The desire of many to look young for their age has led to the establishment of a large cosmetics industry. However, the features of appearance that primarily determine how old women look for their age and whether genetic or environmental factors predominately influence such features are largely unknown. We studied the facial appearance of 102 pairs of female Danish twins aged 59 to 81 as well as 162 British females aged 45 to 75. Skin wrinkling, hair graying and lip height were significantly and independently associated with how old the women looked for their age. The appearance of facial sun-damage was also found to be significantly correlated to how old women look for their age and was primarily due to its commonality with the appearance of skin wrinkles. There was also considerable variation in the perceived age data that was unaccounted for. Composite facial images created from women who looked young or old for their age indicated that the structure of subcutaneous tissue was partly responsible. Heritability analyses of the appearance features revealed that perceived age, pigmented age spots, skin wrinkles and the appearance of sun-damage were influenced more or less equally by genetic and environmental factors. Hair graying, recession of hair from the forehead and lip height were influenced mainly by genetic factors whereas environmental factors influenced hair thinning. These findings indicate that women who look young for their age have large lips, avoid sun-exposure and possess genetic factors that protect against the development of gray hair and skin wrinkles. The findings also demonstrate that perceived age is a better biomarker of skin, hair and facial aging than chronological age. The ability to estimate age has evolved as it enables an individual to evaluate, for example, the suitability of a potential mate The influence of particular features on the perception of age depends on the context in which a subject is viewed. For example, photographs can be viewed with or without hair and clothing cues  were carried out in the Danish twin and British populations. Perceived age data generated from the facial images were found to be significantly and strongly correlated, after controlling for chronological age, with facial skin wrinkling and wrinkle depth . However, hair aging features could be important modulators of age perception. Therefore, hair recession , hair thinning on the top of the head  and hair graying were measured in the Danish twin population along with how old the twins looked in passport-type photographs. Hair thinning and graying were found to be weakly but significantly correlated with each other , althougA comparison between the perceived ages of the Danish twins in the facial images and the passport-type images, generated by the same assessors, revealed that the twins looked older for their age in the facial images . Taken in conjunction with the hair colorant result, the cues present in the passport–type images that can be modified to convey youthfulness  were most likely responsible for the twins looking younger in the passport-type images than in the facial images. There was no significant correlation for any of the hair aging features with the skin aging features or the perceived age data generated from the facial images. However, despite the differences between the facial and passport-type images the correlation between the perceived age data from the facial images and the passport-type images was high . Thus, tIt is important in gerontology research to utilize markers of the biological age of an individual and/or their tissues to enable the identification of factors that influence aging over and above generational differences that chronological age (or a proxy thereof) would identify in a population. Here, perceived age was found to be a good biomarker of aging as significant correlations were found between skin and hair aging features and perceived age after adjusting for chronological age . DiffereTo determine whether the skin, hair and lip features were related to perceived age independently of each other as well as chronological age, linear regression models were utilized to predict perceived age in both populations. For the perceived ages generated from the Danish twin passport-type images and excluding those who used hair dye, only skin wrinkles and hair graying had significant prediction in a linear model . When haFor the Danish facial images, wrinkles, lip height and hair recession were independently predictive of how old the twins looked for their age . As the The amount of variation in the perceived age data explained by chronological age and the aging appearance features included in the linear models were 73% and 86% for the facial images of the Danish twin and British subjects respectively; there was, therefore, considerable variation in the data unaccounted for. Age-related changes to subcutaneous tissue have been extensively documented and implicated as affecting facial appearance We assessed the similarity of features of facial appearance in mono- and dizygotic twins. The classic twin-study methodology is based on the fact that monozygotic twins have identical genotypes whereas dizygotic twins share, on average, half of their gene variants and, thus, are no more genetically related than ordinary siblings. A greater phenotypic similarity in monozygotic than dizygotic twin sisters is to be expected if there is a substantial genetic component in the etiology of the condition. By comparing the correlation in the appearance of a feature in monozygotic twin pairs to dizygotic twin pairs see SI  it can bHeritability analyses of the skin aging features in the twin population demonstrated that 41–60% of the variation in sun-damage, skin wrinkling, wrinkle depth and pigmented age spot measures were explained by genetic factors . In suppHere, we found that lip height was mainly influenced by genetic factors . Lip sizSome genes have been implicated in the biological pathways that influence hair graying in mice The size of influence that genetic factors can have on a feature tends to be dependent upon the environmental conditions in which a population exists Here, we have found that skin wrinkles, lip height and hair graying were significantly and independently correlated with how old women looked for their age. In addition, evidence that sun-exposure significantly influences how old women look for their age through its effects on skin wrinkling was found. Furthermore, we have quantified the influence of genetic factors on skin, hair and facial aging features and found evidence that subcutaneous tissue plays a role in how old women look for their age. Collectively, these findings will help direct future investigations into why appearances change with age and enable the use of perceived age, with consideration to the type of photographic image, in epidemiological approaches to identify the genetic and environmental factors that influence skin, hair and facial aging.Caucasian twins aged 59–81 years were recruited in Denmark and informed written consent obtained. The study protocol was approved by the Research Ethics Committee for the Region of Southern Denmark. Zygosity established by the Applied Biosystems AmpFλSTR Identifiler kit indicated self-reported zygosity was accurate for all but 3 dizygotic twins; these twins were re-classified as monozygotic. British Caucasian subjects aged 45–75 years were recruited in southern England and gave informed written consent, and the study was approved by the Unilever Colworth Ethical Committee. Recruitment of the British and Danish subjects was carried out to give an even spread of subjects across the chronological age range of each study  to the lowest point of the lips directly below, and another cropped image created from the top of the fore-head to the bottom of the chin (to measure face height). Variations in the lip height measures could have been caused by differences in the distance of the subject to the camera and by subject head size. Thus, the vertical height of the lip image was then measured in pixels and adjusted for face height in pixels (lip height/face height) to limit the impact of such variations and to benchmark lip height relative to the size of the face.To generate the composite images, software was employed which merges together facial images by blending together the face shape, skin color and skin topology from each image. To capture face shape, one hundred and fifty six landmark points were located on each frontal eyes-open photograph creating a delineated image. The face shape position data was used to compute an average face shape, and the color information warped onto this average shape before the mean color values were calculated In the Danish twin study, for all analyses  22 of the twins were excluded due to either twin pair having non-cosmetic surgical treatments performed on their face and to balance the design of the assessment of age in facial images see . Due to All assessors were unaware of presentation designs, the presence of technical replicates, subject ages and age ranges. Technical reproducibility  was examDifferences in the feature data within twin pairs were compared between the monozygotic and dizygotic twins using intra-class correlations. For hair thinning and hair recession, as the majority of scoring occurred in the first two grades, the data were dichotomized for the heritability estimation and tetrachoric rather than intra-class correlations were calculated. Intra-pair correlations, tetrachoric correlations and heritability estimates were calculated by constraining the means and variances to be equal across the arbitrary categories of twin 1 and 2 and across zygosity. Structural equations were fitted (using Mx version 1.7.01) to a set of models of the twin data with all possible combinations of additive genetic effects, dominance genetic effects, shared environmental effects and unique environmental effects Supporting Information S1(0.04 MB DOC)Click here for additional data file.Figure S1Scatter plots representative of correlations presented in the main manuscript. a) Facial wrinkling versus perceived age from facial images after adjusting for chronological age. b) Hair grayness versus perceived age from passport-type images after adjusting for chronological age. c) Wrinkle depth measures from beside the left eye for monozygotic twins (x-axis) and their sisters (y-axis). d) Wrinkle depth measures from beside the left eye for dizygotic twins (x-axis) and their sisters (y-axis). Graph lines are linear fits of the y-axis data onto the x-axis data and are representative of the correlation values in the main manuscript.(6.20 MB TIF)Click here for additional data file.Figure S2Representative images for hair aging measures. a) A 45-degree angle image of a subject with little to no hair recession (left-hand image) and a subject with grade 3 recession on the Hamilton-Norwood scale (right-hand side). b) An image of a subject with little to no hair thinning (left-hand image) and a subject with grade 3 thinning on the Sinclair scale (right-hand side). c) Example of a 45-degree image (left hand image) used to extract an area of hair from the left-hand temporal area of the head (centre image) and image analysis of gray (white) and non-gray (green) pixels in the image (right-hand image).(4.43 MB TIF)Click here for additional data file.Table S1Aging appearance feature and chronological age unadjusted inter-correlation values.(0.05 MB DOC)Click here for additional data file.Table S2Multivariate linear modeling to predict perceived age excluding hair graying or facial wrinkle measures.(0.03 MB DOC)Click here for additional data file.


