bluuebunny/crossref_metadata_2025 huggingface dataset:
Multi‐temporal Digital Photogrammetric Analysis for Quantitative Assessment of Soil Erosion Rates in the Landola Catchment of the Upper Orcia Valley (Tuscany, Italy)
Authors: Aucelli Pietro P. C. , Conforti Massimo , Della Seta Marta , Del Monte Maurizio , D'uva Lorenzo , Rosskopf Carmen M. , Vergari Francesca
Published: September 2014

This paper focuses on the analysis of the slope and catchment erosion dynamics in a typical Mediterranean context and its sensitivity to recent climatic and socio‐economic changes. The main objective of the present study is to test the reliability of digital photogrammetric analysis to evaluate the time and space evolution of erosion processes mainly triggered by surface running waters and landslides for about the last 60 years. The selected test area is the Landola catchment, a minor tributary of the Upper Orcia River Valley (Southern Tuscany). The Upper Orcia valley is a key site for the comprehension of denudation processes typically acting in Mediterranean badland areas thanks to the following: (i) the availability of long‐lasting erosion monitoring datasets (20 years' long direct measurements at erosion ‘hot spots’); (ii) its representativeness as a sub‐humid Mediterranean badland area; and (iii) the rapidity of development of erosion processes, which makes it suitable as an open‐air laboratory for the study of badland dynamics. The outputs of this work highlight that the application of high‐resolution digital photogrammetric methodologies can represent a powerful and low‐cost tool to evaluate rates and spatial–temporal distribution of denudation processes, as confirmed by the validation through field point monitoring in areas close to the study area. The results obtained for the study area confirm that high erosion rates are a persistent environmental problem for the Upper Orcia Valley, which is not solved up to now, despite various land conservation interventions. The performed multi‐temporal analysis shows a slight decrease in the average water erosion rate during the last 60 years and a parallel increase in the frequency of mass wasting events. These variations are most likely related to a complex interplay between land use changes that have affected the study area during the studied period, revealing a very delicate equilibrium between farming activities and erosion processes. Copyright © 2014 John Wiley & Sons, Ltd.
PNA binding to the non‐template DNA strand interferes with transcription, suggesting a blockage mechanism mediated by R‐loop formation
Authors: Belotserkovskii Boris P. , Hanawalt Philip C.
Published: August 2014

Peptide Nucleic Acids (PNAs) are artificial DNA mimics with superior nucleic acid binding capabilities. T7 RNA polymerase (T7 RNAP) transcription upon encountering PNA bound to the non‐template DNA strand was studied in vitro. A characteristic pattern of blockage signals was observed, extending downstream from the PNA binding site, similar to that produced by G‐rich homopurine‐homopyrimidine (hPu‐hPy) sequences and likely caused by R‐loop formation. Since blocked transcription complexes in association with stable R‐loops may interfere with replication and in some cases trigger apoptosis, targeted R‐loop formation might be employed to inactivate selected cells, such as those in tumors, based upon their unique complement of expressed genes. © 2014 The Authors. Molecular Carcinogenesis published by Wiley Periodicals, Inc.
Endostatin inhibits the tumorigenesis of hemangioendothelioma via downregulation of CXCL1
Authors: Guo Lifang , Song Nan , He Ting , Qi Feifei , Zheng Song , Xu Xue‐Gang , Fu Yan , Chen Hong‐Duo , Luo Yongzhang
Published: August 2014

Hemangioendotheliomas could be repressed by various anti‐angiogenic agents in animal models. It was unclear whether the agents target hemangioendothelioma cells directly. This study elucidated the mechanism by which endostatin inhibited hemangioendothelioma progression. Expression of the endostatin receptors nucleolin and integrin α5β1 in hemangioendothelioma was assessed by immunohistochemistry. The effects of endostatin on the hemangioendothelioma‐derived cells (EOMA) were evaluated by proliferation and apoptosis assays and by angiogenesis array screening. This revealed the contribution of the Chemokine (C‐X‐C motif) ligand 1 (CXCL1) to hemangioendothelioma progression, which was explored in vitro and in vivo. The clinical relevance of CXCL1 expression in hemangioendothelioma was also evaluated using tissue array. EOMA cells expressed nucleolin and integrin α5β1 and bound to endostatin. Endostatin did not alter proliferation or hypoxia‐induced apoptosis in EOMA cells but it did impair the pro‐angiogenic capacity of the cells. Endothelial cell migration was induced by CXCL1 produced by EOMA cells and endostatin downregulated CXCL1 production by inactivating its transcriptional factor, nuclear factor kappa‐light‐chain‐enhancer of activated B cells (NF‐κB). In vivo, the knockdown of CXCL1 significantly impaired EOMA cell growth in nude mice; endostatin had no effect when CXCL1 was overexpressed. A strong correlation was observed between CXCL1 levels and hemangioendothelioma occurrence in patients. CXCL1, which was responsible for hemangioendothelioma progression by stimulating angiogenesis, was impaired by endostatin via inactivation of NF‐κB in an animal model. In vascular lesions in patients, CXCL1 expression was a negative prognostic factor. CXCL1‐inhibting agents such as endostatin may constitute a useful approach to treat the malignant or intermediate vascular lesions. © 2014 Wiley Periodicals, Inc.
Focal amyotrophy in multiple sclerosis
Authors: Malik Rabia , Irodenko Viktoriya , Zimmermann Lara , Green Ari , Layzer Robert
Published: September 2014

