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OBJECT High-grade gliomas are the most common form of adult brain cancer, and patients have a dismal survival rate despite aggressive therapeutic measures. Intratumoral hypoxia is thought to be a main contributor to tumorigenesis and angiogenesis of these tumors. Because hypoxia-inducible factor 1α (HIF-1α) is the major mediator of hypoxia-regulated cellular control, inhibition of this transcription factor may reduce glioblastoma growth. METHODS Using an orthotopic mouse model with U87-LucNeo cells, the authors used RNA interference to knock down HIF-1α in vivo. The small interfering RNA (siRNA) was packaged using a novel multifunctional surfactant, 1-(aminoethyl) iminobis[N-(oleicylcysteinylhistinyl-1-aminoethyl)propionamide] (EHCO), a nucleic acid carrier that facilitates cellular uptake and intracellular release of siRNA. Stereotactic injection was used to deliver siRNA locally through a guide-screw system, and delivery/uptake was verified by imaging of fluorescently labeled siRNA. Osmotic pumps were used for extended siRNA delivery to model a commonly used human intracranial drug-delivery technique, convection-enhanced delivery. RESULTS Mice receiving daily siRNA injections targeting HIF-1α had a 79% lower tumor volume after 50 days of treatment than the controls. Levels of the HIF-1 transcriptional targets vascular endothelial growth factor (VEGF), glucose transporter 1 (GLUT-1), c-MET, and carbonic anhydrase-IX (CA-IX) and markers for cell growth (MIB-1 and microvascular density) were also significantly lower. Altering the carrier EHCO by adding polyethylene glycol significantly increased the efficacy of drug delivery and subsequent survival. CONCLUSIONS Treating glioblastoma with siRNA targeting HIF-1α in vivo can significantly reduce tumor growth and increase survival in an intracranial mouse model, a finding that has direct clinical implications.

Background Chronic pelvic pain accounts for up to 30% of outpatient gynecologic visits in the United States, potentially affecting up to 40% of the female population during their lifetime. Pelvic congestion syndrome (PCS) is defined as chronic pelvic pain resulting from reflux or obstruction of the gonadal, gluteal, or periuterine veins, sometimes associated with perineal or vulvar varices. It can also be caused by compression of the left renal vein (LRV) between the superior mesenteric artery and the aorta, also known as the nutcracker syndrome. Whereas PCS accounts for up to 30% of patients presenting with chronic pelvic pain, it is frequently underdiagnosed. We reviewed the literature to investigate the current state of the diagnosis and treatment of this disorder. Methods An online database search was performed with MEDLINE. MeSH headings included PCS, chronic pelvic pain, ovarian vein reflux, nutcracker syndrome, renal vein obstruction, pelvic varicosities, labial varicosities, embolization, treatment, and therapies. Results Our MEDLINE search revealed more than 3756 references to chronic pelvic pain. Specific references to PCS, pelvic chronic pain, ovarian vein reflux, nutcracker syndrome, renal vein obstruction, pelvic varicosities, labial varicosities, embolization, treatment, and therapies, however, included only 260 references. Thirty-seven references were small series including fewer than 50 patients or individual case reports documenting medical, surgical, or endovascular treatment of PCS. The majority of these papers demonstrated successful treatment of symptoms from PCS with embolization of one or both ovarian veins in addition to treatment of refluxing internal iliac vein branches. In addition, open surgery and, more recently, endovascular stenting of LRV obstruction have shown some promise in alleviating symptoms attributed to nutcracker syndrome. Conclusions Diagnosis of PCS requires a careful history, physical examination, and noninvasive imaging. Several large case series have demonstrated the efficacy of embolotherapy in the reduction of pelvic pain; thus, it is the most favored treatment option for patients with PCS. For patients with outflow obstruction due to nutcracker syndrome, a limited number of studies have demonstrated remission of symptoms with stenting of the LRV as an alternative to open surgery.

Chronic venous occlusion is frequently associated with moderate to severe postphlebetic syndrome and sometimes venous ulceration affecting negatively quality of life. Despite a widely adopted strategy of early thrombus removal, patients commonly present at a later stage with extensive chronic total occlusions. This chapter describes tips and techniques for endovascular recanalization and stenting of major veins to provide adequate venous outflow and relieve peripheral venous hypertension

Background Genomic studies have revealed that multiple genes are mutated at varying frequency in endometrial cancer (EC); however, the relevance of many of these mutations is poorly understood. An EC-specific recurrent mutation in the MAX transcription factor p.His28Arg was recently discovered. We sought to assess the functional consequences of this hotspot mutation and determine its association with cancer-relevant phenotypes. Methods MAX was sequenced in 509 endometrioid ECs, and associations between mutation status and clinicopathologic features were assessed. EC cell lines stably expressing MAXH28R were established and used for functional experiments. DNA binding was examined using electrophoretic mobility shift assays and chromatin immunoprecipitation. Transcriptional profiling was performed with microarrays. Murine flank (six to 11 mice per group) and intraperitoneal tumor models were used for in vivo studies. Vascularity of xenografts was assessed by MECA-32 immunohistochemistry. The paracrine pro-angiogenic nature of MAXH28R-expressing EC cells was tested using microfluidic HUVEC sprouting assays and VEGFA enzyme-linked immunosorbent assays. All statistical tests were two-sided. Results Twenty-two of 509 tumors harbored mutations in MAX, including 12 tumors with the p.His28Arg mutation. Patients with a MAX mutation had statistically significantly reduced recurrence-free survival (hazard ratio = 4.00, 95% confidence interval = 1.15 to 13.91, P = .03). MAXH28R increased affinity for canonical E-box sequences, and MAXH28R-expressing EC cells dramatically altered transcriptional profiles. MAXH28R-derived xenografts statistically significantly increased vascular area compared with MAXWT and empty vector tumors (P = .003 and P = .008, respectively). MAXH28R-expressing EC cells secreted nearly double the levels of VEGFA compared with MAXWT cells (P = .03, .005, and .005 at 24, 48, and 72 hours, respectively), and conditioned media from MAXH28R cells increased sprouting when applied to HUVECs. Conclusion These data highlight the importance of MAX mutations in EC and point to increased vascularity as one mechanism contributing to clinical aggressiveness of EC.