Blunt traumatic injury and acute dissection of thoracic aorta is increasing in incidence in seriously multi-trauma patients, remaining highly lethal. Early identification and repair is the key to a successful outcome. We report an unusual case of a 62-year-old man involved in a motor vehicle accident after subarachnoid hemorrhage due to an intracranial artery aneurysm rupture. The post-traumatic aorta dissection was overlooked during the initial evaluation and was found incidentally later during an attempt for endovascular treatment of the intracranial aneurysm. The pitfalls in the diagnostic approach of this patient are discussed and the paramount importance of the correct interpretation of all the available clinical and investigational findings in multiple injured patients are highlighted. Multiply-injured patients are always a diagnostic and therapeutic clinical challenge. Only a very careful study and interpretation of the trauma history and conditions, the clinical presentation and examination and the appropriate radiological investigation will identify all the related injuries . Such inA 62-year-old, white, Caucasian, British-origin, male lorry driver was admitted to the hospital late on a Friday night after an unwitnessed single vehicle road accident. His lorry was by the side of the road and he was found unconscious in the vehicle and immediately transferred to the local District General Hospital. On admission, he had already fully recovered, being alert and orientated but he had no recollection of the accident. He was haemodynamically stable, with normal vital signs and no neurological deficit. He complained only at a moderate headache. Physical examination has revealed a bruise on the upper part of his left anterior chest wall, left shoulder and forehead. The rest of the examination was entirely normal. The radiological investigation that followed included cervical spine and left arm X-rays in which no fracture was noted. A mobile AP chest X-ray was also done on admission, in which it was demonstrated a dilated aortic arch . A subarfirst was the misdiagnosis of posttraumatic instead of aneurismal subarachnoid hemorrhage, which was the actual cause of the accident. This was due to the inability of the patient to describe the event due to retrograde posttraumatic amnesia as well as due to the inexperience of the admitting physician to identify the hinds of the brain CT scan indicating the aneurismal origin of the subarachnoid hemorrhage. The second was the underestimation of the chest injury, regarding either the clinical signs or the chest X-rays. It is reported that 65% of chest trauma in multiple injured patients may be overlooked in plain chest X-rays [Acute traumatic injury of the thoracic aorta is a relatively common injury of deceleration accidents, usually high-speed motor vehicle accidents  that stit X-rays . Similart X-rays .The present case report underlines the major importance of the correct interpretation of all the available information and data  regarding multiple-injured patients. A systemic process to this particular type of patients is extremely valuable. Early diagnosis of an aortic dissection in a multiply injured patient is often difficult but also particularly important for the final outcome. The early identification of all the possible injuries and their thorough clinical and radiological investigation are of paramount importance for an effective treatment approach and a favorable clinical outcome.


Detailed information about protein interactions is critical for our understanding of the principles governing protein recognition mechanisms. The structures of many proteins have been experimentally determined in complex with different ligands bound either in the same or different binding regions. Thus, the structural interactome requires the development of tools to classify protein binding regions. A proper classification may provide a general view of the regions that a protein uses to bind others and also facilitate a detailed comparative analysis of the interacting information for specific protein binding regions at atomic level. Such classification might be of potential use for deciphering protein interaction networks, understanding protein function, rational engineering and design.Protein binding regions (PBRs) might be ideally described as well-defined separated regions that share no interacting residues one another. However, PBRs are often irregular, discontinuous and can share a wide range of interacting residues among them. The criteria to define an individual binding region can be often arbitrary and may differ from other binding regions within a protein family. Therefore, the rational behind protein interface classification should aim to fulfil the requirements of the analysis to be performed.We extract detailed interaction information of protein domains, peptides and interfacial solvent from the SCOWLP database and we classify the PBRs of each domain family. For this purpose, we define a similarity index based on the overlapping of interacting residues mapped in pair-wise structural alignments. We perform our classification with agglomerative hierarchical clustering using the complete-linkage method. Our classification is calculated at different similarity cut-offs to allow flexibility in the analysis of PBRs, feature especially interesting for those protein families with conflictive binding regions.The hierarchical classification of PBRs is implemented into the SCOWLP database and extends the SCOP classification with three additional family sub-levels: Binding Region, Interface and Contacting Domains. SCOWLP contains 9,334 binding regions distributed within 2,561 families. In 65% of the cases we observe families containing more than one binding region. Besides, 22% of the regions are forming complex with more than one different protein family..The current SCOWLP classification and its web application represent a framework for the study of protein interfaces and comparative analysis of protein family binding regions. This comparison can be performed at atomic level and allows the user to study interactome conservation and variability. The new SCOWLP classification may be of great utility for reconstruction of protein complexes, understanding protein networks and ligand design. SCOWLP will be updated with every SCOP release. The web application is available at  Protein interactions are essential for intra-cellular communication in biological processes. Proteins are composed of small units or domains that can physically interact together forming multi-domain protein complexes. A single protein can have several binding regions, and each region can engage distinct ligands, either simultaneously or at successive stages of signalling .In our previous work we developed the SCOWLP database , which cBinding regions in protein domains can form separated patches, but also some protein families bind through multiple binding regions with different ranges of residue overlapping. Furthermore, some observed protein interfaces are the result of non-biological artefacts  and are often difficult to distinguish from the biological ones, creating discrepancy among the current resources ,7. Some Hierarchical clustering comprises a whole family of clustering methods differing only on the manner inter-cluster distance is defined (the linkage function). The more common aggregation methods are single-, complete- and average-linkage. Complete and single-linkage are extreme procedures with completely different properties. Complete-linkage uses the similarity between the furthest pair of objects from two clusters. In contrast to these requirements, single-linkage only uses the nearest pair of objects from each cluster. Both methods have an extreme conception of homogeneity of a cluster. Single-linkage leads to grouping and may result in a few large and heterogeneous clusters . CompletWe present a classification of PBRs from all existing contacting domains from the SCOWLP database, which includes detailed information about proteins, peptides and solvent interaction. Peptide and solvent interactions are highly represented in the PDB and are highly informative in protein interactions . For ourThe PBRs classification extends the SCOWLP relational database by four additional tables describing the hierarchical classification at binding region, interface and contacting domain level. The content of the classification is given at similarity zero, which offers a general view of the regions that protein families use for recognition. In addition, our classification offers different similarity cut-offs to allow flexibility in the analysis of the PBRs. The classification of PBRs was performed as follows Fig. :wet spots) are also taken into account. We consider "interface" all domain-domain interactions; that means those belonging to the same protein and also to different proteins. SCOWLP contains 79,803 interfaces contained in 2,561 SCOP families. We grouped the domains participating in each interface by SCOP families, obtaining for each family a list of contacting domains with the residues forming part of the binding region.An accurate definition of the interacting residues is crucial to have a proper clustering of a family PBR. We extracted all protein interfaces from the SCOWLP database, in which the interactions are defined at atomic level and based on their physiochemical properties ,15. ProtA reliable alignment is indispensable to calculate the similarities among binding regions. For this purpose we used MAMMOTH, which has shown proven accuracy to structurally align protein families . We perfSi) based on the number of interacting residues that overlap and the length of both interacting regions by . This value is divided by the average number of the interacting residues in both domains excluding the interacting residues located in gap regions in the structural alignment (IRgaps).where Si, we clustered the binding regions of each SCOP family using the agglomerative hierarchical algorithm  visvs. variation of the interactions. In this example we easily are able to analyze (at structure and sequence level) all the interfaces of the PTB domain with different phospho-tyrosine peptides and their interaction patterns. In the example, the three main recognition regions described for the X11 PTB and a peptide motif from the Alzeimer's amyloid precursor protein  are displayed and structurally aligned with the recognition regions of other peptides known to bind PTBs in this region. Also, specific differences in the interaction pattern can be further analyzed individually by clicking on each PDB entry code. Analysis of the conservation/variability of the interactions describing an interface may be of great utility for understanding energetic and evolutionary aspects of protein interactions and for helping in rational engineering and design.In Figure Classification of the regions that a protein family uses to recognize binding partners is important for understanding the interactome. Protein binding regions are often irregular, discontinuous and can share interacting residues among them, making their clustering difficult, and arbitrary. A suitable classification requires proper measurements of similarity between protein binding regions and an appropriate clustering approach. Our approach consists on hierarchical clustering of the PBRs included in the SCOWLP database, which contains detailed interfacial information of proteins, peptides and solvent. We use the complete-linkage method and a similarity index obtained by mapping interacting residues in non-gap regions of pair-wise structural alignments. This approach provides a dilatation of the differences among clusters, making it suitable to isolate poorly separated clusters. In addition, we introduce flexibility in the usage of different similarity cut-offs for PBRs analysis. Our results show that, from 2,561 families containing binding regions, 65% use more than one binding region to interact. Furthermore, from all existing binding regions in SCOWLP, 22% are interacting with more than one protein family. In order to be able to analyze all family binding regions of the PDB in a detailed and comparative fashion we have implemented our PBR classification into the SCOWLP web application.The current SCOWLP classification and its web application represent a complete framework for the study of protein interfaces and comparative analysis of protein family binding regions. Mining of this information may be of great utility for understanding energetic and evolutionary aspects of protein interactions, reconstruction of protein complexes, understanding protein networks and rational ligand design..SCOWLP classification of PBRs is freely available at JT performed the classification of family binding regions. JT and MP designed the web application. JT and GA performed the PSAs. MTP coordinated and supervised the project. All authors have read and approved the final manuscript.


