bluuebunny/crossref_metadata_2025 huggingface dataset:
Characteristics of Lung Cancers Harboring NRAS Mutations
Authors: Ohashi Kadoaki , Sequist Lecia V. , Arcila Maria E. , Lovly Christine M. , Chen Xi , Rudin Charles M. , Moran Teresa , Camidge David Ross , Vnencak-Jones Cindy L. , Berry Lynne , Pan Yumei , Sasaki Hidefumi , Engelman Jeffrey A. , Garon Edward B. , Dubinett Steven M. , Franklin Wilbur A. , Riely Gregory J. , Sos Martin L. , Kris Mark G. , Dias-Santagata Dora , Ladanyi Marc , Bunn Paul A. , Pao William
Published: March 2013

Purpose: We sought to determine the frequency and clinical characteristics of patients with lung cancer harboring NRAS mutations. We used preclinical models to identify targeted therapies likely to be of benefit against NRAS-mutant lung cancer cells.

Experimental Design: We reviewed clinical data from patients whose lung cancers were identified at six institutions or reported in the Catalogue of Somatic Mutations in Cancer (COSMIC) to harbor NRAS mutations. Six NRAS-mutant cell lines were screened for sensitivity against inhibitors of multiple kinases (i.e., EGFR, ALK, MET, IGF-1R, BRAF, PI3K, and MEK).

Results: Among 4,562 patients with lung cancers tested, NRAS mutations were present in 30 (0.7%; 95% confidence interval, 0.45%–0.94%); 28 of these had no other driver mutations. 83% had adenocarcinoma histology with no significant differences in gender. While 95% of patients were former or current smokers, smoking-related G:C>T:A transversions were significantly less frequent in NRAS-mutated lung tumors than KRAS-mutant non–small cell lung cancer [NSCLC; NRAS: 13% (4/30), KRAS: 66% (1772/2733), P < 0.00000001]. Five of 6 NRAS-mutant cell lines were sensitive to the MEK inhibitors, selumetinib and trametinib, but not to other inhibitors tested.

Conclusion: NRAS mutations define a distinct subset of lung cancers (∼1%) with potential sensitivity to MEK inhibitors. Although NRAS mutations are more common in current/former smokers, the types of mutations are not those classically associated with smoking. Clin Cancer Res; 19(9); 2584–91. ©2013 AACR.
Urinary TMPRSS2:ERG and PCA3 in an Active Surveillance Cohort: Results from a Baseline Analysis in the Canary Prostate Active Surveillance Study
Authors: Lin Daniel W. , Newcomb Lisa F. , Brown Elissa C. , Brooks James D. , Carroll Peter R. , Feng Ziding , Gleave Martin E. , Lance Raymond S. , Sanda Martin G. , Thompson Ian M. , Wei John T. , Nelson Peter S. ,   for the Canary Prostate Active Surveillance Study Investigators
Published: March 2013

Purpose: Active surveillance is used to manage low-risk prostate cancer. Both PCA3 and TMPRSS2:ERG are promising biomarkers that may be associated with aggressive disease. This study examines the correlation of these biomarkers with higher cancer volume and grade determined at the time of biopsy in an active surveillance cohort.

Experimental Design: Urine was collected after digital rectal examination prospectively as part of the multi-institutional Canary Prostate Active Surveillance Study (PASS). PCA3 and TMPRSS2:ERG levels were analyzed in urine collected at study entry. Biomarker scores were correlated to clinical and pathologic variables.

Results: In 387 men, both PCA3 and TMPRSS2:ERG scores were significantly associated with higher volume disease. For a negative repeat biopsy, and 1% to 10%, 11% to 33%, 34% or more positive cores, median PCA3, and TMPRSS2:ERG scores increased incrementally (P < 0.005). Both PCA3 and TMPRSS2:ERG scores were also significantly associated with the presence of high-grade disease. For a negative repeat biopsy, Gleason 6 and Gleason ≥7 cancers, the median PCA3, and TMPRSS2:ERG scores also increased incrementally (P = 0.02 and P = 0.001, respectively). Using the marker scores as continuous variables, the ORs for a biopsy in which cancer was detected versus a negative repeat biopsy (ref) on modeling was 1.41 (95% CI: 1.07–1.85), P = 0.01 for PCA3 and 1.28 (95% CI: 1.10–1.49), P = 0.001 for TMPRSS2:ERG.

Conclusions: For men on active surveillance, both PCA3 and TMPRSS2:ERG seem to stratify the risk of having aggressive cancer as defined by tumor volume or Gleason score. Clin Cancer Res; 19(9); 2442–50. ©2013 AACR.
Using Neurobiological Measures to Predict and Assess Treatment Outcome of Psychotherapy in Posttraumatic Stress Disorder: Systematic Review
Authors: Zantvoord Jasper B. , Diehle Julia , Lindauer Ramón J.L.
Published: March 2013

