bluuebunny/crossref_metadata_2025 huggingface dataset:
Protection of intestinal injury during heat stroke in mice by interleukin‐6 pretreatment
Authors: Phillips Neil A. , Welc Steven S. , Wallet Shannon M. , King Michelle A. , Clanton Thomas L.
Published: November 2014

Key points

Heat stroke afflicts thousands of humans each year, worldwide.

The immune system responds to hyperthermia exposure resulting in heat stroke by producing an array of immunological proteins, such as interleukin‐6 (IL‐6). However, the physiological functions of IL‐6 and other cytokines in hyperthermia are poorly understood.

We hypothesized that IL‐6 plays a protective role in conditions of heat stroke. To test this, we gave small IL‐6 supplements to mice prior to exposing them to hot environments sufficient to induce conditions of heat stroke.

Pretreatment with IL‐6 resulted in improved ability to withstand heat exposure in anaesthetized mice, it protected the intestine from injury, reducing the permeability of the intestinal barrier, and it attenuated the release of other cytokines involved in inflammation.

The results support the hypothesis that IL‐6 is a ‘physiological stress hormone’ that plays an important role in survival during acute life‐threatening conditions such as heat stroke.

The role of interleukin‐6 (IL‐6) in hyperthermia and heat stroke is poorly understood. Plasma IL‐6 is elevated following hyperthermia in animals and humans, and IL‐6 knockout mice are more intolerant of severe hyperthermia. We evaluated the effect of IL‐6 supplementation on organ injury following severe hyperthermia exposure in anaesthetized mice. Two hours prior to hyperthermia, mice were treated with 0.6 μg intraperitoneal IL‐6, or identical volumes of saline in controls. Mice were anaesthetized, gavaged with FITC–dextran for measures of gastrointestinal permeability, and exposed to incremental (0.5°C every 30 min) increases in temperature. Heating stopped when maximum core temperature (Tc) of 42.4°C was attained (Tc,max). The mice recovered at room temperature (≈22°C) for 30 or 120 min, at which time plasma and tissues were collected. IL‐6‐treated mice, on average, required ≈25 min longer to attain Tc,max. Injury and swelling of the villi in the duodenum was present in untreated mice after 30 min of recovery. These changes were blocked by IL‐6 treatment. IL‐6 also reduced gastrointestinal permeability, assayed by the accumulation of FITC–dextran in plasma. Plasma cytokines were also attenuated in IL‐6‐treated animals, including significant reductions in TNFα, MCP‐1 (CXCL2), RANTES (CCL5) and KC (CCL5). The results demonstrate that IL‐6 has a protective influence on the pattern of physiological responses to severe hyperthermia, suggesting that early endogenous expression of IL‐6 may provide a protection from the development of organ damage and inflammation.
In vivo roles for myosin phosphatase targeting subunit‐1 phosphorylation sites T694 and T852 in bladder smooth muscle contraction
Authors: Chen Cai‐Ping , Chen Xin , Qiao Yan‐Ning , Wang Pei , He Wei‐Qi , Zhang Cheng‐Hai , Zhao Wei , Gao Yun‐Qian , Chen Chen , Tao Tao , Sun Jie , Wang Ye , Gao Ning , Kamm Kristine E. , Stull James T. , Zhu Min‐Sheng
Published: November 2014

Key points

Force production and maintenance in smooth muscle is largely controlled by myosin regulatory light chain (RLC) phosphorylation, which relies on a balance between Ca2+/calmodulin‐dependent myosin light chain kinase (MLCK) and myosin light chain phosphatase (MLCP) activities.

MYPT1 is the regulatory subunit of MLCP that biochemically inhibits MLCP activity via T694 or T852 phosphorylation in vitro.

Here we separately investigated the contribution of these two phosphorylation sites in bladder smooth muscles by establishing two single point mutation mouse lines, T694A and T852A, and found that phosphorylation of MYPT1 T694, but not T852, mediates force maintenance via inhibition of MLCP activity and enhancement of RLC phosphorylation in vivo.

Our findings reveal the role of MYPT1 T694/T852 phosphorylation in vivo in regulation of smooth muscle contraction.

Force production and maintenance in smooth muscle is largely controlled by different signalling modules that fine tune myosin regulatory light chain (RLC) phosphorylation, which relies on a balance between Ca2+/calmodulin‐dependent myosin light chain kinase (MLCK) and myosin light chain phosphatase (MLCP) activities. To investigate the regulation of MLCP activity in vivo, we analysed the role of two phosphorylation sites on MYPT1 (regulatory subunit of MLCP) that biochemically inhibit MLCP activity in vitro. MYPT1 is constitutively phosphorylated at T694 by unidentified kinases in vivo, whereas the T852 site is phosphorylated by RhoA‐associated protein kinase (ROCK). We established two mouse lines with alanine substitution of T694 or T852. Isolated bladder smooth muscle from T852A mice displayed no significant changes in RLC phosphorylation or force responses, but force was inhibited with a ROCK inhibitor. In contrast, smooth muscles containing the T694A mutation showed a significant reduction of force along with reduced RLC phosphorylation. The contractile responses of T694A mutant smooth muscle were also independent of ROCK activation. Thus, phosphorylation of MYPT1 T694, but not T852, is a primary mechanism contributing to inhibition of MLCP activity and enhancement of RLC phosphorylation in vivo. The constitutive phosphorylation of MYPT1 T694 may provide a mechanism for regulating force maintenance of smooth muscle.
In the beginning: a personal reminiscence on the origin and legacy of ClC‐0, the ‘Torpedo Cl− channel’
Authors: Miller Christopher
Published: November 2014

