Microscopic Colitis (MC) is characterized by chronic watery diarrhea, grossly normal appearing colonic mucosa during conventional white light endoscopy, and biopsy showing microscopic inflammation. We report a case of collagenous colitis with gross endoscopic findings. A 71-year-old female with past medical history of coronary artery disease, carotid artery disease, hypertension, and diabetes mellitus type 2 was being evaluated for recurrent intermittent diarrhea. Patient denied any abdominal pain, weight loss, or any blood in stool. Patient was not on any medications and lab work was within normal limits. Colonoscopy was required to further evaluate patient's diarrhea. Colonoscopy revealed multiple scattered segments throughout the colon with increased nodularity and loss of vascular markings in the hepatic flexure, descending colon and cecum Figures . These fMicroscopic examination showed lymphocytic colitis with marked thickening of the superficial collagen table consistent with collagenous colitis. The submucosal collagen was dense and paucicellular with several entrapped lymphocytes and capillaries (red arrow). The lamina propria displays an increase in eosinophils, plasma cells, and lymphocytes (black arrow) .Microscopic Colitis (MC) is characterized by chronic watery diarrhea, grossly normal appearing colonic mucosa during conventional white light endoscopy, and biopsy showing microscopic inflammation. It accounts for 4%–13% of patients evaluated for chronic diarrhea and divided into lymphocytic and collagenous colitis . CertainAlthough identical clinically, both types of colitis have distinct microscopic findings. Lymphocytic colitis is characterized by intraepithelial lymphocytosis  while collagenous colitis is diagnosed by thickening of subepithelial collagen layer of more than 10 micrometer [By definition colonic mucosa has a normal appearance in MC. Yet distinct endoscopic findings, particularly for collagenous colitis, have been described in the literature. These findings include alteration of mucosal vascular pattern, mucosal abnormalities such as red spots, increased mucosal nodularity, or textural alteration, and pseudomembranes . Recent advance in endoscopy may enhance the ability to detect MC. A newly developed post processing light filters such as i-Scan  helps to enhance the visualization of mucosal pattern and vascular architecture. Chromoendoscopy using indigocarmine dye sprays may show a mosaic pattern of mucosa in lymphocytic colitis and a nodular, grooved pattern in collagenous colitis . These nMicroscopic Colitis is traditionally known to have normal colonic mucosa on endoscopy. Recent advance in endoscopic techniques has shown that various mucosal abnormalities such as alteration of mucosal vascular pattern and increased mucosal nodularity are associated with MC. These newer techniques will allow us to get targeted biopsy, which will increase the yield of endoscopic diagnosis of MC.


Borrelia burgdorferi infection. Little has been published in the medical literature about patients with chronic Lyme disease or their relationships with healthcare providers. The objective of this study was to gain insights into the health beliefs and experiences of patients with chronic Lyme disease.Chronic Lyme disease is a term that describes a constellation of persistent symptoms in patients who may or may not have serologic evidence of This was a qualitative, descriptive study in which face-to-face in-depth interviews were conducted with patients who were diagnosed with or self-identify as having chronic Lyme disease. Patients were recruited through Connecticut-based Lyme disease mailing lists and support groups. A coding structure was developed using an iterative process. Transcribed interviews were coded using Atlas.ti software and analyzed for emergent topics and themes. Interviews were conducted until thematic saturation was achieved.A total of 12 interviews were conducted. Four major themes emerged. Patients reported: (1) diminished health status associated with chronic Lyme disease; (2) concerns about persistence of symptoms ; (3) two divergent types of physician-patient relationships ; and (4) seeking and receiving unconventional care .Our findings show that patients report a marked decrease in health status associated with chronic Lyme disease and are often unsatisfied with care in conventional settings. Negative experiences with providers were associated with reports of dismissive, patronizing, or condescending attitudes. Positive experiences were associated with providers reported to be attentive, optimistic, and supportive. Patient-centered approaches that acknowledge suffering and focus on continuity of care and symptomatic relief may result in increased patient satisfaction.


Increasing the use of pharmacotherapies for alcohol dependence has the potential to improve patient outcomes and reduce health-care costs by reducing hospital admissions. This randomized controlled trial (RCT) evaluated the cost-effectiveness of tailored mailed feedback on general practitioner (GP) prescribing for alcohol dependence and alcohol-related hospital admissions. General practitioners (N = 115) in 10 communities randomized to the experimental arm of the Alcohol Action in Rural Communities (AARC) project received tailored mailed feedback on their prescribing of acamprosate and naltrexone. Segmented regression analysis examined the impact of the intervention relative to GPs’ prescribing and inpatient hospital admissions for alcohol dependence in those communities. Incremental cost-effectiveness ratios were estimated to compare costs per additional prescription written and costs per inpatient admission averted. Trend analysis showed GPs significantly increased their prescribing of acamprosate  and significantly decreased their prescribing of naltrexone . Rates of alcohol-related inpatient admissions for alcohol dependence decreased significantly in the experimental group compared with the control group . Similar to evidence showing SBI can improve patient outcomes, this study showed mailed tailored feedback to GPs achieved cost-effective increases in their prescribing of acamprosate, with a subsequent and plausibly causal reduction in inpatient hospital admissions for alcohol dependence. Demonstrating the capacity of brief intervention in primary-care settings to reduce demand for tertiary care services appears to be a promising direction for the SBI field. A large-scale RCT of the cost benefit of tailored feedback to GPs appears warranted.


We used ecologic niche modeling of outbreaks and sporadic cases of filovirus-associated hemorrhagic fever (HF) to provide a large-scale perspective on the geographic and ecologic distributions of Ebola and Marburg viruses. We predicted that filovirus would occur across the Afrotropics: Ebola HF in the humid rain forests of central and western Africa, and Marburg HF in the drier and more open areas of central and eastern Africa. Most of the predicted geographic extent of Ebola HF has been observed; Marburg HF has the potential to occur farther south and east. Ecologic conditions appropriate for Ebola HF are also present in Southeast Asia and the Philippines, where Ebola Reston is hypothesized to be distributed. This first large-scale ecologic analysis provides a framework for a more informed search for taxa that could constitute the natural reservoir for this virus family. Mononegavirales, family Filoviridae) are unknown potential reservoirs, including bats, rodents, arthropods, and plants   to the nearest 0.001°. Although assigned geographic coordinates may not fix the exposure point precisely, they represent our best guess as to its position and are likely to be representative of the coarse-scale ecologic conditions. Distributional data for filovirus-associated HF occurrences in hominids were accumulated from the literature . Occurrehttp://www.lifemapper.org/desktopgarp/). In general, GARP focuses on modeling ecologic niches (the conjunction of ecologic conditions wherein a species can maintain populations without immigration) Ecologic niches and potential geographic distributions were modeled by using the Genetic Algorithm for Rule-set Prediction (GARP) (Occurrence points are divided evenly into training (for model building) and test  datasets. GARP works in an iterative process of rule selection, evaluation, testing, and incorporation or rejection: a method is chosen from a set of possibilities  and applied to the training data to develop or evolve a rule. Predictive accuracy is evaluated on the basis of the test data. Rules may evolve in ways that mimic DNA evolution . Change in predictive accuracy between iterations is used to evaluate whether particular rules should be incorporated into the model; the algorithm runs 1,000 iterations or until convergence. Model quality was evaluated through independent test dataset reserved prior to modeling; a chi-square test was used to compare observed success in predicting the distribution of test points with that expected under a random model .http://edcdaac.usgs.gov/gtopo30/hydro/), and climate characteristics, including daily temperature range; mean annual precipitation; maximum, minimum, and mean annual temperatures; solar radiation; frost days; wet days; and vapor pressure . These coverages are worldwide and provide a consistent view of ecologic variation across regions studied. GARP’s predictive ability has been tested under diverse circumstances . The resulting dataset represents unique combinations of environments and predictions; its attributes table provides the model prediction for all environmental combinations to permit visualization of ecologic variation. We also compared ecologic conditions inside and outside of the modeled Ebola HF distribution within 11 regularly spaced circular windows (radius 50 km); comparisons were summarized through Mann-Whitney U-statistics, permitting a nonparametric visualization of the strength of association of each ecologic dimension  with the range limit.-7). Although subsequent modeling was done without subsetting to maximize occurrence data, these preliminary results nonetheless indicated excellent predictivity of our distributional hypoptheses. The geographic distribution of filovirus disease spreads generally across the humid Afrotropics A. OutlieFiloviridae in general , a complementary distributional area was predicted D. Marbur Sequential omission of Ebola virus species from analyses provided a view of ecologic similarity of species  Inspection of niche models of Ebola HF occurrences (Marburg HF excluded) in ecologic space  provided Distributional limits are complex results of multiple causal agents. A species is seldom limited on all sides by a single factor; rather, distributional limits are the combined result of many such factors. Inspection of the ecologic dimensions coincident with modeled geographic limits of Ebola HF occurrences  showed s Given the mysterious origin of Ebola Reston virus  A. ProjecThe ecologic niche characteristics reconstructed for filovirus species disease outbreaks coincided closely with phylogenetic patterns in the group  , GARP predictions will be overly large. Jackknife manipulations (systematic omission of ecologic dimensions to assess sensitivity to coverage density) can, to some degree, help in assessing sensitivity to coverage completeness Detailed understanding of the geography and ecology of filovirus HF outbreaks represents an underexplored avenue of investigation regarding natural transmission cycles of filoviruses. We assembled available information regarding filovirus HF outbreaks and used various analytical tools to arrive at a detailed understanding of geography and ecology of filovirus disease occurrences. Consequently, we can now assemble criteria by which potential reservoir taxa might be judged. If one assumes a fair degree of host specificity in this host-parasite system, patterns of codistribution and cophylogeny can be expected. Hence, criteria include the following: 1) African Ebola virus reservoirs would be distributed principally in evergreen broadleaf forest; 2) the main focus of the geographic distribution of the reservoir(s) would be in the Congo Basin; 3) a disjunct  distributional area would be present in West Africa; 4) a related taxon in eastern Africa would range in more arid habitats; 5) the reservoir would belong to a clade more broadly distributed across Africa and Southeast Asia. Assessment of potential reservoir taxa by using these criteria has begun , with the idea of eventually testing hypotheses of host associations through ecologic niche comparison methods