Background: Trauma-focused cognitive-behavioral therapy (TF-CBT) and eye movement desensitization and reprocessing (EMDR) are effective treatments for posttraumatic stress disorder. However, little is known about their neurobiological effects. The usefulness of neurobiological measures to predict the treatment outcome of psychotherapy also has yet to be determined. Methods: Systematic review of randomized controlled trials (RCTs) focused on neurobiological treatment effects of TF-CBT or EMDR and trials with neurobiological measures as predictors of treatment response. Results: We included 23 publications reporting on 16 separate trials. TF-CBT was compared with a waitlist in most trials. TF-CBT was associated with a decrease in heart rate and blood pressure and changes in activity but not in volume of frontal brain structures and the amygdala. Neurobiological changes correlated with changes in symptom severity. EMDR was only tested against other active treatments in included trials. We did not find a difference in neurobiological treatment effects between EMDR and other treatments. Publications on neurobiological predictors of treatment response showed ambiguous results. Conclusion: TF-CBT was associated with a reduction of physiological reactivity. There is some preliminary evidence that TF-CBT influences brain regions involved in fear conditioning, extinction learning and possibly working memory and attention regulation; however, these effects could be nonspecific psychotherapeutic effects. Future trials should use paradigms aimed specifically at these brain regions and physiological reactivity. There are concerns regarding the risk of bias in some of the RCTs, indicating that methodologically more rigorous trials are required. Trials with neurobiological measures as predictors of treatment outcome render insufficient results to be useful in clinical practice.
Upregulation of Intestinal NHE3 Following Saline Ingestion
Authors: Pasham Venkanna , Rotte Anand , Gu Shuchen , Yang Wenting , Bhandaru Madhuri , Rexhepaj Rexhep , Pathare Ganesh , Lang Florian
Published: March 2013

Background: Little is known about the effect of salt content of ingested fluid on intestinal transport processes. Osmosensitive genes include the serum- and glucocorticoid-inducible kinase SGK1, which is up-regulated by hyperosmolarity and cell shrinkage. SGK1 is in turn a powerful stimulator of the intestinal Na+/H+ exchanger NHE3. The present study was thus performed to elucidate, whether the NaCl content of beverages influences NHE3 activity. Methods: Mice were offered access to either plain water or isotonic saline ad libitum. NHE3 transcript levels and protein abundance in intestinal tissue were determined by confocal immunofluorescent microscopy, RT-PCR and western blotting, cytosolic pH (pHi) in intestinal cells from 2',7'-bis-(2-carboxyethyl)-5-(and-6)-carboxyfluorescein (BCECF) fluorescence and Na+/H+ exchanger activity from the Na+ dependent realkalinization following an ammonium pulse. Results: Saline drinking significantly enhanced fluid intake and increased NHE3 transcript levels, NHE3 protein and Na+/H+ exchanger activity. Conclusions: Salt content of ingested fluid has a profound effect on intestinal Na+/H+ exchanger expression and activity.
Association between Ozone Exposure and Onset of Stroke in Allegheny County, Pennsylvania, USA, 1994-2000
Authors: Xu Xiaohui , Sun Yilun , Ha Sandie , Talbott Evelyn O. , Lissaker Claudia T.K.
Published: March 2013

Background: Epidemiological studies have shown adverse short-term effects of air pollution on health including cardiovascular morbidity and mortality. However, air pollution-related stroke has received less attention. Methods: In this study, we performed a time-stratified case-crossover analysis to evaluate the relationships between stroke hospital admissions and O3, among patients aged 65 years and older in Allegheny County, Pa., USA, between 1994 and 2000. We also examined whether the effects of air pollutants differed across strata defined by patient demographic characteristics and ambient temperature. Results: Exposures to O3 on the current day increase the risk of total stroke hospitalization by 1.9% (95% CI: 0.01-3.8) per interquartile range increase in concentration. Furthermore, the results suggest that males were more sensitive to adverse health effects of O3 on stroke hospitalization than females. Conclusion: These results suggest that O3 has an adverse effect on stroke hospitalization. Specific patient subgroups, such as males, may be at increased risk.
Seasonal Variation in the Incidence of Aneurysmal Subarachnoid Hemorrhage Associated with Age and Gender: 20-Year Results from the Yamaguchi Cerebral Aneurysm Registry
Authors: Ishihara Hideyuki , Kunitsugu Ichiro , Nomura Sadahiro , Koizumi Hiroyasu , Yoneda Hiroshi , Shirao Satoshi , Oka Fumiaki , Morihiro Yusuke , Yoshino Hiroko , Suzuki Michiyasu ,   Yamaguchi Neurosurgical Association
Published: March 2013

Background: This study was a cerebral aneurysm registry study conducted in a region with few climatic differences. Based on data collected for over 20 years, seasonal variations and characteristics of subarachnoid hemorrhage (SAH) due to ruptured aneurysms were analyzed. Methods: This study included 5,007 patients in the Yamaguchi Prefecture with aneurysmal SAH between 1986 and 2005. Incidence rates by month, sex, age, severity, and aneurysm site were analyzed. Results: In women, seasonal variation was observed, in particular among those aged ≥50 years. Among those aged 50-69 years, the highest incidence was in October, and the nadir was in June (peak-to-trough ratio = 1.72). At age ≥70 years, this was slightly different, with the highest incidence in December and the nadir in July (peak-to-trough ratio = 1.48). However, there was no seasonal variation in men overall; it was limited to elderly men at age ≥70 years, with the highest incidence in January and the nadir in July (peak-to-trough ratio = 2.9). Aneurysm site and severity showed no relationship with seasonal variation. Conclusion: The present study shows seasonal variations in the onset of SAH. Seasonal variations in SAH differed depending on age and sex.
On Being Indigenous: An Essay on the Hermeneutics of ‘Cultural Identity'
Authors: Chandler Michael J.
Published: March 2013

The range of cultural resources distributed along developmental pathways open to young persons as they frame the outlines of their own identities is not fixed, but inevitably varies across historical moments. The young lives most touched by such transitional circumstances arguably belong to those that find themselves growing up in times of dramatic cultural change - the lives, for example, of refugee and immigrant children, and especially of those indigenous youth still riding out the successive waves of earlier postcolonial storms. This essay is about forming an identity in such troubled times, and about how individual parents and whole rearing communities might choose to selectively intervene. The thesis of this paper is that the material contents of cultures in transition ordinarily have shorter ‘shelf lives' and earlier ‘best before' dates than do those processes and practices at work in the procedural background. Consequently, it is argued that a parent's or a community's best hopes for success in aiding young people in their identity struggles lie along instructional pathways that feature the signature tools and processes, rather than the material contents, of cultures in radical transition.
Prognostic Significance of Pretreatment 18F-FDG PET/CT in Patients with Relapsed/Refractory B-Cell Non-Hodgkin's Lymphoma Treated by Radioimmunotherapy Using 131I-Rituximab
Authors: Lim Ilhan , Park Joon Yeun , Kang Hye Jin , Hwang Jae Pil , Lee Seung Sook , Kim Kyeong Min , Choi Tae Hyun , Yang Sung Hyun , Kim Byung Il , Choi Chang Woon , Lim Sang Moo
Published: March 2013

