bluuebunny/crossref_metadata_2025 huggingface dataset:
Yeast prions form infectious amyloid inclusion bodies in bacteria
Authors: Espargaró Alba , Villar-Piqué Anna , Sabaté Raimon , Ventura Salvador
Published: December 2012

Background

Prions were first identified as infectious proteins associated with fatal brain diseases in mammals. However, fungal prions behave as epigenetic regulators that can alter a range of cellular processes. These proteins propagate as self-perpetuating amyloid aggregates being an example of structural inheritance. The best-characterized examples are the Sup35 and Ure2 yeast proteins, corresponding to [PSI+] and [URE3] phenotypes, respectively.

Results

Here we show that both the prion domain of Sup35 (Sup35-NM) and the Ure2 protein (Ure2p) form inclusion bodies (IBs) displaying amyloid-like properties when expressed in bacteria. These intracellular aggregates template the conformational change and promote the aggregation of homologous, but not heterologous, soluble prionogenic molecules. Moreover, in the case of Sup35-NM, purified IBs are able to induce different [PSI+] phenotypes in yeast, indicating that at least a fraction of the protein embedded in these deposits adopts an infectious prion fold.

Conclusions

An important feature of prion inheritance is the existence of strains, which are phenotypic variants encoded by different conformations of the same polypeptide. We show here that the proportion of infected yeast cells displaying strong and weak [PSI+] phenotypes depends on the conditions under which the prionogenic aggregates are formed in E. coli, suggesting that bacterial systems might become useful tools to generate prion strain diversity.
100% Orange juice consumption is associated with better diet quality, improved nutrient adequacy, decreased risk for obesity, and improved biomarkers of health in adults: National Health and Nutrition Examination Survey, 2003-2006
Authors: O’Neil Carol E , Nicklas Theresa A , Rampersaud Gail C , Fulgoni III Victor L
Published: December 2012

Background

Consumption of 100% orange juice (OJ) has been positively associated with nutrient adequacy and diet quality, with no increased risk of overweight/obesity in children; however, no one has examined these factors in adults. The purpose of this study was to examine the association of 100% OJ consumption with nutrient adequacy, diet quality, and risk factors for metabolic syndrome (MetS) in a nationally representative sample of adults.

Methods

Data from adults 19+ years of age (n = 8,861) participating in the National Health and Nutrition Examination Survey 2003-2006 were used. The National Cancer Institute method was used to estimate the usual intake (UI) of 100% OJ consumption, selected nutrients, and food groups. Percentages of the population below the Estimated Average Requirement (EAR) or above the Adequate Intake (AI) were determined. Diet quality was measured by the Healthy Eating Index-2005 (HEI-2005). Covariate adjusted logistic regression was used to determine if consumers had a lower odds ratio of being overweight or obese or having risk factors of MetS or MetS.

Results

Usualper capitaintake of 100% OJ was 50.3 ml/d. Among consumers (n = 2,310; 23.8%), UI was 210.0 ml/d. Compared to non-consumers, consumers had a higher (p < 0.05) percentage (% ± SE) of the population meeting the EAR for vitamin A (39.7 ± 2.5 vs 54.0 ± 1.2), vitamin C (0.0 ± 0.0 vs 59.0 ± 1.4), folate (5.8 ± 0.7 vs 15.1 ± 0.9), and magnesium (51.6 ± 1.6 vs 63.7 ± 1.2). Consumers were also more likely to be above the AI for potassium (4.1 ± 0.8 vs 1.8 ± 0.2). HEI-2005 was significantly (p < 0.05) higher in consumers (55.0 ± 0.4 vs 49.7 ± 0.3). Consumers also had higher intakes of total fruit, fruit juice, whole fruit, and whole grain. Consumers had a lower (p < 0.05) mean body mass index (27.6 ± 0.2 vs 28.5 ± 0.1), total cholesterol levels (197.6 ± 1.2 vs 200.8 ± 0.75 mg/dL), and low density lipoprotein-cholesterol levels (112.5 ± 1.4 vs 116.7 ± 0.93 mg/dL). Finally, compared to non-consumers of 100% OJ, consumers were 21% less likely to be obese and male consumers were 36% less likely to have MetS.

Conclusion

The results suggest that moderate consumption of 100% OJ should be encouraged to help individuals meet the USDA daily recommendation for fruit intake and as a component of a healthy diet.
Combined use of anti-ErbB monoclonal antibodies and erlotinib enhances antibody-dependent cellular cytotoxicity of wild-type erlotinib-sensitive NSCLC cell lines
Authors: Cavazzoni Andrea , Alfieri Roberta R , Cretella Daniele , Saccani Francesca , Ampollini Luca , Galetti Maricla , Quaini Federico , Graiani Gallia , Madeddu Denise , Mozzoni Paola , Galvani Elena , La Monica Silvia , Bonelli Mara , Fumarola Claudia , Mutti Antonio , Carbognani Paolo , Tiseo Marcello , Barocelli Elisabetta , Petronini Pier Giorgio , Ardizzoni Andrea
Published: December 2012

Background

The epidermal growth factor receptor (EGFR) is an established target for anti-cancer treatment in different tumour types. Two different strategies have been explored to inhibit this pivotal molecule in epithelial cancer development: small molecules TKIs and monoclonal antibodies. ErbB/HER-targeting by monoclonal antibodies such as cetuximab and trastuzumab or tyrosine-kinase inhibitors as gefitinib or erlotinib has been proven effective in the treatment of advanced NSCLC.

