Allgemeiner Zugang zu Polyaminen mit Ethan-1,2-diamin-Einheiten: Synthese von nicht natürlich vorkommenden homologen und isomerenN1,4-Di(4-cumaroyl)sperminen

The synthesis of the three N,N′-di(4-coumaroyl)tetramines, i.e., of (E,E)-N-{3-[(2-aminoethyl)amino]propyl}-3,3′-bis(4-hydroxyphenyl)-N,N′-(ethane-1,2-diyl)bis[prop-2-enamide] (1a), (E,E)-N-{4-[(2-aminoethyl)amino]butyl}-3,3′-bis(4-hydroxyphenyl)-N,N′-(ethane-1,2-diyl)bis[prop-2-enamide] (1b), and (E,E)-N-{6-[(2-aminoethyl)amino]hexyl}-3,3′-bis(4-hydroxyphenyl)-N,N′-(ethane-1,2-diyl)bis[prop-2-enamide] (1c), is described. It proceeds through stepwise construction of the symmetric polyamine backbone including protection and deprotection steps of the amino functions. Their behavior on TLC in comparison with that of 1,4-di(4-coumaroyl)spermine (=(E,E)-N-{4-[(3-aminopropyl)amino]butyl}-3,3′-bis(4-hydroxyphenyl)-N,N′-(propane-1,3-diyl)bis[prop-2-enamide]; 2) is discussed.

Nedd4-2-dependent ubiquitylation and regulation of the cardiac potassium channel hERG1

The voltage-gated cardiac potassium channel hERG1 (human ether-à-gogo-related gene 1) plays a key role in the repolarization phase of the cardiac action potential (AP). Mutations in its gene, KCNH2, can lead to defects in the biosynthesis and maturation of the channel, resulting in congenital long QT syndrome (LQTS). To identify the molecular mechanisms regulating the density of hERG1 channels at the plasma membrane, we investigated channel ubiquitylation by ubiquitin ligase Nedd4-2, a post-translational regulatory mechanism previously linked to other ion channels. We found that whole-cell hERG1 currents recorded in HEK293 cells were decreased upon neural precursor cell expressed developmentally down-regulated 4-2 (Nedd4-2) co-expression. The amount of hERG1 channels in total HEK293 lysates and at the cell surface, as assessed by Western blot and biotinylation assays, respectively, were concomitantly decreased. Nedd4-2 and hERG1 interact via a PY motif located in the C-terminus of hERG1. Finally, we determined that Nedd4-2 mediates ubiquitylation of hERG1 and that deletion of this motif affects Nedd4-2-dependent regulation. These results suggest that ubiquitylation of the hERG1 protein by Nedd4-2, and its subsequent down-regulation, could represent an important mechanism for modulation of the duration of the human cardiac action potential.

Quantitative motor unit action potential analysis in 2 paraspinal neck muscles in adult Royal Dutch Sport horses

BACKGROUND: Reference values for quantitative electromyography (QEMG) in neck muscles of Royal Dutch Sport horses are lacking. OBJECTIVE: Determine normative data on quantitative motor unit action potential (QMUP) analysis of serratus ventralis cervicis (SV) and brachiocephalicus (BC) muscle. ANIMALS: Seven adult normal horses (mean age 9.5 standard deviation [SD] +/- 2.3 years, mean height 1.64 SD +/- 4.5 cm, and mean rectal temperature 37.6 SD +/- 0.3 degrees C). METHODS: An observational study on QMUP analysis in 6 segments of each muscle was performed with commercial electromyography equipment. Measurements were made according to formerly published methods. Natural logarithm transformed data were tested with ANOVA and posthoc testing according to Bonferroni. RESULTS: Mean duration, amplitude, phases, turns, area, and size index (SI) did not differ significantly among the 6 segments in each muscle. Mean amplitude, number of phases, and SI were significantly (P < .002) higher in SV than BC, 520 versus 448 muV, 3.0 versus 2.8 muV, and 0.48 versus 0.30 muV, respectively. In SV 95% confidence intervals (CI) for amplitude, duration, number of phases, turns, polyphasia area, and SI were 488-551 muV, 4.3-4.6 ms, 2.9-3.0, 2.4-2.6, 7-12%, 382-448, and 0.26-0.70, respectively; in BC this was 412-483 muV, 4.3-4.7 ms, 2.7-2.8, 2.4-2.6, 4-7%, 393-469, and 0.27-0.34, respectively. Maximal voluntary activity expressed by turns/second did not differ significantly between SV and BC with a 95% CI of 132-173 and 137-198, respectively. CONCLUSIONS AND CLINICAL IMPORTANCE: The establishment of normative data makes objective QEMG of paraspinal muscles in horses suspected of cervical neurogenic disorders possible. Differences between muscles should be taken into account.

