It is well-established that smoking and depression are associated in adolescents, but the temporal ordering of the association is subject to debate.Longitudinal studies in English language which reported the onset of smoking on depression in non clinical populations (age 13-19) published between January 1990 and July 2008 were selected from PubMed, OVID, and PsychInfo databases. Study characteristics were extracted. Meta-analytic pooling procedures with random effects were used.Fifteen studies were retained for analysis. The pooled estimate for smoking predicting depression in 6 studies was 1.73 . The pooled estimate for depression predicting smoking in 12 studies was 1.41 . Studies that used clinical measures of depression were more likely to report a bidirectional effect, with a stronger effect of depression predicting smoking.Evidence from longitudinal studies suggests that the association between smoking and depression is bidirectional. To better estimate these effects, future research should consider the potential utility of: (a) shorter intervals between surveys with longer follow-up time, (b) more accurate measurement of depression, and (c) adequate control of confounding. Co-occurrence of tobacco use and depression has long been a major concern because of the substantially increased risk to health. Most 2--2-12 butSeveral hypotheses have been put forward to explain the possible mechanisms underlying the association between smoking and depression. The "self-medication" hypothesis suggests that depression may lead to smoking because people smoke to relieve symptoms of depression. -20 In coAdolescence is regarded as the key period for the study of the onset of smoking and depression co-occurrence. The period of adolescence represents the peak of the incidence of both smoking and depression. More speWhile cross-sectional studies find that depression and smoking are associated among adolescents, longitudinal studies are needed to address temporality. Since Kandel and Davis  reportedThis review focuses on longitudinal studies wherein temporality can be ascertained, and it provides a quantitative summary of estimates of the association between smoking and depression among adolescents.English language studies published between January 1990 and December 2007 were extracted from the PubMed, OVID, and PsychInfo databases using the following abstract keywords: (a) smoking, tobacco, cigarettes; (b) depress* (c) child*, adolescen*, youth; (d) longitudinal, cohort, follow-up. Titles and abstracts were then screened to determine if publications met the following inclusion criteria: (1) the association between smoking and depression was studied longitudinally; (2) the outcome (either the onset of depression or the onset of smoking) was measured when subjects were aged 13 -19 years; (3) the study population was broadly representative of adolescents ; and (4) the effect of smoking on the onset of depression, or the effect of depression on the onset of smoking was reported explicitly as a risk, hazard, or odds ratio. Studies that examined related but distinct mental health constructs including anxiety, stress, and negative affect were not included. Additional studies that met the inclusion criteria were identified by scanning references in the reports retained in the primary search, and through searching the Internet through Google Scholar. For cohorts with multiple relevant publications, the latest publication with the longest follow-up that reported on outcomes in adolescents was selected to avoid duplication.The following data were abstracted from each study retained: country in which the study had been conducted; sample size; year(s) of data collection; time period over which the relationship was estimated; participants' age/grade, the definition of smoking; the definition of depression; covariates included in the multivariate modeling; the analytic method; and the parameter estimate of the unadjusted association between smoking and depression . Finally, the estimate of effect(s) after controlling for covariates was recorded. The quality of the studies included in this review was characterized across factors that may affect generalizability and internal validity in cohort studies. Several While there was considerable variability in methods of analysis and the description of results, we undertook a quantitative synthesis of data across studies. The log scale estimate and its standard error were entered into Stata 10.0  and poolThe database search yielded 191 publications. Eight additional reports were obtained through a search of references. Sixteen publications were excluded because they did not analyze the data longitudinally . Screening of titles and abstracts for inclusion and exclusion criteria produced a total of 55 relevant publications representing 17 different cohorts. Four studies from separate cohorts -34 did nTable Studies retained for analysis varied on a number of criteria measuring "quality" that may have affected internal validity or generalizability  ) and smoking predicting depression ) were both statistically significant despite the relatively small number of studies and wide variability in study designs and measures.This analysis revealed moderately strong evidence supporting a relationship whereby smoking predicts depression among adolescents. Only one study  found thConversely, the results also may be interpreted to suggest that depression leading to smoking is the more likely pathway. Smokers may use nicotine as a means of 'self-medicating' symptoms such as depressed mood and fatigue that are related to depression; nicotine has been shown to produce an elevation in mood. NicotineThe current analysis cannot refute the hypothesis that the relationship between smoking and depression is spurious. It is possible that if the two conditions are causally related, the relationship may reflect several potential causal mechanisms in which: (a) depression precedes smoking, (b) smoking precedes depression, (c) there is a bidirectional relationship between smoking and depression, (d) the relationship is a function of unknown risk factors, or (e) there are subgroups in which the relationship between smoking and depression differs. To address these issues, the nature of the relationship between depression and smoking should be investigated further. While temporality is an important condition for causality, there are other issues in the current literature of prospective studies that limit our ability to draw robust conclusions about the nature, causal or otherwise, of the relationship between smoking and depression. These issues should inform future research and are discussed below.The conceptualization, the definition and the method of measurement of exposure can affect the interpretation of an association. Studies that used a clinically based definition of depression were generally consistent in showing that the magnitude of effect was greater for depression predicting smoking than smoking predicting depression; however, only 5 studies used diagnostic interviews to measure depression. Measures of depressive symptomatology may have more random measurement error than diagnostic interviews, attenuating parameter estimates towards the null. Furthermore, cut-points for depressive symptomatology scales unnecessarily discard information.Interval censoring may affect the interpretation of the temporal sequence of events if both depression and smoking occur during the same interval. For example, smokers may experience rapid fluctuations in mood (compared to non-smokers), as result of intermittent periods of withdrawal, followed by short-term relief after smoking. These raSample selection may introduce bias. A previous history of depression increases the risk of future depression, which suggests that estimates should be adjusted for a history of depression. SelectinThe magnitude of the association between depression and smoking has been shown to be substantially reduced after controlling for such variables as school performance, socio-economic status, and alcohol use.,58-60 DuThe evidence is consistent with a hypothesis that the association between smoking and depression may differ among different subgroups. There is some indication that the relationship between depression and smoking is specific to females or among youth with friends who smoke.,34,45 ThThis paper used strict inclusion criteria to include as homogenous a population of studies as possible in order to perform the pooled analysis. As such, studies that used techniques such as growth curve modeling ,69,70, cThe pooled estimates should be interpreted with caution because they are based on studies with heterogeneous measures of exposure and outcomes, and differing study designs. Estimates adjusted for covariates were selected from each study, but the variables included to control for confounding varied from study to study. There may therefore be residual confounding of the pooled estimate, which could inflate the estimate away from the 'true' value.Several studies were excluded because the outcome was measured in young adulthood rather than adolescence.,74 It coWhile the association between smoking and depression is not in doubt, the reasons underlying the association matter both for those affected by both depression and smoking, but also for the development and implementation of interventions. Understanding the causal mechanisms underlying the relationship could allow for the development of interventions for adolescents with these conditions, and possibly prevent the implementation of interventions based on an erroneous causal mechanism that may have negligible or even iatrogenic effects. If, for example, some individuals smoke in order to control symptoms of depression, interventions that focus solely on smoking could be ineffective, or indeed, potentially dangerous. However, if smoking exacerbates depression symptoms, excluding those who are depressed from treatment could lead to further harm. Further research into identifying the nature of the association should be initiated.The authors declare that they have no competing interests.MC performed the literature search, the quantitative analysis and drafted the manuscript. JEC, JOL, JR supervised the search and contributed to the conceptualization of the project including statistical design. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:Quality table. Quality Assessment of included longitudinal studies on the association of depression and smoking.Click here for file


