bluuebunny/crossref_metadata_2025 huggingface dataset:
Modulation of polymorphonuclear neutrophil functions by astrocytes
Authors: Xie Luokun , Poteet Ethan C , Li Wenjun , Scott Amanda E , Liu Ran , Wen Yi , Ghorpade Anuja , Simpkins James W , Yang Shao-Hua
Published: September 2010

Background

Neuroinflammation is a complex process involving cells from the immune system and the central nerve system (CNS). Polymorphonuclear neutrophils (PMN) are the most abundant class of white blood cells, and typically the first type of leukocyte recruited to sites of inflammation. In the CNS, astrocytes are the most abundant glial cell population and participate in the local innate immune response triggered by a variety of insults. In the present study, we investigated the impacts of astrocytes on PMN function.

Methods

Primary astrocyte cultures were derived from postnatal C57BL/6 mice and primary neutrophils were isolated from 8 to 12 weeks old C57BL/6 mice. PMNs respiratory burst was analyzed by H2DCFDA assay. For phagocytosis assay, neutrophils were incubated with FITC-labeled E. coli and the phagocytosis of E coli was determined by flow cytometer. PMNs degranulation was determined by myeloperoxidase assay. Cytokine expression was determined by real-time PCR. To determine the involvement of different signaling pathway, protein lysates were prepared and western blots were conducted to assess the activation of Akt, Erk1/2, and p38.

Results

Using ex vivo neutrophils and primary astrocyte cultures, our study demonstrated that astrocytes differentially regulate neutrophil functions, depending upon whether the interactions between the two cell types are direct or indirect. Upon direct cell-cell contact, astrocytes attenuate neutrophil apoptosis, respiratory bust, and degranulation, while enhancing neutrophil phagocytic capability and pro-inflammatory cytokine expression. Through indirect interaction with neutrophils, astrocytes attenuate apoptosis and enhance necrosis in neutrophils, augment neutrophil phagocytosis and respiratory burst, and inhibit neutrophil degranulation. In addition, astrocytes could augment Akt, Erk1/2, and p38 activation in neutrophils.

Conclusions

Astrocytes differentially regulate neutrophil functions through direct or indirect interactions between the two cell types. The diversified actions of astrocytes on neutrophils might provide protection against potential microbial infections given compromised blood-brain barrier integrity under certain neuropathological conditions. The complex actions of astrocytes on neutrophils could provide further insight to harness the inflammatory response to promote CNS repair.
Rationale and design of EXPLORE: a randomized, prospective, multicenter trial investigating the impact of recanalization of a chronic total occlusion on left ventricular function in patients after primary percutaneous coronary intervention for acute ST-elevation myocardial infarction
Authors: van der Schaaf René J , Claessen Bimmer E , Hoebers Loes P , Verouden Niels J , Koolen Jacques J , Suttorp Maarten J , Barbato Emanuele , Bax Matthijs , Strauss Bradley H , Olivecrona Göran K , Tuseth Vegard , Glogar Dietmar , Råmunddal Truls , Tijssen Jan G , Piek Jan J , Henriques José PS ,   EXPLORE investigators
Published: September 2010

Background

In the setting of primary percutaneous coronary intervention, patients with a chronic total occlusion in a non-infarct related artery were recently identified as a high-risk subgroup. It is unclear whether ST-elevation myocardial infarction patients with a chronic total occlusion in a non-infarct related artery should undergo additional percutaneous coronary intervention of the chronic total occlusion on top of optimal medical therapy shortly after primary percutaneous coronary intervention. Possible beneficial effects include reduction in adverse left ventricular remodeling and preservation of global left ventricular function and improved clinical outcome during future coronary events.

Methods/Design

The Evaluating Xience V and left ventricular function in Percutaneous coronary intervention on occLusiOns afteR ST-Elevation myocardial infarction (EXPLORE) trial is a randomized, prospective, multicenter, two-arm trial with blinded evaluation of endpoints. Three hundred patients after primary percutaneous coronary intervention for ST-elevation myocardial infarction with a chronic total occlusion in a non-infarct related artery are randomized to either elective percutaneous coronary intervention of the chronic total occlusion within seven days or standard medical treatment. When assigned to the invasive arm, an everolimus-eluting coronary stent is used. Primary endpoints are left ventricular ejection fraction and left ventricular end-diastolic volume assessed by cardiac Magnetic Resonance Imaging at four months. Clinical follow-up will continue until five years.

Discussion

The ongoing EXPLORE trial is the first randomized clinical trial powered to investigate whether recanalization of a chronic total occlusion in a non-infarct related artery after primary percutaneous coronary intervention for ST-elevation myocardial infarction results in a better preserved residual left ventricular ejection fraction, reduced end-diastolic volume and enhanced clinical outcome.

Trial registration

trialregister.nl NTR1108.
Use of anchorchip-time-of-flight spectrometry technology to screen tumor biomarker proteins in serum for small cell lung cancer
Authors: Du Jie , Yang Shuanying , Lin Xiuli , Bu Lina , Nan Yandong , Huo Shufen , Shang Wenli
Published: September 2010

Background

The purpose of this study is to discover potential biomarkers in serum for the detection of small cell lung cancer (SCLC).

Methods

74 serum samples including 30 from SCLC patients and 44 from healthy controls were analyzed using ClinProt system combined with matrix-assisted laser desorption/ionization time-of-flight masss spectrometry (MALDI-TOF-MS). ClinProt software and genetic algorithm analysis selected a panel of serum markers that most efficiently predicted which patients had SCLC.

