Purpose. Systematic reviews of case-control and prospective studies showed a positive association between habitual salt intake and gastric cancer. Given new studies published thereafter, we carried out a meta-analysis to assess the association between dietary salt intake and gastric cancer. Methods. Case-control studies and cohort studies published between January 1992 and January 2012 on PubMed and Embase were searched. We quantified associations between salt intake and gastric cancer with meta-analysis. Results. Eleven studies (7 case controls and 4 cohorts) finally were included in the meta-analysis . The combined odds ratio showed significantly positive association between high salt intake and gastric cancer compared with low salt intake . In subgroup meta-analysis, findings were slightly different when analyses were restricted to salty food intake  as well as in Asia . There was no evidence that sample size, exposure assessment substantially influenced the estimate of effects. Conclusions. The systemic review supports the hypothesis that dietary salt intake is positively associated with the risk of gastric cancer.  Dietary factors are important environmental risk determinants for cancer development. The role of dietary factors in gastric cancer was studied in the last 40 years and received particularly attention recently. It is difficult to establish a causal relationship between salt intake and gastric cancer due to methodological limitations among which is the valid measurement of accurate salt intake. Therefore, the conclusion is still unclear. In 2007, the Second Expert Report from the World Cancer Research Fund  supporteThis paper was planned, conducted, and reported according to the PRISMA statement . We perfCitations selected from the initial search were subsequently screened for eligibility. The list of references was independently screened by two reviewers. Cohort and case-control studies were included in the systematic review when all the following criteria were met: (1) original research addressing the association between the consumption of salt or salted foods and the occurrence of gastric cancer in humans; (2) prospective design; (3) adult population; (4) exposure defined as salt or salted foods by the authors of each study or including foods with high contents of salt as defined in the latest report of the World Cancer Research Fund and the American Institute for Cancer Research ; (5) diagnosis of gastric cancer determined prospectively as outcome ; (6) indication of the number of participants exposed and the rate or number of events in different categories of salt/sodium intake; (7) articles written in English. We designed a data collection form before selecting eligible studies. The following data were extracted independently by two authors using a unified data form, the first author's full name, year of publication, country, gender, age, range of followup, study population, the events and mortality of gastric cancer, types of estimate of habitual sodium intake, and factors controlled and matched or adjusted variables in the design or data analysis. The results of the two authors were compared, and a consensus result would be achieved if there were any disagreement.The Newcastle-Ottawa Scale  was usedWe evaluated the differences between low salt consumption and high salt consumption on the occurrence of gastric cancer. The original data from the studies was used to calculate the summary OR with its 95% confidence intervals (CIs) in all analyses. A random-effects model was used to account for between-study heterogeneity and publication bias. The method of Mantel-Haenszel test  was usedP < 0.10) and the I2 statistic ; Although we observed a positive association, there were many methodological limitations in human studies which prevent valid measurements used to assess salt consumption effectively . For exaThe World Cancer Research Fund and the American Institute for Cancer Research published in 2007 a large systematic review and meta-analysis, which concerned the effect of salt in the development of gastric cancer . A 17-arSeveral mechanisms which suggested that salt intake may increase gastric cancer risk have been postulated although there has been no consistent conclusion.H. pylori infection [Intragastric high salt concentration destroys the mucosal barrier, through the increase of surface mucous cell mucin and decrease of gland mucous cell mucin , leadingnfection .Intestinal metaplasia is also an important risk factor of gastric cancer. Mucosal damage in the stomach increases the rate of mitosis, leading to excessive cell replication  and hypeH. pylori-colonized mucosa [Helicobacter infection and lead to eventual parietal cell loss and progression to gastric cancer [Gastrin itself may mediate epithelial cell growth in d mucosa  and indud mucosa . Chronicc cancer .H. pylori is one of the important recognized risk factors of gastric cancer. The damage caused by salt may also increase gastric H. pylori colonization. H. pylori responds to changes in the concentration of NaCl in its environment in such a way that growth, cell morphology, survival, and virulence factor expression are all altered by increased salt concentration [H. pylori strain 26695 and enhance the ability of CagA to translocate into gastric epithelial cells and enhance the ability of H. pylori to alter gastric epithelial cell function [ntration . Elevatefunction . Salt may also directly damage gastric mucus, improve inflammatory responses of the gastric epithelium , which mHigh dietary salt intake damages the stomach mucosa that protects the stomach and increases the susceptibility of the mucosal cells to carcinogens from foods, such as N-nitroso compounds. And its repair is associated with inflammatory changes  and leadDespite these advantages, the current meta-analysis, however, had limitations. First, the majority of included studies used questionnaire to assess habitual salt intake which had limited value . Only feSecond, due to the huge heterogeneity of the related data presented in the studies, the number of studies involved in the meta-analysis was relatively small. Therefore, subgroup analyses were difficult to perform.Third, the current meta-analysis is unable to rule out the possible influence of confounding factors on the revealed association. Some confounders were inherent in the included studies. Although each study recruited some known risk factors for adjustment for gastric cancer, these covariates were not consistent and unknown confounders such as mutagens in salted foods cannot be excluded as a potential explanation for the observed findings.Fourth, the cutoff values corresponding to the low and high categories for salt intake variedwidely among the studies, which might also affect the obtained results.In conclusion, the overall current literature on dietary salt intake and the risk of gastric cancer suggested significantly positive association. Due to the nature of the association, more well-designed prospective studies that use unified measures of dietary salt intake are needed to fully characterize such an association, and it is impossible to perform a large randomized, controlled clinical trial to clarify the cause-effect relationship. Therefore, future observational study with recommended salt assessment method and maximized exclusion of confounders from salted foods is necessary.


This special issue highlights current research by emerging leaders in the fields of functional and evolutionary anatomy. Evolutionary morphology is concerned with the ways in which anatomical structures respond to environmental pressures, both within the lifetime of an individual and over geological time. Evolutionary morphology as a discipline is focused on understanding the factors influential in primate evolution and evolutionary innovations. These considerations are reflected in this special issue with authors' contributions drawn from diverse areas including comparative and functional anatomy, evolutionary biology, neurobiology, biomechanics, and growth and development. Several papers in this special issue focus on the anatomical study of adaptation by focusing on the functional morphology of feeding. M. N. Muchlinski (University of Kentucky) and J. M. G. Perry (Midwestern University) investigate adaptations to nectar feeding in the skull of strepsirrhines (the clade including lemurs and lorises). These authors find that strepsirrhine nectar feeders have elongated midfaces and suggest that these primates are cross-pollinators that played a key role in the coevolution of primates and flowering plants. An examination of the musculature related to feeding was carried out by J. M. G. Perry and colleagues (Midwestern University) in select strepsirrhine species. These authors analyzed physiological cross-sectional area of masticatory muscles in order to estimate the potential bite force a particular species could generate in living primates which can, in turn, inform our understanding of food processing behaviors in extinct primates represented in the fossil record. within strepsirrhine species. This study has important implications for the study of scaling questions in general. Tying together the study of feeding behavior and body size, A. Hartstone-Rose  and J. M. G. Perry (Midwestern University) investigate the relationship between maximum ingested food size and body size. These authors previously found that there is a strong scaling relationship between these two variables within species of strepsirrhine primates but their present study shows a lack of scaling relationships Four papers in this special issue focus on the issues of growth and development in primate evolutionary morphology. T. Ito and colleagues  tackle the issue of macaque evolutionary history by examining allometry of the bony face in two closely related macaque species. Macaques present a range of interspecific body sizes, which itself can cause confusion when trying to interpret evolution of morphological features among species. Results of their present study demonstrate that some craniofacial morphologies in macaques are the result of differences in body size alone while others seem to be genuinely adaptive, giving these features greater weight in phylogenetic analyses. Emphasis on the skull continues with an investigation into the relationship between the growing mandible and permanent molars in baboons and apes by J. C. Boughner (University of Saskatchewan). During the transition from deciduous to permanent dentition, increased space for molars must be created in the mandible and this growth and development relationship must be timed properly. J. C. Boughner finds that there are different rates of mandibular growth and shape development between baboons and apes from infancy through adulthood. These results highlight the strong selective pressures among timing of growth and development of the dentition and the mandible and how tight this relationship needs to be. Moving to the growth and development of the entire body plan, D. R. Bolter (Modesto College) compares growth and development of crested langurs, arboreal monkeys, with that of vervet monkeys, terrestrial animals. Using data from limb growth, brain growth, and body mass, this author finds that growth trajectories differ markedly between these species throughout ontogeny. These findings highlight the complex interplay among diet, phylogeny, ecology, and locomotion in the evolution of growth and development. Three papers in this special issue examine adaptive morphologies of primate locomotion. The primate lower limb has long been the focus of investigations in evolutionary morphology. J. J. Baker and colleagues (Slippery Rock University) examine the relationship between growth and development lower limb musculature relative to locomotor style in strepsirrhine species. These