There is no published evidence of how patient concerns change during the first six weeks following total knee arthroplasty (TKA). An understanding of the recovery process from the patient's perspective will inform clinicians on how to best educate patients about their post-operative concerns. Our objectives were to (1) quantify the level of importance for each of 32 previously identified concerns pre-operatively, and across the first six weeks following primary TKA and, (2) convey this change in importance post-operatively using the components of the International Classification of Functioning, Disability and Health (ICF).The objectives were achieved using a repeated measures design. Convenience sampling was used to recruit 54 consecutive patients undergoing primary TKA at a hospital in Ontario, Canada. Pre-operatively and at two, four and six weeks post-operatively subjects rated the level of importance for each of the 32 previously identified patient concernsThe importance rating of patient concerns in all four ICF components changed from before surgery to two weeks after surgery. Patient concerns in the Participation component became increasingly important after the first two weeks following surgery. Post-operatively from week two to week four, changes in importance ratings were also found in the Body Function and Activity components, but not in the Environmental Factors component.Changes in patient concerns mirror their early recovery from TKA surgery. Consistent with this, Participation restrictions become increasingly important to patients after discharge from acute care suggesting that clinicians should think of managing patient expectations for return to societal roles early in post-operative rehabilitation. Osteoarthritis (OA) of the knee is a common cause of pain and disability in the elderly population . DependiWhen evaluating the success of any treatment, opinions of patients are of great significance . This isEven though patients are routinely referred for physical therapy in the acute post-operative phase (0–6 weeks) after TKA, there is no published evidence of how patient concerns change during this early period of recovery. An understanding of the recovery process from the patient's perspective will inform the clinician's approach to patient education during rehabilitation.Many of the outcome measures used to quantify change following primary TKA are based on patients' perceptions of their status, but the choice of outcomes is rarely grounded in a conceptual framework ,9. The IIn an earlier study, to identify concerns that patients had about their recovery from surgery, we performed individual face-to-face cross-sectional interviews with 30 patients during the first six weeks following primary TKA for OA. All patient concerns were identified by asking patients to answer one specific question, "What is important to you right now with respect to your recovery from knee replacement surgery?". During the interview it was emphasized that patients should only identify what was important during that particular week of the interview. Patients were allowed to report as many concerns as they wished, all of which were recorded verbatim in writing. The primary investigator (RR) conducted all interviews. We grouped patient comments on the basis of common themes, identifying 32 concerns about surgical recovery that we then linked to the components of the ICF . Seven oParticipants were English-speaking ambulatory patients with knee OA who were waiting for a primary TKA. Sample size calculations were based on a concurrent study of responsiveness of the WOMAC [unpublished]. Convenience sampling was used to recruit consecutive patients from the waiting lists of orthopaedic surgeons working in a large tertiary care hospital. Each subject participated in four evaluation sessions: pre-operatively and at two, four and six weeks after surgery. During each evaluation session subjects rated the level of importance for each of the 32 concerns identified in our earlier study  and wereDescriptive statistics were used to summarize the pre-operative characteristics of subjects. We described change in clinical status between each time point by evaluating each subscale of the KOOS with a repeated-measures analysis of variance (ANOVA) and Bonferroni post-hoc testing . To quanFifty-seven subjects were contacted and consented to take part in the study. One person withdrew from the study without any explanation and two people did not return phone calls to set up an appointment, leaving 95% of recruits who completed the study (n = 54). There were no missing data. Of the 54 subjects who completed the study, 48% (n = 26) were men. The average age (standard deviation) of the sample was 68.1 (8.9) years. Clinical characteristics of the subjects along with their preoperative scores for the KOOS, WOMAC and NPRS are shown in Table As mentioned earlier, during each evaluation session subjects were given the opportunity to identify any additional concerns regarding their recovery from knee replacement surgery. No additional concerns were provided by subjects at any of the four evaluation sessions. On visual inspection, the importance ratings for the 32 concerns identified in our earlier study  were ske23df = 34.29; Activity: χ23df = 20.61; Participation: χ23df = 90.91; Environmental Factors: χ23df = 14.37). Post-hoc testing revealed a significant change in importance between the pre-operative evaluation and post-operative week two for all four ICF components (p < 0.0001). Participation was the only ICF component that demonstrated a significant change in importance between all four-time points (p < 0.0001). The importance of the Body Function and Activity components changed significantly from before surgery through to post-operative week four (p < 0.001).The Friedman's ANOVA results are shown in Figure This study was conducted to gain a quantitative understanding of how the importance of patient concerns change during the first six weeks following primary TKA. It showed that the importance of some concerns change over time while others do not. In the discussion that follows we suggest these changes reflect the clinical aspects of the delivery of care and the early recovery process. We also propose that the importance ratings provide direct evidence that supports the differentiation of the Activity and Participation components of the ICF in the clinical context of this study. To the best of our knowledge, this is the first study of this nature.The Friedman's ANOVA revealed the importance rankings of all four ICF components changed over time. Post hoc testing showed that concerns in the ICF Body Function component were ranked higher at post-operative week two compared to before surgery. The WHO has defined Body Function  as physiGoing through surgery and recovery may also explain the pattern of change in the Activity and Participation importance ratings. Post hoc testing showed that patients ranked concerns in these components as being less important two weeks after surgery. Due to the nature of the surgery it is common for patients to experience impairments with certain body functions , which generally lead to limitations in the activities that they can perform. Researchers have reported a decline in physical function in the first month following TKA surgery . ConsistJust like the Body Function component, patient concerns that mapped to the Environmental Factors component were ranked higher two weeks after surgery. Due to the immediate decline in physical function , patientTwo concerns that were not covered by the ICF components, 'receiving appropriate information regarding what to expect with rehabilitation following your surgery' and 'being independent' were of great importance to patients before surgery and remained at the same level of importance throughout the first six weeks of recovery. The first emphasizes the importance of education from the patient perspective. In this regard, Soever and MacKay  have docThere is considerable debate regarding the need to distinguish between the Activity component and the Participation component of the ICF -14,27. WAll participants in the study were recruited from a single tertiary care hospital. This may be viewed as decreasing the generalizability of this study to other settings. Even though the results may not be applicable to all TKA populations, the patient demographics and pre-operative functional status findings were comparable to that of other TKA studies ,29-31. TIn conclusion the study shows the level of importance that patients assign to concerns about recovery from TKA surgery, is a reflection of the stage they are in, during the surgical and rehabilitation process. In particular, Participation restrictions become increasingly important to patients from two to six weeks after surgery, suggesting that patients do think about their return to activities at the societal level early in their postoperative rehabilitation. Clinicians can use this knowledge to integrate their approach to education, goal setting and managing expectations about return to participation roles after TKA surgery.The authors declare that they have no competing interests.RR, AMD and BMC designed the study. RR collected and analyzed the data and drafted the manuscript with regular feedback from AMD and BMC. All authors read and approved the final manuscript.


Intra-articular osteotomy is considered in the rare case of malunion after a fracture of the distal humerus to restore humeral alignment and gain a functional arc of elbow motion. Traumatic and iatrogenic disruption of the limited blood flow to the distal end of the humerus resulting in avascular necrosis of capitellum or trochlea is a major pitfall of the this technically challenging procedure. Two cases are presented which illustrate the potential problems of intra-articular osteotomy for malunion of the distal humerus. Distal humerus fractures are uncommon, accounting for only 2 percent of all fractures . Open reIn the rare case of malunion, intra-articular or supracondylar osteotomy to restore humeral alignment and provide a more useful arc of motion is legitimate. In the case of an extra-articular osteotomy to correct flexion or extension alignment, treatment can be indicated despite the presence of posttraumatic arthrosis of an incongruent elbow joint. However, intra-articular osteotomy treatment is only considered when the patient is seen early and secondary post-traumatic arthritis is at an early stage , 6.Intra-articular corrective osteotomy for malunited fractures of the distal humerus is technically demanding and the literature on this subject scarce –9. This Our patient was a 48-year-old dentist who was seen 10 months after a high energy fall that resulted in a complex type C3 intra-articular fracture of her left nondominant distal humerus . InitialShe underwent corrective a transverse osteotomy 18 months after her initial injury. A midline posterior incision, with medial and lateral skin flaps elevated, was used. The olecranon osteotomy provided a complete overview of the dorsal distal humerus, including the radiohumeral joint and the ulnar nerve. An oscillating saw was used to create a trapezoid wedge to correct overlength varus of the lateral column and flexion of the capitellum in order to realign capitellum and trochlea. Extreme caution was taken no to disrupt the anterior blood supply of the capitellum. A second supracondylar wedge was resected to correct cubitus varus and 20 degrees of internal rotation. The capitellum radii was fixed to the ulnar condyle using an isolated lag screw . Iliac cShe had loss of anterior translation of the distal end of the humerus resulting in 90 degrees of flexion and 5 degrees of hyperextension of the left elbow . The patTo the best of our knowledge, this is the first report to specifically address intra-articular osteotomy to treat distal humerus malunion. However, small series have been published as part of surgical technique and clinical outcome papers on intra- and extra-articualar malunion . McKee aThe cornerstone of treatment of fractures of the distal humerus is operative reduction and internal fixation –13. PessNonunion and malunion of distal humerus fractures treated operatively is rare. Only 2% of all fractures involve the distal humerus, and 2% of these result in malunion. Intra-articular osteotomy for malunion to achieve a functional arc of motion and to prevent subsequent posttraumatic arthritis in the elbow joint is rarely indicated in the young demanding patient. Therefore, experience with treatment of intra-articular malunited fractures is very limited and reports seldom appear in literature –9. We feIf the patient present at an early stage, an intra-articular osteotomy is considered if original fracture lines can be osteotomized and posttraumatic arthrosis is limited. Extra-articular osteotomy is indicated when intra-articular congruency of the elbow joint cannot be restored and secondary posttraumatic arthrosis is too advanced , 6. PreoStability of the elbow joint and a functional arc of motion were achieved in this case. After intra-articular osteotomy, the patient had only 90 degrees of flexion due to loss of anterior translation of the distal humerus . InitialSurgical reconstruction of the intra-articular malunited distal humerus is technically challenging but can improve function in the young active adult by restoring intrinsic anatomy of the elbow.


