramen of Morgagni. They are usually discovered incidentally or when they become symptomatic due to intestinal involvement (occlusive symptoms) or when respiratory dysfunction occurs.6et al.[et al.[In a review of the literature, Rodriquez et al. and Iso l.[et al. have desThey are usually asymptomatic and often found incidentally on chest radiography. Routine radiographic studies are usually sufficient to arrive at the diagnosis, but a CT scan and sonography may be necessary. Surgery is appropriate for the management of symptomatic adult patients with Morgagni hernias, particularly those with findings of intestinal strangulation, with laparoscopic treatment an alternative approach in selected cases. Few sympThis case report highlights the unusual presentation of obstructed viscera within a Morgagni's hernia in a senile and elderly patient. Of special emphasis are the various modalities used to diagnose this condition. Although uncommon, herniation of the omentum and the bowel can occur in the adult through the foramen of Morgagni. This report highlights a case scenario where an elderly patient may require emergency intervention on presentation because of the risk of strangulation of the bowel.


We report here a case of epithelioid sarcoma in the forearm of a 33-year-old male presenting with symptoms and signs of carpal tunnel syndrome originating from the direct involvement of the median nerve. Due to the slow growing of the tumor, the patient noticed the presence of tumor mass in his forearm after several months from the initial onset of the symptoms. Magnetic resonance imaging showed an 8 × 4 cm mass involving the median nerve in the middle part of the forearm, and histological analysis of the biopsy specimen revealed the diagnosis of epithelioid sarcoma. Radical surgical resection was performed in conjunction with adjuvant chemotherapy. The function of the flexors were restored by the multiple tendon transfers  with superficial cutaneous branch of radial nerve transfer to the resected median nerve. The function of the affected hand showed excellent with the DASH disability/symptom score of 22.5, and both the grasp power and sensory of the median nerve area has recovered up to 50% of the normal side. The patient returned to his original vocation and alive with continuous disease free at 3.5-year follow-up since initial treatment.  Epithelioid sarcoma (ES) is a rare distinctivesoft tissue neoplasm with a predilection for the distal part of extremities,more often in upper than lower extremities, involving the subcutaneous tissue,tendon and fascia, and more often occurring in young adults and in the malethan female –3. It moWe report a case of ES in the forearmpresenting median nerve palsy as carpal tunnel syndrome clinically, and beingtreated by initial surgery in a form of radical resection of the bulk of tumorwith finger flexors and median nerve as well. We describe the results ofsuccessful restoration of the finger flexors and median nerve function withmultiple tendon transfers and nerve transfer from radial superficial cutaneousnerve branch after the radical resection of the tumor located in the forearm.opponens pollicis and abductorpollicis brevis muscles.A 33-year-old male presented with complaintsof progressive sensory disturbance in median nerve area on his right hand sincethe Spring of 2005, and consulted a doctor in a district hospital then. Initialclinical assessment was the carpal tunnel syndrome, and he was conservativelytreated with medication for a while with a wrist brace. However, median nervepalsy gradually progressed with weakening of flexor carpi radialis (FCR), flexor digitorum superficialis (FDS), flexor digitorum profundus (FDP), and flexor pollicis longus (FPL)  see . Open bPL) see , then he2/5 d) and adriamycin was administered; however tumor showed no regression of the size, therefore thesurgery was performed in January 2006. Resection with curative wide surgicalmargin was achieved by en-block tumor mass resection in conjunction withsurrounding tissues including median nerve and a part of ulnar artery, FDS,FCR, FDP, FPL, and palmaris longus (PL). After the resection, reconstruction offinger flexor was performed in a way of tendon transfers with extensor indicus proprius (EIP) to flexor digitorum superficialis (FDS); extensor carpi radialis longus (ECRL) to flexor digitorum profundus (FDP);brachioradialis (BrR) to flexor pollicislongus (FPL), and extensor digitiminimi (EDM) for opponens reconstruction. The superficial cutaneous branch of radial nerve was transferredto the distal end of the resected median nerve in order to recover the sensorydeficit of median nerve under the sacrifice of sensory on dorsal side.Chemotherapy consisted of two courses ofifosfamide and adriamycin  was administered, then rehabilitationhas started. The fusion gene of SYT-SSX was not detected by reversetranscriptase-polymerase chain reaction in the specimen from definitivesurgery. Thus, the final diagnosis was confirmed as epithelioid sarcoma. He hasgained finger mobility and gotten back to his vocation within 3 months afterthe therapy. After 3 years of operation, the patient is alive with continuous disease free. The function of the affected hand showed DASH score of disability/symptomscore of 22.5 and optional component score  of 50 Epithelioid sarcoma (ES) is a rare malignantsoft tissue neoplasm, usually slow and indolent growing, but very aggressive inoccasion. Thus, the clinical behavior and outcome is unpredictable , 11. InHistologically, ES is often mistaken forbenign entities as well as other type of malignancies including synovialsarcoma. The metaplastic conversion of mesenchymal cells to epithelia in a fashion that is notdissimilar to synovial sarcoma is a possible cause , 13. TheAggressive radical excision seems to be mosteffective in preventing local recurrence as well as the occurrence of distantmetastasis. Halling et al. reported that no recurrence was observed in the patientstreated with wide or radical resection with adjuvant therapy of eitherchemotherapy or radiotherapy . HoweverThe administration of chemotherapy andradiotherapy for epithelioid sarcomas is still controversial. We cannotdetermine the advantage of the chemotherapy consisted of IFO, ADM, and CDDPfrom our case, because of the inefficiency as a neoadjuvant and the very shortfollowup duration. Several authors described that the use of chemotherapy andradiotherapy had no significant effect on the long-term survival , 11, 19.