Introduction: The assumption that multiple sclerosis (MS) is purely a white matter disease has been challenged in recent years by observations of axonal damage and neuronal loss in gray matter of the cortex, subcortex, and spinal cord. Methods: We report the case of a 71‐year‐old man with primary progressive MS and longstanding right arm weakness who presented with intermittent right arm pain. Results: Neurological examination showed atrophy, weakness, and hyporeflexia, and electromyography (EMG) showed acute and chronic partial denervation in multiple segments of the right arm. Magnetic resonance imaging (MRI) demonstrated asymmetric volume loss and increased T2 signal in the right anterior spinal cord from C3 to C7, with no evidence of nerve root compression. Conclusions: Lower motor neuron involvement of his right arm was caused by MS with involvement of either the anterior horn cells or the intraspinal motor nerve roots. Muscle Nerve 51: 137–140, 2015
Skeletal muscle satellite cells: Mediators of muscle growth during development and implications for developmental disorders
Authors: Dayanidhi Sudarshan , Lieber Richard L.
Published: September 2014

Satellite cells (SCs) are the muscle stem cells responsible for longitudinal and cross‐sectional postnatal growth and repair after injury and which provide new myonuclei when needed. We review their morphology and contribution to development and their role in sarcomere and myonuclear addition. SCs, similar to other tissue stem cells, cycle through different states, such as quiescence, activation, and self‐renewal, and thus we consider the signaling mechanisms involved in maintenance of these states. The role of the SC niche and their interactions with other cells, such as fibroblasts and the extracellular matrix, are all emerging as major factors that affect aging and disease. Interestingly, children with cerebral palsy appear to have a reduced SC number, which could play a role in their reduced muscular development and even in muscular contracture formation. Finally, we review the current information on SC dysfunction in children with muscular dystrophy and emerging therapies that target promotion of myogenesis and reduction of fibrosis. Muscle Nerve 50: 723–732, 2014
Electromyographic diagnosis of multifocal pyomyositis
Authors: Spolter Yonatan S. , Katirji Bashar , Preston David C.
Published: September 2014

Introduction: Multifocal pyomyositis is a rare inflammatory myopathy caused by bacterial infection and abscess formation in multiple skeletal muscles. To date, electromyography (EMG) of pyomyositis has not been reported. Methods: We describe the EMG findings of a patient with pathologically proven multifocal pyomyositis. Results and Conclusions: Muscles affected by pyomyositis demonstrate EMG features similar to those of other inflammatory myopathies. Other features such as acute entrapment neuropathy may exist concomitantly due to nerve compression from muscle abscess formation. Muscle Nerve 51: 293–296, 2015
Assessment of renal function during high‐dose methotrexate treatment in children with acute lymphoblastic leukemia
Authors: Ylinen Elisa , Jahnukainen Kirsi , Saarinen‐Pihkala Ulla M. , Jahnukainen Timo
Published: August 2014

Background

High‐dose methotrexate (HD‐MTX) is potentially nephrotoxic. The feasibility of novel biomarkers to indicate renal injury due to HD‐MTX infusion was studied in children with acute lymphoblastic leukemia (ALL).

Procedure

Markers for glomerular and tubular injury were evaluated prospectively after HD‐MTX infusion in 20 children with ALL. Plasma creatinine, cystatin C, and neutrophil gelatinase‐associated lipocalin (NGAL) were measured 24–48 hr before MTX‐infusion and 24, 36, 48, and 72 hr after starting the HD‐MTX treatment, and thereafter daily until the MTX concentration was below 0.1 µmol/L. Urine NGAL, β2‐microglobulin, and creatinine concentrations as well as dipstick and urinalysis were performed at the same time points.

Results

In children with ALL, HD‐MTX treatment at 5 g/m2 over 24 hr was well tolerated and none of the patients developed significant glomerular or tubular dysfunction. The mean plasma cystatin C level increased significantly (P < 0.001) from 0.83 mg/L at baseline to 0.94 mg/L at 36 hr after starting the HD‐MTX treatment. The cystatin C concentration remained within reference range in all but two patients (10%). There was no significant change in plasma creatinine level during or after HD‐MTX treatment, the values being normal in all patients. Plasma and urea NGAL did not increase during or after the HD‐MTX treatment.

Conclusions

Our results suggest that plasma cystatin C concentration alone is a sensitive marker to monitor renal function during and after HD‐MTX infusion in pediatric ALL patients. Plasma or urine NGAL do not provide any further advantage in the follow‐up of these patients. Pediatr Blood Cancer 2014;61:2199–2202. © 2014 Wiley Periodicals, Inc.
Feasibility and preliminary efficacy of the effects of flavanoid‐rich purple grape juice on the vascular health of childhood cancer survivors: A randomized, controlled crossover trial
Authors: Blair Cindy K. , Kelly Aaron S. , Steinberger Julia , Eberly Lynn E. , Napurski Char , Robien Kim , Neglia Joseph P. , Mulrooney Daniel A. , Ross Julie A.
Published: August 2014

Background

Childhood cancer survivors have an increased risk of developing cardiovascular disease following treatment, yet few interventions have been evaluated to reduce this risk. Purple grape juice (pGJ), a rich source of flavonoids with antioxidant properties, has been shown in adults to reduce oxidative stress and improve endothelial function. We examined the effects of supplementing meals with pGJ on microvascular endothelial function and markers of oxidative stress and inflammation in 24 cancer survivors (ages 10–21 years).

Procedure

In a randomized controlled crossover trial consisting of two, 4 week intervention periods, each preceded by a 4 week washout period, subjects received in random order 6 ounces twice daily of pGJ and clear apple juice (cAJ; similar in calories but lower in flavonoids). Measurements were obtained before and after each supplementation period; change was evaluated using mixed effects ANOVA.

Results

pGJ did not improve endothelial function, measured using digital reactive hyperemia, compared with cAJ (mean change: pGJ 0.06, cAJ 0.22; difference of mean change [95% CI]: −0.16 [−0.42 – 0.11], P = 0.25). No significant changes in plasma concentrations of oxidized‐LDL, myeloperoxidase, or high sensitivity C‐reactive protein were observed.

