Defibrillator generator replacements in patients with left ventricular assist device support: The risks of hematoma and infection.

BACKGROUND: The majority (89%) of left ventricular assist device (LVAD) patients have an implantable cardioverter-defibrillator (ICD) in place. Due to the advances of modern-day LVAD therapy, more patients are on support for longer. This inevitably leads to more LVAD patients facing ICD generator battery depletion. Until now, there are insufficient data regarding periprocedural risks of generator replacements in a high-risk group like the LVAD cohort. METHODS: A retrospective, single-center analysis of pocket-related outcomes of all ICD generator replacements in LVAD and Non-LVAD patients between January 2014 and December 2018. The primary outcome was the combined endpoint of clinically significant pocket hematoma and/or cardiac implantable electronic device (CIED) infection in the first 6 months after ICD generator exchange. The clinically significant hematoma was defined as hematoma requiring reoperation, prolongation of hospitalization, or interruption of anticoagulation. The cumulative incidence function was calculated for the primary endpoint. RESULTS: Two hundred seventy-seven patients underwent ICD generator exchange in our clinic in this time. Of these, 251 patients had a complete 6-month follow-up regarding clinically significant pocket hematomas and pocket infections. One hundred ninety patients had no LVAD, and 61 patients were on LVAD support. The rate of the primary combined endpoint clinically significant pocket hematoma and/or CIED infection was 3.5 times higher in LVAD patients compared to the non-LVAD cohort (event rate 39.14 vs 11.07 per 100 patient-years, p = 0.048). Clinically significant pocket hematomas necessitating revision occurred nearly 4 times more often in the LVAD group (p = 0.042). Pocket device infection rates were around 16 times higher in LVAD patients compared to non-LVAD patients (p = 0.002). CONCLUSIONS: Compared to Non-LVAD patients, LVAD patients exhibit a relevant higher rate of clinically significant pocket hematoma and CIED infection after ICD generator exchange. This information should additionally be considered in the decision-making process regarding the indication for ICD generator exchange.

A novel palladium-catalyzed intramolecular redox reaction.

[reaction: see text] A new type of palladium-catalyzed redox reaction is described, forming enones from 2-(2-bromobenzyl)-ketones with an overall loss of HBr. The scope and limitations of the reaction are demonstrated by a series of cyclic and acyclic substrates. The mechanism most probably involves the formation of an intramolecular arylpalladium enolate and is related to the oxidation of silyl enol ethers with palladium acetate.

Chiral acetals as stereoinductors: diastereoface selective alkylation of dihydrobenzoxazine-derived amide enolates

Novel dihydrobenzoxazine-derived acetals of type 3 have been developed for asymmetric C-alkylations of propionyl amide enolates. High stereoselectivities are obtained for amides 15 and 22 which are rationalized in terms of intramolecular metal chelate formation.

[Evaluation of the display quality of different modalities in digital radiology]. / Evaluation der Abbildungsqualität unterschiedlicher Befundungsmodalitäten in der digitalen Radiologie.

PURPOSE: To evaluate the display quality of digital radiographies on different monitors in comparison to hard-copy films on view boxes. MATERIALS AND METHODS: Radiographs of different statistical phantoms simulating common pathologies of the chest, such as interstitial pneumonia, pneumothorax and pulmonary nodules, were acquired. Under same ambient light condition, the radiographs were rated as to the presence or absence of a simulated pathological finding using a confidence scale. The evaluation was performed on a grey-scale monitor, a color monitor, two LC displays and two different light boxes by four experienced radiologists. Sensitivity and specificity were determined in a ROC analysis for each viewing modality and phantom. The area under the curve (Az) was acquired cumulatively including the results of all investigators. A total of 4200 rating decisions were included. The chi (2)-test was performed for significance analysis using the a and b parameters of two ROC-curves (alpha = 0.05). RESULTS: The rating of the included LC displays (Az = 0.7009 - 0.9608) and color monitors (Az = 0.7993 - 0.9591) showed a significant loss of diagnostic validity in comparison to the grey-scale monitor (Az = 0.8435 - 0.9762) and the view boxes (Az = 0.8228 - 0.9891). CONCLUSION: LC displays and color monitor included in this study cannot be recommended for diagnostic viewing. The loss of diagnostic validity might be attributable to the viewing-angle-dependent contrast of LC displays. However, no loss in diagnostic validity could be assessed for the tested grey-scale monitor.

How Stable Are Epoxides? A Novel Synthesis of Epothilone B.

Remarkable stability of the oxirane function is displayed over a number of synthetic operations in a novel synthesis of the antitumor compound epothilone B (see scheme). The cis-epoxide, generated very early by dihydroxylation of an (E)-olefin, was resistant to more than ten synthetic steps under a wide variety of reaction conditions. TBS=tert-butyldimethylsilyl.

Valerenic acid derivatives as novel subunit-selective GABAA receptor ligands - in vitro and in vivo characterization.

