IARC Monographs evaluation of the carcinogenicity of benzene

The results of the recent IARC Monographs evaluation of the carcinogenicity of benzene have now been published in The Lancet Oncology.
This summary article presents the conclusions of the IARC Monographs Meeting 120, which reviewed all relevant published scientific literature currently available. This new evaluation updates the previous evaluation of benzene by the IARC Monographs in 2009.
The full scientific assessment will be published as Volume 120 of the IARC Monographs.

Loomis D, Guyton KZ, Grosse Y, Lauby-Secretan B, El Ghissassi F, Bouvard V, et al. Carcinogenicity of benzene
Lancet Oncol, Published online 27 October 2017; http://ift.tt/1aeEb18 S1470-2045(17)30832-X


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NYU Dentistry awarded $3.6 million by NIH for cavity prevention research in rural New Hampshire

The National Institute on Minority Health and Health Disparities, part of the National Institutes of Health, has awarded a research team at New York University College of Dentistry funding to study cavity prevention and cost effectiveness in school-based dental programs in New Hampshire. The $3.6 million, five-year grant will fund a statewide program in six rural New Hampshire counties providing dental care to approximately 12,000 children, from preschool to sixth grade, in over 40 schools.

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Cartoon Analgesia in the Pediatric Plastic Surgery Population

No abstract available

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Topographic Analysis of the Supratrochlear Artery and the Supraorbital Artery: Implication for Improving the Safety of Forehead Augmentation

No abstract available

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Do Bacteria and Biofilm Play a Role in Double-Capsule Formation around Macrotextured Implants?

Background: The double capsule is a complication mostly described in aggressive macrotextured implants. Mechanical shear stress applied onto an immature periprosthetic capsule has been linked to their formation. The authors aim to demonstrate the role of bacterial phenotype and biofilm in the development of the double capsule. Methods: Seven double capsules formed at the interface of macrotextured breast expander implants were studied using scanning electron microscopy. Two samples for each surface of the inner capsule layer (the prosthesis interface and the intercapsular space) were analyzed for bacteria cell size, bacterial density, and biofilm deposition. Results: Although all routine bacterial cultures were negative, the prosthesis interface had both higher bacteria load and biofilm deposition compared with the intercapsular space (Mann-Whitney U test, p = 0.004 and p = 0.008, respectively). Moreover, bacteria cell sizes were significantly smaller at the prosthesis interface in six of seven samples. Comparison of bacteria density and biofilm dispersion showed an increase of biofilm extracellular matrix deposition over 2000 cells/mm2 (linear regression, p = 0.0025). These results indicate a common trend among bacteria species. Conclusions: Bacterial expression between the different surfaces of the double capsule displays significant differences; bacteria at the prosthesis interface are mostly in a biofilm state, whereas they demonstrate a planktonic phenotype at the intercapsular space. When a sufficient amount of bacteria are present at a specific location, quorum sensing may trigger a biofilm phenotypic switch in planktonic bacteria cells. Biofilm formation may alter capsule formation through immune response, thereby weakening capsule strength and facilitating extracellular matrix delamination and double-capsule formation. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, V.

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Subfascial Primary Breast Augmentation with Fat Grafting: A Review of 156 Cases: Correction

No abstract available

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Five Steps to Internal Mammary Vessel Preparation in Less than 15 Minutes

Background: Modern breast reconstruction often involves microvascular reconstruction. The most common recipient vessels are the internal mammary artery and vein. Recently, there has been great focus on efficiency, but much of this emphasis has been directed to faster flap harvest or recovery protocols for expeditious discharge. An equally important aspect is internal mammary vessel preparation. Methods: Breast reconstruction was performed in 415 patients (715 breasts) using autologous tissue (850 flaps) from 2012 to 2016. In 97.6 percent of these breast reconstructions, the internal mammary vessels were used. The preparation of these vessels was routinely performed using the five-step technique described here. Results: Internal mammary preparation time ranged from 7 to 45 minutes (median, 15 minutes). The procedure involves five simplified steps, as follows: step 1, the rib is exposed by splitting the pectoralis major muscle; step 2, the perichondrium anterior to the cartilage is incised and dissected away from the cartilage; step 3, the cartilage is removed with a rongeur; step 4, laterally the perichondrium is elevated and incised (under direct vision, this perichondrium is then split directly over the vessels and the cranial and caudal flaps are resected); and step 5, careful dissection is performed on the artery and vein. Conclusions: Safe preparation of recipient vessels in microvascular reconstruction is essential for success. In modern breast reconstruction, the internal mammary artery and vein are typically used. Exposure of these vessels should be predictable and efficient. The authors have found that a systematic approach using the above five steps accomplishes these goals.

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Establishment of an Acquired Lymphedema Model in the Mouse Hindlimb: Technical Refinement and Molecular Characteristics

No abstract available

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Evidence-Based Clinical Practice Guideline: Autologous Breast Reconstruction with DIEP or Pedicled TRAM Abdominal Flaps

Summary: The American Society of Plastic Surgeons commissioned a multistakeholder Work Group to develop recommendations for autologous breast reconstruction with abdominal flaps. A systematic literature review was performed and a stringent appraisal process was used to rate the quality of relevant scientific research. The Work Group assigned to draft this guideline was unable to find evidence of superiority of one technique over the other (deep inferior epigastric perforator versus pedicled transverse rectus abdominis musculocutaneous flap) in autologous tissue reconstruction of the breast after mastectomy. Presently, based on the evidence reported here, the Work Group recommends that surgeons contemplating breast reconstruction on their next patient consider the following: the patient's preferences and risk factors, the setting in which the surgeon works (academic versus community practice), resources available, the evidence shown in this guideline, and, equally important, the surgeon's technical expertise. Although theoretical superiority of one technique may exist, this remains to be reported in the literature, and future methodologically robust studies are needed.

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Discussion: Mixed Reality with HoloLens: Where Virtual Reality Meets Augmented Reality in the Operating Room

No abstract available

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Fat Grafting in Hollow Upper Eyelids and Volumetric Upper Blepharoplasty

Background: Periorbital volume loss creates a shadow frame, and traditional excisional blepharoplasties may aggravate the situation. Divergence in filling treatments establishes a demand for simple and reproducible techniques to achieve consistent results. Here, the author's hollow upper eyelid evaluation and treatment approach are presented. Methods: A retrospective photographic analysis was conducted of 32 women who underwent fat grafting for hollow upper eyelids between 2012 and 2016. Preoperative and postoperative evaluations of upper eyelid ratios at the medial and lateral corneal limbus, together with lateral contour modifications, were used to determine the efficacy of the technique to restore youthful proportions and contours. Results: Preoperative analysis showed 20 eyelids with an inner shadow, or A-pattern; and 44 eyelids with the complete extension of the hollow, or C-pattern. Three patients presented mild blepharoptosis, and eight patients had undergone a previous upper blepharoplasty. Mean grafting volume was 0.4 cc in the deep plane and 2.8 cc in the superficial plane. Fat grafting exclusively was performed in six patients, improving all ratios and correcting the A-pattern deformity. Volumetric upper blepharoplasty combining fat grafting in two levels and orbicularis oculi muscle imbrication was performed in 26 patients, correcting every inverted ratio (p

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Breast Cleavage Remodeling with Fat Grafting: A Safe Way to Optimize Symmetry and to Reduce Intermammary Distance

Background: In their descriptions of the ideal breast, most studies have focused primarily on the dimensions, shape, and proportions. The distance between the breasts has only very rarely been considered. The intermammary distance and the medial symmetry between the breasts are important parts of the outcome of surgery and have a strong bearing on patient satisfaction. However, the control surgeons have over these factors is only relative, and depends heavily on the underlying anatomical characteristics of the patients. Methods: Eighty-six patients undergoing breast augmentation, breast reduction, or mastopexy and breast reconstruction with separated or asymmetric breasts underwent fat grafting in the medial quadrants. Intermammary distances were measured before fat grafting and 12 months later. Complications were also recorded. Results: This technique obtained a statistically significant reduction in the mean intermammary distance (p

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Evidence-Based Medicine: Face Lift

No abstract available

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Impact of Patient Subtype and Surgical Variables on Abdominoplasty Outcomes: A 12-Year Massachusetts General Hospital Experience

Background: The traditional abdominoplasty is one of the most common surgical procedures performed. This study evaluates the impact of different surgical techniques and clinical patient factors on abdominoplasty outcomes. Methods: A retrospective review of consecutive patients undergoing abdominoplasty was performed. Results: Seven hundred seventy-nine patients with a mean age of 43.7 years and a body mass index of 27 kg/m2 underwent abdominoplasty. The majority were women (92.9 percent), and massive weight loss was present in 34.8 percent. Abdominoplasty techniques included traditional (59.4 percent), belt lipectomy (17.9 percent), fleur-de-lis (16.4 percent), umbilical float (9.2 percent), and mini-abdominoplasty (2.8 percent). Half of the study population [n = 384 (49.3 percent)] had concurrent surgical procedures. Total complications (23.0 percent) consisted primarily of wound- and scar-related complications (15.3 percent). Approximately 60 percent of patients received heparin chemoprophylaxis, with overall thromboembolic and hematoma rates less than 1 percent. Univariate analysis revealed that massive weight loss (p = 0.04), fleur-de-lis (p = 0.03) or belt lipectomy (p = 0.05) techniques, and concurrent medial thigh lift (p

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Optimizing Outcomes in Pharyngoesophageal Reconstruction and Neck Resurfacing: 10-Year Experience of 294 Cases

No abstract available

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Injection of Compressed Diced Cartilage in the Correction of Secondary and Primary Rhinoplasty: A New Technique with 12 Years’ Experience

Background: There are instances where small or large pockets are filled with diced cartilage in the nose, without use of wrapping materials. For this purpose, 1-cc commercial syringes were used. The obtained results were partial and incomplete. For better and improved results, the author designed new syringes, with two different sizes, which compress the diced cartilage for injection. Methods: The author presents his experience accrued over the past 12 years with 2366 primary, 749 secondary, 67 cleft lip and nose, and a total of 3182 rhinoplasties, using his new syringe design, which compresses diced cartilage and injects the diced cartilages as a conglutinate mass, simulating carved costal cartilage, but a malleable one. Results: In 3125 patients, the take of cartilage graft was complete (98.2 percent) and a smooth surface was obtained, giving them a natural appearance. In 21 patients (0.65 percent), there was partial resorption of cartilage. Correction was performed with touch-up surgery by reinjection of a small amount of diced cartilage. In 36 patients (1.13 percent), there was overcorrection that, 1 year later, was treated by simple rasping. Conclusions: Compared with diced cartilage wrapped with Surgicel or fascia, the amount of injected cartilage graft is predictable because it consists purely of cartilage. The injected diced cartilage, because it is compressed and becomes a conglutinated mass, resembles a wood chip and simulates carved cartilage. It is superior to carved cartilage in that it is moldable, time saving, and gives a good result with no late show or warping. The injection takes only a few minutes.

