bluuebunny/crossref_metadata_2025 huggingface dataset:
Impact of Undetected Comorbidity on Treatment and Outcomes of Breast Cancer
Authors: Griffiths Robert I. , Gleeson Michelle L. , Valderas José M. , Danese Mark D.
Published: February 2014

Preexisting comorbidity adversely impacts breast cancer treatment and outcomes. We examined the incremental impact of comorbidity undetected until cancer. We followed breast cancer patients in SEER-Medicare from 12 months before to 84 months after diagnosis. Two comorbidity indices were constructed: the National Cancer Institute index, using 12 months of claims before cancer, and a second index for previously undetected conditions, using three months after cancer. Conditions present in the first were excluded from the second. Overall, 6,184 (10.1%) had≥1undetected comorbidity. Chronic obstructive pulmonary disease (38%) was the most common undetected condition. In multivariable analyses that adjusted for comorbidity detected before cancer, older age, later stage, higher grade, and poor performance status all were associated with higher odds of≥1undetected comorbidity. In stage I–III cancer, undetected comorbidity was associated with lower adjusted odds of receiving adjuvant chemotherapy (Odds Ratio (OR) = 0.81, 95% Confidence Interval (CI) 0.73–0.90,P<0.0001;OR=0.38, 95% CI 0.30–0.49,P<0.0001; index score 1 or≥2, respectively), and with increased mortality (Hazard Ratio (HR) = 1.45, 95% CI 1.38–1.53,P<0.0001;HR=2.38, 95% CI 2.18–2.60,P<0.0001; index score 1 or≥2). Undetected comorbidity is associated with less aggressive treatment and higher mortality in breast cancer.
The Relationship between Nocturnal Hypoxemia and Left Ventricular Ejection Fraction in Congestive Heart Failure Patients
Authors: Mirzaaghazadeh Mohammad , Bahtouee Mehrzad , Mehdiniya Fariba , Maleki Nasrollah , Tavosi Zahra
Published: February 2014

Congestive heart failure (CHF) is a major cause of mortality and morbidity. Among patients with heart failure, sleep disordered breathing (SDB) is a common problem. Current evidence suggests that SDB, particularly central SDB, is more prevalent in patients with CHF than in the general population, but it is underdiagnosed as SDB symptoms that are less prevalent in CHF. The main aims of this study were to determine the relationship between nocturnal hypoxemia and left ventricular ejection fraction in patients with chronic heart failure. By means of echocardiography, 108 patients with left ventricular ejection fraction ≤45% were divided into mild, moderate, and severe CHF. Hypoxemia was recorded overnight in the hospital and was measured by portable pulse oximetry. In the 108 patients with CHF, 44 (40.7%) were severe, 17 (15.7%) moderate, and 47 (43.6%) mild CHF. 95 (88%) of patients with CHF had abnormal patterns of nocturnal hypoxemia suggestive of Cheyne-Stokes respiration. Ejection fraction correlated negatively with dip frequency. There was no correlation between nocturnal hypoxemia with BMI and snoring. This study confirms strong associations between sleep apnea and heart disease in patients with CHF. Overnight oximetry is a useful screening test for Cheyne-Stokes respiration in patients with known heart failure.
Latency-Associated Nuclear Antigen of Kaposi Sarcoma–Associated Herpesvirus Promotes Angiogenesis through Targeting Notch Signaling Effector Hey1
Authors: Wang Xing , He Zhiheng , Xia Tian , Li Xiaofan , Liang Deguang , Lin Xianzhi , Wen Hao , Lan Ke
Published: February 2014

Notch signaling has been implicated in the pathogenesis of Kaposi sarcoma. Kaposi sarcoma is an angioproliferative neoplasm that originates from Kaposi sarcoma–associated herpesvirus (KSHV) infection. Previously, we showed that the KSHV LANA protein can stabilize intracellular Notch in KSHV-infected tumor cells and promote cell proliferation. However, whether Notch signaling functions in pathologic angiogenesis of Kaposi sarcoma remains largely unknown. Hey1, an essential downstream effector of the Notch signaling pathway, has been demonstrated to play a fundamental role in vascular development. In the present study, we performed whole transcriptome, paired-end sequencing on three patient-matched clinical Kaposi sarcoma specimens and their corresponding adjacent stroma samples, with an average depth of 42 million reads per sample. Dll4, Hey1, and HeyL displayed significant upregulation in Kaposi sarcoma. Further verification based on immunohistochemistry analysis demonstrated that Hey1 was indeed highly expressed in Kaposi sarcoma lesions. Using the Matrigel plug assay, we showed that downregulation of Hey1 and γ-secretase inhibitor treatment caused dramatic reduction in the formation of new blood vessels in mice. Interestingly, LANA was responsible for the elevated level of Hey1 through inhibition of its degradation. Importantly, Hey1 stabilized by LANA promoted the neoplastic vasculature. Taken together, our data suggest that hijacking of the proangiogenic property of Hey1 by LANA is an important strategy utilized by KSHV to achieve pathologic angiogenesis and that Hey1 is a potential therapeutic target in Kaposi sarcoma. Cancer Res; 74(7); 2026–37. ©2014 AACR.
Diagnostic Delay and Sociodemographic Predictors of Stage at Diagnosis and Mortality in Unilateral and Bilateral Retinoblastoma
Authors: Ramírez-Ortiz Marco A. , Ponce-Castañeda M. Veronica , Cabrera-Muñoz M. Lourdes , Medina-Sansón Aurora , Liu Xinhua , Orjuela Manuela A.
Published: February 2014

Background: More invasive retinoblastoma, characterized by increased morbidity and mortality, with lower rates of eye salvage and higher rates of extraocular dissemination, seems more prevalent in resource-poor countries. The relationship of diagnostic delay (lag time) and sociodemographic factors on the extent of disease at diagnosis has not been examined separately for unilateral and bilateral retinoblastoma.

