Sera from patients with heparin-induced thrombocytopenia generate platelet-derived microparticles with procoagulant activity: an explanation for the thrombotic complications of heparin-induced thrombocytopenia

Heparin-induced thrombocytopenia is characterized by moderate thrombocytopenia and thrombotic complications, whereas quinine/quinidine-induced thrombocytopenia usually presents with severe thrombocytopenia and bleeding. Using flow cytometry and assays of procoagulant activity, we investigated whether sera from patients with these immune drug reactions could stimulate normal platelets to generate platelet-derived microparticles with procoagulant activity. Sera or purified IgG from patients with heparin-induced thrombocytopenia stimulated the formation of platelet-derived microparticles in a heparin-dependent fashion. Further studies showed that heparin-induced thrombocytopenia sera also produced a marked increase in procoagulant activity. In contrast, sera from patients with quinine- or quinidine-induced thrombocytopenia did not generate platelet-derived microparticles nor generate increased procoagulant activity. However, quinine/quinidine-induced thrombocytopenia sera produced a significant increase in the binding of IgG to platelets in a drug-dependent fashion, whereas sera from patients with heparin-induced thrombocytopenia demonstrated no drug-dependent binding of IgG to platelets. We also observed increased levels of circulating microparticles in patients with acute heparin-induced thrombocytopenia compared with control patients. Our observations indicate that the generation of procoagulant platelet-derived microparticles in vivo is a plausible explanation for the thrombotic complications observed in some patients with heparin-induced thrombocytopenia.     

A humanised tissue‐engineered bone model allows species‐specific breast cancer‐related bone metastasis in vivo

Bone metastases frequently occur in the advanced stages of breast cancer. At this stage, the disease is deemed incurable. To date, the mechanisms of breast cancer‐related metastasis to bone are poorly understood. This may be attributed to the lack of appropriate animal models to investigate the complex cancer cell–bone interactions. In this study, two established tissue‐engineered bone constructs (TEBCs) were applied to a breast cancer‐related metastasis model. A cylindrical medical‐grade polycaprolactone‐tricalcium phosphate scaffold produced by fused deposition modelling (scaffold 1) was compared with a tubular calcium phosphate‐coated polycaprolactone scaffold fabricated by solution electrospinning (scaffold 2) for their potential to generate ectopic humanised bone in NOD/SCID mice. While scaffold 1 was found not suitable to generate a sufficient amount of ectopic bone tissue due to poor ectopic integration, scaffold 2 showed excellent integration into the host tissue, leading to bone formation. To mimic breast cancer cell colonisation to the bone, MDA‐MB‐231, SUM1315, and MDA‐MB‐231BO breast cancer cells were cultured in polyethylene glycol‐based hydrogels and implanted adjacent to the TEBCs. Histological analysis indicated that the breast cancer cells induced an osteoclastic reaction in the TEBCs, demonstrating analogies to breast cancer‐related bone metastasis seen in patients.     

On-line determination of serum bactericidal activity using recombinant luminescent bacteria

Intensity of luminescence quenching in recombinant strains of Escherichia coli with cloned lux-operones by human blood serum is directly proportional to the degree of bactericidal effect assessed by nephelometric and bacteriological methods. This correlation was most characteristic of E. coli with luminescence genes from Photobacterium leiognathi, which substantiates its use in the development of the kinetic bioluminescent method to determine of serum bactericidal activity. The possibility of using this method for evaluation of activity of classic and alternative pathways of compliment activation was demonstrated by using zymosan or EGTA-Mg²⁺-treated sera and C1-C5-deficient sera. __________ Translated from Byulleten’ Eksperimental’noi Biologii i Meditsiny, Vol. 142, No. 8, pp. 200–204, August, 2006     

Laminopathies in Russian families

Mutations in LMNA gene produce a wide spectrum of disorders called laminopathies. In this article, the first cases of laminopathies from Russia are reported. In 10 unrelated families, 9 different mutations were identified: Asp47His, Gly232Arg, c.[781_783delAAG, 781insGTGGAGCAGTATAAGAAA], Arg249Gln (in two families), Arg377His, Arg541His, Ala350Pro, Leu52Pro, and Gly635Asp. Mutations Arg249Gln, Arg377His, and Arg541His were reported previously, others are novel. Four cases present de novo mutations, among them two cases with Arg249Gln are found. Because this mutation occurred de novo also in other reported cases, a mutational 'hot spot' was supposed. Three phenotypes were observed: autosomal dominant (AD) Emery–Dreifuss muscular dystrophy (EDMD), limb-girdle MD type 1B, and AD dilated cardiomyopathy with conduction defect type 1A (DCM1A). Atypical clinical presentations were a very severe EDMD and an infantile DCM1A.     

Ovarian tissue grafting: Lessons learnt from our experience with 55 grafts

Purpose

Uncertainties remain regarding the clinical efficacy of ovarian tissue cryopreservation and grafting. We report a retrospective analysis of reproductive outcomes and lessons learnt following 55 ovarian tissue transplant procedures at our center from 2006 to 2019.

Methods

We analyzed variables related to graft success such as tissue volume, follicular density, total follicular volume, and age on the duration of graft function.

Results

Follicular density and total follicular volume correlate positively with duration of graft function. All clinical pregnancies in our cohort occurred in women who were aged 35 or less at the time of ovarian tissue cryopreservation.

Conclusion

Graft success, as determined by eventual pregnancy and the longevity of graft function, may be impacted by factors including age at cryopreservation, follicular density, and total follicular volume.

     

Major congenital malformations and residential proximity to a regional industrial park including a national toxic waste site: An ecological study

Background  

Public concern about exposure to emissions from the regional industrial park (IP), including 17 chemical plants and the national industrial toxic waste site, initiated this study of the possible association between major congenital malformations (MCM) and residence near the IP in Israel's Southern District.     

Electrophysiological correlates of azimuth and elevation cues for sound localization in human middle latency auditory evoked potentials

OBJECTIVE: To study, in humans, the effects of sound source azimuth and elevation on primary auditory cortex binaural activity associated with sound localization. DESIGN: Middle Latency Auditory Evoked Potentials (MLAEPs) were recorded from three channels, in response to alternating polarity clicks, presented at a rate of 5/sec, at nine virtual spatial locations with different azimuths and elevations. Equivalent dipoles of Binaural Interaction Components (BICs) of MLAEPs were derived from 15 normally and symmetrically hearing adults by subtracting the response to binaural clicks at each spatial location from the algebraic sum of responses to stimulation of each ear alone. The amplified potentials were averaged over 4000 repetitions using a dwell time of 78 micro sec/address/channel. Variations in magnitudes, latencies and orientations of the dipole equivalents of cortical activity were noted in response to the nine spatial locations. RESULTS: Middle-latency BICs included six major components corresponding in latency to the vertex-neck recorded components of MLAEP. A significant decrease of equivalent dipole magnitude was observed for two of the components: Pa2 in response to clicks in the backward positions (medium and no elevation); and Nb in response to clicks in the back and front positions (medium and no elevation) in the midsagittal plane. In the coronal plane, Pa2 equivalent dipole magnitude significantly decreased in response to right-horizontal (no elevation) clicks. Significant effects on equivalent dipole latencies of Pa2 were found for backward positions (no elevation) in the midsagittal plane. No significant effects on Pa2 and Nb equivalent dipole orientations were found across stimulus conditions. CONCLUSIONS: The changes in equivalent dipole magnitudes and latencies of MLAEP BICs across stimulus conditions may reflect spectral tuning in binaural primary auditory cortex neurons processing the frequency cues for sound localization.