Aims: It was the aim of this paper to identify prognostic factors in patients with relapsed or refractory B-cell non-Hodgkin's lymphomas, treated by radioimmunotherapy (RIT) with radioiodinated human/murine chimeric anti-CD20 monoclonal antibody rituximab (131I-rituximab). Methods: Twenty-four patients were enrolled prospectively and were treated with unlabeled rituximab 70 mg and a therapeutic activity (median 7.3 GBq) of 131I-rituximab. Contrast-enhanced 18F-FDG PET/CT scans were performed before and after 1 month of RIT. Tumor sizes and maximum standardized uptake values (SUVmax) of scans were measured. Results: Four of the 24 patients survived. High SUVmax in a pretreatment scan was found to be related to poorer overall survival (OS) and progression-free survival (p = 0.04 and 0.02, respectively). Furthermore, a large tumor size in a pretreatment scan was associated with poorer OS but not with progression-free survival (p < 0.01 and p = 0.07, respectively). By multivariate analyses, a high SUVmax, a large tumor size in a pretreatment scan and diffuse large B-cell lymphoma histology were significantly associated with poorer OS [p = 0.04/hazard ratio (HR) = 3.54, p < 0.01/HR = 5.52, and p = 0.02/HR = 3.38, respectively). Conclusion: SUVmax and tumor size determined by a pretreatment 18F-FDG PET/CT result as significant predictors of OS in patients with relapsed or refractory B-cell non-Hodgkin's lymphoma treated by RIT.
The Concept of Situation and the Microgenesis of the Conscious Purpose in Cultural Psychology
Authors: Clarà Marc
Published: March 2013

The importance of the specific environment for understanding the microgenesis of psychological processes is well documented. It can be argued, however, that the theoretical framework of cultural psychology which is usually referred to as cultural-historical activity theory (CHAT) underconceptualizes this aspect, thereby hampering its ability to provide an adequate theoretical explanation of some microgenetic processes. More specifically, it is difficult for CHAT to explain the formation of the conscious purpose of activity - that is, its intentional aspect. This paper proposes to introduce the concepts of situation, circumstance and practical relations into CHAT. By means of an example it is argued that these concepts can explain the intentional aspect of activity, which no other current concepts in CHAT are able to do. Consequently, it is suggested that there is a strong case for incorporating these concepts within CHAT.
MR and Targeted Molecular MRI of Vulnerable Plaques
Authors: Yang Jiping , Yang Haiqing , Cao Liqing , Li Shujun
Published: March 2013

Plaque rupture or erosion represents a major cause of stroke and the acute coronary syndrome. Information on plaque morphology and composition is essential to identify patients at increased risk for acute cardio- and cerebrovascular events, and may play a key role in individualizing therapeutic strategies and monitoring the effect of interventions. The rapidly emerging field of MR and targeted molecular MRI allows to qualitatively and quantitatively characterize plaque features. We aimed to review the literature regarding the current most promising advanced techniques to image vulnerable atherosclerotic plaques.
The Changes of Serum Angiotensin-Converting Enzyme 2 in Patients with Pulmonary Arterial Hypertension due to Congenital Heart Disease
Authors: Dai Hai-long , Guo Yue , Guang Xue-feng , Xiao Zhi-cheng , Zhang Ming , Yin Xiao-long
Published: March 2013

Background: Angiotensin-converting enzyme 2 (ACE2), a primary component of the vasoprotective axis in the renin-angiotensin system (RAS), has recently been found to have regulatory actions in hypoxic pulmonary hypertension and monocrotaline-induced pulmonary hypertension. We explored the hypothesis that the level of ACE2 protein contents may be decreased in patients with pulmonary arterial hypertension (PAH) due to congenital heart disease (CHD). Objective: We observed the serum ACE2 protein contents in patients with PAH due to CHD (CHD-PAH), and investigated their correlation with mean pulmonary arterial pressure (mPAP). Methods: One hundred and four patients with CHD and 33 normal control patients (group A) were involved in the research. The patients with CHD were divided into 55 cases of nonpulmonary hypertension (group B), 25 cases of mild to moderate pulmonary hypertension (group C) and 24 cases of severe pulmonary hypertension (group D). The serum level of ACE2 protein contents were detected by enzyme-linked immunosorbent assay (ELISA), and the relationship between these contents and mPAP were analyzed. Results: ACE2 protein contents significantly declined as mPAP increased. The mPAP was negatively correlated with the level of ACE2 protein contents. Conclusions: These results demonstrated that ACE2 may play an important regulatory role in CHD-PAH.
Comparison of Voice Quality after Laser Cordectomy with That after Radiotherapy or Chemoradiotherapy for Early Glottic Carcinoma
Authors: Tomifuji Masayuki , Araki Koji , Niwa Katsuki , Miyagawa Yoshihiro , Mizokami Daisuke , Kitagawa Yoko , Yamashita Taku , Matsunobu Takeshi , Shiotani Akihiro
Published: March 2013

