bluuebunny/crossref_metadata_2025 huggingface dataset:
What is heart failure?
Authors: Clark Andrew L.
Published: April 2012

It is a commonplace in writings about heart failure (HF) that it has become an ‘epidemic’ in Western societies in particular. In truth, the incidence of HF is not rising, but the prevalence is. HF is thus not a true epidemic, which properly is a rise in the age-specific incidence. The major causes for its increasing prevalence are threefold: although the incidence of acute myocardial infarction may be falling, more patients survive acute coronary disease and go on to develop chronic HF; treatment of chronic HF has dramatically improved, and so many more patients survive for much longer; and the population generally is ageing — and HF is a disease of older people. Although HF is a modern blight, it has been known for thousands of years. There is some suggestion from the Ebers papyrus (dated around 1500 BCE) that the ancient Egyptians recognized it (‘When there is inundation of the heart, the saliva is in excess, and therefore the body is weak’), and Hippocrates (460–370 BCE) gave a muchquoted description of cardiac cachexia: ‘The flesh is consumed and becomes water … the abdomen fills with water; the feet and legs swell; the shoulders, clavicles, chest, and thigh melt away.’ It was not until after Harvey described the circulation of the blood that the HF syndrome truly began to be related to the heart, with Richard Lower perhaps giving the first textbook discussion of HF in 1669. Treatment for HF with venesection, perhaps one of the few instances in which the procedure might be helpful, was formally described in 1696. William Withering described the formaluse of Digitalis extracts, giving birth to clinical pharmacology, although cardiac glycosides had undoubtedly been used for hundreds,and perhaps thousands, of years previously.The modern era of HF treatment truly began with the discovery of mercurial, and then thiazide and subsequently loop, diuretics in thelate 1950s and early 1960s. Perhaps the most important single trialin HF therapy demonstrating the beneficial effects of angiotensinconverting enzyme (ACE) inhibitors was published in 1987.
Diagnosing heart failure
Authors: Dargie Henry J. , McDonagh Theresa A.
Published: April 2012

It is often said that heart failure (HF) is not a diagnosis per se but aclinical syndrome consisting of a constellation of symptoms andsigns, which are ultimately due to cardiac dysfunction. Neverthelessit is important to diagnose the presence of HF accurately in orderto facilitate the general and specific treatments that can modify itstraditionally poor outlook.The diagnosis of HF involves three distinct yet related phases. First there is the confirmation that the patient has HF, secondlythe nature of the underlying cardiac dysfunction needs to be determined,and thirdly the actual aetiology of the cardiac dysfunction should be identified. Following confirmation of the diagnosis of HF some basic diagnostictests must also be performed to determine the starting statusof key parameters prior to initiation of therapy and to establish thepresence of comorbidities.
Prognostication
Authors: Gardner Roy S.
Published: April 2012

Recent advances in medical therapy, notably angiotensin converting enzyme (ACE) inhibitors, β‎ -adrenoreceptor antagonists, and aldosterone antagonists, as well as device therapy have improved that prognosis such that even in patients with chronic heart failure (CHF) who are in New York Heart Association (NYHA) class IV, the annual mortality can be as low as 9.7%. Nevertheless, many patients do not respond to medical therapy and remain symptomatically very limited with a poor prognosis. It is for such patients that cardiac transplantation and ventricular assist devices are options. However, identifying such patients is one of the great challenges of HF management.

The 1-year mortality following cardiac transplantation is approximately 19%. The selection of candidates for cardiac transplantation is therefore heavily involved with identifying those patients whose annual mortality from HF exceeds this rate and who might therefore benefit prognostically from a transplant. There are over 300 prognostic markers described in patients with HF, the most significant of which are shown in Table 25.1. Many studies have been carried out looking at clinical, haemodynamic, and neurohormonal variables to assist with risk stratification, although it is important to look at such data in the context of the latest disease-modifying therapy. The traditional markers, including left ventricular ejection fraction (LVEF) and the peak oxygen uptake (pVo2), consistently offer useful prognostic information, although scoring systems involving a combination of markers have also been developed. More recently, neurohormones have been shown to demonstrate the greatest prognostic potential in identifying patients at the greatest risk of an adverse outcome.
Right heart failure
Authors: Clark Andrew L.
Published: April 2012

Most discussions of heart failure (HF) focus on the left ventricleand its dysfunction. The right heart is, of course, commonlyaffected in HF, both by the same disease processes as affect the leftheart, and as a consequence of left heart disease. The right heartitself is much less commonly affected in isolation, but patients withheart disease do commonly present with ‘right HF’.
Aldosterone antagonists
Authors: Rekhraj Sushma , Szwejkowski Benjamin R. , Struthers Allan
Published: April 2012

Heart failure (HF) is a condition which is associated with a highmorbidity and mortality rate despite advancements in treatmentoptions such as angiotensin converting enzyme (ACE) inhibitorsand β‎ -blockers. Half of all HF patients are dead within 4 years.Numerous neurohormonal mechanisms are involved in the pathophysiologyof HF including the renin–angiotensin–aldosteronesystem (RAAS), the sympathetic nervous system, and argininevasopressin (AVP). With regards to the RAAS, plasma aldosteronelevels are 20-fold higher in HF than in normal individuals. Innormal individuals with normal sodium intake, plasma aldosteronelevels are 5–15 ng/dL (139–416 pmol/L) compared to plasma levels up to 300 ng/dL (8322 pmol/L) in HF patients. Aldosterone has been confirmed to play a pivotal role in the HF syndromeas highlighted by two landmark studies, RALES and EPHESUS. Inthe past, the importance of aldosterone was underappreciated asit was falsely assumed that ACE inhibitors will block aldosteronesynthesis. However, further studies have found this not to be true.
Digoxin
Authors: Coats Andrew J.S.
Published: April 2012