One of the potential benefits of surgical audit is improved hospital cost-efficiencies arising from lower resource consumption associated with fewer adverse events. The aim of this study was to estimate the potential cost-savings for Australian hospitals from improved surgical performance for colorectal surgery attributed to a surgical self-audit program.We used a mathematical decision-model to investigate cost differences in usual practice versus surgical audit and synthesized published hospital cost data with epidemiological evidence of adverse surgical events in Australia and New Zealand. A systematic literature review was undertaken to assess post-operative outcomes from colorectal surgery and effectiveness of surgical audit. Results were subjected to both one-way and probabilistic sensitivity analyses to address uncertainty in model parameters.If surgical self-audit facilitated the reduction of adverse surgical events by half those currently reported for colorectal cancer surgery, the potential cost-savings to hospitals is AU$48,720  for each surgeon treating 20 cases per year. A smaller 25% reduction in adverse events produced cost-savings of AU$24,960 per surgeon . Potential hospital savings for all operative colorectal cancer cases was estimated at AU$30.3 million each year.Surgical self-audit has the potential to create substantial hospital cost-savings for colorectal cancer surgery in Australia when considering the widespread incidence of this disease. The study is limited by the current availability and quality of data estimates abstracted from the published literature. Further evidence on the effectiveness of self-audit is required to substantiate these findings. An 'adverse event' is defined as the unintentional harm arising to patients from an episode of health care and not due to the disease process itself . AdverseSurgical audit is a quality improvement process considered integral to patient care and outcomes and for the ongoing professional development of surgeons. Royal Colleges of Surgeons in Australia and the UK are firmly committed to and strongly endorse the daily practice of auditing in its various forms within a supportive, legally protective environment . IdeallyComputerized audit systems with dedicated software offer several advantages for auditing where surgeons or hospital staff can enter the required data, produce reports and graphs of outcomes quickly, update their cumulated cases over time, perform risk-adjusted assessments of outcomes and have the ability to pool case reports anonymously within surgical units, regions or nationally ,5. In coThe financial toll to hospitals and health care systems for adverse surgical events is substantial primarily due to the attendant high costs incurred for extended hospital stays . An addiThe purpose of this study was to estimate the potential cost-savings relating to improved surgical outcomes for colorectal surgery attributed to a computerised self-audit program. We used a modelling approach to synthesize published hospital cost data with epidemiological evidence of adverse surgical events occurring in Australasia.A decision-analytical model was constructed in TreeAge Pro 2009 software  Figure . Two strper se) and therefore was not included as a separate outcome. Finally, '30-day mortality' was included in our model as the surgical literature indicates that a proportion of these are likely to be attributed to adverse events and omitting them would otherwise underestimate costs of adverse events.Several steps were involved in populating the model parameters and analysis. First, we identified the common types and frequencies of surgical adverse events relating to colorectal cancer in Australia and NZ along with evidence on the effectiveness of surgical audit for colorectal cancer surgery. A systematic literature review was undertaken to locate Australian and NZ studies reporting post-operative outcomes for a series of patients undergoing surgery for colorectal cancer. Studies were included if they were published after 2000 (to reflect current practice), had observational study designs and involved surgeries for colorectal cancer patients where post-operative outcomes were reported. PubMed and Medline databases were used to search for journal articles in the English language with the following terms in their title: colorectal, colon, rectal, surgery, surgical or management combined with adverse events, complications, post-operative, morbidity, performance, outcomes. A selection of the most commonly reported adverse events were included in the model; anastomotic leakage, wound infection, DVT, respiratory problems , re-operation and 30-day mortality . Although 'length of stay' in hospital was also a common outcome reported, this is a consequence of arising complications, it is implicit in the valuation of costs  and included inpatient costs for colon and rectal surgical admissions with or without complications. Costs for surgical admissions were derived from the National Hospital Cost Data Collection 2006-2007  listing Third, the model was calculated by summing the expected (mean) cost values at each tree node for each type of adverse event for the 'self-audit' and 'usual practice' arms and aggregated separately. These values are based on the probabilities of the adverse events derived from the literature and their attendant costs. An expected mean cost for one surgical episode in each arm was produced. The cost-savings arise from the reduced level of the 'surgery plus complications' DRG cost estimates in the audit arm compared to the usual practice arm. However, as the cost of adverse events is embedded in the DRG estimates and intrinsically linked to the surgical episode where there is uncertainty in the exact level of resources consumed, sensitivity analyses on the DRG cost estimates were performed. One-way sensitivity analyses on all cost and epidemiological parameters were undertaken to investigate the robustness of the base results to plausible changes in the data estimates  discuss the 'degree of preventability' of adverse surgical events [The evidence-base for 'audit and feedback' interventions is very large for clinical studies across a huge range of medical topics. A Cochrane systematic review of 118 studies on this topic showed small to moderate improvements in outcomes overall  . Howeverl events . A propol events . In the l events . These il events . Finallyl events  althoughThe data used to populate the model included estimates reported in the published literature however a number of assumptions were also necessary Table . The expExpected mean costs for the two options are more precise from a probability sensitivity analysis Table . For eacWe used a mathematical model to synthesize the published evidence on the extent of surgical adverse events and attendant costs for colorectal cancer surgery in Australia. The advantage of this type of model is that it explicitly identifies the options and parameters under consideration and allows for detailed sensitivity and scenario (what-if) analyses. Our findings showed that if self-audit facilitated the reduction of adverse surgical events by half those currently reported for colorectal cancer surgery, the potential annual hospital cost-savings was $48,000 for each surgeon treating 20 cases per year and could range from $18,000 to $90,000. The wide range of potential cost-savings reflects the combined uncertainty of published estimates on adverse events rates, different surgical casemix and the potential variation in the accompanying costs. The potential cost-savings is substantial when considering the widespread incidence of this disease and the cost containment goals in all hospitals.The study is limited by the current availability and quality of data estimates abstracted from the published literature. The 11 studies providing estimates on adverse event rates were inconsistent in the use of standard definitions and methods used to measure the various types of adverse events. This appears to be a common problem internationally as confirmed in a large UK review on the topic of monitoring adverse events . The curThe lack of evidence on the effectiveness level of audit programs for surgery is also a limitation of the study. This is probably because of, in part, the confronting nature of the topic, the possible legal and social ramifications, time pressures and overall reluctance of doctors to be involved in this kind of study. As assumptions were made about this effect size, the findings should be considered as exploratory. Furthermore, the effectiveness level of surgical audit is governed, in part, by the initial adverse event rates with greater improvements possible when rates are relatively high to begin with ,23. HoweThe analysis also relied on an aggregated national costing report on episodes of colorectal surgery in Australian hospitals . While tUsing best-available evidence on the outcomes of colorectal cancer surgery in Australia and NZ and exploring the cost-savings accompanying lower hospital resource consumption from improvements in surgical performance, we found substantial economic dividends accruing for hospitals. A computerised self-audit program operating with frequent data input is a low-cost tool to facilitate potential improvements in surgical performance.AR-DRG: Australian-Refined Diagnostic Related Group; AU: Australian; CI: Confidence interval; CUSUM: Cumulative sum analysis; DVT: Deep vein thrombosis; NZ: New Zealand.http://www.surgicalperformance.com.L Gordon received an honorarium from A Obermair for undertaking the analysis. A Obermair has a financial interest in the online self-audit software mentioned in this article and available at LG performed the data analyses and drafted the manuscript. AO assisted with interpretation, presentation of the findings and provided clinical expertise and input into the overall findings. Both authors have contributed substantively to writing the manuscript and have approved the final version.L Gordon is a health economist with a special interest in the area of cancer and population health research. A Obermair holds clinical research (chief investigator) roles in areas of surgery in gynaecology oncology, projects that are funded through the National Health and Medical Research Council.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2482/10/4/prepubReview studies reporting on adverse surgical outcomes following surgery for colorectal cancer. Tabulated results of the systematic review on studies reporting on adverse surgical outcomes following surgery for colorectal cancer.Click here for file


