bluuebunny/crossref_metadata_2025 huggingface dataset:
Rest-Activity Cycle Disturbances in the Acute Phase of Moderate to Severe Traumatic Brain Injury
Authors: Duclos Catherine , Dumont Marie , Blais Hélène , Paquet Jean , Laflamme Elyse , de Beaumont Louis , Wiseman-Hakes Catherine , Menon David K. , Bernard Francis , Gosselin Nadia
Published: December 2013

Background. Sleep-wake disturbances are among the most persistent sequelae after traumatic brain injury (TBI) and probably arise during the hospital stay following TBI. These disturbances are characterized by difficulties sleeping at night and staying awake during the day. Objective. The aim of the present study was to document rest-activity cycle consolidation in acute moderate/severe TBI using actigraphy and to assess its association with injury severity and outcome. Methods. In all, 16 hospitalized patients (27.1 ± 11.3 years) with moderate/severe TBI wore actigraphs for 10 days, starting in the intensive care unit (ICU) when continuous sedation was discontinued and patients had reached medical stability. Activity counts were summed for daytime (7:00-21:59 hours) and nighttime periods (22:00-6:59 hours). The ratio of daytime period activity to total 24-hour activity was used to quantify rest-activity cycle consolidation. An analysis of variance was carried out to characterize the evolution of the daytime activity ratio over the recording period. Results. Rest-activity cycle was consolidated only 46.6% of all days; however, a significant linear trend of improvement was observed over time. Greater TBI severity and longer ICU and hospital lengths of stay were associated with poorer rest-activity cycle consolidation and evolution. Patients with more rapid return to consolidated rest-activity cycle were more likely to have cleared posttraumatic amnesia and have lower disability at hospital discharge. Conclusions. Patients with acute moderate/severe TBI had an altered rest-activity cycle, probably reflecting severe fragmentation of sleep and wake episodes, which globally improved over time. A faster return to rest-activity cycle consolidation may predict enhanced brain recovery.
New Treatment of Vertigo Caused by Jugular Bulb Abnormalities
Authors: Hitier Martin , Barbier Charlotte , Marie- Aude Thenint , Moreau Sylvain , Courtheoux Patrick , Patron Vincent
Published: December 2013

Objective. Jugular bulb abnormalities can induce tinnitus, hearing loss, or vertigo. Vertigo can be very disabling and may need surgical treatments with risk of hearing loss, major bleeding or facial palsy. Hence, we have developed a new treatment for vertigo caused by jugular bulb anomalies, using an endovascular technique. Patients. Three patients presented with severe vertigos mostly induced by high venous pressure. One patient showed downbeat vertical nystagmus during the Valsalva maneuver. The temporal-bone computed tomography scan showed a high rising jugular bulb or a jugular bulb diverticulum with dehiscence and compression of the vestibular aqueduct in all cases. Intervention. We plugged the upper part of the bulb with coils, and we used a stent to maintain the coils and preserving the venous permeability. Results. After 12- to 24-month follow-up, those patients experienced no more vertigo, allowing return to work. The 3-month arteriographs showed good permeability of the sigmoid sinus and jugular bulb through the stent, with complete obstruction of the upper part of the bulb in all cases. Conclusion. Disabling vertigo induced by jugular bulb abnormalities can be effectively treated by an endovascular technique. This technique is minimally invasive with a probable greater benefit/risk ratio compare with surgery.
Acta from the EndoFLIP® Symposium
Authors: Perretta Silvana , McAnena Oliver , Botha Abrie , Nathanson Leslie , Swanstrom Lee , Soper Nathaniel J. , Inoue Haruiro , Ponsky Jeffrey , Jobe Blair , Marescaux Jacques , Dallemagne Bernard
Published: December 2013

Laparoscopic fundoplication (LF) is a surgical treatment for gastroesophageal reflux disease (GERD) that has been performed for more than 20 years. High-volume centers of excellence report long-term success rates greater than 90% with LF. On the other hand, general population-based outcomes are reported to be markedly worse, leading to a nihilistic perception of the procedure on the part of the medical referral population. The lack of standardization of the technique and the lack of tools to calibrate objectively the repairs are probably among the causes of variability in the outcomes and may explain the decline in the number of LF procedures in recent years. The functional lumen imaging probe (EndoFLIP®) device is essentially a “smart bougie” in the form of a balloon catheter that measures shape and compliance of the gastroesophageal junction (GEJ) during surgery using impedance planimetry. With approximately 3 years of international experience gained with this tool, a symposium was convened in October 2012 in Strasbourg, France, with the aim of determining if intraoperative EndoFLIP use could provide standardization of surgical treatment of GERD through the understanding of physiological changes occurring to the GEJ during fundoplication. This article provides a brief history of the EndoFLIP system and reviews data previously published on the use of EndoFLIP to characterize the GEJ in normal subjects. It then summarizes the data from the 5 high-volume international sites with expert surgeons performing LF presented in Strasbourg to objectively profile the characteristics of a normal postoperative GEJ.
Early Arrival or Trespassing? Leadership, School Security, and the Right to the School
Authors: Irby Decoteau J. , Thomas Christopher
Published: December 2013