Digoxin is the oldest drug in use in cardiovascular medicine. William Withering, a physician working in Birmingham in the second half of the 18th century, first described in the scientific literature the use of extracts of the foxglove plant (Digitalis purpurea), which he said had been used as a cure for dropsy, now recognized as including a description of a disease of peripheral oedema probably caused by heart failure (HF) in many cases. Foxglove extract includes digitalis alkaloids and thus digoxin, a pure alkaloid, which has a consecutive use going back nearly a quarter of a millennium. That it is still in regular use and that it remains one of the most debated and argued about of all cardiovascular drugs says a lot about the changes in our processes for evaluating and accepting therapeutic advances in cardiovascular medicine over the last half century.
Cardiac rehabilitation and chronic heart failure
Authors: Piepoli Massimo F. , Clark Andrew L.
Published: April 2012

All patients with established chronic heart failure (CHF), with orwithout an implantable cardioverter defibrillator (ICD) and with orwithout cardiac resynchronization therapy (CRT), require a multifactorialcardiac rehabilitation (CR) approach. The role of the multidisciplinaryapproach is considered elsewhere.The traditional model of care delivery is thought to contribute tofrequent hospitalizations. During these brief episodic encounters,little attention is paid to the numerous barriers to effective CHFtreatment and the possible treatment of the common modifiablefactors that are the cause of disease progression and thus hospitalreadmissions. To face these limitations, a CHF disease multidimensionalmanagement programme is necessary to curb the risingcost of management and to improve morbidity and mortality for individual patients. CR is the ideal comprehensive structured disease interventionsince it best addresses the complex interplay of medical, psychological,and behavioural factors facing CHF patients. It is a coordinatedmultidimensional intervention designed to stabilize orslow disease progression, alleviate symptoms, improve exercisetolerance, and enhance quality of life, thereby reducing morbidity and mortality. In CHF populations, such a programme has beenproven to improve functional capacity, recovery and emotionalwell-being and to reduce hospital admissions in CHF patients.Exercise training as a key component in a CR programme mayimprove survival and reduce hospitalization in stable heart failure(HF) patients. It is recommended for all stable CHF patients. Thereis no evidence that it should be limited to any particular HF patientsubgroup based on aetiology, NYHA class, left ventricular function,or medication (class of recommendation I, level of evidence A).Despite the virtues of CR, only a small percentage of eligible HFpatients ever get referred, due to barriers such as lack of physicianand patient-family awareness of its benefits, and logistical or financialconstraints. Patients with CHF are a patient population thatchallenges CR with the need to employ active strategies to disseminateand implement appropriate standards of care.
Revascularization and remodelling surgery
Authors: Pepper John R.
Published: April 2012

There is a wide spectrum of clinical presentations of coronary heartdisease ranging from mild asymptomatic single-vessel disease,through multivessel disease with mild or moderate left ventriculardysfunction, to severe endstage ischaemic cardiomyopathy. As theseverity of left ventricular disease increases, so does the potential benefit of surgical intervention to the patient’s outcome. Unfortunately the clarity of the specific indications for coronary arterybypass grafting decreases. For example, in a patient with multivesselcoronary artery disease and moderate left ventricular dysfunction,the indications for coronary artery bypass grafting (CABG) are clear and well-defined by multiple large-scale prospective and retrospectivestudies. In contrast, for a patient with severe ischaemiccardiomyopathy and potentially graftable coronary arteries who isbeing evaluated for a variety of treatment options including medicaltreatment, resynchronization therapy, percutaneous coronaryintervention, coronary bypass grafting, valvular reconstruction,ventricular remodelling, mechanical assistance, and transplantation,the exact role of CABG is not so clear.Nevertheless, there is persuasive experimental and clinical evidencethat revascularization and perfusion of ischaemic or injuredmyocardium enhances cardiomyocyte integrity and contractility,thereby augmenting ventricular function. Thus the drive to revascularizeis strong. In this high-risk population, the challenge is toidentify those patients who will derive the most long-term benefitwhile incurring the least perioperative risk.
Eps15R is required for bone morphogenetic protein signalling and differentially compartmentalizes with Smad proteins
Authors: Callery Elizabeth M. , Park Chong Yon , Xu Xin , Zhu Haitao , Smith James C. , Thomsen Gerald H.
Published: April 2012

Transforming growth factor β superfamily members signal through Smad transcription factors. Bone morphogenetic proteins (BMPs) act via Smads 1, 5 and 8 and TGF-βs signal through Smads 2 and 3. The endocytic adaptor protein Eps15R, or ‘epidermal growth factor (EGF) receptor pathway substrate 15-related protein’ is a component of EGF signal transduction, mediating internalization of the EGF receptor. We show that it interacts with Smad proteins, is required for BMP signalling in animal caps and stimulates Smad1 transcriptional activity. This function resides in the Asp-Pro-Phe motif-enriched ‘DPF domain’ of Eps15R, which activates transcription and antagonizes Smad2 signalling. In living cells, Eps15R segregates into spatially distinct regions with different Smads, indicating an unrecognized level of Smad compartmentalization.
The Study of Release of Chlorhexidine from Preparations with Modified Thermosensitive Poly-N-isopropylacrylamide Microspheres
Authors: Musial Witold , Voncina Bojana , Pluta Janusz , Kokol Vanja
Published: April 2012

