Machine learning neuroimaging researchers have often relied on regularization techniques when classifying MRI images. Although these were originally introduced to deal with “ill-posed” problems it is rare to find studies that evaluate the ill-posedness of MRI image classification problems. In addition, to avoid the effects of the “curse of dimensionality” very often dimension reduction is applied to the data.Baseline structural MRI data from cognitively normal and Alzheimer's disease (AD) patients from the AD Neuroimaging Initiative database were used in this study. We evaluated here the ill-posedness of this classification problem across different dimensions and sample sizes and its relationship to the performance of regularized logistic regression (RLR), linear support vector machine (SVM) and linear regression classifier (LRC). In addition, these methods were compared with their principal components space counterparts.In voxel space the prediction performance of all methods increased as sample sizes increased. They were not only relatively robust to the increase of dimension, but they often showed improvements in accuracy. We linked this behavior to improvements in conditioning of the linear kernels matrices. In general the RLR and SVM performed similarly. Surprisingly, the LRC was often very competitive when the linear kernel matrices were best conditioned. Finally, when comparing these methods in voxel and principal component spaces, we did not find large differences in prediction performance.We analyzed the problem of classifying AD MRI images from the perspective of linear ill-posed problems. We demonstrate empirically the impact of the linear kernel matrix conditioning on different classifiers' performance. This dependence is characterized across sample sizes and dimensions. In this context we also show that increased dimensionality does not necessarily degrade performance of machine learning methods. In general, this depends on the nature of the problem and the type of machine learning method. The term CoD was introduced by Richard Bellman while working on optimization problems a priori knowledge, such as selecting only the voxels falling in the hippocampal and parahippocampal tissue, produced significantly greater classification accuracies.Recent work provides evidence that dimension reduction for classifying brain MRI images may not be necessary to achieve a high level of prediction performance in some situations. Reports in the fMRI literature 1 penalty to the elastic net case We have recently proposed solving similar structural MRI classification problems associated with AD following a different path, which is based on large-scale regularization. We use regularized logistic regression (RLR) based on a coordinate-wise descent technique as implemented in the GLMNET library Most of the methods described above that are capable of handling sMRI or fMRI high dimensional data are related, in one way or another to regularization theory. Regularization techniques have been widely adopted by machine learning researchers because of their capacity to deal with problems with small sample sizes and large numbers of variables, situations for which traditional statistical techniques are not well suited Although regularization methods are often applied to deal with the sMRI image classification problems, it is rare to find in the literature an analysis of this problem ill-posedness, even though regularization techniques were first created to deal with the ill-posedness of practical problems. The present study provides a view of the classification of MRI images from the perspective of linear ill-posed problems. For these the degree of ill-posedness is linked to the conditioning and structure of singular values of the linear kernel matrices www.adni-info.org.Data used in the preparation of this article were obtained from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database (adni.loni.ucla.edu). The ADNI was launched in 2003 by the National Institute on Aging (NIA), the National Institute of Biomedical Imaging and Bioengineering (NIBIB), the Food and Drug Administration (FDA), private pharmaceutical companies and non-profit organizations, as a $60 million, 5-year public private partnership. The primary goal of ADNI has been to test whether serial magnetic resonance imaging (MRI), positron emission tomography (PET), other biological markers, and clinical and neuropsychological assessment can be combined to measure the progression of mild cognitive impairment (MCI) and early Alzheimer's disease (AD). Determination of sensitive and specific markers of very early AD progression is intended to aid researchers and clinicians to develop new treatments and monitor their effectiveness, as well as lessen the time and cost of clinical trials. The Principal Investigator of this initiative is Michael W. Weiner, MD, VA Medical Center and University of California – San Francisco. ADNI is the result of efforts of many coinvestigators from a broad range of academic institutions and private corporations, and subjects have been recruited from over 50 sites across the U.S. and Canada. The initial goal of ADNI was to recruit 800 adults, ages 55 to 90, to participate in the research. These would include approximately 200 cognitively normal older individuals to be followed for 3 years, 400 people with MCI to be followed for 3 years and 200 people with early AD to be followed for 2 years. For up-to-date information, see We used ADNI subject data collected from 50 clinic sites that had their own individual IRB approval. Study subjects gave written informed consent at the time of enrollment for data collection, storage and research and completed questionnaires approved by each participating sites' Institutional Review Board (IRB). The data were anonymized before being shared. We used baseline structural MRI data from 727 subjects. Of these, 205 were cognitively normal controls (CN), 171 had AD, and 351 had mild cognitive impairment (MCI) at baseline We used baseline 1.5 T T1-weighted MRI data as described in the ADNI acquisition protocol http://www-stat.stanford.edu/~tibs/glmnet-matlab/). The general form of the optimization problem solved by the library is of the form:th sample or feature vector containing the GM voxels entering the analysis, th label , 1 and L2 penalties. The regularization parameter We evaluated the performance of logistic regression with elastic net regularization as implemented in the GLMNET library This is the most common classification technique used to analyze sMRI data Kloppel and colleagues used hard-margin (HM) and soft margin (SM) linear SVM to classify structural MRI images SVM based on the representer theorem and the properties of the reproducing kernel Hilbert spaces The linear regression classifier is estimated by solving the least squares problem:2 regularization based on coordinate descent techniques Principal component analysis (PCA) is a powerful tool for dimension reduction that is often used in biomedical applications to deal with high-dimensional problems. After standardization of the data, we used the princomp MATLAB function to project the GM imaging data (matrix X) corresponding to CN and AD ADNI participants into principal component space. The performance of LRC, RLR and SVM are evaluated. To estimate the SVM we did not follow the kernel implementation described above, instead we used the LIBLINEAR library (version 1.8). It provides a fast implementation of the SVM with LTo evaluate classifier performance, in all cases we reserved a fixed dataset of 100 randomly selected participants (50 CN and 50 AD) for testing. Training datasets were randomly generated based on the remaining CN and AD participants. To estimate the optimal values of the regularization parameters both in voxel and PC spaces, we combined 10-fold cross-validations (CV) and grid search. For RLR we set the parameter We computed overall classification accuracy to evaluate classifier performance as:In the context of discrete problems ill-posedness often translates into ill-conditioning of the linear kernel matrix. A common approach for evaluating the degree of ill-posedness for these problems is the study of linear kernel matrix conditioning via the use of the singular value decomposition(SVD) The evaluation was based on the GM images of the CN and AD participants that were vectorized and used as samples to estimate the different classification models. For each sample size and dimension, computations were repeated 100 times for different samples of CN and AD participants selected at random. The imaging data were always normalized by subtracting the mean and dividing by the standard deviation in a voxel-wise fashion.We studied the impact of dimension and training dataset sample size in the voxel space on RLR, LRC and SM-SVM in terms of prediction performance  when discriminating between GM images of AD and CN ADNI participants. The sample size was varied from 20 to 210  with balanced numbers of CN and AD participants. We varied the dimensions, given by the number of voxels included in the analysis, from To study the conditioning of the linear kernel associated with classification of sMRI images using our ADNI dataset we estimated the singular values, rank and the condition numbers of all linear kernel matrices (K) across all samples sizes, dimensions and iterations tested in Experiment # 1.We compared across 100 iterations the prediction performance of RLR, LRC, and SVM both in voxel and PC spaces for a very large dimension (D = 750 K voxels) and a large but fixed sample size (210). To select the optimal number of components for each iteration, we estimated classification accuracy for different sets of components generated by adding one component at a time, starting from the first component up to the total number of components. The maximum value of accuracy obtained across different sets of components was taken as the final result for a given iteration.The results of the first experiment describing the impact of dimension and sample size in the voxel space on the RLR and SM-SVM performances are presented in Most of the results of the second experiment are shown in In general, the ill-conditioning effects we discuss are very mild since all the kernel matrices were full rank and the reciprocal of their condition numbers were very far from the machine's precision. However, effects due to differences in conditioning did exist, and they influenced the performance of these methods as we have shown. In The main results of the Experiment # 3 are presented in This study provides a better understanding of the impact of dimension on linear classification methods that directly operate on high-dimensional neuroimaging spaces defined by voxels. It provides further evidence to dispel the common belief that due to the Curse of Dimensionality (CoD), feature selection is always necessary to achieve good performances in high-dimensional problem. Our research produced strong evidence about the robustness of several linear classifiers to increased dimensionality (up to 750 K voxels) in the context of sMRI data classification.Some researchers have pointed out that the effect of the CoD on a machine learning algorithm depends on how it deals with sample neighborhoods 2 regularized logistic regression and linear SVM was reported, with much smaller dimensions, fixed sample size and no optimization of regularization parameters.It is striking how competitive the LRC performed  with the much more sophisticated regularized methods, such as RLR and SVM. These results are possibly related to a phenomenon characteristic of high dimensional spaces called “data piling”, recently discovered and studied There are several limitations in our study. We have evaluated the impact of dimension in a specific manner: by changing the threshold of the DARTEL study customized GM template, we generated problems of different number of variables. Although other ways of evaluating the effect of dimension could be devised, the approach chosen here naturally appears in the problem. In a GM voxel space analysis, we would first introduce the voxels with higher probability of being located in the GM tissue since it has been reported by several groups Finally, we are not arguing that feature selection is not necessary or useful. Nor have we claimed that the methods studied here are the best solution to the problem of sMRI brain images classification. Our point is that, in some problems as the one we studied the commonly assumed devastating effect of dimension on classifiers performance is not necessarily present. The huge differences in dimensions between the voxel and PC spaces were not reflected in large differences in performance of these three methods. There are different factors that can influence the impact of dimension on a machine learning algorithm as for example the ill-posedness of the problem defined by the nature of the data. Therefore, the usefulness of feature selection in general will depend on the nature of the specific problem, employed machine learning algorithm, signal to noise ratio  of the data, and other factors.Figure S16.The performances of a hard margin (HM)-SVM and SM-SVM were compared across sample sizes and two dimensions 50 K and 750 K using a similar setup as in Experiment # 1. The HM-SVM shows, in general, a similar behavior to its regularized counterpart, although in situations of worse conditioning of the kernel matrices in this study (50 K and larger samples sizes) it underperforms in a similar fashion as the LRC does. The HM-SVM was implemented by setting the parameter C to 10(TIF)Click here for additional data file.