Methods: At diagnosis, consenting parents of 179 Mexican children with retinoblastoma were interviewed about initial symptoms and household demographic characteristics. Clinical presentation was classified using St. Jude's, International Staging System (ISS), and International Intraocular Retinoblastoma Classification (IIRC) criteria. Lag time (delay between noting symptoms and diagnosis) and sociodemographic factors were examined as predictors for higher stage at diagnosis and overall survival (OS).

Results: In bilateral disease, lag time predicts stage at diagnosis using St. Jude's, and ISS criteria (P < 0.005 in multivariate regression), and OS (P < 0.05, Cox hazards), but not extent of intraocular disease (by IIRC). In unilateral disease, lag time predicts neither extent of disease (using ISS, St Jude's, and IIRC), nor OS. Indicators of prenatal poverty, including lower maternal education and the presence of dirt flooring in the home, predict more advanced disease by IIRC for bilateral retinoblastoma, and for unilateral by ISS, and St Jude's (P < 0.001) as well as OS (P < 0.05).

Conclusion: These results suggest unilateral and bilateral retinoblastoma differs in factors governing progression and extraretinal extension, possibly reflecting underlying biologic heterogeneity.

Impact: This demonstrates differing effect of social factors on extent of intra- and extraocular disease depending on laterality with implications for screening strategies. Cancer Epidemiol Biomarkers Prev; 23(5); 784–92. ©2014 AACR.
A Phase I, Multicenter, Open-Label, First-in-Human, Dose-Escalation Study of the Oral Smoothened Inhibitor Sonidegib (LDE225) in Patients with Advanced Solid Tumors
Authors: Rodon Jordi , Tawbi Hussein A. , Thomas Anne L. , Stoller Ronald G. , Turtschi Christian P. , Baselga Jose , Sarantopoulos John , Mahalingam Devalingam , Shou Yaping , Moles Melissa A. , Yang Lin , Granvil Camille , Hurh Eunju , Rose Kristine L. , Amakye Dereck D. , Dummer Reinhard , Mita Alain C.
Published: February 2014

Purpose: This phase I trial was undertaken to determine the maximum tolerated dose (MTD), dose-limiting toxicities (DLT), safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity of the novel smoothened inhibitor sonidegib (LDE225), a potent inhibitor of hedgehog signaling, in patients with advanced solid tumors.

Experimental Design: Oral sonidegib was administered to 103 patients with advanced solid tumors, including medulloblastoma and basal cell carcinoma (BCC), at doses ranging from 100 to 3,000 mg daily and 250 to 750 mg twice daily, continuously, with a single-dose pharmacokinetics run-in period. Dose escalations were guided by a Bayesian logistic regression model. Safety, tolerability, efficacy, pharmacokinetics, and biomarkers in skin and tumor biopsies were assessed.

Results: The MTDs of sonidegib were 800 mg daily and 250 mg twice daily. The main DLT of reversible grade 3/4 elevated serum creatine kinase (18% of patients) was observed at doses ≥ the MTD in an exposure-dependent manner. Common grade 1/2 adverse events included muscle spasm, myalgia, gastrointestinal toxicities, increased liver enzymes, fatigue, dysgeusia, and alopecia. Sonidegib exposure increased dose proportionally up to 400 mg daily, and displayed nonlinear pharmacokinetics at higher doses. Sonidegib exhibited exposure-dependent reduction in GLI1 mRNA expression. Tumor responses observed in patients with medulloblastoma and BCC were associated with evidence of hedgehog pathway activation.

Conclusions: Sonidegib has an acceptable safety profile in patients with advanced solid tumors and exhibits antitumor activity in advanced BCC and relapsed medulloblastoma, both of which are strongly associated with activated hedgehog pathway, as determined by gene expression. Clin Cancer Res; 20(7); 1900–9. ©2014 AACR.
Antitumor Activity of the Glutaminase Inhibitor CB-839 in Triple-Negative Breast Cancer
Authors: Gross Matt I. , Demo Susan D. , Dennison Jennifer B. , Chen Lijing , Chernov-Rogan Tania , Goyal Bindu , Janes Julie R. , Laidig Guy J. , Lewis Evan R. , Li Jim , MacKinnon Andrew L. , Parlati Francesco , Rodriguez Mirna L.M. , Shwonek Peter J. , Sjogren Eric B. , Stanton Timothy F. , Wang Taotao , Yang Jinfu , Zhao Frances , Bennett Mark K.
Published: February 2014

Glutamine serves as an important source of energy and building blocks for many tumor cells. The first step in glutamine utilization is its conversion to glutamate by the mitochondrial enzyme glutaminase. CB-839 is a potent, selective, and orally bioavailable inhibitor of both splice variants of glutaminase (KGA and GAC). CB-839 had antiproliferative activity in a triple-negative breast cancer (TNBC) cell line, HCC-1806, that was associated with a marked decrease in glutamine consumption, glutamate production, oxygen consumption, and the steady-state levels of glutathione and several tricarboxylic acid cycle intermediates. In contrast, no antiproliferative activity was observed in an estrogen receptor–positive cell line, T47D, and only modest effects on glutamine consumption and downstream metabolites were observed. Across a panel of breast cancer cell lines, GAC protein expression and glutaminase activity were elevated in the majority of TNBC cell lines relative to receptor positive cells. Furthermore, the TNBC subtype displayed the greatest sensitivity to CB-839 treatment and this sensitivity was correlated with (i) dependence on extracellular glutamine for growth, (ii) intracellular glutamate and glutamine levels, and (iii) GAC (but not KGA) expression, a potential biomarker for sensitivity. CB-839 displayed significant antitumor activity in two xenograft models: as a single agent in a patient-derived TNBC model and in a basal like HER2+ cell line model, JIMT-1, both as a single agent and in combination with paclitaxel. Together, these data provide a strong rationale for the clinical investigation of CB-839 as a targeted therapeutic in patients with TNBC and other glutamine-dependent tumors. Mol Cancer Ther; 13(4); 890–901. ©2014 AACR.
HIFs Enhance the Transcriptional Activation and Splicing of Adrenomedullin
Authors: Sena Johnny A. , Wang Liyi , Pawlus Matthew R. , Hu Cheng-Jun
Published: February 2014

