Cost-Effectiveness and Resource Allocation (CERA) is now in its seventh year, and is an excellent example of how open access publishing can improve dissemination. Now the journal is through its infancy, it is time to reflect on its orientation and to define the strategy for the years to come. Firstly, the journal will pay particular attention to stimulating and publishing studies originating from low- and middle-income countries. Second, CERA will continue to solicit contributions originating from high-income countries, but with the caveat that such studies should be of interest to the broad international readership of the journal. Third, the journal encourages submissions on methodological work from any setting, that is generalisable between low-, middle-, and high income countries. Fourth, CERA recognizes the development of national health accounts and expenditure tracking as a first step to improved resource allocation, and solicit manuscripts of this nature. Finally, CERA recognizes that cost and cost-effectiveness analysis alone may not provide sufficient information to decision makers to guide their choices on the allocation of resources, and therefore encourages submission of studies that advance the broader field of priority-setting.The journal  Cost-Effectiveness and Resource Allocation (CERA) is now in its seventh year. In this period, it has published 93 papers on various aspects of cost-effectiveness analysis, including conceptual or methodological work, economic evaluations, and policy analysis related to resource allocation at a national or international level. CERA is an Open Access online journal. The importance of this form of dissemination is well-recognized by research funders, such as the Medical Research Council and the Wellcome Trust, who insist that findings from research they fund is published in open access journals. CERA is an excellent example of how open access publishing can improve dissemination as illustrated by the large number of accesses to its articles: the 10 most popular articles have been accessed more than 8,000 times each, with the top-three accessed more than 21,000 times each. [Established in 2003, Now the journal is through its infancy, it is time to reflect on its orientation and to define the strategy for the years to come. This allows the journal to anticipate trends in cost-effectiveness and resource allocation in health, and to be an important journal in its field.CERA aims to bridge this gap and be a home for this type of information. As part of its new approach to stimulating studies from the developing world, CERA offers fee-waivers for submissions originating from low-income countries.Firstly, the journal will pay particular attention to stimulating and publishing studies originating from low- and middle-income countries. There will never be sufficient resources available to allow all possible means of improving health to be provided to all people who might benefit from them. Rigorous comparisons of the relative health improvements from alternative uses of scarce resources are critical for informed decision-making. While this is true in any setting, the resource constraints are much more severe in low- and middle-income countries. Of all peer-reviewed articles on cost-effectiveness analysis published by journals in 2007, only 7% were set in developing nations and just eight were in Africa . CERA aiacross different settings . Where the focus is on the developed world, we request authors to explain why the results might be of more general relevance as well.Second, CERA will continue to solicit contributions originating from high-income countries, but with the caveat that such studies should be of interest to the broad international readership of the journal. In the past few years, the journal has received an increasing number of pharmacoeconomic submissions relating to specific interventions that focus on small patient numbers, mainly in high-income countries. We invite researchers in high-income countries to submit empirical work that has strong relevance Third, we encourage methodological work from any setting, that is generalisable between low-, middle-, and high income countries. An example is the work by Mitton and Donaldson, on the principles, practice and challenges in health care priority setting. Another is the article by Bachmann and colleagues from South-Africa on the development of methods for analyzing cost effectiveness data from cluster randomized trials .Fourth, CERA recognizes the development of national health accounts and expenditure tracking as a first step to improved resource allocation. We thereby solicit manuscripts that document the development or application of methodological advances in health accounting and resource tracking.Finally, CERA recognizes that cost and cost-effectiveness analysis alone may not provide sufficient information to decision makers to guide their choices on the allocation of resources, and the implementation of interventions. Additional evidence on other relevant criteria, such as the budget impact of an intervention, whether an intervention targets disadvantaged populations, or the strength of evidence of its effectiveness is typically required. Additional challenges exist in addressing the many managerial questions decision-makers may have regarding the implementation of complex interventions. These questions can be considered to be part of the broader priority-setting process. CERA therefore encourages submission of studies that advance the broader field of priority-setting, in terms of methodological or conceptual contributions, as well as empirical case studies.To help in this process, Richard Grieve and Kathryn Antioch have agreed to serve as Associate Editors. Richard Grieve has a particular interest in methods, while Kathryn Antioch will focus largely on studies from the developed world.The authors declare that they have no competing interests.All authors contributed to writing the manuscript, and all authors read and approved the final manuscript.


