Synthesis, Structures and Their Application in the Suzuki-Miyaura Cross Coupling Reaction

A series of novel palladium(ii) acetylacetonato complexes bearing mesoionic carbenes (MICs) have been synthesized and characterized. The synthesis of the complexes of type (MIC)Pd(acac)I (MIC = 1-mesityl-3-methyl-4-phenyl-1,2,3-triazol-5-ylidene (1), 1,4-(2,4,6-methyl)-phenyl-3-methyl-1,2,3-triazol-5-ylidene (2), 1,4-(2,6-diisopropyl)-phenyl-3-methyl-1,2,3-triazol-5-ylidene (3); acac = acetylacetonato) via direct metalation starting from the corresponding triazolium iodides and palladium(ii) acetylacetonate is described herein. All complexes were characterized by 1H- and 13C-NMR spectroscopy and high resolution mass spectrometry. Additionally, two of the complexes were characterized by single crystal X-ray crystallography confirming a square- planar coordination geometry of the palladium(ii) center. A delocalized bonding situation was observed within the triazolylidene rings as well as for the acac ligand respectively. Complex 2 was found to be an efficient pre- catalyst for the Suzuki-Miyaura cross coupling reaction between aryl-bromides or -chlorides with phenylboronic acid. View Full-Tex

Automedicação em adultos de baixa renda no município de São Paulo

OBJECTIVE: To estimate the self-medication prevalence in low-income adults and identify associated factors. METHODS: Data from a population survey performed in São Paulo municipality, Southeastern Brazil in 2005, were used. The sample strategy included two domains, favelas and non-favelas, with clustered sampling performed in two stages with a total of 3,226 eligible individuals. In addition to sociodemographic and economic characteristics, the multiple logistic regression included: use of medicines in the 15 days preceding interview, access to medicines (free, purchased or other) and type of morbidities treated (chronic or acute). RESULTS: The proportion of self-medication was 27% to 32%. Self-medication was strongly associated with acute morbidity, ability to purchase medicines, age less than 47 years and the medicine group that acts on the central nervous system. The medicinal group that acts on the central nervous system was the most common utilized in self-medication. CONCLUSIONS: Free access to medicines was shown to be a protective factor for self-medication. The distribution of medicines and appropriate health care should be considered when providing patient counseling and for reducing health risks from irrational medicine use.OBJETIVO: Estimar la proporción da automedicación en adultos de baja renta e identificar factores asociados. MÉTODOS: Se utilizaron datos de pesquisa poblacional realizado en el municipio de Sao Paulo, Sureste de Brasil, en 2005, cuyo plan de muestreo incluyó dos dominios, barrio y no barrio, con muestreo por conglomerados en dos fases, totalizando 3.226 individuos elegibles. Además de las características sociodemográficas y económicas, se analizaron: uso de medicamentos en los 15 días anteriores a la entrevista, tipo de acceso (gratuito, comprado u otra) a los medicamentos y los tipos de morbilidades (crónicas o agudas) tratadas, en análisis de regresión logística múltiple. RESULTADOS: La proporción de automedicación fue de 27% a 32%. La automedicación estuvo fuertemente asociada a la morbilidad aguda, al acceso al medicamento por compra, a la edad menor de 47 años y medicamentos del grupo terapéutico que actúan en el sistema nervioso central. El grupo que actúa en el sistema nervioso central fue el más utilizado en la automedicación. CONCLUSIONES: El acceso gratuito a los medicamentos se mostró como factor de protección para la automedicación. La distribución de medicamentos y la atención adecuada deben ser considerados para orientación y reducción de los riesgos que el uso irracional de medicamentos puede generar para la salud.OBJETIVO: Estimar a proporção de automedicação em adultos de baixa renda e identificar fatores associados. MÉTODOS: Foram utilizados dados de inquérito populacional realizado no município de São Paulo em 2005, cujo plano amostral incluiu dois domínios, favela e não favela, com amostragem por conglomerados em dois estágios, totalizando 3.226 indivíduos elegíveis. Além de características sociodemográficas e econômicas, foram analisados: uso de medicamentos nos 15 dias anteriores à entrevista, tipo de acesso (gratuito, comprado ou outra) aos medicamentos e os tipos de morbidades (crônicas ou agudas) tratadas, em análise de regressão logística múltipla. RESULTADOS: A proporção de automedicação foi de 27% a 32%. Automedicação esteve fortemente associada à morbidade aguda, ao acesso ao medicamento por compra, à idade menor que 47 anos e medicamentos do grupo terapêutico que atuam no sistema nervoso central. O grupo que atua no sistema nervoso central foi o mais utilizado na automedicação. CONCLUSÕES: O acesso gratuito aos medicamentos mostrou-se fator de proteção para a automedicação. A distribuição de medicamentos e o atendimento adequado devem ser considerados para orientação e redução dos riscos que o uso irracional de medicamentos pode gerar à saúde

