Benefits of early reperfusion in patients presenting with acute ST elevation myocardial infarction (STEMI) are well known. The American College of Cardiology / American Heart Association guidelines recommend triage decisions are made within 10 minutes of performing initial electrocardiogram (ECG). Since many patients presenting with ischemic symptoms may have ST elevation (STE) at baseline, not all STE signify transmural ischemia. Benign patterns can be easy to find in some cases. However, patients with benign STE at baseline  may have ongoing ischemia and present with Non-ST elevation myocardial infarction (NSTEMI) or even STEMI superimposed on the benign pattern. The ability of clinicians to distinguish between ischemic and non ischemic STE varies widely and is affected by prevalence of such changes in patient population. More studies need to be done to delineate the criteria to clearly distinguish between ischemic and non ischemic ST elevation. The electrocardiogram (ECG) plays an important part in appropriate management of patients presenting with chest pain. Patients diagnosed with acute STEMI are triaged to receive urgent reperfusion therapy with either primary percutaneous coronary intervention (pPCI) or thrombolytic therapy and those judged not to have ST elevation receive conservative treatment early on . The AmeReperfusion decisions should be made within 10 minutes of initial ECG in patients presenting with suspected STEMI according to ACC/AHA STEMI guidelines . TherefoThe ST segment is at the same horizontal level as that of adjacent T- P or P- R segments or iso-electric in the majority of individuals  and deviNormally, the ST segment is iso-electric with the TR and TP segments and reflects ventricular depolarization. It is a classic teaching that STE with upwardly convex or straight is consistent with STEMI and STE which is concave is morphology is consistent with NISTE. The ACC/AHA guidelines also mention that STEMI is less likely if associated ST elevations are concave versus convex . DifficuEarly repolarization usually manifests as STE of 0.1- 0.4 mV in the lateral leads (mainly V5- V6), accompanied with a characteristic notch at J point . InvolveProminent J point notching- also known as Osborne waves may be seen transiently in hypothermia , and shoLeads V1- V3 most commonly demonstrate the normal variant pattern  Figure . It is oIt is observed most commonly in leads V1 – V3  . Common Diffuse STE with reciprocal ST depressions in leads AVR and V1 are hallmark features of stage 1 pericarditis . DiffuseLBBB is associated with secondary ST- T wave abnormality which leads to deviation of ST segment in the opposite direction to major QRS deflection . It is iSecondary repolarization changes, as seen with LBBB, may also be seen with non specific IVCD . CompariThe Brugada syndrome associated NISTE manifests as RBBB-like pattern and STE in anterior leads  Antzele. There iTakotsubo’s syndrome is a form of reversible myocardial dysfunction which is preceded by intense physical or emotional stress and is more commonly seen in post menopausal women. Presenting features may include chest pain or dyspnea and ECG shows STE in precordial leads in up to 80% of patients  along wiThe ACC/AHA STEMI guidelines recommend urgent reperfusion therapy in patients presenting within 12 hours of symptoms suggestive of myocardial ischemia and STE in ≥ 2 adjacent precordial leads (> 0.1 mV at J point) . No menthttp://hqmeded-ecg.blogspot.com/2008/11/65-yo-male-with-recent-rule-out.html). The magnitude of STE may change over time and is highly dependent on the heart rate, increasing with tachycardia and decreasing with slow heart rate . These dynamic changes should be differentiated from evolving changes of STEMI. The ACC/AHA guidelines  recommenIn clinical practice, many cases of true STEMI are easily identified. In those patients where differentiation is difficult, combining clinical presentation with interpretation of ECG by a skilled electrocardiographer who has access to previous tracings and occasionally, repeating ECG can increase the yield of interpretation.


The purpose of this retrospective study is to examine the incidence and imaging appearance of pelvic malignancies in a symptomatic patient population being screened for MRgFUS treatment.373 women with symptomatic uterine fibroids were screened with MRI exams with and without contrast utilizing T2 coronal and axial, T2 fat suppressed sagittal, T1 axial precontrast images, and post contrast fat saturated images in 3 planes. Uterine masses were classified by their intensity on T2 weighted images relative to normal myometrium . The enhancement pattern was also categorized as homogenous or inhomogeneous. Any extra-uterine masses were also noted as well as any other incidental pelvic findings.Results: Of the 373 patients (ages 26-61) that underwent pelvic screening for MRgFUS treatment, 19 presented with findings suspicious for cancer and after further evaluation, 7 of these patients (1.9 %) were confirmed to have a pelvic malignancy. 5 patients had a uterine sarcoma, 1 had endometrial carcinoma and 1 had ovarian carcinoma. Three out of the five sarcomas appeared markedly heterogeneous on T2 weighted images with ill-defined dark areas and bright fluid components and demonstrated heterogeneous, poorly defined areas of enhancement throughout. The remaining 2 sarcomas appeared more fluid in nature with eccentric, enhancing soft tissue components and multiple septations.vs. minimally invasive procedures). It is equally important to avoid delayed diagnosis and unintended treatment of malignant diseases with non-excisional approaches at this time. MRI pelvis exams may also help direct patients with more typical benign uterine fibroids to both non-invasive treatments (MRgFUS or uterine artery embolization (UAE)) or surgery . The more liberal use of MRI pelvis exams to screen and characterize pelvic pathology in symptomatic women can help avoid recent deleterious outcomes with morcellation procedures of unsuspected malignancies. With increasing familiarity with the MR appearance of uterine pathology and attentive evaluation of screening studies, early diagnosis of pelvic malignancy may be achieved.The endometrial carcinoma appeared as an intra-cavitary mass with ill-defined margins with a blood clot in the endometrium. This finding is highly unusual, as a large endometrial clot is not typically seen in cases where irregular bleeding was noted for fibroids. The ovarian carcinoma appeared as an extra-uterine mass with metastatic spread to the pelvic lymph nodes. Malignancy was considered in the remaining 12 patients due to the MRI imaging characteristics listed in Table


In Table 2 of the manuscript originally published online, the waist-difference values for women were incorrect. They have been corrected here.


Nonlabens ulvanivorans, which was recently isolated. To our knowledge, this is the first published genome of a characterized ulvan-degrading bacterium. Revealing the ulvan utilization pathways may provide access to a vast marine biomass source that has yet to be exploited.Here we report the draft genome sequence of the bacterium  Ulvales (Chlorophyta) are worldwide-distributed green seaweeds   paired-end sequencing. Four samples were loaded into one lane to receive 58 million passed filter reads for each sample. Data were analyzed using the de-novo assemblers AbySS (Flavobacteriaceae (between 1 and 6 copies) (rs AbySS  and Velvrs AbySS . The finUlva degradation and Ulvales cell wall polysaccharide utilization. Furthermore, it may allow for better characterization and even modification of these untapped polysaccharides in the near future.The first draft genome sequence of an ulvan-degrading bacterium provides a major step toward the unveiling of other enzymes that participate in JPJI00000000. The version described in this paper is version JPJI01000000This whole-genome shotgun project has been deposited at DDBJ/EMBL/GenBank under the accession number


A focused bedside ultrasound over the patient’s region of maximal discomfort revealed a thickened bowel wall and several small contiguous hypoechoic projections surrounding a hyperechoic center, suggestive of diverticulitis (A 72-year-old otherwise healthy female presented to the emergency department with two weeks of worsening abdominal pain. She was afebrile with normal vital signs. Her physical examination was notable for moderate abdominal tenderness without rebound to the left and suprapubic regions of the abdomen. Laboratory studies were remarkable for a white blood cell count of 13,000/mmiculitis . She wasiculitis .Acute diverticulitis resulting from inflammation of colonic diverticulum affects over half the population greater 65 years of age.5Particularly in cases of suspected uncomplicated diverticulitis, abdominal ultrasound may reach the diagnostic reliability of CT.2