Adrenomedullin (ADM) is important for tumor angiogenesis, tumor cell growth, and survival. Under normoxic conditions, the ADM gene was found to produce two alternative transcripts, a fully spliced transcript that produces AM and PAMP peptides and intron-3–retaining transcript that produces a less functionally significant PAMP peptide only. ADM is a well-established hypoxia inducible gene; however, it is not clear which ADM isoform is induced by hypoxia. In this study, it was determined that various cancer and normal cells express two predominant types of ADM transcripts, a AM/PAMP peptide producing full-length transcript in which all introns are removed, and a nonprotein producing I1-3 transcript in which all introns are retained. Interestingly, hypoxia preferentially induced the full-length isoform. Moreover, hypoxia-inducible factors (HIF), but not hypoxia per se, are necessary and sufficient to increase splicing of ADM pre-mRNA. ADM splicing reporters confirmed that transcriptional activation by HIF or other transcription factors is sufficient to enhance splicing. However, HIFs are more potent in enhancing ADM pre-mRNA splicing than other transcriptional activators. Thus, ADM intron retention is not a consequence of abnormal splicing, but is an important mechanism to regulate ADM expression. These results demonstrate a novel function of HIFs in regulating ADM expression by enhancing its pre-mRNA splicing. Importantly, using endogenous and cloned ADM gene, further evidence is provided for the coupling of transcription and RNA splicing.

Implications: Here, a novel function of HIFs in regulating ADM gene expression is identified by enhancing ADM pre-mRNA splicing. Mol Cancer Res; 12(5); 728–41. ©2014 AACR.
Efficacy of Sulbactam and Its Combination with Imipenem, Colistin and Tigecycline in an Experimental Model of Carbapenem-Resistant Acinetobacter baumannii Sepsis
Authors: Dinc Gokcen , Demiraslan Hayati , Elmali Ferhan , Ahmed Salman Shaheer , Metan Gokhan , Alp Emine , Doganay Mehmet
Published: February 2014

Background: In recent years, multidrug-resistant Acinetobacter baumannii has been reported as an important nosocomial pathogen, and treatment options are limited. The aim of this study was to investigate the additional effect of sulbactam on monotherapy with colistin, tigecycline and imipenem in experimental sepsis with carbapenem-resistant A. baumannii in mice. Methods: Sepsis was developed in 8- to 10-week-old BALB/c mice by an intraperitoneal injection of A. baumannii. Antibiotic was given intraperitoneally 2 h after bacterial inoculation. Each experimental group had 15 mice and was divided into 3 subgroups. Mice were sacrificed at 24, 48 or 72 h. Lung, liver, heart and spleen samples were cultured, and homogenates of lung and liver were used to detect the number of colony-forming units per gram. Bacterial clearance was compared in lung and liver at different time points. Results: Imipenem did not decrease the bacterial load, but the other antibiotics showed significant bactericidal activity compared with the control group, and the combination of imipenem with sulbactam decreased the bacterial load in lung and liver. However, the addition of sulbactam to colistin and tigecycline had no significant effect on bacterial counts. Only the addition of sulbactam to imipenem showed better bactericidal activity compared to imipenem alone. Conclusions: These results suggested that combining sulbactam with tigeycline or colistin does not increase the efficiency of these antibiotics.
Showing No Spot Sign Is a Strong Predictor of Independent Living after Intracerebral Haemorrhage
Authors: Havsteen Inger , Ovesen Christian , Christensen Anders F. , Hansen Christine Krarup , Nielsen Jens Kellberg , Christensen Hanne
Published: February 2014

Background: A spot sign on computed tomography angiography (CTA) is a potentially strong predictor of poor outcome on ultra-early radiological imaging. The aim of this study was to assess the spot sign as a predictor of functional outcome at 3 months as well as long-term mortality, with a focus on the ability to identify patients with a spontaneous, acceptable outcome. Methods: In a prospective, consecutive single-centre registry of acute stroke patients, we investigated patients with spontaneous intracerebral haemorrhage (ICH) admitted within 4.5 h after symptom onset from April 2009 to January 2013. The standard work-up in our centre included CTA for spot sign status, unless a contraindication was present. Modified Rankin Scale (mRS) scores were assessed at 3 months in the outpatient clinic or by telephone interviews. Long-term mortality was assessed by electronic chart follow-up for up to 1,500 days. Results: Of the 128 patients, 37 (28.9%) had a spot sign on admission CTA. The presence of a spot sign was associated with larger median admission haematoma volume [38.0 ml (IQR 18.0-78.0) vs. 12.0 ml (5.0-24.0); p < 0.0001] and higher median National Institutes of Health Stroke Scale score [19 (IQR 12-23) vs. 12 (6-16); p < 0.0001]. Three months after stroke, the median functional outcome was considerably better in patients without spot sign [mRS score 3 (IQR 2-4) vs. 6 (4-6); p < 0.0001]. The absence of a spot sign showed a sensitivity and specificity for good outcome (mRS scores 0-2) of 0.91 and 0.36, respectively. The presence of a spot sign was, in multivariate models, an independent inverse predictor of good 3-month outcome (OR 0.17; 95% CI: 0.03-0.88) as well as a prominent independent predictor of poor 3-month outcome (mRS scores 5-6; OR 3.40; 95% CI: 1.10-10.5) and death during follow-up (HR 3.04; 95% CI: 1.45-6.34). Patients with a spot sign surviving the acute phase had long-term survival comparable to patients with no spot sign. Conclusion: The absence or presence of a spot sign is a reliable ultra-early predictor of long-term mortality and functional outcome in patients with spontaneous ICH.
Does Vestibular End-Organ Function Recover after Gentamicin-Induced Trauma in Guinea Pigs?
Authors: Bremer Hendrik G. , Versnel Huib , Hendriksen Ferry G.J. , Topsakal Vedat , Grolman Wilko , Klis Sjaak F.L.
Published: February 2014

