bluuebunny/crossref_metadata_2025 huggingface dataset:
Retroperitoneal lymphadenectomy and resection for testicular cancer: an update on best practice
Authors: Heidenreich Axel , Pfister David
Published: May 2012

Clinical stage I testicular nonseminomatous germ cell tumours (NSGCTs) are highly curable. Following orchidectomy a risk-adapted approach using active surveillance (AS), nerve-sparing retroperitoneal lymph node dissection (nsRPLND) and primary chemotherapy is recommended by the current guidelines. Clinical stage I is defined as negative or declining tumour markers to their half-life following orchidectomy and negative imaging studies of the chest, abdomen and retroperitoneum. Active surveillance can be performed in low-risk and in high-risk NSGCTs with an anticipated relapse rate of about 15% and 50%. The majority of patients will relapse with good and intermediate prognosis tumours which have to be treated with three to four cycles chemotherapy. About 25–30% of these patients will have to undergo postchemotherapy retroperitoneal lymph node dissection (PC-RPLND) for residual masses. Primary chemotherapy with one or two cycles of cisplatin (Platinol), etoposide and bleomycin (PEB) is a therapeutic option for high-risk clinical stage I NSGCT associated with a recurrence rate of only 2–3% and a minimal acute and long-term toxicity rate. nsRPLND, if performed properly, will cure about 85% of all high-risk patients with clinical stage I NSGCT without the need for chemotherapy. PC-RPLND forms an integral part of the multimodality treatment in patients with advanced testicular germ cell tumours (TGCTs). According to current guidelines and recommendations, PC-RPLND in advanced seminomas with residual tumours is only indicated if a positron emission tomography (PET) scan performed 6–8 weeks after chemotherapy is positive. In nonseminomatous TGCT, PC-RPLND is indicated for all residual radiographic lesions with negative or plateauing markers. Loss of antegrade ejaculation represents the most common long-term complication which can be prevented by a nerve-sparing or modified template resection. The relapse rate after PC-RPLND is around 12%, however it increases significantly to about 45% in cases with redo RPLND and late relapses. Patients with increasing markers should undergo salvage chemotherapy. Only select patients with elevated markers who are thought to be chemorefractory might undergo desperation PC-RPLND if all radiographically visible lesions are completely resectable. PC-RPLND requires a complex surgical approach and should be performed in experienced, tertiary referral centres only.
“I Need Help and I Know I Need Help. Why Won’t Nobody Listen to Me?”
Authors: Huey Laura , Fthenos Georgios , Hryniewicz Danielle
Published: May 2012

In the present study, we draw on interviews conducted with 79 homeless women in Detroit and Chicago to reveal the extent to which women in our sample have experienced multiple forms of trauma and other significant stressors over their life course, events that we show have had serious negative effects on their mental and emotional well-being. We then look at their ability to access counseling services and consider barriers to service use. For those women who have utilized counseling services, we examine their reported satisfaction with the services accessed and identify certain deficiencies. Based on our findings, we conclude that it could reasonably be argued that the ‘pathological homeless woman’ is a construct tied to women’s experiences with a health care system that frequently fails them.
Levels of peripheral CD4+FoxP3+ regulatory T cells are negatively associated with clinical response to adoptive immunotherapy of human cancer
Authors: Yao Xin , Ahmadzadeh Mojgan , Lu Yong-Chen , Liewehr David J. , Dudley Mark E. , Liu Fang , Schrump David S. , Steinberg Seth M. , Rosenberg Steven A. , Robbins Paul F.
Published: May 2012

CD4+FoxP3+ regulatory T cells (Tregs) have been shown to suppress T cell–mediated host immune responses against self- and nonself-antigens; however, the impact of CD4+ Tregs on human antitumor immune responses and their influence on cancer treatment are unknown. In the present study, we explored the factors that influence CD4+ Treg reconstitution in patients receiving adoptive immunotherapy following conditioning regimens designed to enhance T-cell function and evaluated potential associations between CD4+ Treg levels and clinical responses to therapy. The analysis of 4 trials employing nonmyeloablative chemotherapy with or without total body irradiation (TBI) before adoptive T-cell transfer revealed that the percentage and number of reconstituting CD4+FoxP3+ Tregs observed in the peripheral blood was higher in nonresponders than in responders. The addition of TBI resulted in a further depletion of CD4+ Tregs, and the degree of depletion was dependent on the TBI dose. The number of administered doses of IL-2 was found to be positively associated with peripheral Treg reconstitution. These observations provide strong evidence that endogenous CD4+ Tregs have a negative impact on cancer therapy, and suggest that strategies reducing Treg levels may provide clinical benefit to cancer patients. All 5 clinical trials are registered at www.clinicaltrials.gov as NCT00001832, NCT00096382, NCT00335127, NCT00509496, and NCT00513604.
RNAi screen identifies MAPK14 as a druggable suppressor of human hematopoietic stem cell expansion
Authors: Baudet Aurélie , Karlsson Christine , Safaee Talkhoncheh Mehrnaz , Galeev Roman , Magnusson Mattias , Larsson Jonas
Published: May 2012

We report on a forward RNAi screen in primary human hematopoietic stem and progenitor cells, using pooled lentiviral shRNA libraries deconvoluted by next generation sequencing. We identify MAPK14/p38α as a modulator of ex vivo stem cell proliferation and show that pharmacologic inhibition of p38 dramatically enhances the stem cell activity of cultured umbilical cord blood derived hematopoietic cells. p38 inhibitors should thus be considered in strategies aiming at expanding stem cells for clinical benefit.
Oral contraceptives do not appear to affect cystic fibrosis disease severity
Authors: Kernan Natalie G. , Alton Eric W.F.W. , Cullinan Paul , Griesenbach Uta , Bilton Diana
Published: May 2012

Several studies suggest that sex may affect cystic fibrosis (CF) disease severity, with females with CF being more severely affected. In this context, it has been suggested that sex hormones may influence the CF phenotype. A large proportion of females with CF regularly use oral contraceptives (OCs), but the effect of their use on disease severity is unclear. Here, we retrospectively assessed the effects of OCs on clinical outcomes in females with CF.