A Coupled Mathematical Model of the Intracellular Replication of Dengue Virus and the Host Cell Immune Response to Infection

Dengue virus (DV) is a positive-strand RNA virus of the Flavivirus genus. It is one of the most prevalent mosquito-borne viruses, infecting globally 390 million individuals per year. The clinical spectrum of DV infection ranges from an asymptomatic course to severe complications such as dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS), the latter because of severe plasma leakage. Given that the outcome of infection is likely determined by the kinetics of viral replication and the antiviral host cell immune response (HIR) it is of importance to understand the interaction between these two parameters. In this study, we use mathematical modeling to characterize and understand the complex interplay between intracellular DV replication and the host cells' defense mechanisms. We first measured viral RNA, viral protein, and virus particle production in Huh7 cells, which exhibit a notoriously weak intrinsic antiviral response. Based on these measurements, we developed a detailed intracellular DV replication model. We then measured replication in IFN competent A549 cells and used this data to couple the replication model with a model describing IFN activation and production of IFN stimulated genes (ISGs), as well as their interplay with DV replication. By comparing the cell line specific DV replication, we found that host factors involved in replication complex formation and virus particle production are crucial for replication efficiency. Regarding possible modes of action of the HIR, our model fits suggest that the HIR mainly affects DV RNA translation initiation, cytosolic DV RNA degradation, and naïve cell infection. We further analyzed the potential of direct acting antiviral drugs targeting different processes of the DV lifecycle in silico and found that targeting RNA synthesis and virus assembly and release are the most promising anti-DV drug targets

Vascular Responses following Light Therapy: A Pilot Study with Healthy Volunteers

(1) Background: Studies have reported the effectiveness of light therapy in various medical conditions. Our pilot study aimed to assess the effect of Maharishi light therapy (MLT) on physiological parameters, such as the heart rate (HR), HR variability (HRV), blood pressure (BP), BP variability (BPV), and the retinal microvasculature of healthy participants; (2) Methodology: Thirty (14 males and 16 females) healthy, non-smoking participants between 23 and 71 years old (46 ± 18 years) were included in this randomized crossover study. Each participant was tested with a placebo (using LED light) and gem lights, 24 h apart. Hemodynamic parameters were recorded during the session, and 24 h heart rate and BP levels were assessed via mobile devices. Retinal vascular responses were captured with fundus images and the subsequent analysis of retinal vessel widths. A linear model, using repeated measures ANOVA, was used to compare the responses across the sexes and to assess the effect of the MLT; (3) Results: Changes in the central retinal artery equivalent (CRAE) (p < 0.001) and central retinal vein equivalent (CRVE) (p = 0.002) parameters were observed. CRAE and CRVE decreased under MLT and increased under the placebo condition from before to after. However, the baseline values of the participants already differed significantly before the application of any therapy, and the variation in the retinal vessel diameters was already large in the baseline measurements. This suggests that the observed effect results may only reflect naturally occurring fluctuations in the microcirculation and not the effect of MLT. Furthermore, no significant effects were observed in any other investigated parameters; (4) Conclusion: Our study with healthy participants finds significant changes in retinal parameters, but the biological variation in the baseline measurements was large to begin with. This suggests that the observed effect results only reflect naturally occurring fluctuations in the microcirculation and not the effect of MLT. However, in the future, larger studies in which MLT is applied for longer periods and/or in patients with different diseases could discover the physiological impacts of this type of therapy.publishedVersio

Serum Concentrations of Cholinesterase Inhibitors in Patients With Alzheimer's Dementia Are Frequently Below the Recommended Levels