Isolated patellofemoral osteoarthritis can be treated with patellofemoral arthroplasty.We present two cases of isolated patellofemoral osteoarthritis treated with Low Contact Stress patellofemoral arthroplasty; in both cases the polyethylene mobile-bearing of the patellar component dissociated from the metal backing. One patient had a revision to a Richards patellofemoral prosthesis, and in the second patient the arthroplasty was converted to a total knee prosthesis because of clinically important femorotibial osteoarthritis.The possible failure mechanisms are described. We suggest avoiding the use of a metal-backed mobile-bearing patellar component due to the risk of dissociation. In patients older than 55 years, isolated patellofemoral osteoarthritis occurs in 24% of women and in 11% of men radiographically [We report two cases of patients who experienced a dissociation of the mobile-bearing polyethylene patellar component following patellofemoral arthroplasty using the Low Contact Stress Patellofemoral Joint Replacement prosthesis.A 61-year-old Dutch Caucasian male patient presented with a 5-year history of left sided anterior knee pain with an increase in symptoms over the previous two years. On physical examination, there was full range of motion with no signs of patellofemoral instability, and radiographic studies demonstrated isolated degenerative changes of the patellofemoral compartment without signs of associated patellofemoral dysplasia. There was no history of knee surgery or trauma. Previous treatment with physical therapy had failed to alleviate symptoms. The patient underwent patellofemoral arthroplasty with the Low Contact Stress (LCS) Patellofemoral Joint Replacement prosthesis  through a medial parapatellar incision. Stability  and impingement (catching) was tested over a full range of motion using trial implants before the definitive components were cemented in place. Immediate postoperative radiographs  confirmed adequate position of the prosthesis. Direct postoperative protected weight bearing with crutches was allowed, and he received antithrombotic prophylaxis with warfarin for eight weeks. During follow-up examinations at 2 weeks and 2 months postoperatively, normal healing was observed with 120 degrees of flexion. At three months postoperatively, the patient presented with subjective instability and audible crepitations and clicking. There was no history of recent injury or trauma. At 7 months postoperatively, he again presented with increasing pain and a mobile swelling proximal to the patella. Radiographs showed a displaced polyethylene liner of the patella . RevisioA 55-year-old Dutch Caucasian woman was referred to our clinic with signs of dissociation of the polyethylene liner of a metal-backed patellar component in the right knee. Six years previously, she underwent an uneventful primary LCS patellofemoral arthroplasty with an uncemented patellar component. The patient reported a recent minor fall with direct injury to the anterior side of the knee, and later complained of persistent pain and noise arising from the knee while rising from a chair and climbing stairs. Walking on a level surface was uncomfortable with pain on both medial and lateral sides of the knee. Clinical examination showed no evident wasting of the quadriceps muscle, likely due to considerable obesity. Physical examination showed moderate valgus malalignment of both knees. No restriction of movement was observed with 0 to 130 degrees of flexion; however, a typical metal-on-metal grinding sound was heard from the anterior knee compartment during flexion and extension of the knee. There was significant tenderness on both medial and lateral femorotibial joint lines. Radiographs showed a displaced polyethylene liner of the patella with moderate femorotibial osteoarthritis . We adviThe retrieved polyethylene patellar component showed a fracture radially extending from the center of the specimen to the markedly thinned superolateral periphery . This reSince the introduction of patellofemoral hemiarthroplasty by McKeever in 1949 , multiplTo improve on the results of the Richards prosthesis and to avoid the high rate of patellar revisions, Merchant designed a modular patellofemoral prosthesis . The patThe reason for dissociation of the polyethylene component in the cases reported here remains uncertain. Failure of the metal-backed polyethylene patellar components in total knee arthroplasty has been well documented in the literature ,10. SeveIn our first patient, dissociation probably occurred at three months postoperatively. Also, the retrieved specimen was not fractured and showed no signs of wear. Given the fact that malposition with catching and locking is one of the main modes of failure in patellofemoral arthroplasty, it is most likely that the polyethylene liner was hooked and dislodged. Because neither of our patients had a history of patellofemoral instability prior to arthroplasty, unrecognized surgical prosthetic malalignment, especially rotation of the femoral component, could have led to patellar subluxation and catching. The operative records do not describe instability before cementing the definitive components in place, and the postoperative radiographs show adequate position of the prosthesis. In the second patient, the wear and subsequent fracturing and dissociation at 6 years postoperatively may be related to a combination of factors, including obesity, faulty patellar tracking, mild flexion of the femoral component, and overstuffing of the anterior compartment . The locIn the first patient we revised the patellofemoral prosthesis to the Richards type II prosthesis, which we have used in more than 200 patients since 1976. No technical difficulties were encountered during revision. In the second patient revision of the uncemented patellar component resulted in a substantial loss of bone, thereby making the revision difficult. Because of clinically important degenerative changes in the femorotibial compartments, a total knee prosthesis was inserted. The results of conversion to a total knee arthroplasty are comparable to the results of primary total knee arthroplasty ,12.We believe that the patellar component in patellofemoral arthroplasty should be compatible with current total knee designs. However, based on our experiences with the LCS Patellofemoral Joint Replacement, we suggest avoiding the use of a metal-backed, mobile-bearing patellar component. In addition to the risk of dissociation, revision of the non-cemented component may result in substantial loss of bone. Furthermore, the LCS Patellofemoral Joint Replacement patellar component is only compatible with the LCS total knee prosthesis. We consider a symmetrical dome-shaped cemented polyethylene component the best choice.


We report an unusual case of solitary osteolytic tibial metastasis from a primary endometrial cancer in a 62-year-old woman. The primary cancer was treated with total abdominal hysterectomy and bilateral salpingo-oophorectomy combined with postoperative external beam radiotherapy, while the tibial metastasis was treated with an above knee amputation. The rarity of the case lies on the fact that metastases distally to the elbow and knee are uncommon and endometrial cancer rarely gives distal bone metastases and particularly solitary to the extremities. Metastatic cancer to the skeleton is the most common malignant bone tumors. Despite the improved efficacy of cancer treatment that resulted to prolonged survival rates during the last years, the prevalence of bone metastases was further increased. Consequently, orthopaedic surgeons are more likely involved in the diagnosis and treatment of this form of bone tumor and particularly the solitary ones. In a large autopsy series of 1000 metastatic cases, bone metastases were found in 27% [Solitary skeletal metastases are the most challenging to validate. A true isolated bone metastasis seldom occurs, with an incidence of only 2-3% of all skeletal spread situations [Endometrial adenocarcinoma usually metastasises to lymph nodes, lung, and liver . Bone meIn August 2006, a 62-year-old woman was admitted to the Orthopaedic Department of the University Hospital of Ioannina, Greece, with pain to the distal third of the right tibia and to the right ankle. She reported a 2-month history of pain which was initially intermittent, gradually progressed in intensity and became constant, with no history of previous trauma. The pain was not relieved with nonsteroidal anti-inflammatory drugs. Weight bearing activities exacerbated the symptoms. The patient had a history of total abdominal hysterectomy and bilateral salpingo-oophorectomy in January 2006 due to a stage II endometrial cancer. The histological evaluation showed grade III endometrial endometrioid adenocarcinoma with areas of undifferentiated carcinoma. The latter component had morphological characteristics of a small-cell carcinoma, where a proliferation of small-size epithelial cells growing in solid sheets was observed. Consequently, at the 45th postoperative day the patient underwent external beam radiotherapy with a linear accelerator (6 MV) and a total radiation dose of 45 Gy and intracavitary brachytherapy of 25 Gy with a high-dose-rate Co-60 unit. All clinical and imaging examinations after the end of radiotherapy were negative for the presence of local or systemic disease.On physical examination swelling of the distal third of the right tibia with a palpable soft-tissue mass to the frontal plane was observed. Apart from a slight discolouration of the overlying skin, no other pathological findings were noticed. The laboratory evaluation  was normal except a slight elevation of C-reactive protein and erythrocyte sedimentation rate. The alkaline phosphate level was normal. Plain radiographs revealed an osteolytic lesion to the distal third of the tibia with cortical destruction . The CT-The options of palliative radiotherapy or a bellow knee amputation were presented to the patient but no consent was provided by her who initially refused any further treatment. A splint was applied to the tibia and a discharge of the extremity was advised. The patient rereferred to our department 3 months later with an obvious deterioration in the tibial mass with increased dimensions, obvious soft-tissue mass in plain radiographs and skin infiltration . An abovSkeletal metastases are the most common variety of malignant bone tumours. They can be solitary or multiple and they could have a lytic, blastic, or mixed appearance mainly based on the origin of the primary tumour. In particular, osteolytic metastases are the most common, representing about 75% of all metastatic lesions . CancersEndometrial carcinoma remains one of the most frequent gynecological malignancies occurring predominantly in postmenopausal women. The most common sites of distant metastases from endometrial cancer involve the lymph nodes, the lung, and the liver . The occThe rarity of the present case report of a tibial metastasis from endometrial cancer consists of two facts: (a) it is a solitary lytic metastasis, distal to the knee, and (b) the primary neoplasm is endometrial adenocarcinoma. Most of endometrial cancers metastatic to the bones were of high stage and often poorly differentiated. The fact that in our case the histological examination of the primary cancer displayed areas of dedifferentiated neoplasm could explain its metastatic propensity. Our literature search identified 5 other reported cases of tibial metastases from endometrial cancer , 14, 15.


A series of 458 cases of carcinoma of the penis occurring in Ugandan Africans is analysed. These were derived from the records of a country-wide biopsy service over the 5-year period 1964-68.Where circumcision is practised the incidence of this tumour is very low.However, the geographical variation also showed marked differences in the uncircumcised, regardless of tribal antecedents and sometimes over quite small distances.It is suggested, therefore, that in Uganda other aetiological factors apart from circumcision are operative and that these factors vary with geographical location rather than with tribal affiliation.


ALPL). The symptoms are highly variable in their clinical expression, and relate to numerous mutations in this gene. The first clinical sign of the disease is often a premature loss of deciduous teeth, mostly in the moderate forms.Hypophosphatasia (HP) is a rare inherited disorder characterized by a wide spectrum of defects in mineralized tissues and caused by deficiency in the tissue non-specific alkaline phosphatase gene (The purpose of this study was to document the oral features of HP patients and to relate theses features to the six recognized forms of HP in 5 patients with known genotype and to investigate the genotype-phenotype correlations.ALPL gene were tested by DNA sequencing in SESEP laboratory.Clinical and radiographic examinations were carried out. We collected medical and dental history in the kindred and biochemical data. Finally, mutations in the We have for the first time related the known dental anomalies which occur as integral features of HP to the recognized clinical forms of HP. We also pointed out striking dental abnormalities which were never described in association with this rare disease. Accurate genotype-phenotype severity correlations were observed.This work allowed us to compare orodental manifestations in all the clinical forms of HP within the patient's sample. According to the severity of the disorder, some dental defects were infrequent, while other were always present. The long term prognosis of the permanent teeth varies from a patient to another. As premature loss of primary teeth is often the first, and sometimes the only visible symptom of the milder forms, the paediatric dentist plays a critical role in the detection and diagnosis of the disease. ALPL, MIM 171760) encoding the tissue-nonspecific alkaline phosphatase (TNAP) .Here patients 1, 2 and 3 carry two heterozygous mutations, one moderate (c.571G>A or c.526G>A), the other one severe  . This isWe found in our series very good correlation between the severity of the symptoms and the AP value at time of diagnosis. Variation in clinical expression is currently known to correlate well with variable residual enzyme activity. Generally, the more severe the disease, the lower the serum AP activity level appropriate for age . NeverthALPL gene is also of greater importance for prediction of recurrence risk in future pregnancies, carrier detection and prenatal diagnosis. The molecular diagnosis of each patient increases the knowledge of the level of severity of symptoms associated with each ALPL mutation and improves our ability to provide a better prognosis.Screening for the mutations in the According to Hartsfield, premature exfoliation of primary teeth in children younger than 5 years of age should suggest a genetic or a systemic disease in the absence of trauma, especially, in children younger than 3 years of age . The difMilder forms of HP still pose problems for timely and accurate diagnosis ,29. HereALPL: tissue non-specific alkaline phosphatase gene; DNA: desoxyribo nucleic acid; TNAP: tissue-nonspecific alkaline phosphatase; AP: alkaline phosphatase.HP: hypophosphatasia; Written consent for publication was obtained from the patients and/or their relatives.The authors declare that they have no competing interests.