Syndromic retinitis pigmentosa (RP) is the result of several mutations expressed in rod photoreceptors, over 40 of which have so far been identified. Enormous efforts are being made to relate the advances in unraveling the patho-physiological mechanisms to therapeutic approaches in animal models, and eventually in clinical trials on humans. This review summarizes briefly the current clinical management of RP and focuses on the new exciting treatment possibilities. To date, there is no approved therapy able to stop the evolution of RP or restore vision. The current management includes an attempt at slowing down the degenerative process by vitamin supplementation, trying to treat ocular complications and to provide psychological support to blind patients. Novel therapeutic may be tailored dependant on the stage of the disease and can be divided in three groups. In the early stages, when there are surviving photoreceptors, the first approach would be to try to halt the degeneration by correction of the underlying biochemical abnormality in the visual cycle using gene therapy or pharmacological treatment. A second approach aims to cope with photoreceptor cell death using neurotrophic growth factors or anti-apoptotic factors, reducing the production of retino-toxic molecules, and limiting oxidative damage. In advanced stages, when there are few or no functional photoreceptors, strategies that may benefit include retinal transplantation, electronic retinal implants or a newly described optogenetic technique using a light-activated channel to genetically resensitize remnant cone-photoreceptor cells. The term retinitis pigmentosa (RP) encompasses a heterogeneous group of disorders that result in an initial loss of rod photoreceptors, followed by a detrimental effect on cone photoreceptors, inner nuclear layers, ganglion cells and retinal pigment epithelium (RPE) , 2.Rods represent 95% of all the photoreceptors in the humans  and are The photoreceptors consist of an outer segment (OS), an inner segment, a cell body and a synaptic terminal where neurotransmission occurs to second order neurons. The OS discs are renewed in a circadian rhythm from the base of the photoreceptor OS, the RPE engulfs the distal discs where they undergo degradation by phagocytosis, thus keeping the length of the OS constant . Each OShttp://www.sph.uth.tmc.edu/retnet/sum-dis.htm for updated genes and loci). These include mutations in rhodopsin, enzymes of the phototransduction cascade, structural protein mutations in peripherin/RDS or ABCA4, genes expressed in RPE and coding proteins involved in vitamin A metabolism such as RPE65. These mutations may affect the renewal and shedding of the photoreceptor OS, the visual transduction cycle and/or the vitamin A (retinol) metabolism [Non-syndromic RP is the result of several mutations expressed in rod photoreceptors, 44 of which have been identified so far   gene augmentation therapies, where a normal gene is inserted into the genome to replace nonviable or diseased genes using a carrier vector, (2) gene silencing therapies, in which the expression of the mutated gene is inhibited by use of ribozyme or RNA interference. In autosomal recessive and X-linked RP, mutations usually lead to a loss of function and the principle of gene therapy is to introduce a wild-type version of the mutated gene into the cells in which normal functioning of this gene is required . SuccessThis therapy has been most extensively studied in Leber’s congenital amaurosis (LCA) with mutation in RPE65, which interrupts function of the visual cycle . PrelimiAutosomal dominant conditions are mainly caused by toxic gain of function mutations that result in either a mutated protein or a negative effect of the encoded protein. Mutations within the rhodopsin gene account for approximately 25% of the cases of autosomal dominant RP, the rest are not linked to rhodopsin. In RP the aberrant gene product is detrimental to the photoreceptors and ultimately results in cell death. Two approaches have been proposed to silence the abnormal gene: ribozymes and RNA interference (siRNA).Ribozymes can be designed to cleave mutant mRNA molecules so that the mutant rhodopsin is not produced . The usevia AAV serotype 5 vector mediated gene transfer [siRNA, on the other hand, is a mutation independent technique for posttranslational gene silencing . Complettransfer , 48. ThePharmacological agents can also compensate for a biochemical defect and can be a good choice in those cases where some aspects of the patho-physiological mechanism are known. The main advantage of such treatment is that the eventual toxicity of the drug is known and can be modulated. This strategy may be applicable to RP with a primary deficit in chromophore biosynthesis causing an alteration of the visual cycle. Examples include LCA owing to mutations in the LRAT and RPE65 genes.The first experiments aimed at bypassing the biochemical defect caused by the absence of RPE65 were performed by oral administration of 9-cis-retinyl acetate in RPE65-deficient mice , 50. EleHigh doses of retinoids have been shown to be toxic in numerous studies, including teratogenic effects. However, acute and prolonged treatment of mice with 9-cis-retinoids did not cause obvious adverse effects, raising the hope for a trial of chromophore supplementation in humans .RP is a genetically heterogeneous disease where only 60% of the mutations are known . GeneticThere have been a number of examples of neurotrophic factors being successfully tested in animal models for neurodegenerative diseases, but failing to bring any benefit over placebo when tested in human clinical trials, such as glial cell-derived neurotrophic factor (GDNF) for Parkinson disease  or ciliaA number of agents that slow photoreceptor death in animal models have been identified: basic fibroblast-derived growth factor (bFGF), brain-derived neurotrophic factor (BDNF), cardiotrophin-1, nerve growth factor (NGF), fibroblast growth factor (FGF) and CNTF.et al. demonstrated the neuroprotective effect of bFGF in 1990 [Faktorovich  in 1990 . Since i in 1990 . HoweverThe use of encapsulated cells secreting CNTF into the vitreous has been extensively studied and has shown preservation of retinal integrity in different animal models . A phaseet al. reported their non-specific approach targeting the apoptotic pathway involving a family of cysteine proteases known as caspases [A final common pathway of all types of RP is photoreceptor cell death . Leonardcaspases . The X-lin vitro after both short and prolonged exposure, an effect that was also evident after in vivo application via intravitreal injection. These findings highlight the importance of calpain activation for photoreceptor cell death but also for photoreceptor survival and propose the use of highly specific calpain inhibitors to prevent or delay RP [Recent evidence derived from studies on retinal degeneration (rd1) human homologous mouse model for RP suggests that photoreceptor cell death may result primarily from non-apoptotic mechanisms, where photoreceptor cell death appears to be governed by, among other things, changes in cyclic nucleotide metabolism, down-regulation of the transcription factor CREB, and excessive activation of calpain and PARP . Pharmacdelay RP .Cone death in RP is also caused by lack of surviving factors released by the normal retina. This has been confirmed by the discovery that rods generate a diffusible factors stimulating cone survival in the retinal degeneration mouse model . One of Gene therapy and neuroprotective agents play a role in rescuing and preventing the loss of photoreceptors. However, in advanced stages of the disease, where the loss of photoreceptors is already established, and for the majority of patients in which the mutation is not known, the electronic implants or artificial retina can be an option for restoration of vision.via the optic nerve and pathway. Hence, these devices must be able to connect with viable secondary neurons. Several studies have demonstrated the viability of these secondary neurons in patients with RP [One of the best examples of electronic devices used in medicine are the cochlear implants to treat deafness . In the  with RP . Optical with RP  and studThere are four main types of electronic implants developed so far: cortical visual prosthesis, supra-choroidal implant, epiretinal implant and subretinal implants.It is based on direct stimulation of the visual cortex bypassing the eye. A group from the Illinois Institute of Technology is planning the first human intra-cortical visual prosthesis .et al. have implanted on rabbit retina a multi-chip flexible stimulator in the supra-choroidal sclera, successfully obtaining Electrically Evoked Potential on visual cortex evoked by the multi-chip stimulator [Tokuda imulator .et al. [The implant is tacked to the surface of the inner retina. Three groups are involved with this type of implant: the Learning Retina Implant developed by Feucht et al. , the EPIet al. , and theet al. .et al. from the University of Tubingen, Germany, have implanted a subretinal prosthesis in humans and have detected restoration of photoreceptor function via electronic devices electrically coupled to inner retinal neurons [The implant is placed subretinal above the RPE. Theoretically, this is the most physiological placement, as it is placed were