Most pathogenesis studies focus on pathogen virulence attributes that mediate host colonization, toxicity, or immune evasion. Some studies focus on how pathogens employ active mechanisms to acquire essential nutrients such as iron and vitamins from the host by producing siderophores or avidins. In order to prevent pathogen nutrient acquisition, host cells employ a process called nutritional immunity to sequester these nutrients, particularly iron, from invading pathogens How and where do intracellular pathogens obtain sufficient amounts of energy and nutrients to support their replication? Pathogens may either parasitize existing energy stores or manipulate the host cell to create usable energy and anabolic precursor metabolites. Several recent studies have identified the host AMP-activated protein kinase (AMPK) and mammalian target of rapamycin (mTOR) kinases as two important regulators of cellular metabolism whose activities are often altered during infection. However, the AMPK/mTOR pathway also regulates autophagy, which can destroy cytosolic pathogens. While the evasion of autophagy by pathogens is well appreciated, recent work suggests that both the AMPK/mTOR pathway and autophagy itself can provide intracellular metabolites that support intracellular pathogen replication.During times of limited nutrient availability, intracellular ATP levels fall, with a corresponding increase in AMP levels. Within eukaryotic cells the increased AMP∶ATP ratio induces AMPK activity, which in turn initiates a series of signaling events that stimulate energy and nutrient acquisition In order to achieve optimal levels of proliferation, many pathogens must manipulate activity of AMPK and mTOR. Interestingly, several viral pathogens have evolved strategies that allow for the induction of both AMPK and mTOR activity. For example, infection with human cytomegalovirus (HCMV) increases both AMPK and mTOR activity Simian virus 40 (SV40) infection also stimulates both AMPK and mTOR activity. SV40 small T antigen is both necessary and sufficient for AMPK activation Mycobacterium tuberculosis and Chlamydia trachomatis utilize fatty acids derived from lipid droplets Enveloped viruses require host lipids to generate the virion membrane. Activated mTOR stimulates fatty acid and lipid synthesis, and therefore could prove beneficial for virus assembly. In fact, host lipid metabolism is essential for the hepatitis C virus (HCV) life cycle and is highly regulated during infection AMPK activation also inhibits the replication of several arboviruses, including Rift Valley fever virus (RVFV) Leishmania donovani amastigotes (the parasitic form that grows inside macrophages) preferentially generate energy through fatty acid oxidation and amino acid catabolism L. donovani acquires fatty acids and amino acids from the infected host cell. Consistent with this finding, transcriptomic analysis of macrophages infected with the related parasite Leishmania major suggests that infected cells increase glucose transport, glycolysis, and starch degradation Leishmania alters host metabolic processes, a reasonable hypothesis is that intracellular Leishmania activates AMPK to benefit parasite replication. Activated AMPK could stimulate increased glucose utilization and autophagy, thus creating elevated levels of anabolic precursor pools for parasite growth. Parasite replication requires the Leishmania protein GP63, which cleaves and inactivates mTOR to reduce type I interferon production, thus AMPK activation could further benefit parasite replication by inhibiting mTOR It takes a lot of energy to make hundreds, thousands, or potentially millions of new parasites, bacteria, or viruses. It seems logical that intracellular pathogens that undergo significant intracellular growth would activate AMPK due to the energetic demands placed on the infected cell. Activation of AMPK could provide several benefits for intracellular pathogens. The increased glucose uptake, glycolysis, and fatty acid breakdown would increase available intracellular energy and nutrient pools needed for pathogen replication. For example, Francisella tularensis growth is impaired in autophagy-deficient host cells. Bacterial growth was restored in autophagy-deficient cells by supplying the infected cells with excess pyruvate or amino acids. Since F. tularensis replicates within the cytosol of host cells, our results suggest that intracellular F. tularensis uses autophagy to increase cytosolic nutrient pools that support bacterial growth F. tularensis avoids engulfment by classical autophagosomes Autophagy is an essential cellular process that recycles cellular constituents from macromolecular complexes under conditions of nutrient stress. As discussed above, autophagy is positively regulated by AMPK and negatively regulated by mTOR. However, autophagy also functions as a host defense mechanism that destroys intracellular pathogens through a process termed xenophagy. While generally viewed as detrimental for intracellular pathogens, some bacteria and viruses use autophagosomes as a replicative niche AMPK and mTOR are critical regulators of host cell metabolism making them logical targets for manipulation by invading pathogens. The energetic burden of the host cell to create hundreds or more pathogens should deplete cellular ATP levels, thus activating AMPK. AMPK induction stimulates host processes to produce energy and nutrients that the pathogen could then steal from the host. This idea suggests AMPK activation may be a common theme among infection by successful intracellular pathogens. On the other hand, mTOR signaling stimulates protein and lipid synthesis, which could be beneficial for many viral pathogens; whereas mTOR modulation is likely less important for free-living bacteria pathogens and parasites that supply their own biosynthetic and translation machinery. Identifying what nutrient sources are required for intracellular growth and how host metabolic signaling is manipulated by infection is being investigated in viral pathogenesis, yet remains poorly understood in bacterial and parasitic pathogenesis.Manipulating host metabolism is an attractive approach to controlling infection as targeting the host rather than the pathogen should considerably reduce the ability of pathogens to develop drug resistance. Several drugs already in clinical use target the AMPK or mTOR kinases to treat diseases such as cancer and diabetes. The studies described above suggest that these drugs may have additional uses in treating infections with intracellular pathogens. As our understanding of pathogen manipulation of host metabolism grows, it may also be possible to develop inhibitors of specific host metabolic pathways hijacked by intracellular pathogens. Identifying the essential nutrients required for intracellular pathogen proliferation and the host pathways manipulated to acquire these nutrients will be a significant step in understanding the requirements for viral, bacterial, and parasitic pathogenesis and identifying new targets for novel therapeutics.


Poecilia parae, a colour polymorphic fish, exhibit five distinct phenotypes: drab-coloured (immaculata), striped (parae), structural-coloured (blue) and carotenoid-based red and yellow morphs. Previous work indicates that immaculata males employ a sneaker strategy, whereas the red and yellow morphs exploit female preferences for carotenoid-based colours. Mating strategies favouring the maintenance of the other morphs remain to be determined. Here, we report the role of agonistic male-male interactions in influencing female mating preferences and male mating success, and in facilitating the evolution of AMSs.Intense competition for access to females can lead to males exploiting different components of sexual selection, and result in the evolution of alternative mating strategies (AMSs). Males of P. parae morphs during indirect and direct interactions with sexually receptive females. Two morphs, parae and yellow, use aggression to enhance their mating success  by 1) directly monopolizing access to females, and 2) modifying female preferences after winning agonistic encounters. Conversely, we found that the success of the drab-coloured immaculata morph, which specializes in a sneak copulation strategy, relies in its ability to circumvent both male aggression and female choice when facing all but yellow males.Our study reveals variation in aggressiveness among Strong directional selection is expected to deplete genetic variation, yet many species show striking genetically-based polymorphisms. Most studies evoke frequency dependent selection to explain the persistence of such variation. Consistent with a growing body of evidence, our findings suggest that a complex form of balancing selection may alternatively explain the evolution and maintenance of AMSs in a colour polymorphic fish. In particular, this study demonstrates that intrasexual competition results in phenotypically distinct males exhibiting clear differences in their levels of aggression to exclude potential sexual rivals. By being dominant, the more aggressive males are able to circumvent female mating preferences for attractive males, whereas another male type incorporates subordinate behaviours that allow them to circumvent male aggression and female mating preferences. Together, these and previous results indicate that exploiting different aspects of social interactions may allow males to evolve distinct mating strategies and thus the long term maintenance of polymorphisms within populations. Intense sexual selection can lead to competing males evolving alternative ways to obtain fertilizations, thereby enhancing their reproductive success . In geneUta stansburiana), males have evolved AMSs  and the relative fitness of each strategy fluctuates depending on the frequency of the competing strategies from one generation to the next )A and MB representing total proportion of time spent with male A or B, respectively, positive values of this index (MA - MB) would indicate a preference for male A and negative values a preference for male B. To determine whether there was a switch in female mating preferences after observing male-male interactions, we subtracted the post-male competition preference score from the pre-male competition preference score . We determined if females switched or enhanced their mate preferences between trials using a paired t-test. Preference scores were arcsine transformed to meet the assumptions of parametric tests  into two categories: aggressions received and initiated. Both categories (aggressions received and initiated) were analysed using Kruskal-Wallis non-parametric ANOVAs. To determine which morphs were attacked less and attacked more, we ran multiple comparisons of mean ranks. We also performed Kruskal-Wallis non-parametric ANOVAs and multiple comparisons of mean ranks to analyse aggressions received and initiated during the open aquarium experiments. To compare whether there were differences in the number of attacks performed by males during direct and indirect interactions with females, we used a Mann-Whitney test. Finally, the difference in number of gained or lost copulations to the competitors was analysed with Wilcoxon matched pair tests. All data sets were tested for normality and analysed with STATISTICAJLHG conceived the study, carried out the experiments, analysed the results and drafted the manuscript in partial fulfilment of a doctoral degree at Syracuse University, New York (USA). JACU contributed to the study design, supervised the study, edited and revised the manuscript critically. Both authors have read and approved the final manuscript.This file includes: Table A1 with additional information of the standard body lengths (mm) of males used during the experiments. Table A2 presents a brief description of aggressive behaviours commonly displayed by males of Poecilia parae. Figure A1 presents a simplified view of the experimental settings.Click here for file


