419 Extended Length Peripheral Catheters Placed Under Ultrasound Guidance Are Associated With Increased Risk of Computed Tomography Contrast Extravasation

Study Objectives: Ultrasound guided intravenous catheter (USGIV) placement is a safe and effective alternative for traditional vascular access in patients with known difficult intravenous (IV) access. However, multiple studies have shown increased risk of computed tomography (CT) contrast extravasation. These studies are retrospective and did not control for the USGIV catheter length. This study assesses the risk of CT contrast extravasation through 2.5-inch 18-gauge USGIV versus standard 1.16-inch catheters placed by traditional landmark technique.

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418 Emergency Medicine Clinicians' Views and Practices for Identifying Opioid Misuse in the Era of Prescription Drug Monitoring Programs

To describe emergency medicine (EM) clinicians' experience and application with prescription drug monitoring programs (PDMP) and to characterize their opinions on information believed to suggest opioid misuse behavior (OMB).

http://ift.tt/2wyeXxK

430 Characterizing Community Naloxone Programs and Opioid Overdose Trends in the United States

To characterize the current state of opioid overdose (OOD) in the United States, as well as the community naloxone programs that exist to combat overdose; to identify variables that could be used to predict when increases in overdose would occur, and when high potency synthetic opioids (HPSO) are likely present.

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305 Language Assistance for Limited English Proficiency Patients in the Emergency Department: Determining the Unmet Need

Many patients who present to public emergency departments (EDs) have limited english proficiency (LEP). LEP patients have worse understanding of their conditions and high rates of ED recidivism often due to poor understanding of their care. LEP patients are entitled to language assistance under title IV of the 1964 Civil Rights Act. The objective of this study is to characterize the unmet need for language assistance in a public ED.

http://ift.tt/2wxTGUP

1 Chest Pain Care Patterns Across the Carolinas: Determining the Readiness for Widespread HEART Pathway Dissemination

Greater than 50% of patients who present to the ED with chest pain are admitted but <10% are ultimately diagnosed with ACS. This pervasive over-triage costs $10-13 billion annually. The HEART Pathway uses a validated clinical decision aid and serial troponin measures to provide real-time decision support to providers. In prior studies, the HEART Pathway decreased hospitalizations, stress testing, and hospital length of stay, without increasing adverse events, demonstrating efficacy at a single site.

http://ift.tt/2xcg6OK

337 Accuracy of Landmark-Guided Glenohumeral Intra-Articular Injections in Patients With Anterior Shoulder Dislocations

The shoulder joint is the most commonly dislocated joint and accounts for more than 70,000 emergency department (ED) visits per year in the United States alone. Current evidence suggests that intra-articular injection of the shoulder with local anesthetic agents can provide adequate analgesia to facilitate reduction and obviate the need for more resource intensive methods such as procedural sedation. However, studies have not determined the rate at which landmark-guided shoulder joint injections (LGI) truly deposit local anesthetic into the joint space.

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2 Effectiveness of Provider-Focused Interventions to Eliminate Care Disparities: Results from the Equity in Diagnostic Imaging Trial (EDIT)

African Americans have almost twice the incidence of subarachnoid hemorrhage (SAH) compared to Whites, yet studies indicate they are less likely to receive neuroimaging when presenting to the emergency department (ED) with headache, even when adjusting for age, sex, co-morbidity and acuity. Regulatory efforts and quality initiatives to reduce CT imaging for ED patients with headache may exacerbate this disparity and increase the likelihood that Black patients, who are at higher risk for SAH, do not receive an appropriate ED workup for severe headache.

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373 Concussions in the Emergency Department: A Retrospective Analysis of Clinical Decision Guidelines Utilization

Head injuries are a common chief complaint in clinics, urgent care facilities, and emergency departments (ED) alike. In the setting of known head injury, the possibility for significant pathology can be daunting for clinicians. The decision to obtain advanced imaging should be guided by evidence-based medicine; however, in many cases, imaging or transfer to a higher level of care is viewed as unnecessary. Few studies have evaluated head injuries and concussions in the emergency department in comparison to imaging guidelines.

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3 Out-of-Hospital to Emergency Department Data Exchange: A SAFR Transition of Care

Electronic health records and the digital revolution are dramatically changing the way health care is delivered. Because electronic patient data can be shared among providers, physicians and nurses, it has the potential to vastly improve care, reduce errors, and enhance patient safety across the continuum of care. One area that remains largely unconnected from this growing exchange of patient data are Emergency Medical Services (EMS). Paramedics often do not have access to electronic patient data creating gaps of care.

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203 Acute Care Redesign and Alternative Payment for Emergency Medicine Within Accountable Care Organizations: A Qualitative Study

Accountable care organizations (ACOs) are physician and hospital networks that provide care for populations of patients with the goal of improving quality while reducing cost. It is unknown how care redesign within ACOs impacts acute unscheduled care delivery and payment for emergency medical care.

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4∗ Serum GFAP and UCH1-L1 Predict Traumatic Injuries on Head CT Scan After Mild-Moderate Traumatic Brain Injury: Results of the ALERT-TBI Multicenter Study

There exists a critical unmet medical need to improve the assessment and management of traumatic brain injury (TBI), a leading cause of injury, death and disability in the United States. Despite growing recognition and research of the importance and potential of biomarkers for TBI, there are currently no FDA-cleared or approved objective blood tests for TBI or concussion. Ubiquitin C-terminal hydrolase-L1 (UCH-L1) and glial fibrillary acidic protein (GFAP) are two novel biomarker candidates that are highly brain specific and are detectable in the serum shortly after TBI.

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321 A Step Towards Nil Mortality in Organophosphorus Compound Poisoning: Development of an Algorithm

Tamilnadu, an agriculture-based state in India, suffered severe drought during 2014 to 2016 when the number of suicides increased among farmers. Organophosphorus compound (OPC) poisoning is a common method of committing suicide among farmers since it is easily available as pesticides. Mortality rate in OPC poisoning in India is 15%.

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5 Pilot of a Modified HEART Score and Serial High Sensitivity Troponin T Pathway to Reduce Chest Pain Observations

Recent innovations have led to markedly decreased admission rates and reductions in 30-day major adverse cardiac event (MACE) rates to 0.5% in Europe, which is improved over previous U.S. national estimated rates of missed acute myocardial infarction (2.1%) and unstable angina (2.3%). High sensitivity troponin T (hs-TnT) has recently been approved by the FDA. Our objective is to decrease "nonproductive" chest pain observations by reducing variability in assessments of patients presenting to the emergency department (ED) with chest pain (or other potentially ischemic symptoms), through the use of a modified HEART score and serial hs-TnT measurements at 0 and 1 hour, while simultaneously maintaining or improving patient outcomes.

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389 My Visit Board: Improving Patient Understanding of Emergency Department Care

Improve the patient experience in the emergency department (ED) by providing information identifying the role of the various emergency department staff members, communicating expected wait times, and providing targeted health information.

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6 Telehealth for Low-Acuity EMS: One Fire-Based System Experience With 10,000 Patients

Emergency Medical Services (EMS) transports thousands of patients via ambulance every day to emergency departments (ED) for primary care, regardless of the existing acuity. American College of Emergency Physicians and National Association of EMS Physicians believe EMS systems may encounter patients who do not need advanced life support-level care or evaluation; in these circumstances transportation by alternate means or to an alternate destination may be appropriate. We aim to measure the number of Emergency Telehealth and Navigation (ETHAN) mobile integrated health care (MIH) patients who were triaged for alternative out-of-hospital transportation and destination.

http://ift.tt/2xcg5dE

357 Lyophilized Plasma in Out-of-Hospital Resuscitation: Risk Benefit Balance

Plasma can be used in out-of-hospital care to assist with the resuscitation of patients with significant hemorrhage and coagulopathy instead of crystalloids or colloids. Previous studies of trauma victims have demonstrated its potential benefit, either isolated or with blood transfusion. The use of fresh frozen plasma (FFP) in the out-of-hospital setting is challenging. Lyophilized (freeze dried) plasma is markedly easier to use in the out-of-hospital setting; it is deployed by numerous military forces on the combat theater.

http://ift.tt/2wy6iLz

7 Validation and Integration of a Stroke Algorithm (VISA Study): Out-of-Hospital Identification of Large Vessel Occlusion Stroke in a Suburban/Rural EMS Service

We sought to compare performance of the Southeast Texas Assessment and Transport Stroke Tool Severity Criteria (STATS) and Rapid Arterial Occlusion Evaluation (RACE) for diagnosing large vessel occlusion stroke in a suburban/rural EMS Population.

http://ift.tt/2xbYEKv

211 Emergency Department Revisits Within Three Days of an Emergency Department Discharge for Urinary Tract Infection Among Geriatric Patients

Emergency department (ED) visits for urinary tract infections (UTI) are common among the elderly. Elderly patients have higher rates of complications and treatment failures from UTIs. The purpose of this study was to identify and describe repeat visits to the ED within 3 days following an ED visit with a discharge diagnosis of UTI among geriatric patients.

http://ift.tt/2wxYFVB

8 Dissemination of a Protocol to Expedite Home Treatment of Low-Risk Patients With Venous Thromboembolism With Monotherapy Anticoagulation

Monotherapy anticoagulation has been used in two emergency departments (EDs) in Indianapolis, IN in to treat and discharge patients with venous thromboembolism (VTE) [PMID: 26113241, 27143861]. Here, we describe the process and outcomes of dissemination and implementation of this protocol, including emergency physician supervised follow-up clinics in two large hospitals in the Dallas-Ft. Worth metroplex of Texas. We hypothesized low rates of recurrent VTE and clinically significant bleeding at 30 days.

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345 Appropriateness of Trauma Alert Activation and Validation of a Two-Tiered System for Trauma Alert Activation at an Academic Medical Center

Level 1 Trauma Centers credentialed by the American College of Surgeons (ACS) follow established criteria for the activation of Trauma Alerts (TA) which trigger multiple hospital resources. These include rules for trauma activation (TA) based on physiologic, anatomic, and "mechanism of injury" (MOI) characteristics of victims. TAs are dichotomized into Level A and Level B based on these criteria. This project was designed to characterize the appropriateness of initiating TAs at our institution and to compare discharge rates of Level A versus Level B activations.

http://ift.tt/2wxIqI4

Laparoscopic pancreaticoduodenectomy for tumors of the head of pancreas; 10 cases for a single center experience

OBJECTIVE: The tumors of the head of the pancreas are one of the leading causes of cancer-related death in Western countries. The current gold standard for these tumors is a Whipple procedure. This procedure did not change in its surgical steps since when it was initially introduced in 1935. More recently, a laparoscopic approach with similar outcomes has been described. The aim of this paper is to describe the laparoscopic surgical technique performed in our unit, reporting single center postoperative outcomes.

PATIENTS AND METHODS: From the 1st January 2013 to the 31st December 2015 a database was created. Data about patients who underwent a laparoscopic pancreaticoduodenectomy (LPD) were collected prospectively. All patients were preoperatively assessed with blood samples, tumor markers, CT chest abdomen and pelvis and/or MRI pancreas. Only patients with specific characteristics were considered eligible for an LPD: performance status 0, body mass index (BMI) less than 30 kg/m2, a small neoplastic lesion (< 3.5 cm) confined to the pancreas, the absence of infiltrated organs and/or blood vessels (T1 or T2). Postoperative data and complications were recorded and described according to the Clavien-Dindo classification and the international study group of pancreatic surgery definitions.

