Pain management is a critical but complex issue for the relief of acute pain, particularly for postoperative pain and severe pain in cancer patients. It also plays important roles in promoting quality of care. The introduction of pain management decision support systems (PM-DSS) is considered a potential solution for addressing the complex problems encountered in pain management. This study aims to investigate factors affecting acceptance of PM-DSS from a nurse anesthetist perspective.A questionnaire survey was conducted to collect data from nurse anesthetists in a case hospital. A total of 113 questionnaires were distributed, and 101 complete copies were returned, indicating a valid response rate of 89.3%. Collected data were analyzed by structure equation modeling using the partial least square tool.2=.487) and perceived usefulness  significantly affected nurse anesthetists’ PM-DSS acceptance (R2=.640). Thus, the critical role of information quality in the development of clinical decision support system is demonstrated.The results show that perceived information quality , computer self-efficacy , and organizational structure , both significantly impact nurse anesthetists’ perceived usefulness of PM-DSS. Information quality  significantly impacts nurse anesthetists’ perceptions of PM-DSS ease of use. Furthermore, both perceived ease of use (β=.436, p<.001, RThe findings of this study enable hospital managers to understand the important considerations for nurse anesthetists in accepting PM-DSS, particularly for the issues related to the improvement of information quality, perceived usefulness and perceived ease of use of the system. In addition, the results also provide useful suggestions for designers and implementers of PM-DSS in improving system development. Nursing staff are the major group of healthcare professionals who perform crucial functions in delivering nursing care to inpatients. In addition, they work with patients and other caregivers and in collaboration with medical staff as members of multidisciplinary teams. Therefore, inappropriate or incompetent nursing actions endanger patient safety ,2. TradiPain is regarded as the fifth vital sign in health assessment of patients’ statuses. Nurses, especially those with expertise in pain management, are valuable resources as health care organizations alter their pain assessment and management processes to meet pain standards . RelieviPrior study indicated that individualized pain management should take into account the onset, type, site, duration, intensity, and temporal patterns of the pain, concurrent medical conditions . In addiThe success of pain management depends on nurse anesthetists constantly monitoring patient statuses and making appropriate clinical assessments and analgesics based on patients’ statuses. Consequently, it is critical to provide a pain management decision support system (PM-DSS) for nurse anesthetists to assist in pain assessment, diagnosis, and intervention . RandellThe pain management decision support system (PM-DSS), a CDSS and subsystem of healthcare or hospital information systems (HIS), provides decision support capabilities to healthcare professionals during patient pain management. Quinzio et al.  found thThe PM-DSS records relevant aspects of pain management, ranging from patient admission to clinical care or hospice care units. Patient demographics and laboratory data are imported from the HIS and are supplemented with data that has been imported automatically from previous procedures and pain assessments. Data from respirators and vital-sign monitors are automatically gathered at defined intervals where compatible device interfaces are available .Prior studies have found that users’ acceptance of information technology (IT) is crucial in determining whether IT promotion is successful ,24. TherThis study investigated factors affecting PM-DSS acceptance from the perspective of nurse anesthetists using PM-DSS in a case hospital that implemented the system to support pain management decision processes. The research question of this study was “what critical factors affect nurse anesthetists’ PM-DSS acceptance?” The study results can help hospital managers understand the factors that affect PM-DSS use, thereby providing a reference when systems are introduced or promoted in the future.The remainder of this paper is organized as follows. Methods describes the theoretical foundations, theoretical framework, instruments and participants, and methods for data analysis. Results shows the results. Discussion details an in-depth examination of the findings of this study. Finally, we address implications and offer a conclusion in Conclusions.The key to successful information systems lies in evaluating system acceptance from the users’ perspective . The TecWu et al.  argued tStudies have been conducted to evaluate HIT from partial dimensions of the HOT-fit framework ,41. RandTo provide an in-depth investigation on factors affecting PM-DSS acceptance from the perspective of nurse anesthetists, we propose an extended TAM, as shown in Figure The IS barrier includes considerations of (1) system quality, that is, system response, system reliability, and security, and (2) information quality, meaning integrity, accuracy, format, completeness, and timeliness of information . The devThe human  barrier includes (1) user self-efficacy  ,46, and The organizational barrier involves the following: (1) Organizational structure is a tool and instrument used by enterprises to achieve their objectives and to dominate and coordinate decision-making activities , and it Perceived usefulness represents users’ subjective beliefs in the benefits of using HIT to achieve job goals within medical practice . When nu1: IS factors have a significant impact on nurse anesthetists’ perceived PM-DSS usefulness.H1a: PM-DSS system quality affects nurse anesthetists’ perceived PM-DSS usefulness.H1b: PM-DSS information quality affects nurse anesthetists’ perceived PM-DSS usefulnessH2: IS factors have a significant impact on nurse anesthetists’ perceived PM-DSS ease of use.H2a: PM-DSS system quality affects nurse anesthetists’ perceived PM-DSS ease of use.H2b: PM-DSS information quality affects nurse anesthetists’ perceived PM-DSS ease of use.H3: Human factors significantly affect nurse anesthetists’ perceived PM-DSS usefulness.H3a: Computer self-efficacy affects nurse anesthetists’ perceived PM-DSS usefulness.H3b: Personal innovativeness affects nurse anesthetists’ perceived PM-DSS usefulness.H4: Human factors significantly affect nurse anesthetists’ perceived PM-DSS ease of use.H4a: Computer self-efficacy affects nurse anesthetists’ perceived PM-DSS ease of use.H4b: Personal innovativeness affects nurse anesthetists’ perceived PM-DSS ease of use.H5: Organizational factors significantly affect nurse anesthetists’ perceived PM-DSS usefulness.H5a: Organizational structure affects nurse anesthetists’ perceived PM-DSS usefulness.H5b: The organizational environment affects nurse anesthetists’ perceived PM-DSS usefulness.H6: Organizational factors significantly affect nurse anesthetists’ perceived PM-DSS ease of use.H6a: Organizational structure affects nurse anesthetists’ perceived PM-DSS ease of use.H6b: The organizational environment affects nurse anesthetists’ perceived PM-DSS ease of use.H7: Nurse anesthetists’ perceived PM-DSS ease of use affects system acceptance.H8: Nurse anesthetists’ perceived PM-DSS usefulness of PMDSS affects system acceptance.HThe initial research framework and questionnaires were developed through a literature review, and were revised by three experts in the anesthetic and medical-information field. These experts evaluated the content validity of the questionnaire, in which the measurement of expert validity is based on a content validity index (CVI) of 0.8 , and theWe collected empirical data from nurse anesthetists with more than one year of experience in interventional pain management. The case hospital was a private facility with 2100 beds, which had existed for over 40 years. The hospital is an early adopter in introducing innovative HIT in Taiwan, such as HIS, picture archiving and communication systems (PACS), and EMRs. The hospital is the earliest adopter in implementing mobile healthcare technology, namely mobile nursing information systems, to provide nursing staff with a more efficient manner in obtaining required information from HISs in a timely manner by using a portable information device and wireless technology. In 2010, the hospital established a PM-DSS to provide enhanced clinical diagnostic services and improve patient satisfaction. At present, the hospital has incorporated mobile healthcare technology into the PM-DSS to improve patient safety and quality of care. Nurse anesthetists were asked to use the PM-DSS in the processes of pain management. For these reasons, the hospital was selected as the case hospital in this study.strongly disagree) to 5 (strongly agree).This study employed a survey methodology using a 39-item structured questionnaire, which was composed of two major parts: (1) recording the respondents’ demographic data, and (2) investigating factors affecting the acceptance of a PM-DSS. The questionnaire items were measured using a 5-point Likert scale, scored from 1  before the surveys were distributed and collected. After receiving approval from the IRB of the target hospital, research was conducted from mid-December to mid-January, 2011. Study participation was voluntary. Responses were anonymous and untraceable to individual nurses.The reliability and validity of the measurement model were assessed by confirmatory factor analysis (CFA) -65 by usThe survey was distributed to 113 nurse anesthetists of the case hospital, and 101 completed questionnaires were returned, indicating a valid response rate of 89.3%. This high response rate can be attributed to the top management support and voluntary participation of the respondents of the case hospital. All respondents were women. Most (91.0%) had a graduate diploma, and 83.1% had over 5 years of clinical practice experience. Most respondents 76.2%) were aged between 31 and 40 years. Almost all respondents (97%) have over 5 years of HIS experiences, and all respondents had more than 3 months of PM-DSS experience. Thus, the sample demographics showed that most respondents were experienced users in HISs and had rich experiences in clinical practice. The demographic data of the partcipants were shown in Table % were agAssessing the measurement model of this study involved testing the reliability, convergent validity, and discriminate validity . The relp < .001) in IS characteristics, computer self-efficacy  in human characteristics, and organizational structure  in organizational characteristics had a significant impact on nurse anesthetists’ perceptions of PM-DSS usefulness, supporting H1b, H3a, and H5a. Information quality  in IS factors significantly affects nurse anesthetists’ perceptions of PM-DSS ease of use, supporting H2b. Finally, perceived ease of use  and perceived usefulness  significantly affected PM-DSS acceptance (R2 = .640), supporting H7 and H8. This implied that perceived ease of use and perceived usefulness account for 64% of the total explained variance in nurse anesthetists’ acceptance of PM-DSS. However, inconsistent with our hypotheses, the data show that system quality, personal innovativeness, and organizational environment have no significant impact on perceived usefulness  and perceived ease of use .SEM was used to test the structural model and to enable examining the effects among the nine latent variables. As shown in Figure This study proposed an extended TAM by incorporating Davis’ original TAM framework  and the Consistent with findings obtained by Lu et al. , the resThe results show that perceived information quality, computer self-efficacy, and organizational structure all have a significant impact on nurse anesthetists’ perceived usefulness of a PM-DSS. The most significant influences on nurse anesthetists’ perceived usefulness of a PM-DSS were, in rank order, perceived information quality, computer self-efficacy, and organizational structure. We found perceived information quality to be a significant factor influencing PM-DSS perceived usefulness. Our findings also indicated a consistent result with prior CDSS-related studies ,71.Because the perceived information quality generated by a PM-DSS has a considerable influence on clinical decision making, nurse anesthetists need high information quality when providing clinical, medical, and care services for patients. Thus, PM-DSS development