Results

The diagnostic pattern combined with 5 potential biomarkers could differentiate SCLC patients from healthy persons, with a sensitivity of 90%, specificity of 97.73%. Remarkably, 88.89% of stage I/II patients were accurately assigned to SCLC.

Conclusions

Anchorchip-time-of-flight spectrometry technology will provide a highly accurate approach for discovering new biomarkers for the detection of SCLC.
A yeast's eye view of mammalian reproduction: cross-species gene co-expression in meiotic prophase
Authors: Li Yunfei , Lam Ka-sum , Dasgupta Nairanjana , Ye Ping
Published: September 2010

Background

Meiotic prophase is a critical stage in sexual reproduction. Aberrant chromosome recombination during this stage is a leading cause of human miscarriages and birth defects. However, due to the experimental intractability of mammalian gonads, only a very limited number of meiotic genes have been characterized. Here we aim to identify novel meiotic genes important in human reproduction through computational mining of cross-species and cross-sex time-series expression data from budding yeast, mouse postnatal testis, mouse embryonic ovary, and human fetal ovary.

Results

Orthologous gene pairs were ranked by order statistics according to their co-expression profiles across species, allowing us to infer conserved meiotic genes despite obvious differences in cellular synchronicity and composition in organisms. We demonstrated that conserved co-expression networks could successfully recover known meiotic genes, including homologous recombination genes, chromatin cohesion genes, and genes regulating meiotic entry. We also showed that conserved co-expression pairs exhibit functional connections, as evidenced by the annotation similarity in Gene Ontology and overlap with physical interactions. More importantly, we predicted six new meiotic genes through their co-expression linkages with known meiotic genes, and subsequently used the genetically more amenable yeast system for experimental validation. The deletion mutants of all six genes showed sporulation defects, equivalent to a 100% validation rate.

Conclusions

We identified evolutionarily conserved gene modules in meiotic prophase by integrating cross-species and cross-sex expression profiles from budding yeast, mouse, and human. Our co-expression linkage analyses confirmed known meiotic genes and identified several novel genes that might be critical players in meiosis in multiple species. These results demonstrate that our approach is highly efficient to discover evolutionarily conserved novel meiotic genes, and yeast can serve as a valuable model system for investigating mammalian meiotic prophase.
Evaluation of the bacterial diversity of Pressure ulcers using bTEFAP pyrosequencing
Authors: Smith Drake M , Snow David E , Rees Eric , Zischkau Ann M , Hanson J Delton , Wolcott Randall D , Sun Yan , White Jennifer , Kumar Shashi , Dowd Scot E
Published: September 2010

Background

Decubitus ulcers, also known as bedsores or pressure ulcers, affect millions of hospitalized patients each year. The microflora of chronic wounds such as ulcers most commonly exist in the biofilm phenotype and have been known to significantly impair normal healing trajectories.

Methods

Bacterial tag-encoded FLX amplicon pyrosequencing (bTEFAP), a universal bacterial identification method, was used to identify bacterial populations in 49 decubitus ulcers. Diversity estimators were utilized and wound community compositions analyzed in relation to metadata such as Age, race, gender, and comorbidities.

Results

Decubitus ulcers are shown to be polymicrobial in nature with no single bacterium exclusively colonizing the wounds. The microbial community among such ulcers is highly variable. While there are between 3 and 10 primary populations in each wound there can be hundreds of different species present many of which are in trace amounts. There is no clearly significant differences in the microbial ecology of decubitus ulcer in relation to metadata except when considering diabetes. The microbial populations and composition in the decubitus ulcers of diabetics may be significantly different from the communities in non-diabetics.

Conclusions

Based upon the continued elucidation of chronic wound bioburdens as polymicrobial infections, it is recommended that, in addition to traditional biofilm-based wound care strategies, an antimicrobial/antibiofilm treatment program can be tailored to each patient's respective wound microflora.
Genome-wide analysis of mRNA decay patterns during early Drosophiladevelopment
Authors: Thomsen Stefan , Anders Simon , Janga Sarath Chandra , Huber Wolfgang , Alonso Claudio R
Published: September 2010

Background

The modulation of mRNA levels across tissues and time is key for the establishment and operation of the developmental programs that transform the fertilized egg into a fully formed embryo. Although the developmental mechanisms leading to differential mRNA synthesis are heavily investigated, comparatively little attention is given to the processes of mRNA degradation and how these relate to the molecular programs controlling development.

Results

Here we combine timed collection of Drosophila embryos and unfertilized eggs with genome-wide microarray technology to determine the degradation patterns of all mRNAs present during early fruit fly development. Our work studies the kinetics of mRNA decay, the contributions of maternally and zygotically encoded factors to mRNA degradation, and the ways in which mRNA decay profiles relate to gene function, mRNA localization patterns, translation rates and protein turnover. We also detect cis-regulatory sequences enriched in transcripts with common degradation patterns and propose several proteins and microRNAs as developmental regulators of mRNA decay during early fruit fly development. Finally, we experimentally validate the effects of a subset of cis-regulatory sequences and trans-regulators in vivo.