This unapologetically subjective essay recalls the Torpedo Cl– channel in the years when it had neither a molecular identity nor proper name (ClC‐0), and membership in a large superfamily. I discuss the circumstances surrounding its discovery and subsequent research through the 1980s that revealed its unusual molecular architecture and other strange mechanistic characteristics.
Are interventions for low-income groups effective in changing healthy eating, physical activity and smoking behaviours? A systematic review and meta-analysis
Authors: Bull Eleanor R , Dombrowski Stephan U , McCleary Nicola , Johnston Marie
Published: November 2014

Objective

To conduct a systematic review and meta-analysis examining the effectiveness of behavioural interventions targeting diet, physical activity or smoking in low-income adults.

Design

Systematic review with random effects meta-analyses. Studies before 2006 were identified from a previously published systematic review (searching 1995–2006) with similar but broader inclusion criteria (including non-randomised controlled trials (RCTs)). Studies from 2006 to 2014 were identified from eight electronic databases using a similar search strategy.

Data sources

MEDLINE, EMBASE, PsycINFO, ASSIA, CINAHL, Cochrane Controlled Trials, Cochrane Systematic Review and DARE.

Eligibility criteria for selecting studies

RCTs and cluster RCTs published from 1995 to 2014; interventions targeting dietary, physical activity and smoking; low-income adults; reporting of behavioural outcomes.

Main outcome measures

Dietary, physical activity and smoking cessation behaviours.

Results

35 studies containing 45 interventions with 17 000 participants met inclusion criteria. At postintervention, effects were positive but small for diet (standardised mean difference (SMD) 0.22, 95% CI 0.14 to 0.29), physical activity (SMD 0.21, 95% CI 0.06 to 0.36) and smoking (relative risk (RR) of 1.59, 95% CI 1.34 to 1.89). Studies reporting follow-up results suggested that effects were maintained over time for diet (SMD 0.16, 95% CI 0.08 to 0.25) but not physical activity (SMD 0.17, 95% CI −0.02 to 0.37) or smoking (RR 1.11, 95% CI 0.93 to 1.34).

Conclusions

Behaviour change interventions for low-income groups had small positive effects on healthy eating, physical activity and smoking. Further work is needed to improve the effectiveness of behaviour change interventions for deprived populations.
The Safety Tips for ATV Riders (STARs) programme: short-term impact of a school-based educational intervention
Authors: Jennissen Charles A , Peck Jeffrey , Wetjen Kristel , Hoogerwerf Pam , Harland Karisa K , Denning Gerene M
Published: November 2014

Background

Since 1985, one-third of all US all-terrain vehicle (ATV)-related injuries and one-quarter of deaths involved victims <16 years of age. ATV safety education of youth could help reduce these tragedies.

Objectives

To assess the efficacy of theSafetyTips forATVRiders(STARs) school-based programme targeting adolescents.

Methods

A survey was anonymously administered before and after the programme to determine demographics, knowledge and reported likelihood of using the information learned.

Results

Over 4600 students in 30 Iowa schools participated from November 2010 to April 2013. Initially, 52% knew most ATVs are designed for one rider, 25% knew the recommended vehicle size for their age range and 42% knew riding on Iowa's roads was legal only for agricultural purposes. After the programme, this increased to 92%, 82% and 76%, respectively (p<0.0001 in each case), with 61% of students correct on all three. Better preintervention scores were associated with being males, higher riding frequency and being from isolated rural communities. After the programme, 48% and 32% said they were likely/very likely versus unlikely/very unlikely to use the safety information learned, respectively; younger students, females and infrequent riders reported higher likelihoods.

Conclusions

STARs increased short-term ATV safety knowledge and almost half the participants reported they would use the safety information presented. Males and frequent riders seemed more resistant, but some groups that may be more vulnerable to potential ATV crash and injury appeared amenable to the training with higher increases in postprogramme scores and greater intention of improving safety behaviours.
“There are bugs in condoms”: Tanzanian close-to-community providers' ability to offer effective adolescent reproductive health services
Authors: Dusabe John , Mchome Zaina , Nnko Soori , Changalucha John , Obasi Angela
Published: November 2014

Objectives

Young people in Tanzania are known to access reproductive health services from a range of close-to-community providers outside formal health settings such as drug stores, village AIDS committees, traditional healers and traditional birth attendants (TBAs). However, questions remain about the quality of services such agents provide. This study investigated their capacity to provide adolescent reproductive health (ARH) services and explored their readiness and ability to integrate with the mainstream health sector through community referral interventions.

Methods

Thirty-five focus group discussions exploring close-to-community provider experiences and attitudes to ARH service provision were carried out in two districts in Northern Tanzania. Discussions were conducted in Kiswahili, digitally recorded, verbatim-transcribed, translated and back-translated from Swahili to English. A thematic analysis was conducted using NVivo 9.

Results

The major close-to-community cadres providing reproductive health services were drug stores, traditional healers, TBAs and village health workers. They reported being the first port of call for adolescents seeking reproductive health services, but their knowledge of ARH needs was poor. They had negative attitudes to, and lacked the necessary resources for, the provision of such services for adolescents. Some were particularly unwilling to provide condom services and were prejudiced against adolescents using them. There was poor integration between the close-to-community providers and the formal health sector, further limiting their ability to provide adequate services.

