For treatment of Graf class IIb dysplastic hips at walking onset a treatment concept with abduction splints allowing patterns as walking and crawling under constant abduction control was investigated. However, as the splint still incapacitates child movements the research question remains whether the physiologically progressing maturation of hips can be significantly altered using such abduction splints for walking children.Of 106 children showing late hip dysplasia, 68 children treated with the Hoffman-Daimler (HD-splint) abduction splint were compared with 38 children with neglect of the abduction treatment in this retrospective study. Radiographic analyses were performed measuring the development of the age dependent acetabular angle.2 = 0,31 respectively r2 = 0,33). No statistical difference between both treatment groups was apparent.The regression analysis for splint treatment showed a significant linear regression for both splint treatment and no splint treatment group (rConsidering the characteristics of this study, there seems to be no strong rationale supporting the use of an abduction device in growing children. As no significant difference between treatment groups is apparent, a future controlled prospective study on splinting effects can be considered ethically allowed. Developmental dysplasia of the hip is a gradually progressing disorder reflecting anatomically different situations reaching from mild subluxation of the femoral head to full luxation of the hip. The disorder is caused by malformations of anatomic structures that have developed during the embryologic period. The pathology of developmental dislocation of the hip is associated with a loose hyperelastic capsule, elongated ligamentum teres and slight eversion of the hypertrophied acetabular rim. While the femoral head is normal in shape, excessive femoral and acetabular antetorsion may be present causing anatomic instability of the hip joint -5.Subluxation and luxation are conditions that always lead to symptomatic degenerative hip disease -7. DepenWhile dislocated hips after birth present clinical features as the Ortolani's and Barlow's sign , subluxaGraf Class II b hips are defined as hips of babies older than three month, exhibiting an alpha angle of 50–59 degrees. Radiographs show an acteabular angle of more than 30 degrees. The morphology shows a stable, but deficient bony shape of the acetabulum and femur and a broadened cartilage roof. Class IIb hips show a deficit of bony maturation and therefore need treatment options. Usually, the use of abduction devices is expanded until walking onset at approximately age 8 month. With the increased mobility of the baby, an abduction and flexion harness becomes an increasing handicap.For treatment of Graf class IIb hips at age of walking onset an abduction splint with ball and socket joints was introduced, allowing patterns as walking and crawling under constant abduction control. However, the splint still incapacitates child movements and is generally not liked by parents and custodians. Thus, an estimated number of untreated cases can be considered leading to the research question, whether the physiologically progressing maturation of hips can be significantly improved using such abduction splints for walking children.Between1998 and 2004 106 children were treated with the Hoffman-Daimler (HD-splint) abduction apparatus . The acetabular angle (AC) following Hilgenreiner was measured for all hips and assigned to the respective radiographic age. Fig. .Regression analyses were performed between age as dependent variable and AC-angle as independent variable. Differences in regressions between the no splint group and the abduction splint group were compared using an analysis of covariance.88% of all hips were graded mild dysplastic . Similarly, the regression analysis for the no splint treatment group showed a significant regression for splint treatment . There was no difference between both treatment groups regarding regression quotients as analyzed with ANOVA. Over time both groups showed a decline of the acetabular angle (AC) from 26+-6 degrees at 12 month to 17 ± 5 degrees at 70 month.The goal of this study was to assess the effect of an abduction splint during onset of walking age in children on the maturation of dysplastic hips. In a retrospective study on 106 children no difference was obtainable between a group of children treated with this abduction device and a group of children neglecting such devices. From the data of this study no rationales were found indicating a sufficient effect of this abduction device in the presented treatment context.The concept of continuous abduction in growing children with mild dysplastic hip symptoms was introduced before ,24. As mAnother reason for the analogy of results in both groups may be based on the group assortment and group size. The design of this study was purely retrospective and differences between both groups were developed by the behavior of children and parents. Furthermore the groups were not balanced regarding the initial magnitude of the AC-angles. With slightly higher initial AC-angles in the HD-splint group an influence of the splint in decreasing AC-angles could be underestimated in this analysis.The reason, why babies reach walking onset with symptomatic hips despite detection and treatment may have several reasons: First, the diagnosis may be late and abduction therapy introduced several month after birth; second, initial errors in ultrasound screening may have underestimated the hip condition and led to neglect of sufficient therapy. As a third reason the insufficient development of hips initially graded class I has been described. In these patients the maturation of the acetabular roof does not progress sufficiently. Causes of this development remain unclear.When interpreting the results of this study several shortcomings have to be addressed: first, the treatment group were different with 36 to 68 group size. Second, the radiographic follow ups for each patient were different, thus there is a tendency to overweight patients with multiple follow ups in this study. Third, the initial therapeutic decision for splint treatment happened during an age range form 6 to 18 months. Thus, the comparison of patients with different ages of treatment initiation may influence the validity of the presented data.The effect of an abduction splint during onset of walking in children on the maturation of dysplastic hips remains unclear. From data of this study there is no strong rationale supporting the use of an abduction device in growing children, however, the results have to be weighted according to the characteristics of the study design. On the other hand, this study gives strong support for the ethical validity of a controlled prospective study, as no siginifcant difference between treatment groups can be expected.The author(s) declare that they have no competing interests.HW and HK designed the study profile, participated in the patient selection, data assessment and drafted the manuscript. TP provided radiographic digitization and angle measurements. FT participated in mathematical analysis. DH participated in the design of the study. CS participated in its design and coordination and helped to draft the manuscript. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:


Gardner's syndrome can occasionally be complicated with intra-abdominal desmoid tumor. These tumors usually remain asymptomatic but can exhibit symptoms due to intestinal, vascular and ureteral compression and obstruction.A rare case of a 41-year-old male patient with Gardner's syndrome complicated with intra-abdominal desmoid tumor, which first presented as acute abdomen, is presented.Extra-abdominal manifestations of Gardner's syndrome along with a palpable abdominal mass would raise suspicion for the presence of a desmoid tumor in the majority of cases. In life-threatening cases, surgical treatment should be considered as a palliative approach, though the extent of excision remains debatable GardnerHereditary desmoid disease has also been found to be caused, at least in some cases, by mutation in the APC gene , whereasDesmoid tumors are benign and are characterized by fibroblastic proliferation of fascial and musculoaponeurotic origin. They usually remain asymptomatic for a long time before symptoms of intestinal, vascular and ureteral compression and obstruction evolve. They may cause obstructive jaundice or bowel obstruction and fistulization. A rare manifestation involves neural paralysis  due to compression ,8. The rA 41-year-old male was admitted to the Emergency Department complaining for acute sharp abdominal pain followed by abdominal distention, nausea, vomiting and bloody stools. The patient was a heavy smoker (70 cig/24 h) and reported mild abdominal distention during the last month and an episode of anal bleeding 4 years ago, which had been attributed to hemorrhoids. His mother died after surgical operation for multiple polyposis coli.The physical examination revealed abdominal distention, hypoactive bowel sounds, and a large palpable intra-abdominal mass with peritoneal signs. A palpable osteomatosis of the right mandible, multiple sebaceous cysts and subcutaneous fibromas of the trunk and head were observed. The absence of intestinal sounds, the distention and the abdominal contraction suggested acute abdomen. The blood analysis suggested leukocytosis (WBC 18110/μL out of which 94% were neutrophils) and anemia (Hct 29.3% and Hb 7.7 g/dl).Abdominal ultrasound revealed a large mass with necrotic lesions. Triplex study of the mass indicated decreased internal circulation with measurable velocity. An abdominal CT scan that performed after oral gastrographin administration and IV contrast medium infusion, revealed a large intra-abdominal neoplastic mass consisting of tissues of variable density. The mass was extended from the pancreas to the pelvic entrance figure . The tumThe patient was surgically treated. After entering the abdominal cavity a large solid neoplasmatic mass which invaded parts of the small and large