Πέμπτη, 25 Μαΐου 2017

hrHPV E5 oncoprotein: immune evasion and related immunotherapies

The immune response is a key factor in the fight against HPV infection and related cancers, and thus, HPV is able to promote immune evasion through the expression of oncogenes. In particular, the E5 oncogene i...

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Food transit duration is associated with the number of stage II transport cycles when eating solid food

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Publication date: September 2017
Source:Archives of Oral Biology, Volume 81
Author(s): Takashi Hiraoka, Jeffrey B. Palmer, Martin B. Brodsky, Mitsumasa Yoda, Haruhi Inokuchi, Akio Tsubahara
ObjectiveWhen eating solids, stage II transport (St2Tr) propels triturated food into the pharynx for bolus formation and storage before swallowing. Although the existence of St2Tr is acknowledged, the reason for its existence remains unclear. Understanding it may facilitate development of food appropriate for individuals with dysphagia. The purpose of this study was to explore how measures of duration of eating and swallowing affect the number of St2Tr cycles.DesignVideofluorography was performed on 13 healthy subjects eating 6-g squares of banana, tofu, and cookies. Measurements included the number of St2Tr cycles, duration of processing (from food entering the mouth to onset of swallowing), pre-upper esophageal sphincter (UES) transit duration (from onset of swallowing to onset of UES transit), UES transit duration (leading edge to trailing edge passing the UES), and total sequence duration (from onset of swallowing to terminal swallow). Principal component (PC) analysis was used to identify factors affecting the number of St2Tr cycles. Analysis of covariance was performed using the 1st PC as an independent variable for predicting the number of St2Tr cycles.ResultsAll four duration measures were significantly positively correlated with the number of St2Tr cycles. Analysis revealed two orthogonal PCs with variable loading. The 1st PC was a function of the timing variables. The 2nd PC was a function of the number of swallows.ConclusionsThe number of St2Tr cycles was associated with measures of food transit duration and was greater with harder foods before processing and more viscous foods just before swallowing.



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Mild encephalitis/encephalopathy with reversible splenial lesion (MERS) in adults-a case report and literature review

Mild encephalitis/encephalopathy with reversible splenial lesion (MERS) is a rare clinico-radiological entity characterized by the magnetic resonance imaging (MRI) finding of a reversible lesion in the corpus ...

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Flu-like illness, fever, malaise and chills, followed by severe nonpleuritic chest pain and shortness of breath

Chronic migraine headache and acute shortness of breath associated with nausea, vomiting, diaphoresis and increasing retrosternal chest pain..Increased frequency of his migraine headaches associated with vague retrosternal chest pain and epigastric pain...................................................................................................................Flu-like illness, fever, malaise and chills, followed by severe nonpleuritic chest pain and shortness of breath................................................................................Palpitations, fatigue, vague chest discomfort, and cardiomegaly and pulmonary congestion visible on chest radiograph. He had developed a flu-like illness with low-grade fever, chills, myalgia and headache a week earlier. There had been no preceding cough, hemoptysis, orthopnea, paroxysmal nocturnal dyspnea or ankle edema. .....................................................................................................................................Eosinophilic myocarditis (EM)........................................................................................................Therapeutic effect of anti-IL-5 on eosinophilic myocarditis with large pericardial effusion


Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182
6948891480

13. Akademia Dermatologii i Alergologii Słupsk − Ustka − Dolina Charlotty 09−12 lutego 2017 roku

Publication date: Available online 24 May 2017
Source:Alergologia Polska - Polish Journal of Allergology
Author(s): Maciej Kaczmarski




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Neoadjuvant chemotherapy with trastuzumab, docetaxel, and carboplatin administered every 3 weeks for Japanese women with HER2-positive primary breast cancer: efficacy and safety

Abstract

Background

This phase II neoadjuvant study evaluated the efficacy and safety of a triweekly regimen of docetaxel and carboplatin in combination with trastuzumab (TCbH) in Japanese women with human epidermal growth factor receptor type2 (HER2)-positive primary breast cancer.

Methods

Patients with HER2-positive, stage I–III invasive breast cancer received six courses of trastuzumab (8 mg/kg loading dose, then 6 mg/kg, day 1), docetaxel (75 mg/m2, day 1), and carboplatin (area under the curve: 6, day 1) every 3 weeks. The primary endpoint was pathological complete response (pCR) of both breast and axillary lymph node disease.

Results

Fifty patients were enrolled in this study. Median age was 58 (range 32–75) years. All patients underwent definitive surgery. Thirty-three (66%) patients completed the chemotherapy course, while the treatment was delayed or discontinued in the other 17 (34%) patients because of adverse events (AEs). The pCR rate was 52%; the overall response rate was 66%. Grade 3/4 AEs due to nonhematological toxicity were anorexia (4%), diarrhea (2%), and rash (2%), and those due to hematological toxicity were neutropenia (36%), anemia (12%), and thrombocytopenia (2%).

Conclusion

Although the triweekly six-course regimen of TCbH achieved a high pCR rate, hematological AEs frequently occurred during the latter part of the chemotherapy course. One-third of patients experienced delayed or discontinued chemotherapy.

Clinical registration number: http://www.umin.org.auUMIN000013513.



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Anti-transglutaminase 6 Antibody Development in Children With Celiac Disease Correlates With Duration of Gluten Exposure.

Objectives: Antibodies against transglutaminase 6 (anti-TG6) have been implicated in neurological manifestations in adult patients with genetic-gluten intolerance and it is unclear whether autoimmunity to TG6 develops following prolonged gluten exposure. We measured the anti-TG6 in children with celiac disease (CD) at the diagnosis time to establish a correlation between these autoantibodies and the duration of gluten exposure. We investigated a correlation between anti-TG6 and the presence of neurological disorders. Methods: Anti-TG6 (IgA/IgG) were measured by ELISA in sera of children with biopsy-proven CD and of children suffering from gastrointestinal disorders. CD-patients positive for anti-TG6 were retested after 2 years of gluten-free diet (GFD). Results: We analyzed the sera of 274 CD-children and of 121 controls. Anti-TG6 were detected in 68/274 (25%) CD-patients and in 19/121 (16%) controls, with significant difference between the two groups (p = 0.04). None of the CD-patients and of the controls testing positive for anti-TG6 were suffering from neurological disorders. Eleven/18 (61%) CD-patients with other autoimmune diseases were positive for anti-TG6. In CD-patients a significant correlation between the gluten exposure before the CD-diagnosis and anti-TG6 concentration was found (p = 0.006 for IgA; p

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Celiac Disease Symptom Resolution: Effectiveness of the Gluten Free Diet.

Objective: To evaluate the efficacy of the gluten free diet (GFD) on gastrointestinal and extra-intestinal symptom resolution and identify predictors for persistence of symptoms in all celiac patients at the University of Chicago. Methods: We conducted a retrospective chart review from 2002 to 2015. Gastrointestinal (GI) symptoms included: abdominal pain, bloating, constipation, diarrhea, failure to thrive/weight loss, nausea, reflux and vomiting. Extra-intestinal (EI) symptoms included: abnormal liver enzymes, arthralgia/arthritis, dermatitis herpetiformis, alopecia, fatigue, headache, anemia, stomatitis, myalgia, psychiatric disorders, rashes, seizures, neuropathy, short stature, delayed puberty, osteoporosis, and infertility. Results: A total of 554 patients (227 children) with Celiac Disease (CeD) were included. Abdominal pain, diarrhea and failure to thrive were the most common GI symptoms in children while diarrhea, bloating, and abdominal pain were most common in adults. Short stature, fatigue, and headache were the most common EI symptoms in children while iron deficiency anemia, fatigue and headache/psychiatric disorders were most common in adults. Children had significantly higher rates of EI and GI symptom resolution as compared to adults, with greater rates of improvements in GI versus EI symptoms at >24 months. Long duration of symptoms, female sex and non-adherence to a GFD were the most important significant predictors of failure to clinically improve. Conclusions: On a strict GFD, children report greater rates of both GI and EI symptom resolution as compared to adults with greater rates of improvement in GI over EI symptoms. Early recognition of CeD and close attention to diet adherence may help in symptom resolution. (C) 2017 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology,

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Induction Therapy With Biosimilar Infliximab in Children With Crohn's Disease.

Introduction: In most European countries, an infliximab biosimilar (CT-P13) is currently in common use. In vitro and in vivo studies have proved a high similarity between CT-P13 and the reference infliximab. CT-P13 was licensed for use in patients with Crohn's diseases (CD) based on the extrapolation of data from preclinical studies and clinical trials in rheumatology indications. The aim of this study was to assess the similarity between CT-P13 and the originator infliximab in induction therapy in CD paediatric patients. Methods: Thirty-six CD paediatric patients from three Polish academic centres who started biological therapy with CT-P13 were enrolled in this prospective, observational study. Patients received three induction doses (5 mg/kg) of CT-P13 at weeks 0, 2, 6. Assessment was performed before the first infusion and at week 14. Results: Overall 34/36 (94.4%) patients completed induction therapy with CT-P13. A clinical response or remission after three initial doses was achieved in 31/36 (86%) and 24/36 (67%) of patients, respectively. Clinically and statistically significant decreases in Paediatric Crohn's Disease Activity Index, C-reactive protein and erythrocyte sedimentation rate were observed in the responders group. An allergic reaction during infusion, which led to treatment discontinuation, was observed in one case. Conclusion: Induction therapy with CT-P13 in children with CD is effective. The profile appears similar to that reported for the reference infliximab. No unexpected adverse events occurred. (C) 2017 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology,

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Anti-transglutaminase 6 Antibody Development in Children With Celiac Disease Correlates With Duration of Gluten Exposure.