In this article, we review studies of astrocytic-neuronal interactions and their effects on the activity of oxytocin (OXT) neurons within the magnocellular hypothalamo-neurohypophysial system. Previous work over several decades has shown that withdrawal of astrocyte processes increases OXT neuron excitability in the hypothalamic supraoptic nucleus (SON) during lactation. However, chronically disabling astrocyte withdrawal does not significantly affect the functioning of OXT neurons during suckling. Nevertheless, acute changes in a cytoskeletal element of astrocytes, glial fibrillary acidic protein (GFAP), occur in concert with changes in OXT neuronal activity during suckling. Here, we compare these changes in GFAP and related proteins with chronic changes that persist throughout lactation. During lactation, a decrease in GFAP levels accompanies retraction of astrocyte processes surrounding OXT neurons in the SON, resulting from high extracellular levels of OXT. During the initial stage of suckling, acute increases in OXT levels further strengthen this GFAP reduction and facilitate the retraction of astrocyte processes. This change, in turn, facilitates burst discharges of OXT neurons and leads to a transient increase in excitatory neurochemicals. This transient neurochemical surge acts to reverse GFAP expression and results in postburst inhibition of OXT neurons. The acute changes in astrocyte GFAP levels seen during suckling likely recur periodically, accompanied by rhythmic changes in glutamate metabolism, water transport, gliotransmitter release, and spatial relationships between astrocytes and OXT neurons. In the neurohypophysis, astrocyte retraction and reversal with accompanying GFAP plasticity also likely occur during lactation and suckling, which facilitates OXT release coordinated with its action in the SON. These studies of the dynamic interactions that occur between astrocytes and OXT neurons mediated by GFAP extend our understanding of astrocyte functions within the central nervous system.


The emergence of spontaneous bursting events in developing neuronal networks likely depends on the evolving network connectivity. Theoretical models have shown that hierarchical network structures embedding clusters of strongly inter-connected neurons are optimal for initiating and sustaining spontaneous activity . It is cTo test this we chronically manipulated activity-dependent structural plasticity by inhibition of protein kinase C (PKC) in developing networks of cortical neurons in vitro. Previous studies showed that PKC inhibition in developing cerebellum promotes dendritic outgrowth and arborization of Purkinje cells and impairs pruning of climbing fibers. We found that developmental inhibition of PKC in cortical cell cultures increased dendritic outgrowth, impaired neurite fasciculation and clustering and abolished network pruning. This resulted in more homogeneous and potentially better connected networks fig. . As a re


This study investigated procedural errors made during root canal preparation using stainless steel and nickel-titanium (NiTi) instruments by undergraduate students, using two diagnostic imaging methods.n=20; group 1: K-Flexofile, group 2: K3, and group 3: BioRace). The root canals were filled with gutta-percha and AH Plus. Periapical radiographs and cone beam computed tomography (CBCT) images were obtained to detect procedural errors made by undergraduate students during root canal preparation. Two examiners evaluated the presence or absence of fractured instruments, perforations and canal transportations. The agreement between observers was assessed using the kappa coefficient. The Kolmogorov-Smirnov, Fisher exact, ANOVA and Tukey tests were used for statistical analysis. The level of significance was set at 5%.Sixty human molars were divided into three groups (There were no significant differences in detecting procedural errors between two- and three-dimensional diagnostic imaging methods. There were no significant differences in procedural errors between stainless steel and NiTi instruments. Mean preparation time was recorded in minutes, and results were significantly different between the three groups. NiTi instruments had the lowest mean preparation time.Both periapical radiographs and CBCT identified procedural errors, however, three-dimensional images offered more diagnostic resources. The frequency of procedural errors was low for any of the endodontic instruments despite being used by inexperienced operators. Centralizing ability and apical transportation were not influenced by mechanical motion or type of instrument used. Hartmann et al. . Further research should investigate new concepts and technologies that raise opportunities for discussion, reflection and changes in the scientific world.The frequency of procedural errors  during the preparation of canals of maxillary and mandibular molars using stainless steel and NiTi instruments was low regardless of diagnostic imaging method when used by inexperienced operators.


Cartilage-hair hypoplasia (CHH) is a rare autosomal recessive disorder characterized by short-limbed skeletal dysplasia. Some patients also develop defects in cell-mediated immunity and antibody production. Granulomatous inflammation has been described in patients with various forms of primary immunodeficiencies but, to date, has not been reported in patients with Cartilage-hair hypoplasia.To describe granulomatous inflammation as a novel feature in patients with CHH, assess associated immunodeficiency and evaluate treatment options.In a retrospective, observational study, we collected clinical data on 21 patients with CHH in order to identify and further characterize individuals with granulomatous inflammation.Four unrelated patients with CHH (with variable degrees of combined immunodeficiency) developed epithelioid cell granulomatous inflammation in the skin and visceral organs. Anti Tumor necrosis factor alpha monoclonal antibody therapy in 3 of these patients led to significant regression of granulomas. However, one treated patient developed fatal progressive multifocal leukoencephalopathy due to the JC polyomavirus. In two patients, immune reconstitution after allogeneic hematopoietic stem cell transplantation led to the complete disappearance of granulomas.To the best of our knowledge, this is the first report of granulomatous inflammation in patients with CHH. Although Tumor necrosis factor alpha antagonists may effectively suppress granulomas, the risk of severe infectious complications limits their use in immunodeficient patients.


DNA methylation may play a role in the etiology of neuropsychiatric disorders through abnormal genomic methylation patterns regulating genes involved in brain development or physiology. In this study we explored the DNA methylation profile of depression in the prefrontal cortex because converging evidence from brain imaging and postmortem studies has implicated this region in depression neuropathology.et al., doi: 10.4161/epi.6.11.17876). Overall, these data represent relatively unbiased coverage of the genome, including CpG-rich domains such as CpG islands and repetitive elements.In order to better understand both the wild type genomic DNA methylation patterns and aberrant methylation events occurring in disease states we profiled DNA methylation patterns in human postmortem brains of 12 depressed and non-psychiatric controls using the methylation mapping and paired-end sequencing (Methyl-MAPS) method. Methyl-MAPS is an enzymatic-base method that can delineate the methylation status of greater than 80% of CpG sites genome-wide  across all RefSeq annotated genes, but significant variations were detected proximal to the TSS (referred to as “CpG island shores”). We observed statistically significant methylation loss in CpG island shores in depressed cases compared to controls. These findings were replicated in purified neuronal cell populations. Using an independent sample of depressed cases and matched non-psychiatric controls, we isolated neuronal nuclei from the dorsal prefrontal cortex of 11 depressed cases and 11 controls. Due to limited quantities of neuronal DNA typically obtained from isolation of nuclei using fluorescence-activated cell sorting, we used the Illumina HumanMethylation450 BeadChip. DNA methylation differences in CpG island shores revealed that, of the CpG dinucleotides with significant methylation differences, >95% showed loss of methylation in depressed brains. The underlying mechanism involved in the loss of methylation in depression psychopathology is unclear. However, the global 5-hydroxymethylcytosine levels in neuronal DNA from the same sample specimens also showed a loss of hydroxymethylation in depressed brains compared to controls. Although these data were not statistically significant, they revealed an important trend in loss of hydroxymethylation and the possible mechanism for DNA demethylation in brains of depressed patients. Gene ontology analysis of genes with significant methylation differences (primarily loss of methylation) in depressed vs. controls identified a number of cellular functions. Of note, the fourth most significant gene set identified was involved in programmed cell death and 74% of the genes in this set were associated with neuronal cell death. These changes in methylation dynamics suggest a possible mechanism linking neuronal cell death associated with oxidative stress and inflammation in the depressed brain.