Elevated mitogen-activated protein kinase p38 (p38 MAPK) signaling has been implicated in various experimental and human glomerulopathies, and its inhibition has proven beneficial in animal models of these diseases. p38 MAPK signaling is partially mediated through MK2 and MK3, two phylogenetically related protein kinases that are its direct substrates. The current study was designed to determine the specific roles of MK2 and MK3 in a mouse model of acute proliferative glomerulonephritis, using mice with disrupted MK2 and/or MK3 genes. We found that the absence of MK3 alone worsened the disease course and increased mortality slightly compared to wild-type mice, whereas the absence of MK2 alone exhibited no significant effect. However, in an MK3-free background, the disease course depended on the presence of MK2 in a gene dosage-dependent manner, with double knock-out mice being most susceptible to disease induction. Histological and renal functional analyses confirmed kidney damage following disease induction. Because the renal stress response plays a crucial role in kidney physiology and disease, we analyzed the stress response pattern in this disease model. We found that renal cortices of diseased mice exhibited a pronounced and specific pattern of expression and/or phosphorylation of stress proteins and other indicators of the stress response , partially in a MK2/MK3 genotype-specific manner, and without induction of a general stress response. Similarly, the expression and activation patterns of other protein kinases downstream of p38 MAPK  depended partially on the MK2/MK3 genotype in this disease model. In conclusion, MK2 and MK3 together play crucial roles in the regulation of the renal stress response and in the development of glomerulonephritis, which can potentially be exploited to develop novel therapeutic approaches to treat glomerular disease. Acute proliferative glomerulonephritis (APGN) typically results in reduced glomerular filtration and acute kidney injury. Several animal models have been developed to study APGN experimentally, including a mouse model in which APGN is induced by injecting an antiserum raised against mesangial cells (AMC serum) The mitogen-activated protein kinase p38 (p38 MAPK) is involved in numerous signaling pathways, including cytokine signaling, which plays a role in various inflammatory and other conditions such as asthma, rheumatoid arthritis, Crohn's disease, atherosclerosis, and cancer in vitro and in vivo using p38 MAPK inhibitors Increased p38 MAPK signaling has been reported in podocytes in both human APGN, as well as in experimental models of glomerulonephritis Amniota  with other Bilateria taxa (e.g. lower vertebrates) containing only one ortholog MK2 and MK3 are phylogenetically closely related enzymes MAPK signaling networks exhibit remarkable complexity and involve multiple feedback mechanisms. For example, inactive (dephosphorylated) MK2 and MK3 form a stable complex with inactive (dephosphorylated) p38 MAPK in the nucleus The small heat shock protein (sHSP) HSPB1  is a major substrate of both MK2 and MK3, and its phosphorylation is frequently used to monitor the activity of these protein kinases cf. . Murine Based on the above, we hypothesized that MK2 and/or MK3 play important roles in renal injury during glomerular disease. To address this hypothesis, we analyzed the roles of these protein kinases in glomerular injury in a mouse model of APGN, using mice with disrupted MK2 and MK3 genes.Mice were housed in animal facilities accredited by the American Association of Laboratory Animal Care, with free access to pelleted food and water. All animal experiments were conducted in accordance with the guidelines of the National Institute of Health and were approved by the Institutional Animal Care and Use Committee of the Research Institute at Nationwide Children's Hospital (AR09-00002). Mice were euthanized by inhalation of carbon dioxide in accordance with the American Veterinary Medical Association guidelines on euthanasia. Severely ill mice were sacrificed for humane reasons.+/−MK3+/−MK2) male C57BL/6 mice were crossed with wild-type C57BL/6 females . Offspring were genotyped and used for further breeding, eventually resulting in a sufficient number of mice with the various genotypes as included in this study: +/+MK3+/+MK2 (wild-type), −/−MK3+/+MK2 (MK2 knock-out), +/+MK3−/−MK2 (MK3 knock-out), +/−MK3−/−MK2 (MK2 heterozygote MK3 knock-out) and −/−MK3−/−MK2 (MK2/MK3 double knock-out). More details on mouse genotyping are given in the Supporting Information  were injected via tail veins on four consecutive days with 100 µl sheep AMC serum, as described Urine was collected from mice on days 0, 4, 8, 12 by applying gentle abdominal pressure. Urinary creatinine was measured with a colorimetric assay using picric acid, a modified Jaffe reaction, according to the manufacturer's recommendations . Urinary protein was measured using the benzethonium chloride method as previously described Blood urea nitrogen (BUN) and serum creatinine were determined as described in the Supporting Information .For light microscopy, kidneys were harvested on days 0, 8 and 16 after AMC serum treatment. Right kidneys were fixed in 4% paraformaldehyde and processed for paraffin embedding, while left kidneys were snap frozen in liquid nitrogen for later protein extraction (see below). Paraffin sections (2 µm) were stained with periodic acid-Schiff (PAS) stain, periodic acid-methenamine silver stain, or Masson's trichrome stain. The localization of HSPB1 in renal cortices was determined by immunofluorescence microscopy on paraffin sections g for 5 min, and the supernatant was divided into aliquots and stored at −80°C. For SDS-PAGE, homogenates were mixed with 5× SDS sample buffer, yielding a final concentration of 1.0 mg/ml total protein in 62.5 mM Tris-HCl, pH 6.8; 2% SDS; 10% glycerol, 5% 2-mercaptoethanol; and 0.05% bromophenol blue. For IEF-PAGE, homogenates were adjusted to 6 M urea; 2% ampholytes 3–10; 2% Triton X-100; and 10 mM DTT , and containing 3.3 mg/ml total protein.Frozen kidney cortices (stored at −80°C after snap freezing) were homogenized at 4°C in tissue protein extraction reagent T-PER  in the presence of protease and phosphatase inhibitors  at 20 µl per mg tissue, using a Dounce homogenizer. Lysates were centrifuged at 14,000× Electrophoretic procedures were performed according to standard protocols Isoelectric focusing polyacrylamide gel electrophoresis (IEF-PAGE) was performed using a 1∶1 mixture of 3–10 and 5–7 ampholytes . IEF-PAGE followed by western blotting was used to determine the relative distribution of the various HSPB1 isoforms  within each sample, irrespective of the amounts of total HSPB1 present in the samples. Different from SDS-PAGE/western blotting, here sample loading aimed to provide similar strengths of total HSPB1 signals across all samples.Following the electro-transfer, the PVDF membranes were incubated with primary and appropriate secondary antibodies. The following primary antibodies (Ab) were used: anti-MK2 rabbit polyclonal Ab , anti-MK3 rabbit monoclonal Ab , anti-β-actin rabbit monoclonal Ab , anti-eIF2α mouse monoclonal Ab , anti-phospho-eIF2α rabbit monoclonal Ab , anti-CHOP mouse monoclonal Ab , anti-HSPB1 rabbit polyclonal Ab , anti-phospho-HSPB1-Ser86 rabbit polyclonal Ab , anti-GRP78 rabbit polyclonal Ab , anti-Hsp70 mouse monoclonal Ab , anti-HSPB8 mouse monoclonal Ab , anti-HSPB6 rabbit polyclonal Ab , anti-MK5 rabbit monoclonal Ab , anti-phospho-MK5 rabbit polyclonal Ab , anti-MNK1 rabbit monoclonal Ab , anti-phospho-Mnk1 polyclonal Ab , anti-MSK1 rabbit polyclonal Ab , anti-phospho-MSK1 rabbit polyclonal Ab , and anti-GAPDH mouse monoclonal Ab . Subsequently, the PVDF membranes were incubated with the appropriate horseradish peroxidase-conjugated anti-mouse or anti-rabbit IgG secondary antibodies .Proteins were visualized with the ECL chemiluminescence system  and detected by exposure to X-ray film. Representative blots from at least three independent experiments are shown.P<0.05.A 28-day survival curve was generated using the Kaplan-Meier method. The log-rank test was applied for comparison between curves. Statistical significance was defined as post hoc testing using PRISM version 5.01 . Additionally, unpaired Student t-tests were applied to determine differences between sample groups. Probability values were considered significant at P<0.05.The proteinuria and BUN data are presented as scatter plots that show each individual sample value, as well as the mean and standard deviation (S.D.). Statistical significance was determined by one-way ANOVA followed by Dunnett's −/−MK3+/+MK2) resulted in similar mortality to that of wild-type mice following treatment, indicating that MK2 is dispensable for mediating resistance in the presence of MK3. Deletion of MK3 (+/+MK3−/−MK2) moderately increased the mortality to ∼46% at day 28, indicating a role for MK3 in the response to the AMC serum that cannot be fully compensated for by MK2. However, deletion of MK3 combined with either partial (+/−MK3−/−MK2) or complete (−/−MK3−/−MK2) absence of MK2, resulted in a further significant increase in mortality to ∼62% and ∼77%, respectively.Breeding and genotyping of mice with various MK2 and MK3 genotypes was as specified in the These data indicate that MK2 and MK3 cooperate following induction of glomerulonephritis with the AMC serum. In an MK3-free background, survival depended on MK2 in a gene dosage-dependent manner.Proteinuria was analyzed as a functional indicator of glomerular injury in response to the AMC serum. At day 0, mice of all genotypes exhibited similarly low urinary protein/creatinine ratios, suggesting that deletion of MK2, MK3, or both had no major impact on baseline renal function . After AAs a second indicator of renal injury, albuminuria was visualized electrophoretically for selected mice . ConsistRenal functional injury was further evaluated by determination of BUN which is known to increase in this disease model +/−MK3−/−MK2), which correlated well with the increased proteinuria observed in this group (cf. −/−MK3−/−MK2) which exhibited the poorest survival rate and the most severe proteinuria at day 4 did not gain weight is probably related to the early death of most of these mice before day 8. The few surviving mice in this group developed proteinuria only at a slow rate  wild-type mice , panel aPrior to AMC serum treatment, the kidneys of wild-type mice , panel aOverall, the observed histologic lesions were similar to those previously described in the mouse strain FVB/N, although in that study no formation of crescents was reported MK2 and/or MK3 genes on this pathway in renal cortices, phosphorylation of HSPB1 was analyzed by two different methods: i) IEF-PAGE followed by western blotting to show the relative distribution of the various HSPB1 isoforms  within each sample, and ii) SDS-PAGE followed by western blotting to show the amounts of phosphorylated HSPB1 (p-Ser86) present in each sample.p38 MAPK→MK2/MK3 signaling resulted in the phosphorylation of the HSPB1 in cultured podocytes +/+MK3−/−MK2), thus confirming that MK2, rather than MK3, primarily contributed to HSPB1 phosphorylation. Consistent with this, deletion of MK2 reduced the degree of HSPB1 phosphorylation in response to the AMC serum as compared to wild-type mice, both in the presence (−/−MK3+/+MK2) and absence (−/−MK3−/−MK2) of MK3. Increased amounts of phosphorylated HSPB1 in response to the AMC serum were confirmed by SDS-PAGE using an antibody that specifically recognized phosphorylated Ser86 (panel b). The fact that residual HSPB1 phosphorylation was observed even after deletion of both MK2 and MK3 suggested the contribution of yet another protein kinase, most likely MK5 IEF-PAGE revealed that in untreated wild-type animals, HSPB1 exists mainly in the 0p isoform, with little to no detectable 1p and 2p isoforms, respectively , panel a+/+MK3−/−MK2; −/−MK3−/−MK2), and seemed to correlate with the increased mortality in these genotypes , while HSPB8 was maximally induced in the absence of MK2 , even though its baseline expression level was elevated in the MK2/MK3 double knock-out mice.Interestingly, in addition to phosphorylation of HSPB1, we also observed a robust increase in expression of this sHSP on day 8 in response to the AMC serum , panel cypes cf. . Thus, tIn order to determine if induction of these three sHSPs reflected a generalized renal cortical stress response, we also determined the expression and induction of the inducible form of HSP70 . Surprisingly, expression of HSP70 remained constant across all genotypes, whether treated or untreated , panel c−/−MK3−/−MK2) resulted in increased phosphorylation of eIF2α. In response to the AMC serum, phosphorylation did not change in wild-type mice, as opposed to mice with deleted MK2 (−/−MK3+/+MK2) or MK3 (+/+MK3−/−MK2) which exhibited increased or decreased phosphorylation of eIF2α, respectively. Interestingly, the response to the AMC serum in the absence of both MK2 and MK3 (−/−MK3−/−MK2) resulted in a marked reduction in phosphorylation of eIF2α. In this situation, the absence of MK3 seemed to override the absence of MK2. For comparison, the total amount of eIF2α remained constant in these mice irrespective of the genotype or treatment (panel d).We also analyzed indicators of the UPR of the endoplasmic reticulum, including induction of the growth arrest-associated protein C/EBP homologous protein-10 (CHOP) In order to verify equal loading on the gels, β-actin was visualized on all blots throughout the experiment .We also analyzed renal cortical HSPB1 induction using immunofluorescence microscopy . In untrTaken together, baseline expression and/or phosphorylation of a number of sHSPs and indicators of the UPR, as well as their pathophysiological response patterns following the AMC serum treatment, appeared to be regulated in part by MK2 and MK3. The site of the renal stress response was primarily in the tubular compartment.As mentioned above, deletion of MK2 and/or MK3 is known to affect the entire p38 MAPK signaling network through feedback mechanisms −/−MK3+/+MK2, −/−MK3−/−MK2), while AMC serum treatment increased MK5 activation moderately in all knock-out genotypes. In the absence of both MK2 and MK3 (−/−MK3−/−MK2), this increased MK5 activity is reflected by the increased phosphorylation of HSPB1 seen in response to the AMC serum  reduced MNK1 expression, whereas the absence of MK3 alone (+/+MK3−/−MK2) slightly increased its expression. The absence of both MK2 and MK3 (−/−MK3−/−MK2), however, resulted in a greatly increased baseline MNK1 expression. Following treatment with AMC serum, a strong induction of MNK1 was observed in the presence of MK3 only , in contrast to the decreased MNK1 expression observed in the absence of MK3 . This pattern of MNK1 expression was in contrast to its pattern of activation (phosphorylation) in response to AMC serum. The activation of MNK1 in all genotypes implied that this was largely independent of the MK2/MK3 genotypes, although it was more pronounced in the absence of MK3 . For comparison, the extent of baseline MNK1 activation was independent of the MK2/MK3 genotype. This behavior of MNK1 is noteworthy, since its AMC serum-induced activation was in direct contrast to its simultaneously reduced expression in the absence of MK3 . In summary, both MK2 and MK3 have pronounced effects on the expression and degree of activation of MNK1, both before and after induction of APGN.Baseline expression of MNK1 depended somewhat on both MK2 and MK3 expression, although with disparate consequences : The abs+/+MK3+/+MK2, −/−MK3+/+MK2) , whereas MSK1 activation in response to AMC serum decreased in all genotypes, suggesting that this effect is not regulated by MK2 or MK3. Similar to MNK1, MSK1 also showed a disparate pattern of expression and activation, although the specific regulation of these two protein kinases was different. In summary, MK3 has an apparent inhibitory effect on baseline MSK1 activation.In contrast to MNK1, baseline MSK1 expression was essentially constant in all genotypes, with only a slight induction noted in response to AMC serum in the presence of MK3 (−MK3+/+) . ConversIn order to verify equal loading on the gels, GAPDH was visualized for all samples .Manipulation of p38 MAPK signaling is emerging as an auspicious novel therapeutic strategy in inflammatory and other disorders, including NS. Our group recently demonstrated that a MK2 inhibitor protected cultured podocytes from an injury that mimics NS, similar to that reported for a p38 MAPK inhibitor −/−MK3+/+MK2) exhibited no apparent phenotype, it can be assumed that MK3 fully replaces the lost functions of MK2. The fact that the MK3 knock-out mice (+/+MK3−/−MK2) performed poorer than the wild type mice suggests that MK2 apparently cannot completely compensate for the loss of MK3, which may indicate that MK3 has a specific function. However, to a certain degree MK2 can compensate for the loss of MK3, which was obvious when the different MK2 genotypes  were compared in an MK3-free background. Consistent with this, MK2/MK3 double knock-out mice (−/−MK3−/−MK2) exhibited the poorest performance.Our mortality data suggest that MK2 and MK3 together play crucial roles in the development of glomerulonephritis, with both MKs exerting partially redundant but also specific functions. Since the MK2 knock-out mice  where activation of MNK1 was accompanied by deactivation of MSK1.Although p38 MAPK signaling includes housekeeping functions, activation of this signaling pathway is also part of the stress response system 50 as that for MK2, but is otherwise highly specific since it did not affect ∼200 other tested protein kinases A surprising finding was the involvement of another protein kinase, in addition to MK2 and MK3, in HSPB1 phosphorylation. The best known candidate protein kinase is MK5, which phosphorylates HSPB1 at identical sites to that of MK2 and MK3 The fact that we observed increased HSPB1 phosphorylation in some settings cf.  but no cThe observed effects of MK2 and MK3 on the expression or activation of the various MKs, both at baseline and in response to AMC serum, are also summarized in The group with the highest mortality (MK2/MK3 double knock-out mice) exhibited several characteristic abnormal patterns of expression and/or phosphorylation of the stress response indicators and of the MKs studied, in baseline conditions and/or following disease induction. These aberrant responses included expression of HSPB8, CHOP, and MNK1, and phosphorylation of eIF2α and MK5 cf. , 7. We eIn recent years inappropriately activated signaling pathways in podocytes or other renal cells have been recognized as causes for renal injury. Examples include increased Notch signaling in the podocytes of patients with glomerular proteinuria In summary, our study found that MK2 and MK3 play critical, interconnected roles in the regulation of the development of glomerulonephritis and the renal stress response. These data also support the concept that partial and selective inhibition of MK2 represents an attractive potential therapeutic approach for the treatment of glomerular disease. However, further understanding of this pathway and the interactions among its members is needed to optimize the benefits of such an approach.Figure S1MK2 and MK3 knock-out genotypes of C57/BL6 mice as used in this study. (A) PCR genotyping using allele-specific primers. The positions of PCR products specific for wild-type (wt) and knock-out (ko) alleles of MK2 and MK3 are indicated on the right. The two leftmost lanes show molecular mass markers with the positions of 1000 and 300 bp indicated (bars). (B) Expression of MK2 and MK3 in mice with different MK2 and MK3 genotypes, as shown by western blotting and using an MK2- and MK3-specific antibodies.(TIF)Click here for additional data file.Figure S2Effect of MK2 and MK3 genotypes on BUN in response to the AMC serum. The BUN values collected at day 0 prior to AMC serum injection and at days 4, 8, and 12 following AMC serum injection were plotted for each surviving mouse. Horizontal bars indicate the means and error bars represent S.D. At days 8 and 12, all means were significantly different from the baseline values at day 0 of the same genotype group. The trend of BUN values was consistent with the proteinuria data, with the MK2/MK3 double knock-out mice being most susceptible to injury.(TIF)Click here for additional data file.Text S1Additional information on mouse genotyping and determinations of blood urea nitrogen, blood creatinine and body weight.(DOC)Click here for additional data file.