the damaged photoreceptors are located. Zrenner  neurons . The impet al. [Another project based on the subretinal implant is the Boston Retinal Implant Project developed by Rizzo et al. . They haSeveral clinical studies have demonstrated the tolerance of the implanted devices, with the exception of the EPI-RET with a large IOL-type receiver unit that caused retinal disruption in a rabbit model . HoweverIn order to properly assess the performance of these artificial retinas there is a need for development of standardized visual tests. These should be able to detect small improvements in vision in patients with advanced RP and capture aspects that relate to a better quality of life .Devices with new, sophisticated designs and increasing numbers of electrodes as well the possibility of using adjunctive therapy, such as neurotrophic agents , could aA novel mechanism to create electric signals in the visual pathway that substitute for the usual input from photoreceptors, besides for electronic retinal implants, is the use of a light-activated channel.In most retinal degenerations, photoreceptor degeneration precedes inner retinal degeneration by several years. It has been suggested introduction of bacterial rhodopsin through gene transfer can render the cells of inner retina photosensitive, thus substituting for the usual input from photoreceptors. There was a restoration of basic vision driven behavior in the rodent. Expression of the bacterial protein channelrhodopsin-2 would generate a light-gated cation channel within the cellular membrane that would allow for depolarization events upon light stimuli .In RP, cone photoreceptors survive longer and may be accessible to therapeutic manipulation. Busskamp and colleagues reactivated the remnant cones in two mouse models of RP by the introduction of a bacterial form of rhodopsin, halorhodopsin, through AAV mediated gene transfer . The reaRetinal transplant is another therapeutic strategy to restore vision in patients with advanced degenerative retinal disease and it is an area of increasing interest in retinal research. The same principle of retinal prosthesis can be applied to retinal transplant, but in this case new cells instead of electronic devices replace the degenerated photoreceptors. The retina is a good substrate for stem cell therapies, as it has the optimal combination of ease of surgical access, combined with the possibility to assess transplanted cells directly through the clear ocular media .Different tissues can be source of cells that can be used for transplantation: fetal tissue, embryonic stem cells, neural stem cells, somatic cells, induced pluripotent stem cells and RPE.via trophic signals from the donor tissue [Studies using whole sheets of fetal neural retina transplanted into the subretinal space have shown survival and differentiation of the grafted tissue , 84. Somr tissue -87.The main limitation of this type of transplant is physical because when transplanting the whole neural retina there is a problem with space and disorganization of host neural retina. It would be more physiological to try to transplant only a sheet of immature photoreceptors .Stem cells that could be used for photoreceptor replacement are embryonic stem cells (ESC) and neural stem cells (NSC) isolated from the adult mammalian brain and the adult ciliary margin of the mouse and human eye . LimitatAlso known as somatic cell nuclear transfer (SCNT). The basis of this technique is to create embryonic stem cells that could differentiate into photoreceptors from an adult somatic cell of the patient . One of iPSC are a type of pluripotent stem cell artificially derived from a non-pluripotent cell, typically an adult somatic cell, by forcing the expression of specific genes. Depending on the methods used, reprogramming of adult cells to obtain iPSC may pose significant risks that could limit its use in humans. For example, if viruses are used to genomically alter the cells, the expression of oncogenes may potentially be triggered . The metet al. published a series of 10 patients affected by RP and dry age-related macular degeneration (AMD) who received implants of neural retinal progenitor cell layers with RPE [The RPE constitutes with the photoreceptor layer a functional unit that provides the transducing interface for visual perception  and it awith RPE . The stuwith RPE . The hypwith RPE .The treatment of RP patients by photoreceptor precursor cell transplantation to the human retina remains a promising strategy for retinal repair. For retinal dystrophies caused by photoreceptor-specific gene mutations, autologous adult derived cells do not initially appear to be the best source of new retinal neurons, as the genetic mutation will remain. Future treatment for retinal degeneration due to photoreceptor cell loss may require a combination of gene and cell therapeutic strategies , 95.The future for treating this group of devastating inherited diseases has never looked brighter. Approaches to therapy for RP now include: gene therapy, neurotrophic growth factors, anti-apoptotic agents, ribozyme therapy, RNAi, retinal transplantation, dietary supplementation, retinal prostheses, and stem cell therapy .However, there remain several hurdles:The success of these treatments depends on proper patient selection, which may include the stage of the disease, the patient’s age, systemic and environmental factors and well set out outcome measures of improvement.Successful translation of new therapies also requires animal models of the disease. There are different natural and transgenic RP animal models that have different times to developing photoreceptor degeneration. It may be difficult to decide which model is most relevant to a specific study. Some of the mutations between humans and animals are not similar. The mutation and the phenotype in the animal model must be viewed with some degree of caution; it cannot be assumed that these are truly representative of the disease that is occurring in the patient until the phenotypes are critically examined using the same criteria.There is tremendous genetic heterogeneity associated with the RP phenotype and accurate genetic characterization is essential for specific gene therapies. It is not known whether partial reversal of the biochemical defect will change the course of progressive retinal degeneration. Although RPE65-LCA has been extensively studied, a predictive relation between a pair of mutant RPE65 alleles and resulting disease severity is currently unknown. There may be considerable intraretinal variation of retinal dysfunction, degeneration and RPE health. Better understanding of the contribution of specific genotypes to disease severity may allow such predictions in the future.Human results suggest that there may even be differences between foveal and extra-foveal cones and this may explain the lack of foveal functional improvement demonstrable with gene therapy to date . Thus trThe importance of the RPE has not yet been established. In late stages, with evidence of diffuse disease of the retinal pigment epithelium, the genes that are transfected into the photoreceptor cells may not be sustainable by the RPE. Some patients have changes not only in the RPE, but also in the choroidal circulation.Another issue is the variation in clinical presentation of patients with RP. It will be important for clinical trials in RP to randomize patients along the lines of recognizable phenotypes, because there could be a different response to various therapeutic procedures among the various phenotypes.So far gene therapy trials have involved patients with almost no vision. The next daunting step is to include patients with expanses of useful and sometimes only moderately abnormal vision. High expectations for remarkable visual recoveries may have to be replaced by the less exciting but still useful outcome of slowed progression of these ultimately blinding disorders.Effective delivery of the therapy, both genetic material and neurotrophic factors to the target tissue has been a formidable task. The blood-retinal barrier prevents most drugs administered topically or systemically from reaching an effective dose in the retina. One of the key methods would involve methods to introduce the molecule without causing a retinal detachment. This has been achieved to some extent with CNTF encapsulated cell technology, thereby achieving adequate intraocular concentration of the drug and limiting systemic toxicity. However, weekly, monthly or yearly intraocular injections represent distinct disadvantages to patients who require treatment during a lifetime. Longer follow up is needed to establish the success of CNTF technology, which may then be applicable for other treatment types.Translational clinical research initiatives are finally offering hope to relatives and patients with RP. Genotyping is one of the biggest resource challenges we face. State- of-the-art clinical facilities are needed to administer and evaluate novel investigational therapies. Even if the promise of gene replacement therapy is fully realized, the basic research and clinical trials that precede successful gene therapy take years. We suggest that research should be directed to identifying the patho-physiological processes common to all the photoreceptor degenerations and a more general treatment would fill an enormous therapeutic gap.


