Pn Ring Size Dependence on NHC-Induced Ring Contraction Reactions of [CoCp‴(η4-P4)], [Ta(CO)2Cp″(η4-P4)], and [FeCp*(η5-P5)]: A DFT Study.

The facile ring contraction of [CoCp‴(η4-P4)] and [Ta(CO)2Cp″(η4-P4)] to [CoCp‴(η3-P3)][(MeNHC)2P] and [Ta(CO)2Cp″(η3-P3)] [(MeNHC)2P] induced by MeNHC and the absence of the ring contraction of [FeCp*(η5-P5)] under the same conditions are studied by density functional theory (DFT) computations. The latter is estimated to be thermodynamically the least favorable reaction and also has a very high energy barrier. The similar strain energies of P3 and P4 rings and the lower strain energy of the P5 ring play a decisive role in the ring contraction capability of these [TM-cyclo-Pn] complexes. Theoretical approaches involving NBO and IBO analysis have been employed to provide a qualitative picture of the overall reactions. The role of substituents and the nature of transition metals in determining the energetics of these reactions has also been studied and an isolobal perspective on these systems affords a simplified picture.

A Benzodiphosphaborolediide.

The first example of a diphosphaborolediide, the benzo-fused [C6 H4 P2 BPh]2- (12- ), is prepared from ortho-bis(phosphino)benzene (C6 H4 {PH2 }) and dichlorophenylborane, via a sequential lithiation approach. The dilithio-salt can be obtained as an oligomeric THF solvate or discrete TMEDA adduct, both of which are fully characterized, including by X-ray diffraction. Alongside NICS calculations, data strongly suggest some aromaticity within 12- , which is further supported by preliminary coordination studies that demonstrate η5 -coordination to a zerovalent molybdenum center, as observed crystallographically for the oligomeric [{Mo(CO)3 (η5 -1)}{µ-η1 -Mo(CO)3 (TMEDA)}2 ] ⋅ [µ-Li(THF)][µ-Li(TMEDA)].

ORAI1 Mutations with Distinct Channel Gating Defects in Tubular Aggregate Myopathy.

Calcium (Ca2+ ) is a physiological key factor, and the precise modulation of free cytosolic Ca2+ levels regulates multiple cellular functions. Store-operated Ca2+ entry (SOCE) is a major mechanism controlling Ca2+ homeostasis, and is mediated by the concerted activity of the Ca2+ sensor STIM1 and the Ca2+ channel ORAI1. Dominant gain-of-function mutations in STIM1 or ORAI1 cause tubular aggregate myopathy (TAM) or Stormorken syndrome, whereas recessive loss-of-function mutations are associated with immunodeficiency. Here, we report the identification and functional characterization of novel ORAI1 mutations in TAM patients. We assess basal activity and SOCE of the mutant ORAI1 channels, and we demonstrate that the G98S and V107M mutations generate constitutively permeable ORAI1 channels, whereas T184M alters the channel permeability only in the presence of STIM1. These data indicate a mutation-dependent pathomechanism and a genotype/phenotype correlation, as the ORAI1 mutations associated with the most severe symptoms induce the strongest functional cellular effect. Examination of the non-muscle features of our patients strongly suggests that TAM and Stormorken syndrome are spectra of the same disease. Overall, our results emphasize the importance of SOCE in skeletal muscle physiology, and provide new insights in the pathomechanisms involving aberrant Ca2+ homeostasis and leading to muscle dysfunction.

The developmental transcriptome atlas of the biofuel crop Camelina sativa.

Camelina sativa is currently being embraced as a viable industrial bio-platform crop due to a number of desirable agronomic attributes and the unique fatty acid profile of the seed oil that has applications for food, feed and biofuel. The recent completion of the reference genome sequence of C. sativa identified a young hexaploid genome. To complement this work, we have generated a genome-wide developmental transcriptome map by RNA sequencing of 12 different tissues covering major developmental stages during the life cycle of C. sativa. We have generated a digital atlas of this comprehensive transcriptome resource that enables interactive visualization of expression data through a searchable database of electronic fluorescent pictographs (eFP browser). An analysis of this dataset supported expression of 88% of the annotated genes in C. sativa and provided a global overview of the complex architecture of temporal and spatial gene expression patterns active during development. Conventional differential gene expression analysis combined with weighted gene expression network analysis uncovered similarities as well as differences in gene expression patterns between different tissues and identified tissue-specific genes and network modules. A high-quality census of transcription factors, analysis of alternative splicing and tissue-specific genome dominance provided insight into the transcriptional dynamics and sub-genome interplay among the well-preserved triplicated repertoire of homeologous loci. The comprehensive transcriptome atlas in combination with the reference genome sequence provides a powerful resource for genomics research which can be leveraged to identify functional associations between genes and understand the regulatory networks underlying developmental processes.

