Maternal obesity during pregnancy is an important public health problem in Western countries. Currently, obesity prevalence rates in pregnant women are estimated to be as high as 30 %. In addition, approximately 40 % of women gain an excessive amount of weight during pregnancy in Western countries. An accumulating body of evidence suggests a long-term impact of maternal obesity and excessive weight gain during pregnancy on adiposity, cardiovascular and metabolic related health outcomes in the offspring in fetal life, childhood and adulthood. In this review, we discuss results from recent studies, potential underlying mechanisms and challenges for future epidemiological studies. Obesity, cardiovascular disease and type 2 diabetes are major public health problems. These common diseases have a large impact on morbidity and mortality in the general adult population –4. VarioIn Western countries, maternal obesity during pregnancy is an important adverse risk factor for an excessive nutritional in utero environment , 34. CurAs described previously, both maternal prepregnancy obesity and excessive gestational weight gain seem to have persistent effects on various childhood outcomes . This reMaternal prepregnancy obesity and excessive weight gain during pregnancy are important risk factors for a variety of adverse fetal outcomes Table . A meta-It is well-known that maternal prepregnancy obesity and excessive gestational weight gain are associated with an increased risk of large-size-for gestational age at birth , 43. A rFewer studies assessed the direct influence of maternal obesity during pregnancy on placental and fetal cardiovascular and metabolic development. It has been shown that maternal prepregnancy obesity is associated with higher placental weight, placental vascular dysfunction, placental inflammation and alterations in placental transporters activity and mitochondrial activity –55. A stThus, both maternal prepregnancy obesity and excessive gestational weight gain lead to increased risks of adverse fetal outcomes. Overall, maternal prepregnancy obesity appears to be more strongly associated with adverse fetal outcomes than excessive maternal gestational weight gain , 47.Maternal prepregnancy obesity and excessive gestational weight gain are associated with an increased risk of obesity in childhood and adolescence Table . A meta-Several studies aimed to identify critical periods of maternal weight during pregnancy for childhood outcomes. A study performed among 5154 UK mother-offspring pairs showed that especially gestational weight gain in the first 14 weeks of pregnancy was positively associated with offspring adiposity at 9 years of age . In lineThus, next to the risks of adverse fetal outcomes, maternal prepregnancy obesity and excessive gestational weight gain may lead to increased risks of adiposity and adverse cardiovascular risk factors in childhood and adolescence.Multiple studies have shown that a higher maternal prepregnancy body mass index is associated with a higher adult body mass index in the offspring, independent from socio-demographic and lifestyle-related confounding factors –76 Tabl. SimilarThus, in line with the associations of maternal prepregnancy obesity and excessive gestational weight gain with childhood outcomes, these adverse maternal exposures are associated with an increased risk of adiposity and cardiovascular and metabolic disease and mortality in the adult offspring.The major limitation of these observational studies is confounding. Various family-based socio-demographic, nutritional, lifestyle related and genetic characteristics may explain the observed associations of maternal prepregnancy body mass index and gestational weight gain with adverse health outcomes in the offspring. Few studies used more sophisticated study designs to obtain further insight into the role of confounding in the observed associations, including sibling comparison studies, maternal and paternal offspring comparisons analyses, Mendelian randomization studies, and randomized controlled trial analyses, as described previously .First, sibling comparison studies enable better control for potential confounding factors shared within families . A sibliSecond, several studies compared the strength of associations of maternal and paternal body mass index with offspring outcomes as an aid to further disentangle underlying mechanisms. Stronger associations for maternal body mass index suggest direct intrauterine mechanisms, whereas similar or stronger associations for paternal body mass index suggest a role for shared family-based, lifestyle-related characteristics or genetic factors . StudiesThird, Mendelian randomization approaches use genetic variants, known to be robustly associated with the exposure of interest and not affected by confounding, as an instrumental variable for a specific exposure . AssociaFourth, randomized controlled trials are considered as the golden standard for causality studies. Because randomized studies are difficult to perform when maternal prepregnancy obesity and excessive gestational weight gain are the major exposures of interest, previous studies focused on influencing determinants of obesity and excessive gestational weight gain, such as dietary factors and physical activity levels . Based oAltogether, results from studies specifically designed to explore the causality for the associations of maternal obesity during pregnancy with offspring outcomes are not conclusive yet.The mechanisms underlying the associations of maternal obesity or excessive gestational weight gain with cardiovascular and metabolic disease in the offspring are not known yet. The fetal overnutrition hypothesis suggests that increased placental transfer of nutrients to the developing fetus in obese mothers and mothers with high levels of gestational weight gain, may subsequently affect fetal development, fetal fat deposition and the development of the hypothalamic-endocrine system that controls appetite and energy metabolism –93. ThesMaternal prepregnancy obesity and excessive gestational weight gain are complex traits, which reflect multiple components. Maternal prepregnancy obesity reflects maternal nutritional status, fat accumulation and low-grade inflammation, whereas maternal weight gain during pregnancy additionally reflects maternal and amniotic fluid expansion and growth of the fetus, placenta and uterus .Maternal prepregnancy obesity is an indicator of a poor quality maternal diet. Both macronutrients and micronutrients intake related to a Western diet may influence fetal cardiovascular and metabolic development, through influences on placental transfer and subsequently offspring fat deposition, adipocyte function, pancreatic function and food preference , 94. A sMaternal prepregnancy obesity and excessive gestational weight gain partly reflect maternal fat accumulation, which is important for fetal development . HoweverLow grade systemic inflammation may be involved in pathways leading from maternal obesity or excessive gestational weight gain to adverse offspring outcomes. Obesity is associated with low-grade systemic inflammation and oxidative stress, also during pregnancy –118. AddBoth maternal obesity and excessive gestational weight gain as well as the correlated nutritional, body fat distribution, metabolic and inflammatory exposures may lead to programming effects in the offspring through several pathways.Epigenetic changes in the offspring are likely to play an important role in developmental programming . EpigeneOffspring from mothers with prepregnancy obesity or excessive gestational weight gain during pregnancy have higher fetal growth rates and are at increased risk of being born large for their gestational age. Higher birth weight is associated with an increased risk of obesity in later life . The assThe associations of maternal prepregnancy body mass index and gestational weight gain with adverse cardiovascular and metabolic outcomes in the offspring appear to be largely mediated through offspring obesity. However, direct cardiovascular and metabolic programming effects of maternal obesity during pregnancy may also be present . Animal Thus, multiple mechanisms may be involved in the intra-uterine pathways leading from maternal obesity and excessive weight gain during pregnancy to long-term adverse offspring health outcomes.Current evidence from epidemiological studies suggests that maternal obesity and excessive weight gain during pregnancy have important adverse consequences on cardiovascular and metabolic development from fetal life onwards, leading to disease in later life. Yet, there remain important issues to be addressed. These include identification of the extent of causality of the observed associations, the underlying exposures and their critical periods, the developmental adaptations, and the potential for development of preventive strategies Table .Table 3KFirst, despite extensive adjustment for potential confounding factors in these observational studies, residual confounding may still be an issue. The causality of the observed associations needs to be further addressed. Large observational studies that are able to apply more sophisticated methods, such as parent-offspring comparison studies, sibling comparison studies and Mendelian randomization-studies are needed to obtain further insight into the causality of the associations of interest. Long-term follow-up of participants in trials focused on reducing maternal weight throughout pregnancy will also provide further insight into the causality. Large meta-analyses are needed to obtain further insight into the strength, consistency and independency of the associations.Second, the underlying mechanisms of the observed associations of maternal obesity during pregnancy with offspring health outcomes remain unclear. Animals studies have identified multiple pathways that may be involved in these associations, but these pathways remain largely unexplored in humans. Maternal prepregnancy obesity and excessive gestational weight gain are complex traits, which reflect multiple lifestyle-related and biological components, which complicates identification of potential underlying pathways. Future studies may benefit from detailed assessments of the studied exposures and outcomes throughout the life-course, which could provide further insight into potential underlying mechanisms. Studies with repeated maternal weight measurements during pregnancy available can identify critical periods of maternal weight gain. To obtain further insight into the different components associated with offspring outcomes, studies are needed with more detailed measurements of maternal nutritional status, body composition, metabolic and inflammatory measures, pregnancy-related hemodynamic adaptations and fetal growth. For the offspring outcomes, more detailed measurements of growth, body composition and cardio-metabolic factors, including cardiac structures, endothelial function, pulse wave velocity, lipid spectrums and glucose responses, might also lead to further insight into the underlying growth, vascular and metabolic mechanisms present in the observed associations. Since early pregnancy appears to be a critical period for offspring outcomes, studies are needed with detailed maternal measurements from early pregnancy onwards to already assess their influence on placental and embryonic growth and development. Long-term follow up of participants in observational studies is needed to assess the influence on the risk of obesity and related cardio-metabolic disorders throughout the life-course. In addition, it is of interest to conduct follow-up studies of the third generation offspring from these large observational studies, as this may provide further insight into the intergenerational effects of maternal obesity during pregnancy on especially female offspring.Third, further research is needed focused on prevention of adverse health outcomes in offspring through optimizing maternal prepregnancy body mass index, weight gain and diet during pregnancy. Studies are needed to assess the optimal amounts of maternal weight gain for short-term and long-term maternal and offspring health outcomes to further improve the IOM recommendations for gestational weight gain. Identification of specific maternal dietary components associated with offspring health outcomes is needed to improve maternal dietary recommendations during pregnancy. Long term follow up of mothers and their children participating in randomized trials focused on improving maternal diet and reducing maternal weight throughout pregnancy will provide insight into the effectiveness of these maternal lifestyle interventions during pregnancy for improving long-term health of offspring.Maternal prepregnancy obesity and excessive weight gain during pregnancy seem to be important risk factors for an adverse in utero environment and long-term adverse cardiovascular and metabolic outcomes in the offspring. Well-designed epidemiological studies are needed to identify the extent of causality of the observed associations, the underlying exposures and their critical periods, the developmental adaptations, and the potential for development of preventive strategies to improve long-term health outcomes of offspring.