Results

In this study we explored the potential of combining either erlotinib with cetuximab or trastuzumab to improve the efficacy of EGFR targeted therapy in EGFR wild-type NSCLC cell lines. Erlotinib treatment was observed to increase EGFR and/or HER2 expression at the plasma membrane level only in NSCLC cell lines sensitive to the drug inducing protein stabilization. The combined treatment had marginal effect on cell proliferation but markedly increased antibody-dependent, NK mediated, cytotoxicity in vitro. Moreover, in the Calu-3 xenograft model, the combination significantly inhibited tumour growth when compared with erlotinib and cetuximab alone.

Conclusion

Our results indicate that erlotinib increases surface expression of EGFR and/or HER2 only in EGFR-TKI sensitive NSCLC cell lines and, in turns, leads to increased susceptibility to ADCC both in vitro and in a xenograft models. The combination of erlotinib with monoclonal antibodies represents a potential strategy to improve the treatment of wild-type EGFR NSCLC patients sensitive to erlotinib.
Ethanolamine utilization in Vibrio alginolyticus
Authors: Khatri Neelam , Khatri Indu , Subramanian Srikrishna , Raychaudhuri Saumya
Published: December 2012

Ethanolamine is used as an energy source by phylogenetically diverse bacteria including pathogens, by the concerted action of proteins from the eut-operon. Previous studies have revealed the presence of eutBC genes encoding ethanolamine-ammonia lyase, a key enzyme that breaks ethanolamine into acetaldehyde and ammonia, in about 100 bacterial genomes including members of gamma-proteobacteria. However, ethanolamine utilization has not been reported for any member of the Vibrio genus. Our comparative genomics study reveals the presence of genes that are involved in ethanolamine utilization in several Vibrio species. Using Vibrio alginolyticus as a model system we demonstrate that ethanolamine is better utilized as a nitrogen source than as a carbon source.

Reviewers

This article was reviewed by Dr. Lakshminarayan Iyer and Dr. Vivek Anantharaman (nominated by Dr. L Aravind).
Data reduction for cough studies using distribution of audio frequency content
Authors: Barton Antony , Gaydecki Patrick , Holt Kimberley , Smith Jaclyn A
Published: December 2012

Background

Recent studies suggest that objectively quantifying coughing in audio recordings offers a novel means to understand coughing and assess treatments. Currently, manual cough counting is the most accurate method for quantifying coughing. However, the demand of manually counting cough records is substantial, demonstrating a need to reduce record lengths prior to counting whilst preserving the coughs within them. This study tested the performance of an algorithm developed for this purpose.

Methods

20 subjects were recruited (5 healthy smokers and non-smokers, 5 chronic cough, 5 chronic obstructive pulmonary disease and 5 asthma), fitted with an ambulatory recording system and recorded for 24 hours. The recordings produced were divided into 15 min segments and counted. Periods of inactive audio in each segment were removed using the median frequency and power of the audio signal and the resulting files re-counted.

Results

The median resultant segment length was 13.9 s (IQR 56.4 s) and median 24 hr recording length 62.4 min (IQR 100.4). A median of 0.0 coughs/h (IQR 0.0-0.2) were erroneously removed and the variability in the resultant cough counts was comparable to that between manual cough counts. The largest error was seen in asthmatic patients, but still only 1.0% coughs/h were missed.

Conclusions

These data show that a system which measures signal activity using the median audio frequency can substantially reduce record lengths without significantly compromising the coughs contained within them.
Palindromic sequence impedes sequencing-by-ligation mechanism
Authors: Huang Yu-Feng , Chen Sheng-Chung , Chiang Yih-Shien , Chen Tzu-Han , Chiu Kuo-Ping
Published: December 2012

Background

Current next-generation sequencing (NGS) platforms adopt two types of sequencing mechanisms: by synthesis or by ligation. The former is employed by 454 and Solexa systems, while the latter by SOLiD system. Although the pros and cons for each sequencing mechanism have more or less been discussed in a number of occasions, the potential obstacle imposed by palindromic sequences has not yet been addressed.

Methods

To test the effect of the palindromic region on sequencing efficacy, we clonally amplified a paired-end ditag sequence composed of a 24-bp palindromic sequence flanked by a pair of tags from the E. coli genome. We used the near homogeneous fragments produced from Mme I digestion of the amplified clone to generate a sequencing library for SOLiD 5500xl sequencer.

Results

Results showed that, traditional ABI sequencers, which adopt sequencing-by-synthesis mechanism, were able to read through the palindromic region. However, SOLiD 5500xl was unable to do so. Instead, the palindromic region was read as miscellaneous random sequences. Moreover, readable tag sequence turned obscure ~2 bp prior to the palindromic region.

Conclusions

Taken together, we demonstrate that SOLiD machines, which employ sequencing-by-ligation mechanism, are unable to read through the palindromic region. On the other hand, sequencing-by-synthesis sequencers had no difficulty in doing so.
Hematometra presenting as an acute abdomen in a 13-year-old postmenarchal girl: a case report
Authors: Klimek Peter , Klimek Miriam , Kessler Ulf , Oesch Valerie , Wolf Rainer , Stranzinger Enno , Mueller Michael D , Zachariou Zacharias
Published: December 2012

Introduction

Most underlying diseases for abdominal pain in children are not dangerous. However some require rapid diagnosis and treatment, such as acute ovarian torsion or appendicitis. Since reaching a diagnosis can be difficult, and delayed treatment of potentially dangerous diseases might have significant consequences, exploratory laparoscopy is a diagnostic and therapeutic option for patients who have unclear and potentially hazardous abdominal diseases. Here we describe a case where the anomaly could not be identified using a laparoscopy in an adolescent girl with acute abdomen.

Case presentation

A 13-year old postmenarchal caucasian female presented with an acute abdomen. Emergency sonography could not exclude ovarian torsion. Accurate diagnosis and treatment were achieved only after an initial laparoscopy followed by a laparotomy and after a magnetic resonance imaging scan a further laparotomy. The underlying disease was hematometra of the right uterine horn in a uterus didelphys in conjunction with an imperforate right cervix.