Alzheimer's disease (AD) is a major neurodegenerative disorder leading to amnesia, cognitive impairment and dementia in the elderly. Usually this type of lesions results from dysfunctional protein cooperations in the biological pathways. In addition, AD progression is known to occur in different brain regions with particular features. Thus identification and analysis of crosstalk among dysregulated pathways as well as identification of their clusters in various diseased brain regions are expected to provide deep insights into the pathogenetic mechanism.Here we propose a network-based systems biology approach to detect the crosstalks among AD related pathways, as well as their dysfunctions in the six brain regions of AD patients. Through constructing a network of pathways, the relationships among AD pathway and its neighbor pathways are systematically investigated and visually presented by their intersections. We found that the significance degree of pathways related to the fatal disorders and the pathway overlapping strength can indicate the impacts of these neighbored pathways to AD development. Furthermore, the crosstalks among pathways reveal some evidence that the neighbor pathways of AD pathway closely cooperate and play important tasks in the AD progression.Our study identifies the common and distinct features of the dysfunctional crosstalk of pathways in various AD brain regions. The global pathway crosstalk network and the clusters of relevant pathways of AD provide evidence of cooperativity among pathways for potential pathogenesis of the neuron complex disease. Recently, systems biology approaches such as network-based methods have been successfully applied to elucidate the mechanism of diseases -3. For iBiological processes in a cell are carried out through interactions among many proteins , which aThe system complexity is coming from not only the cooperations of proteins in the form of pathways but also the interactions of pathways, i.e., the crosstalks of these pathways ,14. HereIn this paper, we focus on the spatial pathway clusters in different AD brain regions and the crosstalks among pathways by integrating protein-protein interaction (PPI) and gene expression data. Specifically we define dysfunctions of pathway as the responsive scores of these involved protein interactions from control cases to disease cases. Currently, several computational methods  have beeTo this end, we propose a network-based analysis for the crosstalks among AD related pathways in different AD brain regions by integrating protein-protein interactions and region-specific gene expression profiles. Initially, we build a protein network of pathways by collecting KEGG AD pathway and its neighbor pathways. Then, we propose a new scoring scheme to define the dysfunctions of protein interactions by combining gene expression and co-expression information. The crosstalks of these dysfunctional pathways are identified by their overlapping relationship in six AD brain regions. In addition, we cluster AD related pathways into groups by their significance of overlapping and the related pathways are sorted by their scores of dysregulation. Finally, we demonstrate that the brains process comprehensive crosstalk between pathways on the protein level due to AD progression in various regions.We built a network of pathways by integrating the pathway information from KEGG  and the β-amyloid accumulation, which is the main phenotype in AD patient brains [β accumulation [After weighting the network edges by integrating gene expression and co-expression data in six AD brain regions (see Methods), we can evaluate if the interactions among pathways are significant. The overlapping score and its significance can be used as a measurement of close relationship among them. Then a similarity matrix of these pathways was built and used to group the pathways into clusters. Figure t brains . Thus tht brains . It is amulation . The sig2+ signaling, which leads to transient increases in cytoplasmic free calcium that subsequently activates the calcium kinase and the phosphatase calcineurin [2+ is often crucial to AD, which is regarded as the calcium hypothesis [From the clusters, we identified the pathway modules with close relationships. The crosstalk of dysregulated pathways exist not only in the same clusters of pathway, but also exist within all its neighbor pathways. As to these AD related pathways, we defined the dysfunction score and its significance criterion (see Methods). We individually identified the significance of their dysfunctions in six AD brain regions. Table cineurin . It is npothesis . If the pothesis . In summThe rank of dysfunctional significance implies the degree of inflections from neighbor pathways to AD pathway. In EC region, there are several other dysfunctionally significant neighbors in addition to the top 5 pathways in Table n is the number of nodes in the network, ƒ is the number of proteins annotated with a particular GO function, m is the number of proteins involved in the pathway and k is the frequency of the GO term. We identified the GO function enrichment of the pathways in six brain regions respectively. The results of the top three GO terms in part of the pathways are shown in Figure ß accumulation in AD progression. The significant functions of neighbor pathways provide a flow of transporting of molecules  of substances into, out of, within, or between cells . Other pathways introduce one or more phosphate groups into a phosphoinositide (GO:0046854). Especially, Apoptosis pathway (hsa04210) enriches the conversion of proteins, and induces or sustains apoptosis to an active form (GO:0008633). From the significant GO enrichments, we know the crosstalk of GO biological processes during the disease development between the pathways in various brain regions. The most popular hypotheses of AD mechanism is the amyloid cascade hypothesis and tau hypothesis, and the disease is caused by the accumulation of abnormally folded Aß and tau proteins in the brain [where he brain . The GO In this work, we identified the dysfunctional crosstalk of AD related pathways in different brain regions based on a