This review will focus on the often overlooked roles of PARylation in chromatin remodeling, epigenetics, and transcription to explain why some cancers may be unresponsive to Parp inhibition. We predict that understanding the impact of PARylation on gene expression will lead to alternative approaches to manipulate the Parp pathway for therapeutic benefit.Poly(ADP-ribose) polymerase (Parp) is an enzyme responsible for catalyzing post-translational modifications through the addition of poly(ADP-ribose) chains (known as PARylation). Modification by PARylation modulates numerous cellular processes including transcription, chromatin remodeling, apoptosis, and DNA damage repair. In particular, the role of Parp activation in response to DNA damage has been intensely studied. Tumors bearing mutations of the breast cancer susceptibility genes, Brca1/2, are prone to DNA breakages whose restoration into functional double-strand DNA is Parp dependent. This concept has been exploited therapeutically in Brca mutated breast and ovarian tumors, where acute sensitivity to Parp inhibitors is observed. Based on  Breast cancer is an epidemic afflicting approximately one out of every nine women  and gemcitabine showed improved overall survival  of varying degrees of homology , all of whom use NAD+ as a substrate to catalyze the addition of ADP-ribose moieties onto target proteins  locus  glycohydrolase (known as Parg). Parg catabolizes ADP-ribose polymers synthesized by Parp-1. This enzymatic activity has been demonstrated to impair Parp-mediated chromatin remodeling In addition to histone H1 removal, Parp-1 configures chromatin through modification of proteins involved in remodeling and organizing chromatin structure. PARylation generally results in protein activation, but can also result in functional suppression of chromatin remodelers. For example, PARylation is inhibitory to the function of the repressive remodeling complex Iswi , together with histone deacetylases (Hdacs), results in a repressive complex, inactivating the transcription of genes involved in cardiomyocyte differentiation through deacetylation of histones .Finally, we propose that Parg represents an attractive therapeutic target Figure . The undParp-1 is an important activator of transcription and probably plays an important role in promoting transcription of tumor suppress genes. Therefore, we postulate Parp inhibitors may actually have pro-oncogenic effects on some cell populations. But, what is the impact of inhibiting Parg on these same processes? While the overall impact of Parg on gene regulation remains unclear at this time, it has been shown that Parg can block Parp-1 mediated chromatin remodeling and transcriptional activation in specific circumstances. Therefore, we speculate Parg inhibition might heighten the effects of PARylation, thus promoting the transcription of tumor suppressor genes. Further, in cancer cells having defects in the PARylation pathway such as aberrantly dePARylated Ctcf, Parg inhibition might serve to correct these deficiencies.in vivo (Marienfeld et al., in vitro data showing growth inhibitory activity of Parg inhibition or knockdown in multiple types of cancer (Fauzee et al., Supporting these rationale for Parg inhibition being a novel approach for anti-cancer therapy are several reports indicating Parg inhibition has potent anti-tumor effects against cholangiocarinoma The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Acute liver failure related to hepatitis B infection may occur after acute HBV infection or during an exacerbation (flare) of a chronic HBV infection. The condition is associated with a very high morbidity and mortality rate.We present the diagnosis and management difficulties of a four-case series admitted to our clinic during the last year, with severe acute liver failure, with encephalopathy that required medical management, intensive care and organ support, including artificial extracorporeal liver support.In the presence of acute liver failure and serological evidence of hepatitis B viral infection, differentiating between acute infection and exacerbation (flare) of chronic infections remains a challenge. Mortality rates remain high inspite of recent medical advance.


NATbox: Network Analysis Toolbox in the language R that houses a battery of BSL algorithms in conjunction with suitable statistical tools for modelling FRs in the form of acyclic networks from gene expression profiles and their subsequent analysis.There has been recent interest in capturing the functional relationships (FRs) from high-throughput assays using suitable computational techniques. FRs elucidate the working of genes in concert as a system as opposed to independent entities hence may provide preliminary insights into biological pathways and signalling mechanisms. Bayesian structure learning (BSL) techniques and its extensions have been used successfully for modelling FRs from expression profiles. Such techniques are especially useful in discovering undocumented FRs, investigating non-canonical signalling mechanisms and cross-talk between pathways. The objective of the present study is to develop a graphical user interface (GUI), i) impute missing observations in the given data (ii) model FRs and network structure from gene expression profiles using a battery of BSL algorithms and identify robust dependencies using a bootstrap procedure, (iii) present the FRs in the form of acyclic graphs for visualization and investigate its topological properties using network analysis metrics, (iv) retrieve FRs of interest from published literature. Subsequently, use these FRs as structural priors in BSL (v) enhance scalability of BSL across high-dimensional data by parallelizing the bootstrap routines.NATbox is a menu-driven open-source GUI implemented in the R statistical language for modelling and analysis of FRs from gene expression profiles. It provides options to (http://bioinformatics.ualr.edu/natboxWiki/index.php/Main_Page.NATbox provides a menu-driven GUI for modelling and analysis of FRs from gene expression profiles. By incorporating readily available functions from existing R-packages, it minimizes redundancy and improves reproducibility, transparency and sustainability, characteristic of open-source environments. NATbox is especially suited for interdisciplinary researchers and biologists with minimal programming experience and would like to use systems biology approaches without delving into the algorithmic aspects. The GUI provides appropriate parameter recommendations for the various menu options including default parameter choices for the user. NATbox can also prove to be a useful demonstration and teaching tool in graduate and undergraduate course in systems biology. It has been tested successfully under Windows and Linux operating systems. The source code along with installation instructions and accompanying tutorial can be found at  Classical biological experiments have focused on understanding changes in the expression of single genes across distinct biological states. Such differential gene expression analyses while useful may not provide sufficient insight into their interactions or functional relationships (FRs). Understanding FRs is crucial as genes work in concert as a system as opposed to independent entities. On a related note, phenotype formation is mediated by pathways comprising of complex interactions between several genes as opposed to a single gene. Recent development of high-throughput assays in conjunction with sophisticated computational tools has enabled modelling such interactions and gain system-level understanding.Several commercial and non-commercial software packages have been developed in the past for modelling gene interactions. Ontology-based packages ,2 that rBayesian structure learning (BSL) techniques  have beehttp://bioinformatics.ualr.edu/natboxWiki/index.php/Main_Page.Several open-source packages are available for BSL and can be used to model gene networks -13. Howei) determine missing values in a given data using the functions LLSimpute, also implemented in the R-package pcamethods [ii) Learn acyclic network structure using BSL routines from the R-package deal [dynamicGraph [iii) identify what the author term as 1st order network structure using a resampling procedure and (iv) reconstruct coherent sub-regulatory networks using an extended version of the algorithm CODENSE [Prior to a detailed description of NATbox functionalities, we briefly review those of a closely related package BNArray  which waamethods  (ii) Leaage deal . SubsequmicGraph  (iii) id CODENSE . In the The comparisons are also enclosed under Table i. GUI: NATbox provides a convenient menu-driven graphical user interface (GUI) developed using Tcl/Tk for modelling and analysis of gene expression networks. This has to be contrasted with BNArray [ BNArray , which iii. Input/output: The input data in NATbox is assumed to be in tab-delimited text format, similar to that of BNArray. In NATbox, the rows of the input file represent independent experiments whereas the columns represent the names of the genes. However, in BNArray the rows represent the genes of interest and the columns represent their expression across experiments. Unlike NATbox, BNArray does not specify whether the experiments need to be independent or dependent.iii. Missing values: Gene expression profiles often have missing values. For instance, in microarray data such missing values are common and may be attributed to experimental artefact, improper hybridization and non-specific binding of the probes. It is prudent to use suitable statistical techniques to accommodate such data sets rather than discard them. NATbox provides an option to determine missing values using nearest-neighbour averaging approach (menu: File), impute.knn (R-package impute) which has been found to perform well for high-dimensional data sets [LLSImpute) [pcamethods).ata sets . BNArraySImpute)  algorithiv. Functional relationships: NATbox provides the option to model functional relationships using a battery of Bayesian structure learning techniques from the R-package (bnlearn) [menu: Bayesian Networks). It is important to note that they model the network structure solely from the joint probability distribution in the absence of explicit temporal information. The tab-delimited input data should be in the form of a matrix where the columns represents the number of genes, and rows the number of repeated (independent) experiments. Each element in the matrix represents the expression value of that gene in a given experiment.bnlearn)   : GS is b• Incremental Association Markov Blanket Algorithm (IAMB) : IAMB is• Fast Incremental Association Markov Blanket Algorithm (Fast-IAMB) : Fast-IA• Interleaved Incremental Association Markov Blanket Algorithm (Inter-IAMB) : Inter-I• Max-Min Parents Children Algorithm (MMPC) : MMPC ismutual information, mutual information for Gaussian distributed data, fast mutual information, Pearson's χ2, Akaike information criterion) as well as numerical/continuous distributions  are provided. NATbox also provides an interface to the search and score algorithm  from bnlearn. HC searches the model space and retrieves the best model using a scoring criterion which is also provided. Several choices of scoring criterion are provided for categorical/discrete  and numerical/continuous distributions (Gaussian posterior density). Each BSL technique works under implicit assumptions and may result in spurious conclusions when these assumptions are violated. NATbox provides a battery of BSL techniques to alleviate such concerns. For instance, constraint-based techniques can be affected by sample sizes and are sensitive to initial results of the conditional independence tests. Search and score algorithms can result in local optima, hence may benefit from multiple random restarts unlike constraint-based approaches.Several choices of conditional independence tests for categorical/discrete  are deemed robust. Bootstrap procedures can be computationally demanding for high-dimensional data sets. Search and score techniques such as hill-climbing implicitly require several random restarts during the confidence estimation. NATbox provides an option to parallelize bootstrapping across multiprocessor or multi-core processor by invoking the appropriate routines from the R-package SNOW (Simple Network Of Workstations) [nfidence  of an edtations) . Such patations)  is shownθ > 0.8) on the acyclic graph learned from the given data, Fig. dynamicGraph [The results of the bootstrap are written onto a tab-delimited file. An option is also provided for highlighting the robust FRs (micGraph  for visuwhitelisting (include) and blacklisting (exclude) FRs. Such priors impose constraints on the network structure which implicitly rely on prior knowledge and needs to be chosen prudently in order to avoid bias during learning. However, a proper choice can alleviate uncertainty and improve accuracy of the conclusions. A text retrieval interface is provided for identifying structural priors and can be useful for investigating well-established signalling mechanisms.In addition, NATbox GUI also provides options for incorporating  structural priors in BSL by vi. Network analysis metrics: BSL techniques are useful in inferring the cause-effect relationships and network structure from the gene expression profiles. However, they provide no insight into the network's topological properties. NATbox incorporates social network analysis metrics and motif finder from the package (igraph) [menu: Network Analysis Metrics) for investigating the topological properties of the networks generated using BSL techniques. Such metrics can be especially useful in investigating large networks. The input is assumed to be a binary adjacency matrix of the network constructed using BSL with ones and zeros representing the presence/absence of an edge respectively. Since BSL results in directed acyclic graphs, the corresponding binary adjacency matrix need not be symmetric. The centrality measures  along with their respective parameter options are provided for the user. A detailed discussion of these centrality measures are deferred to [igraph [igraph package incorporated into NATBox also provides option to save the acyclic network in formats compatible with Cytoscape [(igraph)  under . The user has the option to input the (a) pairs of gene names (co-occurrence) of interest through the GUI or (b) upload a two-column matrix of FRs of interest or those identified as robust by the bootstrap procedure. For well-documented studies, an integrated approach that incorporates the results from the Text Retrieval  in justifying the choice of whitelisted (include) and/or blacklisted (edges) in BSL. The Text Retrieval results are in html format, with a list of PUBMED identifiers hyper-linking to the respective abstracts/articles in PUBMED. The results of text retrieval on gene expression data from [ata from  is showni) expand the choice of structure learning algorithms including dynamic bayesian networks (ii) improve statistical inference of the network features (ii) parallelization of the implemented routines across multi-core and multi-processor machines of BSL functions as well as bootstrapping (iii) provide a web-interface so as to obviate the need for local installation of the toolbox (iv) enhance text retrieval so as to accommodate advanced text mining approaches.Modelling and analysis of gene expression networks is an area of active research. Several tools have been proposed in the literature for the same. Recently, Bayesian structure learning (BSL) techniques in conjunction with high throughput assays were used successfully to capture functional relationships. Existing packages may demand the user to have considerable programming expertise. NATbox provides a convenient menu-driven GUI along with appropriate parameter recommendations including default parameter choices for modelling and analysis of gene expression networks. It incorporates diverse functionalities from existing R-packages. This in turn encourages transparency and reproducibility, characteristic of open-source environment. NATbox can also be used as a teaching and demonstration tool for graduate courses in systems biology. Immediate future enhancements to the toolbox include (The authors declare that they have no competing interests.bnlearn package and was involved in trouble shooting the Bayesian structure learning routines. RN wrote the manuscript.SSC and MAB implemented the toolbox under RN's guidance. MS developed the