intestine was recognized. The abdominal tumor was resected, along with the involved parts of the small intestine and the right colon Figure . The excPostoperative ophthalmologic examination of the fundus, revealed the characteristic black spots of congenital hypertrophy of the retinal pigment epithelium typical of Gardner syndrome. Full length colonoscopy was scheduled after patient's discharge. Unfortunately the patient died three months later from acute myocardial infarction. We failed to identify clinically any only obvious risk factors for the subsequent AMI except smoking.The histological examination of the specimen revealed desmoid tumor. Further cytogenetic studies along with APC mutation analysis confirmed the diagnosis. Mutation was identified in exon 9 and codon 1444.th postoperative day.Extra-abdominal manifestations of Gardner's syndrome along with a palpable abdominal mass would raise suspicion for the presence of a desmoid tumor in the majority of cases. Computed tomography would help to establish the diagnosis -12. The Gardner's syndrome consists of extensive adenomatous polyps of the colon, sebaceous cysts, osteomatosis of the skull and the mandible, and cutaneous and subcutaneous fibromas. In some cases this entity is complicated with other malignancies to include periampullary neoplasms and intra-abdominal desmoid tumor. Some authors described a rare co-existence with small bowel adenomas, carcinomas of the thyroid and adrenal gland and hepatoblastomas. The incidence of adrenal adenomas in patients with Gardner syndrome is yet unidentified, as relevant literature is inadequate ,13.Intra-abdominal desmoid tumors remain asymptomatic for long periods, and the initial symptoms are usually due to intestinal, vascular or ureteric compression and obstruction, while in rare cases neural paralysis or fistula may be the first sign . Once deThe unique feature of our case is that the prevailing symptom of the tumor was the acute abdomen. Although the diagnosis of Gardner's syndrome was evident due to the presence of various clinical signs suggestive of the disease, the etiology of acute abdomen in our patient remained unclear. Intestinal perforation might be an explanation, but the surgical procedure provided no proof for this speculation. As no similar reports in the literature were identified, this case report is of special interest.CT scan contributes not only in the diagnosis of the lesion but also in the definition of the extension in the adjacent visceral structures. A possible disadvantage of the CT scan is the inability to distinguish a desmoid tumor from a soft tissue sarcoma. The differential diagnosis of the tumor characteristics can be supported by MRI, although this study cannot assess the margin of the lesion. Recent data suggest that preoperative performance of both CT and MRI may be helpful for accurate diagnosis as well as assessment of the disease extent ,10.Though they are not cancer and do not metastasize, desmoids can cause significant morbidity and occasionally death through local/regional invasion of critical structures . NeverthIn general, surgery is not indicated in patients with intraabdominal desmoid tumors and should be reserved for life threatening complications since surgery  is associated with high recurrence rates (over 65%) and may involve major small bowel resection with its consequences. In these patients medical treatment , chemotherapy  and radiotherapy or combination of them can result tumor remission .In life-threatening cases, surgical treatment should be considered as a palliative approach, though the extent of excision remains debatable . Some auThe kind and extent of resection are determined by the location of the tumor and the adjacent structures that are involved. In our case we tried to achieve an adequate resection margin, thus we excised the part of the small and large intestine that was involved in the lesion. As a suspicious lesion in the right adrenal was identified in the CT scan, colectomy, lumpectomy and enterectomy was combined with right adrenalectomy; this decision was supported by the fact that abdominal desmoid tumors might co-exist with adrenal carcinoma. This combined procedure leads to excision of the lesion in adequate macroscopic and microscopic free of disease margins.The role of adjuvant radiotherapy and chemotherapy in the treatment of desmoid tumors still remains unclear. Some authors believe that radiotherapy contributes in the local control of the disease . Recent Gardner's syndrome should be suspected in patients with osteomatosis, multiple sebaceous cysts and cutaneous and subcutaneous fibromas. Although the appropriate treatment of intra-abdominal tumors remains unclear we believe that wide resection in adequate margin offer the best alternative for local control of the tumor.The author(s) declare that they have no competing interests.HA: Had made substantial contributions to conception and the patient's treatment. FD: Collected the data and wrote the manuscript. PV: Corrected the manuscript. FG: Collected the data and contributed to the manuscript writing. RS: Corrected and approved the manuscript and participate to the patient's treatment. SP: Contributed to the conception, corrected and approved the manuscript.All authors read and approved the final manuscript.


Noninvasive imaging of cardiac electrophysiology is still a major goal despite all recent technical innovations. This review gives an overview about the historical background, recent developments and possible future applications of noninvasive imaging of cardiac electrophysiology. The basic research according the standard 12-lead electrocardiogram (ECG) dates from the Dutch physician Einthoven, who used a string galvanometer to record myocardial currents at about the year 1900. The so called "Einthoven" leads depict potential differences between the right and the left arm (lead I), the right arm and the left leg (lead II), and the left arm and the left leg (lead III). Later on, Goldberger introduced three more leads providing three additional projections of the electrical heart vector . The Goldberger and Einthoven leads provide bipolar signals, as electrical potential differences of two distinct sites are obtained. Frank N. Wilson and coworkers developed a vacuum tube amplifier which allowed recordings of potential variations at single leads placed on the anterolateral chest. Therefore, Wilson introduced an "indifferent electrode", the "Wilson central terminal (WCT)". Contrary to the Einthoven and Goldberger leads, the signals measured between the Wilson leads V1-6 and the indifferent WCT are unipolar signals. Due to the anatomical localization on the chest, the Wilson leads provide higher signal amplitudes and give some additional information about spatial differences of cardiac electrophysiology. So far, the 12-lead ECG remains the primary clinical tool for noninvasive assessment of cardiac electrophysiology and there have been only little clinical developments, except for stress testing and Holter ECG, over the last decades.To increase spatial resolution of the body surface electrocardiogram, different studies have tried to increase the sampling density by increasing the number of ECG leads . For visA further progress in imaging of cardiac electrophysiology was the introduction of field computation techniques such as the finite element method. It has been demonstrated that a single patch of tissue, when  activated by pacing, results in a negative potential. Consecutively, a sharp drop of activation occurs in the resulting activation wave front. Immediately, the potential magnitude changes to positive or negative values in the order of some milivolts. This results in the occurrence of two potential maxima. The maxima mark the activated wavefront, and an imaginary line connecting the maxima is parallel to fiber orientation . AlthougIntegral maps are computed by the integral calculus of the potential in a defined time interval and its interpolation to the torso surface. QRS integrals represent the activation sequence , ST-T integral reflect the repolarization sequence , and QRST integrals relate to differences in action potential integrals, independent of the activation sequence.The QT-dispersion is a widely used parameter which reflects the heterogeneity of repolarization. Here, the QT time interval in each lead is assessed and a measure for dispersion of repolarization  is assessed. One major limitation of QT dispersion is the poorly defined end of the T-wave, especially in leads with small T-wave amplitudes.In the last years, intracardiac maps have gained special importance in clinical use for e.g. electrophysiological studies. Therefore, intracardiac maps are obtained with intracardiac catheters with integrated magnetic sensors (e.g. CARTO™), which allows recording of endocardial signals as well as the corresponding anatomical location of the catheter tip. This method allows electroanatomic imaging of activation time maps with sufficient spatiotemporal resolution using color-coded plots.This novel method uses an ill-posed mathematical theorem for an inverse projection of functional information contained in the body surface ECG to the epicardial source. As NICE is a functional imaging method, patient's individual cardiac anatomy is assessed by magnetic resonance imaging or computer tomography. An individual computer model of cardiac anatomy is computed for each patient . AdditioElectrocardiographic imaging tries to calculate and display the electrical activity from the epicardium from surface ECG signals using a boundary element (BEM) or finite element method (FEM) for computation of the epicardial electrical activation. When considering this inverse mathematical problem a regularization method (Tikhonov) is used to solve this ill-posed problem ,10. CompIn contrast to electrocardiographic imaging, which can be applied to any time interval of the cardiac activation, activation time imaging (ATI) is limited to the time interval of atrial or ventricular depolarization . Early studies used an uniform dipole layer model for describing the source which uses the assumption of isotropic conductivity . More recently a bidomain model has been applied. The biophysically familiar action potential enters the source term and therefore it can also be applied (in principle) to anisotropic models of the myocardium.The strong constraint of a step-like activation function with a fixed amplitude and rise time limits the application of action potential imaging. A weaker but still strong limitation is that the action potential is restricted by a lower and upper bound  and monotonically increasing during activation . By impo