A nine years old boy, who had suffered septic arthritis at the age of two years and presented now with a limp, hip instability, leg length discrepancy. The patient was treated by adductor tenotomy and upper tibial pin traction. When head remnant reached the level of the acetabulum, open reduction and Pemberton osteotomy was done to achieve cover of the femoral head. The purpose of this report is to highlight the six years followup of reconstruction of sequale of septic arthritis of hip joint. The ultimate goal of the management of sequelae of septic arthritis of the hip centers around stabilizing the hip with minimal loss of movement, thereby improving the gait. The outcome of the treatment for septic arthritis of hip depends on the age of the patient and clinico-radiological status of the hip. Choi'sA boy aged nine years complained of painless limp on the left side and came walking on his tiptoes. He had suffered septic arthritis of left hip at the age of two years. On examination, there was muscle wasting around the hip and thigh, with no fullness in the Scarpa's triangle. Greater trochanter was proximally migrated. The patient had Trendelenberg gait, with fixed flexion and adduction deformity of 30°, no rotational deformity and shortening of 4cm. Further flexion of the hip was possible up to 120°. No abduction or rotations were possible. The telescopy was neither appreciable nor demonstrable. Skiagram of the pelvis revealed coxa breva with subluxated head of femur with deformed and bifurcated neck .Magnetic resonance imaging (MRI) was not done as the patient could not afford it.Initially, open adductor tenotomy was done and tibial pin traction was applied for 21 days, continued till the head or the deformed neck could be brought to the level of the acetabulum. The open reduction of the hip was performed through anterior illio-femoral approach using a bikini incision. We found a small head and bifurcated neck and soft tissue occupying the medial acetabulum. We could reduce the head into the acetabulum, which was quite stable. Pemberton's osteotomy, also offered a good lateral cover to the head. A subcutaneous K-wire was passed across the hip joint from the trochanter . Hip spiThe involvement of hip in septic arthritis is particularly difficult to detect. It is often diagnosed late, leading to irreversible damage to the articular cartilage, blood supply to the epiphysis and sometimes absorption of head and neck, resulting in severe shortening and disability. ZwierzchovoskiDifferent procedures have been described for different stages of sequelae of septic arthritis of hip. All procedures advocated for the management of septic arthritis of hip grouped under Choi type I-IV, have variable results. Some of the suggested surgical treatment for children according to Choi's classification is:Type I: Almost normal hip or mild coxa magna. It needs no reconstruction.Type II: Deformed epiphysis, physis, metaphysis may result in coxa breva or progressive coxa vara or coxa valgus. It needs surgical intervention to prevent subluxation.Type III: Malalignment of femoral neck, excessive anteversion or retroversion with pseudoarthrosis. It neccesitates a realignment surgery for proximal femur or bone grafting for Pseudo-arthrosis.Type IV: Destruction of the head and neck of femur with the presence of remnant of medial base of neck. Complex clinical problems with limb length inequality -needs reconstructive surgery.356Our patient was grouped under Choi'sAdductor tenotomy with skeletal traction before performing an open reduction and Pemberton's osteotomy helps in bringing the greater trochanter down to the level of the hip. We chose Pemberton's osteotomy to cover the head and gain some length. Pemberton's and Dega's osteotomyOur procedure has given a satisfactory acceptable function of hip in a Choi type IV sequelae of septic arthritis of hip below 10-12 years of age.


The Ninth Meeting on Human Genome Variation and Complex Genome Analysis was held in Sitges, Spain, in September 2007. This annual meeting, which originally focused on single nucleotide polymorphisms (SNPs), broadened its scope from 2006 onward to encompass the entire range of genomic variability. Maintaining the relatively small format of 200 delegates, the meeting gathered leading investigators in copy number variation (CNV), SNP association studies, ultrasequencing, population genetics, statistical analysis, and database management, as well as young investigators who initiated careers in these fields. The two-and-a-half-day meeting combined sponsorship by several academic institutions and corporate entities in a venue that facilitated interaction and communication between the participants.The Sitges venue was particularly conducive to the formal and informal discussions that have long characterized this meeting. These discussions were wide-ranging, and while they often began in the meeting rooms, they usually continued through meals and into the evening.A key focus was the question of how to facilitate the continued success of genome-wide association studies (GWAS). It has been widely appreciated that large-scale collaboration has been hugely beneficial to early GWAS, and there was considerable discussion at the meeting of the need to establish and maintain the bioinformatics infrastructure necessary to make maximum use of the data being generated. While initial efforts toward building such infrastructure in the United States and Europe have made impressive inroads in serving both data and results of GWAS (summarized by a number of the participants—see below), the need for richer resources allowing integration of GWAS across more phenotypes, including expression phenotypes from multiple human tissues, was apparent. Such resources would allow more rapid and broad-based assessment of functional relationships among genetic variations (SNP and CNV), expression phenotypes, disease states, and related quantitative traits. There was also widespread sentiment that larger samples sizes, while clearly desirable, would, in the end, provide only a fraction of the contribution of genetic variation to complex disorders. Advances in analytic approaches coupling statistical genetics with bioinformatics may prove to be fruitful in extending results of GWAS.There was vigorous discussion of the likely contribution of structural variation to human genetic disease. Although a number of participants confirmed the contribution of CNVs to various human disorders, known CNVs are highly skewed toward the lower end of the minor allele frequency spectrum. This skewing was thought to reflect an initial bias toward detection of larger CNVs; a discovery bias which precludes a comprehensive understanding of the contribution of this class of genetic variants to human disease and reduces the likelihood of being able to reliably “tag” CNVs even if most were the consequence of a single (rather than recurrent) events. As technology improvements allow detection of smaller CNVs that may have a higher minor allele frequency as well as more precise delineation of the exact sequences involved, we will not only get a more accurate picture of the contribution of these variants to disease but also gain insights into the dynamics, the evolutionary history, and the consequences of such variants. A key question is whether such sites are generally uniquely created, with a single originating event, or rather are commonly regenerated, due perhaps to the presence of repetitive elements. This will determine whether such variants can be tagged and indirectly interrogated  or will need to be directly interrogated, which will in turn influence the design of later generation platforms for GWAS.Technology, particularly the newest sequencing technologies, was also a major topic of discussion. A number of new approaches as well as more streamlined versions of existing technologies were discussed. The meeting certainly highlighted the steady steps toward the eventual goal of sequencing entire human genomes at reasonable financial cost and with efficient computational algorithms.http://hgv2007.nci.nih.gov; http://www.tcag.ca/hgv2008) and in Abstracts of the meeting and an expanded version of the meeting report can be found on the meeting Web sites  in recent months on the identification of genetic variants that predispose to common human cancers; the studies were based on a stepwise approach used in GWAS followed by meta-analysis on data from several other groups. Xavier Estivill  reported a common genomic feature of disorders for which CNVs have been detected, namely the presence of segmental duplications in the vicinity. Moreover, all CNV loci that have been found associated with common disorders are both complex and multi-allelic, making it difficult to tag these CNVs with SNPs. Pui-Yan Kwok  sounded a cautionary note regarding quality control of genotype data in the context of automated genotype data production.Highlights of the presentations include the considerable progress reported by Samuel Levy  reported the details of the sequencing, assembly, and variant detection in the genome of Craig Venter. Using newly developed genome assembly strategies and comparative genome-to-genome mapping methods, they identified 25 Mb of diploid sequence differences, representing more than 4 million DNA variants, thereby increasing the estimate of DNA sequence differences between unrelated humans to 5–10 times more than previously thought. Sanjeev Bhaskar  and Ivo Gut  described their efforts in high-throughput, targeted sequencing using a variety of approaches. George Church  showed that 1% of the genome harboring most causative alleles for medical and nonmedical traits could be targeted for sequencing using strategies he and others have developed. He pointed out that by combining these approaches with paired-end tags for rearrangements  and allele-specific RNA quantification, an affordable analysis of the human genome could be achieved at the individual level.In the area of sequencing the individual genome, one of the most challenging problems is the assembly of the sequences and the large number of differences between sequences, including many structural variation changes. Steve Scherer  reported the recent findings on chromosome rearrangements and imbalances in autism spectrum disorders, with evidence showing that chromosome rearrangements in autism are likely to be involved in 10%–20% of all cases. Barbara Trask  reported on the important role CNVs played in the evolution of three families of chemosensory receptors  that help an organism interact with its environment. George Perry and Charles Lee  presented data about the distribution of amylase gene (AMY1) copies in different populations that showed a positive or directional selection on AMY1 copy number in human populations with diets high in starch but neutral evolution on AMY1 copy number in low-starch populations. Joris Veltman  presented the use of dense bacterial artificial chromosome (BAC) arrays and SNP arrays to identify CNVs underlying mental retardation. The use of parallel approaches and data sharing by investigators from different countries has allowed them to identify new syndromes that were previously unrecognized. Matthew Hurles  reported on the use of ultrasequencing technologies to identify and characterize structural variation. He also presented data on the development of a comprehensive map for common CNVs using high-density oligonucleotide arrays with 42 million probes across the genome. Finally, he stressed the need for improved methods for CNV genotyping and quantification to deal with multiallelic CNVs and with differential biases in assessing CNVs in cases and controls. To facilitate the precise quantification of copy numbers of particular genes in subjects, John Armour  described the development of paralogue ratio tests (PRTs) that improve