bluuebunny/crossref_metadata_2025 huggingface dataset:
Identification of Resistance to New Virulent Races of Rust in Sunflowers and Validation of DNA Markers in the Gene Pool
Authors: Qi Lili , Gulya Tom , Seiler Gerald J. , Hulke Brent S. , Vick Brady A.
Published: September 2010

Sunflower rust, caused by Puccinia helianthi, is a prevalent disease in many countries throughout the world. The U.S. Department of Agriculture (USDA)-Agricultural Research Service, Sunflower Research Unit has released rust resistant breeding materials for several decades. However, constantly coevolving rust populations have formed new virulent races to which current hybrids have little resistance. The objectives of this study were to identify resistance to race 336, the predominant race in North America, and to race 777, the most virulent race currently known, and to validate molecular markers known to be linked to rust resistance genes in the sunflower gene pool. A total of 104 entries, including 66 released USDA inbred lines, 14 USDA interspecific germplasm lines, and 24 foreign germplasms, all developed specifically for rust resistance, were tested for their reaction to races 336 and 777. Only 13 of the 104 entries tested were resistant to both races, whereas another six were resistant only to race 336. The interspecific germplasm line, Rf ANN-1742, was resistant to both races and was identified as a new rust resistance source. A selection of 24 lines including 19 lines resistant to races 777 and/or 336 was screened with DNA markers linked to rust resistance genes R1, R2, R4u, and R5. The results indicated that the existing resistant lines are diverse in rust resistance genes. Durable genetic resistance through gene pyramiding will be effective for the control of rust.
Cannabinoid and cholinergic systems interact during performance of a short-term memory task in the rat
Authors: Goonawardena Anushka V. , Robinson Lianne , Hampson Robert E. , Riedel Gernot
Published: September 2010

It is now well established that cannabinoid agonists such as Δ9–tetrahydrocannabinol (THC), anandamide, and WIN 55,212-2 (WIN-2) produce potent and specific deficits in working memory (WM)/short-term memory (STM) tasks in rodents. Although mediated through activation of CB1 receptors located in memory-related brain regions such as the hippocampus and prefrontal cortex, these may, in part, be due to a reduction in acetylcholine release (i.e., cholinergic hypofunction). To determine the interaction between cannabinoid and cholinergic systems, we exposed rats treated with WIN-2 or cholinergic drugs to a hippocampal-dependent delayed nonmatch to sample (DNMS) task to study STM, and recorded hippocampal single-unit activity in vivo. WIN-2 induced significant deficits in DNMS performance and reduced the average firing and bursting rates of hippocampal principal cells through a CB1 receptor-mediated mechanism. Rivastigmine, an acetylcholinesterase inhibitor, reversed these STM deficits and normalized hippocampal discharge rates. Effects were specific to 1 mg/kg WIN-2 as rivastigmine failed to reverse the behavioral and physiological deficits that were observed in the presence of MK-801, an NMDA receptor antagonist. This supports the notion that cannabinoid-modulated cholinergic activity is a mechanism underlying the performance deficits in DNMS. Whether deficits are due to reduced nicotinic or muscarinic receptor activation, or both, awaits further analysis.
Endoplasmic Reticulum Protein Quality Control and Its Relationship to Environmental Stress Responses in Plants
Authors: Liu Jian-Xiang , Howell Stephen H.
Published: September 2010

The endoplasmic reticulum (ER) has a sophisticated quality control (QC) system to eliminate improperly folded proteins from the secretory pathway. Given that protein folding is such a fastidious process and subject to adverse environmental conditions, the ER QC system appears to have been usurped to serve as an environmental sensor and responder in plants. Under stressful conditions, the ER protein folding machinery reaches a limit as the demands for protein folding exceed the capacity of the system. Under these conditions, misfolded or unfolded proteins accumulate in the ER, triggering an unfolded protein response (UPR). UPR mitigates ER stress by upregulating the expression of genes encoding components of the protein folding machinery or the ER-associated degradation system. In Arabidopsis thaliana, ER stress is sensed and stress signals are transduced by membrane-bound transcription factors, which are activated and mobilized under environmental stress conditions. Under acute or chronic stress conditions, UPR can also lead to apoptosis or programmed cell death. Despite recent progress in our understanding of plant protein QC, discovering how different environmental conditions are perceived is one of the major challenges in understanding this system. Since the ER QC system is one among many stress response systems in plants, another major challenge is determining the extent to which the ER QC system contributes to various stress responses in plants.
Treatment of alopecia areata with 308‐nm excimer lamp
Authors: OHTSUKI Akiko , HASEGAWA Toshio , IKEDA Shigaku
Published: September 2010

Alopecia areata is considered to be a T‐cell mediated autoimmune disorder. The 308‐nm excimer lamp is thought to be capable of inducing T‐cell apoptosis in vitro, suggesting that the lamp might be effective for the treatment of alopecia areata. We examined the effectiveness of the 308‐nm excimer lamp for the treatment of alopecia areata. We recruited three patients with single alopecia areata lesions that were resistant to conventional treatment. The lesions were exposed to a 308‐nm excimer lamp at 2‐weekly intervals. Hair regrowth was observed in all three patients after approximately 10 treatment sessions. Our study showed that exposure to the 308‐nm excimer lamp effectively induced hair regrowth in solitary alopecia areata lesions. Apart from erythema, there were no significant adverse effects. Therefore, we suggest that it may be considered as a treatment modality for recalcitrant alopecia areata.
Calcium‐binding protein S100P is a novel diagnostic marker of cholangiocarcinoma
Authors: Hamada Shin , Satoh Kennichi , Hirota Morihisa , Kanno Atsushi , Ishida Kazuyuki , Umino Jun , Ito Hiromichi , Kikuta Kazuhiro , Kume Kiyoshi , Masamune Atsushi , Katayose Yu , Unno Michiaki , Shimosegawa Tooru
Published: September 2010