Conclusion

This report demonstrates that the usual approach for patients with acute abdominal pain may not be sufficient in emergency situations.
Multivariate methods and software for association mapping in dose‐response genome‐wide association studies
Authors: Brown Chad C , Havener Tammy M , Medina Marisa Wong , Krauss Ronald M , McLeod Howard L , Motsinger‐Reif Alison A
Published: December 2012

Background

The large sample sizes, freedom of ethical restrictions and ease of repeated measurements make cytotoxicity assays of immortalized lymphoblastoid cell lines a powerful new in vitro method in pharmacogenomics research. However, previous studies may have over‐simplified the complex differences in dose‐response profiles between genotypes, resulting in a loss of power.

Methods

The current study investigates four previously studied methods, plus one new method based on a multivariate analysis of variance (MANOVA) design. A simulation study was performed using differences in cancer drug response between genotypes for biologically meaningful loci. These loci also showed significance in separate genome‐wide association studies. This manuscript builds upon a previous study, where differences in dose‐response curves between genotypes were constructed using the hill slope equation.

Conclusion

Overall, MANOVA was found to be the most powerful method for detecting real signals, and was also the most robust method for detection using alternatives generated with the previous simulation study. This method is also attractive because test statistics follow their expected distributions under the null hypothesis for both simulated and real data. The success of this method inspired the creation of the software program MAGWAS. MAGWAS is a computationally efficient, user‐friendly, open source software tool that works on most platforms and performs GWASs for individuals having multivariate responses using standard file formats.
Partial purification and properties of cyclodextrin glycosiltransferase (CGTase) from alkalophilic Bacillus species
Authors: Mora Marlene M Martínez , Sánchez Karel Hernández , Santana Reynaldo Villalonga , Rojas Arley Pérez , Ramírez Héctor L , Torres-Labandeira Juan José
Published: December 2012

Cyclodextrin glucanotransferase (CGTase, EC 2.4.1.9) is an unique enzyme capable of converting starch and related substrates into cyclodextrins (CDs). In this paper, we report an one step gel purification method of CGTase from Bacillus sp. and later enzyme characterization. The Bacillus sp. strain was isolated from a Colocacia esculenta rizospheric soil sample and the CGTase production was carried out in alkaline medium (pH=10). The CGTase purification from the culture supernatant was performed by gel filtration. The enzyme was purified in one step with a recovery of 87.3% activity and 40-fold purification for specific enzymatic activity of 2.24 U/mg. Optimal activity was observed at pH 5.0 in citrate-phosphate buffer, and the enzyme retained almost 100 % of its activity between pH 5.5 and 10 after incubation for 1 h at 4°C. The enzyme exhibited maximum activity at 55°C and showed a T50% of 70°C. The ratio of α:β:γ CD formed by the enzyme was 0.74:1:0.61 for soluble starch and 0.29:1:0.85 for cocoyam starch.
The association between depression, socio-economic factors and dietary intake in mothers having primary school children living in Rey, south of Tehran, Iran
Authors: Payab Moloud , Motlagh Ahmad-reza Dorosty , Eshraghian Mohammadreza , Rostami Reza , Siassi Fereydoun , abbasi Behnood , Ahmadi Mehrnaz , Karimi Tina , Mahjouri Mohammad Yoosef , Seifirad Soroush
Published: December 2012

Background

According to the WHO report released in 2000, about 121 million people worldwide suffer from depression. The present study aimed to explore factors influencing depression in mothers from Rey, South of Tehran, Iran; who had elementary school children.

Methods

The cross-sectional survey was conducted in spring 2010. Four hundred thirty mothers who had elementary school children, were selected through a two stage cluster sampling. Beck Depression Inventory (BDI) was used to assess depression in the mothers and a 24-hour food recall was used to collect information regarding their dietary intake. General information regarding economic condition and socio-economic status were also gathered using a questionnaire. The data was analyzed using chi-square, one-way analysis of variance and simple regression tests.

Results

In our study, 51.4% of the mothers suffered from depression. There was an inverse correlation between the educational level of the mothers and the heads of household, their occupational status, their marital status, their socio-economic condition and depression. Conversely, any increase in the family size worsened the depression. The daily intake of different macronutrients, except for fat, was lower in individuals of depressed group.

Conclusion

The present study emphasized the fact that more attention should be paid to the educational level and economic condition of the family in order to reduce maternal depression. Family size also plays an important role in this regard.
Neutrophil and endothelial adhesive function during human fetal ontogeny
Authors: Nussbaum Claudia , Gloning Anna , Pruenster Monika , Frommhold David , Bierschenk Susanne , Genzel-Boroviczény Orsolya , von Andrian Ulrich H , Quackenbush Elizabeth , Sperandio Markus
Published: December 2012

Leukocyte recruitment is ontogenetically regulated during fetal life, with strongly impaired adhesiveness of fetal leukocytes and endothelial cells, during early fetal development.

