Pharmacogenetics of the local thrombolysis in patients with deep vein thrombosis

Thrombophilia, the state of increased tendency for blood clotting, is considered the disorder of a complex etiology, caused by both environmental and genetic factors. As gene variants predisposing to thrombophilia and influencing the increased risk of vein thrombosis might influence response to local thrombolysis, the aim of the work was to characterize the pharmacogenetic conditions for local streptokinase treatment in patients with a deep vein thrombosis (DVT) of lower extremities based on the following polymorphism analyses: G1691A polymorphism of factor V (FV), G20210A polymorphism of prothrombin (PT), A4250G (Thr312Ala) polymorphism of fibrinogen-alpha (FGA), G(-455)A polymorphism of fibrinogen-beta (FGB), 4G/5G polymorphism of plasminogen activator inhibitor type 1(PAI-1) and insertion/deletion (I/D) polymorphism of tissue plasminogen activator (t-PA). The study included 40 DVT patients who underwent a local thrombolytic treatment within 14-day period from diagnosis. Full recanalization was achieved in 20 subjects (50%) [group R(+)], whereas incomplete or total lack of recanalization was identified in the remaining 20 patients [group R(-)]. No major complications of thrombolytic treatment occurred in the studied group. In the case of prothrombin gene all individuals carried homozygous wild type genotype (GG). Prevalence of the genotypes and alleles of the remaining five polymorphisms did not differ significantly between the groups R(+) and R(-). Neither sex nor age, smoking or time period from diagnosis to introduction of the thrombolytic treatment significantly influenced treatment efficacy. The results of the study suggest that a local thrombolysis with streptokinase introduced within two week period from the diagnosis is a safe and efficient method of treatment for deep vein thrombosis of lower extremities. However, size of the group is insufficient to clearly determine the association between investigated polymorphisms and efficacy of local treatment with streptokinase.     

Demonstrated health care cost savings for women: findings from a community health worker intervention designed to address depression and unmet social needs

To evaluate the impact of a community health worker intervention (CHW) (referred to as Personalized Support for Progress (PSP)) on all-cause health care utilization and cost of care compared with Enhanced Screening and Referral (ESR) among women with depression. A total of 223 patients (111 in PSP and 112 in ESR randomly assigned) from three women’s health clinics with elevated depressive symptoms were enrolled in the study. Their electronic health records were queried to extract all-cause health care encounters along with the corresponding billing information 12 months before and after the intervention, as well as during the first 4-month intervention period. The health care encounters were then grouped into three mutually exclusive categories: high-cost (> US$1000 per encounter), medium-cost (US$201–$999), and low-cost (≤ US$200). A difference-in-difference analysis of mean total charge per patient between PSP and ESR was used to assess cost differences between treatment groups. The results suggest the PSP group was associated with a higher total cost of care at the baseline; taking this baseline difference into account, the PSP group was associated with lower mean total charge amounts (p = 0.008) as well as a reduction in the frequency of high-cost encounters (p < 0.001) relative to the ESR group during the post-intervention period. Patient-centered interventions that address unmet social needs in a high-cost population via CHW may be a cost-effective approach to improve quality of care and patient outcomes.

     

Pain associated with the musculoskeletal system in children from Warsaw schools

Objective

To assess the prevalence of pain in the musculoskeletal system and possible reasons for these complaints among early age children from Warsaw schools.

Material and methods

The study was conducted in 34 randomly selected primary schools in Warsaw in 2011. 2748 survey-questionnaires were given to parents or legal guardians by children. Of these, 1509 surveys were subject to a final analysis. The survey included 66 questions regarding, among other things, pain in the musculoskeletal system in children. Additionally, there were questions about possibly occurring diseases, any postural defects, significant obesity, as well as effects of these complaints on the child''s physical activity. Survey data regarded 6–7-year-old children.

Results

In the group of 1509 respondents, 242 children (16%) complained about pain in the musculoskeletal system. Pain was located most frequently in the knee joints, and more rarely in the spine and joints in the upper extremities. In the group of children who complained about pain, moderate physical activity was statistically significantly limited. According to parents, physicians did not diagnose any medical conditions in 106 children. Joint disease was diagnosed in 33 children. Postural defects were diagnosed in 589 children. In 123 children complaining about pain at least one postural defect was diagnosed. Such defects were diagnosed statistically significantly more rarely (p = 0.011) in 1234 children who did not complain about pain (460 children). Platypodia or other foot deformation was observed in 25% of these children, spinal curvature in 12%, abnormal knee joint position in 11% and uneven hip position in 2% children. Of note, 17% of all children were significantly overweight. In overweight children the prevalence of pain, especially in the knee joints and feet, was significantly higher.

Conclusions

This study aims to underline the problem of musculoskeletal pain in early-age children which limits their physical activity. Also the authors draw attention to the issue of postural defects in a large group of school children. This issue undoubtedly requires more attention and a plan how to create more effective methods of prevention.     