The sole focus of models of insight on bio-medical perspectives to the complete exclusion of local, non-medical and cultural constructs mandates review. This study attempted to investigate the impact of insight, psychopathology, explanatory models of illness on outcome of first episode schizophrenia.Patients diagnosed to have DSM IV schizophrenia (n = 131) were assessed prospectively for insight, psychopathology, explanatory models of illness at baseline, 6, 12 and 60 months using standard instruments. Multiple linear and logistic regression and generalized estimating equations (GEE) were employed to assess predictors of outcome.We could follow up 95 (72.5%) patients. Sixty-five of these patients (68.4%) achieved remission. There was a negative relationship between psychosis rating and insight scores. Urban residence, fluctuating course of the initial illness, and improvement in global functioning at 6 months and lower psychosis rating at 12 months were significantly related to remission at 5 years. Insight scores, number of non-medical explanatory models and individual explanatory models held during the later course of the illness were significantly associated with outcome. Analysis of longitudinal data using GEE showed that women, rural residence, insight scores and number of non-medical explanatory models of illness held were significantly associated with BPRS scores during the study period.Insight, the disease model and the number of non-medical model positively correlated with improvement in psychosis arguing for a complex interaction between the culture, context and illness variables. These finding argue that insight and explanatory models are secondary to psychopathology, course and outcome of the illness. The awareness of mental illness is a narrative act in which people make personal sense of the many challenges they face. The course and outcome of the illness, cultural context, acceptable cultural explanations and the prevalent social stigma interact to produce a complex and multifaceted understanding of the issues. This complexity calls for a nuanced framing of insight. The term insight, employed in the context of self-awareness, has been used in many different ways. It ranges from a basic awareness of one’s situation to a deeper intellectual understanding and emotional appreciation of issues. It has also been used differently by different disciplines  to imply particular understanding. Assessment in clinical psychiatry terms insight as “a patient’s capacity to understand the nature, significance and severity of his or her illness”. Such awResearch related to insight and schizophrenia has changed substantially over the past few decades. Older trans-cultural studies by the World Health Organization employed uni-dimensional and all-or-none perspectives in the elicitation of insight,3. They Nevertheless, the more recent approaches have also been criticised-17. TheiMany investigations, from non-western cultures, have recorded the simultaneous presence of multiple and contradictory models of illness in people,18-23. NPluralistic societies employ multiple approaches to health and illness. Disease models of causation are almost universal in rural India and in low and middle-income countries for illnesses of short duration . In This study attempted to study the impact of local cultural explanations, attributions and actions on the long-term outcome of first episode schizophrenia in Vellore, India. It employs a cohort design where the patients were followed-up for 5 years after the initial recruitment.2. The 122-bed hospital provides short-term care psychiatric care for the town, the district and a much wider rural area beyond. The department treats a variety of mental and behavioural disorders with a multi-disciplinary and eclectic approach using standard pharmacological and psychological therapies. The hospital has a daily outpatient clinic in which about 350–400 patients are seen. Patients requiring hospitalization are admitted for a period of 2–6 weeks.This study was carried out in the Department of Psychiatry, Christian Medical College, Vellore, Tamil Nadu, south India. The total area of Vellore district is 4314.29 kmThe hospital follows standard protocols for the treatment of patients with schizophrenia. Antipsychotic medication  are drugs of choice and employed in adequate doses  and for a period of about 2 years for people with first episode of psychosis. Clozapine is reserved for patients who do not respond to at least 2 antipsychotic drugs given in adequate dose for at least 6–12 weeks. All patients admitted to the hospital also receive psychoeducation, supportive psychotherapy and occupational therapy. Patients with specific problems related to marriage, sex, interpersonal and vocational issues are helped by psychological interventions .The details of the cohort are described in other publications,18,19. TStructured Clinical Interview forDSM-III R Patient version(SCID-P): We used the Structured Clinical Interview for DSM-III R Patient version (SCID-P) to assess psychopathology and confirm diagnosis and disability  and positively with the total number of non-medical models . BPRS total score , PANSS total score , disability  and the number of nonmedical explanatory models  remained statistically significantly associated with insight after adjustment for age, sex, literacy and residence using multiple linear regression.th year follow up was significantly correlated negatively with psychopathology  and disability  and positively with insight scores . BPRS total score , PANSS total score , disability  and insight score  remained statistically significantly associated with the total number of non-medical models after adjustment for age, sex, literacy and residence using multiple linear regression.The total number of non-medical explanatory models at 5TableThe association between remission and changes in SAIE and BPRS scores between baseline and 6 and 12 months were tested for statistical significance. The only significant variable associated with remission were reduction in BPRS score between baseline and 12 months , which remained significant  after logistic regression analysis adjusting for other clinically significant variables. Changes in insight scores during the first year of treatment were not associated with outcome at 5 years.FiguresThe data was analysed using Generalized Estimating Equations (GEE) to assess the impact of serial assessments of SAI-E scores and the number of non-medical models on serial BPRS scores. Baseline variables significantly associated with remission and the number of visits to the hospital were entered as fixed variables in the model to adjust for their effects. Women , rural residence , SAI-E scores  and number of non-medical models  were significantly associated with BPRS scores. The non-significant variables in the model were: number of meals per day, duration of untreated psychosis, fluctuating initial course, and number of visits to hospital.th year and the gap in psychopathology and insight assessments between 12 and 60 months are limitations.This is probably the first study with a large sample and a long period of follow-up, which has systematically examined psychopathology, insight, indigenous explanatory models of illness and outcome in schizophrenia. Its strengths include prospective cohort, detailed and repeated standard assessments of psychopathology and insight, assessment of both disease models and non-medical explanatory models of illness, a 5-year follow-up, and multivariate statistical procedures to adjust for confounders and to analyze repeated and correlated data. The fact that about a quarter of the original sample could not be examined at the 5The study has documented heterogeneity of outcome in schizophrenia. It recorded the simultaneous acceptance of multiple and contradictory explanatory models of illness and diverse sources of help seeking. Psychopathology, insight and explanatory models changed over the 5-year period. The proportion of patients holding disease models steadily increased over time with over half the subjects preferring it as the best explanation at 5 years. The number of patients holding non-medical models was high at recruitment, reduced over the first year of treatment and then rose dramatically. Urban residence, fluctuating course of the initial illness, improvement in functioning at 6 months and lower psychosis rating at 12 months were significantly related to remission. Insight scores and non-medical explanatory models held during the later course of the illness were significantly associated with outcome at 5 years. Disease models were associated with remission while non-medical were associated with poorer outcome. However, there was interaction between medical and non-medical models. The presence of the disease model and at least one indigenous model had a stronger impact on remission than the disease explanation per se. Analysis of longitudinal data showed that women, rural residence, insight scores and the number of non-medical explanatory models of illness held were significantly associated with BPRS scores during the study period.Many investigations have recorded the simultaneous presence of multiple and contradictory models of illness in people,18-23. TThe reduction of psychotic symptoms and improved functioning during the first year of treatment is associated with an increase in the use of disease explanations and a marked reduction of causal non-medical beliefs. However, the number of people subscribing to disease explanations tends to plateau with only about half the subjects preferring it at 5 years. The pattern of change in the number of indigenous models of illness employed argues that they help coping. Their manifest reduction at 6- and 12-month follow-up coincides with the reduction in psychosis for all patients. Their marked increase at 60 months suggests their role as a coping strategy when the pattern of course and outcome of illness becomes established. Previous studies have documented the inverse relationship between psychopathology and insight,19,47-49The fact that pretreatment illness variables, improvement in functioning and reduction in psychopathology determined outcome at points in time before insight scores and explanatory models were significant suggest their major role in the process. The bivariate statistical association during the early course of illness between insight, explanatory models and outcome, lost their statistical significance when baseline and clinical variables were included in the multivariable analysis arguing that such relationships are confounded by illness characteristics. The independent predictor status of insight and explanatory models for clinical remission only becomes significant late in the course of illness. The positive relationship between insight and the number of non-medical explanatory models of illness, their negative relationship with psychopathology argues their impact on outcome is possibly secondary to the inherent nature of the disease. The relationships persisted after adjusting for the number of hospital visits.These findings challenge the direction of the relationship between insight and psychopathology arguing that insight may be secondary to psychopathology. The association of insight and non-medical explanatory models to long-term outcome later in the course of illness suggests that explanatory models are coping mechanisms rather than being causally related to outcome.The inverse correlation between insight scores and psychopathology in earlier reports,47-49 diThe heterogeneity of clinical features, course, outcome and treatment response of schizophrenia probably reflects different diseases, illnesses and trajectories. The fact that non-medical beliefs held during the later part of the illness were associated with non-remission and treatment non-response suggests that patients with a worse course and outcome and poorer response to treatment may select such explanatory models to cope with the devastating impact of their illness.Pluralistic societies employ multiple approaches to health and illness. The simultaneous use of contradictory models suggests their use in coping with different aspects of the condition. The facMental illness and their labels are stigmatizing across cultures leading to much prejudice and discrimination. This is particularly significant in people with residual and poor outcome schizophrenia whose limited response to medication, adverse effects and continued symptoms demands the need for explanations, which go beyond simple disease. Non-medical, supernatural and external explanatory models seem to be preferred to disease explanations in order to cope with the devastation of the disease in people who have not recovered with treatment. They seem to be culturally acceptable mechanism to cope with complex and incapacitating outcomes. The persistence of multiple explanatory models of across cultures for chronic illnesses may suggest an evolutionary advantage.Medicine and psychiatry, despite their attempts at a universal understanding of mental disorders, cannot do justice to patients without the recognition of the contexts and the sharing