Role of prothrombin 19911 A>G polymorphism,blood group and male gender in patients with venous thromboembolism: Results of a German cohort study

Journal of Thrombosis and Thrombolysis - The role of the A>G polymorphism at position 19911 in the prothrombin gene (factor [F] 2 at rs3136516) as a risk factor for venous thromboembolism...     

The coordinated action of G-CSF and ELR + CXC chemokines in neutrophil mobilization during acute inflammation

In this study, we have identified a unique combinatorial effect of the chemokines KC/MIP-2 and the cytokine granulocyte colony-stimulating factor (G-CSF) with respect to the rapid mobilization of neutrophils from the bone marrow in a model of acute peritonitis. At 2 hours following an intraperitoneal injection of thioglycollate, there was a 4.5-fold increase in blood neutrophil numbers, which was inhibited 84% and 72% by prior administration of blocking mAbs against either the chemokines KC/MIP-2 or G-CSF, respectively. An intraperitoneal injection of G-CSF acted remotely to stimulate neutrophil mobilization, but did not elicit recruitment into the peritoneum. Further, in vitro G-CSF was neither chemotactic nor chemokinetic for murine neutrophils, and had no priming effect on chemotaxis stimulated by chemokines. Here, we show that, in vitro and in vivo, G-CSF induces neutrophil mobilization by disrupting their SDF-1alpha-mediated retention in the bone marrow. Using an in situ perfusion system of the mouse femoral bone marrow to directly assess mobilization, KC and G-CSF mobilized 6.8 x 10(6) and 5.4 x 10(6) neutrophils, respectively, while the infusion of KC and G-CSF together mobilized 19.5 x 10(6) neutrophils, indicating that these factors act cooperatively with respect to neutrophil mobilization.     

Ten years' experience in aortic valve replacement with homografts in 389 cases

BACKGROUND AND AIM OF THE STUDY: Aortic valve replacement using homografts is an accepted alternative to the use of other replacement devices, and has been established at the authors' institution for more than 10 years. METHODS: Since 1992, a total of 389 homografts was implanted, and 332 patients (mean age 54 years, 72% males) were followed up. The initial patients (n = 75) had subcoronary implantation, all subsequent patients had root replacement. Both aortic grafts (AG) and pulmonary grafts (PG) were used. Follow up was conducted with regard to the factors 'graft origin', 'implantation technique' and 'gender', and included clinical examination, ECG and transthoracic echocardiography on an annual basis. RESULTS: Overall 30-day mortality was 5.4% (AG patients 3.9%, PG patients 13.5%; p = 0.09). Among late deaths (n = 22), six were valve-related (all prosthetic infection). Four minor thrombembolic events were recorded due to amaurosis fugax and transient ischemic attacks (TIA). Freedom from reoperation was 86.5%. Indication for graft replacement was greater after subcoronary implantation than after root implantation (p = 0.04). Reoperation was necessary in 24 patients due to restenosis (n = 4), regurgitation grade >II (n = 5), paravalvular leak (n = 2) and prosthetic infection (n = 13). At the latest echocardiographic follow up, mean peak pressure gradient was 15.60 +/- 11.76 mmHg, homograft regurgitation grade was 0.82 +/- 0.66, left ventricular end-diastolic diameter (EDD) was 49.1 +/- 7.54 mm, and mean aortic root diameter was 30.54 +/- 5.48 mm. When comparing parameters at a mean of five years postoperatively, the pressure gradient increased from 10.26 to 15.02 mmHg, regurgitation grade increased from 0.53 to 0.81, and EDD decreased from 52.3 to 50.4 mm. Other variables showed no significant differences. CONCLUSION: The present results confirmed good midterm-results for aortic valve replacement with homografts. These prostheses are vulnerable to infection, and root replacement was superior to the subcoronary implantation technique.     

Ubiquitylation of synphilin-1 and alpha-synuclein by SIAH and its presence in cellular inclusions and Lewy bodies imply a role in Parkinson's disease

Parkinson's disease (PD) is a neurodegenerative disease characterized by Lewy body formation and death of dopaminergic neurons. Mutations in alpha-synuclein and parkin cause familial forms of PD. Synphilin-1 was shown to interact with alpha-synuclein and to promote the formation of cytosolic inclusions. We now report that synphilin-1 interacts with the E3 ubiquitin-ligases SIAH-1 and SIAH-2. SIAH proteins ubiquitylate synphilin-1 both in vitro and in vivo, promoting its degradation by the ubiquitin-proteasome system. Inability of the proteasome to degrade synphilin-1/SIAH complex leads to a robust formation of ubiquitylated cytosolic inclusions. Ubiquitylation is required for inclusion formation, because a catalytically inactive mutant of SIAH-1, which still binds to synphilin-1, fails to promote inclusions. Like synphilin-1, alpha-synuclein associates with SIAH in intact cells, but the interaction with SIAH-2 was much stronger that with SIAH-1. In vitro experiments show that SIAH-2 monoubiquitylates alpha-synuclein. Further evidence that SIAH proteins may play a role in inclusion formation comes from the demonstration of SIAH immunoreactivity in Lewy bodies of PD patients.     