Purpose of the Study: The present study aimed to compare the voice quality after each type of cordectomy with that after radiotherapy (RT) or chemoradiotherapy (CRT) for early glottic carcinoma. Procedures: The GRBAS perceptive scale [consisting of 5 domains: grade (G), roughness (R), breathiness (B), asthenia (A), and strain (S)], aerodynamic tests and acoustic analyses, and the Voice Handicap Index questionnaire were evaluated for 58 laser cordectomy cases and 40 RT or CRT cases. Multiple comparison tests were conducted between each type of cordectomy and RT or CRT. Results: No statistical difference was found between type I/II cordectomy and RT for T1 glottic carcinoma (T1RT), whereas T1RT showed a significantly better outcome than type III cordectomy (G score: p = 0.016, maximum phonation time: p < 0.01, mean flow rate: p < 0.01). Type IV cordectomy was equivalent to RT or CRT for T2 glottic carcinoma (T2RT/CRT), while types V and VI showed a worse voice quality than T2RT/CRT (G score: p = 0.038 to type VI, B score: p = 0.025 to type V and p = 0.032 to type VI, A score: p = 0.017 to type VI). Conclusions: Voice quality after laser cordectomy differs according to the type of cordectomy. Surgeons should inform patients about the expected voice quality after each treatment modality.
Effects of Comprehensive Health Assessment and Targeted Intervention on Chair Rise Capacity in Active and Inactive Community-Dwelling Older People
Authors: Tikkanen Päivi , Lönnroos Eija , Sipilä Sarianna , Nykänen Irma , Sulkava Raimo , Hartikainen Sirpa
Published: March 2013

Background: Being able to rise from a chair is an important daily life activity that requires sufficient lower extremity muscle power and postural control. Objective: To assess the effects of an individually tailored intervention on the chair rise capacity of active and inactive community-dwelling older men and women. Methods: This study included a community-based sample of ≥75-year-olds who were randomized into intervention (n = 299) and control (n = 260) groups. The intervention started in 2004 and ended in December 2006; all the participants of the intervention group received individually targeted physical activity counseling annually and had an opportunity to participate in supervised strength and balance training once a week. Chair rise tests were conducted annually. The mixed model of linear regression was used for unadjusted measurements and age, and the Mini-Mental State Examination and functional comorbidity index adjusted comparisons of effects of the intervention. Results: The intervention improved the chair rise capacity in physically active women (adjusted mean difference -1.67 s, 95% confidence interval -3.21 to -0.13, p = 0.02). There was no improvement in inactive women or in men, regardless of their physical activity level. Conclusion: Intervention showed a positive effect on the chair rise capacity of physically active community-dwelling older women.
From a Regional Cohort of Extremely Low Birth Weight Infants: Cardiac Function at the Age of 7 Years
Authors: Kwinta Przemko , Jagła Mateusz , Grudzień Andrzej , Klimek Małgorzata , Zasada Magdalena , Pietrzyk Jacek Jozef
Published: March 2013

Background: The long-term impact of prematurity on cardiac structure and function has not yet been fully discovered. Objectives: To assess long-term cardiac complications in the regional cohort of extremely low birth weight (ELBW) children born in 2002-2004. Material and Methods: Eighty-one children born as ELBW infants (91% of the available cohort) with a median birth weight of 890 g (25-75th percentile: 760-950) were evaluated at the mean age of 6.7 years. The control group included 40 children born full-term, selected from one general practice in the district. Echocardiography and 24-hour ambulatory blood pressure measurements (ABPM) were performed. The primary outcome variable was the presence of cardiac complications such as left ventricular hypertrophy (LVH), diastolic dysfunction or systolic dysfunction. Results: LVH was diagnosed in 4/81 ELBW children and 2/40 control children (p = 1.0). Concentric remodeling was detected in 8 (10%) subjects from the ELBW group and in 2 (5%) from the control group (p = 0.49). There were no patients with diastolic or systolic dysfunction in either group. After having expressed the results of M-mode echocardiography as z-scores for body surface area (BSA), statistically significant differences were observed for right-ventricle dimension in diastole (-1.49 ± 1.25 vs. -0.31 ± 0.91; p < 0.001), LV inner dimension in diastole (-0.53 ± 1.26 vs. 0.13 ± 0.94; p = 0.01) and left atrium (-0.93 ± 1.07 vs. -0.15 ± 1.02; p < 0.01). Heart rate (HR) was significantly faster in ELBW children (92.9 ± 8.4 vs. 86.7 ± 7.4 bpm; p = 0.01 adjusted for BSA) and they also had significantly higher night-time blood pressure [mean (z-score): 1.15 vs. 0.2; p = 0.02] without nocturnal dipping (night-time dipping <10%: 13 (16.7%) vs. 2 (5.2%), p = 0.13). Conclusions: No differences were found between the groups in the occurrence of cardiac complications. Ex-preterm ELBW children at age 6 may have a faster HR, smaller cardiac dimensions on echocardiography and higher nocturnal blood pressure. The clinical relevance of these findings is unknown.
E-Cadherin and β-Catenin Expression during Urothelial Carcinogenesis Induced by N-butyl-N-(4-hydroxybutyl) nitrosamine in Mice
Authors: Vasconcelos-Nóbrega C. , Costa C. , Vala H. , Colaço A. , Santos L. , Lopes C. , Oliveira P.A.
Published: March 2013