should consider the capacities of a PM-DSS to integrate data from different sources; system accuracy, timeliness, and completeness of generated information; and the degree of compliance of information display methods and definition with professional requirements . Thus, hUser self-efficacy refers to the ability that people have in believing that they must apply IT systems to complete specific tasks . ConsistOrganizational structure is a tool used by enterprises to achieve their objectives and to dominate and coordinate decision-making activities . ConsistAlthough several critical factors affecting PM-DSS acceptance by nurse anesthetists have been identified, perceived system quality, personal innovativeness, and organizational environment were found to have no significant effect on perceived ease of use and perceived usefulness of a PM-DSS. System quality includes the characteristics of system response, system reliability, and security. Contrary to the findings of prior studies ,39, the Personal innovativeness represents the degree to which a person is willing to risk testing an innovation ,48. A prAn organizational environment is the environment in which an organization exists, including external competition, influence of government policies, characteristics of the target audience, and source of funds required for unit operations ,54,55. RThe study results show that perceive ease of use and perceived usefulness have a significant impact on PM-DSS acceptance. This implied that, first, PM-DSS acceptance by nurse anesthetists is affected mainly by their perceptions of perceived usefulness, and second, by their perceptions of the perceived ease of use. The findings are consistent with the results of prior studies that investigated the acceptance of systems from the perspectives of health care professionals ,39,76,77Pain management is a critical but complex issue in the relief of acute pain, particularly for postoperative and severe pain in cancer patients. The introduction of a pain management-decision support system is critical for nurse anesthetists in assisting pain assessment, diagnosis, and intervention. This investigates factors affecting acceptance of PM-DSS from nurse anesthetists’ perspectives. Compared with TAM-based research, our proposed extended TAM model demonstrated a highly totally explained variance better than do traditional TAM (40%) or TAM2 (59%) studies . In addiThe findings of this study are subject to three major limitations. First, the study was performed in a single medical center hospital because the development of PM-DSS in Taiwan is in an early stage. In addition, the data derived from questionnaires was provided by participants with more than 3 months of experience using PM-DSS. Respondents answered questions based on their perceptions, experiences, and understandings. Consequently, the data collected may not be adequately objective. Therefore, the respondents may not sufficiently represent the nurse anesthetist’ population, inhibiting the generalization of this study. Second, we only tested cross-sectional data collected by nurse anesthetists in one period. Finally, the use of PM-DSS in the case hospital is mandatory. Therefore, the findings of this study should be carefully evaluated when applied to a context of voluntary use.This study proposed and validated an extended TAM derived from Davis’ original TAM framework and the HOT-fit framework proposed by Yusof et al. to investigate the factors affecting PM-DSS acceptance by nurse anesthetists. The findings showed that nurse anesthetists’ PM-DSS acceptance is substantially affected by the perceived usefulness and perceived of use of the system, which is consistent with the results of most TAM studies. In addition, the results showed that perceived information quality is the most significant factor affecting perceived ease of use and perceived usefulness. In addition, nurse anesthetists’ computer self-efficacy and organizational structure affected PM-DSS acceptance in this study. Through this study, factors influencing nurse anesthetists’ PM-DSS acceptance were identified, which can help hospital managers devise appropriate strategies in the early stages of system development when healthcare ISs are introduced.This study demonstrates the critical role of perceived information quality on the successful implementation of PM-DSS, and the results are consistent with prior CDSS studies -71 in thThe author declares that they have no competing interests.J-LH is the first author of this paper. She took the responsibilities for the conception and design of the study and collection, analysis and interpretation of data. She also helped to compile the submitted paper and made required modifications of the paper. W-CW is the second author of this paper. She is an expert in nurse-anesthetist with over twenty-year experience. She provided assistances in research design, data collection and interpretation. R-FC is the corresponding author of this paper. He helped to propose adequate research concepts and strategies of this study. He also provided useful suggestions in research design and the collection, analysis and interpretation of data. All authors read and approved the final manuscript.CIN-Computers, Informatics, Nursing, International Journal of Medical Informatics, Journal of Nursing Research, Telemedicine and e-Health, and Total Quality Management & Business Excellence.Ju-Ling Hsiao is an assistant professor of department of Hospital and Health Care Administration at the Chia-Nan University of Pharmacy and Science. Her research interests include nursing informatics, electronic medical record, and hospital information systems. Her published works have appeared in Wen-Chu Wu completed his MS degree in Hospital and Health Care Administration at the Chia-Nan University of Pharmacy and Science. She is a nurse anesthetist and have worked as nursing administrator in a medical center for the past twenty years. Her research interests include studies of pain management, nursing informatics, and hospital information systems.CIN-Computers, Informatics, Nursing, International Journal of Medical Informatics, Journal of Nursing Research, Telemedicine and e-Health, and Total Quality Management & Business Excellence.Rai-Fu Chen is an assistant professor of department of Information Management at the Chia-Nan University of Pharmacy and Science. His research interests include medical informatics, electronic medical record, and healthcare information systems. His published works have appeared in The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1472-6947/13/16/prepub


Breast cancer (BC) is one of the leading causes of death among women worldwide. Immunostimulatory treatment has increasingly been used as adjuvant therapy in the last few years, in patients with melanoma and other cancer forms, often with an induction of autoimmunity as a consequence of a successful treatment. We aimed at investigating if coexisting autoimmune diseases (AD) or hypersensitivities (HS) similarly to the side effects of immunostimulatory treatment resulted in a better overall survival, compared to patients without these disorders.The patient material used was a consecutive clinical material consisting of 1705 patients diagnosed with BC between 1980 and 2010 in Sweden. The patients were stratified according to coexisting AD, HS or lack of both. Overall survival was calculated using Kaplan-Meier and the Cox proportional hazard model.Our main finding was that BC patients with estrogen receptor (ER) negative tumors together with preexisting AD or HS had a statistically significant better overall survival  compared to patients without. Premenopausal BC patients with a coexistence of AD or HS had a better overall survival, but this was not statistically significant.For patients with premenopausal or ER-negative BC, coexistence with AD or HS was associated with a better overall survival. Although these findings require validation, and the mechanisms responsible need to be found, they hint to possible new treatment strategies for BC, especially for those with ER-negative tumors and potentially for premenopausal patients.The online version of this article (doi:10.1186/2193-1801-2-357) contains supplementary material, which is available to authorized users. Immunomodulatory antibodies have been used in phase III trials on metastatic melanoma to enhance anti-tumor immunity. One target protein studied in clinical trials for cancer treatment is Cytotoxic T-Lymphocyte Antigen 4 (CTLA-4). CTLA-4 is expressed on the surface of upregulated T-cells and has an inhibitory effect on T-cell activation. CTLA-4 plays an important role in the induction of tolerance to self-antigens , ever-use of hormonal replacement therapy (HRT) and ever-use of oral contraceptive pills (OCP). Tumor stage, ER-status of the tumor and the date of diagnosis were gathered from pathological reports and patients’ charts. Follow-up was performed until Jan 1st 2011 using the Swedish Civil Register as source. Informed consent was collected from all patients and the study was approved by an ethical board in Sweden (No 110–92).The study material was a cohort consisting of 1705 patients diagnosed with BC. Part of the patient material has been used in previous studies   were calculated using cox proportional hazard. Both the AD and the HS groups were analyzed separately, adjusted for age at diagnosis of BC only, then adjusted for age at diagnosis of BC and TNM-stage and further with each age cut-off added. The AD-HS group was analyzed with the same adjustments initially and then adjustment for screening as well. The following variables were used: age at diagnosis of BC (linear), tumor size status , and positive node status , occurrence of distant metastasis (y/n) and screening (y/n).HR for the AD-HS group was calculated in the subgroups of patients with ER-positive and ER-negative tumors and postmenopausal and premenopausal BC patients. Exclusion criteria included confirmed distant metastasis at diagnosis or carcinoma in situ. Exclusion criteria were set to reduce positive impact on survival in the AD-HS group and due to the low number of metastases. Adjustments were initially made for age at BC diagnosis, secondly age at BC diagnosis and T-stage and N-stage and finally adjustment for screening was added. The following variables were used: age at diagnosis of BC (linear), tumor size status , and positive node status  and screening (y/n).All HR were estimated with 95% confidence intervals (CI). Two-tailed p-values were used for all analyses. A p-value of less than 0.05 was regarded as statistically significant.Out of the 1705 BC patients in this study, 125 (7.3%) had an AD and 72 (4.2%) had HS   . Adding adjustment for TNM-stage as well, a better overall survival effect remained but not statistically significant . Additional adjustment for screening showed a non-statistically significant tendency towards better overall survival . Including only patients younger than 50 years old at BC diagnosis in the analysis the AD-HS group had a tendency towards a better overall survival   is associated with survival, but it has opposite effects in ER-positive compared to ER-negative BC patients. A high LI of ER-positive BC patients was associated with a worse prognosis. However, a high LI in ER-negative BC patients was associated with a better overall survival for these patients. LI occurs as a reaction of the organism to the growing tumor mass. Further, Calabro et al., suggest, that the results might reflect intrinsic differences in the biology of the breast-tumor subtypes and also a difference in tumor immune surveillance. ER-status seems to be important for this differentiation . During this period of time, criteria for diagnosis and available treatments have varied, chiefly for BC, but also for AD, which is another reason why these results needs to be validated in an independent material.Patients with ER-negative BC had a statistically significant better overall survival when they had a history of AD or a HS. The overall survival was better among premenopausal patients with AD or HS compared to patients without AD or HS. These findings need to be validated in an independent material. If an over-activated immune system that accompanies a coexisting AD or HS gives a longer survival for BC patients, an immune activation is a possible future target for treatment, especially for patients with ER negative tumors and for young patients.This study has been approved by an ethical board and complies with the current laws of Sweden.Additional file 1: Table S1: Diseases generally considered as autoimmune: thyrotoxicosis, Autoimmune thyroiditis, Insulin dependent diabetes, Primary adrenocortical insufficiency , Celiac disease, Pernicious anemia, Autoimmune hemolytic anemia, Idiopathic thrombocytopenic purpura, Multiple sclerosis, Guillain Barre syndrome, Iridocyclitis, Wegener’s granulomatosis, Crohn’s disease, Ulcerative colitis, Primary biliary cirrhosis, Chronic hepatitis, Interstitial cystitis, Endometriosis, Pemphigoid, Pemphigus, Psoriasis vulgaris, Alopecia areata, Vitiligo, Seropositive rheumatoid arthritis, Dermatopolymyositis, Myositis, Polymyalgia rheumatica, Myasthenia gravis, Systemic sclerosis, Systemic lupus erythematosis, Sjogren’s syndrome. 