Patients after fractures become more and more immobile. Necessary stimuli decrease further. It comes to progressive deconditioning, whereby the vicious circle is complete, because it results in decreasing muscle cross-sectional area as well as bone strength. Accordingly, therapy concepts have to focus on maintenance and increasing muscle force and power. An established method is intensive resistance exercise training aimed to hypertrophy. Also the training program must ensure that forces reach the minimal effective strain and leads to bone remodelling. High-load resistance exercises effectively increase muscle and bone at the same time.Bone and muscle are dynamic tissues. Muscle adapts to stimuli above thresholds (energetic emptying > exhaustion). Wolff’s law states that structural bone adaptation is driven by the experienced bone strains. Osteocytes within our bones regulate bone formation and degradation in response to mechanical stimuli. The largest strains emerge from muscle contractions. A lot of diseases are associated with secondary muscle weakness (sarcopenia) and reduced bone density (osteoporosis). Both deficits cause an increase in fall incidence. About every 4


Yersinia pestis, are highly variable in their response to plague ranging from near deterministic extinction  to a low probability of extinction despite persistent infection . Much of the work to understand this variability has focused on specific host characteristics, such as population size and resistance, and their role in determining plague dynamics. Here, however, we advance the idea that the relative importance of alternative transmission routes may vary causing shifts from epizootic to enzootic dynamics. We present a model that incorporates host and flea ecology with multiple transmission hypotheses to study how transmission shifts determine population responses to plague. Our results suggest enzootic persistence relies on infection of an off-host flea reservoir and epizootics rely on transiently maintained flea infection loads through repeated infectious feeds by fleas. In either case, early-phase transmission by fleas  has been observed in laboratory studies, and we show that it is capable of driving plague dynamics at the population level. Sensitivity analysis of model parameters revealed that host characteristics  vary in importance depending on transmission dynamics, suggesting that host ecology may scale differently through different transmission routes enabling prediction of population responses in a more robust way than using either host characteristics or transmission shifts alone.Host populations for the plague bacterium,  Yersinia pestis, remains a public health concern because of its high virulence in multiple mammal species, including humans, and its role in past pandemics in humans. Despite its historical importance and the continued threat of human cases, plague is primarily a disease of rodents and their fleas. Consequently, humans are at greatest risk of exposure to Y. pestis during plague epizootics when rodent hosts die in large numbers increasing potential exposures to sick or dead animals and infectious fleas Plague, caused by the bacterium However, rodent species show high variability in their population-level response to plague infection, and the mechanisms that determine outbreak conditions are not fully understood. The variability in host response can be compartmentalized into two classes: either enzootic  or epizootic . This classification enables predictions that can be based on observable intra-population dynamics rather than invoking landscape-level maintenance mechanisms involving the interaction of plague dynamics in multiple species Rhombomys opimus) in Kazakhstan, show high levels of prolonged resistance , rarely survive plague infection Previous research on plague dynamics depended on observation of host characteristics to differentiate between epizootic and enzootic populations. For example, enzootic hosts, such as great gerbils  allows for the maintenance of infection levels in fleas and increases infectious duration for early-phase transmission Y. pestis has survived in carcasses and soil for several days under both field and laboratory conditions Experimentally studying transmission routes in natural systems is nearly impossible, but laboratory experiments have identified effective transmission routes that could also affect population responses to plague infection. In particular, early-phase transmission by un-blocked fleas  has been shown to be a viable alternative to blocked-flea transmission in several flea species under laboratory conditions Y. pestis dynamics that incorporates three routes of plague transmission: 1) the booster-feed infection cycle; 2) the build-up of infectious, questing fleas; and 3) contact with carcass-derived material. We parameterize the model for an epizootic host, the black-tailed prairie dog, and for an enzootic host, the California ground squirrel (Spermophilus beecheyi). We sequentially remove or reduce each transmission route to understand how the influence of each route may vary between characteristic epizootic and enzootic hosts. We also use sensitivity analysis of model parameters to quantify the importance of transmission routes across a broader range of species and to explore how previously identified host characteristics interact with transmission to improve prediction of plague dynamics.In order to simultaneously consider how multiple transmission routes interact to determine plague dynamics, we present a general model of We developed an ordinary differential equation (ODE) model consisting of both host and flea submodels  causing fleas to transition to EP stage 2 , while the infectious, questing flea reservoir increases almost throughout . InfectiSystematic removal of transmission routes helped provide a clearer picture of each in plague dynamics, especially for epizootic behavior . For thea, was positively correlated with enzootic probability but had little effect on extinction probability. Increasing transmission efficiency from EP2, Lβ, increased extinction probability as did an increase in the transition rate between EP1 and EP2 for fleas taking non-infectious blood meals, Eθ.Our multi-parameter sensitivity analysis was consistent with the relative importance of transmission routes described above and revealed that model results were sensitive to parameters influential to both the booster-feed infection cycle and the infectious, questing flea reservoir ; Fig. 3.ϕ, and shorter host exposure periods . However, increased host resistance, p, and increased host carry capacity, K, served to decrease epizootic behavior. In contrast, enzootic probability was increased by increasing host carrying capacity and declined with higher rates of resistance loss, shorter host exposure periods, and decreasing host connectance . Sensitivities that are not reported were not significant.Population responses to plague infection were also sensitive to several host parameters in the model . Among tOur model produced characteristic enzootic and epizootic behaviors, and model behaviors for our specific parameterizations were consistent with empirical observations of plague activity in the hosts they were based on, black-tailed prairie dogs and California ground squirrels. The agreement with natural systems highlights our ability to reliably compare the shifting roles of transmission routes in creating each dynamic. In particular, the booster-feed infection cycle is primarily responsible for epizootic behavior. While laboratory experiments have demonstrated that the booster feed infection cycle results in the maintenance of infection levels in fleas B; Our sensitivity analysis supports the role of shifting transmission dynamics in determining plague dynamics in the host population. We found that epizootic behavior  was strongly affected by flea characteristics that determine both the strength and turnover rate of the booster-feed infection cycle, while enzootic potential was strongly influenced by flea questing efficiency adding support to the involvement of a flea reservoir in the maintenance of plague at the population level While the flea reservoir may be important in connecting spatially distinct groups of hosts, we also hypothesize that questing fleas may act as a bridge in enzootics, connecting temporally separated pools of susceptible hosts generated from a resistant refuge. This endogenously derived temporal bridge contrasts with more traditionally hypothesized exogenous sources of re-infection. Bat rabies virus may display a similar endogenous bridging mechanism by entering a quiescent state during host hibernation, thus creating a bridge between birth pulses that refresh the susceptible pool Most of the previous research on the variability in population responses to plague infection has focused on host traits, and our sensitivity analysis confirmed some of these observations, particularly the importance of host resistance and population size as observed in Asian great gerbils However, while our analysis confirms previous observations on the role of host characteristics in determining disease dynamics, it is important to note that these traits do not act independently of transmission routes to determine population response and thus, the effects of host traits may depend on the specific transmission routes operating. For example, we found that increasing host carrying capacity generally increased enzootic potential in our sensitivity analysis. However, our specific results for prairie dogs and California ground squirrels exhibited the opposite of the expected responses with black-tailed prairie dogs having larger population sizes but higher probabilities of extinction. Here, knowledge of transmission shifts may be more informative. Specifically, the importance of booster-feeds in epizootics, a transmission route that relies on continued contact between hosts and fleas, may create a situation where increasing host abundance leads to large epizootic potential that cannot be maintained. This is in contrast to enzootic hosts where an endogenous bridging mechanism like infectious, questing fleas overcomes issues of host limitation. The maintenance of infection potential in a flea reservoir may also alter the traditionally hypothesized role of resistance in promoting enzootics. In this case, resistance may primarily be important in avoiding epizootics and becomes important in promoting enzootics only when infectious, questing fleas dominate transmission. Thus, host and flea characteristics may scale up through transmission routes allowing for more robust predictions than when considering either host or flea characteristics alone.Figure S1Flow chart for the host sub model. The three transmission routes included in the model are highlighted: booster-feed infection cycle (blue), infectious, questing flea reservoir (green), and infectious carcasses (orange).(TIF)Click here for additional data file.Figure S2Flow chart for the flea submodel. The relationship between the booster-feed infection cycle (blue) and infectious flea reservoir (green) is highlighted.(TIF)Click here for additional data file.Table S1Alternate flea parameter values. Parameter values for the prairie dog flea O. tuberculata cynomuris. Other flea species are provided for comparison.(DOC)Click here for additional data file.Text S1Alternate flea submodel which prevents the buildup of infectious, questing fleas.(DOC)Click here for additional data file.Text S2Parameter fitting and estimation.(DOC)Click here for additional data file.Text S3Detailed prairie dog and California ground squirrel model outputs.(DOC)Click here for additional data file.