School leaders are under constant pressure to ensure that schools are safe and to demonstrate that student safety and discipline are priorities. In many districts, schools rely on local law enforcement, school police, or security personnel to assist with promoting and maintaining safe schools. To encourage school leaders to think critically about the role of law enforcement and security personnel in schools, we present a school-level case where a principal is arrested for intervening to stop the arrest of a student. The case is appropriate for school- and district-level leadership courses that examine social, political, and cultural contexts that shape decision making.
Importance factors of coherent systems: A review
Authors: Dutuit Yves , Rauzy Antoine
Published: December 2013

Importance factors are indicators of the risk significance of the components of a system. They are widely used in probabilistic safety analyses to rank components according to their contribution to the global risk. In this article, we review definitions and interpretations of importance factors in the case the support model is a coherent fault tree, and failures of components are described by basic events of that fault tree. First, we show that each importance factor characterizes the probability of a certain set of minterms. The notion of critical states, that is, minterms in which failing/repairing the component suffices to fail/repair the system, plays a central role in this process. Then, we discuss assessment algorithms for the two main technologies at hand: minimal cutsets and binary decision diagrams. Finally, we draw some practical conclusions from these developments. This article thus contributes to clarify mathematical and algorithmic foundations of importance factors.
Autism in children
Authors: Redshaw Emma L , Smith Helen E
Published: December 2013

Autistic spectrum disorders are life-long complex disorders that typically present in the first 3 years of life. This article focuses on promoting awareness of early signs and symptoms, as familiarity with them can facilitate timely recognition and referral of the child for expert management. Caring for an autistic child has a significant psychological impact on the well-being of parents and family, and the GP can be key in coordinating care, particularly at the time of transition from paediatric to adult services.
The Conundrum of Calcaneal Spurs
Authors: Moroney Paul J. , O’Neill Barry J. , Khan-Bhambro Khalid , O’Flanagan Shay J. , Keogh Peter , Kenny Paddy J.
Published: December 2013

Background: Chronic plantar heel pain is a common and potentially debilitating condition, often caused by plantar fasciitis. Plantar calcaneal spurs were originally considered the cause of plantar fasciitis but are now regarded as an incidental finding by most authors. We aimed to test this hypothesis and to investigate predisposing factors for the development of spurs. Methods: We reviewed all lateral ankle X rays taken in our institution over a 6-month period and identified all X rays demonstrating calcaneal spurs. Then, we identified a similar number of age- and sex-matched controls without spurs. We contacted both groups by telephone and compared symptoms of heel pain, plantar fasciitis, associated comorbidities, and foot and ankle outcome scores (FAOSs). Results: We reviewed the X rays of 1103 consecutive patients and found a spur prevalence of 12.4%, more common in women and older patients. Questioning of the spur group and control group found a higher body mass index in the spur group. Patients with spurs were 4 times more likely to have diabetes mellitus and 10 times more likely to have lower-limb osteoarthritis. Patients with spurs had more foot pain and poorer FAOS than the control group, even when patients with plantar fasciitis were excluded. Conclusion: Our results demonstrate that the presence of a plantar calcaneal spur may be an indicator of foot pain independent of plantar fasciitis. Although spurs may not cause foot pain themselves, they may be an indication of other associated conditions. Clinical relevance: We have demonstrated the relevance of a radiographic finding once considered irrelevant.

Level of Evidence: Prognostic, Level III: Case-control study
Lapidus Arthrodesis Plus Osteochondral Autograft Transplantation in the Management of Hallux Rigidus With an Elevated First Ray
Authors: Klos Kajetan , Simons Paul
Published: December 2013

The range of joint-sparing treatments for advanced hallux rigidus is still very limited. The authors describe an osteochondral autograft transplantation technique combined with Lapidus arthrodesis as a novel method of obtaining a relatively symptom-free first metatarsophalangeal joint function in patients with hallux rigidus and first-ray elevation.

Level of Evidence: Level V
“Trying to Find the Middle Ground”
Authors: Eversman Michael H.
Published: December 2013

U.S. federal drug policy has long emphasized criminalization and incarceration, and many negative policy outcomes have disproportionately impacted communities of color and Blacks in particular. The framework of harm reduction informs a range of alternative policy strategies from decriminalization to legalization, treating drugs more as a public health than a criminal justice issue. While Black communities are seen as opposing harm reduction with illicit drugs, Black leadership has recently supported ending the war on drugs. Using in-depth interviews with 21 substance abuse service providers in a Northeastern U.S. urban hub, this study explores views toward the potential impact of, and support for, harm reduction illicit drug policies in Black U.S. communities. Cognizant of the racially skewed impact of drug policies, respondents endorsed policy changes but were generally mixed on harm reduction, opposing liberalization of “hard” drugs, yet supporting it for marijuana given its link to race-based policing. Respondents indicate many Black communities need more than drug policy change, at best seeing harm reduction as only part of larger scale reinvestment. Findings inform considerations of reforming drug policy strategies and priorities for these communities, given views toward illicit drugs and racially skewed outcomes of current drug policy.
Randomized Trial of Lower Extremity Splinting to Manage Neuropathic Pain and Sleep Disturbances in People Living with HIV/AIDS
Authors: Sandoval Roberto , Roddey Toni , Giordano Thomas Peter , Mitchell Katy , Kelley Carolyn
Published: December 2013

Background/Aims:

Distal symmetrical peripheral neuropathy (DSPN) and sleep disturbances are among the most common complications reported in people living with the human immunodeficiency virus infection and acquired immunodeficiency syndrome (PLWHA). DSPN-pain is predominantly managed by using systemic agents with little evidence supporting their analgesic efficacy. The purpose of this study is to evaluate the effect of nighttime lower extremity splinting application on DSPN-related pain and sleep disturbances compared to a parallel splint liner application in PLWHA.