novel network-based method. In the AD protein network, we first built the network of pathways by integrating KEGG pathways information and protein-protein ensemble interactions. The crosstalk of pathways underlying their interaction significance and their dysfunctional score were detected by corresponding gene transciptome information in six disease brain regions respectively. The analysis of dysfunctional crosstalk with AD pathway is based on the pathway clusters and all its neighbor pathways as well as their clusters related to AD pathway. Some of the identified dysfunctional crosstalk between the pathways are consistent with our knowledge for AD. Some of them provides valuable alternatives for AD mechanism, especially from the pathway relationship perspective. The interaction of these dysfunctional pathways provides more insights for the AD progression in various brain regions.When identifying the crosstalk between the pathways in AD disease brain regions, we only chose AD pathway and its neighbor pathways. Temporarily, many important pathways in KEGG were not considered in this study if they do not contain overlapped genes with the AD pathway. In other words, we only studied the neighbor pathways with direct interaction with AD pathway. The strategy is based on the straightforward assumption that the nearest neighbor pathways imply the close relationship with AD pathway. We acknowledge that the pathways with indirect interactions with AD pathway might also transfer potential dysfunctions to AD and then are important for the pathway clusters and dysfunctional processes. These pathways should be further explored in future.Additionally, our method can be similarly applied to all the annotated pathways. Moreover, clustering of those AD related pathways into pathway clusters provide more information. The similar clusters in different brain regions show that the crosstalks among these pathways are relatively consistent in different brain tissues. This indicates the common or identical dysfunctions in various AD brain regions. The clusters containing AD pathway imply that the neurodegenerative diseases have close relationships, which provide evidence for the effectiveness of our method.We collected AD related gene sets of pathway and linked the genes by our integrated PPI network. Then we mapped the region-specific gene expression profiling to the protein interaction network. The edges are scored by the Fisher's method by combining the statistical significance p-values of differential expression and co-expression. The dysfunctions between two proteins are simultaneously evaluated by their gene expression and correlation in various disease brain regions individually. The edge-scoring scheme considers the differential expression from the control to the disease and the correlation information in the disease cases. The meta-analysis is applied to integrate p-values between the interacting proteins with independence assumption . In the We clustered AD and its neighbor pathways by their statistical significance of overlapping scores. The interaction significance are represented as a distance matrix. From hierarchical clustering, we identified the pathway correlations and detected their relationship in six AD brain regions respectively. We identified the crosstalk of these pathways in the clustered groups as well as with their neighbor pathways, especially with AD pathway. The crosstalk between pathways other than AD pathway might also contribute to AD by their cooperative dysfunctions. In this paper, we considered the nearest neighbor pathways with AD pathway. A future research direction is to identify the dysfunction of indirect interaction between one pathway and AD pathway. Moreover, the crosstalk with AD pathway is not only related to the interaction, but also related to their own dysfunctions. We identified the significant dysfunctions of the pathways in every brain regions. Some of them are those with high interaction significance with AD pathway. These pathways are important for the dysfunctional crosstalk with AD process during the development in various brain regions. We identified the crosstalk among these pathways and provided detailed analysis of the interactive dysfunctions with AD pathway. We also identified the biological processes enrichments underlying these interacted pathways. The GO functional linkages of these pathways provided more implications for their dysfunctional crosstalk.We identified the pathway clusters in six functionally important brain regions respectively. There are some regional features of the crosstalk, such as the difference of the rank of pathways in Table In this paper, a network-based approach was used to analyze the crosstalks among AD related pathways. The clusters of pathways were identified and the related pathways were ranked by their dysfunctional scores. The dysfunctional crosstalks of pathways are found and analyzed in six AD brain regions. The results are consistent with our prior knowledge of AD. The crosstalk of pathways presents new alternative insights for AD pathology. Our work shows that comprehensive and system-wide analysis provides evidence for neurodegenerative AD disorder and complements the traditional component-based approaches.We downloaded the AD pathway and all its neighbor pathways from KEGG. Here the neighbor pathways are defined as those pathways which have at least one overlapping gene with AD pathway. In total there are 77 neighbor pathways in KEGG intersecting with AD pathway  and diff(y) are differential expression assessments of gene x and gene y, respectively. corr(x‚y) represents their correlation between gene x and gene y. f is a general data integration method that can handle multiple data sources differing in statistical power. Where k = 3, p1 and p2 are the p-values of differential expression of two nodes, p3 is the p-value of their co-expression. The gene profiles for different specific regions of AD were mapped respectively and we obtained six condition-based weighted protein interaction networks  of every pathway, i.e.,To define the dysfunction of a pathway 6 times on randomly generated pathways of the same size