Conclusions

Our work advances the current understanding of the processes controlling mRNA degradation during early Drosophila development, taking us one step closer to the understanding of mRNA decay processes in all animals. Our data also provide a valuable resource for further experimental and computational studies investigating the process of mRNA decay.
Hepatitis C Virus Seromarkers and Subsequent Risk of Hepatocellular Carcinoma: Long-Term Predictors From a Community-Based Cohort Study
Authors: Mei-Hsuan Lee , Yang Hwai-I , Lu Sheng-Nan , Jen Chin-Lan , Yeh Shiou-Hwei , Liu Chun-Jen , Chen Pei-Jer , You San-Lin , Wang Li-Yu , Chen Wei J. , Chen Chien-Jen
Published: September 2010

Purpose

Hepatitis C virus (HCV) contributes to one third of hepatocellular carcinoma cases worldwide. Long-term predictors for HCV-related hepatocellular carcinoma are essential for early intervention. Serum HCV RNA and ALT levels and HCV genotype were assessed for their predictability of hepatocellular carcinoma risk.

Methods

A prospective cohort of 925 participants positive for antibodies against HCV and age 30 to 65 years was recruited and followed from 1991 to 2006. Serum HCV RNA and ALT levels and HCV genotypes at enrollment and during follow-up were examined. Newly developed hepatocellular carcinoma was identified by health examination and computerized linkage with national cancer registration and death certification profiles. Multivariate adjusted hazard ratios with 95% CIs were estimated using Cox regression models.

Results

Fifty-five participants newly developed hepatocellular carcinoma during 8,476 person-years of follow-up, giving an incidence rate of 648.9 per 100,000 person-years. The cumulative hepatocellular carcinoma risk increased from 1.1% for HCV RNA seronegative status to 6.4% for low HCV RNA levels and to 14.7% for high HCV RNA levels (P < .001). The cumulative risk also increased with elevated serum ALT levels from 1.7% for persistently ≤ 15 U/L to 4.2% for ever more than 15 U/L but never more than 45 U/L and to 13.8% for ALT ever ≥ 45 U/L (P < .001). Having HCV genotype 1 was associated with a higher cumulative hepatocellular carcinoma risk (12.6%) than not having HCV genotype 1 (4.5%; P < .001).

Conclusion

Elevated serum levels of HCV RNA and ALT and HCV genotype 1 infection are independent risk predictors of hepatocellular carcinoma. These findings have strong implications for the management of chronic HCV.
Factors for Hematopoietic Toxicity of Carboplatin: Refining the Targeting of Carboplatin Systemic Exposure
Authors: Schmitt Antonin , Gladieff Laurence , Laffont Céline M. , Evrard Alexandre , Boyer Jean-Christophe , Lansiaux Amélie , Bobin-Dubigeon Christine , Etienne-Grimaldi Marie-Christine , Boisdron-Celle Michèle , Mousseau Mireille , Pinguet Frédéric , Floquet Anne , Billaud Eliane M. , Durdux Catherine , Le Guellec Chantal , Mazières Julien , Lafont Thierry , Ollivier Florent , Concordet Didier , Chatelut Etienne
Published: September 2010

Purpose

Area under the curve (AUC) dosing is routinely carried out for carboplatin, but the chosen target AUC values remain largely empirical. This multicenter pharmacokinetic-pharmacodynamic (PK-PD) study was performed to determine the covariates involved in the interindividual variability of carboplatin hematotoxicity that should be considered when choosing individual target AUCs.

Patients and Methods

Three hundred eighty-three patients received carboplatin as part of established regimens. A semi-physiologic population PK-PD model was applied to describe separately the time course of absolute neutrophil and platelet counts using NONMEM software. The plasma ultrafiltrable carboplatin concentration (CCarbo) was assumed to inhibit the proliferation of blood cell precursors through a linear model: drug effect = slope × CCarbo. The slope corresponds to the patients' sensitivity to carboplatin hematotoxicity. The relationships between the patients' sensitivity to the neutropenic or thrombopenic effects of carboplatin and various covariates, including associated chemotherapies, demographic, biologic, and pharmacogenetic data, were studied.

Results

The sensitivity of carboplatin-induced thrombocytopenia decreased in the case of concomitant paclitaxel chemotherapy (slope decreased by 24%), whereas it increased with coadministration of etoposide and gemcitabine (slope increased by 45% and 133%, respectively). For neutropenia, the sensitivity increased when carboplatin was combined with other cytotoxics (slope increased by 76%).

Conclusion

This study provides useful information to clinicians to better estimate the hematopoietic toxicity of carboplatin and thus choose more rationally carboplatin target AUCs as a function of pretreatment or concomitantly administered chemotherapies. For example, an AUC of 5 mg/mL · min is associated with a risk of grade 3 or 4 thrombocytopenia of 2% in combination with paclitaxel versus 38% with gemcitabine in a non-pretreated patient.
Best Supportive Care Compared With Chemotherapy for Unresectable Gall Bladder Cancer: A Randomized Controlled Study
Authors: Sharma Atul , Dwary Amit Dutt , Mohanti Bidhu Kalyan , Deo Surya V. , Pal Sujoy , Sreenivas Vishnu , Raina Vinod , Shukla Nootan Kumar , Thulkar Sanjay , Garg Pramod , Chaudhary Surendra Pal
Published: September 2010

Purpose

We designed this study to evaluate efficacy of modified gemcitabine and oxaliplatin (mGEMOX) over best supportive care (BSC) or fluorouracil (FU) and folinic acid (FA) in unresectable gall bladder cancer (GBC).

Patients and Methods

Patients with unresectable GBC were enrolled for single center randomized study. Arm A, BSC; arm B, FU 425 mg/m2 and FA 20 mg/m2 intravenous (IV) bolus weekly for 30 weeks (FUFA); arm C, gemcitabine 900 mg/m2 and oxaliplatin 80 mg/m2 IV infusion on days 1 and 8 every 3 weeks for maximum of six cycles. Eighty-one patients were randomly assigned, arms A (n = 27), B (n = 28), and C (n = 26).