The incidence and mortality of cholangiocarcinoma are increasing despite improvements in the diagnostic method. Since the sensitivity of brushing cytology for cholangiocarcinoma is not satisfactory, a novel diagnostic marker needs to be established. A recent report has suggested upregulation of the calcium‐binding protein S100P in cholangiocarcinoma. The expression status of S100P in normal bile duct and cholangiocarcinoma tissues was assessed by immunohistochemistry. The expression levels of S100P mRNA in the brushing cytology samples during endoscopic retrograde cholangiopancreatography (ERCP) from benign biliary strictures and cholangiocarcinoma were assessed by real‐time reverse transcription–polymerase chain reaction (RT‐PCR). The sensitivity and specificity of each diagnostic strategy was compared. S100P was frequently expressed in the cholangiocarcinoma tissues, but not in the normal bile duct. The brushing cytology samples from the cholangiocarcinoma cases revealed higher expression levels of S100P compared with the benign biliary strictures. The relative expression level of S100P could determine the cholangiocarcinoma at higher sensitivity than classical cytology, and the combination of the S100P expression level and cytology yielded a sensitivity of 90.0%, with a specificity of 92.0%. Calcium‐binding protein S100P is a novel marker of cholangiocarcinoma. Detecting the S100P expression levels in brushing cytology samples has a diagnostic value, which will be helpful for better diagnosis of cholangiocarcinoma. (Cancer Sci 2011; 102: 150–156)
Expression of IGFBP7 in acute leukemia is regulated by DNA methylation
Authors: Heesch Sandra , Bartram Isabelle , Neumann Martin , Reins Jana , Mossner Maximilian , Schlee Cornelia , Stroux Andrea , Haferlach Torsten , Goekbuget Nicola , Hoelzer Dieter , Hofmann Wolf‐Karsten , Thiel Eckhard , Baldus Claudia D.
Published: September 2010

The important role of insulin‐like growth factor binding protein 7 (IGFBP7) as a tumor suppressor in solid tumors has been revealed in several studies. Interestingly, in a recent study IGFBP7 was also shown to be aberrantly expressed in acute leukemia. Moreover, in acute T‐lymphoblastic leukemia (T‐ALL), high IGFBP7 expression predicts primary therapy resistance. In order to elucidate the mechanisms underlying aberrant IGFBP7 expression, we used pyrosequencing technology to investigate the DNA methylation of IGFBP7 in 109 T‐ALL patient samples. Aberrant methylation was shown and hypomethylation was associated with an early immunophenotype and co‐expression of the stem cell markers CD117 (P < 0.001) and CD34 (P < 0.001). In concordance, gene expression profiles of 86 T‐ALL patients revealed upregulation of stem cell markers (CD34 and CD133) as well as genes associated with poor outcome and pathogenesis of leukemia (MN1, BAALC, FLT3) in the high IGFBP7 expression group. In conclusion, aberrant IGFBP7 expression is regulated by DNA methylation in acute leukemia. Hypomethylation of the gene is likely to characterize an immature and a more malignant subtype of the disease. (Cancer Sci 2011; 102: 253–259)
Can stand‐alone computer‐based interventions reduce alcohol consumption? A systematic review
Authors: Khadjesari Zarnie , Murray Elizabeth , Hewitt Catherine , Hartley Suzanne , Godfrey Christine
Published: September 2010

Aim To determine the effects of computer‐based interventions aimed at reducing alcohol consumption in adult populations.

Methods The review was undertaken following standard Cochrane and Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA) guidance for systematic reviews. The literature was searched until December 2008, with no restrictions on language. Randomized trials with parallel comparator groups were identified in the form of published and unpublished data. Two authors independently screened abstracts and papers for inclusion. Data extraction and bias assessment was undertaken by one author and checked by a second author. Studies that measured total alcohol consumption and frequency of binge drinking episodes were eligible for inclusion in meta‐analyses. A random‐effects model was used to pool mean differences.

Results Twenty‐four studies were included in the review (19 combined in meta‐analyses). The meta‐analyses suggested that computer‐based interventions were more effective than minimally active comparator groups (e.g. assessment‐only) at reducing alcohol consumed per week in student and non‐student populations. However, most studies used the mean to summarize skewed data, which could be misleading in small samples. A sensitivity analysis of those studies that used suitable measures of central tendency found that there was no difference between intervention and minimally active comparator groups in alcohol consumed per week by students. Few studies investigated non‐student populations or compared interventions with active comparator groups.

Conclusion Computer‐based interventions may reduce alcohol consumption compared with assessment‐only; the conclusion remains tentative because of methodological weaknesses in the studies. Future research should consider that the distribution of alcohol consumption data is likely to be skewed and that appropriate measures of central tendency are reported.
The CHOICE trial: adalimumab demonstrates safety, fistula healing, improved quality of life and increased work productivity in patients with Crohn’s disease who failed prior infliximab therapy
Authors: Lichtiger S. , Binion D. G. , Wolf D. C. , Present D. H. , Bensimon A. G. , Wu E. , Yu A. P. , Cardoso A. T. , Chao J. , Mulani P. M. , Lomax K. G. , Kent J. D.
Published: September 2010

Aliment Pharmacol Ther 2010; 32: 1228–1239

Background  Adalimumab induces and maintains remission in adults with Crohn’s disease.

Aim  To evaluate safety, fistula healing, quality of life and work productivity in adalimumab‐treated patients who failed infliximab, including primary nonresponders.