Until 1993 it was commonly accepted that regeneration of vestibular hair cells was not possible in mammals. Two histological studies then showed structural evidence for spontaneous regeneration of vestibular hair cells after gentamicin treatment. There is less evidence for functional recovery going along with this regenerative process; in other words, do regenerated hair cells function adequately? This study aims to address this question, and in general evaluates whether spontaneous functional recovery may occur, in the short or long term, in mammals after ototoxic insult. Guinea pigs were treated with gentamicin for 10 consecutive days at a daily dose of 125 mg/kg body weight. Survival times varied from 1 day to 16 weeks. Vestibular short-latency evoked potentials (VsEPs) to linear acceleration pulses were recorded longitudinally to assess otolith function. After the final functional measurements we performed immunofluorescence histology for hair cell counts. Auditory brainstem responses (ABRs) to click stimuli were recorded to assess cochlear function. As intended, gentamicin treatment resulted in significant loss of utricular hair cells and accompanying declines in VsEPs. Hair cell counts 8 or 16 weeks after treatment did not significantly differ from counts after shorter survival periods. Maximal functional loss was achieved 1-4 weeks after treatment. After this period, only 2 animals showed recovery of VsEP amplitude - all other animals did not reveal signs of regeneration or recovery. In contrast, after initial ABR threshold shifts there was a small but significant recovery. We conclude that spontaneous recovery of otolith function, in contrast to cochlear function, is very limited in guinea pigs. These results support the concept of intratympanic gentamicin treatment where gentamicin is used for chemoablation of the vestibular sensory epithelia.
Pulmonary Cryptococcosis with Trachea Wall Invasion in an Immunocompetent Patient: A Case Report and Literature Review
Authors: Sun Li , Chen Hui , Shao Changzhou , Song Yuanlin , Bai Chunxue
Published: February 2014

Cryptococcosis causes significant morbidity and mortality in the world. Pulmonary cryptococcosis is a kind of subacute or chronic pulmonary fungal disease. We present a case of pulmonary cryptococcosis with a trachea wall invasion-like malignant tumor in an immunocompetent patient and a literature review. The 44-year-old man, a nonsmoker, suffered from mild dyspnea and white sputum with intermittent blood streaks. A computed tomography (CT) scan of his chest showed two possibly malignant lesions in the right hilum and upper-right field of his lung, which have higher uptake values of fluorodeoxyglucose on positron emission tomography (PET)/CT. Lung biopsy pathology showed scattered fungal spores and positive periodic acid-Schiff (PAS) staining. The immune status and blood tumor markers were all normal in this patient. The titer of Cryptococcus antigen latex agglutination test was 1:1,280. Under fiberoptic bronchoscopy, a prominent new mass on the right wall of the trachea blocked most of the right main bronchus. To reduce the symptoms of airway obstruction, treatment by bronchoscopy, i.e. ablation and endotracheal stent, was used. As his symptoms were aggravated by the use of itraconazole, amphotericin B liposome was used as antifungal treatment. All these methods led to a better prognosis. We conclude that pulmonary cryptococcosis may mimic lung neoplasms radiologically and bronchoscopically, even in immunocompetent patients.
Epithelioid Trophoblastic Tumor: Report of Two Cases in Postmenopausal Women with Literature Review and Emphasis on Cytological Findings
Authors: Almarzooqi Saeeda , Ahmad Al-Safi Rema'a , Fahad Al-Jassar Waleed , Akhter Syed M.J. , Chiab-Rassou Yamina , Albawardi Alia
Published: February 2014

Background: Epithelioid trophoblastic tumor (ETT) is a rare gestational trophoblastic neoplasm of intermediate trophoblasts. It was first described by Shih and Kurman [Am J Surg Pathol 1998;22:1393-1403] who outlined its clinicopathologic characteristics in 14 cases, establishing it as a distinct entity of gestational trophoblastic tumors. It represents 1.39% of all gestational trophoblastic diseases. Most cases are reported in reproductive-age women following a prior gestation with a time interval between 2 weeks and 30 years. ETT is extremely rare in postmenopausal women. It is commonly misdiagnosed as a squamous cell carcinoma (SCC), poorly differentiated carcinoma or another gestational trophoblastic tumor. Limited data is available regarding its cytological features on Pap smears. Cases: We report 2 cases of uterine ETT occurring in postmenopausal women. In both cases, an initial diagnosis of an SCC and a poorly differentiated carcinoma was rendered. We highlight the features of ETT helpful in differentiating it from other mimickers with emphasis on rarely reported cytological features of this neoplasm. Conclusion: ETT is a rare tumor with characteristic cytological features, but is commonly confused with SCC. A high index of suspicion is needed to make the correct diagnosis or to raise the consideration of ETT, especially in cases with an increased β-human chorionic gonadotropin.
Certolizumab-Induced Uveitis: A Case Report and Review of the Literature
Authors: Moisseiev Elad , Shulman Shiri
Published: February 2014