The field of ocular inflammation and uveitis is growing rapidly and recent developments have improved the diagnosis and therapy of uveitic entities. Advances in diagnostics including imaging technologies such as laser flare photometry, fluorescein angiography, indocyanine green angiography, ultrasonography, optical coherence tomography, confocal scanning and electrophysiologic studies on one hand, and microbiological techniques on the other, have led to a better understanding of the causes of new emerging cases of uveitis as well as older established entities. Such changes mandate that all ophthalmologists, particularly uveitis specialists, be constantly updated on such rapidly evolving changes. Globalization, ethnic and geographical differences, and immigration are among other reasons that should encourage practicing ophthalmologists to familiarize themselves with evolving patterns and current etiologies of uveitis.The current issue of the Journal of Ophthalmic and Vision Research (JOVR) is dedicated to different aspects of advances in the diagnosis and management of uveitis. JOVR is a young journal passing its infancy; it is now 6 years old and maturing into an internationally recognized publication. JOVR is now indexed in Scopus and Pubmed Central as well as many other databases. This journal is a forum for reflecting advances in all ophthalmology subspecialties, including ocular inflammation and uveitis.The Society for Ophthalmo-Immuno-infectiology in Europe (SOIE) was founded in 2005 by Carl P. Herbort, the guest editor of this issue special of JOVR. He recently established a sister organization, the Society for Ophthalmo-Immunoinfectiology in Europe and the Middle East (SOIEME) in 2011. This special issue of JOVR on uveitis can be considered as the beginning steps for collaborations between SIOE members in European countries and their SIOEME counterparts, including uveitis specialists practicing in the Middle East, particularly Iran.Seven articles constitute the contribution of Iranian authors to this special issue; these include three original articles, one review, two case reports and one challenging case. One of the original articles, a collaboration of Nashtaei and colleagues7This issue is the product of a year and a half of collaboration among SOIE, SOIEME, and Iranian ophthalmologists from Shahid Beheshti University of Medical Sciences under the leadership of Carl P Herbort that will hopefully expand the knowledge of all ophthalmology trainees, retina and uveitis specialists, and other physicians interested in inflammatory eye diseases.I acknowledge the editorial staff of JOVR, Dr Rastegarpour, Dr Golbafian and Ms Payab for their continuous efforts, and express gratitude to Dr Ahmadieh and Dr Yazdani, the editors of JOVR, for allowing unrestricted use of journal space and facilities.