Polyploid evolution of the Brassicaceae during the Cenozoic era.

The Brassicaceae (Cruciferae) family, owing to its remarkable species, genetic, and physiological diversity as well as its significant economic potential, has become a model for polyploidy and evolutionary studies. Utilizing extensive transcriptome pyrosequencing of diverse taxa, we established a resolved phylogeny of a subset of crucifer species. We elucidated the frequency, age, and phylogenetic position of polyploidy and lineage separation events that have marked the evolutionary history of the Brassicaceae. Besides the well-known ancient α (47 million years ago [Mya]) and ß (124 Mya) paleopolyploidy events, several species were shown to have undergone a further more recent (∼7 to 12 Mya) round of genome multiplication. We identified eight whole-genome duplications corresponding to at least five independent neo/mesopolyploidy events. Although the Brassicaceae family evolved from other eudicots at the beginning of the Cenozoic era of the Earth (60 Mya), major diversification occurred only during the Neogene period (0 to 23 Mya). Remarkably, the widespread species divergence, major polyploidy, and lineage separation events during Brassicaceae evolution are clustered in time around epoch transitions characterized by prolonged unstable climatic conditions. The synchronized diversification of Brassicaceae species suggests that polyploid events may have conferred higher adaptability and increased tolerance toward the drastically changing global environment, thus facilitating species radiation.

Percutaneous closure of an iatrogenic fistula from the left ventricle to the coronary sinus.

A patient with a history of rheumatic mitral valve disease and valve replacement in childhood presented with severe, persistent dyspnea. During an electrophyisiologic procedure, she was discovered to have a fistula from the left ventricle to the coronary sinus. She had severe pulmonary hypertension and elevated filling pressures, with a significant left-to-right shunt. Percutaneous closure of the fistula was performed using two vascular plugs. Subsequently the patient's hemodynamics improved and her symptoms subsided. Here, we describe the case and review the literature.

Empowering immigrant youth in Chicago: utilizing CBPR to document the impact of a Youth Health Service Corps program.

Community-based participatory research (CBPR) is an approach that engages community residents with a goal of influencing change in community health systems, programs, or policies. As such, CBPR is particularly relevant to historically marginalized communities that often have not directly benefited from the knowledge research produces. This article analyzes a youth empowerment program, Chicago's Youth Health Service Corps, from a CBPR perspective. The purpose of this work was (1) to discuss Youth Health Service Corps as a health promotion program, (2) examine the use of CBPR within the immigrant community, and (3) discuss preliminary findings using a model on critical youth empowerment.

ANO5 gene analysis in a large cohort of patients with anoctaminopathy: confirmation of male prevalence and high occurrence of the common exon 5 gene mutation.

Limb girdle muscular dystrophy type 2L or anoctaminopathy is a condition mainly characterized by adult onset proximal lower limb muscular weakness and raised CK values, due to recessive ANO5 gene mutations. An exon 5 founder mutation (c.191dupA) has been identified in most of the British and German LGMD2L patients so far reported. We aimed to further investigate the prevalence and spectrum of ANO5 gene mutations and related clinical phenotypes, by screening 205 undiagnosed patients referred to our molecular service with a clinical suspicion of anoctaminopathy. A total of 42 unrelated patients had two ANO5 mutations (21%), whereas 14 carried a single change. We identified 34 pathogenic changes, 15 of which are novel. The c.191dupA mutation represents 61% of mutated alleles and appears to be less prevalent in non-Northern European populations. Retrospective clinical analysis corroborates the prevalently proximal lower limb phenotype, the male predominance and absence of major cardiac or respiratory involvement. Identification of cases with isolated hyperCKaemia and very late symptomatic male and female subjects confirms the extension of the phenotypic spectrum of the disease. Anoctaminopathy appears to be one of the most common adult muscular dystrophies in Northern Europe, with a prevalence of about 20%-25% in unselected undiagnosed cases.