BACKGROUND:\ud \ud Metformin might reduce insulin requirement and improve glycaemia in patients with type 1 diabetes, but whether it has cardiovascular benefits is unknown. We aimed to investigate whether metformin treatment (added to titrated insulin therapy) reduced atherosclerosis, as measured by progression of common carotid artery intima-media thickness (cIMT), in adults with type 1 diabetes at increased risk for cardiovascular disease.\ud \ud METHODS:\ud \ud REMOVAL was a double-blind, placebo-controlled trial undertaken at 23 hospital diabetes clinics in five countries (Australia, Canada, Denmark, the Netherlands, and the UK). Adults aged 40 years and older with type 1 diabetes of at least 5 years' duration and at least three of ten specific cardiovascular risk factors were randomly assigned (via an interactive voice response system) to oral metformin 1000 mg twice daily or placebo. Participants and site staff were masked to treatment allocation. The primary outcome was averaged mean far-wall cIMT, quantified annually for 3 years, analysed in a modified intention-to-treat population (all randomly assigned participants with post-randomisation data available for the outcome of interest at any given timepoint, irrespective of subsequent adherence or study participation), using repeated measures regression. Secondary outcomes were HbA1c, LDL cholesterol, estimated glomerular filtration rate (eGFR), incident microalbuminuria (not reported), incident retinopathy, bodyweight, insulin dose, and endothelial function, also analysed in all participants with post-randomisation data available for the outcome of interest at any given timepoint. This trial is registered with ClinicalTrials.gov, number NCT01483560.\ud \ud FINDINGS:\ud \ud Between Dec 14, 2011, and June 24, 2014, 493 participants entered a 3 month run-in to optimise risk factor and glycaemic control (single-blind placebo in the final month). Of 428 randomly assigned patients, 219 were allocated to metformin and 209 to placebo. Progression of mean cIMT was not significantly reduced with metformin (-0·005 mm per year, 95% CI -0·012 to 0·002; p=0·1664), although maximal cIMT (a prespecified tertiary outcome) was significantly reduced (-0·013 mm per year, -0·024 to -0·003; p=0·0093). HbA1c (mean 8·1% [SD 0·9] for metformin and 8·0% [0·8] for placebo at baseline) was reduced on average over 3 years by metformin (-0·13%, 95% CI -0·22 to -0·037; p=0·0060), but this was accounted for by a reduction at the 3-month timepoint (-0·24%, -0·34 to -0·13; p

Anticoagulation is the cornerstone for the treatment of deep venous thrombosis and pulmonary embolism. On occasion, this is not possible because of bleeding complications or, rarely, breakthrough pulmonary embolism associated with this treatment method. The development of vena cava interruption in the 1970s was a critical advance in the treatment of these patients. Placement of inferior vena cava (IVC) filters has been steadily increasing since their introduction. Nonetheless, the incidence of complications associated with placement of these devices is largely unknown. Most of the evidence regarding IVC filter complications relies on case reports, with scarce data coming from larger randomized controlled trials. We aimed to present a summary addressing long-term complications of IVC filters as published in recent articles addressing problems such as IVC thrombosis and IVC filter migration, perforation, fracture, embolization, and tilting. We performed a PubMed search and Google Scholar search using different combinations of "long term," "complications," "IVC filter," and "vena cava filter." We reviewed the available English publications and reported the findings in this summary.

Background: Timing of birth is a major determinant of newborn health. African American women are at increased risk for early birth, particularly via the inflammatory pathway. Variants of the IL1RN gene, which encode the interleukin-1 receptor antagonist (IL-1Ra) protein, are implicated in early birth. The biological pathways linking these variables remain unclear. Evidence also suggests that inflammatory pathways differ by race; however, studies among African American women are lacking. Objectives: We assessed whether an IL1RN variant was associated with timing of birth among African American women and whether this relationship was mediated by lower anti-inflammatory IL-1Ra production or related to a decrease in inhibition of proinflammatory IL-1β production. Methods: A candidate gene study using a prospective cohort design was used. We collected blood samples at 28–32 weeks of gestation among African American women experiencing an uncomplicated pregnancy (N = 89). IL1RN single-nucleotide polymorphism (SNP) rs2637988 was genotyped, and lipopolysaccharide-stimulated IL-1Ra and IL-1β production was quantified. Medical record review determined timing of birth. Results: Women with GG genotype gave birth earlier than women with AA/AG genotypes (b* = .21, p = .04). There was no indirect effect of IL1RN SNP rs2637988 allele status on timing of birth through IL-1Ra production, as evidenced by a nonsignificant product of coefficients in mediational analyses (ab = .006, 95% CI [−0.05, 0.13]). Women with GG genotype showed less inhibition of IL-1β production for a unit positive difference in IL-1Ra production than women with AA/AG genotypes (b* = .93, p = .03). Greater IL-1β production at 28–32 weeks of pregnancy was marginally associated with earlier birth (b* = .21, p = .05). Discussion: Women with GG genotype may be at risk for earlier birth because of diminished IL-1β inhibition, allowing for initiation of a robust inflammatory response upon even mild immune challenge. Study of inflammatory contributions to early birth among African American women may be key to identifying potential prognostic markers of risk and targeted preventive interventions.

AIMS:The organization and maturation of ventricular cardiomyocytes from the embryonic to the adult form is crucial for normal cardiac function. We have shown that a polarity protein, Scrib, may be involved in regulating the early stages of this process. Our goal was to establish whether Scrib plays a cell autonomous role in the ventricular myocardium, and whether this involves well-known polarity pathways.METHODS AND RESULTS:Deletion of Scrib in cardiac precursors utilizing Scrib(flox) mice together with the Nkx2.5-Cre driver resulted in disruption of the cytoarchitecture of the forming trabeculae and ventricular septal defects. Although the majority of mice lacking Scrib in the myocardium survived to adulthood, they developed marked cardiac fibrosis. Scrib did not physically interact with the planar cell polarity (PCP) protein, Vangl2, in early cardiomyocytes as it does in other tissues, suggesting that the anomalies did not result from disruption of PCP signalling. However, Scrib interacted with Rac1 physically in embryonic cardiomyocytes and genetically to result in ventricular abnormalities, suggesting that this interaction is crucial for the development of the early myocardium.CONCLUSIONS:The Scrib-Rac1 interaction plays a crucial role in the organization of developing cardiomyocytes and formation of the ventricular myocardium. Thus, we have identified a novel signalling pathway in the early, functioning, heart muscle. These data also show that the foetus can recover from relatively severe abnormalities in prenatal ventricular development, although cardiac fibrosis can be a long-term consequence.

