Vinyl radical induced Michael additions: Total synthesis of (±)-seychellene

A new strategy for the total synthesis of (±)-seychellene which involves (i) a regiospecific construction of a bicyclo(2.2.2)octene moiety having a methyl group at the bridgehead and (ii) a vinyl radical induced intramolecular Michael addition is described.

Estudo sobre o uso do pentacloreto de nióbio, como ácido de Lewis, na síntese de enaminas através da reação de adição de Michael

The NbCl5 being a strong electrophile, is a potential candidate to act as a Lewis acid, and therefore it mediates various organic reactions. For this reason, it has received continuous attention by Brazilian researchers, especially in recent decades, since Brazil holds the largest reserves of niobium, besides being the largest producer of this element. The Michael addition reaction is one of the most widely used for forming carbon-carbon bonds and takes place by the addition of nucleophiles to activated olefins. Although this type of reaction is usually catalyzed by base, there are reports in the literature on the use of various Lewis acids in this type of reaction. The synthesis of enamines based acetilenodicarboxilates and amines, aromatic or alkyl, by Michael addition reaction is quite interesting, since these are valuable synthetic intermediates for the synthesis of heterocyclic and they are used in multicomponent reactions. The derivatives of anilino-fumarate also have a great potential for medical application. In this study we investigated the use of niobium pentachloride as Lewis acid to catalyze the Michael additions between the derivatives of aniline and acetilenodicarboxilates the synthesis of enamines

Iron-Promoted Nucleophilic Additions to Diimine-Type Ligands: A Synthetic and Structural Study

We report here three examples of the reactivity of protic nucleophiles with diimine-type ligands in the presence of FeII salts. In the first case, the iron-promoted alcoholysis reaction of one nitrile group of the ligand 2,3-dicyano-5,6-bis(2-pyridyl)-pyrazine (L1) permitted the isolation of an stable E-imido−ester, [Fe(L1‘)2](CF3SO3)2 (1), which has been characterized by spectroscopic studies (IR, ES-MS, Mössbauer), elemental analysis, and crystallographically. Compound 1 consists of mononuclear octahedrally coordinated FeII complexes where the FeII ion is in its low-spin state. The iron-mediated nucleophilic attack of water to the asymmetric ligand 2,3-bis(2-pyridyl)pyrido[3,4-b]pyrazine (L2) has also been studied. In this context, the crystal structures of two hydration−oxidation FeIII products, [Fe(L2‘)2](ClO4)3·3CH3CN (2) and trans-[FeL2‘‘Cl2] (3), are described. Compounds 2 and 3 are both mononuclear FeIII complexes where the metals occupy octahedral positions. In principle, L2 is expected to coordinate to metal ions through its bipyridine-type units to form a five-membered ring; however, this is not the case in compounds 2 and 3. In 2, the ligand coordinates through its pyridines and through the hydroxyl group attached to the pyrazine imino carbon after hydration, that is, in an N,O,N tridentate manner. In compound 3, the ligand has suffered further transformations leading to a very stable diamido complex. In this case, the metal ion achieves its octahedral geometry by means of two pyridines, two amido N atoms, and two axial chlorine atoms. Magnetic susceptibility measurements confirmed the spin state of these two FeIII species:  compounds 2 and 3 are low-spin and high-spin, respectively.

The impact of delayed blood centrifuging, choice of collection tube, and type of assay on 25-hydroxyvitamin D concentrations