Evaluation of Cobas TaqMan MTB for Direct Detection of the Mycobacterium tuberculosis Complex in Comparison with Cobas Amplicor MTB

The Roche Cobas Amplicor MTB assay, recently replaced by the Roche Cobas TaqMan MTB assay, was one of the first commercially available assays for detection of the Mycobacterium tuberculosis complex based on nucleic acid amplification. We reported previously on the limited specificity of the Cobas Amplicor MTB assay, in particular for positive samples with an optical density at 660 nm (OD₆₆₀) of <2.0. Using a selected set of respiratory samples, which were scored as false positive by the Cobas Amplicor test, we demonstrate here that the specificity of the Cobas TaqMan assay is significantly improved. In addition, our study of a set of 133 clinical samples revealed that the Cobas TaqMan MTB assay showed significantly less PCR inhibition than the Cobas Amplicor test. An overall concordance of 98.2% was observed between the two assays. In a subsequent prospective study, we evaluated the performance of the Roche Cobas TaqMan MTB assay on 1,143 clinical specimens, including respiratory (n = 838) and nonrespiratory (n = 305) specimens. Using culture as the gold standard, we found a sensitivity of 88.4% and a specificity of 98.8% for the 838 respiratory specimens, compared to a sensitivity of 63.6% and a specificity of 94.6% for the 305 nonrespiratory specimens. We conclude that the Cobas TaqMan MTB assay is a significantly improved tool for the direct detection of M. tuberculosis DNA in clinical specimens.     

Adult trkB Signaling in Parvalbumin Interneurons is Essential to Prefrontal Network Dynamics

Inhibitory interneurons expressing parvalbumin (PV) are central to cortical network dynamics, generation of γ oscillations, and cognition. Dysfunction of PV interneurons disrupts cortical information processing and cognitive behavior. Brain-derived neurotrophic factor (BDNF)/tyrosine receptor kinase B (trkB) signaling regulates the maturation of cortical PV interneurons but is also implicated in their adult multidimensional functions. Using a novel viral strategy for cell-type-specific and spatially restricted expression of a dominant-negative trkB (trkB.DN), we show that BDNF/trkB signaling is essential to the integrity and maintenance of prefrontal PV interneurons in adult male and female mice. Reduced BDNF/trkB signaling in PV interneurons in the medial prefrontal cortex (mPFC) resulted in deficient PV inhibition and increased baseline local field potential (LFP) activity in a broad frequency band. The altered network activity was particularly pronounced during increased activation of the prefrontal network and was associated with changed dynamics of local excitatory neurons, as well as decreased modulation of the LFP, abnormalities that appeared to generalize across stimuli and brain states. In addition, our findings link reduced BDNF/trkB signaling in prefrontal PV interneurons to increased aggression. Together our investigations demonstrate that BDNF/trkB signaling in PV interneurons in the adult mPFC is essential to local network dynamics and cognitive behavior. Our data provide direct support for the suggested association between decreased trkB signaling, deficient PV inhibition, and altered prefrontal circuitry.SIGNIFICANCE STATEMENT Brain-derived neurotrophic factor (BDNF)/tyrosine receptor kinase B (trkB) signaling promotes the maturation of inhibitory parvalbumin (PV) interneurons, neurons central to local cortical dynamics, γ rhythms, and cognition. Here, we used a novel viral approach for reduced BDNF/trkB signaling in PV interneurons in the medial prefrontal cortex (mPFC) to establish the role of BDNF/trkB signaling in adult prefrontal network activities. Reduced BDNF/trkB signaling caused pronounced morphologic alterations, reduced PV inhibition, and deficient prefrontal network dynamics. The altered network activity appeared to manifest across stimuli and brain states and was associated with aberrant local field potential (LFP) activities and increased aggression. The results demonstrate that adult BDNF/trkB signaling is essential to PV inhibition and prefrontal circuit function and directly links BDNF/trkB signaling to network integrity in the adult brain.     

Diversity of Culex torrentium Martini, 1925 — a potential vector of arboviruses and filaria in Europe

Culex torrentium is one of the most common mosquito species in Germany. Due to its sympatric occurrence as well as its similar morphological and ecological characteristics, it has often been confused with another common species, Culex pipiens. Both species are known to be potential vectors for different arboviruses (not only in Germany) with C. torrentium being a possible vector for Sindbis or Ockelbo virus. In our study, we analyzed the genetic variability in a 658 bp fragment of the cytochrome c oxidase subunit I gene (coxI) of C. torrentium, from nine localities in the Frankfurt/Rhine-Main Metropolitan Region. The results of our genetic survey indicate a higher genetic diversity in this gene region for C. torrentium than for the morphologically similar C. pipiens. Our findings may explain the difficulties in the past to find morphological characteristics that apply to all populations of C. torrentium, when attempting to separate them clearly from C. pipiens, by any other criteria than male genitalia. Being ornithophilic, possible hybrids between C. torrentium and the humanophilic C. pipiens biotype molestus, could potentially serve as important vectors for zoonotic diseases. Therefore, we recommend that greater emphasis is placed on the ecological characteristics, population structure, and the taxonomy of this often neglected species, in the future.     

The diagnosis and management of allergic reactions in patients sensitized to non-specific lipid transfer proteins

Sensitization to one or more non-specific lipid transfer proteins (nsLTPs), initially thought to exist mainly in southern Europe, is becoming accepted as a cause of allergic reactions to plant foods across Europe and beyond. The peach nsLTP allergen Pru p 3 is a dominant sensitizing allergen and peaches a common food trigger, although multiple foods can be involved. A frequent feature of reactions is the requirement for a cofactor (exercise, alcohol, non-steroidal anti-inflammatory drugs, Cannabis sativa) to be present for a food to elicit a reaction. The variability in the food and cofactor triggers makes it essential to include an allergy-focused diet and clinical history in the diagnostic workup. Testing on suspected food triggers should also establish whether sensitization to nsLTP is present, using purified or recombinant nsLTP allergens such as Pru p 3. The avoidance of known trigger foods and advice on cofactors is currently the main management for this condition. Studies on immunotherapy are promising, but it is unknown whether such treatments will be useful in populations where Pru p 3 is not the primary sensitizing allergen. Future research should focus on the mechanisms of cofactors, improving diagnostic accuracy and establishing the efficacy of immunotherapy.