Role of kinin B2 receptor signaling in the recruitment of circulating progenitor cells with neovascularization potential

Reduced migratory function of circulating angiogenic progenitor cells (CPCs) has been associated with impaired neovascularization in patients with cardiovascular disease (CVD). Previous findings underline the role of the kallikrein-kinin system in angiogenesis. We now demonstrate the involvement of the kinin B2 receptor (B(2)R) in the recruitment of CPCs to sites of ischemia and in their proangiogenic action. In healthy subjects, B(2)R was abundantly present on CD133(+) and CD34(+) CPCs as well as cultured endothelial progenitor cells (EPCs) derived from blood mononuclear cells (MNCs), whereas kinin B1 receptor expression was barely detectable. In transwell migration assays, bradykinin (BK) exerts a potent chemoattractant activity on CD133(+) and CD34(+) CPCs and EPCs via a B(2)R/phosphoinositide 3-kinase/eNOS-mediated mechanism. Migration toward BK was able to attract an MNC subpopulation enriched in CPCs with in vitro proangiogenic activity, as assessed by Matrigel assay. CPCs from cardiovascular disease patients showed low B(2)R levels and decreased migratory capacity toward BK. When injected systemically into wild-type mice with unilateral limb ischemia, bone marrow MNCs from syngenic B(2)R-deficient mice resulted in reduced homing of sca-1(+) and cKit(+)flk1(+) progenitors to ischemic muscles, impaired reparative neovascularization, and delayed perfusion recovery as compared with wild-type MNCs. Similarly, blockade of the B(2)R by systemic administration of icatibant prevented the beneficial effect of bone marrow MNC transplantation. BK-induced migration represents a novel mechanism mediating homing of circulating angiogenic progenitors. Reduction of BK sensitivity in progenitor cells from cardiovascular disease patients might contribute to impaired neovascularization after ischemic complications.     

A counterpoint paper: Comments on the electrocardiographic part of the 2018 Fourth Universal Definition of Myocardial Infarction endorsed by the International Society of Electrocardiology and the International Society for Holter and Noninvasive Electrocardiology

The Fourth Universal Definition of Myocardial Infarction (FUDMI) focuses on the distinction between nonischemic myocardial injury and myocardial infarction (MI), along with the role of cardiovascular magnetic resonance, in order to define the etiology of myocardial injury. As a consequence, there is less emphasis on updating the parts of the definition concerning the electrocardiographic (ECG) changes related to MI. Evidence of myocardial ischemia is a prerequisite for the diagnosis of MI, and the ECG is the main available tool for (a) detecting acute ischemia, (b) triage, and (c) risk stratification upon presentation. This review focuses on multiple aspects of ECG interpretation that we firmly believe should be considered for incorporation in any future update to the Universal Definition of MI.     

Antitumor Effects of Recombinant Antivascular Protein ABRaA-VEGF121 Combined with IL-12 Gene Therapy

Development and neoplastic progression strongly rely on tumor microenvironment cells. Various kinds of cells that form such tumor milieu play substantial roles in angiogenesis and immunosuppression. Attempts to inhibit tumor vascularization alter tumor milieu and enhance immune response against the tumor. Anticancer therapeutic strategy bringing together antiangiogenic and immunostimulating agents has emerged as a promising approach. We here investigated whether therapy directed against preexisting vessels, combined with an immunomodulatory factor would be equally effective in arresting tumor growth. To this goal, we investigated the effectiveness of ABRaA-vascular endothelial growth factor isoform 121 (VEGF₁₂₁), an antivascular drug constructed by us. It is a fusion protein composed of VEGF₁₂₁, and abrin A chain (translation-inhibiting toxin). We used it in combination with interleukin (IL-12) gene therapy and tried to inhibit B16-F10 melanoma tumor growth. ABRaA-VEGF₁₂₁ is a chimeric recombinant protein capable of destroying tumor vasculature and triggering necrosis in the vicinity of damaged vessels. IL-12 cytokine, in turn, activates both specific and non-specific immune responses. Our results demonstrate that combination of ABRaA-VEGF₁₂₁ antivascular agent with immunostimulatory cytokine IL-12 indeed inhibits tumor growth more effectively than either agent alone, leading to complete cure of ca. 20 % mice. Post-therapeutic analysis of tumors excised from mice treated with combination therapy showed decreased numbers of blood microvessels in the tumor microenvironment, lowered numbers of regulatory T lymphocytes, as well as showed higher levels of CD4⁺ and CD8⁺ as compared to control mice. It seems that bringing together antivascular strategy and the action of immunostimulating agents indeed inhibits growth of tumors.     

The Role of Sex Differences in Autophagy in the Heart During Coxsackievirus B3-Induced Myocarditis

Under normal conditions, autophagy maintains cardiomyocyte health and integrity through turnover of organelles. During stress, oxygen and nutrient deprivation, or microbial infection, autophagy prolongs cardiomyocyte survival. Sex differences in induction of cell death may to some extent explain the disparity between the sexes in many human diseases. However, sex differences in gene expression, which regulate cell death and autophagy, were so far not taken in consideration to explain the sex bias of viral myocarditis. Coxsackievirus B3 (CVB3)-induced myocarditis is a sex-biased disease, with females being substantially less susceptible than males and sex hormones largely determine this bias. CVB3 was shown to induce and subvert the autophagosome for its optimal viral RNA replication. Gene expression analysis on mouse and human, healthy and CVB3-infected, cardiac samples of both sexes, suggests sex differences in autophagy-related gene expression. This review discusses the aspects of sex bias in autophagy induction in cardiomyocytes.