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ASPS/PSF Sponsored Symposia and Workshops

No abstract available

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Managing Alar Flare in Rhinoplasty

Summary: Alar flare is a common feature that contributes to the width of the lower third of the nose. In the right patient, alar flare reduction can improve nasal harmony and facial aesthetic balance; however, it is also difficult to correct if conducted inappropriately or overzealously. The unique anatomy and diverse morphologies of the alar lobule, and the dynamic relationship between flare and changes in tip projection, must be considered. The authors provide guidelines for flare reduction: when it is appropriate and how to tailor the excision pattern to safely and effectively refine nasal width. Alar flare is classified into three types according to alar rim shape on basal view analysis. By designing the excision pattern based on specific flare type, the lower third of the nose is narrowed without creating an operated appearance. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, V.

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Gender Affirmation: Medical & Surgical Perspectives

No abstract available

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The Evolution of Chemical Peeling and Modern-Day Applications

Summary: Despite the growth of technically more sophisticated skin resurfacing modalities, such as those based on light, radiofrequency, and ultrasound, chemical peel procedures have risen 5 to 25 percent over the past year alone. Chemexfoliation carries historical significance and has markedly evolved since its inception in ancient times. As a result of plastic surgery and dermatologic advancements, modern-day chemexfoliation offers plastic surgeons additional safe and effective options for patients with rhytides, dyschromias, and other signs of light- and environment-induced skin damage. This review discusses the historical evolution of chemexfoliation procedures, highlights modern-day practice habits, and touches on the clinically relevant applications of chemical peels.

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Reply: The Anterior Intercostal Artery Flap: Anatomical and Radiologic Study

No abstract available

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Esophageal Adenocarcinoma–Derived Extracellular Vesicle MicroRNAs Induce a Neoplastic Phenotype in Gastric Organoids

There have been no reports describing the effects of cancer cell–derived extracellular vesicles (EVs) on three-dimensional organoids. In this study, we delineated the proneoplastic effects of esophageal adenocarcinoma (EAC)–derived EVs on gastric organoids (gastroids) and elucidated molecular mechanisms underlying these effects. EVs were identified using PKH-67 staining. Morphologic changes, Ki-67 immunochemistry, cell viability, growth rates, and expression levels of miR-25 and miR-210, as well as of their target mRNAs, were determined in gastroids co-cultured with EAC-derived extracellular vesicles (c-EVs).

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Endothelial Cells as Precursors for Osteoblasts in the Metastatic Prostate Cancer Bone

Prostate cancer cells metastasize to the bones, causing ectopic bone formation, which results in fractures and pain. The cellular mechanisms underlying new bone production are unknown. In a recent study, Lin and colleagues, by using state-of-the-art techniques, including prostate cancer mouse models in combination with sophisticated in vivo lineage-tracing technologies, revealed that endothelial cells form osteoblasts induced by prostate cancer metastasis in the bone. Strikingly, genetic deletion of osteorix protein from endothelial cells affected prostate cancer–induced osteogenesis in vivo.

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Targeting the Cohesive Cluster Phenotype in Chordoma via β1 Integrin Increases Ionizing Radiation Efficacy

Chordoma is a rare, radiation-resistant, skull-base and spinal tumor with high local recurrence containing mixed cell-adhesion phenotypes. We characterized DNA damage response (DDR) signaling (γH2AX, pKAP1, pATM) and survival response to ionizing radiation (IR) in human chordoma samples (42 resections, 23 patients) to test if blocking cell adhesion sensitizes U-CH1 tumor cells to IR. U-CH1 cells expressed brachyury, YAP, and laminin adhesion receptors (CD49c, CD49f, CD44), and approximately 15% to 20% of U-CH1 cells featured an α6 integrin-dependent (CD49f) cohesive cluster phenotype, which confers therapeutic resistance and aids metastasis.

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Directional Migration in Esophageal Squamous Cell Carcinoma (ESCC) is Epigenetically Regulated by SET Nuclear Oncogene, a Member of the Inhibitor of Histone Acetyltransferase Complex

Directional cell migration is of fundamental importance to a variety of biological events, including metastasis of malignant cells. Herein, we specifically investigated SET oncoprotein, a subunit of the recently identified inhibitor of acetyltransferases (INHAT) complex and identified its role in the establishment of front–rear cell polarity and directional migration in Esophageal Squamous Cell Carcinoma (ESCC). We further define the molecular circuits that govern these processes by showing that SET modulated DOCK7/RAC1 and cofilin signaling events.

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Lunatic Fringe and p53 Cooperatively Suppress Mesenchymal Stem-Like Breast Cancer

Claudin-low breast cancer (CLBC) is a poor prognosis molecular subtype showing stemness and mesenchymal features. We previously discovered that deletion of a Notch signaling modulator, Lunatic Fringe (Lfng), in the mouse mammary gland induced a subset of tumors resembling CLBC. Here we report that deletion of one copy of p53 on this background not only accelerated mammary tumor development but also led to a complete penetrance of the mesenchymal stem-like phenotype. All mammary tumors examined in the Lfng/p53 compound mutant mice displayed a mesenchymal/spindloid pathology.

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Nilotinib Enhances Tumor Angiogenesis and Counteracts VEGFR2 Blockade in an Orthotopic Breast Cancer Xenograft Model with Desmoplastic Response

Vascular endothelial growth factor (VEGF)/VEGF receptor (VEGFR)-targeted therapies predominantly affect nascent, immature tumor vessels. Since platelet-derived growth factor receptor (PDGFR) blockade inhibits vessel maturation and thus increases the amount of immature tumor vessels, we evaluated whether the combined PDGFR inhibition by nilotinib and VEGFR2 blockade by DC101 has synergistic therapy effects in a desmoplastic breast cancer xenograft model. In this context, besides immunohistological evaluation, molecular ultrasound imaging with BR55, the clinically used VEGFR2-targeted microbubbles, was applied to monitor VEGFR2-positive vessels noninvasively and to assess the therapy effects on tumor angiogenesis.

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Associate Registry

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The JOE Publication Award

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CE Registry

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Table of Contents

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Donor Honor Roll

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Editorial Board

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Corrigendum

Corrigendum to 'Effectiveness in the Removal of Endotoxins and Microbiological Profile in Primary Endodontic Infections Using 3 Different Instrumentation Systems: A Randomized Clinical Study' [Journal of Endodontics 43 (2017) 1237–1245]

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Real-time elastography for the detection of fibrotic and inflammatory tissue in patients with stricturing Crohn’s disease

Abstract

Purpose

The distinction between active inflammation and fibrosis of the bowel wall is essential for therapeutic decisions in stricturing Crohn's disease. We aimed to assess whether real-time elastography (RTE) with strain ratio measurement could be useful in differentiating fibrotic from inflamed bowel strictures and to evaluate the possible relationship between US techniques and the histology of the stenotic bowel wall.

Materials and methods

Bowel ultrasonography (including RTE, color-Doppler and CEUS examination) was prospectively evaluated in 26 patients with symptomatic stricturing Crohn's disease, before surgery. RTE was adopted to evaluate bowel stiffness: five loops of 20 RTE frames were recorded for each stenotic segment and the mean strain ratio (MSR) was obtained. Histology scoring systems both for inflammation and fibrosis were established for surgical specimens.

Results

No significant correlation was found between MSR and fibrosis score (P = 0.877). Color-Doppler score was significantly related to gut wall and submucosal thicknesses (P = 0.006 and P = 0.032, respectively). There was no significant correlation between the number of vessels counted at histology and color-Doppler and CEUS examinations (P = 0.170 and P = 0.302, respectively).

Conclusion

MSR detection was not able to distinguish fibrotic from inflammatory tissue in our selected population. This result could be influenced by the presence of the superimposed inflammation. Larger cohort of patients, further analysis with shear wave elastography, and validated histopathology classification systems for fibrosis and inflammation are necessary to assess if intestinal fibrosis could be reliably detected on the basis of bowel elastic properties.

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Association between serious psychological distress and nonparticipation in cancer screening and the modifying effect of socioeconomic status: Analysis of anonymized data from a national cross-sectional survey in Japan

BACKGROUND

It is unclear whether individuals who have serious psychological distress (SPD) are less likely to participate in screening tests for gastric cancer, lung cancer, and other types of cancer. Of the few studies that have examined the association between SPD and participation in cancer screening, none have reported modifying effects of educational, marital, or employment status.

METHODS

The authors analyzed a national representative data set from the 2010 Comprehensive Survey of Living Conditions of Japan., including individuals aged <69 years who met the national program criteria for each type of cancer screening (colorectal, gastric, and lung cancers, n = 29,926; breast cancer, n = 15,423; and cervical cancer, n = 24,735). SPD was defined as a score of 13 or greater on the Kessler 6 scale. Logistic regression analyses were conducted to examine the association between SPD and participation in cancer screening, and multivariate analyses stratified by socioeconomic status also were conducted.