Methods:

Forty-six PLWHA and DSPN were randomized to nighttime wearing of bilateral lower extremity splints or the liners only. Pain and sleep outcomes were measured at baseline, week 3, and week 6. The pain was measured using the Neuropathic Pain Scale and sleep using the Pittsburgh Sleep Quality Index.

Results:

Pain and sleep scores improved in both groups over time. The median percentage pain reduction at week 6 was 8% in the liner group and 34% in the splint group. The change in pain scores in the splint group was found to be significant over time, P < .0005. The contrast between the splint and liner groups was underpowered (26%) and was not found to be significant, P > .05. Sleep scores improved 20% from baseline to the end of the study in both groups; all participants were classified as poor sleepers.

Conclusion:

The 6-week use of nighttime splints reduces DSPN-pain possibly by providing peripheral inhibition of external stimuli. Future studies are needed to validate this inhibitory intervention to manage DSPN in PLWHA and other neuropathic conditions.
HIV Treatment as Prevention in Jamaica and Barbados
Authors: Barrow Geoffrey , Barrow Christine
Published: December 2013

This discursive article introduces HIV treatment as prevention (TasP) and identifies various models for its extrapolation to wider population levels. Drawing on HIV surveillance data for Jamaica and Barbados, the article identifies significant gaps in HIV response programming in relation to testing, antiretroviral treatment coverage, and treatment adherence, thereby highlighting the disparity between assumptions and prerequisites for TasP success. These gaps are attributable, in large part, to sociocultural impediments and structural barriers, severe resource constraints, declining political will, and the redefinition of HIV as a manageable, chronic health issue. Antiretroviral treatment and TasP can realize success only within a combination prevention frame that addresses structural factors, including stigma and discrimination, gender inequality and gender-based violence, social inequality, and poverty. The remedicalization of the response compromises outcomes and undermines the continued potential of HIV programming as an entry point for the promotion of sexual, health, and human rights.
Ritonavir-Boosted Lopinavir as Maintenance Monotherapy in HIV-Infected Patients Who Achieved Viral Suppression during a Second-Line Protease Inhibitor–Based Regimen
Authors: Siripassorn Krittaecho , Chottanapund Suthat , Prasithsirikul Wisit , Manosuthi Weerawat
Published: December 2013

Eligibility criteria were (1) having previously failed first-line nonnucleoside reverse transcriptase inhibitor–based regimens and (2) having achieved virologic suppression >6 months while receiving a protease inhibitor (PI)-based regimen as second-line treatment. Eligible participants were randomized to receive either (1) ritonavir-boosted lopinavir (LPV/r) monotherapy (n = 29) or (2) LPV/r with optimized background regimens (OBRs; n = 31). Median duration of viral suppression before randomization was 45 months. At week 48, viral suppression during LPV/r monotherapy was 86.2% and did not differ from the suppression achieved with LPV/r with OBRs (87.1%, P = 1.000). However, persistent viremia during LPV/r monotherapy tended to be higher than during LPV/r with OBRs (10.3% versus 3.2%, P = .346). History of viral blip during virologic suppression with second-line PI-based regimen is a predictor of achieving viral suppression at all visits (adjusted relative risk 0.255 [95% confidence interval 0.080-0.821], P = .022). Use of LPV/r monotherapy as maintenance regimen in this study produced persistent viremia that tended to be higher than LPV/r monotherapy with OBRs.
CD4 Counts and Mortality in Virologically Suppressed US Veterans
Authors: Drechsler Henning , Zhang Song , Holodniy Mark , Bedimo Roger
Published: December 2013

We used the Veterans Health Administration (VA) HIV Clinical Case Registry (CCR) to evaluate the association between annual CD4 averages and all-cause mortality in HIV-infected veterans during their initial episode of suppressive highly active antiretroviral therapy (HAART). We observed 1083 deaths in 14 769 patients. Unadjusted mortality rates in the top and bottom CD4 quintiles differed significantly from the mid CD4 strata. Mortality in the top CD4 quintile (≥720 cells/mm3) was 14.1/1000 patient-years, 95% confidence interval (CI): 10.1-18.2, compared with 20.4 (CI: 15.5-25.3) in the next lower CD4 stratum (530-719 cells/mm3). This difference was significant in Cox proportional hazards model, controlling for demographics, hepatitis co-infections, low-level viremia, HAART adherence, and refill rates of individual antiretrovirals (HR: 1.4, CI: 1.13-1.73). Our results support early HAART initiation as advocated by the current US treatment guidelines for HIV infection.
A Simple Effective Protocol to Increase Prenatal Detection of Critical Congenital Heart Disease
Authors: Letourneau Karen M. , McDonald Keith , Soni Reeni , Karlicki Fern , Horne David , Hall Philip F. , Fransoo Randall
Published: December 2013

Prenatal diagnosis of congenital heart disease (CHD) during routine obstetric sonography has been aptly named the sonographer’s Achilles heel. Although CHD occurs more commonly than any other major congenital abnormality, the detection rate remains low. The goal of this study was to improve the prenatal diagnosis of CHD during routine obstetric sonography through the development and implementation of a simple and effective screening protocol.
Sonographic Evaluation of Secondary Hyperparathyroidism
Authors: Arabie Penny
Published: December 2013