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Because expressive and receptive language help to maintain emotional connections to caregivers and support the management of AD patients' functional needs, language plays a critical role in patients' emotional and physical health. Using data from a large prospective clinical trial comparing two doses of donepezil in patients with moderate to severe AD, we performed a post hoc analysis, the Severe Impairment Battery-Language scale (SIB-L) and a new 21-item SIB-derived language scale (SIB[lang]) were used to explore differences in language function between the treatment groups. Correlations between SIB-L and SIB[lang] scores and scores on the severe version of the Alzheimer's Disease Cooperative Study-Activities of Daily Living inventory (ADCS-ADL-sev), the Clinician's Interview-Based Impression of Severity-plus caregiver input/Clinician's Interview-Based Impression of Change-plus caregiver input (CIBIS-plus/CIBIC-plus) and the MMSE were also investigated.In the original randomized, double-blind clinical trial, 1,467 patients with moderate to severe AD  score 0 to 20) were randomized 2:1 to receive donepezil 23 mg/day or to continue on donepezil 10 mg/day for 24 weeks. In this P = 0.0013; SIB[lang] treatment difference 0.8, P = 0.0009). Similar results were observed in a cohort of patients with more severe baseline disease (MMSE score 0 to 16). At baseline and week 24, correlations between the SIB-derived language scales and the ADCS-ADL-sev and CIBIC-plus were moderate, but the correlations were stronger between the language scales and the MMSE scores.At week 24, treatment with donepezil 23 mg/day was associated with an improvement in language in the full intention-to-treat population, whereas language function declined in the group treated with donepezil 10 mg/day (SIB-L treatment difference 0.8, Patients with moderate to severe AD receiving donepezil 23 mg/day showed greater language benefits than those receiving donepezil 10 mg/day as measured by SIB-derived language assessments. Increasing the dose of donepezil to 23 mg/day may provide language benefits in patients with moderate to severe AD, for whom preservation of language abilities is especially critical.NCT00478205ClinicalTrials.gov identifier:  An estimated 5.1 million Americans over 65 years of age have Alzheimer's disease (AD), and more than half of these individuals are classified as having moderate or severe disease -4. In paEffective treatment of the loss of language abilities presupposes the availability of reliable instruments for evaluating such function. Commonly used tools such as the Alzheimer's Disease Assessment Scale-cognitive subscale, which is primarily a clinical trial measure developed to track the progression of AD symptoms , and theN-methyl-D-aspartate receptor antagonist, in moderate to severe AD (baseline MMSE score <15), 21 of the 24 items were found to have a factor loading >0.5 and were subsequently included in a new language scale, the SIB Language scale (SIB-L). Three of the twenty-four items had a factor loading <0.5 and were excluded from the SIB-L; the maximal SIB-L score is 41. A subsequent post hoc analysis of data from the same four trials, but which excluded patients who did not have language deficits at baseline, demonstrated significant differences on the SIB-L favoring active treatment over placebo, but SIB-L scores were decreased compared with baseline in both treatment arms  scale scores for the 23 mg/day and 10 mg/day treatment groups were analyzed using an analysis of covariance model with terms for baseline score, country and treatment. For each end point, the least squares (LS) or adjusted mean for each treatment group was calculated, as were between-treatment differences (donepezil 23 mg/day compared with donepezil 10 mg/day) in adjusted means, 95% confidence intervals (95% CIs) for the differences and the Relationships between SIB-L and SIB[lang] scale scores and scores on the MMSE, the Clinician's Interview-Based Impression of Severity-plus caregiver input  and CIBIC-plus, and the severe version of the Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL-sev) were examined. The ADCS-ADL-sev scale was analyzed both as a complete unit and when separated into two subscales reflecting basic and instrumental ADL abilities. Pearson correlation coefficients were calculated for baseline, week 24 and change from baseline scores. Because higher scores on the SIB-derived language scales, the MMSE and the ADCS-ADL-sev indicate less impairment, correlation coefficients between these measures are positive. Since higher scores on the CIBIS-plus/CIBIC-plus scales indicate greater impairment, correlation coefficients for relationships between SIB-L or SIB[lang] scores and CIBIS-plus/CIBIC-plus scores are negative.The full ITT population comprised 1,371 patients, 909 of whom received donepezil 23 mg/day and 462 of whom received donepezil 10 mg/day. Demographics and baseline disease characteristics were similar for both donepezil treatment groups (Table P < 0.001)  scores were moderately correlated with scores on the ADCS-ADL-sev (5) Table . BaselinAt week 24, correlations between SIB-L and SIB[lang] scores and scores on the ADCS-ADL-sev and MMSE were marginally but consistently stronger than at baseline Table . In contCorrelations between change from baseline in SIB-L and SIB[lang] scores and change from baseline in scores on other assessments were generally of weak to moderate strength, with the MMSE scores showing the strongest correlation Table . LikewisThe already fragile relationships in the lives of patients with AD can become profoundly disrupted as patients lose the ability to communicate coherently. Attachment to caregivers and others becomes compromised, and the effect of such detachment on caregivers can be deleterious. Furthermore, it is difficult for clinicians and caregivers to render optimal care in the absence of clear input from patients regarding what they are feeling or concerned about. When language comprehension deteriorates, it is also likely to further increase caregiving stress, as patients have difficulty understanding conversation and even simple directions. Moreover, decline in language is associated with increased risk of mortality . Therefopost hoc analysis, we found that treatment with donepezil 23 mg/day resulted in significant improvement in language ability compared with donepezil 10 mg/day in patients with moderate to severe AD as measured by the two SIB-derived language scales: the SIB-L, and the SIB[lang].In the primary study of donepezil 23 mg/day versus donepezil 10 mg/day, patients treated with donepezil 23 mg/day showed significant improvement in cognition, as measured by the SIB, compared with patients taking donepezil 10 mg/day  scales. Moreover, there is clearly some overlap between certain aspects of language impairment, such as word-finding difficulty, and more general memory retrieval problems. Nevertheless, the items included in the SIB-L and SIB[lang] scales cover a broad range of language functions, including processes that are not highly dependent on memory, and, as such, treatment effects on memory are likely to account for a relatively small portion of the observed language improvements. Ultimately, the direct and indirect mechanisms whereby donepezil 23 mg/day provides improved language benefits over the donepezil 10 mg/day dose need to be determined in adequately designed prospective studies.post hoc analysis of the specific language effects of memantine in patients with moderate to severe AD (MMSE scores 3 to 14) enrolled in six clinical trials, memantine was associated with significantly better SIB language subscale scores compared with placebo; however, scores in both groups declined from baseline to the end of the study (six months)  scores were moderately correlated with baseline scores for the ADCS-ADL-sev and CIBIS-plus, suggesting that language abilities and functional abilities may be interrelated in the moderate to severe AD population. However, correlations for change from baseline scores were only of moderate to weak strength. As Farlow and colleagues  scores for all relationships explored. However, correlations between the language scales and the MMSE were substantially stronger for baseline and week 24 scores  that was sponsored by Eisai Inc. Editorial assistance was provided by PAREXEL Inc. and was funded by Eisai Inc. and Pfizer Inc. The article-processing charge was financed by Eisai Inc. and Pfizer Inc. SHF has served as a paid scientific consultant to Pfizer Inc related to donepezil and several investigational compounds . His institution has received grant/contract support from Pfizer Inc for the conduct of clinical trials of dementia and to support educational programs. He has also served as a scientific consultant to other companies marketing or developing drugs for cognition, including Lundbeck, Elan, Janssen AI, Eli Lilly, Merz, Novartis, Toyama, Bellus Health, Bayer Healthcare, Accera, Otsuka, Sunovion, Symphony Icon and Torrey Pines, and his institution has received grant/contract support for clinical trials from Pfizer, Eli Lilly, Janssen AI, Baxter and Bristol-Myers Squibb. He also has stock options from Accera, Intellect Neurosciences, MedAvante and Symphony Icon. FAS has no financial competing interests to report. He has served on a Data Safety Monitoring Committee for Pfizer Inc for which the University of Kentucky received reimbursement . JS has been paid as a consultant to Eisai Inc., Pfizer Inc, Forest Pharmaceuticals and Novartis. JS currently receives royalties from the original Severe Impairment Battery on which this reduced scale is based. SR is an ex-employee of Eisai Inc. JM is an employee of Pfizer Inc. YS is an employee of Eisai Inc. YX was an employee of Pfizer Inc.The analyses described in this article derive from a phase III clinical study  language subscale.Click here for file


Finding duplicates is an important phase of systematic review. However, no consensus regarding the methods to find duplicates has been provided. This study aims to describe a pragmatic strategy of combining auto- and hand-searching duplicates in systematic review and to evaluate the prevalence and characteristics of duplicates.Literatures regarding portal vein thrombosis (PVT) and Budd-Chiari syndrome (BCS) were searched by the PubMed, EMBASE, and Cochrane library databases. Duplicates included one index paper and one or more redundant papers. They were divided into type-I (duplicates among different databases) and type-II  duplicates. For type-I duplicates, reference items were further compared between index and redundant papers. Of 10936 papers regarding PVT, 2399 and 1307 were identified as auto- and hand-searched duplicates, respectively. The prevalence of auto- and hand-searched redundant papers was 11.0% (1201/10936) and 6.1% (665/10936), respectively. They included 3431 type-I and 275 type-II duplicates. Of 11403 papers regarding BCS, 3275 and 2064 were identified as auto- and hand-searched duplicates, respectively. The prevalence of auto- and hand-searched redundant papers was 14.4% (1640/11403) and 9.1% (1039/11403), respectively. They included 5053 type-I and 286 type-II duplicates. Most of type-I duplicates were identified by auto-searching method . Nearly all type-II duplicates were identified by hand-searching method . Compared with those identified by auto-searching method, type-I duplicates identified by hand-searching method had a significantly higher prevalence of wrong items . Most of wrong items originated from EMBASE database.Given the inadequacy of a single strategy of auto-searching method, a combined strategy of auto- and hand-searching methods should be employed to find duplicates in systematic review. Systematic review is characterized as explicitly formulated, reproducible, and up-to-date summary of the effects of health care interventions Herein, we attempted to describe