High cross-taxon congruence in species diversity patterns is essential for the use of surrogate taxa in biodiversity conservation, but presence and strength of congruence in species turnover patterns, and the relative contributions of abiotic environmental factors and biotic interaction towards this congruence, remain poorly understood. In our study, we used variation partitioning in multiple regressions to quantify cross-taxon congruence in community dissimilarities of vascular plants, geometrid and arciinid moths and carabid beetles, subsequently investigating their respective underpinning by abiotic factors and biotic interactions. Significant cross-taxon congruence observed across all taxon pairs was linked to their similar responses towards elevation change. Changes in the vegetation composition were closely linked to carabid turnover, with vegetation structure and associated microclimatic conditions proposed causes of this link. In contrast, moth assemblages appeared to be dominated by generalist species whose turnover was weakly associated with vegetation changes. Overall, abiotic factors exerted a stronger influence on cross-taxon congruence across our study sites than biotic interactions. The weak congruence in turnover observed particularly between plants and moths highlights the importance of multi-taxon approaches based on groupings of taxa with similar turnovers, rather than the use of single surrogate taxa or environmental proxies, in biodiversity assessments. Obtaining a good understanding of the mechanisms that underlie species richness and species composition presents one of the most significant challenges facing ecologists, biogeographers and conservation planners alike13485610Previous studies of diversity congruence have primarily focused on α-diversity within natural or semi-natural ecosystem, while few studies have focused on the effects of anthropogenic disturbance gradient on cross-taxa congruence in species turnover patterns121313861110186131721High cross-taxon congruence has been related both to similarities in the response patterns of these taxa to changes in environmental variables and to biotic interactions5192324212235242891322302662233Our study builds on earlier investigations showing that the α-diversity patterns of four taxonomic groups, vascular plants and three insect taxa , are highly non-congruent in our study area composed of plots situated along both altitudinal and anthropogenic gradients in an anthropogenically transformed mountainous landscape matrix5In establishing the degree of cross-taxon congruence in species turnover patterns across these four taxonomic groups, we particularly focused on the partial contributions of environmental factors and biotic interactions. We first of all hypothesize that a strong congruency exists between vascular plants and carabid beetles. Both taxa are chiefly composed of weak dispersers, with plants strongly relying on passive dispersal and with most carabid species known to chiefly disperse over limited distances of only up to 50 mWe recorded a total of 415 vascular plant species, while 14692 specimens representing 110 species of geometrids and 1543 individuals representing 20 arctiinid species were caught in light traps, and 3663 carabids representing 73 species were sampled in the pitfall traps. Each study site and habitat had its own, unique species of vascular plants. For carabids, all study sites, but not all habitat types at all sites contained unique species. For geometrids, only woodland and grassland habitats harbored unique species. Two sites, Dayushu and Gaojiaying, and none of the habitats harbored unique arctiinid species .The non-metric multidimensional scaling (NMDS) showed that both moth assemblages formed very distinct study site-specific clusters . A clearThe turnover in all taxonomic groups was significantly correlated with elevation and also the habitat type ‘cultivated land’, with the latter being particularly significant for vascular plants and carabids (P < 0.001). Additionally, vascular plants were significantly correlated with all environmental variables except soil texture and landscape diversity (SHDI). Apart from elevation and cultivated land, carabid turnover was also significantly linked to the % of semi-natural land area (SNP), while arctiinid turnover was additionally correlated with changes in total N and soil texture .All comparisons of turnover patterns between pairs of taxa showed significant positive correlations in There are two contrasting views on the role of environmental conditions on cross-taxon congruence. A range of studies links significant cross-taxon congruence to common response patterns of the different taxa to changes in key environmental factors1618191017The most important environmental determinant of turnover across taxa was elevation, which commonly represents a whole array of environmental factors. These include temperature, radiation and barometric pressure, which all show monotonic responses to changes in elevation, as well as precipitationBeyond the influence of elevation, the strong overall congruence observed between the turnover in vascular plants and carabids can be explained by both of them additionally reacting strongly towards a similar set of additional environmental variables, particularly to land cultivation and the proportion of semi-natural land present in the plot vicinity. These parameters chiefly reflect the anthropogenic disturbance gradient, with the results confirming our expectations. Cultivation impacted on the species composition of both vascular plants and carabids due to its direct associations with habitat management43Biotic interactions, including trophic interactions, host–parasitoid interactions, but also intraspecific interactions at the same trophic level, may promote cross-taxon congruence112416In contrast to our second hypothesis and these studies, the assemblage structure of the two herbivorous moth taxa which rely heavily on the vegetation as key food resource for their caterpillars and as nectar source of adult moths5292836et al.et al.et al.With most ground beetles being predatory or omnivorous244244Our results are indicative of a highly complex and variable interplay of environmental factors and potential biotic interaction in explaining cross-taxon congruence in turnover patterns of the investigated taxon pairs. These differentiations are also expected in relation to spatial scales and biogeographic processes acting within them21025Spatial differentiations in species assemblages also strongly relate to dispersal limitations, with the species composition between two sites generally increasing in dissimilarity with increased geographic distance26134A key finding of our study is the low congruence between vascular plants and herbivorous, pollinating moth taxa in this anthropogenically transformed landscape matrix, especially once the influence of abiotic factors is controlled for. Previous studies across a variety of taxonomic groups, natural ecosystems and spatial scales, have also reported low cross-taxon congruence of species turnover patterns between insect and other taxa or between different groups of insects49172021459132417However, our results also indicate that the subset of taxa could be representative of biodiversity4et al.Our study was conducted at four distinct sites in our large study region  located within the mountain ranges between Beijing and the Inner Mongolian Plateau in northern China. The four study sites were located within the vicinity of four villages  situated at elevations of about 500 m, 900 m, 1400 m and 1650 m, and therefore covering substantial proportions of the regional elevation gradient. Three representative habitat types were subsequently selected at each site according to the prevailing management intensity, natural vegetation and farming regime  placed above a plastic funnel leading into a plastic bucket. The weak light source allows targeted attraction of moths from the direct vicinity of the trapet al.The exact latitude, longitude and elevation of each plot were established using maps and a Garmin GPS III. Differences in latitude and longitude between plots were subsequently transformed into geographic distances and treated separately, while changes in elevation were jointly considered with the other environmental parameters in the analysis. Five soil samples were randomly taken from the upper 20 cm of the mineral soil at each plot and then mixed. These samples were analyzed for their contents in SOM, total nitrogen, and soil pH  which we used here, the index provides an overview of changes in the structure of the entire assemblage. To investigate changes in vascular plant assemblages where complete sampling can be assumed, a Sørensen dissimilarity matrix based on presence–absence data of all plant species per plot was calculated. All dissimilarity matrices were computed using COMPAH96Dissimilarities of species composition between sampling plots for each of the three insect taxa were calculated based on the Chord-Normalized Expected Species Shared  index. This index is particularly tailored for cases where samples are incomplete, contain many rare species and are of different size and diversityWe tested the correlation between the dissimilarity matrices for each taxon and each environmental distance matrices using partial Mantel tests. When significant spatial correlationsin species turnover patterns were found across all four taxa , the geoWe finally used variation partitioning in a series of Multiple Regressions on distance matrices (MRMs) to quantify the proportion of variation in taxonomical dissimilarity between plots that can be explained by the dissimilarity matrix of another taxon, as well as by geographic and environmental distanceet al.We therefore adopted the procedure introduced by Jones All mantel tests and MRMs were calculated using the Ecodist-PackageHow to cite this article: Duan, M. et al. Disentangling effects of abiotic factors and biotic interactions on cross-taxon congruence in species turnover patterns of plants, moths and beetles. Sci. Rep.6, 23511; doi: 10.1038/srep23511 (2016).