Objectives: Antibodies against transglutaminase 6 (anti-TG6) have been implicated in neurological manifestations in adult patients with genetic-gluten intolerance and it is unclear whether autoimmunity to TG6 develops following prolonged gluten exposure. We measured the anti-TG6 in children with celiac disease (CD) at the diagnosis time to establish a correlation between these autoantibodies and the duration of gluten exposure. We investigated a correlation between anti-TG6 and the presence of neurological disorders. Methods: Anti-TG6 (IgA/IgG) were measured by ELISA in sera of children with biopsy-proven CD and of children suffering from gastrointestinal disorders. CD-patients positive for anti-TG6 were retested after 2 years of gluten-free diet (GFD). Results: We analyzed the sera of 274 CD-children and of 121 controls. Anti-TG6 were detected in 68/274 (25%) CD-patients and in 19/121 (16%) controls, with significant difference between the two groups (p = 0.04). None of the CD-patients and of the controls testing positive for anti-TG6 were suffering from neurological disorders. Eleven/18 (61%) CD-patients with other autoimmune diseases were positive for anti-TG6. In CD-patients a significant correlation between the gluten exposure before the CD-diagnosis and anti-TG6 concentration was found (p = 0.006 for IgA; p

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Celiac Disease Symptom Resolution: Effectiveness of the Gluten Free Diet.

Objective: To evaluate the efficacy of the gluten free diet (GFD) on gastrointestinal and extra-intestinal symptom resolution and identify predictors for persistence of symptoms in all celiac patients at the University of Chicago. Methods: We conducted a retrospective chart review from 2002 to 2015. Gastrointestinal (GI) symptoms included: abdominal pain, bloating, constipation, diarrhea, failure to thrive/weight loss, nausea, reflux and vomiting. Extra-intestinal (EI) symptoms included: abnormal liver enzymes, arthralgia/arthritis, dermatitis herpetiformis, alopecia, fatigue, headache, anemia, stomatitis, myalgia, psychiatric disorders, rashes, seizures, neuropathy, short stature, delayed puberty, osteoporosis, and infertility. Results: A total of 554 patients (227 children) with Celiac Disease (CeD) were included. Abdominal pain, diarrhea and failure to thrive were the most common GI symptoms in children while diarrhea, bloating, and abdominal pain were most common in adults. Short stature, fatigue, and headache were the most common EI symptoms in children while iron deficiency anemia, fatigue and headache/psychiatric disorders were most common in adults. Children had significantly higher rates of EI and GI symptom resolution as compared to adults, with greater rates of improvements in GI versus EI symptoms at >24 months. Long duration of symptoms, female sex and non-adherence to a GFD were the most important significant predictors of failure to clinically improve. Conclusions: On a strict GFD, children report greater rates of both GI and EI symptom resolution as compared to adults with greater rates of improvement in GI over EI symptoms. Early recognition of CeD and close attention to diet adherence may help in symptom resolution. (C) 2017 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology,

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Induction Therapy With Biosimilar Infliximab in Children With Crohn's Disease.

Introduction: In most European countries, an infliximab biosimilar (CT-P13) is currently in common use. In vitro and in vivo studies have proved a high similarity between CT-P13 and the reference infliximab. CT-P13 was licensed for use in patients with Crohn's diseases (CD) based on the extrapolation of data from preclinical studies and clinical trials in rheumatology indications. The aim of this study was to assess the similarity between CT-P13 and the originator infliximab in induction therapy in CD paediatric patients. Methods: Thirty-six CD paediatric patients from three Polish academic centres who started biological therapy with CT-P13 were enrolled in this prospective, observational study. Patients received three induction doses (5 mg/kg) of CT-P13 at weeks 0, 2, 6. Assessment was performed before the first infusion and at week 14. Results: Overall 34/36 (94.4%) patients completed induction therapy with CT-P13. A clinical response or remission after three initial doses was achieved in 31/36 (86%) and 24/36 (67%) of patients, respectively. Clinically and statistically significant decreases in Paediatric Crohn's Disease Activity Index, C-reactive protein and erythrocyte sedimentation rate were observed in the responders group. An allergic reaction during infusion, which led to treatment discontinuation, was observed in one case. Conclusion: Induction therapy with CT-P13 in children with CD is effective. The profile appears similar to that reported for the reference infliximab. No unexpected adverse events occurred. (C) 2017 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology,

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A Story in Black and White

Strong engagement from expert radiologists is essential in ensuring the optimal function of a multidisciplinary group focused on the treatment of head and neck cancer. Active participation in multidisciplinary conference can be among the most rewarding roles for radiologists. Despite many benefits to radiologist involvement in multidisciplinary teams, there are obstacles and challenges that can prevent full participation. This article highlights the key issues that should be considered by radiologists and multidisciplinary team leaders when planning participation in a new or existing multidisciplinary group that focuses on the care of patients with head and neck cancer.

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Hereditary and non-hereditary branches of family eligible for BRCA test: cancers in other sites

Abstract

Background

The analysis of relationships of BRCA alterations with cancer at sites other than breast/ovary may provide innovative information concerning BRCA pathogenic role and support additional clinical decisions. Aim of this study is to compare presence of cancers in other sites in members of hereditary (H) and not-hereditary (nH) branches of families of patients eligible to BRCA test.

Methods

We retrospectively analyzed the incidence of cancer in other sites in members of 136 families eligible for hereditary breast/ovarian cancer genetic counseling at Centro Studi Tumori Eredo-familiari of our Institute; we compared the frequency of other cancer types in 1156 members of the H-branch with respect to 1062 members of nH-Branch. The families belonging to a proband case and with informative members in at least three generation entered the present study.

Results

The frequency of other Cancers in members of H-branch was significantly higher than that in members of nH-branch (161 vs 75 cancers; p < 0.0001). In specific, members of H-branch had a significantly higher probability to have more lung cancer (38 vs 9;p < 0.0006), kidney cancer (23 vs 5;p < 0.0005), liver cancer (13 vs 3;p < 0.02) and larynx cancer (14 vs 4;p < 0.03). Interestingly, to belong to H-branch resulted significantly associated with a higher probability of lung cancer (OR 4.5; 2.15–9.38 95%C.I.), liver cancer (OR: 4.02; 1.14–14.15 95% C.I.) and larynx cancer (OR:3.4; 1.12–10.39 95%C.I.) independently from Gender and Age.

Conclusions

Members belonging to the H-branch of families of patients eligible to BRCA test have a higher risk of tumors in lung, larynx and liver. Clinicians should consider the increased risk for these cancers to activate prevention/early diagnosis practices in members of families with breast/ovarian familial cancer syndrome.



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Long-term use of pegylated liposomal doxorubicin to a cumulative dose of 4600 mg/m2 in recurrent ovarian cancer.

Pegylated liposomal doxorubicin (PLD) is used widely in gynecologic oncology and other oncology disciplines. Native doxorubicin use is associated with the potential for significant toxicity. Cardiac toxicity in particular limits lifetime dose. PLD has not been shown to be associated with clinical cardiac toxicity. We report on the long-term use of PLD in a patient with recurrent high-grade serous ovarian cancer to a lifetime dose of 4600 mg/m2. This therapy was associated with long-term stable disease, good performance status, and minimal adverse effects. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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Hypoxia as a target for drug combination therapy of liver cancer.

Hepatocellular carcinoma (HCC) is the third most frequent cause of cancer deaths worldwide. The standard of care for intermediate HCC is transarterial chemoembolization, which combines tumour embolization with locoregional delivery of the chemotherapeutic doxorubicin. Embolization therapies induce hypoxia, leading to the escape and proliferation of hypoxia-adapted cancer cells. The transcription factor that orchestrates responses to hypoxia is hypoxia-inducible factor 1 (HIF-1). The aim of this work is to show that targeting HIF-1 with combined drug therapy presents an opportunity for improving outcomes for HCC treatment. HepG2 cells were cultured under normoxic and hypoxic conditions exposed to doxorubicin, rapamycin and combinations thereof, and analyzed for viability and the expression of hypoxia-induced HIF-1[alpha] in response to these treatments. A pilot study was carried out to evaluate the antitumour effects of these drug combinations delivered from drug-eluting beads in vivo using an ectopic xenograft murine model of HCC. A therapeutic doxorubicin concentration that inhibits the viability of normoxic and hypoxic HepG2 cells and above which hypoxic cells are chemoresistant was identified, together with the lowest effective dose of rapamycin against normoxic and hypoxic HepG2 cells. It was shown that combinations of rapamycin and doxorubicin are more effective than doxorubicin alone. Western Blotting indicated that both doxorubicin and rapamycin inhibit hypoxia-induced accumulation of HIF-1[alpha]. Combination treatments were more effective in vivo than either treatment alone. mTOR inhibition can improve outcomes of doxorubicin treatment in HCC. This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. http://ift.tt/1iwynXF Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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A survey of renal impairment pharmacokinetic studies for new oncology drug approvals in the USA from 2010 to early 2015: a focus on development strategies and future directions.

The US Food and Drug Administration (FDA) issued a guidance document in 2010 on pharmacokinetic (PK) studies in renal impairment (RI) on the basis of observations that substances such as uremic toxins might result in altered drug metabolism and excretion. No specific recommendations for oncology drugs were included. We surveyed the publicly available FDA review documents of 29 small molecule oncology drugs approved between 2010 and the first quarter of 2015. The objectives were as follows: (i) summarize the impact of RI on PK at the time of the initial new drug application; (ii) identify limitations of the guidance; and (iii) outline an integrated approach to study the impact of RI on these drugs. Our survey indicates that the current FDA guidance does not appear to provide clear strategic or decision pathways for RI studies in terms of small molecule oncology drugs. The FDA review documents indicate an individualized approach to the review because of the complex pharmacologic nature of these drugs and patient populations. Overall, the strategy for carrying out a RI study during clinical development or as a postmarketing study requires integration with the totality of data, including mass balance, absolute bioavailability, drug-drug interaction, hepatic dysfunction, population PK, exposure-response analysis, the therapeutic window for best guidance, and determination of the optimal doses for special oncology populations. This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://ift.tt/1hexVwJ Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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Role of the uridine/cytidine kinase 2 mutation in cellular sensitiveness toward 3'-ethynylcytidine treatment of human cancer cells.