Data from 681 females were available, of whom 42% had taken OCs for varying periods of time. We first performed an inter-patient analysis comparing annual change in % predicted forced expiratory volume in 1 s, body mass index and total days of intravenous antibiotic use over a 5-yr study period in 57 females exposed to and 57 females not exposed to OCs. There were no differences between the two groups. We next performed an intra-patient analysis of the same outcomes over a 3-yr period of OC exposure and a 3-yr period of no OC exposure in the same patient (exposure followed by non-exposure, n=27; non-exposure followed by exposure, n=23), but again did not detect any differences in any of the clinical outcomes.

Our data suggests that the use of OCs does not affect CF disease severity.
Predicting survival in pulmonary arterial hypertension in the UK
Authors: Lee Wai-Ting Nicola , Ling Yi , Sheares Karen K. , Pepke-Zaba Joanna , Peacock Andrew John , Johnson Martin Keith
Published: May 2012

Contemporary prognostic equations in pulmonary arterial hypertension (PAH) derived from US and French cohorts may not perform as well in the UK as a locally derived scoring scheme. The aim of the study was to develop and validate a UK risk score to predict prognosis in PAH.

Baseline mortality predictors identified by multivariate Cox analysis in 182 incident PAH patients were used to derive the Scottish composite score (SCS). Its prognostic performance in an independent UK cohort was compared with the French registry and Pulmonary Hypertension Connection (PHC) registry equations using Brier scores (BS).

The SCS based on age, sex, aetiology, right atrial pressure, cardiac output and 6-min walk distance predicted survival in the validation cohort (hazard ratio (HR) 1.7 per point increase; p<0.001) and provided further prognostic stratification in World Health Organization (WHO) functional class III patients (HR 1.8 per point increase; p<0.001). It was more accurate than the French registry equation in predicting 1-yr survival (BS: 0.092versus0.146; p=0.001) and 2-yr survival (0.131versus0.255; p<0.001). There was no significant difference in BS between the SCS and PHC registry equation.

The SCS predicts survival and can be used to supplement WHO functional class in prognostication.
Large-scale transcriptome sequencing and gene analyses in the crab-eating macaque (Macaca fascicularis) for biomedical research
Authors: Huh Jae-Won , Kim Young-Hyun , Park Sang-Je , Kim Dae-Soo , Lee Sang-Rae , Kim Kyoung-Min , Jeong Kang-Jin , Kim Ji-Su , Song Bong-Seok , Sim Bo-Woong , Kim Sun-Uk , Kim Sang-Hyun , Chang Kyu-Tae
Published: May 2012

Background

As a human replacement, the crab-eating macaque (Macaca fascicularis) is an invaluable non-human primate model for biomedical research, but the lack of genetic information on this primate has represented a significant obstacle for its broader use.

Results

Here, we sequenced the transcriptome of 16 tissues originated from two individuals of crab-eating macaque (male and female), and identified genes to resolve the main obstacles for understanding the biological response of the crab-eating macaque. From 4 million reads with 1.4 billion base sequences, 31,786 isotigs containing genes similar to those of humans, 12,672 novel isotigs, and 348,160 singletons were identified using the GS FLX sequencing method. Approximately 86% of human genes were represented among the genes sequenced in this study. Additionally, 175 tissue-specific transcripts were identified, 81 of which were experimentally validated. In total, 4,314 alternative splicing (AS) events were identified and analyzed. Intriguingly, 10.4% of AS events were associated with transposable element (TE) insertions. Finally, investigation of TE exonization events and evolutionary analysis were conducted, revealing interesting phenomena of human-specific amplified trends in TE exonization events.

Conclusions

This report represents the first large-scale transcriptome sequencing and genetic analyses of M. fascicularis and could contribute to its utility for biomedical research and basic biology.
A comparative genomics perspective on the genetic content of the alkaliphilic haloarchaeon Natrialba magadii ATCC 43099T
Authors: Siddaramappa Shivakumara , Challacombe Jean F , DeCastro Rosana E , Pfeiffer Friedhelm , Sastre Diego E , Giménez María I , Paggi Roberto A , Detter John C , Davenport Karen W , Goodwin Lynne A , Kyrpides Nikos , Tapia Roxanne , Pitluck Samuel , Lucas Susan , Woyke Tanja , Maupin-Furlow Julie A
Published: May 2012

Background

Natrialba magadii is an aerobic chemoorganotrophic member of the Euryarchaeota and is a dual extremophile requiring alkaline conditions and hypersalinity for optimal growth. The genome sequence of Nab. magadii type strain ATCC 43099 was deciphered to obtain a comprehensive insight into the genetic content of this haloarchaeon and to understand the basis of some of the cellular functions necessary for its survival.

