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Background Obtaining steroid-free remission in Ulcerative Colitis (UC) is a clinically important parameter that can mitigate the development of disease-related complications and lead to improved quality of life. Aims A systematic review to assess the effects and safety of methotrexate for induction in patients with UC. Methods MEDLINE, EMBASE, CENTRAL were searched from inception to August 20, 2020. Randomized controlled trials (RCTs) comparing methotrexate with placebo or an active comparator in patients with active ulcerative colitis were considered for inclusion. The primary outcome measure was the proportion of patients who achieved clinical remission and withdrawal from steroids as defined by the studies and expressed as a percentage of the total number of patients randomized (intention-to-treat analysis). The overall quality of the evidence supporting the primary outcome was assessed using the GRADE criteria. Results Three studies (n=212) were included in the review. Two studies were randomized controlled trials comparing methotrexate to placebo for induction of remission of active ulcerative colitis. The first study (n = 67) compared oral methotrexate (12.5 mg/week) to placebo. Forty-seven percent (14/30) of methotrexate patients achieved clinical remission and complete withdrawal from steroids during the study period compared to 49% (18/37) of placebo patients (RR 0.96, 95% CI 0.58 to 1.59). A GRADE analysis indicated that the overall quality of the evidence supporting this outcome was low due to very sparse data. The second study (n=111) compared subcutaneous/intramuscular methotrexate 25 mg/week to placebo. The primary outcome, steroid-free remission at week 16, was present in 32% (19/60) of patients on methotrexate in comparison to 20%(10/51) of patients in the placebo arm (RR 1.62; 95% CI 0.83 to 3.15; P-value of 0.15). A GRADE analysis indicated downgrading of the evidence to low given very sparse data (29 events). An additional head-to-head randomised controlled study (n = 34) compared oral methotrexate (15 mg/week) to 6-mercaptopurine (1.5 mg/kg/day) and 5-aminosalicylic acid (3 g/day). This final study was judged to be at high risk of bias due to an open-label design. At 30 weeks, 58% (7/12) of methotrexate patients achieved clinical remission and withdrawal from steroids compared to 79% (11/14) of 6-mercaptopurine patients (RR 0.74, 95% CI 0.43 to 1.29) and 25% (2/8) of 5-aminosalicylic acid patients (RR 2.33, 95% CI 0.64 to 8.49). GRADE analyses indicated that the overall quality of the evidence was very low due to very sparse data and high risk of bias. Conclusions Methotrexate demonstrated no benefit over placebo or active comparators for the induction of steroid-free remission. Future research is ongoing to explore the utility of combination therapy with monoclonal antibody biologic therapy for the treatment of active ulcerative colitis. Funding Agencies None

We present a rare case of prostatic endobronchial metastases that was successfully treated with total androgen blockade (TAB). This case demonstrates prolonged remission on continuous TAB and continued remission employing intermittent therapy.

This chapter summarizes research on the reproductive neuroendocrine effects of neuropeptide Y (NPY) and related peptides, especially pancreatic polypeptide (PP). NPY research actually began with studies of avian and bovine PP isolated from pancreatic extracts. The degree of sequence homology between NPY and PP prompted immunohistochemists to preabsorb aPP and bPP antisera with NPY before use. Piscine forms of PP are more similar to mammalian NPY than the mammalian PPs. Prepro-NPY is processed to generate three peptides, an N-terminal signal peptide of 28 residues, NPY itself composed of 36 amino acids, and a C-terminal flanking peptide of NPY called C-terminal flanking peptide of NPY. A serious limitation in NPY research at this time is the lack of specific NPY receptor agonists and antagonists to study the physiology and pharmacology of NPY receptors. The biochemical and anatomical studies of NPY receptors have relied on a molar excess of NPY to displace binding of radiolabeled NPY.

Two experiments investigated the effects of the number of health recommendations (e.g., quit smoking; relax for a day) contained in a health-promotion message on recommendation recall and intentions to enact the recommendations. We hypothesized that if recommendations are stored individually, a higher number of presented recommendations will increase the number of recalled recommendations. As the number of recommendations increases, however, recipients are likely to summarize more recommendations as part of a single, more general theme (or header), resulting in a decrease in the proportion of recalled recommendations. Two experiments ( N = 193 and N = 266) found that the total number of recalled recommendations increased and the proportion of recalled recommendations decreased with the number of presented recommendations. Experiment 2 replicated the findings with the number and the proportion of intended behaviors. The implications of these findings for future behavioral health interventions are discussed.

Directing attention voluntarily to the location of a visual target results in an amplitude reduction (desynchronization) of the occipital alpha rhythm (8-14Hz), which is predictive of improved perceptual processing of the target. Here we investigated whether modulations of the occipital alpha rhythm triggered by the involuntary orienting of attention to a salient but spatially non-predictive sound would similarly influence perception of a subsequent visual target. Target discrimination was more accurate when a sound preceded the target at the same location (validly cued trials) than when the sound was on the side opposite to the target (invalidly cued trials). This behavioral effect was accompanied by a sound-induced desynchronization of the alpha rhythm over the lateral occipital scalp. The magnitude of alpha desynchronization over the hemisphere contralateral to the sound predicted correct discriminations of validly cued targets but not of invalidly cued targets. These results support the conclusion that cue-induced alpha desynchronization over the occipital cortex is a manifestation of a general priming mechanism that improves visual processing and that this mechanism can be activated either by the voluntary or involuntary orienting of attention. Further, the observed pattern of alpha modulations preceding correct and incorrect discriminations of valid and invalid targets suggests that involuntary orienting to the non-predictive sound has a rapid and purely facilitatory influence on processing targets on the cued side, with no inhibitory influence on targets on the opposite side.

The approach to reducing the current harm from the COVID-19 disease is to mandate or encourage an array of social distancing behaviors. These behaviors have the negative effects of reducing GDP, personal incomes, and increasing unemployment leading to calls for opening up the economy and thereby reducing social distancing. This makes more sense to do in developing economies which lack the private and public safety nets to compensate for the lost income. However, if this opening-up policy is followed, we suggest that social distancing be maintained at the level that minimizes deaths.

