Modulation of systemic hemostatic parameters by enoxaparin during gestation in women with thrombophilia and pregnancy loss

Recurrent pregnancy loss (PL) is associated with maternal thrombophilia and prophylaxis with low molecular weight heparin (LMWH) can improve pregnancy outcome in this setting.The aim of this study was to investigate the modulation of systemic hemostatic parameters by enoxaparin in women with recurrent PL and to evaluate plasmatic parameters that would potentially enable monitoring LMWH prophylaxis effect during pregnancy. Study group included 87 women with thrombophilia and PL treated with enoxaparin 40 mg daily vs. 40 mg twice daily. The control group comprised 40 women with normal pregnancies. Blood samples have been collected throughout the period starting at 5-10 weeks of gestation until 6-10 weeks postpartum. The determined plasmatic markers included: anti-Xa activity, total and free tissue factor pathway inhibitor (TFPI), D-dimer, prothrombin fragment 1+2 (PT1+2), activated protein C resistance (APC-SR) and free protein S. Successful pregnancy outcome was recorded in 70 (80.5%) women treated with enoxaparin, without correlation to enoxaparin dosage. Seventeen women (19.5%) had pregnancy loss at 16+/-7 (6-32) weeks of gestation. Anti-Xa levels at 10-15 weeks of gestation were higher (0.39+/-0.38 u/ml) in the successful pregnancy outcome group compared to the abortion group (0.22+/-0.2 u/ml). Prophylactic anti-Xa activity levels (0.28+/-0.13 u/ml) were documented from 15 weeks of gestation until delivery in the successful pregnancy outcome group. Significant increase in anti-Xa, total TFPI and free TFPI levels (P<0.001) was achieved after beginning of LMWH prophylaxis in successful pregnancy outcome group but not in the abortion group. D-dimer and PT1+2 levels appeared to be significantly increased while APC-SR and free protein S levels gradually decreased during pregnancy, with no difference between study groups. These results suggest that LMWH prophylaxis during pregnancy enables modulation of systemic hemostatic parameters via inhibition of factor Xa and increase in plasmatic total and free TFPI levels.     

Clinical and molecular features in a cohort of Middle Eastern patients with epidermolysis bullosa

Background

Epidermolysis bullosa (EB) features skin and mucosal fragility due to pathogenic variants in genes encoding components of the cutaneous basement membrane. Based on the level of separation within the dermal-epidermal junction, EB is sub-classified into four major types including EB simplex (EBS), junctional EB (JEB), dystrophic EB (DEB), and Kindler EB (KEB) with 16 EB-associated genes reported to date.

Methods

We ascertained a cohort of 151 EB patients of various Middle Eastern ethnic backgrounds.

Results

The cohort was comprised of EBS (64%, 97/151), DEB (21%, 31/151), JEB (12%, 18/151), and KEB (3%, 5/151). KRT14 and KRT5 variants were most common among EBS patients with 43% (42/97) and 46% (45/97) of EBS patients carrying mutations in either of these two genes, respectively. Truncal involvement was more common in KRT14-associated EBS as compared to EBS due to KRT5 mutations (p < .05). Mutations in COL17A1 and laminin 332-encoding genes were identified in 55% (10/18) and 45% (8/18) of JEB patients. Scarring alopecia, caries, and EB nevi were most common among JEB patients carrying COL17A1 mutations as compared to laminin 332-associated JEB (p < .05). Abnormal nails were evident in most DEB and JEB patients while poikiloderma was exclusively observed in KEB (p < .001).

Conclusions

EB patients of Middle Eastern origin were found to feature specific phenotype–genotype correlations of relevance to the diagnosis and genetic counseling of patients in this region.     

Impact of self-assembly properties on antibacterial activity of short acyl-lysine oligomers

We investigated both the structural and functional consequences of modifying the hydrophobic, lipopeptide-mimetic oligo-acyl-lysine (OAK) N(alpha)-hexadecanoyl-l-lysyl-l-lysyl-aminododecanoyl-l-lysyl-amide (c(16)KKc(12)K) to its unsaturated analog hexadecenoyl-KKc(12)K [c(16(omega7))KKc(12)K]. Despite similar tendencies for self-assembly in solution (critical aggregation concentrations, approximately 10 muM), the analogous OAKs displayed dissimilar antibacterial properties (e.g., bactericidal kinetics taking minutes versus hours). Diverse experimental evidence provided insight into these discrepancies: whereas c(16(omega7))KKc(12)K created wiry interconnected nanofiber networks, c(16)KKc(12)K formed both wider and stiffer fibers which displayed distinct binding properties to phospholipid membranes. Unsaturation also shifted their gel-to-liquid transition temperatures and altered their light-scattering properties, suggesting the disassembly of c(16(omega7))KKc(12)K in the presence of bacteria. Collectively, the data indicated that the higher efficiency in interfering with bacterial viability emanated from a wobbly packing imposed by a single double bond. This suggests that similar strategies might improve hydrophobic OAKs and related lipopeptide antibiotics.     