A nucleosidic medicine, 1-(3-C-ethynyl-[beta]-D-ribo-pentofuranosyl)cytosine [3'-ethynylcytidine (ECyd)], is a potent inhibitor of RNA polymerase I and shows anticancer activity to various human solid tumors in vitro and in vivo. ECyd is phosphorylated to 3'-ethyntlcytidine 5'-monophosphate by uridine/cytidine kinase 2 (UCK2) and subsequently further to diphosphate and triphosphate (3'-ethyntlcytidine 5'-diphosphate, 3'-ethyntlcytidine 5'-triphosphate). 3'-Ethyntlcytidine 5'-triphosphate is an active metabolite that can inhibit RNA polymerase I competitively, causing cancer cell death. Here, to identify the UCK2 mutation for detecting responder or nonresponder to ECyd, we investigated the relationship between point mutation of the UCK2 gene and response to ECyd in various human solid tumors. We identified several functional point mutations including the splice-site mutation of the UCK2 gene IVS5+5 G>A. In addition, we found that the IVS5+5 G>A variant generates an aberrant mRNA transcript, namely, truncated mRNA was produced and normal mRNA levels were markedly decreased in the ECyd-resistant cancer cell line HT1080. We concluded that these findings strongly suggest that the IVS5+5 G>A variant would affect the expression level of the UCK2 transcript, resulting in decreased sensitivity to ECyd. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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The anatomy and physiology of normal and abnormal swallowing in oropharyngeal dysphagia

Abstract

Background

Eating and drinking are enjoyable activities that positively impact on an individual's quality of life. The ability to swallow food and fluid is integral to the process of eating. Swallowing occupies a dual role being both part of the enjoyment of eating and being a critically important utilitarian activity to enable adequate nutrition and hydration. Any impairment to the process of swallowing can negatively affect a person's perception of their quality of life. The process of swallowing is highly complex and involves muscles in the mouth, pharynx, larynx, and esophagus. The oropharynx is the anatomical region encompassing the oral cavity and the pharynx. Food must be masticated, formed into a bolus and transported to the pharynx by the tongue whereas fluids are usually held within the mouth before being transported ab-orally. The bolus must then be transported through the pharynx to the esophagus without any matter entering the larynx. The muscles needed for all these steps are coordinated by swallowing centers within the brainstem which are supplied with sensory information by afferent nerve fibers from several cranial nerves. The swallowing centers also receive modulatory input from higher centers within the brain. Hence, a swallow has both voluntary and involuntary physiologic components and the term dysphagia is given to difficult swallowing while oropharyngeal dysphagia is difficult swallowing due to pathology within the oropharynx.

Purpose

Problems affecting any point along the complex swallowing pathway can result in dysphagia. This review focuses on the anatomy and physiology behind normal and abnormal oropharyngeal swallowing. It also details the common diseases and pathology causing oropharyngeal dysphagia.

Thumbnail image of graphical abstract

Eating and drinking are enjoyable activities that positively impact on an individual's quality of life. The ability to swallow food and fluid is integral to the process of eating. Swallowing occupies a dual role being both part of the enjoyment of eating and being a critically important utilitarian activity to enable adequate nutrition and hydration. Several disease processes can adversely affect the normal process of swallowing. Examples include strokes and trauma. This review focuses on the anatomy and physiology behind normal and abnormal oropharyngeal swallowing.



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Clinical characteristics of functional dyspepsia depending on chemosensitivity to capsaicin

Abstract

Background

Augmented chemosensitivity to capsaicin has been demonstrated in approximately half of functional dyspepsia (FD) patients.

Aim

We determined clinical characteristics of FD patients with and without chemical hypersensitivity at baseline and after capsaicin ingestion for 4 weeks.

Methods

N=49 outpatients with confirmed FD received an oral sensitivity test with 0.75 mg capsaicin at three occasions, before and after ingesting 0.25 mg capsaicin tid for 4 weeks. Symptomatic response to capsaicin allowed stratification to a capsaicin positive (chemosensitive) and a capsaicin negative (not chemosensitive) patient group. Symptom diaries were completed in the week before and during capsaicin ingestion.

Results

A total of 53% FD had a positive capsaicin test, Crohnbach alpha was 0.85. Basic clinical characteristics were comparable in capsaicin positive and negative FD, but median daily aggregate upper gastrointestinal symptoms scores were significantly higher in capsaicin positive (median: 9.4; 5.4/11.7) than in capsaicin negative patients (6.6; 4.1/8.1) (P<.05). After capsaicin ingestion, upper gastrointestinal symptoms scores were reduced by −3.3 (−4.9/−1.9; P<.001) in capsaicin positive and −2.6 (−3.8/−0.3; P<.05) in capsaicin negative patients. Lower abdominal symptoms were comparable in capsaicin positive and negative patients at baseline (NS). After capsaicin ingestion lower gastrointestinal symptoms scores were reduced by −1.0 (−1.8/−0.1; P<.05) in capsaicin positive but not significantly altered (−0.6; −1.7/+0.9; NS) in capsaicin negative patients. After long-term capsaicin ingestion, the capsaicin test turned negative in 53% of chemosensitive patients (P<.01).

Conclusions

Differences in upper GI symptoms distinguished capsaicin positive and negative patients. Symptom improvement after long-term capsaicin ingestion was indirect proportional to the capsaicin test result.

Thumbnail image of graphical abstract

Median daily aggregate and individual lower gastrointestinal symptom scores (25%/75%) during the 5 weeks observation period in patients with chemical hypersensitivity (capsaicin positive) and without chemical hypersensitivity (capsaicin negative). Asterisks denote significant difference to the run-in week (week -1). *P<0.05; **P<0.01.



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Prognostic impact of the cumulative dose and dose intensity of everolimus in patients with pancreatic neuroendocrine tumors

Abstract

The aim of this work is to assess if cumulative dose (CD) and dose intensity (DI) of everolimus may affect survival of advanced pancreatic neuroendocrine tumors (PNETs) patients. One hundred and sixteen patients (62 males and 54 females, median age 55 years) with advanced PNETs were treated with everolimus for ≥3 months. According to a Receiver operating characteristics (ROC) analysis, patients were stratified into two groups, with CD ≤ 3000 mg (Group A; n = 68) and CD > 3000 mg (Group B; n = 48). The response rate and toxicity were comparable in the two groups. However, patients in group A experienced more dose modifications than patients in group B. Median OS was 24 months in Group A while in Group B it was not reached (HR: 26.9; 95% CI: 11.0–76.7; P < 0.0001). Patients who maintained a DI higher than 9 mg/day experienced a significantly longer OS and experienced a trend to higher response rate. Overall, our study results showed that both CD and DI of everolimus play a prognostic role for patients with advanced PNETs treated with everolimus. This should prompt efforts to continue everolimus administration in responsive patients up to at least 3000 mg despite delays or temporary interruptions.

Thumbnail image of graphical abstract

The aim of this work is to assess if cumulative dose (CD) and dose intensity (DI) of everolimus may affect survival of advanced pancreatic neuroendocrine tumors (PNETs) patients. Median OS was 24 months in Group A (with cumulative dose ≤ 3000 mg) while in Group B (with cumulative dose > 3000 mg), it was not reached (HR: 26.9; 95% CI: 11.0–76.7; P < 0.0001). This should prompt efforts to continue everolimus administration in responsive patients up to at least 3000 mg despite delays or temporary interruptions.



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Reduced cortical excitatory synapse number in APOE4 mice is associated with increased calcineurin activity.

Synaptic loss is a symptom of Alzheimer's disease (AD) that is associated with the onset of cognitive decline and the loss of executive function. The strongest genetic risk factor for AD is the APOE4 allele, which results in both a greater risk of developing AD as well as an earlier age of onset of AD. Dendritic spines, the anatomical substrate of the excitatory synapse, are reduced in the cortex of humanized APOE4 mice but the reason for this synaptic decline is unknown. Calcineurin, a calcium/calmodulin dependent phosphatase, is a mediator of dendritic spine retraction. We used humanized APOE mice to examine how APOE genotype altered calcineurin activity and found that APOE4 mice have 35% higher cortical calcineurin activity compared with APOE3 mice. This occurred in the absence of any increase in calcineurin protein levels or mRNA expression. The elevation in calcineurin was associated with 10% fewer dendritic spine number in layer II/III of the cortex. Treatment with the calcineurin inhibitor FK506 reduced calcineurin activity by 64% and resulted in normalization of dendritic spine numbers in APOE4 mice. In conclusion, we found that the APOE4 gene in mice was associated with elevated calcineurin activity and fewer dendritic spine numbers compared with APOE3 mice. Importantly, calcineurin in APOE4 remained sensitive to pharmacological inhibition and spine density can be rescued by treatment with FK506. (C) 2017 Wolters Kluwer Health | Lippincott Williams & Wilkins

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Grb2-associated binder-1 is required for extrafusal and intrafusal muscle fiber development.

The neuregulin-1 (NRG1) signaling pathway plays an important role in the development of the peripheral neuromuscular system, including in muscle spindle and postnatal myelination. We previously showed that NRG1 on the axonal membrane regulates peripheral nerve myelination through Grb2-associated binder 1 (Gab1), a scaffolding mediator of receptor tyrosine kinase signaling. Here, we determined the role of Gab1 in the development of muscles and the muscle spindle using muscle-specific conditional Gab1 knockout mice. The mutant mice showed general retardation in muscular growth and hypotrophy of extrafusal muscle fibers. In addition, the muscle-specific Gab1 knockout mutant exhibited significant underdevelopment of muscle spindles, which are normally regulated by NRG1, and abnormal proprioceptive behavior. Furthermore, the selective knockdown of Gab1 in C2C12 muscle cells reduced NRG1-induced expression of Egr3, a critical transcription factor for muscle spindle development. However, Gab2 knockout mice did not show any defects in the development of muscles or muscle spindles. Our findings suggest that Gab1 is an essential signaling molecule in mediating axonal NRG1 signaling for the development of both extrafusal and intrafusal muscle fibers. (C) 2017 Wolters Kluwer Health | Lippincott Williams & Wilkins

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Association of circulating high-sensitivity C-reactive protein with late recurrence after ischemic stroke.