RESULTS

SPD was significantly associated with a lower odds ratio (OR) for participation in screening for colorectal cancer (OR, 0.743; 95% confidence interval [CI], 0.638-0.866), gastric cancer (OR, 0.823; 95% CI, 0.717-0.946), and lung cancer (OR, 0.691; 95% CI, 0.592-0.807). Only educational status significantly modified the effect of SPD on participation in these 3 types of cancer screening (P < .05).

CONCLUSIONS

Individuals with SPD, especially those with lower education levels, were less likely to participate in screening for colorectal, gastric, and lung cancers. Individuals with SPD should be encouraged and supported to participate in cancer screening tests. Cancer 2017. © 2017 American Cancer Society.

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Prognostic Significance of Focal Adhesion Kinase in Node-Negative Breast Cancer

Background: Focal adhesion kinase (FAK) is a cytoplasmic tyrosine kinase that plays an important role as a mediator of cell migration, invasion, proliferation and survival. Conflicting results for the prognostic role of FAK in breast cancer (BC) prompted us to determine its impact. Methods: Patients with node-negative BC entered this retrospective study. FAK expression was determined by immunohistochemistry (n = 335). The prognostic impact of FAK was examined with Cox regression analyses and Kaplan-Meier estimation in the whole cohort as well as in different molecular subtypes. Results: 151 (45.1%) had a FAK-positive BC. In univariate analyses, FAK expression showed a significant impact for shorter disease-free survival (DFS) (hazard ratio (HR) 1.54, 95% confidence interval (CI) 1.04-2.28, p = 0.030) but not for metastasis-free survival and overall survival. Significant prognostic relevance for DFS (HR 1.76, 95% CI 1.05-2.97, p = 0.033) was observed in particular in estrogen receptor-positive HER2-negative BC patients, most notably in luminal B-like tumors (HR 2.32, CI 1.20-4.48, p = 0.012). However, FAK lost its prognostic impact in multivariate Cox regression analysis. Conclusion: FAK was associated with impaired DFS in univariate analysis. Prognostic relevance for DFS was most pronounced in luminal B-like BC. However, FAK expression was not associated with an independent impact on survival for BC in multivariate analysis.
Breast Care 2017;12:329-333

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Dual HER2 Blockade

Breast Care 2017;12:345-349

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Rare-variant association tests in longitudinal studies, with an application to the Multi-Ethnic Study of Atherosclerosis (MESA)

Abstract

Over the past few years, an increasing number of studies have identified rare variants that contribute to trait heritability. Due to the extreme rarity of some individual variants, gene-based association tests have been proposed to aggregate the genetic variants within a gene, pathway, or specific genomic region as opposed to a one-at-a-time single variant analysis. In addition, in longitudinal studies, statistical power to detect disease susceptibility rare variants can be improved through jointly testing repeatedly measured outcomes, which better describes the temporal development of the trait of interest. However, usual sandwich/model-based inference for sequencing studies with longitudinal outcomes and rare variants can produce deflated/inflated type I error rate without further corrections. In this paper, we develop a group of tests for rare-variant association based on outcomes with repeated measures. We propose new perturbation methods such that the type I error rate of the new tests is not only robust to misspecification of within-subject correlation, but also significantly improved for variants with extreme rarity in a study with small or moderate sample size. Through extensive simulation studies, we illustrate that substantially higher power can be achieved by utilizing longitudinal outcomes and our proposed finite sample adjustment. We illustrate our methods using data from the Multi-Ethnic Study of Atherosclerosis for exploring association of repeated measures of blood pressure with rare and common variants based on exome sequencing data on 6,361 individuals.

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Clinical and radiographic evaluation of pulpectomy in primary teeth: a 18-months clinical randomized controlled trial

To avoid untoward changes when primary teeth are replaced by permanent teeth, resorption of the material used in primary teeth root canal filling should occur at the same rate as root resorption. The Aim of th...

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Clinical and radiographic evaluation of pulpectomy in primary teeth: a 18-months clinical randomized controlled trial

To avoid untoward changes when primary teeth are replaced by permanent teeth, resorption of the material used in primary teeth root canal filling should occur at the same rate as root resorption. The Aim of th...

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Reflection

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Paediatric dentistry: A multidisciplinary approach

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Stress and burnout research project

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Community dental team screen factory workers for mouth cancer

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Dental education: A gentle touch

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Patient benefits: Incorrect advice

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From the archive: Sydney turns 100

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An estimated carbon footprint of NHS primary dental care within England. How can dentistry be more environmentally sustainable?

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Eavesdroppers and nosey neighbours required

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Alternative sugars: Syrup

Elaine Gardner, British Dietetic Association (BDA) Spokesperson, discusses the sugar content in syrup and provides related oral health advice.

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Is it time to digitally enable dentistry with the rest of healthcare?

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Spreading the word about a devastating disease

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Abscess with osteomyelitis of the clivus after adenoidectomy: An uncommon complication of a common procedure

Publication date: Available online 26 October 2017
Source:European Annals of Otorhinolaryngology, Head and Neck Diseases
Author(s): E. Moreddu, C. Le Treut, J.-M. Triglia, R. Nicollas




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Expanding the scope of quality measurement in surgery to include nonoperative care: Results from the American College of Surgeons National Surgical Quality Improvement Program emergency general surgery pilot

BACKGROUND: Patients managed nonoperatively have been excluded from risk-adjusted benchmarking programs, including the American College of Surgeons (ACS) National Surgical Quality Improvement Program (NSQIP). Consequently, optimal performance evaluation is not possible for specialties like emergency general surgery (EGS) where nonoperative management is common. We developed a multi-institutional EGS clinical data registry within ACS NSQIP that includes patients managed nonoperatively to evaluate variability in nonoperative care across hospitals and identify gaps in performance assessment that occur when only operative cases are considered. METHODS: Using ACS NSQIP infrastructure and methodology, surgical consultations for acute appendicitis, acute cholecystitis, and small bowel obstruction (SBO) were sampled at 13 hospitals that volunteered to participate in the EGS clinical data registry. Standard NSQIP variables and 16 EGS-specific variables were abstracted with 30-day follow-up. To determine the influence of complications in nonoperative patients, rates of adverse outcomes were identified, and hospitals were ranked by performance with and then without including nonoperative cases. RESULTS: Two thousand ninety-one patients with EGS diagnoses were included, 46.6% with appendicitis, 24.3% with cholecystitis, and 29.1% with SBO. The overall rate of nonoperative management was 27.4%, 6.6% for appendicitis, 16.5% for cholecystitis, and 69.9% for SBO. Despite comprising only 27.4% of patients in the EGS pilot, nonoperative management accounted for 67.7% of deaths, 34.3% of serious morbidities, and 41.8% of hospital readmissions. After adjusting for patient characteristics and hospital diagnosis mix, addition of nonoperative management to hospital performance assessment resulted in 12 of 13 hospitals changing performance rank, with four hospitals changing by three or more positions. CONCLUSION: This study identifies a gap in performance evaluation when nonoperative patients are excluded from surgical quality assessment and demonstrates the feasibility of incorporating nonoperative care into existing surgical quality initiatives. Broadening the scope of hospital performance assessment to include nonoperative management creates an opportunity to improve the care of all surgical patients, not just those who have an operation. LEVEL OF EVIDENCE: Care management, level IV; Epidemiologic, level III.

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Development of the emergency preservation and resuscitation for cardiac arrest from trauma clinical trial

BACKGROUND: Patients who suffer a cardiac arrest from trauma rarely survive, even with aggressive resuscitation attempts, including an emergency department thoracotomy. Emergency Preservation and Resuscitation (EPR) was developed to utilize hypothermia to buy time to obtain hemostasis before irreversible organ damage occurs. Large animal studies have demonstrated that cooling to tympanic membrane temperature 10°C during exsanguination cardiac arrest can allow up to 2 hours of circulatory arrest and repair of simulated injuries with normal neurologic recovery. STUDY DESIGN: The Emergency Preservation and Resuscitation for Cardiac Arrest from Trauma trial has been developed to test the feasibility and safety of initiating EPR. Select surgeons will be trained in the EPR technique. If a trained surgeon is available, the subject will undergo EPR. If not, the subject will be followed as a control subject. For this feasibility study, 10 EPR and 10 control subjects will be enrolled. STUDY PARTICIPANTS: Study participants will be those with penetrating trauma who remain pulseless despite an emergency department thoracotomy. INTERVENTIONS: Emergency Preservation and Resuscitation will be initiated via an intra-aortic flush of a large volume of ice-cold saline solution. Following surgical hemostasis, delayed resuscitation will be accomplished with cardiopulmonary bypass. OUTCOME MEASURES: The primary outcome will be survival to hospital discharge without significant neurologic deficits. Secondary outcomes include long-term survival and functional outcome. IMPLICATIONS: Once data from these 20 subjects are reviewed, revisions to the inclusion criteria and/or the EPR technique may then be tested in a second set of EPR and control subjects.