Results

The genome of Nab. magadii consists of four replicons with a total sequence of 4,443,643 bp and encodes 4,212 putative proteins, some of which contain peptide repeats of various lengths. Comparative genome analyses facilitated the identification of genes encoding putative proteins involved in adaptation to hypersalinity, stress response, glycosylation, and polysaccharide biosynthesis. A proton-driven ATP synthase and a variety of putative cytochromes and other proteins supporting aerobic respiration and electron transfer were encoded by one or more of Nab. magadii replicons. The genome encodes a number of putative proteases/peptidases as well as protein secretion functions. Genes encoding putative transcriptional regulators, basal transcription factors, signal perception/transduction proteins, and chemotaxis/phototaxis proteins were abundant in the genome. Pathways for the biosynthesis of thiamine, riboflavin, heme, cobalamin, coenzyme F420 and other essential co-factors were deduced by in depth sequence analyses. However, approximately 36% of Nab. magadii protein coding genes could not be assigned a function based on Blast analysis and have been annotated as encoding hypothetical or conserved hypothetical proteins. Furthermore, despite extensive comparative genomic analyses, genes necessary for survival in alkaline conditions could not be identified in Nab. magadii.

Conclusions

Based on genomic analyses, Nab. magadii is predicted to be metabolically versatile and it could use different carbon and energy sources to sustain growth. Nab. magadii has the genetic potential to adapt to its milieu by intracellular accumulation of inorganic cations and/or neutral organic compounds. The identification of Nab. magadii genes involved in coenzyme biosynthesis is a necessary step toward further reconstruction of the metabolic pathways in halophilic archaea and other extremophiles. The knowledge gained from the genome sequence of this haloalkaliphilic archaeon is highly valuable in advancing the applications of extremophiles and their enzymes.
IL-8 as a urinary biomarker for the detection of bladder cancer
Authors: Urquidi Virginia , Chang Myron , Dai Yunfeng , Kim Jeongsoon , Wolfson Edward D , Goodison Steve , Rosser Charles J
Published: May 2012

Background

Current urine-based assays for bladder cancer (BCa) diagnosis lack accuracy, so the search for improved biomarkers continues. Through genomic and proteomic profiling of urine, we have identified a panel of biomarkers associated with the presence of BCa. In this study, we evaluated the utility of three of these biomarkers, interleukin 8 (IL-8), Matrix metallopeptidase 9 (MMP-9) and Syndecan in the diagnosis of BCa through urinalysis.

Methods

Voided urines from 127 subjects, cancer subjects (n = 64), non-cancer subjects (n = 63) were analyzed. The protein concentrations of IL-8, MMP-9, and Syndecan were assessed by enzyme-linked immunosorbent assay (ELISA). Data were also compared to a commercial ELISA-based BCa detection assay (BTA-Trak©) and urinary cytology. We used the area under the curve of a receiver operating characteristic (AUROC) to compare the performance of each biomarker.

Results

Urinary protein concentrations of IL-8, MMP-9 and BTA were significantly elevated in BCa subjects. Of the experimental markers compared to BTA-Trak©, IL-8 was the most prominent marker (AUC; 0.79; 95% confidence interval [CI], 0.72-0.86). Multivariate regression analysis revealed that only IL-8 (OR; 1.51; 95% CI, 1.16-1.97, p = 0.002) was an independent factor for the detection of BCa.

Conclusions

These results suggest that the measurement of IL-8 in voided urinary samples may have utility for urine-based detection of BCa. These findings need to be confirmed in a larger, prospective cohort.
Capillary electrophoresis for the assay of fixed-dose combination tablets of artesunate and amodiaquine
Authors: Amin N’Cho Christophe , Blanchin Marie-Dominique , Aké Michèle , Montels Jérôme , Fabre Huguette
Published: May 2012

Background

Quality control of drugs in formulations is still a major challenge in developing countries. For the quality control of artesunate and amodiaquine tablets in fixed-dose combination, only liquid chromatographic methods have been proposed in the literature. There are no capillary electrophoretic methods reported for the determination of these active substances, although this technique presents several advantages over liquid chromatography (long lifetime, low price of the capillary, low volumes of electrolyte consumption) in addition to simplicity. In this paper, a reliable capillary electrophoresis method has been developed and validated for the quality control of these drugs in commercial fixed-dose combination tablets.

Methods

Artesunate and amodiaquine hydrochloride in bilayer tablets were determined by micellar electrokinetic capillary chromatography (MEKC). Analytes were extracted from tablets by sonication with a solvent mixture phosphate buffer pH 7.0-acetonitrile containing benzoic acid as internal standard. Separation was carried out on Beckman capillary electrophoresis system equipped with fused silica capillary, 30 cm long (20 cm to detector) × 50 μm internal diameter, using a 25 mM borate buffer pH 9.2 containing 30 mM sodium dodecyl sulfate as background electrolyte, a 500 V cm−1 electric field and a detection wavelength of 214 nm.

Results

Artesunate, amodiaquine and benzoic acid were separated in 6 min. The method was found to be reliable with respect to specificity,linearity of the calibration line (r2 > 0.995), recovery from synthetic tablets (in the range 98–102%), repeatability (RSD 2–3%, n = 7 analytical procedures). Application to four batches of commercial formulations with different dosages gave content in good agreement with the declared content.

Conclusion

The MEKC method proposed is reliable for the determination of artesunate and amodiaquine hydrochloride in fixed-dose combination tablets. The method is well-suited for drug quality control and detection of counterfeit or substandard medicines.
Osteoblast-secreted collagen upregulates paracrine Sonic hedgehog signaling by prostate cancer cells and enhances osteoblast differentiation
Authors: Zunich Samantha M , Valdovinos Maria , Douglas Taneka , Walterhouse David , Iannaccone Philip , Lamm Marilyn L G
Published: May 2012

Background

Induction of osteoblast differentiation by paracrine Sonic hedgehog (Shh) signaling may be a mechanism through which Shh-expressing prostate cancer cells initiate changes in the bone microenvironment and promote metastases. A hallmark of osteoblast differentiation is the formation of matrix whose predominant protein is type 1 collagen. We investigated the formation of a collagen matrix by osteoblasts cultured with prostate cancer cells, and its effects on interactions between prostate cancer cells and osteoblasts.