Conclusion

After 4 weeks of daily consumption of flavonoid‐rich pGJ, no measurable change in vascular function was observed in these childhood cancer survivors. Pediatr Blood Cancer 2014;61:2290–2296. © 2014 Wiley Periodicals, Inc.
Medication errors on oral chemotherapy in children with acute lymphoblastic leukemia in a developing country
Authors: Oberoi Sapna , Trehan Amita , Marwaha Ram Kumar
Published: August 2014

Background

Medication errors occur universally. Inappropriate administration of chemotherapy drugs can have adverse effects in cancer patients. Our objective was to assess the rate and type of medication errors in children with acute lymphoblastic leukemia (ALL) receiving oral chemotherapy in outpatient setting.

Procedure

Prescription and administration of oral chemotherapy drugs in children with ALL were evaluated prospectively to determine rate and type of medication errors. Errors were defined as prescription (physician) level or administration (patient) level errors.

Results

Two hundred eighty‐nine drugs were prescribed to 121 patients. Medication errors occurred in 36 (12.5%) prescriptions; 21(7.3%) were administration errors, 13 (4.5%) were prescribing errors, and two errors occurred at both levels. Mercaptopurine (6‐MP) was significantly associated with higher rates of errors (Odds ratio [OR] = 2.1, 95% CI [confidence interval] 1–4.1) whereas lapses were less with dexamethasone (OR = 0.25, 95% CI 0.09–0.67). As a result of medication errors 28 (23.1%) patients received inappropriate doses. Twenty five (21%) patients received sub‐optimal doses whereas three got higher doses of chemotherapy. On univariate analysis, socioeconomic status, education status of the caregiver, 6‐MP and methotrexate were significantly associated with errors (P ≤ 0.05). On multivariate analysis, ≤ primary school education of the caregiver and prescription of methotrexate were independent predictors of errors.

Conclusions

Medication errors affected nearly one fourth of the children receiving oral chemotherapy. Future studies are needed to look at effective interventions to avoid chemotherapy associated errors especially amongst the lower strata of society. Pediatr Blood Cancer 2014;61:2218–2222. © 2014 Wiley Periodicals, Inc.
Pediatric secondary chronic myeloid leukemia following cardiac transplantation for anthracycline‐induced cardiomyopathy
Authors: Menon Neethu Mohan , Katsanis Emmanuel , Khalpey Zain , Whitlow Puja
Published: August 2014

Chronic myeloid leukemia (CML) is a clonal myeloproliferative disorder of the hematopoietic stem cell that is exceptionally rare in the first five years of life, particularly as a secondary malignancy. This report describes a case of secondary CML in a four‐year‐old female occurring after AML treatment. Interestingly, CML developed while on immunosuppression for a heart transplant due to anthracycline‐induced cardiomyopathy. Pediatr Blood Cancer 2015;62:166–168. © 2014 Wiley Periodicals, Inc.
Sequential and hierarchical chromosomal changes and chromosome instability are distinct features of high hyperdiploid pediatric acute lymphoblastic leukemia
Authors: Alpár Donát , Pajor Gábor , Varga Péter , Kajtár Béla , Pótó László , Mátics Róbert , Vojcek Ágnes , Ottoffy Gábor , Szuhai Károly , Pajor László
Published: August 2014

Background

Pathogenesis of the non‐random accumulation of extra chromosomes in the low and high hyperdiploid (HeL, HeH) pre‐B pediatric acute lymphoblastic leukemia (B‐pALL) is largely unknown, and has been clarified with respect only to tetrasomic chromosomes. We analyzed the hierarchy of changes in chromosome number and chromosomal instability, as well as clonal heterogeneity and evolution, in the untreated bone marrow cell samples from 214 B‐pALL patients.

Procedure

Applying relocation, 2 × 4 color interphase fluorescence in situ hybridization was used to detect copy number alterations (CNAs) of the most commonly involved chromosomes, 4, 6, 10, 14, 17, 18, 21, and X. This approach allowed us to acquire a dataset correlated for all eight parameters.

Results

Based on chromosome number, an average of 6.9 and 10.2, whereas according to unique constellation 15.3 and 26.7 subclones could be identified in the HeL and HeH subgroups, respectively. Cluster analysis revealed the order of CNAs to chromosomes was highly conserved, and network analysis indicated changes in chromosome number were sequential for 80–90% of all numerical aberrations. Significant chromosome instability was revealed in both subgroups of leukemia.

Conclusions

Data generated using this new approach indicate that chromosomal instability, which causes heterogeneity in the subclonal landscape, and the sequential changes to chromosome numbers, are both determining factors in the pathomechanism of the hyperdiploid B‐pALL. These new observations could prompt research into the mitotic machinery of leukemic cells to identify new therapeutic targets for treating this disease. Pediatr Blood Cancer 2014;61:2208–2214. © 2014 Wiley Periodicals, Inc.
Reduced‐intensity conditioning for hematopoietic cell transplantation of chronic granulomatous disease
Authors: Oshrine Benjamin , Morsheimer Megan , Heimall Jennifer , Bunin Nancy
Published: August 2014

Hematopoietic cell transplantation (HCT) is the only available curative therapy for chronic granulomatous disease (CGD), but its use is limited by transplant‐related mortality (TRM) in patients who often come to transplant with existing infections or organ dysfunction. Reduction in the intensity of the preparative regimen mitigates these risks, but increases the potential for mixed donor‐recipient chimerism (MC) that may progress to graft loss. Recently a busulfan‐based reduced‐intensity conditioning (RIC) regimen has been described with excellent survival and little MC. We report our experience with a similar RIC regimen at our institution, demonstrating problems with donor chimerism and graft loss. Pediatr Blood Cancer 2015;62:359–361. © 2014 Wiley Periodicals, Inc.
Transient abnormal myelopoiesis of a newborn not associated with chromosome 21 abnormalities or GATA1 mutations
Authors: Nakashima Megan O. , Shetty Shashirekha , Chicka Michael , Flagg Aron , Eng Charis , Cotta Claudiu V.
Published: August 2014