Attenuation of the immune response contributes to the high rate of neonatal infections, particularly in premature infants. Whereas our knowledge of innate immune functions in mature neonates is growing, little is known about the ontogeny of neutrophil recruitment. We investigated neutrophils and ECs in the course of gestation with respect to rolling and adhesive functions. With the use of microflow chambers, we demonstrate that the neutrophilˈs ability to roll and adhere directly correlates with gestational age. These adhesion-related abilities are very rare in extremely premature infants (<30 weeks of gestation), which may correlate with our observation of markedly reduced expression of PSGL-1 and Mac-1 on neutrophils in preterm infants. In parallel, the capacity of HUVECs to mediate neutrophil adhesion under flow increases with gestational age. In addition, HUVECs from extremely premature infants exerting the lowest ability to recruit adult neutrophils show a diminished up-regulation of E-selectin and ICAM-1. Finally, by following neutrophil function postnatally, we show that maturation of PMN recruitment proceeds equivalently during extra- and intrauterine development. Thus, PMN recruitment and EC adhesion-related functions are ontogenetically regulated in the fetus, which might contribute significantly to the high risk of life-threatening infections in premature infants.
Anisotropic parsimonious prestack depth migration
Authors: Oropeza Ernesto V. , McMechan George A.
Published: December 2012

An efficient Kirchhoff-style prestack depth migration, called “parsimonious” migration, was developed a decade ago for isotropic 2D and 3D media by using measured slownesses to reduce the amount of ray tracing by orders of magnitude. It is conceptually similar to “map” migration, but its implementation has some differences. We have extended this approach to 2D tilted transversely isotropic (TTI) media and illustrated it with synthetic P-wave data. Although the framework of isotropic parsimonious may be retained, the extension to TTI media requires redevelopment of each of the numerical components, calculation of the phase and group velocity for TTI media, development of a new two-point anisotropic ray tracer, and substitution of an initial-angle isotropic shooting ray-trace algorithm for an anisotropic one. The model parameterization consists of Thomsen’s parameters ([Formula: see text], [Formula: see text], [Formula: see text]) and the tilt angle of the symmetry axis of the TI medium. The parsimonious anisotropic migration algorithm is successfully applied to synthetic data from a TTI version of the Marmousi2 model. The quality of the image improves by weighting the impulse response by the calculation of the anisotropic Fresnel radius. The accuracy and speed of this migration makes it useful for anisotropic velocity model building. The elapsed computing time for 101 shots for the Marmousi2 TTI model is 35 s per shot (each with 501 traces) in 32 Opteron cores.
Integrated application of heliborne and ground electromagnetic surveys for mapping EM conductor for uranium exploration and its subsurface validation, North Delhi Fold Belt, Rajasthan, India: A case study
Authors: Chaturvedi A. K. , Lotter Cas , Tripathi Shailesh , Maurya A. K. , Patra Indrajit , Parihar P. S.
Published: December 2012

A fracture-controlled uranium deposit was identified in Proterozoic Ajabgarh metasediments of the North Delhi Fold Belt within the Khetri subbasin at Rohil, Sikar district, Rajasthan, India. Uranium mineralization in the area is associated with geologic structures, albitization, and pyroxenization of metasediments and conductors such as metallic sulfides and carbonaceous phyllites/graphitic schists. To locate uranium mineralization akin to Rohil in nearby thick soil covered areas, this association was targeted through heliborne geophysical surveys. High-resolution heliborne magnetic and time domain electromagnetic (TEM) surveys were conducted around Rohil. The survey delineated several targets with favorable geologic structures and conductors such as graphitic schist for further uranium exploration. One favorable target near Chappar village was taken up for follow-up exploration work. The EM conductor mapped from heliborne survey was subsequently validated through ground time-domain electromagnetic surveys and subsurface exploration. Modeling of heliborne and ground-based electromagnetic data revealed the presence of subsurface conducting bodies with comparable model parameters. Drilling established the presence of a subsurface conductor up to a depth of 300 m, which was attributed to the presence of graphite and sulfides (pyrrhotite) along foliation plane of carbon phyllite/graphitic schist/quartz-biotite schist and calc-silicate rock. Further detailed laboratory investigations (petrology/X-ray diffraction) of selected core samples from the conductive zones confirmed the presence of pyrrhotite and graphite responsible for EM signature. This study, carried out by using multiparameter data sets, proved the efficacy of heliborne surveys in locating favorable targets for uranium exploration in Ajabgarh group of rocks.
Randomized Phase III Placebo-Controlled Trial of Letrozole Plus Oral Temsirolimus As First-Line Endocrine Therapy in Postmenopausal Women With Locally Advanced or Metastatic Breast Cancer
Authors: Wolff Antonio C. , Lazar Ann A. , Bondarenko Igor , Garin August M. , Brincat Stephen , Chow Louis , Sun Yan , Neskovic-Konstantinovic Zora , Guimaraes Rodrigo C. , Fumoleau Pierre , Chan Arlene , Hachemi Soulef , Strahs Andrew , Cincotta Maria , Berkenblit Anna , Krygowski Mizue , Kang Lih Lisa , Moore Laurence , Hayes Daniel F.
Published: December 2012

Purpose

Recent data showed improvement in progression-free survival (PFS) when adding everolimus to exemestane in patients with advanced breast cancer experiencing recurrence/progression after nonsteroidal aromatase inhibitor (AI) therapy. Here, we report clinical outcomes of combining the mammalian target of rapamycin (mTOR) inhibitor temsirolimus with letrozole in AI-naive patients.

Patients and Methods

This phase III randomized placebo-controlled study tested efficacy/safety of first-line oral letrozole 2.5 mg daily/temsirolimus 30 mg daily (5 days every 2 weeks) versus letrozole/placebo in 1,112 patients with AI-naive, hormone receptor–positive advanced disease. An independent data monitoring committee recommended study termination for futility at the second preplanned interim analysis (382 PFS events).

Results

Patients were balanced (median age, 63 years; 10% stage III, 40% had received adjuvant endocrine therapy). Those on letrozole/temsirolimus experienced more grade 3 to 4 events (37% v 24%). There was no overall improvement in primary end point PFS (median, 9 months; hazard ratio [HR], 0.90; 95% CI, 0.76 to 1.07; P = .25) nor in the 40% patient subset with prior adjuvant endocrine therapy. An exploratory analysis showed improved PFS favoring letrozole/temsirolimus in patients ≤ age 65 years (9.0 v 5.6 months; HR, 0.75; 95% CI, 0.60 to 0.93; P = .009), which was separately examined by an exploratory analysis of 5-month PFS using subpopulation treatment effect pattern plot methodology (P = .003).