RESULTS: In a time interval of 36 months, 31 patients with an initially considered resectable pancreatic cancer were referred. 11 patients were found to have metastasis during the preoperative workout. Only 10 patients were considered eligible for a LPD. Six of them were men (60%). The mean BMI was 25.01 kg/m2 (19.6-29.8). 5 patients, who underwent to LPD did not have any comorbidities. An overall 50% of all patients were jaundice at the time of diagnosis with a mean bilirubin level of 181.3 µmol/L (119.7-307.8). All patients with a direct bilirubin greater than 250 µmol/L underwent a preoperative percutaneous biliary drainage. In the majority of the LPD performed (50%), the histology reported a pancreatic adenocarcinoma. Other postoperative histology described were: IPMN (20%), ampullar neoplasia (20%) and neuroendocrine tumor (10%). Neo-adjuvant chemotherapy was never considered indicated. The reported postoperative complications were: 1 anastomotic bleeding, 2 pancreatic fistula, 1 infected intra-abdominal collection and 1 delay gastric emptying. The pancreatic fistulas were considered grade A and grade B. One fatality after LPD occurred because of an uncontrollable, diffuse severe hemorrhagic gastritis associated with a GJ anastomosis bleeding in the POD 25. The mean hospital stay was 12.3 days (8-25). The mean operative time was 224 min (170-310). There were no intraoperative complications. The main intraoperative blood loss was 220 ml (180-400) and intraoperative blood transfusions were not required. The resection margins were negative (R0) in 100% of cases and the mean lymph nodes harvested were 24 (18-40). The LPD is still a not common practice. Our results are comparable with those reported in literature about the open technique. These remarkable surgical outcomes are probably related to the extremely careful preoperative patient selection performed. The indication for a laparoscopic vs. an open pancreaticoduodenectomy was based on a CT scan pancreas performed less than 30 days before the planned date of surgery and a careful preoperative assessment. A low complication rate and a relative short stay in hospital were associated to a good quality of life in the early postoperative period and an early referral for postoperative chemotherapy. Good clinical outcomes were associated with outstanding oncological results.

CONCLUSIONS: Laparoscopic pancreaticoduodenectomy is a feasible surgical procedure. Remarkable oncological and surgical outcomes can be achieved with a morbidity and mortality rate in line with the data reported by the large series of open procedures.

L'articolo Laparoscopic pancreaticoduodenectomy for tumors of the head of pancreas; 10 cases for a single center experience sembra essere il primo su European Review.

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Corrigendum to “Imaging techniques for the assessment of fracture repair”[Injury 45 (Supplement (2)) (2014) S16–S22]

Publication date: Available online 14 September 2017
Source:Injury
Author(s): P. Augat, E.F. Morgan, T.J. Lujan, T.J. MacGillivray, W.H. Cheung




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Fragility fractures: A complex interaction of the health care system- the patient and the bone: Can we do better?

Publication date: Available online 13 September 2017
Source:Injury
Author(s): Matthew Smith, Peter V. Giannoudis




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Use of Ganga Hospital Open Injury Severity Scoring for determination of salvage versus amputation in open type IIIB injuries of lower limbs in children—An analysis of 52 type IIIB open fractures

Publication date: Available online 12 September 2017
Source:Injury
Author(s): K. Venkatadass, Tarani Sai Prasanth Grandhi, S. Rajasekaran
Introduction and aimsOpen injuries in children are rare compared to adults. In children with major open injuries, there is no specific scoring system to guide when to amputate or salvage the limb. The use of available adult scoring systems may lead to errors in management. The role of Ganga Hospital Open Injury Severity Scoring (GHOISS) for open injuries in adults is well established and its applicability for pediatric open injuries has not been studied. This study was done to analyse the usefulness of GHOISS in pediatric open injuries and to compare it with MESS(Mangled Extremity Severity Score).MethodsAll children (0–18 years) who were admitted with Open type IIIB injuries of lower limbs between January 2008 and March 2015 were included. MESS and GHOISS were calculated for all the patients. There were 50 children with 52 type IIIB Open injuries of which 39 had open tibial fractures and 13 had open femur fractures.ResultsOut of 52 type IIIB open injuries, 48 were salvaged and 4 were amputated. A MESS score of 7 and above had sensitivity of 25% for amputation while GHOISS of 17 and above was found to be more accurate for determining amputation with sensitivity of 75% and specificity of 93.75%.ConclusionGHOISS is a reliable predictor of injury severity in type IIIB open fractures in children and can be used as a guide for decision-making. The use of MESS score in children has a lower predictive value compared to GHOISS in deciding amputation versus salvage. A GHOISS of 17 or more has the highest sensitivity and specificity to predict amputation.



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Computed Tomography Findings in Young Children with Minor Head Injury Presenting to the Emergency Department Greater than 24hrs Post Injury

Publication date: Available online 11 September 2017
Source:Injury
Author(s): Renana Gelernter, Giora Weiser, Eran Kozer
BackgroundLarge studies which developed decision rules for the use of Computed tomography (CT) in children with minor head trauma excluded children with late presentation (more than 24hours).Objective: To assess the prevalence of significant traumatic brain injury (TBI) on CT in infants with head trauma presenting to the emergency department (ED) more than 24hours from the injury.MethodsA retrospective chart review of infants less than 24 months old referred for head CT because of traumatic brain injury from January 2004 to December 2014 in Assaf-Harofeh medical center was conducted. We used the PECARN definitions of TBI on CT to define significant CT findings.Results344 cases were analyzed, 68 with late presentation.There was no significant difference in the age between children with late and early presentation (mean 11.4 (SD 5.6) month Vs 10. 5 (SD 7.0) month, P=0.27). There was no significant difference between the groups in the incidence of significant TBI (22% Vs 19%, p=0.61). Any TBI on CT (e.g. fracture) was found in 43 (63%) patients with late presentation compared with 116 (42%) patients with early presentation (p=0.002, OR 2.37, 95% CI 1.37 to 4.1).ConclusionA similar rate of CT-identified traumatic brain injury was detected in both groups.‏There was no significant difference in the incidence of significant TBI on CT between the groups.‏ Young children presenting to the ED more than 24 hours after the injury may have abnormal findings on CT.



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Avoiding over-telescoping to improve outcomes in cephalomedullary nailing

Publication date: Available online 9 September 2017
Source:Injury
Author(s): Wen-Feng Xiong, Sun-Jun Hu, Shi-Min Chang




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ACCURACY OF SHOCK INDEX VERSUS ABC SCORE TO PREDICT NEED FOR MASSIVE TRANSFUSION IN TRAUMA PATIENTS

Publication date: Available online 15 September 2017
Source:Injury
Author(s): Rebecca Schroll, David Swift, Danielle Tatum, Stuart Couch, Jiselle B. Heaney, Monica Llado-Farrulla, Shana Zucker, Frances Gill, Griffin Brown, Nicholas Buffin, Juan Duchesne
BackgroundVarious scoring systems have been developed to predict need for massive transfusion in traumatically injured patients. Assessments of Blood Consumption (ABC) score and Shock Index (SI) have been shown to be reliable predictors for Massive Transfusion Protocol (MTP) activation. However, no study has directly compared these two scoring systems to determine which is a better predictor for MTP activation. The primary objective was to determine whether ABC or SI better predicted the need for MTP in adult trauma patients with severe hemorrhage.MethodsThis was a retrospective cohort study which included all injured patients who were trauma activations between January 1, 2009 and December 31, 2013 at an urban Level I trauma center. Patients <18 years old or with traumatic brain injury (TBI) were excluded. ABC and SI were calculated for each patient. MTP was defined as need for >10 units PRBC transfusion within 24hours of emergency department arrival. Sensitivity, specificity, and area under the receiver operating characteristic curve (AUROC) were used to evaluate scoring systems' ability to predict effective MTP utilization.ResultsA total of 645 patients had complete data for analysis. Shock Index ≥1 had sensitivity of 67.7% (95% CI 459.5% to 82.6%) and specificity of 81.3% (95% CI 78.0% to 84.3%) for predicting MTP, and ABC score ≥2 had sensitivity of 47.0% (95% CI 29.8% to 64.9%) and specificity of 89.8% (95% CI 87.2% to 92.1%). AUROC analyses showed SI to be the strongest predictor followed by ABC score with AUROC values of 0.83 and 0.74, respectively. SI had a significantly greater sensitivity (P=0.035), but a significantly weaker specificity (P <0.001) compared to ABC score.ConclusionABC score and Shock Index can both be used to predict need for massive transfusion in trauma patients, however SI is more sensistive and requires less technical skill than ABC score.



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A modified deltoid splitting approach with axillary nerve bundle mobilization for proximal humeral fracture fixation

Publication date: Available online 8 September 2017
Source:Injury
Author(s): Young Ho Shin, Young Ho Lee, Ho Sung Choi, Min Bom Kim, Sung Hee Pyo, Goo Hyun Baek
IntroductionThe deltopectoral and the deltoid splitting approach are commonly used for the treatment of proximal humeral fractures. While the deltopectoral approach requires massive soft tissue devascularization, the deltoid splitting approach needs an additional skipped incision to avoid axillary nerve injury. The purpose of this study was to describe a modified anterolateral deltoid splitting approach with axillary nerve bundle mobilization in the treatment of proximal humeral fractures and to assess its radiologic and clinical outcomes.Patients and methodsTwenty-two consecutive patients with proximal humeral fractures were treated with minimally invasive plate osteosynthesis by using a modified anterolateral deltoid splitting approach with axillary nerve bundle mobilization. The patients were divided into two groups: 10 patients of Neer type 2 or 3 fractures vs. 12 patients of Neer type 4 fractures. The mean age of the study population was 63.5 years (range: 30–80 years). Six patients had valgus impacted fractures, and nine had fractures with medial comminution.ResultsFracture union was achieved in all cases. The mean time to union was 8.6 weeks (range: 6–12 weeks). Major complications, such as avascular necrosis of the humeral head and varus collapse at the fracture site, were not observed. No patients had clinically detectable sensory deficits in the axillary nerve distribution or paralysis of the anterior deltoid muscle. The mean neck-shaft angle at the final follow-up was 136.9° (range, 115°–159°). The mean visual analog score for patient satisfaction was 9.1 (range, 6–10), and the mean Neer scores were 93.5 (range, 84–100). There were no significant differences between the two groups with respect to radiologic and clinical outcomes except Neer scores: 95.8 (range: 86–100) in Neer type 2 or 3 fractures and 91.7 (range: 84–99) in Neer type 4 fractures.ConclusionThe use of a modified anterolateral deltoid splitting approach with axillary nerve bundle mobilization in the treatment of proximal humeral fractures yielded excellent outcomes. This approach is a useful alternative to the deltopectoral or the deltoid splitting approaches in the treatment of proximal humeral fractures.