Transient abnormal myelopoiesis (TAM) is a disorder of Down syndrome newborns characterized by megakaryocytic blasts indistinguishable from acute myeloid leukemia (AML), which undergoes spontaneous remission. Acquired GATA1 mutations are present in blasts of both TAM and the subsequent AML which sometimes develops. We present a unique case of a newborn with leukemic megakaryoblasts indistinguishable from those of TAM who had neither extra material from chromosome 21 in the germline or blasts, nor evidence of GATA1 mutations. These findings suggest there are other genetic abnormalities that can lead to TAM besides GATA1 mutation in the setting of trisomy 21. Pediatr Blood Cancer 2015;62:353–355. © 2014 Wiley Periodicals, Inc.
Lung function at 6 and 18 months after preterm birth in relation to severity of bronchopulmonary dysplasia
Authors: Thunqvist Per , Gustafsson Per , Norman Mikael , Wickman Magnus , Hallberg Jenny
Published: September 2014

Many preterm infants with bronchopulmonary dysplasia (BPD) demonstrate impaired lung function and respiratory symptoms during infancy. The relationships between initial BPD severity, lung function and respiratory morbidity are not fully understood. We aimed to investigate the association between BPD severity and subsequent lung function and whether lung function impairment is related to respiratory morbidity.

Study design and methods

In this longitudinal cohort study, 55 infants born preterm (23–30 weeks of gestation) with mild or moderate/severe BPD, based on oxygen requirement at 36 gestational weeks, were followed up at 6 and 18 months postnatal age. Respiratory symptoms, such as recurrent or chronic chough and wheeze, were noted and patient records were scrutinized. Lung function was assessed by passive lung mechanics, whole body plethysmography, and tidal and raised volume rapid thoraco‐abdominal compression techniques. Results were related to published normative values.

Results

Besides residual functional capacity (FRC) and respiratory system compliance (Cso) assessed at 18 months, all measures of lung function were significantly below normative values. Moderate/severe BPD differed significantly from mild BPD only with respect to reduced Cso. At follow‐up at 6 and 18 months, participants with respiratory symptoms showed lower; maximal forced expiratory flow at FRC (FRC) (P = 0.006, P = 0.001), forced mid‐expiratory flows (MEF50) (P = 0.006, P = 0.048), and Cso (P = 0.004, P = 0.015) as compared to participants without symptoms.

Conclusions

In the present study BPD severity did not predict lung function, but may be associated with impaired alveolarization, indicated by reduced Cso. Respiratory morbidity was associated with reduced airway function and respiratory compliance in infancy after preterm birth. Pediatr Pulmonol. 2015; 50:978–986. © 2014 Wiley Periodicals, Inc.
Clinical activity of enzalutamide in Docetaxel‐naïve and Docetaxel‐pretreated patients with metastatic castration‐resistant prostate cancer
Authors: Nadal Rosa , Zhang Zhe , Rahman Hibba , Schweizer Michael T. , Denmeade Samuel R. , Paller Channing J. , Carducci Michael A. , Eisenberger Mario A. , Antonarakis Emmanuel S.
Published: August 2014

BACKGROUND

Two randomized clinical trials have demonstrated a survival advantage with enzalutamide over placebo in both docetaxel (D)‐pretreated and D‐naïve metastatic castration‐resistant prostate cancer (mCRPC) patients. Cross‐resistance between androgen receptor‐directed therapies and taxanes has been suggested, possibly leading to lower efficacy of enzalutamide in the post‐D setting.

METHODS

We aimed to examine the impact of prior D treatment on the clinical activity of enzalutamide in patients with mCRPC. We retrospectively reviewed an institutional database to identify men with mCRPC treated with standard‐of‐care enzalutamide. Patients were classified as D‐naïve or D‐pretreated. The efficacy end points were prostate‐specific antigen (PSA) response rates (≥ 50% PSA decline), time to PSA progression (TTPP) and clinical/radiographic progression‐free survival (PFS) in response to enzalutamide. Differences between groups (D‐naïve and D‐pretreated) were assessed by univariate and multivariable analyses using logistic and Cox regression models.

RESULTS

One‐hundred‐seven (107) consecutive patients were included: 60 were D‐pretreated and 47 were D‐naïve. PSA responses were 43.2% in D‐naïve patients and 25.4% in D‐pretreated patients (P = 0.089). Median TTPP was 7.2 months (95% CI = 4.5 – 17.2) in the D‐naïve group versus 2.6 mo (95% CI = 1.9 – 3.5) in the D‐pretreated group (P < 0.0001). Median PFS was not reached for D‐naïve men and was 3.3 mo (95% CI = 2.5 – 4.8) for D‐pretreated men (P < 0.0001). After adjusting for potential confounders including prior abiraterone use, differences remained statistically significant for TTPP (HR = 2.32; 95% CI = 1.19 – 4.50; P = 0.013) and marginally significant for PFS (HR = 1.90; 95% CI = 0.94 – 3.84; P = 0.073) in multivariable analyses. Among patients who achieved a PSA response to enzalutamide (n = 34), results suggested a trend towards shorter duration of response in D‐pretreated patients.