Advances in optical coherence tomography have enabled a better appreciation of the role of pathologic choroidal changes in a variety of retinal disease. A “pachychoroid” (pachy-[prefix]: thick) is defined as an abnormal and permanent increase in choroidal thickness often showing dilated choroidal vessels and other structural alterations of the normal choroidal architecture. Central serous chorioretinopathy is just one of several pachychoroid-related macular disorders. This review summarizes the current state of knowledge of the pachycoroid spectrum and the hallmark features seen with multimodal imaging analysis of these entities Rapid progress in retinal imaging has provided new insights into a variety of chorioretinal disorders. Advances in optical coherence tomography (OCT) are perfect examples of this trend. Following the first descriptions of retinal OCT imaging –3, the sThree different layers of choroidal tissue may be differentiated between Bruch’s membrane and the sclera-choroidal junction: choriocapillaris is the innermost portion; Sattler’s layer, composed of small oval vascular patterns, and Haller’s layer consisting of large outer oval vascular patterns . This quThe term pachychoroid (pachy-[prefix]: thick) was proposed as a term indicating an abnormal and permanent increase in choroidal thickness, This entity often occurs in eyes with central serous chorioretinopathy (CSC) or CSC-like features –19. EyesCentral Serous ChorioretinopathyCentral serous chorioretinopathy is characterized by the presence of subretinal fluid often associated with serous pigment epithelial detachment (PED). Abnormalities of the choroidal circulation are believed to play an important role in the pathophysiology of this entity. Choroidal congestion and hyperpermeability have been frequently described in this disease –22. The Pachychoroid Pigment Epitheliopathyformae frustae of CSC, similar in nature to the findings often seen in the fellow eye of patients presenting with unilateral acute CSC.Pachychoroid pigment epitheliopathy (PPE) is a newly described entity with characteristic features on multimodal imaging of the macula . This enFundus examination often shows an orange-reddish appearance and absence of normal tessellation what indicates an underlying pachychoroid. Present changes in pigment include: RPE alterations that might be mistaken for age-related maculopathy (ARM), a pattern dystrophy of the RPE or non-neovascular age-related macular degeneration (AMD). These changes may include sub-RPE deposits similar in appearance to typical drusen.OCT imaging shows numerous, scattered small elevations of the RPE representing RPE hyperplasia and sub-RPE drusen-like deposits . OccasioIndocyanine green angiography (ICGA) reveals choroidal hyperpermability as mid-phase hyperfluorescence that co-existent with the areas of RPE disturbances.Fundus autofluorescence shows areas of granular hypoatuofluorescence and mixed stippled hyper- and hypoautofluorescence. Signs of antecedent subretinal fluid, such as gravitational tracts, zonal areas of hyperautofluorescence or focal areas of speckled hyperautofluorescence are never seen in PPE.Pachychoroid NeovasculopathyPachychoroid neovasculopathy (PNV) is considered a late complication of PPE and chronic CSC in patients who presumably carry a genetic risk for choroidal neovascularization . The uniOptical coherence tomography imaging in PNV shows a broad shallow elevation of the RPE representing neovascular proliferation within Bruch’s membrane (26). This form of type 1 neovascularization is typically found overlying an area of localized choroidal thickening with dilated choroidal vessels .Indocyanine green angiography often shows both mid-phase patchy areas of choroidal hyperpermability and a discrete plaque of late hyperfluorescence corresponding to type 1 neovascular tissue.Eventually, polypoidal choroidal vasculopathy (PCV) may develop, within or at the margins of the slow-growing type 1 neovascular tissue. The polyps may produce an exudative maculopathy that includes both lipid deposition and hemorrhagic complications. The polyps are easily identified with ICGA as early focal areas of intense hyperfluorescence that may show either late leakage or “wash-out” appearance depending on their degree of activity.Enhanced depth imaging and SS OCT have enabled a better appreciation of the role of pathologic choroidal changes in CSC. Furthermore, they have helped defining an expanded spectrum of pachychoroid-related macular disorders. Recognition of these entities is important as they may mimic other diagnoses that have different natural courses and treatments. For example, the clinical appearance of PPE may simulate ARM, AMD, or pattern dystrophies. Similarly, without choroidal imaging, PNV may easily be mistaken for neovascular AMD.sui generis.The occurrence of PCV in eyes with PNV adds further evidence that PCV is a natural evolution of type 1 neovascular proliferation rather than a disease In our experience, eyes with exudation due to PNV, irrespective of the presence of PCV, are more resistant to anti-vascular endothelial growth factor (anti-VEGF) agents than eyes with choroidal neovascularization (CNV). This is presumably due to the typical AMD and myopic macular degeneration. Thus, the recognition of an underlying pachychoroid in neovascularized maculo- pathies may have important implications regarding their management. Since the photodynamic therapy is intended to reduce choroidal thickness and hyperpermeability, it surely warrants further exploration ,30.


Upper tract urothelial carcinomas (UTUC) have high prevalence rates in patients with chronic kidney disease (CKD), including dialysis patients and kidney transplant recipients. Analgesic nephropathy, Balkan endemic nephropathy, and aristolochic acid (AA) nephropathy share the common association with the development of CKD and UTUC. Genome studies allow identification of patients with genetic predisposition to Balkan endemic nephropathy and AA nephropathy. Furthermore, the identification of aristolactam deoxyribonucleic acid (DNA) adducts now provides robust evidence for AA exposure in UTUC patients, even in the absence of recallable exposure history. Diagnosis and treatment of UTUC in CKD patients are challenging. Clinical diagnosis of UTUCs in CKD patients with the available urological and imaging methods is much more difficult than in patients with normal renal function due to atrophic kidneys and poor excretory functions in these patients. High prevalence rates of contralateral upper tract and urinary bladder involvements of UC in CKD, either at presentation or recurrence, raise concerns of the necessity and techniques as well as perioperative risk of complete urinary tract exenteration. The standard treatment of radical nephroureterectomy with bladder cuff excision for UTUC patients may result in deterioration of renal function, rendering adjuvant chemotherapy unsuitable. This special issue collectively addresses these important topics regarding UTUC in CKD patients.The authors in one paper nominate three mutant genes  in Balkan endemic nephropathy patients, which are associated with angiogenesis. This finding suggests that angiogenesis might play an important role in the development of Balkan endemic nephropathy. Another paper shows an elevated risk of urothelial carcinomas (UC) in ESRD patients with the analysis of a national wide cohort in Taiwan. Female patients have 9–18 folds of increased risk of UC as compared to 4–14 folds in male ESRD patients, which may reflect female predominance in AA consumption. One paper discusses the challenges of UTUC diagnosis in CKD patients. It reviews the detection rate of UTUCs in dialysis patients and kidney transplant recipients with the use of a variety of imaging and urological methods in the literature. Combination use of urological and imaging methods has been suggested for diagnosing UTUCs in symptomatic dialysis patients and kidney transplant recipients.Another paper develops a predictive model for postoperative renal insufficiency in UTUC patients undergoing radical nephroureterectomy, which help in selecting eligible patients for cisplatin based adjuvant chemotherapy. Older age, lower estimated glomerular filtration rate before surgery, smaller tumor size, renal pelvis tumor, and absence of hydronephrosis or multifocal tumors are predictors for ineligibility for adjuvant chemotherapy. One paper describes modified incision complete urinary tract exenteration for UC in dialysis patients, providing short operative time, early oral feeding, and no major perioperative complications of this modified surgical procedure. Another paper reviews epidemiological evidence of AA exposure associated with occurrence of nephropathy and UC, including AA exposure scenarios in Belgium, Taiwan, and the Danube River as well as occupational exposure in Chinese herbalists. The identification of aristolactam DNA adducts in these patients further corroborates biological plausibility of AA exposure contributing to the occurrence of UTUC.Li-Jen  WangJoëlle L. NortierBin  Tean  TehCheng-Keng  ChuangShen-Yang  Lee


Tuberculosis (TB) remains a major global health problem, because (i) diagnosis is usually made too late to avoid spread of infection to contacts; (ii) vaccination with bacillus Calmette–Guérin (BCG) does not prevent the most prevalent pulmonary disease; and (iii) defaulting from lengthy chemotherapy leads to an increase in drug resistant strains. The continued impact of human immunodeficiency virus (HIV) co-infections remains a major aggravating factor in TB resurgence. Intensive research on the specificity and function of immunological responses is of major importance since protective host defense is critically dependent on T cells, which selectively recognize only certain antigens and epitopes of the tubercle bacillus. Such knowledge is therefore necessary for designing a novel effective vaccine and better diagnostic tools. The specificity of the host immune response may also help to explain how the intracellular tubercle bacilli evade host resistance, probably by decoy pro-inflammatory actions of some of their antigens and/or immunomodulatory constituents, which lead to chronic infection and lung pathology.Mycobacterium tuberculosis (Mtb). The abundant occurrence of major histocompatibility complex (MHC) class II-permissive epitopes in tubercle bacilli has important implications for the development of both subunit vaccines and diagnostic tests  proteins, and new HLA-class Ia or Ib (HLA-E) restricted Mtb epitopes, recognized by classical and non-classical CD8 T cells . Several test kits can detect latent Mtb infection with better specificity than the tuberculin based skin test. However, these kits still need improving on their sensitivity and fail to distinguish active TB from latent infection. Moreover, biomarkers for predicting the risk of latent TB progressing into active TB are yet to be found (be found , 3, 4. Fbe found .Identifying those antigenic determinants, which lead to host protection, is mandatory for designing more effective vaccination strategies. A recently failed vaccine trial in children employed Ag85A, which is highly immunogenic, but changes in its expression in infected cells could influence the susceptibility of infected cells to host immunity . Hence, Although classical CD4 and CD8 T cells recognize peptide epitopes bound to MHC, molecules with different chemical structures could be of potential importance. Thus, T cells recognizing lipid antigens may contribute to natural host protection and might potentially be exploited for subunit based vaccination . AnotherIn conclusion, further research on Mtb antigen and epitope specificities seems mandatory for realizing the crucially important aims of both prophylactic and post exposure vaccination against TB. Advancing the knowledge of antigenic determinants is essential also for differentiating patients with active TB from latently infected healthy subjects. There is potential in the ambitious search for specific immunological biomarkers for predicting the reactivation of TB in populations, both without and with HIV infection. These endeavors will undoubtedly need to be combined with better knowledge of the functional phenotypes of the respective T cell subsets. Other potential avenues are the construction of fusion proteins with improved vaccine adjuvanticity  and the 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.