Results

Complete response plus partial response in the three groups was 0 (0%), four (14.3%), and eight (30.8%) respectively (P < .001). Two patients in the mGEMOX arm and one patient in the FUFA arm underwent curative resection after chemotherapy. One patient in the mGEMOX arm had complete pathologic response. Median overall survival (OS) was 4.5, 4.6, and 9.5 months for the BSC, FUFA, and mGEMOX arms (P = .039), respectively. Progression-free survival (PFS) was 2.8, 3.5, and 8.5 months for the three groups (P < .001). There was no difference in grade 3/4 toxicities in the chemotherapy arms except transaminitis, which was more prevalent in mGEMOX arm (P = .04). Two patients in the FUFA arm and 10 patients in the mGEMOX arm had grade 3 or 4 myelosuppression. Two patients in the mGEMOX group had neutropenic fever that resolved with antibiotics.

Conclusion

This randomized controlled trial confirmed the efficacy of chemotherapy (mGEMOX) compared with BSC and FUFA in improving OS and PFS in unresectable GBC.
Cardiovascular Risk Factors and Morbidity in Long-Term Survivors of Testicular Cancer: A 20-Year Follow-Up Study
Authors: Haugnes Hege S. , Wethal Torgeir , Aass Nina , Dahl Olav , Klepp Olbjørn , Langberg Carl W. , Wilsgaard Tom , Bremnes Roy M. , Fosså Sophie D.
Published: September 2010

Purpose

To evaluate the prevalence of cardiovascular risk factors and long-term incidence of cardiovascular disease (CVD) in survivors of testicular cancer (TC).

Methods

Overall, 990 men treated for unilateral TC (1980 to 1994) were included in this national follow-up study (2007 to 2008). They were categorized into four treatment groups: surgery (n = 206), radiotherapy only (RT; n = 386), chemotherapy only (n = 364), and combined RT/chemotherapy (n = 34). Age-matched male controls from the general population (ie, NORMs) were included (n = 990). Survivors of TC who were diagnosed with CVD before or within 2 years after the TC diagnosis were excluded from analyses of CVD end points.

Results

Median observation time was 19 years (range, 13 to 28 years). All cytotoxic treatment groups had significantly increased prevalences of antihypertensive medication, and survivors in the RT and RT/chemotherapy groups had higher prevalences of diabetes (RT: odds ratio [OR], 2.3; 95% CI, 1.5 to 3.7; RT/chemotherapy: OR, 3.9; 95% CI, 1.4 to 10.9) compared with NORMs. Overall 74 survivors of TC (8.0%) experienced atherosclerotic disease during follow-up. Increased risks for atherosclerotic disease were observed in age-adjusted Cox regression analyses after any cytotoxic treatment when compared with surgery only (RT: hazard ratio [HR], 2.3; 95% CI, 1.04 to 5.3; chemotherapy: HR, 2.6; 95% CI, 1.1 to 5.9; RT/chemotherapy: HR, 4.8; 95% CI, 1.6 to 14.4). Treatment with cisplatin, bleomycin, and etoposide (BEP) alone had a 5.7-fold higher risk (95% CI, 1.9 to 17.1 fold) for coronary artery disease compared with surgery only and a 3.1-fold higher risk (95% CI, 1.2 to 7.7 fold) for myocardial infarction compared with NORMs.

Conclusion

Treatment with infradiaphragmatic RT and/or cisplatin-based chemotherapy, particularly the BEP regimen, increases the long-term risk for CVD in survivors of TC.
Castration-Dependent Pharmacokinetics of Docetaxel in Patients With Prostate Cancer
Authors: Franke Ryan M. , Carducci Michael A. , Rudek Michelle A. , Baker Sharyn D. , Sparreboom Alex
Published: September 2010

Purpose

To assess whether the low incidence of severe neutropenia in castrated men with prostate cancer treated with docetaxel is the result of changes in systemic clearance.

Patients and Methods

A total of 10 noncastrated and 20 castrated men with prostate cancer were studied to achieve 80% power (α = .05) to detect at least a 25% change in the clearance of docetaxel. The erythromycin breath test was evaluated to determine hepatic activity of cytochrome P450 3A4 (CYP3A4), the main docetaxel-metabolizing enzyme. Additional studies were performed in rats and transfected cells overexpressing human or rodent transporters.

Results

Docetaxel clearance was increased by approximately 100% in castrated men and was associated with a two-fold reduction in area under the curve (P = .0001), although hepatic activity of CYP3A4 was unchanged (P = .26). In rats, castration was associated with higher uptake of docetaxel in the liver and a concurrent increase in the expression of rOat2 (Slc22a7), an organic anion transporter that regulates, in part, the transfer of docetaxel from the circulation into hepatocytes.