CONCLUSIONS

The clinical activity of enzalutamide appears to be blunted in patients who have previously received docetaxel chemotherapy. These results support the concept of cross‐resistance between these two agents. Prostate 74:1560–1568, 2014. © 2014 Wiley Periodicals, Inc.
Performance of serum prostate‐specific antigen isoform [‐2]proPSA (p2PSA) and the prostate health index (PHI) in a Chinese hospital‐based biopsy population
Authors: Na Rong , Ye Dingwei , Liu Fang , Chen Haitao , Qi Jun , Wu Yishuo , Zhang Guiming , Wang Meilin , Wang Wenying , Sun Jielin , Yu Guopeng , Zhu Yao , Ren Shancheng , Zheng S. Lilly , Jiang Haowen , Sun Yinghao , Ding Qiang , Xu Jianfeng
Published: August 2014

BACKGROUND

The use of serum [‐2]proPSA (p2PSA) and its derivative, the prostate health index (PHI), in detecting prostate cancer (PCa) have been consistently shown to have better performance than total prostate‐specific antigen (tPSA) in discriminating biopsy outcomes in western countries. However, little is known about their performance in Chinese men. Our objective is to test the performance of p2PSA and PHI and their added value to tPSA in discriminating biopsy outcomes in Chinese men.

METHODS

Consecutive patients who underwent prostate biopsy in three tertiary hospitals in Shanghai, China during 2012–2013 were recruited. Serum tPSA, free PSA (fPSA), and p2PSA were measured centrally using Beckman Coulter's DxI 800 Immunoassay System. The primary outcome is PCa and the secondary outcome is high‐grade PCa (Gleason Score of 4 + 3 or worse). Discriminative performance was assessed using the area under the receiver operating characteristic curve (AUC), detection rate and Decision Curve Analysis (DCA).

RESULTS

Among 636 patients who underwent prostate biopsy, PHI was a significant predictor of biopsy outcomes, independent of other clinical variables. The AUC in discriminating PCa from non‐PCa was consistently higher for PHI than tPSA in the entire cohort (0.88 vs. 0.81) as well as in patients with tPSA at 2–10 ng/ml (0.73 vs. 0.53), at 10.1–20 ng/ml (0.81 vs. 0.58), and at tPSA >20 ng/ml (0.90 vs. 0.80). The differences were statistically significant in all comparisons, P < 0.01. To detect 90% of all PCa in the cohort, 362 and 457 patients would need to be biopsied based on PHI and tPSA cutoff, respectively, a 21% reduction for PHI. Similar results were found for discriminating high‐grade PCa.

CONCLUSIONS

PHI provides added value over tPSA in discriminating PCa and high‐grade PCa in patients who underwent prostate biopsy in China. Prostate 74:1569–1575, 2014. © 2014 Wiley Periodicals, Inc.
Si‐related color centers in nanocrystalline diamond thin films
Authors: Potocký Štěpán , Holovský Jakub , Remeš Zdeněk , Müller Martin , Kočka Jan , Kromka Alexander
Published: September 2014

The successful growth of nanocrystalline diamond (NCD) thin films with optically active Si‐related color centers was realized on glass and molybdenum substrates by the microwave plasma chemical vapor deposition (CVD) with focused or linear antenna plasma reactors. Diamond coatings were characterized by Raman spectroscopy, scanning electron microscopy, and photoluminescence (PL) spectroscopy. Increased of a‐Si interlayer thickness resulted in reduction of stress in NCD film and increased renucleation of NCD films. The PL spectra showed that the Si‐color center is only observed in the focused plasma system. The influence of the substrate material as well as the a‐Si interlayer on the density of Si‐related color center was not confirmed in our setup.
A Phase I Cluster‐Based Method for Analyzing Nonparametric Profiles
Authors: Chen Yajuan , Birch Jeffrey B. , Woodall William H.
Published: September 2014

A cluster‐based method has been used successfully to analyze parametric profiles in Phase I of the profile monitoring process. Performance advantages have been demonstrated when using a cluster‐based method of analyzing parametric profiles over a non‐cluster based method with respect to more accurate estimates of the parameters and improved classification performance criteria. However, it is known that, in many cases, profiles can be better represented using a nonparametric method. In this study, we use the cluster‐based method to analyze profiles that cannot be easily represented by a parametric function. The similarity matrix used during the clustering phase is based on the fits of the individual profiles with p‐spline regression. The clustering phase will determine an initial main cluster set that contains greater than half of the total profiles in the historical data set. The profiles with in‐control T2 statistics are sequentially added to the initial main cluster set, and upon completion of the algorithm, the profiles in the main cluster set are classified as the in‐control profiles and the profiles not in the main cluster set are classified as out‐of‐control profiles. A Monte Carlo study demonstrates that the cluster‐based method results in superior performance over a non‐cluster based method with respect to better classification and higher power in detecting out‐of‐control profiles. Also, our Monte Carlo study shows that the cluster‐based method has better performance than a non‐cluster based method whether the model is correctly specified or not. We illustrate the use of our method with data from the automotive industry. Copyright © 2014 John Wiley & Sons, Ltd.
Intrinsic reaction coordinate: Calculation, bifurcation, and automated search
Authors: Maeda Satoshi , Harabuchi Yu , Ono Yuriko , Taketsugu Tetsuya , Morokuma Keiji
Published: September 2014

The intrinsic reaction coordinate (IRC) approach has been used extensively in quantum chemical analysis and prediction of the mechanism of chemical reactions. The IRC gives a unique connection from a given transition structure to local minima of the reactant and product sides. This allows for easy understanding of complicated multistep mechanisms as a set of simple elementary reaction steps. In this article, three topics concerning the IRC approach are discussed. In the first topic, the first ab initio study of the IRC and a recent development of an IRC calculation algorithm for enzyme reactions are introduced. In the second topic, cases are presented in which dynamical trajectories bifurcate and corresponding IRC connections can be inaccurate. In the third topic, a recent development of an automated reaction path search method and its application to systematic construction of IRC networks are described. Finally, combining these three topics, future perspectives are discussed. © 2014 Wiley Periodicals, Inc.
Pcgf6, a Polycomb Group Protein, Regulates Mesodermal Lineage Differentiation in Murine ESCs and Functions in iPS Reprogramming
Authors: Zdzieblo D. , Li X. , Lin Q. , Zenke M. , Illich D. J. , Becker M. , Müller Albrecht M.
Published: September 2014