authors find that infant strepsirrhines show no difference in proximal-distal distribution of muscle mass between generalized arboreal quadrupeds versus leapers, but adult specimens show discrete differences in proximal-distal distributions. These results suggest that ontogenetic development of proximal-distal lower limb muscle mass distributions may be especially important in primates with specialized locomotor modes. Further exploration of lower limbs comes from J. B. Hanna (West Virginia School of Osteopathic Medicine) and D. Schmitt (and Duke University) who synthesize the literature base on triceps surae muscle group across primate taxa into a review of variation in fiber type distribution and muscle mass. These authors show that the triceps surae group is similar among the distantly related great apes, atelines, and lorises, and they relate this morphological similarity to the similar locomotor style that they all use, vertical climbing. These results are especially interesting in light of the potential evolutionary tie between vertical climbing and bipedalism.Osteological correlates of lower limb locomotor behavior are explored by K. J. Weinstein (Dickinson College) by using variety of macaque species. Macaques, like humans, occupy a wide range of altitudes and climates, and the author investigates the relationship among these ecological variables and lower limb morphology. Her results show that high elevations and temperature climates are associated with short lower limbs while low elevations and tropical climates are associated with long lower limbs. These results lend support to the influence of ecological factors on evolution of lower limb morphology.Primate brain evolution has been one of the dominant research themes in primate evolutionary morphology. Whether evolution of specific parts of the brain is adaptive or more the result of general scaling principles has been debated. S. D. Dobson (Dartmouth College) and C. C. Sherwood (The George Washington University) explore this debate by examining volumes of the facial motor nucleus in brains of catarrhine primates. These authors demonstrate that volume of this nucleus is not correlated with volume of other motor nuclei, suggesting that behavioral and ecological factors may be important in its evolution. Results of this investigation have potentially important implications for the ability of brainstem motor nuclei to evolve independent of other developmentally linked structures, the notion of the “mosaic” evolution of the primate brain.The development and use of nonprimate animal models has provided valuable insight into many areas of primate evolution, human growth and development, and the processual events associated with them. S. J. Rehorek and colleagues (Slippery Rock University) evaluate the utility of a laboratory rabbit model to understanding the development of the lacrimal region and nasolacrimal duct of humans. The nasolacrimal duct connects the orbital and nasal cavities, two key areas both in primate evolution and human growth and development. These authors use three-dimensional reconstruction of serially sectioned juvenile rabbits to depict the nasolacrimal duct course. While they find some similarities between rabbits and haplorhine primates, the authors ultimately conclude that there is poor congruity between nasolacrimal duct morphology in rabbits and humans. This result bears great significance as it indicates that rabbits are a poor choice for an animal model of the human lacrimal region in general. The 11 articles in this special issue cover a wide range of topics in the field of primate evolutionary morphology. The diversity of topics in this special issue reflects the breadth of interests of emerging evolutionary morphologists. This field of research is rapidly expanding and providing answers to many intriguing questions focused on primate evolution. Our ultimate hope for this special issue is that it serves as a stimulus for further research into primate evolutionary morphology. We are enormously grateful to the contributing authors for their scholarly contributions to the study of primate evolutionary morphology. We also offer our sincere thanks to the many reviewers who gave so generously of their time and thoughts on each paper.Anne M. BurrowsKathleen M. MuldoonAdam D. Sylvester


Despite evidence that up to 35% of patients with cancer experience significant distress, access to effective psychosocial care is limited by lack of systematic approaches to assessment, a paucity of psychosocial services, and patient reluctance to accept treatment either because of perceived stigma or difficulties with access to specialist psycho-oncology services due to isolation or disease burden. This paper presents an overview of a randomised study to evaluate the effectiveness of a brief tailored psychosocial Intervention delivered by health professionals in cancer care who undergo focused training and participate in clinical supervision.Health professionals from the disciplines of nursing, occupational therapy, speech pathology, dietetics, physiotherapy or radiation therapy will participate in training to deliver the psychosocial Intervention focusing on core concepts of supportive-expressive, cognitive and dignity-conserving care. Health professional training will consist of completion of a self-directed manual and participation in a skills development session. Participating health professionals will be supported through structured clinical supervision whilst delivering the Intervention. In the stepped wedge design each of the 5 participating clinical sites will be allocated in random order from Control condition to Training then delivery of the Intervention. A total of 600 patients will be recruited across all sites. Based on level of distress or risk factors eligible patients will receive up to 4 sessions, each of up to 30 minutes in length, delivered face-to-face or by telephone. Participants will be assessed at baseline and 10-week follow-up. Patient outcome measures include anxiety and depression, quality of life, unmet psychological and supportive care needs. Health professional measures include psychological morbidity, stress and burnout. Process evaluation will be conducted to assess perceptions of participation in the study and the factors that may promote translation of learning into practice.This study will provide important information about the effectiveness of a brief tailored psychological Intervention for patients with cancer and the potential to prevent development of significant distress in patients considered at risk. It will yield data about the feasibility of this model of care in routine clinical practice and identify enablers and barriers to its systematic implementation in cancer settings.ACTRN12610000448044 Approximately 35% of patients with cancer experience clinically significant distress, patients with poorer prognosis and those with higher levels of disease burden being especially at risk . The IntLimited access to suitably qualified professionals to provide psychosocial care may undermine clinician enthusiasm about detecting distress - why identify a problem if it cannot be addressed? But even in settings with access to specialist staff, psychosocial care is not uniformly offered. For example a cross-sectional survey found that psychosocial advice was provided for up to 50% of patients at diagnosis, but at completion of treatment patients were seldom given advice about adjustment to survivorship , despiteIn addition to the obvious workforce barriers to provision of optimal psychosocial care, broader systems issues are likely to play a role. In clinical services under severe pressure to provide patient care despite limited resources, psychosocial care may be assigned a lower priority than biomedical care. In these settings, absence of defined pathways to routinely assess and address psychosocial need means that these issues "slip under the radar", with the consequence that patient need is unmet. Depression and anxiety have a profound adverse impact on well-being of patients with medical illness  and thusprevent the development of disorder such as depression.Given the limitations of health professionals' identification of patient distress, implementation of systematic evidence-based approaches to screening and detection of distress is essential to ensure that patients' needs are appropriately identified . Instrumindividualised approach, for example addressing issues such as dignity and personal integrity [Having identified patient distress, a critical next step is to determine the severity and sources of distress. International research highlights the need to move beyond generic  approaches to an ntegrity . This isntegrity  - only tntegrity ,19 meanintegrity . In addintegrity . A furthAnother strategy to enhance acceptability to patients and improve sustainability is to adopt more flexible approaches to the delivery and style of interventions. For example telephone-based counselling is likely to be highly acceptable to patients from rural areas or those with disease burden which limits travel. Randomised trials of telephone-based interventions have been successful in improving patient pain and depression  and distThe study's primary aim is to evaluate the effectiveness of a brief psychosocial Intervention in reducing depression and anxiety in patients with cancer who are distressed, but not severely depressed, or who are at risk of becoming depressed. The Intervention will be delivered by health professionals who have participated in focused training and who receive clinical supervision during delivery of the Intervention. Additional aims are to examine the impact of the psychosocial Intervention on patient unmet needs, quality of life, and scores of demoralisation.Secondary aims are to examine any impact on stress and burnout and psychological adjustment of the health professionals who deliver the psychosocial Intervention, to assess the feasibility of integration of the Intervention into clinical practice, and to identify health professional, systems and patient barriers to the implementation of this model of systematic tailored psychosocial Interventions in clinical care.It is hypothesised that:1. Patients receiving the Intervention will demonstrate greater improvement in depression/anxiety scores and reduction in depression/anxiety "caseness" compared with patients receiving Usual Care.2. The Intervention will be associated with lower rates of depression/anxiety and increasing reduction in depression/anxiety scores over time in patients of the cancer services.3. There will be no changes in health professional stress and burnout.This study comprises two discrete components:a) Training of health professionals who will deliver the psychosocial Interventionb) Delivery of the psychosocial Intervention by the trained health professionals.The design for this randomised study is a stepped-wedge cluster design, a type of crossover design in which different clusters  cross over in one direction only, from Control to Training then Intervention . At the tailored to the level of need of the patient, eligible patients receiving a "low-intensity" or "medium-intensity" Intervention, allocated according to the Algorithm depicted in Table The nature of the Intervention will be in addition to either the presence of risk factors or current distress (DT score 4 or greater) will receive the low-intensity Intervention. This consists of a suite of consumer resources demonstrated to be effective and acceptable, including the consumer version of the Clinical Practice Guidelines for the Psychosocial Care of Adults with Cancer: Cancer, how are you travelling? [Patients who have a Hospital Anxiety and Depression Scale (HADS)  score ofvelling? . The resvelling?  