Conclusion

It is recommended that castration- and/or hormone-related changes in the clearance of oncology drugs should be considered as a possible risk factor for treatment failure.
Lack of Adrenomedullin in the Central Nervous System Results in Apparently Paradoxical Alterations on Pain Sensitivity
Authors: Fernández Ana P. , Serrano Julia , Martínez-Murillo Ricardo , Martínez Alfredo
Published: September 2010

Adrenomedullin (AM) is a regulatory peptide, coded by the adm gene, which is involved in numerous physiological processes, including pain sensitivity. Previous studies have shown that intrathecal injection of AM induced hyperalgesia in the rat. Here, we explore pain sensitivity in a mouse conditional knockout for adm in neurons of the central nervous system, including the spinal cord and dorsal root ganglia. Double immunofluorescence in wild-type (WT) animals shows that AM immunoreactivity is found in calcitonin gene-related peptide-positive neurons of the dorsal root ganglia but not in neurons that bind isolectin B4. Mice lacking adm had modified expression of canonical sensorial neuropeptides, having significantly more calcitonin gene-related peptide and less substance P and enkephalin than their WT littermates. Furthermore, the spinal cord of adm knockout mice expressed higher levels of the AM receptor components, suggesting a compensation attempt to deal with the lack of afferent AM signaling. Behavioral nociceptive tests also found differences between genotypes. In the tail-flick test, which measures mostly spinal reflexes, the adm-null animals had a longer latency than their WT counterparts. On the other hand, in the hotplate test, which requires encephalic processing, mice lacking adm had shorter latencies than normal littermates. These results suggest that AM acts as a nociceptive modulator in spinal reflexes, whereas it may have an analgesic function at higher cognitive levels. This study confirms the important role of AM in pain sensitivity processing but unveils a more complex scenario than previously surmised.
YibK is the 2′-O-methyltransferase TrmL that modifies the wobble nucleotide in Escherichia coli tRNALeu isoacceptors
Authors: Benítez-Páez Alfonso , Villarroya Magda , Douthwaite Stephen , Gabaldón Toni , Armengod M.-Eugenia
Published: September 2010

Transfer RNAs are the most densely modified nucleic acid molecules in living cells. In Escherichia coli, more than 30 nucleoside modifications have been characterized, ranging from methylations and pseudouridylations to more complex additions that require multiple enzymatic steps. Most of the modifying enzymes have been identified, although a few notable exceptions include the 2′-O-methyltransferase(s) that methylate the ribose at the nucleotide 34 wobble position in the two leucyl isoacceptors tRNALeuCmAA and tRNALeucmnm5UmAA. Here, we have used a comparative genomics approach to uncover candidate E. coli genes for the missing enzyme(s). Transfer RNAs from null mutants for candidate genes were analyzed by mass spectrometry and revealed that inactivation of yibK leads to loss of 2′-O-methylation at position 34 in both tRNALeuCmAA and tRNALeucmnm5UmAA. Loss of YibK methylation reduces the efficiency of codon–wobble base interaction, as demonstrated in an amber suppressor supP system. Inactivation of yibK had no detectable effect on steady-state growth rate, although a distinct disadvantage was noted in multiple-round, mixed-population growth experiments, suggesting that the ability to recover from the stationary phase was impaired. Methylation is restored in vivo by complementing with a recombinant copy of yibK. Despite being one of the smallest characterized α/β knot proteins, YibK independently catalyzes the methyl transfer from S-adenosyl-L-methionine to the 2′-OH of the wobble nucleotide; YibK recognition of this target requires a pyridine at position 34 and N6-(isopentenyl)-2-methylthioadenosine at position 37. YibK is one of the last remaining E. coli tRNA modification enzymes to be identified and is now renamed TrmL.
TbRGG2 facilitates kinetoplastid RNA editing initiation and progression past intrinsic pause sites
Authors: Ammerman Michelle L. , Presnyak Vladimir , Fisk John C. , Foda Bardees M. , Read Laurie K.
Published: September 2010

TbRGG2 is an essential kinetoplastid RNA editing accessory factor that acts specifically on pan-edited RNAs. To understand the mechanism of TbRGG2 action, we undertook an in-depth analysis of edited RNA populations in TbRGG2 knockdown cells and an in vitro examination of the biochemical activities of the protein. We demonstrate that TbRGG2 down-regulation more severely impacts editing at the 5′ ends of pan-edited RNAs than at their 3′ ends. The initiation of editing is reduced to some extent in TbRGG2 knockdown cells. In addition, TbRGG2 plays a post-initiation role as editing becomes stalled in TbRGG2-depleted cells, resulting in an overall decrease in the 3′ to 5′ progression of editing. Detailed analyses of edited RNAs from wild-type and TbRGG2-depleted cells reveal that TbRGG2 facilitates progression of editing past intrinsic pause sites that often correspond to the 3′ ends of cognate guide RNAs (gRNAs). In addition, noncanonically edited junction regions are either absent or significantly shortened in TbRGG2-depleted cells, consistent with impaired gRNA transitions. Sequence analysis further suggests that TbRGG2 facilitates complete utilization of certain gRNAs. In vitro RNA annealing and in vivo RNA unwinding assays demonstrate that TbRGG2 can modulate RNA–RNA interactions. Collectively, these data are consistent with a model in which TbRGG2 facilitates initiation and 3′ to 5′ progression of editing through its ability to affect gRNA utilization, both during the transition between specific gRNAs and during usage of certain gRNAs.
Portfolio Development for Foundation Doctors – Step® Foundation Day 1
Authors: Popat R
Published: September 2010

The careers of foundation-year doctors since the advent of Modernising Medical Careers (MMC) have significantly differed from those of our predecessors. Long gone are the days when doctors could spend a few years plying their trade as senior house officers in different subspecialties, taking their time to develop an extensive skill set before finally settling on the area in which they wished to forge their career.
Non-Elective Admission of Patients Aged 75 Years and Over to the Surgical Assessment Unit of an Acute Hospital
Authors: Akoh JA , Radford F , Legrys H
Published: September 2010