our methods to find duplicates among the PubMed, EMBASE, and Cochrane library databases in systematic review and to evaluate the prevalence and characteristics of duplicates.Literatures in two fields were retrieved to minimize the potential selection bias. They included “portal vein thrombosis” and “Budd-Chiari syndrome” literatures. The selection of the two fields was primarily attributed to our research interests in the two vascular disorders of the liver type I (duplicates among databases) and II (duplicate publications). Type I duplicates were defined as one paper was simultaneously recorded in one database twice or more times or in two or three databases . All literatures were expressed in Vancouver reference type. In the Endnote library, QX used the “After auto-searched redundant papers were removed, the remaining literatures were alphabetically ordered according to the first authors’ names. Then, duplicates were identified among the literatures by the same first author. In details, ifNotably, if the first author’s name was wrongly spelt or missing or the authors’ order was reversed in some database, we would miss some duplicates. Accordingly, to minimize the quantity of missed duplicates, the literatures were also alphabetically ordered according to the titles. Then, duplicates were identified among the literatures with the same titles. YM and JJ were responsible for the literatures regarding portal vein thrombosis, and QX and RW for the literatures regarding Budd-Chiari syndrome. QX and YM were also responsible for rechecking the accuracy of their tasks. Disagreement would be resolved by discussion among the four review authors.We just compared the difference of reference items between index and redundant papers of type I duplicates, but not type II duplicates. This behavior was primarily attributed to the fact that nearly all type II duplicates had different journal’s name, volume, issue, and page between index and redundant papers. QX and YM extracted the detailed information of type I duplicates  into an Excel table . Then, QX and YM compared the difference of reference items between index and redundant papers, and identified “acceptable or unacceptable” duplicate publications in order to distinguish whether or not they had wrong information.see examples in Difference between index and redundant paper(s) would be considered acceptable to readers and reference reviewers, if the information was expressed in different styles. These different styles included: 1) punctuation, space, or case was different; 2) author’s middle name was omitted; 3) title of non-English language paper and non-English language journal’s name were translated into different words, but their meanings were identical; 4) journal’s name was expressed in full or abbreviated style; 5) publication date was expressed in “year” or “year month (day)” style; and 6) volume, issue, or page was expressed in different styles, but their meanings were identical (see examples in Difference between index and redundant paper(s) would be considered unacceptable to readers and reference reviewers, if the information was wrongly expressed. These wrong styles included: 1) author’s name and order, title of English language paper, and/or journal’s name was wrongly recorded, added, or missing; and 2) publication date, volume, issue, and/or page was wrong or missing  was calculated as follows:The proportion of type I and II duplicates was compared between auto-searching and hand-searching methods. The prevalence of different and wrong items in type I duplicates was compared between auto-searching and hand-searching methods. Two-tailed P values <0.05 were considered statistically significant. The statistical analyses were performed in SPSS 12.0 .Overall, 10936 papers were identified via the three databases, including 6733 from PubMed database, 4002 from EMBASE database, and 201 from Cochrane library database  was the most commonly different item, followed by journal’s name , title , page , issue , volume , and author  Table 4.EMBASE database had the highest proportion of wrong information regarding page, issue, and volume items  was the most commonly different item in hand-searched duplicates, followed by publication date , author , title , page , volume , and issue  Table 4.EMBASE database had the highest proportion of wrong information regarding author, title, journal, and publication date items. Cochrane library database had the highest proportion of wrong information regarding volume and page items. PubMed database had the highest proportion of wrong information regarding issue item (The number of duplicates identified by auto-searching methods was larger than that identified by hand-searched duplicates (2399 versus 1307). Most of type I duplicates were identified by auto-searching methods . The proportion of type I duplicates among the auto-searched duplicates was significantly higher than that among the hand-searched duplicates . Nearly all type II duplicates were identified by hand-searching methods . The proportion of type II duplicates among the auto-searched duplicates was significantly lower than that among the hand-searched duplicates .Compared with those identified by auto-searching methods, type I duplicates identified by hand-searching methods had a significantly higher prevalence of different and wrong items .Overall, 11403 papers were identified via the three databases, including 5894 from PubMed database, 5278 from EMBASE database, and 231 from Cochrane library database  was the most commonly different item, followed by journal’s name , title , page , issue , author , and volume  Table 2.EMBASE database had the highest proportion of wrong information regarding page, issue, and volume items  was the most commonly different item in hand-searched duplicates, followed by title , author , publication date , page , volume , and issue  Table 4.EMBASE database had the highest proportion of wrong information regarding author, title, journal’s name, and publication date items. Cochrane library database had the highest proportion of wrong information regarding volume, issue, and page items . Most of type I duplicates were identified by auto-searching methods . The proportion of type I duplicates among the auto-searched duplicates was significantly higher than that among the hand-searched duplicates . Nearly all type II duplicates were identified by hand-searching methods . The proportion of type II duplicates among the auto-searched duplicates were significantly lower than that among the hand-searched duplicates .Compared with those identified by auto-searching methods, type I duplicates identified by hand-searching methods had a significantly higher prevalence of different and wrong items .Finding duplicates among different databases is an indispensable and important phase of systematic review. The phase is not as easy as we expected according to our previous experiences of systematic reviews A major finding of our study was that a large number of duplicates could be found among the three databases in systematic review. Notably, about 10% of literatures remained duplicates among the three databases after auto-searching duplicates, which strongly suggested the necessity of hand-searching duplicates in systematic review.We further compared the difference of reference items between index and redundant papers of type I duplicates. Nearly all type I duplicates had different items between index and redundant papers. Regardless of the literatures regarding portal vein thromobosis or Budd-Chiari syndrome and auto-searched or hand-searched duplicates, “journal’s name”, “publication date”, and “title” were three most commonly different items. Most of them were acceptable, for example, journal’s name was expressed in full or abbreviated style, publication date was expressed in “year” or “year month” style, and titles used different punctuations and/or cases in different databases. This finding could be potentially explained by the fact that each database had its own special reference type. Other items were uncommon, but were mostly unacceptable. For example, author, volume, issue, or page was wrong or missing. These mistakes should be corrected, thereby decreasing the prevalence of type I duplicates.see examples in In addition, our study explored the origin of wrong information in type I duplicates. Regardless of the literatures regarding portal vein thrombosis or Budd-Chiari syndrome, EMBASE database had the highest proportion of wrong information regarding author, title, journal, and publication date items. These mistakes in EMBASE database were severe . This phenomenon could be readily explained by the fact that the authors, titles, and publication years were often different between index and redundant papers among type II duplicates. Additionally, the wrong reference items were rarely observed among type I duplicates identified by auto-searching methods, but very frequently among those identified by hand-searching methods. This finding also suggested the limitation of auto-searching duplicates, in which “author”, “title”, and “publication date” items should be exactly matched between two literatures. Accordingly, the necessity of combining auto- and hand-searching methods should be fully recognized in finding duplicates in systematic reviews.Several limitations of this study should be clearly recognized. First, the selection of portal vein thrombosis and Budd-Chiari syndrome literatures was based on our subjectivity. Accordingly, the conclusions achieved by analyzing these literatures might be unsuitable for the literatures from other fields. But it should be noted that we employed a comprehensive search strategy and literatures of two fields to strengthen our conclusions. And given that the results were similar between portal vein thrombosis and Budd-Chiari syndrome literatures, it was possible that these findings of our study might be generalizable. Certainly, further studies should be warranted to compare the frequency of wrong information from a random sample of literatures among the three databases. Second, only three databases were searched in our study. This behavior might underestimate the prevalence of duplicates among databases. However, given that PubMed, EMBASE, and Cochrane library were three most common databases used for systematic review, our results should be a representative sample. Third, only two approaches were employed in this study to identify hand-searched duplicates. It was not easy to find duplicates as both the first author’s name and title were different between index and redundant papers. Thus, the prevalence of duplicates might be underestimated. Fourth, a minority of full texts could not be obtained to identify the origin of wrong information. However, it should be noted that we tried our best to contact with the authors and seek help from our and other University libraries. And these unavailable full texts did not substantially influence our judgment on the proportion of wrong information in different databases.In conclusions, a high prevalence of duplicates could be identified among the PubMed, EMBASE, and Cochrane Library databases in systematic review. These findings were primarily attributed to the effect of a pragmatic strategy of combining auto- and hand-searching methods to find duplicates. Indeed, a single strategy of auto-searching method was inadequate to find duplicates, especially type II duplicates. In general, to enhance the transparency of systematic review, PRISMA might require the reporting of the detailed information regarding the methods to find duplicates and the quantity of duplicates identified by different methods. In addition, considering that wrong reference items were frequently observed in type I duplicates identified by hand-searching methods, we strongly recommended that the information of every reference should be strictly examined and carefully inputted by database administrators.File S1Duplicates identified by auto-searching method in portal vein thrombosis literatures.Click here for additional data file.File S3Type-II duplicates identified by hand-searching method in portal vein thrombosis literatures.(XLS)Click here for additional data file.File S4Duplicates identified by auto-searching method in Budd-Chiari syndrome literatures.(XLS)Click here for additional data file.File S5Type-I duplicates identified by hand-searching method in Budd-Chiari syndrome literatures.(XLS)Click here for additional data file.File S6Type-II duplicates identified by hand-searching method in Budd-Chiari syndrome literatures.(XLS)Click here for additional data file.