Assessing equity in health care through the national health insurance schemes of Nigeria and Ghana: a review-based comparative analysis.

BACKGROUND: Nigeria and Ghana have recently introduced a National Health Insurance Scheme (NHIS) with the aim of moving towards universal health care using more equitable financing mechanisms. This study compares health and economic indicators, describes the structure of each country's NHIS within the wider healthcare system, and analyses impacts on equity in financing and access to health care. METHODS: The World Bank and other sources were used to provide comparative health and economic data. Pubmed, Embase and EconLit were searched to locate studies providing descriptions of each NHIS and empirical evidence regarding equity in financing and access to health care. A diagrammatical representation of revenue-raising, pooling, purchasing and provision was produced in order to analyse the two countries' systems. RESULTS: Over the period 2000-2010, Ghana maintained a marked advantage in life expectancy, infant mortality, under-5 year mortality, and has a lower burden of major diseases. Health care expenditure is about 5% of GDP in both countries but public expenditure in 2010 was 38% of total expenditure in Nigeria and 60% in Ghana. Financing and access are less equitable in Nigeria as, inter alia, private out-of-pocket expenditure has fallen from 80% to 66% of total spending in Ghana since the introduction of its NHIS but has remained at over 90% in Nigeria; NHIS membership in Nigeria and Ghana is approximately 3.5% and 65%, respectively; Nigeria offers a variable benefits package depending on membership category while Ghana has uniform benefits across all beneficiaries. Both countries exhibit improvements in equity but there is a pro-rich and pro-urban bias in membership. CONCLUSIONS: Major health indicators are more favourable in Ghana and overall equity in financing and access are weaker in Nigeria. Nigeria is taking steps to expand NHIS membership and has potential to expand its public spending to achieve greater equity. However, heavy burdens of poverty, disease and remote settings make this a substantial challenge. Ghana's relative success has to be tempered by the high number of exemptions through taxation and the threat of moral hazard. The results and methods are anticipated to be informative for policy makers and researchers in both countries and other developing countries more widely.

Signs and symptoms of childhood cancer: a guide for early recognition.

Although cancer in children is rare, it is the second most common cause of childhood mortality in developed countries. It often presents with nonspecific symptoms similar to those of benign conditions, leading to delays in the diagnosis and initiation of appropriate treatment. Primary care physicians should have a raised index of suspicion and explore the possibility of cancer in children who have worrisome or persisting signs and symptoms. Red flag signs for leukemia or lymphoma include unexplained and protracted pallor, malaise, fever, anorexia, weight loss, lymphadenopathy, hemorrhagic diathesis, and hepatosplenomegaly. New onset or persistent morning headaches associated with vomiting, neurologic symptoms, or back pain should raise concern for tumors of the central nervous system. Palpable masses in the abdomen or soft tissues, and persistent bone pain that awakens the child are red flags for abdominal, soft tissue, and bone tumors. Leukokoria is a red flag for retinoblastoma. Endocrine symptoms such as growth arrest, diabetes insipidus, and precocious or delayed puberty may be signs of endocranial or germ cell tumors. Paraneoplastic manifestations such as opsoclonus-myoclonus syndrome, rheumatic symptoms, or hypertension are rare and may be related to neuroblastoma, leukemia, or Wilms tumor, respectively. Increased suspicion is also warranted for conditions associated with a higher risk of childhood cancer, including immunodeficiency syndromes and previous malignancies, as well as with certain genetic conditions and familial cancer syndromes such as Down syndrome, Li-Fraumeni syndrome, hemihypertrophy, neurofibromatosis, and retinoblastoma.

Long-term day-case treatment of peripheral neuromuscular disease with intravenous immunoglobulin: the practice of a regional day-case service in Preston, Lancashire.