Conclusions

Although close-to-community providers are considered a key resource in the community, most have limited capacity to provide ARH services. Without capacity-building investments such as training and cooperation with the mainstream health sector, their contribution to positive reproductive health outcomes is limited, or could indeed lead to adverse outcomes.
Republished: A novel approach to the treatment of a direct carotid–cavernous fistula in a patient with Ehlers–Danlos syndrome type IV
Authors: Nakagawa Ichiro , Park Hun Soo , Wada Takeshi , Takayama Katsutoshi , Nakagawa Hiroyuki , Kichikawa Kimihiko , Nakase Hiroyuki
Published: November 2014

We report a case of a direct carotid–cavernous fistula (CCF) in a patient with Ehlers–Danlos syndrome type IV who presented with progressive chemosis and diplopia. To prevent potential lethal arterial wall injury due to the fragility of the arterial vessel wall, the ipsilateral carotid artery and internal jugular vein were surgically exposed for direct insertion of endovascular sheaths, and transvenous embolization was performed using triple microcatheters with detachable coils. The clinical course was uneventful, and chemosis and diplopia subsequently resolved. By the 6 month follow-up, MRI revealed no recurrence of the CCF. These techniques offer a unique access alternative for endovascular treatment, thereby reducing the risks associated with arterial dissection that often accompanies transfemoral access in this particular condition.
A meta-analysis of prospective randomized controlled trials evaluating endovascular therapies for acute ischemic stroke
Authors: Fargen Kyle M , Neal Dan , Fiorella David J , Turk Aquilla S , Froehler Michael , Mocco J
Published: November 2014

Introduction

A recent randomized controlled trial (RCT), the Multicenter Randomized CLinical trial of Endovascular treatment for Acute ischemic stroke in the Netherlands (MR CLEAN), demonstrated better outcomes with endovascular treatment compared with medical therapy for acute ischemic stroke (AIS). However, previous trials have provided mixed results regarding the efficacy of endovascular treatment for AIS. A meta-analysis of all available trial data was performed to summarize the available evidence.

Methods

A literature search was performed to identify all prospective RCTs comparing endovascular therapies with medical management for AIS. Two datasets were created: (1) all patients randomized after confirmation of large vessel occlusion (LVO) (consistent with the contemporary standard of practice at the majority of centers); and (2) all patients with outcome data who underwent randomization regardless of qualifying vascular imaging. The pre-specified primary outcome measure was modified Rankin Scale score of 0–2 at 90 days. A fixed-effect model was used to determine significance.

Results

Five prospective RCTs comparing endovascular therapies with medical management were included in dataset 1 (1183 patients) and six were included in dataset 2 (1903 total patients). Endovascular therapies were associated with significantly improved outcomes compared with medical management (OR 1.67, 95% CI 1.29 to 1.16, p=0.0001) for patients with LVO (dataset 1). This benefit persisted when patients from all six RCTs were included, even in the absence of confirmation of LVO (OR 1.27, 95% CI 1.05 to 1.54, p=0.019; dataset 2).

Conclusions

A meta-analysis of prospective RCTs comparing endovascular therapies with medical management demonstrates superior outcomes in patients randomized to endovascular therapy.
Comparative efficacy and safety of mavacoxib and carprofen in the treatment of canine osteoarthritis
Authors: Payne‐Johnson M , Becskei C , Chaudhry Y , Stegemann M R
Published: November 2014

A multi‐site, masked, randomised parallel group study employing a double dummy treatment design was performed in canine veterinary patients to determine the comparative efficacy and safety of mavacoxib and carprofen in the treatment of pain and inflammation associated with osteoarthritis for a period of 134 days. Treatments were administered according to their respective summaries of product characteristics. Of 139 dogs screened, 124 were suitable for study participation: 62 of which were dosed with mavacoxib and 62 with carprofen. Both treatments resulted in a very similar pattern of considerable improvement as indicated in all parameters assessed by both owner and veterinarian. The primary efficacy endpoint ‘overall improvement’ was a composite score of owner assessments after approximately six weeks of treatment. Both drugs were remarkably effective, with 57/61 (93.4 per cent) of mavacoxib‐treated dogs and 49/55 (89.1 per cent) of carprofen‐treated dogs demonstrating overall improvement and with mavacoxib's efficacy being non‐inferior to carprofen. The treatments had a similar safety profile as evidenced by documented adverse events and summaries of clinical pathology parameters. The positive clinical response to treatment along with the safety and dosing regimen of mavacoxib makes it an attractive therapy for canine osteoarthritis.
Validation of the accuracy of needle placement as used in diagnostic local analgesia of the maxillary nerve for investigation of trigeminally mediated headshaking in horses
Authors: Wilmink S. , Warren‐Smith C. M. R. , Roberts V. L. H.
Published: November 2014

Diagnostic local anaesthesia of the maxillary nerve is a valuable aid in the diagnosis of trigeminally mediated headshaking in horses. Our objective is to validate the accuracy of needle placement in this procedure and to identify any correlation between accuracy of the technique and operator experience. Using a small volume of contrast medium, the procedure was performed bilaterally on 30 horse cadaver heads by three groups with different levels of experience with the technique. The location of deposition was then identified using computed tomography (CT). Contrast medium was deposited around the target site in 53.3% (32/60) of injections. An experienced operator succeeded in deposition around the target area significantly (p<0.05) more often (80%, 16/20) than did the less and non‐experienced performers (40%, 16/40). A negative response to diagnostic local anaesthesia of the maxillary nerve does not disprove facial dysaesthesia as the cause of headshaking in that horse as a false negative response could arise due to failure to deposit local anaesthetic around the target area. Increased experience in performing the procedure decreases the probability of false negative results.
Intramuscular administration of alfaxalone for sedation in rabbits
Authors: Huynh Minh , Poumeyrol Séverine , Pignon Charly , Le Teuff Gwenaël , Zilberstein Luca
Published: November 2014