The aim of this study was to investigate and compare the release rates of chlorhexidine (CX) base entrapped in the polymeric beads of modified poly-N-isopropylacrylamides (pNIPAMs) at temperatures below and over the volume phase transition temperature (VPTT) of synthesized polymers: pNIPAM-A with terminal anionic groups resulting from potassium persulfate initiator, pNIPAM-B with cationic amidine terminal groups, and pNIPAM-C comprising anionic terminals, but with increased hydrophobicity maintained by the N-tert-butyl functional groups. The preparations, assessed in vitro below the VPTT, release an initial burst of CX at different time periods between 120 and 240 min, followed by a period of 24 h, when the rate of release remains approximately constant, approaching the zero-order kinetics; the release rates for the polymers beads are as follows: pNIPAM-C>pNIPAM-B>pNIPAM-A. The pattern of release rates at temperature over the VPTT is as follows: pNIPAM-C>pNIPAM-A>pNIPAM-B. In the presence of pNIPAM-C, the duration between the start of the release and the attained minimal inhibitory concentration (MIC) for most of the microbes, in conditions over the VPTT, increased from 60 to 90 min. The release prolongation could be ascribed to some interactions between the practically insoluble CX particle and the hydrophobic functional groups of the polymer.
Understanding Autism in Schizophrenia
Authors: Ballerini Arnaldo
Published: April 2012

Detachment from external reality, distancing from others, closure into a sort of virtual hermitage, and prevalence of inner fantasies, are the descriptive aspects of autism. However, from an anthropological-phenomenological point of view, in schizophrenia, the autistic mode of life can arise from a person’s being confronted with a pathological crisis in the obviousness of the intersubjective world, essentially a crisis in the intersubjective foundation of human presence. The “condition of possibility” of the autistic way of being is the deficiency of the operation that phenomenology call empathetic-intuitive constitution of the Other, an Other which is the naturalness of evidence of being a subject like me. The theme of the Other, of intersubjectivity, has become so central in the psychopathological analysis of schizophrenic disorders because the modifications of interhuman encounter cannot be seen as the secondary consequences of symptoms but constitute the fundamental disorder of schizophrenic alienation. Revision of the concept of autism from the original definition, centered on the prevalence of inner fantasies, leads to the profound change with the vision of autism as “loss” and “void.” I call attention to possibility of phenomenological research to understand autistic world starting from this “void.”
Comparison of BTX Profiles and Their Mutagenicity Assessment at Two Sites of Agra, India
Authors: Singla Vyoma , Pachauri Tripti , Satsangi Aparna , Kumari K. Maharaj , Lakhani Anita
Published: April 2012

In the present study, the concentrations of three volatile organic compounds (VOCs), namely, acronym for benzene, toluene, and xylenes (BTX) were assessed because of their role in the tropospheric chemistry. Two representative sites, a roadside and a petrol pump, were chosen for sample collection. VOCs were collected using SKC-activated charcoal tubes and SKC personal sampler and characterized by gas chromatograph using flame ionization detector. Among BTX, benzene had the highest concentration. At the roadside, mean concentration of benzene, toluene, o-,m-xylene, and p-xylene were 14.7 ± 2.4 μgm−3, 8.1 ± 1.2 μgm−3, 2.1 ± 0.8 μgm−3, and 5.1 ± 1.2 μgm−3, respectively. At the petrol pump, the mean concentrations of benzene, toluene, o-,m-xylene and p-xylene were 19.5 ± 3.7 μgm−3, 12.9 ± 1.1 μgm−3, 3.6 ± 0.5 μgm−3and 11.1 ± 1.5 μgm−3, respectively, and were numerically higher by a fraction of 2. Monthly variation of BTX showed maximum concentration in winter. Inter-species ratios and inter-species correlation indicated traffic as the major source of BTX. Extracts of samples were positive in both Salmonella typhimurium tester strains TA98 and TA100 without metabolic activation suggesting the presence of direct mutagens in ambient air that can cause both frame-shift and base-pair mutation. The mutagenic response was greater for TA100 than TA98 suggesting greater activity for base-pair mutagenicity than frame-shift mutagenicity and was found to be statistically significant.
Psychomotor Functions and Interval Timing in Patients Receiving Intravenous Anesthesia for Endoscopic Procedures: The Pilot Study
Authors: Płotek Włodzimierz , Cybulski Marcin , Kluzik Anna , Grześkowiak Małgorzata , Jelonek Jacek , Switała Wojciech , Janicki Jakub , Drobnik Leon
Published: April 2012

Introduction. The aim of this study was to evaluate two measures in a cognitive examination: psychomotor function and the perception of time (PT) in patients after intravenous anesthesia for endoscopic procedures.Material and Methods. We tested 23 anesthetized patients (Anesthesia Group, AG) and 17 not anesthetized patients (Control Group, CG). The Dufour Cross-Shaped Apparatus (DA) was used to assess quick reactions. Perception of time (PT) was measured for 1-, 2-, 5-, and 7-second intervals. The tests were performed before the anesthesia was administered and 1.5, 3, and 6 hours after the procedure was completed.Results. The intervals that were generated and the reproduced visual stimuli were shorter than the patterns. The reproduced 1- and 2-second auditory stimuli were longer than the patterns. The remaining reproduced auditory impulses were shorter than the patterns.Conclusions. In anesthetized patients, quick psychomotor reactions and the ability to time intervals are preserved 1.5 h and later after intravenous anesthesia for endoscopy.
Gender and Age-Dependent Etiology of Community-Acquired Urinary Tract Infections
Authors: Magliano Enrico , Grazioli Vittorio , Deflorio Loredana , Leuci Antonia Isabella , Mattina Roberto , Romano Paolo , Cocuzza Clementina Elvezia
Published: April 2012