with thePatients who have a HADS score of 8-21 inclusive will receive the medium-intensity Intervention, irrespective of the presence or absence of risk factors Simple provision of information alone has been demonstrated to be insufficient to treat depressed patients , meaningAll medium-intensity Intervention sessions will have the following core principles:• Focus on engagement with the patient• Eliciting and exploring key patient concerns• Establishment of an agreed treatment plan with the patient, focusing on strategies to address Distress. This treatment plan will be developed in consultation with the patient after review of their self-report on the Distress Thermometer as above. The treatment plan will incorporate detailed assessment and referral for further assistance as necessary, for example with practical concerns, financial issues, or physical symptoms such as pain or nausea. The need for referral will depend on the background training of the health professional delivering the Intervention - for example, a nurse will often be able to assess and initiate symptom management whilst a radiation therapist would refer the patient to a doctor or nurse.• Regular review of this plan and its progress through the process of Clinical Case Review .based on the patient's self-reported areas of concern as identified on the Distress Thermometer. During their training health professionals will acquire the necessary skills to critically analyse the nature of the patient's concerns and devise a tailored Intervention specific to the patient's needs. Examples of specific techniques which may be used by the health professional in the medium-intensity Intervention depending on patient need are provided in Table The medium-intensity Intervention has been designed to ensure flexibility to select the most appropriate strategies to assist each patient, All health professionals delivering the medium-intensity Intervention will participate in Clinical Case Review  facilitated by an experienced consultation-liaison psychiatrist. Sessions will be conducted in group format on a weekly basis. Health professionals will use these sessions to discuss the patients for whom they have delivered the medium-intensity Intervention, including discussion of specific components of the Intervention, difficulties encountered by the health professional, and be assisted to devise strategies to respond. A pre-determined structure will be followed to ensure consistency of Clinical Case Review across sites.each session in a structured logbook noting precise details of all Intervention contacts with each patient including date, duration, mode (face-to-face or telephone), themes discussed and referrals such as to physiotherapy, or medical review of pain.The health professional will record details of Patients who have high levels of distress as measured on the HADS (scores of 22 or greater) have needs beyond the training of the health professionals participating in this study and require a high-intensity Intervention. All patients in this category will be referred for Specialised Treatment (high-intensity Intervention) with an appropriately qualified practitioner via a pre-defined clinical pathway at the respective site.no current distress (DT Score < 4) and no risk factors  will not receive any additional information or psychosocial support related to coping with cancer beyond the normal clinical practice at the site where they are receiving cancer care. They will continue to participate in follow-up or cancer-specific treatment as usual. They will not have contact with the trained health professionals at that site other than in the usual course of clinical care.Patients with Health professionals from the disciplines of nursing, occupational therapy, speech pathology, nutrition and dietetics, physiotherapy or radiation therapy will be eligible to participate in training if they: 1) have at least 12 months' clinical experience in oncology (2) are currently engaged in patient contact (minimum of 6 hours per week) 3) have a commitment to undertake the necessary training and (4) are working in a setting in which they can deliver the Intervention. Health professionals who meet the selection criteria will be offered entry into the study by the Investigators and will complete baseline measures before receiving a self-directed training manual and participating in a day-long skills development session. The core elements of the training will be (1) Supportive/expressive - encouraging expression of emotions; validating the individual's experiences; empathic listening, and provision of information (2) Cognitive-behavioural - teaching skills in problem-solving; identifying and challenging automatic thoughts; reframing; relaxation training and guided imagery (3) Dignity-conserving - encouraging reflection on themes of coherence, isolation, hope, helplessness, purpose and courage, as well as practical needs. This training will be completed over a period of 10 weeks. Psychologists, social workers and psychiatrists will not be eligible to participate as (1) it is considered that their core skills encompass the material included in the training, and (2) patients may be referred to these professionals as part of the intervention, for example a patient may be referred to a social worker because of financial concerns (as per Table  have a c have at Inclusion criteria are: (1) aged 18 years or over (2) consecutive patients attending outpatient oncology clinics at each site (3) currently receiving active treatment for cancer OR have completed active treatment within the previous 2 months OR have been diagnosed with recurrent/advanced cancer within the previous 2 months. Exclusion criteria are: (1) inability to speak and read English, (2) receiving current specialised psychological treatment from a psychologist, psychiatrist, or other trained counsellor, (3) currently taking antidepressant medication, (4) health status precludes ability to complete questionnaires and participate in up to four psychosocial Intervention sessions and follow-up at 10 weeks, and (5) recruited in any previous Epoch of this study .We will recruit 20 patients per site per Epoch (with the exception of the Training Epochs during which no patients will be recruited) with a total sample size of 600 patients. No patient who has been recruited in a previous Epoch will be eligible to participate in subsequent Epochs. Primary outcome measure is change in HADS score over ten weeks from enrolment to follow-up. Estimates of HADS in similar populations  are a meEthical approval for this study has been obtained from the Human Research Ethics Committees of Royal Brisbane and Women's Hospital and the University of Queensland. The study design will be guided by the CONSORT statement . Each siDemographic details, including professional background and training will be obtained at intake. The following measures will be completed at baseline and on completion of the study when the health professional has completed delivery of the psychosocial Intervention.The General Health Questionnaire 28 (GHQ)  will be Occupational stress and burnout will be assessed with the Maslach Burnout Inventory (MBI) , a widelSemi-structured interviews will be conducted with a subset of five health professionals from each site to examine their perceptions of the Training and delivery of the Intervention, including practical aspects of delivery and impediments to the Intervention, as well as reflections about their experience of Clinical Case Review and perceived impact of participation in the study on their clinical practice.Demographic details, disease stage and current treatment status will be obtained at intake. The following measures will be completed at baseline and 10-week follow-up.The Distress Thermometer will be used to assess distress. The Distress Thermometer is a self-rated instrument in which patients indicate their Distress , nominating the source of Distress: Practical; Physical; Family; and Emotional or Spiritual/Religious . A cut-oThe Psychosocial Checklist is a structured template based on evidence in the Clinical Practice Guidelines for the Psychosocial Care of Adults with Cancer about known risk factors for development of depression and anxiety in cancer patients . It has The Hospital Anxiety and Depression Scale (HADS)  will be The Supportive Care Needs Survey-Short-Form SCNS-SF 34  will assFACT-G   is a widEQ-5 D (EuroQoL)  is a briDS  is a 24 item self-report scale with a Cronbach alpha of .96, measuring depression commonly seen in the physically ill . Norms hPatients will maintain a record of visits to General Practitioners and any contact with community or hospital-based support services, using a structured template.We will compute and compare the average change in HADS scores among patients enrolling during Intervention Epochs with scores of patients enrolling during Control Epochs. The strength of the stepped-wedge design is that we will be able to account for systematic differences between sites and times during the trial, and also for case-mix differences between patients.We will use a patient-level hierarchical analysis model to accommodate these potentially confounding factors. With this model, we can adjust for case-mix differences between sites, as well as allow for specific site characteristics (other than presence/absence of the Intervention). A generalised estimating equation (GEE) linear or logistic model will be implemented  to estimSemi-structured interviews with health professionals will be tape-recorded, transcribed verbatim and analysed to determine similarity of themes or differences between barriers to delivery of supportive care previously identified . ClinicaA random selection of 10% of all HP log books will be examined to determine adherence to the training and identify patterns of referral (for example because of pain) and delineate professional, patient or system barriers to delivery of the Intervention.This study will examine the effectiveness and feasibility of a model of psychosocial care in which patients are systematically screened for psychosocial needs and risk and then assigned to receive therapy tailored to their precise level of need. Use of novel and readily accessible service providers to deliver the Intervention after participation in focused training is an innovative approach designed to improve patient access to timely psychosocial care, and represents an efficient approach in the face of limited access to scarce psychosocial resources. Inclusion of patients who are considered at risk of anxiety and depression even if not currently distressed is an important strategy to examine the potential to prevent the development of more serious distress. The brief flexible mode of delivery as part of cancer clinicians' routine practice is aimed to address the stigma of psychosocial care and facilitate uptake by patients whose physical condition would make attendance for longer therapies difficult. Incorporation of clinical supervision is a central platform to assist health professionals delivering the Intervention, ensure quality of care, monitor patient responses and reduce the potential for development of health professional stress. The incorporation of in-depth interviews with health professional participants and detailed analysis of the process of clinical supervision will provide fine-grained insights into enablers and barriers of this model of care and guide refinement before its more widespread implementation. Recognition of emotional distress as a vital clinical sign in cancer care has been a major achievement in cancer care policy. One of the barriers to achieving the intended goals of such policy in psychosocial care is the effective translation of the substantial body of evidence regarding screening and psychosocial treatments into routine clinical practice by a range of cancer clinicians in a range of settings. This study aims to help address this gap in knowledge, by training health professionals who work closely with cancer patients in daily practice. More importantly an innovative component of this study is the support and mentoring of health professionals providing psychosocial care as a strategy to bridge knowledge and practice change, while using mixed methodology to study the processes of such clinical practice change.beyondblue, the National Depression Initiative. He absented himself from reviews of grant applications and was not involved in discussion of any funding decisions.DC is a member of the Research Advisory Group of JT, BK and DC developed the study concept, aims and initiated the project. PY, SA, DJ, SC, MH and LMcF assisted further in the refinement of the concept and development of the protocol. JT, BK, DC, SA and MH will implement the protocol and oversee collection of data. JT, BK and DC will provide health professional training and clinical supervision, in consultation with other authors. JT was responsible for the drafting of the manuscript. All authors have read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2407/11/48/prepub