We investigated the association between serum levels of high-sensitivity C-reactive protein (hs-CRP) and stroke recurrence events in a cohort of patients with acute ischemic stroke (IS). We prospectively studied 286 patients with acute IS who were admitted within 24 h after the onset of symptoms. Serum levels of hs-CRP, and National Institutes of Health stroke scale (NIHSS) were measured at admission. The primary endpoint was stroke recurrence 1 year after stroke onset. We used logistic regression models to assess the relationship between hs-CRP levels and the risk of recurrent stroke. In multivariable models, hs-CRP levels were associated with an increased risk of an NIHSS greater than 6 [odds ratio=1.17; 95% confidence interval (CI)=1.05-1.48; P=0.021]. Among the participants, stroke recurrence was found in 48 (16.8%) cases. In multivariate analyses, the third and fourth quartiles of hs-CRP were significantly associated with stroke recurrence during the observation period compared with the first quartile group (P

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Keyboard: A Novel Bayesian Toxicity Probability Interval Design for Phase I Clinical Trials

The primary objective of phase I oncology trials is to find the maximum tolerated dose (MTD). The 3+3 design is easy to implement but performs poorly in finding the MTD. A newer design, such as the modified toxicity probability interval (mTPI) design, provides better accuracy to identify the MTD but tends to overdose patients. We propose the keyboard design, an intuitive Bayesian design that conducts dose escalation and de-escalation based on whether the strongest key, defined as the dosing interval that most likely contains the current dose, is below or above the target dosing interval. The keyboard design can be implemented in a simple way, similar to the traditional 3+3 design, but provides more flexibility for choosing the target toxicity rate and cohort size. Our simulation studies demonstrate that compared to the 3+3 design, the keyboard design has favorable operating characteristics in terms of identifying the MTD. Compared to the mTPI design, the keyboard design is safer, with a substantially lower risk of treating patients at overly toxic doses, and has the better precision to identify the MTD, thereby providing a useful upgrade to the mTPI design. Freely available, open-source software facilitates the application of the keyboard design.



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Obesity is Independently Associated With Increased Risk of Hepatocellular Cancer-related Mortality: A Systematic Review and Meta-Analysis.

Objective: Excess body weight is associated with increased risk of developing hepatocellular cancer (HCC), but its effect on HCC-related mortality remains unclear. We performed a systematic review and meta-analysis to assess the association between premorbid obesity and HCC-related mortality. Materials and Methods: Through a systematic literature search-up to March 2016, we identified 9 observational studies (1,599,453 individuals, 5705 HCC-related deaths) reporting the association between premorbid body mass index (BMI), and HCC-related mortality. We estimated summary adjusted hazard ratio (aHR) with 95% confidence intervals (CIs), comparing obese (BMI>30 kg/m2) and overweight (BMI, 25 to 29.9 kg/m2) individuals with normal BMI individuals using random-effects model. Results: On meta-analysis, compared with individuals with normal BMI, obese (aHR, 1.95; 95% CI, 1.46-2.46), but not overweight individuals (aHR, 1.08; 95% CI, 0.97-1.21), had higher HCC-related mortality, with moderate heterogeneity. On subgroup analysis, magnitude of increased mortality was higher in obese men (aHR, 2.50; 95% CI, 2.02-3.09; 3 studies) as compared with obese women (aHR, 1.45; 95% CI, 1.08-1.97; 2 studies). The impact of premorbid obesity on HCC-related mortality was observed only in western populations (aHR, 2.10; 95% CI, 1.77-2.48; 4 studies), but not Asian populations (aHR, 1.10; 95% CI, 0.63-1.92; 1 study). There was limited assessment of competing risk because of advanced liver disease. Conclusions: On the basis of this meta-analysis, premorbid obesity may be independently associated with a 2-fold risk of HCC-related mortality. This association was more pronounced in men and western populations. Strategies targeting obesity-associated metabolic abnormalities may provide novel pathways for HCC therapy. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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Impact of the Primary Information Source Used for Decision Making on Treatment Perceptions and Regret in Prostate Cancer.

Objective: To assess the impact of the primary source of information used by prostate cancer patients to select a radiation treatment on their overall treatment experience and on treatment regret. Methods: Patients with low to favorable intermediate-risk prostate cancer treated with stereotactic body radiation therapy, intensity-modulated radiation therapy, or high-dose rate brachytherapy were surveyed. The questionnaire explored the decision-making experience, treatment experience, and treatment regret. Results: In total, 322 consecutive patients were surveyed with an 86% (n=276) response rate. In total, 48% (n=132) selected their radiation oncologist as the primary information source, 23% (n=62) selected their urologist, 16% (n=44) selected the Internet, 6% (n=17) selected other patients, and 8% (n=21) selected other. In total, 39% of patients who selected the Internet as their primary information source reported their actual treatment experience to be worse than expected versus 13% of respondents who selected their urologist, 12% who selected other patients, and 2% who selected their radiation oncologist (P

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Treatment and Outcomes of Primary Urethra Cancer.

Background: Urethral cancer is a rare malignancy, representing

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Prevention of Trastuzumab and Anthracycline-induced Cardiotoxicity Using Angiotensin-converting Enzyme Inhibitors or [beta]-blockers in Older Adults With Breast Cancer.

Purpose: Although clinical trials have provided some data on the benefit of angiotensin-converting enzyme inhibitors (ACEIs) or [beta]-blockers (BBs) in patients with chemotherapy-induced cardiotoxicity, evidence of ACEIs/BBs on prevention of trastuzumab and/or anthracycline-induced cardiotoxicity outside trials is limited. Materials and Methods: A cohort study of 142,990 women (66 y and above) newly diagnosed with breast cancer from 2001 to 2009 was conducted using the Surveillance, Epidemiology, and End Results-Medicare-linked database. The ACEI/BB exposure was defined as filled prescription(s) before or after the initiation of trastuzumab/anthracyclines. The nonexposed group was defined as those who had never been prescribed ACEIs/BBs. Cumulative rates of cardiotoxicity and all-cause mortality were estimated and marginal structural Cox models were used to determine factors associated with cardiotoxicity and all-cause mortality adjusting for baseline covariates and use of chemotherapy. All statistical tests were 2 sided. Results: The final sample included 6542 women. Adjusted hazard ratio for cardiotoxicity and all-cause mortality for the ACEI/BB exposed group were 0.77 (95% confidence interval, 0.62-0.95) and 0.79 (95% confidence interval, 0.70-0.90) compared with the nonexposed group, respectively. Starting ACEIs/BBs=6 months were also associated with decreased risk of cardiotoxicity and all-cause mortality. Baseline characteristics, including age, non-Hispanic black, advanced cancer, region, comorbidity, preexisting cardiovascular conditions, lower socioeconomic status, and concomitant treatment were significantly associated with an elevated risk of all-cause mortality and/or cardiotoxicity (all P

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Ocular Changes Over 60 Minutes in Supine and Prone Postures

Some astronauts are returning from long duration spaceflight with structural ocular and visual changes. We investigated both the transient and sustained effects of changes in the direction of the gravity vector acting on the eye using changes in body posture. Intraocular pressure (IOP-Perkins tonometer), ocular geometry (axial length, corneal thickness, and aqueous depth-noncontact biometer), and the choroidal (volume and subfoveal thickness optical coherence tomography) was measured in 10 subjects (5M, 5F). Measures were taken over the course of 60 minutes and analyzed with repeated measures ANCOVA to assess the effects of posture and time. In the supine position, choroidal volume increased significantly with time (average value at < 5 minutes = 8.8±2.3 mm3, 60 minutes = 9.0±2.4 mm3, p = 0.03). In the prone position, IOP and axial length increased with time (IOP at < 5 minutes 15±2.7 mmHg, 60 minutes = 19.8±4.1 mmHg, p < 0.0001; Axial length at < 5 minutes = 24.29±0.77 mm, 60 minutes = 24.31±0.76 mm, p = 0.002). Each increased exponentially, with time constants of 5.3 minutes and 14 minutes respectively. Prone corneal thickness also increased with time (< 5 minutes = 528±35 μm, 60 minutes = 537±35 μm 3, p < 0.001). Aqueous depth was shortened in the prone position (baseline = 3.22±0.31 mm, 60 minutes = 3.18±0.32 mm, p < 0.0001), but did not change with time. The data show that changes in the gravity vector have pronounced transient and sustained effects on the geometry and physiology of the eye.



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Changes in brachial artery endothelial function and resting diameter with moderate-intensity continuous but not sprint interval training in sedentary men

Moderate-intensity continuous training (MICT) improves peripheral artery function in healthy adults, a phenomenon that reverses as continued training induces structural remodeling. Sprint interval training (SIT) elicits physiological adaptations similar to MICT despite a lower exercise volume and time-commitment; however, its effect on peripheral artery function and structure is largely unexplored. We compared peripheral artery responses to 12 weeks of MICT and SIT in sedentary, healthy men (age=27±8 years). Participants performed MICT (45-min of cycling at 75% peak heart rate; n=10) or SIT (3x20-sec 'all out' cycling sprints with 2 min of recovery; n=9) and responses were compared to a non-training control group (CTL, n=6). Allometrically scaled brachial flow-mediated dilation (FMD) increased 2.2% after 6 weeks of MICT and returned to baseline levels by 12 weeks, but did not change in SIT or CTL (group x time interaction, p=0.04). Brachial artery diameter increased after 6 and 12 weeks (main effect, p=0.03), with the largest increases observed in MICT. Neither training protocol affected popliteal relative FMD and diameter, or central and lower-limb arterial stiffness (carotid distensibility, central and leg pulse wave velocity) (p>0.05 for all). While earlier and more frequent measurements are needed to establish the potential presence and time course of arterial responses to low-volume SIT, our findings suggest that MICT was superior to the intense, but brief and intermittent SIT stimulus at inducing brachial artery responses in healthy men.



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Post-exercise cold-water immersion modulates skeletal muscle PGC-1{alpha} mRNA expression in immersed and non-immersed limbs: evidence of systemic regulation.