the precision, economy, and throughput for complex CNV genotyping.The intensity of CNV research was evident in the presentations of several groups at the HGV2007 meeting. For example, Nancy Cox  reviewed general approaches for direct and indirect assessment of CNV information to study common disorders. She reported on the use of TUNA (Testing Untyped Alleles) to utilize linkage disequilibrium (LD) to interrogate CNVs for which multilocus LD tags can be constructed. Don Conrad  described new methodology for integrating CNVs into the study of genetic traits. Iuliana Ionita  reported on the development of an extension of a family-based association test (FBAT) approach to analyze CNV data with family-based designs.Combining CNV and SNP data in GWAS is a major challenge for statistical geneticists, and a number of groups presented strategies to tackle this problem. Vivian Cheung  reported on research to identify genetic variation affecting interindividual gene expression. Of 3,500 genes with variable expression levels, 235 were associated with SNPs  in a GWAS. Manolis Dermitzakis  discussed the elevated density of genes, evolutionary rates, and gene functions, noting data consistent with the possibility that some of these regions have been positively selected in the human population due to advantageous gene dosage effects of copy number variants. Jaume Bertranpetit  discussed the possibilities of computing population recombination rates from SNP frequency data. They found that most of the variation is among major human groups and a minor component of population variation is within continents, with most recombination hotspots conserved among human populations. Esteban González-Burchard  provided fundamental evidence of genetic differences between racial and ethnic populations relevant to differences in genetic risk for Alzheimer disease and HIV resistance. Gilles Thomas  presented data on population stratification in two genome-wide studies in breast cancer and prostate cancer. Their results showed evidence of population structure on the European continent and pointed to the need to correct for population stratification in searching for association in European populations. In addition to the GWAS approach, Angel Carracedo  discussed classical approaches to identifying genetic variations associated with both toxicity and efficacy. He emphasized the challenges of the current applications in clinical practice and the changes in labeling that have been recommended by the regulatory agencies in Europe and United States  for about ten drugs).Yum Lina Yip  gave a presentation on archiving single amino acid polymorphisms in the UniProt/Swiss-Prot knowledge base, with >30,000 single amino acid polymorphisms (SAPs) in about 6,000 human proteins already archived and many more to come. Andrew Devereau  reported on the use of a variation database for diagnostic molecular laboratories. This tool allows data from different laboratories and different sources to be integrated and analyzed for the interpretation of its clinical significance. Anthony Brookes  presented progress toward developing HGVbaseG2P, a database of genotype-to-phenotype (G2P) relationships, which aims to pull together a comprehensive view of the world's genetic association study findings. He also described GEN2PHEN (http://www.gen2phen.org/), a European Commission Integrated Project designed to help provide globally relevant solutions for G2P databasing. Ewan Birney  presented an overview of the Ensembl infrastructures for genomic information, from its storage through to analysis and visualization. The data included variation information for more than 6,000 human individuals and resequencing data from six. James Ostell  described several of the resources of the National Center for Biotechnology Information (NCBI), including the Database of Genotype and Phenotype (dbGaP), which holds phenotype data from long-term clinical and cohort studies, and is linked to large-scale genotype results on the participants or to medical sequencing data in support of GWAS. Lincoln Stein  presented the new features and tools of the HapMap Web site and discussed progress toward providing views of resequencing data, particularly as it moves toward sequencing entire human genomes. Carole Charlier  reported on the use of Patrocles, a database of polymorphic miRNA-mediated gene regulation that assists in the identification of SNPs that affect such regulation. Lars Feuk  described the latest version of the Database of Genomic Variants, which contains all the published CNVs in the genome. This database faces the challenges of definition of CNV boundaries, detection of false positives, and determination of accurate population frequency information.Another important topic of discussion at the meeting was the current status and future needs for central genomic databases in the area of human variation. Anne Cambon-Thomsen  reviewed the issue of human biobanks for studying human genome variation. She reported on the networking of biobanks  and described some of the conflicting interests that have to be balanced, such as participant privacy, potential risks and benefits, methodological guidance for interpretation and use of data, professional recognition of investigators, sharing of samples and data, intellectual property rights, and characteristics of a centralized data repository or other repository.The meeting also devoted discussion to the ethical aspects of individualized sequencing. http://www.tcag.ca/hgv2008/) will be held 15–17 October 2008, in Toronto, Canada. That meeting will focus, in part, on further steps for the sequencing and resequencing of the human genome.The Sitges meeting also included more than 150 posters presented over the three-day meeting. The prevailing view was that each attendee left the meeting with new ideas in a field that is moving rapidly at the cutting edge of discovery of the genetic variants that will define disease predisposition and help to uncover new biological pathways for understanding human health and disease. The HGV2008 meeting (Text S1 Meeting Abstracts: Meeting Program Booklet Including the Meeting Agenda and All Abstracts(14.7 MB PDF)Click here for additional data file.Text S2Full Meeting Report: An extended version of the meeting report(0.08 MB DOC)Click here for additional data file.


In recent decades low-income countries experienced an increasing trend in dental caries among children, particularly recorded in 12-year olds, which is the principal WHO indicator age group for children. This increases the risks of negative affects on children's life. Some data exist on the oral health status of children in low-income countries of Southeast Asia. However, information on how oral health is associated with socio-behavioural factors is almost not available. The aims of this study were to: assess the level of oral health of Lao 12-year-olds in urban and semi-urban settings; study the impact of poor oral health on quality of life; analyse the association between oral health and socio-behavioural factors; investigate the relation between obesity and oral health.A cross sectional study of 12-year old schoolchildren chosen by multistage random sampling in Vientiane, Lao P.D.R (hereafter Laos). The final study population comprised 621 children. The study consisted of: clinical registration of caries and periodontal status, and scores for dental trauma according to WHO; structured questionnaire; measurement of anthropometric data. Frequency distributions for bi-variate analysis and logistic regression for multivariate analysis were used for assessment of statistical association between variables.Mean DMFT was 1.8 (SEM = 0.09) while caries prevalence was 56% (CI95 = 52-60). Prevalence of gingival bleeding was 99% (CI95 = 98-100) with 47% (CI95 = 45-49) of present teeth affected. Trauma was observed in 7% (CI95 = 5-9) of the children. High decay was seen in children with dental visits and frequent consumption of sweet drinks. Missed school classes, tooth ache and several impairments of daily life activities were associated with a high dD-component. No associations were found between Body Mass Index (BMI) and oral health or common risk factors. The multivariate analyses revealed high risk for caries for children with low or moderate attitude towards health, a history of dental visits and a preference for drinking sugary drinks during school hours. Low risk was found for children with good or average perception of own oral health. High risk for gingival bleeding was seen in semi-urban children and boys.Although the caries level is low it causes considerable negative impact on daily life. School based health promotion should be implemented focussing on skills based learning and attitudes towards health. Historically diseases of the oral cavity have been viewed separately from those of the rest of the body. In recent years however efforts have been made to recognize oral health as an integral part of overall health . MoreoveDental caries is the most prevalent chronic disease among children worldwide. While dental caries has decreased in many industrialised countries the contrary is the case in many low-income countries . The incOral epidemiological information is available from studies carried out in South East Asian countries, e.g. China and Thailand, and low to moderate caries levels among children are revealed. Petersen et al  found a The aim of this study is to describe the oral health status of 12-year old urban and semi-urban Lao schoolchildren and how oral health is linked to socio-behavioural risk factors. Furthermore, the aim is to ascertain the impact of poor oral health on the quality of life of children in a low-income country, to analyse the association of socio-demographic and behavioural factors with oral health and to investigate possible relationships between obesity and oral health and risk factors for chronic disease. These aspects are crucial to oral health promotion and integration of oral disease prevention into the Lao school health initiative.According to the 2007/08 Human Development Index Laos is ranked number 130 out of 177 countries. For the population of 5.6 million oral health care is provided by a limited number of dentists  mainly ond grade classes were randomly chosen and all 11-13 year old children in the selected classes were asked to participate. According to information from the educational authorities, enrolment rates for schools eligible to participate in the study were above 90% for both sexes. Parents and children were informed about the study and aware of the fact that the participants could withdraw from the study at any time. The response rate was 94% and the final sample comprised of 621 children. The schools were visited at least twice and no further attempt was made to include non-attendants.This study was carried out in September and October 2006 in Vientiane as a cross sectional survey of 12-year old schoolchildren. The sample size was estimated from information on dental caries prevalence parameters observed in previous epidemiological studies carried out in Laos. Multistage sampling was applied to ensure that the final study population would match the categories mentioned in the objective of the survey. Ten secondary schools were selected to represent schools of urban and semi-urban settings. Of each school, 2The survey involved a structured self-administered questionnaire followed by an oral examination, and measurements of height and weight. The completion of the questionnaire and the clinical examination were conducted at the same day. The clinical examination assessed the dentition status, gingival health and dental trauma and was based on the methods and criteria described by the World Health Organization (WHO) . Dental An international oral epidemiologist (PEP) ensured calibration of the