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AbstractBackgroundThe etiology of irritable bowel syndrome (IBS) is not been fully elucidated, but childhood trauma may disturb the brain–gut axis and therefore be important. Thus, we conducted a family based case–control study of IBS cases and their relatives with the aims to (i) determine the frequency of childhood trauma among IBS cases and controls as well as their relatives, and (ii) assess childhood trauma among IBS cases with affected relatives (familial IBS).MethodsOutpatients with IBS, matched controls, and their first‐degree relatives completed a self‐report version of Bremner' Early Trauma Inventory. Percent of cases and controls with a family history were compared and odds ratios were computed using chi‐squared test; recurrence risks to relatives were computed using logistic regression and generalized estimating equations.Key ResultsData were collected from 409 cases, 415 controls, 825 case relatives, and 921 control relatives. IBS cases had a median age of 50 and 83% were women. Of IBS cases, 74% had experienced any general trauma compared to 59% among controls, yielding an odds ratio of 1.56 (95% CI: 1.13–2.15, p < 0.008). There were no statistical differences between IBS relatives and control relatives with regards to lifetime trauma.Conclusions & InferencesIBS is associated with childhood trauma, and these traumas often occur prior to onset of IBS symptoms. This provides further insight into how traumatic childhood events are associated with development of adult IBS.

Levorphanol (levo-3-hydroxy- N-methylmorphinan) is a step 3 opioid first developed in the 1940s as an alternative to morphine. Levorphanol belongs to the morphinan opioid series. Levorphanol has greater potency than morphine and is a potent N-methyl-D aspartate (NMDA) antagonist. Levorphanol interferes with the uptake of norepinephrine and serotonin, which makes it potentially useful for neuropathic pain. Glucuronidation changes Levorphanol to Levorphanol-3-glucuronide with excretion by the kidney. Levorphanol has a long half-life and may accumulate with repeated dosing. Levorphanol can be administered orally, intravenously, and subcutaneously. This article provides an update regarding the pharmacodynamics, pharmacology, and clinical efficacy of this often overlooked step 3 opioid.

Background Aneurysmal bone cysts (ABCs) are a benign aggressive tumor that occurs rarely in the pelvis in the pediatric population. Pelvic ABCs may involve the triradiate cartilage and/or the acetabulum, which increases the technical difficulty of surgical treatment and has potential implications on the growth and development of the hip joint. This study examines the clinical presentation, rate of surgical complications, and recurrence rate, as well as, long-term clinical and functional outcomes of children with pelvic ABCs treated at a single institution by a single treatment modality. Methods Between 1988 and 2008, 142 children with histologically confirmed ABCs were treated at our institution. Seventeen (12 %) tumors were located in the pelvis. A total of 13 pelvic ABCs (5 ilium-periacetabular, 4 pubic, 3 ilium-iliac wing, and 1 ischium) were included in this study. There were eight male and five female patients with a mean age of 12.9 years (range 4.1–17.5 years) at the time of surgery. The Toronto Extremity Salvage Score (TESS), the Musculoskeletal Tumor Society 1993 (MSTS’93) score, and the Short Form Health Survey Sf-36 were obtained at a minimum 5-year follow-up in all patients (mean follow-up 11.5 years, range 5.5–19.8 years). The mean age at follow-up was 24.3 years (range 14.6–32.6 years). Results All patients were treated surgically with intralesional curettage extended with a high-speed burr and bone grafting. Eight patients received adjunctive therapy with phenol. Five patients had preoperative selective arterial embolization. Of the 13 patients, 1 had a local recurrence diagnosed at 6 months after surgery. The only complication in the cohort was a superficial wound infection. At the latest follow-up, all patients were free of disease. The mean TESS score was 95 and the mean MSTS’93 score was 93 %. The mean self-rated general health score, according to the SF-36 was 87 % of total points possible. Conclusions Extended curettage and bone grafting of pelvic ABCs in the pediatric population can yield high clinical and functional scores at an average of 11 years follow-up with a low rate of complications and recurrence. Level of evidence IV, case series.