We report the case of a 64-year-old woman with rheumatoid arthritis and bilateral visual deterioration. The patient had been treated with certolizumab, a new tumor necrosis factor alpha (TNFα) antagonist, and her findings were consistent with bilateral uveitis, suggestive of sarcoidosis. Here, we review the literature on TNFα antagonist-induced sarcoidosis and report the first case of uveitis induced by certolizumab. Awareness of the possibility of this unique complication is important for both rheumatologists and ophthalmologists who treat patients with this new agent.
Nutzung eines webbasierten Selbsthilfeprogramms für Traumaopfer: Auswertung von Dropout-Raten und ihren Prädiktoren
Authors: Wang Zhiyun , Küffer Andreas , Wang Jianping , Maercker Andreas
Published: February 2014

Hintergrund: In der vorliegenden Studie wird das Login- und Nutzungsverhalten von traumatisierten Personen aus China für ein webbasiertes Selbsthilfeprogramm beschrieben. Methode: Von 428 Personen, die einen Screening-Fragebogen ausgefüllt hatten, entsprachen 323 den Aus- und Einschlusskriterien, und 103 Personen ließen sich für ein Interventions-/Wartelistendesign randomisieren. Die Adhärenz wurde mittels Dropout-Raten über die Anzahl der Besuchstage auf der Internetseite und die Anzahl an besuchten Seiten gemessen. Ergebnisse: Von den 103 Teilnehmern nutzten 59.2% das Programm über eine Zeitdauer von 1 Monat. 39.8% der Personen lieferten Follow-up-Daten. Von 61 Nutzern besuchten 83.6% die Website an 5 oder weniger Tagen und 29.2% zeigten eine starke Nutzung der Seite (> 100 aufgerufene Seiten). Die Analysen zeigten, dass die Anzahl der Besuchstage mit dem wahrgenommenen familiären Unverständnis korreliert, und dass die Anzahl besuchter Seiten mit dem wahrgenommenen generellen Unverständnis und dem bewältigungsbezogenen Selbstwert assoziiert ist. Schlussfolgerungen: Es zeigten sich ähnlich hohe Abbruchraten wie bei anderen webbasierten Interventionen (WBI) ohne Therapeutenkontakt. Um die Nutzung zu verbessern, sollten weitere WBI für posttraumatische Belastungsstörungen (PTBS) spezifisch auf die Bedürfnisse der Personen eingehen, die wegen negativer sozialer Reaktionen um ihre soziale Anerkennung als Traumaopfer besorgt sind (z.B. generelles und familiäres Unverständnis).
Enhancement of Drug-Specific Lymphocyte Proliferation Using CD25hi-Depleted CD3+ Effector Cells
Authors: Srinoulprasert Yuttana , Pichler Werner J.
Published: February 2014

Background: The lymphocyte transformation test (LTT) is used for in vitro diagnosis of drug hypersensitivity reactions. While its specificity is over 90%, sensitivity is limited and depends on the type of reaction, drug and possibly time interval between the event and analysis. Removal of regulatory T cells (Treg/CD25hi) from in vitro stimulated cell cultures was previously reported to be a promising method to increase the sensitivity of proliferation tests. Objective: The aim of this investigation is to evaluate the effect of removal of regulatory T cells on the sensitivity of the LTT. Methods: Patients with well-documented drug hypersensitivity were recruited. Peripheral blood mononuclear cells, isolated CD3+ and CD3+ T cells depleted of the CD25hi fraction were used as effector cells in the LTT. Irrelevant drugs were also included to determine specificity. 3H-thymidine incorporation was utilized as the detection system and results were expressed as a stimulation index (SI). Results: SIs of 7/11 LTTs were reduced after a mean time interval of 10.5 months (LTT 1 vs. LTT 2). Removal of the CD25hi fraction, which was FOXP3+ and had a suppressive effect on drug-induced proliferation, resulted in an increased response to the relevant drugs. Sensitivity was increased from 25 to 82.35% with dramatically enhanced SI (2.05 to 6.02). Specificity was not affected. Conclusion: Removal of Treg/CD25hi cells can increase the frequency and strengths of drug-specific proliferation without affecting specificity. This approach might be useful in certain drug hypersensitivity reactions with borderline responses or long time interval since the hypersensitivity reaction.
Extracellular Superoxide Dismutase Ameliorates Skeletal Muscle Abnormalities, Cachexia, and Exercise Intolerance in Mice with Congestive Heart Failure
Authors: Okutsu Mitsuharu , Call Jarrod A. , Lira Vitor A. , Zhang Mei , Donet Jean A. , French Brent A. , Martin Kyle S. , Peirce-Cottler Shayn M. , Rembold Christopher M. , Annex Brian H. , Yan Zhen
Published: February 2014

Background—

Congestive heart failure (CHF) is a leading cause of morbidity and mortality, and oxidative stress has been implicated in the pathogenesis of cachexia (muscle wasting) and the hallmark symptom, exercise intolerance. We have previously shown that a nitric oxide–dependent antioxidant defense renders oxidative skeletal muscle resistant to catabolic wasting. Here, we aimed to identify and determine the functional role of nitric oxide–inducible antioxidant enzyme(s) in protection against cardiac cachexia and exercise intolerance in CHF.

Methods and Results—

We demonstrated that systemic administration of endogenous nitric oxide donor
S
-nitrosoglutathione in mice blocked the reduction of extracellular superoxide dismutase (EcSOD) protein expression, as well as the induction of
MAFbx/Atrogin-1
mRNA expression and muscle atrophy induced by glucocorticoid. We further showed that endogenous EcSOD, expressed primarily by type IId/x and IIa myofibers and enriched at endothelial cells, is induced by exercise training. Muscle-specific overexpression of EcSOD by somatic gene transfer or transgenesis (muscle creatine kinase [MCK]-EcSOD) in mice significantly attenuated muscle atrophy. Importantly, when crossbred into a mouse genetic model of CHF (α-myosin heavy chain–calsequestrin),
MCK-EcSOD
transgenic mice had significant attenuation of cachexia with preserved whole body muscle strength and endurance capacity in the absence of reduced HF. Enhanced EcSOD expression significantly ameliorated CHF-induced oxidative stress,
MAFbx/Atrogin-1
mRNA expression, loss of mitochondria, and vascular rarefaction in skeletal muscle.