Mechanisms mediating post-exercise cold-induced increases in PGC-1α gene expression in human skeletal muscle are yet to be fully elucidated, but may involve local cooling effects on AMPK and p38 MAPK related signalling and/or increased systemic β-adrenergic stimulation. We aimed to therefore examine whether post-exercise cold-water immersion enhancement of PGC-1α mRNA is mediated through local or systemic mechanisms. Ten subjects completed acute cycling (8x5 min at ~80% peak power output) followed by seated-rest (CON) or single-leg cold-water immersion (CWI; 10 min, 8°C). Muscle biopsies were obtained pre-, post- and 3 h post-exercise from a single limb in the CON condition but from both limbs in CWI (thereby providing tissue from a CWI and non-immersed limb, NOT). Muscle temperature decreased up to 2 h post-exercise following CWI (-5°C) in the immersed limb, with lesser changes observed in CON and NOT (-3°C; P<0.05). No differences between limbs were observed in p38MAPK phosphorylation at any time point (P<0.05), whilst a significant interaction effect was present for AMPK phosphorylation (P=0.031). Exercise (CON) increased gene expression of PGC-1α 3 h post-exercise (~5-fold; P<0.001). CWI augmented PGC-1α expression above CON in both the immersed (CWI; ~9-fold; P=0.003) and NOT limbs (~12-fold; P=0.001). Plasma Normetanephrine concentration was higher in CWI vs. CON immediately post-immersion (860 vs. 665 pmol/L; P=0.034). We report for the first time that local cooling of the immersed limb evokes transcriptional control of PGC1-α in the non-immersed limb, suggesting increased systemic β-adrenergic activation of AMPK mediates, in part, post-exercise cold-induction of PGC-1α mRNA.



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Influence of maximal fat oxidation on long-term weight loss maintenance in humans

Impaired maximal fat oxidation has been linked to obesity and weight regain after weight loss. The aim was to investigate the relationship between maximal fat oxidation (MFO) and long-term weight loss maintenance. Eighty subjects (mean(SD)) (Age: 36(13) yrs; BMI: 38(1) kg/m2) were recruited from a total of 2420 former participants of an 11-12-week lifestyle intervention. Three groups were established based on % weight loss at follow-up (5.3(3.3) yrs): Clinical weight loss maintenance (CWL) >10% weight loss, moderate weight loss (MWL) 1-10%, and weight regain (WR). Body composition (Dual X-ray Absorptiometry) and fat oxidation (indirect calorimetry) during incremental exercise were measured at follow-up. Blood and a muscle biopsy were sampled. At follow-up, a u-shaped parabolic relationship between MFO and % weight loss was observed (r=0.448, p<0.001). Overall differences between CWL, MWL and WR were observed in MFO (mean [95%CI]) (0.46 g/min [0.41-0.52]; 0.32 [0.27-0.38]; 0.45 [0.38-0.51]; p=0.002), maximal oxygen uptake (VO2max) (49 ml/min/FFM [46-51]; 43, [40-47]; 41 [39-44]; p=0.007), HAD-activity (123 µmol/g/min [113-133]; 104 [91-118]; 97 [88-105]; p<0.001), muscle protein content of CD36 (1.1 AU [1.0-1.2]; 0.9 [0.8-1.0]; 0.9 [0.8-0.9]; p=0.008) and FABPpm (1.0 AU [0.8-1.2]; 0.7 [0.5-0.8]; 0.7 [0.5-0.9]; p=0.008) body fat (33% [29-38]; 42 [38-46]; 52 [49-55]; p<0.001) and plasma triglycerides (0.8 mmol/l [0.7-1.0]; 1.3 [0.9-1.7]; 1.6 [1.0-2.1]; p=0.013). CWL and WR both had higher MFO compared to MWL, but based upon different mechanisms. CWL displayed higher VO2max and intramuscular capacity for fat oxidation, while abundance of lipids at whole-body level and in plasma was higher in WR.



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Automated Quality Control of Forced Oscillation Measurements: Respiratory Artifact Detection with Advanced Feature Extraction

The forced oscillation technique (FOT) can provide unique and clinically relevant lung function information with little cooperation with subjects. However, FOT has higher variability than spirometry, possibly because strategies for quality control and reducing artifacts in FOT measurements have yet to be standardized or validated. Many quality control procedures either rely on simple statistical filters or subjective evaluation by a human operator. In this study, we propose an automated artifact removal approach based on the resistance against flow profile, applied to complete breaths. We report results obtained from data recorded from children and adults with and without asthma. Our proposed method has 76% agreement with a human operator for the adult dataset and 79% for the paediatric dataset. Furthermore, we assessed the variability of respiratory resistance measured by FOT using within-session variation (wCV), between-session variation (bCV). In the asthmatic adults test dataset, our method was again similar to that of the manual operator for wCV (6.5 vs. 6.9%), and significantly improved bCV (8.2 vs. 8.9%). In the pediatric test dataset, the wCV of our proposed automated method yielded similar variability to the manual operator (8.2 compared to 8.6%). Our combined automated breath removal approach based on advanced feature extraction offers better or equivalent quality control of FOT measurements compared to an expert operator and computationally more intensive methods in terms of accuracy and reducing intra-subject variability.



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Green tea EGCG enhances cardiac function restoration through expression of survival signaling in DM rats with autologous adipose tissue-derived stem cell

The present study tests a hypothesis that cardioprotective effects mediated by autologous adipose-derived stem cells (ADSC) in rats afflicted with insulin-dependent diabetes mellitus (IDDM), may be synergistically enhanced by oral treatment with green tea epigallocatechin gallat (ECCG). Wistar rats were divided into sham, DM, DM+ADSC (autologous transplanted 1x106 cells/rat) and DM+ADSC+E (E, green tea oral administration EGCG). Heart tissues were isolated for all rats and investigations were performed after 2-months treatment. In the groups of sham, DM and DM+ADSC, we can find that DM induces cardiac-dysfunction (sham and DM) and autologous transplantation of ADSC can partially recover cardiac functions (DM and DM+ADSC) in DM rats. Compared to DM+ADSC, significant improvement in cardiac-functions can be observed in DM+ADSC+E in echocardiographic data, histological observations and even in cellular protein expression. Oral administration of green tea EGCG and autologous transplantation of ADSC show synergistically beneficial effects on diabetic cardiacmyopathy in DM rats.



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Thoraco-lumbar selective fusion in adolescent idiopathic scoliosis with Lenke C modifier curves: clinical and radiographic analysis at 10-year follow-up

Abstract

Purpose

To examine the radiological and clinical outcomes of a single-center case series of selective thoracic fusions (STF) in adolescent idiopathic scoliosis with Lenke C modifier curves, with a long-term follow-up.

Methods

We evaluated at 6 months and 10 years different radiological parameters on both thoracic and lumbar districts: coronal curves, sagittal curves, apical vertebral translation (AVT), and apical vertebral rotation (AVR). The clinical outcome was determined using the SRS 22 score. Data were also analyzed dividing the patients by their Risser and Lenke scores.

Results

In examining 90 patients we reported a radiological benefit from STF on both thoracic and lumbar districts. The corrections in the values of both coronal curves, AVT, and AVR are relevant at 6 months and do not significantly vary at the latest follow-up. Sagittal curves are not relevantly affected at any time point. All the SRS 22 score evaluations showed significant improvement at 6 months, in particular, the self-image analysis. A further improvement was also reported at 10 years, in particular in pain and function scores. At no time point were significant differences retrieved by comparing SRS 22 results as divided by Risser or Lenke grading systems.

Conclusions

STF is an effective treatment option both in clinical and radiographical terms. The results at 10-year follow-up confirm both the stability of the correction and the improvement of the clinical outcome scores. Risser and Lenke grading systems are not relevant variables predictive of clinical efficacy.



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Answer to the Letter to the Editor of R. K. Rajnish et al. concerning “The effect of total hip arthroplasty on sagittal spinal–pelvic–leg alignment and low back pain in patients with severe hip osteoarthritis” by W. Weng et al. Eur Spine J (2016);25(11):3608–3614



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Results of lumbar spondylodeses using different bone grafting materials after transforaminal lumbar interbody fusion (TLIF)

Abstract

Purpose

Can a mixture of hydroxyapatite (HA) and autologous bone from decompression sites produce similar results when used for transforaminal lumbar interbody fusion (TLIF)? In the current literature, autologous iliac crest bone grafts (ICBGs) have been reported the gold standard for this procedure. Indeed, to date, no clinical data have confirmed that a mixture of equal volumes of HA and local autologous bone produce similar results in term of fusion as the same volume of autologous ICBG alone.

Methods

Study design/setting This study was approved by the local ethics committee and completed in a prospective, randomized, single-blinded manner. The results of lumbar fusion using TLIF and different bone grafting materials were compared. Patient sample The patient sample included patients with spinal lumbar degenerative disease. Outcome measures The clinical outcome was determined using the Oswestry Low Back Pain Disability Questionnaire (ODI) and Visual Analog Scale (VAS). The radiological outcomes and fusion rates were determined with radiographs evaluated using the McAfee criteria and computed tomography (CT) data evaluated by the Williams criteria. Three blinded investigators (one radiologist and two orthopedic surgeons) assessed the data. The secondary variables included donor site morbidity. Methods The patients were admitted to our department for orthopedic surgery with degenerative lumbar pathologies (L2–S1) that required stabilization in one or two segments using a TLIF procedure. The patients were 18–80 years old. Only those patients who had degenerative lumbar pathologies and agreed to be educated about the study were included. The patients were divided into the following two randomized groups: group A: TLIF procedure using autologous ICBGs alone; and group B: TLIF procedure using local bone from decompression site mixed with hydroxyapatite. Each group received equal graft volumes. The mixture in group B consisted of equal volumes of local autograft (5 cc) and synthetic bone (5 cc). A graft volume of 10 cc was used at each fusion level. The patients were followed up at three appointments at 1.5, 6 and 12 months postoperatively. Every patient received detailed education about the course of the study.

Results

Forty-eight patients finished the study (2 patients dropped out). The radiographic fusion rate did not significantly differ between the two groups. Based on the CT criteria, 83.3% of the patients showed fusion in both groups after 12 months. Furthermore, 95.3% of the patients in group A and 91.7% of the patients in group B showed bony spondylodeses according to the radiographic criteria at the 12-month follow-up. The donor site morbidity consisted of one patient with a wound infection and one with a hematoma in group A and two patients with persistent pain in group B. Group A also included one patient with cage subsidence of 4 mm and archived fusion after 12 months. In group B, one patient had a pedicle screw breakage and achieved fusion after 6 months. The clinical outcomes were similar between the two groups. In both groups, the VAS and ODI data improved during the follow-up period (p < 0.05). No patients required additional surgeries.