as that of pathway P. The frequency of scores that are larger than Sp is used as the significance p-value of pathway P to describe its dysregulation in one specific brain region. In every region, we get a ranked list of dysfunctional pathways (see Figure . To estimate a p-value for significance of this pathway, we iteratively compute similar scores 10AD: Alzheimer's disease; EC: entorhinal cortex; HIP: hippocampus; MTG: middle temporal gyrus; PC: posterior cingulated cortex; SFG: superior frontal gyrus; VCX: visual cortex; PPI: protein-protein interaction; GO: gene ontology; NCBI: national center for biotechnology information; KEGG: Kyoto encyclopedia of genes and genomes; HPRD: human protein reference database; MINT: molecular interactions database; BIND: biomolecular interaction network database; BioGrid: biological general repository for interaction datasets; IntAct: molecular interaction database; GEO: gene expression omnibus; RMA: Robust multi-array average; DAVID: Database for annotation, visualization and integrated discoveryThe authors declare that they have no competing interests.ZPL and LC conceived the research. ZPL designed and performed the study and YW improved it. XSZ gave valuable suggestions and improvements. LC and XSZ supervised the project. All authors wrote and approved the manuscript.Description of AD related pathways.Click here for fileSource data of the constructed protein network of pathways.Click here for file


Cor triatriatum is a rare congenital heart defect characterized by the presence of a fibromuscular membrane dividing the left atrium into two distinct chambers. Lipomatous hypertrophy of the atrial septum is an infrequently observed benign abnormality caused by large fatty tissue deposits in the interatrial septum. An increased incidence of atrial arrhythmias is described in both pathologies, while a significant obstruction of blood flow mimicking mitral stenosis is typically manifested in cor triatriatum. We report the case of a 75-year-old woman with a previously undescribed association of the above stated abnormalities detected by both transthoracic and transeosophageal echocardiography. Diagnosis was confirmed by means of computed tomography. The singular physiologic and anatomic factors underlying survival until such a late age are described. The diagnostic, therapeutic and surgical management is discussed and a short review of the literature performed. Cor triatriatum (CT), first described by Church in 1868, is a rare congenital heart disease . It is characterized by the presence of a fibromuscular diaphragm which divides the left atrium into two chambers: a posterosuperior chamber receiving blood flow from the pulmonary veins and an anteroinferior chamber communicating with the mitral valve and the left atrial appendage. The two chambers generally communicate through one or more openings in the intra-atrial membrane ,6. No unLH of the interatrial septum was first described by Prior in 1964, as a consequence of the detection of a non-encapsulated hypertrophic alteration of the normal structures of the interatrial septum . This tuSurgical therapy is used to treat LH of the interatrial septum only in patients displaying an obstruction of the superior caval vein or an intractable rhythm disturbance . In our If complete excision of the tumour is scheduled, reconstruction of the interatrial septum using either autologous pericardium or Dacron must be undertaken . On the A 75-year-old female patient was referred to our clinical Centre following the onset of increasing dyspnea, fatigue and chronic fibrillation. The patient had a medical history of arterial hypertension treated with beta blockers and calcium antagonists and rheumatic arthritis.2). Systemic blood pressure was 132/87 and respiratory rate was 21 breaths per min. Upper venous congestion was visible from the pulse of jugular veins. Heart sounds were arrhythmic and wadded with a grade 1-2/6 systolic murmur over the left sternal edge. Basal and medium lungs auscultation revealed crackling wheezes.Physical examination revealed an obese subject . In addition, the most parts of fatty tissue mass were removed, and sent for urgent histological evaluation. Pathohistological examination of the resected tissue showed a pattern typical of LH Due to invasion of the tumour into the skeleton of the heart and histological findings of non-malignancy, no attempt was made to remove the tumour mass. Ultimately, subsequent to cardioplegic arrest of the heart, coronary artery bypass grafting was performed.The postoperative course was uncomplicated and the patient was discharged from hospital one week after surgery with a saturation of 98%.In conclusion, this previously unreported association of CT and LH of the atrial septum contributed to the development of atrial fibrillation and subsequent heart failure. Clinical presentation of CT was delayed by the original probably large opening in the diaphragm. Subsequent fibrosis and calcification of the orifice manifested on ageing, and the development of both mitral stenosis and atrial fibrillation may account for the late conversion to a symptomatic state.Transthoracic and transoesophageal echocardiography and computed tomography (or magnetic resonance imaging) represent the diagnostic tools of choice. Computed tomography was performed in order to better define the three-dimensional anatomy of the lesions, with a view to cardiac surgery. On the contrary, both transthoracic and transoesophageal echocardiography provide only bi-dimensional images. In this respect, three-dimensional echocardiography could be a potential alternative to computed tomography, being even more safe (no exposure to radiations) and cost-effective . The tecCT: cor triatriatum; LH: lipomatous hypertrophy.Written informed consent was obtained from the patient for the publication of her case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.The authors declare that they have no competing interests.PPB: acquisition of data, conception and design - RT: revising the manuscript critically - GM: final approval of the version to be published. All authors have read and approved the final manuscript.