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Nerve injuries to the volar aspect of the hand: A comparison of the reliability of the Weber static test versus the gauze test

Publication date: Available online 8 September 2017
Source:Injury
Author(s): Charles Bijon, Juan José Hidalgo Diaz, Chiara Pizza, Sybille Facca, Alexis Pereira, Philippe Liverneaux
When examining lacerations to the volar aspect of the hand a gauze test may usually be performed to detect nerve injuries. However, published literature suggests that its sensitivity and specificity are lower than 100%. The aim of this study was to determine whether a Weber static (main hypothesis) and dynamic test or a Semmes-Weinstein test (secondary hypotheses) could be a more reliable test than the gauze test to rule out any nerve injury and avoid unnecessary wound explorations.Our case series included a total of 102 patients presenting with 123 palmar lacerations and 158 nerve injuries. On arrival at the emergency department, every patient was tested for epicritic sensation at the pulp of the injured and contralateral fingers with the Weber static and dynamic tests and the Semmes-Weinstein monofilament test. All lacerations underwent exploration under anesthetic to rule out nerve injury.The sensitivities of the gauze test, the Weber static test, the Weber dynamic test and the Semmes Weinstein monofilament test were proven to be 82.5%, 98.6%, 97.9% and 86.7% respectively. The specificities of the gauze test, the Weber static test, the Weber dynamic test and the Semmes Weinstein monofilament test were 79%, 79%, 79% and 78.9% respectively.Examination of lacerations to the volar aspect of the hand to rule out any nerve injuries should include a Weber static test instead of a gauze test. A negative Weber static test should not however discourage a surgical exploration of the laceration to rule out tendinous or vascular injury.



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When does intraoperative 3D-imaging play a role in transpedicular C2 screw placement?

Publication date: Available online 8 September 2017
Source:Injury
Author(s): Cornelius Jacobs, Philip P. Roessler, Sebastian Scheidt, Milena M. Plöger, Collin Jacobs, Alexander C. Disch, Klaus D. Schaser, Tony Hartwig
IntroductionThe stabilization of an atlantoaxial (C1-C2) instability is demanding due to a complex atlantoaxial anatomy with proximity to the spinal cord, a variable run of the vertebral artery (VA) and narrow C2 pedicles. We perfomed the Goel & Harms fusion in combination with an intraoperative 3D imaging to ensure correct screw placement in the C2 pedicle. We hypothesized, that narrow C2 pedicles lead to a higher malposition rate of screws by perforation of the pedicle wall. The purpose of this study was to describe a certain pedicle size, under which the perforation rate rises.Patients and methodsIn this retrospective study, all patients (n=30) were operated in the Goel & Harms technique. The isthmus height and pedicle diameter of C2 were measured. The achieved screw position in C2 was evaluated according to Gertzbein & Robbin classification (GRGr).ResultsA statistically significant correlation was found between the pedicles size (isthmus height/pedicle diameter) and the achieved GRGr for the right (p=0.002/p=0.03) and left side (p=0.018/p=0.008). The ROC analysis yielded a Cut Off value for the pedicle size to distinguish between an intact or perforated pedicle wall (GRGr 1 or ≥2). The Cut-Off value was identified for the isthmus height (right 6.1mm, left 5.4mm) and for the pedicle diameter (6.6mm both sides).ConclusionThe hypothesis, that narrow pedicles lead to a higher perforation rate of the pedicle wall, can be accepted. Pedicles of <6.6mm turned out to be a risk factor for a perforation of the pedicle wall (GRGr 2 or higher). Intraoperative 3D imaging is a feasible tool to confirm optimal screw position, which becomes even more important in cases with thin pedicles. The rising risk of VA injury in these cases support the additional use of navigation.



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Mirror trends of plasticity and stability indicators in primate prefrontal cortex

Abstract

Research on plasticity markers in the cerebral cortex has largely focused on their timing of expression and role in shaping circuits during critical and normal periods. By contrast, little attention has been focused on the spatial dimension of plasticity-stability across cortical areas. The rationale for this analysis is based on the systematic variation in cortical structure that parallels functional specialization and raises the possibility of varying levels of plasticity. Here we investigated in adult rhesus monkeys the expression of markers related to synaptic plasticity or stability in prefrontal limbic and eulaminate areas that vary in laminar structure. Our findings revealed that limbic areas are impoverished in three markers of stability: intracortical myelin, the lectin Wisteria floribunda agglutinin, which labels perineuronal nets, and parvalbumin, which is expressed in a class of strong inhibitory neurons. By contrast, prefrontal limbic areas were enriched in the enzyme calcium/calmodulin-dependent protein kinase II (CaMKII), known to enhance plasticity. Eulaminate areas have more elaborate laminar architecture than limbic areas and showed the opposite trend: they were enriched in markers of stability and had lower expression of the plasticity related marker CaMKII. The expression of glial fibrillary acidic protein (GFAP), a marker of activated astrocytes, was also higher in limbic areas, suggesting that cellular stress correlates with the rate of circuit reshaping. Elevated markers of plasticity may endow limbic areas with flexibility necessary for learning and memory within an affective context, but may also render them vulnerable to abnormal structural changes, as seen in neurologic and psychiatric diseases.

This article is protected by copyright. All rights reserved.

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Frequency-dependent regulation of intrinsic excitability by voltage-activated membrane conductances, computational modeling and dynamic clamp

Abstract

As one of the most unique properties of nerve cells, their intrinsic excitability allows them to transform synaptic inputs into action potentials. This process reflects a complex interplay between the synaptic inputs and the voltage-dependent membrane currents of the postsynaptic neuron. While neurons in natural conditions mostly fire under the action of intense synaptic bombardment and receive fluctuating patterns of excitation and inhibition, conventional techniques to characterize intrinsic excitability mainly utilize static means of stimulation. Recently we have shown that voltage-gated membrane currents regulate the firing responses under current step stimulation and under physiologically more realistic inputs in a differential manner. At the same time, a multitude of neuron types have been shown to exhibit some form of subthreshold resonance that potentially allows them to respond to synaptic inputs in a frequency-selective manner. In the present study we performed virtual experiments in computational models of neurons to examine how specific voltage-gated currents regulate their excitability under simulated frequency-modulated synaptic inputs. The model simulations and subsequent dynamic clamp experiments on mouse hippocampal pyramidal neurons revealed that the impact of voltage-gated currents in regulating the firing output is strongly frequency-dependent and mostly affecting the synaptic integration at theta-frequencies. Notably, robust frequency-dependent regulation of intrinsic excitability was observed even when conventional analysis of membrane impedance suggested no such tendency. Consequently, plastic or homeostatic regulation of intrinsic membrane properties can tune the frequency-selectivity of neuron populations in a way that is not readily expected from subthreshold impedance measurements.

This article is protected by copyright. All rights reserved.

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Altered Cav1.2 function in the Timothy Syndrome mouse model produces ascending serotonergic abnormalities

Abstract

Polymorphism in the gene CACNA1C, encoding the pore-forming subunit of Cav1.2 L-type calcium channels, has one of the strongest genetic linkages to schizophrenia, bipolar disorder, and major depressive disorder: psychopathologies in which serotonin signaling has been implicated. Additionally, a gain-of-function mutation in CACNA1C is responsible for the neurodevelopmental disorder Timothy Syndrome that presents with prominent behavioral features on the autism spectrum. Given an emerging role for serotonin in the etiology of autism spectrum disorders, we investigate the relationship between Cav1.2 and the ascending serotonin system in the Timothy Syndrome type 2 (TS2-neo) mouse, which displays behavioral features consistent with the core triad of ASD. We find that TS2-neo mice exhibit enhanced serotonin tissue content and axon innervation of the dorsal striatum, as well as decreased serotonin turnover in the amygdala. These regionally specific alterations are accompanied by an enhanced active coping response during acute stress (forced-swim), serotonin neuron Fos-activity in the caudal dorsal raphe, and serotonin type 1A receptor dependent feedback-inhibition of the rostral DRN. Collectively, these results suggest that the global gain of function Cav1.2 mutation associated with Timothy Syndrome has pleotropic effects on the ascending serotonin system including neuroanatomical changes, regional differences in forebrain serotonin metabolism and feedback regulatory control mechanisms within the dorsal raphe. Altered activity of the ascending serotonin system continues to emerge as a common neural signature across several ASD mouse models, and the capacity for Cav1.2 L-type calcium channels to impact both serotonin structure and function has important implications for several neuropsychiatric conditions.

This article is protected by copyright. All rights reserved.

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Inflammation alters AMPA-stimulated calcium responses in dorsal striatal D2 but not D1 spiny projection neurons

Abstract

Neuroinflammation precedes neuronal loss in striatal neurodegenerative diseases and can be exacerbated by the release of proinflammatory molecules by microglia. These molecules can affect trafficking of AMPARs. The preferential trafficking of calcium-permeable versus impermeable AMPARs can result in disruptions of [Ca²⁺]_i and alter cellular functions. In striatal neurodegenerative diseases, changes in [Ca²⁺]_i and L-type voltage-gated calcium channels (VGCCs) have been reported. Therefore, the present study sought to determine whether a proinflammatory environment alters AMPA-stimulated [Ca²⁺]_i through calcium-permeable AMPARs and/or L-type VGCCs in dopamine-2 and dopamine-1 expressing striatal spiny projection neurons (D2 and D1 SPNs) in the dorsal striatum. Mice expressing the calcium indicator protein, GCaMP in D2 or D1 SPNs, were utilized for calcium imaging. Microglial activation was assessed by morphology analyses. To induce inflammation, acute mouse striatal slices were incubated with lipopolysaccharide (LPS). Here we report that LPS treatment potentiated AMPA responses only in D2 SPNs. When a nonspecific VGCC blocker was included, we observed a decrease of AMPA-stimulated calcium fluorescence in D2 but not D1 SPNs. The remaining agonist induced [Ca²⁺]_i was mediated by calcium-permeable AMPARs because the responses were completely blocked by a selective calcium-permeable AMPAR antagonist. We used isradipine, the highly selective L-type VGCC antagonist to determine the role of L-type VGCCs in SPNs treated with LPS. Isradipine decreased AMPA-stimulated responses selectively in D2 SPNs after LPS treatment. Our findings suggest that dorsal striatal D2 SPNs are specifically targeted in proinflammatory conditions and that L-type VGCCs and calcium-permeable AMPARs are important mediators of this effect.

This article is protected by copyright. All rights reserved.

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FoxP expression identifies a Kenyon cell subtype in the honeybee mushroom bodies linking them to fruitfly αβc neurons

Abstract

The arthropod mushroom bodies (MB) are a higher order sensory integration center. In insects, they play a central role in associative olfactory learning and memory. In Drosophila melanogaster (Dm), the highly ordered connectivity of heterogeneous MB neuron populations has been mapped using sophisticated molecular genetic and anatomical techniques. The MB-core subpopulation was recently shown to express the transcription factor FoxP with relevance for decision-making. Here we report the development and adult distribution of a FoxP-expressing neuron population in the MB of honeybees (Apis mellifera, Am) using in situ hybridization and a custom-made antiserum. We found the same expression pattern in adult bumblebees (Bombus terrestris, Bt). We also designed a new Dm transgenic line that reports FoxP transcriptional activity in the MB-core region, clarifying previously conflicting data of two other reporter lines. Considering developmental, anatomical and molecular similarities, our data are consistent with the concept of deep homology of FoxP expression in neuron populations coding reinforcement-based learning and habit formation.