Engineering cell platforms for myocardial regeneration

INTRODUCTION: Various engineered 'cell-platforms' have been reported in recent years for the possible treatment of myocardial infarction (MI) and end-stage heart failure. These engineered platforms rely on two key factors: cells and/or biomaterial scaffolds for the regeneration of the infarcted heart tissue. AREAS COVERED: Two major cell-platform approaches are described and broadly categorized as 'injectable cell platforms' and 'patch-based cell platforms'. The recent advancements in these cell-platforms in terms of their relative successes in-vivo as well as their clinical feasibility are summarized. Natural as well as synthetic scaffolds, with or without the cellular component, are compared with cell based therapy alone. This review focuses on achievements, as well as the gaps that are presently checking any progress towards producing clinically relevant panacea for myocardial regeneration. EXPERT OPINION: Cardiac and induced pluripotent stem cells will probably be the focus of future research. The combined cell-biomaterial scaffold therapy is superior to cell therapy alone. Nevertheless, encouraging pre-clinical successes have limited translation into clinical practice due to limited cell survival post transplantation, inadequate construct thicknesses for human-sized hearts and the traditional use of 'flat (2D) tissue culture' techniques. The development of complementary dynamic 3D cultivation platforms will probably lead to improved outcomes and enable fast screening of various therapeutic approaches.     

Cerebriform fibrous proliferation vs. proteus syndrome.

Proteus syndrome is a rare, congenital hamartomatous syndrome that presents with a wide range of abnormalities. Regardless of different manifestations found in different patients, there exists three mandatory criteria for the diagnosis of this syndrome: a mosaic distribution of the lesions, a progressive course, and sporadic occurrence. When these criteria are met, the presence of additional connective tissue nevi, which are encountered mostly on the plantar surface of the feet, suffices for the diagnosis of Proteus syndrome. The authors present a 48-year-old woman who had been evaluated for a lesion on the plantar aspect of her left foot that was diagnosed as keloid and was treated unsuccessfully. In the light of the literature and with the help of histopathological reevaluation, the authors thought this unique lesion may be a localized form of Proteus syndrome.     

Guanine polynucleotides are self‐antigens for human natural autoantibodies and are significantly reduced in the human genome

In the course of investigating anti‐DNA autoantibodies, we examined IgM and IgG antibodies to poly‐G and other oligonucleotides in the sera of healthy persons and those diagnosed with systemic lupus erythematosus (SLE), scleroderma (SSc), or pemphigus vulgaris (PV); we used an antigen microarray and informatic analysis. We now report that all of the 135 humans studied, irrespective of health or autoimmune disease, manifested relatively high amounts of IgG antibodies binding to the 20‐mer G oligonucleotide (G20); no participants entirely lacked this reactivity. IgG antibodies to homo‐nucleotides A20, C20 or T20 were present only in the sera of SLE patients who were positive for antibodies to dsDNA. The prevalence of anti‐G20 antibodies led us to survey human, mouse and Drosophila melanogaster (fruit fly) genomes for runs of T20 and G20 or more: runs of T20 appear > 170 000 times compared with only 93 runs of G20 or more in the human genome; of these runs, 40 were close to brain‐associated genes. Mouse and fruit fly genomes showed significantly lower T20/G20 ratios than did human genomes. Moreover, sera from both healthy and SLE mice contained relatively little or no anti‐G20 antibodies; so natural anti‐G20 antibodies appear to be characteristic of humans. These unexpected observations invite investigation of the immune functions of anti‐G20 antibodies in human health and disease and of runs of G20 in the human genome.     

Retardation of calcium oxalate precipitation by glutamic-oxalacetic-transaminase activity

Summary It has been found that calcium oxalate stone formers have low UGOT activity compared to healthy individuals (controls). Urine from stone formers with no GOT activity and no effect on calcium oxalate precipitation was incubated with GOT for various periods. Subsequently calcium oxalate precipitation was decreased and found to be considerably retarded i.e., the pathological urine after the incubation acted in a way similar to that of normal urine. The yield of Glutamic-Oxalacetic Transaminase (GOT) activity is gultamic acid. It was shown that glutamic acid has a significant retardation effect on the precipitation of calcium oxalate stone formation. Therefore it may be suggested that GOT activity involved in glutamic acid creation in situ, has a role in kidney stone formation.