Factors associated with the incidence of type 2 diabetes mellitus in HIV-infected participants in the Swiss HIV Cohort Study

BACKGROUND: Human immunodeficiency virus (HIV)-infected persons may be at increased risk for developing type 2 diabetes mellitus because of viral coinfection and adverse effects of treatment. METHODS: We studied associations of new-onset diabetes mellitus with hepatitis B virus and hepatitis C virus coinfections and antiretroviral therapy in participants in the Swiss HIV Cohort Study, using Poisson regression. RESULTS: A total of 123 of 6513 persons experienced diabetes mellitus during 27,798 person-years of follow-up (PYFU), resulting in an incidence of 4.4 cases per 1000 PYFU (95% confidence interval [CI], 3.7-5.3 cases per 1000 PYFU). An increased incidence rate ratio (IRR) was found for male subjects (IRR, 2.5; 95% CI, 1.5-4.2), older age (IRR for subjects >60 years old, 4.3; 95% CI, 2.3-8.2), black (IRR, 2.1; 95% CI, 1.1-4.0) and Asian (IRR, 4.9; 95% CI, 2.2-10.9) ethnicity, Centers for Disease Control and Prevention disease stage C (IRR, 1.6; 95% CI, 1.04-2.4), and obesity (IRR, 4.7; 95% CI, 3.1-7.0), but results for hepatitis C virus infection or active hepatitis B virus infection were inconclusive. Strong associations were found for current treatment with nucleoside reverse-transcriptase inhibitors (IRR, 2.22; 95% CI, 1.11-4.45), nucleoside reverse-transcriptase inhibitors plus protease inhibitors (IRR, 2.48; 95% CI, 1.42-4.31), and nucleoside reverse-transcriptase inhibitors plus protease inhibitors and nonnucleoside reverse-transcriptase inhibitors (IRR, 3.25; 95% CI, 1.59-6.67) but were not found for treatment with nucleoside reverse-transcriptase inhibitors plus nonnucleoside reverse-transcriptase inhibitors (IRR, 1.47; 95% CI, 0.77-2.82). CONCLUSIONS: In addition to traditional risk factors, current treatment with protease inhibitor- and nucleoside reverse-transcriptase inhibitor-containing regimens was associated with the risk of developing type 2 diabetes mellitus. Our study did not find a significant association between viral hepatitis infection and risk of incident diabetes.

Course of psychological variables in whiplash injury--a 2-year follow-up with age, gender and education pair-matched patients

This study evaluated the course of psychological variables during a 2-year follow-up in patients after common whiplash of the cervical spine. From a sample of 117 non-selected patients with common whiplash (investigated on average 7.2 +/- 4.2 days after trauma) a total of 21 suffered trauma-related symptoms over 2 years following initial injury. These patients (symptomatic group) were compared with 21 age, gender and education pair-matched patients, who showed complete recovery from trauma-related symptoms during the 2-year follow-up (asymptomatic group). Both groups underwent standardised testing procedures (i.e., Freiburg Personality Inventory and Well-Being Scale) at referral, and at 3, 6 and 24 months. In the symptomatic group during follow-up no significant changes in rating of neck pain or headache were found. Significant differences between the groups and significant deviation of scores over time were found on the Well-Being and Nervousness Scales. There was a lack of significant difference between the groups on the Depression Scale, indicating a possible somatic basis for changes in psychological functioning in the investigated sample. With regard to scales of Extraversion or Neuroticism, there were neither significant differences between the groups nor significant deviation over time. These results highlight that patients' psychological problems are rather a consequence than a cause of somatic symptoms in whiplash.

Cardiac toxicity with anti-HER-2 therapies: what have we learned so far?

Trastuzumab, a monoclonal antibody that blocks HER-2 receptor, improves the survival of women with HER-2-positive early and advanced breast cancer when given with chemotherapy. Lapatinib, a dual tyrosine kinase inhibitor of EGFR and HER-2, is approved for the treatment of metastatic breast cancer patients after failure of prior anthracycline, taxanes and trastuzumab therapies in combination with capecitabine. Importantly, cardiac toxicity, manifested as symptomatic congestive heart failure or asymptomatic left ventricular ejection fraction decline, has been reported in some of the patients receiving these novel anti-HER-2 therapies, particularly when these drugs are used following anthracyclines, whose cardiotoxic potential has been recognized for decades. This review will focus on the incidence, natural history, underlying mechanisms, management, and areas of uncertainty regarding trastuzumab-and lapatinib-induced cardiotoxicity.

1,2-Bis(2-benzimidazolyl)-1,2-ethanediol, a chiral, tridentate, facially coordinating ligand

The ligand 1,2-bis(1H-benzimidazol-2-yl)-1,2-ethanediol, 1, and its methylated derivative 2 are readily synthesized from tartaric acid, and act as chiral, facially coordinating tridentate ligands, forming complexes of composition ML2 with octahedral transition metals. The copper(II) complexes show distorted 4 + 2 coordination with benzimidazoles occupying the equatorial sites and alcohol functions weakly binding in the axial sites. Nickel(II) complexes in three different states of protonation show regular octahedral geometry with the alcohols mutually cis. Deprotonation of the coordinated alcohol produces little structural change but the monodeprotonated complex forms a hydrogen bonded dimer. Magnetic measurements show the hydrogen bonded bridge to offer a pathway for weak antiferromagnetic coupling. UV-Visible spectroscopy shows the ligand to have a field intermediate between water and pyridine. The diastereoselectivity of complexation depends on the geometry: nickel(II) shows a weak preference for the homochiral complex, whereas copper(II) forms almost exclusively homochiral complexes.