Background Validation of carotid duplex ultrasound velocity criteria (CDUS VC) to grade the severity of extracranial carotid artery stenosis has traditionally been based on conventional angiography measurements. In the last decade, computed tomographic angiography (CTA) has largely replaced conventional arch and carotid arteriography (CA) for diagnostic purposes. Given the low number of CA being performed, it is impractical to expect noninvasive vascular laboratories to be validated using this modality. CDUS VC have not been developed with the use of CTA-derived measurements. The objective was to determine optimal CDUS VC from CTA-derived measurements with the North American Symptomatic Carotid Endarterectomy Trial (NASCET) method for 50% and 80% stenosis. Methods A retrospective review of all patients who underwent CDUS and CTA from 2000 to 2009 was performed. Vessel diameters were measured on CTA, and corresponding CDUS velocities were recorded. Percent stenosis was calculated using the NASCET method. Receiver operating characteristic (ROC) curves were generated for internal carotid artery (ICA) peak systolic velocity (PSV), ICA end diastolic velocity (EDV), and ICA PSV to common carotid artery PSV ratio (PSVR) for 50% and 80% stenosis. Velocity cut points were determined with equal weighting of sensitivity and specificity. Results A total of 575 vessels were analyzed to create the ROC curves. A 50% stenosis analysis yielded ideal cut points for PSV, EDV, and PSVR of 130 cm/sec, 42 cm/sec, and 1.75. An 80% stenosis analysis yielded ideal cut points for PSV, EDV, and PSVR of 297 cm/sec, 84 cm/sec, and 3.06. Conclusions CTA-derived CDUS VC appeared to be reliable in defining 50% and 80% stenosis in patients with carotid artery stenosis. Although CDUS VC defined in this study were different from many of the previously published VC for the same percent stenosis, there were many similarities to those reported by the Society of Radiologists in Ultrasound consensus conference. We feel that CTA should be the gold standard imaging technique for validating CDUS VC.

ObjectiveThe single puncture intravascular ultrasound (IVUS)-guided bedside placement of inferior vena cava (IVC) filters has been shown to be an effective technique. The major disadvantage of this procedure is a steep learning curve that can lead to an increased risk of filter malposition. In an effort to increase the safety and efficacy of IVUS-guided bedside IVC filter placement, we proposed that preoperative planning could reduce the incidence of IVUS-guided filter malpositions. As a first step, we examined the correlation between preoperative abdominal computed tomography (CT) scan measurements and intraprocedural IVUS derived measurements of vena cava anatomy and its surrounding structures. As a second step, we attempted to determine the safety of this protocol by assessing the incidence of malposition.MethodsA retrospective review of prospectively collected data was performed on all patients receiving bedside IVUS-guided filters from July 1, 2010 to August 31, 2011. Measurements of the IVC length from the atrial-IVC junction to the midportion of the crossing right renal artery, the lowest renal vein, and iliac vein confluence were obtained prior to IVC filter placement by both CT-based measurement, as well as intraprocedural IVUS pullback lengths. Regression analysis (significant for P < .05) was used to determine the correlation between these imaging modalities.ResultsForty-six patients had adequate CT scans available to perform the analysis and were candidates for bedside IVUS-guided IVC filter placement. All IVUS-guided filters were placed using a single puncture technique with the Cook Celect Filter. This study found there was a close correlation between IVUS and CT derived measurements of the right atrium to right renal artery distance, lowest renal vein distance, and iliac confluence distance. In addition, we found that the IVUS distances from the atrial-IVC junction to the right renal artery and lowest renal vein were statistically similar. Nine patients had 10 vascular anatomic variations, all identified by both IVUS and CT. There were no complications or malpositions of IVC filters using this protocol.ConclusionsThese data suggest that IVUS pullback measurements from the right atrium used in combination with preprocedure CT derived measurements of the distance from the right atrium to the lowest renal vein and iliac vein confluence provide an accurate roadmap for the placement of bedside IVC filters under IVUS guidance. We provide a method for organizing this information in a preplanning document to aid this procedure. We suggest this easily employed technique be more fully utilized to help decrease the incidence of malpositioned filters using single puncture IVUS guidance.

BACKGROUND The Senior Visiting Surgeon (SVS) program at Landstuhl Regional Medical Center (LRMC), Germany, was developed during the wars in Afghanistan and Iraq as a measure to build military-civilian interaction in trauma care and research. The objective of this study was to provide a summary of the program including workload and experiences. An additional objective was to identify factors needed for sustainment of this program during an interwar period. METHODS An electronic, 34-question survey was distributed to 192 surgeons who participated in the SVS program at LRMC, either through the American Association for the Surgery of Trauma or the Society of Vascular Surgery between 2005 and 2012. The survey was composed of multiple-choice and open-ended questions. RESULTS The response rate was 61% (n = 118), with 24% (n = 28) indicating previous military service. These 117 respondents provided 24.5 months of volunteer coverage at LRMC, with 22% (n = 26) performing multiple, 2-week rotations. Visiting surgeons participated in two to five operative cases per week, with the majority of operations related to the management of soft tissue wounds and burns followed by abdominal and vascular procedures, conducted daily multidisciplinary intensive care unit rounds, and collaborated with military surgeons in research projects resulting in 22 publications. More than half (n = 59) of the respondents maintained contact with military colleagues during the 12 months following the rotation. The majority of surveyed surgeons support continuation of the SVS at military facilities in the United States and hosting military surgeons at their civilian trauma center. CONCLUSION This study is the first to quantify the SVS program during the wars in Afghanistan and Iraq. Visiting surgeons provided more than 2 years of combat casualty care during these, the longest wars in US history. Continuation of this program will require expanded military-civilian interaction in trauma care, training, and research during any interwar period.