It is with a sense of happiness and pride that I complete my term as the Editor-in-Chief of the Journal of Cutaneous and Aesthetic Surgery, after a fruitful three years term. It has been a satisfying term as the journal which started as a biannual journal has progressed in to quarterly journal. The number of articles being submitted to the journal website is steadily increasing, and impact factor is also on the rise. Articles  are being submitted from across the globe, not only from dermatology, but also from other fields such as plastic surgery, maxillofacial surgery, general surgery etc. We also started focus issues, on several topics such as fillers, hair restoration, sclerotherapy, and the current one on vitiligo surgery. The financial health of the journal is sound, and we managed to publish the issues without taxing the association funds. And most importantly, the journal has got indexed, the first journal in the field of aesthetic and cutaneous surgery in India to do so. That this could be done with in first two years of starting the journal is a matter of great satisfaction.This could not have happened without the support of several sources- the executive committee (2008-2010) of Association of Cutaneous Surgeons Association (I), headed by Dr. Somesh Gupta, Past presidents Drs Niti Khunger, Narendra Patwardhan, Sharad Mutalik, Secretary Manas Chatterjee have all been very supportive. Our publisher, Dr. Sahu and his diligent staff at Medknow publishers have been truly extraordinary in publishing the journals on time. My sincere thanks to them.The editorial board members, both national and international, have been very cooperative. I specially single out with gratitude, Dr. Uwe Wollina who was very encouraging at all times. My most sincere thanks are due to my editorial team of assistant and deputy editors, Drs KC Nischal, Kumaresan, Anitha Raghunath, Nandini AS, Anitha BS and HM Omprakash - with out their support, the journal publication would have been impossible.Lastly, I thank the contributors who submitted excellent articles to the journal and the members of our association who encouraged and appreciated our efforts.Personally, it has been a truly learning, enjoyable experience, which I will cherish for a long time. I leave with a sense of achievement, as I hand over the baton to Dr. Somesh Gupta, a most capable and dynamic person, under whom, I have no doubt that the journal will scale greater heights.


Introduction. Preoperative identification of patients with inadequate hamstring grafts for anterior cruciate ligament reconstruction is still a subject of interest. Purpose. The purpose of this study was to determine whether the semitendinosus tendon length is adequate for four-strand graft harvested by common technique (without bone plug) and whether there is correlation of gracilis and semitendinosus tendon grafts length and diameter of quadrupled graft with anthropometric parameters. Materials and Methods. In this retrospective study, 61 patients  undergoing ACL reconstruction using four-strand hamstring autograft tendons were included. Results. The length of semitendinosus tendon, harvested by the common technique, was in 21% of our cases inadequate in order to be used alone as a four-strand graft especially in females (43%). There was moderate correlation between semitendinosus and gracilis graft diameter and patient's height and weight and fair correlation to BMI. We found no statistically important predictor for graft diameter in female patients. Conclusions. The length of semitendinosus tendon, harvested by common technique, is usually inadequate to be used alone as a four-strand graft especially in females. The most reliable predictor seems to be patient's height in males. In female patients, there is no statistically important predictor. The anterior cruciate ligament (ACL) is the most commonly reconstructed ligament of the knee . An injuIt is widely accepted that four-strand hamstring autograft represents a successful option for ACL reconstruction –7. A posScott and Insall report that the length of normal ACL is 38 mm (25–41 mm) and the width is 10 mm (7–12 mm), on average . In ordeThe purpose of this retrospective study was to determine whether alone the ST tendon length is adequate for four-strand graft harvested by common technique and whether there is correlation of G and ST grafts length and diameter with anthropometric parameters. Sixty-one consecutive patients  undergoing ACL reconstruction using four-strand hamstring autograft tendons were included in this retrospective study. Age, gender, height, weight, and Body Mass Index (BMI) for each patient were recorded preoperatively.Surgical operation was performed by the same surgeon in all cases, and hamstring tendon autografts (ST-G) were harvested by the same way. An oblique incision was performed on the skin over the pes anserinus attachment area on the proximal tibia. Subcutaneous fat was incised and attentive blood hemostasis was performed. The sartorius fascia was incised parallel to the direction of G tendon. On the next step, G tendon was dissected . The tenAdequate length of ST tendon graft as only four-strand graft for single-bundle ACL reconstruction was considered to be 28 cm. Adequate diameter of four-strand hamstring autograft (ST-G) was considered to be more than 7 mm. t-test was used to identify differences between the mean values of continuous variables according to gender. Chi-square statistics (χ2) was done to investigate any possible association of the categorical variables with the diameter of the graft. Bivariate correlation coefficients (Pearson r) and multiple linear regressions were calculated to evaluate any possible association between clinical data and intraoperatively measured hamstring graft lengths and diameters. Higher correlation coefficients indicate stronger relationships between variables. Statistical package SPSS version 18.0; SPSS, Chicago, III for Windows was used for analyses. A P value of 0.01 was taken as the level of significance. In statistical analysis, independent samples Anthropometric measurements including the average age, weight, height and BMI, and gender of patients participating in this study are shown in Female patients were lighter and shorter with lower BMIs, and had shorter length and smaller diameter hamstring grafts with statistical significance in comparison with males.Linear regression analyses separated by gender, considering height and BMI had showed existing statistically important correlation with graft size (diameter) only in males Figures  and 6. Considering the whole sample, hamstring graft size was correlated to patient's height and BMI Figures  and 8.Only height of patients was correlated with length of gracilis and semitendinosus graft and not BMI Figures  and 10.Pearson's correlation tests analysis in the whole sample indicates that hamstring graft size (diameter) was correlated to patient's height, BMI, and also weight. Height and weight of patients was correlated with length of G and ST tendon graft but not BMI . AccordiSimple linear regression indicated that patient BMI and height explained approximately 17.1% and 24.7%, respectively, of the variation in quadrupled graft diameter.r = 0.33; R2 = 0.171; P = 0.01),diameter = 5.887 + 0.056 (BMI) .diameter = 2.237 + 0.028 (height in cm) ,GL = 3.456 + 0.132 (height in cm) .SL = 6.508 + 0.129 (height in cm)  and ST graft length (SL):When we separated these analyses by gender, we found that height and probably BMI only referring to G length were the best predictors for graft diameter in male patients. We found no statistically important predictor for graft diameter in female patients .In our study in one out of five patients (21%) the length of ST tendon, harvested by the common technique, was inadequate in order to be used alone as a four-strand graft. Especially in female patients, the length of ST tendon was less than 28 cm in 43.75%. Moreover, according to our findings, height and weight are considered to be moderate predictors of the adequacy of the semitendinosus tendon length when using alone ST four-strand graft or of the four-strand ST and G graft diameter for ACL single-bundle reconstruction harvested by common technique (without bone plug). The most reliable predictor seems to be patient's height in males. In female patients, there is no such statistically important predictor. The use of ST and G grafts seems to have good results in many studies –21, whilAccording to Vernon et al., the use of ST tendon alone is adequate in almost all cases  and the Referring to graft diameter and according to our results, the majority of patients (86.7%) had an adequate quadrupled graft diameter (7 to 8 mm), while 10% of patient's grafts were inadequate (less than 7 mm). Referring to female patients, this percent becomes 25%. Only 2 patients (3.3%) had graft diameter greater than 8 mm . Pinheirr = 0.567), then to height  and finally to BMI . Treme et al. in a study of 50 consecutive patients observed a positive effect of the BMI on graft diameter [Hamstring graft size according to our study could be predicted by evaluating preoperatively some simple anthropometric parameters. According to our results ST, and G graft diameter was most strongly correlated to patient's weight  and then with weight  of patient's, but there was no correlation with BMI. Also in a study of 80 patients, Pinheiro et al. claim that height is the most important variable that influences most the graft length [The lengths of the hamstring graft can also be predicted by preoperative anthropometric measurements. In our study, the length of G and ST graft was most strongly correlated with height , the surgeon should decide whether further augmentation of the ACL graft with G tendon would be necessary.Hamstring grafts less than 7 mm in diameter and 28 cm in length are not so rare. According to our findings we come to the conclusion that the length of ST tendon, harvested by the common technique, is usually inadequate in order to be used alone as a four-strand graft especially in females. Identification of these patients is still a subject of research. The potential of size prediction of autograft hamstring tendons in ACL reconstruction could contribute to choose the best graft and surgical technique individualized on patient's needs and in accordance with their special characteristics. By that way the possibilities of a good postsurgical result would be multiplied in difficult cases of patients like women, children, and professional athletes or revision of ACL. Also special surgical techniques such as quadrupled ST double-bundle ACL reconstruction and the DBST  technique could be used more wisely avoiding unnecessary complications such as scar formation, pain, and operating time and infection risk. Height and weight are considered to be moderate predictors of the adequacy of the semitendinosus tendon length when using alone ST four-strand graft or of the four-strand ST and G graft diameter for ACL single-bundle reconstruction harvested by common technique (without bone plug). The most reliable predictor seems to be patients' height in males. In female patients, there is no such statistically important predictor.