of personal narratives. Psychiatry with its focus on objective behaviours, symptom checklists and diagnostic criteria has reduced the importance of patient experience and narratives. IllnessThe lack of laboratory tests to diagnose mental disorders tends to raise doubts about their diagnostic certainty making many patients and their families uncertain and uncomfortable about psychiatric labels. In addiThe subjective dimension of insight has been conceptualized as a particular form of narrative production, called narrative insight. ExplanaThere is a need to reconcile personal narratives with the biomedical model so that many personal strategies employed to coping with mental illness are not devalued or dismissed. Such experiential knowledge, although personal, will have to be recast in each case. It will help translate experience, provide legitimate frameworks and create a language and interface for improved communication. The refIt has been argued that insight is shaped by psychology  and constraints of biology (i.e. cognitive impairment and anosognosia) and is influenced by social constructions of illness ,7. Its cThe association of disease models of illness in those with good response to treatment and the correlation between non-medical illness explanations and poor response suggests their role in coping. The complex interaction between disease and indigenous models and the impact on remission argues for a nuanced understanding of the relationships between explanatory models and outcome. The complexity of schizophrenia, its heterogeneity in course and outcome, its varied response to antipsychotic medication and its unpredictable impact on diverse aspects of life seem to elicit a multifaceted response from people who suffer from it, their relatives and from society.Insight is not just the possession of discrete facts about the nature of mental illness. Nor is it only an acknowledgement of a particular experience as abnormal. It is also not an acceptance of a singular truth about the person and his/her life. An awareness of a mental illness is a narrative act in which people make personal sense of the many challenges they face. Such challenges include persistent psychotic symptoms, negative syndrome, cognitive deficits, impaired social relations, perpetual instability and livelihood issues. The patient’s narrative of the illness would then vary according complexity of the problem and context. The insight narrative would also vary according to its role in coping and adapting to the new challenges and demands. The cultural context, acceptable cultural explanations and the prevalent social stigma related to mental illness would interact with the person’s illness to produce a particular understanding. The complexity of issues calls for a nuanced framing of insight.Alternative conceptualisations of insight have employed findings from investigations in the non-western cultures-24,27,54Alternative dimensions have been suggested for the assessment of insight Table14,54].,54.14,54The findings argue for the fact that the assessment of insight should be against the local cultural standards including disease models rather than universal yardsticks . The assessment of insight should evaluate awareness, attribution and action. People with psychosis who are able to re-label their psychotic experience, offer non-delusional explanations for changes in themselves, which correspond to beliefs about illness held by the subculture, admit to the need for restitution, and seek locally available help, can be said to possess insight. The results recommend the use of universal conventions  to assess insight in people with psychosis rather than the use of uniform criteria which focus solely on the biomedical model of disease.Many people hold multiple causal and treatment models of their illness. This isResearch into insight in psychosis should also include non-medical belief models and move beyond pure biomedical explanations. There is a need to develop and refine instruments, which are able to capture diverse belief systems commonly employed by people with mental illness and also elicit local explanatory models of illness, their attribution and help seeking.The findings of this study mandate replication. The sole use of biomedical perspectives in the evaluation of response to complex diseases needs to be replaced with a broad based approach and understanding of coping across cultures. People employ diverse approaches to maintain mental health. The partial solutions offered by individual systems of medicine force people to employ diverse and multiple strategies to cope with distressing symptoms and intractable problems. Consequently, there is a need for a non-judgemental approach to the explanatory models employed by people with mental illness. While antipsychotic medication has a powerful impact on outcome, the use of other strategies especially in chronic conditions to cope with the variable impairment, disability and handicap, even among those with clinical remission, suggest the need to allow patients to use multiple strategies to regain and maintain mental health.Cultural knowledge, empathy and an understanding of its complex interaction, which impact diseases and shape the illness response, is crucial to providing culturally sensitive care. Presenting biomedical perspectives without dismissing patient beliefs and negotiating a shared treatment plan without claiming exclusivity are cardinal. This will allow mental health professionals to bridge the disease-illness and the healing-cure divides across all cultures and settings. The complexity of the issues demonstrated highlight the need for a nuanced understanding of issues related to insight, explanatory models of illness and culture in schizophrenia and for other chronic illness.This 5-year cohort study of people with first episode schizophrenia systematically examined psychopathology, insight, explanatory models, course and outcome. Illness variables at baseline and during the early course of the illness predicted outcome at 5 years, while insight scores and non-medical explanatory models later in the course of illness were associated with long-term outcome. The positive relationship between insight and the number of non-medical explanatory models of illness, their negative relationship with psychopathology argues that association with outcome is possibly secondary to the inherent nature of the disease. These findings challenge the direction of the relationship between insight and psychopathology. They argue that insight and explanatory models are coping mechanisms secondary to psychopathology and course of the illness rather than being causally related to outcome.Insight, the disease model and the number of non-medical model positively correlated with improvement in psychosis arguing for a complex interaction between the culture, context and illness variables. The awareness of mental illness is a narrative act in which people make personal sense of the many challenges they face. The course and outcome of the illness, cultural context, acceptable cultural explanations and the prevalent social stigma interact to produce a complex and multifaceted understanding of the issues. This complexity of issues related to disease, illness, context and culture call for a nuanced framing of insight.The authors do not have any competing interest to declare.KSJ, SDM, HC and SJ designed the study. SJ collected the data. VJ and KSJ analysed the data. KSJ wrote the paper. All authors have read and approved the final draft.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-244X/12/159/prepub


Estradiol is a steroid hormone that regulates the structure and function of the female reproductive system. In addition to its genomic effects, which are mediated by activated nuclear receptors, estradiol elicits a variety of rapid signaling events independently of transcriptional or genomic regulation. These nongenomic actions influence the milieu of the genital tract, which changes the ability of pathogens to infect the genital tract. This review discusses our current knowledge regarding the mechanisms and relevance of nongenomic estradiol signaling in the genital tract that could change the ability of pathogens to invade epithelial cells. PubMed was searched through January 1980 for papers related to estradiol actions in the ovary, fallopian tube, uterus and cervix. The mechanisms conveying these rapid effects consist of a multitude of signaling molecules and include cross-talk with slower transcriptional actions. The nongenomic actions of estradiol that influence the infectious abilities of pathogens occur either directly on the genital tract cells or indirectly by modulating the local and systemic immune systems. Additional in-depth characterization of the response is required before the normal and pathological reproductive functions of the nongenomic estradiol pathway can be targeted for pharmacological intervention. Despite the existence of public health programs and appropriate antibiotics for nearly 60 years, sexually transmitted infections (STIs) continue to be a problem worldwide . In womeIn the literature, we found nongenomic effects of the estradiol in different target tissues, which can be related with the physiology of the female reproductive tract and with effects in the immune system. These actions are summarized in the Additional file On the other hand, we found effects of estradiol in the different sections of the female reproductive tract and in the immune system. These effects are summarized in the following subindexes by highlighting in the nongenomic effects at the end of each subscript. Finally, we relate these effects with the rapid effects in the immune system that can influence the pathogenic infection.The female reproductive tract environment can be subdivided into two major areas: the non-sterile vagina and ectocervix and the sterile endometrium and fallopian tubes. Each of these sections of the female reproductive tract is summarized in the subsections 1.1, 1.2 and 1.3.The vagina is the entrance to the female genital tract, and the vaginal portion of the ectocervix is structurally and immunologically similar to the vagina. The vagina’s luminal surface is lined with non-keratinized, squamous epithelium that is 150–200 μm thick, and the epithelial cells produce a hydrophilic layer of glycoprotein called the glycocalyx, which provides moisture and protection. Epithelial cell proliferation and maturation are under hormonal regulation, and at peak estrogen levels, the vaginal epithelium attains its maximum thickness with the superficial cells containing intracytoplasmic glycogen .Candida albicans and Trichomonas vaginalis in the vagina and Human Papilloma Virus (HPV) in the ectocervix. Even after stimulation, vaginal and ectocervical cells are negative in CD14 and TLR4 tool-like receptors (TLR) [Infections in these sections are primarily restricted to rs (TLR) .The endocervix is lined with simple epithelium composed of columnar cells with basally located nuclei and a fine granular cytoplasm filled with mucus droplets. These cells are interspersed with occasional ciliated, non-secretory columnar cells .Chlamydia trachomatis and Neisseria gonorrhoeae.The latter cells mobilize and distribute the mucus. They may impede the ascent of bacteria because of their sweeping motion. The major pathogens that establish infections at this site are Approximately 20–60 mg of cervical mucus is produced each day; the mucus provides a protective covering for the cervix and vagina and acts as a barrier to inhibit sperm and pathogens from entering the uterus . The mucThere are differences between the immune system components of epithelial, endocervical, ectocervical and vaginal cells. In the case of toll-like receptors, studies have reported a similar pattern of expression on endocervical epithelial cells and in the lower tract . In contEndometrial epithelial cells synthesize an array of chemokines and cytokines, which play a central role in the controlled endometrial inflammatory response observed in implantation, pregnancy and menstruation. Estradiol regulates this phenomenon by modifying the expression and secretion of molecules that ensure fertilization and embryo viability. In the fallopian tube, estradiol likely regulates oviductal transport  by affecInnate immune responses are activated by the binding of microbial pathogen-associated molecular patterns (PAMPs) to TLRs found on phagocytic and epithelial cells. This PAMP-TLR binding induces the secretion of antimicrobial peptides, cytokines and chemokines that attract phagocytic cells to the affected tissue, activating natural killer (NK) cells. Another mechanism of cytokine release to the extracellular medium is mediated by the inflammasome, which is a macromolecular structure that regulates the expression and release of IL-1β  and simuSeveral natural antimicrobial peptides are expressed in the genital tract, and their expression levels are regulated in some cases by cyclic changes in estradiol and progesterone. For example, (HD-5) expression was highest during the early secretory phase of the cycle in endometrial cells. The concentrations of the