Secondary hyperparathyroidism (SHPT) is one of the most common abnormalities of mineral metabolism in patients with chronic kidney disease. This case study is a report of a patient referred for sonography based on computed tomography findings of multiple supraclavicular lymph nodes. Sonography was able to localize two enlarged parathyroid glands (adenomas) and to guide fine-needle aspiration for histopathologic tissue diagnosis in this patient with SHPT.
Detection of Fetal Aneuploidy Using Cell-Free DNA
Authors: Webb Kristin E.
Published: December 2013

Cell-free fetal DNA (cffDNA) is a highly accurate screening test for major aneuploidies. Despite high detection rates and low false-positive rates compared to current screening methods, cffDNA testing is approved for use in only the high-risk population and is expensive for low-risk women because of a lack of insurance coverage. As the technology improves and research demonstrates the efficacy of cffDNA testing in the general population, insurance coverage of this test likely will be extended to all women. At that time, cffDNA testing in most cases will replace current screening methods. Furthermore, cffDNA testing may become a routine diagnostic test, effectively rendering most invasive diagnostic procedures obsolete.
Upper Extremity Kinematics in Sonographers During Kidney Scanning
Authors: Pocratsky Jennifer , Ashby Blake , Beasley Jeanine
Published: December 2013

To understand the mechanisms involved that lead to the high prevalence of work-related musculoskeletal disorders in sonographers, this motion capture study evaluated upper extremity kinematics during kidney scans. The purpose of this study was to provide an evaluation of joint ranges of motion during scanning, which could be helpful in assessing risk of injury. A Vicon MX motion capture system recorded reflective marker positions while four sonographers scanned a volunteer’s kidneys. The results indicated that sonographers were scanning with their shoulders in flexion, abduction, and external rotation. The elbows were in flexion and the wrists in extension in all cases with the exception of portions of one scan. Shoulder abduction and wrist extension angles exceeded acceptable published limits. These results could be used to improve patient and sonographer positioning, equipment adjustability, and transducer design.
Prenatal Diagnosis of Bladder Exstrophy
Authors: Wolniakowski April , Szlachetka Kam , Thornburg Loralei L.
Published: December 2013

Bladder exstrophy is a rare congenital abnormality where the urinary bladder, anterior pelvis, and genitalia fail to close in the midline, resulting in the bladder being located externally along the anterior pelvic wall. The incidence is 1 per 40 000 live births and has a male predominance. Common prenatal sonographic findings include an absent urinary bladder, normal amniotic fluid, and an inferior abdominal mass. The absence of the bladder in the second trimester with normal amniotic fluid volumes should prompt evaluation for this abnormality. Advances in ultrasound technology including the use of 3D and 4D imaging have led to an increase in prenatal diagnosis of this condition. The earlier diagnosis has aided in delivery at an appropriate center and timely surgical planning, allowing for a better outcome.
Detection of Ureteral Stones With Transvaginal Sonography
Authors: Vega Carolina
Published: December 2013

Transabdominal sonography has proved to be an efficacious imaging technology to diagnose urolithiaisis. However, the location of the calculus may cause a sonographic examination to be limited. Since the majority of ureteral stones are located in the distal ureter, calculi may not always be visualized transabdominally, especially if the bladder is not full. This case study demonstrates the use of transvaginal sonography in the diagnosis of distal ureterolithiasis and discusses the optimal visualization of a ureteral stone in a female patient using transvaginal sonography. The case demonstrates the importance of this imaging method when distal urinary tract stones are suspected.
Facilitating accrual to cancer control and supportive care trials: the clinical research associate perspective
Authors: VanHoff David , Hesser Tanya , Kelly Katherine Patterson , Freyer David , Stork Susan , Sung Lillian
Published: December 2013

Background

Accrual to Cancer Control and Supportive Care (CCL) studies can be challenging. Our objective was to identify facilitators and perceived barriers to successful Children’s Oncology Group (COG) CCL accrual from the clinical research associate (CRA) perspective.

Methods

A survey was developed that focused on the following features from the institutional perspective: (1) Components of successful accrual; (2) Barriers to accrual; (3) Institutional changes that could enhance accrual; and (4) How COG could facilitate accrual. The survey was distributed to the lead CRA at each COG site with at least 2 CCL accruals within the previous year. The written responses were classified into themes and sub-themes.

Results

57 sites in the United States (n = 52) and Canada (n = 5) were contacted; 34 (60%) responded. The four major themes were: (1) Staff presence and dynamics; (2) Logistics including adequate numbers of eligible patients; (3) Interests and priorities; and (4) Resources. Suggestions for improvement began at the study design/conception stage, and included ongoing training/support and increased reimbursement or credit for successful CCL enrollment.