Most health-care professional training programs lack educational curricula on substance use disorders and strategies for early intervention or referral to treatment. The University of Missouri-Kansas City Screening, Brief Intervention and Referral to Treatment (UMKC-SBIRT) training project educates baccalaureate nursing, advanced practice nursing, and master’s of social work students through didactics threaded throughout coursework; role-plays with classmates and faculty; standardizes patient practice; and offers clinical experience to help students achieve competency.In year one of the training grant, students completed surveys prior to, immediately after, and 30 days after SBIRT training. Surveys covered attitudes and knowledge. Skills were assessed by expert coding of an audiotaped interaction with a standardized patient actor using an SBIRT fidelity scale. Qualitative feedback regarding training experience, knowledge, and attitudes was collected at post-training focus groups.Students showed increased knowledge of SBIRT, improved perceptions toward working with patients who use substances, increased comfort in dealing with substance use issues, and progress in developing skills to provide SBIRT interventions.Training on SBIRT can be readily implemented into nursing and social work education, improving future health professionals’ perceptions and providing a valuable skill through which they can help patients lead healthier lives.


During aging, many neurodegenerative disorders are associated with reduced neurogenesis and a decline in the proliferation of stem/progenitor cells. The development of the stem cell (SC), the regenerative therapy field, gained tremendous expectations in the diseases that suffer from the lack of treatment options. Stem cell based therapy is a promising approach to promote neuroregeneration after brain injury and can be potentiated when combined with supportive pharmacological drug treatment, especially in the aged. However, the mechanism of action for a particular grafted cell type, the optimal delivery route, doses, or time window of administration after lesion is still under debate. Today, it is proved that these protections are most likely due to modulatory mechanisms rather than the expected cell replacement. Our group proved that important differences appear in the aged brain compared with young one, that is, the accelerated progression of ischemic area, or the delayed initiation of neurological recovery. In this light, these age-related aspects should be carefully evaluated in the clinical translation of neurorestorative therapies. This review is focused on the current perspectives and suitable sources of stem cells (SCs), mechanisms of action, and the most efficient delivery routes in neurorestoration therapies in the poststroke aged environment. With an increased aging population, the prevalence of age-related diseases will increase. The aging process is associated with a higher risk factor for stroke in both men and women and remains an important health issue without an accepted therapeutic strategy, except thrombolysis with recombinant tissue plasminogen activator for ischemic stroke , 2. StudStem cell therapy is focused on the functional improvement in the early stages after stroke rather than tissue replacement. Also, due to plastic capacity and tropism for damaged tissue, stem cells can be a useful tool for gene therapy in regenerative medicine , 9. CellAccording to their source, stem cells can be obtained from blastocyst cells (embryonic stem cells (ESCs)), adult stem cells (bone marrow derived stem cells (BMSCs) derived from peripheral blood or other tissues like adipose tissue), umbilical cord blood cells, and induced pluripotent stem cells (iPSCs). Bone marrow mononuclear cells (BM-MNCs), bone marrow derived mesenchymal stem stromal cells (BM-MSCs), umbilical cord stem cells (UCSCs), and neural stem cells (NSCs) are the most promising cells for recovery after cerebral ischemia. However, stem cells must be fully investigated for safety and therapeutic potential on animal models of neurological diseases in order to use it for clinical applications.Bone marrow derived mononuclear cells (BM-MNCs) are a promising tool for acute stroke therapy, but most preclinical trials were performed using young animals without comorbidities. Preclinical pilot studies using autologous BM-MNCs have already been performed. In one study, Savitz and colleagues showed that the IV administration of BM-MNC extracted from the iliac crest is safe and feasible in stroke patients between 18 and 80 years old . HoweverAlso, the administration route has a greater impact on the biodistribution, migration, and survival of transplanted stem cells. Using single photon emission computed tomography/computed tomography (SPECT/CT) and helical CT scan after intra-arterial (IA) and intravenous (IV) administration of BM-MNCs and BM-MSCs, Mäkelä end colleagues showed that the BM-MNCs accumulated in the spleen and bones and the BM-MSCs had relatively higher uptake in the kidneys. The IA transplantation decreased the deposition of BM-MSCs in the lungs and increased uptake especially in the liver. However, both administration routes using porcine model were found to be safe . IntrastIntrastriatal administration of the stem cell (SC) in the aged rats with striatal infarct leads to an elevated cell density in the ischemic area and can be monitored by magnetic resonance imaging (MRI). Injection of NPCs into lesioned striatum promotes a hypothetical neuronal network weeks later that can improve functional outcome .Preclinical data suggests that autologous bone marrow derived mononuclear cell therapy attenuates the effects of inflammation in the early posttraumatic brain injury period .One clinical trial indicated that the IV administration of 280.75 million BM-MNCs at 18,5 days after stroke onset is safe, but there is no beneficial effect of treatment on stroke outcome . Also, WIn the last decade, cells derived from the human umbilical cord (HUC) have emerged as a potential therapeutic alternative for stroke because of their capacity to differentiate into neural progenitor cells and their unlimited availability. Umbilical cells consist of a mixture of both hematopoietic stem cells (HSCs) and mononuclear fraction of mesenchymal stem cells (MSCs). An advantage of umbilical cord blood (UCB) derived cells is that the regulatory T-cells administration (1–5% from HUC cells) can prevent graft versus host diseases and can improve neurogenesis in the aging brain , 19.Studies on HUC-derived cell population in rat model showed that the IA administration of cord blood mononuclear cells (cbMNCs) and cord blood mesenchymal stromal cells (cbMSCs) at 24 h after stroke onset is associated with a reduction in neurological deficit and infarct area . Also, icbMNCs tend to restore the reduction of brain-derived neurotrophic factor (BDNF) level after stroke, increase the glutathione peroxidase-4 (GPx-4) mRNA expression, and decrease the number of activated microglia resulting in decreased neuroinflammation and neuronal cell death and increased neurologic recovery , 22.Wharton's jelly, part of the umbilical cord, contains myofibroblast-like stromal cells originated from mesenchyme that possess many unexplored advantages compared with adult stem cells. Wharton's jelly derived cells may secrete macromolecules like glycoproteins, mucopolysaccharides, glycosaminoglycans, or extracellular matrix proteins and showed capacity to differentiate into neural progenitor cells which improved neovascularization, myelination, and neurogenesis in an animal model of stroke –25.However, other studies using cryopreserved cbMNC failed to demonstrate neurorestorative properties in spontaneously hypertensive rats (SHR) stroke model .Adipose derived stem cells (ASCs) can be obtained from adipose tissue with minimal side effects and are able to differentiate into multiple cells that play an important role in the recovery of damaged tissue. Studies before have showed that the ASCs, in specific condition, can differentiate into the cells that express neuronal markers (NeuN and nestin) and glial markers  . In animβ) that can be increased in hypoxic conditions  [ASCs were found to produce different growth factors like vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), platelet-derived growth factor (PDGF), and transforming growth factor (TGF- stroke) , 29. In  stroke) .The recently discovered possibility to reprogram human adult somatic cells (iPS) has added a very exciting tool to the profile of the available SC and provided new perspective for neurorestorative therapy. iPS possess the potential and characters of embryonic stem cells, self-renewal and pluripotency, which allow the production of unlimited amount of precursor cells or all cell types of the body. On the other side, iPS allow the possibility to create biobanks and to avoid graft rejection. An advantage is that iPS can be obtained from blood cells and fibroblasts that are easily accessible. Chau and colleagues proved that the iPS can improve recovery after stroke in neonatal rats (P7) and adult brain by multiple mechanisms that promote angiogenesis and neurogenesis and provide essential trophic factors –34. HoweDespite these exciting findings, these studies still lack proof of mechanisms of iPS that promote the improvement of functional outcome after stroke in aged brain.Although rehabilitation is important for improving functional recovery in the early stages after stroke, it does not provide a replacement for the lost neuronal cells and ultimately brain function. Neural tissue transplantation has been first explored as an experimental technique for tissue repair and functional recovery after stroke –39. The Many studies report that stem cell therapy in combination with other compounds appears to be more effective than monotherapies alone. Our group showed that the combination of BM-MSCs with granulocyte colony-stimulating factor (G-CSF) promotes angiogenesis in the ischemic area of the aged brain, without significant improvement of cognitive function , 44.Association of UCB cells with G-CSF was showed to reduce neuroinflammation, enhance neurogenesis, and improve functional outcome after traumatic brain injury (TBI) , 46.The study by Cui et al. revealed that a combination of subtherapeutic doses of UCB cells and simvastatin amplified endogenous angiogenesis and increased and enhanced vascular remodeling by increasing Ang1/Tie2 signalling pathway in the ischemic brain .Gene therapy has been described as a powerful tool in treating nerve injury. Pereira and colleagues showed that the vascular endothelial growth factor (VEGF) gene and granulocyte colony-stimulating factor (G-CSF), delivered using endothelial progenitor cells (EPCs), promote regeneration and improve functional outcome , 49.VEGF delivery using endothelial progenitor cells (EPCs) was found to increase migration and proliferation of human endothelial cells after ultrasonic microbubble transfection . EPCs caThe efficacy of stem cell therapies so far is discouragingly low mainly because the time course of interactions between host neuroinflammatory response, the main obstacle to exogenous-mediated neuronal precursor cells, and exogenously administered stem cells is still unknown. Although MSC transplantation into the brain has ascribed beneficial effects in preclinical studies of neurodegenerative or neuroinflammatory disorders , 54, onlTo conclude, these findings strongly suggest that UCB derived cells have significant neurogenic potential but this potential has to be used in a more efficient manner to treat neurological diseases like stroke in aged people. Antineuroinflammatory therapies are a potential target to promote regeneration and repair in diverse injury and neurodegenerative conditions by stem cell therapy. Therefore, the challenge now is to determine in detail the cross talk between different populations of immune cells and grafted neural stem progenitor cells (NSPCs) at different phases after stroke in aged brain. In