Urobatis halleri, as a model species. First, we examined the effects of temperature  on vertebral elemental incorporation . Second, we tested the relationship between water and subsequent vertebral elemental composition by manipulating dissolved barium concentrations . We also evaluated the influence of natural variation in growth rate on elemental incorporation for both experiments. Finally, we examined the accuracy of classifying individuals to known environmental histories (temperature and barium treatments) using vertebral elemental composition. Temperature had strong, negative effects on the uptake of magnesium (DMg) and barium (DBa) and positively influenced manganese (DMn) incorporation. Temperature-dependent responses were not observed for lithium and strontium. Vertebral Ba/Ca was positively correlated with ambient Ba/Ca. Partition coefficients (DBa) revealed increased discrimination of barium in response to increased dissolved barium concentrations. There were no significant relationships between elemental incorporation and somatic growth or vertebral precipitation rates for any elements except Zn. Relationships between somatic growth rate and DZn were, however, inconsistent and inconclusive. Variation in the vertebral elemental signatures of U. halleri reliably distinguished individual rays from each treatment based on temperature (85%) and Ba exposure (96%) history. These results support the assumption that vertebral elemental composition reflects the environmental conditions during deposition and validates the use of vertebral elemental signatures as natural markers in an elasmobranch. Vertebral elemental analysis is a promising tool for the study of elasmobranch population structure, movement, and habitat use.Differences in the chemical composition of calcified skeletal structures  have proven useful for reconstructing the environmental history of many marine species. However, the extent to which ambient environmental conditions can be inferred from the elemental signatures within the vertebrae of elasmobranchs  has not been evaluated. To assess the relationship between water and vertebral elemental composition, we conducted two laboratory studies using round stingrays,  The trace and minor elemental composition of biomineralized structures can provide insight into the environmental conditions in which the elements were deposited. Elemental assays of coral skeletons and foraminifera tests, for example, have been commonly applied as surrogates of past climatic or oceanographic conditions  –3. RecenThe most widespread and expanding application of elemental markers in biomineralized structures has occurred using the otoliths of fishes ,5. OtoliThe elemental composition of biogenic calcified structures is not a simple reflection of environmental conditions. A variety of physiological barriers and processes are encountered as elements are taken up from the water through the gills or intestine, transferred through the blood plasma, and eventually incorporated into biomineralized structures . PhysiolSharks, skates, and rays (elasmobranchs) are cartilaginous fishes that lack otoliths. Elasmobranch skeletons are composed of mineralized cartilage, an impure (non-stochiometric) form of carbonated calcium phosphate (hydroxyapatite) . Like thChemical analyses of elasmobranch vertebrae to date have been predominately directed toward age validation ,27 and dUrobatis halleri, as a model species. We manipulated environmental concentrations of barium (Ba) to determine the extent to which vertebral elemental ratios reflect the ambient environment. Finally, we evaluated the utility of these elemental markers to distinguish the environmental history experienced by individual rays using multivariate classification models. These experiments allowed us to test the following hypotheses: (i) elemental incorporation in vertebrae is mediated by water temperature; (ii) vertebral Ba to calcium ratios (Ba/Ca) reflects water Ba/Ca; (iii) growth rate does not significantly influence vertebral elemental composition; and (iv) vertebral elemental markers can distinguish individuals based on differences in environmental history. This investigation represents the first attempt to evaluate the utility of vertebral chemistry as potential records of environmental history in elasmobranchs.Key assumptions regarding vertebral elemental incorporation in relation to the physical and chemical environment must be evaluated before broader ecological questions and hypotheses can be addressed using naturally occurring elemental markers in elasmobranchs. We quantified the effects of temperature and growth rate on vertebral elemental incorporation through controlled laboratory studies using the round stingray, This investigation was conducted with a permit from the California Department of Fish and Game (803099-01) and in strict accordance with guidelines established by the American Fisheries Society and National Institutes of Health for the use of fishes in research. Experimental protocol was approved by Oregon State University’s Institutional Animal Care and Use Committee (3783).Urobatis halleri, is a benthic, live-bearing elasmobranch that occurs in estuaries and nearshore coastal soft bottom habitats from Panama to Eureka, California, USA ) experiment.Correlations (r) between partition coefficients (DThe number (n) of round rays  included in growth rate estimates, observed range of individual somatic growth rates (mm disc width month-1), and vertebral precipitation rates (μm radius month-1) are reported for each treatment. Significant p-values are indicated by bold font.(PDF)Click here for additional data file.


Vascular injury represents less than 1% of all injuries, but deserves special attention because of its severe complications. Amputation or retention of a painful functionless limb is the most untoward result of severe vascular injury or inadequate treatmet. Thus, vascular injury needs a judicious and multidimensional approach.This retrospective study was done to asess the outcome of minor modifications of the methodology of extremity fasciotomy by making it liberal with respect to incision and definition.Out of 55 patients in 2008, 45 patients (Group A) had either no fasciotomy or limited primary fasciotomy, 10 patients (Group B) had primary liberal fasciotomy. Another group from 2008 onwards had undergone primary liberal fasciotomy in all the 45 patients (Group C).In group A, we had 5 amputations and one death. In group B, there were no amputations or deaths and from group C, we had one amputation and no deaths.Blunt and distal traumatic vascular injury of the extremities and its repair should always combined with primary liberal fasciotomy, which although increases manageable morbidity, avoids disability . Vascular injury represents less than 1% of all injuries, but deserves special attention because of their severe complications. Amputation or retention of a painful functionless limb is the most untoward result of severe vascular injury or inadequate treatment, so vascular injury needs a judicious and multidimensional approach. Patients with pain out of proportion to injury, pain upon passive stretching, sensory changes, weakness or parasthesia after vascular repair indicate vascular compromise due to compartment syndrome and need immediate fasciotomy. Popliteal artery injuries continue to result in maximum limb loss, possibility due to use of limited fasciotomy.This study was done to assess the outcome of minor modifications of the methodology of extremity fasciotomy by making it liberal with respect to incision and definition.We studied 55 patients in 2008 with firearm or splinter vascular injuries of extremities; 45 patients (Group A) underwent different methods of vascular repair either without primary fasciotomy or with limited fasciotomy. Only 10 patients (Group B) had liberal primary fasciotomy. After 2008 to date, we treated 45 patients (Group C) with different types of vascular injuries, by different reparatory methods all of which received primary liberal fasciotomy.Assessment included emergency work-up: clinical examination, CBC, KFT, ECG, chest x-ray, USG abdomen, color flow Doppler, blood grouping and cross-matching; only 6 patients were subjected to pre-operative angiography.Vascular repair was done by primary end-to-end anastomosis or reverse sephanous vein graft either without fasciotomy or with varied limits of fasciotomy.Limited fasciotomy included superficial incision with inadequately cut deep fascia, isolated compartment fasciotomy, inadequate length of fasciotomy not passing across proximal and distal joints. Liberal fasciotomy included cutting through skin, deep fascia as well as outer covering of underlying exposed muscles (epimysium), till muscle pouts out. Oozing blood from muscle indicates adequate blood flow through the repaired vessel as well as adequacy of fasciotomy, thus it has therapeutic as well as diagnostic importance. Checking muscle viability with low voltage electric cautery stimulation. Confirming muscle viability helps in adequate debridement to prevent infective complications of dead tissue.We use S-shaped incision both at elbow and popliteal fossa, closure of this incision does not cause any constricting effect, while in case of liberal primary fasciotomy, the same incision is extended. The repaired vessel is loosely covered either by surrounding fat or muscle to prevent desiccation of the vessel. Curved fasciotomy incisions decompress the maximum area of the extremity and avoids superficial venous injury.Ensure muscle pouting along fasciotomy wound. All-compartmental fasciotomy is better than isolated-compartment fasciotomy. Dressings should not be tight. Avoid entrapment of adventitia in the anastomotic suture line.Passing a Fogarty catheter damages endothelium and increases tendency of thrombosis, thus anticoagulation is recommended.From group A, we had 5 amputations and one death (death due to infective complications of gangrene followed by DIC - despite that the limb was amputated); from group B we had no complications and from group C one amputation and no deaths were recorded; 12 patients from group A needed either extension of fasciotomy or secondary fasciotomy.Most of the patients with liberal primary fasciotomy need care by a plastic surgeon. But 25% patients were discharged and referred to their respective primary health care centers for regular dressings and admitted subsequently for split-thickness skin grafting with favorable results.All those patients with primary liberal fasciotomy even with borderline muscle viability at the time of primary vascular repair had the least amputation rate. There was no significant increase in infection rate. Soaked dressings were changed regularly. One significant complication with primary liberal fasciotomy was pain which needed short interval analgesics. Also changing dressings in these patients was time consuming and significantly painful which demanded extra patience by patient as well as attending resident. These patients have long lasting paresthesia at graft site with varied presentation. Patients in high dependency units with no or limited fasciotomy obscured signs of compartment syndrome due to liberal use of analgesics. Delayed or revised fasciotomy in these patients helped to a very limited extent, and in the long run gave a functionally disabled limb with chronic pain in saved limbs.Delayed fasciotomy, revision fasciotomy and disability due to amputation/vegetative limb or chronic limb parasthesia all have a very strong psychological impact in contrast to less morbidity associated with primary liberal fasciotomy.In patients with primary liberal fasiotomy crossing knee and ankle in lower limb, elbow and wrist in upper limb with cutting some fibers of reticulum at ankle or wrist appreciably improved blood flow. Any vascular injury associated with blunt trauma limb, fracture, venous injury, longer duration of ischemia; below knee/elbow vascular repair needed primary liberal fasciotomy whether the patient had a tense compartment at the time of vascular repair or not.Extensive soakage from fasciotomy wound needs frequent change of dressings, which is painful and cumbersome for patient. Frequent analgesics make patients apprehensive. Painful postural changes and difficulty in assuming comfortable postures effects sleep. Longer hospital stay is uncomfortable.Compartment syndrome is a surgical emergency characterized by raised pressure in an unyielding osteofascial compartment caused by trauma, revascularization, myocyte edema after ischemia-reperfusion injury, or resuscitation -4. The cBlunt and distal traumatic vascular injury of extremities and its repair should be combined with primary liberal fasciotomy, which may although increase manageable morbidity, will avoid lifelong disability. No fasciotomy can be acceptable when chances of compartment syndrome are absolutely nil; however, limited fasciotomy is absolutely discouraged in favor of primary liberal fasciotomy.