Conclusions

The comments resulted in suggestions to facilitate CCL trials in the future. Soliciting input from key team members in the clinical trials process is important to maximizing accrual rates.
Epigenetic modulation of the drug resistance genes MGMT, ABCB1 and ABCG2 in glioblastoma multiforme
Authors: Oberstadt Moritz C , Bien-Möller Sandra , Weitmann Kerstin , Herzog Susann , Hentschel Katharina , Rimmbach Christian , Vogelgesang Silke , Balz Ellen , Fink Matthias , Michael Heike , Zeden Jan-Philip , Bruckmüller Henrike , Werk Anneke N , Cascorbi Ingolf , Hoffmann Wolfgang , Rosskopf Dieter , Schroeder Henry WS , Kroemer Heyo K
Published: December 2013

Background

Resistance of the highly aggressive glioblastoma multiforme (GBM) to drug therapy is a major clinical problem resulting in a poor patient’s prognosis. Beside promoter methylation of the O

6

-methylguanine-DNA-methyltransferase (MGMT) gene the efflux transporters ABCB1 and ABCG2 have been suggested as pivotal factors contributing to drug resistance, but the methylation of ABCB1 and ABCG2 has not been assessed before in GBM.

Methods

Therefore, we evaluated the proportion and prognostic significance of promoter methylation of MGMT, ABCB1 and ABCG2 in 64 GBM patient samples using pyrosequencing technology. Further, the single nucleotide polymorphisms MGMT C-56 T (rs16906252), ABCB1 C3435T (rs1045642) and ABCG2 C421A (rs2231142) were determined using the restriction fragment length polymorphism method (RFLP). To study a correlation between promoter methylation and gene expression, we analyzed MGMT, ABCB1 and ABCG2 expression in 20 glioblastoma and 7 non-neoplastic brain samples.

Results

Despite a significantly increased MGMT and ABCB1 promoter methylation in GBM tissue, multivariate regression analysis revealed no significant association between overall survival of glioblastoma patients and MGMT or ABCB1 promoter methylation. However, a significant negative correlation between promoter methylation and expression could be identified for MGMT but not for ABCB1 and ABCG2. Furthermore, MGMT promoter methylation was significantly associated with the genotypes of the MGMT C-56 T polymorphism showing a higher methylation level in the T allele bearing GBM.

Conclusions

In summary, the data of this study confirm the previous published relation of MGMT promoter methylation and gene expression, but argue for no pivotal role of MGMT, ABCB1 and ABCG2 promoter methylation in GBM patients’ survival.
Systemic effect of catumaxomab in a patient with metastasized colorectal cancer: a case report
Authors: Bezan Angelika , Hohla Florian , Meissnitzer Thomas , Greil Richard
Published: December 2013

Background

Catumaxomab, the first anti-EpCAM antibody, was approved in 2009 for the treatment of malignant ascites in cancer patients with EpCAM positive tumors. We consider this case of interest as treatment with catumaxomab not only prolonged the puncture-free interval but also showed a systemic effect in a patient with metastasized colorectal cancer by regression of a pulmonary metastasis.

Case presentation

We describe the case of a 78 year old patient initially diagnosed with locally advanced colon cancer and one synchronous liver metastasis in September 2010 who was treated by hemicolectomy and simultaneous atypical liver resection. During adjuvant chemotherapy the patient developed a peritoneal carcinomatosis with ascites in March 2011. Palliative chemotherapy was not well tolerated and therefore refused by the patient. Because of disease progression in June 2011 with one pulmonary metastasis and clinically predominant ascites an immunotherapy with intraperitoneal catumaxomab was started in December 2011. After treatment with catumaxomab a puncture free survival of 12 months as well as a regression of the pulmonary lesion was achieved until January 2013.

Conclusion

This case suggests that treatment with catumaxomab does not only improve quality of life by local suppression of malignant ascites but also might have a systemic antitumor effect.
Berberine suppresses tumorigenicity and growth of nasopharyngeal carcinoma cells by inhibiting STAT3 activation induced by tumor associated fibroblasts
Authors: Tsang Chi Man , Cheung Yuk Chun , Lui Vivian Wai-Yan , Yip Yim Ling , Zhang Guitao , Lin Victor Weitao , Cheung Kenneth Chat-Pan , Feng Yibin , Tsao Sai Wah
Published: December 2013

Background

Cortidis rhizoma(Huanglian) and its major therapeutic component, berberine, have drawn extensive attention in recent years for their anti-cancer properties. Growth inhibitory effects of berberine on multiple types of human cancer cells have been reported. Berberine inhibits invasion, induces cell cycle arrest and apoptosis in human cancer cells. The anti-inflammatory property of berberine, involving inhibition ofSignalTransducer andActivator ofTranscription 3 (STAT3) activation, has also been documented.

Methods

In this study, we have examined the effects of berberine on tumorigenicity and growth of nasopharyngeal carcinoma (NPC) cells and their relationship to STAT3 signaling using bothin vivoandin vitromodels.

Results

Berberine effectively inhibited the tumorigenicity and growth of an EBV-positive NPC cell line (C666-1) in athymic nude mice. Inhibition of tumorigenic growth of NPC cellsin vivowas correlated with effective inhibition of STAT3 activation in NPC cells inside the tumor xenografts grown in nude mice.In vitro, berberine inhibited both constitutive and IL-6-induced STAT3 activation in NPC cells. Inhibition of STAT3 activation by berberine induced growth inhibition and apoptotic response in NPC cells. Tumor-associated fibroblasts were found to secret IL-6 and the conditioned medium harvested from the fibroblasts also induced STAT3 activation in NPC cells. Furthermore, STAT3 activation by conditioned medium of tumor-associated fibroblasts could be blocked by berberine or antibodies against IL-6 and IL-6R.