ABSTRACT Xenorhabdus nematophila engages in a mutualistic association with the nematode Steinernema carpocapsae . The nematode invades and traverses the gut of susceptible insects. X. nematophila is released in the insect blood (hemolymph), where it suppresses host immune responses and functions as a pathogen. X. nematophila produces diverse antimicrobials in laboratory cultures. The natural competitors that X. nematophila encounters in the hemolymph and the role of antimicrobials in interspecies competition in the host are poorly understood. We show that gut microbes translocate into the hemolymph when the nematode penetrates the insect intestine. During natural infection, Staphylococcus saprophyticus was initially present and subsequently disappeared from the hemolymph, while Enterococcus faecalis proliferated. S. saprophyticus was sensitive to X. nematophila antibiotics and was eliminated from the hemolymph when coinjected with X. nematophila . In contrast, E. faecalis was relatively resistant to X. nematophila antibiotics. When injected by itself, E. faecalis persisted (∼10 3 CFU/ml), but when coinjected with X. nematophila , it proliferated to ∼10 9 CFU/ml. Injection of E. faecalis into the insect caused the upregulation of an insect antimicrobial peptide, while the transcript levels were suppressed when E. faecalis was coinjected with X. nematophila . Its relative antibiotic resistance together with suppression of the host immune system by X. nematophila may account for the growth of E. faecalis . At higher injected levels (10 6 CFU/insect), E. faecalis could kill insects, suggesting that it may contribute to virulence in an X. nematophila infection. These findings provide new insights into the competitive events that occur early in infection after S. carpocapsae invades the host hemocoel.

Objective— To evaluate the predictive value of abdominal aortic calcium (AAC) for incident cardiovascular disease (CVD) independent of coronary artery calcium (CAC). Approach and Results— We evaluated the association of AAC with CVD in 1974 men and women aged 45 to 84 years randomly selected from the Multi-Ethnic Study of Atherosclerosis participants who had complete AAC and CAC data from computed tomographic scans. AAC and CAC were each divided into following 3 percentile categories: 0 to 50th, 51st to 75th, and 76th to 100th. During a mean of 5.5 years of follow-up, there were 50 hard coronary heart disease events, 83 hard CVD events, 30 fatal CVD events, and 105 total deaths. In multivariable-adjusted Cox models including both AAC and CAC, comparing the fourth quartile with the ≤50th percentile, AAC and CAC were each significantly and independently predictive of hard coronary heart disease and hard CVD, with hazard ratios ranging from 2.4 to 4.4. For CVD mortality, the hazard ratio was highly significant for the fourth quartile of AAC, 5.9 ( P =0.01), whereas the association for the fourth quartile of CAC (hazard ratio, 2.1) was not significant. For total mortality, the fourth quartile hazard ratio for AAC was 2.7 ( P =0.001), and for CAC, it was 1.9, P =0.04. Area under the receiver operating characteristic curve analyses showed improvement for both AAC and CAC separately, although improvement was greater with CAC for hard coronary heart disease and hard CVD, and greater with AAC for CVD mortality and total mortality. Sensitivity analyses defining AAC and CAC as continuous variables mirrored these results. Conclusions— AAC and CAC predicted hard coronary heart disease and hard CVD events independent of one another. Only AAC was independently related to CVD mortality, and AAC showed a stronger association than CAC with total mortality.

