Fibrinogen Bonn (p. Arg510Cys) in the Aα-Chain Is Associated with High Risk of Venous Thrombosis.

INTRODUCTION: Inherited dysfibrinogenemia is a qualitative defect of fibrinogen caused by various mutations among three fibrinogen genes. Dysfibrinogenemia can be associated with an increased risk of thrombosis, bleeding, or both. Here, we report a 36-year-old female with dysfibrinogenemia who experienced two successful pregnancies under thromboprophylaxis after cerebral venous sinus thrombosis (CVST). PATIENTS AND METHODS: In addition to plasmatic coagulation tests, fibrinogen genes FGA, FGB, and FGG were screened using direct genomic DNA sequencing. The structural-functional implications of the detected mutation were analyzed in silico. RESULTS: Inherited dysfibrinogenemia was diagnosed in an index patient after CVST in a risk situation. Anticoagulation with warfarin was stopped after 12 months when the first pregnancy was planned. Pregnancy and spontaneous delivery (2020) was uncomplicated. A second pregnancy was interrupted because of acute cytomegalovirus infection and the third pregnancy was successful in 2022. Pregnancies were accompanied by thromboprophylaxis with enoxaparin 40 mg once daily until 6 weeks postpartum. Substitution of fibrinogen has not become necessary in the index patient so far. Genetic analysis revealed a novel missense mutation (p. Arg510Cys) in the FGA gene ("fibrinogen Bonn") in the index patient, as well as an asymptomatic sister, and their father who experienced recurrent pulmonary embolism. Surface exposure of wild-type Arg510 suggested the mutated Cys510 to form nonnative disulfide bonds with surface-exposed reactive cysteines from other plasma proteins like albumin leading to formation of aggregates and impaired fibrinolysis. CONCLUSIONS: Fibrinogen Bonn might be associated with an increased risk of thrombosis, possibly due to impaired polymerization.

[Perioperative management of coagulation in otorhinolaryngologic surgery]. / Perioperatives Gerinnungsmanagement in der HNO-Heilkunde.

Considering the increasing number of patients suffering from drug-induced coagulation disorders caused by antiplatelet or anticoagulant therapy, the right balance between minimizing the risk of bleeding and the risk of a venous thrombosis or embolism during otorhinolaryngologic (ORL) surgery is becoming increasingly important. According to a recent study, the highest risk of intraoperative bleeding in ORL surgery is associated with transoral tumor surgery, tonsillectomy, thyroidectomy, and glomus tumor surgery. The risk of venous thrombosis or embolism during ORL surgery is estimated to be 1%, and increases to 6% among tumor patients. Currently, there is no general recommendation for perioperative hemostatic management because of the limited available data. In the majority of patients who continue antiplatelet therapy with acetylsalicylic acid (ASS) to prevent thromboembolic events, the perioperative bleeding risk is considered to be acceptable. For patients with dual antiplatelet therapy, surgical procedures should be only performed after adaption of the medication.

Transcriptome-wide analysis of filarial extract-primed human monocytes reveal changes in LPS-induced PTX3 expression levels.

Filarial nematodes modulate immune responses in their host to enable their survival and mediate protective effects against autoimmunity and allergies. In this study, we examined the immunomodulatory capacity of extracts from the human pathogenic filaria Brugia malayi (BmA) on human monocyte responses in a transcriptome-wide manner to identify associated pathways and diseases. As previous transcriptome studies often observed quiescent responses of innate cells to filariae, the potential of BmA to alter LPS driven responses was investigated by analyzing >47.000 transcripts of monocytes from healthy male volunteers stimulated with BmA, Escherichia coli LPS or a sequential stimulation of both. In comparison to ~2200 differentially expressed genes in LPS-only stimulated monocytes, only a limited number of differentially expressed genes were identified upon BmA priming before LPS re-stimulation with only PTX3↓ reaching statistical significance after correcting for multiple testing. Nominal significant differences were reached for metallothioneins↑, MMP9↑, CXCL5/ENA-78↑, CXCL6/GCP-2↑, TNFRSF21↓, and CCL20/MIP3α↓ and were confirmed by qPCR or ELISA. Flow cytometric analysis of activation markers revealed a reduced LPS-induced expression of HLA-DR and CD86 on BmA-primed monocytes as well as a reduced apoptosis of BmA-stimulated monocytes. While our experimental design does not allow a stringent extrapolation of our results to the development of filarial pathology, several genes that were identified in BmA-primed monocytes had previously been associated with filarial pathology, supporting the need for further research.

An approach for the identification of exemplar sites for scaling up targeted field observations of benthic biogeochemistry in heterogeneous environments.