Polycomb group (PcG) proteins comprise evolutionary conserved factors with essential functions for embryonic development and adult stem cells. PcG proteins constitute two main multiprotein polycomb repressive complexes (PRC1 and PRC2) that operate in a hierarchical manner to silence gene transcription. Functionally distinct PRC1 complexes are defined by Polycomb group RING finger protein (Pcgf) paralogs. So far, six Pcgf paralogs (Pcgf1–6) have been identified as defining components of different PCR1-type complexes. Paralog-specific functions are not well understood. Here, we show that Pcgf6 is the only Pcgf paralog with high expression in undifferentiated embryonic stem cells (ESCs). Upon differentiation Pcgf6 expression declines. Following Pcgf6 kockdown (KD) in ESCs, the expression of pluripotency genes decreased, while mesodermal- and spermatogenesis-specific genes were derepressed. Concomitantly with the elevated expression of mesodermal lineage markers, Pcgf6 KD ESCs showed increased hemangioblastic and hematopoietic activities upon differentiation suggesting a function of Pcgf6 in repressing mesodermal-specific lineage genes. Consistant with a role in pluripotency, Pcgf6 replaced Sox2 in the generation of germline-competent induced pluripotent stem (iPS) cells. Furthermore, Pcgf6 KD in mouse embryonic fibroblasts reduced the formation of ESC-like colonies in OSKM-driven reprogramming. Together, these analyses indicate that Pcgf6 is nonredundantly involved in maintaining the pluripotent nature of ESCs and it functions in iPS reprogramming. Stem Cells  2014;32:3112–3125
Human Embryonic Stem Cells Prevent T-Cell Activation by Suppressing Dendritic Cells Function via TGF-Beta Signaling Pathway
Authors: Leshansky Lucy , Aberdam Daniel , Itskovitz-Eldor Joseph , Berrih-Aknin Sonia
Published: September 2014

Human embryonic stem cells (hESCs) represent a potential source of transplantable cells for regenerative medicine, but development of teratoma even in syngenic recipients represents a critical obstacle to safe stem cell-based therapies. We hypothesized that hESCs escape the immune surveillance by regulating the environmental immune system. Using cocultures of hESCs with allogenic peripheral blood mononuclear cells, we demonstrated that hESCs prevent proliferation and activation of human CD4+ T lymphocytes, an effect dependent upon monocytes. Altered expression of key signaling molecules responsible for the crosstalk of monocytes with T cells was detected in the presence of hESCs. Analyzing the mechanism of action, we demonstrated that hESCs were able to downregulate intracellular glutathione levels in both monocytes and CD4+ cells by suppressing glutamate cysteine ligase expression and to alter MHCII and CD80 expression in monocytes. These effects were achieved at least partially via TGF-beta signaling, and both monocyte phenotype and GCLC expression were affected by Caspase-3 proteolytic activity. Altogether, our results demonstrate a novel immune-suppressive mechanism used by hESCs. Stem Cells  2014;32:3137–3149
Pluripotent Stem Cells Derived From Mouse Primordial Germ Cells by Small Molecule Compounds
Authors: Kimura Tohru , Kaga Yoshiaki , Sekita Yoichi , Fujikawa Keita , Nakatani Tsunetoshi , Odamoto Mika , Funaki Soichiro , Ikawa Masahito , Abe Kuniya , Nakano Toru
Published: September 2014

Primordial germ cells (PGCs) can give rise to pluripotent stem cells known as embryonic germ cells (EGCs) when cultured with basic fibroblast growth factor (bFGF), stem cell factor (SCF), and leukemia inhibitory factor. Somatic cells can give rise to induced pluripotent stem cells (iPSCs) by introduction of the reprogramming transcription factors Oct4, Sox2, and Klf4. The effects of Sox2 and Klf4 on somatic cell reprogramming can be reproduced using the small molecule compounds, transforming growth factor-β receptor (TGFβR) inhibitor and Kempaullone, respectively. Here we examined the effects of TGFβR inhibitor and Kempaullone on EGC derivation from PGCs. Treatment of PGCs with TGFβR inhibitor and/or Kempaullone generated pluripotent stem cells under standard embryonic stem cell (ESC) culture conditions without bFGF and SCF, which we termed induced EGCs (iEGCs). The derivation efficiency of iEGCs was dependent on the differentiation stage and sex. DNA methylation levels of imprinted genes in iEGCs were reduced, with the exception of the H19 gene. The promoters of genes involved in germline development were generally hypomethylated in PGCs, but three germline genes showed comparable DNA methylation levels among iEGs, ESCs, and iPSCs. These results show that PGCs can be reprogrammed into pluripotent state using small molecule compounds, and that DNA methylation of these germline genes is not maintained in iEGCs. Stem Cells  2015;33:45–55
Lineage Tracing of Stem and Progenitor Cells of the Murine Corneal Epithelium
Authors: Amitai-Lange Aya , Altshuler Anna , Bubley Jeffrey , Dbayat Noora , Tiosano Beatrice , Shalom-Feuerstein Ruby
Published: September 2014