An increasingly ‘screen-based’ culture raises concerns for the health and well-being of America’s youth. We investigated whether nature-based experiences affected the social well-being of young adults attending a three-week wilderness camp.Online surveys  were administered. We used paired t-tests (N=35) to analyze differences in social well-being as measured by Ryff’s Positive Relations with Others subscale. In situ interviews (n=20) explored relationships between the camp experience, nature, and well-being. Interviewees were selected to produce a maximum variation sample along dimensions of gender, previous nature experiences, and nature connectedness. Analysis of interviews identified elements of social connection and the role played by nature.Quantitative assessment of social well-being showed no significant change . Interview results, however, strongly emphasized social relationships describing the process of making friends, the importance of being part of a group, and how the wilderness environment facilitated connection. Making friends was enhanced by spending time together, listening to each other, and developing intimacy. Being part of a group included subthemes of a sense of community, engaging in group play, working together as a team, and the bonding effect of shared experiences. The natural environment specifically enhanced these processes through loss of ego, breaking down barriers, and limited distractions. This facilitated deeper relationships than would occur in urban surroundings, and afforded social-relatedness , positive feelings , and a sense of interdependence with others .Nature experiences do enhance social well-being among young adults, but this construct is poorly measured by existing instruments. Further research into the effects of nature-based therapies on young people’s well-being is important for society and requires careful selection or development of measures of the social dimension as actually experienced by participants.


Idiopathic purpura fulminans is a cutaneous thrombotic disorder usually caused by autoimmune-mediated protein C or S deficiency. This disorder typically presents with purpura and petechiae that eventually slowly or rapidly coalesce into extensive, necrotic eschars on the extremities. We present the first known case of idiopathic purpura fulminans consistent with prior clinical presentations in the setting of a prothrombotic genetic mutation, but without hallmark biochemical evidence of protein C or protein S deficiency. Another novel feature of our patient's presentation is that discontinuation of anti-coagulation has invariably led to recurrence and formation of new lesions, which is unexpected in idiopathic purpura fulminans because clearance of autoimmune factors should be followed by restoration of anti-coagulant function. Although this disease is rare, infants with suspected idiopathic purpura fulminans should be rapidly diagnosed and immediately anti-coagulated to prevent adverse catastrophic outcomes such as amputation and significant developmental delay.A six-month-old Caucasian boy was brought to our pediatric hospital service with a low-grade fever and subacute, symmetric, serpiginous, stellate, necrotic eschars on his forearms, legs and feet that eventually spread non-contiguously to his toes, thighs and buttocks. In contrast to his impressive clinical presentation, his serologic evaluation was normal, and he was not responsive to corticosteroids and antibiotics. Full-thickness skin biopsies revealed dermal vessel thrombosis, leading to a diagnosis of idiopathic purpura fulminans and successful treatment with low-molecular-weight heparin, which was transitioned to warfarin. Long-term management has included chronic anti-coagulation because of recurrence of lesions with discontinuation of treatment.In infants with necrotic eschars, it is important to first consider infectious, inflammatory and hematologic etiologies. In the absence of etiology for protracted idiopathic purpura fulminans, management should include tissue biopsy, in which thrombotic findings warrant a trial of empiric anti-coagulation. Some infants, including our patient, may need long-term anti-coagulation, especially when the underlying etiology of coagulation remains unidentified and symptoms recur when treatment is halted. Given that our patient still requires anti-coagulation, he may have a yet to be identified autoimmune-mediated mechanism for his truly idiopathic case of protracted purpura fulminans. Purpura fulminans (PF) is caused by a relative deficiency in protein C-mediated hemostasis and is classified by etiology and history into neonatal PF, acute infectious PF and idiopathic or post-infectious PF. Neonatal PF is caused by homozygous or compound heterozygous deficiencies in protein C or protein S and manifests shortly after birth . In contet al. [et al. [et al. [in vitro. All of the patients in the Levin et al. [et al. series had other laboratory abnormalities, including elevated anti-cardiolipin immunoglobulin M (IgM) and IgG antibodies, IgG-containing immune complexes, decreased C4B binding protein and decreased protein C activity.Idiopathic PF, an extremely rare disease, is attributed to the development of anti-protein S antibodies, which form antibody-protein S complexes that are excreted, leading to transient protein S deficiency, hypoactivation of the protein C pathway and dermal vessel hypercoagulability. Important evidence suggests a post-infectious etiology. After D'Angelo et al.  identifi [et al.  discover [et al.  confirmen et al.  case seret al. [et al. [Despite the important work by D'Angelo et al.  and Levi [et al.  with reg [et al. ,10. The  [et al. . These cA previously healthy six-month-old Caucasian boy was brought to our pediatric hospital service for a second opinion regarding a six-week history of necrotic skin lesions on his upper and lower extremities. The lesions were initially petechial and rapidly evolved into escharotic plaques over a 10-day period. They were accompanied by the onset of a low-grade intermittent fever and night sweats. One month after his initial presentation, the lesions had spread to involve the distal, dorsal surface of his feet and toes. His parents denied any trauma, burns or other inciting injuries.He had an extended family history of stroke, miscarriages, deep venous thromboses, pulmonary emboli and multiple sclerosis, but his parents denied any coagulopathies, bleeding disorders or rheumatologic diseases. His social history was non-contributory. His vaccinations were up-to-date, and he had received his most recent ones about three weeks before the onset of the lesions, which included vaccinations for diphtheria-tetanus-acellular pertussis, haemophilus influenzae type B, inactivated polio vaccine, hepatitis B virus, heptavalent pneumococcal vaccine and rotavirus vaccine.Outside investigations included a negative skeletal survey and normal laboratory studies. He received a short, unsuccessful course of methylprednisolone. At the time of presentation, his only other medications were ranitidine  and omeprazole (0.67 mg/kg/day) for gastroesophageal reflux disease and lactulose for a recent history of constipation that began after rice cereal was added to his diet.Upon admission to our hospital, his physical examination revealed an infant who was alert, active and intermittently fussy. His vital signs were heart rate 128 beats/minute, blood pressure 126/94 mmHg, respiratory rate 42 breaths/minute and body temperature 36.9°C. His skin examination revealed blackened, eschar-like, linear but serpiginous, stellate, spatially non-contiguous lesions with peripheral yellow crusting. There were symmetrical necrotic plaques on his forearms, distal legs, dorsal surface of his feet and his toes, including the first two toes on each foot Figures  and 1b. The results of our initial laboratory investigation are shown in Table Neisseria animaloris (2+) and a few white blood cells, and stains of the biopsy were negative for acid-fast organisms, mycobacterium, and fungi. Immunofluorescence staining was negative for IgG, C3 and fibrinogen, while IgA stained weakly positive in rare dermal blood vessels and IgM stained positive in a few scattered blood vessels in the dermis.Punch biopsies from all four limbs revealed a pauci-inflammatory occlusive vasculopathy. Direct immunofluorescence showed strong IgM staining in the superficial and mid-dermal vessels, weak C3 staining in a few superficial vessels and some fibrinogen deposition in the superficial and mid-dermal vessels. Staining for IgG and IgA was negative. Excisional biopsy tissue was cultured and revealed anaerobic Gram-positive cocci (3+), enterococci (3+), The patient was discharged on wet-to-dry dressing changes, and his laboratory abnormalities at dismissal are shown in Table The patient was re-admitted one week later because of progression of his skin disease. Flexion contractures were noted at the elbows and knees. Laboratory values at readmission are shown in Table After the extensive negative work-up and given the lack of a definitive diagnosis, a peripheral inserted central catheter line was placed for the initiation of high-dose IV prednisone (Four mg/kg/day). He was started empirically on IV ampicillin/sulbactam . Corticosteroids were tapered over the next seven days.One week later he showed no clinical improvement. Following interdisciplinary conference and consultation with pediatric coagulation experts, we decided to treat him empirically for idiopathic purpura fulminans with dalteparin (two SQ doses at 250 U/kg/day). This regimen was adjusted to 350 U/kg/day divided into two SQ doses to achieve a therapeutic heparin level. Acetylsalicylic acid was also added. Physical therapists were consulted because of motor skill regression with skin contractures.At his follow-up examination one week later, his parents reported that no new lesions had developed. The eschars had begun to regress centrifugally from their borders, revealing healing pink scars, especially in his upper extremities. After several weeks, peripheral areas of crusting had shed, revealing healed, scarred skin Figures  and 2b.Follow-up at two months demonstrated dramatic healing Figures  and 3b. SMN1 gene at position 91 in codon 31, which causes a frame shift mutation and is consistent with spinal muscular atrophy.About one year after initial presentation, our patient was experiencing developmental delays that were especially noted in gross motor function. Neurology consultation was sought, and their work-up revealed proximal muscle weakness and areflexia. Further investigation revealed that he is heterozygous for a duplication of a thymine nucleoside in his The differential diagnosis for an infant with necrotic skin lesions is listed in Table The most novel divergence of our patient's idiopathic PF from prior cases was the disparity in laboratory evidence. Fascinatingly, our patient had no absolute or relative deficiencies in protein C and S levels or activities, features present in the prior reported cases. Protein C activity was measured using venom activator and chromogenic peptide substrate; therefore, it is possible that a congenital protein C variant may not have been identified that would require a clot-based assay. Protein S antigen was measured using free protein S assay, and protein S activity was measured using a clot-based end point. This protein S assay can be affected by the presence of lupus anti-coagulant or a specific factor V inhibitor, but we did not identify either of these humoral factors.N. animaloris in the progression of his lesions remains undefined. He may have a novel form of idiopathic PF, possibly preceded by an unidentified infection or caused by a defect in protein S that we were unable to detect using conventional laboratory assays. We are also unable to assess the potential contribution of his series of vaccines to his disease presentation, and although it would be unlikely for a child to develop autoantibodies before 6 months of age, we do not rule out the possibility that he may have developed autoantibodies after immunization.Also, the peripheral smear abnormalities, especially the Döhle bodies, can be associated with DIC-linked purpura fulminans, yet we saw no evidence of consumptive coagulopathy characteristic of DIC. The specific role of Another important aberration in the patient's presentation was his age, because