Studies have examined the associations between cancers and circulating 25-hydroxyvitamin D [25(OH)D], but little is known about the impact of different laboratory practices on 25(OH)D concentrations. We examined the potential impact of delayed blood centrifuging, choice of collection tube, and type of assay on 25(OH)D concentrations. Blood samples from 20 healthy volunteers underwent alternative laboratory procedures: four centrifuging times (2, 24, 72, and 96 h after blood draw); three types of collection tubes (red top serum tube, two different plasma anticoagulant tubes containing heparin or EDTA); and two types of assays (DiaSorin radioimmunoassay [RIA] and chemiluminescence immunoassay [CLIA/LIAISON®]). Log-transformed 25(OH)D concentrations were analyzed using the generalized estimating equations (GEE) linear regression models. We found no difference in 25(OH)D concentrations by centrifuging times or type of assay. There was some indication of a difference in 25(OH)D concentrations by tube type in CLIA/LIAISON®-assayed samples, with concentrations in heparinized plasma (geometric mean, 16.1 ng ml−1) higher than those in serum (geometric mean, 15.3 ng ml−1) (p = 0.01), but the difference was significant only after substantial centrifuging delays (96 h). Our study suggests no necessity for requiring immediate processing of blood samples after collection or for the choice of a tube type or assay.

Driving-related eye and head movements are changed by the type of presbyopic correction

Purpose: To investigate whether wearing different presbyopic vision corrections alters the pattern of eye and head movements when viewing dynamic driving-related traffic scenes. Methods: Participants included 20 presbyopes (mean age: 56±5.7 years) who had no experience of wearing presbyopic vision corrections (i.e. all were single vision wearers). Eye and head movements were recorded while wearing five different vision corrections: single vision lenses (SV), progressive addition spectacle lenses (PALs), bifocal spectacle lenses (BIF), monovision (MV) and multifocal contact lenses (MTF CL) in random order. Videotape recordings of traffic scenes of suburban roads and expressways (with edited targets) were presented as dynamic driving-related stimuli and digital numeric display panels included as near visual stimuli (simulating speedometer and radio). Eye and head movements were recorded using the faceLAB™ system and the accuracy of target identification was also recorded. Results: The magnitude of eye movements while viewing the driving-related traffic scenes was greater when wearing BIF and PALs than MV and MTF CL (p≤0.013). The magnitude of head movements was greater when wearing SV, BIF and PALs than MV and MTF CL (p<0.0001) and the number of saccades was significantly higher for BIF and PALs than MV (p≤0.043). Target recognition accuracy was poorer for all vision corrections when the near stimulus was located at eccentricities inferiorly and to the left, rather than directly below the primary position of gaze (p=0.008), and PALs gave better performance than MTF CL (p=0.043). Conclusions: Different presbyopic vision corrections alter eye and head movement patterns. In particular, the larger magnitude of eye and head movements and greater number of saccades associated with the spectacle presbyopic corrections, may impact on driving performance.

The children and sunscreen study : a crossover trial investigating children's sunscreen application thickness and the influence of age and dispenser type.

OBJECTIVES: To measure the thickness at which primary schoolchildren apply sunscreen on school day mornings and to compare it with the thickness (2.00 mg/cm(2)) at which sunscreen is tested during product development, as well as to investigate how application thickness was influenced by age of the child (school grades 1-7) and by dispenser type (500-mL pump, 125-mL squeeze bottle, or 50-mL roll-on). DESIGN: A crossover quasiexperimental study design comparing 3 sunscreen dispenser types. SETTING: Children aged 5 to 12 years from public primary schools (grades 1-7) in Queensland, Australia. PARTICIPANTS: Children (n=87) and their parents randomly recruited from the enrollment lists of 7 primary schools. Each child provided up to 3 observations (n=258). INTERVENTION: Children applied sunscreen during 3 consecutive school weeks (Monday through Friday) for the first application of the day using a different dispenser each week. MAIN OUTCOME MEASURE: Thickness of sunscreen application (in milligrams per square centimeter). The dispensers were weighed before and after use to calculate the weight of sunscreen applied. This was divided by the coverage area of application (in square centimeters), which was calculated by multiplying the children's body surface area by the percentage of the body covered with sunscreen. RESULTS: Children applied their sunscreen at a median thickness of 0.48 mg/cm(2). Children applied significantly more sunscreen when using the pump (0.75 mg/cm(2)) and the squeeze bottle (0.57 mg/cm(2)) compared with the roll-on (0.22 mg/cm(2)) (P<.001 for both). CONCLUSIONS: Regardless of age, primary schoolchildren apply sunscreen at substantially less than 1.00 mg/cm(2), similar to what has been observed among adults. Some sunscreen dispensers seem to facilitate thicker application than others.