Conclusion

Adding temsirolimus to letrozole did not improve PFS as first-line therapy in patients with AI-naive advanced breast cancer. Exploratory analyses of benefit in younger postmenopausal patients require external confirmation.
Prevalence and Type ofBRCAMutations in Hispanics Undergoing Genetic Cancer Risk Assessment in the Southwestern United States: A Report From the Clinical Cancer Genetics Community Research Network
Authors: Weitzel Jeffrey N. , Clague Jessica , Martir-Negron Arelis , Ogaz Raquel , Herzog Josef , Ricker Charité , Jungbluth Chelsy , Cina Cheryl , Duncan Paul , Unzeitig Gary , Saldivar J. Salvador , Beattie Mary , Feldman Nancy , Sand Sharon , Port Danielle , Barragan Deborah I. , John Esther M. , Neuhausen Susan L. , Larson Garrett P.
Published: December 2012

Purpose

To determine the prevalence and type of BRCA1 and BRCA2 (BRCA) mutations among Hispanics in the Southwestern United States and their potential impact on genetic cancer risk assessment (GCRA).

Patients and Methods

Hispanics (n = 746) with a personal or family history of breast and/or ovarian cancer were enrolled in an institutional review board–approved registry and received GCRA and BRCA testing within a consortium of 14 clinics. Population-based Hispanic breast cancer cases (n = 492) enrolled in the Northern California Breast Cancer Family Registry, negative by sequencing for BRCA mutations, were analyzed for the presence of the BRCA1 ex9-12del large rearrangement.

Results

Deleterious BRCA mutations were detected in 189 (25%) of 746 familial clinic patients (124 BRCA1, 65 BRCA2); 21 (11%) of 189 were large rearrangement mutations, of which 62% (13 of 21) were BRCA1 ex9-12del. Nine recurrent mutations accounted for 53% of the total. Among these, BRCA1 ex9-12del seems to be a Mexican founder mutation and represents 10% to 12% of all BRCA1 mutations in clinic- and population-based cohorts in the United States.

Conclusion

BRCA mutations were prevalent in the largest study of Hispanic breast and/or ovarian cancer families in the United States to date, and a significant proportion were large rearrangement mutations. The high frequency of large rearrangement mutations warrants screening in every case. We document the first Mexican founder mutation (BRCA1 ex9-12del), which, along with other recurrent mutations, suggests the potential for a cost-effective panel approach to ancestry-informed GCRA.
90Yttrium-Ibritumomab-Tiuxetan as First-Line Treatment for Follicular Lymphoma: 30 Months of Follow-Up Data From an International Multicenter Phase II Clinical Trial
Authors: Scholz Christian W. , Pinto Antonello , Linkesch Werner , Lindén Ola , Viardot Andreas , Keller Ulrich , Hess Georg , Lastoria Secondo , Lerch Kristina , Frigeri Ferdinando , Arcamone Manuela , Stroux Andrea , Frericks Bernd , Pott Christiane , Pezzutto Antonio
Published: December 2012

Purpose

We report on a multicenter phase II trial of 90yttrium-ibritumomab-tiuxetan (90YIT) as first-line stand-alone therapy for patients with follicular lymphoma (FL).

Patients and Methods

Fifty-nine patients with CD20+ FL grade 1 to 3a in stages II, III, or IV, age 50 years old or older requiring therapy were enrolled. They received 90YIT according to standard procedure. If complete response (CR) or unconfirmed complete response (CRu) without evidence for minimal residual disease (MRD) 6 months after application of 90YIT was achieved, patients were observed without further intervention. The same applied to patients with partial response (PR) or with stable disease (SD). Patients with CR but with persisting MRD were to receive a consolidation treatment with rituximab. Primary end point was the clinical and molecular response rate. Secondary end points were time to progression, safety, and tolerability.

Results

Six months after treatment with 90YIT, 56% of the patients showed a CR or CRu and 31% achieved a PR. After a median follow-up of 30.6 months, the progression-free survival (PFS) was 26 months. There was a trend for shorter PFS in patients with increased lactate dehydrogenase (LDH). Of the 26 patients who had CR 12 months after 90YIT, only three had relapsed. Median time to next treatment has not been reached. The most common toxicities were transient thrombocytopenia and leukocytopenia. Nonhematologic toxicities never exceeded grade 2 according to Common Terminology Criteria for Adverse Events (CTCAE v2.0).

Conclusion

90YIT is well tolerated and achieves high response rates. Patients with increased LDH tend to relapse earlier, and individuals in remission 1 year after 90YIT appear to have long- lasting responses.
Persistent Overall Survival Benefit and No Increased Risk of Second Malignancies With Bortezomib-Melphalan-Prednisone Versus Melphalan-Prednisone in Patients With Previously Untreated Multiple Myeloma
Authors: San Miguel Jesús F. , Schlag Rudolf , Khuageva Nuriet K. , Dimopoulos Meletios A. , Shpilberg Ofer , Kropff Martin , Spicka Ivan , Petrucci Maria Teresa , Palumbo Antonio , Samoilova Olga S. , Dmoszynska Anna , Abdulkadyrov Kudrat M. , Delforge Michel , Jiang Bin , Mateos Maria-Victoria , Anderson Kenneth C. , Esseltine Dixie-Lee , Liu Kevin , Deraedt William , Cakana Andrew , van de Velde Helgi , Richardson Paul G.
Published: December 2012

Purpose

This final analysis of the phase III VISTA trial (Velcade As Initial Standard Therapy in Multiple Myeloma: Assessment With Melphalan and Prednisone) was conducted to determine whether the overall survival (OS) benefit with bortezomib-melphalan-prednisone (VMP) versus melphalan-prednisone (MP) in patients with myeloma who were ineligible for transplantation was maintained after 5 years of follow-up and to explore the risk of second primary malignancies.