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Defining the gastroesophageal junction in trauma: Epidemiology and management of a challenging injury

BACKGROUND: Injuries to the gastroesophageal (GE) junction are infrequently encountered because of the high mortality of associated injuries. Consequently, there is a paucity of literature on the patient demographics and treatment options. The aim of this study was to examine the epidemiology, surgical management, and outcomes of these rare injuries. METHODS: Patients presenting to LAC + USC Medical Center (January 2008 to August 2016) with traumatic esophageal or gastric injury (DRG International Classification of Diseases—9th Rev.—Clinical Modification and 10th Rev. codes) were extracted from the trauma registry. Patient charts were reviewed, and all patients who sustained an injury to the GE junction were enrolled. Patient demographics, injury characteristics, procedures, and outcomes were analyzed. RESULTS: Of the 238 patients who sustained an injury to the esophagus or stomach during the study period, 28 (12%) were found to have a GE junction injury. Mean age was 26 years (range, 14–57 years), 89% male. Mechanism of injury was penetrating in 96% (n = 27), the majority of which were gunshot wounds (n = 22, 81%). Most patients (n = 18, 64%) were taken directly to the operating room. Ten (36%) underwent computed tomography scan before going to the operating room, all demonstrating a GE junction injury. All patients underwent repair via laparotomy. One (4%) also required thoracotomy to facilitate delayed reconstruction. GE junction injuries were typically managed with primary repair (n = 22, 79%). Associated injuries were frequent (n = 26, 93%), and injury severity was high (mean Injury Severity Score, 25 [9–75]). Mortality was 25% (n = 7), and all patients required intensive care unit admission. Most did not require total parenteral nutrition (n = 25, 89%) or a surgically placed feeding tube (n = 26, 93%). Of the 13 patients who presented for clinical follow-up, all but one (n = 12, 92%) were eating independently by the first clinic visit. CONCLUSION: GE junction injuries are uncommon and occur almost exclusively after penetrating trauma. Patients are severely injured with a high mortality rate and frequently have associated intracavitary injuries. Most can be fixed through the abdomen alone and do not require thoracotomy for repair. Despite the severity of injuries, the majority of survivors are eating independently by the first clinic visit. LEVEL OF EVIDENCE: Epidemiological, level V.

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For the patient - evolution in the management of vascular trauma.

There has been an evolution in the diagnosis and management of vascular trauma over the past 100 years. The primary stimulus to these changes has been the increased volume of patients with cervical, truncal, and peripheral vascular injuries during military conflicts and in civilian life. Patients with "hard" signs of a vascular injury are taken to surgery emergently with a few exceptions to be described. In contrast, patients with "soft" signs of a vascular injury undergo a careful physical examination including measurement of vascular index to determine if radiologic imaging is necessary. CT arteriography has become the most commonly utilized method of imaging while duplex ultrasonography is used in some centers. Nonoperative management is now common for nonocclusive injuries diagnosed on CT arteriography. Proximal tourniquets are commonly used to control exsanguinating hemorrhage from injuries to extremities, while balloons can be used to control hemorrhage from difficult to expose areas at operation. Temporary intraluminal shunts are now used in 3-9% of arterial injuries. Operative techniques of repair have been refined and contribute to the excellent results noted in modern trauma centers. (C) 2017 Lippincott Williams & Wilkins, Inc.

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Prognostic significance of postoperative pneumonia after curative resection for patients with gastric cancer

Abstract

Few studies have been designed to investigate the incidence of postoperative pneumonia after radical gastrectomy and its effect on prognosis of these patients. Incidences of postoperative pneumonia after radical gastrectomy in our department between January 1996 and December 2014 were summarized. Their effects on prognosis were retrospectively analyzed using survival curves and Cox regression. A total of 5237 patients were included in this study, 767 (14.4%) of them had complications, including 383 cases of postoperative pneumonia (7.2%). The 5-year overall and disease-specific survival of patients with postoperative pneumonia were both lower than those without this complication (P < 0.001). Stratified analysis demonstrated that this difference existed in all Stage I, II, and III patients (log-rank, P < 0.05). Multivariate analysis revealed that age, neoadjuvant chemotherapy, tumor size, tumor stage, and postoperative pneumonia were independent risk factors for disease-specific survival. Postoperative pneumonia after radical gastrectomy is an independent risk factor for prognosis of gastric cancer patients, especially in stage III.

The study found that postoperative pneumonia after radical gastrectomy is an independent risk factor for prognosis of gastric cancer patients, especially in stage III. The prognoses of these pneumonic patients improve in the last decade.

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Progression-free survival at 2 years post-autologous transplant: a surrogate end point for overall survival in follicular lymphoma

Abstract

Overall survival (OS) is the gold-standard end point for studies evaluating autologous stem cell transplantation (ASCT) in follicular lymphoma (FL), but assessment may be elusive due to the lengthy disease course. We analyzed the validity of two earlier end points, proposed in the setting of first-line chemo-/immunotherapy, as surrogates for OS—progression-free survival (PFS) status at 24 months (PFS24) and complete response at 30 months (CR30) post-ASCT. We also have investigated the clinical features of patients with early progression after ASCT. Data were available for 626 chemosensitive FL patients who received ASCT between 1989 and 2007. Median follow-up was 12.2 years from ASCT. In the PFS24 analysis, 153 (24%) patients progressed within 24 months and 447 were alive and progression-free at 24 months post-ASCT (26 who died without disease progressions within 24 months were excluded). Early progression was associated with shorter OS (hazard ratio [HR], 6.8; P = 0.00001). In the subgroup of patients who received an ASCT in the setting or relapse after being exposed to rituximab, the HR was 11.3 (95% CI, 3.9–30.2; P < 0.00001). In the CR30 analysis, 183 of 596 (31%) response-evaluable patients progressed/died with 30 months post-ASCT. The absence of CR30 was associated with shorter OS (HR, 7.8; P < 0.00001), including in patients with prior rituximab (HR, 8.2). PFS24 and CR30 post-ASCT are associated with poor outcomes and should be primary end points. Further research is needed to identify this population to be offered alternative treatments.

Disease progression within 2 years and absence of CR at 30 months post-ASCT define new high-risk groups who should be ideally identified soon in order to be offered different therapeutic strategies, such as allogenic stem cell transplantation or novel drugs.

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Periodontal disease and pregnancy outcomes

Twenty three systematic reviews were included in this overview of reviews reviews assessing the link between periodontal disease and adverse periodontal outcomes. While a majority of the available reviews suggest an association there are concerns regarding the quality of the primary studies.

The post Periodontal disease and pregnancy outcomes appeared first on National Elf Service.

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HPV

HPV: Human papillomavirus.

MedTerms (TM) is the Medical Dictionary of MedicineNet.com.
We Bring Doctors' Knowledge To You

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Radiomics to predict immunotherapy-induced pneumonitis: proof of concept

Summary

We present the first reported work that explores the potential of radiomics to predict patients who are at risk for developing immunotherapy-induced pneumonitis. Despite promising results with immunotherapies, immune-related adverse events (irAEs) are challenging. Although less common, pneumonitis is a potentially fatal irAE. Thus, early detection is critical for improving treatment outcomes; an urgent need to identify biomarkers that predict patients at risk for pneumonitis exists. Radiomics, an emerging field, is the automated extraction of high fidelity, high-dimensional imaging features from standard medical images and allows for comprehensive visualization and characterization of the tissue of interest and corresponding microenvironment. In this pilot study, we sought to determine whether radiomics has the potential to predict development of pneumonitis. We performed radiomic analyses using baseline chest computed tomography images of patients who did (N = 2) and did not (N = 30) develop immunotherapy-induced pneumonitis. We extracted 1860 radiomic features in each patient. Maximum relevance and minimum redundancy feature selection method, anomaly detection algorithm, and leave-one-out cross-validation identified radiomic features that were significantly different and predicted subsequent immunotherapy-induced pneumonitis (accuracy, 100% [p = 0.0033]). This study suggests that radiomic features can classify and predict those patients at baseline who will subsequently develop immunotherapy-induced pneumonitis, further enabling risk-stratification that will ultimately lead to better treatment outcomes.

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Exogenous pigmentation of skin and nail caused by a millipede in a patient with plantar psoriasis

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Predicting in vivo effect levels for repeat-dose systemic toxicity using chemical, biological, kinetic and study covariates

Abstract

In an effort to address a major challenge in chemical safety assessment, alternative approaches for characterizing systemic effect levels, a predictive model was developed. Systemic effect levels were curated from ToxRefDB, HESS-DB and COSMOS-DB from numerous study types totaling 4379 in vivo studies for 1247 chemicals. Observed systemic effects in mammalian models are a complex function of chemical dynamics, kinetics, and inter- and intra-individual variability. To address this complex problem, systemic effect levels were modeled at the study-level by leveraging study covariates (e.g., study type, strain, administration route) in addition to multiple descriptor sets, including chemical (ToxPrint, PaDEL, and Physchem), biological (ToxCast), and kinetic descriptors. Using random forest modeling with cross-validation and external validation procedures, study-level covariates alone accounted for approximately 15% of the variance reducing the root mean squared error (RMSE) from 0.96 log₁₀ to 0.85 log₁₀ mg/kg/day, providing a baseline performance metric (lower expectation of model performance). A consensus model developed using a combination of study-level covariates, chemical, biological, and kinetic descriptors explained a total of 43% of the variance with an RMSE of 0.69 log₁₀ mg/kg/day. A benchmark model (upper expectation of model performance) was also developed with an RMSE of 0.5 log₁₀ mg/kg/day by incorporating study-level covariates and the mean effect level per chemical. To achieve a representative chemical-level prediction, the minimum study-level predicted and observed effect level per chemical were compared reducing the RMSE from 1.0 to 0.73 log₁₀ mg/kg/day, equivalent to 87% of predictions falling within an order-of-magnitude of the observed value. Although biological descriptors did not improve model performance, the final model was enriched for biological descriptors that indicated xenobiotic metabolism gene expression, oxidative stress, and cytotoxicity, demonstrating the importance of accounting for kinetics and non-specific bioactivity in predicting systemic effect levels. Herein, we generated an externally predictive model of systemic effect levels for use as a safety assessment tool and have generated forward predictions for over 30,000 chemicals.