The number of emergency admissions to hospital has increased in recent years. Greater expectations from patients, the increased use of 'on-call' GP services and increased pressure from the emergency department due to the four-hour wait target are among the causal factors suggested to lower the threshold for admission and increase inappropriate admissions. Increasing age is also associated with increased admission rates and the elderly are the most rapidly increasing group among emergency surgical admissions. Emergency surgery has more risks in the elderly due to reduced cardio-respiratory reserves and greater co-morbidities. In addition, the elderly often have greater social needs, requiring social service input prior to discharge. With the current reduction in community and convalescent beds the length of acute hospital admissions in the elderly is predicted to rise.
Has MMC Improved the Early-Years Trauma and Orthopaedic Surgical Experience?
Authors: Gupta S , Khan AL , Jameson SS , Reed MR , Wallace WA , Sher JL
Published: September 2010

Specialist training in trauma and orthopaedics (T&O) has changed. In August 2007, the Department of Health initiative, Modernising Medical Careers (MMC) was implemented. This was a system of reform and development in postgraduate medical education and training. MMC aimed for the creation of a structured new programme that assures 'high quality of training, better formal supervision and continuous development of acquired competencies, backed up by good evidence' (http://www.mmc.nhs.uk/medical_education/about_ modernising_medical_care.aspx).
Outpatient Experience at ST3 Grade Orthopaedic Trainees: A Cause for Concern
Authors: Gill I , Raju K , Purushothaman B , Ricketts D
Published: September 2010

Prior to 2007 trainees spent a variable number of years as senior house officers prior to advancement to the registrar grade. Experience in service delivery was accumulated but training was often sparse. A common criticism of this system was that it produced trainees who were over-experienced but undertrained and had varying levels of competency.
The Concept of Surgical Assessment: Part 1 – Introduction
Authors: Okoro T , Sirianni C , Brigden D
Published: September 2010

Assessing competency in surgery is an age-old tradition. In the infancy of surgical practice the issue of competency in surgical skills was addressed by the Royal College of Surgeons of Edinburgh, one of the oldest surgical organisations. Competency in surgical skills has taken on an added urgency in contemporary practice because of several high-profile public enquiries into underperforming surgeons, such as the Bristol children's heart surgery affair in the UK, the paediatric cardiac surgery programme at Winnipeg Children's Hospital, Canada, and the Bundaberg Hospital affair in Australia.
Towards a Trauma Network: An Interview with Professor Keith Porter
Authors: Worrall Matthew
Published: September 2010

Arriving at Selly Oak rail station in Birmingham it is hard to avoid the new Queen Elizabeth Hospital Birmingham (QEHB), which dominates the Birmingham skyline and will form a prime hub of the new trauma network for the West Midlands. However, on the day I visit Keith Porter, Professor of Clinical Traumatology with University Hospitals Birmingham, the famous old Selly Oak site is in its last few days before the move to this new state-of-the-art centre.
Operative Experience in Trauma and Orthopaedics: Effect of Changes to Trainees' Working Patterns
Authors: Jameson SS , Gupta S , Lamb A , Sher J , Wallace W , Reed M
Published: September 2010

The European Working Time Regulations (EWTR) started to be incorporated into British law in 1993 (http://tiny.cc/zvi07). Although doctors in training were initially exempt, the legislation was extended in 2004. As of August 2009, the maximum working hours allowed by law should average no more than 48 hours per week, calculated over a six-month period. However, there are additional stipulations that include a minimum of two rest periods lasting at least 24 hours per fortnight and a rest period of not less than 11 consecutive hours per 24-hour period worked for the employer.
Does an ENT Introductory Course Improve Junior Doctors' Confidence in Managing ENT Emergencies?
Authors: Elloy M , Sama A
Published: September 2010

The implementation of the European Working Time Regulations has resulted in significant changes in working patterns in order to provide an emergency service in ear, nose and throat surgery (ENT). In contrast to many surgical specialties, a large proportion of emergency ENT patients can undergo their definitive treatment in a ward-based setting. These skills were previously acquired as targeted on-the-job training during the first few weeks of the attachment.
Surgical portfolios
Authors: Edwards Anusha , Cusick Eleri
Published: September 2010

It is a requirement of revalidation, appraisal and recruitment that all doctors have a portfolio. However, there is very little formal guidance on how to prepare a good one. We present here some advice on how to prepare a portfolio and keep it up to date.
Getting the Most from Conflict Zones: Any Lessons for the NHS?
Authors: Towell Elaine , Cornick Ed
Published: September 2010

Historically, battlefields have been where new techniques are born and where surgical advances have been made. Military trauma surgeons currently deployed in Afghanistan face the daily task of treating military personnel suffering severe, complex injuries from bomb blasts or gunshot wounds and a tour of duty is likely to expose surgeons to more experience of these types of injury than they might face in a whole career working in a UK hospital.
Representations of quivers over a ring and the Weak Krull–Schmidt Theorems
Authors: Girardi Nicola
Published: September 2010

Let R be a ring and Q be a finite quiver, and let be the
number of vertices of Q. Let be the class of
representations of Q by right R-modules with local endomorphism
ring and R-module homomorphisms. The endomorphism ring of a
representation has at most n maximal right
ideals, all of which are also left ideals, and the isomorphism class
of M is determined by n invariants.
The main theorem of this paper states that a finite direct sum of representations in is unique up to n
permutations of m elements. Let . A non-directed graph associated to M is
introduced and is shown to determine the unique decomposition of M
into indecomposable representations. This class of representations
is shown to generalize the known classes of modules for
which a theorem analogous to the case of our
main theorem holds.
Assessment of Oil Dispersion Pesticide Formulations Using Rheology and Near Infrared Centrifugation Techniques
Authors: Qin Kuide , Keeney F. Nelson , Oliver M. Paige
Published: September 2010