Limb shaking Transient Ischemic Attack is a rare manifestation of carotid-occlusive disease. The symptoms usually point towards a seizure like activity and misdiagnosed as focal seizures. On careful history the rhythmic seizure like activity reveals no Jacksonian march mainly precipitated by maneuvers which lead to carotid compression. We here present a case of an elderly gentleman who was initially worked up as suffering from epileptic discharge and then later on found to have carotid occlusion.Elderly gentleman presented with symptoms of rhythmic jerky movements of the left arm and both the lower limbs. Clinical suspicion of focal epilepsy was made and EEG, MRI-Brain with MRA were done. EEG and MRI-Brain revealed normal findings but the MRA revealed complete occlusion of right internal carotid artery. On a follow-up visit jerky movements of the left arm were precipitated by hyperextension and a tremor of 3–4 Hz was revealed. Based on this the diagnosis of low flow TIA was made the patient was treated conservatively with adjustment of his anti-hypertensive and anti-platelet medications.Diagnosis of limb-shaking TIA is important and should be differentiated from other disorders presenting as tremors. Timely diagnosis is important as these patients are shown to benefit from reperfusion procedures either surgical or radiological reducing their risk of stroke. Transient ischemic attacks typically present with neurological deficits such as loss of muscle power, reduced sensation, or loss of vision. Symptoms such as involuntary movements are not generally regarded to be a feature of cerebral ischemic episodes. Often confused with focal motor seizures, limb shaking TIAs are a rare form of TIAs that present as such and therefore pose a diagnostic challenge -6. This A 65-year-old gentleman presented to us complaining of episodes of tremor of the lower limbs. These episodes would occur at 3–4 Hz, lasting for 1 to 2 minutes each in duration, and occur about once per month for the past 5 months, precipitated by standing up and extending the neck. At the time of the episodes, the patient also felt numbness in his left arm leading to decreased strength and a tremor of 3–4 Hz. Consciousness was never impaired and there was no other symptom. The patient had a past history of diabetes and hypertension, and was on anti-hypertensive and oral hypoglycemic medications. On examination the patient was found to have no neurological deficit. However, upon standing and extension of the neck, the patient became dizzy and felt numbness in his left arm. In addition, a swinging tremor of 3–4 Hz was noted in the same arm. These symptoms resolved on sitting.Further investigations were needed. Interictal electroencephalography (EEG) and Video-EEG were normal, while EMG and nerve conduction studies revealed findings suggestive of mild peripheral sensory motor polyneuropathy. MRI of the brain was found to be normal; however, MRA of the anterior circulation revealed lack of flow signals in the right internal carotid artery consistent with complete occlusion. There was good compensatory filling of right anterior and middle cerebral arteries via cross flow from left internal carotid artery. Consistent with the above findings, Doppler ultrasound of the neck showed complete occlusion of the right internal carotid artery, with normal right common carotid, external carotid, and vertebral arteries. The diagnosis of low flow TIA was made.The patient refused to undergo cerebral angiography for possible reperfusion intervention and was treated conservatively with antihypertensive and anti-platelet medications. Anti-lipidemics were also added and the patient hasn't complained of any symptoms for the past 6 months.Since Miller Fisher's first description of temporary limb-shaking syndrome (LSS) associated with carotid stenosis in 1962, this diagnosis has been reported regularly  and to dAn almost invariable clue clinically is that symptoms arise after maneuvers that theoretically provoke cerebral blood hypoperfusion, such as arising from a bed or a chair, as well as hyperextending the neck. One patient had a repeated tendency to drop his key when leaving his car along with an associated tremor-like sensation and clumsiness of his left arm . There iAccording to Galvez-Jimenez et al., limb-shaking syndrome (LSS) is considered to be one of the many secondary or symptomatic dyskinesias of vascular etiology .Like other vascular paroxysmal dyskinesias, it can be explained by the "hypoperfusion theory," in which carotid stenosis and orthostatism lead to decrease cerebral blood flow in critical watershed territories. In an assessment of 51 patients with infarcts in watershed cerebral territories, 12 percent were found to experience focal limb shaking by Bogousslavsky and Regli  In his pElectroencephalographic studies have failed to show epileptiform activity associated with limb-shaking syndrome, although some patients have contralateral slow activity . InductiThe most striking feature of LSS is severe internal carotid artery stenosis, necessitating the examination of carotid bruits in the elderly with orthostatic and/or episodic movement disorder. All 12 patients described by Yanangihara et al had occluded or critically compromised contralateral carotid artery .Management of low flow TIAs focuses on maintaining or improving cerebral blood flow by careful control of blood pressure and surgical revascularization. This divides the approach in surgical and medical modalities. In several cases an improvement of symptoms has been reported after raising blood pressure ,10. In tIn summary, limb shaking is a rather uncommon form of transient ischemic attack that should be recognized and differentiated from conditions like focal motor seizures. We add to literature another case of this rare condition. Recognition will almost invariably point to carotid artery occlusion and timely treatment may not only abolish the attacks in patients but also reduce their risk of stroke.The author(s) declare that they have no competing interests.SA carried out the literature search of limb shaking TIA cases and collected all the data so far published. He then worked with the other two in writing down the paper.MAK was involved in the initial diagnosis of the limb-shaking TIA and management of the patient. Later on worked with the two authors in manuscript preparation. He is the corresponding author as well.BK is the treating neurologist of the patient and was involved in the initial diagnosis of the limb-shaking TIA and management of the patient. Reviewed the manuscript and helped in completing the final draft.The pre-publication history for this paper can be accessed here:


The Active Movement Scale is a frequently used outcome measure for children with obstetric brachial plexus palsy (OBPP). Clinicians observe upper limb movements while the child is playing and quantify them on an 8 point scale. This scale has acceptable reliability however it is not known whether it accurately depicts the movements observed. In this study, therapist-rated Active Movement Scale grades were compared with objectively-quantified range of elbow flexion and extension and shoulder abduction and flexion in children with OBPP. These movements were chosen as they primarily assess the C5, C6 and C7 nerve roots, the most frequently involved in OBPP. Objective quantification of elbow and shoulder movements was undertaken by two-dimensional motion analysis, using the v-scope.Young children diagnosed with OBPP were recruited from the Royal Children's Hospital  Brachial Plexus registry. They participated in one measurement session where an experienced paediatric physiotherapist facilitated maximal elbow flexion and extension, shoulder abduction and extension through play, and quantified them on the Active Movement Scale. Two-dimensional motion analysis captured the same movements in degrees, which were then converted into Active Movement Score grades using normative reference data. The agreement between the objectively-quantified and therapist-rated grades was determined using percentage agreement and Kappa statistics.Thirty children with OBPP participated in the study. All were able to perform elbow and shoulder movements against gravity. Active Movement Score grades ranged from 5 to 7. Two-dimensional motion analysis revealed that full range of movement at the elbow and shoulder was rarely achieved. There was moderate percentage agreement between the objectively-quantified and therapist-rated methods of movement assessment however the therapist frequently over-estimated the range of movement, particularly at the elbow. When adjusted for chance, agreement was equal to chance.Visual estimates of elbow and shoulder movement in children with OBPP may not provide true estimates of motion. Future work is required to develop accurate, clinically-acceptable methods of quantifying upper limb active movements. Since few children attained full range of motion, elbow and shoulder movement should be monitored and maintained over time to reduce disability later in life. Obstetric brachial plexus palsy (OBPP) is a complication of childbirth, which is characterized by one or more nerve conduction blocks within the brachial plexus . These bThe assessment of motor function in young children is more difficult when compared with adolescents and adults . Young cOne such rating scale for the quantification of movement in children with OBPP is the Active Movement Scale. Developed by Clarke and Curtis  it evaluOne advantage of using