In children with Prader Willi syndrome (PWS), besides growth hormone (GH) therapy, control of the food environment and regular exercise, surgical treatment of scoliosis deformities seems the treatment of choice, even though the risks of spinal surgery in this specific population is very high. Therefore the question arises as to whether the risks of spinal surgery outweigh the benefits in a condition, which bears significant risks per se. The purpose of this systematic review of the Pub Med literature was to find mid or long-term results of spinal fusion surgery in patients with PWS, and to present the conservative treatment in a case study of nine patients with this condition.Types of studies included; all kinds of studies; retrospective and prospective ones, which reported upon the outcome of scoliosis surgery in patients with PWS.Types of participants included: patients with scoliosis and PWS.Type of intervention: surgery.Search strategy for identification of the studies; Pub Med; limited to English language and bibliographies of all reviewed articles.Nine patients with PWS from our data-base treated conservatively have been found, being 19 years or over at the time this study has been performed. The results of conservative management are described and related to the natural history and treatment results found in the Pub Med review.From 2210 titles displayed in the Pub Med database with the key word being "Prader Willi syndrome", 5 different papers were displayed at the date of the search containing some information on the outcome of surgery and none appeared to contain a mid or long-term follow-up. The PWS patients treated conservatively from our series all stayed below 70° and some of which improved.If the curve of scoliosis patients with PWS can be kept within certain limits  conservatively, this treatment seems to have fewer complications than surgical treatments. The results of our retrospective study of nine patients demonstrate that scoliosis in this entity plays only a minor role and surgery is unnecessary when high quality conservative management exists.There is lack of the long follow-up studies in post-surgical cases in patients with PWS and scoliosis. The rate of complications of spinal fusion in patients with PWS and scoliosis is very high and the death rates have been found to be higher than in patients with Adolescent Idiopathic Scoliosis (AIS). The long-term side-effects of the intervention are detrimental, so that the risk-benefit ratio favours the conservative approaches over spinal fusion surgery. As pointed out by Molinas et al.  the rareCassidy and Driscoll describe PWS to be a highly variable genetic disorder affecting multiple body systems whose most consistent major manifestations include hypotonia with poor suck and poor weight gain in infancy; mild learning difficulties, hypogonadism, growth hormone insufficiency causing short stature for the family, early childhood-onset hyperphagia and obesity, characteristic appearance, and behavioral and sometimes psychiatric disturbance. PWS is an example of a genetic condition involving genomic imprinting. It can occur by three main mechanisms, which lead to absence of expression of paternally inherited genes in the 15q11.2–q13 region: paternal microdeletion, maternal uniparental disomy, and imprinting defect .Patel et al demonstrated that PWS patients may have significantly raised levels of the inflammatory marker hs-CRP and evidence of microcirculatory dysfunction, both of which are associated with coronary artery disease and early sudden death. The sinus node dysfunction may in itself be a risk factor for sudden cardiac death .Some authors reported on primary lymphedema in a patient with PWS, an association, which is often missed .Patients with PWS drawn from an adult and adolescent PWS clinic have a high rate of sleep-disordered breathing -22. TherObesity and hypogonadism in patients with PWS are also frequently associated with slipped capital femoral epiphysis (SCFE) . SlippedThe Italian National Survey for Prader-Willi syndrome offers an insight into the subject "causes of death in PWS": A total of 212 subjects had received GH treatment, of which 141 were still receiving therapy, while the remaining 71 had stopped. In children and adolescents (233 cases), 89 subjects had never undergone GH therapy. Eighteen PWS patients had died in the past 20 years. Obesity-related cardiovascular and respiratory diseases were the cause of death, both during childhood and after 18 years of age. Three children died suddenly whilst undergoing GH therapy. Respiratory infection and cardiac illness were the causes of death in two cases. There was no definitive cause of death found in the third case . SeveralScoliosis seems a major concern for patients with Prader-Willi syndrome, and a regular  systematic back examination is mandated . The rolBesides GH therapy from early childhood, control of the food environment Figure  and reguIn order to promote an intervention for a specific condition, it must be demonstrated that; 1) the natural history of the