Background: E-cadherin and β-catenin are adhesion molecules that promote integrity and stability of the urothelium. A decrease in their expression is associated with more aggressive tumour phenotypes with the ability to invade and metastasize. Material and Methods: 45 ICR male mice were used, of which 25 received N-butyl-N-(4-hydroxybutyl)nitrosamine (0.05%) in drinking water for a period of 12 weeks. Immunohistochemical expression was evaluated in all urinary bladder preparations for E-cadherin and for β-catenin. Results: Preneoplastic lesions showed staining patterns similar to normal urothelium. In simple and nodular hyperplasia, membrane staining was dominant (66.7-78.6 and 50-100%, respectively). In dysplasia a cytoplasmic pattern was prevalent (86.7-100%). Neoplastic lesions exhibit an abnormal staining pattern (100%) with heterogeneous staining (cytoplasmic, nuclear and membrane staining). A strong correlation was observed between both adhesion molecule staining patterns (r = 0.83; p = 0.039). Conclusions: In mice, as in humans, E-cadherin and β-catenin are valuable tools to investigate cellular adhesion status of urothelium and can be considered as indicators of tumour aggressiveness and evolution.
High Prevalence of Autoimmune Thyroiditis in Children and Adolescents with Vitiligo
Authors: Kroon Marije W. , Vrijman Charlotte , Chandeck Charlotte , Wind Bas S. , Wolkerstorfer Albert , Luiten Rosalie M. , Bos Jan D. , Geskus Ronald B. , van Trotsenburg Paul , van der Veen J.P. Wietze
Published: March 2013

Background/Aims: Vitiligo is considered to be an autoimmune disease and is known to be associated with other autoimmune diseases, particularly affecting the thyroid. In children and adolescents this association has been reported in only a few studies, with varying results. The aim of this study was to examine thyroid function and prevalence of thyroid autoimmunity in children and adolescents with vitiligo and to investigate the utility of screening. Methods: Two hundred and sixty patients with vitiligo were enrolled. Plasma TSH, FT4 and anti-thyroid peroxidase (TPO) antibody concentrations were measured. The prevalence of thyroid dysfunction and autoimmunity were compared to the general healthy paediatric population. Results: Autoimmune thyroiditis (AIT) with thyroid hormone disturbances was diagnosed in 16 patients (6.2%). This is significantly higher than the prevalence reported in the general healthy paediatric population. Increased levels of anti-TPO antibodies (= 30 kU/l), without thyroid hormone disturbances, were found in 27 patients (10.5%). Conclusion: The prevalence of AIT in children and adolescents with vitiligo is significantly higher than in the general population. It may be advantageous to screen thyroid function and antibody levels in all paediatric patients with non-segmental vitiligo. To strengthen recommendations on screening, research on the burden for patients and cost-effectiveness is needed.
In vitro Skin Permeation and Penetration of Nonivamide from Novel Film-Forming Emulsions
Authors: Lunter D. , Daniels R.
Published: March 2013

The purpose of this study was to develop film-forming emulsions (FFE) facilitating long-term treatment of chronic pruritus with capsaicinoids. To this end, oil-in-water emulsions, which comprise dispersions of sustained-release polymers, were examined. Such emulsions form a film when applied to the skin and encapsulate the oily drug solution in a dry polymeric matrix. Permeation of the antipruritic drug nonivamide (NVA) is controlled by the matrix. Permeation rates of NVA from FFE and its concentration in the skin are equivalent to those achieved with a conventional semisolid formulation, but can be maintained for a longer period of time. FFE may therefore improve the treatment of chronic pruritus with capsaicinoids by enhancing patient compliance by means of a sustained-release regimen.
Efficacy of a New Tonic Containing Urea, Lactate, Polidocanol, and Glycyrrhiza inflata Root Extract in the Treatment of a Dry, Itchy, and Subclinically Inflamed Scalp
Authors: Schweiger Dorothea , Baufeld Caroline , Drescher Philip , Oltrogge Bernhardt , Höpfner Simone , Mess Aylin , Lüttke Juliane , Rippke Frank , Filbry Alexander , Max Heiner
Published: March 2013

Background/Aims: Dry, itchy and inflamed scalp conditions are common and often associated with diseases such as atopic dermatitis or psoriasis. To improve these symptoms, we investigated the efficacy of a new tonic containing the active ingredients urea, lactate, polidocanol, and Glycyrrhiza inflata root extract, containing licochalcone A. Study Design/Methods: 30 subjects with dry and itchy scalp conditions underwent a randomized half-head study for 4 weeks, applying the leave-on tonic three times a week on one side of the scalp. Tonic effects on skin hydration, itching, lipids, microinflammation, and substantivity of tonic compounds were determined using corneometry, middle-infrared spectroscopy, direct analysis in real-time mass spectrometry, and enzyme-linked immunosorbent assay. Volunteers performed a self-assessment; changes in scalp condition were documented by in vivo microscopy. Results: After tonic treatment, scalp moisture was significantly increased, whereas scalp itching and tautness were significantly reduced. Results also demonstrated a high substantivity of urea and lactate on the scalp, an increase in triglyceride, and a decrease in free fatty acid levels. The amount of total lipids was unchanged. Analyses of scalp wash-ups verified a significant reduction in important pro-inflammatory markers. Conclusion: Due to the actives urea, lactate, polidocanol, and the anti-inflammatory licochalcone A, the new scalp tonic exhibited excellent performance in alleviating scalp dryness, itching, microinflammation, and in normalizing disturbances of scalp lipids.
A Memory Already like an Elephant's? The Advanced Brain Morphology of the Last Common Ancestor of Afrotheria (Mammalia)
Authors: Benoit Julien , Crumpton Nick , Mérigeaud Samuel , Tabuce Rodolphe
Published: March 2013