To build a detailed circuit diagram in the brain, one needs to measure functional synaptic connections between specific types of neurons. A high-resolution circuit diagram should provide detailed information at subcellular levels such as soma, distal and basal dendrites. However, a limitation lies in the difficulty of studying long-range connections between brain areas separated by millimeters. Brain slice preparations have been widely used to help understand circuit wiring within specific brain regions. The challenge exists because long-range connections are likely to be cut in a brain slice. The optogenetic approach overcomes these limitations, as channelrhodopsin 2 (ChR2) is efficiently transported to axon terminals that can be stimulated in brain slices. Here, we developed a novel fiber optic based simple method of optogenetic stimulation: the laserspritzer approach. This method facilitates the study of both long-range and local circuits within brain slice preparations. This is a convenient and low cost approach that can be easily integrated with a slice electrophysiology setup, and repeatedly used upon initial validation. Our data with direct ChR2 mediated-current recordings demonstrates that the spatial resolution of the laserspritzer is correlated with the size of the laserspritzer, and the resolution lies within the 30 µm range for the 5 micrometer laserspritzer. Using olfactory cortical slices, we demonstrated that the laserspritzer approach can be applied to selectively activate monosynaptic perisomatic GABAergic basket synapses, or long-range intracortical glutamatergic inputs formed on different subcellular domains within the same cell . We discuss significant advantages of the laserspritzer approach over the widely used collimated LED whole-field illumination method in brain slice electrophysiological research. The modular design of molecular optogenetic components enables bidirectional and cell-specific control of neuronal excitabilities in vivoin vivoin vitroOptogenetic approaches have become the method of choice to manipulate neuronal excitability Brain slice preparations have been used extensively to help understand circuit wiring within specific brain regions. To build a detailed circuit diagram, one needs to measure functional synaptic connections between specific types of neurons. A high-resolution circuit diagram should provide detailed information at the subcellular levels . During the past few decades, electrophysiological recordings from connected cortical neurons in brain slices have demonstrated many intra- and inter- laminar connections between specific neuronal subtypes 1) subcellular resolution such that synaptic currents formed on specific cellular compartments can be selectively interrogated [e.g. sCRACM method, 2) a high degree of cell or synaptic specificity; and 3) ease of use with existing electrophysiology setups. So far, the two photon ChR2 activation approach retains the best spatial resolutions (<10 µm). However, this approach requires genetically modified opsin tools and an expensive two photon setup http://www.ephus.org)For brain slice neural circuit interrogations, ideal optogenetic tools should have the following features To combat these limitations, a simple and low-cost novel approach is described below. This is a straight forward fiber optic based local light delivery method that we named laserspritzer; analogous to the picospritzer used by many electrophysiology labs for locally delivering drugs within a small area. We provide experimental data to demonstrate its spatial properties and its application in circuit investigations using olfactory cortical slices. We also discuss the advantages of the laserspritzer over the widely used collimated LED whole-field illumination method.The laserspritzer was made from a multi-mode fiber optic patch cable  with appropriate mating ends (e.g. SMA) to the light source . Step 1. We trimmed and stripped the fiber optic patch cable to expose the cladding and core (250 µm) by about 2–4 cm 1. Step 22 laser power) was collected for further experimentation. Prior to electrophysiology experimentation, we recommend that laser scattering properties be measured in testing brain slices. 2, at physiologically relevant laser intensities , laserspritzers with different tip sizes were used e.g. 1 v. B2. ensities 3. An advThe spatial resolution of the laserspritzer was examined by making whole-cell recordings from ChR2-expressing cells in brain slices from VGAT-ChR2 mice A potential shortfall associated with the laserspritzer is that it does not specifically limit the light scattering within the tissue unlike the two photon stimulation method. We typically minimize light scattering with the laserspritzer by decreasing its tip size 3 and utiOptogenetic methods have been widely used to evoke synaptic releases. Expression of ChR2 within specific presynaptic neurons are achieved by means of virus delivery We sought to compare GABAergic inhibitory synaptic currents induced by the laserspritzer to collimated LED whole-field illuminations. Mice used in this study were vesicular γ-aminobutyric acid transporter-channelrhodopsin2 (H134R)-enhanced yellow fluorescence protein mice . In this line of mice, the ChR2-YFP fusion protein was selectively expressed under the control of a VGAT promoter A potential issue with collimated LED whole-field illumination is that all monosynaptic inputs formed on different cellular compartments are stimulated simultaneously. Thus, the recorded evoked whole-cell ChR2-EPSCs result from the temporal and spatial summation of multiple EPSCs arriving at different subcellular domains (dendrites and soma). This problem is more prominent in cells with large dendritic arbors, such as neocortical pyramidal neurons. To test that our laserspritzer approach can help overcome this issue, we studied long-range intracortical projections formed on different dendritic sites. We chose the olfactory cortex slice because intracortical glutamatergic inputs are formed on specific subcellular domains on distal dendrites in layer IB As shown in Assuming the distribution of synapses is uniform along all distal dendritic arbors in the aPc (which appears to be true, e.g. in vitro.Described here is a fiber optic based simple method of optogenetic stimulation: the laserspritzer approach. This is a convenient and low cost approach that can achieve high spatial resolutions of stimulation and can be easily implemented with an existing slice electrophysiology setup and repeatedly used upon initial validation. Our data, composed of direct ChR2 mediated-current recordings, demonstrates that spatial resolutions created by the laserspritzer lie in the 30 µm range. Using olfactory cortical slices, our data demonstrates that the laserspritzer approach conveys significant advantages over the widely used collimated LED illuminations for both spatial resolutions, and also reduces ChR2 desensitization in brain slices. We provide examples to apply this approach in studying monosynaptic perisomatic GABAergic basket synapses or long-range intracortical glutamatergic inputs formed on different dendritic and somatic domains within the olfactory cortical slices


Chemotherapy-induced liver injury is a well-known phenomenon after neoadjuvant therapy of liver metastasis and contributes to postoperative morbidity and mortality. Still there is no suitable test available to reliably determine functional impairment and hepatic regeneration after chemotherapy.We report two cases of caucasian patients who underwent repeated liver function assessments using LiMAx (maximum liver function capacity), Indocyanine plasma disappearance rate and biochemical liver function parameters in the course of adjuvant oxaliplatin-based chemotherapy.Both patients yielded a decrease from their initial liver function determined by LiMAx. Liver regeneration assessed functional recovery within 4 weeks in case of mild functional impairment after cessation of chemotherapy or within 8 weeks in case of major functional deterioration. Indocyanine plasma disappearance rate and biochemical parameters remained stable or without a clear trend in case of minor functional impairment. This is the first report using a dynamic liver function test to evaluate the impact and recovery from chemotherapy associated liver injury.The LiMAx test might be a sensitive tool to diagnose mild functional impairment after chemotherapy when standard liver function tests have remained within normal ranges and might be capable to assess the course of regeneration after chemotherapy. This could be useful to optimize individual chemotherapy-free interval before liver surgery can be carried out safely. Chemotherapy-induced liver injury (CALI) after receiving potent chemotherapy is a considerable problem in patients undergoing partial liver resection since increased perioperative mortality and morbidity have been reported -3. HowevWhereas previous studies were based on the clinical course and histology of resected liver parenchyma after surgery, less is known about the impact on actual liver function and the course of regeneration after cessation of chemotherapy ,10.Clinical biochemistry usually fail to diagnose reduced liver function after neoadjuvant therapy as standard parameters remain within normal ranges . The freConcerning the chemotherapy-free interval from cessation of chemotherapy to a safe partial liver resection only statistical figures are known in the literature and suggest an interval of six to eight weeks . There iHere we report two cases of patients that both received adjuvant oxaliplatin-based chemotherapy as a consequence of colorectal surgery due to adenocarcinoma. All patients underwent assessment of liver function using common biochemical liver tests, ICG-PDR and LiMAx (maximum liver function capacity) test before, directly after withdrawal as well as 4 and 8 weeks after cessation of chemotherapy. Both patients did not have additional regular drug intake during the study period and did not suffer from any marked comorbidities known to impair liver function.13C-labeled methacetin bolus injection and continuous measurement of 13CO2/12CO2 concentration ratio using a special device  as previously described by Stockmann and colleagues [LiMAx (maximum liver function capacity) reflects the actual enzymatic liver function capacity. The test is based on a bodyweight-adjusted intravenous lleagues . The LiMlleagues -21. LiMAIndocyanine green plasma disappearance rate (ICG-PDR) evaluates hepatic clearance and is suggested to provide additional information on liver function. The test is based on bodyweight-adjusted intravenous injection of ICG followed by pulse spectrophotometry to assess hepatic excretion via a special device . ICG-PDR is considered to be normal over 18%/min ,23.Case 1 reports a 56-year-old male caucasian patient that received 8 cycles of XELOX chemotherapy substituting 5-FU for the oral drug Xeloda. The patient started XELOX chemotherapy with a LiMAx value of 463 μg/kg/h and showed a decrease of functional liver capacity by 56% to 204 μg/kg/h after withdrawal of chemotherapy. ICG-PDR also declined from physiological 19.3%/min prior to chemotherapy to 16.6%/min , however ICG-PDR results in case 2 are inconclusive. This might be explained by general limitations of this testing procedure. ICG-PDR is strongly dependent on blood flow to the liver and the absence of cholestasis -26. Sincet al. .Both LiMAx and ICG-PDR have shown superior prognostic relevance for perioperative mortality and morbidity in patients undergoing partial liver resection compared to standard liver function tests ,20,28,29Certainly we present cases in patients without liver metastases and without indication for liver surgery. However our workgroup has already shown that the sole presence of liver metastasis which is usually advanced in patients that undergo neoadjuvant treatment can also impair liver function making it impossible to discriminate between reduction of liver function by chemotherapy or multiple metastasis in a proof of principle report .This is the first report using a dynamic liver function test in a controlled prospective setting to assess chemotherapy induced liver injury. It suggests an impairment of liver function, which might not be recognised by standard liver function tests and a defined course of regeneration after chemotherapy measurable with dynamic liver function tests. This might help to optimize the chemotherapy-free interval prior to liver surgery and therefore needs to be addressed in a larger cohort.Written informed consent was obtained from both patients for publication of this Case Report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.


A concise synthetic route leading to highly functional erythrina alkaloid skeletons has been developed. The key process is an oxidative carbon-carbon coupling followed by a conjugated addition. Based on this new strategy, a formal synthesis of demethoxyerythratidinone was completed in only 6 steps from 4-aminophenol.


Monoclonal antibody based vaccines are effective and highly specific in disease targeting. Presently, most of the existing broadly neutralizing antibodies are generated against non subtype c viruses. HIV-1 subtype c accounts for more than 90% of infection in India. The disease progression in children is faster than adults.Nine ART drug naïve HIV-1 subtype c infected children were recruited. PBMCs were isolated from all the subjects and pooled. RNA was isolated and cDNA was synthesized followed by amplification of VH and VL chain genes and scFv construction. A human recombinant scFv phage display library of 108 clones was constructed. Diversity of the phage library was checked by DNA sequencing and biopanned with RSC3 core antigen. 60 random clones were screened by phage ELISA. Expression of the scFvs was assessed by SDS-PAGE and Western blotting.The diversity of the phage library was more than 90%. Eight scFv monoclonals showed positive binding in phage ELISA and two best binders were further characterized. Both scFvs didn’t show any reactivity with unrelated antigens. DNA fingerprinting analysis showed both scFvs were distinct. A 32kDa band was obtained in SDS-PAGE and Western blot. Both scFvs showed cross neutralizing activity against a standard panel of pseudoviruses.Here, we have for the first time generated a human recombinant scFv phage display library containing neutralizing clones from HIV-1 infected children. Further characterization of these scFvs generated against CD4 binding site for their epitope mapping would be helpful in the development of an effective HIV-1 vaccine.