This article is protected by copyright. All rights reserved.

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Three shades of grey: detecting brain abnormalities in children with autism by using Source-, Voxel- and Surface-based Morphometry

Abstract

Autistic spectrum disorder (ASD) is a neurodevelopmental disorder characterized by deficits in social interactions, communication and stereotyped behavior. Recent evidence from neuroimaging supports the hypothesis that ASD deficits in adults may be related to abnormalities in a specific frontal-temporal network (Autism-specific Structural Network, ASN). To see whether these results extend to younger children and to better characterize these abnormalities, we applied three morphometric methods on brain grey matter of children with and without ASD.

We selected 39 sMRI images of male children with ASD and 42 typically developing (TD) from the ABIDE database. We used Source-Based Morphometry (SoBM), a whole-brain multivariate approach to identify grey matter networks, Voxel-Based Morphometry (VBM), a voxel-wise comparison of the local grey matter concentration, and Surface-Based Morphometry (SuBM) for the estimation of the cortical parameters.

SoBM showed a bilateral frontal-parietal-temporal network different between groups, including the inferior-middle temporal gyrus, the inferior parietal lobule and the postcentral gyrus; VBM returned differences only in the right temporal lobe; SuBM returned a thinning in the right inferior temporal lobe thinner in ASD, a higher gyrification in the right superior parietal lobule in TD and in the middle frontal gyrus in ASD.

For the first time, we investigated the brain abnormalities in children with ASD by using three morphometric techniques. The results were relatively consistent between methods, stressing the role of an Autism-specific Structural Network in ASD individuals. We also make methodological speculations on the relevance of using multivariate and whole brain neuroimaging analysis to capture ASD complexity.

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The Neurobiological Bases of Autism Spectrum Disorders The R451C-Neuroligin 3 mutation hampers the expression of long-term synaptic depression in the dorsal striatum

Abstract

Autism spectrum disorders (ASDs) comprise a heterogeneous group of disorders with a complex genetic etiology. Current theories on the pathogenesis of ASDs suggest that they might arise from an aberrant synaptic transmission affecting specific brain circuits and synapses. The striatum, which is part of the basal ganglia circuit, is one of the brain regions involved in ASDs.

Mouse models of ASDs have provided evidence for an imbalance between excitatory and inhibitory neurotransmission. Here we investigated the expression of long-term synaptic plasticity at corticostriatal glutamatergic synapses in the dorsal striatum of the R451C-NL3 phenotypic mouse model of autism. This mouse model carries the human R451C mutation in the neuroligin3 (NL3) gene, that has been associated with highly penetrant autism in a Swedish family. The R451C-NL3 mouse has been shown to exhibit autistic-like behaviors and alterations of synaptic transmission in different brain areas. However, excitatory glutamatergic transmission and its long-term plasticity have not been investigated in the dorsal striatum so far. Our results indicate that the expression of long-term synaptic depression (LTD) at corticostriatal glutamatergic synapses in the dorsal striatum is impaired by the R451C-NL3 mutation. A partial rescue of LTD was obtained by exogenous activation of cannabinoid CB1 receptors or enhancement of the endocannabinoid tone, suggesting that an altered cannabinoid drive might underlie the deficit of synaptic plasticity in the dorsal striatum of R451C-NL3 mice.

This article is protected by copyright. All rights reserved.

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Effects of the availability of accurate proprioceptive information on older adults’ postural sway and muscle co-contraction

Abstract

During conditions of increased postural instability, older adults exhibit greater lower-limb muscle co-contraction. This response has been interpreted as a compensatory postural strategy, which may be used to i006Ecrease proprioceptive information from muscle spindles or to stiffen the lower limb as a general response to minimise postural sway. The current study aimed to test these two hypotheses by investigating use of muscle co-contraction during sensory transitions that manipulated proprioceptive input. Surface EMG was recorded from the bilateral tibialis anterior and gastrocnemius medialis muscles, in young (aged 18-30) and older adults (aged 68-80) during blind-folded postural assessment. This commenced on a fixed platform (baseline: 2mins), followed by 3-minutes on a sway-referenced platform (adaptation) and a final 3-minutes on a fixed platform again (reintegration). Sensory reweighting was slower in older adults, as shown by a significantly larger and longer postural sway aftereffect once a stable platform was restored. Muscle co-contraction showed similar aftereffects, whereby older adults showed a larger increase in co-contraction once the stable platform had been restored, compared to young adults. This co-contraction aftereffect did not return to baseline until after 1 minute. Our evidence for high muscle co-contraction during the reintroduction of veridical proprioceptive input suggests that increased co-contraction in older adults is not dependent on contemporaneous proprioceptive input. Rather, it is more likely that co-contraction is a general postural strategy used to minimize postural sway, which is increased during this sensory transition. Future research should examine whether muscle co-contraction is typically a reactive or anticipatory response.

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Long-Range Cortical Dynamics: A Perspective from the Mouse Sensorimotor Whisker System

Abstract

In the mammalian neocortex, the capacity to dynamically route and coordinate the exchange of information between areas is a critical feature of cognitive function, enabling processes such as higher-level sensory processing and sensorimotor integration. Despite the importance attributed to long-range connections between cortical areas, their exact operations and role in cortical function remain an open question. In recent years, progress has been made in understanding long-range cortical circuits through work focused on the mouse sensorimotor whisker system. In this review, we examine recent studies dissecting long-range circuits involved in whisker sensorimotor processing as an entry point for understanding the rules that govern long-range cortical circuit function.

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Does an observer's empathy influence my pain? Effect of perceived empathetic or unempathetic support in a pain test

Abstract

The physiological and behavioural effects of empathy for other's pain have been widely investigated, while the opposite situation, i.e. the influence on one's pain of empathetic feedback from others, remains largely unexplored. Here, we assessed whether and how empathetic and unempathetic comments from observers modulate pain and associated vegetative reactions.

In Study 1, conversations between observers of a pain study were recorded by professional actors. Comments were prepared to be perceived as empathetic, unempathetic, or neutral, and were validated in 40 subjects. In a subsequent pain experiment (Study 2), changes in subjective pain and heart rate were investigated in 30 naïve participants who could overhear the empathetic or unempathetic conversations pre-recorded in study 1.

Subjective pain was significantly attenuated when hearing empathetic comments, as compared to both unempathetic and neutral conditions, while unempathetic comments failed to significantly modulate pain. Heart rate increased when hearing unempathetic remarks, and when receiving pain stimuli, but heart acceleration to nociceptive stimulation was not correlated with pain ratings.

These results suggest that empathetic feedback from observers has a positive influence on pain appraisal, and that this effect may surpass the negative effect of unempathetic remarks. Negative remarks can either trigger feelings of guilt or induce irritation/anger, with antagonistic effects on pain that might explain inter-individual variation. Since in basal conditions heart rate and pain perception are positively correlated, their dissociation here suggests that changes in subjective pain were linked to a cognitive bias rather than changes in sensory input.

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Processing of temporally patterned sounds in the auditory cortex of Seba's short-tailed bat (Carollia perspicillata)

Abstract

This article presents a characterization of cortical responses to artificial and natural temporally-patterned sounds in the bat species Carollia perspicillata, a species that produces vocalizations at rates above 50 Hz. Multi-unit activity was recorded in three different experiments. In the first experiment, amplitude modulated (AM) pure tones were used as stimuli to drive auditory cortex (AC) units. AC units of both ketamine-anesthetized and awake bats could lock their spikes to every cycle of the stimulus modulation envelope, but only if the modulation frequency was below 22 Hz. In the second experiment, two identical communication syllables were presented at variable intervals. Suppressed responses to the lagging syllable were observed, unless the second syllable followed the first one with a delay of at least 80 ms (i.e. 12.5 Hz repetition rate). In the third experiment, natural distress vocalization sequences were used as stimuli to drive AC units. Distress sequences produced by C. perspicillata contain bouts of syllables repeated at intervals of ~60 ms (16 Hz). Within each bout, syllables are repeated at intervals as short as 14 ms (~ 71 Hz). Cortical units could follow the slow temporal modulation flow produced by the occurrence of multisyllabic bouts, but not the fast acoustic-flow created by rapid syllable repetition within the bouts. Taken together, our results indicate that even in fast vocalizing animals, such as bats, cortical neurons can only track the temporal structure of acoustic streams modulated at frequencies lower than 22 Hz.

This article is protected by copyright. All rights reserved.

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Modulating vicarious tactile perception with transcranial electrical current stimulation

Abstract

Our capacity to share the experiences of others is a critical part of social behaviour. One process thought to be important for this is vicarious perception. Passively viewing touch activates some of the same network of brain regions as the direct experience of touch. This vicarious experience is usually implicit, but for some people, viewing touch evokes conscious tactile sensations (mirror-touch synaesthesia). Recent work has attempted to induce conscious vicarious touch in those that do not normally experience these sensations, using transcranial direct current stimulation (tDCS). Anodal tDCS applied to primary somatosensory cortex (SI) was found to induce behavioural performance akin to mirror-touch synaesthesia on a visuotactile interference task. Here, we conducted two experiments that sought to replicate and extend these findings by examining: a) the effects of tDCS and high frequency transcranial random noise stimulation (tRNS) targeted at SI and temporo-parietal junction (TPJ) on vicarious tactile perception, b) the extent to which any stimulation effects were specific to viewing touch to humans versus inanimate agents, and c) the influence of visual perspective (viewing touch from one's own versus another's perspective) on vicarious perception. In Experiment 1, tRNS targeted at SI did not modulate vicarious perception. In Experiment 2, tDCS targeted at SI, but not TPJ, resulted in some modulation of vicarious perception, but there were important caveats to this effect. Implications regarding mechanisms of vicarious perception are discussed. Collectively, the findings do not provide convincing evidence for the potential to modulate vicarious tactile perception with transcranial electrical current stimulation.

This article is protected by copyright. All rights reserved.

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Temporal alignment of anticipatory motor cortical beta lateralisation in hidden visual-motor sequences

Abstract

Performance improves when participants respond to events that are structured in repeating sequences, suggesting that learning can lead to proactive anticipatory preparation. Whereas most sequence-learning studies have emphasized spatial structure, most sequences also contain a prominent temporal structure. We used MEG to investigate spatial and temporal anticipatory neural dynamics in a modified serial reaction-time (SRT) task. Performance and brain activity were compared between blocks with learned spatial-temporal sequences and blocks with new sequences. After confirming a strong behavioural benefit of spatial-temporal predictability, we show lateralisation of beta oscillations in anticipation of the response associated with the upcoming target location, and show that this also aligns to the expected timing of these forthcoming events. This effect was found both when comparing between repeated (learned) and new (unlearned) sequences, as well as when comparing targets that were expected after short vs. long intervals within the repeated (learned) sequence. Our findings suggest that learning of spatial-temporal structure leads to proactive and dynamic modulation of motor cortical excitability in anticipation of both the location and timing of events that are relevant to guide action.

This article is protected by copyright. All rights reserved.