Results

In the presence of exogenous ascorbic acid (AA), a co-factor in collagen synthesis, mouse MC3T3 pre-osteoblasts in mixed cultures with human LNCaP prostate cancer cells or LNCaP cells modified to overexpress Shh (LNShh cells) formed collagen matrix with distinct fibril ultrastructural characteristics. AA increased the activity of alkaline phosphatase and the expression of the alkaline phosphatase geneAkp2, markers of osteoblast differentiation, in MC3T3 pre-osteoblasts cultured with LNCaP or LNShh cells. However, the AA-stimulated increase inAkp2expression in MC3T3 pre-osteoblasts cultured with LNShh cells far exceeded the levels observed in MC3T3 cells cultured with either LNCaP cells with AA or LNShh cells without AA. Therefore, AA and Shh exert a synergistic effect on osteoblast differentiation. We determined whether the effect of AA on LNShh cell-induced osteoblast differentiation was mediated by Shh signaling. AA increased the expression ofGli1andPtc1, target genes of the Shh pathway, in MC3T3 pre-osteoblasts cultured with LNShh cells to at least twice their levels without AA. The ability of AA to upregulate Shh signaling and enhance alkaline phosphatase activity was blocked in MC3T3 cells that expressed a dominant negative form of the transcription factor GLI1. The AA-stimulated increase in Shh signaling and Shh-induced osteoblast differentiation was also inhibited by the specific collagen synthesis inhibitor 3,4-dehydro-L-proline.

Conclusions

Matrix collagen, formed by osteoblasts in the presence of AA, potentiates Shh signaling between Shh-expressing prostate cancer cells and osteoblasts. Collagen and Shh signaling exert a synergistic effect on osteoblast differentiation, a defining event in prostate carcinoma bone metastasis. Investigations into paracrine interactions among prostate cancer cells, osteoblasts, and osteoblast-synthesized matrix proteins advance our understanding of mechanisms contributing to prostate cancer bone metastasis.
Maternal feeding practices, child eating behaviour and body mass index in preschool-aged children: a prospective analysis
Authors: Gregory Jane E , Paxton Susan J , Brozovic Anna M
Published: May 2012

Background

Previous research has found associations between parental feeding practices and children's eating behaviour and weight status. Prospective research is needed to elucidate these relationships.

Methods

One hundred and fifty-six mothers of 2- to 4-year-old children completed questionnaires including measures of maternal feeding practices (pressure to eat, restriction, monitoring and modelling of healthy eating), child eating behaviour (food responsiveness, food fussiness and interest in food), and mother reported child height and weight. The questionnaire was repeated 12 months later. Regression analyses were used to find longitudinal associations between maternal feeding practices, child eating behaviour and child body mass index (BMI).

Results

Modelling of healthy eating predicted lower child food fussiness and higher interest in food one year later, and pressure to eat predicted lower child interest in food. Restriction did not predict changes in child eating behaviour. Maternal feeding practices did not prospectively predict child food responsiveness or child BMI.

Conclusion

Maternal feeding practices appear to influence young children's eating behaviour but not weight status in the short term.
Association of the Frequency of Respiratory Illness in Early Childhood with a Change in the Distribution of Blood Lymphocyte Subpopulations
Authors: Karsh Jacob , Angel Jonathan B , Young Charlene D , Sahni Vanita , Judek Stan , Miller David , Dales Robert E
Published: May 2012

Little is known about the distribution of lymphocyte phenotypes in young children and the association specific phenotypes may have with respiratory illnesses. The objective of this study was to describe lymphocyte distributions in children at approximately 2 years of age and to test for associations with the frequency of respiratory illness during the first 2 years of life. We hypothesized that an increased frequency of illness would be associated with those phenotypes that reflect previous antigen exposure and/or immune activation. Seventy-three children were followed during their first 2 years of life with daily symptom diaries and twice-monthly telephone calls to ascertain the incidence of respiratory illness. After the children reached 2 years of age, the phenotypes of circulating blood lymphocytes were measured by flow cytometry. Associations between illness and phenotypes were adjusted for education level of parents; hours per week in day care; hours per week exposed to environmental tobacco smoke, mould, or water damage in bedroom; and parental history of allergy and asthma. The resulting median lymphocyte count was 4.0 × 109 per litre (standard deviation, 1.3) with a CD4/CD8 count of 2.28, consistent with published values. Illness rates were positively associated with the percentage of CD8+ CD38+ T cells (unadjusted p = .03, adjusted p = .014), CD8+ CD45RO+ T cells (unadjusted p = .06, adjusted p = .036), and CD4+ CD45RO+ T cells (unadjusted p = .01, adjusted p = .005). Our conclusions is that there is an association between the distribution of lymphocyte phenotypes and the incidence of respiratory illness early in life. Future research is recommended to determine the directionality of this association.
Pediatric Hemophagocytic Syndromes: A Diagnostic and Therapeutic Challenge
Authors: Jabado Nada , McCusker Christine , Basile Genevieve de Saint
Published: May 2012