clinical examiners in Laos (NJ and SAY) through duplicate caries examinations of children aged 7-13 not included in the final survey n = 14). The inter-examiner agreement with regards to caries diagnosis was expressed by the percentage agreement and by the Kappa statistics as recommended by the WHO [. The inthttp://www.who.int/oral_health. The questionnaires were formulated in English, translated into Lao and pre-tested among children not included in the study in order to control the reliability and validity [All children taking part in the study were invited to complete a structured questionnaire on socio-behavioural risk factors. The following principal variables were covered: knowledge, attitudes and practices related to oral health; dietary habits; self-assessment of oral and general health status; experience of pain and discomfort; patterns of physical exercise; residential area; and socio-economic situation. Oral health knowledge and attitudes were measured by use of standardised questions and by positive or negative responses to loaded statements . The chivalidity . The resAs part of the clinical examination, all children had their weight and height measured to be able to calculate their body mass index (BMI). Measurements were taken with the children wearing school uniform and no shoes. The height was measured with the child standing adjacent to a wooden pole with an attached centimetre band. Height was measured in full centimetres. The weight was measured on a mechanical weight scale in half or full kilograms. To group the children according to BMI two methods were applied; one using cut points for normal weight and overweight elaborated by TJ Cole on the basis of international data including Asians ; and a sData processing, data analyses and statistical evaluation were performed by means of the Statistical Package for the Social Sciences, SPSS 14.0 and 16.0. The data were described by uni- and bivariate frequency distributions and the prevalence proportion rates of dental caries and gingival bleeding were calculated. Moreover, the mean dmft-DMFT indices and the mean proportion of teeth with gingival bleeding were computed. The statistical evaluation of means was performed by Students t-test where the means of two groups were compared and by ANOVA where the means of more than two groups were compared. The Chi square test was used to compare proportions. In order to assess the relative effect of socio-demographic and behavioural factors on dental caries multiple linear regression and logistic regression analysis were carried out. In the logistic regression analyses presence or absence of caries was used as the dependent variable and the regression coefficient was the odds ratio for caries (OR = P/1-P). The coefficient was tested statistically by the Wald Chi Square test. In the linear regression analyses the caries indices were used as dependent variables and the t-test was used for statistical evaluation of regression coefficients.The total dental caries prevalence (dmft-DMFT) among the children is shown in Table Seven percent of the children had signs of dental trauma (CI95 = 5-9) Table , boys shCaries experience was highly associated with perceived oral health status, especially in regard to the dD-component Table . No signTable As shown in Table Of all children 91% reported the use of fluoridated toothpaste but differences in caries level could not be observed between users of fluoridated and non-fluoridated toothpaste. In children who stated tooth brushing twice daily or more a low dD-component was seen Table . The mM-With respect to the oral health knowledge indices no significant differences in caries level were found. Meanwhile, the pattern for children's attitude towards health was different Table . While tApplying the cut-points suggested by TJ Cole 60% of the children had a normal BMI while 32% were under- and 8% overweight. Significantly more overweight children were observed among urban children compared to semi-urban . Overweight was found especially in the socio-economic advantaged group of children (14%) compared to the disadvantaged group (4%) although findings were not statistically significant. Similar results were found after dividing BMI scores into tertiles. The highest caries level (dmft-DMFT = 2.3) was found among children with normal weight while overweight children had the lowest caries level (1.6) in both methods used.Other factors being equal, the analyses revealed a relatively high dental caries score in children who reported dental visits in recent 12 months and in children with a moderate attitude towards health while a lower caries level was seen among children who perceived their own oral health status as good or average Table . High odIn Laos systematic information about the oral health situation is scarce. Regular data collection does not take place and the only national oral health survey was implemented back in 1991. The present study provides information on the oral health status for urban and semi-urban 12-year old schoolchildren in Vientiane. The survey includes important target groups where it is expected that the oral disease pattern would reflect the changing living conditions and adoption of modern lifestyles. The study focuses on two of the most common chronic oral diseases in this age group, i.e. dental caries and gingival problems. As living conditions, lifestyles, and morbidity profiles are markedly different in urban and rural areas of Laos, this survey cannot be seen as representative for the entire country. It has however most likely relevance to children in and around the larger urban settlements of Laos.In many high-income countries, research can benefit from a number of conditions of importance to sampling of a study population. For example, established population registries provide an opportunity of probability sampling. Furthermore, longitudinal data bases make it possible in studies of health and illness directly to assess the disease risks (RR), while in cross-sectional surveys it is needed to estimate the risk in terms of the Odds Ratio. For example, in Denmark, 98% of the child population and young people up to the age of 18 are covered by the public dental service and a unique population database exists as the children are examined on a regular basis. In low-income countries, such as Laos, however, alternative ways are to be identified in order to select a relevant sample for a survey. The sample for the present study was drawn from a list of well-defined secondary schools and these settings provide for a public health relevant sample and a high number of study units of the age group of interest. Moreover, this selection method allows for the data to be acquired in a timely manner assuring a high response rate at the same time. Nevertheless several aspects should be born in mind when using this approach. Firstly, risk of selection bias is present if children in high numbers are not attending school. The non-attendees are likely to represent a deprived group of the target population with a behavioural and morbidity pattern fairly different from the general population. Secondly, in numerous low-income countries girls are frequently underrepresented in schools, which is definitely also the case for rural areas of Laos. However, the school-approach was justified for this study as enrolment rates are high for both sexes of urban and semi-urban children. Selection bias could still be a problem if children absent from school suffer from acute illness or they are absent for reasons making them different to their peers. It is worth noting that the response rate obtained was surprisingly high, maybe due to the fact that the examination team visited the schools over several days allowing children absent for only a short period to be included.As for the clinical examination an attempt to avoid misclassification was made by training and calibration of the examiners and the standard of reliability set by WHO was achieved . MeanwhiThe relatively low mean DMFT found in this study is in line with those figures found in neighbouring China -10 and TSugars consumption is an important factor in the development of dental caries and the adverse effect is both related to the frequency and the amount of intake of free sugars . The freHaving filled teeth was highly associated to urban location, having a literate mother, and having an advantaged socio-economic position while untreated decay was associated mainly to semi-urban location. These findings may indicate differences in access to health services and different levels of education on oral health. Significant variation in total caries was however only observed across socio-economic groups. Such differences may be related to the financial capacity of buying large amounts of sweets and snacks among the socio-economic advantaged groups.A somewhat high number of children stated tooth brushing at least twice daily (unpublished report by the author). At the same time an extraordinary high prevalence of gingival bleeding was observed in the clinical investigation. This inconsistency could be explained by either over reporting of tooth brushing or simply reflecting a lack of tooth brushing skills. While the tooth brushing technique may be inadequate to the vast majority of the children, they may still gain some caries preventive effect of such practice when using toothpaste with appropriate level of fluoride. An over reporting of toothpaste use is likely and might explain the lack of difference in caries level between fluoride exposed and unexposed children. The low level of decay among frequent brushers could possibly mirror an effect of both mechanical brushing and fluoride effect.The survey revealed a consistency between information on untreated dental caries and the subjective evaluation of own oral health. Similar findings have been reported from Brazil . As for The dominant dD-component reflects the lack of access to curative dental care in Laos and confirms this situation in most low income countries . A high Common risk factors may be responsible for associations between BMI and dental caries level and this assumption has been investigated in a number studies -28. The The observation of a relatively low DMFT in this survey of 12-year-olds should be seen as positive and it is well below the standard formulated for the year 2000 by the WHO . In 1991The low level of dental caries provides a good starting point for oral health promotion and preventive activities. The challenge for health authorities will be continuously to keep the disease level low. In spite of the low level of dental caries the dentists in Laos are not sufficient in number to deal with the treatment need of the population leaving little time for preventive measures. Furthermore, dental health services in general have a strong curative focus and suffer from limited capacity to deliver population-based essential health care. The health authorities should therefore focus on planning and implementation of population-directed oral health promotion programmes through schools, in active collaboration with the education authorities. Schools play an important role by providing a health promoting environment and healthy lifestyles. For the prevention of dental caries access to food items, drinks and snacks rich in sugars should be discouraged and healthy choices have to be supported. Within schools, oral health education also should be oriented towards oral health self-care instrumental to prevention of dental caries and the poor gingival health of children. While the health personnel should provide technical input to such programme, the challenge of the educational system is to apply skills based learning and relate the rather theoretical oral health curriculum directly to the daily life of the children.The authors declare that they have no competing interests.NJ developed the protocol and design of the study, conducted the field work, analysed the data and was responsible for preparation of the manuscript. PEP assisted in the development of the protocol and design, supervised the data analyses and interpretation and contributed to the preparation of the manuscript.Both authors have read and approved the final version of the manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1472-6831/9/29/prepub