African Americans are at heightened risk for coronary heart disease (CHD), with biologic pathways poorly understood. We examined the role of allostatic load (AL) in the association of depressive symptoms with incident CHD among 2,670 African American men and women in the prospective Jackson Heart Study. Depressive symptoms were quantified using the Center for Epidemiologic Studies Depression Scale (CES-D). Incident CHD was ascertained by self-report, death certificate survey, and adjudicated medical record surveillance. Baseline AL was quantified using biologic parameters of metabolic, cardiovascular, immune, and neuroendocrine subsystems and as a combined meta-factor. Sequential models adjusted for demographic, socioeconomic, and behavioral covariates, stratified to examine differences by sex. Greater depressive symptomatology was associated with greater metabolic, cardiovascular, and immune AL (p-values≤0.036) and AL meta-factor z-scores (p = 0.007), with findings driven by observations among females. Each 1-point increase in baseline depressive symptomatology, and 1-SD increase in metabolic AL, neuroendocrine AL, and AL meta-factor z-scores was associated with 3.3%, 88%, 39%, and 130% increases in CHD risk, respectively (p-values0.001). Neuroendocrine AL and AL meta-factor scores predicted incident CHD among males but not females in stratified analyses. Metabolic AL partially mediated the association of depressive symptoms with incident CHD (5.79% mediation, p = 0.044), a finding present among females (p = 0.016) but not males (p = 0.840). Among African American adults, we present novel findings of an association between depressive symptomatology and incident CHD, partially mediated by metabolic AL. These findings appear to be unique to females, an important consideration in the design of targeted interventions for CHD prevention.

[Figure][1] ![Figure][1] ![Figure][1] ![Figure][1] ![Figure][1] On April 7, 2015, Elijah Saunders, MD, a pioneer in hypertension and a founding member of the Association of Black Cardiologists (ABC), passed away after a brief illness. Four days later, his close

The aim of this study was to develop a quantitative 16S rRNA assay for determination of bacterial nucleic acid load in cerebrospinal fluid (CSF) shunt infection and to compare quantitative 16S rRNA polymerase chain reaction (PCR) findings to those of conventional bacterial culture in patients treated for CSF shunt infection. We developed a quantitative 16S rRNA PCR assay that detected bacterial load across a range of 2.5 × 109 down to 2.5 × 104 16S copies/mL CSF under experimental conditions for numerous Gram-positive and Gram-negative organisms. However, when applied to archived CSF samples from 25 shunt infection episodes, correlations between positive bacterial culture and 16S rRNA levels were seen in only half of infections, and 16S rRNA levels dropped precipitously after an initial peak on the first day of sample collection. Bacterial load measured using 16S rRNA PCR does not provide sufficient information beyond bacterial culture to inform CSF shunt infection treatment.

Climate change-associated sea level rise is expected to cause saltwater intrusion into many historically freshwater ecosystems. Of particular concern are tidal freshwater wetlands, which perform several important ecological functions including carbon sequestration. To predict the impact of saltwater intrusion in these environments, we must first gain a better understanding of how salinity regulates decomposition in natural systems. This study sampled eight tidal wetlands ranging from freshwater to oligohaline (0-2 ppt) in four rivers near the Chesapeake Bay (Virginia). To help isolate salinity effects, sites were selected to be highly similar in terms of plant community composition and tidal influence. Overall, salinity was found to be strongly negatively correlated with soil organic matter content (OM%) and C : N, but unrelated to the other studied environmental parameters (pH, redox, and above- and below-ground plant biomass). Partial correlation analysis, controlling for these environmental covariates, supported direct effects of salinity on the activity of carbon-degrading extracellular enzymes (β-1, 4-glucosidase, 1, 4-β-cellobiosidase, β-D-xylosidase, and phenol oxidase) as well as alkaline phosphatase, using a per unit OM basis. As enzyme activity is the putative rate-limiting step in decomposition, enhanced activity due to salinity increases could dramatically affect soil OM accumulation. Salinity was also found to be positively related to bacterial abundance (qPCR of the 16S rRNA gene) and tightly linked with community composition (T-RFLP). Furthermore, strong relationships were found between bacterial abundance and/or composition with the activity of specific enzymes (1, 4-β-cellobiosidase, arylsulfatase, alkaline phosphatase, and phenol oxidase) suggesting salinity's impact on decomposition could be due, at least in part, to its effect on the bacterial community. Together, these results indicate that salinity increases microbial decomposition rates in low salinity wetlands, and suggests that these ecosystems may experience decreased soil OM accumulation, accretion, and carbon sequestration rates even with modest levels of saltwater intrusion.

The formation of the anterior segment of the eye is an intricate process that is dependent to a large degree on the normal development of the lens. Despite intensive study of the role of well-described eye genes, many causes of lenticular and anterior segment anomalies remain elusive. The majority of genes implicated thus far act in an autosomal dominant manner. Autosomal recessive causes are less well described; their diagnosis has been hindered by technological limitations, extreme genetic heterogeneity, a lack of understanding of eye biology and the role of many genes within the genome. The opportunity for the discovery of extremely rare autosomal recessive causes of ocular abnormalities from the study of consanguineous families is large, particularly through the powerful combination of next-generation sequencing with autozygosity mapping. Having begun to overcome the genetic heterogeneity bottleneck, it is increasingly recognised that the interpretation of genetic variants and the association of novel genes with a particular phenotype remain challenging. Nonetheless, increasing understanding of the genetic and mutational basis of lens and anterior segment abnormalities will be of enormous value to our comprehension of eye disease(s). Further, it will improve our ability to accurately interpret putative disease-causing variants with the aim of providing more personalised patient care and avoiding lifelong visual loss in children.

The objective of this report is to describe our experience of pediatric vascular injuries in a U.S. military combat support hospital in Baghdad, Iraq. A retrospective study was designed using Joint Theater Trauma Registry (JTTR) records in order to evaluate the pediatric (age18 years) population presenting with vascular trauma to a combat hospital in Baghdad, Iraq between April 2006 and August 2008. Demographic data comprised casualty, age, gender, and mechanism of injury. Physiologic data included presenting vital signs (rectal temperature, blood pressure, and heart rate), arterial pH, base deficit, hemoglobin (g/dL), and international normalized ratio.Twenty-five children, median age 14 years (range, 5-17 years), median weight 48 kg (range, 15-80 kg) sustained 18 (72%) blast and 7 (28%) gunshot wounds. The mean Injury Severity Score was 25 ± 16.2. The median operative time for the vascular repairs was 189 minutes (range, 41-505 minutes). Patients were tachycardic (mean ± standard deviation, 136 ± 29 bpm), hypotensive (109/63 ± 29/19 mm Hg), and acidemic (pH 7.26 ± 0.07; BD -5.57 ± 5.1 mEq/L) on arrival to the emergency department and were physiologically improved upon admission to the intensive care unit 3 hours later. Repair techniques were ligation (14; 39%), saphenous graft (11; 31%), lateral suture (7; 19%), end anastomosis (2; 5%), patch (1; 3%), and thrombectomy (1; 3%). Twenty-four hour mean transfusion requirements included crystalloid 102 mL/kg (range, 19-253), transfused blood 47 mL/kg (range, 0-119), fresh frozen plasma 14 mL/kg (range, 0-68), and apheresis platelets (1.2 ± 3.68 units). Over a follow-up of 22 ± 5.5 days, the amputation-free survival was 80%.This is the largest reported wartime series to demonstrate in children that damage control resuscitation despite high injury severity permits simultaneous limb salvage.