Conclusions—

EcSOD plays an important antioxidant defense function in skeletal muscle against cardiac cachexia and exercise intolerance in CHF.
Emergence of Hydrogen Sulfide as an Endogenous Gaseous Signaling Molecule in Cardiovascular Disease
Authors: Polhemus David J. , Lefer David J.
Published: February 2014

Long recognized as a malodorous and highly toxic gas, recent experimental studies have revealed that hydrogen sulfide (H
2
S) is produced enzymatically in all mammalian species including man and exerts several critical actions to promote cardiovascular homeostasis and health. During the past 15 years, scientists have determined that H
2
S is produced by 3 endogenous enzymes and exerts powerful effects on endothelial cells, smooth muscle cells, inflammatory cells, mitochondria, endoplasmic reticulum, and nuclear transcription factors. These effects have been reported in multiple organ systems, and the majority of data clearly indicate that H
2
S produced by the endogenous enzymes exerts cytoprotective actions. Recent preclinical studies investigating cardiovascular diseases have demonstrated that the administration of physiological or pharmacological levels of H
2
S attenuates myocardial injury, protects blood vessels, limits inflammation, and regulates blood pressure. H
2
S has emerged as a critical cardiovascular signaling molecule similar to nitric oxide and carbon monoxide with a profound effect on the heart and circulation. Our improved understanding of how H
2
S elicits protective actions, coupled with the rapid development of novel H
2
S-releasing agents, has resulted in heightened enthusiasm for the clinical translation of this ephemeral gaseous molecule. This review will examine our current state of knowledge about the actions of H
2
S within the cardiovascular system with an emphasis on the therapeutic potential and molecular cross talk between H
2
S, nitric oxide, and carbon monoxide.
MicroRNA Regulation and Cardiac Calcium Signaling
Authors: Harada Masahide , Luo Xiaobin , Murohara Toyoaki , Yang Baofeng , Dobrev Dobromir , Nattel Stanley
Published: February 2014

MicroRNAs (miRNAs) are emerging as key control molecules in the regulation of gene expression, and their role in heart disease is becoming increasingly evident. Given the critical role of Ca
2+
handling and signaling proteins in the maintenance of cardiac function, the targeting of such proteins by miRNAs would be expected to have important consequences. miRNAs have indeed been shown to control the expression of genes encoding important Ca
2+
handling and signaling proteins, and are themselves regulated by Ca
2+
-dependent processes. Ca
2+
-related miRNAs have been found to be significant pathophysiological contributors in conditions like myocardial ischemic injury, cardiac hypertrophy, heart failure, ventricular arrhythmogenesis, and atrial fibrillation. This review is a comprehensive analysis of the present knowledge concerning miRNA regulation of Ca
2+
handling processes, the participation of Ca
2+
-regulating miRNAs in the evolution of heart disease, the mutual relationship between Ca
2+
signaling and miRNAs in the control of cardiac function, and the potential value of miRNA-control of Ca
2+
handling as a therapeutic target.
Trimeric Intracellular Cation Channels and Sarcoplasmic/Endoplasmic Reticulum Calcium Homeostasis
Authors: Zhou Xinyu , Lin Peihui , Yamazaki Daiju , Park Ki Ho , Komazaki Shinji , Chen S.R. Wayne , Takeshima Hiroshi , Ma Jianjie
Published: February 2014

Trimeric intracellular cation channels (TRIC) represents a novel class of trimeric intracellular cation channels. Two TRIC isoforms have been identified in both the human and the mouse genomes: TRIC-A, a subtype predominantly expressed in the sarcoplasmic reticulum (SR) of muscle cells, and TRIC-B, a ubiquitous subtype expressed in the endoplasmic reticulum (ER) of all tissues. Genetic ablation of either TRIC-A or TRIC-B leads to compromised K
+
permeation and Ca
2+
release across the SR/ER membrane, supporting the hypothesis that TRIC channels provide a counter balancing K
+
flux that reduces SR/ER membrane depolarization for maintenance of the electrochemical gradient that drives SR/ER Ca
2+
release. TRIC-A and TRIC-B seem to have differential functions in Ca
2+
signaling in excitable and nonexcitable cells.
Tric-a
−/−
mice display defective Ca
2+
sparks and spontaneous transient outward currents in arterial smooth muscle and develop hypertension, in addition to skeletal muscle dysfunction. Knockout of TRIC-B results in abnormal IP
3
receptor–mediated Ca
2+
release in airway epithelial cells, respiratory defects, and neonatal lethality. Double knockout mice lacking both TRIC-A and TRIC-B show embryonic lethality as a result of cardiac arrest. Such an aggravated lethality indicates that TRIC-A and TRIC-B share complementary physiological functions in Ca
2+
signaling in embryonic cardiomyocytes.
Tric-a
−/−
and
Tric-b
+/−
mice are viable and susceptible to stress-induced heart failure. Recent evidence suggests that TRIC-A directly modulates the function of the cardiac ryanodine receptor 2 Ca
2+
release channel, which in turn controls store-overload–induced Ca
2+
release from the SR. Thus, the TRIC channels, in addition to providing a countercurrent for SR/ER Ca
2+
release, may also function as accessory proteins that directly modulate the ryanodine receptor/IP
3
receptor channel functions.
Predicting Future Brain Tissue Loss From White Matter Connectivity Disruption in Ischemic Stroke
Authors: Kuceyeski Amy , Kamel Hooman , Navi Babak B. , Raj Ashish , Iadecola Costantino
Published: February 2014

Background and Purpose—

The Network Modification (NeMo) Tool uses a library of brain connectivity maps from normal subjects to quantify the amount of structural connectivity loss caused by focal brain lesions. We hypothesized that the Network Modification Tool could predict remote brain tissue loss caused by poststroke loss of connectivity.