Background: Acetylcholinesterase inhibitors (AChE-I) are recommended for the treatment of cognitive symptoms but also of behavioral and psychological symptoms in dementia. They are widely used not only in Alzheimer's disease, but also in other forms of dementia. Efficacy of treatment might depend on serum concentration of the respective AChE-I. Objective: In patients with mild to moderate Alzheimer's dementia, we measured serum concentrations of hepatically metabolized donepezil and renally excreted rivastigmine and investigated possible modifiers. Additionally, we looked at correlations between serum concentrations and efficacy for both drugs. Methods: Serum concentrations of donepezil and rivastigmine were measured by liquid chromatography – tandem mass spectrometry (LC-MS/MS). Real-time quantitative polymerase chain reaction (PCR). Allele specific PCR were performed to determine CYP2D6 genotype and gene dose. Clinical efficacy was assessed by changes of the subtest wordlist delayed recall of the Consortium to Establish a Registry for Alzheimer's Disease-Neuropsychological Assessment Battery (CERAD-NAB). Results: Sixty-seven patients treated with a stable dosage of donepezil 10 mg (n=41) or rivastigmine 9.5 mg (n=26) were included. Mean serum concentration of donepezil and rivastigmine were 41.2 and 6.5 ng/ml, respectively. Serum concentrations were below the recommended range in 73% of the subjects in the donepezil group and in 65% of the participants in the rivastigmine group. When applying a dose-related reference, ranges 63% of patients in the donepezil group and 32% in the rivastigmine group had concentrations below the expected range. Gene dose, sex, and duration of treatment significantly predicted donepezil serum concentration (p=0.046, p=0.001, p=0.030 respectively). Only for rivastigmine did the serum concentration significantly contribute to the regression model predicting changes on the subtest word list delayed recall (β=0.472; p=0.019). Conclusions: Serum concentrations of about two thirds of the patients were below the recommended range. When not looking at absolute values but at the dose-related reference ranges, these numbers improved but still 32%, respectively 63% of patients had low serum concentrations. High serum concentrations of rivastigmine predicted clinical response to cognition. Therapeutic drug monitoring might help to identify the cause of poor clinical response to cognition and behavioral and psychological symptoms in patients with AChE-I treatment

Die Gestaltung von Heterogenität in der Primarstufe. Grundlagen und Bedingungen für die Förderung von Grundschulkindern

Anhand von drei Dissertationsprojekten des Forschungs- und Nachwuchskollegs (FuN-Kolleg) „Heterogenität gestalten – starke Grundschulen entwickeln“ werden im Beitrag empirische Zugänge zum produktiven Umgang mit Heterogenität aufgezeigt. In einer systemischen Perspektive wird die Frage, wodurch Schulsegregation gesteuert wird, über eine Befragung von Eltern und eine Analyse von schulstatistischen und VERA-Daten beforscht. Im Kontext von Lernentwicklungsgesprächen wird über eine Befragungs- und Beobachtungsstudie untersucht, welche Beratungskompetenzen von Lehrkräften Lernentwicklungsgespräche beeinflussen. Mit Blick auf qualitätsvolle Kooperationen wird über eine Befragungsstudie abgebildet, inwiefern Professionelle Lerngemeinschaften zur Bearbeitung von Heterogenität genutzt werden. Die drei Fokusse bilden je eine makro-, meso- und mikroperspektivische Betrachtung der Gestaltung von Heterogenität im Primarbereich ab. (DIPF/Orig.

DNA methylation transcriptionally regulates the putative tumor cell growth suppressor ZNF677 in non-small cell lung cancers

In our study, we investigated the role of ZNF677 in non-small cell lung cancers (NSCLC). By comparing ZNF677 expression in primary tumor (TU) and in the majority of cases also of corresponding non-malignant lung tissue (NL) samples from > 1,000 NSCLC patients, we found tumor-specific downregulation of ZNF677 expression (adjusted p-values < 0.001). We identified methylation as main mechanism for ZNF677 downregulation in NSCLC cells and we observed tumor-specific ZNF677 methylation in NSCLC patients (p < 0.0001). In the majority of TUs, ZNF677 methylation was associated with loss of ZNF677 expression. Moreover, ZNF677 overexpression in NSCLC cells was associated with reduced cell proliferation and cell migration. ZNF677 was identified to regulate expression of many genes mainly involved in growth hormone regulation and interferon signalling. Finally, patients with ZNF677 methylated TUs had a shorter overall survival compared to patients with ZNF677 not methylated TUs (p = 0.013). Overall, our results demonstrate that ZNF677 is trancriptionally regulated by methylation in NSCLCs, suggest that ZNF677 has tumor cell growth suppressing properties in NSCLCs and that ZNF677 methylation might serve as prognostic parameter in these patients