The tribe Phyllodoceae is comprised of seven genera (Bejaria, Elliottia, Epigaea, Kalmia, Kalmiopsis, Phyllodoce, and Rhodothamnus). A clade within this tribe, comprised of all genera except Bejaria, was the subject of a phylogenetic study using six molecular markers. The goal of the study was to reconstruct a species-level phylogeny for the purpose of examining the evolution of morphological characters and to provide a framework for future studies in historical biogeography. Twenty-nine of 31 Phyllodoceae species were included in the molecular dataset of sequences from four plastid and two nuclear regions, and the remaining two species were included in a small morphological analysis. Most nodes were strongly supported using combined molecular data and four analytical approaches. Potential morphological synapomorphies were identified for some clades within the group. Evolutionary patterns in some morphological characters are apparent, which provide a basis for future anatomical and developmental ...

Genetic testing is of increasing clinical utility for diagnosing inherited eye disease. Clarifying a clinical diagnosis is important for accurate estimation of prognosis, facilitating genetic counselling and management of families, and in the future will direct gene-specific therapeutic strategies. Often, precise diagnosis of genetic ophthalmic conditions is complicated by genetic heterogeneity, a difficulty that the so-called 'next generation sequencing' (NGS) technologies promise to overcome. Despite considerable counselling and ethical complexities, NGS offers to revolutionize clinical practice. This will necessitate considerable adjustment to standard practice but has the power to deliver a personalized approach to genomic medicine for many more patients and enhance the potential for preventing vision loss.

a b s t r a c t With receptors for red, blue, green, and ultraviolet-A light, birds have tetrachromatic vision. For birds, ultraviolet (UV) light is important for a number of their behaviors, including mate selection, foraging, and nesting. Many captive birds, however, are housed indoors without access to natural light and without UV-supplemented lighting; a practice which may nega- tively impact their welfare. Understanding how birds use UV light, and assessing its relative importance, is necessary to provide optimal care in captive settings. Accordingly, we tested the preference for UV light shown by 67 birds housed at Lincoln Park Zoo, Chicago, USA, and its impact on their behavior. We tested 18 species which represented three natural ecologies typified by different natural light levels: high light dwellers (e.g., birds that live in savannas or seashores), patchy light dwellers (e.g., birds that live in forested areas), and cir- cumpolar dwellers (e.g., birds that live near the poles). Experiment 1 investigated the birds' lighting preferences through simultaneous presentation of areas of their exhibit lit with supplemental ultraviolet light (UV+ zone) and with standard artificial light. Experiment 2 investigated the impact of supplemental UV light on these birds' behavioral repertoire. Birds from high light and circumpolar environments showed a preference for the side of their enclosure to which UV light was added. High light birds were recorded in the UV+ zone during 64% trials and, similarly, circumpolar birds were observed in this UV+ zone for 61% of trials; a significant preference for UV+ zone, P < 0.001 for both. Perhaps mim- icking their natural habitat of part-sun and part-shade, in Experiment 1 birds from patchy light environments split their time evenly within their enclosure (they were recorded in the UV+ zone for 54% of trials). When in an environment with added UV light, birds from patchy light habitats were more sociable: the percentage of their observation trials spent in proximity and in contact with other birds increased from 5% to 11% (P = 0.026). Although certain birds showed a preference for the added UV light, none showed changes in their behavioral repertoire beyond the sociability measure. We discuss this preference for UV- supplemented environments and the management implications for zoos and other captive

Venous thromboembolism is a national health concern. Up to 58% of patients suffering from major multisystem trauma will experience venous thromboembolism if no measures are taken to prevent it. Of those, 10% to 30% will be fatal. The appropriate use of lower extremity compression, anticoagulation, and the use of inferior vena cava (IVC) filters has helped reduce the overall morbidity and mortality from this disease. The development of lower-profile devices and the ability to retrieve IVC filters has led to a liberalization of their use. The majority of the filters used today have achieved U.S. Food and Drug Administration approval through the 510K mechanism (approval based on prior similar devices rather than safety studies of the proposed device), and therefore, no rigorous investigations have been performed on them. Initially seeming safe, a recent increase in reports of filter migration, vena cava perforation, and vena cava thrombosis has prompted the Food and Drug Administration to ask for more information on their patterns of use, safety, efficacy, and retrievability. This report details some of the available data on the subject of IVC filters and the discussion surrounding the topic of prophylactic IVC filters in trauma patients.

The genus Cassiope is comprised of 17 species of dwarf alpine shrubs that exhibit a variety of leaf morphologies, yet have very similar flowers and habits. The genus is circumboreally distributed, with species diversity concentrated in northwestern North America and in eastern Asia. This clade has been previously shown to be strongly supported as sister to the subfamily Ericoideae, but relationships within the genus have never been the subject of any phylogenetic study. The goal of this study was to use three molecular markers from the chloroplast and nuclear genomes to generate a phylogeny of Cassiope. Our initial analyses suggested that three species negatively impacted phylogeny reconstruction by introducing conflict between the nuclear and chloroplast genomes. Reanalysis with those three taxa removed generated a very strongly supported phylogeny, suggesting that these three taxa may be of hybrid origin. Some evolutionary trends in morphology and anatomy are apparent based upon analyses using ...