Neuromuscular disease is one of the most common indications for the use of intravenous immuno-globulin (IVIG). We describe practical aspects of IVIG administration and dosing in long-term treatment, as well as the setting up of a day-case service in a regional neurology unit to provide a streamlined patient experience. An audit of the safety of IVIG administration and patient satisfaction during implementation supported the fact that this is a relatively safe treatment. Standardised assessment methods have been used both to monitor treatment effect and to provide the necessary outcome measures for Department of Health (DOH) monitoring of IVIG use.

Structure and bonding in stannadiphospholes and their dianions SnC2P2R2m (R=H, tBu m=0, -2): a comparative study with C5H5+ and C5H5- analogues.

The potential energy surfaces of both neutral and dianionic SnC(2)P(2)R(2) (R=H, tBu) ring systems have been explored at the B3PW91/LANL2DZ (Sn) and 6-311+G* (other atoms) level. In the neutral isomers the global minimum is a nido structure in which a 1,2-diphosphocyclobutadiene ring (1,2-DPCB) is capped by the Sn. Interestingly, the structure established by X-ray diffraction analysis, for R=tBu, is a 1,3-DPCB ring capped by Sn and it is 2.4 kcal mol(-1) higher in energy than the 1,2-DPCB ring isomer. This is possibly related to the kinetic stability of the 1,3-DPCB ring, which might originate from the synthetic precursor ZrCp(2)tBu(2)C(2)P(2). In the case of the dianionic isomers we observe only a 6π-electron aromatic structure as the global minimum, similarly to the cases of our previously reported results with other types of heterodiphospholes. The existence of large numbers of cluster-type isomers in neutral and 6π-planar structures in the dianions SnC(2)P(2)R(2)(2-) (R=H, tBu) is due to 3D aromaticity in neutral clusters and to 2D π aromaticity of the dianionic rings. Relative energies of positional isomers mainly depend on: 1) the valency and coordination number of the Sn centre, 2) individual bond strengths, and 3) the steric effect of tBu groups. A comparison of neutral stannadiphospholes with other structurally related C(5)H(5)(+) analogues indicates that Sn might be a better isolobal analogue to P(+) than to BH or CH(+). The variation in global minima in these C(5)H(5)(+) analogues is due to characteristic features such as 1) the different valencies of C, B, P and Sn, 2) the electron deficiency of B, 3) weaker pπ-pπ bonding by P and Sn atoms, and 4) the tendency of electropositive elements to donate electrons to nido clusters. Unlike the C(5)H(5)(+) systems, all C(5)H(5)(-) analogues have 6π-planar aromatic structures as global minima. The differences in the relative ordering of the positional isomers and ligating properties are significant and depend on 1) the nature of the π orbitals involved, and 2) effective overlap of orbitals.

Electronic structure and bonding in neutral and dianionic boradiphospholes: R'BC2P2R2 (R = H, tBu, R' = H, Ph).

Classical and non-classical isomers of both neutral and dianionic BC(2)P(2)H(3) species, which are isolobal to Cp(+) and Cp(-), are studied at both B3LYP/6-311++G(d,p) and G3B3 levels of theory. The global minimum structure given by B3LYP/6-311++G(d,p) for BC(2)P(2)H(3) is based on a vinylcyclopropenyl-type structure, whereas BC(2)P(2)H(3)(2-) has a planar aromatic cyclopentadienyl-ion-like structure. However, at the G3B3 level, there are three low-energy isomers for BC(2)P(2)H(3): 1) tricyclopentane, 2) nido and 3) vinylcyclopropenyl-type structures, all within 1.7 kcal mol(-1) of each other. On the contrary, for the dianionic species the cyclic planar structure is still the minimum. In comparison to the isolobal Cp(+) and H(n)C(n)P(5-n)(+) isomers, BC(2)P(2)H(3) shows a competition between pi-delocalised vinylcyclopropenyl- and cluster-type structures (nido and tricyclopentane). Substitution of H on C by tBu, and H on B by Ph, in BC(2)P(2)H(3) increases the energy difference between the low-lying isomers, giving the lowest energy structure as a tricyclopentane type. Similar substitution in BC(2)P(2)H(3)(2-) merely favours different positional isomers of the cyclic planar geometry, as observed in 1) isoelectronic neutral heterodiphospholes EtBu(2)C(2)P(2) (E = S, Se, Te), 2) monoanionic heterophospholyl rings EtBu(2)C(2)P(2) (E = P(-), As(-), Sb(-)) and 3) polyphospholyl rings anions tBu(5-n)C(n)P(5-n) (n = 0-5). The principal factors that affect the stability of three-, four-, and five-membered ring and acyclic geometrical and positional isomers of neutral and dianionic BC(2)P(2)H(3) isomers appear to be: 1) relative bond strengths, 2) availability of electrons for the empty 2p boron orbital and 3) steric effects of the tBu groups in the HBC(2)P(2)tBu(2) systems.