Plants maximize their chances to survive adversities by reprogramming their development according to environmental conditions. Adaptive variations in the timing to flowering reflect the need for plants to set seeds under the most favorable conditions. A complex network of genetic pathways allows plants to detect and integrate external  and/or internal  information to initiate the floral transition. Furthermore different types of environmental stresses play an important role in the floral transition. The emerging picture is that stress conditions often affect flowering through modulation of the photoperiodic pathway. In this review we will discuss different modes of cross talk between stress signaling and photoperiodic flowering, highlighting the central role of the florigen genes in this process. Arabidopsis ecotypes, the transition to flowering is strongly promoted by variations in day length (photoperiod). The photoperiodic pathway promotes flowering when Arabidopsis plants are exposed to long days (LDs) conditions . Photoperiodic flowering is the result of complex interactions between the circadian clock (an endogenous timekeeping mechanism) and external cues, which ultimately results in the activation of a set of floral genes.-CO expression is regulated transcriptionally by the circadian clock through the GIGANTEA (GI)-FLAVIN-BINDING, KELCH REPEAT, F-BOX (FKF1) complex.,FLOWERING LOCUS T (FT) and TWIN SISTER OF FT (TSF) in the phloem companion cells.--SUPPRESSOR OF OVEREXPRESSION OF CONSTANS 1 (SOC1), APETALA1, and FRUITFUL, responsible for triggering the floral transition.,After the floral transition the shoot apical meristem (SAM) changes its identity switching from vegetative to reproductive. In annual Arabidopsis, a facultative LD plant and Rice (Oryza sativa), a facultative short day (SD) plant.Solanum lycopersicum).Florigen gene expression has been demonstrated to play a pivotal role in photoperiodic flowering in different plants including Arabidopsis. However, it is now apparent that the FT promoter conveys several environmental information, in some cases independent of day length. Many plant species are induced to flower following drought stress which results in a drought escape response - DE -.-Arabidopsis DE occurs under LDs but not SDs, thus revealing a strong interdependence of certain drought responses on photoperiod. Genetic screens showed that photoperiod-stimulated GI activity is necessary and sufficient to trigger a drought dependent activation of the florigen genes FT and TSF.LDs promote flowering via activation of the florigen genes in aba1 mutants are impaired in ABA biosynthesis and display reduced accumulations of FT and TSF transcripts, especially under drought conditions. In addition to FT and TSF another FT-like genes MOTHER OF FT AND TFL1 (MFT) all appear to be positively regulated by ABA.,The phytohormone ABA plays a pivotal role in mediating several drought adaptive mechanisms although its precise role in flowering is still poorly understood.Shorea beccariana.SbFT transcript accumulations early in bud development, preceding flower morphological changes. Shorea beccariana grows at the equator where day length and temperature are constant throughout the year. It is thus plausible that drought spells could represent a major external cue to trigger mass flowering in this species via direct activation of FT independent of photoperiod. Photoperiod-independent modes of activation of FT exist also in Arabidopsis where an increase in ambient temperature is reflected in augmented FT transcript accumulation.FT expression largely independent of CO.Some plants use drought stress as a primary cue to flowering. Recent studies suggest that drought stress is involved in the upregulation of the florigen genes in the tropical tree FT activation is unknown. Drought stress results in an increase in FT expression with no evident effect on the physiological circadian oscillation of FT.,FT transcript accumulation depends on variations in CO protein, drought might directly affect CO expression. FLOWERING BHLH 1 (FBH1), a CO positive activator, is phosphorylated in vivo following ABA signaling activation.,CO transcription under drought conditions. Also, EID1-like protein 3 (EDL3), a positive regulator of ABA signaling is an activator of CO. EDL3 transcript is upregulated following ABA applications.CO transcript accumulations we could find only minor variations in CO transcript in wild-type or aba1 mutant plants subjected to drought stress  domain involved in the recruitment of the CO protein to the promoter of FT.,abi3 mutants display high levels of TSF, suggesting a repressive role for ABI3 on TSF expression.MFT is downregulated by ABI3.Drought (via ABA) could affect CO protein activity or stability. For example, besides the well-established role in seed germination the ABA signaling protein ABA INSENSITIVE 3 (ABI3) is involved in the control of flowering time. FT, FT upregulation may occur independently of either CO or GI. For example, warm temperatures results in an acceleration of flowering in the absence of GI and CO activities.co but not gi mutants, although it is unknown whether drought can stimulate FT upregulation in the absence of CO activity.FT activation have been described.,-FT promoter. Other pathways could facilitate the responsiveness of FT to photoperiod-stimulated GI. For example, similarly to gi, cry2 mutants have a defective DE response, despite constitutively accumulating increased ABA levels compared with wild type.,FT.Despite the GI-CO module being responsible for most of the activation of Arabidopsis has 3 florigen genes, of which 2 (FT and TSF) act redundantly to mediate photoperiodic flowering.,,FT and TSF transcripts are found in a non-overlapping pattern of expression.TSF expression (but not FT) can be activated under SDs following exogenous applications of a synthetic Cytokinin (CK).TSF. Because of this reduced dependence on photoperiod, TSF upregulation might also occur in the absence of CO  under drought conditions and contribute to the DE response observed in co mutants. In conclusion, more work is needed to clarify the mode of FT and FT-like genes activations under drought conditions and their specific interdependence with the photoperiodic pathway machinery.FT expression even under inductive photoperiodic conditions. It has been shown that cold temperatures induce the degradation of CO protein via an ubiquitin/proteasome pathway that involves the E3 ubiquitin ligase HIGH EXPRESSION OF OSMOTICALLY RESPONSIVE GENE 1 (HOS1).Not all abiotic stresses are interpreted as an escape signal. For example, cold stress delays flowering and alters the diurnal oscillation of Arabidopsis by interfering with the photoperiodic pathway. Interestingly salt affects FT at 2 different levels, transcriptional and post-transcriptional. Salt stress promotes GI protein degradation through an unknown ubiquitin/proteasome pathway.CO and FT transcripts accumulation. Salt stress delays flowering by activating the floral repressor BROTHER OF FT (BFT), a florigen-like protein with opposite function to FT.BFT is strongly responsive to drought stress and ABA.BFT can be transcriptionally activated under drought conditions in an ABA dependent manner and this regulation is dependent on GI  clearly prevails over BFT. One could hypothesize that the balance between florigen and anti-florigen proteins is necessary to generate an optimal duration of reproductive development according to environmental stress. In this sense BFT may buffer FT action and prevent a premature interruption of inflorescence development. Deciphering the regulatory logic of the different florigen genes is thus an important goal to gain insights into the different flowering adaptations to stress as well as the mechanisms that govern crop seed yield under adverse conditions.A different osmotic stress, salinity, delays flowering in nt on GI . Thus, Bgi mutants display different phenotypes including an increased salt tolerance.,-A question arise as to how plants might coordinate flowering networks with tolerance responses, which allow individual cells to survive under stress conditions. GI is emerging as a key node connecting different abiotic responses with flowering time. Arabidopsis the escape strategy requires a positive integration between photoperiodic and drought-dependent signals. A floral delay strategy takes place upon conditions where growth restraint provides an adaptive advantage over an escape, namely on salt.In conclusion, plant adaptation to stress is complex and involves different strategies. In