Urinary tract infections (UTIs) are among the most frequent community-acquired infections worldwide.Escherichia coliis the most common UTI pathogen although underlying host factors such as patients’ age and gender may influence prevalence of causative agents. In this study, 61 273 consecutive urine samples received over a 22-month period from outpatients clinics of an urban area of north Italy underwent microbiological culture with subsequent bacterial identification and antimicrobial susceptibility testing of positive samples. A total of 13 820 uropathogens were isolated and their prevalence analyzed according to patient’s gender and age group. OverallEscherichia coliaccounted for 67.6% of all isolates, followed byKlebsiella pneumoniae(8.8%),Enterococcus faecalis(6.3%),Proteus mirabilis(5.2%), andPseudomonas aeruginosa(2.5%). Data stratification according to both age and gender showedE. coliisolation rates to be lower in both males aged ≥60 years (52.2%),E. faecalisandP. aeruginosabeing more prevalent in this group (11.6% and 7.8%, resp.), as well as in those aged ≤14 years (51.3%) in whomP. mirabilisprevalence was found to be as high as 21.2%.Streptococcus agalactiaeoverall prevalence was found to be 2.3% although it was shown to occur most frequently in women aged between 15 and 59 years (4.1%). Susceptibility ofE. colito oral antimicrobial agents was demonstrated to be as follows: fosfomycin (72.9%), trimethoprim/sulfamethoxazole (72.9%), ciprofloxacin (76.8%), ampicillin (48.0%), and amoxicillin/clavulanate (77.5%). In conclusion, both patients’ age and gender are significant factors in determining UTIs etiology; they can increase accuracy in defining the causative uropathogen as well as providing useful guidance to empiric treatment.
Heavy Metal Accumulation and the Genotoxicity in Barbel (Barbus barbus) as Indicators of the Danube River Pollution
Authors: Sunjog Karolina , Gačić Zoran , Kolarević Stoimir , Višnjić-Jeftić Željka , Jarić Ivan , Knežević-Vukčević Jelena , Vuković-Gačić Branka , Lenhardt Mirjana
Published: April 2012

The aim of this study was to analyze 16 trace elements (Al, As, B, Ba, Cd, Co, Cr, Cu, Fe, Li, Mn, Mo, Ni, Pb, Sr, and Zn) in different barbel (Barbus barbus) tissues and to detect the presence of genotoxic effects in erythrocytes with the alkaline comet assay. Barbel specimens were collected in the Danube river near Belgrade, Serbia, where the discharge of untreated communal and industrial wastewaters is likely to produce negative effects on fish residing in this area. The highest concentrations of Sr, Mn, Fe, Ba, B, and Al were found in gills, Mo and Cu in liver, and As and Zn in gonads. Concentrations of Zn and Fe were above maximum acceptable concentrations (MACs) in a number of gonad, gill, and liver samples. Three-year-old barbel specimens had higher tail moment and Zn concentrations in gills (1.71 and 51.20 μg/g dw, resp.) than 5-year-old specimens (0.85 and 42.51 μg/g dw, resp.). Results indicate that the younger barbel specimens might be more suitable for the monitoring of environmental pollution.
Bach Adsorption Study for the Extraction of Silver Ions by Hydrazone Compounds from Aqueous Solution
Authors: Mohamad Ali Abdussalam Salhin , Abdul Razak Norfarhah , Ab Rahman Ismail
Published: April 2012

Sorbent materials based on a hydrazone Schiff base compound, C14H11BrN4O4, were prepared either by immobilizing the ligand into sol-gel (SG1) or bonding to silica (SG2). The sorbent materials were characterized by FT-IR, EDX, SEM, TEM, and TGA. The sorption characteristics of a matrix of eight transition metal ions (Ag+, Cu2+, Co2+, Ni2+, Fe3+, Pb2+, Zn2+, and Mn2+) using batch method were studied. Several key parameters that affected the extraction efficiency such as pH, contact time, metal ions concentration, and gel size (for SGl) were investigated and optimized. Under the optimized conditions, the physically immobilized hydrazone sorbent (SG1) exhibits highest selectivity towards Ag+ions, while the chemically bonded hydrazone sorbent (SG2) exhibits high extraction for all metal ions tested. However, for practical applications such as the removal and preconcentration of Ag+, the physically immobilized sorbent (SG1) is preferred.
The Involvement of Angiotensin Type 1 and Type 2 Receptors in Estrogen-Induced Cell Proliferation and Vascular Endothelial Growth Factor Expression in the Rat Anterior Pituitary
Authors: Lawnicka Hanna , Ptasinska-Wnuk Dorota , Mucha Slawomir , Kunert-Radek Jolanta , Pawlikowski Marek , Stepien Henryk
Published: April 2012

The aim of our study was to examine the involvement of renin-angiotensin system (RAS) in estrogen-induced lactotropes proliferation and vascular endothelial growth factor (VEGF) expression in rat pituitary. The study was performed on Fisher 344 rats underwent 8-day treatment with diethylstilboestrol (DES). The proliferation index (PCNA) and VEGF expression in pituitary sections were estimated using immunohistochemical methods. Treatment with DES increased the number of PCNA-positive cells, VEGF-positive cells, and VEGF-positive blood vessels in pituitary. Stimulatory effect of estrogen on cell proliferation and VEGF expression in blood vessels was attenuated by losartan, PD123319, and captopril. VEGF immunoreactivity in pituitary cells of DES-treated rats was decreased by AT1 antagonist and not changed by AT2 blocker and ACE inhibitor. Our findings suggest the involvement of RAS in DES-induced cell proliferation and VEGF expression in pituitary. Both the AT1 and AT2 receptors appear to mediate the estrogen-dependent mitogenic and proangiogenic effects in rat pituitary.
Setup and Validation of Flow Cell Systems for Biofouling Simulation in Industrial Settings
Authors: Teodósio Joana S. , Simões Manuel , Alves Manuel A. , Melo Luís F. , Mergulhão Filipe J.
Published: April 2012