The subendocardial layer of the myocardium is more sensitive to ischaemia than the subepicaridal layer due to interactions between myocardial contraction and blood supply. The transmural perfusion gradients observed in coronary heart disease (CAD) can be visualised with high spatial resolution myocardial perfusion CMR. These gradients are characterised by the extent and intensity of the endo- to epicardial redistribution and by its temporal persistence. The gradientogram method  has been developed to assess and quantify these characteristics of transmural perfusion gradients. The aim of this study was to assess the diagnostic accuracy of the method versus fractional flow reserve (FFR) in patients with suspected CAD.28 patients  with known or suspected CAD underwent high-resolution (1.2 x 1.2 mm in plane) adenosine stress perfusion CMR at 3.0T. FFR was measured in all vessels with >50% severity stenosis. FFR<0.80 was considered hemodynamically significant. Transmural perfusion gradients were measured by the gradientogram plot and initially analysed based on different thresholds of transmural perfusion redistribution. In addition, the following parameters were assessed (units of measurement): radial extent (degrees), peak value , area (degrees*seconds), temporal persistence (seconds) and strength of the gradient .Transmural perfusion gradient analysis alone at thresholds of 5%, 10%, 15% and 20% yielded a diagnostic accuracy for CAD of 0.72, 0.78, 0.83 and 0.78, respectively .The Centre of Excellence in Medical Engineering funded by the Wellcome Trust and the Engineering and Physical Sciences Research Council (EPSRC) under grant number WT 088641/Z/09/Z. Andreas Schuster received grant support from the British Heart Foundation (BHF) (RE/08/003 and FS/10/029/28253) and the Biomedical Research Centre (BRC-CTF 196). Sven Plein was funded by a Wellcome Trust Research Fellowship during the early phase of this study (WT078288).and is currently funded by a British Heart Foundation Senior Research fellowship (FS/10/62/28409). Timothy Lockie was funded by a British Heart Foundation Clinical Research Training Fellowship (FS/08/058/25305).


The goal of this study was to design structural mimics of HIV-1 epitopes that have the potential to induce broadly neutralizing antibodies (bnAbs). The structure of the gp41 membrane proximal external region (MPER), targeted by three bnAbs, requires further definition. Experiments were designed to select epitopes with enhanced binding to MPER bnAbs, to identify neutralization-competent MPER structures, and to determine if selected MPER epitopes can broaden the immune response as potential vaccines.MPER epitopes were selected by biopanning with phage-displayed peptide libraries against bnAbs 4E10, 2F5 and Z13. Epitopes were screened in competition binding assays where M13-displayed epitopes competed with envelope peptides or infectious HIV-1 for antibody binding. In vivo response to MPER was assessed by M13 immunoprecipitation and neutralization competition assays using HIV-positive plasma, and immunogenicity of select epitopes was assessed in BALB/c mice.Forty-six unique 4E10 epitopes were identified, representing both MPER homologous and non-homologous sequences. Fourteen epitopes, capable of competing with MPER peptide and HIV-1 for 4E10 binding, bound HIV-positive IgG. Of these, five epitopes absorbed MPER-specific neutralizing activity in HIV-positive patient plasma. Mouse immunization with the selected neutralization-competent MPER epitopes elicited HIV-1 specific cellular and humoral immune responses and boosted the neutralizing activity of a gp145 Env subunit vaccine.This study demonstrates the diversity of epitope recognition by 4E10 and the unique response to MPER in vivo. The M13-displayed, neutralization-competent structures of the 4E10 epitopes have the potential to elicit and boost HIV-1 neutralizing antibody production in mice. Phage-displayed epitopes can rapidly and inexpensively be selected to provide epitope-specific depth and variation to HIV-1 vaccine designs without requiring modification to major vaccine components.


An introductory overview to the special issue papers on diffraction structural biology in this issue of the journal. An introductory overview to the special issue papers on diffraction structural biology in this issue of the journal. Journal of Synchrotron Radiation presents articles submitted in the context of the 4th International Symposium on Diffraction Structural Biology (ISDSB2013) held at the Fukiage Hall in Nagoya on 26–29 May 2013. It was the fourth in the series of ISDSB symposia initiated in 2003 by the Japan Society for the Promotion of Science (JSPS) and specifically by the University–Industry Cooperative Research Committee (#169) chaired by Professor Noriyoshi Sakabe. The previous conference was held in France, close to Paris at Paris-Sud University (Orsay) and the synchrotron radiation facility SOLEIL, chaired by the late Roger Fourme. ISDSB2013 came back to Japan again.This issue of the The basic concept of the ISDSB symposia is, firstly, to bring together researchers using diffraction and crystallography, and more generally interactions of X-rays, electrons and neutrons with matter, in the study of structural biology, and, secondly, within this domain, to facilitate the interaction between academic and industrial researchers. The interfaces with other active fields in biological ultra-structure using microscopies and spectroscopies (in particular nuclear magnetic resonance) are also respected as vital for the growth of a more systematic understanding of biological function based on structure. The scientific topics covered in ISDSB2013 included the following sessions: (1) synchrotron radiation and free-electron lasers; (2) new methodology and instrumentation; (3) and (4) drug design; (5) electron microscopy; (6) tomography and imaging; (7) neutron diffraction and hydration structure; (8) membrane proteins and macromolecular complexes; (9) protein structure and dynamics. A total of 207 participants, with a number of young scientists and PhD students, from 14 countries took part. The speakers included two Nobel Prize winners, Thomas Steitz and Brian Kobilka, three plenary lecturers  and 31 invited speakers. A poster session was also held and 80 posters were presented. Thirteen commercial and industrial companies presented exhibitions, and a sponsored lunch seminar was also given.The symposium was supported jointly by the #169 Committee of JSPS and by many industrial companies as well as generous individuals. We wish to express our sincere thanks to the University–Industry Cooperation and Research Program Division of the JSPS, to the Industry Club of Japan for their financial contribution through JSPS to print this issue, to the Naito Foundation for supporting the travel fees, and to all companies and persons who contributed their donations and cooperation.