Continental shelf sediments are globally important for biogeochemical activity. Quantification of shelf-scale stocks and fluxes of carbon and nutrients requires the extrapolation of observations made at limited points in space and time. The procedure for selecting exemplar sites to form the basis of this up-scaling is discussed in relation to a UK-funded research programme investigating biogeochemistry in shelf seas. A three-step selection process is proposed in which (1) a target area representative of UK shelf sediment heterogeneity is selected, (2) the target area is assessed for spatial heterogeneity in sediment and habitat type, bed and water column structure and hydrodynamic forcing, and (3) study sites are selected within this target area encompassing the range of spatial heterogeneity required to address key scientific questions regarding shelf scale biogeochemistry, and minimise confounding variables. This led to the selection of four sites within the Celtic Sea that are significantly different in terms of their sediment, bed structure, and macrofaunal, meiofaunal and microbial community structures and diversity, but have minimal variations in water depth, tidal and wave magnitudes and directions, temperature and salinity. They form the basis of a research cruise programme of observation, sampling and experimentation encompassing the spring bloom cycle. Typical variation in key biogeochemical, sediment, biological and hydrodynamic parameters over a pre to post bloom period are presented, with a discussion of anthropogenic influences in the region. This methodology ensures the best likelihood of site-specific work being useful for up-scaling activities, increasing our understanding of benthic biogeochemistry at the UK-shelf scale.

Simulating pathways of subsurface oil in the Faroe-Shetland Channel using an ocean general circulation model.

Little is known about the fate of subsurface hydrocarbon plumes from deep-sea oil well blowouts and their effects on processes and communities. As deepwater drilling expands in the Faroe-Shetland Channel (FSC), oil well blowouts are a possibility, and the unusual ocean circulation of this region presents challenges to understanding possible subsurface oil pathways in the event of a spill. Here, an ocean general circulation model was used with a particle tracking algorithm to assess temporal variability of the oil-plume distribution from a deep-sea oil well blowout in the FSC. The drift of particles was first tracked for one year following release. Then, ambient model temperatures were used to simulate temperature-mediated biodegradation, truncating the trajectories of particles accordingly. Release depth of the modeled subsurface plumes affected both their direction of transport and distance travelled from their release location, and there was considerable interannual variability in transport.

A novel missense mutation in the FGB gene (p.Gly302Arg) leading to afibrinogenemia. Predicted structure and function consequences.

Afibrinogenemia represents the rarest form of fibrinogen deficiency. Causative missense mutations occur rarely and may improve the understanding of fibrinogen structure and function. PATIENTS AND METHODS: The propositus was a 26-year-old Argentinian with afibrinogenemia. FGA, FGB and FGG exons and flanking regions were screened by sequencing and the mutant protein was analyzed in silico. RESULTS: A novel missense mutation in the FGB gene (Bbeta Gly272Arg, p.Gly302Arg) was identified. In silico analysis revealed its location in a highly conserved region, which preserves the core fold of the C-terminal beta-chain and is important for proper secretion. A substitution by a positively charged large Arg residue in this area would most likely disturb the core fold by additional interactions with adjacent residues (p.Asp291, p.Asp297, p.Asp311), or by forming of non-native interactions with other proteins, thereby hindering the action of molecular chaperones. Both alternatives would disturb the regular secretion of the beta-chain. CONCLUSIONS: The novel missense mutation in the FGB gene causes afibrinogenemia most probably by affecting the secretion of the fibrinogen beta-chain.

Proton acceleration by irradiation of isolated spheres with an intense laser pulse.

We report on experiments irradiating isolated plastic spheres with a peak laser intensity of 2-3×10^{20}Wcm^{-2}. With a laser focal spot size of 10 µm full width half maximum (FWHM) the sphere diameter was varied between 520 nm and 19.3 µm. Maximum proton energies of ∼25 MeV are achieved for targets matching the focal spot size of 10 µm in diameter or being slightly smaller. For smaller spheres the kinetic energy distributions of protons become nonmonotonic, indicating a change in the accelerating mechanism from ambipolar expansion towards a regime dominated by effects caused by Coulomb repulsion of ions. The energy conversion efficiency from laser energy to proton kinetic energy is optimized when the target diameter matches the laser focal spot size with efficiencies reaching the percent level. The change of proton acceleration efficiency with target size can be attributed to the reduced cross-sectional overlap of subfocus targets with the laser. Reported experimental observations are in line with 3D3V particle in cell simulations. They make use of well-defined targets and point out pathways for future applications and experiments.