Alfaxalone is a neuroactive steroid derivative of pregnanedione that was recently reintroduced to the market for use as an induction agent in small animal anaesthesia. The aim of this study was to determine an intramuscular alfaxalone dose for safe immobilisation. Ten healthy New Zealand white rabbits were used to evaluate a single intramuscular injection of alfaxalone. The design of the study was a three‐way, complete block, cross‐over trial to compare the effect of alfaxalone at three doses (4, 6 and 8 mg). The mean duration of the effect for the 4, 6 and 8 mg/kg doses was, respectively, 36.9 (95% CI (31.6 to 42.3)), 51.8 (46.4 to 57.2) and 58.4 (52.8 to 63.9) minutes. The loss of the righting reflex was achieved after 3.1 (2.5 to 3.8), 2.4 (1.7 to 3.1) and 2.3 (1.6 to 2.9) minutes, respectively. The mean duration of the effect for the 6 and 8 mg doses was significantly higher than for the 4 mg dose (with estimated differences of 14.8 95% CI (8.8 to 20.8) minutes and 21.4 (15.3 to 27.6) minutes, respectively). No significant dose effect was observed before the loss of the righting reflex (P=0.14). Ear pinching and limb withdrawal were elicited in all groups at every dose. Doses of 4 or 6 mg/kg could be recommended; higher doses do not provide clinical benefits and can be associated with anaesthetic complication.
A Residue Calculus of Isolated Singular Zero Point and Its Application in Z Transform
Authors: Yang Zong-Chang
Published: November 2014

The residue theorem is a powerful tool in mathematics and signal processing, such as it is usually employed for the inverse Laplace transform and the inverse Z transform. With respect to the most commonly rational functional form in the Z transform, a theorem and a new formula for residue calculus based on the singular zero point is introduced. Then two consequences are proposed. Finally, based on the derived theorems, a new convenient algorithm for computing the inverse Z transform is presented. Applications with satisfying results indicate convenience and workability of the proposed method.
DEVELOPMENT AND VALIDATION OF AN IMPROVED TEST SELECTION AND PRIORITIZATION ALGORITHM BASED ON ACO
Authors: SURI BHARTI , SINGHAL SHWETA
Published: November 2014

Regression testing is an important and often costly software maintenance activity. Retesting the software using existing test suite whenever modifications are made to the system, in order to regain confidence in correctness of the system, is called as Regression Testing. Regression test suites are often too large to re-execute in the given time and cost constraints. Reordering of the test suite is done according to appropriate criteria like code, branch, condition and fault coverage, etc. This process is known as Test Suite Prioritization. We can also select a subset of the original test suite on the basis of some criteria, often called as Regression Test Selection. The research problem that arises from this is the choice of technique or process to be used for selecting and prioritizing according to one or more of the chosen criteria(s). Ant Colony Optimization (ACO) is one such technique that was used by Singh et al. for solving Time-Constrained Test Suite Selection and Prioritization problem using Fault Exposing Potential (FEP). In this paper, we propose improvements to the existing algorithm along with details of the time complexity of the algorithm. It was very convincing to implement the technique considering the results obtained. Implementation of the proposed algorithm has also been demonstrated. The tool was repeatedly run on sample programs by changing the time constraint criterion. The analysis shows the usefulness and effectiveness of using ACO technique for test suite selection and prioritization.
Use of the NBME Comprehensive Basic Science Examination as a progress test in the preclerkship curriculum of a new medical school
Authors: Johnson Teresa R. , Khalil Mohammed K. , Peppler Richard D. , Davey Diane D. , Kibble Jonathan D.
Published: November 2014

In the present study, we describe the innovative use of the National Board of Medical Examiners (NBME) Comprehensive Basic Science Examination (CBSE) as a progress test during the preclerkship medical curriculum. The main aim of this study was to provide external validation of internally developed multiple-choice assessments in a new medical school. The CBSE is a practice exam for the United States Medical Licensing Examination (USMLE) Step 1 and is purchased directly from the NBME. We administered the CBSE five times during the first 2 yr of medical school. Student scores were compared with scores on newly created internal summative exams and to the USMLE Step 1. Significant correlations were observed between almost all our internal exams and CBSE scores over time as well as with USMLE Step 1 scores. The strength of correlations of internal exams to the CBSE and USMLE Step 1 broadly increased over time during the curriculum. Student scores on courses that have strong emphasis on physiology and pathophysiology correlated particularly well with USMLE Step 1 scores. Student progress, as measured by the CBSE, was found to be linear across time, and test performance fell behind the anticipated level by the end of the formal curriculum. These findings are discussed with respect to student learning behaviors. In conclusion, the CBSE was found to have good utility as a progress test and provided external validation of our new internally developed multiple-choice assessments. The data also provide performance benchmarks both for our future students to formatively assess their own progress and for other medical schools to compare learning progression patterns in different curricular models.
Fostering improved anatomy and physiology instructor pedagogy
Authors: Mattheis Allison , Jensen Murray
Published: November 2014