We consider and analyze the influence of spike-timing dependent plasticity (STDP) on homeostatic states in synaptically coupled neuronal oscillators. In contrast to conventional models of STDP in which spike-timing affects weights of synaptic connections, we consider a model of STDP in which the time lags between pre- and/or post-synaptic spikes change internal state of pre- and/or post-synaptic neurons respectively. The analysis reveals that STDP processes of this type, modeled by a single ordinary differential equation, may ensure efficient, yet coarse, phase-locking of spikes in the system to a given reference phase. Precision of the phase locking, i.e. the amplitude of relative phase deviations from the reference, depends on the values of natural frequencies of oscillators and, additionally, on parameters of the STDP law. These deviations can be optimized by appropriate tuning of gains (i.e. sensitivity to spike-timing mismatches) of the STDP mechanism. However, as we demonstrate, such deviations can not be made arbitrarily small neither by mere tuning of STDP gains nor by adjusting synaptic weights. Thus if accurate phase-locking in the system is required then an additional tuning mechanism is generally needed. We found that adding a very simple adaptation dynamics in the form of slow fluctuations of the base line in the STDP mechanism enables accurate phase tuning in the system with arbitrary high precision. Adaptation operating at a slow time scale may be associated with extracellular matter such as matrix and glia. Thus the findings may suggest a possible role of the latter in regulating synaptic transmission in neuronal circuits. Spike timing dependent plasticity (STDP) is one of the simplest yet key mechanisms enabling functional adaptation in neuronal systems  is that we would like to be able to deal with realistic cases of neurons having different natural frequencies. As a general rule, the larger the difference between natural frequencies of neural oscillations the larger should be the values of synaptic weights if accurate time-locking of spikes is desired, cf. e.g. For the sake of numerical and analytical tractability we focus predominantly on a simplified spike transmission model using a pair of neuronal oscillators coupled via excitatory synaptic coupling. Synaptic transmission in the model is unidirectional and instantaneous: a spike in the postsynaptic neuron is evoked as soon as the excitatory postsynaptic potential (EPSP) exceeds certain threshold. As a model for pre- and post-synaptic neurons we use Rowat-Selverston neuronal oscillator Methods contains description of the Rowat-Selverston neuronal oscillator and also specifies the class of synaptic coupling considered in the paper. In addition, it presents the concept of phase spiking maps which is used in both numerical and analytical parts of the study. Definitions of specific STDP mechanisms are provided in Results. This is followed by quantitative and qualitative description of the dynamics such mechanisms may induce in the coupled system. The results are summarized and discussed in a brief Discussion. Technical derivations and other auxiliary materials are presented in Appendix S1.The paper is organized as follows. Section We studied dynamical properties of a pair of spiking neuronal oscillators coupled by an excitatory synapse Time scales of the spikes are determined by parameter Synaptic current in (1) is implemented in accordance with the following instantaneous synaptic transmission model:When spiking phase mapspiking phase map as follows:In order to characterize and analyze post- to presynaptic timing in (1), including cases when spiking phase map can be also viewed as a discrete version of the pulse coupled equations. These are typically used in the literature on the analysis of weakly coupled neuronal oscillators for describing dynamics of relative phases in the system. The function phase response curve (PRC). The advantage of using discrete spiking phase map instead of its continuous-time counterpart is that the discrete map, (4), is defined for any values of coupling strengths, provided that both systems oscillate.It was shown in illators . An examDependence of the spiking phase map for (1), and hence the dynamics of (1), on other parameters of the system is illustrated with the one-parameter bifurcation diagrams provided in s emerge . These cs emerge , periodiadaptive STDP regulatory mechanism. A diagram describing this mechanism is schematically presented in We propose a phenomenological model of synaptic transmission in a pair of spiking neuronal oscillators supplied with an The first alternative is illustrated in Dynamics of this phenomenological variable, sinusoid . This ST by  see .reference relative phase: the relative phase between spikes which is to be attained asymptotically. In addition to the STDP curve and the phase offset In addition to the relative spiking phase, The second alternative is illustrated in Let us now formulate the STDP models discussed above mathematically. Consider a pair of spiking neuronal oscillators coupled by an excitatory synapse (see Equations (1) in In the next section we analyze dynamics of the combined system (1), (5) and (6) when the values of Consider system (1), (5), and (8). Dynamics of this configuration for on level , Fig. 2Bon level .The values at which relative phase locks are determined by the values of the control variable, astrophe . In shorue,  see , and theIn order see the range of parameters for which presynaptic STDP can be considered as a viable phase locking mechanism we calculated numerically dependence of  on  . When  iWith regards to the influence of STDP model (5) on behavior of the coupled system an interesting phenomenon can be observed: in-phase oscillations become apparently stable at some critical value of In order to assess stability of the relative phase dynamics we invoke the idea of spiking phase maps see . Here thInvestigating dynamics of (1), (5), (8) numerically we have found that the critical gain oint see . If, howtion see , and themplitude . One canIn the bifurcation diagram in Consider the second mechanism of the postsynaptic STDP feedback – the one in which timing of pre- and post- synaptic events changes excitability of the postsynaptic neuron . In thisLest us investigate dynamics of relative phase for this system. As before, we approach the task by constructing and analyzing the corresponding phase spiking map (see (4), Similarly to what has been observed for the first alternative, STDP feedback stabilizes relative phase in a neighborhood of the reference value. Corresponding PRCs are shown in  cascade  [30]. Inpear see , MethodsThe fact that a set on which the values of Bifurcation diagrams characterizing dynamics of the system are shown in feedback . If we iisappear .In addition to numerical simulations we analyzed stability of the fixed point analytically. The results are presented in ling see , Fig. 4.So far we considered two spike-timing regulatory mechanisms ensuring stable phase locking in the system. According to these results, both mechanisms guarantee locking of relative phases of oscillations a vicinity of the reference subject to the choice of parameters. Yet, as one can see from these results too, phase locking occurs with an error. Dynamics of the system in a neighborhood of the phase locking state, e.g. for the case of postsynaptic feedback, satisfies the following inequality (see (S1.12), According to this,  and (S1.11) in Nevertheless, as we illustrate below, asymptotic reduction of the phase-locking error to zero can be achieved via adjustments of The most simplest model of such fluctuations is, perhaps, the following:In the previous sections of the manuscript we demonstrated how an STDP mechanism affecting neuronal excitability can be used for tuning of time lags between presynaptic and postsynaptic spikes. Even though the model we studied is obviously a simplification the resulting regulatory mechanisms may still be considered as biologically plausible Click here for additional data file.


Bone remodeling is a frequently observed phenomenon in musculoskeletal diseases such as rheumatoid arthritis (RA) and osteoarthritis (OA). The level of imbalance between bone resorption/deposition is responsible for the morphological changes osteopenia/bone erosion/osteosclerosis observed in these arthritic conditions.In RA, increased osteoclastic activity is responsible for the development of focal osteopenia/erosion and systemic osteoporosis. The increased osteoclast activity in RA has been demonstrated to be linked to a dysregulation of pathways including cell-cell interactions, cytokines, and the receptor activator of nuclear factor κB (RANK)/RANK ligand (RANKL) system. Recent studies have shown that joint erosion in RA is linked to a decrease in long-term physical function.Under OA conditions, the subchondral bone is the site of numerous dynamic morphological changes. These changes are associated with a number of local abnormal biochemical pathways related to the altered metabolism of osteoblasts and osteoclasts. At the early stages of the disease process, increased bone loss and resorption is observed with subchondral bone associated with local production of catabolic factors including cathepsin K and MMP-13. Moreover, OA osteoblasts present an abnormal phenotype resulting in increased production of growth hormones and catabolic factors. In addition, factors such as osteoprotegerin (OPG) and RANKL have been found to be expressed and modulated over time in human OA subchondral bone. Their synthesis varies from being reduced in early OA to being increased in the late stages of the disease. This finding may explain that in the early stages of OA, bone remodeling favors resorption and in the more advanced stages of the disease, bone formation is predominant.Magnetic resonance imaging (MRI) studies in knee OA patients have shown that the subchondral bone is frequently the site of signal alterations-bone marrow lesions (BML) - indicative of a great variety of morphological changes. BML and cartilage loss have been linked in several studies. Moreover, studies have identified, in OA patients, a number of risk factors for total knee replacement including BMLs.The paradigms regarding the role of bone lesions in arthritic diseases raise a number of important questions. A comprehensive understanding of the factors that contribute to these changes will provide us with better knowledge of the pathophysiology of the diseases and the role of these structural alterations in patient symptoms and prognosis, as well as guiding the development of new therapeutic strategies.