Guidelines for completing the EURONHEED transferability information checklists.

The structure and methods to complete and derive a quality score from the European Network of Health Economic Evaluation Databases (EURONHEED) transferability information checklists for published economic evaluations were reported and discussed in a previous paper (Boulenger et al. in Eur J Health Econ 6, 334-346, 2005). Within the same paper, the use of the checklists was illustrated through their application to a sample of economic evaluations conducted in France and UK. The transferability information subchecklist, consisting of 16 items from the original 42-point checklist, and methods used to derive it, were validated among 16 health economists across Europe participating in the EURONHEED project. Recent correspondence with other researchers, however, indicates that the checklists are now being utilised in empirical work and the methodology of assessing transferability and generalisability. This supplementary paper provides full details of the guidelines that have been developed and recently updated by the authors, such that the overall and subchecklists can be more widely and consistently completed and utilised. We also briefly discuss associated issues such as weighting of items in the checklists and give further clarifications regarding what we consider the most appropriate applications of the checklists to be.

Are There Benefits in Adding Catechol-O Methyltransferase Inhibitors in the Pharmacotherapy of Parkinson's Disease Patients? A Systematic Review.

BACKGROUND: A qualified consensus suggests that a combination of levodopa with a peripherally acting dopa decarboxylase inhibitor continues to present the gold standard treatment of Parkinson's disease (PD). However, as the disease progresses the therapeutic window of levodopa becomes narrowed. Pharmacological strategies for motor fluctuations are focused on providing less pulsatile and more continuous dopaminergic stimulation. Peripheral catechol-O-methyltransferase (COMT) inhibition improves the bioavailability of levodopa and results in a prolonged response. OBJECTIVE: The primary aim of this study was to investigate the efficacy and safety of the two available COMT inhibitors; entacapone and tolcapone and the recently introduced opicapone. METHODS: Electronic databases were systematically searched for original studies published within the last 37 years. In addition, lists of identified studies, reviews and their references were examined. RESULTS: Twelve studies fulfilled the inclusion criteria. 3701 patients with PD were included in this systematic review. CONCLUSIONS: Adjuvant treatment of PD patients experiencing motor fluctuations with entacapone resulted in improvement of motor function and was well tolerated. Therefore, entacapone presented an acceptable benefit to risk ratio. Tolcapone appeared to result in a greater therapeutic effect. However, this was not consistent across all motor variables and studies, and thus would not support its use, given the current onerous monitoring that is required. Opicapone was not associated with adverse reactions in a phase III trial but did not present a greater efficacy than entacapone, and thus further studies are required in order to illustrate its cost effectiveness.

Ability of Nonstrain Diastolic Parameters to Predict Doxorubicin-Induced Cardiomyopathy: A Systematic Review With Meta-Analysis.

Doxorubicin is an important cause of chemotherapy-induced cardiomyopathy. Prior studies have found conflicting results of whether nonstrain diastolic parameters can predict doxorubicin-induced cardiotoxicity. We performed a systematic review of English written publications using Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The following inclusion criteria were applied: cancer subjects, echo-derived nonstrain diastolic profile, and patients compared before and after treatment to predict systolic dysfunction. The following exclusion criteria were applied: other cardiotoxic agents, non-echo studies, or used protective medications. Meta-analysis was performed using comprehensive meta-analysis software V3 to calculate cumulative means, SD, and odds ratios (ORs). Only 4 studies were designed to predict doxorubicin-induced cardiotoxicity. Of the 7 common parameters identified among studies, only 4 were significant: mitral E [OR: 3.4; 95% confidence interval (CI): 1.5-7.8; P = 0.003]; lateral E' (OR: 3.7; 95% CI: 1.5-9.4; P < 0.005); mitral E/A (OR: 4.3; 95% CI: 2.1-8.9; P < 0.0001); and lateral S' (OR: 2.7; 95% CI: 1.2-5.8; P = 0.01). We found that conventional nonstrain diastolic parameters predicted doxorubicin-induced systolic dysfunction. Whether nonstrain diastolic parameters can be used to supplement strain imaging for predicting doxorubicin-induced systolic function warrants further investigation in larger studies.