Precision medicine tools are currently making their way into the clinic and being utilized to diagnose, prognose, and individualize cancer care. The multi‐gene expression‐based assay, Oncotype DX® (ODX), is a genomic tumor profiling tool that determines the expression of 21 tumor‐ associated genes; it helps determine the risk for distant recurrence and whether chemotherapy is an appropriate course of treatment in patients with early stage, estrogen receptor (ER) positive, HER2 negative, and lymph node negative (or 1–3 positive lymph nodes) invasive BCa. The aim of this study was to determine the overall utilization and uptake of the ODX genomic test in a cross‐sectional analysis of the Virginia Tumor registry, compare utilization in African Americans (AAs) and Caucasian Americans (CAs), and determine the profile of patients referred for testing. Caucasian (89.7%) patients made up the majority of the ODX testers compared to AAs (10.3%) (P

Recent technological developments—in genomics, bioinformatics and high-throughput experimental techniques—are providing opportunities to study ongoing human transposable element (TE) activity at an unprecedented level of detail. It is now possible to characterize genome-wide collections of TE insertion sites for multiple human individuals, within and between populations, and for a variety of tissue types. Comparison of TE insertion site profiles between individuals captures the germline activity of TEs and reveals insertion site variants that segregate as polymorphisms among human populations, whereas comparison among tissue types ascertains somatic TE activity that generates cellular heterogeneity. In this review, we provide an overview of these new technologies and explore their implications for population and clinical genetic studies of human TEs. We cover both recent published results on human TE insertion activity as well as the prospects for future TE studies related to human evolution and health.

Background and Aims: The Crohn’s Disease Endoscopic Index of Severity [CDEIS] and Simplified Endoscopic Score for Crohn’s Disease [SES-CD] demonstrate consistent overall intra- and inter-rater reliability. However, the reliability of some index items is relatively poor. We evaluated scoring conventions to improve the reliability of these items. Methods: Five gastroenterologists with no previous experience scoring the CDEIS or SES-CD were trained on their use. A total of 65 video recordings of colonoscopies were scored blindly by each gastroenterologist before and after additional training on index scoring conventions. Intra-class correlation coefficients [ICCs] assessed the effect of application of these conventions on the reliability of the CDEIS, SES-CD, and a Global Evaluation of Lesion Severity [GELS] score. Results: Following training on scoring conventions, inter-rater ICCs (95% confidence interval [CI]) for the total SES-CD score increased from 0.78 [0.71, 0.85] to 0.85 [0.79, 0.89]. The ICCs for the total CDEIS and GELS scores were not affected: corresponding inter-rater ICCs were 0.74 [0.65, 0.81] and 0.49, [0.38, 0.61] before and 0.73 [0.65, 0.81] and 0.53 [0.42, 0.64] following application of scoring conventions. Estimations of ulcer depth, surface area, anatomical location, and stenosis were important sources of variability. Conclusions: Use of scoring conventions previously developed by expert central readers enhanced the reliability of the SES-CD but did not similarly affect the CDEIS or GELS. As the SES-CD is more likely to be reliable than the CDEIS and can be optimised with targeted training, it is the preferred instrument for use in clinical trials.

Cancer incidence and mortality rates in the United States (US) are not equitably distributed among all population groups, especially for racial and ethnic minorities. While non-genetic factors, including socioeconomic and environmental differences, have long been cited as the main contributors to cancer health disparities (CHD), new evidence points to a possible role of genetic and biological differences in CHD but with limited understanding and remain largely undiscovered. In this study, disparities in cancer survival outcome among US population groups were characterized based on self-identified race and ethnicity (SIRE) and genetic ancestry (GA), using univariate and multivariate survival analyses. Moreover, group-specific gene expression and mutation signatures that contribute to cancer survivorship disparities were systematically analyzed using feature selection and multiple and generalized linear regression models. Kaplan-Meier analysis of overall survival of The Cancer Genome Atlas (TCGA) cohort showed significantly different survival probability for the following GA groups: East Asian (EA) vs. European (EU) in head and neck squamous cell carcinoma (HNSC), African (AF), EA and EU vs. Admixed American (AA) in kidney renal clear cell carcinoma (KIRC), and EA, AA vs. EU and EA vs. AA in skin cutaneous carcinoma (SKCM). Multivariate Cox proportional hazard modeling using GA showed significantly greater risk of mortality for AF compared to EU (hazard ratio(HR)= 1.838, p= 0.021) with breast invasive carcinoma (BRCA) and HNSC (HR= 2.01, p= 0.005), Native Americans (NA) compared to EU (HR= 1.36, p= Citation Format: Kara Keun Lee, John F. McDonald, King I. Jordan. The effect of genetic ancestry and molecular signatures on cancer survival disparities: A pan-cancer analysis [abstract]. In: Proceedings of the AACR Virtual Conference: Thirteenth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2020 Oct 2-4. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(12 Suppl):Abstract nr PO-002.

Evening-type individuals often perform poorly in the morning because of a mismatch between internal circadian time and external social time, a condition recognized as social jet lag. Performance impairments near the morning circadian (~24 hr) trough have been attributed to deficits in attention, but the nature of the impairment is unknown. Using electrophysiological indices of attentional selection (N2pc) and suppression (PD ), we show that evening-type individuals have a specific disability in suppressing irrelevant visual distractions. More specifically, evening-type individuals managed to suppress a salient distractor in an afternoon testing session, as evidenced by a PD , but were less able to suppress the distractor in a morning testing session, as evidenced by an attenuated PD and a concomitant distractor-elicited N2pc. Morning chronotypes, who would be well past their circadian trough at the time of testing, did not show this deficit at either test time. These results indicate that failure to filter out irrelevant stimuli at an early stage of perceptual processing contributes to impaired cognitive functioning at nonoptimal times of day and may underlie real-world performance impairments, such as distracted driving, that have been associated with circadian mismatch.

e15091 Background: Colorectal cancer is one of the three most prevalent cancers. Mortality rates have largely decreased due, in part, to advanced treatments such as platinum-based chemotherapy (e.g. oxaliplatin – OX). Unfortunately, OX induces severe off-target, neurotoxic side-effects in the sensory nervous system that can limit or end treatment and diminish patient quality of life for years. Patient symptoms are often attributed to dying-back degeneration of primary sensory axons despite the absence of conclusive evidence. We tested the hypothesis that proprioceptive disorders persisting after chemotherapy result solely from axon degeneration of muscle proprioceptors. Methods: We used a rat model to test our hypothesis. In a rodent model of OX clinical cancer treatment, one that exhibits sensorimotor deficits in a test of proprioceptive behavior, we performed single-neuron in vivo electrophysiological and immunohistological experiments. We then profiled transcriptomes of sensory neurons to gain unbiased insight into molecular evidence of degeneration. We compared the OX group of rats (n = 18) to healthy, control rats (n = 6) using hierarchical Bayesian analysis. Results: We found no evidence for sensory axon degeneration in electrophysiologic measures of axon conduction or in immunohistochemical analysis of the axon terminals of sensory neurons, OX and control rats were indistinguishable by these measures. Unbiased transcriptional profiling gave little evidence of neuronal degeneration, although genes related to axon transport showed signs of dysregulation. Structural degeneration was also ruled out by finding that all sensory neurons fired in response to stretch. Nonetheless, anomalous firing patterns were observed, e.g. decreased spike activity in response to mechanosensory stimulation, consistent with changes in ion channel physiology. Conclusions: Our findings reject the hypothesis that nerve degeneration is required to explain OX-related sensorimotor disorders. Our research suggests biological mechanisms that are alternative to axon degeneration in explaining sensorimotor changes due to OX.