Phragmites australis over four years to determine their effects on potential denitrification rates relative to three untreated Phragmites sites and adjacent sites dominated by native Typha angustifolia. Sediment ammonium increased following the removal of vegetation from treated sites, likely as a result of decreases in both plant uptake and nitrification. Denitrification potentials were lower in removal sites relative to untreated Phragmites sites, a pattern that persisted at least two years following removal as native plant species began to re-colonize treated sites. These results suggest the potential for a trade-off between invasive-plant management and nitrogen-removal services. A balanced assessment of costs associated with keeping versus removing invasive plants is needed to adequately manage simultaneously for biodiversity and pollution targets.Establishing relationships between biodiversity and ecosystem function is an ongoing endeavor in contemporary ecosystem and community ecology, with important practical implications for conservation and the maintenance of ecosystem services. Removal of invasive plant species to conserve native diversity is a common management objective in many ecosystems, including wetlands. However, substantial changes in plant community composition have the potential to alter sediment characteristics and ecosystem services, including permanent removal of nitrogen from these systems via microbial denitrification. A balanced assessment of costs associated with keeping and removing invasive plants is needed to manage simultaneously for biodiversity and pollution targets. We monitored small-scale removals of  Invasive species are often presumed to degrade ecosystem functioning. By causing local extinctions, invasives are thought to reduce biodiversity , which iPhragmites australis  were analyzed with a one-way ANOVA. A separate two-way ANOVA was used to compare Phragmites and Typha communities sampled at the reference sites at two additional sampling times . Measurements of sediment nitrogen and carbon collected August 2010-September 2012 were also analyzed with a two-way ANOVA to compare the three dominant vegetation groups. For each two-way ANOVA, potential interactions between vegetation type and sampling time were tested for significance.Differences in plant traits  measured in September 2012 among the three dominant vegetation types  that were sampled across all “sampling times” , both before and after herbicide treatment. For these ANOVAs, significant impacts of herbicide treatment on dependent variables  were tested as planned comparisons within the interaction term (treatment x sampling time). In the second statistical design, we compared four treatments  for sampling times that occurred after herbicide treatment . For these ANOVAs, significance of herbicide treatment was assessed for the dependent variables listed above and additional measurements added in 2011 [total organic carbon and nitrogen content of sediments] using planned comparisons of treatments.Measurements of denitrification potential, sediment porewater nutrients, and total sediment organic content were analyzed at the stand scale using two-way ANOVA. Because the “Reference-The sediment properties and processes we measured are notoriously variable as a result of measurement difficulties and spatial variability , and samPhragmites sampling times were used to test for significant differences between sites where Phragmites was removed relative to sites where Phragmites was left intact. Planned comparisons of Reference-Typha and Reference-Phragmites were used to test whether sites dominated by plant species differed when left undisturbed. Though we attempted to control for phenology by sampling at peak biomass in each of our sampling years (late August/early September), we acknowledge that other factors such as temperature may influence sediment chemistry and microbial activity. The sampling conducted in June 2012 was added to provide further insight into the short-term trajectory of sediment recovery in treated sites. Planned comparisons of treatment and reference sites statistically control for interannual and seasonal variability when detecting treatment effects. All statistical analyses were performed in JMP [Planned comparisons of Ramshorn-Removal and Reference-d in JMP . Graphs d in JMP . CompletPeltandra virginica . For Phragmites-dominated communities, this correlation was weak and of small effect  across all treatments throughout our study. Therefore, only results of porewater ammonium are reported. Following initial herbicide treatment, porewater ammonium concentrations in removal sites increased by over an order of magnitude relative to all vegetated sites .Phragmites-dominated reference locations Click here for additional data file.


