D-Dimers Predict Stroke Subtype when Assessed Early

Early classification of ischemic stroke subtype is important for secondary stroke prevention and may guide further investigations.

Is there a place for D-dimers in acute type A aortic dissection?

Plasma concentrations of D-dimer may prove a valuable addition in the diagnostic work-up of acute type A aortic dissection, but not as means of predicting mortality.

The cell surface receptor FGFRL1 forms constitutive dimers that promote cell adhesion

FGFRL1 is a novel member of the fibroblast growth factor (FGF) receptor family. Utilizing the FRET (fluorescence resonance energy transfer) technique, we demonstrate that FGFRL1 forms constitutive homodimers at cell surfaces. The formation of homodimers was verified by co-precipitation of differentially tagged FGFRL1 polypeptides from solution. If overexpressed in cultivated cells, FGFRL1 was found to be enriched at cell-cell contact sites. The extracellular domain of recombinant FGFRL1 promoted cell adhesion, but not cell spreading, when coated on plastic surfaces. Adhesion was mediated by heparan sulfate glycosaminoglycans located at the cell surface. It could specifically be blocked by addition of soluble heparin but not by addition of other glycosaminoglycans. When the amino acid sequence of the putative heparin-binding site was modified by in vitro mutagenesis, the resulting protein exhibited decreased affinity for heparin and reduced activity in the cell-binding assay. Moreover, a synthetic peptide corresponding to the heparin-binding site was able to neutralize the effect of heparin. With its dimeric structure and its adhesion promoting properties, FGFRL1 resembles the nectins, a family of cell adhesion molecules found at cell-cell junctions.

Distamycin-NA: A DNA Analog with an Aromatic Heterocyclic Polyamide Backbone. Part 1. Synthesis and structural analysis of monomers and dimers containing the nucleobase uracil

The synthesis of the monomeric building block 13 and its constitutional isomer 12 of a new type of DNA analog, distamycin-NA, is presented (Schemes 1 and 2). This building block consists of a uracil base attached to a thiophene core unit via a biaryl-like axis. Next to the biaryl-like axis on the thiophene chromophore, a carboxy and an amino substituent are located allowing for oligomerization via peptide coupling. The proof of constitution and the conformational preferences about the biaryl-like axis were established by means of X-ray analyses of the corresponding nitro derivatives 10 and 11. Thus, the uracil bases are propeller-twisted relative to the thiophene core, and bidentate H-bonds occur between two uracil bases in the crystals. The two amino-acid building blocks 12 and 13 were coupled to give the dimers 15 and 16 using dicyclohexylcarbodiimide (DCC) in THF/LiCl and DMF, respectively. While the dimer 15 showed no atropisomerism on the NMR time scale at room temperature, its isomer 16 occurred as distinct diastereoisomers due to the hindered rotation around its biaryl-like axis. Variable-temperature 1H-NMR experiments allowed to determine a rotational barrier of 19 ± 1 kcal/mol in 16. The experimental data were complemented by AM1 calculations.

Excitonic splittings in molecular dimers: why static ab initio calculations cannot match them

After decades of research on molecular excitons, only few molecular dimers are available on which exciton and vibronic coupling theories can be rigorously tested. In centrosymmetric H-bonded dimers consisting of identical (hetero)aromatic chromophores, the monomer electronic transition dipole moment vectors subtract or add, yielding S0 → S1 and S0 → S2 transitions that are symmetry-forbidden or -allowed, respectively. Symmetry breaking by 12C/13C or H/D isotopic substitution renders the forbidden transition weakly allowed. The excitonic coupling (Davydov splitting) can then be measured between the S0 → S1 and S0 → S2 vibrationless bands. We discuss the mass-specific excitonic spectra of five H-bonded dimers that are supersonically cooled to a few K and investigated using two-color resonant two-photon ionization spectroscopy. The excitonic splittings Δcalc predicted by ab initio methods are 5–25 times larger than the experimental excitonic splittings Δexp. The purely electronic ab initio splittings need to be reduced (“quenched”), reflecting the coupling of the electronic transition to the optically active vibrations of the monomers. The so-called quenching factors Γ < 1 can be determined from experiment (Γexp) and/or calculation (Γcalc). The vibronically quenched splittings Γ·Δcalc are found to nicely reproduce the experimental exciton splittings.