Participation in sailing by people with disabilities, particularly in small sailboats, is widely regarded as having positive outcomes on self-esteem and general health for the participants. However, a major hurdle for people with no previous experience of sailing, even by those without disabilities, is the perception that sailing is elitist, expensive, and dangerous. Real-time "ride-on" sailing simulators have the potential to bridge the gap between dry-land and on-the-water sailing. These provide a realistic, safe, and easily supervised medium in which nonsailors can easily and systematically learn the required skills before venturing out on the water. The authors report a 12-wk pilot therapeutic sailing program using the VSail-Access sailing simulation system followed by on-water experience. After completion of the training, all subjects demonstrated the ability to navigate a simple course around marker buoys (triangular configuration) on the computer screen, the ability to sail independently in winds of moderate strength (up to 14 knots) on water, and measurable improvements in their psychologic health. In addition, the subjects were able to participate in a sports activity with their respective family members and experienced a sense of optimism about their future. Language: en

To examine the effect of long-term lower extremity functional electrical stimulation (FES) cycling on the physical integrity and functional recovery in people with chronic spinal cord injury (SCI).Retrospective cohort, mean follow-up 29.1 months, and cross-sectional evaluation.Washington University Spinal Cord Injury Neurorehabilitation Center, referral center.Twenty-five people with chronic SCI who received FES during cycling were matched by age, gender, injury level, and severity, and duration of injury to 20 people with SCI who received range of motion and stretching.Lower extremity FES during cycling as part of an activity-based restorative treatment regimen.Change in neurological function: motor, sensory, and combined motor-sensory scores (CMSS) assessed by the American Spinal Injury Association Impairment scale. Response was defined as ≥ 1 point improvement.FES was associated with an 80% CMSS responder rate compared to 40% in controls. An average 9.6 CMSS point loss among controls was offset by an average 20-point gain among FES subjects. Quadriceps muscle mass was on average 36% higher and intra/inter-muscular fat 44% lower, in the FES group. Hamstring and quadriceps muscle strength was 30 and 35% greater, respectively, in the FES group. Quality of life and daily function measures were significantly higher in FES group.FES during cycling in chronic SCI may provide substantial physical integrity benefits, including enhanced neurological and functional performance, increased muscle size and force-generation potential, reduced spasticity, and improved quality of life.

Previous studies report professional athletes return to play following arthroscopic microfracture of the hip for chondral defects. Our hypothesis is that professional hockey players undergoing arthroscopic microfracture for chondral defects of the hip achieve the same performance they had pre-injury and compared to matched controls. Seventeen professional hockey players underwent arthroscopic microfracture for an Outerbridge grade IV chondral lesion. Concomitant procedures for labral pathology or FAI were included. Performance data for the full season preceding and following index procedure were analysed, in addition to two matched control players per subject. Data were collected at two points, 2 years apart. Eighty-two per cent (14/17) of players who underwent arthroscopic microfracture returned to play. The year prior to injury for the 14 players who returned was compared to the average of their individual controls. There was no statistical difference between the groups for age, number of seasons in the league, games played, time on ice, points, save percentage, and shots against goal. Post-operatively, there was no statistical difference between the treatment and control groups regarding performance measures. There was a trend towards a decrease in games played and points post-operatively compared with controls. The treatment group decreased 11 games played, while the controls decreased five games. The treatment group also decreased 14 points, while the controls decreased three points for the season. Professional hockey players with a discrete, full-thickness chondral defect of the hip are able to return to elite performance level following an arthroscopic microfracture procedure when compared to pre-injury outcomes and controls. III.

Although stromal cell signaling has been shown to play a significant role in the progression of many cancers, relatively little is known about its importance in modulating ovarian cancer development. The purpose of this study was to investigate the process of stroma activation in human ovarian cancer by molecular analysis of matched sets of cancer and surrounding stroma tissues. RNA microarray profiling of 45 tissue samples was carried out using the Affymetrix (U133 Plus 2.0) gene expression platform. Laser capture microdissection (LCM) was employed to isolate cancer cells from the tumors of ovarian cancer patients (Cepi) and matched sets of surrounding cancer stroma (CS). For controls, ovarian surface epithelial cells (OSE) were isolated from the normal (noncancerous) ovaries and normal stroma (NS). Hierarchical clustering of the microarray data resulted in clear separations between the OSE, Cepi, NS, and CS samples. Expression patterns of genes encoding signaling molecules and compatible receptors in the CS and Cepi samples indicate the existence of two subgroups of cancer stroma (CS) with different propensities to support tumor growth. Our results indicate that functionally significant variability exists among ovarian cancer patients in the ability of the microenvironment to modulate cancer development.