The autonomic nervous system (ANS) and innate immunity are intimately linked. Heart rate variability (HRV) analysis is a widely employed method to assess cardiac ANS activity, and changes in HRV indices may correlate with inflammatory markers. Here, we investigated whether baseline HRV predicts the innate immune response. Second, we investigated whether the magnitude of the inflammatory response correlated with HRV alterations.Escherichia coli O:113). Of these, 12 healthy volunteers were administered LPS again 2 weeks later. HRV was determined at baseline (just prior to LPS administration) and hourly thereafter until 8 hours post LPS. Plasma cytokine levels were determined at various time points.Forty healthy volunteers received a single intravenous bolus of 2 ng/kg endotoxin (lipopolysaccharide (LPS), derived from Baseline HRV indices did not correlate with the magnitude of the LPS-induced inflammatory response. Despite large alterations in HRV following LPS administration, the extent of the inflammatory response did not correlate with the magnitude of HRV changes. In subjects that were administered LPS twice, inflammatory cytokines were markedly attenuated following the second LPS administration, while LPS-induced HRV alterations were similar. See Figure HRV indices do not predict the innate immune response in a standardized model of systemic inflammation. The innate immune response results in HRV changes; however, no correlations with inflammatory cytokines were observed. These findings suggest that cardiac ANS activity may not reflect ANS outflow to other organs involved in the innate immune response. Furthermore, the magnitude of endotoxemia-related HRV changes does not reflect the extent of the inflammatory response.


An asymptomatic issueless young staff nurse underwent pre-employment health screening and USG abdomen showed multiple hypodense lesions in liver. Further screening with whole body positron emission tomography-computed tomography (PET-CT) scan showed significantly FDG avid mass involving most of the right lobe of liver with multiple large FDG avid lymph nodal metastases. Unsuspected focal abnormal, FDG avid, hyperdense mural nodule was seen in uterus, which is the site of primary. With the advent of sophisticated medical instrumentation in the diagnostic workup for malignancies, detailed investigations fail to reveal the primary site of origin for a subset of patients with metastatic carcinoma. This is often referred to as Carcinoma of Unknown Primary (CUP) or occult primary malignancy.The exact incidence of CUP in the United States is not precisely known, but it is definitely underreported. Its actual incidence is most probably between 2 and 6%. In 15–25Clinical presentation of cancer of unknown primary origin is extremely variable and depends on the extent and type of organ involvement. Investigations are usually guided by any positive findings on initial evaluation. Patients have early dissemination of their cancer without symptoms at the primary site. The symptoms often depend on the site of metastases, like ascites may be the initial presentation in a patient with a GI or an ovarian malignancy, etc.The patient was an issueless, 32-year-old staff nurse undergoing pre-employment health checkup. USG abdomen showed a large heterogenous lobulated mass with predominant hypoechogenicity suggestive of possible atypical hemangioma or possible evolving abscess. Magnetic resonance imaging (MRI) of abdomen showed a large heterogenous enhancing hypodense lesion with altered signal intensity with a large exophytic component in the right lobe of liver suggestive of possible hepatic adenoma/atypical hemangioma/possible neoplasm. Fine needle aspiration cytology (FNAC) followed by trucut biopsy was suggestive of possible metastatic rhabdomyosarcoma.18F FDG (Fluoro Deoxyglucose) intravenously in euglycemic status. After 1 hour, the patient was imaged. Images showed large hypodense, significantly FDG avid, non-enhancing mass involving most of the right lobe of liver [Standard Uptake Value (SUV) max 30 g/ml]. Multiple large FDG avid, left axillary, porta hepatic, celiac and retropancreatic lymph nodal metastases were also present. Portal vein was seen encased by the tumor at porta hepatis. Inferior venacava was obstructed below the liver and collateralized via azygos and hemiazygous system. [Whole body positron emission tomography-computed tomography (PET-CT) scan was done using 8 mCi on  system. . Inferio system. .The patient underwent further pelvic USG and was biopsy proven. The patient was started on chemotherapy and is doing well for the past 6 months. Follow-up CT of abdomen showed recession in size of liver metastases.Rhabdomyosarcoma is primarily a disease affecting children; it rarely affects adults. Common sites of involvement are the head and neck 28%), extremities 24%), and genitourinary tract (18%).8%, extre Uterine %, and geMost uterine sarcomas fall into the category of leiomyosarcoma, endometrial stromal sarcoma, or undifferentiated sarcoma.5 MetastaRhabdomyosarcoma is subdivided into three general types histologically as follows.Embryonal rhabdomyosarcoma: This usually occurs in head and neck locations with small round or oval tumor cells and a finely granular eosinophilic cytoplasm. Well-differentiated tumors demonstrate elongated, strap-shaped or tadpole-shaped rhabdomyoblasts.Alveolar rhabdomyosarcoma is the next variety comprising relatively small, poorly differentiated round and oval cells aggregated into irregular clusters or nests separated by fibrous septa. An occasional variant, referred to as the botryoid type, shows a diffuse myxoid or mucoid matrix with thinly scattered primitive mesenchymal cells. The characteristic feature of this type is a peripheral zone of increased cellularity, sometimes known as the “cambium layer.”Pleomorphic rhabdomyosarcoma shows randomly arranged eosinophilic cells with considerable variation in cell size and shape, as well as variation in nuclear size and shape. The pleomorphic cells are often admixed with small, primitive mesenchymal cells. This tumor is often so undifferentiated that the identification of the cell of origin is difficult or impossible. Positive immunostains for desmin and myoglobin are helpful as in our case.Regardless of the histologic subtype, special stains are often quite useful for differentiating rhabdomyosarcoma from other neoplasms. The trichrome stain is especially useful because it colors rhabdomyoblasts bright red while myofilaments and cross-striations have fuchsinophilic properties, also highlighted by PTAH (deep purple color). Myxoid stroma may be positive for hyaluronidase with acid mucopolysaccharide staining, although many other tumors also have positive stroma with these stains. The most418F FDG PET-CT is an important screening tool for the evaluation of unknown primaries as well as for staging and follow-up of several malignancies.[In patients with metastatic disease, prognosis is poor with a 5-year event-free survival rate of less than 30%. 18F FDG gnancies.8 FDG PETOur patient was unique, as she was a young asymptomatic lady presenting with multiple large liver and nodal secondaries, which is relatively an uncommon site for metastases. The patient had no previous history of menorrhagia or metrorrhagia as usually expected in uterine rhabdomyosarcomas. Incidentally detected mural nodule in uterus helped in finding the site of hidden primary malignancy.