International Journal of Clinical Oncology [The authors have retracted this article  as it coOncology . Lead au


There were multiple errors in the affiliations. The correct affiliations are:Roland M. FriedrichInstitute for Mathematics, Humboldt University Berlin, Berlin, Germany andDepartment of Neuropsychology, Max Planck Institute for Human Cognitive and Brain Sciences, Leipzig, GermanyAngela D. FriedericiDepartment of Neuropsychology, Max Planck Institute for Human Cognitive and Brain Sciences, Leipzig, Germany


A peer-reviewed journal would not survive without the generous time and insightful comments of the reviewers, whose efforts often go unrecognized. Journal of Negative Results in BioMedicine has been blessed by the support of highly-qualified peer reviewers, and the Editor-in-Chief, Bjorn Olsen, and staff of the journal would like to show their appreciation by thanking the following for their invaluable assistance with review of manuscripts for the journal in Volume 12 (2013). Seena AjitUnited States of AmericaMohammed Al-GayyarEgyptLeonard BieloryUnited States of AmericaLeif BjermerSwedenRollin BrantCanadaChristine ChambersCanadaBradley ChippsUnited States of AmericaAldo ClericoItalyHans Edmund EckelAustriaMichael EisenhutUnited KingdomVera FarahBrazilFran GengoUnited States of AmericaBarbara HeroGermanyMelissa JamersonUnited States of AmericaTimo KoskenkorvaFinlandShozo KusachiJapanWalter LehmacherGermanyMaura MassiminoItalyBryony McNeillAustraliaCathryn MellershUnited KingdomEvelyn Marielle MonninkhofNetherlandsTakashi NagasawaJapanAnja NiehoffGermanyMelanie NoelUnited States of AmericaRobert OlneyUnited States of AmericaIsabel PalmeirimPortugalMichael PolkeyUnited KingdomDavid PriceUnited KingdomTheodore PriceUnited States of AmericaTimothy PrickettNew ZealandDieter ReinhardtCanadaJan RingersNetherlandsTibor RohacsUnited States of AmericaCelena Scheede-BergdahlCanadaFrode SlindeSwedenRoger StuppSwitzerlandEtsuji SuzukiJapanSoshi TakaoJapanJean TchervenkovCanadaDag ThelleSwedenSamuel VergesFranceDongfeng ZhangChina


With the establishment of the online publishing system of Journal of Dental Research, Dental Clinics, Dental Prospects (JODDD), the journal started to enjoy a broader audience outside its publishing home in Iran. In fact, visitors to the JODDD website from other English, and even non-English-speaking countries, outnumber visitors from Iran, which again puts an emphasis on the importance of scholarly communication in an international language, despite the fact that publishing in English by non-natives has been quite an effort for the editorial team. Nonetheless, the editorial team of JODDD is glad to be able to publish a journal that can attract an international readership.In the third volume of the journal, we published articles from international contributors outside Iran. We are looking forward to seeing more submissions from all around the world, and hope that JODDD will become a forum for researchers, clinicians and educators in the field of dentistry and related sciences in this part of the world. We are optimizing our process to help authors prepare manuscripts that can be quickly and efficiently reviewed, edited, and finally published. We have made efforts to reduce the time for reviewing of manuscripts, which will result in the timely publication of research results.In addition to the Expert Medica database for health professionals (EMCARE), JODDD is now indexed in WHO Index Medicus for the Eastern Mediterranean Region (IMEMR), the Directory of Open Access Journals (DOAJ) and Index Copernicus. With higher visibility that these databases bring to the articles published in JODDD in addition to the Google Scholar search engine, authors will enjoy a broader readership for their articles.In this issue, we have focused on a pre-malignant lesion that often degrades the quality of life of the involved individuals. Oral lichen planus is important for the dental practitioner from multiple standpoints. Lichen planus is a chronic inflammatory and immunologic mucocutaneous lesion. Patients usually complain of lichen planus symptoms following the onset of the symptoms and signs for the rest of their lives. It is considered a pre-malignant lesion, and therefore, its diagnosis and treatment need special attention. Tabriz University of Medical Sciences, which is home to JODDD, has been planning to be recognized as the national reference center for the lichen planus.We are grateful to Dr. Ardeshir Lafzi, the Editor-in-Chief, who is leaving Tabriz University of Medical Sciences, and this oral lichen planus special issue is the last issue edited by Dr. Lafzi. The fourth volume of the journal will continue under the editorship of Dr. Naser Asl Aminabadi, associate professor, Department of Pediatric Dentistry, Tabriz University of Medical Sciences. We also have to thank the members of our editorial board, who have fulfilled their three-year assignment, and our reviewers, who are listed in the appendix of this issue. We hope to have more international editorial board members, the presence of whom will encourage other professionals in the field to participate in shaping our journal and cooperation for the advancement of sharing knowledge in this field.


Microbial Ecology in Health and Disease to an Open Access publication model and a dedicated publishing house has now started to bear fruit.The shift of Microbial Ecology in Health and Disease was entered into online evaluation by Thomson Reuters (ISI), the company offering this citation indexing service. However, it will probably take 3–4 years before the journal actually obtains an official Impact Factor due to the way in which this factor is calculated. But now the process has started. Personally, my first priority is to publish high-quality research papers that will be read by researchers all over the world; if these papers are also cited by these researchers, I will only be happy.The so-called Impact Factor is one of several ranking indicators that are important for the development of a scientific journal, and I am therefore pleased to inform our authors and readers that, in July 2012, Microbial Ecology in Health and Disease be accepted for inclusion, PMC will submit a citation to PubMed as soon as an article in the journal is live in PMC, i.e. a couple of days after it has been published on the journal's website.For a long time we have wanted to have the journal included in PubMed Central/PubMed and the journal is now finally in for evaluation by the Selection Group at the National Library of Medicine (NLM), and we hope for a verdict soon. PubMed Central (PMC) is the free archive of biomedical and life sciences journal literature at the U.S. National Institutes of Health's NLM, and is designed to provide permanent access to all of its content, even as technology evolves and current digital literature formats potentially become obsolete. Should their journal, and they are only charged a publication fee of €300 as compared to the non-member fee of €800. In fact, €300 is a comparatively small fee for publication in an Open Access journal. To get Microbial Ecology in Health and Disease to now lift I therefore encourage you to submit at least one paper to the journal in the near future – either from your own group or for the wider network you are working within – so that the evaluations currently going on at NLM and Thomson Reuters, as described above, may eventually turn out to the journal's advantage.The key problem of this long waiting has not been because of the quality of the content we publish but because the inflow of manuscripts is too slow. In fact, as Chief Editor, that is at present my major concern. In particular, I am somewhat surprised that so few SOMED members contribute with their work. After all it is Then I want to share some new ideas with you:There is still a lot of turbulence around the word “probiotics”. Regulatory rules vary considerably worldwide, thus creating problems for researchers as well as producers. In the months to come – and before the next SOMED conference in Kosice in September 2013 – letters from you describing your experiences and/or opinion of this subject are highly appreciated.I also want to receive proposals for new thematic clusters. The cluster of articles around the topic “Autism Spectrum Disorders” turned out to be a great success and has encouraged me to embark on new special issues – it could be either proceedings from a conference as was the case with the Autism collection of papers, or simply by inviting researchers in a particular field to contribute a paper on a clearly defined theme. “Probiotics” and/or “Fecal transplantation” might be two suitable topics. Ideas for other special issues are very welcome.in toto any longer; but your old work might turn out to be of interest when applying today's technology to these as yet unsolved problems. Therefore, I kindly ask you to submit letters or notes to be published under the heading “Notes from the past for the future”. I will try to put them into a proper historical perspective if and when they are published.I also want to encourage you to re-view any old documents with “unpublished results” that you have jotted down over the years. I am sure many of you will find some interesting notes revolving around problems that still are not solved. Surely, your experiments may have been done by “yesterday's technology” and may not deserve to be published Microbial Ecology in Health and Disease. I hope you will submit one or more papers soon, and perhaps even respond to one or more of the above suggestions to make the journal an even more interesting and lively forum for research and debate in our field of expertise. Only together can we make 2013 the best year ever for Microbial Ecology in Health and Disease.To conclude, I want to thank you for your continued interest in Tore MidtvedtEditor-in-ChiefKarolinska Institute, November 2012