Patients and Methods

In all, 682 patients received up to nine 6-week cycles of VMP or MP and were then observed every 12 weeks or less. Data on second primary malignancies were collected by individual patient inquiries at all sites from 655 patients.

Results

After median follow-up of 60.1 months (range, 0 to 74 months), there was a 31% reduced risk of death with VMP versus MP (hazard ratio [HR], 0.695; P < .001; median OS 56.4 v 43.1 months). OS benefit with VMP was seen across prespecified patient subgroups (age ≥ 75 years, stage III myeloma, creatinine clearance < 60 mL/min). Sixty-three percent of VMP patients and 73% of MP patients had received subsequent therapy. Time to next therapy (median, 30.7 v 20.5 months; HR, 0.557; P < .001) was longer with VMP than with MP. Among patients who received subsequent therapies, survival from start of subsequent therapy was similar following VMP (median, 28.1 months) or MP (median, 26.8 months; HR, 0.914). Following VMP/MP, incidence proportions of hematologic malignancies (1%/1%) and solid tumors (5%/3%) and exposure-adjusted incidence rates (0.017/0.013 per patient-year) were similar and were consistent with background rates.

Conclusion

VMP resulted in a significant reduction in risk of death versus MP that was maintained after 5 years' follow-up and despite substantial use of novel-agent-based salvage therapies. There is no emerging safety signal for second primary malignancies following VMP.
Feasibility Study on Ultrasound-Assisted Emulsification Microextraction-Near Infrared Spectroscopy Technique for the Determination of Traces of Nonylphenol in Water Samples
Authors: Yuan Wenbo , Xiang Bingren , Yu Liyan , Zhu Liangzhen
Published: December 2012

An ultrasound-assisted emulsification microextraction-near infrared spectroscopy (USAEME-NIR) technique was applied for quantitative analysis of traces of nonylphenol in water samples. Development of the USAEME procedure included optimisation of some important parameters such as extracting temperature, time for ultrasonic-assisted emulsification and the ionic strength. Under optimised conditions, 200 μL carbon tetrachloride was injected into a 20 mL water sample and ultrasonically emulsified for 15 min. The organic phase was taken for NIR analysis after centrifuging. Using a least squares-support vector machine regression (LS-SVMR) model, the linearity and accuracy were satisfactory in the range of 600–6000 μgL−1. Promising results, with r2 = 0.99, RMSEP=44.8 μgL−1 and RPD=8.9, were achieved when the model was used to analyse for nonylphenol in water samples from local factories and sewage treatment works. The results showed that rapid determination of trace contaminants in water samples by NIR is feasible using the USAEME-NIR technique.
Non-Invasive Estimation of Skin Thickness by near Infrared Diffuse Reflection Spectroscopy—Separate Determination of Epidermis and Dermis Thickness
Authors: Miyamae Yuta , Kawabata Marie , Yamakawa Yumika , Tsuchiya Junko , Ozaki Yukihiro
Published: December 2012

This paper reports a non-invasive method for estimating skin thickness by using near infrared diffuse reflectance (NIR-DR) spectroscopy. Skin thickness is an important skin property in cosmetology, dermatology and pharmaceutical science. It varies significantly between the face and other body parts and changes with age and environment factors. Differences in skin thickness reflect the structural conditions of the epidermis and dermis. However, current methods for measuring skin thickness are complex and require cumbersome equipment. Therefore, we herein propose a NIR-DR and partial least squares (PLS) regression method for non-destructive skin thickness estimation. NIR-DR spectra were measured for UV-irradiated and non-irradiated skin on the backs of hairless mice and denuded back skin. Skin thickness increased gradually with the amount of UV irradiation, while changing little with physiological age. To obtain reference data, optical microscope measurements were carried out for denuded skin and total thickness and thickness of epidermis and dermis were determined. PLS regression was performed for the whole spectrum and selected regions specific for particular functional groups in order to estimate total thickness and thickness of epidermis and dermis. In the 6939–5990 cm−1 and 5242–4609 cm−1 regions, the bands due to amide groups of proteins appeared to contribute to models with the best coefficients of determination ( R2CV) and standard error of cross-validation results; for total thickness, thickness of epidermis, and dermis, these were 0.79 and 25.80 urn, 0.72 and 21.87 μm and 0.77 and 8.16 μm, respectively. The results revealed that the wavenumbers contributing to the prediction of skin thickness differ between the epidermis and dermis.
Detection and Quantification of Ruminant Meal in Processed Animal Proteins: A Comparative Study of near Infrared Spectroscopy and near Infrared Chemical Imaging
Authors: Riccioli Cecilia , Pérez-Marín Dolores , Guerrero-Ginel José Emilio , Fearn Tom , Garrido-Varo Ana
Published: December 2012

This study compared the performance of single-point near infrared spectroscopy (NIR) and near infrared chemical imaging (NIR-CI) for the detection and quantification of ruminant meat meal in processed animal proteins (PAPs). A set of 126 fish-meal samples adulterated with controlled amounts (0.25% to 16%) of ruminant meal were analysed using the two techniques. Comparison of results showed that spectra obtained by NIR-CI provided better qualitative information, whereas more accurate quantitative predictions were obtained using NIR spectroscopy. NIR-CI thus offers greater potential for species discrimination/identification, whilst NIR spectroscopy is better suited for the quantification of meal derived from a given species in PAPs. These findings represent a first step in the analysis of mixed-species processed animal proteins and suggest that NIR-CI, by providing valuable information on species origin, is a promising tool that could be used as part of the EU feed control programme aimed at eradicating and preventing Bovine Spongiform Encephalopathy (BSE) and related diseases.
Book Reviews
Authors: Rand Graham K.
Published: December 2012

In Book Reviews, we review an extensive and diverse range of books. They cover theory and applications in operations research, statistics, management science, econometrics, mathematics, computers, and information systems. In addition, we include books in other fields that emphasize technical applications. The editor will be pleased to receive an email from those willing to review a book, with an indication of specific areas of interest. If you are aware of a specific book that you would like to review, or that you think should be reviewed, please contact the editor.