he was older than the expected age for neonatal PF and younger than all of the other reported cases of idiopathic PF that we reviewed. While our patient's initial response to anti-coagulation therapy was the aspect of his presentation and outcome, which fit most closely with that of idiopathic PF, his long-term need for anti-coagulation is not consistent with the previously described etiology of this disease.The photographs associated with this case offer a dramatic example of clinical management for the pediatrician or dermatologist who may see similar lesions in a non-septic infant with an unrevealing laboratory evaluation. The decision to empirically anti-coagulate represented our best scientific response to the overlapping and non-specific findings for idiopathic PF.In light of his impressive response to treatment as depicted in the final set of images Figure , we wishResponses to treatment in the referenced cases were similar to those of our patient. Lesions regressed as early as one day after therapy was initiated. Protein C and protein S levels often took weeks to months to return to normal reference levels. As noted in Table We report the first known case of idiopathic PF without protein C or S deficiency and necessitating chronic anti-coagulation. Pediatric patients presenting with indolent, symmetric, necrotic, eschar-like lesions who have an unrevealing infectious, inflammatory and hematologic work-up should undergo an empiric trial of anti-coagulation to help prevent downstream catastrophic consequences of PF. Starting anti-coagulation decisively may also help to prevent developmental delays in rapidly growing infants with this disease.Written informed consent was obtained from the patient's next-of-kin for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.per os (by mouth); PT: prothrombin; RBC ALA: red blood cell Δ-aminolevulinic acid; SQ: subcutaneous.ACE: angiotensin-converting enzyme; ANA: anti-nuclear antibody; aPTT: activated partial thromboplastin time; ASD: atrial septal defect; AST/ALT: alanine/aspartate transaminase; AT III: anti-thrombin III; BUN: blood urea nitrogen; Cr: creatinine; CRP: C-reactive protein; DRVVT: dilute Russell's viper venom test; ECG: electrocardiogram; ESR: erythrocyte sedimentation rate; HSP: Henoch-Schonlein purpura; PDA: patent ductus arteriosus; PO: The authors declare that they have no competing interests.FM, KP, EB and CB admitted the patient to the pediatric hospital service, performed the patient work-up and wrote the case report. FM was a major contributor in writing the manuscript and did the literature review. DD and VR conducted additional dermatologic and hematologic investigations, respectively. All authors read and approved the final manuscript.


Sleep homeostasis is characterized by a positive correlation between sleep length and intensity with the duration of the prior waking period. A causal role for brain-derived neurotrophic factor (BDNF) in sleep homeostasis has been suggested, but the underlying mechanisms remain unclear. Cortistatin, a neuropeptide expressed primarily in a subset of cortical GABAergic interneurons, is another molecule implicated in sleep homeostasis.We confirmed that sleep deprivation leads to an increase in cortical cortistatin mRNA expression. Disruption of activity-dependent BDNF expression in a genetically modified mouse line impairs both baseline levels of cortistatin mRNA as well as its levels following sleep deprivation. Disruption of activity-dependent BDNF also leads to a decrease in sleep time during the active (dark) phase.Our studies suggest that regulation of cortistatin-expressing interneurons by activity-dependent BDNF expression may contribute to regulation of sleep behavior. Sleep behavior is dependent on two processes; circadian regulation as well as homeostatic regulation ,2. CircaBDNF, Arc, Homer and NGFI-A in the cerebral cortex, and the extent of SWA, a sensitive marker for sleep pressure and sleep need [A recent study provided a biological link between synaptic plasticity in the cerebral cortex and sleep homeostasis . There ieep need . A key feep need .BDNF is widely expressed in the developing and mature brain, and plays an important role in neuronal survival and differentiation during development, and in synaptic plasticity in the adult brain -13. BothCells expressing the neuropeptide cortistatin define a subset of GABAergic interneurons, which are found in highest abundance in the cerebral cortex and hippocampus ,26. CortIn the present study, we show that a genetic manipulation that leads to disruption of activity-dependent BDNF expression results in impairments in sleep regulation and behavior that are consistent with a deficit in sleep homeostasis. In parallel, we show that this genetic alteration leads to misregulation of cortistatin gene expression. Our results suggest that BDNF regulation of sleep homeostasis may, at least in part, be mediated via activity-dependent BDNF regulation of a subpopulation of cortistatin-expressing interneurons.Bdnf gene transcription is driven by at least nine different promoters, each of which drives transcription of a short, 5' non-coding exon, which is spliced to a 3' common coding exon [Bdnf from promoter IV, the promoter most sensitive to neuronal activity [Bdnf promoter IV locus (BDNF-KIV) [Bdnf mRNA in the medial prefrontal cortex (mPFC) in the BDNF-KIV and their wild type (WT) littermates in regular, resting housing conditions without any manipulation. Surprisingly, we found that in addition to complete disruption of promoter IV-driven transcription, there was a significant dampening of basal Bdnf transcription, including transcription driven by promoters I, II, III, VI, and IXa in the resting condition, whereas basal transcription driven by promoters V and VIII was less affected  . In thesDNF-KIV) . The aimBdnf transcription is truly disrupted in the BDNF-KIV mice despite dampening of basal Bdnf expression, we measured levels of individual Bdnf transcripts in response to electroconvulsive shock (ECS), a condition in which neuronal activity is dramatically enhanced. As expected, in the WT mPFC, transcription driven by promoter IV was increased by the largest magnitude, while more moderate induction was seen from promoters I, II, III, VI and IXa  period and at the end of the rest  period in WT and BDNF-KIV mPFC. Three observations were made. First, Bdnf transcription from promoters I, II, III, IV and IXa increased during wakefulness in the WT animals . To gain insight into the role of individual e Figure . This su+ in embryo-derived cultured cortical neurons and that the in vivo increase in BDNF protein induced by kainic acid in the frontal cortex was completely abolished in BDNF-KIV mice [Bdnf promoters may contribute to the complete lack of BDNF protein induction in response to multiple neuronal-activity manipulations. These data, in conjunction with our previous studies, suggest that the BDNF-KIV line is an ideal model to study the impact of loss of activity-dependent BDNF expression.We followed up these experiments by determining the effects of SD on BDNF protein expression in WT and mutant animals. In agreement with our mRNA results we found that there was a moderate decrease in the baseline levels of BDNF protein expression in the mutant animals, but that the induction of BDNF expression following SD was highly impaired in the mutant animals Figure . ConsistKIV mice . Thus, tBdnf transcripts in WT animals under baseline conditions . There was no significant change in the mRNA expression levels of these markers between WT and mutant animals either at baseline or following SD , with the most striking down-regulation in Cort expression  period -39. ThesBdnf and Cort expression increase as sleep pressure builds. Consistent with this notion, we observed a rise in both Bdnf and Cort gene expression in WT animals after exposure to SD. However, in BDNF-KIV animals the levels of BDNF mRNA and protein as well as Cort gene expression were impaired. The genetic manipulation in the BDNF-KIV animals results in complete disruption of promoter IV-derived BDNF and down-regulation of additional Bdnf transcripts, resulting in a complete loss of the SD-induced increase in BDNF protein expression. Interestingly, transcription driven by promoter I was the most highly regulated in response to SD. In comparison to the 2-fold increase in promoter IV-driven transcription, promoter I driven transcription was elevated 12-fold. This difference is quite striking compared to the effects of ECS, which enhanced promoter IV activity by ~3-fold and promoter I activity by ~2-fold. Indeed, following SD, exon I-containing transcripts became the most highly expressed in the mPFC, with exon I-containing transcripts being expressed 4-fold more abundantly than exon IV-containing transcripts. Since the large SD-induced increase in exon I-driven transcription is significantly attenuated in addition to the complete disruption of promoter IV-driven activity, the BDNF-KIV mutant animals provide a very useful tool for studying the effects of activity-dependent BDNF expression on sleep homeostasis and behavior.We report here that BDNF-KIV mice slept less overall than WT mice. This decrease was accounted for by less sleep in the later parts of the active (dark) cycle and a delay in entering the rest phase. With progression of the active cycle or in response to SD, both BDNF has been implicated in the development and function of the cortical inhibitory system at multiple levels ,43-45. SCort gene expression is highest at the end of the circadian active period and increases dramatically in response to SD [In the adult brain cortistatin expression is correlated with sleep need and its administration promotes slow-wave activity (SWA) ,35. Cortse to SD ,35. Funcse to SD ,35. Intese to SD . This tise to SD ,53.Crhbp, a binding protein that acts to sequester corticotropin releasing hormone (CRH) may also define this subset of interneurons. Crhbp expression is also misregulated in the BDNF-KIV mice, is induced following sleep deprivation, and has been co-localized with NPY-positive interneurons [It has been reported that enhancing BDNF expression via exploratory activity during waking is causally linked to homeostatic sleep mechanisms ,10. Somerneurons . Recent rneurons . Future Cort gene expression. Our results raise the possibility that BDNF regulation of sleep behavior may, at least in part, be mediated via activity-dependent BDNF regulation of cortistatin-positive interneurons.In conclusion, we have shown that a genetic manipulation that disrupts activity-dependent BDNF expression results in behavioral impairments that are consistent with a deficit in sleep homeostasis. We also show that this genetic alteration leads to a substantial misregulation of BDNF-KIV animals were generated as described previously , and furECS was delivered to mice under isoflurane inhalation anesthesia via bilateral ear clip electrodes using an Applegate Electronics ES3 unit. The stimulus current was 60 mA, 60 Hz, sine wave of 1 s duration. The presence of tonic seizures immediately after the shock was confirmed by observing the extension of all limbs and forward head extension that normally last for about 10-15 s in each cohort regardless of genotype. Mice were returned to their cages 10 min following the procedure.Total sleep deprivation (12 h) was carried out according to previously described protocols ,56. AnimSleep behavior was analyzed using automated home cage monitoring for up to 48 h. Videos were captured within a sound-attenuated, temperature controlled environment with a constant white noise background designed by KM and RJS and built by CleverSys using digital cameras and CaptureStar software . Infrared lights were used for illumination during dark phase recording. Automated video analysis of home cage behavior was performed using HomeCageScan software . Behavior was detected by utilizing information about the entire body of the animal, identifying animal body parts such as head, tail, forelimbs, hind limbs, upper/lower back, abdomen, etc., and using the sequence data to automatically recognize and analyze animal behavior in durations > 6 frames (30 frames/s).Mice were quickly decapitated and brains rapidly removed from the skull. Brains were cut into 3mm coronal slices with the use of a brain block  and submerged in RNALater (Ambion). Slices remained in RNALater at 4°C for 3 d before microdissection of the mPFC. After microdissection, tissues pieces were transferred to Trizol  and dounce homogenized. Following crude extraction, RNA was further purified on an RNeasy Column with on-column DNase treatment according to manufacturer's instructions . 