Virtually reconstructed and natural endocranial casts are used in the study of brain evolution through geological time. We here present work investigating the paleoneurological evolution of afrotherian mammals. Using microCT-generated endocasts we show that, with the exception of the subfamilies Macroscelidinae and Tenrecoidea, most Afroinsectiphilia display a more or less gyrencephalic and ventrally expanded neopallium, two derived features that are unexpected for these insectivore-grade afrotherians. This implies that the endocranial cast morphology at the root of the afrotherian clade may have been more advanced than previously thought. The reconstructed endocranial morphology of the Afrotheria's last common ancestor reaches the level of complexity of some early Cenozoic archaic ungulates. Our result gives support to the hypothesis of an ungulate-like ancestral body plan for Afrotheria. It also implies that the a priori ‘primitive' suite of traits evident in the brain of Afroinsectivora, especially in the tenrecs, may have been secondarily acquired. Implications on the overestimation of the divergence age of Afrotheria are discussed.
Right Ventricular Performance in Preterm and Term Neonates: Reference Values of the Tricuspid Annular Peak Systolic Velocity Measured by Tissue Doppler Imaging
Authors: Koestenberger Martin , Nagel Bert , Ravekes William , Gamillscheg Andreas , Pichler Gerhard , Avian Alexander , Heinzl Bernd , Binder Corinna , Cvirn Gerhard , Urlesberger Berndt
Published: March 2013

Background: The tricuspid annular peak systolic velocity (S′) is an echocardiographic measurement to assess systolic right ventricular function in adults and children. Objective: We determined growth and birth weight-related changes of S′ to establish reference values in preterm and term neonates. Methods: A prospective study was conducted in a group of 290 preterm and term neonates (gestational age 26 + 0 to 40 + 6 weeks of gestation; birth weight 660-4,460 g). A correlation of S′ values with established tricuspid annular plane systolic excursion (TAPSE) values was performed. Results: The S′ ranged from a mean of 4.5 cm/s (Z-score ± 2 SD: 3.6-5.5 cm/s) in preterm neonates in week 260-6 of gestation to 7.8 cm/s (Z-score ± 2 SD: 5.5-10.1 cm/s) in term neonates in week 400-6 of gestation. The S′ values increased from 26 to 40 weeks of gestation. S′ and week of gestation are strongly correlated: Pearson's correlation coefficient was 0.66 for week of gestation - S′ (p < 0.001). A significant correlation was found between S′ and TAPSE values (r = 0.67; p < 0.001). Conclusion: Z-scores of S′ values were calculated and percentile charts were established to serve as reference data for preterm and term neonates with structurally normal hearts.
Dalteparin Dosing in High-Flux Haemodialysis and Haemodiafiltration
Authors: Sridharan Sivakumar , Berdeprado Jocelyn , Sivalingam Murugan , Farrington Ken
Published: March 2013

Background: Low-molecular-weight heparins are being increasingly used as an alternative to unfractionated heparin for anticoagulation of the haemodialysis (HD) circuit. Data on dalteparin use in high-flux HD and haemodiafiltration (HDF) are limited. We examined the safety and efficacy of dalteparin in this setting to enable recommendations on the optimal dose range. Methods: This prospective study was conducted in a single dialysis unit. Subjects who had been receiving dalteparin for at least 10 HD sessions were studied. Anti-Xa activity was measured for all subjects at the start of the HD session, at 60 min into HD and at the end of dialysis. Results: 55 subjects were studied. None had detectable anti-Xa activity at the start of the session. Using adequacy criteria based on target anti-Xa activity >0.4 IU/ml at 1 h and <0.4 IU/ml at the end of dialysis, 39 (71%) patients had adequate anticoagulation, 12 (22%) patients were under-anticoagulated and 4 (7%) were over-anticoagulated. The mean dose in the adequately anticoagulated group was 60.7 ± 11.7 IU/kg, in the under-anticoagulated group 39.3 ± 9.6 IU/kg and in the over-anticoagulated group 70.1 ± 14.6 IU/kg. The optimal dose of dalteparin appears to be 60 ± 10 IU/kg, which facilitates the achievement of the target anti-Xa activity in the range of 0.4-0.75 IU/ml at 1 h and <0.4 IU/ml at the session end. Conclusion: Dalteparin is a safe and effective anticoagulant for patients on high-flux HD and HDF. The optimal dose appears to be 60 ± 10 IU/kg. The desirable target range of anti-Xa activity is 0.4-0.75 at 1 h and <0.4 IU/ml at the session end.
Socio-Economic Disparities in the Distribution of Cardiovascular Risk in Chronic Kidney Disease Stage 3
Authors: Fraser Simon D.S. , Roderick Paul J. , McIntyre Natasha J. , Harris Scott , McIntyre Christopher W. , Fluck Richard J. , Taal Maarten W.
Published: March 2013

Background/Aims: For most people with chronic kidney disease (CKD), cardiovascular disease (CVD) risk exceeds risk of progression to end-stage renal disease. This study aimed to investigate the distribution of cardiovascular risk in CKD stage 3 by socio-economic status (SES; measured by area deprivation and educational attainment) and CKD diagnosis awareness. Methods: 1,741 patients with CKD 3 recruited from primary-care practices for the Renal Risk in Derby Study were assessed for cardiovascular risk factors. Ten-year cardiovascular risk, estimated using Framingham and QRISK2 risk prediction algorithms in eligible subgroups, was dichotomised at ≥20% (a threshold for clinical action in the UK), and compared by SES and awareness of CKD diagnosis using logistic regression. Results: Patients with lower SES had greater adjusted odd ratios (OR) of smoking, diabetes and previous CVD, but not of central obesity, hypertension, elevated total/high-density-lipoprotein cholesterol ratio or albuminuria. Using Framingham scoring (n = 672), the adjusted OR of having ≥20% 10-year risk were 2.87 [95% confidence interval (CI) 1.41-5.84] in the lowest deprivation quintile compared to the highest, 2.52 (95% CI: 1.52-4.00) in those without qualifications compared to those with qualifications, and 1.54 (95% CI: 1.09-2.17) in those unaware of their CKD diagnosis compared to those aware of it. QRISK2 scoring (n = 1,071) showed a similar association with education status [OR: 2.45 (95% CI: 1.63-3.67)] and lack of CKD awareness [OR: 1.46 (95% CI: 1.05-2.03)], but not with deprivation [OR: 1.12 (95% CI: 0.55-2.27)]. Conclusion: An elevated CVD risk is associated with a lower education status and lack of awareness of CKD diagnosis in people with CKD 3.
Idiopathic Erythrocytosis in Dialysis Patients: A Case Report and Literature Review
Authors: Sheqwara Jawad , Alkhatib Yaser , Dabak Vrushali , Kuriakose Philip
Published: March 2013