Methods  After a ≥8‐week infliximab washout, patients with moderate‐to‐severe Crohn’s disease received open‐label adalimumab as induction (160/80 mg at weeks 0/2) and maintenance (40 mg every other week) therapies. At/after 8 weeks, patients with flare/nonresponse could receive weekly therapy. Minimum study duration was 8 weeks, continuing until the commercial availability of adalimumab for Crohn’s disease.

Results  Of 673 patients enrolled, 17% were infliximab primary nonresponders and 83% were initial responders. Three percent of patients had serious infections (mainly abscesses). Complete fistula healing was achieved by 34/88 (39%) patients with baseline fistulas. Improvements in quality of life and work productivity were sustained from week 4 to week 24 for all patients, as well as the subgroup of primary nonresponders.

Conclusions  Blinded clinical trials have shown adalimumab to be both an effective first‐line therapy for anti‐TNF‐naïve patients and an important treatment option for infliximab‐refractory or ‐intolerant patients. This trial presents open‐label experience to support further the safety and effectiveness of adalimumab in patients who failed infliximab therapy, including primary nonresponders (NCT00338650).
The effects of dose and timing of esomeprazole administration on 24‐h, daytime and night‐time acid inhibition in healthy volunteers
Authors: Wilder‐Smith C. , Röhss K. , Bokelund Singh S. , Sagar M. , Nagy P.
Published: September 2010

Aliment Pharmacol Ther 2010; 32: 1249–1256

Background  Symptoms of gastro‐oesophageal reflux disease (GERD) may persist despite daily treatment with a proton pump inhibitor (PPI).

Aim  To compare the pharmacodynamic effect of various esomeprazole dosage and timing regimens in healthy volunteers.

Methods  The effect of different esomeprazole dosage regimens [20 mg once daily (od) before breakfast or dinner; 20 mg twice daily (b.d.); 40 mg od before breakfast, dinner or at bedtime; and 40 mg b.d.] on 24‐h, daytime and night‐time acid inhibition was evaluated in a randomized, seven‐way crossover study in healthy volunteers. Each regimen was taken for 5 days.

Results  Over the 24‐h period (day 5), esomeprazole 20 mg b.d. was associated with superior acid inhibition vs. all 20 mg and 40 mg od regimens (P < 0.05), but was less effective than esomeprazole 40 mg b.d. (P < 0.05). Dosing with esomeprazole 20 mg or 40 mg od before breakfast gave improved 24‐h and daytime acid inhibition vs. the corresponding administration before dinner or at bedtime (all P < 0.05). Night‐time acid inhibition was improved when esomeprazole 40 mg od was administered before dinner or at bedtime vs. before‐breakfast dosing (P < 0.05).

Conclusion  Varying the dose and timing of esomeprazole administration may provide acid inhibition appropriate for the symptom pattern of individual patients with GERD.
Serum HBsAg quantification to predict response to peginterferon therapy of e antigen positive chronic hepatitis B
Authors: Chan H. L.‐Y. , Wong V. W.‐S. , Chim A. M.‐L. , Chan H.‐Y. , Wong G. L.‐H. , Sung J. J.‐Y.
Published: September 2010

Aliment Pharmacol Ther 2010; 32: 1323–1331

Background  On‐treatment predictors of response to peginterferon can guide individualization of therapy in chronic hepatitis B virus infection.

Aim  To investigate the use of serum hepatitis B surface antigen quantification to predict sustained response.

Methods  Hepatitis B e antigen‐positive chronic hepatitis B patients who received peginterferon for 32–48 weeks with or without lamivudine combination were studied. Sustained response was defined as hepatitis B e antigen seroconversion and chronic hepatitis B virus DNA <10 000 copies/mL until 12 months post‐treatment.

Results  Twenty‐one of 92 (23%) patients achieved sustained response. At month 6, the area under receiver operating characteristics curve for hepatitis B surface antigen to predict sustained response was 0.77 (95% confidence interval 0.65–0.89, P < 0.001). An hepatitis B surface antigen cutoff at 300 IU/mL at month 6 could give the maximum combination of sensitivity (62%) and specificity (89%) to predict sustained response. Nine of 21 (43%) sustained responders vs. 9 of 71 (13%) nonsustained responders had >1 log hepatitis B surface antigen reduction at month 6 (P < 0.001). Combined hepatitis B surface antigen ≤300 IU/mL and >1 log reduction at month 6 had sensitivity, specificity, positive and negative predictive values of 43%, 96%, 75% and 85% to predict sustained response, respectively.

Conclusion  On‐treatment serum hepatitis B surface antigen can predict response to peginterferon therapy in chronic hepatitis B.
The effect of propofol and desflurane anaesthesia on human hepatic blood flow: a pilot study*
Authors: Meierhenrich R. , Gauss A. , Mühling B. , Bracht H. , Radermacher P. , Georgieff M. , Wagner F.
Published: September 2010

This study tested the hypothesis that propofol is associated with a higher hepatic blood flow in humans compared with desflurane. Using a cross over study design, 10 patients received first propofol and then desflurane, and a further 10 patients received desflurane and then propofol. Blood flow index in the right and middle hepatic veins, stroke volume index and cardiac index were assessed by transoesophageal echocardiography. Mean arterial blood pressure, stroke volume index and cardiac index were the same in both groups. Propofol was associated with significantly greater blood flow index in the right hepatic vein (median (IQR [range]) 199 (146–237 [66–388]) vs. 149 (112–189 [42–309]) ml.min−1.m−2; p = 0.005) and middle hepatic vein (150 (122–191 [57–341]) vs. 125 (92–149 [47–362]) ml.min−1.m−2; p < 0.001) compared with desflurane. In routine clinical conditions, propofol anaesthesia was associated with significantly greater hepatic blood flow than desflurane anaesthesia.
Cardiac effects of muscarinic receptor antagonists used for voiding dysfunction
Authors: Andersson Karl‐Erik , Campeau Lysanne , Olshansky Brian
Published: September 2010