this rating scale is that is quantifies movement in categories, such as "motion greater than half range". This procedure theoretically produces less variability in scoring and may provide higher reliability coefficients and smaller measurement errors compared to direct measurement of active movement . HoweverData collection was part of a larger study which investigated the intra- and inter-rater reliability of two-dimensional motion analysis (using the v-scope [Eshed Robotics Inc]) to quantify elbow and shoulder movement in young children with OBPP. Detailed information regarding the v-scope and the method of movement quantification can be found in another publication . Prior tAll families of children on the OBPP registry at the Royal Children's Hospital, aged between six months and four and a half years were eligible to participate in this study, irrespective of their functional status, residential location or method of management. Case notes were used to confirm the diagnosis of OBPP and to gather demographic information about the child.The v-scope, a two-dimensional motion analysis system was used to quantify the maximal range of elbow flexion and extension and shoulder abduction and flexion. Its three transmitting towers were configured in an L-shape and they located the position of up to four "buttons" which were placed by an experienced paediatric physiotherapist on standardized landmarks on the child's affected upper limb, trunk and chest. The location of these "buttons" was based on a pilot study of 10 non-impaired children. Each child was positioned on the floor in the centre of the towers' fields at a distance of 1.5 meters from the towers.The same, experienced paediatric physiotherapist facilitated the maximal range of elbow flexion and extension, shoulder abduction and flexion through play or by tapping the corresponding muscle group, according to the procedures outlined by Curtis et al . Three rDemographic characteristics of the participants and the maximal range of elbow flexion and extension, shoulder abduction and flexion were summarised using descriptive statistics. Data were extracted from the v-scope program and exported into Microsoft Excel 2005. Angles that depict the maximum range of elbow flexion and extension, shoulder abduction and flexion were calculated by dot product from the vectors for adjacent segments, which were gained from the X, Y and Z co-ordinates of the "buttons". This produced values, in degrees, for maximal elbow flexion and extension, shoulder abduction and flexion. Three maximal angles for each movement were subsequently identified, averaged and used in all analyses. As three Active Movement Scale grades were generated for each direction of movement, the mode was used in all analyses. Analyses revealed that the Active Movement Score did not change between repetitions for any of the movements.To determine the accuracy of the therapist-rated Active Movement Score grades for each direction of movement, therapist-rated grades were compared with objectively-quantified Active Movement Score grades. Objectively-quantified Active Movement Score grades were generated by collapsing the maximal angles gained by the v-scope, measured in degrees, into the appropriate categories on the Active Movement Scale. This required knowledge of what constitutes half range of elbow flexion and extension, shoulder abduction and flexion. Normative values described by Boone et al  were subOur sample consisted of 30 children with OBPP , aged between 0.6 and 4.6 years. Most participants were diagnosed with a C5, C6 (43%) or C5, C6, C7 (37%) nerve conduction block and few underwent a primary nerve repair within the first year of life (n = 4). None of the participants had undergone secondary shoulder or elbow surgery.The average range of elbow flexion and extension, shoulder abduction and flexion is presented in Table Table This is the first known study that has compared therapist-rated Active Movement Scale grades with objectively-quantified active range of elbow flexion and extension and shoulder abduction and flexion in children with OBPP. We found that there was little agreement in the muscle grades, with the paediatric physiotherapist most frequently over-estimating the movement gained. This discrepancy was most apparent between grades 6 and 7, when the therapist graded the movement as "full motion" (grade 7) when it was less than what is considered full movement in children with "normal" elbows and shoulders. This more frequently occurred at the elbow rather than at the shoulder.Overestimation of range of elbow flexion and extension may have occurred due to error in interpreting what constitutes half range at this joint. Ninety degrees of flexion at the elbow tends to be easy to visualize as the forearm is horizontal when the subject is in the sitting position . This isOur choice of norms may also have contributed to the lack of agreement between the two sets of Active Movement Scale grades. Currently, there is little evidence regarding what is "normal" range of movement at the elbow and shoulder in young children. One hundred and twenty degrees has been used as "normal" range of movement at the elbow by clinicians treating children with OBPP . HoweverA hand-held goniometer was used to produce the norms by Boone et al . This meDespite these limitations, it is acknowledged that there is error associated with all types of measurements. However, the aim of clinical measurement is to reduce this error as much as possible during assessment and to consider the degree of measurement error when interpreting the results . DevelopWe also found that children with OBPP rarely gain full range of elbow flexion and extension, shoulder flexion and abduction. Lack of elbow and shoulder range of movement may compromise the ability to perform daily tasks . Since rThe main finding of this study is that visual estimates of elbow and shoulder movement in children with OBPP may not provide true estimates of motion. Since decisions regarding the optimal management strategies, including whether surgery is indicated, are often made based on this type of assessment, clinicians should interpret their results with care. Moreover future work is required to develop accurate, clinically-acceptable methods of quantifying upper limb active movements. A secondary finding was that few children attained full range of motion. Hence, elbow and shoulder movement should be monitored and maintained over time to reduce disability in adolescence and adulthood.The author(s) declare that they have no competing interests.AB participated in the study design, preparation of the ethics application, trained research assistants, monitored the project for quality, entered data, data analysis and manuscript preparation. MG participated in the study design, preparation of the ethics application and writing of the manuscript.


The traumatic bone cyst (TBC) is an uncommon nonepithelial lined cavity of the jaws. The lesion is mainly diagnosed in young patients most frequently during the second decade of life. The majority of TBCs are located in the mandibular body between the canine and the third molar. Clinically, the lesion is asymptomatic in the majority of cases and is often accidentally discovered on routine radiological examination usually as an unilocular radiolucent area with a "scalloping effect". The definite diagnosis of traumatic cyst is invariably achieved at surgery. Since material for histologic examination may be scant or non-existent, it is very often difficult for a definite histologic diagnosis to be achieved. We present a well documented radiographically and histopathologically atypical case of TBC involving the ramus of the mandible, which is also of possible iatrogenic origin. The literature is briefly reviewed. The traumatic bone cyst (TBC) is an uncommon nonepithelial lined cavity of the jaws. Since it was first described by Lucas in 1929,The lesion is mainly diagnosed in young patients most frequently during the second decade of life ,11-13. TThe definite diagnosis of traumatic cyst is invariably achieved at surgery when an empty bone cavity without epithelial lining is observed, leaving very little except normal bone and occasional fibrous tissue curetted from the cavity wall for the histopathologist. Sometimes, the cavity contains a straw-coloured fluid of bright blood -4,10,11.Since material for histologic examination may be scant or non-existent, it is very often difficult for a definite histologic diagnosis to be achieved ,11,21. MThe widely recommended treatment for TBCs is surgical exploration followed by curettage of the bony walls. The surgical exploration serves as both a diagnostic manoeuvre and as definitive therapy by producing bleeding in the cavity. Haemorrhage in the cavity forms a clot which is eventually replaced by bone ,15,22,23The following is an account of a well documented radiographically and histopathologically atypical case of TBC involving the ramus of the mandible, which is also of possible iatrogenic origin.rd molar surgically extracted. The preoperative panoramic X-ray did not reveal any findings other than the semi-impacted 3rd molar . The lesion was asymptomatic and was discovered accidentally on routine radiographic examination. The radiographic, histopathological and operative findings of the case fit with the literature. Regarding the sex of the patient, some authors tend to disprove the previously reported higher incidence of occurrence in men and believe that sex distribution is quite even ,10. FinaPerhaps the most universal agreement on TBCs is that their aetiology and pathogenesis have not yet been clearly understood. Trauma can be an important factor in the development of TBCs although questions regarding mode, intensity, frequency and pathogenesis must be answered before reaching any final conclusions. Clear, complete and detailed reporting of cases is the only way in which material can be collected for analysis of these problems. In our case, "iatrogenic" trauma appears to be the principal etiologic factor; however, unequivocal proof is lacking.