Preterm birth (PTB) occurs among 1:11 U.S. white women and 1:7.5 African American women and is a significant driver of racial disparities in infant mortality. Maternal stress is the most common clinical phenotype underlying spontaneous PTB. Specific patterns of stress and biological mediators driving PTB remain unclear. We examined the effect of childhood stress on birth timing among African American women and evaluated maternal cortisol elevation as a biological mediator. A prospective observational design was employed, with a single study visit at 28–32 weeks gestation and medical record review. The Stress and Adversity Inventory was administered, which provides a comprehensive estimate of childhood stress, stress in adulthood, and five core characteristic subscales (interpersonal loss, physical danger, humiliation, entrapment, role disruption). Venipuncture was performed between 11:00am and 4:00pm and plasma cortisol quantified by ELISA. Analyses controlled for stress in adulthood. Among a final sample of 89, cumulative childhood stress predicted birth timing ( p = 0.01). The association was driven by stress related to interpersonal loss and physical danger, with support for maternal cortisol as a biological mediator ( ab = 0.02, 95% CI [0.001, 0.045]; ab = 0.02, 95% CI [0.001, 0.043], respectively). Results were similar, overall, in sub-group analyses among spontaneously laboring women ( n = 53); however, role disruption arose as an additional predictor, as mediated by cortisol elevations ( ab = 0.03, 95% CI [0.005, 0.074]). Of note, cortisol was no longer supported as a mediator linking physical danger to birth timing after adjusting for sleep quality and hours awake prior to venipuncture ( ab = 0.02, 95% CI [−0.0001, 0.046]). We provide preliminary evidence that, independent of stress in adulthood, childhood stress of specific core characteristics may shape birth timing, with cortisol elevation as a biological mediator. Further investigation is warranted and may bolster the development of biologically-informed screening tools for the prediction and targeted prevention of stress-related PTB.

The mier family consists of three related genes encoding ELM2-SANT containing proteins. MIER1 has been well characterized and is known to function in transcriptional repression through its ability to recruit HDAC1 and 2. Little is known about MIER2 or MIER3 function and no study characterizing these two proteins has been published. In this report, we investigate MIER2 and MIER3 localization and function. Confocal analysis revealed that, while MIER2 and MIER3 are mainly nuclear proteins, a substantial proportion (32%) of MIER2 is localized in the cytoplasm. Co-immunoprecipitation experiments demonstrated that the MIER proteins do not dimerize; that MIER2, but not MIER3, can recruit HDACs; and that recruitment is cell line-dependent. MIER2 was associated with HDAC1 and HDAC2 in HEK293 cells, but only with HDAC1 in MCF7 and HeLa cells. Little or no MIER3 co-immunoprecipitated with either HDAC1 or 2 in any of the three cell lines tested. By contrast, HDAC1 and 2 were readily detected in MIER1α complexes in all three cell lines. Histone deacetylase assays confirmed that MIER2, but not MIER3 complexes, have associated deacetylase activity, leading to the conclusion that MIER3 does not function in HDAC recruitment in these cell lines. In contrast to what has been reported for other ELM2-SANT associated HDACs, addition of D-myo-inositol-1,4,5,6-tetrakisphosphate led to only a small increase in MIER1α associated deacetylase activity and no effect on that associated with MIER2. Deletion analysis revealed that HDAC recruitment occurs through the ELM2 domain. Finally, using site-directed mutagenesis, we show that, like MIER1, 228W in the ELM2 domain is a critical residue for HDAC recruitment by MIER2.

Although inflammatory bowel disease (IBD) is a failure in maintaining tolerance to the intestinal microbiota, few studies have investigated the use of immunologic tolerance as a treatment approach for IBD. We hypothesized that induction of immune tolerance at a distal site could suppress intestinal inflammation through a process of bystander regulation.Epicutaneous tolerance was induced by topical application of ovalbumin (OVA) using a Viaskin patch for 48 hours. In some experiments, a single feed of ovalbumin was used to drive epicutaneous tolerance-induced regulatory T cells (Tregs) to the intestine. The mechanism of tolerance induction was tested using neutralizing antibodies against TGF-β, IL-10, and Treg depletion using Foxp3-DTR mice. The capacity of skin-draining Tregs, or epicutaneous tolerance, to prevent or treat experimental IBD was tested using T-cell transfer colitis, dextran sodium sulfate (DSS) colitis, and ileitis in SAMP-YITFc mice. Weight loss, colonic inflammatory cytokines and histology were assessed.Epicutaneous exposure to ovalbumin induced systemic immune tolerance by a TGF-β-dependent, but IL-10 and iFoxp3 Treg-independent mechanism. Skin draining Tregs suppressed the development of colitis. Epicutaneous tolerance to a model antigen prevented intestinal inflammation in the dextran sodium sulfate and SAMP-YITFc models and importantly could halt disease in mice already experiencing weight loss in the T-cell transfer model of colitis. This was accompanied by a significant accumulation of LAP and Foxp3 Tregs in the colon.This is the first demonstration that epicutaneous tolerance to a model antigen can lead to bystander suppression of inflammation and prevention of disease progression in preclinical models of IBD.

Congenital vascular malformations may involve arterial, venous, and lymphatic structures and are present in 1.5% of the population. By definition, they exist at the time of birth, but clinical manifestations can evolve during life. As a vascular condition typically involving the extremities, the vascular laboratory diagnostics can be a challenge regarding imaging and test interpretation. Testing utilizes the same instrumentation applied to evaluation of peripheral arterial disease and dialysis access fistula. Other imaging modalities such as computer tomography (CT) scans, magnetic resonance imaging, and radioisotope studies can be used to assess the involvement of surrounding vital structures and even quantify the amount of blood flow shunted through a malformation or a fistula. Duplex testing combined with indirect physiologic testing of the limb and digit arterial perfusion is vital for the clinical decision-making regarding treatment modalities. In this chapter, the assessment of patients with known or suspected congenital arteriovenous malformations is described with an emphasis on clinical interpretation and relevance to symptoms and signs.