Antimuscarinic agents are the main drugs used to treat patients with the overactive bladder (OAB) syndrome, defined as urgency, with or without urgency incontinence, usually with increased daytime frequency and nocturia. Since the treatment is not curative and since OAB is a chronic disease, treatment may be life‐long. Antimuscarinics are generally considered to be ‘safe’ drugs, but among the more serious concerns related to their use is the risk of cardiac adverse effects, particularly increases in heart rate (HR) and QT prolongation and induction of polymorphic ventricular tachycardia (torsade de pointes). An elevated resting HR has been linked to overall increased morbidity and mortality, particularly in patients with cardiovascular diseases. QT prolongation and its consequences are not related to blockade of muscarinic receptors, but rather linked to inhibition of the hERG potassium channel in the heart. However, experience with terodiline, an antimuscarinic drug causing torsade de pointes in patients, has placed the whole drug class under scrutiny. The potential of the different antimuscarinic agents to increase HR and/or prolong the QT time has not been extensively explored for all agents in clinical use. Differences between drugs cannot be excluded, but risk assessments based on available evidence are not possible.
Influence of polymorphisms within the methotrexate pathway genes on the toxicity and efficacy of methotrexate in patients with juvenile idiopathic arthritis
Authors: Yanagimachi Masakatsu , Naruto Takuya , Hara Takuma , Kikuchi Masako , Hara Ryoki , Miyamae Takako , Imagawa Tomoyuki , Mori Masaaki , Kaneko Tetsuji , Morita Satoshi , Goto Hiroaki , Yokota Shumpei
Published: September 2010

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• Methotrexate (MTX), which causes adverse effects, such as liver and/or renal dysfunction, is the most common disease‐modifying antirheumatic drug used for the treatment of rheumatoid arthritis and articular‐type juvenile idiopathic arthritis (JIA).

• Pharmacogenetic studies analysing the MTX pathway genes would aid in the development of more personalized therapy.

• Results regarding the influence of gene polymorphisms on the toxicity and efficacy of MTX are conflicting, and there are marked differences between racial groups in pharmacogenetics.

WHAT THIS STUDY ADDS

• The non‐TT genotype at γ‐glutamyl hydrolase (GGH) T16C is associated with a high risk of liver dysfunction due to MTX, even after adjustment for duration of MTX treatment.

• Longer time interval from disease onset to MTX treatment and rheumatoid factor positivity are associated with lower efficacy of MTX in Japanese patients, as reported previously in Caucasian patients with JIA.

AIMS We investigated whether several polymorphisms within the methotrexate (MTX) pathway genes were related to the toxicity and efficacy of MTX in 92 Japanese patients with articular‐type juvenile idiopathic arthritis (JIA).

METHODS Eight gene polymorphisms within the MTX pathway genes, namely, RFC, BCRP, MTHFR (two), FPGS, γ‐glutamyl hydrolase (GGH; two) and ATIC, were genotyped using TaqMan assays. Liver dysfunction was defined as an increase in alanine transaminase to five times the normal upper limit. Non‐responders to MTX were defined as patients refractory to MTX and were therefore treated with biologics.

RESULTS The non‐TT genotype at GGH T16C was associated with a high risk of liver dysfunction (P = 0.028, odds ratio = 6.90, 95% confidence interval 1.38–34.5), even after adjustment for the duration of MTX treatment. A longer interval from disease onset to treatment (8.5 and 21.3 months, P = 0.029) and rheumatoid factor positivity (P = 0.026, odds ratio = 2.87, 95% confidence interval 1.11–7.39) were associated with lower efficacy of MTX.

CONCLUSIONS The non‐TT genotype at GGH T16C was associated with a high risk of liver dysfunction, presumably because the C allele of GGH C16T may reduce the activity of GGH. The time interval before MTX treatment and rheumatoid factor positivity were associated with the efficacy of MTX treatment. The pharmacogenetics of the MTX pathway genes affects the toxicity and efficacy of MTX in Japanese JIA patients.
Weekly versus twice weekly bortezomib given in conjunction with rituximab, in patients with recurrent follicular lymphoma, mantle cell lymphoma and Waldenström macroglobulinaemia
Authors: Agathocleous Agathoclis , Rohatiner Ama , Rule Simon , Hunter Hannah , Kerr Jonathan Paul , Neeson Susan M. , Matthews Janet , Strauss Sandra , Montoto Silvia , Johnson Peter , Radford John , Lister Andrew
Published: September 2010

The combination of bortezomib and rituximab was evaluated in patients with mantle cell lymphoma (MCL), follicular lymphoma (FL) and Waldenström macroglobulinaemia (WM), in a Phase I and later, a randomized Phase II study. In the randomized study, 42 patients with recurrent/refractory disease received either: bortezomib 1·3 mg/m2 on days 1, 4, 8 and 11 of a 3‐week cycle with rituximab 375 mg/m2 on day 1 (21 patients) or: bortezomib 1·6 mg/m2 and rituximab on days 1, 8, 15 and 22 of a 5‐week cycle (with rituximab being given only in cycles 1 and 4).Twenty‐eight patients were withdrawn (toxicity 16, progression 7, and ‘patient choice’ 5). The main toxicities were neurological, gastro‐intestinal and haematological. The overall response rate was 28/42(67%) and by histology: MCL 11/19, FL 8/15, and WM 9/10. Ten of 28 responding patients remained progression‐free at 1–3·5 years. Toxicity and efficacy were equivalent between the two groups. The combination has significant toxicity but is effective, particularly in patients with WM.
The class‐I HDAC inhibitor MGCD0103 induces apoptosis in Hodgkin lymphoma cell lines and synergizes with proteasome inhibitors by an HDAC6‐independent mechanism
Authors: Buglio Daniela , Mamidipudi Vidya , Khaskhely Noor M. , Brady Helen , Heise Carla , Besterman Jeffrey , Martell Robert E. , MacBeth Kyle , Younes Anas
Published: September 2010