The End-Cretaceous Impact Winter Killed Off Slow-Growing Plants The end-Cretaceous mass extinction caused the selective extinction of plant species with slow-growth strategies, consistent with an impact winter hypothesis. The Chicxulub bolide impact caused the end-Cretaceous mass extinction of plants, but the associated selectivity and ecological effects are poorly known. Using a unique set of North Dakota leaf fossil assemblages spanning 2.2 Myr across the event, we show among angiosperms a reduction of ecological strategies and selection for fast-growth strategies consistent with a hypothesized recovery from an impact winter. Leaf mass per area (carbon investment) decreased in both mean and variance, while vein density (carbon assimilation rate) increased in mean, consistent with a shift towards “fast” growth strategies. Plant extinction from the bolide impact resulted in a shift in functional trait space that likely had broad consequences for ecosystem functioning. Sixty-six million years ago the Chicxulub bolide impacted the Earth, marking the Cretaceous–Paleogene boundary (KPB). This event caused the planet's most recent mass extinction, but the selectivity and functional consequences of the extinction on terrestrial plants has been largely unknown. A key untested hypothesis has been that a subsequent impact winter would have selected against slow-growing evergreen species, a possible cause of the modern dominance of high-productivity deciduous angiosperm forests. We tested this hypothesis using fossil leaf assemblages across a 2-million-year interval spanning the KPB. We assess two key ecological strategy axes—carbon assimilation rate and carbon investment—using leaf minor vein density and leaf mass per area as proxies, respectively. We show that species that survive the KPB have fast-growth ecological strategies corresponding to high assimilation rates and low carbon investment. This finding is consistent with impact winter leading to the nonrandom loss of slow-growing evergreen species. Our study reveals a dramatic example of the effect of rapid catastrophic environmental change on biodiversity. The Cretaceous–Paleogene boundary (KPB) is marked by the Chicxulub bolide impact and mass extinction Here we test if the extinction event was selective for functional traits related to plant ecological strategies. We measure functional traits from fossil leaf assemblages spanning a 2.2 Myr interval across the KPB and assess four differing selection scenarios for functional traits: (i) directional selection—a shift in phenotype space, caused by novel postboundary environments replacing preboundary environments; (ii) stabilizing selection—a reduction in phenotype space caused by postboundary conditions making some strategies temporarily nonviable; (iii) diversifying selection—an increase in phenotype space due to a wider range of postboundary conditions; or (iv) a lack of selection, because previous adaptations were unrelated to survival after major catastrophe.We assess evidence for these selection scenarios using functional traits 2]) Alternatively, longer-term temperature change may also have selected for certain traits across the KPB. Multiple proxies show a brief warming during the latest Cretaceous, starting approximately 300,000 y before the boundary near the base of Chron 29r, followed by a rapid return to cooler temperatures approximately 50,000 y before the boundary, which were then maintained through the earliest Paleogene 2 leaf area (LA)], and leaf minor vein density . Variation in these traits reflects a tradeoff between the transport of water and carbon We evaluate the causes and consequences of ecological change across the KPB by producing records of two central leaf functional traits that reflect variation in ecological strategies: leaf mass per area , because lower carbon dioxide availability could select for higher hydraulic capacity to maintain productivity 2] 2] decrease across the KPB therefore could be a key driver to our findings of an observed shift in VD. One hypothetical driver of lower [CO2] could be enhanced chemical weathering, via late-Cretaceous Deccan volcanism 2] dynamics within the time interval of interest. More detailed assessments of atmospheric composition and temperature across the KPB would be needed before this prediction could be tested.The increase in VD from the late Cretaceous to the early Paleogene in our data parallels the increases in VD seen across angiosperm taxa in the early-mid Cretaceous and then again across the KPB 2]. Although selection against low hydraulic capacity in low [CO2] environments should occur for all plants, for nonangiosperms and shade species, low values of VD appear to have successfully persisted in the fossil record across the Cretaceous There is an important criticism of the proposed mechanism coupling between VD and [COObserved trait dynamics across the KPB likely ramify to influence ecosystem functioning. Because of the close linkage between leaf economic traits and ecosystem resource fluxes We analyzed fossils of nonaquatic nonmonocot angiosperm taxa from sites previously collected from the Hell Creek and Fort Union Formations, now located in southwestern North Dakota. The stratigraphy of these sites and the identification of specimens has been described previously During the summer of 2013, we examined all appropriate specimens at the Denver Museum of Nature and Science (DMNH) and Yale Peabody Museum (YPM). We digitally photographed specimens with (1) intact petioles at the point of insertion with the leaf blade and (2) LAs that could be directly measured or confidently reconstructed. For each image, leaves were separated from their rock matrix using the lasso tool in Adobe Photoshop; LA and petiole width (PW) were then measured using ImageJ following the protocol of During June 2012, we examined all appropriate specimens at DMNH, including holomorphotypes on loan from YPM . We selected specimens that appeared to have complete preservation of the minor venation network in at least one region of the fossil, discarding all others . In specimens containing more than one leaf, we made a measurement for each leaf. We captured a digital image of each leaf fossil centered on the region of interest using a dissecting microscope coupled to a digital camera . Illumination was provided by ring-light. Image resolution was 243 pixels per millimeter.−1) and intervein distance  are related as:We then estimated VD using a line-counting program Each specimen was originally assigned a facies type by the original collector (table 3 in n = 40).We calculated time series of VD and LMA using a binning approach. We first assigned each specimen to a 1-m depth interval defined by integer-rounding the measured stratigraphic depth. Within each bin we calculated species-at-site mean trait values, then used these to compute site means. We used these site-means to infer the distribution  of trait values within each bin. Because VD and LMA data were not always available within the same bin, we used piecewise linear interpolation to infer LMA values at each bin for which VD values were available  was obtained from a leaf margin analysis of the same fossil floras using the range-through mean annual temperature values corresponding to the supplementary table 8 of c using the error estimates provided in the original source, using the mean plus (minus) one standard deviation as the upper (lower) quartile. When no standard deviations were available, we assigned a standard deviation equivalent to the mean of all other standard deviations (2.8°C).An index of temperature Click here for additional data file.Figure S2LMA data, broken out by stratigraphy and facies. Symbols indicate species at-site means. Black points, data for each category; gray points, all other data.(PDF)Click here for additional data file.Figure S3LMA of species with different stratigraphic ranges and abundances. High LMA leaves are common in species that are found only in the Cretaceous but drop out at all abundances in species that cross the KPB or are found only in the Paleogene. Each point represents a species. Abundance data come from the quantitative census of Wilf and Johnson (PDF)Click here for additional data file.Figure S4Correlations between traits for time series data shown in (PDF)Click here for additional data file.Data S1VD data for all measured specimens.(CSV)Click here for additional data file.Data S2LMA data for all measured specimens.(CSV)Click here for additional data file.Data S3Temporally binned VD and LMA values, paired with proxy temperature values.(CSV)Click here for additional data file.


Anal. Biochem. 474 (2015) 69–79].This data article contains three benchmark datasets for training and testing iDNA-Methyl, a web-server predictor for identifying DNA methylation sites [Liu et al.  Specifications table1•DNA methylation plays an important role in regulating a variety of biological processes and is very important for basic research and drug development as well.•The datasets presented here are good for testing DNA methylation site identifying algorithms because of their realistic, highly unbalanced nature.•For the first dataset , users c2http://www.jci-bioinfo.cn/iDNA-Methyl, a web-server predictor for identifying DNA methylation sites. The DNA sample was formulated by combining its trinucleotide composition (TNC) and the pseudo amino acid components (PseAAC) of the sequence translated from the DNA sample according to its genetic codons. Sliding a window of nucleotides along each of the DNA sequences taken from MethDB (http://www.methdb.de/), and DNA sample was formulated by combining its trinucleotide composition (TNC) and the pseudo amino acid components (PseAAC) of the sequence translated from the DNA sample according to its genetic codons. In real world, the data very unbalanced. Target-jackknife was used to optimize the unbalanced benchmark dataset and minimize the consequence of this kind of mis-prediction.I.The first dataset  containsII.The 2nd dataset  is the oIII.The 3rd dataset  is the oThe data presented here are three benchmark datasets for training and testing iDNA-Methyl


Arterial stiffness is an independent predictor of cardiovascular mortality and can be assessed by CMR measurement of aortic distensibility (AD) and pulse wave velocity (PWV). We sought to determine AD and PWV in patients with severe symptomatic aortic stenosis and identify changes following TAVI compared to SAVR.Forty-eight patients underwent identical paired 1.5T CMR scans . Brachial artery blood pressure was recorded by Dinamap . Multi-phase steady state free precession (SSFP) cine imaging (50 phases) was acquired in a axial plane to the thoracic aorta at the level of the pulmonary artery bifurcation (Ascending aorta (AA) and proximal descending aorta (PDA)). AD (mmHg-1) was calculated following the contouring of the aortic region of interest, Figure 27 SAVR patients  and 21 TAVI patients  were studied before and 6 months following valve replacement. Arterial pulse pressure significantly increased following SAVR  but not after TAVI . AD significantly decreased post SAVR  whereas there was no change observed in the TAVI group . PWV significantly increased post-SAVR  whereas there was no change observed in the TAVI group .In patients with severe aortic stenosis, SAVR but not TAVI is associated with a significant increase in PWV and decrease in AD at 6 months. This increase in aortic stiffness may be a consequence of the different techniques of valve replacement and has potential long-term implications on cardiovascular mortality.This study was part-funded by the British Heart Foundation (BHF) (PG/11/126/29321). GP McCann and CD Steadman have received support from the NIHR Leicester Cardiovascular BRU.