Pediatric hemophagocytic syndrome (HS) is a severe and often fatal clinical disorder. This syndrome is frequently unrecognized, and thus, affected children may receive suboptimal management, leading to an increase in mortality. The purpose of this review is to provide a clinical guide to (1) the recognition of HS based on clinical, biologic, and pathologic features; (2) the identification of the primary cause of HS in a given affected child; and (3) the initiation of effective treatment in a timely manner.
Antigen and Memory CD8 T Cells: Were They Both Right?
Authors: Epelman Slava , Mody Christopher H
Published: May 2012

Picture yourself as a researcher in immunology. To begin your project, you ask a question: Do CD8 T cells require antigen to maintain a memory response? This question is of prime importance to numerous medical fields. In chronologic order, you digest the literature, but unfortunately, you hit a major stumbling block in the 1990s. The crux of the problem is that which so often happens in science: two well-recognized, capable groups emerge with diametrically opposed conclusions, leaving you pondering which set of wellcontrolled data to believe. Fortunately, years later, a surprising group of articles sheds light on this mystery and subtly reconciles these two positions.
Navigating the Updated Anaphylaxis Parameters
Authors: Kemp Stephen F
Published: May 2012

Anaphylaxis, an acute and potentially lethal multi-system clinical syndrome resulting from the sudden, systemic degranulation of mast cells and basophils, occurs in a variety of clinical scenarios and is almost unavoidable inmedical practice. Healthcare professionalsmust be able to recognize its features, treat an episode promptly and appropriately, and be able to provide recommendations to prevent future episodes. Epinephrine, administered immediately, is the drug of choice for acute anaphylaxis. The discussion provides an overview of one set of evidence-based and consensus parameters for the diagnosis and management of anaphylaxis.
Self-reported asthma and allergies in top athletes compared to the general population - results of the German part of the GA2LEN-Olympic study 2008
Authors: Thomas Silke , Wolfarth Bernd , Wittmer Caroline , Nowak Dennis , Radon Katja ,   GA2LEN-Olympic study-Team
Published: May 2012

Background

Prevalence of asthma and allergies in top athletes is high. However, most previous studies did not include a general population comparison group. We aimed to compare the prevalence of asthma, allergies and medical treatment in different groups of German top athletes to the general population.

Methods

Prior to the 2008 Summer Olympic Games, 291 German candidates for participation (65%) completed a questionnaire on respiratory and allergic symptoms. Results were compared to those of a general population study in Germany (n = 2425, response 68%). Furthermore, associations between types of sports and the self-reported outcomes were calculated. All models were adjusted for age, sex, level of education and smoking.

Results

Athletes reported significantly more doctors' diagnosed asthma (17% vs. 7%), more current use of asthma medication (10% vs. 4%) and allergic rhinitis (25% vs. 17%) compared to the general population. After adjustment, top athletes only had an increased Odds Ratio for doctor's diagnosed asthma (OR: 1.6; 95% CI 1.1-2.5). Compared to the general population, athletes in endurance sports had an increased OR for doctor's diagnosed asthma (2.4; 1.5-3.8) and current use of asthma medication (1.8; 1.0-3.4). In this group, current wheeze was increased when use of asthma medication was taken into account (1.8; 1.1-2.8). For other groups of athletes, no significantly increased ORs were observed.

Conclusions

Compared to the general population, an increased risk of asthma diagnosis and treatment was shown for athletes involved in endurance sports. This might be due to a better medical surveillance and treatment of these athletes.
Effects of the K65R and K65R/M184V reverse transcriptase mutations in subtype C HIV on enzyme function and drug resistance
Authors: Xu Hong-Tao , Martinez-Cajas Jorge L , Ntemgwa Michel L , Coutsinos Dimitrios , Frankel Fernando A , Brenner Bluma G , Wainberg Mark A
Published: May 2012

Background

We investigated the effects of mutations K65R and K65R plus M184V on enzymatic function and mechanisms of drug resistance in subtype C reverse transcriptase (RT).

Methods

Recombinant subtype C HIV-1 RTs containing K65R or K65R+M184V were purified fromEscherichia coli. Enzyme activities and tenofovir (TFV) incorporation efficiency by wild-type (WT) and mutant RTs of both subtypes were determined in cell-free assays. Efficiency of (-) ssDNA synthesis and initiation by subtype C RTs was measured using gel-based assays with HIV-1 PBS RNA template and tRNA3Lysas primer. Single-cycle processivity was assayed under variable dNTP concentrations. Steady-state analysis was performed to measure the relative inhibitory capacity (ki/km) of TFV-disphosphate (TFV-DP). ATP-dependent excision and rescue of TFV-or ZDV-terminated DNA synthesis was monitored in time-course experiments.

Results

The efficiency of tRNA-primed (-)ssDNA synthesis by subtype C RTs was: WT > K65R > K65R+M184V RT. At low dNTP concentration, K65R RT exhibited lower activity in single-cycle processivity assays while the K65R+M184V mutant showed diminished processivity independent of dNTP concentration. ATP-mediated excision of TFV-or ZDV-terminated primer was decreased for K65R and for K65R+M184V RT compared to WT RT. K65R and K65R+M184V displayed 9.8-and 5-fold increases in IC50 for TFV-DP compared to WT RT. The Ki/Km of TFV was increased by 4.1-and 7.2-fold, respectively, for K65R and K65R+M184V compared to WT RT.