Inhibition of histone deacetylase 6 (HDAC6)‐dependent aggresome function by pan HDAC inhibitors was recently reported to be a key mechanism underlying the synergistic activity between proteasome inhibitors and HDAC inhibitors in a variety of tumour types. Because these combinations induce significant thrombocytopeniain vivo, we examined whether less toxic, isotype‐selective HDAC inhibitors may still synergize with proteasome inhibitors, and if so, by what mechanisms. Here, we showed that the class I HDAC inhibitor, MGCD0103, has a potent antiproliferative activity in Hodgkin lymphoma (HL) cell lines. Furthermore, MGCD0103 induced tumour necrosis factor α (TNF‐α) expression and secretion, which was associated with nuclear factor (NF)‐κB activation. Selective inhibition of TNF‐α expression by short interfering mRNA, or inhibition of MGCD0103‐induced NF‐kB activation by proteasome inhibitors enhanced MGCD0103‐induced cell death. Thus, our results demonstrate that MGCD0103 may synergize with proteasome inhibitors by HDAC6‐independent mechanisms, providing mechanistic rationale for exploring this potentially less toxic combination for the treatment of lymphoma.
Novel interactions between UFH and TFPI in children
Authors: Newall Fiona , Johnston Linda , Summerhayes Robyn , Lane Geoff , Cranswick Noel , Monagle Paul , Ignjatovic Vera
Published: September 2010

The impact of age upon therapeutic response to unfractionated heparin (UFH) in children is proposed to reflect quantitative and potentially qualitative differences in coagulation proteins across childhood. This study explores the UFH‐dependent tissue factor pathway inhibitor (TFPI) release in children compared to previously published data in adults. Children <16 years of age undergoing cardiac angiography formed the population for this prospective cohort study. TFPI release was measured prior to (baseline) and at 15, 30, 45 and 120 min post‐UFH dose. This study demonstrated that, whilst the immediate release of TFPI post‐UFH was similar in children compared to adults, TFPI release in children remained increased and consistent for a significantly longer period post‐UFH administration compared to adults. Plasma TFPI levels in children did not demonstrate an UFH concentration –dependent reduction, as has been previously reported in adults. The prolonged TFPI‐mediated anticoagulant levels observed in children administered UFH may contribute to the increased rate of major bleeding reported in children compared to adults. Furthermore, we postulate that this sustained UFH‐dependent increase in TFPI levels in children may influence the binding of UFH to competitive plasma proteins, such as those involved in the immunological response to UFH associated with heparin‐induced thrombocytopenia.
ASXL1 mutation is associated with poor prognosis and acute transformation in chronic myelomonocytic leukaemia
Authors: Gelsi‐Boyer Véronique , Trouplin Virginie , Roquain Julien , Adélaïde José , Carbuccia Nadine , Esterni Benjamin , Finetti Pascal , Murati Anne , Arnoulet Christine , Zerazhi Hacène , Fezoui Hacène , Tadrist Zoulika , Nezri Meyer , Chaffanet Max , Mozziconacci Marie‐Joëlle , Vey Norbert , Birnbaum Daniel
Published: September 2010

Chronic myelomonocytic leukaemia (CMML) is a haematological disease currently classified in the category of myelodysplastic syndromes/myeloproliferative neoplasm (MDS/MPN) because of its dual clinical and biological presentation. The molecular biology of CMML is poorly characterized. We studied a series of 53 CMML samples including 31 cases of myeloproliferative form (MP‐CMML) and 22 cases of myelodysplastic forms (MD‐CMML) using array‐comparative genomic hybridisation (aCGH) and sequencing of 13 candidate genes including ASXL1, CBL, FLT3, IDH1, IDH2, JAK2, KRAS, NPM1, NRAS, PTPN11, RUNX1, TET2 and WT1. Mutations in ASXL1 and in the genes associated with proliferation (CBL, FLT3, PTPN11, NRAS) were mainly found in MP‐CMML cases. Mutations of ASXL1 correlated with an evolution toward an acutely transformed state: all CMMLs that progressed to acute phase were mutated and none of the unmutated patients had evolved to acute leukaemia. The overall survival of ASXL1 mutated patients was lower than that of unmutated patients.
Southwest Oncology Group Study S0530: a phase 2 trial of clofarabine and cytarabine for relapsed or refractory acute lymphocytic leukaemia
Authors: Advani Anjali S. , Gundacker Holly M. , Sala‐Torra Olga , Radich Jerald P. , Lai Raymond , Slovak Marilyn L. , Lancet Jeffrey E. , Coutre Steve E. , Stuart Robert K. , Mims Martha P. , Stiff Patrick J. , Appelbaum Frederick R.
Published: September 2010