High resolution study of the spatial distributions of abyssal fishes by autonomous underwater vehicle.

On abyssal plains, demersal fish are believed to play an important role in transferring energy across the seafloor and between the pelagic and benthic realms. However, little is known about their spatial distributions, making it difficult to quantify their ecological significance. To address this, we employed an autonomous underwater vehicle to conduct an exceptionally large photographic survey of fish distributions on the Porcupine Abyssal Plain (NE Atlantic, 4850 m water depth) encompassing two spatial scales (1-10 km(2)) on and adjacent to a small abyssal hill (240 m elevation). The spatial distributions of the total fish fauna and that of the two dominant morphotypes (Coryphaenoides sp. 1 and C. profundicolus) appeared to be random, a result contrary to common expectation but consistent with previous predictions for these fishes. We estimated total fish density on the abyssal plain to be 723 individuals km(-2) (95% CI: 601-844). This estimate is higher, and likely more precise, than prior estimates from trawl catch and baited camera techniques (152 and 188 individuals km(-2) respectively). We detected no significant difference in fish density between abyssal hill and plain, nor did we detect any evidence for the existence of fish aggregations at any spatial scale assessed.

Decadal Change in Sediment Community Oxygen Consumption in the Abyssal Northeast Pacific.

Long time-series studies are critical to assessing impacts of climate change on the marine carbon cycle. A 27-year time-series study in the abyssal northeast Pacific (Sta. M, 4000 m depth) has provided the first concurrent measurements of sinking particulate organic carbon supply (POC flux) and remineralization by the benthic community. Sediment community oxygen consumption (SCOC), an estimate of organic carbon remineralization, was measured in situ over daily to interannual periods with four different instruments. Daily averages of SCOC ranged from a low of 5.0 mg C m-2 day-1 in February 1991 to a high of 31.0 mg C m-2 day-1 in June 2012. POC flux estimated from sediment trap collections at 600 and 50 m above bottom ranged from 0.3 mg C m-2 day-1 in October 2013 to 32.0 mg C m-2 day-1 in June 2011. Monthly averages of SCOC and POC flux correlated significantly with no time lag. Over the long time series, yearly average POC flux accounted for 63 % of the estimated carbon demand of the benthic community. Long time-series studies of sediment community processes, particularly SCOC, have shown similar fluctuations with the flux of POC reaching the abyssal seafloor. SCOC quickly responds to changes in food supply and tracks POC flux. Yet, SCOC consistently exceeds POC flux as measured by sediment traps alone. The shortfall of ~37 % could be explained by sediment trap sampling artifacts over decadal scales including undersampling of large sinking particles. High-resolution measurements of SCOC are critical to developing a realistic carbon cycle model for the open ocean. Such input is essential to evaluate the impact of climate change on the oceanic carbon cycle, and the long-term influences on the sedimentation record.

Neoplasm-induced bleeding in inherited, heterozygous FXIII-A deficiency.

UNLABELLED: Inherited mild factor XIII deficiency belongs to one of the most underdiagnosed bleeding disorders so far. This is, because most patients do not develop bleeding complications in daily life. Patient, methods: A man (age: 64 years) without a history of bleeding presented with painful swelling of neck, weight loss, anemia and episodic bleeding from the right tonsil necessitating tonsillectomy. Histologic and immunohistochemical evaluation revealed cytokeratin-positive epitheloid angiosarcoma. Blood coagulation status showed significantly elevated D-dimer and decreased FXIII levels (FXIII-activity 35%, FXIIIA-Ag 16-26%). Plasma mixing studies excluded neutralizing antibodies against FXIII. RESULTS: A novel heterozygous F13A1 gene nonsense mutation (p.Glu103Ter, c.307G>T) was found confirming heterozygous FXIII-A deficiency. The same mutation was detected in two further asymptomatic relatives. For further clinical management the patient was transfused with FXIII-concentrate and showed an adequate increase of FXIII ruling out FXIII deficiency to be induced by increased turnover. Despite this haemostatic management and antifibrinolytic treatment the patient had to undergo several revisions due to delayed, Hb relevant bleeding after cervical lymph nodes extirpation and resection of tonsil. Two chemotherapy cycles with paclitaxel and palliative radiotherapy of the neck area were performed, but the patient died unfortunately two months after diagnosis. CONCLUSIONS: It is a unique case showing the combination of a highly aggressive angiosarcoma and presence of inherited FXIII deficiency. It is also a rare example demonstrating the benefit of FXIII genotyping besides the expected acquired FXIII deficiency possibly due to neoplasm induced increased consumption by elevated crosslinking of fibrin fibers.