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Isolation, purification, structural elucidation and antimicrobial activities of kocumarin, a novel antibiotic isolated from actinobacterium Kocuria marina CMG S2 associated with the brown seaweed Pelvetia canaliculata

Publication date: Available online 26 October 2017
Source:Microbiological Research
Author(s): Bushra Uzair, Farid Menaa, Barkat Ali Khan, Faryal Vali Mohammad, Viqar Uddin Ahmad, Ryad Djeribi, Bouzid Menaa
AimsScreening of seaweed-associated bacteria capable of producing antimicrobials.Methods and resultsFifteen microbial strains, associated to the brown seaweed Pelvetia canaliculata (Linnaeus) attached to the rocks of Sonmiani Beach (Karachi, Pakistan), were screened. Crude extract filtrates of CMG S2 strain grew on Zobell marine agar (ZMA) had the most remarkable antimicrobial activity. Based on its phenotypic aspects (e.g. Gram-positive, microccoid form), biochemical characteristics (e.g. halotolerance) and genetic analyses, CMG S2 is identified as a putatively new Kocuria marina type strain belonging to the actinobacteria's class and micrococcaceae family. Thereby, the nucleotide sequence analysis of its full-length 16S ribosomal ribonucleic acid (rRNA) gene (GenBank accession number EU073966.1) displayed highest identity (i.e. 99%) and score (2630) with K. marina KMM 3905. Phylogenic trees analysis using the neighbor-joining method showed closest evolutionary distance of CMG S2 with KMM 3905 strain and K. carniphila (DC2201) specie. Interestingly, a unique ultraviolet (UV)-bioactive compound was purified from CMG S2 crude extracts by flash silica gel column and thin-layer chromatography techniques (TLC). Its chemical structure was unraveled as 4-[(Z)-2 phenyl ethenyl] benzoic acid (PEBA, later named kocumarin) by nuclear magnetic resonance (NMR) spectroscopy techniques. Importantly, kocumarin demonstrated prominent and rapid growth inhibition against all tested fungi and pathogenic bacteria including methicillin-resistant Staphylococcus aureus (MRSA), with a minimal fungal inhibitory concentration (MFC) of 15–25μg/mL and a minimal (bacterial) inhibitory concentration (MIC) of 10–15μg/mL.Significance and impact of the studyKocumarin represents a new promising natural antibiotic for in vivo and environmental applications.

Graphical abstract

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Autophagy and the Unfolded Protein Response Promote Pro-fibrotic Effects of TGF{beta}1 in Human Lung Fibroblasts

Background: Idiopathic pulmonary fibrosis (IPF) is a lethal fibrotic lung disease in adults with limited treatment options. Autophagy and the unfolded protein response (UPR), fundamental processes induced by cell stress, are dysregulated in lung fibroblasts and epithelial cells from humans with IPF. Methods: Human primary cultured lung parenchymal and airway fibroblasts from non-IPF and IPF donors were stimulated with TGFβ1 with or without the inhibitors of autophagy or UPR (IRE1α inhibitor). We monitored temporal changes in abundance of protein markers of autophagy (LC3βII, Atg5-12), UPR (BIP, IRE1α, cleaved XBP1), and fibrosis (collagen 1α2, fibronectin) using immunoblotting. Using fluorescent immunohistochemistry we profiled autophagy (LC3βII) and UPR (BIP, XBP1) markers in human non-IPF and IPF lung tissue. Results: TGFβ1-induced collagen1α2 and fibronectin protein production was significantly higher in IPF lung fibroblasts compared to lung and airway fibroblasts from non-IPF donors. TGFβ1 induced the accumulation of LC3βII in parallel with collagen 1α2 and fibronectin, but, autophagy marker content was significantly lower in lung fibroblasts from IPF subjects. Inhibition of autophagy flux significantly reduced TGFβ1-induced collagen and fibronectin in fibroblasts from the lungs of non-IPF and IPF donors. Conversely, only in lung fibroblasts from IPF donors did TGFβ1 induce UPR markers. IRE1α inhibitor decreased TGFβ1-induced collagen 1α2 biosynthesis and fibronectin in IPF lung fibroblasts, but not those from non-IPF donors. Conclusions: The IRE1 pathway of the UPR is uniquely induced by TGFβ1 in lung fibroblasts from human IPF donors, and is required for excessive biosynthesis of collagen and fibronectin in these cells.

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Simvastatin Decreases Hyperoxic Oxygen-Induced Acute Lung Injury by Upregulating eNOS

Statins, which are 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase competitive inhibitors, not only lower blood cholesterol, but also exert pleiotropic and beneficial effects in various diseases. However, the effects of statins on acute lung injury (ALI) induced by hyperbaric oxygen (HBO) have not been investigated. The present study is the first to investigate the effects of simvastatin in ALI induced by HBO in 8 - 9 week old C57BL/6 mice exposed to 0.23 MPa (= 2.3 atmosphere absolute (ATA)) hyperoxia ( 95% O2) for 6 hrs. Mice were either given simvastatin (20 mg/kg/day) in saline or a saline vehicle for 3 days before oxygen exposure. Lung tissue, serum, and bronchoalveolar lavage fluid (BALF) were collected for analysis of pro-apoptotic proteins, low-density lipoprotein cholesterol (LDL-C) levels, and lung inflammation. Simvastatin treatment significantly reduced lung permeability, serum LDL-C levels, tissue apoptosis, and inflammation. However, simvastatin treatment had no effect on antioxidant enzyme activity, nicotinamide adenine dinucleotide phosphate oxidase 4 (NADPH4) expression, and Akt phosphorylation levels. Furthermore, we investigated the role of endothelial nitric oxide synthase (eNOS) in simvastatin protection through inhibiting eNOS activity with NG-Nitro-L-arginine methyl ester (L-NAME; 20 mg/kg). Results showed that the beneficial effects of simvastatin on ALI induced by HBO (anti-inflammatory, anti-apoptotic, lipid-lowering, and reduction in lung permeability) were reversed. These results showed that simvastatin curbs HBO-induced lung edema, permeability, inflammation, and apoptosis via upregulating eNOS expression, and that simvastatin could be an effective therapy to treat prolonged HBO exposure.

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12-lipoxygenase and 12-hydroxyeicosatetraenoic acid regulate hypoxic angiogenesis and survival of pulmonary artery endothelial cells via PI3K/Akt pathway

Dysfunction and injury of endothelial cells play critical roles in the pulmonary arterial hypertension, which including the aberrant proliferation, suppressed apoptosis and excessive angiogenesis.12-lipoxygenase and 12-hydroxyeicosatetraenoic acid pathway, which has been considered as a crucial mediator, elevates pulmonary vascular resistance and pulmonary arterial pressure. However, the mechanisms underlying the bioactivity of 12-hydroxyeicosatetraenoic acid in pulmonary vasculature especially in endothelial cells are still elusive. Thus, we aim to determine the key role of 12-lipoxygenase/12-hydroxyeicosatetraenoic acid in angiogenesis and survival of pulmonary artery endothelial cells, and ascertain the signaling pathways participated in the pathological process. Here we identify that hypoxia increases the formation of endogenous 12-hydroxyeicosatetraenoic acid through stimulation of 12-lipoxygenase. Furthermore, we initiate that 12-hydroxyeicosatetraenoic acid promotes endothelial cells migration and tube formation, whereas it inhibits the serum deprivation-induced apoptotic responses under hypoxia. Particularly, the regulatory effects of 12-lipoxygenase/12-hydroxyeicosatetraenoic acid on pulmonary artery endothelial cells, at least in part, depend on the PI3K/Akt signaling activation. Taken together, these results may serve a significant implication for understanding of pulmonary hypertension and offer a potential therapeutic concept focusing on 12-lipoxygenase/12-hydroxyeicosatetraenoic acid signaling system.

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Lung disease phenotypes caused by over-expression of combinations of alpha, beta, and gamma subunits of the epithelial sodium channel in mouse airways

The epithelial Na+ channel (ENaC) regulates airway surface hydration. In mouse airways, ENaC is composed of three subunits, alpha (α), beta (β), and gamma (), which are differentially expressed (α > β > ). Airway-targeted overexpression of the β subunit results in Na+ hyperabsorption causing airway surface dehydration, hyperconcentrated mucus with delayed clearance, lung inflammation, and perinatal mortality. Notably, mice overexpressing the α or subunit do not exhibit airway Na+ hyperabsorption nor lung pathology. To test whether overexpression of multiple ENaC subunits produced Na+ transport and disease severity exceeding that of βENaC-Tg mice, we generated double (αβ, α, β) and triple (αβ) transgenic mice and characterized their lung phenotypes. Double αENaC-Tg mice were undistinguishable from WT littermates. In contrast, double βENaC-Tg mice exhibited airway Na+ absorption greater than βENaC-Tg mice, which was paralleled by worse survival, decreased mucociliary clearance, and more severe lung pathology. Double αβENaC-Tg mice exhibited Na+ transport rates comparable to βENaC-Tg littermates. However, αβENaC-Tg mice had poorer survival and developed severe parenchymal consolidation. In situ hybridization (RNAscope®) analysis revealed both alveolar and airway αENaC-Tg overexpression. Triple αβENaC-Tg mice were born in Mendelian proportions but died within the first day of life and the small sample size prevented analyses of cause(s) of death. Cumulatively, these results indicate that over-expression of βENaC is rate limiting for generation of pathologic airway surface dehydration. Notably, airway co-overexpression of β and ENaC had additive effects on Na+ transport and disease severity, suggesting dose-dependency of these two variables.