Clofarabine and cytarabine target different steps in DNA synthesis and replication, are synergistic in vivo, and have non‐overlapping toxicities, making this combination a potentially promising treatment for acute lymphocytic leukaemia. Thirty‐seven patients were treated. The median age was 41 years, 44% of patients were either in ≥2nd relapse or had refractory disease and 59% of patients had poor risk cytogenetics. Six out of 36 patients (17%) achieved a complete remission with or without complete count recovery; median overall survival was 3 months. Nucleoside transporter expression did not predict outcome. This regimen lacked sufficient activity to warrant further testing.
Non‐malignant haematology research in the UK: looking forward to new opportunities
Authors: Collins P. W. , Baglin T. P. , Dang R. , Evans G. , Greaves M. , Laffan M. , Pasi K. J. , Rose P. , Stanworth S. , Toh C. H. , Gower J. ,   on behalf of the UK Non‐Malignant Haematology Speciality Group
Published: September 2010

Over the last few years there has been rapid and radical change in the way clinical research in the UK is funded and supported within the NHS. This has resulted from restructuring and major new investment in research infrastructure, co‐ordinated through Clinical Local Research Networks (CLRNs) and equivalent organisations in the devolved nations. CLRNs have resources to support local researchers undertake studies that have been adopted on to the national research portfolio. For example, CLRNs can help with gaining local approvals or provide research nurses to recruit patients, undertake study procedures and perform data entry. CLRNs can establish Local Speciality Groups in a number of areas of medicine, including non‐malignant haematology. These new networks offer non‐malignant haematology access to significant new resources and a major opportunity to support clinical research for the benefit of our patients.
Coho salmon productivity in relation to salmon lice from infected prey and salmon farms
Authors: Connors Brendan M. , Krkošek Martin , Ford Jennifer , Dill Lawrence M.
Published: September 2010

1. Pathogen transmission from open net‐pen aquaculture facilities can depress sympatric wild fish populations. However, little is known about the effects of pathogen transmission from farmed fish on species interactions or other ecosystem components. Coho salmon Oncorhynchus kisutch smolts are susceptible hosts to the parasitic salmon louse Lepeophtheirus salmonis as well as a primary predator of juvenile pink Oncorhynchus gorbuscha salmon, a major host species for lice.

2. We used a hierarchical model of stock‐recruit dynamics to compare coho salmon population dynamics across a region that varies in salmon louse infestation of juvenile coho and their pink salmon prey.

3. During a period of recurring salmon louse infestations in a region of open net‐pen salmon farms, coho salmon productivity (recruits per spawner at low spawner abundance) was depressed approximately sevenfold relative to unexposed populations. Alternate hypotheses for the observed difference in productivity, such as declines in coho prey, perturbations to freshwater habitat or stochasticity, are unlikely to explain this pattern.

4. Lice parasitizing juvenile coho salmon were likely to be trophically transmitted during predation on parasitized juvenile pink salmon as well as directly transmitted from salmon farms.

5. Synthesis and applications. The finding that species interactions may cause the effects of pathogen transmission from farmed to wild fish to propagate up a marine food web has important conservation implications: (i) the management of salmon aquaculture should consider and account for species interactions and the potential for these interactions to intensify pathogen transmission from farmed to wild fish, (ii) the ecosystem impact of louse transmission from farmed to wild salmon has likely to have been previously underestimated and (iii) comprehensive monitoring of wild salmon and their population dynamics in areas of intensive salmon aquaculture should be a priority to determine if open net‐pen salmon aquaculture is ecologically sustainable.
Why students leave in the UK: an integrative review of the international research literature
Authors: Cameron Joan , Roxburgh Michelle , Taylor Julie , Lauder William
Published: September 2010

Aims and objectives.  The purpose of this integrative review of the literature was to find and review international research studies that explored student attrition to determine what is known about the topic and to identify gaps in the research with a view to addressing the situation in the UK.

Background.  Attrition from nursing programmes is a serious problem in the UK. It is recognised as a complex phenomenon, not attributable to a single cause. Regardless of actual attrition rates and trends, departments of nursing are challenged to perform in a business‐like manner. Consequently, every student lost to a programme of study equates to a financial penalty for the department and to the future workforce and community.

Design.  Integrative review of the literature.

Method.  Using electronic databases and specific search terms, 18 articles were identified and reviewed. Findings from the identified international research literature were analysed using qualitative content analysis.

Results.  Four broad themes that accounted for factors of relevance to attrition were identified: Social, Prediction, Programme and Personal.

Conclusions.  Retention studies are fraught with methodological problems. These include incomplete or inaccurate data and low response rates. Attrition early in programmes may be attributed to a failure to understand the roles of nurses in contemporary societies. This has led to dissatisfaction with programmes and academic failure, as students may underestimate the intellectual demands of their programmes. Attrition later in the programme may be attributed to a combination of personal factors that culminate in a personal crisis.

Relevance to clinical practice.  The research literature suggests that stereotyping of nurses is a major factor in attrition. Both professions need to find ways of communicating contemporary roles to wider society.
An evaluation of a community dietetics intervention on the management of malnutrition for healthcare professionals
Authors: Kennelly S. , Kennedy N. P. , Rughoobur G. F. , Slattery C. G. , Sugrue S.
Published: September 2010

Background:  Healthcare professionals working in the community setting have limited knowledge of the evidence‐based management of malnutrition. The present study aimed to evaluate a community dietetics intervention, which included an education programme for healthcare professionals in conjunction with the introduction of a community dietetics service for patients ‘at risk’ of malnutrition. Changes in nutritional knowledge and the reported management of malnourished patients were investigated and the acceptability of the intervention was explored.

Methods:  An education programme, incorporating ‘Malnutrition Universal Screening Tool (MUST)’ training, was implemented in eight of 10 eligible primary care practices (14 general practitioners and nine practice nurses attended), in seven private nursing homes (20 staff nurses attended) and two health centres (53 community nurses attended) in conjunction with a community dietetics service for patients at risk of malnutrition. Nutritional knowledge was assessed before, immediately after, and 6 months after the intervention using self‐administered, multiple‐choice questionnaires. Reported changes in practice and the acceptability of the education programme were considered using self‐administered questionnaires 6 months after the intervention.