Triplicate microcosms of fecal slurries were enriched with lactate and/or starch. Metabolic products  were measured and microbial community compositions determined using Illumina 16S rRNA sequencing over 12-hour intervals. We report that patterns of change in short chain fatty acid levels and pH in our in vitro system are similar to those seen in in vivo laminitis induction models. Community differences between microcosms with disparate abilities to clear excess lactate suggest profiles conferring resistance of starch-induction conditions. Where lactate levels recover following starch induction conditions, propionate and acetate levels rise correspondingly and taxa related to Megasphaeraelsdenii reach levels exceeding 70% relative abundance. In lactate and control cultures, taxa related to Veillonellamontpellierensis are enriched as lactate levels fall. Understanding these community differences and factors promoting the growth of specific lactate utilizing taxa may be useful to prevent acidosis under starch-induction conditions.Laminitis is a chronic, crippling disease triggered by the sudden influx of dietary starch. Starch reaches the hindgut resulting in enrichment of lactic acid bacteria, lactate accumulation, and acidification of the gut contents. Bacterial products enter the bloodstream and precipitate systemic inflammation. Hindgut lactate levels are normally low because specific bacterial groups convert lactate to short chain fatty acids. Why this mechanism fails when lactate levels rapidly rise, and why some hindgut communities can recover is unknown. Fecal samples from three adult horses eating identical diets provided bacterial communities for this  Horses are hindgut fermenters, adapted to grazing continually on marginal forages that change seasonally, thus slowly . The hinLaminitis is a chronic, crippling disease, accounting for 15% of all lameness in horses in the United States, with over 27% unable to return to normal work, and 4.7% mortality . It is cFirmicutes, with Bacteroidetes, Proteobacteria, and Verrucomicrobia as other major phyla. Studies have detected a greater proportion of fibrolytic bacteria than starch and lactate utilizing bacteria in the cecum than in the colon [Surveys of equine hindgut bacteria using culture based methods  and 16S he colon ,21, reflin vivo models of laminitis induction using starch gruel or oligosaccharide [Streptococcus bovis/ equinus group , have bincrease ,26,27. Bincrease ,28. In oincrease .Lactate levels in the hindgut are normally low due to the activity of lactate utilizing bacteria. It is unclear why this mechanism fails during conditions of starch induction. While studies of lactate producers have pointed to specific taxa that proliferate during the developmental stage of laminitis ,26,27, lin vitro model system to track bacterial metabolites and community shifts over time in response to enrichment with starch and/or lactate. Patterns of changes in lactate concentration and pH were similar to those reported in published in vivo studies [In this study we used fecal samples collected from 3 healthy, adult horses eating an identical pasture based diet in an  studies ,23. IlluThis study was carried out in accordance with the guidelines set forth by the Morris Animal Foundation and applied by the Institutional Animal Care and Use Committee at the University of Massachusetts, Amherst. We thank Dr. Carlos Gradil  for generously lending his time and expertise in sampling, and the Hadley Farm, University of Massachusetts, Amherst, MA for providing three horses for this study.Fecal samples were manually collected from the midrectum of three Morgan geldings cohoused at the University of Massachusetts, Hadley Farm and fed identical hay based diets. None of the animals had received antibiotics, anthelmenthics, or other medications for at least three months prior to sampling. Samples were protected from oxygen exposure during collection by inverting the glove around each as it was removed, and placing each immediately in a container evacuated of oxygen. Samples were kept as close to 39°C as possible in a heated, insulated container during transport and the following steps of dilution and inoculation. In an anaerobic chamber, samples were diluted to make a 10% slurry in anaerobic dilution media prepared as described by Bryant . This slp-phenylenediamine and 187.5 µl 10 mM iron (III) chloride were added, stoppered immediately, and incubated for 20 minutes at room temperature. The resulting suspension was spun down and the absorbance of the supernatant was measured at 670 nm in comparison to standard solutions . pH was determined using EMD colorphast pH strips .Short chain fatty acids  were measured for samples taken over the time course using high performance liquid chromatography (HPLC)  with an Aminex HPX-87H column . Headspace gases were analyzed using a gas chromatograph  fitted with a HayeSep DB column 100/120 . Hydrogen sulfide levels were measured using the methylene blue assay as in Cline  modifiedDNA was extracted from each sample as described elsewhere ,34 with GTGCCAGCMGCCGCGGTAA-3’) and universal reverse 806R (5’- Illumina adapter- Golay bar code- Reverse primer pad- Reverse primer linker- GGACTACHVGGGTWTCTAAT-3’). Each PCR reaction mixture contained 10 ng of genomic DNA, 2.5 µl 10X buffer, 2.0 µl MgCl2 (25 mM), 2.0 µl dNTP (2.5 mM each), 5.0 mM (each) forward and reverse primers, 1.25 µl (25 µg) BSA , 0.25 µl (1.25 U) Ex Taq , and molecular grade water to reach a volume of 25 µl. PCR was performed with 3 min of initial denaturation at 94°C followed by 30 cycles of the following program  followed by a final extension at 72 °C for 7 min. PCR products were cleaned using Qiagen MinElute kit  as directed and quantified using the Quant-iT PicoGreen assay . Equal concentrations were pooled and sequenced using the Illumina MiSeq platform at the Dana Farber Cancer Institute, Molecular Biology Core Facilities .Amplification of the V4 region of the 16S rRNA gene and attachment of Illumina adaptors and bar codes for multiplexing samples (reverse read only) was done in triplicate as described elsewhere . BrieflySequences were demultiplexed and trimmed of bar codes and primer sequences, then filtered for quality and reverse and forward reads were assembled into contigs using FastQC . SequencDespite variation in the pH response between the three horses, in all of the starch and starch/lactate enrichments, the pH dropped to below 6 by hour 12, and reached levels between 4 and 5 by hour 18 . These vThe three horse cultures differed dramatically in the ability to attenuate accumulated lactate. The lactate was reduced to below detectable limits in the control and lactate enriched treatment groups of all three horse cultures, however the peak was higher for horse 3 cultures and took longer to drop. In the starch and starch/lactate enrichments the differences were more dramatic. Lactate persisted at maximum levels in horse 3 cultures over the full time course while dropping for horse 1 and 2 cultures by hour 36.Headspace gases (hydrogen and methane) and hydrogen sulfide levels measured at 12 hour intervals did not show consistent differences between treatment and control conditions due to variation between horses especially for the starch and starch/lactate cultures .As shown in Rarefaction curves of the number of sequences per sample by observed species  indicateFirmicutes were the most abundant group by time 48 in all cultures regardless of enrichment conditions, with a corresponding decline in all other major groups, namely the Verrucomicrobia, Spirochaetes, Proteobacteria, and Bacteroidetes, however at this taxonomic level, clear differences between horse and treatment groups were not apparent.Taxonomic assignments at the phylum level  showed tFirmicutes. The Veillonellaceae, a family with known lactate utilizing species [Veillonellaceae dropped to less than 5% in horse 3 cultures, while in horse 1 and 2 cultures this group was the highest in abundance, making up more than 70% of the total sequences  under control and lactate conditions for horse 3 was also found in horse 1 and 2 cultures, it reached a lower abundance in both. While horse 3 control and lactate enriched cultures were able to attenuate lactate, it persisted in high concentrations in starch and starch/lactate enrichments in which no member of the Veillonellaceae was highly abundant.Identification of specific taxa that were most abundant by hour 48  suggesteMegasphaeraelsdenii (100% identity) was the most abundant OTU in horse 1 and 2 cultures, especially in the starch and starch and lactate enrichments, reaching relative abundances of over 70%. While this OTU was present in single numbers at Time 0 in all three horse samples, and persisted in horse 3 in low numbers under all culture conditions  and represented 97.7% of the Lactobacillaceae sequences across the dataset. This OTU was present in all three horse cultures, reaching abundances of 20% and greater in horse 1 in starch and starch and lactate enrichments at time 36, but then falling to 10% or less by time 48  together accounting for less than 50% of the sequences in this group , followed by an increase in the Lactobacillaceae as the abundance of Streptococcaceae falls.No study thus far has tracked microbial changes over the time course of starch induction in horses using 16S rRNA deep sequencing as described here, however, the changes that we observed in community composition are similar to what has been reported in equine and ruminant culture and probe based studies ,14,43,44Despite a sample size of three horses, we were able to observe between-horse differences in the ability to attenuate accumulated lactate as has been described in previous studies ,23.in vitro model may provide insight into microbial mechanisms of resistance and/or recovery.Certainly the microbial dynamics reported here may not reflect the actual community compositions of the caecum and large intestine of horses who recover or resist conditions of lactic acidosis, however the elucidation of endogenous lactate utilizers that thrive under conditions of low pH following starch enrichment in our Streptococcus species during the first 24 hours of starch induction followed by an increase in Lactobacilli species noted in other studies [Streptococcuslutetiensis group  of the16S gene is inherently limited [Streptococcuslutetiensis group may be especially difficult to distinguish due to their close phylogenetic relationships [While we observed the pattern of increase in  studies ,23 we exus bovis ) to be m studies ,24,29. O limited ,46 for a limited , and susionships ,48. SequStreptococcuslutetiensis and Lactobacillus sp as major lactic acid producers [Megasphaera, Veillonella, Selenomonas, Propionibacterium, and Anaerovibrio as key lactate utilizers. In fact, strains of Megasphaeraelsdenii have been shown to be effective in preventing lactic acidosis in cattle and are under development as probiotic therapies [While studies have pointed to roducers ,28,29, rroducers ,44,49 haherapies –52.in vitro model of starch induction, we report here changes in the abundance of specific microbes associated with the reduction of lactic acid. As we observed at time 0 in this study, 16S rRNA surveys of the equine gut microbiome have shown that under normal conditions, the Veillonellaceae (known lactate utilizers) comprise 1% or less of the total bacterial abundance [in vivo study did not see a difference in the abundance of Veillonellaceae in response to dietary change despite an increase in lactate levels [Veillonellaceae in that study did not increase in abundance as lactate accumulated, or which specific taxa were present in those horses.Using deep sequencing of the 16S rRNA gene of fecal communities challenged with starch, lactate, or both in an bundance –19. One e levels . It is uMegasphaeraelsdenii was highly abundant in all starch and starch/lactate cultures in which lactate accumulated and was attenuated. This taxa was present in very low abundance in cultures in which lactate persisted. It is unclear why this taxa fails to proliferate in any of the horse 3 cultures while reaching such high abundances under all conditions in horse 1 and 2 cultures. A second OTU related to Veillonellamontpellierensis was highly abundant in control and lactate enrichments specifically in horse 2 and 3 cultures, but did not thrive in the starch or starch/lactate enrichments, suggesting that other factors such as pH or competitive interactions exert selective pressure under starch and starch/lactate enrichment conditions.In our study we observed that one particular taxa closely related to Megasphaeraelsdenii OTU and the reduction of lactate, conclusive evidence that this taxa is responsible for reducing lactate levels will require further study. It is possible that other community members with lactate utilizing capabilities are playing active roles as well.While our data indicates a relationship between the presence of the Understanding the factors stimulating or preventing the proliferation of lactate utilizers in the horse gut microbiome could provide valuable information about why some horses are more sensitive to starch induction, and the microbial basis behind mechanisms of resistance.in vitro model for starch induced laminitis in horses as described here could provide a convenient and cost effective means to understand the microbial dynamics underlying colic and laminitis, and test hypotheses for ways to prevent or interrupt the progress of these equine diseases. Specific taxa in the family Veillonellaceae were highly abundant in starch enriched cultures that were able to attenuate lactate. These could provide useful insights into mechanisms of recovery or resistance, and could be valuable, individually or in consortia, as probiotics to prevent starch induced colic and laminitis.A robust Figure S1Hydrogen sulfide concentrations over time by horse.Concentration (mM) of hydrogen sulfide measured by the Cline (methylene blue) assay from each horse and culture condition at 12 hour intervals.(TIF)Click here for additional data file.Figure S2Headspace gas concentrations over time by horse.Concentration (mM) of hydrogen and methane gases measured by gas chromatography from each horse and culture condition at times 9, 20, 32, and 45 hours.(TIF)Click here for additional data file.Figure S3Rarefaction curves by horse.Observed species by number of sequences per sample for each horse dataset generated using a sampling depth of 9685 (the minimum number of sequences per sample and default parameters in QIIME.)(TIF)Click here for additional data file.Table S1Alpha diversity estimates for each sample.Chao1, observed species, Shannon Index and Good’s coverage for each horse dataset generated using default parameters in QIIME.(XLSX)Click here for additional data file.