secreted HD-5 peptide in cervicovaginal lavage were also highest during the secretory phase of the menstrual cycle. Variations of HD-2 have also been observed in which estradiol increases HD-2 secretion in uterine epithelial cells .However, cytokine modifications that occurred in an estradiol-dependent manner and that were not blocked by antagonists of nuclear steroid receptors were recorded ,31. For The decreased transcriptional activity of the NF-kb signaling pathway is another previously reported estradiol effect . Though Estradiol has been reported to directly affect TRAF6 activity through a nongenomic pathway . As obseEstradiol has general anti-inflammatory activity, which explains its effect on TRAF6, its effect on TLR expression and its effect on inflammasome activity. Estradiol inhibits the production of IL-1 mediated by the inflammasome, therefore affecting the caspase 1 pathway.Estradiol also affects the innate immune system by altering the activity levels and numbers of NK cells in the FRT, which both increase during the mid-late secretory phase of the menstrual cycle. NK cells in the FTR are abundant in early pregnancy but progressively disappear from mid-gestation onwards and are absent at term. However, this effect is thought to be regulated by serpin peptidase inhibitor (PI-9) because PI-9 blocks the cell death induced by immune cells via the estrogen genomic pathway . This faThe regulation of antigen presentation is an important control point for the induction or suppression of adaptive immune responses. In the FRT, sex hormones influence antigen presentation by professional antigen-presenting cells (APCs: DC and macrophages) and non-conventional APCs found in the genital tract. Examples of this are estradiol-inhibited APCs in the vagina and the proliferation of B and T cells .Neisseria gonorrhoeae[Neisseria gonorrhoeae when their endogenous estrogen levels are the highest (during proestrus) [Mycoplasma hominis and Ureaplasma urealyticum was affected following estradiol treatment [The cycle stage or the presence of exogenous estrogen affects susceptibility to a number of STIs in humans and animal models . Oral conorrhoeae. Furtheroestrus) . In a moreatment . In animreatment .++. We now know that estradiol affects cAMP, inositol triphosphate, G protein and the MAPK pathway, which are all components of the calcium signaling pathway. The effect of estradiol in these molecules explains their impact on muscle contraction in the genital tract. The modification of these factors directly affects the infectivity of pathogens. Infectivity is also affected by estradiol because of its effect on the innate immune system.The effect of estradiol in pathogenic infections is conditioned by its effects on the nongenomic pathway of the immune system and by its effect on cells of the reproductive tract. Estradiol modification changes ion channel activity by affecting the flow of vaginal secretions and by strongly influencing the intracellular concentration of CaHowever, estradiol registered an effect in a large amount of cytokines and chemokines. Estradiol can modify the secretion of cytokines and chemokines by affecting NF-κB and TRAF6 and by modifying TLRs. The effects of estradiol are summarized in Figure ++: Calcium Ion; HPV: Human Papilloma Virus; TLR: Tool-like receptors; PAMPs: Pathogen-associated molecular pattern; NK: Natural Killer Cells; HD: Human Defensin.STIs: Sexually transmitted infections; PID: Pelvic Inflammatory Disease; FRT: Female Genital Tract; CaThe authors declare that they have no competing interests.PS drafted the manuscript, participated in the design of the study and participated in the analysis of the literature and signal transduction pathways. LV originated the study, participated in its design and coordination and helped draft the manuscript. All authors read and approved the final manuscript.Rapid effects of estradiol in target tissues. Additional File 1 shows different rapid effects of estradiol reported in the literature. The file identifies the physiological effects, the related signaling pathway and the criteria of inclusion in the nongenomic action of estradiol.Click here for file


Accurate delineation of the variable left atrial anatomy is of utmost importance during anatomically based ablation procedures for atrial fibrillation targeting the pulmonary veins and possibly other structures of the atria. Intracardiac echocardiography allows real-time visualisation of the left atrium and adjacent structures and thus facilitates precise guidance of catheter-based ablation of atrial fibrillation. In patients with abnormal anatomy of the atria and/or the interatrial septum, intracardiac ultrasound might be especially valuable to guide transseptal access. Software algorithms like CARTOSound  offer the opportunity to reconstruct multiple two-dimensional ultrasound fans generated by intracardiac echocardiography to a three-dimensional object which can be merged to a computed tomography or magnetic resonance imaging reconstruction of the left atrium. Intracardiac ultrasound reduces dwell time of catheters in the left atrium, fluoroscopy, and procedural time and is invaluable concerning early identification of potential adverse events. The application of intracardiac echocardiography has the great capability to improve success rates of catheter-based ablation procedures. Atrial fibrillation (AF) is the most prevalent sustained cardiac arrhythmia. Catheter-based ablation of AF is usually recommended for patients with symptomatic paroxysmal AF that is resistant to antiarrhythmic drug therapy. This approach is supported by results of randomized and prospective trials comparing antiarrhythmic drug treatment with catheter-based ablation, showing significantly better rhythm control after ablation. In addition, meta-analyses of studies performed mostly in patients with paroxysmal AF, comparing antiarrhythmic drugs and catheter-based ablation, have also clearly supported these findings –5.As catheter-based ablation with electrical isolation of the pulmonary veins (PVs) has become an established therapeutic option for patients with symptomatic AF, accurate recognition of the complex and variable anatomy of the left atrium (LA) is indispensable. Circumferential PV isolation is generally guided by three-dimensional (3D) electroanatomical mapping –8, fluorEndpoints for a circumferential PV isolation procedure are either amplitude reduction within the ablated area , 8, elimIntracardiac ultrasound is a complementary tool to fluoroscopy to guide safe transseptal access. It can be safely used throughout invasive procedures to early detect complications and possibly avoid adverse events. Furthermore, it has helped to improve anticoagulation regimes . The useFor visualisation of cardiac anatomy in general two different ICE technologies are available , 23. TheSector imaging, flexibility in changing the frequency, and full Doppler capabilities make the use of the system with the phased-array ultrasound-tipped catheter preferable, especially in catheter-based ablation procedures. Therefore, the present paper will focus on the clinical application of this system . Vascular access is obtained in most patients via the femoral vein by inserting an 11 F sheath for a 10 F ICE catheter or a 9 F sheath for an 8 F ICE catheter, which is subsequently advanced into the right atrium. The AcuNav ICE catheter provides high-resolution 2D images with a penetration ranging from 2 mm to 12 cm. This allows imaging of the LA with the ICE placed in the right atrium.The use of ICE during interventional cardiac procedures has several advantages compared to transthoracic or transoesophageal echocardiography. In comparison to transoesophageal echocardiography, patient discomfort is less, general anaesthesia is not needed, and there is no risk of aspiration. Transthoracic echocardiography usually does not offer an adequate imaging quality to visualise detailed left atrial anatomy and also would require cumbersome positioning during the ablation procedure by an additional operator.The intracardiac position in the right atrium of the ICE catheter allows detailed visualisation of the LA due to close proximity to cardiac structures . This isThe diameter of the LA is higher in patients with AF than that in patients without AF. Only in 68.6% of patients suffering from AF the anatomical pattern is typical with two right and two left PVs . In compReal-time visualisation of the LA and its adjacent structures is feasible and advantageous for online guiding of mapping and ablation catheters, not least because patients with AF often have atypical anatomical characteristics of the LA.In patients with abnormal anatomy of the interatrial septum (IAS) especially  ICE might be a valuable option to guide safe transseptal access Figures . The ICEAccurate visualisation of the fossa ovalis reduces the risk of complications. The goal of transseptal access is to cross the septum in the posterior region of the fossa ovalis. The more anterior portions of the septum are depicted by views that display the aorta. An anterior puncture is not only less safe but also directs the catheters towards the mitral annulus, left ventricle, and the left atrial appendage. This anterior approach can make manipulations of catheters for an AF ablation procedure difficult because of the posteriorly located ostia of the PVs. Preparing transseptal puncture a Brockenbrough-curved needle is inserted via a transseptal sheath and dilator system and advanced in the posterior region of the fossa ovalis .tenting of the septum at this site. After successful puncture  offers the opportunity to reconstruct multiple 2D ultrasound fans generated by ICE to a 3D object  and has Ablation of AF through PV isolation is a challenging procedure. Success and associated complication rates are largely dependent on the operator and equipment. Due to the complex and varying anatomy of the LA, the LA-PV junction, and the PVs, general anatomical landmarks and fluoroscopic imaging offer vague guidance for left atrial ablation procedures. Image integration, usually with data acquired by CT or MRI of the LA, has thus been employed to accurately guide the safe electrical isolation of the PV ostia . HoweverIntegration of ICE imaging into a 3D reconstruction of the LA and relevant adjacent structures, along with electroanatomic data obtained with the mapping or ablation catheter, is a key upgrade to the utility of ICE for an AF ablation. Endocardial contours of the LA and the PVs can be obtained before transseptal puncture, by advancing the SoundStar 3D Ultrasound Catheter  into the right atrium, the right ventricular outflow tract, and the coronary sinus, if necessary. Real-time imaging ensures correct assessment of the positions of relevant structures, including the oesophagus, which can be accurately outlined and integrated into the model of the LA. This may help to avoid inadvertent heat trauma during ablation. Since the first reports of its use in humans , the CARThe endocardial surface of the LA and its adjacent structures are traced in multiple ICE images creating several ICE fans of left atrial body, left atrial appendage, LSPV, LIPV, RSPV, and RIPV . The resCARTOSound-guided PV isolation was studied with preprocedural MRI only or with the combination of MRI and/or ICE . Total pIntracardiac ultrasound with 3D reconstruction appears to be a safe and effective alternative to MRI and CT data registration, although randomized comparisons are lacking. It is conceivable that this modality will see more widespread use in the near future, as the number of AF ablation treatments increases.For visualisation and navigation of mapping and ablation catheters, ICE is widely used in interventional cardiac electrophysiology. Advances in catheter-based ultrasound transducers and imaging technology provide meticulous images and enable direct real-time visualisation of anatomical structures when performing catheter-based ablation procedures. With an ICE catheter, the same operator is enabled to perform both intracardiac imaging and manipulation of the mapping/ablation catheters.Whereas ablation procedures can be guided by analysis of intracardiac electrocardiograms and fluoroscopy only, the catheter-endocardial tissue contact is not reliably visualised. It has been demonstrated that ICE can ensure adequate catheter-tissue contact in order to achieve transmural lesions  and can Intracardiac ultrasound can provide detailed information on the individual PV anatomy, such as the number of PVs, the presence of common ostia, and additional PVs, which may influence the ablation strategy in anatomical-based isolation procedures . The ICEIntracardiac ultrasound imaging is a valuable tool for early detection of complications during AF ablation procedures and consequently allows for earlier intervention . BecauseUsually thrombus formations form on the transseptal sheaths or the mapping/ablation catheters , 46 and Pericardial effusion can easily be detected and emergency intervention with pericardiocentesis guided by ICE can be performed. Pericardial effusion may occur immediately following catheter perforation of cardiac structures  or in the course of the ablation. Real-time ICE monitoring provides diagnosis of small pericardial effusions prior to hemodynamic changes and has been reported to allow earlier detection of a pericardial effusion than conventional echocardiography .Visualisation of microbubbles by ICE is an important characteristic according to which power settings of the radiofrequency energy delivery can be adjusted to ensure maximal energy delivery at the lowest risk of PV stenosis . In animLeft atrial-oesophageal fistula is a rare but feared possible major adverse event. Intracardiac ultrasound real-time imaging of the posterior LA wall contiguous to the oesophageal anterior wall has proven valuable to prevent damages to the oesophagus. By titration ablation power and/or duration for lesions deployed to the posterior wall of the LA, oesophageal wall oedema and lesion formation can be avoided . AdjustiWith ICE, accurate 2D real-time and/or 3D imaging of the complex anatomy of LA and PVs is feasible. Intracardiac ultrasound improves the efficacy of electrophysiological interventional procedures by exactly identifying anatomical structures and integrating this information with electrophysiological parameters and/or 3D reconstructions of CT/MRI data. Early detection of periprocedural complications optimises emergency management. Implementation of ICE in ablation procedures of AF results in reduction of fluoroscopy/procedure time, potentially reduces complications , and imp