Conclusion

The diminished initiation efficiency of K65R-containing RTs at low dNTP concentrations have been confirmed for subtype C as well as subtype B. Despite decreased excision, this decreased binding/incorporation results in diminished susceptibility of K65R and K65R+M184 RT to TFV-DP.
Protection conferred by a recombinant Marek’s disease virus that expresses the spike protein from infectious bronchitis virus in specific pathogen-free chicken
Authors: Zhang Xiaorong , Wu Yantao , Huang Yezhen , Liu Xiufan
Published: May 2012

Background

In many countries, the predominant field isolates of infectious bronchitis virus (IBV) have been classified as QX-like strains since 1996. However, no commercial vaccines that are specific for this type of IBV are currently available. Therefore, there is an urgent need to develop novel vaccines that prevent QX-like IBV infection.

Results

A recombinant Marek’s disease virus (MDV), rMDV-S1, that expresses the S1 subunit of the spike (S) protein from the QX-like infectious bronchitis virus (IBV) was constructed by inserting the IBV S1 gene into the genome of the CVI988/Rispens strain of MDV. Specific pathogen-free (SPF) chickens that were vaccinated with rMDV-S1 were protected when challenged with the QX-like IBV. They were observed to have mild clinical signs of disease, a short virus-shedding period and low mortality. Additionally, the rMDV-S1 conferred full protection to chickens against virulent MDV, as did the CVI988/Rispens strain.

Conclusions

Our results demonstrate that rMDV-S1 is an effective and promising recombinant vaccine for the prevention of QX-like IBV infection.
The Glucocorticoid-Induced Leucine Zipper (Gilz/Tsc22d3-2) Gene Locus Plays a Crucial Role in Male Fertility
Authors: Suarez Philippe Emmanuel , Rodriguez Elena Gonzalez , Soundararajan Rama , Mérillat Anne-Marie , Stehle Jean-Christophe , Rotman Samuel , Roger Thierry , Voirol Marie-Jeanne , Wang Jian , Gross Olaf , Pétrilli Virginie , Nadra Karim , Wilson Anne , Beermann Friedrich , Pralong François Pierre , Maillard Marc , Pearce David , Chrast Roman , Rossier Bernard Claude , Hummler Edith
Published: May 2012

The glucocorticoid-induced leucine zipper (Tsc22d3-2) is a widely expressed dexamethasone-induced transcript that has been proposed to be important in immunity, adipogenesis, and renal sodium handling based on in vitro studies. To address its function in vivo, we have used Cre/loxP technology to generate mice deficient for Tsc22d3-2. Male knockout mice were viable but surprisingly did not show any major deficiencies in immunological processes or inflammatory responses. Tsc22d3-2 knockout mice adapted to a sodium-deprived diet and to water deprivation conditions but developed a subtle deficiency in renal sodium and water handling. Moreover, the affected animals developed a mild metabolic phenotype evident by a reduction in weight from 6 months of age, mild hyperinsulinemia, and resistance to a high-fat diet. Tsc22d3-2-deficient males were infertile and exhibited severe testis dysplasia from postnatal d 10 onward with increases in apoptotic cells within seminiferous tubules, an increased number of Leydig cells, and significantly elevated FSH and testosterone levels. Thus, our analysis of the Tsc22d3-2-deficient mice demonstrated a previously uncharacterized function of glucocorticoid-induced leucine zipper protein in testis development.
miR-93/106b and Their Host Gene, MCM7, Are Differentially Expressed in Leiomyomas and Functionally Target F3 and IL-8
Authors: Chuang Tsai-Der , Luo Xiaoping , Panda Harekrushna , Chegini Nasser
Published: May 2012

miR-93/106b and their host gene minichromosome maintenance complex component 7 (MCM7) reside at chr7q22, a region frequently rearranged in leiomyomas. We explored the expression of miR-93/106b in leiomyoma and paired myometrium (n = 63) from untreated and patients exposed to hormonal therapies (GnRH agonist, Depo-Provera, and oral contraceptives) from African-Americans and Caucasians and their regulatory functions in isolated paired (n = 15) leiomyoma and myometrial smooth muscle cells and the leiomyosarcoma cell line. At tissue level leiomyomas expressed significantly lower levels of miR-93 and elevated MCM7 as compared with myometrium with limited racial influence or hormonal exposure on their expression. Assessing the regulatory function of miR-93/106b through doxycycline-inducible lentiviral transduction in a microarray analysis, tissue factor (F3) and IL8 were identified as their possible targets. At the tissue level, leiomyomas expressed a significantly lower level of F3 and an elevated IL-8 level, which exhibited an inverse relationship with miR-93 but with limited racial or hormonal influences. The gain of function of miR-93/106b in leiomyoma smooth muscle cells, myometrial smooth muscle cells, and the leiomyosarcoma cell line dose dependently repressed F3 and IL8 through direct interactions with their respective 3′-untranslated region and indirectly through F3 repression inhibited IL8, CTGF, and PAI-1 expression, confirmed by using small interfering RNA silencing or factor Vlla (FVIIa) activation of F3, as well as reducing the rate of proliferation, while increasing caspase-3/7 activity. We concluded that differential expression of miR-93/106b and their direct and/or indirect regulatory functions on F3, IL8, CTGF, and PAI-1 expression, with key roles in inflammation and tissue turnover may be of significance in the outcome of leiomyoma growth and associated symptoms.
Quantitative Effects of Fiscal Foresight
Authors: Leeper Eric M , Richter Alexander W , Walker Todd B
Published: May 2012