Epidemiologic data indicates that Asian diets, which are high in soy protein, reduce a women’s risk of developing breast cancer. However, it has been difficult to dissociate the benefits of soy from other variables including environmental and lifestyle factors. Since prospective studies in humans would take decades to complete, rodent models provide a valuable research alternative.In this study, MTB-IGFIR transgenic mice, which develop mammary tumors resulting from overexpression of the type I insulin-like growth factor receptor (IGF-IR), were utilized. MTB-IGFIR mice were fed a soy-based or casein-based diet throughout all stages of development to reflect soy exposure in Asian cultures. Mammary tumors were initiated at 2 different developmental stages by commencing IGF-IR transgene expression either during puberty or in adult mice.Pgr and Areg, were elevated in mammary tissue from mice fed the soy diet compared to mice fed the casein diet suggesting that high levels of soy may promote mammary tumor development through acting as an estrogen receptor agonist. Mammary tumors from mice fed a soy diet more frequently expressed metaplastic markers such as cytokeratins 5 and 14 as well as p63 and displayed reduced lung metastases compared to mammary tumors from mice fed a casein diet.MTB-IGFIR mice fed a soy-based diet displayed increased tumor incidence and accelerated tumor onset compared to MTB-IGFIR mice fed a casein diet. Two markers of estrogen receptor signaling, Diets consisting of very high levels of soy protein promote mammary tumor development and decrease tumor latency possibly through activating estrogen receptor signaling. Additional studies are required to determine whether a more moderate amount of dietary soy can inhibit oncogene-induced mammary tumorigenesis.The online version of this article (doi:10.1186/s12885-015-1037-z) contains supplementary material, which is available to authorized users. Breast cancer rates vary depending on geographical location with the incidence of breast cancer being relatively high in North America and Western Europe compared to Asian countries such as Japan and China . One facSoy has been shown to contain several putative chemopreventative agents including isoflavones . IsoflavThe protective effects of soy have been demonstrated in case–control and cohort studies in Asian populations in that soy consumption was inversely associated with breast cancer risk -13. ReduSince it is difficult to design studies to assess the causal association between dietary soy and mammary tumor risk as well as the mechanism through which soy modifies mammary tumorigenesis in humans, animal models have also been employed. Most of the animal studies performed to date have explored the impact of soy or specific isoflavones on chemically induced mammary tumors in rodents. Using these models, it has been shown that soy or specific isoflavones inhibit mammary tumor development induced by chemicals such as 7,12-dimethylbenz(a)anthracene (DMBA) and nitrosomethylurea (NMU) -22. It sMore recently, transgenic mice have been used to determine whether dietary soy protects against mammary tumor development. MMTV-Wnt1 mice fed a soy diet after weaning exhibited reduced mammary tumor incidence but significantly shorter tumor latency compared to mice fed a casein diet . In a stThe animal studies performed to date do suffer from some limitations. First, diets high in soy or isoflavones are often initiated during postnatal development while Asian populations presumably consume high levels of soy throughout their lives and thus Asian women are exposed to soy isoflavones during embryonic and postnatal development. Data from human studies suggest that although soy intake at any age decreases breast cancer risk, the greatest decrease in risk was associated with high dietary soy intake during childhood ,29-31. AOur study was designed to minimize the limitations of other animal models. To accomplish this, soy or casein diets were administered to female mice prior to mating and the females were maintained on the same soy or casein diet during lactation. Upon weaning the offspring were also maintained on the soy or casein diet to ensure female MTB-IGFIR transgenic mice were exposed to the soy or casein diet throughout all stages of development. Since it remains unclear when breast cancer initiation occurs, the IGF-IR transgene was induced at two different developmental stages, during puberty and in young, post-pubertal mice. Induction of the IGF-IR transgene at these two stages would simulate a spontaneous genetic alteration acquired in pubertal or young adult women.Pgr and Areg were expressed at higher levels in mammary glands of soy-fed mice suggesting a stimulatory effect of soy on estrogen receptor signaling.Using this experimental design, mice fed a soy-based diet had a significant increase in tumor incidence and shorter tumor latency than mice fed a casein-based diet. Mammary tumors from mice fed a soy diet more frequently expressed markers associated with metaplastic breast cancer including cytokeratin 5, cytokeratin 14, p63 and the presence of osseous matrix. The soy diet appeared to have a protective effect against tumor progression as lung metastases were more frequent in casein-fed mice. Although it is unclear how dietary soy promotes mammary tumorigenesis, two estrogen regulated genes, Animals were housed and cared for following guidelines established by the Central Animal Facility at the University of Guelph and the guidelines established by the Canadian Council of Animal Care. This study was approved by the Animal Care Committee at the University of Guelph (AUP# 1695) and all efforts were made to minimize suffering.MTB-IGFIR transgenic mice were generated in our lab and have been previously described . At the volume = length x width2/2. Tumor specific growth rate (SGR) was estimated using the formula: SGR = ln(V2/V1)/(t2-t1)  found at datam.i2r.a-star.edu.sg/ergdbV2/). Areg is a member of the epidermal growth factor family (EGFR) and is expressed at higher levels than any other EGF family member in the pubertal mammary gland [Areg expression in mammary glands and thus provides a potential mechanism through which dietary soy can influence mammary epithelial proliferation and potentially transformation.The mechanism through which soy isoflavones regulate mammary tumorigenesis remains unclear but most likely involves signaling through ERs. Estrogen is one of the main regulators of mammary epithelial proliferation -54 and sry gland . The AREry gland ,58. Our Fgf10, Fgfr1, Fgfr2, and Tgfα [A number of other genes implicated in mammary gland development were evaluated in the mammary tissue of mice fed soy and casein diets including and Tgfα -61. NoneOne potential protective effect of soy observed in our study was a 3-fold reduction in the percentage of soy-fed mice with metastatic lesions compared to the casein-fed mice when the IGF-IR transgene was induced at 100 days of age. The difference in metastatic incidence however, was not significant due to the small number of casein-fed mice that developed mammary tumors. A decrease in the percentage of soy-fed mice with lung mestatases is consistent with most of the studies in the literature that demonstrate that soy or isoflavones inhibit mammary tumor migration and metastasis -66, howeThe consumption of high levels of dietary soy also appears to impact mammary tumor morphology. Mammary tumors from soy-fed mice more frequently contained a mixture of luminal and basal/mesenchymal cells than mammary tumors from casein fed mice. Tumors expressing luminal and basal cell types have been described in humans and classified as metaplastic breast cancers. This is a rare subtype of breast cancer representing 0.2-5% of all breast cancers and was the focus of a recent commentary in Nature Reviews Cancer . MetaplaAreg. Future studies should examine the impact of different levels of dietary soy on mammary tumor development and whether soy regulates Areg expression. Determining whether lower levels of dietary soy can inhibit mammary tumorigenesis and whether Areg expression has potential as a biomarker for predicting breast cancer risk may have important implications for prevention and treatment of this disease.In conclusion, our study indicates that extremely high levels of dietary soy can promote mammary tumor development induced by overexpression of the tyrosine kinase receptor, IGF-IR. This increased susceptibility to transformation in the soy-fed mice appears to be associated with increased expression of


Cancer cell transformation entails significant alterations in intracellular metabolic pathways one of which is the aerobic glycolysis phenotype . The oriin vitro and in vivo) of the parental and modified cancer cells was carried out.We used two human breast cancer cell lines (MDA-MB-231 & MDA-MB-453) in this study where we cultured these cell lines in the presence of mitochondrial complex I inhibitor (rotenone) inhibitor for 25 generations thereby creating metabolically adapted cell lines counterparts. Metabolic analysis (In vivo analysis of tumor xenografts revealed that metabolically modified MDA231 cells displayed a ~50% reduction in tumor growth/volume accompanied by a reduced in vivo proliferation rate in comparison with the parental MDA231 cells thereby confirming the physiological relevance of metabolic adaptation in preclinical animal models. In conclusion, long-term metabolic adaptation to mitochondrial complex I modulators can be a unique and novel strategy for achieving tumor control in vitro and in vivo.Analysis of metabolic status in the isogenic parental and metabolically modified adaptive breast cancer cells show an overall improvement in mitochondrial function and a reduction in metabolic switch phenotype.


Rice stripe virus (RSV) rice plants were examined by small RNA high-throughput sequencing. Our research confirms that the newly generated siRNAs, which are derived from the engineered inverted repeat construct, is the major contributor of the viral resistance in rice. Further analysis suggests the accuracy of siRNA biogenesis might be affected when siRNAs machinery is excessively used in the transgenic plants. In addition, the expression levels of many known miRNAs are dramatically changed due to RSV infection on both wild type and transgenic rice plants, indicating potential function of those miRNAs involved in plant-virus interacting process.RNA-mediated gene silencing has been demonstrated to serve as a defensive mechanism against viral pathogens by plants. It is known that specifically expressed endogenous siRNAs and miRNAs are involved in the self-defense process during viral infection. However, research has been rarely devoted to the endogenous siRNA and miRNA expression changes under viral infection if the resistance has already been genetically engineered in plants. Aiming to gain a deeper understanding of the RNA-mediated gene silencing defense process in plants, the expression profiles of siRNAs and miRNAs before and after viral infection in both wild type and transgenic anti- TheyCaenorhabditis elegans or Drosophila melanogaster with mutation affecting RNAi machinery have been reported to be more susceptible to viral infections [RNA-mediated gene silencing is known to serve as a self-defensive mechanism against viral pathogens by host cells. Individuals of fections , 12. Furfections –16. Thusfections , 18. Besfections , 20. Durfections –25. Somefections –28. Howefections , 30. Witfections .The usage of ihpRNA-based transgenic plants raises an interesting and important biological question: how does the plant natural defensive system react to virus infection when the viral resistance has been already transgenically introduced? Meanwhile, the fact that miRNAs and siRNAs could interact with each other adds another layer of complexity to this issue. Specifically, the altered expression levels of one might disrupt the existing miRNA-siRNA balance in cells and cause changes in the expression levels of the other by saturating the sRNA-induced silencing machinery since both miRNAs and siRNAs are utilizing an overlapped pathway in their biogenesis and metabolism processes –33.To further explore the underlying mechanisms of viral resistance in plants, our study offers a new perspective as the first study that compares changes of siRNAs and miRNAs expression profiles between wild type and transgenic viral resistant plants. Illumina small RNA deep sequencing is applied onto both wild type and ihpRNA transgenic rice plants before and after RSV infection. Those siRNAs derived from ihpRNA insertion, novel miRNAs and known miRNAs are identified and compared. Our analyses suggest the accuracy of siRNA biogenesis is reduced in transgenic plants. We also find many known miRNAs involved in the antiviral process and their putative gene targets are predicted. Lastly, we discuss the potential mutual impact and interaction between siRNAs and miRNAs for future research.Oryza sativa cv. Aichiasahi (AiA) as the background . To trigger viral defensive processes in plants, each experimental seedling was inoculated with approximately five planthoppers. The viruliferous and virus-free planthoppers (mock group) were introduced respectively into the plant growth chambers at the three-leaf stage of rice for virus inoculation. After 48 h, the planthoppers were removed, and the inoculated seedlings were maintained under 14-h/10-h light/dark cycle at 25°C greenhouse condition until the total RNA was isolated. The leaf materials for the total RNA extraction were obtained from one young leaf per treatment. The young leaves were collected one week after the virus-induced syndromes appeared  and the total RNAs were isolated subsequently.Our RSV resistant transgenic rice plants (T4B1) were engineered with the ihpRNA strategy using 5 of transgenic plants inoculated by virus-free and viruliferous insects respectively. Small RNA-Seq was conducted in Beijing Genomics Institute (BGI) by single-end sequencing. The four sRNA FASTQ files have been deposited in the NCBI Sequence Read Archive (study accession ID: SRP049382). The clean reads were obtained after trimming the sequencing adapters and filtering out the low quality reads. Clean reads ranging from 18–30 nucleotides in length  were used for downstream analyses. Small RNA reads were then mapped to the rice genome to study their genomic origins and small RNA annotation by using SOAP [Small RNA libraries were prepared with Illumina Small RNA library kit by following manufacturer’s protocol. Four libraries were obtained: AiA_VF and AiA_V represented wild type plants inoculated by virus-free insects and viruliferous insects respectively; similarly, T4B1_VF and T4B1_V represented the Ting SOAP  and custing SOAP . All clehttp://www.phytozome.net/) to determine the origin of siRNAs. Varied mismatch settings of mapping were used for biogenesis accruracy analysis.siRNA duplex sequences were identified by Tag2siRNA . After nhttp://sourceforge.net/projects/mireap). To annotate known miRNA reads, all the clean reads are aligned to the rice miRNA precursor database (downloaded from www.mirbase.org). To study the known miRNA expression profiling, annotated miRNA species sequences with at least 3 supported reads were selected. The expression level changes for miRNAs were analyzed using DESeq [The novel miRNA and known miRNA were identified by Mireap (BGI: ng DESeq .http://plantgrn.noble.org/psRNATarget/) was used to predict the putative targets for specific siRNA and miRNA [psRNATaget web server  that are described to be highly expressed (>1000 reads supported) in Du’s paper [Although RSV-derived siRNAs might be the vital reason for this viral resistance in our case, the contribution of miRNA for RSV resistance cannot be ignored. In order to examine the expression profile changes of known miRNAs and to study the possible connection between miRNA profiling with the viral resistance, DESeq was used to compare miRNA expression levels among four libraries , 41. Bei’s paper  presenteThe changes of known miRNA expression profiling were studied using DESeq from three aspects: the impact on expression profiling of known miRNA caused by the engineered ihpRNA construct was studied by comparing AiA_VF and T4B1_VF, the impact caused by viral infection in wild type plants was studied by comparing AiA_VF and AiA_V, and the impact caused by viral infection in transgenic plants was studied by comparing T4B1_VF and T4B1_V respectively. As described in To study the effect of novel miRNAs in transgenic rice plants, putative novel miRNAs see  were preTo study the impact of RSV-derived siRNAs in transgenic rice plants besides their original function of silencing RSV-CP genes, the top 50 highly expressed RSV-derived siRNAs from T4B1_VF were selected as input query sequences for psRNAtarget web server  to prediAs shown in Previous research claims the possible role miRNA plays in the process of self-defensive response to virus . RegardiArabidopsis [The crosstalk of siRNA and miRNA is also briefly examined in our study. Liang et al have reported that manually induced siRNAs can alter the expression level of many miRNA through competing Ago2 loading site . Limitedbidopsis . On the bidopsis . In our Collectively, our results provide the first research of the siRNA and known miRNA profiling changes in an ihpRNA engineered viral-resistant plant using high-throughput sequencing. The siRNA derived from ihpRNA construct is determined as an important contributor to the antivirual resistance in plants. The accuracy of siRNA biogenesis machinery might be influenced if excessively used, but the accuracy of miRNA biogenesis machinery seems not to be affected. In addition, our data analysis does not suggest any novel miRNAs involved in the process of RSV infection. We have also assessed the potential impact of differentially expressed miRNAs due to the insertion of ihpRNA construct or the RSV infection by predicting their targeting genes. In sum, this research will facilitate our understanding of the regulation and function of miRNAs and siRNAs in transgenic plants.S1 Fig(DOCX)Click here for additional data file.S1 Table(DOCX)Click here for additional data file.S2 Table(DOCX)Click here for additional data file.S3 Table(DOCX)Click here for additional data file.S4 TableNormal count represents the population of miRNA reads without SNP. SNP count presents the population of miRNA reads with SNP (mismatches) from their miRNA precursors. The ratio is calculated by dividing SNP count with normal count.(DOCX)Click here for additional data file.