condition is undesirable; 2) the intervention alters this natural history in a favourable and reproducible manner; 3) the complications are minimal and 4) the long term side-effects of the intervention are not detrimental, so that the risk-benefit ratio favours the intervention over the condition's natural history .As already discussed, the natural history of PWS is considerably undesirable. However scientifically we have to demonstrate that the intervention (surgery) alters the natural history of PWS in a favourable and reproducible manner. It is necessary to demonstrate that the long term side-effects of spinal fusion are not detrimental, so that the risk-benefit ratio favours the intervention over the condition's natural history, but the rate of complications has been revealed to be relatively high.Purpose of this systematic review of the Pub Med literature was to find mid or long-term results of spinal fusion surgery in patients with PWS.all kinds of studies, retrospective and prospective ones, obviously reporting on the outcome of scoliosis surgery in patients with PWS have been taken into account.patients with scoliosis and PWS.Search strategy for identification of the studies; Pub Med; limited to English language and bibliographies of all reviewed articles, where appropriate.The search strategy included the terms; 'Scoliosis'; 'Prader Willi syndrome'; 'spine surgery'; 'scoliosis surgery'; 'spondylodesis'; 'spinal instrumentation' and 'spine fusion'.An electronic search was performed and the studies were selected based on title, abstract and key words. When appropriate a full copy of the articles was printed to determine whether or not they met the inclusion criteria. Additionally, the references of all included articles were checked for further papers that might meet the inclusion criteria.A case study of patients with this condition has been investigated to estimate as to whether Prader-Willi patients with scoliosis may benefit from conservative scoliosis management. Nine Patients with this condition have been found in our out-patient database. Five of these patients  today are 19 years and older and therefore are without any significant residual growth. Average Cobb angle was 47 degrees (34 – 66 degrees), average observation time was 6.4 years.th of November, when the search of literature was performed 2210 titles displayed in the PUB Med database with the key word being "Prader Willi syndrome", only.On the 181279 titles displayed with the key words "Prader Willi syndrome" and "Symptoms" and the most important titles are cited in the background section.5 different papers are displayed with respect to treatment outcomes ,38,42-44Accadbled et al.  report oIn another study only one of 92 patients reported to have had spinal fusion had PWS One study, which was not displayed in our search for outcomes of spinal fusion in patients with PWS is a case report only of one patient with Prader Willi syndrome having had spinal surgery .Nine patients with PWS from our data base treated conservatively have been found, being 19 years or over at the time this study has been performed. The results of conservative management are described and related to the natural history and treatment results found in the Pub Med review. Two of the five patients being 19 years or over progressed. Average Cobb angle after follow-up was 52 degrees. No progression beyond 70 degrees has been found after cessation of growth. In one patient the curve deteriorated in response to this patient reducing the brace wearing times and therefore this negative result was clearly due to non-compliance  has to be regarded to be the main indication for spinal fusion -47.Considering the fact that the complications of patients with PWS undergoing this surgery are high ,41,45-47 In this present study only one patient showed a significant progression to 70 degrees due to non-compliance and psychiatric problems Figure . The remIf the curve of scoliosis patients with PWS can be kept within certain limits  conservative treatment should be the preferred treatment option, considering the lack of evidence there is for the long term outcome of surgery and the high risks of this intervention. When treated conservatively according to the latest standards , scoliosOf course we cannot compare our sample of patients to the sample of the series treated surgically by Accadbled , whose aScoliosis rehabilitation -54 demon1. There is no long-term follow up on treatment outcomes available for PWS and scoliosis.2. The rate of complications (including death) of spinal fusion in patients with PWS and scoliosis is very high.3. The long-term side-effects of the intervention are detrimental, so that the risk-benefit ratio favours the conservative approaches over spinal fusion surgery.Written informed consent was obtained from the patients for publication of their cases and any accompanying images.The authors declare that they have no competing interests.HRW: manuscript writing, Pub Med research, Patient acquisition, Patient data base, database searches and Figures. DG: copyediting.