A biofouling simulation system consisting of a flow cell and a recirculation tank was used. The fluid circulates at a flow rate of 350 L⋅ h−1in a semicircular flow cell with hydraulic diameter of 18.3 mm, corresponding to an average velocity of 0.275 m⋅ s−1. Using computational fluid dynamics for flow simulation, an average wall shear stress of 0.4 Pa was predicted. The validity of the numerical simulations was visually confirmed by inorganic deposit formation (using kaolin particles) and also by direct observation of pathlines of tracer PVC particles using streak photography. Furthermore, the validity of chemostat assumptions was verified by residence time analysis. The system was used to assess the influence of the dilution rate on biofilm formation byEscherichia coliJM109(DE3). Two dilution rates of 0.013 and 0.0043 h−1were tested and the results show that the planktonic cell concentration is increased at the lower dilution rate and that no significant changes were detected on the amount of biofilm formed in both conditions.
Emotional Competence as a Positive Youth Development Construct: A Conceptual Review
Authors: Lau Patrick S. Y. , Wu Florence K. Y.
Published: April 2012

The concept of emotional competence as a positive youth development construct is reviewed in this paper. Differences between emotional intelligence and emotional competence are discussed and an operational definition is adopted. Assessment methods of emotional competence with an emphasis on its quantitative nature are introduced. In the discussion of theories of emotional competence, the functionalist and developmental perspectives and the relationships with positive youth development are highlighted. Possible antecedents, especially the influence of early child-caregiver, and expected outcomes of emotional competence are examined. Practical ways to promote emotional competence among adolescents, particularly the role of parents and teachers, and the future direction of research are also discussed.
Characterization of Three O-Methyltransferases Involved in Noscapine Biosynthesis in Opium Poppy
Authors: Dang Thu-Thuy T. , Facchini Peter J.
Published: April 2012

Noscapine is a benzylisoquinoline alkaloid produced in opium poppy (Papaver somniferum) and other members of the Papaveraceae. It has been used as a cough suppressant and more recently was shown to possess anticancer activity. However, the biosynthesis of noscapine in opium poppy has not been established. A proposed pathway leading from (S)-reticuline to noscapine includes (S)-scoulerine, (S)-canadine, and (S)-N-methylcanadine as intermediates. Stem cDNA libraries and latex extracts of eight opium poppy cultivars displaying different alkaloid profiles were subjected to massively parallel pyrosequencing and liquid chromatography-tandem mass spectrometry, respectively. Comparative transcript and metabolite profiling revealed the occurrence of three cDNAs encoding O-methyltransferases designated as SOMT1, SOMT2, and SOMT3 that correlated with the accumulation of noscapine in the eight cultivars. SOMT transcripts were detected in all opium poppy organs but were most abundant in aerial organs, where noscapine primarily accumulates. SOMT2 and SOMT3 showed strict substrate specificity and regiospecificity as 9-O-methyltransferases targeting (S)-scoulerine. In contrast, SOMT1 was able to sequentially 9- and 2-O-methylate (S)-scoulerine, yielding (S)-tetrahydropalmatine. SOMT1 also sequentially 3′- and 7-O-methylated both (S)-norreticuline and (S)-reticuline with relatively high substrate affinity, yielding (S)-tetrahydropapaverine and (S)-laudanosine, respectively. The metabolic functions of SOMT1, SOMT2, and SOMT3 were investigated in planta using virus-induced gene silencing. Reduction of SOMT1 or SOMT2 transcript levels resulted in a significant decrease in noscapine accumulation. Reduced SOMT1 transcript levels also caused a decrease in papaverine accumulation, confirming the selective roles for these enzymes in the biosynthesis of both alkaloids in opium poppy.
Structural and Functional Analysis of VQ Motif-Containing Proteins in Arabidopsis as Interacting Proteins of WRKY Transcription Factors
Authors: Cheng Yuan , Zhou Yuan , Yang Yan , Chi Ying-Jun , Zhou Jie , Chen Jian-Ye , Wang Fei , Fan Baofang , Shi Kai , Zhou Yan-Hong , Yu Jing-Quan , Chen Zhixiang
Published: April 2012