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Autophagy Inhibitor 3-Methyladenine Protects against Endothelial Cell Barrier Dysfunction in Acute Lung Injury

Autophagy is an evolutionarily conserved cellular process that facilitates the continuous recycling of intracellular components (organelles and proteins) and provides an alternative source of energy when nutrients are scarce. Recent studies have implicated autophagy in many disorders including pulmonary diseases. However, the role of autophagy in endothelial cell (EC) barrier dysfunction and its relevance in the context of acute lung injury (ALI) remains uncertain. Here, we provide evidence that autophagy is a critical component of EC barrier disruption in ALI. Using an aerosolized bacterial lipopolysaccharide (LPS) inhalation mouse model of ALI, we found that administration of autophagy inhibitor 3-methyladenine (3-MA), either prophylactically or therapeutically, markedly reduced lung vascular leakage and tissue edema. 3-MA was also effective in reducing the levels of proinflammatory mediators and lung neutrophil sequestration induced by LPS. To test the possibility that autophagy in EC could contribute to lung vascular injury, we addressed its role in the mechanism of EC barrier disruption. Knockdown of ATG5, an essential regulator of autophagy, attenuated thrombin-induced EC barrier disruption, confirming the involvement of autophagy in the response. Similarly, exposure of cells to 3-MA, either prior to or after thrombin, protected against EC barrier dysfunction by inhibiting the cleavage and loss of VE-cadherin at adherens junctions as well as formation of actin stress fibers. 3-MA also reversed LPS-induced EC barrier disruption. Together, these data implicate a role of autophagy in causing lung vascular injury and reveal the protective and therapeutic utility of 3-MA against ALI.

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Endothelial HIF-2{alpha} Contributes to Severe Pulmonary Hypertension by Inducing Endothelial-to-Mesenchymal Transition

Pulmonary vascular remodeling characterized by concentric wall thickening and intraluminal obliteration contributes to the elevated PVR in patients with IPAH. Here we report that increased HIF-2α in lung vascular endothelial cells (LVEC) under normoxic conditions is involved in the development of pulmonary hypertension (PH) by inducing endothelial-to-mesenchymal transition (EndMT), which subsequently results in vascular remodeling and occlusive lesions. We observed significant EndMT and markedly increased expression of SNAI, an inducer of EndMT, in LVEC from IPAH patients and PH animals compared with controls. LVEC from IPAH patients had a higher level of HIF-2α than that from normals, while HIF-1α was upregulated in IPAH-PASMC. The increased HIF-2α level, due to downregulated prolyl hydroxylase domain protein 2 (PHD2), was involved in the enhanced EndMT and upregulated SNAI1/2 in IPAH-LVEC. Moreover, knockdown of HIF-2α (but not HIF-1α) with siRNA decreases both SNAI1/SNAI2 expression in IPAH-LVEC. Mice with EC-specific knockout (KO) of the PHD2 gene, egln1 (egln1EC–/–), developed severe PH under normoxic conditions; while Snai1/2 and EndMT were increased in LVEC of egln1EC–/– mice. EC-specific KO of the HIF-2α gene, hif2a, prevented mice from developing hypoxia-induced PH, whereas EC-specific deletion of the HIF-1α gene, hif1a, or SMC-specific deletion of hif2a, negligibly affected the development of PH. Also, hypoxia (48-72 hrs) increased HIF-1α in normal human PASMC and HIF-2α in normal human LVEC. These data indicate that increased HIF-2α in LVEC plays a pathogenic role in the development of PH by upregulating SNAI1/2, inducing EndMT, and causing obliterative pulmonary vascular lesions and remodeling.

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Assessing the role of immune system in cancer progression from minimal residual disease

The immune system plays a major role in resisting the development and progression of cancer. Analysis of the molecular mechanisms of immune resistance to cancer has led to the formulation of several immunotherapeutic strategies. Although the immune system is portrayed in the literature as an effective tool for primary cancer control, its role in the development of recurrent tumors was relatively unexplored. It is well established that most cancers contain a subpopulation of cancer cells, that possess an inherent survival instinct which aids them to adopt a dormant state when subjected to stress [1–4].

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Assessing the role of immune system in cancer progression from minimal residual disease

The immune system plays a major role in resisting the development and progression of cancer. Analysis of the molecular mechanisms of immune resistance to cancer has led to the formulation of several immunotherapeutic strategies. Although the immune system is portrayed in the literature as an effective tool for primary cancer control, its role in the development of recurrent tumors was relatively unexplored. It is well established that most cancers contain a subpopulation of cancer cells, that possess an inherent survival instinct which aids them to adopt a dormant state when subjected to stress [1–4].

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India Dentist Opens up Patient's Mouth to Find Slithering Maggots, Video Goes Viral

New Delhi, Oct 25: A footage uploaded by an India user on YouTube showed a dentist opening up a woman's mouth only to find it infested with dozens of wriggling maggots. The woman, presumably because of her long white hair, appears to be under sedation and can be heard taking deep breaths in the 56-second long clip.

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Contents

Publication date: November 2017
Source:Health Policy, Volume 121, Issue 11





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Editorial Board

Publication date: November 2017
Source:Health Policy, Volume 121, Issue 11





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Pseudomyxoma pleuri as a Surgical Emergency: a Rare Case Report

Abstract

Pseudomyxoma pleuri is a rare condition and it mostly results from secondary involvement of an abdominal pathology. Massive pleural disease impedes cardiopulmonary functions and threatens life. We are reporting our experience about managing a middle-age lady with a known case of Pseudomyxoma peritonei, who presented to causality with progressive breathing difficulty in acute exacerbation and cardiopulmonary compromise.

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Replication origin flanking roadblocks reveal origin-licensing dynamics and altered sequence dependence [Cell Biology]

In eukaryotes, DNA replication initiates from multiple origins of replication for timely genome duplication. These sites are selected by origin licensing, during which the core enzyme of the eukaryotic DNA replicative helicase, the Mcm2-7 (minichromosome maintenance) complex, is loaded at each origin. This origin licensing requires loading two Mcm2-7 helicases around origin DNA in a head-to-head orientation. Current models suggest that the origin recognition complex (ORC) and cell-division cycle 6 (Cdc6) proteins recognize and encircle origin DNA and assemble an Mcm2-7 double hexamer around adjacent double-stranded DNA. To test this model and assess the location of Mcm2-7 initial loading, we placed DNA protein roadblocks at defined positions adjacent to the essential ORC binding site within S. cerevisiae origin DNA. Roadblocks were made either by covalent crosslinking of the HpaII methyltransferase to DNA or through binding of a transcription-activator-like effector (TALE) protein. Contrary to the sites of Mcm2-7 recruitment being precisely defined, only single roadblocks that inhibited ORC-DNA binding showed helicase loading defects. We observed inhibition of helicase loading without inhibition of ORC-DNA binding only when roadblocks were placed on both sides of the origin to restrict sliding of a helicase-loading intermediate. Consistent with a sliding helicase-loading intermediate, when either one of the flanking roadblocks was eliminated, the remaining roadblock had no effect on helicase loading. Interestingly, either origin-flanking nucleosomes or roadblocks resulted in helicase loading being dependent on an additional origin sequence known to be a weaker ORC-DNA binding site. Together, our findings support a model in which sliding helicase-loading intermediates increase the flexibility of the DNA sequence requirements for origin licensing.

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Conformational dynamics of the TTD-PHD histone reader module of UHRF1 reveals multiple histone binding states, allosteric regulation and druggability [Molecular Biophysics]

UHRF1 is a key mediator of inheritance of epigenetic DNA methylation patterns during cell division and is a putative target for cancer therapy. Recent studies indicate that interdomain interactions critically influence UHRF1's chromatin-binding properties, including allosteric regulation of its histone binding. Here, using an integrative approach that combines small angle X-ray scattering (SAXS), NMR spectroscopy, and molecular dynamics (MD) simulations, we characterized the dynamics of the TTD-PHD histone reader module, including its 20-residue interdomain linker. We found that the apo TTD-PHD module in solution comprises a dynamic ensemble of conformers, approximately half of which are compact conformations, with the linker lying in the TTD peptide-binding groove. These compact conformations are amenable to cooperative, high-affinity histone binding. In the remaining conformations, the linker position was in flux, and the reader adopted both extended and compact states. Using a small-molecule fragment screening approach, we identified a compound, 4-benzylpiperidine-1-carboximidamide (BPC), that binds to the TTD groove, competes with linker binding and promotes open TTD-PHD conformations that are less efficient at H3K9me3 binding. Our work reveals a mechanism by which the dynamic TTD-PHD module can be allosterically targeted with small molecules to modulate its histone reader function for therapeutic or experimental purposes.

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Presynaptic mGluR5 receptor controls glutamatergic input through protein kinase C-NMDA receptors in paclitaxel-induced neuropathic pain [Neurobiology]

Chemotherapeutic drugs such as paclitaxel cause painful peripheral neuropathy in many cancer patients and survivors. Although NMDA receptors (NMDARs) at primary afferent terminals are known to be critically involved in chemotherapy-induced chronic pain, the upstream signaling mechanism that leads to presynaptic NMDAR activation is unclear. Group I metabotropic glutamate receptors (mGluRs) play a role in synaptic plasticity and NMDAR regulation. Here we report that the Group I mGluR agonist (S)-3,5-dihydroxyphenylglycine (DHPG) significantly increased the frequency of miniature excitatory postsynaptic currents (EPSCs) and the amplitude of monosynaptic EPSCs evoked from the dorsal root. DHPH also reduced the paired-pulse ratio of evoked EPSCs in spinal dorsal horn neurons. These effects were blocked by the selective mGluR5 antagonist 2-methyl-6-(phenyl-ethynyl)-pyridine (MPEP), but not by an mGluR1 antagonist. MPEP normalized the frequency of miniature EPSCs and the amplitude of evoked EPSCs in paclitaxel-treated rats but had no effect in vehicle-treated rats. Furthermore, mGluR5 protein levels in the dorsal root ganglion and spinal cord synaptosomes were significantly higher in paclitaxel- than in vehicle-treated rats. Inhibiting protein kinase C (PKC) or blocking NMDARs abolished DHPG-induced increases in the miniature EPSC frequency of spinal dorsal horn neurons in vehicle- and paclitaxel-treated rats. Moreover, intrathecal administration of MPEP reversed pain hypersensitivity caused by paclitaxel treatment. Our findings suggest that paclitaxel-induced painful neuropathy is associated with increased presynaptic mGluR5 activity at the spinal cord level, which serves as upstream signaling for PKC-mediated tonic activation of NMDARs. mGluR5 is therefore a promising target for reducing chemotherapy-induced neuropathic pain.