Limbic circuitry disruptions have been implicated in the psychopathology and cognitive deficits of schizophrenia, which may involve white matter disruptions of the major tracts of the limbic system, including the fornix and the cingulum. Our study aimed to investigate regionally specific abnormalities of the fornix and cingulum in schizophrenia using diffusion tensor imaging (DTI). We determined the fractional anisotropy (FA), radial diffusivity (RD), and axial diffusivity (AD) profiles along the fornix and cingulum tracts using a fibertracking technique and a brain mapping algorithm, the large deformation diffeomorphic metric mapping (LDDMM), in the DTI scans of 33 patients with schizophrenia and 31 age-, gender-, and handedness-matched healthy controls. We found that patients with schizophrenia showed reduction in FA and increase in RD in bilateral fornix, and increase in RD in left anterior cingulum when compared to healthy controls. In addition, tract-based analysis revealed specific loci of these white matter differences in schizophrenia, that is, FA reductions and AD and RD increases occur in the region of the left fornix further from the hippocampus, FA reductions and RD increases occur in the rostral portion of the left anterior cingulum, and RD and AD increases occur in the anterior segment of the left middle cingulum. In patients with schizophrenia, decreased FA in the specific loci of the left fornix and increased AD in the right cingulum adjoining the hippocampus correlated with greater severity of psychotic symptoms. These findings support precise disruptions of limbic-cortical integrity in schizophrenia and disruption of these structural networks may contribute towards the neural basis underlying the syndrome of schizophrenia and clinical symptomatology. Limbic circuitry disruptions have been implicated in the psychopathology and cognitive deficits of schizophrenia Diffusion tensor imaging (DTI) is a specific neuroimaging technique that enables measure of the restricted water diffusion in brain tissue. Fractional anisotropy (FA) derived from the diffusion tensor may be influenced by myelination, orientation, coherence, packing density and structural integrity of neural fiber tracts Voxel or region of interest To date, efforts to examine the white matter differences within the limbic white matter bundles (cingulum and fornix) in a detailed manner covering the entire tracts have been sparse. Recently, Segal et al Thirty three right-handed patients with schizophrenia and thirty one age-, gender- and handedness-matched healthy controls were recruited from the Institute of Mental Health, Singapore and the community respectively for this study. The study was approved by the Institutional Review Boards of the Institute of Mental Health, Singapore, as well as that of the National Neuroscience Institute, Singapore. All subjects gave their written informed consent following a complete description of the study. Socio-demographic and clinical information for the two groups of subjects are given in All diagnoses were made by a psychiatrist using information obtained from the clinical history, mental status examination, existing medical records, interviews with significant others as well as the administration of the Structured Clinical Interview for DSM-IV disorders-Patient Version (SCID-P) 2 and 1 baseline with b = 0 sec/mm2 were obtained.Single-shot echo-planar DTI  was acquired using a 3-Tesla whole body Philips scanner with a SENSE head coil. 42 axial slices with 3.0 mm thickness were acquired parallel to the anterior–posterior commissure line; the imaging matrix was 112×109 with a field of view of 230 mm×230 mm, which was zero-filled to 256×256. 15 diffusion weighted images (DWIs) with b = 800 sec/mm3, http://www.mristudio.org) Within each subject, DWIs were first corrected for motion and eddy current distortions using affine transformation to the image without diffusion weighting. These DWIs were then registered to Mori's single-subject DTI atlas (resolution: 1×1×1 mmThe fornix and cingulum bundles in each hemisphere were reconstructed from the mean DTI using the Fiber Assignment Continuous Tracking (FACT) method Two ROIs were manually drawn on the color map. The first ROI was placed on the most anterior coronal plane where the body of fornix is visible on the color map  and the lower segment along the ventral side of the hippocampus (CGH: cingulum adjoining the hippocampus) Both fornix and cingulum bundles were extracted using the FACT fibertracking approach on the averaged DTI. The coordinates of the multiple ROIs in Mori's DTI atlas where each bundle passes through were recorded and easily reproduced using the fibertracking method. However, since the tracking was performed only on the averaged DTI, misalignment of the DTI data across subjects could affect the result of the fiber tracking, especially for small structures like the fornix. To ensure that the fornix of each subject overlapped with the ROI of the fornix extracted from the averaged DTI using the fiber tracking method, we manually segmented the fornix of five subjects  and covariates of age, years of education, and illness duration were performed on the mean FA, RD and AD values in each bundle to elucidate abnormalities in schizophrenia.To detect local differences for values of FA, RD and AD between the two diagnostic groups, the respective values at each point on the mean curve of each bundle was first smoothed by averaging the values of its closest five neighboring points along the curve. Linear regression with the main effects of diagnostic group (control versus schizophrenia) and covariates of age, years of education, and illness duration were then used to examine local differences in FA, RD and AD between the two diagnostic groups. The statistical results were visualized at an overall significance level of 0.05 after Bonferroni correction.Partial correlation analysis was performed to investigate the relationship between the DTI measures within each ROI and psychopathological measures assessed by PANSS in patients with schizophrenia when controlling for age, years of education, and illness duration. To detect the specific location along each bundle where the DTI measure is associated with the psychopathology, the same partial correlation analysis was performed on every point of each bundle. The statistical results were visualized at an overall significance level of 0.05 after Bonferroni correction.Compared to healthy controls, patients with schizophrenia had fewer years of education (p = 0.0005). There was no statistically significant difference in age (p = 0.0744) and sex (p = 0.8754) between the two groups. The average duration of illness in patients with schizophrenia was 12.7 years.Compared to control subjects, patients with schizophrenia showed reductions in FA along the specific regions of the left fornix (For the CGC bundle, the rostral region of the left anterior CGC showed lower FA and higher RD in patients with schizophrenia than in control subjects but no significant difference in AD (Even though the ROI-based analysis did not reveal significant correlations of the PANSS scores with any DTI measures, the tract-based analysis found significant negative correlations of the FA values in the loci of left fornix near to the hippocampus with PANSS total score (This is the first study on schizophrenia to map regionally specific FA, RD, and AD differences along the entire fornix and cingulum in a detailed manner. In the traditional ROI-based analysis, we found significant reductions in FA and increases in RD in bilateral fornix, and RD increase in the left anterior cingulum in patients with schizophrenia compared to controls. Tract-based analysis further revealed specific loci of these white matter differences in schizophrenia in that FA reductions and RD increases occur in the region of the left fornix more distal from the hippocampus and in the rostral portion of the left anterior cingulum. In addition, the white matter properties at specific loci of the left fornix and the right cingulum were associated with psychopathology in patients with schizophrenia. These findings support precise disruptions of limbic-cortical integrity in schizophrenia.Our finding of the mean FA reduction in the left fornix of patients with schizophrenia using tract-based analysis was consistent with findings of earlier studies where tract-based analysis were used Based on tract-based analysis, mean FA reduction in the left anterior CGC in schizophrenia is consistent with previous findings implicating the anterior cingulate region in schizophrenia Regionally specific increase in RD was also found in the rostral region of the left middle CGC. There was a simultaneous increase in AD in this region, which was not picked up by the ROI-based analysis of the entire left middle CGC bundle. These results point to abnormalities in the bundle, which may be due to altered cytoarchitecture leading to increased CSF in this specific region. Compared to the anterior and posterior CGC, the middle CGC showed relatively higher FA and AD and lower RD. The relatively higher mean FA in the middle CGC compared to the anterior and posterior CGC may be related to the composition of long and short neural fibers and the changes along their connections with other brain regions In our study, the white matter differences in the cingulum within schizophrenia were mainly limited to the anterior cingulum but not posterior cingulum, which indicates disruption of connections between the anterior cingulate and the prefrontal cortex which is germane to observed deficits of executive functioning in schizophrenia. Takei et al The negative correlations between FA along specific region of the left fornix and PANSS total, positive and general psychopathology scores are in contrast to the previous finding of absence of correlation between mean FA of fornix, delineated with the ROI-based approach, and psychotic symptomatology There were several methodological strengths and limitations in this study. In terms of strengths, first, we employed the tractography on the averaged DTI such that the fornix and cingulum were delineated only in the subjects' overlapped region. Thus, it potentially reduced partial volume effects at the boundary of each structure on DTI measures. Second, we specifically examined the limbic white matter bundles using the DTI tractographic approach in addition to ROI-based analysis. This tractographic approach has higher specificity and sensitivity compared with conventional ROI or VBM approaches In summary, we employed a tractographic approach to examine region specific FA, RD, and AD differences in the fornix and cingulum bundles. Our results suggested that regionally-specific white matter differences occurred at left fornix and the left anterior and middle cingulum in schizophrenia, which may be due to underlying demyelination of these fiber bundle regions, resulting in the disruption of limbic and cortical connectivities in schizophrenia. Furthermore, decreased FA at the left fornix and increased AD at right cingulum correlated with greater severity of psychotic symptoms in patients with schizophrenia, suggesting that disruption of white matter integrity may contribute towards the neural basis of clinical symptomatology. Considering the role of the hippocampus and cingulate gyrus in schizophrenia neurobiology, further investigation of region specific brain gray and white matter changes over time is needed to better understand the interactional nature of the relationship between these limbic structures and other related cortical and subcortical brain structures in the context of illness onset, progression and response to treatment.