The following books are reviewed in this issue of Interfaces, 42(6), November–December 2012: Not for Free: Revenue Strategies for a New World, Saul J. Berman; Queueing Networks: A Fundamental Approach, Richard J. Boucherie and Nico M. Van Dijk, eds.; Rational Decision Making, Franz Eisenführ, Martin Weber, and Thomas Langer; Trends in Multiple Criteria Decision Analysis, Salvatore Greco, Matthias Ehrgott, and José Rui Figueira, eds.; You're Next!, Terry Green; Multiple Criteria Decision Making: From Early History to the 21st Century, Murat Köksalan, Jyrki Wallenius, and Stanley Zionts; A Strategy for Using Multicriteria Analysis in Decision-Making: A Guide for Simple and Complex Environmental Projects, Nolberto Munier.
Ranolazine-Induced Severe Bladder Hypotonia; Fatal Varicella-Zoster Vasculopathy Associated with Adalimumab Therapy; SIADH Induced by a Single Dose of Cyclophosphamide; Tetany, Hypomagnesemia, and Proton Pump Inhibitors; Unnecessary Surgery for Acute Abdomen Caused by ACE Inhibitor Use; Atazanavir-Associated Renal Stones and Biliary Stones; Drug-Induced Hallucinations Associated with Amantadine and Tizanidine
Authors: Shuster Joel
Published: December 2012

The purpose of this feature is to heighten awareness of specific adverse drug reactions (ADRs), discuss methods of prevention, and promote reporting of ADRs to the US Food and Drug Administration's (FDA's) MEDWATCH program (800-FDA-1088).
Implementation and Outcome Assessment of an Inpatient Antimicrobial Stewardship Program
Authors: Hagert Brandie L. , Williams Cristin , Wieser Catherine M. , Rohrich Melissa A. , Lo Tze Shien , Newman William P. , Koo Ji M.
Published: December 2012

Background

An antimicrobial stewardship program (ASP), aiming to optimize antimicrobial usage, was implemented at a Veterans Affairs Health Care System (VA HCS).

Objective

The main objective of this study was to compare antimicrobial usage before and after implementation of an ASP and to assess ASP interventions.

Method

This retrospective study was conducted at the Fargo VA HCS. A total of 1,017 inpatient charts were reviewed for 2 distinct time periods, February through September 2008 (pre ASP) and February through September 2010 (post ASP). The data that were collected and analyzed included the number of hospitalized patients prescribed antimicrobials, antimicrobial therapy duration, duration of hospital stay, and inpatient antimicrobial costs. Subgroup analyses were performed on the top 5 antimicrobials and the top 6 indications. The number, types of, and overall acceptance rate of ASP interventions were also assessed.

Results

When the pre- to post-ASP periods were compared, the percentage of patients on antimicrobial therapy decreased from 36.8% to 25% ( P < .001), the median duration of antimicrobial therapy significantly decreased ( P = .02), and the defined daily dose (DDD) per 1,000 patient bed days was reduced for piperacillin/tazobactam, vancomycin, and ciprofloxacin. In addition, the total inpatient antimicrobial costs decreased by $48,044 (25%). The overall ASP intervention acceptance rate was 81.6% (315 out of 386 total interventions).

Conclusion

The results of this study show that ASP implementation has been highly accepted by providers and has been associated with a reduction in the number of patients prescribed antimicrobials, median duration of antimicrobial therapy, and antimicrobial inpatient costs.
Diffusion Abnormalities in Pediatric Mild Traumatic Brain Injury
Authors: Mayer Andrew R. , Ling Josef M. , Yang Zhen , Pena Amanda , Yeo Ronald A. , Klimaj Stefan
Published: December 2012

Pediatric mild traumatic brain injury (pmTBI) is the most prevalent neurological insult in children and is associated with both acute and chronic neurobehavioral sequelae. However, little is known about underlying pathophysiology and how injuries change as a function of recovery. Fractional anisotropy, axial diffusivity, and radial diffusivity were examined in 15 semi-acute pmTBI patients and 15 well-matched controls, with a subset of participants returning for a second visit. A novel analytic strategy was applied to capture spatially heterogeneous white matter injuries (lesions) in addition to standard analyses. Evidence of cognitive dysfunction after pmTBI was observed in the domains of attention (p= 0.02,d= −0.92) and processing speed (p= 0.05,d= −0.73) semi-acutely. Region of interest (ROI) and voxelwise analyses indicated increased anisotropic diffusion for pmTBI patients, with an elevated number of clusters with high anisotropy. Metrics of increased anisotropy were able to objectively classify pmTBI from healthy controls at 90% accuracy but were not associated with neuropsychological deficits. Little evidence of recovery in white matter abnormalities was observed over a 4-month interval in returning patients, indicating that physiological recovery may lag behind subjective reports of normality. Increased anisotropic diffusion has been previously linked with cytotoxic edema after TBI, and the magnitude and duration of these abnormalities appear to be greater in pediatric patients. Current findings suggest that developing white matter may be more susceptible to initial mechanical injury forces and that anisotropic diffusion provides an objective biomarker of pmTBI.
Generation of Intensity Selectivity by Differential Synaptic Tuning: Fast-Saturating Excitation But Slow-Saturating Inhibition
Authors: Zhou Mu , Tao Huizhong W. , Zhang Li I.
Published: December 2012