Monomeric and dimeric IgG fractions show differential reactivity against pathogen-derived antigens

Polyvalent Ig preparations, derived from the pooled plasma of thousands of healthy donors, contain a complex mix of both 'acquired' and natural antibodies directed against pathogens as well as foreign and self/auto antigens (Ag). Depending on their formulation, donor pool size, etc., liquid Ig preparations contain monomeric and dimeric IgG. The dimeric IgG fraction is thought to represent mainly idiotype-antiidiotype Ab pairs. Treatment of all IgG fractions at pH 4 effectively monomerizes the IgG dimers resulting in separated idiotype-antiidiotype Ab pairs and thus in a comparable F(ab')(2) binding site availability of the different IgG fractions. Previously, we identified an increased anti-self-reactivity within the monomerized dimer fraction. This study addressed if, among the different IgG fractions, an analogous preferential reactivity was evident in the response against different pathogen-derived protein and carbohydrate antigens. Therefore, we assessed the activity of total unseparated IgG, the monomeric and dimeric IgG fractions against antigenic structures of bacterial and viral antigens/virulence factors. All fractions showed similar reactivity to protein antigens except for exotoxin A of Pseudomonas aeruginosa, where the dimeric fraction, especially when monomerized, showed a marked increase in reactivity. This suggests that the production of antiidiotypic IgG antibodies contributes to controlling the immune response to certain categories of pathogens. In contrast, the monomeric IgG fractions showed increased reactivity towards pathogen-associated polysaccharides, classically regarded as T-independent antigens. Taken together, the differential reactivity of the IgG fractions seems to indicate a preferential segregation of antibody reactivities according to the nature of the antigen.

Racemates revisited: heterochiral assemblies and the example of DL-thalidomide

The existence of racemic compounds, comprised of pairs of opposite enantiomers as discrete molecular entities, has been accepted for over a century. However, their ability to remain as associated dimers when in solution is uncertain, if not generally doubted. In this article, data has been assembled to provide evidence for the presence of intact dimeric heterochiral assemblies in solution and presents DL-thalidomide as a probable example of this phenomenon.

Dosing lepirudin in patients with heparin-induced thrombocytopenia and normal or impaired renal function: a single-center experience with 68 patients

The recommended dose (bolus 0.4 mg/kg followed by 0.15 mg/kg per hour) of lepirudin, a direct thrombin inhibitor licensed for treatment of heparin-induced thrombocytopenia (HIT), is too high. Starting in 2001, we omitted the bolus and reduced maintenance dose by at least one-third. Analyzing 53 HIT patients treated between January 2001 and February 2007, we observed that therapeutic anticoagulation intensity already 4 hours after lepirudin start had been reached with the following initial lepirudin doses (median): 0.078 mg/kg per hour [creatinine clearance (CrCl) more than 60 mL/min], 0.040 mg/kg per hour (CrCl 30-60 mL/min), and 0.013 mg/kg per hour (CrCl < 30 mL/min). The efficacy of this treatment was documented by increasing platelets and decreasing D-dimers. Based on this experience, we derived a lepirudin dosing regimen, which was prospectively evaluated treating 15 HIT patients between March 2007 and February 2008. We show that omitting the initial lepirudin bolus and administering 0.08 mg/kg per hour in patients with CrCl more than 60 mL/min, 0.04 mg/kg per hour in patients with CrCl 30-60 mL/min, and 0.01 to 0.02 mg/kg per hour in those with CrCl less than 30 mL/min is efficacious and safe, as documented by increasing platelet counts, decreasing D-dimer levels, and rare thrombotic (1 of 46) and major bleeding (4 of 46) complications.