Results:  A significant increase in nutritional knowledge 6 months after the intervention was observed (P < 0.001). The management of malnutrition was reported to be improved, with 69% (38/55) of healthcare professionals reporting to weigh patients ‘more frequently’, whereas 80% (43/54) reported giving dietary advice to prevent or treat malnutrition. Eighty‐percent (44/55) of healthcare professionals stated that ‘MUST’ was an acceptable nutrition screening tool.

Conclusion:  An education programme supported by a community dietetics service for patients ‘at risk’ of malnutrition increased the nutritional knowledge and improved the reported management of malnourished patients in the community by healthcare professionals.
Regulation of the 18 kDa heat shock protein in Mycobacterium ulcerans: an alpha‐crystallin orthologue that promotes biofilm formation
Authors: Pidot Sacha J. , Porter Jessica L. , Tobias Nicholas J. , Anderson Jeffrey , Catmull Deanne , Seemann Torsten , Kidd Stephen , Davies John K. , Reynolds Eric , Dashper Stuart , Stinear Timothy P.
Published: September 2010

Mycobacterium ulcerans is the causative agent of the debilitating skin disease Buruli ulcer, which is most prevalent in Western and Central Africa. M. ulcerans shares > 98% DNA sequence identity with Mycobacterium marinum, however, M. marinum produces granulomatous, but not ulcerative, lesions in humans and animals. Here we report the differential expression of a small heat shock protein (Hsp18) between strains of M. ulcerans (Hsp18+) and M. marinum (Hsp18‐) and describe the molecular basis for this difference. We show by gene deletion and GFP reporter assays in M. marinum that a divergently transcribed gene called hspR_2, immediately upstream of hsp18, encodes a MerR‐like regulatory protein that represses hsp18 transcription while promoting its own expression. Naturally occurring mutations within a 70 bp segment of the 144 bp hspR_2‐hsp18 intergenic region among M. ulcerans strains inhibit hspR_2 transcription and explain the Hsp18+ phenotype. We also propose a biological role for Hsp18, as we show that this protein significantly enhances bacterial attachment or aggregation during biofilm formation. This study has uncovered a new member of the MerR family of transcriptional regulators and suggests that upregulation of hsp18 expression was an important pathoadaptive response in the evolution of M. ulcerans from a M. marinum‐like ancestor.
Nitric oxide‐sensitive and ‐insensitive interaction of Bacillus subtilis NsrR with a ResDE‐controlled promoter
Authors: Kommineni Sushma , Yukl Erik , Hayashi Takahiro , Delepine Jacob , Geng Hao , Moënne‐Loccoz Pierre , Nakano Michiko M.
Published: September 2010

NsrR is a nitric oxide (NO)‐sensitive transcription repressor that controls NO metabolism in a wide range of bacteria. In Bacillus subtilis, NsrR represses transcription of the nitrite reductase (nasDEF) genes that are under positive control of the ResD–ResE two‐component signal transduction system. Derepression is achieved by reaction of NO with NsrR. Unlike some NsrR orthologues that were shown to contain a NO‐sensitive [2Fe–2S] cluster, B. subtilis NsrR, when purified anaerobically either from aerobic or from anaerobic Escherichia coli and B. subtilis cultures, contains a [4Fe–4S] cluster. [4Fe–4S]‐NsrR binds around the −35 element of the nasD promoter with much higher affinity than apo‐NsrR and binding of [4Fe–4S]‐NsrR, but not apo‐protein, is sensitive to NO. RNA polymerase and phosphorylated ResD make a ternary complex at the nasD promoter and NsrR dissociates the preformed ternary complex. In addition to the −35 region, NsrR binds to two distinct sites of the upstream regulatory region where ResD also binds. These interactions, unlike the high‐affinity site binding, do not depend on the NsrR [4Fe–4S] cluster and binding is not sensitive to NO, suggesting a role for apo‐NsrR in transcriptional regulation.
The actinobacterial signature protein ParJ (SCO1662) regulates ParA polymerization and affects chromosome segregation and cell division during Streptomyces sporulation
Authors: Ditkowski Bartosz , Troć Paulina , Ginda Katarzyna , Donczew Magdalena , Chater Keith F. , Zakrzewska‐Czerwińska Jolanta , Jakimowicz Dagmara
Published: September 2010

Bacterial chromosome segregation usually involves cytoskeletal ParA proteins, ATPases which can form dynamic filaments. In aerial hyphae of the mycelial bacterium Streptomyces coelicolor, ParA filaments extend over tens of microns and are responsible for segregation of dozens of chromosomes. We have identified a novel interaction partner of S. coelicolor ParA, ParJ. ParJ negatively regulates ParA polymerization in vitro and is important for efficient chromosome segregation in sporulating aerial hyphae. ParJ–EGFP formed foci along aerial hyphae even in the absence of ParA. ParJ, which is encoded by sco1662, turned out to be one of the five actinobacterial signature proteins, and another of the five is a ParJ paralogue. We hypothesize that polar growth, which is characteristic not only of streptomycetes, but even of simple Actinobacteria, may be interlinked with ParA polymer assembly and its specific regulation by ParJ.
The SAM‐responsive SMK box is a reversible riboswitch
Authors: Smith Angela M. , Fuchs Ryan T. , Grundy Frank J. , Henkin Tina M.
Published: September 2010