WRKY transcription factors are encoded by a large gene superfamily with a broad range of roles in plants. Recently, several groups have reported that proteins containing a short VQ (FxxxVQxLTG) motif interact with WRKY proteins. We have recently discovered that two VQ proteins from Arabidopsis (Arabidopsis thaliana), SIGMA FACTOR-INTERACTING PROTEIN1 and SIGMA FACTOR-INTERACTING PROTEIN2, act as coactivators of WRKY33 in plant defense by specifically recognizing the C-terminal WRKY domain and stimulating the DNA-binding activity of WRKY33. In this study, we have analyzed the entire family of 34 structurally divergent VQ proteins from Arabidopsis. Yeast (Saccharomyces cerevisiae) two-hybrid assays showed that Arabidopsis VQ proteins interacted specifically with the C-terminal WRKY domains of group I and the sole WRKY domains of group IIc WRKY proteins. Using site-directed mutagenesis, we identified structural features of these two closely related groups of WRKY domains that are critical for interaction with VQ proteins. Quantitative reverse transcription polymerase chain reaction revealed that expression of a majority of Arabidopsis VQ genes was responsive to pathogen infection and salicylic acid treatment. Functional analysis using both knockout mutants and overexpression lines revealed strong phenotypes in growth, development, and susceptibility to pathogen infection. Altered phenotypes were substantially enhanced through cooverexpression of genes encoding interacting VQ and WRKY proteins. These findings indicate that VQ proteins play an important role in plant growth, development, and response to environmental conditions, most likely by acting as cofactors of group I and IIc WRKY transcription factors.
Isocitrate dehydrogenase 1 is downregulated during early skin tumorigenesis which can be inhibited by overexpression of manganese superoxide dismutase
Authors: Robbins Delira , Wittwer Jennifer A. , Codarin Sarah , Circu Magdalena L. , Aw Tak Yee , Huang Ting‐Ting , Van Remmen Holly , Richardson Arlan , Wang David B. , Witt Stephan N. , Klein Ronald L. , Zhao Yunfeng
Published: April 2012

Isocitrate dehydrogenase 1 (IDH1), a cytosolic enzyme that converts isocitrate to alpha‐ketoglutarate, has been shown to be dysregulated during tumorigenesis. However, at what stage of cancer development IDH1 is dysregulated and how IDH1 may affect cell transformation and tumor promotion during early stages of cancer development are unclear. We used a skin cell transformation model and mouse skin epidermal tissues to study the role of IDH1 in early skin tumorigenesis. Our studies demonstrate that both the tumor promoter TPA and UVC irradiation decreased expression and activity levels of IDH1, not IDH2, in the tumor promotable JB6 P+ cell model. Skin epidermal tissues treated with dimethylbenz[α]anthracene/TPA also showed decreases in IDH1 expression and activity. In non‐promotable JB6 P‐cells, IDH1 was upregulated upon TPA treatment, whereas IDH2 was maintained at similar levels with TPA treatment. Interestingly, IDH1 knockdown enhanced, whereas IDH1 overexpression suppressed, TPA‐induced cell transformation. Finally, manganese superoxide dismutase overexpression suppressed tumor promoter induced decreases in IDH1 expression and mitochondrial respiration, while intracellular alpha‐ketoglutarate levels were unchanged. These results suggest that decreased IDH1 expression in early stage skin tumorigenesis is highly correlated with tumor promotion. In addition, oxidative stress might contribute to IDH1 inactivation, because manganese superoxide dismutase, a mitochondrial antioxidant enzyme, blocked decreases in IDH1 expression and activity. (Cancer Sci, doi: 10.1111/j.1349‐7006.2012.02317.x, 2012)
Halofuginone inhibits multiple myeloma growth in vitro and in vivo and enhances cytotoxicity of conventional and novel agents
Authors: Leiba Merav , Jakubikova Jana , Klippel Steffen , Mitsiades Constantine S. , Hideshima Teru , Tai Yu‐Tzu , Leiba Adi , Pines Mark , Richardson Paul G. , Nagler Arnon , Anderson Kenneth C.
Published: April 2012

Multiple Myeloma (MM), a malignancy of plasma cells, remains incurable despite the use of conventional and novel therapies. Halofuginone (HF), a synthetic derivative of quinazolinone alkaloid, has recently been shown to have anti‐cancer activity in various preclinical settings. This study demonstrated the anti‐tumour activity of HF against a panel of human MM cell lines and primary patient‐derived MM cells, regardless of their sensitivity to conventional therapy or novel agents. HF showed anti‐MM activity in vivo using a myeloma xenograft mouse model. HF suppressed proliferation of myeloma cells alone and when co‐cultured with bone marrow stromal cells. Similarly, HF induced apoptosis in MM cells even in the presence of insulin‐like growth factor 1 or interleukin 6. Importantly, HF, even at high doses, did not induce cytotoxicity against CD40 activated peripheral blood mononuclear cells from normal donors. HF treatment induced accumulation of cells in the G0/G1 cell cycle and induction of apoptotic cell death associated with depletion of mitochondrial membrane potential; cleavage of poly (ADP‐ribose) polymerase and caspases‐3, 8 and 9 as well as down‐regulation of anti‐apoptotic proteins including Mcl‐1 and X‐IAP. Multiplex analysis of phosphorylation of diverse components of signalling cascades revealed that HF induced changes in P38MAPK activation; increased phosphorylation of c‐jun, c‐jun NH(2)‐terminal kinase (JNK), p53 and Hsp‐27. Importantly, HF triggered synergistic cytotoxicity in combination with lenalidomide, melphalan, dexamethasone, and doxorubicin. Taken together, these preclinical studies provide the preclinical framework for future clinical studies of HF in MM.
Marked genetic heterogeneity in familial myelodysplasia/acute myeloid leukaemia
Authors: Holme Harriet , Hossain Upal , Kirwan Michael , Walne Amanda , Vulliamy Tom , Dokal Inderjeet
Published: April 2012