The Crohn's Disease Endoscopic Index of Severity (CDEIS) and the Simple Endoscopic Score for Crohn's Disease (SES-CD) are commonly used to assess Crohn's disease (CD) activity; however neither instrument is fully validated. We evaluated the responsiveness to change of the SES-CD and CDEIS using data from a trial of adalimumab, a drug therapy of known efficacy. Paired video recordings (N=112) of colonoscopies (baseline and week 8-12) obtained from patients with CD who participated in a trial of adalimumab therapy were reviewed in random order, in duplicate, by four central readers (56 pairs of videos by 2 groups of readers). Responsiveness of the SES-CD and the CDEIS was evaluated by comparing correlations between the observed and pre-specified predictions of change scores for these endoscopic indices with a global endoscopic evaluation of severity (GELS), a patient reported outcome (PRO2), and the Crohn's disease activity index (CDAI), and by calculation of the standardized effect size, and Guyatt's Responsiveness statistic (GRS) using 2 definitions of change; (1) treatment assignment and (2) an absolute change in total PRO2 of 50. The potential application of effect size estimates was demonstrated by calculating hypothetical sample sizes for comparing two independent groups. The impact of removing stenosis as an index item and adjusting for the number of segments observed was also assessed. Changes in both endoscopic instruments and the GELS were highly correlated. The SES-CD displayed numerically higher effect sizes for both definitions of change. The standardized effect size and GRS estimates (95% confidence interval) for the SES-CD based on treatment assignment were 0.84 (0.53, 1.15) and 0.79 (0.48, 1.09). Corresponding values for the CDEIS were 0.72 (0.42, 1.02) and 0.75 (0.45, 1.06). The standardized effect size and GRS estimates for the SES-CD based on an absolute change in total PRO2 of 50 points or greater were 0.76 (0.49, 1.02) and 0.93 (0.64, 1.21). Corresponding values for CDEIS were 0.70 (0.44, 0.97), 0.83 (0.55, 1.10). Removal of stenosis as an index item and adjusting for observed segments did not improve responsiveness estimates. Although both the SES-CD and CDEIS are valid measures of endoscopic disease activity that are moderately responsive to changes in endoscopic disease activity, the SES-CD displayed numerically greater responsiveness in this data set

A functionalized nanohydrogel siRNA delivery system and a mouse model of serous ovarian cancer were used to test predictions from previous cell line studies that knockdown of EGFR (epidermal growth factor receptor) may be of clinical significance in the treatment of epithelial tumors especially with respect to the enhancement of platinum based therapies. Our results support these predictions and suggest that targeted delivery of EGFR siRNA may be an effective strategy for the treatment of ovarian and other epithelial tumors associated with elevated levels of EGFR and especially those demonstrating resistance to platinum-based therapies.

Background Maintenance of remission is a major issue in inflammatory bowel disease. In ulcerative colitis, the evidence for the effectiveness of azathioprine and 6-mercaptopurine for the maintenance of remission is still controversial. Objectives To assess the effectiveness and safety of azathioprine and 6-mercaptopurine for maintaining remission of ulcerative colitis. Search methods The MEDLINE, EMBASE and Cochrane Library databases were searched from inception to 30 July 2015. Both full randomized controlled trials and associated abstracts were included. Selection criteria Randomized controlled trials of at least 12 months duration that compared azathioprine or 6-mercaptopurine with placebo or standard maintenance therapy (e.g. mesalazine) were included. Data collection and analysis Two authors independently extracted data using standard forms. Disagreements were solved by consensus including a third author. Study quality was assessed using the Cochrane risk of bias tool. The primary outcome was failure to maintain clinical or endoscopic remission. Secondary outcomes included adverse events and withdrawal due to adverse events. Analyses were performed separately by type of control (placebo, or active comparator). Pooled risk ratios were calculated based on the fixed-effect model unless heterogeneity was shown. The GRADE approach was used to assess the overall quality of evidence for pooled outcomes. Main results Seven studies including 302 patients with ulcerative colitis were included in the review. The risk of bias was high in three of the studies due to lack of blinding. Azathioprine was shown to be significantly superior to placebo for maintenance of remission. Fourty-four per cent (51/115) of azathioprine patients failed to maintain remission compared to 65% (76/117) of placebo patients (4 studies, 232 patients; RR 0.68, 95% CI 0.54 to 0.86). A GRADE analysis rated the overall quality of the evidence for this outcome as low due to risk of bias and imprecision (sparse data). Two trials that compared 6-mercaptopurine to mesalazine, or azathioprine to sulfasalazine showed significant heterogeneity and thus were not pooled. Fifty per cent (7/14) of 6-mercaptopurine patients failed to maintain remission compared to 100% (8/8) of mesalazine patients (1 study, 22 patients; RR 0.53, 95% CI 0.31 to 0.90). Fifty-eight per cent (7/12) of azathioprine patients failed to maintain remission compared to 38% (5/13) of sulfasalazine patients (1 study, 25 patients; RR 1.52, 95% CI 0.66 to 3.50). One small study found that 6-mercaptopurine was superior to methotrexate for maintenance of remission. In the study, 50% (7/14) of 6-mercaptopurine patients and 92% (11/12) of methotrexate patients failed to maintain remission (1 study, 26 patients; RR 0.55, 95% CI 0.31 to 0.95). One very small study compared azathioprine with cyclosporin and found that there was no significant difference between patients failing remission on azathioprine (50%, 4/8) or cyclosporin (62.5%, 5/8) (1 study, 16 patients, RR 0.80 95% CI 0.33 to 1.92). When placebo-controlled studies were pooled with aminosalicylate-comparator studies to assess adverse events, there was no statistically significant difference between azathioprine and control in the incidence of adverse events. Nine per cent (11/127) of azathioprine patients experienced at least one adverse event compared to 2% (3/130) of placebo patients (5 studies, 257 patients; RR 2.82, 95% CI 0.99 to 8.01). Patients receiving azathioprine were at significantly increased risk of withdrawing due to adverse events. Eight per cent (8/101) of azathioprine patients withdrew due to adverse events compared to 0% (0/98) of control patients (5 studies, 199 patients; RR 5.43, 95% CI 1.02 to 28.75). Adverse events related to study medication included acute pancreatitis (3 cases, plus 1 case on cyclosporin) and significant bone marrow suppression (5 cases). Deaths, opportunistic infection or neoplasia were not reported. Authors' conclusions Azathioprine therapy appears to be more effective than placebo for maintenance of remission in ulcerative colitis. Azathioprine or 6-mercaptopurine may be effective as maintenance therapy for patients who have failed or cannot tolerate mesalazine or sulfasalazine and for patients who require repeated courses of steroids. More research is needed to evaluate superiority over standard maintenance therapy, especially in the light of a potential for adverse events from azathioprine. This review updates the existing review of azathioprine and 6-mercaptopurine for maintenance of remission in ulcerative colitis which was published in the Cochrane Library (September 2012).