Accumulating evidence supports the dogma that the corneal epithelium is regenerated by stem cells located exclusively in the limbal niche, at the corneal periphery. Accordingly, limbal stem cells (LSCs) give rise to progenitors that proliferate and migrate centripetally to repopulate the corneal epithelium, which has a short turnover. Moreover, LSC loss leads to corneal opacity and blindness, while limbal grafting restores patients' vision. However, contradicting data suggested that the limbus does not participate in corneal homeostasis and that the cornea contains stem cells. As of today, only indirect evidence for limbal cell migration under homeostasis or injury has been demonstrated. Here, we performed lineage tracing experiments using R26R-Confetti mice to follow K14+ limbal/corneal epithelial cells stochastically induced to express one out of four fluorescent genes. In homeostasis, radial limbal stripes of slow migrating cells proceeded toward the corneal center while, infrequently, slow cycling limbal clones resembling quiescent stem cells were observed. Additionally, rare corneal clones that did not migrate centripetally, but survived for over 4 months, were inspected. In contrast to limbal stripes, corneal clusters had minor contribution to tissue replenishment in homeostasis. Corneal cells, however, significantly contributed to mild wound repair while large limbal streaks appeared within a week following severe wounding that coincided with partial loss of corneal transparency. This data suggest that the mouse limbus largely contributes to corneal renewal while corneal progenitor cells have a long turnover and, therefore, may be able to maintain the corneal epithelium for several months. Stem Cells  2015;33:230–239
Percutaneous Injection of Autologous Bone Marrow Concentrate Cells Significantly Reduces Lumbar Discogenic Pain Through 12 Months
Authors: Pettine Kenneth A. , Murphy Matthew B. , Suzuki Richard K. , Sand Theodore T.
Published: September 2014

Degenerative disc disease (DDD) induces chronic back pain with limited nonsurgical options. In this open label pilot study, 26 patients (median age 40 years; range 18–61) received autologous bone marrow concentrate (BMC) disc injections (13 one level, 13 two levels). Pretreatment Oswestry disability index (ODI) and visual analog scale (VAS) were performed to establish baseline pain scores (average 56.5 and 79.3, respectively), while magnetic resonance imaging was independently scored according to the modified Pfirrmann scale. Approximately 1 ml of BMC was analyzed for total nucleated cell (TNC) content, colony-forming unit-fibroblast (CFU-F) frequency, differentiation potential, and phenotype characterization. The average ODI and VAS scores were reduced to 22.8 and 29.2 at 3 months, 24.4 and 26.3 at 6 months, and 25.0 and 33.2 at 12 months, respectively (p ≤ .0001). Eight of twenty patients improved by one modified Pfirrmann grade at 1 year. The average BMC contained 121 × 106 TNC/ml with 2,713 CFU-F/ml (synonymous with mesenchymal stem cells). Although all subjects presented a substantial reduction in pain, patients receiving greater than 2,000 CFU-F/ml experienced a significantly faster and greater reduction in ODI and VAS. Subjects older than 40 years who received fewer than 2,000 CFU-F/ml experienced an average pain reduction of 33.7% (ODI) and 29.1% (VAS) at 12 months, while all other patients' average reduction was 69.5% (ODI, p = .03) and 70.6% (VAS, p = .01). This study provides evidence of safety and feasibility in the nonsurgical treatment of DDD with autologous BMC and indicates an effect of mesenchymal cell concentration on discogenic pain reduction. Stem Cells  2015;33:146–156
Alcohol Ads on Public Transit: Policies From Major Metropolitan Areas in the United States
Authors: Mart Sarah , Blakemore Jessica
Published: September 2014

The harm and costs to society from underage drinking are significant, conservatively estimated at $27 billion annually in the United States. Youth exposed to more alcohol advertising start drinking earlier, consume more, and experience more alcohol‐related problems. Despite contributions of alcohol advertising to youth exposure and harm, some cities look to alcohol ads on public transit for new revenue. We conducted this limited study to describe the presence and types of alcohol advertising policies for public transit in major metropolitan areas in the United States. We analyzed policies from agencies in major metropolitan areas to find whether they ban or allow alcohol advertising on public transit. We then categorized alcohol ad ban language according to its location in agency policy, contract requirements, or government policy. Thirteen agencies (50 percent) explicitly banned alcohol advertising in contract language, formal agency policy, government policy, or a combination of these. Another 13 (50 percent) allowed alcohol advertising. Despite industry claims, agencies and cities can refuse alcohol ads and adopt formal policy to ban alcohol advertising on public transit. Future revenue could be gained from advertising products that do not pose serious threats to public health and safety, especially to youth.
Optimal U.S. State Alcohol Excise Taxes to Recover Government Cost of Excessive Consumption
Authors: Shafer Holley
Published: September 2014

Excessive alcohol consumption causes $223 billion in economic harm each year, including $94 billion in direct cost to federal, state, and local governments. The median for direct costs to states is $2.9 billion. For each U.S. state, revenues from specific alcohol excise taxes in 2006 and net revenues for control states were compared with recent state estimates of direct government cost of excessive consumption. Optimal state excise tax rates to internalize government costs were then calculated. Optimal state tax rates per ethanol gallon (gallon of pure alcohol) range from $77.70 to $276.28, with a mean of $185.95. Current state tax rates per ethanol gallon range from $0.24 to $26.05. The average per‐drink tax increase needed to achieve the optimal rate is $0.84, and the median is $0.85. New Hampshire has the lowest increase needed to achieve the optimal rate, at $0.35 per standard drink, and Oklahoma the highest at $1.25. Currently no state levies excise taxes at a rate that internalizes its direct government costs. Recommendations include levying tax rates volumetrically across beverage types and indexing tax rates to inflation. State policymakers may use the estimated optimal tax rates, along with assessment of state‐level factors contributing to excessive consumption, to increase the effectiveness of their states' alcohol policies.
Single molecular shuttle-junction: Shot noise and decoherence
Authors: Lai Wenxi , Zhang Chao , Ma Zhongshui
Published: September 2014