Osseointegrated endosseous implants are widely used for the rehabilitation of completely and partially edentulous patients, being the final prosthodontic treatment more predictable and the failures extremely infrequent. A case of fracture of an endosseous dental implant, replacing the maxillary first molar, occurring in a middle-age woman, 5 years after placement is reported.The difficult management of this rare complication of implant dentistry together with the following rehabilitation is described. Additionally, the authors performed an accurate analysis of the removed fractured implant both by the stereomicroscope and by the confocal laser scanning microscope.The fractured impant showed the typical signs of a fatigue-induced fracture in the coronal portion of the implant together with numerous micro-fractures in the apical one. Three dimensional imaging performed by confocal laser scanning microscope led easily to a diagnosis of "fatigue fracture" of the implant. The biomechanical mechanism of implant fractures when overstress of the implant components due to bending overload is discussed.When a fatigue-induced fracture of an dental implant occurs in presence of bending overload, the whole implant suffers a deformation that is confirmed by the alterations (micro-fractures) of the implant observable also in the osseointegrated portion that is easily appraisable by the use of stereomicroscope and confocal laser scanning microscope without preparation of the sample. Neverecrosis) ,5 that aecrosis) ,7. Insteecrosis) .The aim of this report is to describe the pathology and the management of a case of implant fracture occurring in the posterior maxilla of a middle age woman who was rehabilitated by implant-retained partial fixed prosthesis; an accurate microscopic evaluation by using stereo and confocal laser scanning microscopy of the fractured implant and the surrounding bone was performed demonstrating that it was a "fatigue fracture" of the implant due to increased stress and bending overload forces originates from inadequate implant diameter in relation to the site needing rehabilitation.A middle-age woman was referred to our department for raised mobility of a fixed implant-supported prosthesis replacing the first and second right maxillary premolar and the first molar; the patient referred that implants were placed in September 1996 and loaded after six months. The clinical examination revealed a cemented metal-ceramic prosthesis supported by two thread osseointegrated implants which was easily removed together with the fractured coronal portion; radiographic examination showed the residual portion of the implant  in 1.6 position and a marginal crater-like bone loss; no signs of perimplantitis or lack of osseointegration were observable Fig. . Under lThe fractured implant was observed both at the stereo-microscope and at the confocal laser scanning microscope; it totally measured 3,75 mm of diameter and 13 mm of length and was transversally fractured at the level of the third-fourth thread; the endosseous residual portion was well-osseointegrated as confirmed by the histological evaluation of the perimplant bone which showed no signs of perimplantitis or fibrous integration of the implant Fig. .After removed the bone, at the stereomicroscope the fracture surface presented the typical features of the fatigue fracture observed by other authors using fractography with scanning electronic microscope -13; besiFor such distinction authors used confocal laser scanning microscope (Nikon Eclipse C1) with the following configuration: surface scanning method by using Argon-ion laser source at 488 nm wavelength; 1.92 msec time of scanning, B/W imaging, 10 steps of 3D scanning with plans at 3.4 μm distance, volume rendering 3D rewconstruction mode. The confocal laser scanning microscopy (CLSM) allowed to perform an analysis of the surface both with three-dimensional reconstruction and with an evaluation of the depth of the defects by serial scanning at different focal plans  as showed in figure Considering the appearance on 3D reconstruction and the presence of the defects in all scanned plans, authors agreed in defining them as microfractures or craks of the apical portion of the implant though well-osseointegrated due to fatigue."bending overload", a term introduced by Rangert et al. in 1995 [Excluding lack of osseointegration and perimplantitis, the main causes of dental implant failure can result from technical problems relating both to prosthesis and to implant components. The latter includes above all abutment screw fracture, which is a complication with an increasing rate of incidence, and implant fracture which remains extremely rare -12. Thes in 1995 , is the  in 1995 -17.lucus minoris resistenziae, being the implant internally filleted and consequently extremely thin, upon which overstress promotes the creation of numerous micro-fractures that can result, after a variable time range, in a complete fatigue fracture. Ideally, implants with internal abutment connection should be more suitable to this complication.The mechanism of fracture has a multi-factorial aetiology; when number, position, dimension, design of implant and restoration are inadequate to the site needing rehabilitation, the situation of bending overload is present and an initial bone loss around the implant begins. If no correction of the prosthesis is introduced, the coronal screws become as soon as exposed and a crater-like appearance of the surrounding bone is observable. At this time, the coronal portion of the implant represents a Besides, the findings of cracks on the root of the screw thread led us to sustain that bending overload creates a deformation of whole implant with consecutive micro-fractures, as previously described in experimental studies -21. The The author(s) declare that they have no competing interests.All authors have contributed equally in the realization of this paper.


To evaluate the levels of circulating immune complexes, trace elements  in serum of patients with oral submucous fibrosis (OSMF), oral leukoplakia (L), and oral squamous cell carcinoma (SCC), analyze the alteration and identify the best predictors amongst these parameters for disease occurrence and progression.Circulating immune complexes (CIC) were estimated using 37.5% Polyethylene Glycol 6000(PEG) serum precipitation. Serum estimation of copper (Cu), Iron (Fe) and selenium (Se) was done using the Oxalyl Dihydrazide method, Colorimetric Dipyridyl method and the Differential Pulse Cathodic Stripping Voltametry respectively.The data analysis revealed increased circulating immune complex levels in the precancer and cancer patients. Serum copper levels showed gradual increase from precancer to cancer patients. However, serum iron levels were decreased significantly in the cancer group. Selenium levels showed marked decrease in the cancer group. Among CIC, serum, copper, iron and selenium the best predictors for the occurrence of lesions were age, serum iron, CIC, serum selenium in the decreasing order.The present study shows that these immunological and biological markers may be associated with the pathogenesis of oral premalignant and malignant lesions and their progressions. Concerted efforts would, therefore, help in early detection, management, and monitoring the efficacy of treatment. Oral cancer the sixth most common cancer worldwide continues to be the most prevalent cancer related to the consumption of tobacco, alcohol and other carcinogenic products. While tIncreasing awareness on part of the providers of treatment, as well as the population in general, has led to a large proportion of patients presenting with earlier stage of the disease.Epidemiological studies indicate that intervention at an early stage might reduce oral carcinoma related deaths. The discovery of immunological markers at a clinical, histological and molecular level has marked the end of an era of groping in the dark for clues to the basis of cancer. Significant reduction in mortality can be achieved my advances in early diagnosis and implementation of multidisciplinary treatment programmes leading to improvement of survivorship and better quality of life.In India, oral cancer is prevalent in most areas where tobacco related practices are observed. For development of oral cancer, tobacco is the single greatest risk factor. This is due to higher concentration of carcinogenic exposure and failure to clean the carcinogens from the mucosal surface. If one observes the mouths of heavy tobacco users, the accumulation of tobacco residue may be correlated with areas of the oral cavity involved . AlcoholThe development of oral cancer is a multistep process arising from pre-existing potentially malignant lesions. Leukoplakia is the most common precancer representing 85% of such lesions. HistoloLikewise, the incidence of oral submucous fibrosis (OSMF) is increasing like an epidemic, targeting the younger generation. The etiology for OSMF is still obscure and a varied number of factors have been proposed. Of these, areca nut use is the most important and persistent finding in history taking.Intensive studies have documented the role of immune complexes as modulators of both cellular and humoral immune response. The occurrence of circulating immune complexes (CIC) as a marker for tumor burden and prognosis in the sera of patients with oral precancer and cancer is now well established. Recent advances in the fields of CIC, tumor progression, drug resistance, tumor cell heterogeneity and metastasis have resulted in a renewed interest in the development of non- specific immunotherapeutic modalities .The overall consensus is that only a small percentage of the detected CIC in vivo represent tumor associated antigens complexed with antibodies. The bulk of CIC most likely represent auto antibodies or the