Perineuronal nets (PN) form a specialized extracellular matrix around certain highly active neurons within the central nervous system and may help to stabilize synaptic contacts, promote local ion homeostasis, or play a protective role. Within the ocular motor system, excitatory burst neurons and omnipause neurons are highly active cells that generate rapid eye movements – saccades; both groups of neurons contain the calcium-binding protein parvalbumin and are ensheathed by PN. Experimental lesions of excitatory burst neurons and omnipause neurons cause slowing or complete loss of saccades. Selective palsy of saccades in humans is reported following cardiac surgery, but such cases have shown normal brainstem neuroimaging, with only one clinicopathological study that demonstrated paramedian pontine infarction. Our objective was to test the hypothesis that lesions of PN surrounding these brainstem saccade-related neurons may cause saccadic palsy.Together with four controls we studied the brain of a patient who had developed a permanent selective saccadic palsy following cardiac surgery and died several years later. Sections of formalin-fixed paraffin-embedded brainstem blocks were applied to double-immunoperoxidase staining of parvalbumin and three different components of PN. Triple immunofluorescence labeling for all PN components served as internal controls. Combined immunostaining of parvalbumin and synaptophysin revealed the presence of synapses.Excitatory burst neurons and omnipause neurons were preserved and still received synaptic input, but their surrounding PN showed severe loss or fragmentation.Our findings support current models and experimental studies of the brainstem saccade-generating neurons and indicate that damage to PN may permanently impair the function of these neurons that the PN ensheathe. How a postulated hypoxic mechanism could selectively damage the PN remains unclear. We propose that the well-studied saccadic eye movement system provides an accessible model to evaluate the role of PN in health and disease. Saccades are rapid conjugate eye movements that bring target images onto the fovea for exploring visual scenes, reading, and resetting the eyes during optokinetic or vestibular nystagmus. Two critical components of the brainstem saccade network are premotor burst neurons (PBN) and omnipause neurons (OPN). PBN include excitatory burst neurons (EBN) and inhibitory burst neurons (IBN) firing up to 1,000 spikes/s during saccades  and in tPerineuronal nets (PN) are condensed, extracellular matrices of macromolecules ensheathing fast-firing neurons such as PBN and OPN. PN consist of a hyaluronic acid backbone attached to glycoproteins and chondroitin sulfate proteoglycans (CSPG) such as aggrecan (ACAN) and hyaluronan and proteoglycan link protein (HPLN1) . PN may Infarction, metabolic or degenerative disorders targeting PBN or OPN may slow or abolish saccades –13. DrawSimilar cases have been reported without neuropathologic evaluation –26, typiA previously reported  healthy Ten months postoperatively, general neurological examination was notable only for diffuse hyporeflexia. Visual acuity, pupils, visual fields, and fundoscopic examination were normal. Straight-ahead fixation was steady, and no saccadic intrusions or nystagmus were seen with ophthalmoscopy. She made no reflexive saccades, and volitional saccades consisted of extremely slow eye movements that eventually reached the target, except for slightly faster downward saccades . PursuitEye movements were recorded with video-oculography. Horizontal saccades were absent during a random saccade paradigm, but sinusoidal smooth pursuit was normal across all frequencies tested. Vertical eye movements demonstrated similar findings. Additionally, rotary chair sinusoidal vestibular and optokinetic testing generated normal vestibular slow phases and optokinetic ocular following reflex, but absent vestibular and optokinetic quick phases of nystagmus.The patient was last examined two years later and was clinically unchanged except for some emerging memory complaints. She remained on warfarin for her mechanical valve. Subsequently, she developed cirrhosis attributed to increasing alcohol abuse. Memory loss remained mild. Eight years after her cardiac surgery, with an increased bleeding diathesis from over-anticoagulation and liver dysfunction, she developed massive hematemesis and melena from a bleeding peptic ulcer, profound anemia, shock, renal failure, and somnolence. She expired in hospice one week later.ex vivo 7 tesla MRI, as previously described [The whole brain was collected the day of death and fixed in 10% formalin for 2 weeks. Next, the brain was suspended in Fomblin  for escribed . After r2O2 resulting in a bluish-black reaction product [After deparaffinizing and antigen retrieval by boiling the sections 3x10 minutes in a microwave in 0.01M citrate buffer (pH 6) the slides were transferred to 0.1M phosphate-buffered saline . Saccade-related neurons were identified by immunostaining with mouse monoclonal antibodies directed against non-phosphorylated neurofilaments  and the calcium-binding protein parvalbumin . Antigen binding sites were detected with incubation with biotinylated horse antibodies recognizing mouse IgG  for 2 h at room temperature. Following 3 buffer washes and an 1 h incubation with ExtrAvidin-peroxidase conjugates  immunoreactivities were visualized with nickel-enhanced diaminobenzidine (DAB-Ni) and H product .PN were detected by immunostaining for different components with either mouse monoclonal anti-cat chondroitin sulfate proteoglycan , or anti- human aggrecan core protein , or polyclonal goat anti-human link protein . Synapses were identified with affinity-purified rabbit antibodies directed against the presynaptic vesicle protein synaptophysin , which was visualized by the avidin-biotin-technique and DAB-Ni as described above. In selected sections, double immunoperoxidase staining was applied to concomitantly detect PN or synapses and PAV-positive saccade-related neurons. Thereby, PN-related antibodies or synaptophysin were revealed by immunoperoxidase double staining with bluish-black DAB-Ni followed by immunodetection of PAV with plain DAB producing a brown reaction product.In selected sections, main components of PN were visualized by triple immunofluorescence labeling. The tissue was primarily blocked with 5% normal donkey serum in TBS (containing 0.3% Triton X-100) for 1 hour and then incubated with a cocktail consisting of polyclonal rabbit anti-CSPG  [For normal controls, the brains of 4 subjects from the Neurobiobank Munich who died without any history of ocular motor or relevant neurological disorders were evaluated. All cases underwent identical neuropathological examination, immunostaining with monoclonal mouse antibodies against human-PHF-Tau , beta-Amyloid 17–24 , alpha-synuclein  and polyconal rabbit anti-TDP-43 , as well as triple immunofluorescence labeling.Control 1 (shown in figures) was a 62-year-old male who died of pancreatic cancer without brain metastases or hepatic encephalopathy whose neuropathological examination demonstrated small old hemorrhages in the adenohypophysis, arteriosclerosis, and Braak stage I of Alzheimer changes . ControlWritten consent was obtained from all patient and control subjects or the next of kin for use of these tissue samples in research. The patient provided written consent for video recording (that authorizes publication among other uses). The next of kin of the patient has provided written informed consent for brain autopsy and (as outlined in the PLOS consent form) to publish these case details and the video. Control samples were collected as part of the Neurobiobank Munich. The Neurobiobank Munich and this research project have been approved by the ethics committee of the Ludwig Maximilians University.in vivo and ex vivo 7 tesla MRI studies [As previously reported, gross inspection of the brain was unremarkable  and was  studies . Atheros studies . The tisThe gross and histologic examination of the pons in the region of the abducens and omnipause neurons found no lesion. Staining the OPN area with LFB-PAS, GFAP, and CR3/43 showed no evidence of demyelination, reactive gliosis, or abnormal microglia activation . ImmunolImmunostaining patterns of HPLN1- and ACAN-based PN in the abducens nuclei  and arouIn the nucleus raphe interpositus (RIP) of control subjects, all PAV-positive OPN were ensheathed by PN immunostained for ACAN, CSPG, or HPLN1 . In the The PAV-positive putative excitatory saccadic burst neurons in the PPRF and in the RIMLF were ensheathed only by fragments of PN, unlike in the control case . As alsoWe describe a patient with profound enduring saccadic palsy following cardiac surgery whose brain showed preserved saccade-generating neurons but disruption of the PN that are thought to be essential for normal functioning of these neurons. These findings raise a number of important issues for discussion regarding the localization of saccade dysfunction, the role of PN, broader damage to the central nervous system, mechanisms of injury, and implications for understanding PN function.Brainstem neurons that generate saccades (PBN and OPN) receive descending inputs from cortical eye fields, via the basal ganglia, superior colliculus, and cerebellum ,33. The Additional evidence that this selective saccadic palsy was due to a brainstem process comes from studies of chemical lesions or pharmacological inactivation of the PPRF, RIMLF, or OPN in macaque reporting selective slowing or absence of saccades with spared pursuit and vestibular eye movements –42. Suchselective saccadic palsy spares ocular motor nuclei and supranuclear pathways from the cerebral hemispheres, basal ganglia, and cerebellum involved in pursuit and vestibular eye movements. While there was some focal loss of cerebellar Purkinje cells, which are susceptible to ischemia or alcohol [We conclude that our patient’s saccadic palsy was due to dysfunction of the brainstem saccade-generating network of neurons because of her isolated loss of horizontal, vertical, and torsional saccades and reflexive quick phases but preserved pursuit, vergence, and vestibular eye movements. This  alcohol ,45, thes alcohol  but have alcohol . The patThe main novel finding of this clinicopathologic study is that neurons in the brainstem reticular formation’s saccadic network appeared histologically normal with preserved synapses despite their loss of function. However, our immunostaining demonstrated that PN surrounding OPN and EBN were absent or severely fragmented. Great methodological care ensured that poor PN staining was not due to effects of preservation, fixation, or postmortem delay by using three antibodies to detect different PN components (even in the same section with immunofluorescence). Furthermore, intact PN were present in adjacent related  and unrelated (superior olive) areas. This finding supports the critical role current models place for OPN and EBN in generating normal velocity saccades . It alsoSeveral functions have been suggested for PN that may underlie the mechanism for malfunction of OPN and EBN . PN coulin vivo and in vitro spontaneous epileptiform discharges from the CA3 area months after global ischemia, combined with loss of GABAergic interneurons, a finding associated with aberrant sprouting of glutamatergic fibers leading to enhanced synaptic excitation and reduced synaptic inhibition in temporal lobe epilepsy models [Damage to PN might also explain other phenomena following cardiac surgery. PN surround GABAergic projection neurons in portions of the globus pallidus and substantia nigra as well as in subpopulations of striatal and thalamic inhibitory neurons . Hypoxiay models . WhetherHow could saccade-related PN be damaged during cardiopulmonary bypass while sparing the highly active neurons they enwrap? PN may be particularly vulnerable to hypoxia, as a focal cerebral ischemia rat model found that ischemia damages PN more than the ensheathed neurons in the peri-infarct zone . Unlike Selective saccadic palsy could be developed into an animal model to clarify the role of PN. Saccades are an ideal system for studying neural control of movement since they are well understood and can be measured precisely ,57. The Understanding the role of PN in different disorders may create therapeutic opportunities. Status epilepticus is associated with reduced PN-stabilizing components and aggrecan expression . The rolIn summary, this study provides the first evidence that saccadic palsy following cardiac surgery can be caused by damage to supporting tissues surrounding saccadic network neurons rather than to the neurons themselves. It also suggests an accessible model in which eye movements could be used to study the unique role and requirements of PN experimentally. However, some caution is required in interpreting our results, which rest on careful studies of one patient. More studies are required to confirm our findings, including examination of PN in patients without saccadic palsy who have died of exsanguination.S1 MovieTo make rapid head-free gaze shifts, the patient used exaggerated head turns associated with blinks; contraversive vestibular slow phases moved the eyes into the corner of the orbits until the head was maximally rotated, and then the eyes slowly drifted toward the target. She made no reflexive saccades. With the head fixed, volitional saccades consisted of extremely slow eye movements that eventually reached the target, except for slightly faster downward saccades. Pursuit was smooth and full in range both horizontally and vertically, even at higher frequencies. Visually enhanced vestibulo-ocular reflex was normal. When she viewed a horizontally rotating optokinetic drum, her eyes became fixed laterally in the orbits without any corrective quick phases. Torsional head rolling produced normal ocular counter-rolling but without any torsional quick phases. See text for additional details not shown in the movie.(M4V)Click here for additional data file.


We would like to comment on the excellent review by Chen and colleagues highlighting the safety and efficacy of combining extracorporeal membrane oxygenation (ECMO) and continuous renal replacement therapy (CRRT) for fluid and electrolyte control .As a high-flow system equipped with heparin-coated membranes and circuits, ECMO requires no or only minimal additional anticoagulation to assure circuit patency ,3. In coFor these reasons, we strongly argue against the combined use of ECMO and CRRT within a single circuit. In addition, a separate CRRT device can perfectly run under a proper dedicated anticoagulation therapy . This permits avoidance of ECMO-induced anticoagulant dilution, resulting in less thrombotic events .


The Drug Addiction Treatment Act of 2000 created an opportunity for primary care physicians and addiction treatment agencies to integrate, as primary care physicians became able to prescribe opiate treatment medications from their practices. Fourteen years later, a National Institute on Drug Abuse evidence-based practice implementation trial in Ohio is finding that physician capacity is becoming a primary barrier to use of buprenorphine. This presentation will document: a) the degree of the physician capacity barrier for specialty addiction treatment providers wanting to expand their buprenorphine programs; b) strategies being considered to overcome this barrier, including telemedicine; and c) what workflow challenges implementation of telemedicine can expect .The mixed-methods approach documents physician capacity limitations and to what degree telemedicine is being considered to remedy physician capacity shortfalls. Data collection includes written surveys from 47 treatment centers; qualitative interviews with 39 treatment centers; and patient simulations of VA telemedicine programs. For the data analysis, summary statistics are provided, including characteristics of organizational participants and buprenorphine prescribing patterns. The qualitative inductive analysis is designed to identify contextual and process factors that affect telemedicine implementation.Fifty percent (sample = 42) of Ohio treatment providers report lack of access to buprenorphine-prescribing physicians as a barrier to implementation and expanded use of buprenorphine. Thirty-eight percent of those identifying this barrier consider telemedicine as an option to access physician prescribers. Barriers to telemedicine implementation are technology incompatibility; inability for telemedicine sites and specialty treatment providers to agree on dosing protocols (including diversion prevention expectations); and workflow interruptions that occur due to patient and clinical information not being effectively transferred between telemedicine sites and community treatment providers. Organizational strategies to overcome lack of physician capacity and telemedicine implementation challenges are discussed.The lack of physician-prescribing capacity for buprenorphine is preventing this evidence-based practice from achieving higher penetration rates among specialty treatment providers. Telemedicine provides one solution to re-allocate the distribution of this scarce resource. However, there will also be challenges in implementing telemedicine that need to be understood, and evidence-based strategies need to be developed to overcome these challenges. Successful use of telemedicine may ultimately lead to greater integration between primary care and specialty addiction treatment.Clinicaltrials.gov NCT01702142NIDA 5R01DA030431-03