The expression of thymidine phosphorylase (TP) and the density of microvessel in advanced gastric carcinoma were examined by immunohistochemistry to evaluate the significance of TP. The expression of TP was negative in 72 cases, positive in 54. The microvessel density correlated with the expression of TP. In total cases, patients with TP-positive tumours survived longer than those with TP-negative tumours. In patients treated with fluorouracil derivatives (FUs), the expression of TP significantly correlated with favourable prognosis and with unfavourable prognosis in those not treated with FUs. The patients with TP-positive tumours, the prognosis of patients treated with FUs was significantly better than that of those not treated with FUs. In patients with TP-positive tumours, treatment with FUs and lymph node metastasis were independent prognostic factors according to the Cox proportional hazards model. Depth of invasion and lymph node metastasis were independent prognostic factors in patients with TP-negative tumours. The determination of the expression of TP might be useful for predicting the efficacy of post-operative chemotherapy using FUs to prevent recurrence in advanced gastric carcinoma patients who undergo curative gastrectomy. © 1999 Cancer Research Campaign


Classic Lemierre's syndrome is a septic internal jugular venous (IJV) thrombophlebitis secondary to oropharyngeal anaerobic infection in adolescent and young adult. Though upper respiratory tract infection is the most common antecedent, it has also been described following skin, soft tissues, genitourinary and gastrointestinal infections. Fusobacteria necrophorum is the commonest pathogen isolated from blood and tissue cultures but other bacteria like Eikenella correndens, Bacteroides melaninogenicus and Non Group A Streptococcal species have also been reported. The overall incidence of Lemierre's and Lemierre's like syndromes has declined since the first case report in 1936. There is however, a resurgence of cases in recent years due to more judicious use of antibiotics for treatment of upper respiratory tract infection among medical practitioners. The main stay of treatment of complete Lemierre's syndrome is prolonged antibiotic coverage and surgical drainage of nonresolving abscesses. Currently, there is no consensus opinion on the use of anticoagulation in patient with complete Lemierre's syndrome complicated by septic internal jugular thrombosis and embolism. High index of suspicion is required for early diagnosis of Lemierre's and Lemierre's like syndromes. Early and effective antibiotics therapy may prevent the development full spectrum of the syndrome and its associated complication.  Fusobacteria necrophorum but other organisms like Eikenella corrodens, Bacteroides melaninogenicus, and nongroup A Streptococcal species have also been isolated in some cases  scan of neck showed a lesion with air-fluid interface, consistent with an abscess, in the right parapharyngeal space with surrounding inflammatory changes. The inflammation extended into the parotid gland, carotid sheath, the masticator muscles, as well as the retropharyngeal space, with mild mass effect noted on the airway. The upper part of internal jugular vein could not be visualized, possibly due to compression or thrombosis of upper third of the internal jugular vein. Further imaging was done with magnetic resonance angiography and venography [MRA/MRV] which confirmed the above findings and also showed the absence of blood flow in the upper third of internal jugular vein due to compression from the adjacent soft tissue mass and abscess.Complete blood count showed white cell count of 13,000/mmThe patient was treated with intravenous ceftriaxone and clindamycin for five days and then discharged home on oral clindamycin to complete a 14-day course of antibiotics as per the recommendation of an infectious disease consult. Repeat CT scan of the neck on day 7 of treatment showed subtle residual asymmetry of soft tissue of neck without abscess formation and normal anatomy of the rest of tissues.Since the first comprehensive review of 20 cases of “human necrobacillosis” or Lemierre's syndrome by Lemierre in 1936, several variants and Lemierre's-like syndrome have been reported and described. Classic Lemierre's syndrome is an anaerobic oropharyngeal infection complicated by septic thrombophlebitis of the internal jugular vein. It typically occurs after an upper respiratory tract infection in adolescents and young adults [The overall incidence of Lemierre's and Lemierre's-like syndromes is low 0.9–2.3 cases per million per year in Europe 5, 6). The incidence is said to be higher between the ages of 16–23 years with male predominance , 6. The . This ca Our patient, a 5-year-old male developed the oropharyngeal infection after a pencil tip injury to the pharynx. He presented with a deep pharyngeal tissue abscess associated unilateral neck swelling, fever, and reduced oral intake. We postulate that the injury could have resulted in inoculation of oral microflora, possibly Fusobacteria and other organisms, into the deep pharyngeal spaces and this lead to the development of abscess. Though our patient had negative blood culture and tissue culture was not done, there was clear evidence of severe infection from the toxic look of the child, neutrophilic leukocytosis, and CT scan findings of deep pharyngeal tissue abscess associated with compression of adjoining structures including internal jugular vein. The otolaryngology service was consulted to obtain tissue for culture. However, the procedure could not be performed due to the deep seated nature of the infection, making the procedure technically difficult. Moreover, the patient had very good response to broad spectrum antibiotic therapy. The occlusion of internal jugular vein, secondary to external pressure from the abscess rather than thrombophlebitis of classic Lemierre's syndrome, may represent an early stage in the pathogenesis of septic thrombophlebitis. The early diagnosis and effective antibiotic therapy in this case possibly prevented progression to thrombosis. With advancement of diagnostic technology and early effective antibiotic therapy, a full spectrum of Lemierre's disease may not occur.  The mainstay of treatment of Lemierre's syndrome is prolonged antibiotic coverage and surgical drainage of nonresolving abscesses. The diagnosis should be confirmed with both aerobic and anaerobic tissue and blood cultures. The choice of antibiotics should initially be broad spectrum and subsequently changed according to the sensitivity of microorganisms from tissue and blood cultures. Our patient received ceftriaxone and clindamycin intravenously followed by oral clindamycin to complete a 14-day course compared to the usual (3–6)-week course of antibiotics recommended for advanced Lemierre's syndrome. This is because our patient did not develop the third stage, septic thrombophlebitis and metastatic abscesses, which requires prolonged treatment.Currently, there is no consensus opinion on the use of anticoagulation in a patient with complete Lemierre's syndrome with septic internal jugular thrombosis and embolisms. There is no available literature on randomized controlled trial to assess the efficacy of anticoagulation on septic venous thrombosis . Bach et In conclusion, a high index of suspicion is required for the diagnosis of Lemierre's and Lemierre's-like syndromes. Early and effective antibiotic therapy may prevent the development of full spectrum of the syndrome and associated complications.


Generalised spike wave (GSW) discharges are the electroencephalographic (EEG) hallmark of absence seizures, clinically characterised by a transitory interruption of ongoing activities and impaired consciousness, occurring during states of reduced awareness. Several theories have been proposed to explain the pathophysiology of GSW discharges and the role of thalamus and cortex as generators. In this work we extend the existing theories by hypothesizing a role for the precuneus, a brain region neglected in previous works on GSW generation but already known to be linked to consciousness and awareness. We analysed fMRI data using dynamic causal modelling (DCM) to investigate the effective connectivity between precuneus, thalamus and prefrontal cortex in patients with GSW discharges.We analysed fMRI data from seven patients affected by Idiopathic Generalized Epilepsy (IGE) with frequent GSW discharges and significant GSW-correlated haemodynamic signal changes in the thalamus, the prefrontal cortex and the precuneus. Using DCM we assessed their effective connectivity, i.e. which region drives another region. Three dynamic causal models were constructed: GSW was modelled as autonomous input to the thalamus (model A), ventromedial prefrontal cortex (model B), and precuneus (model C). Bayesian model comparison revealed Model C (GSW as autonomous input to precuneus), to be the best in 5 patients while model A prevailed in two cases. At the group level model C dominated and at the population-level the p value of model C was ∼1.Our results provide strong evidence that activity in the precuneus gates GSW discharges in the thalamo-(fronto) cortical network. This study is the first demonstration of a causal link between haemodynamic changes in the precuneus - an index of awareness - and the occurrence of pathological discharges in epilepsy. The existence of a link between physiological and environmental factors and the occurrence of epileptic seizures is well documented in the literature Such a link is particularly evident in patients affected by Idiopathic Generalized Epilepsy (IGE) in whom, for example, sleep deprivation, alcohol and stress seem to act as activating factors for seizures occurrence The prototypical seizure type in IGE is the absence with its electroencephalographic hallmark, generalised spike and wave (GSW) discharges. Clinically, absences are characterized by a blank stare and impaired consciousness. Activities requiring vigilant attention have been coupled with a lesser likelihood of absences whereas an increased frequency of these seizures during relaxation is well established Recent functional imaging studies have revealed the existence of a set of brain regions which show increased functional and metabolic activity during rest, compared to attention-demanding tasks The DMN shows decreased activity both during attention-demanding tasks and equally during states of reduced vigilance and, especially the posteromedial cortical regions, during altered states of consciousness EEG-correlated functional magnetic resonance imaging (EEG-fMRI) studies have shown a common pattern of blood oxygen level-dependent (BOLD) signal decrease in the precuneus and the other default mode areas, together with a thalamic BOLD signal increase, during ictal and interictal GSW discharges in vivo intracellular recordings in the GAERS rat model (Genetic Absence Epilepsy Rats from Strasbourg), Polack and colleagues The pathophysiological substrate of GSW remains enigmatic and several studies, both in animals and humans, have tried to answer the historical debate regarding the putative role of the thalamus and cortex as generators. Data from invasive recordings and manipulations in well-validated genetic models of absence epilepsy have supported the hypothesis that absence seizures are of cortical origin. Depth