Intensity defines one fundamental aspect of sensory information and is specifically represented in each sensory modality. Interestingly, only in the central auditory system are intensity-selective neurons evolved. These neurons are characterized by nonmonotonic response-level functions. The synaptic circuitry mechanisms underlying the generation of intensity selectivity from nonselective auditory nerve inputs remain largely unclear. Here, we performedin vivowhole-cell recordings from pyramidal neurons in the rat dorsal cochlear nucleus (DCN), where intensity selectivity first emerges along the auditory neuraxis. Our results revealed that intensity-selective cells received fast-saturating excitation but slow-saturating inhibition with intensity increments, whereas in intensity-nonselective cells excitation and inhibition were similarly slow-saturating. The differential intensity tuning profiles of the monotonic excitation and inhibition qualitatively determined the intensity selectivity of output responses. In addition, the selectivity was further strengthened by significantly lower excitation/inhibition ratios at high-intensity levels compared with intensity-nonselective neurons. Our results demonstrate that intensity selectivity in the DCN is generated by extracting the difference between tuning profiles of nonselective excitatory and inhibitory inputs, which we propose can be achieved through a differential circuit mediated by feedforward inhibition.
Three Types of Neurochemical Projection from the Bed Nucleus of the Stria Terminalis to the Ventral Tegmental Area in Adult Mice
Authors: Kudo Takehiro , Uchigashima Motokazu , Miyazaki Taisuke , Konno Kohtarou , Yamasaki Miwako , Yanagawa Yuchio , Minami Masabumi , Watanabe Masahiko
Published: December 2012

Dopaminergic (DAergic) neurons in the ventral tegmental area (VTA) play crucial roles in motivational control of behaviors, and their activity is regulated directly or indirectly via GABAergic neurons by extrinsic afferents from various sources, including the bed nucleus of the stria terminalis (BST). Here, the neurochemical composition of VTA-projecting BST neurons and their outputs to the VTA were studied in adult mouse brains. By combining retrograde tracing with fluorescencein situhybridization for 67 kDa glutamate decarboxylase (GAD67) and vesicular glutamate transporters (VGluTs), VTA-targeting BST neurons were classified into GAD67-positive (GAD67+)/VGluT3-negative (VGluT3−), GAD67+/VGluT3+, and VGluT2+neurons, of which GAD67+/VGluT3−neurons constituted the majority (∼90%) of VTA-projecting BST neurons. GABAergic efferents from the BST formed symmetrical synapses on VTA neurons, which were mostly GABAergic neurons, and expressed GABAAreceptor α1 subunit on their synaptic and extrasynaptic membranes. In the VTA, VGluT3 was detected in terminals expressing vesicular inhibitory amino acid transporter (VIAAT), plasmalemmal serotonin transporter, or neither. Of these, VIAAT+/VGluT3+terminals, which should include those from GAD67+/VGluT3+BST neurons, formed symmetrical synapses. When single axons from VGluT3+BST neurons were examined, almost all terminals were labeled for VIAAT, whereas VGluT3 was often absent from terminals with high VIAAT loads. VGluT2+terminals in the VTA exclusively formed asymmetrical synapses, which expressed AMPA receptors on postsynaptic membrane. Therefore, the major mode of the BST–VTA projection is GABAergic, and its activation is predicted to disinhibit VTA DAergic neurons. VGluT2+and VGluT3+BST neurons further supply additional projections, which may principally convey excitatory or inhibitory inputs, respectively, to the VTA.
Severity of Infantile Nystagmus Syndrome-Like Ocular Motor Phenotype Is Linked to the Extent of the Underlying Optic Nerve Projection Defect in ZebrafishbelladonnaMutant
Authors: Huber-Reggi Sabina P. , Chen Chien-Cheng , Grimm Lea , Straumann Dominik , Neuhauss Stephan C. F. , Huang Melody Ying-Yu
Published: December 2012

Infantile nystagmus syndrome (INS), formerly known as congenital nystagmus, is an ocular motor disorder in humans characterized by spontaneous eye oscillations (SOs) and, in several cases, reversed optokinetic response (OKR). Its etiology and pathomechanism is largely unknown, but misrouting of the optic nerve has been observed in some patients. Likewise, optic nerve misrouting, a reversed OKR and SOs with INS-like waveforms are observed in zebrafishbelladonna(bel) mutants. We aimed to investigate whether and how misrouting of the optic nerve correlates with the ocular motor behaviors inbellarvae.

OKR and SOs were quantified and subsequently the optic nerve fibers were stained with fluorescent lipophilic dyes. Eye velocity during OKR was reduced in larvae with few misprojecting optic nerve fibers and reversed in larvae with a substantial fraction of misprojecting fibers. All larvae with reversed OKR also displayed SOs. A stronger reversed OKR correlated with more frequent SOs. Since we did not find a correlation between additional retinal defects and ocular motor behavior, we suggest that axon misrouting is in fact origin of INS in the zebrafish animal model. Depending on the ratio between misprojecting ipsilateral and correctly projecting contralateral fibers, the negative feedback loop normally regulating OKR can turn into a positive loop, resulting in an increase in retinal slip. Our data not only give new insights into the etiology of INS but may also be of interest for studies on how the brain deals with and adapts to conflicting inputs.