0.5 ug of RNA was converted to cDNA using Superscript III (Invitrogen) according to the manufacturer's instructions.Bdnf probes were adapted from previously published reports and ordered as custom TaqMan probes [Gad1, Calb1, Calb2, Pvalb, Sst, Npy, Cort, Tac1, Crhbp and Gapdh) were ordered as inventoried TaqMan probes (Applied Biosystems). Each reaction was carried out in triplicate on a 4S Realplex Mastercycler . PCR was carried out for 40 cycles of 95°C for 15 s and 60°C for 60 s. Relative quantification of template was performed using the ΔΔCt method with experimental cDNA data being normalized to the control Gapdh level. Absolute quantifications for the ratios of of individual transcript abundance was performed by extrapolating Ct value data to a standard curve, which was derived from serial dilution amplifications with known amounts of plasmid DNA containing the cloned sequence from PCR amplicons of individual Bdnf transcripts.10ng of reverse transcribed cDNA was subsequently used for each reaction with MGB FAM labeled TaqMan probes  in 1X Gene Expression Master Mix (Applied Biosystems). Sequences for exon-specific n probes  , sonicated and further extracted for 1 h with addition of 0.9% SDS. Protein levels were normalized using a standard BCA assay (Pierce) and then used for measurement of BDNF protein levels with a commercial BDNF ELISA according to the manufacturer's instructions .GraphPad Prism was used for all statistics including Students t-test, one-way ANOVA with Newman-Keuls post hoc analysis and two-way ANOVA. *p < 0.05, **p < 0.01 and ***p < 0.001.BDNF: Brain-derived neurotrophic factor; CRH: corticotropin releasing hormone; ECS: electroconvulsive shock; EEG: electroencephalogram; GFP: green fluorescent protein; mPFC: medial prefrontal cortex; PGK: phosphoglycerate kinase; SD: sleep deprivation; SWA: Slow-wave activity; WT: wild-type.KM, RJS, DVJ and DRW declare no competing financial or non-financial competing interests. BL is a paid employee of Glaxo-Smith Kline.KM conceived the study, designed the experiments, carried out the qPCR and immunoassay studies and drafted the manuscript. RJS participated in designing and coordinating experiments and carried out qPCR experiments. DVJ carried out behavioral experiments. DRW contributed to study design and analysis. BL contributed to study design, analysis and drafted the manuscript. All authors have read and approved the final manuscript.Additional file 1. Table S1: "ANOVA table"Click here for file


Atopic asthma is a chronic inflammatory pulmonary disease characterised by recurrent episodes of wheezy, laboured breathing with an underlying Th2 cell-mediated inflammatory response in the airways. It is currently treated and, more or less, controlled depending on severity, with bronchodilators e.g. long-acting beta agonists and long-acting muscarinic antagonists or anti-inflammatory drugs such as corticosteroids , leukotriene modifiers, theophyline and anti-IgE therapy. Unfortunately, none of these treatments are curative and some asthmatic patients do not respond to intense anti-inflammatory therapies. Additionally, the use of long-term oral steroids has many undesired side effects. For this reason, novel and more effective drugs are needed. In this review, we focus on the CD4+ Th2 cells and their products as targets for the development of new drugs to add to the current armamentarium as adjuncts or as potential stand-alone treatments for allergic asthma. We argue that in early disease, the reduction or elimination of allergen-specific Th2 cells will reduce the consequences of repeated allergic inflammatory responses such as lung remodelling without causing generalised immunosuppression. Asthma is a serious chronic inflammatory lung disease characterised by recurrent episodes of wheezy laboured breathing with prolonged expiration accompanied by dry coughing and viscous mucus. These symptoms result from bronchoconstriction, bronchial mucosal thickening by oedema, eosinophilic infiltration, bronchial wall remodelling and excessive mucus production with plugging of the conducting airways in the lungs. These airway changes lead to increased bronchial hyperreactivity to a variety of allergic and non-allergic stimuli. Obstruction is usually reversible, either spontaneously or in response to appropriate therapy. Asthma affects approximately 300 million people worldwide and can be fatal. Atopic or allergic asthma generally occurs in childhood or young adulthood (under the age of 40) in about 70-80% of cases and is caused by common allergens e.g. pollens, house dust, animal dander, inhalants, foods, drugs and occupationally encountered dust. Atopic asthma is characterised by detectable allergen-specific IgE and a positive skin test upon allergen provocation. The most severe chronic refractory asthma accounts for 5-10% of adults with asthma and is characterised by persistent symptoms and frequent exacerbations, despite treatment with high dose inhaled and/or oral corticosteroids and inhaled β2 adrenoceptor agonists. These patients are at greater risk of fatal and near-fatal exacerbations and display serious unremitting symptoms, resulting in a considerable impact on quality of life, disproportionate use of health care resources and adverse effects from regular systemic steroid use.The allergic immune response is a complex process beginning with the activation of allergen-specific Th2 cells by antigen presenting cells (APCs) followed by their proliferation, cytokine production, helper functions and the emergence of memory cells Figure . The resSalmonella minnesota . Th2 ceThe interplay between cells and cytokines involved in Th2-mediated disease is complex. Th2 cells secrete and express a variety of cytokines and receptors . In the -/- mice . Such biewed in ]. They hiewed in , includiiewed in ,142. Moriewed in .Th2 cells and/or their secreted effector molecules mediate the immune response to allergens and are triggered by exposure to specific allergens leading to allergic asthma. Thus, inhibiting or eliminating Th2 cells is a beneficial strategy for treating asthma as long as generalised immunosuppression is avoided. Additionally, it is especially important to consider targeting Th2 cells early in disease because when disease is chronic additional factors may cause perpetuation. Although there are a myriad of potential Th2 targets (Figure Aside from anti-IgE therapy for severe asthma, there are no major new drugs for the treatment of asthma in the last 20 years. The latest research in allergic asthma that has elucidated key factors governing Th2 immunity and identified potential targets is predominantly from animal models. Now, the challenge is to discover candidates, which best translate from animal models to patients. However, choosing the most effective new drug target candidate is especially difficult because human data is often lacking or incomplete. Additionally, the use of accurate, predictive biomarkers to evaluate Th2-modulating drugs such as FEV1, Quality of Life, reduction in steroid use, decrease allergen-induced late phase response and others are important to ensure that the efficacy/adverse effect profiles are standardised and enable easier decision-making for the best candidates. We would argue that the most promising new compounds for the clinic are those in which proof of concept in patients is established e.g. anti-IL-13 antibodies and CRTH2 antagonists. Other candidates currently tested in the clinic are anti-IL-5, anti-IL-4 and anti-IL-9 compounds and CCR4 antagonists. However, based on available human data, we suggest that the epithelial cell-derived cytokines TSLP, IL-25 and IL-33, which drive Th2 responses are the most promising candidates, with TLSP the clear frontrunner.Steroids are efficient for treating asthma because they inhibit numerous pro-inflammatory responses and induce numerous anti-inflammatory pathways. Thus, targeting a single mediator may not suffice for the treatment of allergic asthma because of the redundant immune and inflammatory pathways involved upon allergen challenge. Thus, we suggest that targeting more than one molecule simultaneously using dual specific antibody/protein platforms to engineer new drugs will be the next major approach in drug discovery. However, while this approach creates a scenario in which numerous targets can be combined, the caveat is that optimal candidates must be carefully chosen. Another important consideration for the therapeutic strategy for allergic asthma is that drugs may need to be developed for specific subtypes of disease in which particular cellular and molecular pathways drive the disease. One example is the anti-IL-5 mAb, which is only effective in asthmatics with very high sputum and lung eosinophil numbers. This example suggests that it is beneficial to better categorise patients and consider personalised medicine based on a clear classification of disease.These are exciting times for Th2 cell immunology as the results of basic research are defining key molecular and cellular components in the response to allergens. This information is already being converted to targets that are being tested in the clinic. Currently, irrespective of approach, we consider that a successful strategy for the treatment of allergic asthma will include a selective inhibition of Th2 cells with the ultimate aim of eliminating allergen-specific Th2 immune responses. We anticipate that new candidates will be approved in the near future and offer treatment options for patients suffering with asthma and other allergic diseases.AHR: Airway hyperresponsiveness; AI: Allergen immunotherapy; APC: Antigen presenting cell Bcl: B cell lymphoma; Th: CD4+ T helper; CKR: Chemokine receptor; CRTH2: Chemoattractant receptor-homologous molecule expressed on TH2 cells; CpG: Cytosine-guanine dinucleotides; CpG-ODN: Cytosine-phosphate-guanine oligonucleotides; CTLA-4: Cytoxic lymphocyte antigen- 4; DC: Dendritic cell; DP1: D prostanoid receptor 1; EGF: Epidermal growth factor; ERK: Extracellular signal regulated kinase FasL: Fas ligand; GM-CSF: Granulocyte-macrophage colony-stimulating factor; HDAC: Histone deacetylases; Ig: Immunoglobulin; ISS-ODNs: Immunostimulatory oligodeoxynucleotides; ICAM: Intercellular adhesion molecule; IFN: Interferon; IL: Interleukin; JAK: Janus kinase; JNK: Jun kinase mAb: monoclonal antibody; MAPK: Mitogen-activated protein kinases; PDE: Phosphodiesterase; PI3K: Phosphoinositide 3-kinase; PD-1: Programmed death-1; PG: Prostaglandin; Siglec: Sialic acid binding Ig-like lectins; STAT: Signal transducer and activator of transcription; SOCS: Suppressor of cytokine signalling; Treg: regulatory T cell; TSLP: Thymic stromal lymphopoietin; TLR: Toll-like receptor; TGF: Transforming growth factor; TNF: Tumour necrosis factor; VCAM: Vascular cell adhesion molecule; VLA: Very late antigen.Berislav Bosnjak - was employee of GlaxoSmithKline Research Centre Zagreb Ltd. until December 2008. No other competing interests.Barbara Stelzmüller - noneKlaus J. Erb - is an employee of BoerhingerIngelheim Pharma, Respiratory Diseases Research, Biberach an der Riss, GermanyMichelle M. Epstein - received funding from BoerhingerIngelheim Pharma, Respiratory Diseases Research, Biberach an der Riss, Germany for collaborative projectBB - was involved in drafting the manuscript, revising it critically for important intellectual content; and has given final approval of the version to be published.BS - made substantial contributions to conception of the review, was involved in drafting the manuscript, revising it critically for important intellectual content; and has given final approval of the version to be published.KE - made substantial contributions to conception of the review, was involved in drafting the manuscript, revising it critically for important intellectual content; and has given final approval of the version to be published.ME - made substantial contributions to conception of the review, was involved in drafting the manuscript, revising it critically for important intellectual content; and has given final approval of the version to be published.