electrode recordings from the thalamus and suprasylvian cortex in cats have shown a primary role of the neocortex in producing seizures consisting of spike and wave complexes However, despite the suggestion of the involvement of dorsal cortical regions  in GSW discharges from neuroimaging studies Dynamic Causal Modelling (DCM) offers the possibility of characterising the effective connectivity, defined as “the influence that one neural system exerts over another”, in other words: it can be used to test which brain region drives which We applied DCM to EEG-correlated fMRI data to understand the dynamic interaction between brain regions known to be involved in the initiation and cessation of GSW discharges and with a brain region known to be related to conscious awareness, the precuneus. We compared a family of models of effective connectivity focusing on a set of cortical regions and the thalamus. We tested and compared the following models in relation to the GSW discharges: when treated as autonomous input GSW activity enters the cortico-thalamic loop: 1. via the thalamus ; 2. via the ventromedial prefrontal cortex (vmPFC) ; or 3. via the precuneus ; see In order to apply DCM analysis, we re-analysed the resting-state EEG-fMRI data of 32 IGE patients studied previously 2, 64×64 matrix) were acquired over a 35-min session on a 1.5 Tesla Horizon EchoSpeed MRI scanner . Patients were asked to rest with their eyes closed and to keep still.The methods pertaining to data acquisition are described elsewhere http://www.fil.ion.ucl.ac.uk/spm/).FMRI data were processed and analysed using SPM8b  was constructed to assess the presence of regional GSW-related BOLD signal changes. GSW events were represented as variable-duration blocks beginning at the onset of GSW as identified on the MR-synchronised EEG by two expert observers (AEV and RT) and ending upon GSW cessation.Motion-related effects were modelled in the GLM by 24 regressors of the 6 scan realignment parameters and a Volterra expansion of these The GSW event blocks were convolved with the canonical hemodynamic response function (HRF), and its temporal and dispersion derivatives, to form regressors testing for GSW-related BOLD signal changes. Significant positive and negative BOLD signal changes correlated with GSW were identified by means of an F-contrast across the three regressors of interest and recorded as activation and deactivation depending on the response shape. The resulting SPMs were thresholded at p<0.001 http://ric.uthscsa.edu/project/talairachdaemon.html); the Talairach coordinates and equivalent Z-scores of the selected regions are listed in The DCM analysis was performed for three ROI: thalamus, vmPFC, precuneus. For all ROI we used spherical volumes with a 5 mm radius. For ROI selection within the thalamus we chose the axial slice that showed the largest cluster and placed the ROI so as to cover the region. In patients with bilateral thalamus involvement, we selected only one ROI, on the side of the largest cluster. For ROI selection within vmPFC, we placed the ROI in the axial slice within the Brodmann Area 10 and the side containing the largest area of signal BOLD change. The precuneus ROI was placed within the medial sagittal slice, rostrally to the middle of the parieto-occipital sulcus. In patients showing bilateral precuneus involvement, we placed the ROI on the side of the largest cluster. The ROI positions were defined using Talairach Daemon, The regional responses were filtered, whitened and the nuisance effects  were subtracted to leave only GSW-related effects. To account for the effect of scan nulling of large motion events  Using the DCM module as implemented in SPM8b three linear models were constructed. Each comprised the three ROI as reciprocally (forward and backward) connected regions and GSW event blocks considered as autonomous input to each of the three regions, one at a time a) GSW as autonomous input on the thalamus (Model A), b) GSW as autonomous input on vmPFC (Model B), c) GSW as autonomous input on the precuneus (Model C). Hence, three models were evaluated per subject - ln p(2y | m). If this difference is greater than about 3 (i.e. the relative likelihood is greater than 20∶1) then one asserts that there is strong evidence in favour of one of the models. This is commonly calculated based on the F value of each model, which is the negative marginal log-likelihood or negative log-evidence: F = −ln p(y | m). For more details about BMC, see After the estimation of parameters of each competing model, they were compared using Bayesian Model Comparison (BMC) where the evidence of each model, computed from estimated parameters distributions, is used to quantify the model plausibility Assuming that data from each subject are conditionally independent, the evidence at the group level is obtained by multiplying the marginal likelihood, or, equivalently, by adding the log-evidences from each subject Good quality EEG was obtained following pulse and gradient artefact subtraction, allowing reliable identification of epileptiform discharges see . EEG disIn accordance with the selection criteria, significant GSW-associated BOLD signal changes were found in the thalamus, in the frontal lobe limited to the vmPFC, and precuneus see . FrontalF values (i.e. the negative log-evidence) in absolute numbers. p value calculated for each model were extremely close to zero for models B and A, and close to 1 for model C, demonstrating the latter to be very likely at the population level.Assuming that all patients in the group are representative of IGE we generalized the results of group analysis to the population level. The We investigated the causal relationship between neuronal activity as reflected by BOLD signals in three brain regions, namely the thalamus, the vmPFC and the precuneus, in relation to the onset and offset of GSW in 7 patients affected by IGE. The thalamus and the frontal cortex are key structures in well established hypotheses on GSW generation Applying DCM to fMRI data simultaneously acquired with EEG we found that, for the models tested, in five out of seven patients studied, electroencephalographic discharges first affected the precuneus. This finding became more evident at the group and population level so that the evidence in favour of model C (GSW as autonomous input to precuneus) was significantly higher than for models A  and B (GSW as autonomous input to vmPFC). In the remaining two cases, BMC showed model A to be the best. The discrepancy between the results of the analysis of the single subjects is not unexpected. We note that in one of the pioneer DCM studies on evoked potentials, Garrido et al Our finding, that GSW onset and offset are more directly linked to the neural activity  in the precuneus than in the other tested regions, implies a dependency of the cortico-thalamic loop on the precuneus and hence its state, i.e. a causal link. A possible interpretation is that changes in the precuneus state , which reflects spontaneous fluctuations in awareness, act on the thalamic- cortical network facilitating the development of GSW. This is in contra-distinction to previous suggestions A similar hypothesis has been already proposed by Archer et al Additionally, an fMRI study showed BOLD signal decrease in the posterior cingulate in IGE subjects following photic stimulation whether or not GSW occurred, while control subjects showed no change in this region According to the current thinking of the pathophysiology of GSW, there are two prerequisites for the occurrence of this pathological activity: 1) the pathological thalamo- cortical interactions and 2) the so-called mild diffuse epileptogenic state of the cortex The precuneus' neuronal state, and hence the level of awareness, may, consequently, reflect a “physiological initiator” of generalized synchronous discharges. The existence of a transient facilitating state of the brain which increases cerebral susceptibility to GSW generation has been recently demonstrated in patients with absences, by synchronization measures and MEG source imaging methods Previous EEG-fMRI studies showed BOLD signal decrease in the DMN in relation to GSW apparently not correlated with clinical manifestations While there is little evidence of a strict consequentiality between a particular state of vigilance and the occurrence of GSW discharges, there is a notable lack of studies focusing on the possible role of cortical structures (particularly the precuneus) other than the thalamus and frontal cortex in GSW. However, evidence from scalp EEG source reconstruction analysis suggests that the precuneus participates in the generation of fast sleep spindles at 14 Hz In contrast to surface electrophysiological recordings, fMRI studies with concurrent EEG in patients with GSW discharges have shown common significant haemodynamic changes not only in the thalamus and frontal cortex, but also in the precuneus and other brain regions  of the DMN FMRI's relatively homogeneous sensitivity across the brain relative to that of scalp EEG may explain why recent EEG-fMRI studies have been able to reveal precuneal involvement in epilepsies characterized by impaired consciousness and in particular associated with GSW The application of connectivity analysis techniques based on fMRI data may improve our understanding of the interactions between brain regions haemodynamically involved during GSW discharges. David et al., applied DCM analysis to fMRI data acquired in an animal model of absences Brain connectivity based on fMRI data, can be investigated via two different approaches: functional connectivity and effective connectivity analysis. Functional connectivity is data-driven and assesses statistical dependencies between fMRI signals from different brain regions without consideration of the underlying neuronal activity. In contrast, analyses of effective connectivity test hypotheses based on modelling of neuronal activity and a forward model describing how this activity is translated into the fMRI signals There are different approaches for modelling effective connectivity from functional MRI, which include structural equation modelling (SEM), vector-autoregression models and DCM The causal link revealed in our study (i.e. precuneus activity facilitates GSW) is limited to onset and offset of GSW discharges. Therefore, our findings do not preclude a reverse causal relationship in which GSW accompanied by impairment of consciousness leads to (further) deactivation of the precuneus. This could be addressed by studying ictal GSW data using a similar methodological approach.In common with all DCM-based inferences, our conclusions are valid solely with respect to the family of tested models; there may be brain areas which are involved in the GSW generation processes that were overlooked because of their apparent lack of haemodynamic involvement.In this study we have demonstrated an active role in generalised epilepsy for the precuneus, a region previously neglected in electrophysiological studies of GSW. Using Dynamic Causal Modelling based on EEG-fMRI data we showed that the precuneus not only is strongly connected with the frontal cortex and the thalamus but also that the neuronal activity in this area may facilitate epileptic activity within a thalamo-cortical loop, the existence of which is well established. These findings suggest that GSW may arise through the direct influence of the neuronal state of the precuneus associated with spontaneous changes in the level of awareness.Table S1Description of fMRI results for the cases that did not satisfy the selection criteria for the DCM analysis. Summary of results for all cases for which GSW activity was captured during EEG-fMRI but did not meet the selection criteria for the DCM analysis (extracted from (0.06 MB DOC)Click here for additional data file.