Conclusions

Both groups demonstrated equivalent clinical outcomes. HA and autologous bone from decompression sites can achieve similar fusion rates to those achieved with identical volumes of the gold standard autologous graft. The graft mixture can be used for one- or two-level lumbar spondylodeses to avoid donor site morbidity.



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Incomplete burst fractures of the thoracolumbar spine: a review of literature

Abstract

Purpose

The purpose of this review was to analyze the biomechanical basis of incomplete burst fractures of the thoracolumbar spine, summarize the available treatment options with evidence from the literature, and to propose a method to differentiate fracture severity.

Methods

The injury pattern, classification, and treatment strategies of incomplete burst fractures of the thoracolumbal spine have been described following a review of the literature. All level I–III studies, studies with long-term results and comparative studies were included and summarized.

Results

Details of five randomized control trials were included. Additionally, three comparative studies and two studies with long-term outcomes were detailed in this review. The fracture severity reported in the included studies varied tremendously. Most classification used did not adequately describe the complexity of fracture configuration. A wide variety of treatment strategies were outlined, ranging from non-operative therapy to aggressive surgical intervention with combined anterior-posterior approaches. Thus, the treatment of incomplete burst fractures of the thoracolumbar spine is quite diverse and remains controversial.

Conclusions

Incomplete burst fractures can differ tremendously regarding the degree of instability they confer to the thoracolumbar spine. Based on a detailed review of the literature, it is clear that good results can be obtained with both non-operative and operative strategies to treat these injuries. In the authors’ opinion, the intervertebral disc plays a key role in determining the long-term clinical and radiological outcome. Thus, an incorporation of the intervertebral disc pathology into the existing classification systems would be a valuable prognostic factor.



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Effect of Oxy133, an osteogenic oxysterol, on new bone formation in rat two-level posterolateral fusion model

Abstract

Purpose

The aim of our study was to determine the effect of Oxy133 and rhBMP2 on fusion rates and new bone formation in a rat posterolateral fusion (PLF) model. Furthermore, we examined whether Oxy133 could inhibit the adipogenesis that is often present in rhBMP2-induced fusions.

Methods

Sixty-four male Lewis rats underwent two levels PLF (L3–L5). All animals were randomly divided into eight groups based on the test compound that they received: control (DMSO), low-dose rhBMP2 (0.5 µg), high-dose rhBMP2 (5 µg), low-dose Oxy133 (5 mg), high-dose Oxy133 (20 mg), low rhBMP2 + high Oxy133, high rhBMP2 + high Oxy133, and low rhBMP2 + low Oxy133. Fusion rates were assessed 8 weeks after surgery with manual palpation and plain radiographs. Bone parameters were measured using microCT. Histology was used to evaluate adipogenesis.

Results

No fusion was observed in the control group. Based on the manual palpation, 100% fusion was observed in all other groups except in the low-dose rhBMP2 group (69%). At 8 weeks based on X-rays, 100% fusion was observed in the following groups: high-dose rhBMP2, low-dose Oxy133, and low rhBMP2 + low Oxy133. In the other groups, the fusion rates were between 95 and 97%, except for the low rhBMP2 group (72%). We observed similar values in BV/TV ratio at L3–4 when Oxy133 groups were compared to rhBMP2 groups alone (44.62% in high-dose Oxy133 vs. 41.47% in high-dose rhBMP2 and 47.18% in low-dose Oxy133 vs. 54.98% in low-dose rhBMP2). Trabecular thickness was slightly lower in Oxy133 groups compared to rhBMP2 when comparing low- and high-dose groups from each group (118.44 µm for high-dose Oxy133 vs. 122.39 µm for high-dose rhBMP2 and 123.51 µm for low-dose Oxy133 vs. 135.74 µm for low-dose rhBMP2). At the same time, trabecular separation was lower in Oxy133 groups compared to rhBMP2 groups. Similar trends in bone parameters were observed at the L4–5 levels. Fusion masses with low- and high-dose Oxy133 had significantly less adipocytes than rhBMP2 groups that showed robust adipocyte formation.

Conclusion

In our study, both low-dose and high-dose Oxy133 produced solid fusions with bone densities similar or higher than in the BMP2 groups. High-dose Oxy133 group had significantly less adipocytes than high- or low-dose rhBMP2 groups. Furthermore, high-dose Oxy133 was able to significantly inhibit high-dose BMP2-induced adipogenesis when combined together. Consistent with the previous reports, our preliminary findings suggest that Oxy133 has a significant potential as an alternative to rhBMP2 in spine fusion.



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Erratum to: The outcome of primary brachial plexus reconstruction in extended Erb’s obstetric palsy when two roots are available for intraplexus neurotization



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Erratum to: The outcome of primary brachial plexus reconstruction in extended Erb’s obstetric palsy when only one root is available for intraplexus neurotization



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Erratum to: question mark ear deformity-revisited



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PTK7 is a novel oncogenic target for esophageal squamous cell carcinoma

Abstract

Background

Overexpression of PTK7 has been found in multiple cancers and has been proposed to serve as a prognostic marker for intrahepatic cholangiocarcinoma. Its role in esophageal cancer, however, remains to be clarified. We hypothesize that PTK7 positively regulates tumorigenesis of esophageal cancer.

Methods

We examined PTK7 expression pattern in human esophageal squamous carcinoma by Oncomine expression analysis and by immunohistochemistry (IHC) staining. We knocked down PTK7 in two esophageal squamous cell carcinoma cell lines, TE-5, and TE-9, by siRNA, and evaluated cell proliferation, apoptosis, and migration ofPTK7-defective cells. Expressions of major apoptotic regulators and effectors were also determined by quantitative real-time PCR in PTK7-defective cells. We further overexpressed PTK7 in the cell to evaluate its effects on cell proliferation, apoptosis, and migration.

Results

Both Oncomine expression and IHC analyses showed that PTK7 is overexpressed in clinical esophageal squamous cell carcinoma tumors. PTK7 siRNA suppressed cell growth and promoted apoptosis of TE-5 and TE-9. PTK7-defective cells further displayed reduced cellular migration that was concomitant with upregulation of E-cadherin. Conversely, overexpression of PTK7 promotes cell proliferation and invasion, while apoptosis of the PTK7-overexpressing cells is repressed. Notably, major apoptotic regulators, such as p53 and caspases, are significantly upregulated in siPTK7 cells.

Conclusions

PTK7 plays an oncogenic role in tumorigenesis and metastasis of esophageal squamous carcinoma. PTK7 achieves its oncogenic function in esophageal squamous cell carcinoma partially through the negative regulation of apoptosis.



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Combining serum miRNAs, CEA, and CYFRA21-1 with imaging and clinical features to distinguish benign and malignant pulmonary nodules: a pilot study

Abstract

Background

Our study was designed to improve the accuracy of determining whether pulmonary nodules are benign or malignant.

Methods

We evaluated the clinical and imaging features and serum markers: neuron specific enolase (NSE), carcino-embryonic antigen (CEA), cytokeratin fragment antigen 21–1 (CYFRA 21–1), miRNA-21-5p, and miR-574-5pof in 39 patients with pathology information. Factors that differed significantly between those with benign versus malignant pulmonary nodules were used to establish a prediction model for identifying malignant nodules.

Results

The studied nodules were 51.3% malignant and 48.7% benign. Age, smoking status, nodule diameter, history of emphysema, vascular sign, burr sign, CYFRA21-1, CEA, miRNA-21-5p, and miRNA-574-5p differed significantly between the benign and malignant nodule groups. Serum levels of CYRFA21-1 and CEA could be used to distinguish between malignant and benign nodules with a positive predictive value (PPV) of 80.0%, a negative predictive value (NPV) of 84.2%, and an area under the receiver operating characteristics curve (AUC) of 0.863. Using the serum levels of miRNA-21-5p and miRNA-574-5p, the PPV was 55%, the NPV was 84.2%, and the AUC was 0.797. When all four serum markers were combined, the PPV was 80%, the NPV was 89.5%, and the AUC was 0.921. We established a prediction model for malignant nodules, including clinical features, imaging features, and serum markers. In cross-validation, the ratio of discriminant conformance was 95%.

Conclusions

Serum levels of miRNA-21-5p and miRNA-574-5p are significantly higher in patients with malignant nodules than in patients with benign nodules and are potential serum biomarkers. Our prediction model could improve malignant nodule diagnosis.



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Efficacy of prophylactic splenectomy for proximal advanced gastric cancer invading greater curvature

Abstract

Background

For proximal gastric cancer invading the greater curvature, concomitant splenectomy is frequently performed to secure the clearance of lymph node metastases. However, prognostic impact of prophylactic splenectomy remains unclear. The aim of this study was to clarify the oncological significance of prophylactic splenectomy for advanced proximal gastric cancer invading the greater curvature.

Methods

Retrospective review of 108 patients who underwent total or subtotal gastrectomy for advanced proximal gastric cancer involving the greater curvature was performed. Short-term and long-term outcomes were compared between the patients who underwent splenectomy (n = 63) and those who did not (n = 45).

Results

Patients who underwent splenectomy showed higher amount of blood loss (538 vs. 450 mL, p = 0.016) and morbidity rate (30.2 vs. 13.3, p = 0.041) compared with those who did not undergo splenectomy. In particular, pancreas-related complications were frequently observed among patients who received splenectomy (17.4 vs. 0%, p = 0.003). However, no significant improvement of long-term outcomes were confirmed in the cases with splenectomy (5-year recurrence-free rate, 60.2 vs. 67.3%; p = 0.609 and 5-year overall survival rates, 63.7 vs. 73.6%; p = 0.769). On the other hand, splenectomy was correlated with marginally better survival in patients with Borrmann type 1 or 2 gastric cancer (p = 0.072).

Conclusions

For advanced proximal gastric cancer involving the greater curvature, prophylactic splenectomy may have no significant prognostic impact despite the increased morbidity rate after surgery. Such surgical procedure should be avoided as long as lymph node involvement is not evident.