Journal of Cellular and Molecular Medicine , ‘Differential proteomic profiling to study the mechanism of cardiac pharmacological preconditioning by resveratrol’ by Karel Bezstarosti, Samarjit Das, Jos. M. J. Lamers and Dipak K. Das, and published in the October 2006 issue in Wiley Online Library (http://onlinelibrary.wiley.com), has been retracted by agreement between the authors, the journal Editor-in-Chief, Professor LM Popescu and Blackwell Publishing Ltd. The retraction has been agreed due to findings of data fabrication in the western blot data in Figure 6 that occurred in the laboratory of Dipak K. Das in an investigation into the work of Dipak K. Das by the University of Connecticut Health Center. Although no questions have been raised concerning the data generated by Karel Bezstarosti and Jos M J Lamers, these authors fully support the retraction.The following article from


Assessment of the SpatialQRS-T Angle by Vectorcardiography: Current Data and Perspectives”, byChristina Voulgari and Nicholas Tentolouris published in Current CardiologyReviews Journal, 251-62 November 2009, Vol.5, No. 4, pp. 251-62.This is with reference to the article entitled, “Elucidation of thespatial ventricular gradient and its link with dispersion ofrepolarization”, by Draisma HH, Schalij MJ, van der Wall EE, Swenne CApublished in Heart Rhythm Journal, 2006, Vol. 3, No.9, pp. 1092-9 in the above mentioned article.The authors have overlooked to cite the paper entitled, “


The congress was supported by Iranian Neurological Association and about 600 physicians and researchers participated in the congress. Prof. Atri, Prof. Federico, Prof. Rostami, Prof. Lotfi, and Dr. Ansarinia, Dr. Salajegheh, Dr. Banikazemi, Dr. Sybilleh, and Dr. Nagga were the international guests of the congress.The 20The congress was managed by Prof. Togha and nicely supported by the president of the Neurological Association, Prof. Pakdaman. The main aim of the congress was to familiarize neurologists and other specialists with the latest scientific achievements in the field of neurology.The interesting characteristics of this congress was that for the first time abstracts of lectures were available online beforehand and were published as a supplement of Iranian journal of neurology ). This was admirably managed by Dr. Fatehi who is the deputy editor of Iranian Journal of Neurology.Teaching coursesNeurologists who were considered expert in a specific field offered the latest instructions and information on prevalent and important diseases. The courses were mostly educational and discussed about the major areas of neurology.Different clinical and research aspects of neurologyThis section comprised 61 lectures about studies conducted by the lecturers. For the first time, one of the most important parts of this program was allocated to neurometabolic diseases. It was systematically designed by Dr. Shalbafan. Our special guest in this field was Prof. Federico from Italy who is the chief editor of Neurological Science Journal .WorkshopsIn this section, scientific aspects of neurology were considered and younger neurologists were trained on techniques like electroencephalography (EEG), electromyography (EMG), transcranial color coded Doppler (TCCD), and botulinum injection protocol for chronic migraine. Furthermore, for the first time in an Iranian neurology congress, two special workshops were held about Medical Digital Library and how to study and review articles.PanelsTwo panels were held during the congress. The first panel discussed different aspects of multiple sclerosis and the other panel reviewed the aspects of stem cell therapy in neurological diseases.Interesting and challenging casesDifferent cases were presented in this popular part of the congress program and favorably managed by Dr. Nabavi.Residents scientific competitionThis was nicely conducted by Dr. Rahmat.Accordingly, several scientific programs were held during four days. The programs were divided into the following 6 categories:The annual neurological congress could unquestionably play an important role in promoting the status of neurology in Iran. Indeed, attendance of participants and neurologists from different parts of the world contributes to establishing a relationship between the Iranian Neurological Association and other international neurology centers across the world.