The SMK (SAM‐III) box is an S‐adenosylmethionine (SAM)‐responsive riboswitch found in the 5′ untranslated region of metK genes, encoding SAM synthetase, in many members of the Lactobacillales. SAM binding causes a structural rearrangement in the RNA that sequesters the Shine‐Dalgarno (SD) sequence by pairing with a complementary anti‐SD (ASD) sequence; sequestration of the SD sequence inhibits binding of the 30S ribosomal subunit and prevents translation initiation. We observed a slight increase in the half‐life of the metK transcript in vivo when Enterococcus faecalis cells were depleted for SAM, but no significant change in overall transcript abundance, consistent with the model that this riboswitch regulates at the level of translation initiation. The half‐life of the SAM–SMK box RNA complex in vitro is shorter than that of the metK transcript in vivo, raising the possibility of reversible binding of SAM. We used a fluorescence assay to directly visualize reversible switching between the SAM‐free and SAM‐bound conformations. We propose that the SMK box riboswitch can make multiple SAM‐dependent regulatory decisions during the lifetime of the transcript in vivo, acting as a reversible switch that allows the cell to respond rapidly to fluctuations in SAM pools by modulating expression of the SAM synthetase gene.
The interaction dynamics of a negative feedback loop regulates flagellar number in Salmonella enterica serovar Typhimurium
Authors: Aldridge Christine , Poonchareon Kritchai , Saini Supreet , Ewen Thomas , Soloyva Alexandra , Rao Christopher V. , Imada Katsumi , Minamino Tohru , Aldridge Phillip D.
Published: September 2010

Each Salmonella enterica serovar Typhimurium cell produces a discrete number of complete flagella. Flagellar assembly responds to changes in growth rates through FlhD4C2 activity. FlhD4C2 activity is negatively regulated by the type 3 secretion chaperone FliT. FliT is known to interact with the flagellar filament cap protein FliD as well as components of the flagellar type 3 secretion apparatus. FliD is proposed to act as an anti‐regulator, in a manner similar to FlgM inhibition of σ28 activity. We have found that efficient growth‐dependent regulation of FlhD4C2 requires FliT regulation. In turn, FliD regulation of FliT modulates the response. We also show that, unlike other flagellar‐specific regulatory circuits, deletion of fliT or fliD did not lead to an all‐or‐nothing response in FlhD4C2 activity. To investigate why, we characterized the biochemical interactions in the FliT : FliD :  FlhD4C2 circuit. When FlhD4C2 was not bound to DNA, FliT disrupted the FlhD4C2 complex. Interestingly, when FlhD4C2 was bound to DNA it was insensitive to FliT regulation. This suggests that the FliT circuit regulates FlhD4C2 activity by preventing the formation of the FlhD4C2:DNA complex. Our data would suggest that this level of endogenous regulation of FlhD4C2 activity allows the flagellar system to efficiently respond to external signals.
Identification of a novel bacteriocin regulatory system in Streptococcus mutans
Authors: Xie Zhoujie , Okinaga Toshinori , Niu Guoqing , Qi Fengxia , Merritt Justin
Published: September 2010

Recently, we described the function of an uncharacterized two‐gene regulatory system consisting of a LytTR family transcription regulator and a putative membrane protein, which we referred to as the hdrRM operon. In this study, we determined that the HdrRM system controls the expression of an analogous uncharacterized regulatory system annotated as SMU.2080 and SMU.2081. Like hdrRM, the SMU.2080–2081 operon encodes a LytTR family transcription regulator and putative membrane protein, which we now refer to as BrsR and BrsM respectively. Examination of the regulatory mechanism of the BrsRM system suggests that BrsM serves to antagonize the function of the transcription regulator BrsR. Further analyses of the regulatory role of BrsR determined that it functions as a transcription activator for a variety of bacteriocins and bacteriocin‐related genes. In vitro electromobility shift assays confirmed that BrsR binds to the promoter regions of several bacteriocin genes and requires the presence of a LytTR family consensus direct repeat in order to stably bind DNA. In addition, we identified a novel regulatory scheme in which both the HdrRM and BrsRM systems coregulate each other and ultimately determine whether bacteriocin production will inhibit competitor organisms or result in lethality to the producer.
Generation of Se‐fortified broccoli as functional food: impact of Se fertilization on S metabolism
Authors: HSU FU‐CHEN , WIRTZ MARKUS , HEPPEL SIMON C. , BOGS JOCHEN , KRÄMER UTE , KHAN MUHAMMAD SAYYAR , BUB ACHIM , HELL RÜDIGER , RAUSCH THOMAS
Published: September 2010

Selenium (Se)‐fortified broccoli (Brassica oleracea var. italica) has been proposed as a functional food for cancer prevention, based on its high glucosinolate (GSL) content and capacity for Se accumulation. However, as selenate and sulphate share the initial assimilation route, Se fertilization could interfere with sulphur metabolism and plant growth. Consequently, GSL accumulation could be compromised. To evaluate these potentially adverse effects of Se fertilization, we performed a comprehensive study on sand‐grown young broccoli plants (weekly selenate applications of 0.8 µmol plant−1 via the root) and field‐grown adult broccoli plants during head formation (single foliar selenate application: 25.3 or 253 µmol plant−1). The results show that under these conditions, Se application does not affect plant growth, contents of cysteine, glutathione, total GSL, glucoraphanin (major aliphatic GSL) or the expression of BoMYB28 (encoding a functionally confirmed master regulator for aliphatic GSL biosynthesis). Conversely, due to the changed expression of sulphate transporters (BoSULTR1;1, 1;2, 2;1, and 2;2), sulphate and total S contents increased in the shoot of young plants while decreasing in the root. We conclude that broccoli can be fertilized with Se without reduction in GSL content, even with Se accumulation exceeding the level recommended for human consumption.