We report a case of acute scrotal hemorrhage from multiple angiokeratomas on scrotum, because of the rarity of the condition and to emphasize the importance of considering this condition in the evaluation of acute scrotal bleeding. Angiokeratomas are well-circumscribed vascular lesions consisting of superficial vascular ectasia with an overlying hyperkeratotic surface.2 There a1A 49-year-old man presented to the emergency department with a history of profuse bleeding from his scrotum following a minor trauma. The patient had similar past episodes of recurrent scrotal bleeding spontaneously or following minor traumas over the previous 5 years. He had no history of any systemic illness. Putting firm pressure on the bleeding points stopped the bleeding. Dermatologic evaluation on the next day revealed numerous, small, bluish-red, warty, vascular nonblanchable papules on his scrotum Figures  and 2. TJohn Addison fordyce first described angiokeratomas of fordyce on the scrotum of a 60-year-old man in 1896. The exac2The major reasons for morbidity of this disease are bleeding, anxiety, and overtreatment due to misdiagnosis by the treating physicians. Spontaneous resolution does not occur, and the angiokeratomas persist unless treated. The patiIn the emergency department, angiokeratoma of fordyce is an important differential diagnosis of scrotal bleeding and must be differentiated from other vascular lesions.If the diagnosis of the disease remains uncertain, then referral to a dermatology clinic for opinion and skin biopsy is warranted.


Tumour angiogenesis has become an important target for antitumour therapy, with most current therapies aimed at blocking the VEGF pathway. However, not all tumours are responsive to VEGF blockers, and some tumours that are responsive initially may become resistant during the course of treatment, thus there is a need to explore other angiogenesis signalling pathways. Recently, the Delta-Notch pathway, and particularly the ligand Delta-like 4 (Dll4), was identified as a new target in tumour angiogenesis. An important feature in angiogenesis is the manifold ways in which the VEGF and Delta-Notch pathways interact. The emerging picture is that the VEGF pathway acts as a potent upstream activating stimulus for angiogenesis, whereas Delta-Notch helps to guide cell fate decisions that appropriately shape the activation. Here we review the two signalling pathways and what is currently known about the ways in which they interact during tumour angiogenesis. Solid tumours require the growth of new blood vessels (angiogenesis) to grow . Tumour At the present time, blocking the VEGF pathway is the best-validated approach to blocking tumour angiogenesis. Studies from a number of years ago showed that the VEGF pathway is central and absolutely essential for early stages of developmental angiogenesis; these findings helped drive the development of VEGF inhibitors for clinical use . HoweverOne such pathway is Delta/Jagged-Notch signalling system, which is generally involved in cell fate decisions. One particular ligand, Dll4, was recently identified as a potentially important new target in tumour angiogenesis. Other members of this pathway, including Notch receptors, are also required for developmental angiogenesis. The emerging picture is that the VEGF pathway acts as a potent upstream activating stimulus for angiogenesis, whereas Delta-Notch helps to shape that activation appropriately. An important feature of angiogenesis is the manifold ways in which the VEGF and Delta-Notch pathways interact.In this review, we briefly summarise the components and features of the VEGF and Delta-Notch pathways, including their roles in developmental and tumour angiogenesis. Then we summarise in more detail what is currently known about the ways in which these pathways interact in the vasculature. A deeper understanding of these interactions should lead to better use of agents that block the Dll4-Notch pathway, alone and in combination with currently used inhibitors of the VEGF pathway.The VEGF system has been conserved from zebrafish to man as a signalling pathway that is essential and rather specific to the vascular and haematopoietic systems. In mammals, the system comprises five secreted ligands  and three primary receptors . In general, the ligands are expressed rather broadly and display multiple splice isoforms of varying size and degree of interaction with the extracellular matrix. An important point is that the expression of VEGF-A is induced by hypoxia, which is a common feature of rapidly growing solid tumours, and constitutes a key signal from a tissue calling for more blood vessels and/or increased vascular function. In contrast to the ligands, the receptors show much more restricted cell-type expression. VEGF-R1 and VEGF-R2 are prominently expressed by vascular endothelial cells in addition to expression by selected other cell types. VEGF-R3 is prominently expressed in lymphatic endothelial cells, although it can also be expressed on activated blood endothelial cells , associated with a near-complete block of haematopoietic and vascular development. Somewhat analogously, deletion of VEGF-C results in a severe block in the development of the lymphatic system. Deletion of the main receptor for VEGF-C, VEGF-R3, results in embryonic lethality associated with blood vascular defects; however, this receptor becomes essential for the development of the lymphatic system slightly later in development  is not lethal and is associated with much more subtle phenotypes. Studies in zebrafish also reveal essential upstream roles for the VEGF system: high-dose morpholino knockdown of VEGF-A in early zebrafish embryos (day 2) results in a near-total absence of vasculature (similar to results in mice), whereas lower dose VEGF-A knockdown results in severe disruption of the dorsal aorta and intersegmental arteries . Subsequently, NICD translocates to the nucleus, where it interacts with the CSL (RBPJ) transcription factor to induce multiple downstream targets, including a family of basic helix-loop-helix proteins, the Hes and Hey genes  to an adjacent Notch receptor cell, resulting in activation of the Notch pathway in one cell and suppression in the adjacent cells. The end result locks the cells into distinct cellular fates; one promoted by Notch signal activation and the other dependent on lack of Notch signalling. Notch receptors are distinct in that they operate both on the cell surface to bind ligand and within the nucleus as transcriptional modulators . The patey genes .Notch1, Dll4 and CSL mutations result in the most severe vascular disruptions. The Notch1 null mice die due to profound defects of angiogenic vascular remodelling, shown most obviously as a failure of proper formation of the major arteries. The mice form a primary vascular plexus, indicating that Notch signals are not required for vasculogenesis and early angiogenesis; however, this plexus fails to remodel into an organised network of larger and smaller vessels  die in utero and display severe vascular anomalies, reminiscent of those seen in Notch1 null mice , including this sarcoma model. Previous studies have shown that individual blockade of VEGF and Dll4-Notch produces very different effects on the morphology and function of tumour vessels  that calls for an increase in vascular function. However, not all cells should respond equally to VEGF, and thus cell fate decisions are essential for generating an efficient response. Subsequently, the Delta-Notch pathway (particularly Dll4 and Notch1) acts among the endothelial cells to respond appropriately to the activating VEGF signal . In turnFurther studies are needed to examine the interaction of the pathways in various tumour settings. We are just beginning to explore how we can take combinatorial advantage of the VEGF and Delta-Notch pathways for treating tumours, and a better conceptual framework within the context of tumour angiogenesis would help guide the experiments. Another issue will be to clarify some of the disparate results on the regulation of VEGF receptors by Delta-Notch activity: does VEGF receptor expression depend on endothelial cell phenotype, on the nature of Notch signal or on the presence of additional stimuli? Another important topic will be to determine how some of the key downstream Notch target genes  affect tumour vessels in the presence of high VEGF levels. Another potentially fruitful approach will be to examine whether other types of endothelial cell fate decisions in development are guided by Delta-Notch. We are at an exciting time for the convergence of basic vascular biology and tumour therapy.