Introduction Vulvodynia is a common pain disorder among women with a major impact on sexual functioning and quality of life. There are few published studies addressing the treatment of the pain of generalized vulvodynia or of generalized vulvodynia accompanying localized pain in the region of the vulvar vestibule. Aim A prospective, noncontrolled pilot study was conducted to assess the efficacy of a novel treatment using caudal epidural, pudendal nerve block, and vulvar infiltration of local anesthetic agents. Main Outcome Measures The main outcome measure was vulvar pain as assessed by the McGill Pain Questionnaire (MPQ). The secondary outcome measures were depressed mood evaluated with the Beck Depression Inventory (BDI) and sexual functioning assessed by the Female Sexual Functioning Inventory (FSFI). Methods Thirty‐two women with vulvodynia met inclusion criteria and 26 women completed the study. The protocol included five treatment sessions with multilevel local anesthetic nerve blockade and a follow‐up contact or visit 2–3 months later. Results There were significant improvements in vulvar pain as determined by both the sensory and affective components of the MPQ and in depression as assessed by the BDI. However, there were no changes in sexual functioning on the FSFI. Conclusion Serial multilevel nerve block administered for the treatment of vulvodynia is a neurophysiologically based modality that may be effective and merits a placebo‐controlled study. McDonald JS and Rapkin AJ. Multilevel local anesthetic nerve blockade for the treatment of generalized vulvodynia: A pilot study. J Sex Med 2012;9:2919–2926.

Background: We planned to systematically review the efficacy of sargramostim (granulocyte colony stimulating factor [GM-CSF]) for remission induction in patients with Crohn's disease (CD). Methods: A literature search to April 2011 was performed to identify all randomized trials studying sargramostim in patients with CD. The Cochrane risk of bias tool was used to evaluate study quality and the GRADE criteria were utilized to assess the overall quality of the evidence. Results: Three randomized studies (total 537 patients) were identified. The risk of bias was low for the three included studies. There was no statistically significant difference in the proportion of patients who achieved clinical remission (GM-CSF 25.3%; placebo 17.5%; relative risk [RR] 1.67; 95% confidence interval [CI] 0.80–3.50; P = 0.17), or 100-point clinical response (GM-CSF 38.3%; placebo 24.8%; RR 1.71 95% CI 0.98–2.97; P = 0.06). There was no statistically significant difference in the proportion of patients (GM-CSF 95.8%; placebo 89.3%) who experienced adverse events (RR 1.07; 95% CI 0.99–1.16; P = 0.08), or serious adverse events (GM-CSF 12.0% vs. placebo 4.8%; RR 2.21; 95% CI 0.84–5.81; P = 0.11). Conclusions: Sargramostim does not appear to be more effective than placebo for induction of clinical remission or improvement in active CD. However, the GRADE analysis indicates that the overall quality of the evidence for the primary and secondary outcomes was low due to sparse data and heterogeneity, indicating that further research likely would have a significant impact on the effect estimates. (Inflamm Bowel Dis 2012;)

This article outlines steps to practical application of functional electrical stimulation (FES) within activity-based restorative therapy (ABRT). Drawing from current evidence, specific applications of FES intended to help restore function lost to spinal cord injury and associated neurologic disease are discussed. The medical and therapeutic indications, precautions, and contraindications are reviewed to help participants with appropriate patient selection, treatment planning, and assessment. Also included are the physiological implications of FES and alterable parameters, including dosing and timing, for a desired response. Finally, approaches to improve cortical representation and motor learning and to transition emerging movement into functional tasks are reviewed.

patients with spinal cord injury (SCI) have many factors that are associated with pressure ulcer formation, including paralysis, loss of sensation, poor nutrition, anemia, and skin maceration related to incontinence. Treatment of these ulcers involves relieving pressure, improving nutrition and skin hygiene, treating infections, removing necrotic tissues, and applying the appropriate dressings. However, some cases are not responsive to the above treatment. Electrical stimulation (ES) is thought to enhance soft tissue healing through promotion of protein synthesis, inhibition of bacterial growth, facilitation of epithelial tissue migration, improvement of blood flow, and tensile strength. This data is mainly based on evidence from animal studies and very few rigorously controlled studies conducted in humans.To demonstrate the effectiveness of ES in the treatment of recalcitrant pressure ulcers.Retrospective case series describing the care of adults with SCI and recalcitrant pressure ulcers. ES was applied directly into the wound bed: 60 minutes per session, 3-5 times per week; with an intensity of 100 milliamperes and a frequency of 100 pulses per second. Polarity was negative initially and was switched weekly. The amplitude and wave form were maintained throughout.The long-standing (11-14 months) pressure ulcers were completely healed after 7 to 22 weeks of treatment with high-voltage ES.This case series demonstrates the effectiveness of ES for enhanced healing of Stage III-IV ulcers otherwise unresponsive to standard wound care. Further study is needed to identify the most effective protocol for ES therapy in the treatment of recalcitrant pressure ulcers.

Background: We aimed to systematically review the efficacy of unfractionated heparin (UFH) or low molecular weight heparins (LMWH) for remission induction in patients with ulcerative colitis (UC). Methods: A literature search to April 2011 was performed to identify all randomized trials studying UFH or LMWH use in patients with UC. The Cochrane Risk of Bias Tool was used to assess study quality. Results: LMWH administered subcutaneously showed no benefit over placebo for any outcome, including clinical remission, and clinical, endoscopic, or histological improvement. High-dose LMWH administered via an extended colon-release tablet demonstrated benefit over placebo for clinical remission (odds ratio [OR] 2.73; 95% confidence interval [CI] 1.32–5.67; P = 0.007), clinical improvement (OR 2.99; 95% CI 1.30–6.87; P = 0.01), and endoscopic improvement (OR 2.25; 95% CI 1.01–5.01; P = 0.05) but not endoscopic remission or histologic improvement. LMWH was not beneficial when added to standard therapy for clinical remission, clinical improvement, endoscopic remission, or endoscopic improvement. One study examining UFH versus corticosteroids for the treatment of severe UC demonstrated the inferiority of UFH for clinical improvement. More patients assigned to UFH had rectal hemorrhage as an adverse event. Conclusions: LMWH administered by extended colon-release tablets may be effective for the treatment of active UC. This benefit needs to be confirmed by further randomized controlled studies. The same benefits were not seen when LMWH was administered subcutaneously at lower doses. There is no evidence to support the use of UFH for the treatment of active UC. (Inflamm Bowel Dis 2011;)

The consequences of neurologic injuries related to transverse myelitis (TM) are long-lasting and require rehabilitative interventions in about two-thirds of cases. Because numerous neural repair mechanisms are dependent on maintenance of an optimal amount of activity both above and below the injury level, rehabilitation and exercise are useful not only for compensatory functional purposes but also as tools in neural system restoration. The application of established neurophysiologic principles to post-TM rehabilitation has substantial impact on optimizing residual functional capabilities while facilitating the processes of central plasticity and reorganization of sensory and motor programming. The process of neurorehabilitation thereby serves both to treat the patient with TM and to help physicians interrogate and dissect the mechanisms involved in spinal cord injury, neuroprotection, and, ultimately, recovery. Post-TM rehabilitation is lifelong and should be integrated into daily living in a home setting as part of the global management of paralysis, a chronic condition with significant comorbidities.