Nachgefragt: 25 Fragen und Antworten zum Stand des Wissens rund um Öko-Landbau und Bio-Lebensmittel - Argumentationsleitfaden zum Ökologischen Landbau für Multiplikatoren

„Ist Bio denn wirklich gesünder?“ Dies ist nur eine der vielen Fragen, die immer wieder gestellt werden, wenn es um Ökologischen Landbau und Bio-Lebensmittel geht. Und: Sie werden mit dem wachsenden Bio-Markt und der zunehmenden Beliebtheit seiner Produkte immer häufiger, immer kritischer und nach wie vor oftmals vorurteilsbeladen und polemisch gestellt. Dieser Argumentationsleitfaden will die Diskussion versachlichen. Auf dem Stand des Wissens stellt er die Vorzüglichkeit der ökologischen Lebensmittelwirtschaft sachlich, fundiert und übersichtlich dar und benennt ebenso Bereiche, bei denen noch Defizite und somit Handlungsbedarf besteht. Damit werden Fragestellungen aufgegriffen, die in der gesellschaftlichen Auseinandersetzung um die biologische Lebensmittelwirtschaft immer wieder zu Diskussionen und Auseinandersetzungen führen. Zu den Themenfeldern Grundlagen, Erzeugung, Verarbeitung, Vermarktung, Qualität, Umweltwirkungen sowie ökologische Lebensmittelwirtschaft und Gesellschaft werden 25 Fragen so beantwortet, dass die wichtigsten Gesichtspunkte zu der jeweiligen Frage „auf einen Blick“ in einer logischen Argumentationskette zur Verfügung stehen. Quellenverweise ermöglichen es, einzelne Sachverhalte zu vertiefen. Damit ist der Argumentationsleitfaden ein wichtiges Instrument für Journalisten und Politiker, die Fragen zur ökologischen Lebensmittelwirtschaft haben, sich schnell und doch umfassend zu informieren. Ebenso soll der Leitfaden für die Multiplikatoren der Branche, wie Verbandsvertreter oder Ausbilder, eine Hilfe in der täglichen Arbeit sein. Sei es, um sich auf eine Podiumsdiskussion vorzubereiten, einem Pressevertreter weiterführende Quellen nennen zu können oder um bei der Verkäuferschulung Antworten auf häufig gestellte Kundenfragen besprechen zu können

Loss of RAF kinase inhibitor protein is involved in myelomonocytic differentiation and aggravates RAS-driven myeloid leukemogenesis

RAS-signaling mutations induce the myelomonocytic differentiation and proliferation of hematopoietic stem and progenitor cells. Moreover, they are important players in the development of myeloid neoplasias. RAF kinase inhibitor protein (RKIP) is a negative regulator of RAS-signaling. As RKIP loss has recently been described in RAS-mutated myelomonocytic acute myeloid leukemia, we now aimed to analyze its role in myelomonocytic differentiation and RAS-driven leukemogenesis. Therefore, we initially analyzed RKIP expression during human and murine hematopoietic differentiation and observed that it is high in hematopoietic stem and progenitor cells and lymphoid cells but decreases in cells belonging to the myeloid lineage. By employing short hairpin RNA knockdown experiments in CD34+ umbilical cord blood cells and the undifferentiated acute myeloid leukemia cell line HL-60, we show that RKIP loss is indeed functionally involved in myelomonocytic lineage commitment and drives the myelomonocytic differentiation of hematopoietic stem and progenitor cells. These results could be confirmed in vivo, where Rkip deletion induced a myelomonocytic differentiation bias in mice by amplifying the effects of granulocyte macrophage-colony-stimulating factor. We further show that RKIP is of relevance for RAS-driven myelomonocytic leukemogenesis by demonstrating that Rkip deletion aggravates the development of a myeloproliferative disease in NrasG12D-mutated mice. Mechanistically, we demonstrate that RKIP loss increases the activity of the RAS-MAPK/ERK signaling module. Finally, we prove the clinical relevance of these findings by showing that RKIP loss is a frequent event in chronic myelomonocytic leukemia, and that it co-occurs with RAS-signaling mutations. Taken together, these data establish RKIP as novel player in RAS-driven myeloid leukemogenesis