Inflammatory external root resorption is one of the major complications after traumatic dental injury. In this case report, we describe treatment of a maxillary central incisor affected by severe, perforating external root resorption. An 18-year-old patient presented with a previously traumatized, root-filled maxillary central incisor associated with pain and sinus tract. Radiographic examination revealed periradicular lesion involving pathologic resorption of the apical region of the root and lateral root surface both mesially and distally. After removal of the root canal filling, the tooth was disinfected with intracanal triple antibiotic paste for 2 weeks. The antibiotic dressing was then removed, and the entire root canal was filled with mineral trioxide aggregate. The endodontic access cavity was restored with composite resin. After 18 months, significant osseous healing of the periradicular region and lateral periodontium had occurred with arrest of external root resorption, and no clinical symptoms were apparent. Inflammatory external root resorption (IERR) is a pathologic condition caused by several etiologic factors including traumatic dental injury. Displacement of the teeth, as well as subsequent repositioning or replantation procedures inevitably causes damage to the root, resulting in denuded areas on the root surface which are chemotactic to phagocytes . This inClinically, teeth are usually not symptomatic in the early period of the process. However, as IERR progresses, the teeth may become symptomatic, and periradicular abscess may develop with increasing tooth mobility. Radiographically, radiolucencies can be observed in the external root surface and adjacent to the bone . EndodonMineral trioxide aggregate (MTA) has emerged as a reliable bioactive material with extended applications in endodontics that include obturation of the root canal space owing to its superior physiochemical properties . In conjThe present case report describes the nonsurgical endodontic retreatment of advanced IERR in a maxillary central incisor, which was treated with complete MTA obturation. An 18-year-old male presented with the chief complaint of pain on mastication and recurrent swelling in the labio-gingival aspect of maxillary left central incisor. He gave a history of traumatic injury seven years earlier. For the first three years after trauma the patient did not take any treatment as the tooth remained asymptomatic. Thereafter the patient started experiencing pain in the tooth and underwent root canal treatment in 21 followed by full coverage restoration by a local dentist. Four years after root canal obturation the tooth again became symptomatic, and the patient was referred to our department for endodontic retreatment of 21. There was no relevant medical history. An intraoral examination revealed labial sinus tract with respect to 21. The tooth did not exhibit significant mobility, and there was no gingival sulcular bleeding on probing. 21 was tender to percussion. Radiographic examination of 21 showed extensive lateral and apical root resorption associated with periapical radiolucency and interdental bone loss both mesially and distally in relation to the resorption defect. The root canal space of 21 was inadequately obturated .Taking into consideration the extent and severity of the resorption, it was planned to do orthograde MTA obturation of the canal space after removing the old root canal filling to arrest the root resorption along the length of the root canal. This internal approach was preferred over surgical management as the latter would have sacrificed the already compromised bone support around 21. Intentional replantation was also not a good option as there was a danger of fracture of the tooth while extraction owing to severity of resorption. The procedure was fully explained to the patient, and informed consent was taken. The endodontic access opening was made through porcelain fused to metal crown using transmetal bur . Previous gutta percha filling was removed using Hedstrom files in conjunction with Endosolv-E . A radiograph taken to ensure complete removal of gutta percha showed uneven radiolucent regions along the external borders of the root, and the outline of original root canal was completely visible . This waThe patient was recalled after 6, 12, and 18 months for clinical and radiographic followup. On clinical examination 21 was functional without sensitivity to percussion or palpation. The tooth showed normal physiologic mobility and no periodontal pockets on probing. The periapical radiograph showed regression in the size of periapical radiolucency with signs of osseous repair and no further progression of external resorption. There was initiation of osseous healing adjacent to mesial and distal resorption sites on the root surface Figures . IERR is initiated by mechanical trauma, resulting in the destruction of cementoblasts and loss of precementum and sometimes cementum in areas of the root surface. The resorptive process is then maintained by bacterial products from the infected root canal which provides the necessary continuous stimulation for the resorbing cells . Thus, t2) for bacterial disinfection of the root canal space. The process is followed by a long-term dressing of densely packed Ca(OH)2 to provide an alkaline Ph inside the dentinal tubules to kill the bacteria and neutralize the endotoxins, which are potent inflammatory stimulators [The conventional and preferred treatment protocol for a progressive IERR consists of chemomechanical preparation of the root canal system including a short-term (1 month) dressing of creamy paste of calcium hydroxide (Ca(OH)mulators , 17.2 has some disadvantages. Because the treatment includes repeated clinical sessions to replace Ca(OH)2, it demands high cooperation and motivation from the patient. In addition, long-term presence of Ca(OH)2 in root canal space can increase the brittleness of the root dentin and the risk of future cervical root fractures especially in immature teeth [2 use in teeth with damaged cementum because of the necrotizing effects of Ca(OH)2 on periodontal cells that repopulate on the root surface. This necrotizing effect can prevent formation of a normal attachment apparatus and result in replacement resorption and ankylosis [Although this treatment protocol has a high success rate , the lonre teeth . There ankylosis .The antibacterial and tissue dissolution action of sodium hypochlorite increases with its concentration, but this is accompanied by an increase in toxicity . As the The development of new bioactive materials such as MTA make possible other therapeutic approaches, including the obturation of the root canal space in complex cases of iatrogenic or pathologic root perforation . In the In the case described here 6, 12, and 18 month radiographic recall showed osseous repair of periapical pathosis. Although reestablishment of the entire periodontal apparatus did not occur, the resorption site remained stable throughout the 18-month followup period. The patient was asymptomatic, with the tooth exhibiting normal sulcular probing depth, mobility, and function. The patient was also pleased with the treatment outcome as a permanent tooth with otherwise hopeless prognosis was maintained. Orthograde retreatment of the present case with MTA proved to be very conservative as it lead to avoidance of surgical treatment with similar prognostic outcomes. However, longer followup for this case is required to be sure of success.


The aim of the study was to assess levels of somatic and mental health distress, well-being, AS WELL AS utilization of primary and specialist health care services among war-related widowed and non-widowed female civilian survivors of war.100 war-related widowed lone mothers and 106 non-widowed mothers who had experienced the Kosovo war ten years previously participated in the study. Measures of somatic, depressive, post-traumatic stress, anxiety, and grief complaints, subjective well-being, and utilization of health care services during the previous three months were used.Compared to non-widowed mothers, widowed lone mothers reported significantly higher levels of somatic, depressive, post-traumatic stress, and anxiety complaints. Further, they reported significantly lower levels of subjective well-being as composed of positive and negative affect and satisfaction with life. More than half of both widowed and non-widowed mothers reported utilization of health care services during the last three months, without significant differences between the groups. However, only three percent of widowed lone mothers and four percent of non-bereaved mothers reported utilization of mental health services during the last three months, despite high levels of mental health distress especially among widowed lone mothers. Among widowed lone mothers, severity of prolonged grief symptoms significantly predicted number of contacts of specialist health care use over and above sociodemographic variables, number of war-related events, and other psychopathology.War-related widowed lone mothers suffer from elevated somatic and mental distress even a decade after the war. The tiny proportion of widowed lone mothers in use of mental health services can be seen as a reflection of lack of previous and current mental health services to meet mental health needs of this population. Since the First World War when opposing armies still fought along static lines of defense, the nature of warfare has drastically changed. Civilians are increasingly exposed to violations of human rights and therefore make up the absolute majority of casualties . ResearcDespite the fact that killing defines the very nature of war like no other feature and despite growing evidence on the detrimental effect of bereavement, research on the impact of loss of family members due to war-related violence on mental health among civilian war survivors has only recently started to emerge -10. In oIn the current study, we aimed at investigating levels of somatic and mental health distress as well as health care utilization among another group of bereaved civilian war survivors: widowed lone mothers. One of the studies on war-related bereavement indicated that widowed mothers might be the most vulnerable group of bereaved war survivors reporting the highest prevalence of prolonged grief among different bereaved individuals . Due to A second goal of this study was to assess utilization of primary and specialist health care services among war-related widowed and non-widowed civilian survivors of war. Assessment of utilization of these services is important given limited health care funds, especially in lower income countries which are disproportionately affected by war. Nevertheless, previous research on use of heath care services among survivors of war has mostly been carried out on veteran populations -16. WithThe current study followed a cross-sectional design and was conducted in Kosovo. After a decade of apartheid in the Kosovar Albanian population imposed by the Milosevic-led Serbian government, a full-scale war began in mid-1998 and was ended by NATO air strikes in June 1999. The study was conducted in 2009  in the region of Drenica. This central Kosovar region was chosen for this survey for feasibility reasons as the study was conducted in cooperation with a psychosocial center in Drenica. Drenica comprises of two out of 30 Kosovar municipalities (Gllogovc and Skenderaj), and 6.5% of the Kosovar population lives in this region. In the rather small country of Kosovo with two million inhabitants no significant cultural differences exist between Drenica and other regions in Kosovo. The violent conflict in Kosovo had first started in 1998 in the region of Drenica, however, it became a countrywide war within a few months affecting all regions in Kosovo. Details of the study and preliminary findings on prevalence rates of mental disorders can be found elsewhere [Exposure to at least one war-related traumatic event was an inclusion criterion for both widowed and married mothers. All potential participants were contacted directly at home without advance notification. Telephone and postal communication in Kosovo do not function effectively, especially in the countryside. Additionally, people in Kosovo have the habit of visiting each other without prior notification. For these reasons and in accordance with prior projects , we deciComplete lists of families who had lost relatives due to war-related violence in the region of Drenica were provided by communal authorities. The wives of the first 146 deceased husbands from the list were contacted, of whom 28 reported not to have children. Of the 118 potential participants, 14 widowed mothers refused to participate in the study, stating that they did not want to talk about their relatives or about the war for emotional reasons, or not having time for the interview. The rate of participation was 88.1% (104/118). Missing values resulted in the exclusion of four participants, thus 100 widowed mothers were