User reported experiences and satisfaction are increasingly used as basis for quality indicators in the health sector. However, there is limited understanding of factors associated with user reported experiences and satisfaction with casualty clinics.A random sample of 542 patients that had contacted any of three casualty clinics from mid April to mid May 2008 was mailed a questionnaire. A reminder was sent to non-respondents after six weeks. Descriptive statistics for four user reported experiences scales and 20 single items are presented. Multivariate regression analysis was used to assess associations between background variables and user reported experiences, and between user reported experiences and user satisfaction.225 (41.5%) patients, carers and guardians returned a completed questionnaire. Users reported most positive experiences with the doctor services and the nursing services at the casualty clinics; on a scale from 0 to 100, where 100 is the best possible experience the doctor scale was 82 and the nursing scale 81. Users reported least positive experiences with the organization of the casualty clinic, with a scale score of 65. Self perceived health was associated with user satisfaction, while self perceived health and age were associated with user reported experiences with organization of the clinics. A range of user reported experience domains were related to user satisfaction, after controlling for socio-demographic variables, including experiences with doctor services at the clinics, organization of the clinics, information and self perceived incorrect treatment.Users report positive experiences with the three casualty clinics, with organization as the aspect with largest improvement potential. The importance of age and health status for users' experiences and satisfaction with casualty clinics was shown, but a range of user reported experiences with the clinics were the most important predictors for user satisfaction. Patient satisfaction and experiences are an important part in the evaluation of health care quality ,2. The pA systematic review of the patient satisfaction literature showed that among socio-demographic factors, age and health status are consistently related to patient satisfaction ; older rThe systematic review on patient satisfaction also found consistent evidence that the most important health service factor affecting patient satisfaction is the patient-practitioner relationship . Health The studies above show that the association between socio-demographic factors and patient satisfaction are equivocal within the primary care out-of-hours field. To some degree the existing evidence contradicts findings from the general patient satisfaction literature. The literature also identifies a need for more research regarding the importance of health service factors for patients' satisfaction including factors related to patient reported experiences. Therefore, our study had two primary aims: i) to assess the association between socio-demographic factors and user reported experiences with primary care out-of-hours services; ii) to assess the association between user reported experiences and user satisfaction, controlling for socio-demographic factors.The analyses were based on a study of three casualty clinics in Norway in 2008. Norway has a two-level public health care system with a small private sector. Four Regional Health Authorities (RHA) under the Ministry of Health and Care services have responsibility for the hospital sector. The 431 municipalities are responsible for organizing primary health care including out-of-hours services . There wThree casualty clinics were chosen to represent different organization types and size of such clinics. The clinics were recruited through the Watchtower project . The stuThe casualty clinics distributed the questionnaires by mail to the patient's home address. We aimed to send out the reminders at two weeks, but due to practical circumstances relating to clinical administration and postal service delays reminders were sent after six weeks. The questionnaires were returned to the Norwegian Knowledge Centre for the Health Services.The Norwegian Social Science Data Services approved the survey which was in accordance with the Helsinki Declaration of 1975, as revised in 1983. The leader of each casualty clinic had the opportunity to exclude individuals from the survey based on ethical considerations.The questionnaire used in this study has undergone a rigorous process of development and evaluation, including a literature review, qualitative interviews with patients, guardians and carers, and input from an expert group of out-of-hours staff ,13. ThesThe questionnaire comprises five parts: parts A and E are completed by all patients; part B concerned telephone contact with the clinic; part C concerned consultation at the casualty clinic; part D concerned home visit from a doctor. The questionnaire comprised a total of 42 items including background questions about patients and guardians. The reference period used for survey questions was "during the last visit/encounter".Based on factor analysis four scales were identified : telephoDescriptive statistics for respondents, the four scales and single items are presented . Multivariate regression analysis was used to assess the association between background variables and five dependent variables including four user reported experiences scales and one item about global satisfaction. Age and health have been found to be consistently related to patient satisfaction  and wereFinally, we assessed the association between user reported experiences and global satisfaction by means of a multivariate regression analysis, controlling for background variables. We controlled for the same background variables as in the first regression. The telephone and nursing scales, which were relevant to a fewer number of respondents, were excluded from this analysis due to small sample sizes. SPSS (15.1) was used to analyze the data.Of the 600 patients included in the study, 58 were excluded due to cancellations and factors such as unknown addresses. Of the 542 patients who were sent a questionnaire, 225 (41.5%) responded. Table Table Table Table In general, age and self perceived health are the most consistent socio-demographic factors related to patient satisfaction . HoweverThe majority of the user reported experiences domains had a significant association with user satisfaction, after controlling for user characteristics. The most important predictor was the experiences the users had with the doctors at the casualty clinic. This concurs with findings from the systematic review of the patient satisfaction literature  and showThe primary aims of this paper were to assess the associations between socio-demographic variables and user satisfaction/experiences, and between user-reported experiences and global satisfaction. Naturally, the sample of three clinics is inadequate to represent the population of clinics in Norway. Also, the number of clinics is too small for multilevel regression, making it difficult to separate individual and clinic level effects. This means that individual level effects might be overestimated, especially if the intraclass correlation coefficient (ICC) is substantial. Future studies in Norway should include a representative sample of casualty clinics, and enough clinics to allow empirical assessment of effects at different levels.The questionnaire is developed specifically for primary care out-of-hours users and includes items of relevance for measurement of user reported experiences with out-of-hours care. It is based on a literature review, interviews with users of out-of-hours services and consultation with an expert group that was designed to ensure the content validity of the questionnaire ,13. CompThe consideration of any differences found through the comparison of user experiences and satisfaction of out-of-hours care with those for general practice care more generally might inform quality improvement initiatives. The EUROPEP questionnaire has been used in large scale surveys of general practice in Norway . HoweverLow response rates are a common problem in patient experience surveys in general , and alsUsers report positive experiences with the three casualty clinics, with organization as the aspect with largest improvement potential. The importance of age and health status for users' experiences and satisfaction with casualty clinics was shown, but a range of user reported experiences with the clinics were the most important predictors for user satisfaction.The authors declare that they have no competing interests.All authors were involved in the development of the questionnaire. KD planned the paper together with the other authors, carried out the statistical analysis, conducted the study together with administrative staff, and drafted most of the paper. OAB planned the paper together with the other authors, wrote parts of the paper, and revised the draft critically and approved the final version. AG planned the paper together with the other authors, revised the draft critically and approved the final version. OF planned the paper together with the other authors, revised the draft critically and approved the final version. HHI planned the paper together with the other authors, revised the draft critically and approved the final version. SH planned the study together with the other authors, revised the draft critically and approved the final version. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2296/11/73/prepub


A 55-year-old female patient presented to our outpatient department with complaints of persistent erythema, oozing and crusting restricted to the left breast over the last 6 months. The patient underwent investigations to rule out the possibility of mammary Paget'S disease, all of which were negative. A possibility of contact dermatitis to topical medication was considered and confirmed by patch testing. Contact dermatitis of the breast area can be due to a number of factors including topical applications of various types.A 55-year-old lady, a college professor, presented to us with a history of persistent itching, erythema, oozing and crusting over the nipple, areola and periareolar region on the left breast of more than 6 months duration. The lesions had been localized to the nipple and immediate periareolar region initially but had started extending recently. She had been using various topical medications for the same including steroids of varying potency. The patient had good response to topical steroids initially but on further use the lesion appeared to be getting worse. The patient had no other significant co-morbidity and was in otherwise good health. On examination we found an ill-defined area of scaling, erythema and minimal crusting over the over the nipple, areola and peri-areolar region on the left breast . There wIn our case the unilateral presentation and the apparent lack of response to topical steroids made us think on the lines of mammary Paget's. Most eczematous lesions of the breast tend to be bilateral like seborrheic and atopic dermatitis though there have been reports of chronic unilateral dermatitis of the nipple areolar complex.57


Territorial subdivisions and geographic borders are essential for understanding phenomena in sociology, political science, history, and economics. They influence the interregional flow of information and cross-border trade and affect the diffusion of innovation and technology. However, it is unclear if existing administrative subdivisions that typically evolved decades ago still reflect the most plausible organizational structure of today. The complexity of modern human communication, the ease of long-distance movement, and increased interaction across political borders complicate the operational definition and assessment of geographic borders that optimally reflect the multi-scale nature of today's human connectivity patterns. What border structures emerge directly from the interplay of scales in human interactions is an open question. Based on a massive proxy dataset, we analyze a multi-scale human mobility network and compute effective geographic borders inherent to human mobility patterns in the United States. We propose two computational techniques for extracting these borders and for quantifying their strength. We find that effective borders only partially overlap with existing administrative borders, and show that some of the strongest mobility borders exist in unexpected regions. We show that the observed structures cannot be generated by gravity models for human traffic. Finally, we introduce the concept of link significance that clarifies the observed structure of effective borders. Our approach represents a novel type of quantitative, comparative analysis framework for spatially embedded multi-scale interaction networks in general and may yield important insight into a multitude of spatiotemporal phenomena generated by human activity. The geographic compartmentalization of maps into coherent territorial units is not only essential for the management and distribution of administrative responsibilities and the allocation of public resources. Territorial subdivisions also serve as an important frame of reference for understanding a variety of phenomena related to human activity. Existing borders frequently correlate with cultural and linguistic boundaries or topographical features The majority of existing administrative and political borders, for example in the United States and Europe, evolved over centuries and typically stabilized many decades ago, during a time when human interactions and mobility were predominantly local and the conceptual separation of spatially extended human populations into a hierarchy of geographically coherent subdivision was meaningful and plausible.However, modern human communication and mobility has undergone massive structural changes in the past few decades Human mobility networks epitomize the complexity of multi-scale connectivity in human populations see . More thAlthough previous studies identified community structures in long-range mobility networks based on topological connectivity http://rocs.northwestern.edu/clips/?assets/Follow_the_Money_SD.mp4).Here we construct a proxy network for human mobility from the geographic circulation of banknotes in the United States. Movement data was collected using the online bill-tracking game wheresgeorge.com. Individuals participating in this game can mark individual bills and return them to circulation; other individuals who randomly receive bills can report this find online along with their current location (zip code). A comprehensive account of the circulation of currency, the wheresgeorge.com dataset, and an analysis of the statistics of travel distances and inter-report times for various denominations are provided in Based on the idea that two counties http://rocs.northwestern.edu/clips/?assets/Follow_the_Money_SD.mp4) to approximate a maximal-modularity subdivision of the multi-scale mobility network depicted in We employ a stochastic Monte-Carlo method (see http://rocs.northwestern.edu/clips/?assets/Follow_the_Money_SD.mp4).Therefore, instead of focusing on a single high-modularity map, we consider an entire ensemble of partitions that can be exploited to recover the underlying community structure and alleviate the aforementioned resolution limit see . We comp borders . These bInvestigating this system of effective mobility borders more closely, we see that although they correlate significantly with territorial state borders , see  they freA key question is what components of the network are responsible for the features observed in the system of effective borders. In order to test the degree to which short-range connections dominate the structure of effective borders we generate an artificial network that lacks short-range connections . ApplyinWe also investigate whether the observed pattern of borders can be accounted for by the prominent class of gravity models  borders  are indeand  see . Compari maps in , they yiThe proposed method successfully extracts the structure of geographic borders inherent in multi-scale mobility networks. Bootstrapping the network indicates that these structures are surprisingly stable in response to perturbations of the network, but neither the modularity measure nor the stochastic algorithm we use to discover partitions provide specific information about the substructures in the network that make these borders so robust. What feature of the network, more specifically which subset of links if any, generates the observed borders? In order to address this question and further investigate the structural stability of the observed patterns, we developed a new and efficient computational technique based on the concept of shortest-path trees (SPT) data see . In factdata see .link significanceThe key advantage of this method is that it can systematically extract properties of the network that match the observed borders. A way to demonstrate this is to measure the frequency y peaked . This istructure . By virtFinally, we performed statistical analyses that quantify the overlap of the effective, mobility-induced borders with those provided by census-related systems. We choose the set of borders separating the states, the borders defined by the districts of the 12 Federal Reserve Banks, and the borders of Economic Areas We conclude that considerable geographic information is not only effectively encoded in human mobility networks, it can also be identified systematically using the techniques presented here. The identification and quantification of geographic borders and a comprehensive assessment of their significance will be very important for understanding dynamic processes driven by human mobility. An important area in which the observed borders potentially facilitate our understanding is the geographic patterns of isoglosses in North American English dialects Although applied here to a network that spans a continent, the proposed concepts are quite general and can be applied on a finer geographical scale. This could lead to new methods for urban design and for planning public transportation systems. The ideas need not be limited to human behavior: tracking of various animals is now widespread, and a dataset of sufficient size, in combination with these techniques, could help understand animal foraging and habitat segmentation. The framework presented here is suitable for a wide range of multi-scale interaction networks for which the underlying effective borders are presently unknown. We believe that our discovery of effective mobility borders in the US is a first step and that these techniques will open the door to promising, quantitative, comparative investigations of many spatially distributed behavioral patterns.Text S1(PDF)Click here for additional data file.