Estradiol attenuates the ATP-induced increase of intracellular calcium concentration ([Ca(2+)](i)) in rat dorsal root ganglion (DRG) neurons by blocking the L-type voltage gated calcium channel (VGCC). Because ATP is a putative nociceptive signal, this action may indicate a site of estradiol regulation of pain. In other neurons, 17β-estradiol (E(2)) has been shown to modulate L-type VGCC through a membrane estrogen receptor-group II metabotropic glutamate receptor (mGluR(2/3)). The present study investigated whether the rapid estradiol attenuation of the ATP-induced increase in [Ca(2+)](i) requires mGluR(2/3). Previously we showed that DRG (L(1)-S(3)) express ERα, P2X(3), and mGluR(2/3) receptors. DRG were acutely dissociated by enzyme digestion and grown in short-term culture for imaging analysis. DRG neurons were stimulated twice, once with ATP (50 μM) for 5 sec and then again in the presence of E(2) (100 nM) or E(2) (100 nM) + LY341495 (100 nM), an mGluR(2/3) inhibitor. ATP induced a transient increase in [Ca(2+)](i) (216.3 ± 41.2 nM). This transient increase could be evoked several times in the same DRG neurons if separated by a 5-min washout. Treatment with estradiol significantly attenuated the ATP-induced [Ca(2+)](i) increase in 60% of the DRG neurons, to 163.3 ± 20.9 nM (P 0.05). These data indicate that the rapid action of E(2) in DRG neurons is dependent on mGluR(2/3) and demonstrate that membrane estrogen receptor-α-initiated signaling involves interaction with mGluRs.

Objective Ovarian cancer (OC) is the most lethal of all gynecological malignancies primarily due to the sloughing-off of highly metastatic cells from primary tumors and their subsequent spread throughout the peritoneal cavity. Since the epithelial-to-mesenchymal transition (EMT) of OC cells located at the periphery of primary tumors is essential to this process, molecular interventions that can block EMT are of potential clinical significance. Members of the miR200 family of microRNAs have been implicated in EMT in other cancers. Our purpose was to determine if miR200 family microRNAs may be involved in EMT in OC and of potential therapeutic value in reducing OC metastasis. Methods Gene expression profiles of two OC cell lines with different metastatic potentials were monitored using qRT-PCR (quantitative reverse transcription polymerase chain reaction). The effect of over-expression of a miR-200 family microRNA (miR-429) in metastatic OC cells was monitored on molecular (qRT-PCR and microarray) and functional (morphology, migration, invasiveness and anchorage independence assays) levels. Results Molecular profiling of two OC cell lines with differing metastatic potentials identified significant differences in previously established epithelial and mesenchymal cell biomarkers including E-cadherin, ZEB1, ZEB2, miR-205 and miR-200 family microRNAs. Ectopic overexpression of miR-429, a member of the miR-200 family of microRNAs, in mesenchymal-like OC cells resulted in reversal of the mesenchymal phenotype (mesenchymal–epithelial transition, MET). Conclusions Our results indicate that miR-429 may not only be a useful biomarker of EMT in ovarian cancer, but also of potential therapeutic value in abating OC metastasis.

Multiligament knee injuries pose a challenging clinical situation to even experienced orthopedic surgeons. Although nonoperative treatment of mild varus instability without a cruciate injury has been shown to have acceptable outcomes, it is now accepted that operative management of multiligament inj

Deep venous thrombosis and septic pulmonary embolism are known to occur in association with pediatric musculoskeletal infections. The authors of recent studies have reported an apparent increase in the incidence of this phenomenon, which appears to be related to the rising occurrence of infections caused by methicillin-resistant Staphylococcus aureus 1. Some authors have suggested that the Panton-Valentine leukocidin gene, which may be expressed by methicillin-resistant Staphylococcus aureus , is responsible for severe consequences of infection including necrotizing pneumonia, deep venous thrombosis, septic pulmonary embolism, and an enhanced local inflammatory response leading to abscess formation in tissues adjacent to the site of infection2-5. We previously reported on thirteen children with deep venous thrombosis that occurred in association with osteomyelitis (eleven), septic arthritis (one), or pyomyositis (one), and we identified characteristics of these children that may help to guide clinicians in assessing the relative propensity of a child with musculoskeletal infection to develop deep venous thrombosis6. In that report, 25% of the children above the age of eight years who had osteomyelitis caused by methicillin-resistant Staphylococcus aureus and who presented with a C-reactive protein level of >6 mg/dL were noted to have deep venous thrombosis, but none of the children with deep venous thrombosis in that report had an upper-extremity infection. The majority of the infections occurred adjacent to the knee, involving either the proximal part of the tibia or the distal part of the femur, with the deep venous thrombosis located in the popliteal or femoral vein. We present here the case of a child with acute osteomyelitis of the humerus associated with a deep venous thrombosis in the ipsilateral upper extremity and septic pulmonary embolism. The parents of the patient were informed that data concerning the case would be submitted for publication, and …

Functional electrical stimulation (FES) can restore control and offset atrophy to muscles after neurological injury. However, FES has not been considered as a method for enhancing CNS regeneration. This paper demonstrates that FES dramatically enhanced progenitor cell birth in the spinal cord of rats with a chronic spinal cord injury (SCI). A complete SCI at thoracic level 8/9 was performed on 12 rats. Three weeks later, a FES device to stimulate hindlimb movement was implanted into these rats. Twelve identically-injured rats received inactive FES implants. An additional control group of uninjured rats were also examined. Ten days after FES implantation, dividing cells were marked with bromodeoxyuridine (BrdU). The ‘cell birth’ subgroup (half the animals in each group) was sacrificed immediately after completion of BrdU administration, and the ‘cell survival’ subgroup was sacrificed 7 days later. In the injured ‘cell birth’ subgroup, FES induced an 82-86 % increase in cell birth in the lumbar spinal cord. In the injured ‘cell survival’ subgroup, the increased lumbar newborn cell counts persisted. FES doubled the proportion of the newly-born cells which expressed nestin and other markers suggestive of tripotential progenitors. In uninjured rats, FES had no effect on cell birth/survival. This report suggests that controlled electrical activation of the CNS may enhance spontaneous regeneration after neurological injuries.