Multiple sclerosis, the most common neurologic disorder of young adults, is traditionally considered to be an inflammatory, autoimmune, demyelinating disease of the central nervous system. Based on this understanding, the initial therapeutic strategies were directed at immune modulation and inflammation control. These approaches, including high-dose corticosteroids for acute relapses and long-term use of parenteral interferon-β, glatiramer acetate or natalizumab for disease modification, are at best moderately effective. Growing evidence supports that, while an inflammatory pathology characterizes the early relapsing stage of multiple sclerosis, neurodegenerative pathology dominates the later progressive stage of the disease. Multiple sclerosis disease-modifying therapies currently in development attempt to specifically target the underlying pathology at each stage of the disease, while avoiding frequent self-injection. These include a variety of oral medications and monoclonal antibodies to reduce inflammation in relapsing multiple sclerosis and agents intended to promote neuroprotection and neurorepair in progressive multiple sclerosis. Although newer therapies for relapsing MS have the potential to be more effective and easier to administer than current therapies, they also carry greater risks. Effective treatments for progressive multiple sclerosis are still being sought. Multiple sclerosis (MS) is a chronic progressive disorder of the central nervous system (CNS). It is traditionally considered to be an inflammatory disorder characterized by episodic CNS demyelination. However, current understanding is that neurodegeneration dominates the progressive stages of the disease. This article summarizes the pathogenesis of MS, reviews approved MS therapies and discusses the proposed mechanisms and likely benefits and risks of new MS therapeutics.MS presents in most people (80%) with clinical relapses characterized by fully or partially-reversible focal neurological deficits . RelapsiClinically significant acute MS relapses are usually treated with high-dose, short-term, intravenous corticosteroids (methylprednisolone 1 g/day for 3-5 days). This shortens relapse duration but does not improve the degree of recovery or the long-term course of the disease . DiseaseSince the release of IFNβ-1b, five other parenteral medications have been approved for the treatment of MS: IFNβ-1a , IFNβ-1a , glatiramer acetate , mitoxantrone  and natalizumab . The IFN products are thought to all have similar mechanisms of action although they differ in the route of administration, rapidity of onset of action and risk of induction of neutralizing antibodies . In contDMT development for MS is an area of active research and many potential agents are in various phases of investigation. Most of these are oral medications or MABs that target specific aspects of inflammation in RRMS. Others are designed to have neuroprotective and neurorestorative effects in PPMS and SPMS Figure .http://www.clinicaltrials.gov. Frequent adverse events associated with fingolimod include nasopharyngitis, dyspnea, headache and nausea. Rare serious adverse events in the trials were skin cancers and two deaths, one each from herpes encephalitis and disseminated varicella, all suggesting an inadequate immune surveillance.Fingolimod (FTY720), a small molecule derived from a fungus and chemically related to sphingosine, causes internalization of sphingosine-1-phosphate (S1P) receptors on lymphocytes, thereby blocking their egress from lymph nodes and thymus. The reversible lymphocytopaenia prevents activated T cells from crossing the BBB and causing inflammation . FingoliThe antimetabolite cladribine, an adenosine analogue, incorporates into DNA and causes the death of rapidly proliferating inflammatory B and T cells, thus resulting in selective and long-lasting lymphocyte depletion. Approved as a therapy for use in hairy-cell leukaemia, early trials indicated that cladribine was effective for RRMS but not SPMS ,26. A rede novo synthesis of pyrimidine, thus reducing activated B and T cell proliferation [There are three oral agents in phase III trials in RRMS, laquinimod, teriflunomide and BG00012. Laquinimode and teriflunomide are thought to work in part by shifting the T-cell balance from pro-inflammatory Th1 cells to anti-inflammatory Th2 cells. Laquinimod is a chemically and pharmacologically distinct derivative of the drug roquinimex, the study of which in RRMS was halted due to significant pulmonary and cardiac toxicity . A 24 weferation . A promiferation  has led feration  led to aBased on the observation that there is a reduction in MS relapses during pregnancy, a condition associated with high levels of and progesterone, it is thought that or progesterone may benefit patients with MS and progesterone have potent anti-inflammatory effects and may also provide neuroprotective benefits by increasing oligodendrocyte precursor cell number and promAlemtuzumab targets the CD52 antigen present on T cells, B cells, monocytes, macrophages and eosinophils, but not stem cells, and causes reversible leukocyte depletion. Alemtuzumab is approved for chronic lymphocytic leukaemia and showed promise in early trials for RRMS  but not Thus far, all of the anti-inflammatory therapies that are effective in RRMS have had minimal or no effect in controlling progressive MS. There is a growing belief that SPMS and PPMS will not respond to anti-inflammatory therapies and that neuroprotective and neurorestorative therapies that affect neuronal integrity will be required for progressive MS. A variety of existing and novel approaches are under investigation as neuroprotective and neurorestorative therapies in progressive as well as relapsing MS Table . TherapeTrials of stem cell transplantation, with the goal of repopulating oligodendrocytes, are underway in people with MS. Remyelination may also be promoted by blocking leucine rich repeat and Ig domain-containing, Nogo Receptor-interacting protein 1 (LINGO-1), a protein on the surface of neurons that inhibits differentiation of precursor oligodendrocytes into mature cells. Antibody blockade of LINGO-1 has shown promise in an animal model of MS . NeurotrCurrent MS therapeutics are moderately effective for modifying disease during its relapsing-remitting phase. There are a number of oral and parenteral agents that target inflammation in development and several are likely to be approved for treatment of RRMS within the next few years. These therapies will likely more effectively control RRMS but will also carry greater known and, as yet, unknown safety risks. These risks and benefits will have to be weighed carefully against the efficacy and proven safety of the IFNs and GA. Furthermore, none of the anti-inflammatory therapies currently in late stage of development are likely to benefit patients with SPMS and PPMS. Development of effective neuroprotective and neurorestorative therapies are needed in order to benefit patients with progressive MS.BBB: blood brain barrier; BDNF: brain-derived neurotrophic; CIS: clinically isolated syndrome; CNS: central nervous system; DMT: disease-modifying therapy; FDA: US Food and Drug Administration; GA: glatiramer acetate; IFN: interferon; LINGO-1: leucine rich repeat and Ig domain-containing, Nogo Receptor-interacting protein 1; MAB: monoclonal antibody; MRI: magnetic resonance imaging; MS: multiple sclerosis; PPMS: primary progressive MS; RRMS: relapsing-remitting MS; SIP: sphingosine-1-phosphate; SPMS: secondary progressive MS.RIS has no competing interests. MHC has received honoraria for speaking from Teva Neuroscience. DB has research grants from the National Institutes of Health, the Department of Veterans Affairs and the National Multiple Sclerosis Society. DB has also received honoraria for speaking/consulting or unrestricted educational grants, from Teva Neuroscience, Biogen Idec, EMD Serono and Bayer USA.RIS and MHC contributed equally to the paper. All authors were involved in the drafting of the manuscript and revision for important intellectual content. All authors read and approved the final manuscript and have given their approval of final published version.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1741-7015/7/74/prepub