Despite widespread calls for reform in undergraduate science, technology, engineering, and mathematics education, effecting lasting change in instructor practice is challenging to achieve. This article describes the results of a 2-yr research study that involved efforts to develop the pedagogical expertise of a group of anatomy and physiology instructors at the college level. Data were collected through a series of individual interviews that included the use of the Teacher Beliefs Inventory questionnaire ( 23 ) along with observations onsite in participants' college classrooms and at process-oriented guided inquiry learning (POGIL) curriculum writing workshops. Findings indicated attitudinal shifts on the part of participants from teacher-centered to more student-centered pedagogy and supported the benefits of long-term professional development for instructors. Here, we documented the successful progress of these professors as they participated in a curriculum development process that emphasized student-centered teaching with the goal of promoting broader change efforts in introductory anatomy and physiology.
Exercise and type 2 diabetes: molecular mechanisms regulating glucose uptake in skeletal muscle
Authors: Stanford Kristin I. , Goodyear Laurie J.
Published: November 2014

Exercise is a well-established tool to prevent and combat type 2 diabetes. Exercise improves whole body metabolic health in people with type 2 diabetes, and adaptations to skeletal muscle are essential for this improvement. An acute bout of exercise increases skeletal muscle glucose uptake, while chronic exercise training improves mitochondrial function, increases mitochondrial biogenesis, and increases the expression of glucose transporter proteins and numerous metabolic genes. This review focuses on the molecular mechanisms that mediate the effects of exercise to increase glucose uptake in skeletal muscle.
Aerobic exercise and other healthy lifestyle factors that influence vascular aging
Authors: Santos-Parker Jessica R. , LaRocca Thomas J. , Seals Douglas R.
Published: November 2014

Cardiovascular diseases (CVDs) remain the leading cause of death in the United States and other modern societies. Advancing age is the major risk factor for CVD, primarily due to stiffening of the large elastic arteries and the development of vascular endothelial dysfunction. In contrast, regular aerobic exercise protects against the development of large elastic artery stiffness and vascular endothelial dysfunction with advancing age. Moreover, aerobic exercise interventions reduce arterial stiffness and restore vascular endothelial function in previously sedentary middle-aged/older adults. Aerobic exercise exerts its beneficial effects on arterial function by modulating structural proteins, reducing oxidative stress and inflammation, and restoring nitric oxide bioavailability. Aerobic exercise may also promote “resistance” against factors that reduce vascular function and increase CVD risk with age. Preventing excessive increases in abdominal adiposity, following healthy dietary practices, maintaining a low CVD risk factor profile, and, possibly, selective use of pharmaceuticals and nutraceuticals also play a major role in preserving vascular function with aging.
Using stimulation of the diving reflex in humans to teach integrative physiology
Authors: Choate Julia K. , Denton Kate M. , Evans Roger G. , Hodgson Yvonne
Published: November 2014

During underwater submersion, the body responds by conserving O2 and prioritizing blood flow to the brain and heart. These physiological adjustments, which involve the nervous, cardiovascular, and respiratory systems, are known as the diving response and provide an ideal example of integrative physiology. The diving reflex can be stimulated in the practical laboratory setting using breath holding and facial immersion in water. Our undergraduate physiology students complete a laboratory class in which they investigate the effects of stimulating the diving reflex on cardiovascular variables, which are recorded and calculated with a Finapres finger cuff. These variables include heart rate, cardiac output, stroke volume, total peripheral resistance, and arterial pressures (mean, diastolic, and systolic). Components of the diving reflex are stimulated by 1) facial immersion in cold water (15°C), 2) breathing with a snorkel in cold water (15°C), 3) facial immersion in warm water (30°C), and 4) breath holding in air. Statistical analysis of the data generated for each of these four maneuvers allows the students to consider the factors that contribute to the diving response, such as the temperature of the water and the location of the sensory receptors that initiate the response. In addition to providing specific details about the equipment, protocols, and learning outcomes, this report describes how we assess this practical exercise and summarizes some common student misunderstandings of the essential physiological concepts underlying the diving response.
The Role of MRI in Prostate Cancer Active Surveillance
Authors: Johnson Linda M. , Choyke Peter L. , Figg William D. , Turkbey Baris
Published: November 2014

Prostate cancer is the most common cancer diagnosis in American men, excluding skin cancer. The clinical behavior of prostate cancer varies from low-grade, slow growing tumors to high-grade aggressive tumors that may ultimately progress to metastases and cause death. Given the high incidence of men diagnosed with prostate cancer, conservative treatment strategies such as active surveillance are critical in the management of prostate cancer to reduce therapeutic complications of radiation therapy or radical prostatectomy. In this review, we will review the role of multiparametric MRI in the selection and follow-up of patients on active surveillance.
Impact of Exogenous Gonadotropin Stimulation on Circulatory and Follicular Fluid Cytokine Profiles
Authors: Baskind N. Ellissa , Orsi Nicolas M. , Sharma Vinay
Published: November 2014