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Epidermal growth factor receptors containing a single tyrosine in their C-terminal tail bind different effector molecules and are signaling-competent [Signal Transduction]

The EGF receptor is a classic receptor tyrosine kinase. It contains nine tyrosines in its C-terminal tail, many of which are phosphorylated and bind proteins containing SH2 or phosphotyrosine-binding (PTB) domains. To determine how many and which tyrosines are required to enable EGF receptormediated signaling, we generated a series of EGF receptors that contained only one tyrosine in their C-terminal tail. Assays of the signaling capabilities of these single-Tyr EGF receptors, indicated that they can activate a range of downstream signaling pathways, including MAP kinase and Akt. The ability of the single-Tyr receptors to signal correlated with their ability to bind Grb2-associated binding protein 1 (Gab1). However, Tyr-992 appeared to be almost uniquely required to observe activation of phospholipase Cg. These results demonstrate that multiply phosphorylated receptors are not required to support most EGF-stimulated signaling but identify Tyr-992 and its binding partners as a unique node within the network. We also studied the binding of the isolated SH2 domain of growth factor receptor-bound protein 2 (Grb2) and the isolated PTB domain of SHC adaptor protein (Shc) to the EGF receptor. Although these adapter proteins bound readily to wild type EGF receptor, they bound poorly to the single-Tyr EGF receptors, even those that bound full-length Grb2 and Shc well. This suggests that in addition to pTyr-directed associations, secondary interactions between the tail and regions of the adapter proteins outside of the SH2/PTB domains are important for stabilizing the binding of Grb2 and Shc to the single-Tyr EGF receptors.

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Resveratrol: a novel type of topoisomerase II inhibitor [Enzymology]

Resveratrol, a polyphenol found in various plant sources, has gained attention as a possible agent responsible for the purported health benefits of certain foods, such as red wine. Despite annual multi-million dollar market sales as a nutriceutical, there is little consensus about the physiological roles of resveratrol. One suggested molecular target of resveratrol is eukaryotic topoisomerase II (topo II), an enzyme essential for chromosome segregation and DNA supercoiling homeostasis. Interestingly, resveratrol is chemically similar to ICRF-187, a clinically-approved chemotherapeutic that stabilizes an ATP-dependent dimerization interface in topo II to block enzyme activity. Based on this similarity, we hypothesized that resveratrol may antagonize topo II by a similar mechanism. Using a variety of biochemical assays, we find that resveratrol indeed acts through the ICRF-187 binding locus, but that it inhibits topo II by preventing ATPase domain dimerization rather than stabilizing it. This work presents the first comprehensive analysis of the biochemical effects of both ICRF-187 and resveratrol on the human isoforms of topo II, and reveals a new mode for the allosteric regulation of topo II through modulation of ATPase status. Natural polyphenols related to resveratrol that have been shown to impact topo II function may operate in a similar manner.

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Organelle-specific single-molecule imaging of {alpha}4{beta}2 nicotinic receptors reveals the effect of nicotine on receptor assembly and cell-surface trafficking [Cell Biology]

Nicotinic acetylcholine receptors (nAChRs) assemble in the endoplasmic reticulum (ER) and traffic to the cell surface as pentamers composed of alpha and beta subunits. Many nAChR subtypes can assemble with varying subunit ratios, giving rise to multiple stoichiometries exhibiting different subcellular localization and functional properties. In addition to the endogenous neurotransmitter acetylcholine, nicotine also binds and activates nAChRs and influences their trafficking and expression on the cell surface. Currently, no available technique can specifically elucidate the stoichiometry of nAChRs in the ER versus those in the plasma membrane. Here, we report a method involving single-molecule fluorescence measurements to determine the structural properties of these membrane proteins after isolation in nanoscale vesicles derived from specific organelles. These cell-derived nanovesicles allowed us to separate single membrane receptors while maintaining them in their physiological environment. Sorting the vesicles according to the organelle of origin enabled us to determine localized differences in receptor structural properties, structural influence on transport between organelles, and changes in receptor assembly within intracellular organelles. These organelle-specific nanovesicles revealed one structural isoform of the α4β2 nAChR was preferentially trafficked to the cell surface. Moreover, nicotine altered nAChR assembly in the ER, resulting in increased production of the receptor isoform that traffics more efficiently to the cell surface. We conclude that the combined effects of the increased assembly of one nAChR stoichiometry and its preferential trafficking likely drive the upregulation of nAChRs on the cell surface upon nicotine exposure

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The TRPC1 Ca2+-permeable channel inhibits exercise-induced protection against high-fat diet-induced obesity and type II diabetes [Molecular Bases of Disease]

The transient receptor potential canonical channel-1 (TRPC1) is a Ca2+ permeable channel found in key metabolic organs and tissues, including the hypothalamus, adipose tissue, and skeletal muscle. Loss of TRPC1 may alter the regulation of cellular energy metabolism resulting in insulin resistance thereby leading to diabetes. Exercise reduces insulin resistance, but it is not known whether TRPC1 is involved in exercise-induced insulin sensitivity. The role of TRPC1 in adiposity and obesity-associated metabolic diseases has not yet been determined. Our results show that TRPC1 functions as a major Ca2+ entry channel in adipocytes. We have also shown that fat mass and fasting glucose concentrations were lower in TRPC1 KO mice that were fed a high-fat (HF) (45% fat) diet and exercised as compared to WT mice fed a HF diet and exercised. Adipocyte numbers were decreased in both subcutaneous and visceral adipose tissue of TRPC1 KO mice fed a HF diet and exercised. Finally, autophagy markers were decreased and apoptosis markers increased in TRPC1 KO mice fed a HF diet and exercised. Overall, these findings suggest that TRPC1 plays an important role in the regulation of adiposity via autophagy and apoptosis and that TRPC1 inhibits the positive effect of exercise on type II diabetes risk under a high-fat diet-induced obesity environment.

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The Natural Product Mensacarcin Induces Mitochondrial Toxicity and Apoptosis in Melanoma Cells [Bioenergetics]

Mensacarcin is a highly oxygenated polyketide that was first isolated from soil-dwelling Streptomyces bacteria. It exhibits potent cytostatic properties (GI50: 0.2 μM) in almost all cell lines of the National Cancer Institute (NCI)-60 cell line screen and relatively selective cytotoxicity against melanoma cells. Moreover, its low COMPARE correlations with known standard antitumor agents indicate a unique mechanism of action. Effective therapies for managing melanoma are limited, so we sought to investigate mensacarcin's unique cytostatic and cytotoxic effects and its mode of action. By assessing morphological and bio-chemical features we demonstrate that mensacarcin activates caspase 3,7-dependent apoptotic pathways and induces cell death in melanoma cells. Upon mensacarcin exposure, SK-Mel-28 and SK-Mel-5 melanoma cells, which have the BRAFV600E mutation associated with drug resistance, show characteristic chromatin condensation as well as distinct PARP-1 cleavage. Flow cytometry identifies a large population of apoptotic melanoma cells and single cell electrophoresis indicates that mensacarcin causes genetic instability, a hallmark of early apoptosis. To visualize mensacarcin's subcellular localization, we synthesized a fluorescent mensacarcin-probe that retained activity. The natural product probe is localized to mitochondria within 20 minutes of treatment. Live-cell bioenergetic flux analysis confirms that mensacarcin disturbs energy production and mitochondrial function rapidly. The subcellular localization of the fluorescently-labeled mensacarcin together with its unusual metabolic effects in melanoma cells provides evidence that mensacarcin targets mitochondria. Mensacarcin's unique mode of action suggests it may be a useful probe for examining energy metabolism, particularly in BRAF-mutant melanoma, and represents a promising lead for the development of new anticancer drugs.

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Flaxseed Consumption Inhibits Chemically-induced Lung Tumorigenesis andModulates Expression of Phase II Enzymes and Inflammatory Cytokines in A/JMice

Flaxseed consumption is associated with reduced oxidative stress and inflammation in lung injury models, and has shown anti-cancer effects for breast and prostate tissues. However, the chemopreventive potential of flaxseed remains unexplored for lung cancer. In this study, we investigated the effect of flaxseed on tobacco smoke carcinogen (NNK)-induced lung tumorigenesis in an A/J mouse model. Mice exposed to NNK were fed a control diet or a 10% flaxseed-supplemented diet for 26 weeks. Flaxseed-fed mice showed reduced lung tumor incidence (78%) and multiplicity, with an average of 2.7 ± 2.3 surface lung tumor nodules and 1.0 ± 0.9 H&E cross-section nodules per lung compared to the control group which had 100% tumor incidence and an average of 10.2 ± 5.7 surface lung tumor nodules and 3.9 ± 2.6 H&E cross-section nodules per lung. Further, flaxseed-fed mice had a lower incidence of adenocarcinomas compared to control-fed mice. Western blotting performed on normal lung tissues showed flaxseed suppressed phosphorylation (activation) of p-AKT, p-ERK, and p-JNK kinases. RNA-Seq data obtained from normal lung and lung tumors of control and flaxeed-fed mice suggested that flaxseed intake resulted in differential expression of genes involved inflammation-mediated cytokine signaling (IL-1,-6,-8,-9, and -12α), xenobiotic metabolism (several CYPs, GSTs, and UGTs), and signaling pathways (AKT and MAPK) involved in tumor cell proliferation. Together, our results indicate that dietary flaxseed supplementation may be an effective chemoprevention strategy for chemically-induced lung carcinogenesis by altering signaling pathways, inflammation, and oxidative stress.