BACKGROUND Glioblastoma multiforme (GBM), a high-grade glioma, is characterized by being diffuse, invasive, and highly angiogenic and has a very poor prognosis. Identification of new biomarkers could help in the further diagnosis of GBM. OBJECTIVE To identify ELTD1 (epidermal growth factor, latrophilin, and 7 transmembrane domain-containing protein 1 on chromosome 1) as a putative glioma-associated marker via a bioinformatic method. METHODS We used advanced data mining and a novel bioinformatics method to predict ELTD1 as a potential novel biomarker that is associated with gliomas. Validation was done with immunohistochemistry, which was used to detect levels of ELTD1 in human high-grade gliomas and rat F98 glioma tumors. In vivo levels of ELTD1 in rat F98 gliomas were assessed using molecular magnetic resonance imaging. RESULTS ELTD1 was found to be significantly higher (P = .03) in high-grade gliomas (50 patients) compared with low-grade gliomas (21 patients) and compared well with traditional immunohistochemistry markers including vascular endothelial growth factor, glucose transporter 1, carbonic anhydrase IX, and hypoxia-inducible factor 1α. ELTD1 gene expression indicates an association with grade, survival across grade, and an increase in the mesenchymal subtype. Significantly high (P < .001) in vivo levels of ELTD1 were additionally found in F98 tumors compared with normal brain tissue. CONCLUSION Results of this study strongly suggests that associative analysis was able to accurately identify ELTD1 as a putative glioma-associated biomarker. The detection of ELTD1 was also validated in both rodent and human gliomas and may serve as an additional biomarker for gliomas in preclinical and clinical diagnosis of gliomas.

The crystalline lens of the eye has long been a model system for the complexities of tissue induction and morphogenesis as well as cell specification and differentiation. The unique protein content of the lens has also been the subject of intensive study in respect to stability, aggregation and longevity in the absence of vasculature and innervations. Cataract, the main pathology of the lens, occurs as a result of direct alterations to protein folding, stability or solubility, or indirectly via altered cellular physiology.

Brain-derived neurotrophic factor (BDNF) is implicated as a causal factor in major depression and is critical to placental development during pregnancy. Longitudinal data on BDNF across the perinatal period are lacking. These data are of interest given the potential implications for maternal mood and fetal growth, particularly among Black women who show ∼2-fold greater risk for delivering low birth weight infants.Serum BDNF, serum cortisol, and depressive symptoms (per CES-D) were assessed during each trimester and 4-11 weeks postpartum among 139 women (77 Black, 62 White). Low birth weight (2500g) was determined via medical record.Serum BDNF declined considerably from 1st through 3rd trimesters (ps≤0.008) and subsequently increased at postpartum (p0.001). Black women exhibited significantly higher serum BDNF during the 1st trimester, 2nd trimester, and postpartum (ps≤0.032) as well as lower serum cortisol during the 2nd and 3rd trimester (ps≤0.01). Higher serum cortisol was concurrently associated with lower serum BDNF in the 2nd trimester only (p0.05). Controlling for race, serum BDNF at both the 2nd and 3rd trimester was negatively associated with 3rd trimester depressive symptoms (ps≤0.02). In addition, women delivering low versus healthy weight infants showed significantly lower serum BDNF in the 3rd trimester (p=0.004). Women delivering low versus healthy weight infants did not differ in depressive symptoms at any time point during pregnancy (ps≥0.34).Serum BDNF declines considerably across pregnancy in Black and White women, with overall higher levels in Blacks. Lower serum BDNF in late pregnancy corresponds with higher depressive symptoms and risk for low birth weight in Black and White women. However, the predictive value of serum BDNF in pregnancy is specific to within-race comparisons. Potential links between racial differences in serum BDNF and differential pregnancy-related cortisol adaptation require further investigation.

VS between the patients’ symptoms and their clinical signs (P 1⁄4 .175 and r 1⁄4 .219). Conclusions: These results indicate that the VCSS and the C of CEAP may also be useful in the assessment of PTS severity, and that the VFI may provide a clinically meaningful hemodynamic evaluation. These results also confirm that the VS remains the gold standard disease specific assessment in the evaluation of PTS.

The complete plastid genome sequence of the American cranberry (Vaccinium macrocarpon Ait.) was reconstructed using next-generation sequencing data by in silico procedures. We used Roche 454 shotgun sequence data to isolate cranberry plastid-specific sequences of"HyRed" via homologycomparisonswithcompletesequencesfromseveral species available at the National Center for Biotechnology Information database. Eleven cranberry plastid contigs were selected for the construction of the plastid genome-based homologies and on raw reads flowing through contigs and connection information. We assembled and annotated a cran- berry plastid genome (82,284 reads; 185x coverage) with a length of 176 kb and the typical structure found in plants, but with several structural rearrangements in the large single-copy region when compared to other plastid asterid genomes. To evaluate the reliability of the sequence data, phylogenetic analysis of 30 species outside the order Ericales (with 54 genes) showed Vaccinium inside the clade Asteridae ,a s reported in other studies using single genes. The cranberry plastid genome sequence will allow the accumulation of crit- ical data useful for breeding and a suite of other genetic studies.

Political mobilization by the Church of Jesus Christ of Latter-Day Saints against ratification of the Equal Rights Amendment (ERA) was more widespread and important than most studies of the episode have acknowledged. Several decades later, the Church is again organized and active in opposing legal recognition of same-sex marriage. In this article, we explore why and how the Latter-Day Saints mobilized on these two issues. We argue that their mobilization can be understood through classic social movement theory, even though the Church is not an economic-based interest group. Furthermore, the Mormons' approach in fighting the ERA — drawing on centralized authority, tapping into established volunteer and communications networks, effectively channeling money and personnel to where they are most needed, and engaging in stealth politics (obscuring the centralized nature of apparently spontaneous action) — is echoed in the fight against same-sex marriage, even though the times and technology have somewhat changed the mobilization dynamic.

Background The 0+5 integrated vascular residency training pathway was established in 2006 to allow for trainee-focused training culminating in vascular surgery certification only. An early concern was whether enough medical students could be recruited directly into a vascular internship without the exposure that a general surgery residency provides. We hypothesized that programs that send a large percentage of their general surgical graduates to vascular fellowships have models that can be adapted to medical student recruitment. Methods Opinions and practices were sought from program directors through survey and from trainees taking the Vascular Surgery In-Training Examination. Results Eight programs were identified that sent 20% or more of their residents to vascular fellowships over the past 5 years (projecting a mean of 1.6 residents entering vascular fellowships in 2011). Almost all such programs have a formal mentoring system in place that match mentors to residents by interest, and almost all send residents to academic meetings before their senior year. Seventy-five percent of such programs have formal vascular lecture exposure to the first and second year medical student classes, offer clinical shadowing experiences, and have time on the vascular service during the MS3 clerkship; 83% offer a third- or fourth-year elective in vascular surgery. Vascular Surgery In-Training Examination responses were collected from 156 fellows and 13 “0+5” residents. Although fellows had initially been attracted to vascular surgery by the technical aspects of the field learned during residency (43%), the most important factor initially attracting medical students was an interested mentor (46%). However, the most important factor for both residents and students in making a final decision was the technical aspects of the field (66% and 63%, respectively). Conclusions Although residents are automatically exposed to the field during residency, students can only be exposed to vascular surgery if a conscious effort is made by interested educators. Programs that send a high proportion of students and residents into vascular surgery tend to have planned exposure at the MS1 and MS2 levels, formal clinical rotations in place at the MS3 and MS4 levels, and pay personal attention to those who display interest. A guide is presented to help specifically plan these steps. Successful recruiting of students into a 0+5 integrated training program requires specific planning and action.