A 15-year-old adolescent presented to us with mild headache, progressive dizziness and recent vomiting since 2 weeks without seizures. There was a history of head injury (neglected) following a stone-throwing incident 2 months earlier. On examination, he was conscious with a left cerebellar syndrome but without other neurologic deficit. Routine biologic data were normal. CT-scan revealed left posterior fossa extradural lesion with hypodensity in the center and calcified wall (A). MRI showed that the lesion was liquid with homogeneous ring enhancement following gadolinium injection and cerebellar compression (B and C). A sub-occipital craniotomy was done and a chronic liquefied hematoma was removed. There was a thick hard calcified wall relatively adherent to the duramater (D). Postoperative period was uneventful and the patient was discharged symptoms free. Histologically, the wall contains large areas of ossification. Ossified chronic epidural hematoma is a very rare complication following head injury. The blood accumulates slowly from a venous source becomes chronic extradural hematoma and becomes calcified or ossified due to an inflammatory reaction of the dura especially in children. This rare phenomenon should be considered in the differential diagnosis of other traumatic epidural and subdural hematomas.


Prone positioning is a therapeutic maneuver to improve arterial oxygenation in patients with acute lung injury that is not implemented in most centers performing adult cardiac surgery. The aim of this study was to review our experience with prone positioning, which has become increasingly used at our center over the last years.From 2010 to 2014, 127 adult patients with postoperative acute respiratory failure were treated with prone positioning in addition to supportive therapy. Preoperative and intensive care unit data obtained from medical records were retrospectively reviewed. Univariate and multivariate logistic regression analyses were performed to identify independent risk factors associated with in-hospital mortality.2/FiO2 ratio were significantly different between groups , but only pre-pronation FiO2 remained highly significant at multivariate analysis . Patients who died showed a higher improvement of the PaO2/FiO2 ratio immediately after pronation compared with survivors . Patients who died had higher pea k white blood cell counts than survivors  and a higher rate of low output syndrome prior to prone positioning . Both variables were found to be independent predictors of mortality at multivariate analysis .In-hospital mortality was 22.8% (n = 29). No complications related to the proning maneuver were recorded. No significant differences were observed in preoperative risk factors between patients who survived (group S) and those who died (group D), except for age  and EuroSCORE II . Age retained statistical significance at multivariate analysis . Pre-pronation values of the PaO2/FiO2 ratio.Prone positioning is a safe treatment option for adult patients with postoperative acute respiratory failure. Its efficacy seems to be closely related to two factors: the optimal timing of application of the procedure and a noncardiogenic etiology as the cause of low PaO


A subset of patients with cancer have evidence of a spontaneous anti-tumor immune response and T cell infiltration into tumor sites. This has prognostic significance and is associated with clinical response to immunotherapeutics in multiple cancers. It has been observed that high mutational load in a tumor also correlates with response to modern immunotherapies though definitive mechanistic data has yet to be shown. Molecular mechanisms underpinning the absence of a T cell response are beginning to be understood with identification specifically of the WNT/β-catenin pathway playing a major role in melanoma.in silico analysis of The Cancer Genome Atlas (TCGA), sorting gene expression profiling and DNA sequencing data across all tumor types included. For each tumor, RNAseq data was subjected to unsupervised clustering on ~15,000 genes expressed in at least 50% of the samples.To better understand the genetic landscape of T cell-inflamed human solid tumors and to investigate molecular pathways that may mediate immune-exclusion, we performed an We discovered 160 genes concordantly clustered with a previously identified 13 gene immune signature across all cancers. Subsequent consensus sample clustering using the concordant genes facilitated division of each tumor into either a high, medium or low T cell-inflamed status. Simultaneously, non-synonymous exonic somatic mutations were retrieved from DNA sequencing data allowing mutational load to be associated with the presence or absence of a T cell-inflamed phenotype in individual samples. Pathway analysis was performed to identify molecular signaling pathways showing activation in low versus high T cell-inflamed tumors.Overall the analysis identified the T cell-inflamed phenotype as being present in approximately 33% of all samples within TCGA with clear cell kidney cancer demonstrating the highest median score and uveal melanoma demonstrating the lowest score. While there was some trend between tumors known to have high mutational load and higher incidence of the T cell-inflamed tumor microenvironment, this correlation was imperfect, and within individual tumors there was no difference in mutational load between high T cell-inflamed tumors and low T cell-inflamed tumors. Pathways analysis again confirmed WNT/β-catenin pathway activation in non-T cell-inflamed melanomas as well as other non-T cell-inflamed cancers. Pathways of interest by individual tumor type are under further investigation.These data suggest that spontaneous anti-tumor immune priming is not driven by mutational load alone. Additionally, it appears likely that tumor-intrinsic molecular pathways will be identified in many tumor types which may suggest rational combination therapy approaches for the future.


Daam1), which is important for the morphogenesis of the eye and other organs. In this study, Patricia Ybot-González’s group sought to further explore the role of the Wnt-PCP pathway in diabetic embryopathies. They induced experimental diabetes in pregnant mice and found that maternal hyperglycaemia induced eye malformations in mouse embryos. In vitro studies confirmed sensibility of eye development to hyperglycaemia and showed reduced expression of Wnt-PCP pathway genes. Notably, Daam1-mutant embryos displayed similar eye malformations, which were worsened by environmental hyperglycaemia. These results show that maternal diabetes can affect embryogenesis by altering Wnt-PCP signalling. Modulating this pathway might thus represent a potential strategy to reduce the impact of diabetic embryopathies. 157Page Congenital malformations in diabetic pregnancy are still a major health concern despite the improvements in glycaemic control strategies. Advancing our understanding of the mechanisms responsible for diabetic embryopathies could help develop strategies to prevent this condition. It is known that maternal hyperglycaemia affects components of the Wnt-PCP signalling pathway, including the dishevelled-associated activator of morphogenesis 1 gene (


Our results clearly indicate that combining Bortezomib with adoptive T cell therapy can sustain T cell activation and function and, thus, enhances tumor immune surveillance. We are also elucidating a microRNA signature regulating immune Notch signaling. Our preliminary data suggest the role of miR-155 and miR-34a in Bortezomib induced regulation of T cell activation. The potential of Bortezomib to modulate anti-tumor Notch signaling and to enhance T cell activity presents exciting opportunities. Therapeutic restoration of immune Notch signaling by Bortezomib could help to break tumor resistance, enhance immune surveillance and sustain robust anti-tumor immunity.The immunosuppressive tumor microenvironment perturbs numerous immune regulatory networks and usurps host antitumor immunity. We discovered that tumor interferes with host hematopoietic Notch system in lung cancer patients. The resultant decrease in immune Notch signaling could be a major causative link in the adequate induction of antitumor immunity. Interestingly, we observed that administration of the FDA- approved proteasome inhibitor drug Bortezomib  to tumor bearing mice can restore Notch signaling in lymphoid cells without increasing tumor cell proliferation or clonogenicity. Moreover, Bortezomib administration altered Notch receptor and ligand expression pattern and increased the expression of Notch target genes Hes1, Hey1 and deltex1 in thymus, lymph node and spleen. Bortezomib administration in tumor bearing mice increased IFN-g production by T cells while the proportion of regulatory T cells was decreased. Our results indicate that the activation of Hes1 and Hey1 is mediated via inhibition of NFkB pathway while deltex1 activation is mediated by PI3K pathway. In another set of experiment, we observed that administration of Bortezomib along with adoptive CD8


Our previous work has demonstrated that Notch signalling modulates cilia length in the zebrafish left-right organizer (LRO) . Howeverdnah7.To link Notch signalling to the regulation of cilia motility genes that may be upstream of Gene expression of potential motility-mediator targets were validated by qPCR in deltaD mutants. Whole mount in situ hybridization was performed to assess dnah7 gene expression in zebrafish embryos at various stages of development. We used high-speed videomicroscopy to study olfactory pit and LRO cilia motility in dnah7 zebrafish morphants. The ultrastructure of static cilia was analysed from embryos injected with dnah7-MO.dnah7.Dnah7 is upregulated in deltaD mutants. Dnah7 is expressed in other organs with motile cilia, such as the olfactory pits, brain ventricles and pronephros. Down-regulation of dnah7 showed also to affect motility in olfactory pits and pronephros. We are validating microarray data by qPCR and will present a model on how Notch signalling may affect the expression of Dnah7 knock-down affects cilia motility in various ciliated organs during zebrafish development. We found specific target genes from the foxj1 and rfx families, which encode regulatory factors that may be involved in a Notch signalling transduction pathway linked to cilia motility.Supported by FCT-ANR/BEX-BID/0153/2012 grant.