An investigation of the C77G and C772T variations within the human protein tyrosine phosphatase receptor type C gene for association with multiple sclerosis in an Australian population

Multiple sclerosis (MS) is a common cause of neurological disability in young adults. The disease generally manifests in early to middle adulthood and causes various neurological deficits. Autoreactive T lymphocytes and their associated antigens have long been presumed important features of MS pathogenesis. The Protein tyrosine phosphatase receptor type C gene (PTPRC) encodes the T-cell receptor CD45. Variations within PTPRC have been previously associated with diseases of autoimmune origin such as type 1 diabetes mellitus and Graves' disease. We set out to investigate two variants within the PTPRC gene, C77G and C772T in subjects with MS and matched healthy controls to determine whether significant differences exist in these markers in an Australian population. We employed high resolution melt analysis (HRM) and restriction length polymorphism (RFLP) techniques to determine genotypic and allelic frequencies. Our study found no significant difference between frequencies for PTPRC C77G by either genotype (Χ2 = 0.65, P = 0.72) or allele (Χ2 = 0.48, P = 0.49). Similarly, we did not find evidence to suggest an association between PTPRC C772T by genotype (Χ2 = 1.06, P = 0.59) or allele (Χ2 = 0.20, P = 0.66). Linkage disequilibrium (LD) analysis showed strong linkage disequilibrium between the two tested markers (D' = 0.9970, SD = 0.0385). This study reveals no evidence to suggest that these markers are associated with MS in the tested Australian Caucasian population. Although the PTPRC gene has a significant role in regulating CD4+ and CD8+ autoreactive T-cells, interferon-beta responsiveness, and potentially other important processes, our study does not support a role for the two tested variants of this gene in MS susceptibility in the Australian population.

A metastatic neuroendocrine anaplastic small cell tumor in a patient with multiple endocrine neoplasia type 1 syndrome : assessment of disease status and response to doxorubicin, cyclophosphamide, etoposide chemotherapy through scintigraphic imaging with 111In-pentetreotide

Extrapulmonary small cell and small cell neuroendocrine tumors of unknown primary site are, in general, aggressive neoplasms with a short median survival. Like small cell lung cancer (SCLC), they often are responsive to chemotherapy and radiotherapy. Small cell lung cancer and well differentiated neuroendocrine carcinomas of the gastrointestinal tract and pancreas tend to express somatostatin receptors. These tumors may be localized in patients by scintigraphic imaging using radiolabeled somatostatin analogues. A patient with an anaplastic neuroendocrine small cell tumor arising on a background of multiple endocrine neoplasia type 1 syndrome is reported. The patient had a known large pancreatic gastrinoma and previously treated parathyroid adenopathy. At presentation, there was small cell cancer throughout the liver and skeleton. Imaging with a radiolabeled somatostatin analogue, 111In- pentetreotide (Mallinckrodt Medical B. V., Petten, Holland), revealed all sites of disease detected by routine biochemical and radiologic methods. After six cycles of chemotherapy with doxorubicin, cyclophosphamide, and etoposide, there was almost complete clearance of the metastatic disease. 111In-pentetreotide scintigraphy revealed uptake consistent with small areas of residual disease in the liver, the abdomen (in mesenteric lymph nodes), and posterior thorax (in a rib). The primary gastrinoma present before the onset of the anaplastic small cell cancer showed no evidence of response to the treatment. The patient remained well for 1 year and then relapsed with brain, lung, liver, and skeletal metastases. Despite an initial response to salvage radiotherapy and chemotherapy with carboplatin and dacarbazine, the patient died 6 months later.

Model-predictive control and closed-loop stability considerations for nonlinear plants described by local ARX-type models

In this paper, a model-predictive control (MPC) method is detailed for the control of nonlinear systems with stability considerations. It will be assumed that the plant is described by a local input/output ARX-type model, with the control potentially included in the premise variables, which enables the control of systems that are nonlinear in both the state and control input. Additionally, for the case of set point regulation, a suboptimal controller is derived which has the dual purpose of ensuring stability and enabling finite-iteration termination of the iterative procedure used to solve the nonlinear optimization problem that is used to determine the control signal.