The myelodysplastic syndromes (MDS) are heterogeneous and can evolve into acute myeloid leukaemia (AML). Rare familial cases are reported in which five disease genes have been identified to date (RUNX1, CEBPA, TERC, TERT and GATA2). Here we report the genetic categorization of 27 families with familial MDS/AML. All of these families were screened for RUNX1, CEBPA, TERC, TERT and GATA2 as well as TET2 and NPM1. Five of the 27 families had telomerase mutations; one had a RUNX1 mutation, while none were found to have TET2, CEBPA or NPM1 mutations. We identified four families with heterozygous GATA2 mutations, each associated with a different phenotype. While one of these mutations is novel, three have been previously reported: one has been described in dendritic cell, monocyte, B and NK lymphoid (DCML) deficiency and one is in a family that has been reported in a series with primary lymphoedema with a predisposition to AML (Emberger syndrome). In summary, genetic characterization was shown in 10 (four GATA2, three TERT, two TERC, one RUNX1) of these families; however 17 remain uncharacterized, highlighting marked genetic heterogeneity in familial MDS/AML and the scope for further functional pathways that could give rise to this group of disorders.
Distinct expression pattern of claudin‐6, a primitive phenotypic tight junction molecule, in germ cell tumours and visceral carcinomas
Authors: Ushiku Tetsuo , Shinozaki‐Ushiku Aya , Maeda Daichi , Morita Shigeki , Fukayama Masashi
Published: April 2012

Ushiku T, Shinozaki‐Ushiku A, Maeda D, Morita S & Fukayama M  (2012) Histopathology Distinct expression pattern of claudin‐6, a primitive phenotypic tight junction molecule, in germ cell tumours and visceral carcinomas

Aims:  This study aimed to clarify claudin‐6 expression patterns in cancers.

Methods and results:  We surveyed claudin‐6 expression by immunohistochemistry using tissue microarray in 860 tumours, including germ cell tumours and major carcinomas. Claudin‐6 was expressed consistently in germ cell tumours (28 of 28, 100%), whereas only 64 (8%) of 832 non‐germ cell tumours demonstrated claudin‐6 expression. Further immunohistochemical study in full tissue sections demonstrated diffuse claudin‐6 staining in all seminomas (n = 14), embryonal carcinomas (n = 10), yolk sac tumours (n = 12) and mononuclear trophoblastic cells of choriocarcinomas (n = 3), and focal staining in immature epithelial components of immature teratomas (n = 6). Additionally, because alpha‐fetoprotein (AFP)‐producing gastric adenocarcinomas and pulmonary high‐grade fetal adenocarcinomas were among the claudin‐6 expressing non‐germ cell tumours in the microarray studies, we predicted that claudin‐6 may be a biomarker for them and studied additional tumours in full sections, which showed claudin‐6 expression in AFP‐producing gastric adenocarcinomas (18 of 20, 90%) and pulmonary high‐grade fetal adenocarcinomas (four of five, 80%). Only one of 11 hepatoblastomas demonstrated focal claudin‐6 staining.

Conclusions:  This study demonstrated that claudin‐6 is a novel diagnostic marker for primitive germ cell tumours and is also expressed frequently in some cancers with a primitive phenotype.
Interactive effects of landscape context constrain the effectiveness of local agri‐environmental management
Authors: Concepción Elena D. , Díaz Mario , Kleijn David , Báldi András , Batáry Péter , Clough Yann , Gabriel Doreen , Herzog Felix , Holzschuh Andrea , Knop Eva , Marshall E. Jon P. , Tscharntke Teja , Verhulst Jort
Published: April 2012

1. Ecological theory predicts that the effectiveness of local agri‐environmental management to enhance species richness at field scales will be the highest at intermediate levels of landscape complexity because of nonlinear effects of landscape context on field‐scale diversity.

2. We examined how landscape complexity determined effectiveness of local agri‐environmental management in terms of effects on species richness of birds, plants, spiders and bees in 232 extensive and intensive paired fields (112 arable fields and 120 grasslands) from 18 regions located in six European countries.

3. As predicted, landscape complexity enhanced field‐scale species richness in a mostly nonlinear (sigmoidal) way, with earlier species richness increases in extensive than in intensive fields along landscape complexity gradients. Length of semi‐natural boundaries (for arable fields) and proportion of unfarmed habitat (for grasslands) were the landscape features influencing species richness.

4. The relationships between effectiveness of local management and landscape complexity for all taxa were best described with hump‐shaped curves, indicating the highest effectiveness at intermediate landscape complexities.

5. Synthesis and applications. We used models to investigate how and why effects of local management intensity on species richness vary along wide gradients of landscape complexity. We conclude that landscape‐scale management options should take priority over local extensification measures within agri‐environmental programmes. These programmes should follow a hierarchical multi‐scale approach directed to address landscape‐scale constraints on local diversity.
The involvement of parents in healthcare decisions where adult children are at risk of lacking decision‐making capacity: a qualitative study of treatment decisions in epilepsy
Authors: Redley M. , Prince E. , Bateman N. , Pennington M. , Wood N. , Croudace T. , Ring H.
Published: April 2012

Background  Patients with intellectual disabilities (ID) receive health care by proxy. It is family members and/or paid support staff who must recognise health problems, communicate with clinicians, and report the benefits, if any, of a particular treatment. At the same time international and national statutes protect and promote the right of people with disabilities to access the highest attainable standards of health on the basis of free and informed consent.

Methods  To consider the role of parent‐proxies in the management of epilepsy in adult children with ID who are at risk of lacking capacity to make decisions about their health care we interviewed 21 mothers.

Findings  These mothers are not pursuing changes in treatment that might improve their son or daughter's epilepsy, nor are they willing to countenance changes in treatment. Clinicians concerned to build and sustain therapeutic alliances with these mothers, our evidence suggests, may well avoid going against their wishes.