included in the analyses. None of the widowed mothers had remarried as it is accepted custom in the Kosovar society that a widowed mother should not remarry. Thus, all 100 participants in this group were widowed lone mothers.The recruitment of married mothers took place in exactly the same localities as the recruitment of widowed mothers. A random walk approach that involved random identification of streets in each locality where bereaved participants were contacted was used to recruit non-bereaved participants as described in prior research . On a paSocio-demographic characteristics of the participants were assessed on a brief structured questionnaire. Potentially traumatic events were measured using an adjusted checklist for war-related events and is based on the first part of the Harvard Trauma Questionnaire . The adjThe Patient Health Questionnaire was used to measure somatic, depressive, and anxiety symptoms ,24. The Posttraumatic stress symptoms were assessed with the Posttraumatic Stress Diagnostic Scale (PDS) . The PDSSymptoms of prolonged grief among widowed lone mothers were assessed with the Prolonged Grief Disorder Interview (PGD-I)  that is Subjective well-being was measured with two instruments. To measure the affective component of subjective well-being, the Positive and Negative Affect Schedule (PANAS)  was admiService use was measured using an adapted version of the Client Service Receipt Inventory . This inThe PGD-I and the Client Service Receipt Inventory were given by the interviewer. However, the interviewers were not aware of the study hypotheses. The interviews were conducted by five female psychologists who had been trained by the first author in conducting clinical interviews (for more details see ).To univariately analyze differences in socio-demographic characteristics, traumatic experiences, levels of distress and well-being, and utilization of care services between groups, x² tests, t-tests, and univariate analyses of covariance (ANCOVA) were used depending on the type of data. Linear multiple regression analyses were performed with the number of contacts of primary health use and specialist physical health use as dependent variables and demographics  and number of war-related events as independent variables in the first block. Levels of depression, posttraumatic stress, and somatization were entered as independent variables in the second block. Finally, levels of prolonged grief were entered as an independent variable in the third block. Given that only three percent of widowed lone mothers and four percent of non-bereaved mothers reported utilization of mental health services during the last three months, we did not conduct regression analysis with number of contacts in mental health care. An alpha level of .05 was used for all analyses, using SPSS V18.Table Widowed lone mothers reported a significantly higher number of war-related traumatic events than non-bereaved married mothers (p = .03). Yet, there was no significant difference in number of war-related traumatic events between bereaved married mothers and widowed lone mothers. The three most frequently reported war-related events in all three groups were “forced evacuation under dangerous conditions” (≥ 81.7% of participants in each group), “lack of shelter” (≥ 74.7% of participants in each group), and combat situation (≥ 60.6% of participants in each group).Pre- and post-war traumatic events were reported only by a minority of participants and there were no significant differences between the groups. Among widowed lone mothers, 16% reported more than one killing of family members during the war. Furthermore, 23% of widowed lone mothers reported death of family members after the war.Levels of somatic complaints, depressive, anxiety, and post-traumatic symptoms, and subjective well-being among all groups are shown in Table 64% of widowed lone mothers, 53.3% of non-bereaved married mothers, and 51.4% of bereaved married mothers reported use of any form of health care during the previous three months. Participants in all groups reported higher use of primary health care services than other services. Only three percent of widowed lone mothers and four percent of non-bereaved married mothers (and none of bereaved married mothers) reported utilization of mental health care services during the last three months. As can be seen in Table Finally, two hierarchical linear regression analyses were performed among widowed lone mothers to examine the role of symptoms of prolonged grief in predicting use of 1) primary care or 2) specialist physical care services. At step one, age, years of education, monthly income, and number of war-related events were entered. At step two, scores of depression, posttraumatic stress, and somatization were entered. At step three, scores of prolonged grief were entered. When number of contacts of primary care use was entered as the dependent variable, demographics and number of war-related variables accounted for significant variance, levels of depression, posttraumatic stress, and somatization accounted for additional variance, and levels of prolonged grief did not account for additional variance  might constitute a significant risk for psychopathology above and beyond other war-related traumatic events and bereavement following natural loss. This finding is strengthened by the fact that bereaved married mothers had experienced loss of first-degree relatives after the war. Thus, more time had passed since the killing of the husband of widowed lone mothers than since the loss of family members among bereaved married mothers, yet widowed lone mothers still reported higher rates of psychopathology. These findings are also in line with findings related to prevalence rates of major depressive episode, post-traumatic stress disorder, generalized anxiety disorder, and suicide risk resulting from this study that have been reported elsewhere . WidowedSeverity of psychopathology among widowed lone mothers is high in comparison to existing literature on survivors of war. For instance, in a recent study with war-related bereaved civilian survivors of war from Kosovo that included only ten percent widowed female war survivors and that used the same instrument to measure posttraumatic stress symptoms as in the current study (PDS), a mean score of posttraumatic stress symptoms of 18.08 was reported . SeveritThe higher levels of severity of mental health and somatic distress among widowed lone mothers who remain lone mothers indicate that this population is particularly at risk for increased psychopathology. These findings are in line with results from bereavement research indicating that bereavement is associated with elevated general health distress as compared to non-bereaved groups . More imSeveral factors such as emotional, functional, and economic difficulties are assumed to play a role in elevated levels of psychopathology. Widowed lone mothers must cope with their own experiences of war, killing of the husband during the war, being a lone mother, and raising children on their own. Loss of the husband due to war-related violence might contribute to psychopathology in different ways, such as the loss of the husband with whom the widow had a strong emotional relationship as a partner, the traumatic circumstances under which the loss of the husband took place, or the loss of the father of the children of the widow. In post-war Kosovar society, loss of the husband meant also loss of the main breadwinner and was accordingly associated to economic difficulties. This is also reflected by the reported unemployment rate of 89% among widowed lone mothers. Although the survey did not differentiate between those who were seeking employment and were unable to find it and those who did not want to work, this extremely high unemployment rate still revealed that 89% of widowed lone mothers did not have a wage-earning job. While war-related widowed women in Kosovo receive social welfare benefits and often also immaterial help from relatives, the total monthly income of the bereaved families in this study was significantly lower than that of married participants. The accepted norm in Kosovar society that a widowed mother should not remarry, resulting into forced lone motherhood, is likely to negatively affect coping mechanisms following exposure to war-related events and the killing of the husband and to hamper attempts at mastering socioeconomic circumstances. Thus, lone motherhood is likely to constitute a significant factor in the elevated rates of psychopathology. In fact, research in Western countries has indicated that lone motherhood is associated with poorer psychological health and higher risk of mortality as compared to partnered motherhood -41. FurtThe fact that widowed lone mothers reported higher number of war-related traumatic events than non-bereaved married mothers needs further explanation. Checklists of traumatic events such as the one used in this study pose a limitation with regard to comparing number of traumatic events among groups exposed to several traumatic events. The very nature of single traumatic events cannot be captured with the existing checklists of traumatic events. This indicates that even after controlling for number of traumatic events in the current study, health distress differences between widowed lone mothers and the comparison groups might exist not only due to the consequences of losing the husband and being a lone mother but also due to the experience of other war-related events. Furthermore, 16% of widowed lone mothers reported war-related loss of first-degree relatives other than the husband as compared to none in the control groups. Although we recruited both bereaved and non-bereaved participants in the same localities, killing of the husband seemed to have increased the likelihood of being exposed to more traumatic events and also losing other family members as compared to participants whose husbands were not killed during war. Our findings should be seen as preliminary and need replication.Civilian war survivors experience a wide array of potentially traumatic events that may have diverse consequences in terms of morbid psychiatric outcomes . TherefoMore than 50% of participants in all groups reported any use of health care services during the last three months. However, the majority of participants reported primary health care utilization only and barely a tiny proportion of participants reported utilization of mental health services during the last three months. Participants were not asked about reasons for seeking and especially not seeking health care services. Furthermore, they were also only asked about utilization of health care during the last three months. However, given the high levels of mental and physical distress especially in the widowed group, it is likely that participants had little or no hope in finding any useful mental health care. This corresponds with reports that in Kosovo primary health care was given special focus following the war in 1998/1999 and that specific interventions for treating mental disorders have only rarely been available . FurtherRecent research with survivors of war seeking mental health treatment in the Balkans , includiThe high levels of psychopathology among war-related widowed lone mothers and the lack of appropriate mental health services call for long-term policies to meet their special mental health needs. Preventing violations to human rights is a humanitarian challenge for the international community. Yet, with many ongoing violent conflicts leading to a steady rise of war-related bereavement the international community also has an obligation to investigate and attenuate the psychological consequences of human rights violations. This appears especially important in post-war societies which themselves lack the ability to offer sufficient mental care to those in need.The authors declare that they have no competing interests.NM carried out the study, participated in its design and its coordination, performed the statistical analyses and drafted the manuscript. PMGE participated in the design of the study and contributed to the interpretation of findings and writing of the manuscript. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-244X/12/39/prepub