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Encoding seasonal information in a two-oscillator model of the multi-oscillator circadian clock

Abstract

The suprachiasmatic nucleus (SCN) is a collection of about 10,000 neurons, each of which functions as a circadian clock with slightly different periods and phases, that work in concert to form and maintain the master circadian clock for the organism. The diversity among neurons confers on the SCN the ability to robustly encode both the 24-hour light pattern as well as the seasonal time. Cluster synchronization brings the different neurons into line and reduces the large population to essentially two oscillators, coordinated by a macroscopic network motif of asymmetric repulsive-attractive coupling. We recount the steps leading to this simplification and rigorously examine the two-oscillator case by seeking an analytical solution. Through these steps, we identify physiologically relevant parameters that shape the behavior of the SCN network and delineate its ability to store past details of seasonal variation in photoperiod.

This article is protected by copyright. All rights reserved.

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A novel method to prevent catheter dysfunction during spray cryotherapy

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Accidental fracture of an EUS-FNA needle

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Use of Volumetric Laser Endomicroscopy to Characterize a Duodenal Neuroendocrine Tumor

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Determination of the Relative Potency of an Anti-TNF Monoclonal Antibody (mAb) by Neutralizing TNF Using an In Vitro Bioanalytical Method

A protocol for the determination of the relative anti-apoptotic activity of an anti-TNFα mAb using a neutralization mechanism with WEHI 164 cells is presented here. This protocol is useful for comparing the neutralization strength of different molecules with the same biological functionality.

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A Magnetic Resonance Imaging Protocol for Stroke Onset Time Estimation in Permanent Cerebral Ischemia

A protocol for stroke onset time estimation in a rat model of stroke exploiting quantitative magnetic resonance imaging (qMRI) parameters is described. The procedure exploits diffusion MRI for delineation of the acute stroke lesion and quantitative T1 and T2 (qT1 and qT2) relaxation times for timing of stroke.

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Dendritic spines provide cognitive resilience against Alzheimer's disease

Abstract

Objective: Neuroimaging and other biomarker assays suggest that the pathological processes of Alzheimer's disease (AD) initiate years prior to clinical dementia onset. However some 30%-50% of older individuals that harbor AD pathology do not become symptomatic in their lifetime. It is hypothesized that such individuals exhibit cognitive resilience that protects against AD dementia. We hypothesized that in cases with AD pathology structural changes in dendritic spines would distinguish individuals that had or did not have clinical dementia.

Methods: We compared dendritic spines within layers II and III pyramidal neuron dendrites in Brodmann Area 46 dorsolateral prefrontal cortex using the Golgi-Cox technique in 12 age-matched pathology-free controls, 8 controls with AD pathology (CAD), and 21 AD cases. We used highly optimized methods to trace impregnated dendrites from brightfield microscopy images which enabled accurate three-dimensional digital reconstruction of dendritic structure for morphologic analyses.

Results: Spine density was similar among control and CAD cases but reduced significantly in AD. Thin and mushroom spines were reduced significantly in AD compared to CAD brains, whereas stubby spine density was decreased significantly in CAD and AD compared to controls. Increased spine extent distinguished CAD cases from controls and AD. Linear regression analysis of all cases indicated that spine density was not associated with neuritic plaque score but did display negative correlation with Braak staging.

Interpretation: These observations provide cellular evidence to support the hypothesis that dendritic spine plasticity is a mechanism of cognitive resilience that protects older individuals with AD pathology from developing dementia. This article is protected by copyright. All rights reserved.

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Human Leukocyte Antigen Variants and Risk of Hepatocellular Carcinoma Modified by HCV Genotypes: A Genome-wide Association Study

Abstract

Background & aims: We conducted a genome-wide association study (GWAS) to discover genetic variants associated with hepatitis C virus (HCV)-related hepatocellular carcinoma (HCC).

Methods: We genotyped 502 HCC cases and 749 non-HCC controls by using the Axiom^TM-CHB genome-wide array. After identifying single nucleotide polymorphism (SNP) cluster located in the human leukocyte antigen region which were potentially associated with HCC, HLA-DQB1 genotyping was performed to analyze 994 anti-HCV seropositives collected in the period of 1991-2013 in a community-based cohort for evaluating long-term predictability of HLA variants for identifying the risk of HCC. Cox proportional hazards models were used to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs) of HLA genotypes for determining the aforementioned HCC risk.

Results: Eight SNPs in the proximity of HLA-DQB1 were associated with HCC (p < 8.7 × 10⁻⁸) in GWAS. Long-term follow-up showed a significant association with HLA-DQB1*03:01 and DQB1*06:02 (p < 0.05). The adjusted HRs associated with HCC were 0.45 (0.30-0.68) and 2.11 (1.34-3.34) for DQB1*03:01 and DQB1*06:02, respectively. After stratification by HCV genotypes, DQB1*03:01 showed protective effects only in patients with HCV genotype 1, whereas DQB1*06:02 conferred risk of HCC only in patients with HCV non-1 genotypes. HLA imputation analyses revealed that HLA-DRB1*15:01, which is in linkage disequilibrium with DQB1*06:02, also increased the risk of HCC (odds ratio = 1.96, 95% CI = 1.31-2.93). Haplotype analysis supported that DQB1*03:01 and DQB1*06:02 are primary protective and susceptible variants, respectively.

Conclusions: HLA-DQB1 was independently associated with HCC. HCV genotypes modified the effects of HLA-DQB1 on the risk of HCC. This article is protected by copyright. All rights reserved.

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In Reply To: Xue et al. “Developing a Prediction Model for Cardiovascular Risk after Orthotopic Liver Transplantation”

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The interplay of type I and type II interferons in murine autoimmune cholangitis as a basis for sex-biased autoimmunity

Abstract

We have reported a murine model of autoimmune cholangitis, generated by altering the AU rich element by deletion of the IFN-γ 3'UTR region (coined ARE-Del^-/-), that has striking similarities to human primary biliary cholangitis (PBC) with female predominance. Previously, we suggested that the gender bias of autoimmune cholangitis was secondary to intense and sustained type I and II IFN signaling. Based on this thesis, and to define the mechanisms that lead to portal inflammation, we specifically addressed the hypothesis that type I IFNs are the driver of this disease. To accomplish these goals, we crossed ARE-Del^-/- mice with IFN type I receptor alpha chain (Ifnar1) knockout mice. We report herein that loss of type I IFN receptor signaling in the double construct of ARE-Del^-/- Ifnar1^-/- mice dramatically reduces liver pathology and abrogated gender bias. More importantly, female ARE-Del^-/- mice have an increased number of germinal center (GC) B cells as well as abnormal follicular formation, sites which have been implicated in loss of tolerance. Deletion of type I IFN signaling in ARE-Del^-/- Ifnar1^-/- mice corrects these GC abnormalities, including abnormal follicular structure. In conclusion, our data implicate type I IFN signaling as a necessary component of the gender bias of this murine model of autoimmune cholangitis. Importantly these data suggest that drugs that target the type I IFN signaling pathway would have potential benefit in the earlier stages of PBC. This article is protected by copyright. All rights reserved.

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Radiosensitization by inhibiting DNA repair – turning the spotlight on homologous recombination

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Developing a Prediction Model for Cardiovascular Risk after Orthotopic Liver Transplantation

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Solving doubts about L-Ornithine L-Aspartate for overt HE: whom and how to treat

Abstract

Randomized controlled trials about the treatment of bouts of overt hepatic encephalopathy (OHE) are difficult to design and interpret, since bouts of OHE i) are relatively short episodes in which the dynamic of the response to treatment is relevant, ii) their occurrence and treatment is frequently linked to precipitating events. The study by Sidhu et al. in this issue of Hepatology is a model of proper design and provides evidence that L-ornithine-L-aspartate infusion for 5 days is an effective add on treatment to speed up recovery from bouts of OHE in comparison with a placebo treatment that does not contain amino acid nutrients. This article is protected by copyright. All rights reserved.

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Late hepatitis B reactivation following DAA-based treatment of recurrent hepatitis C in an anti-HBc-positive liver transplant recipient

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Graft-infiltrating PD-L1hi cross-dressed dendritic cells regulate anti-donor T cell responses in mouse liver transplant tolerance

Abstract

While a key role of cross-dressing has been established in immunity to viral infection and more recently in the instigation of transplant rejection, its role in tolerance is unclear. Here, we investigated the role of intra-graft dendritic cells (DC) and cross-dressing in mouse major histocompatibility complex (MHC)-mismatched liver transplant tolerance that occurs without therapeutic immunosuppression. While donor interstitial DC diminished rapidly following transplantation, they were replaced in the liver by host DC that peaked on postoperative day (POD) 7 and persisted indefinitely. About 60% of these recipient DC displayed donor MHC class I, indicating cross-dressing. By contrast, only a very minor fraction (0-2%) of cross-dressed DC (CD-DC) was evident in the spleen. CD-DC sorted from liver grafts expressed much higher levels of T cell inhibitory programed death ligand 1 (PD-L1) and high levels of IL-10 compared with non CD-DC (nCD-DC) isolated from the graft. Concomitantly, high incidences of programed death protein 1 (PD-1)^hi T cell immunoglobulin and mucin domain containing-3 (TIM-3)⁺ exhausted graft-infiltrating CD8⁺ T cells were observed. Importantly, unlike nCD-DC, the CD-DC failed to stimulate proliferation of allogeneic T cells but markedly suppressed anti-donor host T cell proliferation. CD-DC were much less evident in allografts from DNAX-activating protein of 12kDa (DAP12)^-/- donors that were rejected acutely. Conclusion: These findings suggest that graft-infiltrating PD-L1^hi CD-DC may play a key role in the regulation of alloimmunity and in the induction of liver transplant tolerance. This article is protected by copyright. All rights reserved.

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Changes in trust and the use of Korean medicine in South Korea: a comparison of surveys in 2011 and 2014

Korean medicine (KM) has been widely used in Korea. This study aimed to assess the general perceptions of KM, to investigate the patterns of its usage in 2014, and to compare the results with those of an earli...

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Plectranthus amboinicus essential oil and carvacrol bioactive against planktonic and biofilm of oxacillin- and vancomycin-resistant Staphylococcus aureus

The emergence of multidrug-resistant bacteria is a worldwide concern and in order to find an alternative to this problem, the occurrence of antimicrobial compounds in Plectranthus amboinicus essential oil was inv...

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Cancer-specific mortality of high-risk prostate cancer after carbon-ion radiotherapy plus long-term androgen deprivation therapy

Abstract

The treatment outcomes of patients with high-risk localized prostate cancer (PC) after carbon-ion radiotherapy (CIRT) combined with long-term androgen deprivation therapy (LTADT) were analyzed, and compared with those of other treatment modalities, focusing on PC-specific mortality (PCSM). A total of 1247 patients were enrolled in three phase II clinical trials of fixed-dose CIRT between 2000 and 2013. Excluding patients with T4 disease, 608 patients with high- or very-high-risk PC, according to the National Comprehensive Cancer Network classification system, who received CIRT with LTADT were evaluated.