A double major papilla of Vater is a rare congenital anomaly with only three documented cases described in the literature.We report the case of a 19-year-old man, with chronic ulcerative pancolitis and congenital sphrerocytosis, who underwent endoscopic retrograde cholangiopancreatography because he had persistent elevation of liver enzymes and normal MRI cholangiography. During endoscopic retrograde cholangiopancreatography, a double papilla of Vater with separate drainage for the bile duct and the pancreatic duct was observed.Endoscopic retrograde cholangiopancreatography showed normal pancreatogram and findings compatible with sclerosing cholangitis. The Vaterian system includes the common bile duct and the main pancreatic duct (duct of Wirsurg), which, as they conjoin at the level of duodenum, they form the major papilla of Vater. Variations in the bile duct and pancreatic duct opening are related to the process of rotation and recanalization during embryologic development. Complete non-union of distal common bile duct and duct of Wirsurg gives rise to a double papilla of Vater -3.We report a young man with double papilla of Vater wherein cannulation of the common bile duct and pancreatic duct could be achieved through either orifice independently.A 19-year-old Greek man was referred to our unit for endoscopic retrograde cholangiopancreatography (ERCP) with suspicion of sclerosing cholangitis, because of persistent elevated levels of asparate aminotransferase, alanine aminotransferase and alkaline phosphatase and normal MRI cholangiography.Medical history revealed congenital spherocytosis and ulcerative pancolitis.At ERCP, inspection of the major papilla showed the presence of two separate orifices on a single papilla Fig. . Each orth embryonic week [Interest in the anatomy of the descending duodenum and papilla began with advent of ERCP as diagnostic procedure in the early 1970s. The liver, gallbladder, biliary tree and pancreas originate in the hepatic diverticulum, which develops at the beginning of the 4nic week . At thisnic week . If theynic week .Silvis et al described variations in the normal duodenal papilla at ERCP . They coOur case is intriguing because the patient had two independent papillary structures with two distinct, separate orifices and each orifice demonstrated prominent papillary fronds, typically seen at the ostium of the major papilla. Moreover there was no communication between the two orifices during cannulation with catheter, excluding the development of an acquired choledochoduodenal fistula.Our case demonstrates that if the endoscopist observes two separate papillae in the duodenum, with the proximal one draining the bile duct and the distal one draining the pancreatic duct, without communication between them, this depicts a rare anatomic variation.Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.The authors declare that they have no competing interests.PK performed the endoscopy and was contributor in revising the manuscript critically for important intellectual content. GC was major contributor in writing the manuscript. KF, TK and IP analyzed and interpreted the patient data and were contributors in writing the manuscript. GL, ST, GK, and IP reviewed the relative literature. CZ and JK were major contributors in revising the manuscript critically for important intellectual content. All authors read and approved the final manuscript.


The protein and glycoprotein composition of Triton X-100 extracts of breast biopsies from 17 women with benign breast disease and from 11 women with invasive breast carcinoma were investigated using electrophoresis in SDS-containing gradient polyacrylamide gels, followed by Coomassie Blue (CB) staining and the binding of radio-iodinated wheat germ agglutinin (WGA). Patterns were analysed after the CB-step for differences in protein composition, and after the WGA-step for differences in glycoprotein composition. Tissue extracts from patients with benign breast disease have less CB stained bands than similar extracts from the cancer patients. A particular consistent change was the appearance of an extra band at 58 Kdaltons in the cancer extracts. In contrast to the CB results, WGA detected less major bands, in the 40-60 Kd region, in the cancer extracts than at similar locations in benign extracts. Analysis of blood sera using the above techniques suggested that certain serum proteins could account for some of the WGA changes, but not the changes after CB staining. However, residual contamination of the specimens by blood proteins seemed unlikely because of the washing procedure used, unless these components were very strongly associated with the tissue. Differential synthesis of serum proteins by benign and malignant breast tissue may also explain some of our findings. Examination of the histopathology adjacent to the extracted tissue suggested that the degree of reduction in WGA-binding may be related to the extent of local invasiveness. Other animal and human studies suggest that reduced glycosylation of tumour-associated proteins may be linked to increased malignancy. The current findings may reflect a general pattern of change in tumour glycoprotein composition linked to malignant expression.