Anemia is a common complication in end-stage renal disease (ESRD) patients. On the other hand, idiopathic erythrocytosis is extremely rare, with only a few cases reported in the literature. We present a case of erythrocytosis that developed after initiating hemodialysis. A 68-year-old male with a history of ESRD secondary to diabetes presented with erythrocytosis that started a few months after initiating dialysis in the absence of having received erythropoietin-stimulating agents or iron supplements. His erythropoietin level was elevated, with a negative JAK2 mutation. Blood gases showed normal oxygen and CO2, with slightly elevated carboxyhemoglobin. Tiny foci in both kidneys were noted, representing vascular calcifications or renolithiasis. There was no radiological evidence of neoplasms or cysts. After excluding secondary causes, a diagnosis of idiopathic erythrocytosis was made. The patient underwent intermittent phlebotomies during dialysis, and his hemoglobin went from 18.5 to 14 mg/dl. Erythrocytosis in ESRD patients is very rare. So far, there is no complete understanding of the underlying pathophysiology; however, there seem to be multiple possible reasons for an increased erythropoietin level. Phlebotomy is a successful and easy way to control erythrocytosis in such patients. Angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, currently being used in posttransplant erythrocytosis, might also be considered.
Thirty-Five-Year-Old Woman with Signet Ring Cell Gastric Carcinoma Secondary to the Chernobyl Nuclear Accident: A Case Report
Authors: Mayhall Kim , Ghayouri Masoumeh , Henry Katherine , Margin Veronica , Copolla Domeinico , Shackelford Rodney
Published: March 2013

The 1986 Chernobyl nuclear accident resulted in radiation exposures throughout much of Europe, with the highest exposures within the city of Pripyat, Ukraine, where the accident occurred. We report a woman who was exposed to the Chernobyl accident at age 13. Beginning in her early thirties, she experienced several years of upper abdominal pain that became progressively more severe. At age 35, she underwent upper endoscopy and gastric biopsy. Histological examination revealed a signet ring cell (SRC) gastric carcinoma. The tumor was discovered at an advanced stage and proved unresectable. She died 3 months following her diagnosis. The mean age for SRC gastric carcinoma diagnosis is about 62 years; the median survival following diagnosis is 13 months. The early appearance and aggressive clinical course of this malignancy in relation to the Chernobyl nuclear accident is discussed.
Are Steroids a Beneficial Adjunctive Therapy in the Immunosuppressed Patient with Herpes Simplex Virus Encephalitis?
Authors: Lizarraga Karlo J. , Alexandre Lucien C. , Ramos-Estebanez Ciro , Merenda Amedeo
Published: March 2013

Few reports describe the reactivation of latent herpes simplex virus causing encephalitis (HSVE) in patients undergoing brain radiation therapy and a concomitant steroid regimen. The role for steroid use in the treatment of patients with HSVE has not been fully elucidated. We report the case of a female patient immunosuppressed by steroids and brain radiation who developed HSVE and responded to acyclovir and dexamethasone.
Combined Na
+
/Ca
2+
Exchanger and L-Type Calcium Channel Block as a Potential Strategy to Suppress Arrhythmias and Maintain Ventricular Function
Authors: Bourgonje Vincent J.A. , Vos Marc A. , Ozdemir Semir , Doisne Nicolas , Acsai Karoly , Varro Andras , Sztojkov-Ivanov Anita , Zupko Istvan , Rauch Erik , Kattner Lars , Bito Virginie , Houtman Marien , van der Nagel Roel , Beekman Jet D. , van Veen Toon A.B. , Sipido Karin R. , Antoons Gudrun
Published: March 2013

Background—

L-type calcium channel (LTCC) and Na
+
/Ca
2+
exchanger (NCX) have been implicated in repolarization-dependent arrhythmias, but also modulate calcium and contractility. Although LTCC inhibition is negative inotropic, NCX inhibition has the opposite effect. Combined block may, therefore, offer an advantage for hemodynamics and antiarrhythmic efficiency, particularly in diseased hearts. In a model of proarrhythmia, the dog with chronic atrioventricular block, we investigated whether combined inhibition of NCX and LTCC with SEA-0400 is effective against dofetilide-induced torsade de pointes arrhythmias (TdP), while maintaining calcium homeostasis and hemodynamics.

Methods and Results—

Left ventricular pressure (LVP) and ECG were monitored during infusion of SEA-0400 and verapamil in anesthetized dogs. Different doses were tested against dofetilide-induced TdP in chronic atrioventricular block dogs. In ventricular myocytes, effects of SEA-0400 were tested on action potentials, calcium transients, and early afterdepolarizations. In cardiomyocytes, SEA-0400 (1 μmol/L) blocked 66±3% of outward NCX, 50±2% of inward NCX, and 33±9% of LTCC current. SEA-0400 had no effect on systolic calcium, but slowed relaxation, despite action potential shortening, and increased diastolic calcium. SEA-0400 stabilized dofetilide-induced lability of repolarization and suppressed early afterdepolarizations. In vivo, SEA-0400 (0.4 and 0.8 mg/kg) had no effect on left ventricular pressure and suppressed dofetilide-induced TdPs dose dependently. Verapamil (0.3 mg/kg) also inhibited TdP, but caused a 15±8% drop of left ventricular pressure. A lower dose of verapamil without effects on left ventricular pressure (0.06 mg/kg) was not antiarrhythmic.