Background. The natural cycle is the prototype to which we aspire to emulate in assisted reproduction techniques. Increasing evidence is emerging that controlled ovarian hyperstimulation (COH) with exogenous gonadotropins may be detrimental to oogenesis, embryo quality, and endometrial receptivity. This research aimed at assessing the impact of COH on the intrafollicular milieu by comparing follicular fluid (FF) cytokine profiles during stimulatedin vitrofertilization (IVF) and modified natural cycle (MNC) IVF.Methods. Ten women undergoing COH IVF and 10 matched women undergoing MNC IVF were recruited for this pilot study. 40 FF cytokine concentrations from individual follicles and plasma were measured by fluid-phase multiplex immunoassay. Demographic/cycle/cytokine data were compared and correlations between cytokines were computed.Results. No significant differences were found between COH and MNC groups for patient and cycle demographics, including outcome. Overall mean FF cytokine levels were higher in the MNC group for 29/40 cytokines, significantly so for leukaemia inhibitory factor and stromal cell-derived factor-1α. Furthermore, FF MNC cytokine correlations were significantly stronger than for COH data.Conclusions. These findings suggest that COH perturbs intrafollicular cytokine networks, in terms of both cytokine levels and their interrelationships. This may impact oocyte maturation/fertilization and embryo developmental competence.
A Rare Cause of Postpartum Low Back Pain: Pregnancy- and Lactation-Associated Osteoporosis
Authors: Terzi Rabia , Terzi Hasan , Özer Tülay , Kale Ahmet
Published: November 2014

Pregnancy- and lactation-associated osteoporosis (PLO) is a rare form of osteoporosis. It results in severe low back pain in the last trimester of pregnancy and in the postpartum period, decreases in height, and fragility fractures, particularly in the vertebra. The current case report presents a 32-year-old patient who presented with back and low back pain that began in the last trimester of the pregnancy and worsened at two months postpartum and who was diagnosed with pregnancy- and lactation-associated osteoporosis after exclusion of other causes; the findings are discussed in view of the current literature. PLO is a rare clinical condition causing significant disability. PLO must be kept in mind in the differential diagnosis in patients presenting with low back pain during or after pregnancy. The patients must be evaluated for the risk factors of PLO, and an appropriate therapy must be initiated.
H-Matrices in Fuzzy Linear Systems
Authors: Saberi Najafi H. , Edalatpanah S. A.
Published: November 2014

We consider a class of fuzzy linear system of equations and demonstrate some of the existing challenges. Furthermore, we explain the efficiency of this model when the coefficient matrix is an H-matrix. Numerical experiments are illustrated to show the applicability of the theoretical analysis.
Implementing Second-Order Decision Analysis: Concepts, Algorithms, and Tool
Authors: Larsson Aron , Kuznetsova Alina , Caster Ola , Ekenberg Love
Published: November 2014

We present implemented concepts and algorithms for a simulation approach to decision evaluation with second-order belief distributions in a common framework for interval decision analysis. The rationale behind this work is that decision analysis with interval-valued probabilities and utilities may lead to overlapping expected utility intervals yielding difficulties in discriminating between alternatives. By allowing for second-order belief distributions over interval-valued utility and probability statements these difficulties may not only be remedied but will also allow for decision evaluation concepts and techniques providing additional insight into a decision problem. The approach is based upon sets of linear constraints together with generation of random probability distributions and utility values from implicitly stated uniform second-order belief distributions over the polytopes given from the constraints. The result is an interactive method for decision evaluation with second-order belief distributions, complementing earlier methods for decision evaluation with interval-valued probabilities and utilities. The method has been implemented for trial use in a user oriented decision analysis software.
Control of the Inflammatory Response Mechanisms Mediated by Natural and Induced Regulatory T-Cells in HCV-, HTLV-1-, and EBV-Associated Cancers
Authors: Ouaguia Laurissa , Mrizak Dhafer , Renaud Sarah , Moralès Olivier , Delhem Nadira
Published: November 2014

Virus infections are involved in chronic inflammation and, in some cases, cancer development. Although a viral infection activates the immune system’s response that eradicates the pathogen mainly through inflammatory mechanisms, it is now recognized that this inflammatory condition is also favorable to the development of tumors. Indeed, it is well described that viruses, such as hepatitis C virus (HCV), Epstein Barr virus (EBV), human papillomavirus (HPV) or human T-cell lymphotropic virus type-1 (HTLV-1), are important risk factors for tumor malignancies. The inflammatory response is a fundamental immune mechanism which involves several molecular and cellular components consisting of cytokines and chemokines that are released by various proinflammatory cells. In parallel to this process, some endogenous recruited components release anti-inflammatory mediators to restore homeostasis. The development of tools and strategies using viruses to hijack the immune response is mostly linked to the presence of regulatory T-cells (Treg) that can inhibit inflammation and antiviral responses of other effector cells. In this review, we will focus on current understanding of the role of natural and induced Treg in the control and the resolution of inflammatory response in HCV-, HTLV-1-, and EBV-associated cancers.
Immunomodulatory Effects of Polysaccharide from Marine FungusPhoma herbarumYS4108 on T Cells and Dendritic Cells
Authors: Chen Song , Ding Ran , Zhou Yan , Zhang Xian , Zhu Rui , Gao Xiang-Dong
Published: November 2014