BACKGROUND AND PURPOSE: Subunit-specific modulators of gamma-aminobutyric acid (GABA) type A (GABA(A)) receptors can help to assess the physiological function of receptors with different subunit composition and also provide the basis for the development of new drugs. Valerenic acid (VA) was recently identified as a beta(2/3) subunit-specific modulator of GABA(A) receptors with anxiolytic potential. The aim of the present study was to generate VA derivatives as novel GABA(A) receptor modulators and to gain insight into the structure-activity relation of this molecule. EXPERIMENTAL APPROACH: The carboxyl group of VA was substituted by an uncharged amide or amides with different chain length. Modulation of GABA(A) receptors composed of different subunit compositions by the VA derivatives was studied in Xenopus oocytes by means of the two-microelectrode voltage-clamp technique. Half-maximal stimulation of GABA-induced chloride currents (I(GABA)) through GABA(A) receptors (EC(50)) and efficacies (maximal stimulation of I(GABA)) were estimated. Anxiolytic activity of the VA derivatives was studied in mice, applying the elevated plus maze test. KEY RESULTS: Valerenic acid amide (VA-A) displayed the highest efficacy (more than twofold greater I(GABA) enhancement than VA) and highest potency (EC(50)= 13.7 +/- 2.3 microM) on alpha(1)beta(3) receptors. Higher efficacy and potency of VA-A were also observed on alpha(1)beta(2)gamma(2s) and alpha(3)beta(3)gamma(2s) receptors. Anxiolytic effects were most pronounced for VA-A. CONCLUSIONS AND IMPLICATIONS: Valerenic acid derivatives with higher efficacy and affinity can be generated. Greater in vitro action of the amide derivative correlated with a more pronounced anxiolytic effect in vivo. The data give further confidence in targeting beta(3) subunit containing GABA(A) receptors for development of anxiolytics.

Efficient synthesis of the D-ring fragment of cobyric acid

The synthesis of a highly functionalized 4,5-dihydro-3H-pyrrol, namely, the D-ring fragment 5a of cobyric acid (1), is described in this letter. A very efficient assembly to 5a involves CBS-reduction of 10, a [2,3] Wittig-Still rearrangement, and a stereoselective Michael addition to a nitro olefin.

Total syntheses of epothilones B and D.

Total syntheses of the microtubule stabilizing antitumor drugs epothilone B and D are described, starting from optically pure (S)-malic acid and methyl (R)-3-hydroxy-2-methylpropionate. The synthesis is highly convergent by coupling the three fragments C1-C6 (fragment D), C7-C10 (fragment C), and C11-C21 (fragment B). Key steps are two stereoselective Wittig type olefinations to generate the 12,13- and 16,17-double bonds, an enantioselective Mukaiyama aldol addition to synthesize fragment D, and a sulfone anion allyl iodide alkylation to connect fragments B and C. Finally fragment D was attached to the B + C fragment via aldol addition.

The 12,13-diol cyclization approach for a truly stereocontrolled total synthesis of epothilone B and the synthesis of a conformationally restrained analogue.

A highly convergent and stereocontrolled synthesis of epothilone B (1) has been developed. The epoxide moiety in 1 was generated by regioselective mesylation and base treatment of the 12,13-diol 30 which was formed by a chelate Cram controlled Grignard addition of 14 and methyl ketone 13. Both fragments were synthesized from the chiral carbon pool precursors (S)-citronellol and (S)-lactic acid, respectively. A highly diastereoselective aldol addition of epoxy-aldehyde 7 and the known Southern hemisphere ketone 8 delivered the full carbon skeleton, containing all the stereogenic centers of 1. Functional group manipulation, macrolactonization and removal of two protecting groups then yielded 1. The spatial closeness of the C4-beta-methyl and C6-methyl group in the crystal structure of 1 inspired us to connect them through a methylene bridge to give a cyclohexanone derivative. Thus, the Northern hemisphere aldehyde 7 was added to the enolate of the cyclohexanone 47. Further manipulations and macrolactonization delivered the conformationally restrained epothilone derivative 42.

Synthesis and acetylcholinesterase inhibition of 5-desamino huperzine A derivatives.

(E)- and (Z)-5-Desamino huperzine A derivatives have been synthesized using a new synthetic strategy towards the huperzine A skeleton. These derivatives showed AChE inhibition constants in the low micromolar range and thus display better activity than all previously synthesized C5 derivatives.

[Studies on DNA content of tissues and organs. 1st communication: changes in cell content of some mesenchymal and parenchymatous rat organs during development, maturation, and in part aging (determinations of DNA) (author's transl)]. / Untersuchungen zum DNS-Gehalt von Geweben und Organen. 1. Mitt.: Veränderungen des Zellgehaltes einiger bindegewebiger und parenchymatöser Organe der Ratte während Entwicklung und Reifung, zum Teil auch bei Alterung (DNS-Bestimmungen).

In this study the cell content was analyzed by means of the DNA content of certain mesenchymal and parenchymal organs of the rat. The main aspects were the postnatal stages of development and maturation. Their correlation to aging was examined only on examples, so was their correlation to the prenatal development (on 2 examples: liver and skin). One important result of this research is that a gradual reduction in the exponential growth takes place with increasing maturation and development. The "growth by production" prevails over the "growth by division" (of cells). This is the explanation for the "relative" (= apparent) decrease in the cell content of the tissues and organs analyzed during the decisive postnatal development and maturation phases. In this period the complete differentiation of the cytoplasmic structures and of the differentiation products of the tissues and organs here analyzed occurs. This leads to a shift in their relative amounts to the disadvantage of the cell nuclei, which prevailed in the total weight of tissues and organs during the early phases of development. This concerns determinations of the DNA content related to wet weight even more than such of the DNA content related to dry weight. As already shown clearly, the different tissues and organs of the mammalian organism (here on the example of the rat) grow, mature and age differently. During growth different phases can be distinguished, too, by analysis of the DNA content which partly correlate with phases of growth which were differentiated morphologically. Determinations of DNA contents are necessary as parameters for determinations of the production metabolism (e.g. activities of enzymes, products of formation and differentiation) of the different tissues and organs during their development, maturation and aging.