We compared the difference in left atrial tissue remodeling (LATR) pre-ablation and post-ablation lesion characteristics between three methods for electrical isolation of pulmonary veins  routinely done to treat paroxysmal atrial fibrillation (PAF).Patients presenting with PAF who qualified for a cryo, PVAC or SRF ablation were prospectively followed. DE-MRI of the left atrium (LA) was performed prior to and three months post procedure. The degree of LATR is reported as a percentage of the total LA area.37 patients  were included in this study. Six patients underwent an ablation using PVAC catheter, SRF catheter was used in 14 patients, and 17 patients underwent a cryoballoon ablation. Pre-ablation LATR was comparable in all three cohorts (Figure From our preliminary results, PVAC ablation appears to result in lesser scar formation as compared to Cryo and SRF ablation. The greater recurrence in patients with low scar post-ablation suggests the need to implement an adequate ablation strategy that results in greater scar to maximize successful outcomes. DE-MRI is an appropriate method to compare lesion formation induced by different ablations strategies.None.


Two variants with evidence of association with higher endometrial cancer grade (p-trend<10–6) have been selected for validation in independent sample sets. These SNPs are located in or near genes not previously reported to be involved in cancer aetiology or prognosis and, if confirmed, would represent novel gene targets. Neither of these SNPs fall into the top 1500 SNPs prioritised for validation of association with risk. Results to date suggest that genetic alleles associated with prognostic features, such as cancer grade, may be distinct from those associated with predisposition. GWAS analysis of tumour prognostic features is thus likely to improve understanding of biological pathways influencing outcome for endometrial cancer patients.Endometrial cancer is the most commonly diagnosed gynaecological cancer. Although endometrioid endometrial cancer (80% of cases) generally carries a good prognosis, some patients with this tumour subtype relapse within two years. Identifying genetic variants associated with prognosis could inform clinical decision-making for management at diagnosis, and inform development of chemotherapeutic agents targeting aggressive disease. Genome-wide association studies (GWAS) have been successful in identifying common genetic variation involved in cancer susceptibility. Presently there are limited published studies using GWAS data to identify single nucleotide polymorphisms (SNPs) associated with tumour prognostic indicators, such as grade. We used case data from an endometrial cancer case-control GWAS to assess association of SNPs with endometrial cancer grade. Genome-wide genotyping of 1285 Australian and British women with endometrioid endometrial cancer and reporting Caucasian ethnicity was performed using the Illumina 610K BeadChip. After applying quality control measures, data on 583,366 SNPs for 1220 cases with grade information were used in the analysis. PLINK software was used to assess SNP association with grade , adjusting for study group . Fifty-seven SNPs were found to be significant at <10


Reduced muscle strength- commonly characterized by decreased handgrip strength compared to population norms- is associated with numerous untoward outcomes. Preoperative handgrip strength is a potentially attractive real-time, non-invasive, cheap and easy-to-perform "bedside" assessment tool. Using systematic review procedure, we investigated whether preoperative handgrip strength was associated with postoperative outcomes in adults undergoing surgery.PRISMA and MOOSE consensus guidelines for reporting systematic reviews were followed. MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Clinical Trials (1980-2010) were systematically searched by two independent reviewers. The selection criteria were limited to include studies of preoperative handgrip strength in human adults undergoing non-emergency, cardiac and non-cardiac surgery. Study procedural quality was analysed using the Newcastle-Ottawa Quality Assessment score. The outcomes assessed were postoperative morbidity, mortality and hospital stay.Nineteen clinical studies  comprising 2194 patients were identified between1980-2010. Impaired handgrip strength and postoperative morbidity were defined inconsistently between studies. Only 2 studies explicitly ensured investigators collecting postoperative outcomes data were blinded to preoperative handgrip strength test results. The heterogeneity of study design used and the diversity of surgical procedures precluded formal meta-analysis. Despite the moderate quality of these observational studies, lower handgrip strength was associated with increased morbidity (n = 10 studies), mortality (n = 2/5 studies) and length of hospital stay (n = 3/7 studies).Impaired preoperative handgrip strength may be associated with poorer postoperative outcomes, but further work exploring its predictive power is warranted using prospectively acquired, objectively defined measures of postoperative morbidity. A substantial minority of patients sustain an excess of postoperative complications  and acceThe systematic review was undertaken in accordance with the PRISMA  Preferr.Two of the authors (P.S. and M.A.H.) searched the electronic databases MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Clinical Trials independently using the following population search terms: 'postoperative complications' OR 'perioperative complications' OR 'surgical complications' OR 'surgical outcome'. These search results were combined with 'handgrip dynamometry' OR 'hand grip dynamometry' OR 'hand grip strength' OR 'handgrip strength' OR 'maximal voluntary contraction' in the title or abstract text using the Boolean search operator 'AND'. . The references of retrieved articles were hand searched for any relevant articles not identified in the original search. The study selection criteria were limited to include only studies reported in the English language and those involving human adults undergoing surgery (including cardiac and transplant surgery). Each abstract was screened to identify studies that had assessed handgrip strength prior to surgery. Studies were excluded if postoperative outcomes focussed on upper limb neuromuscular functional outcomes alone.The data were extracted on to a standardized data entry form by each reviewer. Differences between the reviewers were resolved by re-examination of the original manuscript until consensus was obtained. Data extracted for comparison included year of publication, primary author, total number of subjects, mean patient age, proportion of male subjects and co-morbidity (where reported). The method of quantifying or qualifying handgrip strength was recorded.The specific outcomes sought in each article were: (i) mortality, (ii) postoperative morbidity, categorized according to the Post Operative Morbidity Survey, (iii) length of hospital stay . PrimaryThe procedural quality of each trial was assessed using several criteria, although no studies were excluded on the basis of these assessments. The quality of studies was scored according to the Newcastle-Ottawa Quality Assessment Scale  Additio, on a scNineteen studies were identified that compared postoperative outcomes in relation to handgrip strength Table , comprisThe majority of studies measured handgrip strength pre-operatively Table . Eleven Variable definitions for impaired handgrip strength have been used across studies Table . StudiesTable Tables Table Contrary to large population studies, our systematic review of the relationship between preoperative handgrip strength and postoperative outcome did not find compelling data to support the hypothesis that the results of studies in the general population translate to perioperative medicine. The majority of studies were considered to be of reasonable quality. Despite these quality scores, many studies contained important potential confounding factors which varied markedly between studies. A range of different instruments have been employed to measure grip strength, with other corroborative assessments of strength being frequently absent. Due to the substantial variation in the way in which each specified outcome had been defined between studies, plus the lack of analyses testing any one particular association, it was not possible to perform meta-analyses of results or formally test the heterogeneity (consistency) between studies. This marked heterogeneity between studies limits any definitive conclusions for the perioperative environment and renders this preoperative assessment largely unexplored. Nevertheless, several of these studies - albeit with the limitations as discussed above - suggest the role for preoperative handgrip strength assessment should be explored further.Large epidemiological studies have shown that perioperative morbidity is associated with dramatic differences in post-discharge life expectancy across different operations and health systems . The cosThere are also compelling basic biological reasons for establishing the role of handgrip strength in preoperative assessment. Cardiopulmonary reserve is a long-established predictor of cardiovascular and all-cause mortality, in both asymptomatic individuals and patients with cardiovascular disease . CardiacOne limitation of this systematic review is that no original study data were retrieved, although given the heterogeneity of both study design and the surgical populations in question this would have been unlikely to alter the main conclusions. Because only published reports were examined , a formal assessment of publication bias was not undertaken. It remains possible that not all relevant studies may have been identified since unpublished studies were not sought. There is very little perioperative demographic data provided in these studies, including cardiovascular risk and the identification of higher risk patients. Standards of postoperative care were not reported or apparently standardized. Since no interventions were conducted based on preoperative handgrip strength assessment, the studies only provide associative conclusions.This systematic review has generated two significant clinical implications. Firstly, given the compelling general population data that predicts longevity, there is clearly a need for the further prospective assessment of whether preoperative handgrip strength can help stratify risk of adverse postoperative outcomes. Second, these studies demonstrate that handgrip strength is a feasible, pragmatic, real-time bedside tool that may enhance preoperative risk stratification.Impaired preoperative handgrip strength may be associated with increased postoperative morbidity, mortality and prolonged hospital stay following surgery. Given the robust predictive power of this inexpensive, objective bedside test beyond the perioperative population, further studies of its' role in predicting postoperative outcomes appear to be warranted provided prospective, objectively defined measures of morbidity are employed.The authors declare that they have no competing interests.All authors contributed to Study design, Conduct of study, Data analysis and Manuscript preparation.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2253/12/1/prepubChecklist of items demonstrating adherence to PRIMSA systematic review guidelines.Click here for fileNewcastle Ottowa Scale.Click here for file


Petromyzon marinus). This dataset allows the exploration of early vertebrate evolution because the lamprey lineage split from that of other vertebrates before the emergence of hinged jaws, the defining feature of jawed vertebrates . Additionally, lamprey axons are not ensheathed by myelin  is particularly relevant because MBP is an abundant structural myelin constituent essential for myelination in the central nervous system (CNS). The fact that MBP had not been traced in species more ancient than gnathostomata   Figure . The fun) Figure . MBP andOther presumed myelin proteins traced in the lamprey genome are not functionally related to myelin at all, despite an equivalent gene ontology (GO) term. For example, MYT1L (myelin transcription factor-1-like), a neuronal transcription factor , PMP22 , MAL (myelin and lymphocyte protein), and PLP (proteolipid protein) were previously noted to be evolutionarily older than vertebrates (Mazumder et al., Taken together, the lamprey genome does not provide reason to consider that myelin may have evolved in non-jawed vertebrates. More generally, conclusions from genomic datasets on cellular structures come with the danger of misinterpretations if not carefully considered in conjunction with morphological analyses (Bullock et al.,