Discussion  Our research highlights the interactional contingencies of a hitherto neglected three‐way clinical relationship comprising parent‐proxy, an adult at risk of lacking decision‐making capacity, and a treating clinician. This is a relationship, our findings suggest, where little importance is attached to either patient consent, or involvement in treatment decisions.
Validation of the attitudes toward intellectual disability – ATTID questionnaire
Authors: Morin D. , Crocker A. G. , Beaulieu‐Bergeron R. , Caron J.
Published: April 2012

Background  Individuals with an intellectual disability (ID) continue to experience major obstacles towards social, educational and vocational integration. Negative attitudes toward persons with ID has remained relevant over time and has led to discrimination and stigma.

Objective  The present study describes the development of a new questionnaire for tapping into the general population's attitudes toward individuals with ID and addresses its psychometric properties.

Methods  Adopting a multidimensional perspective, the Attitudes Toward Intellectual Disability Questionnaire (ATTID) was developed from a series of previously validated instruments and principles from the Montreal Declaration on Intellectual Disability (2004). The ATTID was administered by phone to 1605 randomly selected adult men and women, stratified by region in the Province of Quebec, Canada.

Results  The ATTID yielded a five‐factor structure overlapping the tri‐partite model of attitudes. The cognitive component was represented by two factors: knowledge of capacity and rights and knowledge of causes of ID. The affective component tapped into two factors: discomfort and sensitivity/compassion. Finally, the behavioural component emerged as a single factor. The ATTID had good internal consistency with Cronbach's alpha coefficients ranging from 0.59 to 0.89 for the five factors and of 0.92 for the overall questionnaire. Test–retest reliability yielded correlations from 0.62 to 0.83 for the five factors.

Conclusion  The ATTID can be used to measure attitudes among different populations and allows comparisons over time within the same population as a function of various intervention strategies for de‐stigmatising ID.
Family functioning in families with a child with Down syndrome: a mixed methods approach
Authors: Povee K. , Roberts L. , Bourke J. , Leonard H.
Published: April 2012

Background  This study aimed to explore the factors that predict functioning in families with a child with Down syndrome using a mixed methods design. The quantitative component examined the effect of maladaptive and autism‐spectrum behaviours on the functioning of the family while the qualitative component explored the impact of having a child with Down syndrome on family holidays, family activities and general family functioning.

Methods  Participants in this study were 224 primary caregivers of children with Down syndrome aged 4–25 years (57.1% male; 42.9% female) currently residing in Western Australia (74.0% in metropolitan Perth and 26.0% in rural Western Australia).

Results  Maladaptive and autism‐spectrum behaviour were associated with poorer family functioning. Mean total scores on the measures of family functioning and marital adjustment were comparable to that of families of typically developing children. Consistent with the quantitative findings, normality was the most common theme to emerge in the qualitative data. Child problem behaviours were also identified by parents/carers as having a negative impact on the family.

Conclusions  This study has implications for the development of programs to support families with a child with Down syndrome and may dispel some of the myths surrounding the impact of intellectual disability on the family.
Parents of children with and without intellectual disability: couple relationship and individual well‐being
Authors: Norlin D. , Broberg M.
Published: April 2012

Background  Research on parents of children with intellectual disability (ID) has identified a range of risk and protective factors for parental well‐being. In family research, the association between marital quality and depression is a vital field of investigation. Still little research has addressed how aspects of the couple relationship affect the adaptation of parents of children with ID. The present study examined predictive links between couple relationship factors (marital quality and coparenting quality) and individual well‐being.

Methods  Data were obtained through self‐report questionnaires completed by parents of children with ID (mothers, n = 58; and fathers, n = 46) and control children (mothers, n = 178; and fathers, n = 141). To test the hypothesis that couple relationship factors predicted individual well‐being, multiple regression analyses were performed controlling for the following risk factors identified by previous research: child self‐injury/stereotypic behaviour, parenting stress, and economic risk.

Results  Marital quality predicted concurrent well‐being, and coparenting quality predicted prospective well‐being. Mothers of children with ID reported lower well‐being than other parents.

Conclusions  There is a continued need for investigation of the details of the links between couple relationship and individual well‐being in parents of children with ID. Couple relationship factors should be given consideration in clinical interventions.
Oestrogen‐Dependent Suppression of Pulsatile Luteinising Hormone Secretion andKiss1mRNA Expression in the Arcuate Nucleus During Late Lactation in Rats
Authors: Yamada S. , Uenoyama Y. , Deura C. , Minabe S. , Naniwa Y. , Iwata K. , Kawata M. , Maeda K.‐I. , Tsukamura H.
Published: April 2012

Follicular development and ovulation are strongly suppressed during lactation in mammals via a profound suppression of gonadotrophin secretion. The present study aimed to examine the role of oestrogen feedback action in suppressing luteinising hormone (LH) secretion and hypothalamic kisspeptin expression during the latter half of lactation. Plasma LH concentrations kept at low levels throughout the lactating period in intact and oestrogen‐replaced ovariectomised (OVX) lactating rats, whereas plasma LH concentrations gradually elevated from day 10 postpartum in lactating OVX rats. OVX lactating rats showed frequent LH pulses at late lactation, although the LH pulses were significantly inhibited by an oestrogen replacement, which is much less effective on LH release in nonlactating rats. Oestrogen replacement in lactating OVX rats significantly reduced the number ofKiss1mRNA‐expressing cells in the arcuate nucleus (ARC) at late lactation, although the same oestrogen treatment did not affect the number ofKiss1‐expressing cells in nonlactating controls. Exogenous kisspeptin challenge (0.2 nmol) into the third cerebroventricle significantly increased LH secretion in lactating OVX, lactating OVX + subcutaneous 17β‐oestradiol and intact lactating rats at day 16 postpartum. These results suggest that LH pulse suppression during late lactation could be a result of the enhanced oestrogen‐dependent suppression of ARC kisspeptin expression.