Chronic regurgitation of gastric acids in patients with gastroesophageal reflux disease may cause dental erosion, which can lead in combination with attrition or bruxism to extensive loss of coronal tooth tissue.This clinical report describes treatment of severe tooth wear of a gastroesophageal reflux disease patient who is 54-year-old Turkish male patient. After his medical treatment, severe tooth wear, bruxism and decreased vertical dimensions were determined. The vertical dimension was re-established and maxillary and mandibular anterior and posterior teeth were prepared for metal-ceramic restorations. Metal-ceramic fixed partial dentures were fabricated as full mouth restorations for both maxillary and mandibular arches because of splinting all teeth. And then maxillary stabilization splint was fabricated for his bruxism history.Significant loss of coronal tooth structure must taken into consideration. Gastroesophageal reflux disease by itself or in combination with attrition, abrasion or bruxism may be responsible for the loss. An extensive diagnostic evaluation is essential for the medical and dental effects of the problem. Gastroesophageal reflux disease (GERD), is defined as involuntary muscle relaxing of the upper esophageal sphincter, which allows refluxed acid to move upward through the esophagus into the oral cavity . Dental It was reported that GERD was diagnosed by endoscopy, where visual identification of mucosal inflammation and oseophagitis was used to identify the existence of GERD . The degIt is recognized that refluxed acid attacks the palatal surfaces of the upper incisor teeth first, later, if the condition continues, erosion of the occlusal surfaces of the posterior teeth in both arches and the labial or buccal surfaces results from an extended period of acid reflux ,12. It iA simplified wear index has been proposed to define wear on four levels; no wear, enamel exposure, mild and severe dentine exposure. The classification is not only dependent upon the severity of the wear but also the age of the patient .3. The smaller the value of the relationship between the basal surface and the external surface, the more severe the aggression received by the epithelium. The values obtaied represent an irritation of the palatal epithelium, which in turn is reflected by a deepening of the epithelial crests in the connective tissue and of the connective papillae in the epithelium. Individuals with the more severe cases of reflux have a more compromised epithelium [The authors concluded that patients diagnosed with GERD were at a high risk of developing dental erosion. The buffering capacity of the stimulated saliva from the control subjects was significantly greater than patients with symptoms of GERD . Also, sithelium .Oral symptoms associated with GERD are burning mouth syndrome, dental sensitivity, loss of vertical dimension, and esthetic problems . Tooth wThis case report presents the clinical findings, diagnosis, medical and dental rehabilitation of a patient with GERD with severe tooth erosion.A 54-year-old Turkish man came to our clinic Department of Prosthetic Dentistry, 19 Mayis University, Faculty of Dentistry with the lack of esthetics and function of his teeth. In his medical examination he had gastroesophageal reflux disease history for about 4-5 years and had paid no attention because of any symptoms affecting his life. Also, brushing teeth behaviour was once a day and bruxism history was present. In his clinical examination there was generalize dental erosion including dentin on the occlusal, buccal and palatinal surfaces of maxillary teeth; occlusal and buccal surfaces of mandibular teeth and cervical lesions were seen , 2 and 3Impressions of both arches were made with irreversible hydrocolloid  and poured with a type V dental stone . After determining the occlusal vertical dimension with mounted diagnostic casts and face dimensions, there was decreased vertical dimension. Diagnostic casts were mounted on a semi-adjustable articulator  using a face-bow transfer  and a centric relation record . First of all the patient was referred to a gastroenterologist. The epithelial irritation of esophagus was reported in the endoscopic examination and results confirmed GERD. The appropriate pharmacologic agent has been prescribed and the GERD was controlled. After the medical treatment, a maxillary acrylic resin  splint was fabricated with flat occlusal scheme for the increase of vertical height and for protection of the teeth against further gastric acid and bruxism. Acrylic resin was applied in 1 mm and 2 mm increments to the occlusal surface of the splint over a 30 day period to establish a 3 mm increase in occlusal vertical dimension (OVD). No complaints like muscle pain or discomfort and difficulty in function occurred after the increase in OVD. After re-establishing the vertical dimension, maxillary and mandibular anterior and posterior teeth that were restored with resin-based composite restorations  were prepared for metal-ceramic restorations, and laboratory-processed provisional restorations  were fabricated at the new OVD and cemented with zinc-oxide eugenol . A full contoured wax-up on the mounted casts made it possible to evaluate tooth dimensions to achieve optimal esthetics. Definitive impressions of the prepared maxillary and mandibular teeth were obtained using polysiloxane impression material . Working casts were generated from Type IV die stone and mounted into the articulator using interocclusal records. Shade determination  was made. Metal-ceramic fixed partial dentures  were fabricated as full mouth restorations for both maxillary and mandibular arches because of splinting all teeth, evaluated intra-orally, and adjusted . The patContemporary dentistry offers many treatment options, from conservative to invasive for tooth loss: direct resin composite restorations, laboratory-made adhesive restorations , laboratory-made full crown restorations . An acidic environment affects the solubility of dental hard tissue. Gastric contents may have an acidity below pH 1; regurgitation therefore can have a severe demineralizing effect on tooth structure and restorative materials . It was This clinical report describes the dental treatment of a GERD patient by fabricating metal-ceramic fixed partial dentures after his medical diagnosis and treatment.


In spite of their rarity, cystic neoplasms of the pancreas are characterized by existing or potential malignancy that cannot be ignored during decisive process with regard to the choice of treatment. Diagnostic difficulties in the differentiation of pancreatic pseudocyst and cystic pancreatic neoplasm can lead to misdiagnosis and inappropriate treatment, since clinical symptoms, preoperative imaging tests and even endoscopic retrograde cholangiopancreatography are often not sufficient to establish the correct diagnosis. We present a case of pancreatic cyst with no typical features of pseudocyst in the medical interview, treated by Child's subtotal pancreatectomy by reason of the high risk of neoplasia suggested by radiological and endoscopic examinations. Cystic tumors account for 10% of all pancreatic cysts, but only 1% of all pancreatic malignancies . DespiteWe present a case of pancreatic cyst without a history of trauma or panceratitis. A Polish Caucasian 38-year-old woman was admitted to the University Hospital in 2004 because of erythrocyturia presented in routine urine analysis. Patient occasionally felt left-sided abdominal pain occurring after abstaining from eating with an accompanying weakness retiring after eating sweets. For 2-3 months she occasionally observed nausea after meals.Patient underwent an abdominal ultrasound and computed tomography (CT) that revealed normal-sized liver and spleen, both without any focal changes and a gall bladder devoid of shading stones with visible polyps. Between the left lobe of the liver, stomach and the body of the pancreas there was thin walled pancreatic cyst with a diameter of 8 cm and a density of 9 HU Figure . The panAfter control CT that confirmed right pararenal abscess, complete healing Child's subtotal pancreatectomy and cholecystectomy were performed by open way. In the neck of the pancreas polycyclic, encapsulated, not connate to the environment formation was found Figure . On accoThe post-operative course was uneventful. Patient was discharged home within 7 days in a good general condition. There were no symptoms of glucose intolerance after normal diet administration.The microscopic examination revealed considerable fibrosis and dispersed lymphocyte swelling in the pancreatic cyst. Tissue samples of the pancreas presented chronic non-specific pancreatitis with fibrosis. In the gallbladder chronic non specific high grade cholecystitis was recognized.Patient was visited at home in 2007. She felt well, with no severe complaints and with correct periodic findings and normal glucose metabolism.In most of cases of pancreatic fluid collections radical surgery is not necessary. Pseudocysts require drainage via the papilla, if they connect with the pancreatic duct, internal drainage (cystogastrostomy or Roux-en-Y) or cystoduodenostomy, CT or echo guided drainage ,10. If tThe clinical manifestation of cysts and cystic tumors can be identical or they often can be asymptomatic. Symptoms as abdominal discomfort or abdominal pain, nausea, vomiting, diarrhea, fever and leukocytosis, icterus, recurrence pancreatitis, bleeding from the digestive tract, abdominal mass are typical in both pseudocyst and neoplasm cases. In the history of presented patient there were no alcohol abuse nor biliary lithiasis. The aetiology of chronic pancreatitis in this case remain unknown, however similar events are described and idiopatic pancreatitis account for up to 25% cases of chronic pancreatitis . The masCT is found to be a very helpful tool in detection of pancreatic tumors, with sensitivity over 90% (when direct and undirect signs are used for diagnosis), but is not an ideal tool for differentiation exocrine tumors of the pancreas . ComputePreoperative tumors markers might be helpful in decision making and postoperative management of pancreatic neoplasms. Tumor markers were not controlled in described case because of negative opinion of senior gastroenterological consultant.Tumor markers are used mainly in patients already diagnosed with cancer for monitoring their response to treatment. In our case indications for the operation was strong enough without controlling tumor markers, especially in the face of fact that in early stages of carcinoma levels of Ca 19-9 (the most promising marker) may not be elevated and in some diseases of liver or pancreas it also can be temporarily raised. Unfortunately, there is no ideal tumor marker for pancreatic carcinoma.ERCP has been used for the diagnosis and treatment of pancreatic diseases for years. Some cystic tumors and 60% of pseudocysts are connected to the Wirsung's duct and this communication suggests a diagnosis of rather pseudocyst than cystic neoplasm. ERCP can show a communication of the lesion with the main pancreatic duct, but it isn't a perfect method for confirming or expelling the recognition of neoplasm. ERCP can help with establishing a tissue diagnosis of pancreatic neoplasms by: brush cytology, intraductal biopsy and fine needle aspiration, but because of low sensitivity of duct brushings and the potential morbidity connected with ERCP, this method is often replaced by endoscopic ultrasound . ERCP iMRI (T2-weighted image) and magnetic resonance cholangiopancreatography are able to display the whole cystic lesion  with theIn the presented case, strong suggestion of cystic tumor made by radiologist and endoscopist was taken into consideration in surgical treatment decision making. The pancreatic cyst was qualified preoperatively as pre or neoplasmatic one. On exploration there were no criteria of malignancy or suspicion of premalignant cystic tumor. Operating surgeon decide to preserve portal vein without resection leaving part of cystic wall. The idea of that was the resection of this part in case of malignancy after microscopic postoperative examination. The decision would be made on intraoperative examination but after consultation with pathologist there was no suspected place inside the cyst and the team decide to carefully analyze the cyst in routine manner. The microscopy confirmed benign character of the lesion thus patient underwent normal follow-up without radicalisation of surgery necessity.In our case, the risk of malignancy of the lesion was too high to observe the patient. The medical interview was atypical for pancreatic pseudocyst and diagnostic difficulties in differentiation between pseudocyst and cystic tumor exerted influence on the choice of operative intervention as the best treatment strategy. In consideration of imperfection of nowadays diagnostic tools we adjudged radical operative intervention as the reasonable and well documented method of treatment. In retrospective analysis presented case might be the chronic subclinical pancreatitis with post ERCP exacerbation and infection manifested as pararenal retroperitoneal abscess. Taking all together the better choice in doubtful cases of pancreatic cystic lesions seems to standardize diagnostic procedure.Written informed consent was obtained from the patient 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.The authors declare that they have no competing interests.AG analyzed and interpreted the patient and was the contributor in writing the manuscript. SH performed surgery, and was a major contributor in writing the manuscript. SD participates in data interpretation and contributes in manuscript writing. ZS supervise the whole case presentation and assist in discussion writing. All authors read and approved the final manuscript.