Oil dispersion (OD), as a formulation type in the pesticide industry, has become more important over the past few years. This increased importance is due to (1) new water sensitive active ingredients, (2) the compatibility of active ingredient mixtures, (3) the need to build-in adjuvancy properties, and (4) customer preference of liquid formulations. Unlike well known technologies such as aqueous suspension concentrates (SCs), for which scientists have extensive experience in formulation practices resulting in readily available technologies for developing a stable formulation, OD is a relatively new technology. Technical knowledge for developing a stable OD formulation is still an area that needs significant investigation. The present work seeks to determine useful criteria for characterizing and predicting long term stability of OD formulations using readily accessible technologies such as rheological measurements and centrifugation. The characterization results are reported for systems that are commercially available from two agricultural companies.
Sorption and Thermal Properties of Insulating Mortars with Expanded and Vitrified Small Ball
Authors: Fang Ping , Mukhopadhyaya Phalguni , Kumaran Kumar , Shi Caijun
Published: September 2010

Expanded vitrified small hollow ball (EVSB), made from a special type of perlite mineral is one of the recently developed materials in China. It is widely used as a cementitious thermal insulating mortar for building envelope construction in hot-humid areas of southern China. However, EVSB is a porous material sensitive to environmental moisture. The thermal insulating property of the EVSB mortar is dependent on its moisture transport and storage characteristics. In this study, hygroscopic sorption properties of EVSB mortars have been investigated in comparison with those of normal expanded perlite particle (NEPP) mortars. The Brunauer, Emmett and Teller specific surface area and the Barrett, Joyner and Halenda pore size distribution, as well as the scanning electron microscope micromorphologies of the mortars were assessed. It was observed that EVSB mortars had lower moisture sorption capacity than NEPP mortars when the relative humidity (RH) was higher than 70 % because of its lower total pore volume. The addition of water-repellent admixtures in the mortar decreased the moisture sorption capacity of EVSB mortars but still maintains the same physisorption isothermal characteristics. It is also evident that the thermal conductivity values of both NEPP and EVSB mortars increased rapidly when RH is above 90 %. However, the increased rate of thermal conductivity of NEPP mortars was apparently higher than that of EVSB mortars. It is hoped that finding from this study will help to develop a better understanding of the in situ thermal performance of the EVSB mortar used for the building envelope construction in hot and humid areas of southern China.
The Role of eIF1 in Translation Initiation Codon Selection in Caenorhabditis
elegans
Authors: Maduzia Lisa L , Moreau Anais , Poullet Nausicaa , Chaffre Sebastien , Zhang Yinhua
Published: September 2010

The selection of a proper AUG start codon requires the base-pairing interactions between the codon on the mRNA and the anticodon of the initiator tRNA. This selection process occurs in a pre-initiation complex that includes multiple translation initiation factors and the small ribosomal subunit. To study how these initiation factors are involved in start codon recognition in multicellular organisms, we isolated mutants that allow the expression of a GFP reporter containing a non-AUG start codon. Here we describe the characterization of mutations in eif-1, which encodes the Caenorhabditiselegans translation initiation factor 1 (eIF1). Two mutations were identified, both of which are substitutions of amino acid residues that are identical in all eukaryotic eIF1 proteins. These residues are located in a structural region where the amino acid residues affected by the Saccharomyces cerevisiae eIF1 mutations are also localized. Both C. elegans mutations are dominant in conferring a non-AUG translation initiation phenotype and lead to growth arrest defects in homozygous animals. By assaying reporter constructs that have base changes at the AUG start codon, these mutants are found to allow expression from most reporters that carry single base changes within the AUG codon. This trend of non-AUG mediated initiation was also observed previously for C. elegans eIF2β mutants, indicating that these two factors play a similar role. These results support that eIF1 functions in ensuring the fidelity of AUG start codon recognition in a multicellular organism.
Exploiting Natural Variation inSaccharomyces cerevisiaeto Identify Genes for Increased Ethanol Resistance
Authors: Lewis Jeffrey A , Elkon Isaac M , McGee Mick A , Higbee Alan J , Gasch Audrey P
Published: September 2010

Ethanol production from lignocellulosic biomass holds promise as an alternative fuel. However, industrial stresses, including ethanol stress, limit microbial fermentation and thus prevent cost competitiveness with fossil fuels. To identify novel engineering targets for increased ethanol tolerance, we took advantage of natural diversity in wild Saccharomyces cerevisiae strains. We previously showed that an S288c-derived lab strain cannot acquire higher ethanol tolerance after a mild ethanol pretreatment, which is distinct from other stresses. Here, we measured acquired ethanol tolerance in a large panel of wild strains and show that most strains can acquire higher tolerance after pretreatment. We exploited this major phenotypic difference to address the mechanism of acquired ethanol tolerance, by comparing the global gene expression response to 5% ethanol in S288c and two wild strains. Hundreds of genes showed variation in ethanol-dependent gene expression across strains. Computational analysis identified several transcription factor modules and known coregulated genes as differentially expressed, implicating genetic variation in the ethanol signaling pathway. We used this information to identify genes required for acquisition of ethanol tolerance in wild strains, including new genes and processes not previously linked to ethanol tolerance, and four genes that increase ethanol tolerance when overexpressed. Our approach shows that comparative genomics across natural isolates can quickly identify genes for industrial engineering while expanding our understanding of natural diversity.
Increasing Prevalence of Medically Complex Children in US Hospitals
Authors: Burns Katherine H. , Casey Patrick H. , Lyle Robert E. , Bird T. Mac , Fussell Jill J. , Robbins James M.
Published: September 2010

OBJECTIVE:

In this study we used national data to determine changes in the prevalence of hospital admissions for medically complex children over a 15-year period.