Enthesitis Related Arthritis Category of Juvenile Idiopathic Arthritis (JIA-ERA) is the most common category of JIA seen in Asian Indians. Transcriptome analysis is a useful tool to analyse pathways involved in disease pathogenesis. Peripheral blood mononuclear cells (PBMC) and SFMC analysis showed involvement of innate immune cells in JIA-ERA. However PBMC/SFMC have variable number of different cells and that can affect interpretation. No data is available on cell type specific transcriptome analysis of blood and synovial fluid in children with JIA-ERA.To study the cell type specific transcriptome analysis of blood and synovial fluid in children with JIA-ERA.Six samples each of peripheral blood and synovial fluid were collected from patients with ERA-JIA. Blood from 6 healthy controls was also collected. Mononuclear cells were separated by density gradient centrifugation. B cells, T cells and monocytes were separated using MACS columns and purity assessed by flow cytometry. After RNA extraction and checking the quality of RNA (RIN > 8) microarray was done using Illumina chips WG 12 for whole PBMC/SFMC population, T cells, B cells and monocytes. Some of the significant genes were validated by qRT-PCR.Unsupervised hierarchical clustering revealed that cell subsets could be distinguished based on their gene expression profile. No significant differences were observed between PBMC of patients and healthy controls. Comparison of SFMC and PBMC reconfirmed the results seen earlier. Among T cells and B cells the differential athways identified were related to inflammation like Cell adhesion, antigen processing, cytokine and chemokine signaling,BCR signaling and leukocyte migration.Results obtained with monocytes are summarized below in table Monocyte probably play a major role in pathogenesis of JIA-ERA and TLR signalling may be the pathway involved.None declared.


Dear Editor-in-Chief,A recent article published in the Journal of Human Kinetics  describeResistance exercise with blood flow restriction (REBFR) is considered alternative training for enhancing strength and muscle size (hypertrophy) to high intensity conventional resistance training . It is often recommended to include REBFR in clinical population, including hypertension (HTA), as this type of training carries a lower risk of injury. Additionally, it has been reported that REBFR is safe . For insTherefore, further investigation is required to assess the physiological effects on hypertensive subjects comparing: a) resistance training with different levels of blood flow restriction; b) different intensities in resistance training; c) REBFR versus traditional resistance training; d) REBFR versus traditional aerobic training in hypertensive subjects.


Cardiovascular disease (CVD) is the major cause of mortality in industrialized countries. Atherosclerosis is characterized by a long lag time between onset and clinical manifestations. There is evidence that CVD initiate before birth by developmental changes in utero. Genetic and environmental factors may interact in specific periods of life , giving rise to altered developmental plasticity and epigenetic modifications with abnormal phenotypic expression of genetic information without altering DNA sequence. Nutritional imbalances and other environmental clues may cause intrauterine growth delay, decreased gestational age, low birth weight and postnatal catch-up growth. Fetal exposure to maternal hypercholesterolemia has been associated with increased risk and progression of atherosclerosis. Oxidative stress seems to play a major role in the atherosclerotic process by activating both platelets and monocytes forming proinflammatory and proaterogenic substances, resulting in endothelial dysfunction, decreased flow-mediated dilation, and increased carotid intima-media thickness ,2. CVD p


Orangutans are an endangered species whose natural habitats are restricted to the Southeast Asian islands of Borneo and Sumatra. Along with the African great apes, orangutans are among the closest living relatives to humans. For potential species conservation and functional genomics studies, we derived induced pluripotent stem cells (iPSCs) from cryopreserved somatic cells obtained from captive orangutans.OCT4, SOX2, KLF4, and c-MYC factors. Candidate orangutan iPSCs were characterized by global gene expression and DNA copy number analysis. All were consistent with pluripotency and provided no evidence of large genomic insertions or deletions. In addition, orangutan iPSCs were capable of producing cells derived from all three germ layers in vitro through embryoid body differentiation assays and in vivo through teratoma formation in immune-compromised mice.Primary skin fibroblasts from two Sumatran orangutans were transduced with retroviral vectors expressing the human We demonstrate that orangutan skin fibroblasts are capable of being reprogrammed into iPSCs with hallmark molecular signatures and differentiation potential. We suggest that reprogramming orangutan somatic cells in genome resource banks could provide new opportunities for advancing assisted reproductive technologies relevant for species conservation efforts. Furthermore, orangutan iPSCs could have applications for investigating the phenotypic relevance of genomic changes that occurred in the human, African great ape, and/or orangutan lineages. This provides opportunities for orangutan cell culture models that would otherwise be impossible to develop from living donors due to the invasive nature of the procedures required for obtaining primary cells.The online version of this article (doi:10.1186/s13104-015-1567-0) contains supplementary material, which is available to authorized users. Pongo pygmaeus) and Sumatra (Pongo abelii) .Gene expression scores and .cel files supporting the results of this article are available in the National Center for Biotechnology Information (NCBI) Gene Expression Omnibus (GEO) repository [Series Accession Number GSE69603 and


To examine acute alterations in lower-extremity sagittal plane joint moments due to isolated and/or combined experimental knee joint pain and effusion during walking.Nineteen able-bodied subjects walked four different conditions , with a week between each condition. We used previously-used injury models of pain  and joinThe FANOVAs detected between-session differences for the involved (right) and uninvolved legs (left; Figure Stimulation of the receptors specific to joint pressure appears to cause higher impact on alterations in sagittal plane joint moment compared to the nociceptor stimulation. Simultaneous knee joint pain and effusion produced a summative effect on sagittal plane joint moments. Since knee joint effusion and pain are common symptoms in knee joint injuries, both variables should be controlled in acute and chronic phase of rehabilitation in order to avoid altered joint moments.


Increased aortic stiffness may lead to insufficient flow wave dampening and subsequent transmission of excessive pulsatile energy towards end-organs such as the brain. It has been shown that CMR-assessed aortic stiffness may augment cerebral small vessel disease in patients with hypertension, as assessed by conventional structural magnetic resonance imaging (MRI). However, in addition to these overt brain abnormalities, currently it is unknown whether aortic stiffening relates to subtle changes in brain tissue integrity, which may be a precursor to overt brain abnormalities. Diffusion tensor imaging (DTI) in the brain has been used to evaluate such subtle changes in tissue integrity. The aim of this study was to assess the association between aortic arch pulse wave velocity (PWV) as a marker of arterial stiffness and brain changes assessed by conventional structural MRI as well as DTI in patients with hypertension.78 patients with hypertension  were prospectively included. Aortic imaging was performed using 1.5T MRI. To assess PWV over the aortic arch, one-directional through-plane velocity-encoded MRI was performed, planned perpendicular to the ascending aorta and additionally transecting the proximal descending aorta  and grey matter integrity  (Table Our data suggest that aortic arch stiffness is independently associated with changes in brain tissue integrity in patients with hypertension. Subtle changes in brain microstructure are related to increased stiffness of the aortic arch, even in absence of overt brain abnormalities.N/A.


Stroke is the leading cause of disability in the United States. Despite the high incidence and mortality of stroke, sensitive and specific brain-based biomarkers predicting persisting disabilities are lacking. Both neuroimaging techniques like electroencephalography (EEG) and non-invasive brain stimulation (NIBS) techniques such as transcranial magnetic stimulation (TMS) have proven useful in predicting prognosis, recovery trajectories and response to rehabilitation in individuals with stroke. We propose, however, that additional synergetic effects can be achieved by simultaneously combining both approaches. Combined TMS-EEG is able to activate discrete cortical regions and directly assess local cortical reactivity and effective connectivity within the network independent of the integrity of descending fiber pathways and also outside the motor system. Studying cortical reactivity and connectivity in patients with stroke TMS-EEG may identify salient neural mechanisms underlying motor disabilities and lead to novel biomarkers of stroke pathophysiology which can then be used to assess, monitor, and refine rehabilitation approaches for individuals with significant disability to improve outcomes and quality of life after stroke. Stroke is the fourth leading cause of death  have shown promise in identifying neurophysiological mechanisms associated with network reorganization in the human brain after stroke. Neuroimaging approaches have identified functional neural correlates of impaired arm movements after stroke demonstrating relationships between brain function and motor impairment  at rest and during isotonic contraction TMS can noninvasively and transiently modulate cortical excitability in the human brain  or offline imaging approaches   in response to a single TMS pulse has been repeatedly confirmed , several other TEP-based indices have been employed to index certain aspects of cortical reactivity or effective connectivity Table . For exaTMS-EEG has provided candidate biomarkers for a variety of different neurologic conditions. Altered TEPs, in particular a reduced N100 component of the TEP evoked at M1, have been identified in children with attention deficit hyperactivity disorder (ADHD)  Electrical confounds: magneto-electric induction creates fast and high amplitude currents in the EEG electrodes and leads (during stimulation itself and when recharging capacitors) and also electrode-electrolyte interface polarization (Ilmoniemi and Kicić, Concurrent TMS-EEG has the potential to improve our understanding of the neurobiology of stroke and stroke recovery by offering a sophisticated paradigm to non-invasively characterize human brain excitability and connectivity after stroke. Revealing the causal mechanisms of altered cortical excitability and cortical network reorganization has important clinical implications. If successful, TMS-EEG could provide new tools to improve prognosis, refine treatment approaches, monitor recovery trajectories and individualize care to improve recovery outcomes for patients after stroke.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.