Conclusions—

In chronic atrioventricular block dogs, SEA-0400 treatment is effective against TdP. Unlike specific inhibition of LTCC, combined NCX and LTCC inhibition has no negative effects on cardiac hemodynamics.
Impaired Assembly and Post-translational Regulation of 26S Proteasome in Human End-Stage Heart Failure
Authors: Day Sharlene M. , Divald Andras , Wang Ping , Davis Frank , Bartolone Sarah , Jones Richard , Powell Saul R.
Published: March 2013

Background—

This study examined the hypothesis that 26S proteasome dysfunction in human end-stage heart failure is associated with decreased docking of the 19S regulatory particle to the 20S proteasome. Previous studies have demonstrated that 26S proteasome activity is diminished in human end-stage heart failure associated with oxidation of the 19S regulatory particle Rpt5 subunit. Docking of the 19S regulatory particle to the 20S proteasome requires functional Rpt subunit ATPase activity and phosphorylation of the α-type subunits.

Methods and Results—

An enriched proteasome fraction was prepared from 7 human nonfailing and 10 failing heart explants. Native gel electrophoresis assessed docking of 19S to 20S proteasome revealing 3 proteasome populations (20S, 26S, and 30S proteasomes). In failing hearts, 30S proteasomes were significantly lower (
P
=0.048) by 37% suggesting diminished docking. Mass spectrometry–based phosphopeptide analysis demonstrated that the relative ratio of phosphorylated:non phosphorylated α7 subunit (serine
250
) of the 20S proteasome was significantly less (
P
=0.011) by almost 80% in failing hearts. Rpt ATPase activity was determined in the enriched fraction and after immunoprecipitation with an Rpt6 antibody. ATPase activity (ρmol PO
4
/μg protein per hour) of the total fraction was lowered from 291±97 to 194±27 and in the immunoprecipitated fraction from 42±12 to 3±2 (
P
=0.005) in failing hearts.

Conclusions—

These studies suggest that diminished 26S activity in failing human hearts may be related to impaired docking of the 19S to the 20S as a result of decreased Rpt subunit ATPase activity and α7 subunit phosphorylation.
Effects of Exercise on Left Ventricular Systolic and Diastolic Properties in Patients With Heart Failure and a Preserved Ejection Fraction Versus Heart Failure and a Reduced Ejection Fraction
Authors: Zile Michael R. , Kjellstrom Barbro , Bennett Tom , Cho Yong , Baicu Catalin F. , Aaron Mark F. , Abraham William T. , Bourge Robert C. , Kueffer Fred J.
Published: March 2013

Background—

The purpose of the current study was to define exercise-induced changes in indices of left ventricular (LV) systolic and diastolic properties in patients with chronic heart failure (HF), compare these changes in patients with HF and a reduced ejection fraction (EF) versus HF and a preserved EF, and compare the hemodynamic responses to activities of daily living with symptom-limited upright exercise.

Methods and Results—

Subjects with HF and a preserved EF (n=8) and subjects with HF and a reduced EF (n=5) underwent symptom-limited Naughton protocol treadmill exercise tests. Implantable hemodynamic monitor data and echocardiographic data were obtained before exercise and at peak exercise. Implantable hemodynamic monitor data were obtained during activities of daily living during a 24-hour time period. In patients with HF and a reduced EF, limited exercise time (639±164 seconds) was associated with a marked rise in right ventricular systolic, diastolic, and estimated pulmonary artery diastolic (ePAD) pressures and an increase in LV end diastolic volume (EDV). LV systolic properties, namely EF, end systolic elastance, stroke work, and preload recruitable stroke work, all decreased. The ePAD/EDV ratio increased; to a large extent, this was dependent on an increase in EDV. By contrast, in HF and a preserved EF, limited exercise time (411±128 seconds) and the marked rise in right ventricular systolic, diastolic, and ePAD pressures were associated with no change in LV EDV. LV systolic properties increased or were unchanged; ePAD/EDV ratio increased during exercise, but the increase was independent of a change in EDV. The ranges of right ventricular systolic, diastolic, and ePAD pressures during activities of daily living were higher than the ranges of these values during the exercise stress test.

Conclusions—

Although exercise limitations were similar between HF and a reduced EF and HF and a preserved EF, there were significant differences in exercise-induced changes in LV systolic and diastolic properties. These differences likely reflect the different pathophysiologies of these clinical syndromes of HF.
Threat sensitivity in the San Marcos salamander: effects of predator diet and prey experience
Authors: Epp Kristen J.
Published: March 2013

Prey must constantly balance foraging and predator avoidance demands. Avoidance response efficiency may be improved when prey match the intensity of their avoidance behaviours to a perceived level of predatory threat (threat sensitivity). Additionally, experience with predators may influence the intensity of avoidance responses. I examined the possibility that experience with predators in the natural habitat would influence threat sensitive avoidance behaviours of an aquatic salamander, Eurycea nana, by comparing the intensity of avoidance responses to predators that had been fed a neutral diet (low-risk) or a diet of conspecifics (high-risk) between laboratory-reared and recently-collected adult salamanders. I found that laboratory-reared salamanders exhibited graded responses to low- and high-risk predators consistent with threat-sensitive predator avoidance. Predator-experienced salamanders (recently-collected), however, responded less intensely to all predators and their responses showed little evidence of threat sensitivity. These less intense responses observed in experienced salamanders may result from mechanisms of adaptive forgetting, which allow prey to respond to environmental variation. I discuss implications of these results for E. nana and other prey as well as highlighting the need for researchers to consider the longer-term experiences of prey used in studies of predation risk.