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Emerging Treatments in Eating Disorders

Abstract

Eating disorders (EDs), including anorexia nervosa, bulimia nervosa, and binge-eating disorder, constitute a class of common and deadly psychiatric disorders. While numerous studies in humans highlight the important role of neurobiological alterations in the development of ED-related behaviors, the precise neural substrate that mediates this risk is unknown. Historically, pharmacological interventions have played a limited role in the treatment of eating disorders, typically providing symptomatic relief of comorbid psychiatric issues, like depression and anxiety, in support of the standard nutritional and psychological treatments. To date there are no Food and Drug Administration-approved medications or procedures for anorexia nervosa, and only one Food and Drug Administration-approved medication each for bulimia nervosa (fluoxetine) and binge-eating disorder (lisdexamfetamine). While there is little primary interest in drug development for eating disorders, postmarket monitoring of medications and procedures approved for other indications has identified several novel treatment options for patients with eating disorders. In this review, I utilize searches of the PubMed and ClinicalTrials.gov databases to highlight emerging treatments in eating disorders.



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Effectiveness of hemostatic gelatin sponge as a packing material after septoplasty: A prospective, randomized, multicenter study

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Publication date: Available online 25 May 2017
Source:Auris Nasus Larynx
Author(s): Sung-Dong Kim, Sung-Lyong Hong, Min-Jung Kim, Joo-Yeon Kim, Yong-Wan Kim, Soo-Kweon Koo, Kyu-Sup Cho
ObjectiveAlthough hemostatic gelatin sponge is a gelatin-based packing material with a powerful hemostatic effect, there were no studies in regard to its efficacy for packing material after septoplasty. The purpose of this study was to investigate the efficacy of hemostatic gelatin sponge nasal packing on patient’s subjective symptoms, hemostasis, and wound healing following septoplasty.Subjects and methodsSeventy six adult patients with nasal septum deviation requiring septoplasty were included. Following surgery, one nasal cavity was packed with hemostatic gelatin sponge and the other one with polyvinyl acetate. Patients’ subjective symptoms while the packing was in situ, hemostatic properties, patients’ pain on removal, degree of bleeding on removal of the packing, time for hemostasis after removal, postoperative wound healing, and the cost of the pack were evaluated.ResultsBoth packs were equally effective in the control of postoperative bleeding following septoplasty. However, hemostatic gelatin sponge packing was significantly more comfortable while in situ and less painful on removal of the pack. The polyvinyl acetate packing was associated with significantly more bleeding on removal, therefore much time was needed to control hemorrhage. There was no significant difference in the cost of the pack used and outcome of wound healing.ConclusionThe use of hemostatic gelatin sponge after septoplasty results in significantly less discomfort and greater patient satisfaction with no adverse reactions when compared with polyvinyl acetate packing. Therefore, hemostatic gelatin sponge may be a useful packing material after septoplasty.



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Aortic Arch Origin of the Left Vertebral Artery: An Anatomical and Radiological Study with Significance for Avoiding Complications with Anterior Approaches to the Cervical Spine

Abstract

Introduction: Complications from anterior approaches to the cervical spine are uncommon with normal anatomy. However, variant anatomy might predispose one to an increased incidence of injury during such procedures. We hypothesized that left vertebral arteries that arise from the aortic arch instead of the subclavian artery might take a more medial path in their ascent making them more susceptible to iatrogenic injury.

Materials and Methods: Fifty human adult cadavers were examined for left vertebral arteries having an aortic arch origin and these were dissected along their entire cervical course. Additionally, two radiological databases of CTA and arteriography procedures were retrospectively examined for cases of aberrant left vertebral artery origin from the aortic arch over a two-year period.

Results: Two cadaveric specimens (4%) were found to have a left vertebral artery arising from the aortic arch. The retrospective radiological database analysis identified 13 cases (0.87%) of left vertebral artery origin from the aortic arch. Of all cases, vertebral arteries that arose from the aortic arch were much more likely to not only have a more medial course (especially their preforaminal segment) over the cervical vertebral bodies but also to enter a transverse foramen that was more cranially located than the normal C6 entrance of the vertebral artery.

Conclusions: Spine surgeons who approach the anterior cervical spine should be aware that an aortic origin of the left vertebral artery is likely to be closer to the midline and less protected above the C6 vertebral level. This article is protected by copyright. All rights reserved.



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Medical students and professional anatomists do not perceive gender bias within imagery featuring anatomy

Abstract

Previous studies suggest that, while both medical students and professional anatomists recognise the importance of gender issues and do not wish to associate with sexism, most are unaware of the possible negative aspects of sexism within anatomy (Morgan et al., 2014, 2016). To further investigate these issue, we provided second year medical students at Cardiff University (n=293) and at the University of Paris Descartes, Sorbonne Paris Cité (n= 142) and professional anatomists in Europe (n= 208) with a questionnaire inviting them to address the possibility that gender factors within anatomical imagery (both historical and contemporary) hinder the dispassionate representation of anatomy. Ethical approval for the survey was obtained from the universities at both Cardiff and Paris. In the light of previous findings, the hypothesis tested was that medical students and professional anatomists do not perceive a gender bias when reflected in imagery that is based upon anatomical iconography. Our survey results support this hypothesis and suggest that most students and anatomists are unaware of the possible negative aspects of sexism within the culture of anatomy. We consequently recommend that teachers of anatomy and authors of anatomical textbooks should be aware of the possibility of adverse effects on professional matters relating to equality and diversity issues when using imagery. This article is protected by copyright. All rights reserved.



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Early-stage non-small cell lung cancer in the USA: patterns of care and survival among elderly patients at least 80 years old

Abstract

Background

The purpose of this study was to analyze the patterns of care of local therapies and their impact on overall survival (OS) among elderly patients with early-stage non-small cell lung cancer (NSCLC) in the USA.

Methods

The National Cancer Database was queried for patients at least age 80 years with NSCLC diagnosed in 2004–2013 with clinical stage T1–3N0M0. Local therapy was analyzed over time and by age. Multivariable (MVA) models were performed to investigate the impact of prognostic factors on OS.

Results

Among 40,561 patients meeting inclusion criteria, 17,418 (43%), 13,008 (32%), and 10,135 (25%) of patients underwent surgical resection, radiotherapy, and observation, respectively, as their initial mode of local therapy. Overtime, while the utilization of surgical managements generally remained stable, the utilization of conventionally fractionated radiotherapy and observation decreased in favor of stereotactic body radiotherapy (SBRT, p < 0.001). Among operable patients (n = 16,377), after MVA several factors were associated with OS including the choice of local therapy favoring resection over conventionally fractionated radiotherapy and observation (HR compared to lobectomy 1.362, and 2.656, respectively, each p < 0.001). In contrast, there was no statistical difference in OS between resection and SBRT among operable patients (HR for SBRT 1.128, p = 0.156).

Conclusions

The utilization of SBRT as the definitive local therapy in elderly patients with early-stage NSCLC is increasing in the USA. Given its generally favorable toxicity profile, SBRT should be considered in the substantial proportion of elderly patients still not receiving any definitive local therapy. Among medically operable elderly patients, OS was similar between resection and SBRT.



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Clinical outcomes following stereotactic body radiation therapy (SBRT) for non-resectable pancreatic adenocarcinoma

Abstract

Objectives

The purpose of this study was to report on progression-free survival (PFS), overall survival (OS), and related toxicities following stereotactic body radiation therapy (SBRT) for non-resectable pancreatic cancer (PCa).

Methods

The RSSearch® Patient Registry was screened for PCa patients treated with SBRT. The relationship between PFS, OS, and potential prognostic factors were evaluated using the Kaplan-Meier method and continuous log-rank analysis, and the correlation between treatment planning and toxicity incidence was examined by logistic regression.

Results

Sixty patients met inclusion criteria. Twenty-three patients (38.33%) had received adjuvant gemcitabine. Following SBRT, median PFS was 6.07 months (range: 2.33 - 34.4 months) and median OS was 8.55 months (range: 2.66 - 78.53 months). Single-fraction SBRT trended towards poorer median PFS (5.13 vs. 6.76 months; p = 0.0122) with no significant difference in median OS (10.3 vs. 7.17 months; p = 0.8896). PCas located in the head had a significantly higher median OS (9.58 months) as compared to those in the body (5.66 months; p = 0.0376). Adjuvant gemcitabine did not result in superior PFS (5.12 vs. 6.35 months; p = 0.52) or OS (8.67 vs. 7.07 months; p = 0.6010). Eight (13.3%) and six (10%) patients reported acute and late toxicities, respectively, that were all Grade 1 or 2. Single-fraction SBRT was associated with an increased risk of toxicity incidence (5/9 patients vs. 3/51 patients; p = 0.001).

Conclusion

SBRT was well-tolerated by PCa patients with fractionated SBRT trending towards superior PFS and less toxicity as compared to single-fraction SBRT.



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Current practices in the management of stage IB, grade 3 endometrial cancer in the United States

Abstract

Objectives

Endometrial cancer is the most common gynecologic malignancy in the United States (US). Most patients are diagnosed with early stage disease and those with stage IB, grade 3 disease have inferior outcomes. Due to the heterogeneity among these patients, existing data has failed to yield cohesive recommendations to guide management decisions. The present study sought to analyze current practices regarding the use of adjuvant radiation for these patients.

Methods

The Surveillance, Epidemiology, and End Results Program was used to find all cases of endometrial cancer diagnosed between 2009 and 2013 in patients aged 18 or older. Data regarding the age (<60 versus ≥60), race (white versus non-white), tumor size (less than or equal to 4 cm versus >4 cm), type of surgery performed (less than the total hysterectomy and bilateral salpingo-oophrectomy, TH/BSO, versus greater than or equal to TH/BSO), number of nodes examined (<10 versus ≥10), radiation sequence with surgery (none versus adjuvant radiation), and type of radiation (brachytherapy versus external beam radiation versus both) was extracted from the database. We compared type of treatment administered based on the presence of risk factors. We also analyzed survival outcomes based on these clinic-pathologic factors.

Results

There were no differences between patients receiving surgery alone versus adjuvant radiation based on any parameter. Among those who received radiation, we found no differences between the type of radiation administered, except with respect to tumor size. Patients with small tumors (<4 cm) were more likely to be offered VBT alone (p = 0.03). The overall survival (OS) estimate for the group as a whole was 89% at 59 months. The OS for VBT alone and EBRT alone was 89%, while for the combination, it was 91%. Large tumor size and sub-optimal surgery were associated with inferior survival.