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A Novel Application of Structural Equation Modeling Estimates the Association between Oxidative Stress and Colorectal Adenoma

In vitro evidence implicates oxidative stress in many adverse health conditions, including colorectal neoplasia. In human studies, however, oxidative stress is measured by imperfect biomarkers, which are inconsistently associated with health outcomes. Structural equation modeling (SEM) offers one possible solution by modeling a latent (unobserved) construct from multiple biomarkers. Our goal was to investigate the association of a latent oxidative stress variable with colorectal adenoma. Using SEM, we analyzed pooled data from two cross-sectional studies of colorectal adenoma (n=526) that measured five plasma biomarkers of oxidative stress and inflammation that comprised the latent oxidative stress variable: F2-isoprostanes (FIP), fluorescent oxidation products (FOP), mitochondrial DNA (MtDNA) copy number, -tocopherol (Gtoc), and C-reactive protein (CRP). Higher levels of oxidative stress were associated with colorectal adenoma (odds ratio=3.23 per standard deviation increase in oxidative stress, 95% confidence interval: 1.28, 8.18). The latent variable estimate was considerably stronger than the associations of adenoma with the individual biomarkers, which were modest and mostly non-significant. Risk factors were associated with adenoma via the oxidative stress pathway, particularly overweight and obesity with an OR=1.50, 95% CI: 1.10, 2.81; and OR=2.95, 95% CI: 1.28, 12.45, respectively. Oxidative stress may be positively associated with colorectal adenoma and important risk factors may act through this mechanism, but the cross-sectional design of the current study precludes observing the directionality of associations. The presence of an adenoma could affect levels of the circulating biomarkers thus we should be cautious of strong conclusions until the findings are replicated in a follow-up study.

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Genetic variants in metabolic signaling pathways and their interaction with lifestyle factors on breast cancer risk: A random survival forest analysis

Genetic variants in the insulin-like growth factor-I (IGF-I)/insulin resistance axis may interact with lifestyle factors, influencing postmenopausal breast cancer risk, but these interrelated pathways are not fully understood. In this study, we examined 54 single-nucleotide polymorphisms (SNPs) in genes related to IGF-I/insulin phenotypes and signaling pathways and lifestyle factors in relation to post-menopausal breast cancer, using data from 6,567 postmenopausal women in the Women's Health Initiative Harmonized and Imputed Genome-Wide Association Studies. We employed a machine learning method, two-stage random survival forest analysis. We identified 3 genetic variants (AKT1 rs2494740, AKT1 rs2494744, and AKT1 rs2498789) and 2 lifestyle factors (body mass index [BMI] and dietary alcohol intake) as the top 5 most influential predictors for breast cancer risk. The combination of the 3 SNPs, BMI, and alcohol consumption (≥ 1 gm/day) significantly increased the risk of breast cancer in a gene and lifestyle dose-dependent manner. Our findings provide insight into gene-lifestyle interactions and will enable researchers to focus on individuals with risk genotypes to promote intervention strategies. These data also suggest potential genetic targets in future intervention/clinical trials for cancer prevention in order to reduce the risk for breast cancer in postmenopausal women.

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NF-kB promotes ovarian tumorigenesis via classical pathways supporting proliferative cancer cells and alternative pathways supporting ALDH+ cancer stem-like cells

Understanding the mechanisms supporting tumor-initiating cells (TIC) is vital to combat advanced stage recurrent cancers. Here we show that in advanced ovarian cancers NF-kB signaling via the RelB transcription factor supports TIC populations by directly regulating the cancer stem-like associated enzyme aldehyde dehydrogenase (ALDH). Loss of RelB significantly inhibited spheroid formation, ALDH expression and activity, chemoresistance, and tumorigenesis in subcutaneous and intrabursal mouse xenograft models of human ovarian cancer. RelB also affected expression of the ALDH gene ALDH1A2. Interestingly, classical NF-kB signaling through the RelA transcription factor was equally important for tumorigenesis in the intrabursal model, but had no effect on ALDH. In this case, classical signaling via RelA was essential for proliferating cells, whereas the alternative signaling pathway was not. Our results show how NF-kB sustains diverse cancer phenotypes via distinct classical and alternative signaling pathways, with implications for improved understanding of disease recurrence and therapeutic response.

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Generation of recombinant affinity reagents against a two-phosphosite epitope of ATF2

Publication date: Available online 26 October 2017
Source:New Biotechnology
Author(s): Jennifer McGinnis, Brian K. Kay
Activating Transcription Factor 2 (ATF2) plays an important role in mammalian cell proliferation, apoptosis and DNA repair. Its activation is dependent on the sequential phosphorylation of residue threonine 71 (T71) followed by threonine 69 (T69) in its transactivation domain. While these modifications can be directed by a variety of kinases, the time to reach full phosphorylation is dependent on which signaling pathway has been activated, which is thought to be important for proper temporal regulation. To explore this phenomenon further, there have been ongoing efforts to generate affinity reagents for monitoring phosphorylation events in cellular assays. While phospho-specific antibodies have been valuable tools for monitoring cell signaling events, those raised against a peptide containing two or more adjacent phosphosites tend to cross-react with that peptide's various phospho-states, rendering such reagents unusable for studying sequential phosphorylation. As an alternative, we have employed the N-terminal Forkhead-associated 1 (FHA1) domain of yeast Rad53p as a scaffold to generate recombinant affinity reagents via phage display and were successful in generating a set of reagents that can distinguish between the dual-phosphorylated epitope, 63-IVADQpTPpTPTRFLK-77, and the mono-phosphorylated epitope, 63-IVADQpTPTPTRFLK-77, in the human ATF2 transactivation domain.



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Global metabolomic profiling of uterine leiomyomas

Global metabolomic profiling of uterine leiomyomas

British Journal of Cancer, Published online: 26 October 2017; doi:10.1038/bjc.2017.361

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Intratumoural PD-L1 expression is associated with worse survival of patients with Epstein–Barr virus-associated gastric cancer

Intratumoural PD-L1 expression is associated with worse survival of patients with Epstein–Barr virus-associated gastric cancer

British Journal of Cancer, Published online: 26 October 2017; doi:10.1038/bjc.2017.369

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Tetracycline use and risk of incident skin cancer: a prospective study

Tetracycline use and risk of incident skin cancer: a prospective study

British Journal of Cancer, Published online: 26 October 2017; doi:10.1038/bjc.2017.378

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Head and neck merkel cell carcinoma: a retrospective case series and critical literature review with emphasis on treatment and prognosis.

Merkel cell carcinoma (MCC) is a rare cutaneous malignancy with a high recurrence and mortality rates. More than half of MCCs occur in the head and neck region. This paper aims to present a retrospective case series study of primary MCCs of the head and neck (HN-MCCs) treated in our department over 12 years. A critical review of the current literature is also included in order to provide up-to-date information on MCCs with special emphasis laid on treatment modalities and disease prognosis. Six patients were identified and their characteristics, treatment modalities, and outcomes are reported.

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Australian startup prepares former military personnel to fill the IT skills shortage

Sydney-based Tom Moore returned to the daily grind from serving in Afghanistan, and after a poor transition process, founded a company that aims to change the way the veteran workforce is perceived by industry and upskill ex-military personnel for a career in technology.

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Treating laryngopharyngeal reflux: Evaluation of an anti-reflux program with comparison to medications

To determine if an anti-reflux induction program relieves laryngopharyngeal reflux (LPR) symptoms more effectively than medication and behavioral changes alone.

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Pediatric airway study: Endoscopic grading system for quantifying tonsillar size in comparison to standard adenotonsillar grading systems

Current grading systems may not allow clinicians to reliably document and communicate adenotonsillar size in the clinical setting. A validated endoscopic grading system may be useful for reporting tonsillar size in future clinical outcome studies. This is especially important as tonsillar enlargement is the cause of a substantial health care burden on children.

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Treating laryngopharyngeal reflux: Evaluation of an anti-reflux program with comparison to medications

To determine if an anti-reflux induction program relieves laryngopharyngeal reflux (LPR) symptoms more effectively than medication and behavioral changes alone.

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Pediatric airway study: Endoscopic grading system for quantifying tonsillar size in comparison to standard adenotonsillar grading systems

Current grading systems may not allow clinicians to reliably document and communicate adenotonsillar size in the clinical setting. A validated endoscopic grading system may be useful for reporting tonsillar size in future clinical outcome studies. This is especially important as tonsillar enlargement is the cause of a substantial health care burden on children.

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Interferon response to RSV by bronchial epithelium from children with asthma is inversely correlated with pulmonary function

RSV-infected bronchial epithelial cells from children with asthma and obstructive physiology demonstrate greater expression of type I and III IFN-associated genes than cells from children without airway obstruction. Furthermore expression of IFN-associated genes inversely correlate with lung function.

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Anti-apoptotic Serine Protease Inhibitors contribute towards the survival of allergenic Th2 cells

The mechanisms regulating the maintenance of persistent Th2 cells that potentiate allergic inflammation are not well understood.

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Chronic Rhinosinusitis: Endotypes, Biomarkers and Treatment Response

It is increasingly recognized that chronic rhinosinusitis (CRS) comprises a spectrum of different diseases with distinct clinical presentations and pathogenic mechanisms. Defining the distinct phenotypes and endotypes of CRS impacts prognosis and most importantly is necessary as the basis for making therapeutic decisions. The need for individualized defining of pathogenic mechanisms prior to initiating therapy extends to virtually all therapeutic considerations. This is clearly crucial with antibiotics where, barring an influence from their off-target anti-inflammatory pharmacological effects, an understanding of the role of individual biome predicts likelihood of therapeutic benefit.

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Lower Plasma Choline Levels are Associated with Sleepiness Symptoms

Sleepiness and cardiovascular disease share common molecular pathways; thus, metabolic risk factors for sleepiness may also predict cardiovascular disease risk. Daytime sleepiness predicts mortality and cardiovascular disease, although the mechanism is unidentified. This study explored the associations between subjective sleepiness and metabolite concentrations in human blood plasma within the oxidative and inflammatory pathways, in order to identify mechanisms that may contribute to sleepiness and cardiovascular disease risk.

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