Methods—

Baseline and follow-up MRIs (10.7±7.5 months apart) from 26 patients with acute ischemic stroke (age, 74.6±14.1 years, initial National Institutes of Health Stroke Scale, 3.1±3.1) were collected. Lesion masks derived from diffusion-weighted images were superimposed on the Network Modification Tool’s connectivity maps, and regional structural connectivity losses were estimated via the Change in Connectivity (ChaCo) score (ie, the percentage of tracks connecting to a given region that pass through the lesion mask). ChaCo scores were correlated with subsequent atrophy.

Results—

Stroke lesions’ size and location varied, but they were more frequent in the left hemisphere. ChaCo scores, generally higher in regions near stroke lesions, reflected this lateralization and heterogeneity. ChaCo scores were highest in the postcentral and precentral gyri, insula, middle cingulate, thalami, putamen, caudate nuclei, and pallidum. Moderate, significant partial correlations were found between baseline ChaCo scores and measures of subsequent tissue loss (
r
=0.43,
P
=4.6×10
–9
;
r
=0.61,
P
=1.4×10
–18
), correcting for the time between scans.

Conclusions—

ChaCo scores varied, but the most affected regions included those with sensorimotor, perception, learning, and memory functions. Correlations between baseline ChaCo and subsequent tissue loss suggest that the Network Modification Tool could be used to identify regions most susceptible to remote degeneration from acute infarcts.
Three Alternatives to Measure the Human-Likeness of a Handshake Model in a Turing-like Test
Authors: Nisky Ilana , Avraham Guy , Karniel Amir
Published: February 2014

In the Turing test, a computer model is deemed to think intelligently if it can generate answers indistinguishable from those of a human. We proposed a Turing-like handshake test for testing motor aspects of machine intelligence. The test is administered through a telerobotic system in which an interrogator holds a robotic stylus and interacts with another party—human, artificial, or a linear combination of the two. Here, we analyze and test experimentally the properties of three versions of the Turing-like handshake test: Pure, Weighted, and Noise. We follow the framework of signal detection theory, and propose a simplified model for the interrogator human-likeness evaluation; we simulate this model and provide an assessment of the statistical power of each version of the handshake test. Our simulation study suggests that the choice of the best test depends on how well the interrogator identifies a human handshake when compared with a model. The Pure test is better for intermediate and large levels of interrogator confusion, and the Weighted and Noise tests are good for low levels of confusion. We then present the results of an experimental study in which we compare among three simple models for a human handshake. We demonstrate that it is possible to distinguish between these handshake models, and discuss the relative advantage of each measure and future possible handshake models and Turing-like tests, in measuring and promoting the design of human-like robots for robotics rehabilitation, teleoperation, and telepresence.
Assessing the Incremental Validity of Spirituality in Predicting Nurses’ Burnout
Authors: Galea Michael
Published: February 2014

This population study examined the incremental validity of spirituality in predicting burnout among Maltese professional nurses. Cross-sectional and mixed-method design was conducted. Measures in this self-report questionnaire included the Maslach Burnout Inventory, Faith Maturity Scale, Satisfaction with Life Scale, Big Five Inventory and a demographic section, together with a brief qualitative section. Response rate was 78%. All hypotheses were supported. Maltese nurses (N = 121) suffer from high levels of burnout, in particular from low professional accomplishment, high levels of depersonalization, and moderate to high emotional exhaustion. Qualitative data supported these findings and suggested that the physical and moral environment of nurses was conducive to an increase of burnout. Furthermore, multiple regression analysis indicated that spirituality predicted burnout after controlling for personality and well-being. This study suggests that spirituality may be an important potential source of resilience for nurses who risk burnout in their employment.
The Coherence Hypothesis: Critical Reconsideration, Reception History and Development of a Theoretical Model
Authors: Jeserich Florian
Published: February 2014

It is still largely unclear which pathways explain the religion-health connection and how these mechanisms work. One such intervening mechanism, coherence, is the focus of this article. Based on database searches and a review of the literature retrieved, I differentiate between six meanings of coherence in religion-related research: 1) consistency; 2) credibility; 3) congruence; 4) confidence; 5) character; and 6) cohesion. In this article, this classification is utilized to analyse the conceptualizations and operationalizations of coherence within a particular strain of research, namely the discourse on the so-called coherence hypothesis. In so doing, I accomplish three objectives: 1) the reconsideration of the classical coherence hypothesis launched by Idler in the mid-1980s; 2) the reconstruction of the history of the reception and modification of the hypothesis by using the example of the work of three influential scholars (Christopher G. Ellison, Linda K. George, and Sebastian Murken); and 3) the development of a new theoretical model of religion, coherence, and health. Since the review yielded that coherence was primarily used within the meaning of confidence and congruence and that personal and social factors have been widely neglected, one advantage of my model is the integration of all six conceptual varieties of coherence within a meaning-making coping framework.
New earthworm records from Turkey, with description of three new species (Oligochaeta: Lumbricidae)
Authors: SZEDERJESI TÍMEA , PAVLÍČEK TOMÁS , COŞKUN YÜKSEL , CSUZDI CSABA
Published: February 2014