Antibiotic resistance is an increasing challenge for health care services worldwide. While up to 90% of antibiotics are being prescribed in the outpatient sector recommendations for the treatment of community-acquired infections are usually based on resistance findings from hospitalized patients. In context of the EU-project called "APRES - the appropriateness of prescribing antibiotic in primary health care in Europe with respect to antibiotic resistance" it was our aim to gain detailed information about the resistance data from Austria in both the scientific and the grey literature.A systematic review was performed including scientific and grey literature published between 2000 and 2010. Inclusion and exclusion criteria were defined and the review process followed published recommendations.Escherichia coli e.g. the highest antibiotic resistance rates can be seen with fluorochiniolones (19%) and trimethoprim/sulfamethoxazole (27%).Seventeen scientific articles and 23 grey literature documents could be found. In contrast to the grey literature, the scientific publications describe only a small part of the resistance situation in the primary health care sector in Austria. Merely half of these publications contain data from the ambulatory sector exclusively but these data are older than ten years, are very heterogeneous concerning the observed time period, the number and origin of the isolates and the kind of bacteria analysed. The grey literature yields more comprehensive and up-to-date information of the content of interest. These sources are available in German only and are not easily accessible. The resistance situation described in the grey literature can be summarized as rather stable over the last two years. For Comprehensive and up-to-date antibiotic resistance data of different pathogens isolated from the community level in Austria are presented. They could be found mainly in the grey literature, only few are published in peer-reviewed journals. The grey literature, therefore, is a very valuable source of relevant information. It could be speculated that the situation of published literature is similar in other countries as well. The increasing prevalence of antibiotic resistance (AR) is one of the major challenges for the healthcare systems worldwide. Antibiotic resistant infections are associated with a 1.3 to 2-fold increase in mortality compared to antibiotic susceptible infections . MoreoveTwo European initiatives provide valuable information on the topic "antibiotic resistance" in Austria: EARS-Net   and ESACIn the year 2010 an EU-project called "APRES - the appropriateness of prescribing antibiotics in primary health care in Europe with respect to antibiotic resistance" started in nine European countries including Austria. One aim of this cross-sectional project is a systematic analysis of antibiotic resistance pattern of two key-bacteria at the community level. The analysis should be the basis for specific regional and national recommendations concerning the antibiotic prescribing behaviour of physicians in primary health care.In the context of this EU-study we have undertaken a systematic literature review of all scientific papers and also of grey and non-English literature concerning the resistance pattern for the primary care sector in Austria in order to summarize existing facts and knowledge. It was our aim to assess strengths and weaknesses of the resistance situation at the community level described for Austria and to identify the sources and origin of the data published.st of January 2000 and the 31st January 2011. For the review process we followed the recommendations of the PRISMA  statement [A systematic literature review was performed of all available literature published between the 1tatement  as it isStreptococcus pyogenes, Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, Klebsiella pneumoniae for the respiratory tract, Escherichia coli, Proteus mirabilis, Klebsiella spp., Staphylococcus saphrophyticus for the urinary tract and Staphylococcus aureus. Literature containing resistance data from the hospital setting only and the literature not describing the origin either from hospital or primary care setting of the samples were excluded. The language of the literature included was English and German.All types of indexed scientific literature were included. The bacteria included were "Grey literature is that which is produced on all levels of government, academics, business, and industry in print and electronic formats but which is not controlled by commercial publishers." [For the specification of the "grey" literature we used the definition of the Luxembourg Convention on Grey Literature: ishers."  EssentiaThe literature search via electronic searches as well as the review process was carried out by two researchers (KH and GW) for the inclusion and exclusion criteria. Disagreement within the review process was resolved by discussion with the fourth author (MM).The literature search was performed during the period from April 1, 2010 until March 29, 2011.For the scientific literature the databases and search engines PubMed, Medline and Embase were used. Search terms were the MeSH  terms "primary health care" OR "ambulatory care" AND "drug Resistance, Bacterial" AND "Austria" which were combined with the search terms "antibiotic resistance" OR "antimicrobial resistance", "primary care" OR "outpatient" OR "general practice" OR "community", in different combinations. According to the terms in English we used the corresponding German terms "Antibiotika", "Resistenzen", "Allgemeinmedizin", "niedergelassener Bereich" and "Österreich". Additionally, manual searches of the references of relevant articles including reviews were performed.http://www.google.at) and Google Scholar (http://scholar.google.at); in addition a systematic search on websites of institutions and organizations dealing with the sampling and determination of bacteria like regional laboratories for infectious diseases, reference centres or organizations that are responsible for public health like the Ministry of Health and linked facilities was performed. The search terms used were the same as for the scientific literature.The search strategy for the grey literature was conducted via the search engines Google  with respect to the method section described in this literature and a "low quality group"  as recommended by Dobbins et al . Only thThe outcome data extracted were: Numbers and characteristics of the included studies, bacteria types described, sampling location in Austria and general antibiotic resistance findings. Further, the sources of the data were documented.After the rejection of the duplicate papers a total of 82 potential scientific papers were identified of which 9 were excluded on the basis of the year published and 40 were excluded after reading the abstract and title. Further 16 papers were excluded after reading the full text. Most of the papers were excluded because the reported incidence of resistance data was exclusively from the hospital sector in Austria (EARS-Net) or other countries than Austria. Seventeen papers were included into the final review. Figure Table E. coli, ESBL-producing E. coli and other bacteria related to community-acquired uncomplicated urinary tract infections [MRSA situation in Austria [Six articles show the resistance pattern of fections ,26,28-31fections ,27,32-34 Austria ,36 and o Austria . No over Austria .E. coli is summarized as following: "The percentage of the ESBL-producing E. coli is with 6% stable over the last two years in the primary care sector. The highest antibiotic resistance rates for E. coli and ESBL-producing E. coli can be seen with fluorochinolones (19%/85%) and trimethoprim/sulfamethoxazole (27%/82%)."[Tables 7%/82%)."All resistance reports included are published in German only and on special websites.This review provides the most comprehensive and up to date information on the pattern of AR at the community level in Austria. This has been achieved by a thorough search of both the scientific and grey literature.Our analysis shows that the seventeen scientific publications included describe only a small part of the resistance situation in the primary health care sector in Austria table . Half ofIn contrast, the grey literature yields more substantial information on the content of interest tables  and 3. MIn contrast, comprehensive and current antibiotic resistance data from the hospital sector or outpatient antibiotic consumption data in Austria are easy to find in the scientific literature due to the longstanding partnership of Austria with the EARS-Net and ESAC network. These standardized data were collected nationwide and published regularly ,43. ThisThe strengths of this review are its focus on the outpatient setting in Austria and its comprehensiveness by the inclusion of both the scientific and the grey literature. In fact, for our purpose the data contained in the grey literature prove very valuable in achieving our aim of comprehensiveness and reduces publication and selection bias. It could be speculated that the situation of published literature is similar in other countries as well. However, recent studies have examined the impact of the inclusion of the grey literature in systematic reviews to describe the status quo of a situation in more detail -51. EspeThe limitations of this literature review are the reliance on previously published research results. Even more difficult is the reliance on the grey literature found due to the non hierarchic search results with the search engine Google. Moreover, in this review we compared the scientific and the grey literature and draw conclusions on their comprehensiveness and on the public health relevance of their content. Since the scientific papers were independently peer-reviewed and the grey literature was published by organizations without that review process this may affect the methodological quality and therefore, the scientific level of evidence. In addition, it is not possible to directly compare the resistance data described in the scientific and grey literature: in the scientific literature the resistance data are mainly analysed for specific diseases like e.g. uncomplicated urinary tract infections in a defined group of patients, in the grey literature the resistance data reported are the result of all isolates analysed for one specific bacterium regardless of a given disease.In this review, comprehensive and up-to-date antibiotic resistance data of different pathogens, isolated from the primary care level in Austria, are presented. They could be found mainly in the grey literature, only few are published in peer-reviewed journals. The grey literature, therefore, is a very valuable source of relevant information and might reveal possibilities for further research.Based on these findings we recommend collecting and publishing also the non-invasive resistance findings on a regular basis in indexed journals like it is done in the EARS-Net and ESAC network.The authors declare that they have no competing interests.KH and GW performed the literature search; KH performed the extraction of the data and drafted the initial manuscript, GW helped with the extraction of the grey literature data; MM conceptualized the study and helped with data interpretation; PA and MM critically revised the manuscript for important content. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2334/11/330/prepubPRISMA 2009 checklist. Checklist including relevant page numbers for identifying various components of the review.Click here for file