Graphene-type sheets of Nb1-xWxS2 : synthesis and in situ functionalization

Enlightened by the discovery of graphenes, a variety of inorganic analogues have been synthesized and characterized in recent years. Solvated Nb1-xWxS2 analogues of graphene-type sheets were prepared by lithiation and exfoliation of multistacked Nb1-xWxS2 coin roll nanowires (CRNWs), followed by in situ functionalization with gold nanoparticles to synthesize gold-loaded Nb1-xWxS2/Au nanocomposites. The Nb1-xWxS2 nanosheets and the corresponding Nb1-xWxS2/Au nanocomposites were characterized by high resolution electron microscopy (HRTEM), energy-dispersive X-ray spectroscopy (EDX), scanning transmission electron microscopy (STEM), dynamic light scattering (DLS) and scanning force microscopy (AFM). The graphene-type sheets are stable in water and other solvents and can be functionalized similarly as chalcogen-terminated surfaces (e.g. with Au nanoparticles).

Patient perspectives of using a web based intervention program for patients with type 2 diabetes and acute coronary syndrome

Introduction Research highlights patients with dual diagnoses of type 2 diabetes and acute coronary syndrome (ACS) have higher readmission rates and poorer health outcomes than patients with singular chronic conditions. Despite this, there is a lack of education programs targeted for this dual diagnosis population to improve self-management and decrease negative health outcomes. There is evidence to suggest that internet based interventions may improve health outcomes for patients with singular chronic conditions, however there is a need to develop an evidence base for ACS patients with comorbid diabetes. There is a growing awareness of the importance of a participatory model in developing effective online interventions. That is, internet interventions are more effective if end users’ perceptions of the intervention are incorporated in their final development prior to testing in large scale trials. Objectives This study investigated patients’ perspectives of the web-based intervention designed to promote self-management of the dual conditions in order to refine the intervention prior to clinical trial evaluation. Methods An interpretive approach with thematic analysis was used to obtain deeper understanding regarding participants’ experience when using web-application interventions for patients with ACS and type 2 diabetes. Semi-structured interviews were undertaken on a purposive sample of 30 patients meeting strict inclusion and exclusion criteria to obtain their perspectives on the program. Results Preliminary results indicate patients with dual diagnoses express more complex needs than those with a singular condition. Participants express a positive experience with the proposed internet intervention and emerging themes include that the web page is seen as easy to use and comforting as a support, in that patients know they are not alone. Further results will be reported as they become available. Conclusion The results indicate potential for patient acceptability of the newly developed internet intervention for patients with ACS and comorbid diabetes. Incorporation of patient perspectives into the final development of the intervention is likely to maximise successful outcomes of any future trials that utilise this intervention. Future quantitative evaluation of the effectiveness of the intervention is being planned.

Global, regional, and national incidence, prevalence, and years lived with disability for 301 acute and chronic diseases and injuries in 188 countries, 1990–2013: a systematic analysis for the Global Burden of Disease Study 2013