YCP, as a kind of natural polysaccharides from the mycelium of marine filamentous fungusPhoma herbarumYS4108, has great antitumor potentialviaenhancement of host immune response, but little is known about the molecular mechanisms. In the present study, we mainly focused on the effects and mechanisms of YCP on the specific immunity mediated by dendritic cells (DCs) and T cells. T cell /DC activation-related factors including interferon- (IFN-)γ, interleukin-12 (IL-12), and IL-4 were examined with ELISA. Receptor knock-out mice and fluorescence-activated cell sorting are used to analyze the YCP-binding receptor of T cells and DCs. RT-PCR is utilized to measure MAGE-A3 for analyzing the tumor-specific killing effect. In our study, we demonstrated YCP can provide the second signal for T cell activation, proliferation, and IFN-γproduction through binding to toll-like receptor- (TLR-) 2 and TLR-4. YCP could effectively promote IL-12 secretion and expression of markers (CD80, CD86, and MHC II)viaTLR-4 on DCs. Antigen-specific immunity against mouse melanoma cells was strengthened through the activation of T cells and the enhancement of capacity of DCs by YCP. The data supported that YCP can exhibit specific immunomodulatory capacity mediated by T cells and DCs.
Pancreatic Mass Leading to Left-Sided Portal Hypertension, Causing Bleeding from Isolated Gastric Varices
Authors: Thrainsdottir Helga , Petursdottir Vigdis , Blöndal Sigurdur , Björnsson Einar S.
Published: November 2014

Mucinous cystic neoplasms (MCN) are an uncommon form of exocrine neoplasms of the pancreas. Symptoms are most often vague and this makes the diagnosis more difficult. The current case is one of three cases yet reported where the MCN caused left-sided portal hypertension leading to the formation of isolated gastric varices and subsequent bleeding from the varices. In the previously reported cases the main symptom was hematemesis. However in the current case the patient experienced no hematemesis, only isolated incidents of dark coloured diarrhea, but the main symptoms were those of iron-deficiency anemia. We present the case report of a 34-year-old woman who presented with dizziness and lethargy and was found to have 12 cm MCN in the pancreas.
Activin Upregulation by NF-κB Is Required to Maintain Mesenchymal Features of Cancer Stem–like Cells in Non–Small Cell Lung Cancer
Authors: Wamsley J. Jacob , Kumar Manish , Allison David F. , Clift Sheena H. , Holzknecht Caitlyn M. , Szymura Szymon J. , Hoang Stephen A. , Xu Xiaojiang , Moskaluk Christopher A. , Jones David R. , Bekiranov Stefan , Mayo Marty W.
Published: November 2014

Soluble growth factors and cytokines within the tumor microenvironment aid in the induction of the epithelial-to-mesenchymal transition (EMT). Although EMT promotes the development of cancer-initiating cells (CIC), cellular mechanisms by which cancer cells maintain mesenchymal phenotypes remain poorly understood. Work presented here indicates that induction of EMT stimulates non–small cell lung cancer (NSCLC) to secrete soluble factors that function in an autocrine fashion. Using gene expression profiling of all annotated and predicted secreted gene products, we find that NF-κB activity is required to upregulate INHBA/Activin, a morphogen in the TGFβ superfamily. INHBA is capable of inducing and maintaining mesenchymal phenotypes, including the expression of EMT master-switch regulators and self-renewal factors that sustain CIC phenotypes and promote lung metastasis. Our work demonstrates that INHBA mRNA and protein expression are commonly elevated in primary human NSCLC and provide evidence that INHBA is a critical autocrine factor that maintains mesenchymal properties of CICs to promote metastasis in NSCLC. Cancer Res; 75(2); 426–35. ©2014 AACR.
A Urokinase Receptor–Bim Signaling Axis Emerges during EGFR Inhibitor Resistance in Mutant EGFR Glioblastoma
Authors: Wykosky Jill , Hu Jingjing , Gomez German G. , Taylor Tiffany , Villa Genaro R. , Pizzo Donald , VandenBerg Scott R. , Thorne Amy Haseley , Chen Clark C. , Mischel Paul S. , Gonias Steven L. , Cavenee Webster K. , Furnari Frank B.
Published: November 2014

EGFR is the most common genetically altered oncogene in glioblastoma (GBM), but small-molecule EGFR tyrosine kinase inhibitors (TKI) have failed to yield durable clinical benefit. Here, we show that in two novel model systems of acquired resistance to EGFR TKIs, elevated expression of urokinase plasminogen activator (uPA) drives signaling through the MAPK pathway, which results in suppression of the proapoptotic BCL2-family member protein BIM (BCL2L11). In patient-derived GBM cells and genetic GBM models, uPA is shown to suppress BIM levels through ERK1/2 phosphorylation, which can be reversed by siRNA-mediated knockdown of uPA. TKI-resistant GBMs are resensitized to EGFR TKIs by pharmacologic inhibition of MEK or a BH3 mimetic drug to replace BIM function. A link between the uPA–uPAR–ERK1/2 pathway and BIM has not been previously demonstrated in GBM, and involvement of this signaling axis in resistance provides rationale for a new strategy to target EGFR TKI-resistant GBM. Cancer Res; 75(2); 394–404. ©2014 AACR.
Akt Inhibition Enhances Expansion of Potent Tumor-Specific Lymphocytes with Memory Cell Characteristics
Authors: Crompton Joseph G. , Sukumar Madhusudhanan , Roychoudhuri Rahul , Clever David , Gros Alena , Eil Robert L. , Tran Eric , Hanada Ken-ichi , Yu Zhiya , Palmer Douglas C. , Kerkar Sid P. , Michalek Ryan D. , Upham Trevor , Leonardi Anthony , Acquavella Nicolas , Wang Ena , Marincola Francesco M. , Gattinoni Luca , Muranski Pawel , Sundrud Mark S. , Klebanoff Christopher A. , Rosenberg Steven A. , Fearon Douglas T. , Restifo Nicholas P.
Published: November 2014