Identifying the earthworm material recently collected in different parts of Turkey (Marmara Region, Upper Mesopotamia, Hatay Province and East Anatolia) resulted in records of 29 earthworm species including three lumbricids new to science: Dendrobaena cevdeti, D. szalokii and Eisenia patriciae spp. nov. In addition, Dendrobaena cognettii is reported for the first time from the country. With this contribution, the number of earthworm species and subspecies registered in Turkey is raised to 80.
A new species of Lasinus Sharp (Coleoptera: Staphylinidae: Pselaphinae) from East China
Authors: YIN ZI-WEI , BEKCHIEV ROSTISLAV , LI LI-ZHEN
Published: February 2014

Lasinus orientalis Yin & Bekchiev, new species, is described from the eastern Chinese provinces of Zhejiang and Jiangxi, with major diagnostic features illustrated. The new species is compared with, and distinguished from related congeners.
A Total Flow Perspective of Atmospheric Mass and Angular Momentum Circulations: Boreal Winter Mean State
Authors: Cai Ming , Shin Chul-Su
Published: February 2014

This paper reports a comprehensive diagnostic analysis of mass and angular momentum (AM) circulations and their budgets in boreal winter using the 32-yr daily NCEP–Department of Energy (DOE) reanalysis (1979–2010). The diagnosis is performed using instantaneous total flows before taking time and zonal average without decomposition of time mean and transient flows and separation of zonal mean and wavy flows. The analysis reveals that embedded in a broad hemispheric thermally direct meridional mass circulation in each hemisphere are three distinct but interconnected thermally direct meridional cells. They are the tropical Hadley cell, the stratospheric cell, and the extratropical zonally asymmetric Hadley cell. The tropical Hadley cell corresponds to the Hadley cell of the classic three-cell model whereas the extratropical Hadley cell and the stratospheric cell correspond to the eddy-driven extratropical residual circulation.

The joint consideration of meridional mass and AM circulations helps to substantiate Hadley’s original view that the hemispheric-wide thermally direct meridional circulation can have broad surface easterly in the tropics and westerly in the extratropics. Because the mass circulation cannot have a net divergence anywhere in long time mean and the earth’s AM decreases toward the poles, the companion AM transport in the equatorward cold air branch inevitably has to be divergent. The downward transfer of westerly AM to the cold air branch by the pressure torque associated with westward tilted baroclinic waves dominates such divergence in the extratropics, explaining the prevailing surface westerly there. In the tropics and polar region where the meridional circulation is nearly zonally symmetric, the dominance of this divergence results in a surface easterly there.
Performance of a New Convective Parameterization Scheme on Model Convergence in Simulations of a Tropical Cyclone at Grey-Zone Resolutions
Authors: Sun Yuan , Yi Lan , Zhong Zhong , Ha Yao
Published: February 2014

The latest version of the Weather Research and Forecasting model (WRFV3.5) is used to evaluate the performance of the Grell and Freitas (GF13) cumulus parameterization scheme on the model convergence in simulations of a tropical cyclone (TC) at gray-zone resolutions. The simulated TC intensity converges to a finite limit as the grid spacing varies from 7.5 to 1 km. The reasons for the model convergence are investigated from perspectives of subgrid-scale processes and thermodynamic and dynamic structures. It is found that the impacts of above factors are notably different with varying model resolutions. The convective heating and drying increase as the grid spacing decreases, which inhibits the explicit microphysical parameterization preventing the simulated TC from overly intensifying. As the grid spacing decreases from 7.5 to 5 km, the TC intensity increases because of a stronger secondary circulation, a larger magnitude and proportion of strong eyewall updraft, and a greater amount of latent heating in the eyewall. As the grid spacing decreases from 5 to 3 km, the radius of maximum wind (RMW) decreases and the radial pressure gradient increases leading to an increase in TC intensity. The simulated TC intensity changes slightly as the grid spacing decreases from 3 to 1 km since the RMW and the storm structure both change little. The slight changes in the simulated TC intensity at such high resolutions indicate a great model convergence. Therefore, the GF13 presents an appropriate option that increases the model convergence in the TC intensity simulation at gray-zone resolution.
A Comparison of Two Heavy Rainfall Events during the Terrain-Influenced Monsoon Rainfall Experiment (TiMREX) 2008
Authors: Tu Chuan-Chi , Chen Yi-Leng , Chen Ching-Sen , Lin Pay-Liam , Lin Po-Hsiung
Published: February 2014

Two contrasting localized heavy rainfall events during Taiwan’s early summer rainy season with the daily rainfall maximum along the windward mountain range and coast were studied and compared using a combination of observations and numerical simulations. Both events occurred under favorable large-scale settings including the existence of a moisture tongue from the tropics. For the 31 May case, heavy rainfall occurred in the afternoon hours over the southwestern windward slopes after a shallow surface front passed central Taiwan. The orographic lifting of the prevailing warm, moist, west-southwesterly flow aloft, combined with a sea breeze–upslope flow at the surface provided the localized lifting needed for the development of heavy precipitation. On 16 June before sunrise, pronounced orographic blocking of the warm, moist, south-southwesterly flow occurred because of the presence of relatively cold air at low levels as a result of nocturnal and rain evaporative cooling. As a result, convective systems intensified as they moved toward the southwestern coast. During the daytime, the cold pool remained over southwestern Taiwan without the development of onshore/upslope flow. Furthermore, with a south-southwesterly flow aloft parallel to terrain contours, orographic lifting aloft was absent and preexisting rain cells offshore diminished after they moved inland. Over northern Taiwan on the lee side, a sea breeze/onshore flow developed in the afternoon hours, resulting in heavy thundershowers. These results demonstrate the importance of diurnal and local effects on determining the location and timing of the occurrences of localized heavy precipitation during the early summer rainy season over Taiwan.