Single molecular shuttle-junction is one kind of nanoscale electromechanical tunneling system. In this junction, a molecular island oscillates depending on its charge occupation, and this charge dependent oscillation leads to modulation of electron tunneling through the molecular island. This paper reviews recent development on the study of current, shot noise and decoherence of electrons in the single molecular shuttle-junction. We will give detailed discussion on this topic using the typical system model, the theory of fully quantum master equation and the Aharonov-Bohm interferometer.
Longitudinal Evolution of the Concentration of Gangliosides GM3 and GD3 in Human Milk
Authors: Giuffrida Francesca , Elmelegy Isabelle Masserey , Thakkar Sagar K. , Marmet Cynthia , Destaillats Frédéric
Published: September 2014

It has been reported that dietary gangliosides may have an important role in preventing infections and in brain development during early infancy. However, data related to the evolution of their concentration over the different stages of lactation are scarce. Liquid chromatography coupled with electrospray ionization high resolution mass spectrometer (LC/ESI‐HR‐MS) has been optimized to quantify the two major ganglioside classes, i.e., aNeu5Ac(2‐8)aNeu5Ac(2‐3)bDGalp(1‐4)bDGlcp(1‐1)Cer (GD3) and aNeu5Ac(2‐3)bDGalp(1‐4)bDGlcp(1‐1)Cer (GM3) in human milk. Gangliosides were extracted using chloroform and methanol, further purified by solid‐phase extraction and separated by reversed‐phase liquid chromatography. Repeatability, intermediate reproducibility, and recovery values were assessed to validate the method. In human milk, GD3 and GM3 could be quantified at the level of 0.1 and 0.2 μg/mL, respectively, with relative standard deviation of repeatability [CV(r)] and intermediate reproducibility [CV(iR)] values ranging from 1.9 to 15.0 % and 1.9 to 22.5 %, respectively. The described method was used to quantify GD3 and GM3 in human milk samples collected from 450 volunteers between 0 and 11 days and at 30, 60 and 120 days postpartum, providing for the first time the concentration of these minor lipids in a large cohort. The content of total gangliosides ranged from 8.1 and 10.7 μg/mL and the mean intake of gangliosides in infants 30, 60 and 120 days postpartum could be estimated at about 5.5, 7.0 and 8.6 mg of total gangliosides per day, respectively, when infants were exclusively breastfed.
Peter Zumthor's ‘Topography of Terror’
Authors: Leoni Claudio
Published: September 2014

This paper discusses Peter Zumthor's project for the Topography of Terror foundation in Berlin, an institution that aims to research, and communicate, the atrocity of Nazi crimes and to work against the forgetting of history. The site where Topography of Terror is based, in the centre of the city, once housed the major institutions from which the Third Reich wrought terror over Europe and from where genocide was organised /1/. It is thus a unique site where the victims are absent and the perpetrators cannot be commemorated: the primary challenge in dealing with the site.

In the late autumn of 2004, Zumthor's project came to an unfortunate end. After eleven years of planning, arguing and constructing, the authorities of Berlin decided to abandon the partially constructed Topography of Terror building and to commission an alternative, while newspapers speculated about spiralling costs, technical problems and the disagreements of those involved. Eventually, in December of the same year, the early stages of Zumthor's construction were demolished. Nevertheless, the project's unique approach to history and remembrance should be discussed further. Unlike most memorials, Zumthor's project did not seek to represent a historical event mimetically or allegorically, but rather tried to embody the limits of representation by confronting the visitor with a non-representational approach to history.
ATHEISTIC AESTHETICS: THE SISYPHUS FRAGMENT, POETICS AND THE CREATIVITY OF DRAMA
Authors: Whitmarsh Tim
Published: September 2014

The famous Sisyphus fragment of a tragedy or satyr play is one of the best known documents of ancient atheism, proposing as it does a social-constructionist theory of the emergence of religion as a form of social control. This article argues that the fragment should be seen not just as a philosophical contribution to Presocratic and sophistic thought on the gods, but also as a work of theatrical poetics: it alludes to Hesiod's foundational role in the articulation of Greek theology, self-reflexively explores the role of the literary author in the creation of belief systems, and unpacks the specific role of the theatre in the manufacture of images of divinity, not just through acting but also through technical effects such as the bronteion.
Sucht im Alter
Authors: Bitar Raoul , Dürsteler Kenneth M. , Rösner Susanne , Grosshans Martin , Herdener Marcus , Mutschler Jochen
Published: September 2014

Angesichts des demografischen Wandels nimmt die Zahl älterer Patienten mit Abhängigkeitserkrankungen zu. In dieser Übersicht werden daher wichtige klinische und therapeutische Aspekte von Sucht im Alter am Beispiel von Alkohol, Benzodiazepinen und Opioiden vorgestellt. So ist täglicher und risikoreicher Alkoholkonsum gerade unter Älteren keine Seltenheit. Dabei ist bei ihnen die Gefahr alkoholbedingter Komplikationen erhöht. Zur Früherkennung sind Laborparameter und Fragebögen wie der AUDIT-C geeignet. In der Primärversorgung haben sich therapeutisch Kurzinterventionen bewährt. Auch der Missbrauch von Benzodiazepinen, insbesondere die Low-dose-Abhängigkeit, kommt unter älteren Menschen gehäuft vor. Dabei erkennen die Patienten selber die Abhängigkeit häufig nicht. Seitens des Arztes sind eine sorgfältige Indikationsstellung, adäquate Dosierung und Kenntnisse der Wechselwirkungen von Benzodiazepinen nötig. Bei einer Abhängigkeit wird eine langsame Dosisreduktion empfohlen. Patienten mit einer Opioidabhängigkeit werden u. a. dank der Substitutionstherapie immer älter. Dabei wirkt sich das Alter des Patienten auf die Wirkung des Substituts aus, wodurch eine Dosisanpassung nötig werden kann. Die Behandlung älterer Patienten sollte auf ihre Bedürfnisse und Ressourcen ausgerichtet sein und ist dann auch effektiv.