Mental fatigue, cognitive disorders, and sleep disturbances seen in chronic fatigue syndrome (CFS) may be attributed to cholinergic deficit. A functional deficiency of cholinergic neurotransmission may cause the hypothalamic-pituitary-adrenal axis hypoactivity seen in CFS. Therefore, we investigated the alterations in stress hormones such as cortisol and dehydroepiandrosterone sulfate (DHEAS) in CFS patients before and after 4-week administration of galantamine hydrobromide, a selective acetylcholinesterase inhibitor, and aimed to investigate whether there are any relationships between the probable hormonal changes and cholinergic treatment.Basal levels of cortisol and DHEAS were measured in 29 untreated CFS patients who were diagnosed according to Centers for Disease Control (CDC) criteria and in 20 healthy controls. In the patient group, four weeks after 8 mg/d galantamine hydrobromide treatment, cortisol and DHEAS levels were measured again. After the treatment 22 patients who stayed in study were divided into two subgroups as responders and nonresponders according to the reduction in their Newcastle Research Group ME/CFS Score Card (NRG) scores.Important findings of this study are lower pre-and post-treatment cortisol levels and in all CFS patients compared to controls ; higher basal DHEAS values and higher DHEAS/cortisol molar ratios which were normalized following four weeks' treatment with 8 mg/d galantamine hydrobromide in the treatment-respondent group .The findings of the decrease in basal DHEAS levels and DHEAS/cortisol molar ratios normalizing with galantamine treatment may give some support to the cholinergic deficit hypothesis in CFS. Diagnostic criteria for chronic fatigue syndrome (CFS) include lymphadenopathy, sore throat, cognitive impairment, headache, muscle and joint pains and tiredness following activity in addition to fatigue that lasts for more than six months, leading to disability and that does not improve with rest.The etiology of CFS is not clear. However, accumulating data suggest that underlying pathophysiology of stress related disorders such as CFS involves alterations in the reactivity of HPA axis response to physical and psychosocial stress and as a consequence it might cause a HPA axis switch from hyper-to hypofunction position.11Recently, dehydroepiandrosterone (DHEA) produced in the zona reticularis of the adrenal cortex and its more stable sulfate derivative  became the focus of attention in addition to glucocorticoids produced in the zona fasciculate in CFS. DHEA and DHEAS are neurosteroids that are also produced in the brain and their release from adrenal cortex is under the control of adrenocorticotrophic hormone (ACTH).15Parker et al.18Studies conducted in both animals and humans demonstrate positive effects of DHEA and DHEAS on memory (promnestic effects) by increasing acetylcholine release from the hippocampus.26In this study, we investigated probable alterations in stress hormones such as cortisol and DHEAS in CFS patients before and after the treatment with galantamine hydrobromide.Twenty-nine CFS patients who were diagnosed according to Centers for Disease Control (CDC)This study was approved by the local Ethics Committee. Written informed consent was obtained from each subject after the study was explained to them.In the patients the first stage involved a standard clinical evaluation and the administration of the following clinical scales: the Hamilton Depression Rating Scale (HAM-D);At the end of the treatment period we separated our patients into two subgroups: responders (n=10) and non-responders (n=12). Twenty percent and more reductions in NRG scores were accepted as a response to treatment arbitrarily.32Serum cortisol levels  and DHEAS levels  were measured by the radioimmunoassay (RIA) method.2 test. The significance of differences between age, body mass index (BMI), and clinical scale scores of the patients and controls was assessed with a t-test for independent groups. To compare hormone levels of the patients and controls a two-way analysis of variance (ANOVA) test was performed by taking the presence of disorder and gender as fixed factors, and age and BMI as covariates. A repeated measure ANOVA test was carried out for the comparison of the hormone levels of the patients before and after the treatment. The same tests were used for analyses of subgroups according to the response to the treatment (responders and non-responders). Pearson's correlation test was performed to investigate the relationships between hormone levels and clinical and demographical variables in the patients and controls. The changes in hormonal values and those in clinical scales were calculated as delta values by subtracting the post-treatment values from the pre-treatment values.Data distributions for each hormonal evaluation were normal according to the Kolmogorov-Smirnov test. The patients and controls were compared with respect to sex using the χNo statistically significant differences were observed between the two groups according to age, gender, or BMI variants. The scores of clinical scales in the patients with CFS were higher than those in the controls . NRG scoThe pre-treatment basal cortisol levels of the patients were significantly lower than those of the controls . No significant difference was found in serum DHEAS levels between the patients and the controls before the treatment , although the patients had elevated DHEAS/cortisol molar ratios compared to the controls . The cortisol values of the patients continued to be low after the treatment compared to the controls ; however, the post-treatment basal DHEAS values and DHEAS/cortisol molar ratios were similar to those of the controls .In the patient group, there was no significant difference in serum cortisol levels and DHEAS/cortisol molar ratio of the patients between before  and after  the treatment, according to a repeated measure