We present a method based on minute-by-minute ICP monitoring and outcome (GOS) to visualize in a clinically useful way the dynamic aspects of secondary injury.A retrospective analysis of data from 165 adult patients from the Brain-IT database [Figure Secondary injury is dynamic such that not only thresholds but also insult duration are relevant. The proposed visualization goes beyond the static 20 mmHg ICP threshold introduced in [


Purpose. To report an unknown complication of laser in situ keratomileusis (LASIK) surgery. Case Presentation. A 28-year-old female presented with photophobia and glare to our eye service. She stated in her medical history that she had undergone femtosecond assisted LASIK surgery in both eyes 15 months ago and her symptoms started just after this surgery. On admission, her best-corrected visual acuity was 10/10 in both eyes. She had mydriatic pupils with no direct light reflex. Examination of the anterior segment revealed bilateral iris atrophy projecting within the LASIK ablation zone and a transillumination defect was remarkable on the slit lamp examination. Conclusion. We hypothesized that this condition may have been caused by the abnormally increased IOP that resulted in ischemia in the iris vascular plexus during the suction process of surgery. Refractive surgery has undergone significant progress and evolution during the past two decades with the advent of the excimer laser. Excimer laser refractive surgical options mainly include photorefractive keratectomy (PRK) and laser in situ keratomileusis (LASIK) . Since FA 28-year-old female presented with photophobia and glare to our eye service. She stated in her medical history that she had undergone femtosecond assisted LASIK surgery in both eyes 15 months ago and her symptoms started just after this surgery. Preoperative medical records of the patient revealed −4.75 (−1.00 × 175) in the right eye and −4.50 (−0.50 × 180) in the left eye and otherwise a normal ophthalmological examination. On admission, her best-corrected visual acuity was 10/10 in both eyes. She had mydriatic pupils with no direct light reflex. Visual fields were full to confrontation in both eyes. Examination of the anterior segment revealed bilateral iris atrophy projecting within the LASIK ablation zone  and a trSeveral flap-related or intraoperative complications of femtosecond assisted LASIK surgery are reported in the literature . HoweverAll these studies show the significant effects of LASIK surgery on intraocular pressure and ocular hemodynamics. In the literature optic neuropathy cases have been reported following LASIK surgery and it has been considered that this complication might be a result of barotrauma or ischemia related to extremely elevated intraocular pressure during a portion of the LASIK procedure –11. Ther


Echocardiography is currently the gold standard for cardiac tissue velocity measurement . Phase cEighteen healthy volunteers underwent cardiac MRI examination on a Signa HDxt 3T scanner . A phase contrast sequence modified to acquire only the central k-space line was used in a mid-ventricular small axis scan plane with through-plane velocity encoding during 128 heartbeats. The frequency encoding direction was angulated to encompass the projection of the left ventricular outflow tract plane . One subject was manually post processed due to failure of automatic detection and a total of 360 heart beats were also discarded. For eleven subjects, velocity curves similar to echocardiographic ones were obtained  as well as MPI were well correlated. This paves the way for the observation of beat to beat intra-subject variability of cardiac indices.None.


There is a suspected link between Brazilian babies born with microcephaly and Zika virus (ZIKV) infection. However, little is know about the brain cell targets and the mechanisms that Zika virus may cause microcephaly. A recent report demonstrated that Zika virus infection increases cell death and dysregulates cell-cycle, resulting in attenuated human neural progenitor cells growth. This study fills a major gap and serves as an entry point to establish a mechanistic link between Zika infection and microcephaly. The recent dramatic rise of infant microcephaly in Brazil has drawn globe attention . There hA recent study from Dr. Guo-li Ming and colleagues of Johns Hopkins School of Medicine has filled a major gap in ZIKV biology. This new research may serve as an entry point to establish a mechanistic link between ZIKV and microcephaly .By using a laboratory protocol of differentiating induced pluripotent stem cells (iPSCs) into forebrain-specific human neural progenitor cells (hNPCs) , Ming anZIKV infection was also found to lead to cell death by activating Cas3. The virus can dysregulate cell-cycle, resulting in attenuated hNPC growth. This is also consistent with the hypothesis that Zika infection may cause microcephaly.This new study provides a tractable experiment system for modeling the impact of ZIKV on neural development. The in vitro hNPC model provides a new tool for investigating the underlying cellular and molecular mechanisms. The robust hNPC cellular phenotype comprises a readily scalable platform for high-throughout screens to anti-ZIKV drugs.


The 2009 outbreak of H1N1 caught many off guard-not least those responsible for tracking the emergence of new influenza strains and outbreaks [Acute lung infection and inflammation such as in influenza pneumonia are associated with the “cytokine storm” that recruits excessive immune cells to infiltrate lung tissue. The infiltrated immune cells clear pathogens by various means such as generating reactive oxygen species that exacerbates tissue damage. Influenza infection also impairs pulmonary functions partially by inducing vascular leakage that facilitates further infiltration of immune cells and pulmonary edema. These phenomena raise the possibility that enhancing lung endothelial barrier integrity during infection and inflammation may ameliorate lung tissue damage, and may be therapeutically useful for acute lung injury –4.Recent studies reveal that angiopoietin-like 4 (ANGPTL4) is upregulated during influenza pneumonia . High-thBacterial pneumonia may present as a primary disease process, or as the final terminal event in individuals who are already debilitated. A historical review of the 1918 influenza pandemic suggests that the majority of deaths were not directly attributed to the influenza virus; rather the mortalities were due to bacterial co-infections. While the objective of anti-inflammatory approaches against influenza pneumonia is to mitigate the devastating impact of hypercytokinemia, such therapies also render the host more susceptible to secondary infections. In contrast, direct regulation on vascular or tissue leakiness may attenuate excessive inflammation without compromising host immune defenses. Although the role of ANGPTL4 in inflammation remains to be fully elucidated, our interrogation of microarray gene expression data of lungs from influenza-infected mice treated with neutralizing ANGPTL4 antibody did not reveal significant diminution of host defenses against bacterial infections. Hence, improving vascular integrity may offer a more effective and probably safer alternative to combat lung infection. Furthermore, ANGPTL4 also shows great potential as a biomarker for pneumonia.Vascular leakage is a hallmark of many infectious diseases, including those caused by dengue virus, severe acute respiratory syndrome (SARS) coronavirus, and Middle East respiratory syndrome (MERS) coronavirus. The roles of ANGPTL4 in these infections are unclear, and certainly warrant future investigations. Importantly, the recent studies on host response factors such as ANGPTL4 provide a new level of understanding with respect to vascular integrity in pulmonary infection and inflammation.


Insulin independence is a realistic therapeutic goal in feline diabetes. Remission is dependent on achieving fast glycemic control. However, without intensive monitoring high insulin doses increase the risk of hypoglycemia. An 11-year old spayed Burmese cat presented with diabetes after steroid treatment for skin allergy. Control of blood glucose was not achieved using low carbohydrate diet plus the recommended q12h treatment with either insulin lente or glargine, with the total dose limited by the risk of hypoglycaemia.The aim was to achieve euglycaemia and insulin-independence.A more frequent insulin treatment was tried. Seven weeks from start of q12h treatment, the total daily dose of insulin glargine was divided across three injections. One week later the frequency of injection was increased to q6h. There was intensive monitoring of capillary blood glucose (Accu-Chek Aviva).There was a prominent glucose nadir after approximately 4h regardless of insulin type. Within four weeks on insulin q8h and q6h blood glucose levels were within the normal range. Weight gain was noted and within one week of caloric restriction insulin was withdrawn completely. One month later fructosamine had normalized and after more than three years the cat remains off insulin with blood glucose levels at the upper limit of the reference range.More frequent insulin injections than recommended in literature may be necessary to achieve glycemic control. Owners are important collaborators in feline diabetes care and with intensive home monitoring more frequent insulin treatment may lead to remission without hypoglycemia.