Conclusion

The current study highlights the fact that there is tremendous variation in the management of patients with stage IB, grade 3 endometrial cancer. Forty percent of patients in the US are not offered adjuvant radiation, despite inferior outcomes among these patients when treated with surgery alone. Clearly defined, uniform guidelines are needed to standardize management decisions for this group of patients. Uniform practice is especially important to cut costs in medicine and standardize treatment across health networks.



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Assessment of Gene Flow Between Gossypium hirsutum and Gossypium herbaceum: Evidence of Unreduced Gametes in the Diploid Progenitor

In the framework of a gene flow assessment, we investigated the natural hybridization rate between Gossypium hirsutum (AADD genome) and G. herbaceum (AA genome). The latter species, a diploid progenitor of G. hirsutum, is spontaneously present in South Africa. Reciprocal crosses were performed without emasculation between G. herbaceum and G. hirsutum. Neither examination of the morphological characteristics nor flow cytometry analysis of the 335 plants resulting from the G. hirsutum x G. herbaceum cross showed any hybrid features. Of the 148 plants produced from the G. herbaceum x G. hirsutum cross, three showed a hybrid phenotype, and their hybrid status was confirmed by SSR markers. Analysis of DNA content by flow cytometry and morphological traits clearly showed that two of these plants were triploid (AAD). The third plant had a flow cytometry DNA content slightly higher than G. hirsutum. In addition, its morphological characteristics (plant architecture, presence and size of petal spots, leaf shape) led us to conclude that this plant was AAAD thus resulting from fertilization with an unreduced AA gamete of the female G. herbaceum parent. Fluorescent In Situ Hybridization (FISH) and meiotic behavior confirmed this hypothesis. To the best of our knowledge, this is the first description of such gametes in G. herbaceum, and it opens new avenues in breeding programs. Furthermore, this plant material could provide a useful tool for studying the expression of genes duplicated in the A and D cotton genome.



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Using RNA-seq for Genomic Scaffold Placement, Correcting Assemblies, and Genetic Map Creation in a Common Brassica rapa Mapping Population

Brassica rapa is a model species for agronomic, ecological, evolutionary and translational studies. Here we describe high-density SNP discovery and genetic map construction for a Brassica rapa recombinant inbred line (RIL) population derived from field collected RNA-seq data. This high-density genotype data enables the detection and correction of putative genome mis-assemblies and accurate assignment of scaffold sequences to their likely genomic locations. These assembly improvements represent 7.1-8.0% of the annotated Brassica rapa genome. We demonstrate how using this new resource leads to a significant improvement for QTL analysis over the current low-density genetic map. Improvements are achieved by the increased mapping resolution and by having known genomic coordinates to anchor the markers for candidate gene discovery. These new molecular resources and improvements in the genome annotation will benefit the Brassicaceae genomics community and may help guide other communities in fine tuning genome annotations.



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Systematic Analysis of the DNA Damage Response Network in Telomere Defective Budding Yeast

Functional telomeres are critically important to eukaryotic genetic stability. Scores of proteins and pathways are known to affect telomere function. Here, we report a series of related genome-wide genetic interaction screens performed on budding yeast cells with acute or chronic telomere defects. Genetic interactions were examined in cells defective in Cdc13 and Stn1, affecting two components of CST, a single stranded DNA (ssDNA) binding complex that binds telomeric DNA. For comparison, genetic interactions were also examined in cells with defects in Rfa3, affecting the major ssDNA binding protein, RPA, which has overlapping functions with CST at telomeres. In more complex experiments, genetic interactions were measured in cells lacking EXO1 or RAD9, affecting different aspects of the DNA damage response, and containing a cdc13-1 induced telomere defect. Comparing fitness profiles across these data sets helps build a picture of the specific responses to different types of dysfunctional telomeres. The experiments show that each context reveals different genetic interactions, consistent with the idea that each genetic defect causes distinct molecular defects. To help others engage with the large volumes of data the data is made available via two interactive web-based tools: Profilyzer and DIXY. One particularly striking genetic interaction observed was that the chk1 mutation improved fitness of cdc13-1 exo1 cells more than other checkpoint mutations (ddc1, rad9, rad17, rad24), whereas in cdc13-1 cells the effects of all checkpoint mutations were similar. We show that this can be explained by Chk1 stimulating resection, a new function for Chk1 in the eukaryotic DNA damage response network.



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Drosophila simulans: A Species with Improved Resolution in Evolve and Resequence Studies

The combination of experimental evolution with high-throughput sequencing of pooled individuals — i.e. Evolve and Resequence; E&R — is a powerful approach to study adaptation from standing genetic variation under controlled, replicated conditions. Nevertheless, E&R studies in Drosophila melanogaster have frequently resulted in inordinate numbers of candidate SNPs, particularly for complex traits. Here, we contrast the genomic signature of adaptation following ~60 generations in a novel hot environment for D. melanogaster and D. simulans. For D. simulans, the regions carrying putatively selected loci were far more distinct, and thus harbored fewer false positives, than those in D. melanogaster. We propose that species without segregating inversions and higher recombination rates, such as D. simulans, are better suited for E&R studies that aim to characterize the genetic variants underlying the adaptive response.



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Evaluation of Penicillin Allergy in the Hospitalized Patient: Opportunities for Antimicrobial Stewardship

Abstract

Purpose of Review

Penicillin allergy is often misdiagnosed and is associated with adverse consequences, but testing is infrequently done in the hospital setting. This article reviews historical and contemporary innovations in inpatient penicillin allergy testing and its impact on antimicrobial stewardship.

Recent Findings

Adoption of the electronic medical record allows rapid identification of admitted patients carrying a penicillin allergy diagnosis. Collaboration with clinical pharmacists and the development of computerized clinical guidelines facilitates increased testing and appropriate use of penicillin and related β-lactams. Education of patients and their outpatient providers is the key to retaining the benefits of penicillin allergy de-labeling.

Summary

Penicillin allergy testing is feasible in the hospital and offers tangible benefits towards antimicrobial stewardship. Allergists should take the lead in this endeavor and work towards overcoming personnel limitations by partnering with other health care providers and incorporating technology that improves the efficiency of allergy evaluation.



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Amy Reed, MD, Morcellator Opponent, Dies of Uterine Cancer

She and her husband sought to ban the use of power morcellators in laparoscopic hysterectomies as too risky after the device upstaged an occult cancer during her own procedure.
Medscape Medical News

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Immunosuppression Drug Therapy in Lung Transplantation for Cystic Fibrosis

Abstract

Cystic fibrosis (CF) is a common indication for lung transplantation (LTx) in children and adults with severe and irreversible lung disease. In the setting of LTx in the CF population, immunosuppressive medications are used to prevent allograft rejection despite the majority of these patients being chronically infected with numerous, and often antibiotic-resistant, pathogens. There is limited evidence for the optimal post-LTx immunosuppression regimen in patients with CF, particularly in children. This article provides a review of immunosuppression regimens in the pediatric and adult CF post-LTx population, investigating drug dosing and monitoring, and medication combinations. Currently used immunosuppressive medications and related systemic adverse effects are reviewed. With limitations of data in the pediatric population, future research should address immunosuppression in these children to help guide pediatric drug management as a means to optimize clinical outcomes after LTx.



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Disulfide high mobility group box-1 causes bladder pain through bladder Toll-like receptor 4

Bladder pain is a prominent symptom in several urological conditions (e.g. infection, painful bladder syndrome/interstitial cystitis, cancer). Understanding the mechanism of bladder pain is important, particul...

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The Role of capsule endoscopy and device assisted enteroscopy for small bowel lesions in Hereditary Hemorrhagic Telangiectasia

Hereditary hemorrhagic telangiectasia (HHT) is an autosomal-dominant disorder leading to telangiectases and arteriovenous malformations of the skin, mucosa, and viscera. Telangiectases in the upper gastrointestinal tract are known, but data regarding possible small-bowel involvement are poor.

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From intraperitoneal onlay mesh repair to preperitoneal onlay mesh repair

Abstract

Laparoscopic repair for ventral and incisional hernias was first reported in the early 1990s. It uses intraperitoneal only mesh placement to achieve a tension-free repair of the hernia. However, in recent years, there has been greater concern about long-term complication involving intraperitoneal mesh placement. Many case reports and case series have found evidence of mesh adhesion, mesh fistulation, and mesh migration into hollow organs including the esophagus, small bowel, and large bowel, resulting in various major acute abdominal events. Subsequent management of these complications may require major surgery that is technically demanding and difficult; in such cases, laparotomy and bowel resection have often been performed. Because of these significant, but not common, adverse events, many surgeons favor open sublay repair for ventral and incisional hernias. Investigators are therefore searching for a laparoscopic approach for ventral and incisional hernias that might overcome the mesh-induced visceral complications seen after intraperitoneal only mesh placement repair. Laparoscopic preperitoneal onlay mesh is one such approach. This article will explore the fundamental of intraperitoneal only mesh placement and its problems, the currently available peritoneal visceral-compatible meshes, and upcoming developments in laparoscopic ventral and incisional hernia repair. The technical details of preperitoneal onlay mesh, as well as its potential advantages and disadvantages, will also be discussed.



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Hybrid approach using laparoscopy and transanal minimally invasive surgery to treat rectal cancer with invasion to the seminal vesicles

Abstract

We treated a 64-year-old man for rectal cancer with direct invasion to the seminal vesicles and no distant metastases by complete resection with laparoscopy and transanal minimally invasive surgery (TAMIS). We inserted the TAMIS device into the anal canal to above the anorectal ring and dissected to prostate level. High ligation of the inferior mesenteric artery and vein was performed by standard medial laparoscopy. The sigmoid and descending colon were mobilized, and in the postrectal space, we dissected to the space made by TAMIS. The membranous peritoneum was dissected on both sides of the rectum to the cul de sac. The peritoneum was dissected anterolaterally to reveal the seminal ducts, which were ligated and dissected on both sides. The seminal vesicles were dissected from the posterior wall of the bladder to the prostate level. The rectal specimen was now fully mobilized. Lower rectal resection with combined laparoscopy and TAMIS provided a better surgical plane than standard laparoscopy.



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