The development of this product resulted from controlled in vitro thrombogenic analysis of an array of potentially hemostatic textile materials and it has been cleared for both external and internal use by the United States Food and Drug Administration for the arrest of hemorrhage. The goal of the study was to assess the hemostatic and adhesive properties of Stasilon® in the setting of life-threatening refractory hemorrhage.Stasilon® produced a non-adherent wound-dressing interface and resulted in the achievement of persistent hemostasis in the operative field.A 39-year-old Caucasian man presented with severe necrotic pancreatitis that failed multiple aggressive attempts to control associated bleeding with electrocautery, suture ligation, and sequential anatomic packing with cotton-based sponges. Subsequent retroperitoneal packing with Stasilon® was demonstrated to be effective in the arrest of refractory hemorrhage.In our patient, Stasilon The goal of this report is to document our experience with the use of Stasilon® in a case of persistent retroperitoneal hemorrhage that could not be controlled by traditional means of securing hemostasis.Uncontrolled hemorrhage is a major contributor to both trauma-associated and intra-operative morbidity and mortality ,2. AchieA 39-year-old Caucasian man presented to our emergency department with a 1-day history of nausea, vomiting, and severe peri-umbilical pain that radiated to the mid-scapular region of his back. The patient had a history of muscular dystrophy, hypertension, and transient renal insufficiency. There was no elicited history of jaundice, cholelithiasis, or bleeding diathesis. The patient used smokeless tobacco products and consumed three or more alcoholic drinks per day. On admission, laboratory results revealed no leukocytosis, a normal serum hemoglobin concentration, and normal renal function. Serum lipase was elevated at 1985 U/l. Transaminases and alkaline phosphate levels were mildly elevated; serum bilirubin was normal. Abdominal ultrasonography demonstrated edema of the pancreatic head without evidence of cholelithiasis. Computed tomographic (CT) imaging with intravenous and oral contrast confirmed inhomogeneous pancreatic enhancement localized to the head and uncinate process without evidence of necrosis or associated hemorrhage. The patient was maintained nil by mouth and admitted to the hospital for intravenous resuscitation and monitoring.The patient developed multiple system organ dysfunction secondary to pancreatitis. On day 28, CT scanning and percutaneous sampling confirmed infected pancreatic necrosis (>50%).The patient was taken to the operating room for laparotomy and exploration of the retroperitoneum. Diffuse fibrinous inflammation of the intra-abdominal contents and omentum was identified as was extensive retroperitoneal necrosis of the pancreas and surrounding peri-pancreatic tissues. An 80% pancreatic necrosectomy was performed which was accompanied by significant retroperitoneal bleeding. Attempts at hemorrhage control with electrocautery and suture ligation were unsuccessful. Associated hypotension required damage control treatment ; the retProgressive coagulopathy and hemodynamic compromise necessitated continued transfusion of blood and blood products and the intravenous administration of activated Factor VII (VIIa). Several hours after ICU admission, the abdomen was re-explored at the bedside for unabated bleeding and continued hypotension, despite correction of coagulopathy. Two liters of hemoperitoneum were evacuated and diffuse microvascular bleeding was encountered in the retroperitoneum of the left upper quadrant. Electrocautery and suture ligation were ineffective and the abdomen was repacked with cotton laparotomy pads and the abdomen left open.Mesenteric angiography was performed after failure to achieve operative hemostasis; this demonstrated splenic arterial thrombosis without active arterial bleeding. Hemodynamics briefly improved and the patient was returned to the operating room for re-exploration and pack removal. The cotton packs were noted to be densely adherent to the retroperitoneum and diffuse re-bleeding occurred after their removal. Cautery and suture ligation again yielded incomplete hemostasis and fresh packs were replaced. Following additional transfusion and resuscitation in the ICU, the patient was returned to the operating room for another attempt at pack removal. Again, hemodynamically significant bleeding occurred from the exposed retroperitoneum upon pack removal. A splenectomy was performed to reduce the potential for collateral bleeding in the setting of proximal splenic arterial thrombosis but significant bleeding continued from the pancreatic bed.® textile  were packed into the retroperitoneal space and pressure was applied for 4 minutes  and regenerated bamboo (35%). The weave pattern is unique and was engineered to optimize the contact surface area between the textile structure and blood components. The Stasilon® fabric can be woven into widths of 1 to 4 inches from continuous filament fiberglass and bamboo precursors but is typically finished as a flat, 4-inch square (4 × 4 inches), single-layer pad that is individually packaged, sealed, depyrogenated, and sterilized with ethylene oxide gas. The manufacturing process can be modified to allow for variations in the dressing length and width including the packaging of sterile rolls of the product.The two component fibers used in the manufacture of Stasilon® application is similar to that of familiar cotton products: sterile dressings are removed from the packaging, placed directly on the wound surface, and pressure is applied. Pre-clinical studies suggest that Stasilon® may offer several clinical advantages over more traditional dressings including the induction of more rapid hemostasis, the corollary absorption of less shed blood, and less associated wound adherence resulting in more stable clot integrity proximate to the wound surface. Stasilon® has been cleared by the United States Food and Drug Administration (USFDA) for external and internal use and has been granted over-the-counter status making it available without a prescription. Although Stasilon® has been cleared for up to 30 days of implantation, we recommend its removal as soon as clinically feasible.The process of Stasilon® as a hemostatic device to curtail uncontrolled hemorrhage from a surgical wound bed. Our patient suffered multiple episodes of life-threatening retroperitoneal exsanguination that were refractory to therapeutic interventions including liberal use of electrocautery and suture ligation, aggressive correction of associated coagulopathy and thrombocytopenia, sequential attempts at cotton-based packing, visceral angiography, and ultimately splenectomy. A single application of Stasilon® packing in our patient resulted in complete resolution of associated hemorrhage, the attainment of hemodynamic stability with the ability to discontinue vasopressor support, and obviated the need for further perioperative transfusion of blood and blood products.In this observational case study, we report the first intra-operative use of Stasilon® rolls were noted to be in direct juxtaposition to the hemostatic retroperitoneal surfaces but were not adherent to the surrounding tissue structures. This property facilitated atraumatic removal of the dressings and left behind stable thrombus on the wound bed. Although the patient ultimately died from multiple system organ dysfunction and complications resulting from severe underlying disease pathophysiology, we believe that the hemostatic properties and reduced tissue adhesion of the novel textile Stasilon® directly contributed to the arrest of the life-threatening retroperitoneal hemorrhage encountered early in the patient's hospital course. Controlled studies of this novel dressing will facilitate objective analysis of its effectiveness.On re-exploration for pack removal 48 hours after placement, the Stasilon® textile dressings in this patient produced robust hemostasis without associated wound adherence and resulted in the successful treatment of refractory hemorrhage. This novel hemostatic textile offers potential clinical advantages for the arrest of bleeding.The use of StasilonCT: computed tomography; ICU: intensive care unit; MRCP: magnetic resonance cholangiopancreatography; USFDA: United States Food and Drug Administration.Written informed consent was obtained from the patient's family for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.At the time of manuscript submission, all authors reported no conflict of interest. Dr. P. Rich currently serves as Chief Medical Officer for Entegrion. All other authors declare they have no competing interest.PR participated in the study design, the surgery, and manuscript preparation. CD participated in the study design and manuscript preparation, VB, DO, SJ, and BC participated in the study design and surgery. All authors read and approved the final manuscript.


Congenital lymphoedema is a rare disorder that may result in disfiguring edema of the male genitalia. The treatment of persistent lymphoedema is surgical and consists of meticulous excision of all subcutaneous layers of the affected skin, combined with reconstruction of the penis and or scrotum. Primary congenital lymphedema is the rarest form of primary lymphedema. Lymphedema of the extremities presents at birth and rarely involves the genitalia. Primary penile lymphedema occurs infrequently and is seen in conjunction with a similar process in the scrotum. The accepted form of treatment is surgery since conservative medical treatment is of little value. Different surgical techniques have been described, but no single procedure has emerged as the ideal treatment.We report a case of scrotal and penile lymphoedema in a 12-year-old child since 5 years. He did not have any history of trauma, infection, or any other cause of secondary lymphoedema. Clinically, he did not have lymphadenopathy. General and systemic examinations were essentially normal. The lower limbs were normal with no signs of lymphoedema. Genital examination revealed a cold, non-tender, large-curved penis measuring 5 inches in length and 5 inches in circumference, looking like a “saxophone” . There wRoutine urinalysis, hematological, and blood biochemical tests were normal. Ultrasonography of testes and lower urinary tract were normal. Serologic study was negative for filariasis. With the diagnosis of primary lymphoedema of penis and scrotum, surgery was planned in which extensive resection of the involved tissue, scrotoplasty by the use of skin flaps of 1/3 of the posterior scrotum, and total excision of the lymphedematous tissue of the penile shaft with cosmetic reconstruction without skin grafting. In this case, a circumferential incision was made 5–10 mm from the coronal sulcus and deepened to the level of Buck's fascia. The skin and subcutaneous tissue were then completely dissected away from the penis. The skin was everted and all of the abnormal lymphedematous tissue excised up to the dermal skin margin. The skin was then tailored to the size of the penile shaft and re approximated. A catheter was placed intra-operatively at the end of surgery. This method was employed with the advantages of (1) shorter hospitalization, (2) lack of morbidity associated with the skin donor site, and (3) satisfactory cosmetic results. Histopathologic examination showed nonspecific chronic inflammation with areas of epidermal thickening and dermal fibrosis. Wound healed primarily and sutures were removed on 14th postoperative day.Lymphedema is the occurrence of chronically swollen extremities or rarely the genitals due to inadequate drainage of interstitial fluid by the lymphatics. Lymphedema is of two types: primary and secondary. Primary lymphedema is uncommon and has female predominance. It may be congenital or familial (Milroy's disease) or idiopathic appearing either at puberty (precox), or after 35 years of age (tardum).2Penile and scrotal lymphedema mostly occurs following an infection or as a reaction to trauma. Idiopathic lymphedema is rarely seen and is caused by a primary obstruction of lymphatic vessels of scrotum.Genital elephantiasis is a functionally disabling and emotionally incapacitating entity. Lymphedema of the male genitalia is caused by reduced lymphatic flow, with subsequent enlargement of the penis and scrotum. Swelling is characterized by severe discomfort, limitations of local hygiene and ambulation, and a progressive loss of sexual and urinary function. These functional disabilities cause extreme emotional stress making surgical intervention imperative. CongenitNo effective medical treatment has been introduced; however patient with spotty occurrence of genital lymphedema may respond to prolonged course of fluoroquinolones. Different surgical methods for the treatment of chronic genital lymphedema have been reported in the literature. Two main methods are as follows:Physiologic methods or lymphangioplasty through which lymphatic discharge from involved regions to new lymphatic channels is obtained.Lymphangiectomy with reconstructive surgery.Lymphangioplasty is used in the cases of recurrent lymphedema; however, this method can not be successful in the cases of chronic fibrosis or lymphedema caused by radiation because of the lack of appropriate lymphatic channels.Various methods of reconstruction of genital elephantiasis involve excision of affected tissue and its reconstruction with or without lymphangioplasty. Out of the several procedures described in the literature, modified Charles procedure looks most promising. These surgical procedures if performed well give remarkably good cosmetic results with tremendous improvement in quality of life of these unfortunate patients with genital elephantiasis.Lymphangiectomy includes the removal of superficial lymphatic network, which is located above the Buck's fascia which is derived from median raphae and prepuce lymphatics. These lymphatics drain to superficial posterior lymphatic channels. A deeper system is located beneath the Buck's fascia and is drained into deep inguinal lymph nodes.- The above method of drainage leads to the success of our surgical method.It is essential to remove involved skin and subcutaneous tissue completely around the penis and the scrotum (reduction scrotoplasty) to prevent lymphedema recurrence followed by reconstructive surgery of penis and scrotum.6 The posSurgical complications of elephantiasis or genital lymphedema include hemorrhage, hematoma, urethral injury, infection, painful erection, decrease of sensation, and scar in suture line. These complications could be reduced by using a proper incision, use of Z plasty instead of longitudinal suture, separating of testes, and cord by an external incision in scrotum before taking any measure, and removal of involved tissue.8