Conclusions

Our observation that berberine effectively inhibited activation of STAT3 induced by tumor-associated fibroblasts suggests a role of berberine in modulating the effects of tumor stroma on the growth of NPC cells. The effective inhibition of STAT3 activation in NPC cells by berberine supports its potential use in the treatment of NPC.
Direct patterning of probe proteins on an antifouling PLL-g-dextran coating for reducing the background signal of fluorescent immunoassays
Authors: Egea Amandine MC , Trévisiol Emmanuelle , Vieu Christophe
Published: December 2013

The limit of detection of advanced immunoassays, biochips and micro/nano biodetection devices is impacted by the non-specific adsorption of target molecules at the sample surface. In this paper, we present a simple and versatile low cost method for generating active surfaces composed of antibodies arrays surrounded by an efficient anti-fouling layer, capable to decrease drastically the fluorescence background signal obtained after interaction with a solution to be analyzed. The technological process involves the direct micro-contact printing of the antibodies probe molecules on a pre-coated PLL-g-dextran thin layer obtained by contact printing using a flat PDMS stamp. Compared to other blocking strategies (ethanolamine blocking treatment, PLL-g-PEG incubation, PLL-g-dextran incubation, printing on a plasma-deposited PEO layer), our surface chemistry method is more efficient for reducing non-specific interactions responsible for a degraded signal/noise ratio.
Veterans Affairs databases are accurate for gout-related health care utilization: a validation study
Authors: Singh Jasvinder A
Published: December 2013

Introduction

The aim of this study was to assess the accuracy of Veterans Affairs (VA) databases for gout-related health care utilization.

Methods

This retrospective study utilized VA administrative and clinical databases. A random sample of gout patients with visits (outpatient, inpatient or emergent/urgent care) with or without the diagnosis of gout (International Classification of Diseases, ninth revision, common modification ICD-9-CM code of 274.x or 274.xx) at the Birmingham VA hospital was selected. A blinded abstractor performed a review of VA electronic health records for the documentation of gout or gout-related terms (gouty arthritis, tophaceous gout, tophus/tophi, acute gout, chronic gout, podagra, urate stones, urate or uric acid crystals and so on) in the chief complaint, history of present illness or assessment and plan for the visit; this constituted the gold standard for gout-related utilization. The accuracy of database-derived gout-related claims was assessed by calculating sensitivity, specificity, and positive and negative predictive values (PPV and NPV).

Results

Of 108 potential visits, 85 outpatient, inpatient or urgent care/emergency room visits to a health care provider (85 patients: 84 men and 1 woman with a mean age of 63 years) and retrievable data from medical records constituted the analyzed dataset. Administrative claims for gout-related utilization with ICD-9 code for gout were accurate with a PPV of 86%, specificity of 95%, sensitivity of 86% and NPV of 95%.

Conclusions

VA databases are accurate for gout-related visits. These findings support their use for studies of health services and outcome studies. It remains to be seen if these findings are generalizable to other settings and databases.
Co-binding by YY1 identifies the transcriptionally active, highly conserved set of CTCF-bound regions in primate genomes
Authors: Schwalie Petra C , Ward Michelle C , Cain Carolyn E , Faure Andre J , Gilad Yoav , Odom Duncan T , Flicek Paul
Published: December 2013

Background

The genomic binding of CTCF is highly conserved across mammals, but the mechanisms that underlie its stability are poorly understood. One transcription factor known to functionally interact with CTCF in the context of X-chromosome inactivation is the ubiquitously expressed YY1. Because combinatorial transcription factor binding can contribute to the evolutionary stabilization of regulatory regions, we tested whether YY1 and CTCF co-binding could in part account for conservation of CTCF binding.

Results

Combined analysis of CTCF and YY1 binding in lymphoblastoid cell lines from seven primates, as well as in mouse and human livers, reveals extensive genome-wide co-localization specifically at evolutionarily stable CTCF-bound regions. CTCF-YY1 co-bound regions resemble regions bound by YY1 alone, as they enrich for active histone marks, RNA polymerase II and transcription factor binding. Although these highly conserved, transcriptionally active CTCF-YY1 co-bound regions are often promoter-proximal, gene-distal regions show similar molecular features.

Conclusions

Our results reveal that these two ubiquitously expressed, multi-functional zinc-finger proteins collaborate in functionally active regions to stabilize one another's genome-wide binding across primate evolution.
Staged miRNA re-regulation patterns during reprogramming
Authors: Henzler Christine M , Li Zhonghan , Dang Jason , Arcila Mary Luz , Zhou Hongjun , Liu Jingya , Chang Kung-Yen , Bassett Danielle S , Rana Tariq M , Kosik Kenneth S
Published: December 2013

Background

MiRNAs often operate in feedback loops with transcription factors and represent a key mechanism for fine-tuning gene expression. In transcription factor-induced reprogramming, miRNAs play a critical role; however, detailed analyses of miRNA expression changes during reprogramming at the level of deep sequencing have not been previously reported.

Results

We use four factor reprogramming to induce pluripotent stem cells from mouse fibroblasts and isolate FACS-sorted Thy1- and SSEA1+ intermediates and Oct4-GFP+ induced pluripotent stem cells (iPSCs). Small RNAs from these cells, and two partial-iPSC lines, another iPSC line, and mouse embryonic stem cells (mES cells) were deep sequenced. A comprehensive resetting of the miRNA profile occurs during reprogramming; however, analysis of miRNA co-expression patterns yields only a few patterns of change. Dlk1-Dio3 region miRNAs dominate the large pool of miRNAs experiencing small but significant fold changes early in reprogramming. Overexpression of Dlk1-Dio3 miRNAs early in reprogramming reduces reprogramming efficiency, suggesting the observed downregulation of these miRNAs may contribute to reprogramming. As reprogramming progresses, fewer miRNAs show changes in expression, but those changes are generally of greater magnitude.