Copper(I) mediated oligomerisation of a phosphaalkyne.

The oligomerisation of tert-butylphosphaalkyne, tBuC[triple bond, length as m-dash]P, mediated by Cu(I) complexes yields an unprecedented C4P5 cage compound, which is stabilised in a matrix of copper(I) iodide.

Are the best available clinical effectiveness data used in economic evaluations of drug therapies?

OBJECTIVES: Use of evidence on clinical effectiveness that is of poor quality or is biased in favour of the therapy under study is a concern in economic evaluations and may contribute to a mistrust of pharmacoeconomic studies. This study aimed to determine whether the authors of economic evaluations use the best available evidence for clinical effectiveness. METHODS: One hundred economic evaluations of drug therapies (published in 2001-2003) were sampled randomly from the National Health Service Economic Evaluation Database, and the source of clinical evidence was identified. For each therapy, alternative, high quality sources of clinical effectiveness data were sought by searching the Database of Abstracts of Reviews of Effects and Health Technology Assessment databases. The magnitude and direction of the effect size in the different sources of evidence were compared. RESULTS: Relevant systematic reviews were found for only 32 of the 100 economic evaluations in the sample. In three cases these reviews had been identified by the authors of the economic evaluations and two of these cases were used in the evaluation. Comparisons were possible in 21 cases. The clinical effects reported in all 21 comparisons were similar in direction but differed in magnitude. Compared to the systematic reviews, the authors of economic evaluations used evidence that was more favourable in five cases, less favourable in four cases, and similar in 12 cases. Six of the economic evaluations and corresponding systematic reviews did not present measures of effectiveness in a manner that allowed comparison. CONCLUSIONS: Authors of economic evaluations have not made sufficient use of the evidence available from systematic reviews of clinical effectiveness. The central role of economic evaluations in health policy makes it essential that improvements in economic methods are accompanied by a structured search for the highest quality information on clinical effectiveness.

Monoclonal antibody therapy for the treatment of asthma and chronic obstructive pulmonary disease with eosinophilic inflammation.

Eosinophils have been linked with asthma for more than a century, but their role has been unclear. This review discusses the roles of eosinophils in asthma and chronic obstructive pulmonary disease (COPD) and describes therapeutic antibodies that affect eosinophilia. The aims of pharmacologic treatments for pulmonary conditions are to reduce symptoms, slow decline or improve lung function, and reduce the frequency and severity of exacerbations. Inhaled corticosteroids (ICS) are important in managing symptoms and exacerbations in asthma and COPD. However, control with these agents is often suboptimal, especially for patients with severe disease. Recently, new biologics that target eosinophilic inflammation, used as adjunctive therapy to corticosteroids, have proven beneficial and support a pivotal role for eosinophils in the pathology of asthma. Nucala® (mepolizumab; anti-interleukin [IL]-5) and Cinquair® (reslizumab; anti-IL-5), the second and third biologics approved, respectively, for the treatment of asthma, exemplifies these new treatment options. Emerging evidence suggests that eosinophils may contribute to exacerbations and possibly to lung function decline for a subset of patients with COPD. Here we describe the pharmacology of therapeutic antibodies inhibiting IL-5 or targeting the IL-5 receptor, as well as other cytokines contributing to eosinophilic inflammation. We discuss their roles as adjuncts to conventional therapeutic approaches, especially ICS therapy, when disease is suboptimally controlled. These agents have achieved a place in the therapeutic armamentarium for asthma and COPD and will deepen our understanding of the pathogenic role of eosinophils.