PATIENTS AND METHODS:

Data from the Nationwide Inpatient Sample, a component of the Healthcare Cost and Utilization Project, was analyzed in 3-year increments from 1991 to 2005 to determine national trends in rates of hospitalization of children aged 8 days to 4 years with chronic conditions. Discharge diagnoses from the Nationwide Inpatient Sample were grouped into 9 categories of complex chronic conditions (CCCs). Hospitalization rates for each of the 9 CCC categories were studied both individually and in combination. Trends of children hospitalized with 2 specific disorders, cerebral palsy (CP) and bronchopulmonary dysplasia, with additional diagnoses in more than 1 CCC category were also examined.

RESULTS:

Hospitalization rates of children with diagnoses in more than 1 CCC category increased from 83.7 per 100 000 (1991–1993) to 166 per 100 000 (2003–2005) (P[r] < .001). The hospitalization rate of children with CP plus more than 1 CCC diagnosis increased from 7.1 to 10.4 per 100 000 (P = .002), whereas the hospitalization rates of children with bronchopulmonary dysplasia plus more than 1 CCC diagnosis increased from 9.8 to 23.9 per 100 000 (P < .001).

CONCLUSIONS:

Consistent increases in hospitalization rates were noted among children with diagnoses in multiple CCC categories, whereas hospitalization rates of children with CP alone have remained stable. The relative medical complexity of hospitalized pediatric patients has increased over the past 15 years.
Clinical Disease Caused byKlebsiellain 2 Unrelated Patients With Interleukin 12 Receptor β1 Deficiency
Authors: Pedraza Sigifredo , Lezana Jose Luis , Samarina Arina , Aldana Ruth , Herrera Maria Teresa , Boisson-Dupuis Stéphanie , Bustamante Jacinta , Pages Perle , Casanova Jean-Laurent , Picard Capucine
Published: September 2010

Patients with interleukin 12 (IL-12)p40 or IL-12 receptor β1 (IL12Rβ1) deficiencies are prone to develop infections caused by mycobacteria and salmonella; other infections have only been rarely observed. In this report we describe 2 unrelated patients with complete autosomal recessive IL12Rβ1 deficiency who suffered from sepsis attributable to Klebsiella pneumoniae. A Mexican boy suffered from disseminated bacille Calmette-Guérin disease and infections caused by K pneumoniae and Candida albicans and had a fatal outcome. A Turkish girl living in France suffered from disseminated Nocardia nova infection and K pneumoniae sepsis. Therefore, Klebsiella infections should be considered in patients with IL12Rβ1 deficiency. Conversely, IL12Rβ1 deficiency should be considered in patients with unexplained klebsiellosis.
Vitamin B12 Optic Neuropathy in Autism
Authors: Pineles Stacy L. , Avery Robert A. , Liu Grant T.
Published: September 2010

Dietary vitamin B12 deficiency was identified as a cause of partially reversible optic neuropathy in 3 autistic children. All of the affected children presented with gradual visual loss. Examination revealed optic atrophy, and further questioning regarding diet revealed that all 3 children had severe food selectivity and highly stereotyped diets that resulted in an almost total lack of animal products in their diets. Vitamin B12 levels were low in all 3 children. Treatment with intramuscular vitamin B12 and normalization of vitamin B12 levels resulted in improvement of visual functioning in all 3 children. These cases illustrate that food selectivity, a known complication of autism, can result in vitamin deficiency that can cause visual loss and optic atrophy. Physicians must have a high index of suspicion when evaluating children with autism and visual loss to detect this rare cause of optic atrophy.
Corticosteroids May Improve Clinical Outcomes During Hospitalization for Henoch-Schönlein Purpura
Authors: Weiss Pamela F. , Klink Andrew J. , Localio Russell , Hall Matt , Hexem Kari , Burnham Jon M. , Keren Ron , Feudtner Chris
Published: September 2010

OBJECTIVE:

To characterize the effect of corticosteroid exposure on clinical outcomes in children hospitalized with new-onset Henoch-Schönlein purpura (HSP).

PATIENTS AND METHODS:

We conducted a retrospective cohort study of children discharged with an International Classification of Diseases, Clinical Modification code of HSP between 2000 and 2007 by using inpatient administrative data from 36 tertiary care children's hospitals. We used stratified Cox proportional hazards regression models to estimate the relative effect of time-varying corticosteroid exposure on the risks of clinical outcomes that occur during hospitalization for acute HSP.

RESULTS:

During the 8-year study period, there were 1895 hospitalizations for new-onset HSP. After multivariable regression modeling adjustment, early corticosteroid exposure significantly reduced the hazard ratios for abdominal surgery (0.39 [95% confidence interval (CI): 0.17–0.91]), endoscopy (0.27 [95% CI: 0.13–0.55]), and abdominal imaging (0.50 [95% CI: 0.29–0.88]) during hospitalization.

CONCLUSIONS:

In the hospital setting, early corticosteroid exposure was associated with benefits for several clinically relevant HSP outcomes, specifically those related to the gastrointestinal manifestations of the disease.