Conclusions

The broad resetting of the miRNA profile during reprogramming that we observe is due to small changes in gene expression in many miRNAs early in the process, and large changes in only a few miRNAs late in reprogramming. This corresponds with a previously observed transition from a stochastic to a more deterministic signal.
Activated macrophages release microvesicles containing polarized M1 or M2 mRNAs
Authors: Garzetti Livia , Menon Ramesh , Finardi Annamaria , Bergami Alessandra , Sica Antonio , Martino Gianvito , Comi Giancarlo , Verderio Claudia , Farina Cinthia , Furlan Roberto
Published: December 2013

MVs are known vehicles of horizontal communication among cells, currently under scrutiny as powerful biomarkers in several pathological processes. The potential advantage of MVs relies on the assumption that their content reflects processes ongoing in pathologically relevant cell types. We have described that MVs of myeloid origin in the CSF are a marker of microglia/macrophage activation. Myeloid cells have different activation types, resulting in diverse functional phenotypes. Knowledge on the activation type of myeloid cells during disease would be of paramount importance for the understanding of ongoing pathogenic processes. We show here that macrophages activated in vitro in different ways all release increased amounts of MVs compared with NS cells. Moreover, we show that macrophage-derived MVs contain a repertoire of mRNAs that is not the result of casual sampling from the parental cells, as it is characterized by distinct mRNA enrichments and species. Nevertheless, mRNA content of MVs clearly allows identification in vivo of the activated phenotype of the cell of origin, indicating carryover of functional macrophage traits. We propose that detection of mRNAs in myeloid MVs permits identification of myeloid cell activation type during disease, allowing for further stratification of pathological processes.
Introduction to this special section: Middle East
Authors: El-Emam Adel
Published: December 2013

The article “Tuning is not necessarily bad—Channel sand delineation from seismic data of the Upper Gharif in Oman” is written by Fuping Zhu et al., with all authors from Petroleum Development of Oman (PDO). Until recently, the channels of the Upper Gharif were considered too thin (only a tenth of a wavelength) for seismic detection, and instead were explored using costly grid drilling. In this article, the authors report on the successful use of seismic data for reservoir characterization and well placement, following careful interpretation of seismic amplitudes in terms of tuning and prior constraints on the sand thicknesses (absence of thick sands, small NTG ratio). The proposed methodology has been developed on Field Z and has successfully predicted the sand thickness encountered in a new well. It is expected that this methodology will be applicable to several Upper Gharif reservoirs which hold a significant portion of PDO's reserve and resource volumes.

Following Zhu's article is a workshop report. In the article “The big rush to the Middle East unconventional reservoirs,” Mohammed Badri of Schlumberger and Saleh Al-Saleh of Saudi Aramco share news of the successful SEG workshop highlighting seismic applications in exploiting unconventional reservoirs.
Phase II Trial of Imatinib in AIDS-Associated Kaposi's Sarcoma: AIDS Malignancy Consortium Protocol 042
Authors: Koon Henry B. , Krown Susan E. , Lee Jeannette Y. , Honda Kord , Rapisuwon Suthee , Wang Zhenghe , Aboulafia David , Reid Erin G. , Rudek Michelle A. , Dezube Bruce J. , Noy Ariela
Published: December 2013

Purpose

Kaposi's sarcoma (KS) is a disease of multifocal vascular proliferation that requires infection with KS herpes virus (KSHV/HHV-8). Activation of the c-kit and platelet-derived growth factor (PDGF) receptors by autocrine/paracrine mechanisms follows endothelial cell KSHV infection. In a pilot study, imatinib, a c-kit/PDGF-receptor inhibitor, induced partial regression of AIDS-associated KS (AIDS-KS) in five of 10 patients.

Patients and Methods

This multicenter phase II study was designed to estimate the response rate to imatinib in AIDS-KS. Secondary objectives included investigation of predictors of response and imatinib pharmacokinetics in patients on antiretrovirals. Patients received imatinib 400 mg/day by mouth for up to 12 months with dose escalation up to 600 mg/day at 3 months if their disease was stable.

Results

Thirty patients were treated at 12 AIDS Malignancy Consortium sites. Ten patients (33.3%) achieved partial response, six (20%) had stable disease, and seven (23.3%) exhibited KS progression. Nine patients completed 52 weeks of imatinib therapy. The median treatment duration was 22.5 weeks. Only five patients (16.7%) discontinued therapy owing to adverse events. Antiretroviral regimens did not significantly alter imatinib metabolism. Activating mutations in PDGF-R and c-kit were not found at baseline or at disease progression. We found no correlation with response with changes in any of the candidate cytokines.