The median follow-up was 88.4 months, and the 5-/10-year PCSM rates were 1.5%/4.3%, respectively. T3b disease, Gleason score of 9-10, and percentage of positive biopsy cores > 75% were associated with significantly higher PCSM on univariate and multivariate analyses. The 10-year PCSM rates of patients having all three (n=16), two (n=74), or one of these risk factors (n=217) were 27.1%, 11.6%, and 5.7%, respectively. Of the 301 patients with none of these factors, only 1 PCSM occurred over the 10-year follow-up (10-year PCSM rate, 0.3%), and significant differences were observed among the four stratified groups (p < 0.001).

CIRT combined with LTADT yielded relatively favorable treatment outcomes in patients with high-risk PC and very favorable results in patients without any of the three abovementioned factors for PCSM. Because a significant difference in PCSM among the high-risk PC patient groups was observed, new categorization and treatment intensity adjustment may be required for high-risk PC patients treated with CIRT.

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The miR-203 inhibits cell proliferation, invasion, and migration of non-small cell lung cancer by downregulating RGS17

Abstract

The involvement of the RGS17 oncogene in promotion of non-small cell lung cancer (NSCLC) has been reported, but the regulation mechanism in NSCLC remains unclear. MicroRNAs (miRNAs) negatively regulate gene expression, and their dysregulation has been implicated in tumorigenesis. To understand the role of microRNAs in RGS17-induced NSCLC, we showed that miR-203 was downregulated during tumorigenesis, and inhibited the proliferation and invasion of lung cancer cells. We then determined if miR-203 regulated NSCLC by targeting RGS17. To characterize the regulatory effect of miR-203 on RGS17, we used lung cancer cell lines, A549 and Calu-1, and the constructed miR-203 and RGS17 overexpression vectors. The CCK8 kit was used to determine the cell proliferation, and the Transwell^® assay was used to measure cell invasion and migration. RT-PCR, western blots, and immunofluorescence were used to analyze the expression of miR-203 and RGS17, and the luciferase reporter assay was used to examine the interaction between miR-203 and RGS17. Nude mice were used to characterize in vivo tumor growth regulation. The expression of miR-203 inhibited the proliferation, invasion, and migration of lung cancer cell lines A549 and Calu-1 by targeting RGS17. The regulatory effect of miR-203 was inhibited after overexpression of RGS17. The luciferase reporter assay showed that miR-203 downregulated RGS17 by direct integration into the 3′-UTR of RGS17 mRNA. In vivo studies showed that the expression of miR-203 significantly inhibited the growth of tumors. Taken together, the results suggested that the expression of miR-203 inhibited tumor growth and metastasis by targeting RGS17.

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Implementation and preliminary clinical outcomes of a pharmacist-managed venous thromboembolism clinic for patients treated with rivaroxaban post emergency department discharge

Abstract

Objective

To describe the implementation, work flow, and differences in outcomes between a pharmacist-managed clinic for the outpatient treatment of venous thromboembolism (VTE) using rivaroxaban versus care by a primary care provider.

Interventions

Patients in the studied health system that are diagnosed with low-risk VTE in the emergency department are often discharged without hospital admission. These patients are treated with rivaroxban and follow up either in a pharmacist-managed VTE clinic or with their primary care provider. Pharmacists in the VTE clinic work independently under a collaborative practice agreement. An evaluation of thirty-four patients, seventeen in each treatment arm, was conducted to compare the differences in treatment-related outcomes of rivaroxaban when managed by a pharmacist versus a primary care provider.

Results

The primary endpoint was a six month composite of anticoagulation treatment-related complications that included a diagnosis of major bleeding, recurrent thromboembolism, or fatality due to either major bleeding or recurrent thromboembolism. Secondary endpoints included number of hospitalizations, adverse events, and medication adherence. There was no difference in the primary endpoint between groups with one occurrence of the composite endpoint in each treatment arm (p=1.000), both of which were recurrent thromboembolic events. Medication adherence assessment was formally performed in 8 patients in the pharmacist group versus 0 patients in the control group. No differences were seen amongst other secondary endpoints.

Conclusions

The pharmacist-managed clinic is a novel expansion of clinical pharmacy services that treats patients with low-risk VTEs with rivaroxaban in the outpatient setting. The evaluation of outcomes provides support that pharmacist-managed care utilizing standardized protocols under a collaborative practice agreement may be as safe as care by a primary care provider.

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Bacterial strategies along nutrient and time gradients, revealed by metagenomic analysis of laboratory microcosms.

Abstract

There is considerable interest in the functional basis of ecological strategies amongst bacteria. We used laboratory microcosms based on culturing of elutant from soil, to study the effects of varying initial nutrient concentration, and time succession, on the community metagenome. We found a distinct set of nutrient related or time related changes in the functional metagenome. For example a high nutrient (copiotrophic) strategy was associated with greater abundance of genes related to cell division and cell cycle, while a low nutrient (oligotrophic) strategy had greater abundance of genes related to carbohydrate metabolism and virulence, disease and defense. We also found time related changes in the functional metagenome, revealing a distinct 'r' related strategy with greater abundance of genes related to regulation and cell signaling, and a 'K' strategy rich in motility and chemotaxis related genes. These different gene-based strategies may help to explain how so many bacterial OTUs coexist in nature, and the functional principles dominating natural communities. In terms of diversity, both the OTU richness and the richness of species assignment of functional genes showed linear correlations with functional gene richness, supporting the hypothesis that greater taxonomic diversity is associated with greater functional diversity, with possible implications for ecosystem stability.

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HLA class I expression predicts prognosis and therapeutic benefits from tyrosine kinase inhibitors in metastatic renal-cell carcinoma patients

Abstract

Purpose

Classical HLA class I antigen is highly involved in antigen presentation and adaptive immune response against tumor. In this study, we explored its predictive value for treatment response and survival in metastatic renal-cell carcinoma (mRCC) patients.

Experimental design

A TKI cohort of 111 mRCC patients treated with sunitinib or sorafenib and a non-TKI cohort of 160 mRCC patients treated with interleukin-2 or interferon-α-based immunotherapy at a single institution were retrospectively enrolled. HLA class I expression and cytotoxic T lymphocyte (CTL) density was assessed by immunohistochemistry on tissue microarrays. Association between HLA class I and CTL was also assessed in the TCGA KIRC cohort.

Results

In the TKI cohort, down-regulated HLA class I was associated with lower objective response rate of TKI therapy (P = 0.004), shorter overall survival (OS) (P = 0.001), and shorter progression free survival (PFS) (P < 0.001). Multivariate Cox regression model defined HLA expression as an independent prognostic factor for both OS [hazard ratio 1.687 (95% CI 1.045–2.724), P = 0.032] and PFS [hazard ratio 2.139 (95% CI 1.376–3.326), P = 0.001]. In the non-TKI cohort, HLA class I was not significantly associated with survival. HLA class I expression was associated with CTL infiltration and function, and its prognostic value was more predominant in CTL high-density tumors (P < 0.001) rather than CTL low-density tumors (P = 0.294).

Conclusions

Classical HLA class I expression can serve as a potential predictive biomarker for TKI therapy in mRCC patients. Its predictive value was restricted in CTL high-density tumors. However, further external validations and functional investigations are still required.

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HLA class I expression predicts prognosis and therapeutic benefits from tyrosine kinase inhibitors in metastatic renal-cell carcinoma patients

Abstract

Purpose

Classical HLA class I antigen is highly involved in antigen presentation and adaptive immune response against tumor. In this study, we explored its predictive value for treatment response and survival in metastatic renal-cell carcinoma (mRCC) patients.

Experimental design

A TKI cohort of 111 mRCC patients treated with sunitinib or sorafenib and a non-TKI cohort of 160 mRCC patients treated with interleukin-2 or interferon-α-based immunotherapy at a single institution were retrospectively enrolled. HLA class I expression and cytotoxic T lymphocyte (CTL) density was assessed by immunohistochemistry on tissue microarrays. Association between HLA class I and CTL was also assessed in the TCGA KIRC cohort.

Results

In the TKI cohort, down-regulated HLA class I was associated with lower objective response rate of TKI therapy (P = 0.004), shorter overall survival (OS) (P = 0.001), and shorter progression free survival (PFS) (P < 0.001). Multivariate Cox regression model defined HLA expression as an independent prognostic factor for both OS [hazard ratio 1.687 (95% CI 1.045–2.724), P = 0.032] and PFS [hazard ratio 2.139 (95% CI 1.376–3.326), P = 0.001]. In the non-TKI cohort, HLA class I was not significantly associated with survival. HLA class I expression was associated with CTL infiltration and function, and its prognostic value was more predominant in CTL high-density tumors (P < 0.001) rather than CTL low-density tumors (P = 0.294).

Conclusions

Classical HLA class I expression can serve as a potential predictive biomarker for TKI therapy in mRCC patients. Its predictive value was restricted in CTL high-density tumors. However, further external validations and functional investigations are still required.

http://ift.tt/2x7d4Kd

Concurrent Improvement in Both Binge Eating and Depressive Symptoms with Naltrexone/Bupropion Therapy in Overweight or Obese Subjects with Major Depressive Disorder in an Open-Label, Uncontrolled Study

Abstract

Introduction

Binge eating disorder (BED) is associated with obesity and major depressive disorder (MDD). Naltrexone extended-release (ER)/bupropion ER (NB) is approved as an adjunct to diet and physical activity for chronic weight management. In a prospectively designed 24-week open-label, single-arm, single-site trial of 25 women with MDD and overweight/obesity, NB reduced weight and depressive symptoms.

Methods

This post hoc analysis investigated the relationship between change in self-reported binge eating behavior (evaluated with the Binge Eating Scale [BES]) and changes in weight, control of eating, and depressive symptoms.

Results

At baseline, 91% of subjects had moderate or severe BES scores, suggesting BED. BES scores were significantly improved from week 4, and by week 24, 83% reported "little or no problem." Improvement in BES scores correlated with improvement in depressive symptoms and control of eating.

Conclusion

NB may be effective in reducing binge eating symptoms associated with MDD and overweight/obesity. Evaluation of NB in BED appears warranted.

Funding

Orexigen Therapeutics, Inc.

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Ocular parameters before and after steep Trendelenburg positioning for robotic-assisted laparoscopic radical prostatectomy

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Do prehospital providers and emergency nurses agree on triage assignment?: an efficacy study.

Objectives: The aim of this study was to investigate the agreement on triage level between prehospital providers and emergency department (ED) nurses in clinical practice when using the same triage system. The objectives were as follows: (a) What is the agreement of triage between prehospital providers and ED nurses, when using Danish Emergency Process Triage (DEPT) correctly? (b) Which part of the triage process yields the highest agreement regarding the final triage? Methods: The study was a prospective and observational efficacy study. Patients transported to the ED by ambulances were included. They were triaged by prehospital providers while being transported by ambulance to the ED, and by ED nurses upon arrival. Triage was done using the DEPT - a five-level triage system based on vital signs and a presenting complaint algorithm. An agreement analysis was performed. Results: DEPT was used correctly by both professions in 292 patients. In 182 (62%) patients the prehospital providers and the ED nurses agreed on the same triage level. This equals to [kappa]=0.47 [95% confidence interval (CI): 0.41-0.56]. When considering the triage based on vital signs the agreement was 72% ([kappa]=0.46; 95% CI: 0.41-0.47), and based on presenting complaint the agreement was 46% ([kappa]=0.41; 95% CI: 0.37-0.44). Conclusion: There was a moderate interrater agreement on triage assignment between ED nurses and prehospital providers. They agreed on final triage more often if they agreed on triage based on vital signs rather than presenting complaints. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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Clinical update regarding general anesthesia-associated neurotoxicity in infants and children.