ANOVA test . After the treatment DHEAS levels (mean±SD: 1114.77±638.60) were significantly decreased compared to those before the treatment (mean±SD: 1536.37±1094.72).When the CFS patients were separated as responders and nonresponders to the treatment, serum cortisol values of the two subgroups did not differ from those of the controls before or after the treatment. The pre-treatment DHEAS values and DHEAS/cortisol molar ratios of the responders were significantly higher than those of the controls . No significant difference was found in the pre-treatment DHEAS/cortisol molar ratios between the non-responders and the controls . There were no statistically significant differences in the pre-treatment DHEAS values and DHEAS/cortisol molar ratios between the responders and the non-responders . A comparison of the pre-treatment and the post-treatment hormone values demonstrated that the pre-treatment DHEAS values were only significantly higher than the post-treatment DHEAS values in responders Figure 1Figure 1.No statistically significant difference was found in the hormonal changes between the male patients and the female patients .A negative correlation was observed between the DHEAS values and age in the patient and control groups as expected . There were strong positive correlations between the changes in the DHEAS values (delta DHEAS) and those in scores of depression (delta HAM-D) and anxiety scores (delta HAM-A) in the responder group , but not in the non-responder group . The correlation between delta DHEAS and delta NRG scores was not statistically significant in the responder or non-responder groups . No correlation was found between the changes in DHEAS/cortisol and those in clinical scales.The important findings of this study are: 1) the absence of any effect of the galantamine treatment on lowered cortisol levels in CFS patients, 2) higher basal DHEAS values and higher DHEAS/cortisol molar ratios which were normalized following four weeks' treatment with 8 mg/d galantamine hydrobromide in the treatment-respondent group.Many studies of patients with CFS have found HPA axis dysregulation and hypocortisolism. In these studies cortisol levels were decreased in 24-hour urine,34The finding of unchanged cortisol level after galantamine treatment of this study is consistent with a recent study by Blacker et al.26How can we explain the finding of the study that while cortisol levels remained lower throughout the galantamine treatment some patients showed symptomatic improvement at partial level? It has been suggested that a functional deficiency of cholinergic neurotransmission may result in hypoactive HPA axis under stress conditionsGiven the findings of lower pre- and post-treatment cortisol levels, higher pre-treatment DHEAS levels compared to post-treatment, and higher DHEAS/cortisol molar ratios in the patient group, we can suggest that there may be a disturbance in the 'metabolic shift' from androgens to glucocorticoids.DHEA/cortisol or DHEAS/cortisol molar ratios were used in many studies as variants that reflected the homeostasis between androgens and glucocorticoids at adrenal level.Some studies have reported lowThe controversies in all these studies might be explained by the differences in clinical characteristics , methodological discrepancies (differences in the timing of blood sampling or laboratory techniques), and other factors that might affect functions of the HPA axis, like inactivity. Our study had the advantages of including pure and untreated CFS patients.When we separated our patients into two subgroups as responders and non-responders to treatment, the pre-treatment basal DHEAS levels and DHEAS/cortisol molar ratios of the responders were significantly higher than those of the controls; however, it was interesting to find the values of the non-responders similar to those of the controls. To our knowledge, these findings are unique in the literature. It was concluded that high levels of pre-treatment DHEAS activity and its ratio to cortisol might be an indicator of the responsiveness to treatment.It is possible to explain the high pre-treatment basal DHEAS levels and DHEAS/cortisol molar ratio in responders and the decrease in DHEAS levels with galantamine hydrobromide treatment in all CFS patients and especially in responders in several ways. The first is that high pre-treatment DHEAS levels and DHEAS/cortisol molar ratio in responders may be due to hypocortisolism supposed to be present in CFS. Improvement in relative hypocortisolism with treatment may provide a return to the normal DHEAS pattern. However, we did not observe any significant increase in cortisol levels. A longer period might be needed for such a finding. The second possible explanation is that some abnormalities in the metabolic pathway of DHEAS like 21-hydroxylase enzyme deficitThere are several limitations of the study. A small number of patients and the absence of placebo control group might have prevented us from observing the therapeutic and hormonal effects of the galantamine more accurately. Additionally, the short duration of the treatment might obscure the long-term effects of the drug on fatigue scores or on the hormones such as cortisol.In conclusion, decreases in basal DHEAS levels and DHEAS/cortisol molar ratios in CFS patients with galantamine treatment may somewhat support the hypothesis that cholinergic deficit may be present in CFS. On the other hand, DHEAS findings of responders suggest that high pre-treatment values of this hormone may be an indicator of the treatment responsiveness. If DHEA and DHEAS levels play an important role in CFS physiopathology, we think that, in addition to the employment of non-invasive techniques like the measurement of cortisol levels in the saliva, the evaluation of DHEA (-S) levels with response to naturalistic stressors  like exercise or social stress in future studies will be beneficial.