Background Up-to-date evidence about levels and trends in disease and injury incidence, prevalence, and years lived with disability (YLDs) is an essential input into global, regional, and national health policies. In the Global Burden of Disease Study 2013 (GBD 2013), we estimated these quantities for acute and chronic diseases and injuries for 188 countries between 1990 and 2013. Methods Estimates were calculated for disease and injury incidence, prevalence, and YLDs using GBD 2010 methods with some important refi nements. Results for incidence of acute disorders and prevalence of chronic disorders are new additions to the analysis. Key improvements include expansion to the cause and sequelae list, updated systematic reviews, use of detailed injury codes, improvements to the Bayesian meta-regression method (DisMod-MR), and use of severity splits for various causes. An index of data representativeness, showing data availability, was calculated for each cause and impairment during three periods globally and at the country level for 2013. In total, 35 620 distinct sources of data were used and documented to calculated estimates for 301 diseases and injuries and 2337 sequelae. The comorbidity simulation provides estimates for the number of sequelae, concurrently, by individuals by country, year, age, and sex. Disability weights were updated with the addition of new population-based survey data from four countries. Findings Disease and injury were highly prevalent; only a small fraction of individuals had no sequelae. Comorbidity rose substantially with age and in absolute terms from 1990 to 2013. Incidence of acute sequelae were predominantly infectious diseases and short-term injuries, with over 2 billion cases of upper respiratory infections and diarrhoeal disease episodes in 2013, with the notable exception of tooth pain due to permanent caries with more than 200 million incident cases in 2013. Conversely, leading chronic sequelae were largely attributable to non-communicable diseases, with prevalence estimates for asymptomatic permanent caries and tension-type headache of 2∙4 billion and 1∙6 billion, respectively. The distribution of the number of sequelae in populations varied widely across regions, with an expected relation between age and disease prevalence. YLDs for both sexes increased from 537∙6 million in 1990 to 764∙8 million in 2013 due to population growth and ageing, whereas the age-standardised rate decreased little from 114∙87 per 1000 people to 110∙31 per 1000 people between 1990 and 2013. Leading causes of YLDs included low back pain and major depressive disorder among the top ten causes of YLDs in every country. YLD rates per person, by major cause groups, indicated the main drivers of increases were due to musculoskeletal, mental, and substance use disorders, neurological disorders, and chronic respiratory diseases; however HIV/AIDS was a notable driver of increasing YLDs in sub-Saharan Africa. Also, the proportion of disability-adjusted life years due to YLDs increased globally from 21·1% in 1990 to 31·2% in 2013. Interpretation Ageing of the world’s population is leading to a substantial increase in the numbers of individuals with sequelae of diseases and injuries. Rates of YLDs are declining much more slowly than mortality rates. The non-fatal dimensions of disease and injury will require more and more attention from health systems. The transition to nonfatal outcomes as the dominant source of burden of disease is occurring rapidly outside of sub-Saharan Africa. Our results can guide future health initiatives through examination of epidemiological trends and a better understanding of variation across countries.

Localization of type 1 diabetes susceptibility to the MHC class I genes HLA-B and HLA-A

The major histocompatibility complex (MHC) on chromosome 6 is associated with susceptibility to more common diseases than any other region of the human genome, including almost all disorders classified as autoimmune. In type 1 diabetes the major genetic susceptibility determinants have been mapped to the MHC class II genes HLA-DQB1 and HLA-DRB1 (refs 1–3), but these genes cannot completely explain the association between type 1 diabetes and the MHC region4, 5, 6, 7, 8, 9, 10, 11. Owing to the region's extreme gene density, the multiplicity of disease-associated alleles, strong associations between alleles, limited genotyping capability, and inadequate statistical approaches and sample sizes, which, and how many, loci within the MHC determine susceptibility remains unclear. Here, in several large type 1 diabetes data sets, we analyse a combined total of 1,729 polymorphisms, and apply statistical methods—recursive partitioning and regression...

DNA looping and translocation provide an optimal cleavage mechanism for the type III restriction enzymes

EcoP15I is a type III restriction enzyme that requires two recognition sites in a defined orientation separated by up to 3.5 kbp to efficiently cleave DNA. The mechanism through which site- bound EcoP15I enzymes communicate between the two sites is unclear. Here, we use atomic force microscopy to study EcoP15I-DNA pre-cleavage complexes. From the number and size distribution of loops formed, we conclude that the loops observed do not result from translocation, but are instead formed by a contact between site- bound EcoP15I and a nonspecific region of DNA. This conclusion is confirmed by a theoretical polymer model. It is further shown that translocation must play some role, because when translocation is blocked by a Lac repressor protein, DNA cleavage is similarly blocked. On the basis of these results, we present a model for restriction by type III restriction enzymes and highlight the similarities between this and other classes of restriction enzymes.