Legislative and implementation lags imply that substantial time evolves between when news arrives about fiscal changes and when the changes actually take place—time when households and firms can adjust their behavior. We identify two types of fiscal news—government spending using the Survey of Professional Forecasters and taxes using the municipal bond market. The main contribution of the paper is a mapping from reduced-form estimates of news into a DSGE framework. We find that news about fiscal policy is a time-varying process and show that ignoring the time variation can have important consequences in a conventional macroeconomic model. (JEL E12, E62, H20, H30, H62)
Fiscal Imbalances and Borrowing Costs: Evidence from State Investment Losses
Authors: Novy-Marx Robert , Rauh Joshua D
Published: May 2012

During the last quarter of 2008, financial losses in state pension funds varied from 12 percent to 68 percent of the revenue generated by the state government. We quantify a sovereign default channel in the state municipal market by examining how changes in bond spreads vary with state pension fund losses, controlling for credit ratings and various measures of the state's fiscal strength. Municipal bond spreads rose by 7–15 basis points for each 10 percent of state-generated revenue lost by states in the lower half of the credit quality spectrum. (JEL H71, H72, H74, H75)
A Model-Based Evaluation of the Debate on the Size of the Tax Multiplier
Authors: Chahrour Ryan , Schmitt-Grohé Stephanie , Uribe Martín
Published: May 2012

The SVAR and narrative approaches to estimating tax multipliers deliver significantly different results. The former yields multipliers of about 1 and the latter of about 3. The two approaches differ along two important dimensions: the identification scheme and the reduced-form transmission mechanism. This paper uses a DSGE-model to evaluate the hypothesis that the difference in multipliers is due to differences in transmission mechanisms. The main finding of the paper is that this hypothesis is rejected. Instead, the observed differences in estimated multipliers are due either to the models failing to identify the same tax shock, or to small-sample uncertainty. (JEL E13, E23, E32, E62, H20)
Rapid Screening Procedures for Zero-One Optimization via Simulation
Authors: Tsai Shing Chih
Published: May 2012

Some existing simulation optimization algorithms (e.g., adaptive random search) become pure random search methods and thus are ineffective for the zero-one optimization via simulation problem. In this paper, we present highly efficient rapid screening procedures for solving the zero-one optimization via simulation problem. Three approaches adopting different sampling rules and providing different statistical guarantees are described. We also propose efficient neighborhood search methods and a simple algorithm for generation of initial solutions, all of which can be incorporated into our rapid screening procedures. The proposed procedures are more adaptive than ordinary ranking and selection procedures because in each iteration they can eliminate inferior solutions and intelligently sample promising solutions from the neighborhood of the survivors. Empirical studies are performed to compare the efficiency of the proposed procedures with other existing ones.
Mesalazine-Induced Interstitial Nephritis; Psychiatric Drug-Induced Fatal Abdominal Compartment Syndrome; Severe Pelvic Organ Prolapse following Initiation of High-Dose Glucocorticoids; Vancomycin-Induced Severe Neutropenia and Rechallenge Leading to Agranulocytosis; Fatalities Associated with Sodium Phosphate Enemas; Prochlorperazine and Akathisia; Nocturnal Leg Cramps and Preceding Drug Use; Distressing Adverse Events with Citalopram and after Antidepressant Switch; Adverse Drug Reaction Deaths in the United States, 1999-2006
Authors: Sinister Joel
Published: May 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). If you have reported an interesting, preventable ADR to MEDWATCH, please consider sharing the account with our readers.
Approvals, Submission, and Important Labeling Changes for US Marketed Pharmaceuticals
Authors: Baker Danial E.
Published: May 2012

This monthly feature will help readers keep current on new drugs, new indications, dosage forms, and safety-related changes in labeling or use. Efforts have been made to ensure the accuracy of this information; however, if there are any questions, please let me know at bakerdan@wsu.edu .
Health Information Technology Happenings in 2011: Part 2
Authors: Fox Brent I. , Felkey Bill G.
Published: May 2012

With this installment, we explore items 6 through 10 in Dr. Farzad Mostashari's list of the 10 most important developments related to health information technology from 2011. We covered items 1 through 5 in March 2012 and close out the list with this installment. Readers are encouraged to consider which topics they come in contact with during regular practice and administrative duties.
Recent Publications on Medications and Pharmacy
Authors: Russett Flint
Published: May 2012

Hospital Pharmacy presents this feature to keep pharmacists abreast of new publications in the medical/pharmacy literature. Articles of interest regarding a broad scope of topics are abstracted monthly.
The critical role of adrenomedullin and its binding protein, AMBP-1, in neuroprotection
Authors: Cheyuo Cletus , Yang Weng-Lang , Wang Ping
Published: May 2012

Chronic neurodegenerative disorders and acute injuries of the central nervous system exert a prohibitive economic burden, which is aggravated by an unmet medical need for the development of effective neurotherapeutics. The evolutionarily conserved neuropeptide, adrenomedullin (AM), and its binding protein, AMBP-1, also known as complement factor H, play important roles in brain physiology, and their expression is altered in brain pathology. In this review, we discuss the molecular regulation of AM and AMBP-1 and the pivotal roles they play in neuroprotection following brain injury. We assess the reciprocal synergistic effects of AM and AMBP-1 and make suggestions for the design of a novel combination neurotherapy devoid of the potential hypotensive effects of AM while optimizing its neuroprotective property.
Analysis of tissue and salivary nicotinamide N-methyltransferase in oral squamous cell carcinoma: basis for the development of a noninvasive diagnostic test for early-stage disease
Authors: Sartini Davide , Pozzi Valentina , Renzi Elisabetta , Morganti Stefano , Rocchetti Romina , Rubini Corrado , Santarelli Andrea , Muzio Lorenzo Lo , Emanuelli Monica
Published: May 2012