reaction to denatured self proteins, microbes, normal lymphocyte, antigens and nuclear antigens. AntigenTrace elements have been extensively studied in recent years to assess whether they have any modifying effects in the etiology of cancer. Copper, iron and selenium are essential for numerous enzymes and therefore it is reasonable to assume that variations in serum level of these biochemical markers maybe associated with the pathogenesis of oral cancer. The importance of these elements in cancer was reported by Schwartz  which opThis study was carried out in Nair Hospital Dental College, Mumbai in association with Bhabha Atomic Research Centre and Topiwala National Medical College, Mumbai.Thirty patients with  Serum CICs were determined using 3.75% Polyethylene Glycol – 6000 (PEG) serum precipitation.2) Serum levels of Copper (Cu) were determined using the Colorimetric Oxalyl Dihydrazide method.3) Serum analysis of Iron (Fe) was done using colorimetric Dipyridyl method.4) Differential Pulse Cathodic Stripping Voltametry to determine serum selenium (Se) .The data was subjected to statistical analysis using the Chi Square Test, Standard Deviation, Student's unpaired t-test, correlation, ANOVA and Linear Regression.Firstly, groupwise comparison of gender among all cases was considered. In the precancer  group, females were 16.70% and males formed 83.30% of the subjects. In the cancer group females formed 40% and males attributed to 60% of the subjects. In comparison with normals, the difference in gender between the three groups was not found to be statistically significant;  indicating that the 3 groups are comparable on the basis of gender }The age (in years) range of the patients with precancerous condition/lesion was 34.10 in the precancer group as compared to 53.97 in cancer group and 33.65 in the normal group. The mean age in precancer and cancer group was higher than normal and the difference was statistically significant {p value1.10E-13  Table No The mean serum selenium content is 63.13, 51.97 and 68.04 ng/ml in precancer, cancer and normal groups respectively. It is significantly decreased in the cancer groups   . The immMajority of our study group consisted of males (66.67%) who had tobacco, areca nut chewing and associated habits. The mean age was higher in the patients suffering from oral carcinoma.Gross et al  reportedChatterjee R. and Guha [32] estimated levels of circulating immune complexes using polyethylene glycol precipitation assay; which they found to be appropriate and concluded that 60% of patients with carcinoma of the buccal mucosa had markedly higher amount of immune complexes. They also noted that the amount of immune complexes present in patient's sera showed no correlation with serum level of IgG, IgA and IgM.Balaram P et al [33] reported increased levels of circulating immune complexes in oral submucous fibrosis patients.In the presence study the levels of CIC show a gradual increase in the precancer group and the cancer group is characterized by a marked increase in levels which was statistically significant. From these results it can be hypothetised that CIC represent the host's physiological and immunological defense response in eliciting specific antibodies upon exposure to most antigenic substances.CIC deposition further leads to inflammation and tissue/cell damage. It also leads to suppression of cell mediated immunity and modulates the humoral response.Circulating immune complexes are normally removed by the mononuclear phagocytic cells. However, circulating immune complexes formations or their defective clearance under certain circumstances becomes detrimental to the host, resulting in pathological deposition. Thus, altering the host immunological response leading to inflammation and tissue injury .High levels of copper in areca nut, a major etiological factor in OSMF plays an initiating role in stimulation of fibrogenesis by up regulation of lysyl oxidase   and therMargalith et al  suggesteIn this study, Serum levels of copper showed gradual increase from precancer to the cancer group as compared to normals which was statistically significant.Serum Iron levels are considered as biochemical indicators for nutritional assessment. Utilization of iron in collagen synthesis  by the hOccurrence of iron deficiency is known to present in oral cancer. Iron is known to play a key role in the development of hepatic fibrosis probably via oxidative stress and lipid peroxidation . Iron isA statistically significant reduction in the serum iron level was present in the precancer group in our study. A decrease in the iron levels in the cancer group, but higher than that of pre cancer groups was found to be significant.Recently, haematological abnormalities in oral leukoplakia was reported by Chellacombe . It was There appears to be an association between the serum iron content and oral carcinogenesis. More detailed studies on a large data base should be instituted to elucidate the exact role of iron.Selenium forms the integral part of the enzyme glutathione peroxidase, type I iodothyronine deiodinase, metalloprotein, fatty acid binding protein and selenoprotein P. therefore selenium is considered as an antioxidant nutrient and the diseases where low selenium is implicated range from nutritional disorders like protein energy malnutrition to degenerative diseases such as cancer .Rajendran R  estimateKrishnaswamy et al  reportedVijaykumar T  reportedThe serum selenium concentration was found to be decreased. The role of selenium is thus complex which can be attributed to its protective antioxidant role.A significant positive correlation as present between the serum circulating immune complexes levels and copper in the precancer group. Both parameters showed a steady increase. There was a significant positive correlation found between age of subjects and circulating immune complexes, serum copper and iron levels in the cancer groupLinear regression estimates the coefficient of the linear equation involving one or more independent variables that best predict the value of the dependent variable. Applying linear regression analysis with type of lesions as dependent variable, we identified age, serum iron, CIC and serum levels of selenium as best predictors for the occurrence and progression of lesions in the decreasing order. However, gender and serum copper failed to show any predictive value for the type of lesion. Estimation of CIC and trace elements might help in early detection, differential diagnosis and treatment planning of oral premalignant and malignant lesions.The present study highlights that circulating immune complexes represent the host's physiological and immunological response in eliciting specific antibodies upon exposure to most antigenic substance.High levels of copper in areca nuts, a major etiological factor in OSMF plays an initiating role in stimulation of fibrinogenesis by up regulation of lysyl oxidase and thereby causing inhibition of degradation of collagen and causing its accumulation thereby causing OSMF. The rise in serum copper may be due to increased turn over of ceruloplasmin in the serum of carcinoma patients.Serum iron levels are considered as biochemical indicators for nutritional assessment. Utilization of iron in collagen synthesis by the hydroxylation of proline and lysine leads to decrease serum iron levels in OSMF patients. In most cases clinical anemia may be a contributing factor. Inadequate intake of food due to burning sensation and vesiculation in the oral cavity might also be an important factor. Reduction in the serum iron level may be due to malnutrition caused by the tumor burden in cancer patients.A decrease in the serum selenium level in oral carcinoma patients can be attributed to the protective antioxidant role in cancer. No similar study has been done on serum levels of circulating immune complexes, trace elements,  as a combination in oral precancer and cancer.An attempt was made to assess these parameters as predictors for disease occurrence and progression. We identified age, serum iron, CIC and serum levels of selenium as best predictors for the occurrence and progression of lesions in the decreasing order.It can be suggested that immunological and biochemical assessment of oral precancer and cancer patients may help in earlier diagnosis and/or prognosis of these lesions. This may also serve in predicting malignant potential of the pre malignant lesions.These efforts maybe of value for proactive intervention of high risk groups. Proactive intervention might be an inconvenience,But the decision is ours,An inconvenience rightly considered,Or a convenience wrongly considered.Dr. Sunali Khanna-Study concept and design, Clinical sample and data collection, Analysis and interpretation of data, Drafting of manuscript.Dr. Freny Karjodkar-Critical revision of manuscript, Administrative and material support and Overall supervision


Recent reports have suggested the presence of oestrogen receptors (ER) in pancreatic carcinoma. Therefore the tumour may be sensitive to hormone manipulation therapy. We examined 23 biopsies of human pancreatic carcinoma tissue for the presence of ER. The tissue was assayed by two methods: Iso-electric focusing (IEF) and ER-ICA an immunocytochemical assay. All biopsies were tested with ER-ICA and ten by IEF. Each biopsy was assessed histologically for tumour content and 20 contained adenocarcinoma. None of the samples of pancreatic carcinoma were positive for ER using the ER-ICA, and none demonstrated the binding peak typical of ER in the IEF assay. These results suggest that in pancreatic carcinoma oestrogen receptor is either absent (or at very low levels), or of a different type to that found in breast and uterine tissue. On theoretical grounds at least, this must raise questions as to the oestrogen sensitivity of pancreatic cancer.