Recently anti-CCP testing has become popular in the diagnosis of rheumatoid arthritis (RA). However, the inadequate reporting of the relevant diagnostic studies may overestimate and bias the results, directing scientists into making false decisions. The aim of the present study was to evaluate the reporting quality of studies used anti-CCP2 for the diagnosis of RA and to explore the impact of reporting quality on pooled estimates of diagnostic measures.PubMed was searched for clinical studies investigated the diagnostic accuracy of anti-CCP. The studies were evaluated for their reporting quality according to STARD statement. The overall reporting quality and the differences between high and low quality studies were explored. The effect of reporting quality on pooled estimates of diagnostic accuracy was also examined.The overall reporting quality was relatively good but there are some essential methodological aspects of the studies that are seldom reported making the assessment of study validity difficult. Comparing the quality of reporting in high versus low quality articles, significant differences were seen in a relatively large number of methodological items. Overall, the STARD score (high/low) has no effect on the pooled sensitivities and specificities. However, the reporting of specific STARD items  has an effect on sensitivity and specificity.The reporting quality of the diagnostic studies needs further improvement since the study quality may bias the estimates of diagnostic accuracy. Rheumatoid arthritis (RA) is a chronic, systemic inflammatory disorder that affects many tissues and organs, mainly synovial joints . The disThe diagnosis of RA is based on clinical criteria and laboratory tests. Regarding the later tests, the presence of the rheumatoid factor (RF), an autoantibody, consists one of the American College of Rheumatology (ACR) criteria for presence and severity of RA . HoweverCurrently, diagnostic studies on anti-CCP assays are publishing with a high rate . Howeverhttp://www.stard-statement.org/). In HSROC analysis, sensitivity and specificity in high vs. low quality studies were found approximately equal; though, a slightly reduced variance of logit-transformed sensitivity and specificity was found in the low quality studies  , the estimates of pooled sensitivities were statistically significant for items 10 and 13 . In addition, the estimates of pooled specificities were statistically significant for items 13 and 16 .The present study investigated the quality of reporting of studies using the anti-CCP2 assay in RA patients according to the STARD statement. The differences between high and low quality studies were explored. The effect of reporting quality on pooled estimates of diagnostic metrics was also examined. Our analysis focused on the reporting of methodological items (items in method and results’ sections). In total, the 103 articles (corresponding to 132 studies) covered a publication period of 23 years. Almost the articles used in our analysis were published after the introduction of STARD statement .Although the overall reporting quality was relatively good (13 items were reported by 70% or more of the studies) there are some essential methodological aspects of the studies  that are seldom reported making it difficult for the reader to assess explicitly the validity of a study. Comparing the quality of reporting in high versus low quality articles, significant differences were seen in a relatively large number of methodological items .Overall, the STARD quality score (high/low) has no effect on pooled sensitivity and pooled specificity. However, the meta-analysis showed an effect for specific STARD items. Studies not reporting sufficiently the methods used in calculating the measures of diagnostic accuracy (item 1), may have overestimated the sensitivity. In addition, the reporting of demographic and clinical characteristics/features of the study population (items 13 and 16) has affected the effect size of specificity, i.e. they have overestimated it, indicating also a spectrum bias .However, the findings of the present synthesis  are compatible with those of earlier reviews  which may question the synthesis of information, and therefore, the generalizability of results.In conclusion, our attempt to assess the reporting quality of diagnostic accuracy studies in RA highlights the need for further improvement. Implementation of the quality reporting statements (e.g. CONSORT) have already improved the quality of reporting in other fields of medical research . Thus, gThe authors declare that they have no competing interests.EZ conceived and supervised the study; EZ and AP drafted the manuscript; AP extracted the data, EZ and AP performed the statistical analysis; DZ and MV extracted the data and performed the statistical analysis of the revised manuscript; EZ and MV drafted the revised manuscript. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2474/13/113/prepubCharacteristics of the studies.Click here for fileEndorsement of STARD statement by journals.Click here for file


Studies have shown that fetal progenitor cells persist in maternal blood or bone marrow for more than 30 years after delivery. Increased trafficking of fetal cells occurs during pregnancy complications, such as hypertension, preeclampsia, miscarriage and intra-uterine growth restriction (IUGR). Women with these pregnancy complications are significantly more often HLA-class II compatible with their spouses. Women who later develop scleroderma also give birth to an HLA-class II child more often. From these prior studies we hypothesized that preeclampsia and other pregnancy complications could be associated with increased levels of fetal cell trafficking, and later be involved in the development of scleroderma.This study was a retrospective multi-centre matched case-control study. One-hundred-and-three women with systemic sclerosis (SSc) and 103 women with no history of SSc or other autoimmune disease were given a questionnaire regarding complications during pregnancy, such as hypertension, intra-uterine growth restriction (IUGR) and miscarriage. Conditional logistic regression analysis was used to assess associations.We found a statistically significantly increased incidence of having had a pregnancy history of hypertension or a fetus with IUGR in women who subsequently developed SSc compared to healthy controls. We found an odds ratio of 2.6 : 1.1 to 4.6) for hypertensive complications during pregnancy and an odds ratio of 3.9 (95% CI: 1.2 to 12.3) for intra-uterine growth restriction for women with SSc compared to healthy controls.This is the first study to show an association between hypertensive complications during pregnancy or IUGR and the development of SSc at a later age. We speculate that the pregnancy abnormalities may have resulted in increased fetomaternal trafficking, which may have played a role in the increased incidence of SSc. Further studies are indicated to examine this putative relationship. Systemic sclerosis (SSc) is a connective tissue disease of unknown origin that is characterized by cutaneous and visceral fibrosis, production of auto-antibodies, and prominent microvascular changes. The similarities of this autoimmune disease to graft versus host disease, which is an iatrogenic form of chimerism, have suggested a common pathway in the pathogenesis of both diseases .Increased trafficking of fetal cells into maternal circulation occurs with pregnancy complications such as preeclampsia -4. In prThe increased incidence of autoimmune disease in women after childbearing years, the long-term persistence of fetal progenitor cells in maternal blood and similarities between certain autoimmune diseases and graft versus host disease, have led to the hypothesis that fetal cell microchimerism is somehow involved in the pathogenesis of some forms of autoimmune disease . Male  could be associated with increased levels of fetal cell trafficking and could later be involved in the development of scleroderma. In order to assess this relationship, we performed a preliminary study to explore such a hypothesis.This retrospective multi-centre matched case-control study was performed at Leiden University Medical Centre (LUMC) and the VU Medical Centre of Amsterdam (VUMC) in the Netherlands. This study was approved by the Medical-Ethical Board of the LUMC.A total of 103 cases were recruited from the rheumatology departments of the LUMC and the VUMC. All cases were women with a diagnosis of SSc after their pregnancies had been completed and who had been pregnant at least once. One hundred and three healthy controls with no history of autoimmune disease were recruited from two different general practitioners' clinics in Venhuizen and Noordwijk, The Netherlands. Cases and controls were matched on age (± 5 years) and number of pregnancies (primiparous vs. multiparous).in utero.All women received detailed study information and a questionnaire. Informed consent was obtained from all cases and controls. Baseline characteristics, such as maternal age, weight and height, as well as smoking habits during pregnancy and total number of pregnancies were obtained via the questionnaire. Information on the subject's obstetric history, including the sex of their children, and complications during pregnancy was obtained. Women were asked if they had hypertensive complications during pregnancy, such as pregnancy-induced hypertension (PIH) or preeclampsia (PE) (hypertension and proteinuria). Information on the use of anti-hypertensive medication and hospital admission during pregnancy, fetal IUGR and fetal death (miscarriage) was also obtained through the questionnaire. IUGR was defined as abnormal growth of the fetus n = 140) and controls (n = 140).Assuming that the incidence of preeclampsia, PIH and IUGR was 25% in the cases and 5% in the controls , the powt-test for means and Chi-square for proportions using SPSS 16.0 . A conditional logistical regression analysis was used to calculate odds ratios between the cases and the matched controls.Baseline characteristics of the cases and controls were compared using the Student The response rates to the questionnaire for the cases and controls were 70% and 74%, respectively. There were no differences in demographic characteristics between cases and controls Table . The meaThere was a statistically significant association between both hypertensive complications and fetal growth restriction with the development of SSc in later life. Non-statistically significant trends were found in women who experienced miscarriage and those who used anti-hypertensive medication during pregnancy and later developed SSc Table .This preliminary study showed a significant difference in the occurrence of hypertensive complications during pregnancy in women who later developed SSc compared to healthy parous women. There was also a significantly increased incidence of fetal growth restriction in the cases. This is the first study to demonstrate an association between a history of hypertensive complications during pregnancy or IUGR and the development of SSc after childbearing age. The same trend, although not statistically significant, was found for the reported use of anti-hypertensive medication during pregnancy or a history of miscarriage.The association between hypertensive complications during pregnancy and/or IUGR and subsequent SSc at a later age could possibly be explained by a number of factors. Pregnancy complications, such as hypertension and IUGR, are associated with increased fetal-maternal trafficking -4. WomenIn this study, we obtained information about the subjects' obstetric history by using retrospective questionnaires. Our conclusions are based on the information provided by the research subjects, which is inherently subjective. A more objective approach would have been to review all of the medical records concerning the obstetrical histories for the cases and controls, but this was not possible due to loss of patient files related to the relatively long interval between pregnancy and the development of SSc. Another bias that could affect the results is that in the control group, women with a history of complications during pregnancy could have been more likely to respond to the questionnaire than women with no history of pregnancy complications. However, this potential bias could only result in an underestimation of the association between pregnancy complications and SSc. In addition, patients with a history of scleroderma may recall their medical histories in more detail than controls, which could have led to an overestimation of the studied pregnancy complications. On the other hand, on average, more than two decades passed between the first pregnancy and the age of onset of scleroderma; therefore, this bias is most likely minimal.In summary, the results of this preliminary study show that in women who later developed SSc, there was an increased incidence of pregnancy complications, such as hypertension and IUGR. Future studies are indicated to more fully explore this relationship, including its possible association with fetomaternal microchimerism.HELLP: hypertension and hemolysis elevated liver function low platelet; IUGR: Intra-uterine growth restriction; MC: microchimerism; PE: preeclampsia; PIH: pregnancy induced hypertension; SSc: systemic sclerosis.The authors declare that they have no competing interests.SAS conceived the design of the study and drafted the report. AJMS, AAS and AEV recruited participants and provided background knowledge for the data analysis and interpretation. JvM and LvW collected data and drafted the report. TWJH and DB provided background knowledge to the data analysis and interpretation. All authors have reviewed the report. All authors have seen and approved the final version for publication.