Conclusion

Imatinib has activity in AIDS-KS. Pharmacokinetic interactions with antiretroviral drugs did not correlate with toxicity. Thirty percent of patients showed long-term clinical benefit and remained on imatinib for the entire year. These results suggest imatinib is well tolerated and may be an alternative therapy for some patients with AIDS-KS.
Prospective Stage-Stratified Approach to AIDS-Related Kaposi's Sarcoma
Authors: Bower Mark , Dalla Pria Alessia , Coyle Chris , Andrews Eileen , Tittle Victoria , Dhoot Sharanjit , Nelson Mark
Published: December 2013

Purpose

Combination antiretroviral therapy (cART) is standard of care for patients with HIV diagnosed with Kaposi's sarcoma (KS), but the current role of systemic chemotherapy is undefined.

Patients and Methods

Since 1998, a prospective stage-stratified approach has been adopted for 469 patients with HIV with KS. Patients with early-stage (T0) KS are treated with cART alone; patients with advanced-stage (T1) KS receive cART plus liposomal anthracycline chemotherapy. Clinical characteristics, overall survival, and KS progression–free survival were analyzed according to stage at presentation and treatment received.

Results

A total of 303 patients presented with T0 stage KS, including 237 who were not receiving cART, and 166 patients had T1 stage KS. Patients with T0 KS had higher CD4 cell counts (P < .001); 90% of patients with T0 KS who were not receiving cART and 84% of those with T1 KS were treated in accordance with the stage-stratified approach. Median follow-up was 4.6 years, and 5-year overall survival was 89%; 54 patients have died, 15 as a result of KS. Overall 5-year survival was 92% for T0 KS and 83% to T1 KS (P = .0024). On-treatment analysis of 213 cART-naive patients with T0 KS treated with cART alone revealed 5-year overall survival of 95% and progression-free survival of 77%. For 140 patients with T1 disease treated with cART and liposomal anthracycline chemotherapy, 5-year overall survival was 85%.

Conclusion

This stage-stratified approach to the management of KS achieves high survival in patients with advanced KS and reduces exposure to chemotherapy in patients with early-stage KS.
Aberrant cochlear hair cell attachments caused by Nectin-3 deficiency result in hair bundle abnormalities
Authors: Fukuda Terunobu , Kominami Kanoko , Wang Shujie , Togashi Hideru , Hirata Ken-ichi , Mizoguchi Akira , Rikitake Yoshiyuki , Takai Yoshimi
Published: December 2013

The organ of Corti consists of sensory hair cells (HCs) interdigitated with nonsensory supporting cells (SCs) to form a checkerboard-like cellular pattern. HCs are equipped with hair bundles on their apical surfaces. We previously reported that cell-adhesive nectins regulate the checkerboard-like cellular patterning of HCs and SCs in the mouse auditory epithelium. Nectin-1 and -3 are differentially expressed in normal HCs and SCs, respectively, and in Nectin-3-deficient mice a number of HCs are aberrantly attached to each other. We show here that these aberrantly attached HCs in Nectin-3-deficient mice, but not unattached ones, show disturbances of the orientation and morphology of the hair bundles and the positioning of the kinocilium, with additional abnormal localisation of cadherin-catenin complexes and the apical-basal polarity proteins Pals1 and Par-3. These results indicate that, owing to the loss of Nectin-3, hair cells contact each other inappropriately and form abnormal junctions, ultimately resulting in abnormal hair bundle orientation and morphology.
How to make a primordial germ cell
Authors: Magnúsdóttir Erna , Surani M. Azim
Published: December 2013

Primordial germ cells (PGCs) are the precursors of sperm and eggs, which generate a new organism that is capable of creating endless new generations through germ cells. PGCs are specified during early mammalian postimplantation development, and are uniquely programmed for transmission of genetic and epigenetic information to subsequent generations. In this Primer, we summarise the establishment of the fundamental principles of PGC specification during early development and discuss how it is now possible to make mouse PGCs from pluripotent embryonic stem cells, and indeed somatic cells if they are first rendered pluripotent in culture.
Independently specified Atoh1 domains define novel developmental compartments in rhombomere 1
Authors: Green Mary J. , Myat Anna M. , Emmenegger Brian A. , Wechsler-Reya Robert J. , Wilson Leigh J. , Wingate Richard J. T.
Published: December 2013

The rhombic lip gives rise to neuronal populations that contribute to cerebellar, proprioceptive and interoceptive networks. Cell production depends on the expression of the basic helix-loop-helix (bHLH) transcription factor Atoh1. In rhombomere 1, Atoh1-positive cells give rise to both cerebellar neurons and extra-cerebellar nuclei in ventral hindbrain. The origin of this cellular diversity has previously been attributed to temporal signals rather than spatial patterning. Here, we show that in both chick and mouse the cerebellar Atoh1 precursor pool is partitioned into initially cryptic spatial domains that reflect the activity of two different organisers: an isthmic Atoh1 domain, which gives rise to isthmic nuclei, and the rhombic lip, which generates deep cerebellar nuclei and granule cells. We use a combination of in vitro explant culture, genetic fate mapping and gene overexpression and knockdown to explore the role of isthmic signalling in patterning these domains. We show that an FGF-dependent isthmic Atoh1 domain is the origin of distinct populations of Lhx9-positive neurons in the extra-cerebellar isthmic nuclei. In the cerebellum, ectopic FGF induces proliferation while blockade reduces the length of the cerebellar rhombic lip. FGF signalling is not required for the specification of cerebellar cell types from the rhombic lip and its upregulation inhibits their production. This suggests that although the isthmus regulates the size of the cerebellar anlage, the downregulation of isthmic FGF signals is required for induction of rhombic lip-derived cerebellar neurons.