Documentation of superfoetation is extremely rare in humans., The younger foetus has invariably been small for gestational age  in all the cases reported in the literature. We report a case where the younger twin was of appropriate size for gestation.The first of twins was of 32 weeks gestation and the baby was of appropriate size and development for the gestational age. The second twin was of 36 weeks gestation. Gestational age was estimated with the New Ballard score, x-ray of the lower limbs, dental age on x-ray, and ophthalmic examination.Bleeding on implantation of the first foetus probably helped demarcate the two pregnancies. Dental age and the New Ballard score can be used to diagnose superfoetation in discordant twins, when detailed first trimester ultra-sound data is not available. Superfoetation implies fertilization and subsequent development of an ovum when a foetus is already present in the uterus. Growth discordance in multiple pregnancies due to placental insufficiency, twin to twin transfusion or aneuploidy need to be differentiated from superfoetation. In most instances the larger twin is nearer appropriate size for gestational age calculated from the last menstrual period (LMP). We report a case where superfoetation was likely superfoetationbecause the smaller of the twin was of appropriate maturity, weight and length for gestational age. These circumstances argued against intrauterine growth retardation in the smaller twin.A 21-year-old mother of two had an ante-natal ultrasound examination done 26 weeks after her last menstrual period (LMP). This showed twins, one was of appropriate size for duration of amenorrhoea while the other was approximately four weeks too large. The ultrasound findings are described in Table Six weeks later, after 32 weeks of amenorrhoea, live twins were delivered. They had not received ante-natal steroids. The first of the twins (Twin A) weighed 980 grams and the next baby (Twin B) weighed 2160 grams. Detailed neurological assessment using the New Ballard Scoring [X-ray chest with mandible showed absence of calcified crowns of the first and second deciduous molar in Twin A and both crowns calcified in Twin B Figure , 4. The Retinal vessels normally reach nasal ora serrata by 36 weeks and periphery on the temporal side by 40 weeks.Ophthalmological examination of Twin Ashowed a hazy cornea and the underlying papillary membrane was not visualised. The retinal vessels had not reached the nasal ora serrata. In Twin B the cornea was clear, there was no papillary membrane and the retinal vessels migration was complete on the nasal side and near complete on the temporal side.Intrauterine growth retardation (IUGR) is the usual cause of discordance in multiple pregnancies. We did not find anyreport in the literature of discordance due to one baby being large-for-date. In this case the smaller twin was of appropriate size and maturity for gestation assessed from LMP. The second twin was approximately a month too large and mature. Superfoetation was considered as a possible explanation for the observation. Bleeding one month after conception occurs in about 8% pregnancies and represents a physiological response to implantation or slight bleed from the endometrium in early pregnancy . We therDetailed neurological and physical assessment is considered the most reliable method of estimation of gestational age, in circumstances where IUGR is suspected and there is uncertainty in using LMP . Using tAmong the evidence listed above, anthropometric measurements and bone maturation are delayed in first-trimester-malnutrition and results in symmetric growth retardation ,5. HowevThe author(s) declare that they have no competing interests.NB, SM, NV and AK investigated the case, searched the literature and helped with the write up, NP helped with the radiological input, and JMP conceived of the study and helped with its write up. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:


VDR) gene was associated with individual risk of hand osteoarthritis (OA). Radiographs of both hands of 295 dentists and of 248 teachers were examined and classified for the presence of OA using reference images. The VDR ApaI and TaqI genotypes were determined by PCR-based methods. No association was observed between the VDR polymorphisms and the odds of overall hand OA. However, the carriers of the VDR t allele or At haplotype were at almost half the odds of symmetrical hand OA  compared with the carriers of the T allele and of the non-At haplotype, respectively. Increased odds of this disease, on the contrary, was observed for women with two copies of the VDR a allele  compared with women with the AA genotype. Conversely, the VDR a allele carriage was associated with a tendency of lowered odds of osteophyte . When the genotype data were used to construct haplotypes, the VDR AaTt joint genotype appeared to pose a remarkably lower odds  of osteophyte compared with the AAtt joint genotype. As a novel finding we observed a joint effect of a low calcium intake and VDR polymorphisms on symmetrical OA; the OR was 2.64 (95% CI = 1.29–5.40) for carriers of the aT haplotype with low daily calcium intake compared with non-carriers of the haplotype with high daily calcium intake. Our results suggest that VDR gene polymorphisms play a role in the etiology of symmetrical hand OA. Moreover, the association between the VDR gene and OA may be modified by calcium intake.We examined whether polymorphisms of the vitamin D receptor ( Osteoarthritis (OA) is the most frequent cause of musculoskeletal disability in developed countries. Two main subsets of the disease are recognized: monoarticular OA and polyarticular OA . DespiteSome of the studies have proposed that genetic susceptibility may be more relevant to OA in women than to OA in men, and that the role of genes in the development and progression of OA may vary between joint groups .Hand OA often aggregates with knee OA ,8,9. EpiVDR gene acts as an important regulator of calcium metabolism and bone cell function ) was calculated based on self-reported height and the weight measured during the clinical examination session. The BMI was placed into tertiles for logistic regression analysis .Weight was measured without shoes to the accuracy of 0.1 kg. The body mass index (BMI)  smokers.Allele and genotype frequencies were compared between individuals with and without OA using Fisher's exact probability test or the chi-square test. Carriage rates for the alleles were calculated as the proportion of individuals with at least one copy of the allele. Each gene locus was also examined for an allele dosage effect, by comparing the numbers of individuals heterozygous and homozygous for the test allele among those with and without OA.VDR haplotypes were statistically reconstructed from population genotype data using the PHASE program with the Markov chain method for haplotype assignments [The ignments .VDR genotypes and hand OA. To evaluate whether the association between the genotypes and OA is modified by daily calcium intake, the odds ratio (OR) of having OA was calculated as a function of daily calcium intake (low intake versus moderate or high intake), of the presence of a risk allele, and of their interaction. An absence of a risk allele and high or moderate daily calcium intake was used as reference group.A set of logistic regression analyses was performed to examine the association between the Crude and adjusted ORs and their 95% confidence intervals (CIs) were calculated using the SPSS statistical package . The ORs were adjusted for the potential confounding factors of age, occupation, height, BMI, use of hormone therapy, daily calcium intake, and coffee and alcohol consumption. Since the crude and adjusted ORs did not differ significantly, only the adjusted ORs are shown.The prevalence of the overall hand OA, symmetrical OA, and osteophytes among the female dentists and teachers aged 45–63 years were 29%, 21%, and 7%, respectively. The basic characteristics of the study subjects by their hand OA status (absence or presence of OA) are summarized in Table VDR ApaI and TaqI loci did not deviate significantly from Hardy–Weinberg equilibrium, and the frequencies agreed with those previously observed in Finnish women [The genotype and allele distributions of the sh women .ApaI and TaqI genotype data. Five of the genotypes  were relatively common, exhibiting frequencies of 28.4%, 21.0%, 18.6%, 16.6%, and 11.8%, whereas the frequency for the AATT genotype was only 3.7%. The frequencies of the VDR aT, At and AT haplotypes were 43%, 34%, and 32%, respectively.Six of the possible nine joint genotypes were reconstructed by the PHASE program  from theVDR genotype groups, but the daily calcium intake was higher in the tt and Tt genotype groups compared with the TT genotype group . The proportion of ever-smokers was higher among the carriers of the aT haplotype compared with the non-carriers .The age, height, BMI, occupation, use of hormone therapy, smoking history, coffee consumption, and alcohol drinking were similar in the VDR gene polymorphisms and the overall odds of hand OA. However, the VDR aa genotype posed an almost doubled odds of symmetrical hand OA  compared with the AA genotype  to lowered odds of osteophyte.No association was observed between individual pe Table . The womle Table  or carryVDR AaTt joint genotype appeared to pose a remarkably lower odds of osteophyte  compared with the AAtt joint genotype  and with a decreased odds of osteophytes . Similarly, there was no statistically significant association between a low calcium intake and OA among subjects without the aT haplotype. However, both factors  acted synergistically to increase the odds of OA. We observed a joint effect of a low calcium intake and carriage of the VDR aT haplotype on symmetrical OA; the OR was 2.64 (95% CI = 1.29–5.40) for carriers of the aT haplotype with a low daily calcium intake compared with non-carriers of the haplotype with a moderate or high daily intake.The separate and joint effects of the VDR a allele appeared to always be associated with the T allele, identical ORs for the VDR a allele carriage and the aT haplotype carriage were seen in the present study  were affected.VDR ApaI and TaqI polymorphisms and the risk of symmetrical hand OA in Finnish women. The VDR aa genotype, which has previously been associated with high bone mass [AA genotype associated with lower bone mass. In contrast, the odds of this disease was almost halved among those with the VDR t allele, which has previously been associated with a higher rate of bone turnover [T allele.Our findings suggest that there may indeed be a relationship between the one mass , posed aturnover  and loweturnover  comparedVDR aT haplotype and hand OA depended on the interaction with dietary calcium intake. A joint effect of a low calcium intake and carriage of the VDR aT haplotype on risk of symmetrical OA exceeded their additive effects, indicating that the VDR aT haplotype is a potential risk factor for OA among women with insufficient calcium intake. These relationships were independent of other risk factors such as age, occupation, BMI, use of hormone therapy, and smoking history.In our study, the association between the VDR alleles and bone mineral density may vary depending on the level of calcium intake [VDR baT haplotype has been related to enhanced abnormality in the calcium regulation