Arabidopsis thaliana. As a consequence, the mitochondrial OXPHOS and ribosomal transcripts were both upregulated, but only the ribosomal proteins were oversynthesized, while the OXPHOS subunits were actually depleted. This finding implies that the heterogeneity of plant mitoribosomes found in vivo could contribute to the functional selectivity of translation under distinct conditions. Furthermore, global analysis indicates that biogenesis of OXPHOS complexes in plants can be regulated at different levels of mitochondrial and nuclear gene expression, however, the ultimate coordination of genome expression occurs at the complex assembly level.The ribosome filter hypothesis posits that ribosomes are not simple non-selective translation machines but may also function as regulatory elements in protein synthesis. Recent data supporting ribosomal filtering come from plant mitochondria where it has been shown that translation of mitochondrial transcripts encoding components of oxidative phosphorylation complexes (OXPHOS) and of mitoribosomes can be differentially affected by alterations in mitoribosomes. The biogenesis of mitoribosome was perturbed by silencing of a gene encoding a small-subunit protein of the mitoribosome in  It is a widely held belief that post-transcriptional control dominates in the regulation of mitochondrial gene expression in plants, but the experimental evidence was until recently limited to events affecting RNA quality and quantity . TranslaEscherichia coli made over 40 years ago  and small subunit (SSU) composed of both proteins and rRNAs. Originally, ribosomes of an organism were viewed as homogeneous entities showing no variation in their rRNA or protein composition despite the observation of a growth rate-dependent ribosome heterogeneity in ears ago . The earscoideum . The ribications . Since tications . Since tArabidopsis was characterized . It should be underlined that the rps10 mutant did not suffer from an insufficiency of wild-type mitoribosomes since the silencing provoked a compensatory response increasing the overall abundance of both small and LSUs. The polymorphic population of mitoribosomes turned out to translate two subsets of mRNAs, those encoding OXPHOS subunits and ribosomal proteins, with altered efficiency compared to the wild-type. The majority of the OXPHOS transcripts were translated less efficiently, whereas most of the mitoribosome protein transcripts were translated with an enhanced efficiency relative to the wild-type. It should be emphasized that in the RPS10-silenced plants the mitochondrial transcripts for both OXPHOS and ribosomal proteins were up-regulated. Thus, the altered translation was not correlated with the transcript level but was due to an altered efficiency of their binding by the mitoribosomes. As a consequence, the rate of synthesis of the OXPHOS proteins was below that observed in wild-type mitochondria despite the over-abundance of their mRNAs. Thus, the diversified mitochondrial translation efficiency modulated profoundly the outcome of the earlier steps of mitochondrial genome expression. The effect of the altered SSU and/or the excess of free LSU on the efficiency of protein synthesis in the rps10 mitochondria was postulated to have resulted from the formation of unique interactions between those subunits and other components of the translation apparatus. It is tempting to speculate that similar translational regulation could occur in wild-type plants, namely under conditions that lead to heterogeneity of mitoribosome population in response to environmental or developmental signals.This finding is fully consistent with the ribosome filter theory. RNAi-mediated silencing leads to the generation of unique, heterogeneous population of ribosomes. Ribosomes lacking the S10 protein coexisted with wild-type ones and an excess of free LSU , which could be involved in translational efficiency by interacting with altered SSU and/or the excess of free LSU. However, no obvious motifs have been found within the 5′ UTR sequences suggesting that these parts of mRNAs are involved in gene-specific translation regulation , whereasA. thaliana mutant with a depletion of the mitochondrial matrix iron-sulfur protein required for NADH dehydrogenase (INDH). INDH waThe data indicating a heterogeneity of plant mitoribosomes combined with the finding that translation could be the overriding regulatory stage of mitochondrial gene expression regulation suggest that in plants the status of the mitoribosomal population could be an essential regulator of expression of mitochondrially encoded proteins in response to developmental or environmental signals. The postulated ribosome-mediated selectivity of mitochondrial translation should be reflected by a poor correlation between the steady-state abundance of mitochondrial transcripts and the encoded proteins. However, despite the recent intense studies of the plant mitochondrial transcriptome and proteome no enough quantitative data exist to substantiate such a claim. Relations between the transcript and the protein level are mainly known for the nuclear-encoded mitochondrial proteins .rps10 mutant, respectively, reached the same conclusion that the ultimate coordination of expression of the two genomes occurs at the level of protein complex assembly. The authors of both those papers assumed that an excess of unassembled subunits were degraded by nuclear-encoded ATP-dependent proteases. Apart from this similarity, there were also differences between the two experimental systems, as the RPS10 silencing mainly down-regulated the biosynthesis of the mitochondrially encoded subunits whereas under sugar starvation the biogenesis of OXPHOS complexes was regulated mostly by curbing the expression of the respective nuclear genes. As a consequence, the nuclear-encoded proteins in rps10 and the mitochondrially encoded proteins under sugar starvation had to be degraded to bring their abundance down to the level of their partners. One is tempted to suggest that depending on the nature or the duration of the stress the direct response of the two collaborating genomes is in fact limited to one or the other and the expression of the second genome is adjusted ultimately at the complex assembly level.Biogenesis of OXPHOS complexes requires balanced production of nuclear- and mitochondrially encoded subunits. Some reports indicate that in plants coordination of the expression of OXPHOS genes between the nuclear and mitochondrial genomes may occur at the transcript level , but recrps10 mutant. An induction of nuclear-encoded mitochondrial proteases and chaperones upon accumulation of unfolded or misfolded proteins in the mitochondrial matrix is a hallmark of the mitochondrial unfolded-protein response (UPRmt) that has been reported for mammals and Caernohabditis elegans . This mechanism was first reported for chloroplasts (Cox1 mRNA, newly synthesized unassembled Cox1 protein, and other Cox assembly factors during Cox1 maturation/assembly (In contrast to plants, where translational regulation has just emerged as an important step of the biogenesis of OXPHOS complexes, a diversity of mitochondrial translation control mechanisms have been reported in other organisms, particularly in nslation . It is unslation . Ample droplasts . In the assembly . Assemblassembly . MitoribA negative feedback mechanism for the regulation of mitochondrial translation based on an interplay between the translation and m-AAA protease, the key component of the mitochondrial quality control system has also been proposed for yeast . The m-Acox1 transcript (cox1 mRNA, whereas Ppr5 is a general negative regulator of mitochondrial translation. Furthermore, in humans another PPR protein – PTCD1 has been proposed to inhibit mitochondrial translation probably by decreasing the stability of the mitochondrial leucine tRNAs (b transcripts (Given the mammalian mitochondrial transcripts contain no or only a short untranslated regulatory 5′ region , it seemanscript . Ppr4 spne tRNAs . Other nnscripts  and PTCDnscripts .In bacteria mRNA abundance is the primary factor controlling the rate of protein synthesis. Recent studies have shown that in plant mitochondria the synthesis of OXPHOS subunits is surprisingly insensitive to the accumulation of respective transcripts . It seemThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.