This study investigates the patterns of recording birth weight data in retrospective surveys and their influence on birth weight estimates in less developed countries. We hypothesise that the method of reporting birth weight in surveys influences the classification of infants in the low birth weight category. Population-level data from Demographic and Health Surveys conducted in six selected countries representing different regions of the world were used. Birth weight data were reported in the survey from either an official health card or from mother's memory. Birth weight distributions were examined in detail and revised low birth weight estimates were calculated accounting for potential heaping and data inconsistencies. There were substantial differences in the distribution of birth weights by method of reporting. The percentage of infants with low birth weight was higher in all six countries for birth weight recalled from memory than when reported from a health card. Health cards displayed less clustering on certain digits than memory recalled weights, but were still highly heaped in certain countries. Heaping of birth weight data on multiples of 500 g was also observed irrespective of any differences in method of reporting. The study concludes that the method of recording birth weight data can affect birth weight estimates in developing countries. Health systems in poor countries should initiate efforts to systematically monitor the recording of birth weight data ensuring for both quality and comparability at the international levels.

Stroke in the neonatal brain is an understudied cause of neurologic morbidity. Recently we have characterized a new immature mouse model of stroke utilizing unilateral carotid ligation alone to produce infarcts and acute seizures in postnatal day 12 (P12) CD-1 mice. In this study, the amount of poststroke neural progenitor proliferation was examined in the subgranular (SGZ) of the dentate gyrus and the subventricular zone (SVZ) 7, 14, and 21days after ischemia (DAI). A single IP injection (50 mg/kg) of bromodeoxyuridine (BrdU) given 2 hr before perfusion fixation labeled newborn cells. Early cell phenotypes were quantified by colabeling with GFAP, nestin, and DCX. Control mice revealed an age-dependent decrease in neural proliferation, with an approximately 50% drop in BrdU-labeled cell counts at P33 compared with P19 both in the SGZ and in the SVZ. Significant reduction in the amount of neural proliferation in the ipsilateral injured SGZ of ligated mice correlated with both the severity of the stroke-injury and the acute seizure scores. Similar correlations were not detected contralaterally. Contralateral SGZ neural proliferation was initially lowered at 7 DAI but normalized by 21 DAI. In both injured and control brains, approximately 90% of newborn SGZ cells colabeled with nestin, approximately 30% colabeled with GFAP, and a few colabeled with DCX. In contrast, poststroke SVZ cell proliferation was enhanced ipsi- more than contralaterally at 7 DAI. In the SVZ, the enhanced neural proliferation normalized to control levels by P33. In conclusion, the neural cell proliferation was differentially altered in the SGZ vs. SVZ after neonatal stroke.

Background & Aims Selective blockade of lymphocyte–vascular endothelium interactions in the gastrointestinal tract is a promising therapeutic strategy for inflammatory bowel disease. This randomized, double-blind, controlled trial assessed the efficacy and safety of MLN0002, a monoclonal antibody targeting the α4β7 integrin, in patients with active Crohn's disease. Methods Patients were randomized to receive MLN0002 2.0 mg/kg (n = 65), MLN0002 0.5 mg/kg (n = 62), or placebo (n = 58) by intravenous infusion on days 1 and 29. The primary efficacy end point was clinical response (≥70-point decrement in the Crohn's Disease Activity Index [CDAI] score) on day 57. Secondary end points were the proportions of patients with clinical remission (CDAI score ≤150) and with an enhanced clinical response (≥100-point decrement in CDAI). Human anti-human antibody levels were measured. Results Clinical response rates at day 57 were 53%, 49%, and 41% in the MLN0002 2.0 mg/kg, MLN0002 0.5 mg/kg, and placebo groups. Clinical remission rates at day 57 were 37%, 30%, and 21%, respectively ( P = .04 for the 2.0 mg/kg vs placebo comparison). At day 57, 12% and 34% of patients in the 2.0- and 0.5-mg/kg groups had clinically significant human anti-human antibody levels (titers > 1:125). There was one infusion-related hypersensitivity reaction. The most common serious adverse event was worsening of Crohn's disease. Conclusions This phase 2 study was suggestive of a dose-dependent beneficial effect of MLN0002 therapy on clinical remission. MLN0002 was well tolerated in patients with active Crohn's disease.

Progress in regenerative medicine seems likely to produce new treatments for neurologic conditions that use human cells as therapeutic agents; at least one trial for such an intervention is already under way. The development of cell-based interventions for neurologic conditions (CBI-NCs) will likely include preclinical studies using animals as models for humans with conditions of interest. This paper explores predictive validity challenges and the proper role for animal models in developing CBI-NCs. In spite of limitations, animal models are and will remain an essential tool for gathering data in advance of first-in-human clinical trials. The goal of this paper is to provide a realistic lens for viewing the role of animal models in the context of CBI-NCs and to provide recommendations for moving forward through this challenging terrain. © 2009 ISCBFM All rights reserved.

Purpose of review Total hip replacement is one of the safest and most clinically efficacious operations in orthopedic surgery. It has been extended to more and more patient populations over the past four decades. The purpose of this review is to present the contemporary data of total hip replacement in two unique patient populations: obese patients and geriatric patients older than 75 years of age. Recent findings There are unique clinical challenges in these patients. In addition, the clinical outcome and complications are different from more routine total hip replacement populations. Summary The recent research has shown that total hip replacement in the obese and elderly populations can be successful, and should not be denied solely based on these two criteria. There is a need for more research to investigate postoperative instability in the obese patient population, and perioperative mental confusion and cognitive function deterioration in the elderly patient population.