of the parathyroid hormone secretion from adenomatous parathyroid cells of primary human parathyroid tumor [VDR genotypes in OA etiology. Our finding, if confirmed, implies a considerable potential for a role of nutritional interventions for OA.Regulation of intracellular calcium plays a key role in hypertension, insulin resistance, and obesity . A protem intake ,26,43-45m intake . The VDRid tumor . HoweverVDR AaTt joint genotype had the lowest odds and those with the AATT genotype the highest odds of hand osteophytes as compared with the AAtt genotype. The direction of these associations contrast the findings in the studies of osteophytes formation in the knee [In the Framingham study  the growthe knee -19 and tthe knee , but agrthe knee .VDR gene polymorphisms. The ApaI polymorphism is unlikely to have functional consequences, however, since it is located in intron 8 and is not affecting any splicing site or transcription factor binding site. Moreover, although the TaqI polymorphism is located in the coding sequence (exon 9) of the VDR gene, it has no effect to the encoded protein sequence [VDR polymorphisms in the VDR functionality, lower VDR mRNA levels were found to be associated with homozygosity for the a and T alleles [The large amount of positive genetic association data in a number of diseases such as osteoporosis, OA, diabetes, and cancer  suggest sequence . Neverth alleles .Our study has several limitations. The cross-sectional study design precluded the assessment of an effect of dietary calcium intake on the incidence or progression of OA. The relatively small number of subjects reduced the power of the study to detect differences. Another limitation arises from the fact that calcium intake was assessed based on a questionnaire, and thus the recall bias may affect the accuracy of information gathered. Finally, vitamin D intake was not assessed in our population.VDR genotype frequencies in this population did not significantly deviate from the Hardy–Weinberg equilibrium and the genotype frequencies were similar to those previously observed in Finnish women [Despite these limitations, the present findings are not anticipated to be caused by selection bias. First, selection on the genotype is unlikely since all study subjects were of homogeneous Finnish origin. Second, the prevalence of hand OA among the women analyzed in this study is similar to that seen in other studies -54. Thirsh women . NeitherVDR genotypes was unbiased. The possibility of non-differential misclassification of osteoarthritis cannot be ruled out. Non-differential misclassification of a binary outcome usually produces bias toward the null.The lower level of interobserver agreement for radiographic findings was not surprising. Despite training and the use of reference images, each reader graded the radiographs according to his or her own inherent standard about what constituted a positive finding. The high intraobserver agreement suggests that the classification criteria applied here are highly reproducible. Because all radiographs were evaluated by one observer who was blind to subjects' genetic data, the high intraobserver repeatability implies that the comparison between subjects with different a priori that the interaction observed in this study would occur, based on the known biology of the VDR gene in regulation of calcium metabolism. Second, our sample was homogeneous in terms of age, gender, ethnicity, and genetic background. Third, haplotypes were constructed taking into account the knowledge that collective grouping of single nucleotide polymorphisms in haplotypes has a stronger association with the phenotype than individual polymorphisms. Finally, to minimize the number of analyses performed, the interaction hypothesis was tested with the risk haplotype only.It could be argued that at least some of the associations found in this study were spurious, considering multiple comparisons were performed. However, there are several arguments to support the consistency of these results rather than attributing them to chance. First, we hypothesized VDR polymorphism in the etiology of symmetrical hand OA. In addition, our findings suggest a detrimental effect of low dietary calcium intake on OA. The findings remain to be weighted in future studies. Further studies into mechanisms underlying the relationships between calcium and OA may improve the understanding of the obtained results.Although the possibility remains that the studied polymorphisms do not directly affect the individual susceptibility of hand OA, but are in linkage disequilibrium with an unknown nearby susceptibility locus, our results provide evidence of the involvement of the BMI = body mass index; CI = confidence interval; DIP = distal interphalangeal; MCP= metacarpophalangeal; PCR = polymerase chain reaction; PIP = proximal interphalangeal; OA = osteoarthritis; OR = odds ratio; VDR = vitamin D receptor.The authors declare that they have no competing interests.SS participated in the design of the study, performed the statistical analysis, and drafted the manuscript. AH and PS carried out the genotyping analysis. TV carried out the evaluation of hand radiographs. KL participated in the evaluation of reliability of radiographs' readings. HR conceived of the study and participated in its design. PLA conceived of the study and participated in its design and coordination. All authors read and approved the final manuscript.


The serine-threonine protein kinase and proto-oncogene Akt has been reported to regulate proliferation and apoptosis in several tissues but there are no data on the involvement of Akt in oesophageal carcinogenesis. Therefore we have examined the activation of Akt in Barrett's oesophagus and oesophageal adenocarcinoma and the functional effects of Akt activation Expression of total and active (phosphorylated) Akt were determined in endoscopic biopsies and surgical resection specimens using immunohistochemistry. The functional effects of Akt were examined using Barrett's adenocarcinoma cells in culture.In normal squamous oesophagus, erosive oesophagitis and non-dysplastic Barrett's oesophagus, phospho-Akt was limited to the basal 1/3 of the mucosa. Image analysis confirmed that Akt activation was significantly increased in non-dysplastic Barrett's oesophagus compared to squamous epithelium and further significantly increased in high-grade dysplasia and adenocarcinoma. In all cases of high grade dysplasia and adenocarcinoma Akt was activated in the luminal 1/3 of the epithelium. Transient acid exposure and the obesity hormone leptin activated Akt, stimulated proliferation and inhibited apoptosis: the combination of acid and leptin was synergistic. Inhibition of Akt phosphorylation with LY294002 increased apoptosis and blocked the effects of acid and leptin both alone and in combination. Activation of Akt was associated with downstream phosphorylation and deactivation of the pro-apoptotic protein Bad and phosphorylation of the Forkhead family transcription factor FOXO1.Akt is abnormally activated in Barrett's oesophagus, high grade dysplasia and adenocarcinoma. Akt activation promotes proliferation and inhibits apoptosis in Barrett's adenocarcinoma cells and both transient acid exposure and leptin stimulate Akt phosphorylation. Downstream targets of Akt include Bad and Forkhead transcription factors. Activation of Akt in obesity and by reflux of gastric acid may be important in the pathogenesis of Barrett's adenocarcinoma The incidence of oesophageal adenocarcinoma (OAC) is continuing to increase in the developed world. Over the last 30 years the incidence in the USA has increased six fold . Most caA greater understanding of the biology of BO is needed to provide us with more targets for preventative and therapeutic interventions as well as markers of progression in BO, to enable more focused screening. Although several genetic and cellular changes have been described, none of these as yet have proven utility ,9. IncreThe protein kinase Akt  is a relatively recently described serine-threonine kinase that has been shown to be important in mediating cell proliferation and cell survival signals in several tissues and cancers ,11. Therin vitro using the OE33 and OE19 Barrett's-derived adenocarcinoma cell lines. These have previously been shown to be suitable functional experimental cellular models for Barrett's epithelium -2, 5-diphenyltetrazolium bromide; OAC, oesophageal adenocarcinoma; PCR, polymerase chain reaction; PBS, phosphate buffered saline pH 7.4; PI3-kinase, phosphatidylinositol 3'-kinase; RT, reverse transcriptase.The author(s) declare that they have no competing interests.ILPB initiated the concept and design of the overall study, performed the kinase phosphorylation assays, performed the image analysis, performed the analysis, statistics and interpretation of the data and wrote the original and final versions of the manuscript. OO designed and performed all the experiments using cultured cells. EC participated in the conception and design of the histopathological study and completed recruitment of all subjects. KEA performed analysis and interpretation of the histopathology. GM participated in the immunocytochemistry and PCR and provided support and discussion during design of the studies. MW performed analysis and interpretation of the histopathology and participated in the conception of the study. All authors have approved the final version of the manuscript.The pre-publication history for this paper can be accessed here:


Infectivity studies indicate that PrPSc may also be present in body fluids, even at presymptomatic stages of the disease, albeit at concentrations well below the detection limits of currently available analytical methods.The definite diagnosis of prion diseases such as Creutzfeldt-Jakob disease (CJD) in humans or bovine spongiform encephalopathy (BSE) in cattle currently relies on the -8 nM [0.24 fg/ml]. A specific signal was detected in six out of six available serum samples from BSE-positive cattle.We developed a highly sensitive method for detecting prion protein aggregates that takes advantage of kinetic differences between seeded and unseeded polymerization of prion protein monomers. Detection of the aggregates was carried out by flow cytometry. In the presence of prion seeds, the association of labelled recombinant PrP monomers in plasma and serum proceeds much more efficiently than in the absence of seeds. In a diagnostic model system, synthetic PrP aggregates were detected down to a concentration of approximately 10ante mortem diagnostic test for prion diseases.We have developed a method based on seed-dependent PrP fibril formation that shows promising results in differentiating a small number of BSE-positive serum samples from healthy controls. This method may provide the basis for an  Sc) of the normal cellular prion protein (PrPC). PrPC is a cell surface glycoprotein expressed in neurons   at room temperature, measurement time was 30 sec per sample.LT participated in the design of the study, carried out the measurements and drafted the manuscript. ANS participated in the analysis of the data. EM prepared the recombinant protein. KK and ST were also involved in protein expression and purification. HS participated in the design and coordination of the study. GB conceived of the study and helped to draft the manuscript. All authors read and approved the final manuscript.