One of the most widely employed quantitative measurements for assessing tumour response to treatment is the tumour diameter (RECIST criteria), usually determined on cross-sectional CT or MRI. This simple measurement is relatively reproducible and reduction in the maximum tumour diameter by 30% or more following therapy is taken as a sign of effective treatment. However, new targeted therapies may be effective without significantly reducing tumour size and other quantitative response criteria are being evaluated.Some of the response criteria being evaluated combine tumour diameter measurement with other quantitative assessment (e.g. CT density). These have been applied towards the evaluation of gastrointestinal stromal tumours (CHOI criteria) and renal cell carcinoma (modified or revised CHOI criteria) undergoing multi-kinase inhibitor treatment; and hepatocellular carcinoma (modified RECIST criteria) treated with novel therapeutics or chemoembolization. In these clinical settings, the applications of such criteria for tumour response assessment have shown better correlation with clinical outcome compared with conventional RECIST criteria. When immunotherapy is administered, conventional RECIST criteria may erroneously ascribe the appearance of new lesions to disease progression; whereas this phenomenon is given due consideration within the immune-related response criteria (irRC).As quantitative imaging becomes increasingly important in oncology, quantitative indices are being applied and developed in CT, MRI and PET imaging for tumour response assessment. Using perfusion CT technique, the change in CT attenuation value with time resulting from the passage of contrast through tissue can be used to calculate quantitative vascular parameters such as permeability surface area product (PS), blood flow (F) and mean transit time (MTT). Using dual energy CT, it is possible to obtain quantitative iodine contrast distribution in soft tissue.MRI is a powerful multiplex imaging technique because depending on how the scans are performed, it can yield different quantitative information. Two of the most widely employed quantitative techniques for tumour assessment are dynamic contrast enhanced MRI (DCE-MRI) and diffusion-weighted MRI (DW-MRI). The former has been used in early phase trials for the assessment of antivascular/ antiangiogenic therapies. The latter has shown potential as an early response biomarker to a range of effective treatments including chemotherapy, radiotherapy, chemoemobolization treatment and novel therapeutics. Other clinical MR techniques include intrinsic susceptible contrast imaging and magnetic resonance spectroscopy (MRS). However, these have currently limited value for assessing tumour response to treatment.PET imaging using 18FDG tracer enables the semi-quantitative standardised uptake value (SUV) to be derived. PET imaging is increasing utilized for tumour response assessment, and forms the basis of standard criteria for assessment of tumour response in lymphoma. By performing dynamic imaging, it is also possible to calculate the quantitative tracer uptake in tissues. The strength of PET imaging is the range of radiolabelled tracers that are now available clinically to probe a range of tissue properties.In early phase trials, quantitative imaging other than tumour size measurements using CT, MRI or PET can provide mechanistic information about drug action, and also therapeutic effects on specific aspects of tumour biology . By using multimodality imaging, there is also an opportunity to corroborate imaging measurements made using one technique with another. However, quantitative techniques require a process of quality control and quality assurance; as well as knowledge of their measurement reproducibility so that they can be applied with confidence in clinical practice.


There are errors in the Data Availability section. The correct data availability information is as follows: The authors confirm that all data underlying the findings are fully available without restriction. All sequence data are in the Short Read Archive (SRA) at the NCBI database under accession numbers: bean LTD SAMN03223377, bean NOI SAMN03223381, bean NTD SAMN03223380, and bean LOI SAMN03223378.


Amyris is a renewable products company providing sustainable alternatives to a broad range of petroleum-sourced products. Amyris applies its industrial synthetic biology platform to convert plant sugars into a variety of molecules - flexible building blocks that can be used in a wide range of products.®, Amyris's brand of farnesene, a long-chain branched hydrocarbon, manufactured using our engineered microbes in fermentation.Amyris's initial portfolio of commercial products is based on BiofeneFirst generation renewable fuels have been an important part of the effort to reduce the world's petroleum dependence and greenhouse gas emissions associated with transportation fuels. However, these first generation renewable fuels have some limitations, ranging from lower energy density than petroleum fuels and lack of fungibility with existing petroleum distribution systems.Amyris renewable fuels are designed to be optimal transportation fuels. Specifically, our fuels are designed to be drop-in, cost competitive replacements for petroleum-derived fuels, compatible with existing engines yet with superior performance.Building on our Biofene hydrocarbon building block, we are currently selling renewable diesel in metropolitan areas in Brazil and are pursuing industry certification for our renewable jet fuel.


Clinically, pancreatic tumors have proven to develop resistance to available treatment options; however, efficacy might be achieved if the required levels of drugs reach the tumor site. Tumor microenvironment (TME) leads to extensive desmoplasia and chemo-resistance, contributing immensely to the invasive and metastatic process of pancreatic carcinoma . DesmoplOur study, published in Cancer Research , provideConsidering the huge fibrotic nature of pancreatic tumors and to overcome the vast heterogeneity observed within the tumors, we have prepared a PLGA [poly(lactic-co-glycolic acid)] based nanoparticle formulation of ormeloxifene and discussed its enhanced efficacy in an article published in Biomaterials . The forIn conclusion, management of TME using this novel therapeutic modality and potential delivery system might add clinical benefit to existing standard treatments utilizing combination treatment regimens. Our studies support the understanding that manipulation of TME may overcome the stromal barrier for effective treatments in pancreatic cancer.


Myeloid-derived suppressor cells (MDSCs) are a naturally occurring immune regulatory population capable of suppressing inflammation, and are often associated with cancer, chronic infection and traumatic injury . GrowingActivation of the inflammasome can be via endogenous damage-associated molecules termed DAMPs Figure . We havein vitro and in the context of GvHD [ex vivo suppressive capacity of MDSC was also reduced. The temporal nature of MDSC loss of function was addressed by applying multiple consecutive doses of MDSC-IL13 , resulting in enhanced overall survival, suggesting MDSC functionality is compromised early due to GvHD conditions and that maintaining a suppressive environment using repetitive MDSC infusions could overcome the loss of suppression of an individual MDSC infusion. In support of an inflammasome mediated loss of function, genetic ablation of the inflammasome-associated adaptor protein ASC (Apoptosis-associated speck-like protein containing a CARD) prevented MDSC inflammasome activation and resulted in improved survival relative to wild-type MDSC in GvHD mice. Moreover, ASC−/− MDSC-IL13 recovered from day 5 post transplant recipients did not produce IL-1β and better retained their capacity to suppress T cell proliferation ex vivo than wild-type MDSC-IL13 recovered from GvHD mice. The translational potential of these findings are supported by the fact that we observed human peripheral blood-derived MDSC to be susceptible to in vitro inflammasome activation and had reduced suppressive function under these conditions.Myeloid cells are uniquely responsive to their environment and in our efforts to improve MDSC function, we investigated their inflammasome activation status both  of GvHD . In as l−/− MDSC, and clinically viable options including mRNA or gene knockdown or knockout technologies such as sh/siRNA or nucleases that target one or more inflammasome components. Pharmacologic agents such as small molecule inhibitors designed to repress inflammasomes currently being developed to circumvent GvHD pathology are expected to act on transferred MDSC as well, and we would predict aid in maintenance of function. Other implications from this work include the potential to conversely promote inflammasome activation locally at the site of tumor burden for the purposeful enhancement of immune activation and anti-tumor immune therapy, as MDSC are nearly ubiquitously observed in the setting of solid tumors. Our findings suggest that the degree of inflammation is critical for MDSC functional support, and anti-tumor therapies may benefit from local or systemic priming of inflammasome activation, converting tumor-associated MDSC and releasing their suppressive potential.Myeloid cells play a critical role in developing, shaping and sustaining immune responses and are remarkably adaptable to their environment. Therefore, adoptive cell therapies using MDSC need to be tailored and monitored carefully, as culture conditions are vastly different then the conditions MDSC are exposed to upon transfer. An important question that remains is elucidating which inciting factors are involved in transplant/GvHD associated inflammasome activation. While ATP/P2x7R and Nlrp3/miR-155 are recognized as important targets with relevance in GvHD, a wide variety of factors are known to activate inflammasomes including DAMPs, bacterial & viral (dsDNA) products and environmental stimuli  and may contribute to MDSC inflammasome activation. Whether it is possible or necessary to globally inhibit these upstream pathways for inflammasome activation is yet unclear. Our future aims are to produce higher functioning MDSC that are capable of sustained function in the harsh early post transplant setting of GvHD. Methods for tailoring MDSC to resist conversion include genetic alterations to prevent inflammasome activation, as seen using ASC


It is becoming clear that immune cells play many important but sometimes conflicting roles in cancer. Immune profile changes at sites of immune-cancer interactions, such as the tumor microenvironment and tumor-draining lymph nodes (TDLNs), may represent a sensitive predictor of local and distant tumor metastasis. However, standard pathologic analysis of tumor sections has remained at the visual assessment of one marker per serial section level; it would be extremely useful to be able to visualize the distributions of multiple phenotyped immune and other cells in-situ in solid tumors to dissect the complex interplay between immune/stromal cells and cancer cells within tumors, tumor-draining lymph nodes (TDLNs), and blood. We generate immune profiles that include complete immunophenotyping and identification of cellular spatial relationships within and between the tumor microenvironment and TDLNs from formalin-fixed paraffin-embedded lymph node and tumor specimens from cancer patients using a combination of multiplexed IHC/IF, multispectral imaging, and automated image analysis which delivers quantitative per-cell measures of each marker. These per-cell intensities are then translated into a phenotype for each cell. We have found that immune cell populations as well as their spatial distributions and clustering patterns have strong correlation with clinical outcome.