Purpose of review: The U.S. Federal Drug Administration (FDA) recently released a warning stating that 'repeated or lengthy use of general anesthetic and sedation drugs during surgeries or procedures in children younger than 3 years or in pregnant women during their third trimester may affect the development of children's brains' ( http://ift.tt/2x7Abo0). The goal of this article is to review the most recent clinical studies which provide evidence that these concerns may be overstated for the majority of healthy young children who require surgery and anesthesia. Recent findings: Three large retrospective matched cohort studies published within the past year provide data on a total of 59 814 children exposed to general anesthesia before age 4 (including 30 021

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Complications and unplanned admissions in nonoperating room procedures.

Purpose of review: The purpose of this article is to review complications and unplanned hospital admissions in patients presenting for ambulatory procedures requiring anesthesia care in the gastrointestinal endoscopy, bronchoscopy, and radiology suites. Recent findings: The range of ambulatory diagnostic and therapeutic procedures being undertaken in the gastrointestinal endoscopy, bronchoscopy, and radiology suites is expanding rapidly. Recent observational studies in gastrointestinal endoscopy confirm low incidences of complications and unplanned admissions. Deep propofol-based sedation is associated with more complications than lighter sedation. Older patients suffer more complications but obstructive sleep apnea does not appear to increase risk. Sedation improves patient comfort during bronchoscopy. Propofol-based sedation is associated with fewer complications than benzodiazepine-based sedation, but all combinations are associated with high patient satisfaction. Obesity and obstructive sleep apnea are not associated with worse outcomes in bronchoscopy patients. Sedation is increasingly required for interventions in the radiology suite. When patients are involved in choosing sedation depth, there is a trend to lighter sedation and high patient satisfaction. Summary: Sedation and anesthesia are required for the increasing number of increasingly complex procedures being undertaken outside the operating suite. Large randomized trials are required to define the optimum sedation drugs, sedation depth and sedation provider. Copyright (C) 2017 YEAR Wolters Kluwer Health, Inc. All rights reserved.

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miR-122 Promotes Metastasis of Clear-Cell Renal Cell Carcinoma by Downregulating Dicer

Abstract

Although overall downregulation of microRNAs (miRNAs) is a general feature of clear-cell renal cell carcinoma (ccRCC), several miRNAs are consistently upregulated, among which miR-122 was markedly increased in ccRCC tissues. This study aims to determine the functional importance and underlying mechanism of miR-122 in ccRCC metastasis. Here we demonstrate that the expression of miR-122 increased in ccRCC tissues, and higher miR-122 expression was found in ccRCC tissues with metastatic disease than in those without metastasis. The increased miR-122 levels were associated with poor metastasis-free survival in ccRCC patients with localized disease. Dicer was validated as a direct functional target of miR-122. Overexpression of miR-122 promoted migration and invasion of ccRCC cells in vitro and metastatic behavior of ccRCC cells in vivo. Inhibition of miR-122 attenuated this metastatic phenotype in vitro. Importantly, miR-122 exerted its pro-metastatic properties in ccRCC cells by downregulating Dicer and its downstream effector, the miR-200 family, thereby inducing epithelial–mesenchymal transition (EMT). Our results suggest an important role of the miR-122/Dicer/miR-200s/EMT pathway in ccRCC metastasis. Furthermore, miR-122 may serve as a biomarker for discriminating ccRCC with metastatic potential. This article is protected by copyright. All rights reserved.

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Contralateral Breast Cancers: Independent Cancers or Metastases?

Abstract

A cancer in the contralateral breast in a woman with a previous or synchronous breast cancer is typically considered to be an independent primary tumor. Emerging evidence suggests that in a small subset of these cases the second tumor represents a metastasis. We sought to investigate the issue using massively parallel sequencing targeting 254 genes recurrently mutated in breast cancer. We examined the tumor archives at Memorial Sloan Kettering Cancer Center for the period 1995-2006 to identify cases of contralateral breast cancer where surgery for both tumors was performed at the Center. We report results from 49 patients successfully analyzed by a targeted massively parallel sequencing assay. Somatic mutations and copy number alterations were defined by state-of-the-art algorithms. Clonal relatedness was evaluated by statistical tests specifically designed for this purpose. We found evidence that the tumors in contralateral breasts were clonally related in 3 cases (6%) on the basis of matching mutations at codons where somatic mutations are rare. Clinical data and the presence of similar patterns of gene copy number alterations were consistent with metastasis for all 3 cases. In 3 additional cases there was a solitary matching mutation at a common PIK3CA locus. The results suggest that a subset of contralateral breast cancers represent metastases rather than independent primary tumors. Massively parallel sequencing analysis can provide important evidence to clarify the diagnosis. However, given the inter-tumor mutational heterogeneity in breast cancer, sufficiently large gene panels need to be employed to define clonality convincingly in all cases. This article is protected by copyright. All rights reserved.

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The impact of P-glycoprotein and Breast Cancer Resistance Protein on the brain pharmacokinetics and pharmacodynamics of a panel of MEK inhibitors

Abstract

Mitogen/extracellular signal-regulated kinase (MEK) inhibitors have been tested in clinical trials for treatment of intracranial neoplasms, including glioblastoma (GBM), but efficacy of these drugs has not yet been demonstrated. The blood-brain barrier (BBB) is a major impediment to adequate delivery of drugs into the brain and may thereby also limit the successful implementation of MEK inhibitors against intracranial malignancies. The BBB is equipped with a range of ATP-dependent efflux transport proteins, of which P-gp (ABCB1) and BCRP (ABCG2) are the two most dominant for drug efflux from the brain. We investigated their impact on the pharmacokinetics and target engagement of a panel of clinically applied MEK inhibitors, in order to select the most promising candidate for brain cancers in the context of clinical pharmacokinetics and inhibitor characteristics. To this end, we used in vitro drug transport assays and conducted pharmacokinetic and pharmacodynamic studies in wildtype and ABC-transporter knockout mice. PD0325901 displayed more promising characteristics than trametinib (GSK1120212), binimetinib (MEK162), selumetinib (AZD6244) and pimasertib (AS703026): PD0325901 was the weakest substrate of P-gp and BCRP in vitro, its brain penetration was only marginally higher in Abcb1a/b;Abcg2^-/- mice, and efficient target inhibition in the brain could be achieved at clinically relevant plasma levels. Notably, target inhibition could also be demonstrated for selumetinib, but only at plasma levels far above levels in patients receiving the maximum tolerated dose. In summary, this study recommends further development of PD0325901 for the treatment of intracranial neoplasms. This article is protected by copyright. All rights reserved.

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Neuroblastoma cells undergo transcriptomic alterations upon dissemination into the bone marrow and subsequent tumor progression

Abstract

Neuroblastoma is the most common extracranial solid tumor in childhood. The vast majority of metastatic (M) stage patients present with disseminated tumor cells (DTCs) in the bone marrow (BM) at diagnosis and relapse. Although these cells represent a major obstacle in the treatment of neuroblastoma patients, insights into their expression profile remained elusive. The present RNA-Seq study of stage 4/M primary tumors, enriched BM-derived diagnostic and relapse DTCs, as well as the corresponding BM-derived mononuclear cells (MNCs) from 53 patients revealed 322 differentially expressed genes in DTCs as compared to the tumors (q < 0.001, |log₂FC|>2). Particularly the levels of transcripts encoded by mitochondrial DNA were elevated in DTCs, whereas e.g. genes involved in angiogenesis were down-regulated. Furthermore, 224 genes were highly expressed in DTCs and only slightly, if at all, in MNCs (q < 8x10⁻⁷⁵ log₂FC > 6). Interestingly, we found the transcriptome of relapse DTCs largely resembling those of diagnostic DTCs with only 113 differentially expressed genes under relaxed cut-offs (q < 0.01, |log₂FC|>0.5). Notably, relapse DTCs showed a positional enrichment of 31 down-regulated genes on chromosome 19, including five tumor suppressor genes: SIRT6, BBC3/PUMA, STK11, CADM4 and GLTSCR2.

This first RNA-Seq analysis of neuroblastoma DTCs revealed their unique expression profile in comparison to the tumors and MNCs, and less pronounced differences between diagnostic and relapse DTCs. The latter preferentially affected down-regulation of genes encoded by chromosome 19. As these alterations might be associated with treatment failure and disease relapse, further functional studies on DTCs should be considered. This article is protected by copyright. All rights reserved.

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Ingested nitrate and nitrite, disinfection by-products, and pancreatic cancer risk in postmenopausal women

Abstract

Nitrate and nitrite are precursors of N-nitroso compounds (NOC), probable human carcinogens that cause pancreatic tumors in animals. Disinfection by-products (DBP) exposures have also been linked with digestive system cancers, but few studies have evaluated relationships with pancreatic cancer. We investigated the association of pancreatic cancer with these drinking water contaminants and dietary nitrate/nitrite in a cohort of postmenopausal women in Iowa (1986-2011). We used historical monitoring and treatment data to estimate levels of long-term average nitrate and total trihalomethanes (TTHM; the sum of the most prevalent DBP class) and the duration exceeding one-half the maximum contaminant level (>½ MCL; nitrate-nitrogen 5mg/L, 40µg/L TTHM) among participants on public water supplies (PWS) >10 years. We estimated dietary nitrate and nitrite intakes using a food frequency questionnaire. We computed hazard ratios (HR) and 95% confidence intervals (CI) using Cox regression and evaluated nitrate interactions with smoking and vitamin C intake. We identified 313 cases among 34,242 women, including 152 with >10 years PWS use (N=15,710). Multivariable models of average nitrate showed no association with pancreatic cancer (HR_p95vs.Q1=1.16, 95%CI: 0.51-2.64). Associations with average TTHM levels were also null (HR_Q4vsQ1=0.70, 95%CI:0.42-1.18). We observed no trend with increasing years of exposure to either contaminant at levels >½ MCL. Positive associations were suggested in the highest dietary nitrite intake from processed meat (HR_p95vs.Q1=1.66, 95% CI 1.00-2.75;p_trend=0.05). We found no interactions of nitrate with known modifiers of endogenous NOC formation. Our results suggest that nitrite intake from processed meat may be a risk factor for pancreatic cancer. This article is protected by copyright. All rights reserved.