Adoptive cell therapy (ACT) using autologous tumor-infiltrating lymphocytes (TIL) results in complete regression of advanced cancer in some patients, but the efficacy of this potentially curative therapy may be limited by poor persistence of TIL after adoptive transfer. Pharmacologic inhibition of the serine/threonine kinase Akt has recently been shown to promote immunologic memory in virus-specific murine models, but whether this approach enhances features of memory (e.g., long-term persistence) in TIL that are characteristically exhausted and senescent is not established. Here, we show that pharmacologic inhibition of Akt enables expansion of TIL with the transcriptional, metabolic, and functional properties characteristic of memory T cells. Consequently, Akt inhibition results in enhanced persistence of TIL after adoptive transfer into an immunodeficient animal model and augments antitumor immunity of CD8 T cells in a mouse model of cell-based immunotherapy. Pharmacologic inhibition of Akt represents a novel immunometabolomic approach to enhance the persistence of antitumor T cells and improve the efficacy of cell-based immunotherapy for metastatic cancer. Cancer Res; 75(2); 296–305. ©2014 AACR.
Effects of Tailored Risk Communications for Skin Cancer Prevention and Detection: The PennSCAPE Randomized Trial
Authors: Glanz Karen , Volpicelli Kathryn , Jepson Christopher , Ming Michael E. , Schuchter Lynn M. , Armstrong Katrina
Published: November 2014

Background: Prevention and early detection measures for melanoma, such as sun avoidance and skin examinations, are important, but are practiced inconsistently. In this replication of the Project SCAPE trial, we sought to determine whether tailored print materials were more effective at improving adherence than generic print materials for patients at increased risk of skin cancer.

Methods: Participants were randomized to receive personalized mailed communications about their skin cancer risk and recommended sun protection, or generic mailings. Participants were Caucasian adults, at moderate or high risk for skin cancer, recruited in outpatient primary care. The main outcomes were overall sun protection behaviors and specific protective behaviors including use of sunscreen, shirt, hat, sunglasses, shade, and sun avoidance; recent sunburns; and skin self-examination and provider skin examination.

Results: One hundred ninety-two (93.2%) subjects completed the study. Six outcome variables showed significant intervention condition effects in mixed effects models: overall sun protection behavior (P = 0.025); sunscreen use (P = 0.026); use of sunglasses (P = 0.011); sunburns in the past three months (P = 0.033); recency of last skin self-exam (P = 0.017); and frequency of skin exams by health care provider (P = 0.016).

Conclusions: Relative to generic communications, tailored risk communications resulted in improved adherence to six skin cancer protective behaviors, including a composite sun protection behavior measure, sunburns, and health care provider skin examinations.

Impact: Tailored interventions can be more effective in improving patient prevention behaviors than nontailored, generic information for patients at moderate to high risk of skin cancer. Cancer Epidemiol Biomarkers Prev; 24(2); 415–21. ©2014 AACR.
Offering Self-Sampling to Non-Attendees of Organized Primary HPV Screening: When Do Harms Outweigh the Benefits?
Authors: Rozemeijer Kirsten , de Kok Inge M.C.M , Naber Steffie K. , van Kemenade Folkert J. , Penning Corine , van Rosmalen Joost , van Ballegooijen Marjolein
Published: November 2014

Background: Human papillomavirus (HPV) self-sampling might be a promising tool to increase effectiveness of primary HPV screening programs when offered to non-attendees. However, effectiveness could decrease if regular attendees “switch” to self-sampling, because self-sampling test characteristics may be inferior. We examined under which conditions the harms would outweigh the benefits.

Methods: The MISCAN-cervix model was used to estimate quality-adjusted life years (QALY) gained and costs of offering HPV self-sampling to non-attendees. We varied the relative CIN2+ sensitivity and specificity (self-sampling vs. regular sampling), extra attendance, risk of extra attendees, and the switching percentage.

Results: Without switching, offering self-sampling is (cost-)effective under every studied condition. If the attendance due to self-sampling increases by ≥6 percentage points, higher primary background risk women (unscreened women who will never attend regular screening) attend and the relative CIN2+ sensitivity and specificity are ≥0.95; it is (cost-)effective to offer self-sampling to non-attendees, even if all regular attendees switch. If the relative sensitivity decreases to 0.90 combined with either a 3 percentage points extra attendance or the absence of higher primary background risk women, QALYs are lost when more than 30% to 20% of the regular attendees switch.

Conclusions: Offering self-sampling will gain health effects if the relative CIN2+ sensitivity is ≥0.95, unscreened attendees are recruited, and the total attendance increases by ≥6 percentage points. Otherwise, switching of regular attendees may decrease the total effectiveness of the program.

Impact: Self-sampling needs to be implemented with great care and advantages of office-based sampling need to be emphasized to prevent switching. Cancer Epidemiol Biomarkers Prev; 24(5); 773–82. ©2014 AACR.

See related commentary by Arbyn and Castle, p. 769
Steroid Sidestep: Evading Androgen Ablation by Abiraterone
Authors: Sharifi Nima
Published: November 2014

Tumor mechanisms of abiraterone resistance in clinical prostate cancer are not well defined. Chen and colleagues report that a T878A androgen receptor mutation occurs in a subset of patients progressing while receiving abiraterone, suggesting that this may be a therapeutically exploitable mechanism of abiraterone resistance in castration-resistant prostate cancer. Clin Cancer Res; 21(6); 1240–2. ©2014 AACR.

See related article by Chen et al., p. 1273