This study explored how the physical context of a species enclosure might affect visitor exploration of the exhibit space. Tracking and timing studies were conducted in 2 different designs of an exhibition space focused on African apes to determine if the new, more naturally designed exhibit was explored in a manner different from the former, more traditionally designed space. Observations of 825 individuals demonstrated that visitors spent 59% more time within the more naturalistic setting and moved more slowly through the space compared with the more traditional structure. In addition, significantly fewer visitors engaged in inappropriate glass tapping within the new space. The naturalistic design seemed to affect certain groups more than others, as females tended to have longer visit durations and adults tended to observe the resident apes more than children. This research highlights the importance of physical context to the overall learning experience of visitors to zoos and assists in unders...

R-flurbiprofen, a nonsteroidal anti-inflammatory drug derivative, has been shown to inhibit colonic adenoma formation in mice. We investigated the effects of R-flurbiprofen on cell proliferation and apoptosis in pituitary adenoma cell lines. GH4C1 rat pituitary cell line cultures and low-passage human primary pituitary cell cultures were treated with varying concentrations of R-flurbiprofen (0.1-1.0 mM). R-flurbiprofen inhibited cell proliferation in a dose-dependent fashion. A terminal deoxynucleotidyl transferase dUTP nick end labeling assay and chromatin condensation/dead cell apoptosis assay demonstrated induction of apoptosis at higher concentrations of R-flurbiprofen. R-flurbiprofen decreases cell proliferation and induces apoptosis in pituitary adenoma cells in vitro. This may be a potential therapy in the management of pituitary adenoma.

Rationnelle Les fistules arterio-veineuses autologues sont frequemment menacees par une obstruction veineuse centrale. Bien que ceci soit frequemment attribue aux catheters centraux et au remodelage veineux neointimal, nous croyons que la compression extrinseque de la veine sous-claviere a la traversee de la jonction costo-claviculaire (JCC) peut jouer un role significatif dans un sous-groupe de dialyses. Methodes Nous avons passe en revue notre experience de la decompression de la JCC pour dysfonctionnement de fistule arterio-veineuse dans notre etablissement. La decompression a suivi les principes du traitement du syndrome du defile thoraco-brachial veineux : decompression osseuse avec la phlebolyse complete, suivi de phlebographie central par la fistule et traitement endovasculaire si besoin. Les patients ont eu une resection de la premiere cote par voie axillaire, ou resection de la clavicule en position en supination dans les cas quand une reconstruction etait prevue. Dans tous les cas, l'exposition minimum a inclus la mobilisation 360° de la veine sous-claviere avec la resection du tissus cicatriciel environnant la jonction jugulaire/innominee. Resultats Un total de 10 patients ayant besoin d'une decompression entre novembre 2008 et fevrier 2010 ont ete inclus. Tous avaient un œdeme severe du bras, quatre avaient un dysfonctionnement de dialyse (saignement de apres cannulation ou echec de maturation), deux avaient une douleur severe du bras, et un avait un faux-anevrysme. Tous les patients avaient une stenose de veine sous-claviere a la JCC a la phlebographie ou a l'echographie endovasculaire. La majorite de patients avaient eu une dilatation par ballon (moyenne : 2,3 tentatives) sans succes. Six patients ont eu une resection par voie axillaire de la premiere cote et quatre une resection de la clavicule mediale. Aucun patient n'a necessite une reconstruction veineuse chirurgicale. En tout, 80% des fistules sont restees fonctionnellement permeable, et tous sauf un patient (qui a eu une ligature) ont eu une disparition complete de l'œdeme de membre superieur. La duree mediane de sejour etait de 2 jours et le suivi moyen etait de 7 mois (extremes, 1-13). Il n'y a eu aucun deces ni morbidite significative. Cinq patients ont eu besoin secondairement de plastie de veine centrale (quatre sous-claviere, moyenne : 1,8 tentative et un tronc veineux innomine) et trois ont necessite la mise en place de stents (deux sous-claviers, un innomine). Conclusion Un nombre significatif de patients presentant l'acces vasculaire pour hemodialyse menace par une obstruction veineuse centrale ont des lesions attribuables a la compression de la JCC. La decompression chirurgicale par resection de la premiere cote ou de la clavicule et phlebolyse a permis une recuperation fonctionnelle asymptomatique chez 80% de ces patients, qui auraient tous perdu leur acces autrement. Puisque la reconstruction chirurgicale est rarement necessaire, la voie axillaire peut etre preferable a la resection de la clavicule. Cette lesion devrait etre specifiquement recherchee, et les principes du traitement du syndrome du defile thoraco-brachial veineux semblent s'appliquer et etre efficaces.

Historically, epidemiology, diagnosis, and management of venous trauma have not been well understood. Venous injuries often have subtle presentations, unclear consequences, and debatable treatment options. Many venous injuries are asymptomatic and are diagnosed only during surgical exploration for other injuries. The obvious venous injury is the one found during surgical exploration of an arterial trauma. Isolated venous injuries are difficult to diagnose and often only discovered if massive swelling or life-threatening hemorrhage occurs. Once discovered, the question is how to treat: ligation or repair. The answer is the prudent use of both methods. For patients at the brink of hemodynamic collapse, ligation is the best choice. For stable patients, an effort should be made to reestablish venous outflow. Definitive repair in unstable patients should not attempted, instead temporary solutions should be used that will allow the patient to leave the operating room quickly and began correction of hypothermia, acidosis, and coagulopathy.