Mycobacterium tuberculosis.Tuberculous aortitis is an unusual presentation of a common disease in Sri Lanka. There were no reported cases of tuberculous aortitis from Sri Lanka. Here we report a case of a 40-year-old woman who developed an ascending aortic aneurysm with severe aortic regurgitation caused by A 40-year-old Sri Lankan female who presented with exertional breathlessness (NYHA II) and weight loss for 4 weeks duration was found to have collapsing pulse and early diastolic murmur at left sternal edge. Transthoracic and transesophageal echocardiogram showed ascending aortic aneurysm with severe aortic regurgitation. Computed tomographic aortography confirmed the diagnosis of aneurysmal dilatation of the ascending aorta. She underwent successful aortic valve replacement and aortic root replacement. The final diagnosis of tuberculous aortitis was made on the basis of macroscopic appearance of inflammation and microscopic confirmation of caseating granuloma. She made a good clinical recovery with category 1 antituberculous chemotherapy.Although most cases of aortitis are non-infectious in Sri Lanka, an infectious etiology must be considered in the differential diagnosis because therapeutic approaches differ widely. Tuberculous aortitis may be under diagnosed in Sri Lanka, a country with intermediate tuberculosis burden, as the histological or microbiological diagnosis is not possible in most cases. The clinical and radiological diagnostic criteria for tuberculous aortitis need to be set out in case of aneurysmal aortic disease in the absence of apparent etiology. Staphylococcal species and Streptococcus pneumoniae which seed the aortic wall with preexisting pathology via the vasa vasorum [Mycobacterium tuberculosis is a rare disease entity, with involvement of the aortic root being exceedingly rare [The diagnosis of rare infectious aortitis should be made accurately as the treatment strategy differ from that of more common non-infectious aortitis such as giant cell arteritis (GCA) and Takayasu arteritis. Bacterial aortitis is most commonly associated with Salmonella,  vasorum . Mycoticgly rare . Aortic gly rare . The diaA 40-year-old Sri Lankan female presented with exertional breathlessness (NYHA II) and weight loss for 4 weeks duration. There was no cough, hemoptysis, evening pyrexia or night sweats and no history of limb claudication. Her past history was negative for connective tissue disorders, vasculitis or tuberculosis. The family history was unremarkable. General examination did not reveal any abnormal physical signs. She had collapsing pulse and blood pressure of 110/40 mmHg in both arms. Early diastolic murmur was heard in both left and right sternal edge. The lung bases were clear and rest of the systemic examination was normal.Chest x-ray showed smooth dilatation of the ascending aorta and walls of it are not parallel to each other. Transthoracic and transeseophageal echocardiogram showed ascending aortic aneurysm (maximum diameter of 54 mm) with severe aortic regurgitation. Cardiac chamber dimensions were within normal limits and left ventricular ejection fraction was normal. Computed tomographic (CT) aortography confirmed the dilatation of aortic root and ascending aorta without dissection or leaking. Acute phase reactants were slightly elevated . Venereal Disease Research Laboratory test (VDRL) was non-reactive. Antinuclear antibody was negative.Cardiology team proceeded their further evaluation with pre-operative coronary angiogram which showed normal epicardial coronary arteries. Aortic valve and root replacement was recommended by the cardiologist. Cardiothoracic surgical team carried out the aortic valve replacement (AVR) with 19 mm bileaflet St Jude Medical mechanical valve and aortic root replacement with 30 mm Albo graft. Surgeon noted evidence of aortitis with external inflammatory adhesions during the surgery. Post-operative period was uneventful. Warfarin therapy was started while closely monitoring the INR and it was kept between 2 and 3. Histological examination of aortic wall revealed granulomatous aortitis with caseous necrosis  consisting of 3 fixed dose combination tablets per day each containing rifampicin 150 mg, isoniazid 75 mg, pyrazinamide 400 mg and ethambutol 275 mg (RHZE). Frequent dose adjustment of warfarin was required during ATT. Continuation phase of ATT was extended for up to 10 months with rifampicin and isoniazid as in the case of disseminated tuberculosis. She made a good clinical recovery with improvement of her symptoms and follow up image showed functioning aortic prosthesis while maintaining INR in therapeutic range.Tuberculous aortitis is a very rare form of extra-pulmonary tuberculosis. It can be caused by direct extension of Mycobacterium tuberculosis from an adjacent focus of infection or by hematogenous spread. Close proximity of distal aortic arch and the descending aorta to a specific group of mediastinal lymph nodes may explain it being the commonest site for tuberculous aortitis, but exceptionally ascending aorta is affected as in this case . The speMany infectious and non-infectious etiologies are associated with aortitis. Negative VDRL test makes the syphilitic aortitis less likely as a cause for ascending aortic aneurysm in this patient. She did not have any typical clinical features or radiological criteria of Takayasu arteritis. Giant cell arteritis was not a consideration in this case as it affects individuals older than 50 years of age . AbsenceTuberculous arteritis is an important consideration in this case as new case finding rate of all tuberculous diseases (pulmonary and extra-pulmonary) are 9000–10,000 in Sri Lankan annually . The diaThe definitive diagnosis was ultimately established by histology of the surgical specimen which confirmed it as granulomatous aortitis with evidence of caseous necrosis. Although positive AFB on ZNS strongly favor the diagnosis of tuberculous aortitis, negative test does not exclude the diagnosis as the sensitivity of this test is very low. Granulomatous aortitis with caseous necrosis more favor the diagnosis of tuberculous aortitis even though no evidence of tuberculosis in another site.She complied with Category one ATT without any drug induced complications, but warfarin therapy to maintain INR in therapeutic range (2–3) needed frequent monitoring and dose adjustments as some of the anti-tuberculous drugs are known liver enzyme inducers. Since this form of tuberculosis is indicative of disseminated disease , we deciInfectious aortitis like tuberculosis should be considered as an etiology for aortic aneurysm. Diagnostic criteria without histological specimens are defined for non-infectious aortitis like Takayasu arteritis and GCA. Surgical biopsy or specimens are often needed for the confirmation of infectious etiology such as tuberculous aortitis though it is not possible in all cases. Noninvasive imaging techniques like MRA are emerging investigation modalities to detect aortic wall inflammation and peri-aortitis. High degree of suspicion in an appropriate clinical setting in combination with imaging may justify the treatment with ATT. Development of diagnostic criteria for tuberculous aortitis based on the clinical findings and imaging may be a future research area.Written informed consent was obtained from the patient for publication of this case report and any accompanying images.


After completing a successful quality improvement (QI) initiative to decrease non-medically indicated scheduled births <39 weeks in 20 large maternity hospitals, the Ohio Perinatal Quality Collaborative (OPQC) aimed to expand this work across Ohio. Our objective was to evaluate the effectiveness of the QI intervention used by OPQC to rapidly spread the 39 week initiative.Participating hospitals were exposed to an 8-month QI intervention to reduce non-medically indicated scheduled deliveries <39 weeks and reflect those improvements in accurate state vital statistics data. The intervention was implemented using a step-wedge design with hospitals divided into three balanced waves. Effectiveness was assessed using interrupted time-series analysis. Interviews with a sample of participants and project call recordings were analyzed using qualitative methods to understand implementation.Seventy of the 72 (97%) eligible hospitals agreed to participate. Hospitals actively participated as evidenced by 95.7% attending the in-person learning session and 80% attending at least three of four monthly group calls. Based on birth registry data, rates of non-medically indicated inductions <39 weeks declined in all waves concurrent with the start of the intervention. Changes related to reducing deliveries <39 weeks were variably implemented--some hospitals described extensive changes as a result of their participation while others who had previously begun work in this area described either small changes or no changes. Participants implemented multiple changes to improve birth registry accuracy.We describe a QI intervention enabling state-wide spread of effective change strategies over 12 months. This intervention could support a model where a network of innovator hospitals develops and tests change strategies and then rapidly spreads successful approaches to a broader population. Such a model has the potential to advance dissemination and implementation science.AHRQ U19HS02114, CDC 31-90000-553005-130488, and Ohio Government Resource Center.


Peroneal artery arteriovenous fistulas and pseudoaneurysms are extremely rare with the majority of reported cases due to penetrating, orthopedic, or iatrogenic trauma. Failure to diagnose this unusual vascular pathology may lead to massive hemorrhage or limb threatening ischemia. We report an interesting case of a 14-year-old male who presented with acute musculoskeletal pain of his lower extremity. Initial radiographs were negative. Further imaging workup revealed a peroneal arteriovenous fistula with a large pseudoaneurysm. After initial endovascular intervention was unsuccessful, the vessels were surgically ligated in the operating room. Pathology revealed papillary endothelial hyperplasia consistent with an aneurysm and later genetic testing was consistent with Ehlers-Danlos syndrome Type IV. This case illustrates an unusual cause of acute atraumatic musculoskeletal pain and uncommon presentation of Ehlers-Danlos syndrome. Arteriovenous fistulas often result from iatrogenic trauma while gaining percutaneous vascular access. Turbulent blood flow and endothelial damage may eventually lead to pseudoaneurysm formation with resulting mass effect and risk of massive hemorrhage. While several case reports have documented peroneal pseudoaneurysms resulting from iatrogenic and orthopedic trauma, there are no known reports of both an arteriovenous fistula and pseudoaneurysm presenting in a patient with an undiagnosed connective tissue disorder. Utilizing multiple imaging modalities, this case nicely documents the unique vascular findings in this interesting case.A healthy 14-year-old male presented with acute onset lower extremity calf pain and swelling that began while playing soccer. He denied trauma to the limb and on physical exam was neurovascularly intact. An MRI to evaluate possible ligamentous injury revealed a large abnormal flow void adjacent to the peroneal artery and vein thought to represent a pseudoaneurysm or arteriovenous malformation . CT angiUltrasound showed a 2.0 × 1.5 cm pseudoaneurysm with swirling of blood flow in the pseudoaneurysm sac giving the characteristic “Yin-Yang” appearance on Color Doppler . Both pePercutaneous intervention was attempted; however, a wire could not be successfully placed distally in the peroneal artery to traverse the pseudoaneurysm neck. The patient subsequently underwent open ligation of the pseudoaneurysm and arteriovenous fistula. Postoperatively his symptoms resolved and genetic analysis revealed a collagen mutation compatible with Vascular Ehlers-Danlos syndrome Type IV.Arteriovenous fistulas (AVF) and pseudoaneurysms (PSA) of the peroneal artery are uncommonly reported in the literature and are extremely rare presenting together. Most pseudoaneurysms result from orthopedic, penetrating, or iatrogenic trauma with the latter often seen after Fogarty balloon embolectomy or percutaneous vascular access , 2. CongWhile the pseudoaneurysm and arteriovenous fistula in this patient were initially thought to be traumatic in origin, genetic testing later revealed a mutation in the COL3A1 gene of collagen 3 compatible with a diagnosis of the Vascular Type 4) Ehlers-Danlos syndrome. Of the 6 major types of Ehlers-Danlos syndrome, Type 4 is one of the most serious types and is most often associated with major vascular complications  Ehlers-D. While vPeroneal artery pseudoaneurysms have been successfully treated by coil embolization of the pseudoaneurysm sac or, alternatively, embolization of the peroneal artery proximally and distally to the pseudoaneurysm neck , 7. Whil