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A naive Bayes algorithm for tissue origin diagnosis (TOD-Bayes) of synchronous multifocal tumors in the hepatobiliary and pancreatic system

Abstract

Synchronous multifocal tumors are common in the hepatobiliary and pancreatic system but because of similarities in their histological features, oncologists have difficulty in identifying their precise tissue clonal origin through routine histopathological methods. To address this problem and assist in more precise diagnosis, we developed a computational approach for tissue origin diagnosis based on naive Bayes algorithm (TOD-Bayes) using ubiquitous RNA-Seq data. Massive tissue-specific RNA-Seq data sets were first obtained from The Cancer Genome Atlas (TCGA) and ∼1,000 feature genes were used to train and validate the TOD-Bayes algorithm. The accuracy of the model was > 95% based on 10-fold cross validation by the data from TCGA. A total of 18 clinical cancer samples (including 6 negative controls) with definitive tissue origin were subsequently used for external validation and 17 of the 18 samples were classified correctly in our study (94.4%). Furthermore, we included as cases studies seven tumor samples, taken from two individuals who suffered from synchronous multifocal tumors across tissues, where the efforts to make a definitive primary cancer diagnosis by traditional diagnostic methods had failed. Using our TOD-Bayes analysis, the two clinical test cases were successfully diagnosed as pancreatic cancer (PC) and cholangiocarcinoma (CC), respectively, in agreement with their clinical outcomes. Based on our findings, we believe that the TOD-Bayes algorithm is a powerful novel methodology to accurately identify the tissue origin of synchronous multifocal tumors of unknown primary cancers using RNA-Seq data and an important step towards more precision-based medicine in cancer diagnosis and treatment. This article is protected by copyright. All rights reserved.

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Tumor-suppressive miR-145 co-repressed by TCF4-β-catenin and PRC2 complexes forms double-negative regulation loops with its negative regulators in colorectal cancer

Abstract

The frequently dysregulated Wnt/β-catenin signaling in different malignancies, by activation of its own or orchestration with other co-factors, regulates various oncogenic or tumor-suppressive genes. Among these genes, miRNAs, which are negative posttranscriptional regulators, are also embedded in the Wnt signaling network. Different from the Wnt-induced oncogenic miRNAs, the specific mechanism underlying the Wnt-repressed tumor-suppressive miRNAs is much less understood. In the present study, firstly by analyzing a ChIP-seq dataset against TCF4, the core transcription factor for initiation of Wnt signaling in colorectal cancer (CRC) cells, we screened out several tumor-suppressive miRNAs potentially regulated by Wnt signaling. Then through siRNA mediated knock-down tests and protein and chromatin immunoprecipitations, we found the TCF4-β-catenin complex can recruit the histone trimethylation complex PRC2 as a co-repressor while binding to the TCF4-binding element (TBE) in the promoter regions of miR-145, miR-132 and miR-212. Thus, upon Wnt signaling activation, the PRC2-mediated trimethylation of histone H3 at lysine 27 increases at these promoter regions, leading to decreased miRNA levels. Furthermore, we found that by targeting TCF4 and SUZ12, the key components of the negative regulation complexes, the tumor-suppressive miR-145 co-repressed by Wnt signaling and histone trimethylation, forms double-negative regulation loops with its negative regulators in CRC cells. And the inverse associations between miR-145 and its targets/negative regulators have also been demonstrated in nude mice and clinical samples. Collectively, we elucidated the detailed molecular mechanism of how dysregulated Wnt/β-catenin signaling and tumor-suppressive miRNAs reciprocally regulate each other in CRC cells. This article is protected by copyright. All rights reserved.

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Dacomitinib-induced diarrhea: Targeting chloride secretion with crofelemer

Abstract

Dacomitinib, an irreversible small-molecule pan-ErbB TKI, has a high incidence of diarrhea which has been suggested to be due to chloride secretory mechanisms. Based on this hypothesis, crofelemer, an anti-secretory agent may be an effective intervention. T84 monolayers were treated with 1µM dacomitinib and 10µM crofelemer, and mounted into Ussing chambers for electrogenic ion analysis. Crofelemer attenuated increases in chloride secretion in cells treated with dacomitinib. Albino Wistar rats (n=48) were treated with 7.5 mg/kg dacomitinib and/or 25 mg/kg crofelemer via oral gavage for 21 days. Crofelemer significantly worsened dacomitinib-induced diarrhea (p=0.0003), and did not attenuate weight loss (p<0.0001). Sections of the ileum and colon were mounted into Ussing chambers, and secretory processes analyzed. This indicated that crofelemer lost its anti-secretory action in the presence of dacomitinib in this model. Mass spectrometry revealed that crofelemer did not change serum concentration of dacomitinib. Serum FITC dextran levels indicated that crofelemer was unable to attenuate dacomitinib-induced barrier dysfunction. Tight junction proteins were visualized with immunofluorescence. Qualitative analysis showed dacomitinib induced proteolysis of ZO-1 and occludin, and internalization of claudin-1, which was not attenuated by crofelemer. Detailed histopathological analysis showed that crofelemer was unable to attenuate dacomitinib-induced ileal damage. Crofelemer worsened dacomitinib-induced diarrhea, suggesting that antisecretory drug therapy may be ineffective in this setting. This article is protected by copyright. All rights reserved.

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Associations of alcohol intake, smoking, physical activity and obesity with survival following colorectal cancer diagnosis by stage, anatomic site and tumor molecular subtype

Abstract

The influence of lifestyle factors on survival following a diagnosis of colorectal cancer (CRC) is not well established. We examined associations between lifestyle factors measured before diagnosis and CRC survival. The Melbourne Collaborative Cohort Study collected data on alcohol intake, cigarette smoking and physical activity, and body measurements at baseline (1990-94) and wave 2 (2003-07). We included participants diagnosed to 31 August 2015 with incident stage I-III CRC within 10-years post exposure assessment. Information on tumor characteristics and vital status was obtained. Tumor DNA was tested for microsatellite instability (MSI) and somatic mutations in oncogenes BRAF (V600E) and KRAS. We estimated hazard ratios (HRs) for associations between lifestyle factors and overall and CRC-specific mortality using Cox regression. Of 724 eligible CRC cases, 339 died (170 from CRC) during follow-up (average 9.0 years). Exercise (non-occupational/leisure-time) was associated with higher CRC-specific survival for stage II (HR = 0.25, 95% CI: 0.10-0.60) but not stage I/III disease (p for interaction = .01), and possibly for colon and KRAS wild-type tumors. Waist circumference was inversely associated with CRC-specific survival (HR = 1.25 per 10 cm increment, 95% CI: 1.08-1.44), independent of stage, anatomic site and tumor molecular status. Cigarette smoking was associated with lower overall survival, with suggestive evidence of worse survival for BRAF mutated CRC, but not with CRC-specific survival. Alcohol intake was not associated with survival. Survival did not differ by MSI status. We have identified pre-diagnostic predictors of survival following CRC that may have clinical and public health relevance. This article is protected by copyright. All rights reserved.

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Exercise prescription for patients with multiple sclerosis; potential benefits and practical recommendations

Multiple sclerosis (MS) can result in significant mental and physical symptoms, specially muscle weakness, abnormal walking mechanics, balance problems, spasticity, fatigue, cognitive impairment and depression...

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Tumor regression grading of gastrointestinal cancers after neoadjuvant therapy

Abstract

Neoadjuvant therapy has been successfully introduced in the treatment of locally advanced gastrointestinal malignancies, particularly esophageal, gastric, and rectal cancers. The effects of preoperative chemo- or radiochemotherapy can be determined by histopathological investigation of the resection specimen following this treatment. Frequent histological findings after neoadjuvant therapy include various amounts of residual tumor, inflammation, resorptive changes with infiltrates of foamy histiocytes, foreign body reactions, and scarry fibrosis. Several tumor regression grading (TRG) systems, which aim to categorize the amount of regressive changes after cytotoxic treatment in primary tumor sites, have been proposed for gastroesophageal and rectal carcinomas. These systems primarily refer to the amount of therapy-induced fibrosis in relation to the residual tumor (e.g., the Mandard, Dworak, or AJCC systems) or the estimated percentage of residual tumor in relation to the previous tumor site (e.g., the Becker, Rödel, or Rectal Cancer Regression Grading systems). TRGs provide valuable prognostic information, as in most cases, complete or subtotal tumor regression after neoadjuvant treatment is associated with better patient outcomes. This review describes the typical histopathological findings after neoadjuvant treatment, discusses the most commonly used TRG systems for gastroesophageal and rectal carcinomas, addresses the limitations and critical issues of tumor regression grading in these tumors, and describes the clinical impact of TRG.

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Apoptotic mechanisms after repeated noise trauma in the mouse medial geniculate body and primary auditory cortex

Abstract

A correlation between noise-induced apoptosis and cell loss has previously been shown after a single noise exposure in the cochlear nucleus, inferior colliculus, medial geniculate body (MGB) and primary auditory cortex (AI). However, repeated noise exposure is the most common situation in humans and a major risk factor for the induction of noise-induced hearing loss (NIHL). The present investigation measured cell death pathways using terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) in the dorsal, medial and ventral MGB (dMGB, mMGB and vMGB) and six layers of the AI (AI-1 to AI-6) in mice (NMRI strain) after a second noise exposure (double-exposure group). Therefore, a single noise exposure group has been investigated 7 (7-day-group-single) or 14 days (14-day-group-single) after noise exposure (3 h, 5–20 kHz, 115 dB SPL peak-to-peak). The double-exposure group received the same noise trauma for a second time 7 days after the initial exposure and was either TUNEL-stained immediately (7-day-group-double) or 1 week later (14-day-group-double) and data were compared to the corresponding single-trauma group as well as to an unexposed control group. It was shown that TUNEL increased immediately after the second noise exposure in AI-3 and stayed upregulated in the 14-day-group-double. A significant increase in TUNEL was also seen in the 14-day-group-double in vMGB, mMGB and AI-1. The present results show for the first time the influence of a repeated noise trauma on cell death mechanisms in thalamic and cortical structures and might contribute to the understanding of pathophysiological findings and psychoacoustic phenomena accompanying NIHL.

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Objectively Measured Physical Activity and Falls in Well-Functioning Older Adults: Findings From the Baltimore Longitudinal Study of Aging.

Objective: Previous work demonstrates the consequences of falling in older adults and the potential of physical activity (PA) to reduce falls, but few studies have used accelerometer-measured PA to compare overall and time-of-day activity patterns of nonfallers, fallers, or subgroups of fallers. Methods: In 840 participants (mean age, 66.7; s = 13.2; range, 26-97) of the Baltimore Longitudinal Study of Aging between 2007 and 2014, PA was measured objectively with Actiheart accelerometers and falling status (faller/nonfaller) was assessed during an in-person interview. Differences in daily PA and PA by time-of-day were assessed using multiple linear regression. Differences in PA (multiple linear regression), and functional status ([chi]2) were further examined in subgroups of "risky" or "normal" fallers. Results: Overall, fallers and nonfallers exhibited similar daily ([beta] = 22.6, P = 0.48) and time-specific PA; however, those who fell doing risky activities were more active overall ([beta] = 243.8, P = 0.002), during the morning ([beta] = 77.3, P = 0.004), afternoon ([beta] = 78.4, P = 0.001), and late afternoon/evening ([beta] = 56.3, P = 0.006) than those who fell doing normal activities. Risky fallers were significantly higher functioning than normal fallers. Conclusions: Persons who fell while engaging in normal activities exhibited lower PA overall and throughout most of the day, and were of lower functional status than persons who fell while engaging in risky or unusual activities, suggesting that engagement in risky or unusual PA is associated with higher functional ability and lower falls risk in older persons. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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