Oral squamous cell carcinoma (OSCC) is the most common form of head and neck cancer worldwide. In recent decades, the 5-year mortality rate is approximately 50% around the world. As reliable biomarkers of oral cancer are still lacking, it is necessary to identify new target molecules for early diagnosis, effective therapy, and monitoring of the disease. In the present work, we focused on the expression of the enzyme nicotinamide N-methyltransferase (NNMT). We analyzed enzyme activity in 37 paired tumor and non-tumor tissues and found that activity levels are significantly higher in tumor compared with adjacent normal oral mucosa. Interestingly, oral epithelium surrounding tumor of unfavorable cases (N+) seems to display higher activity levels compared with that of favorable ones (N0). Western blot analyses were performed to evaluate protein levels in saliva samples from patients with OSCC and healthy subjects. Preliminary results indicated an up-regulation of salivary NNMT in tumor. This study shows a marked increase in enzyme activity in oral cancer and suggests that adjacent normal tissue of unfavorable cases seems to change toward cancer. Moreover, it is conceivable to hypothesize that NNMT could represent a potential biomarker for early and non-invasive diagnosis of oral cancer.
In situ formation of nano-scale PMMA network structures on the surface of immiscible polymer blends by solvent extraction and redeposition
Authors: Giancola Giorgiana , Lehman Richard L.
Published: May 2012

A continuous open structured network, with a high surface area, low solids fraction, and nano-scale domain morphology, was observed to grow from dissolved blend components on cold fractured surfaces of immiscible polymer blends, when reacted with dimethylformamide (DMF). In this work, we showed that the network is comprised of polymethyl methacrylate (PMMA), with a strong glassy character similar to or even in excess of conventional PMMA pellets used in the preparation process, in contrast to the amorphous but not glassy PMMA produced when similar materials were synthesized away from the PMMA host. Fourier transform infrared (FTIR) and differential scanning calorimetry (DSC) analyses confirmed the chemical and physical character of the network. This general network formation phenomenon, which was initially observed in PMMA/high density poly ethylene (HDPE) blends produced by conventional extrusion, PMMA/HDPE blends compression molded from powder precursors, and subsequently on bulk PMMA, produces a unique structure that has potential applications as an interfacial modification substance or as a functional material in biomaterials and catalysis.
Study of rheological and mechanical properties of ternary blends of iPP/LDPE/EPDM
Authors: Bouhelal Said , Cagiao M. Esperanza , Di Lorenzo Maria Laura , Zouai Foued , Khellaf Souhila , Tabet Habiba , Benachour Djafer , Calleja Francisco J. Baltá
Published: May 2012

Compatible blends of isotactic polypropylene (iPP)/low-density polyethylene (LDPE)/ethylene-propylene-diene monomer (EPDM) were prepared by reactive blending in the presence of dicumyl peroxide (DCP). The blends were characterized using different techniques: dynamical rheological analysis (DRA), differential scanning calorimetry (DSC), optical microscopy (OM) and scanning electron microscopy (SEM), dynamical mechanical thermal analysis (DMTA), viscosity and impact strength, to evaluate their properties. Results revealed that the presence of the peroxide in LDPE/EPDM blends gives rise to crosslinking reactions, as is the case in iPP/LDPE/EPDM blends. However, in the latter case, scission reactions of the iPP component also take place. As a consequence of the whole process, morphological changes arise mainly in the amorphous regions, without affecting the degree of crystallinity of the components. The mechanical properties of the blends are consequently improved, due to the crosslinked network thus formed in the blends.
Rheological investigation of shear-enhanced crystallization for polylactide composites with different aspect ratio carbon nanotubes
Authors: Xu Zhaohua , Sun Ning , Li Heng
Published: May 2012

Crystallization processes of polylactide (PLA)/acid oxidized multiwalled carbon nanotube (A-MWCNT) composites were detected by dynamic rheological measurements. The influences of pre-shear, crystallization temperature, concentration and aspect ratio of A-MWCNT, on the crystallization kinetics of PLA, were investigated. The addition of small amounts of A-MWCNT, can more or less accelerate the crystallization of the PLA matrix. Composites with smaller aspect ratio A-MWCNT (A-MWCNT–S) show faster crystallization rates than those with larger aspect ratio A-MWCNT (A-MWCNT–L), due to the more heterogeneous nucleation sites of the former. Pre-shear can significantly promote the crystallization process of PLA composites, and with the increase in shear rate, the crystallization rate becomes faster. Pre-shear results in an accelerated crystallization compared to PLA/A-MWCNT–S composites at the same concentration, without pre-shear, due to a more serious deformation from entanglement to orientation of A-MWCNT–L.
Back to Basics for Bayesian Model Building in Genomic Selection
Authors: Kärkkäinen Hanni P , Sillanpää Mikko J
Published: May 2012

Numerous Bayesian methods of phenotype prediction and genomic breeding value estimation based on multilocus association models have been proposed. Computationally the methods have been based either on Markov chain Monte Carlo or on faster maximum a posteriori estimation. The demand for more accurate and more efficient estimation has led to the rapid emergence of workable methods, unfortunately at the expense of well-defined principles for Bayesian model building. In this article we go back to the basics and build a Bayesian multilocus association model for quantitative and binary traits with carefully defined hierarchical parameterization of Student’s t and Laplace priors. In this treatment we consider alternative model structures, using indicator variables and polygenic terms. We make the most of the conjugate analysis, enabled by the hierarchical formulation of the prior densities, by deriving the fully conditional posterior densities of the parameters and using the acquired known distributions in building fast generalized expectation-maximization estimation algorithms.