Objective The Crohn9s Disease Endoscopic Index of Severity (CDEIS) and Simple Endoscopic Score for Crohn9s Disease (SES-CD) are commonly used to assess Crohn9s disease (CD) activity; however, neither instrument has been fully validated. We assessed intra-rater and inter-rater reliability of these indices. Design Video recordings of colonoscopies obtained from 50 patients with CD who participated in an induction trial of a biological therapy were triplicated and reviewed in random order by four central readers. Data were used to assess intra-rater and inter-rater reliability for CDEIS, SES-CD and a global evaluation of lesion severity (GELS). Subsequently, readers participated in a consensus process that identified common sources of disagreement. Results Intraclass correlation coefficients (ICCs) for intra-rater reliability for CDEIS, SES-CD and GELS (95% CIs) were 0.89 (0.86 to 0.93), 0.91 (0.89 to 0.95) and 0.81 (0.77 to 0.89), respectively, with standard error of measurement (SEM) of 2.10, 2.42 and 1.15. The corresponding ICCs for inter-rater reliability were 0.71 (0.63 to 0.76), 0.83 (0.75 to 0.88) and 0.62 (0.52 to 0.70), with SEM of 3.42, 3.07 and 1.63, respectively. Correlation between CDEIS and GELS was 0.75, between SES-CD and GELS was 0.74 and between CDEIS and SES-CD was 0.92. The most common sources of disagreement were interpretation of superficial ulceration, definition of disease site at the ileocolonic anastomosis, assessment of anorectal lesions and grading severity of stenosis. Conclusions Central reading of CDEIS and SES-CD had ‘substantial’ to ‘almost perfect’ intra-rater and inter-rater reliability; however, the responsiveness of these instruments is yet to be determined. Trial registration number Clinicaltrials.gov NCT01466374.

Members of the public are increasingly consulted over health care and research priorities. Patient involvement in determining cancer research priorities, however, has remained underdeveloped. This paper presents the findings of the first consultation to be conducted\ud with UK cancer patients concerning research priorities. The study adopted a participatory approach using a collaborative model that sought joint ownership of the study with people affected by cancer. An exploratory, qualitative approach was used. Consultation groups were the main method, combining focus group and nominal group techniques. Seventeen groups were held with a total of 105 patients broadly representative of the UK cancer population. Fifteen areas for research were identified. Top priority areas included the impact cancer has on life, how to live with cancer and related support issues; risk factors and causes of cancer; early detection and prevention. Although biological and treatment related aspects of science were identified as important, patients rated the management of practical, social and emotional issues as a higher priority. There is a mismatch between the research priorities identified by participants and the current UK research portfolio. Current research activity should be broadened to reflect the priorities of people affected by the disease.

Background: Neonatal outcomes of infants delivered by family physicians practicing obstetrics and obstetricians/gynecologists have been studied for years. Most of the studies comparing deliveries of family physicians and OB/GYNs have been limited to low risk pregnancies. Family physicians practicing obstetrics are often the only obstetrics providers in rural, underserved areas. They need to be able to practice independently and manage more than just low risk pregnancies.

Integrins mechanically link the cytoskeleton to the extracellular matrix in cardiac myocytes and are thereby involved in mechanotransduction. Integrins appear to be necessary for cardiac myocyte hypertrophy. To determine the effect of increased integrin ligation and signaling on adult cardiac function, a heart-specific truncated α 5 integrin (gain of function) was conditionally expressed in mice. Four days later, we observed an 80% reduction in amplitude of the QRS complex, profound systolic dysfunction, decreased connexin43, loss of gap junctions, and abnormal intercalated discs. Surprisingly, isolated left ventricular myocytes contracted normally and exhibited normal Ca 2+ transients. This suggested that cell/cell electrical and/or mechanical coupling was disrupted. To distinguish electrical from mechanical coupling deficits, we compared the papillary muscle force generated by electrically stimulated versus rapid cooling contractions in which intracellular Ca 2+ is released without electrical depolarization. Both were decreased in the transgenic muscle. However, electrically stimulated contractions were more significantly reduced than rapid cooling contractures. This suggests a component of cell/cell electrical uncoupling. Optical mapping revealed a loss of the normal elliptical isochronal activation pattern implying a loss of preferential conduction through gap junctions. For the first time, we have shown that integrins can regulate both mechanical and electrical coupling in the adult heart, even in the absence of primary hemodynamic alterations. Furthermore, we demonstrated that unregulated integrin activation leads to both contractile dysfunction and arrhythmias.

The treatment of node-positive breast cancer has improved dramatically in the last 3 decades. Adjuvant therapies have evolved from single-agent chemotherapy to anthracycline- and taxane-based polychemotherapeutics to target-specific trastuzumab, with or without endocrine manipulation and with or without PMRT. Almost 85% of patients who have node-positive disease can now enjoy a 5-year DFS. This progress has come from incremental improvements made over the years. In spite of these advances, lingering questions remain. Is it possible to reduce treatment-associated toxicity? Can patient selection be improved based on tumor genomic profiling? Given the high cost of many of these therapies (37,000 dollars with the newer agents versus $391 for the classic six cycles of intravenous CMF), is it possible to achieve equivalent efficacy and yet reduce the economic cost per patient? Only continued clinical trials and cooperative effort among researchers, clinicians, and patients can answer these questions and improve care for breast cancer.

Objective: In a prospective trial, to determine if eIF4E overexpression in breast cancer specimens is correlated with VEGF elevation, increased tumor microvessel density (MVD) counts, and a worse clinical outcome irrespective of nodal status. and Background Data: In vitro, the overexpression of eukaryotic initiation factor 4E (eIF4E) up-regulates the translation of mRNAs with long 5'-untranslated regions (5'-UTRs). One such gene product is the vascular endothelial growth factor (VEGF). Methods: A total of 114 stage I to III breast cancer patients were prospectively accrued and followed with a standardized clinical surveillance protocol. Cancer specimens were quantified for eIF4E, VEGF, and MVD. Outcome endpoints were cancer recurrence and cancer-related death. Results: eIF4E overexpression was found in all cancer specimens (mean ± SD, 12.5 ± 7.6-fold). Increasing eIF4E overexpression correlated with increasing VEGF elevation (r = 0.24, P = 0.01, Spearman's coefficient), and increasing MVD counts (r = 0.35, P < 0.0002). Patients whose tumor had high eIF4E overexpression had shorter disease-free survival (P = 0.004, log-rank test) and higher cancer-related deaths (P = 0.002) than patients whose tumors had low eIF4E overexpression. Patients with high eIF4E had a hazard ratio for cancer recurrence and cancer-related death of 1.8 and 2.1 times that of patients with low eIF4E (respectively, P = 0.009 and P = 0.002, Cox proportional hazard model). Conclusions: In breast cancer patients, increasing eIF4E overexpression in the cancer specimens correlates with higher VEGF levels and MVD counts. Patients whose tumors had high eIF4E overexpression had a worse clinical outcome, independent of nodal status. Thus, eIF4E overexpression in breast cancer appears to predict increased tumor vascularity and perhaps cancer dissemination by hematogenous means.