IntroductionAbandoned cardiovascular implantable electronic device (CIED) leads remain a contraindication to magnetic resonance imaging (MRI) studies, largely due to in vitro data showing endocardial heating secondary to the radiofrequency field. We tested the hypothesis that abandoned CIED leads do not pose an increased risk of clinical harm for patients undergoing MRI.MethodsThis single‐center retrospective study examined the outcomes of patients who had device generators removed before MRI, rendering the device leads abandoned. Information was gathered through chart review. Data collected included lead model, pacing threshold before MRI, anatomic region examined, threshold data after generator reimplantation, and clinical patient outcome.ResultsPatients (n = 19, 11 men and eight women) ranged in age from 19 to 85 at the time of MRI. There was a mean of 1.63 abandoned leads at the time of imaging; none of the leads were MRI conditional. Of the three implantable cardioverter defibrillator (ICD) leads, two of three were dual coil. Most (31/35) of the scans performed were of the central nervous system, including head and spinal imaging. There were no adverse events associated with MRI in any of these patients with abandoned leads within 7 days of the scan. No lead malfunctions or clinically significant change in pacing thresholds were noted with generator reimplantation.ConclusionThe use of MRI in patients with abandoned cardiac device leads appears feasible when performed under careful monitoring, with no adverse events, although the experience is small. MRI did not affect the function of leads that were subsequently reconnected to a cardiac device.

Abstract Despite some advances, pancreatic ductal adenocarcinoma (PDAC) remains generally refractory to current treatments. Desmoplastic stroma, a consistent hallmark of PDAC, has emerged as a major source of therapeutic resistance and thus potentially promising targets for improved treatment. The glycan-binding protein galectin-1 (Gal1) is highly expressed in PDAC stroma, but its roles there have not been studied. Here we report functions and molecular pathways of Gal1 that mediate its oncogenic properties in this setting. Genetic ablation of Gal1 in a mouse model of PDAC (EIa-myc mice) dampened tumor progression by inhibiting proliferation, angiogenesis, desmoplasic reaction and by stimulating a tumor-associated immune response, yielding a 20% increase in relative lifesplan. Cellular analyses in vitro and in vivo suggested these effects were mediated through the tumor microenvironment. Importantly, acinar-to-ductal metaplasia, a crucial step for initiation of PDAC, was found to be regulated by Gal1. Mechanistic investigations revealed that Gal1 promoted Hedgehog pathway signaling in PDAC cells and stromal fibroblasts as well as in Ela-myc tumors. Taken together, our findings establish a function for Gal1 in tumor-stroma crosstalk in PDAC and provide a preclinical rationale for Gal1 targeting as a microenvironment-based therapeutic strategy. Cancer Res; 74(13); 3512–24. ©2014 AACR.

ObjectiveIgG4‐related disease (IgG4RD) causing sinonasal and skull base pathology is uncommonly described. We present a series of suspected IgG4RD patients, with a pertinent review of the literature to highlight diagnostic challenges.Study DesignCase series.SettingAcademic tertiary care center.Subjects and MethodsCase series of patients with IgG4RD or suspected IgG4RD involving the sinonasal cavity and skull base.ResultsWe present 4 patients with atypical sinonasal and/or skull base disease who were noted to have IgG4‐positive plasma cell infiltration on immunohistochemistry of biopsy specimens. IgG4RD, a recently described entity affecting multiple organs, is characterized by lymphoplasmacytic infiltration and often elevated serum IgG4. IgG4RD can masquerade as malignancy or infection but responds to glucocorticosteroid and immunosuppressant therapy. IgG4RD has been infrequently reported presenting as sinonasal or skull base lesions, and definitive diagnostic criteria for these regions are not established. In our series, IgG4RD was suspected in all 4 patients, but only 1 met all current criteria for definitive diagnosis. All 4 patients, however, responded to corticosteroid therapy, and 1 was placed on long‐term azathioprine.ConclusionIgG4RD is rarely described in the sinonasal cavity and skull base, and specific diagnostic criteria for such disease have not been defined. We present a series of patients with IgG4‐positive plasma cell inflammatory pathology who were suspected to have IgG4RD. Our series highlights diagnostic challenges associated with these patients. Tumefactive and destructive sinonasal‐skull base lesions with a plasma cell‐rich infiltrate should incite suspicion of IgG4RD, and immunohistochemistry for IgG4‐positive plasma cells should be performed.