Cardiac Rehabilitation Early after Sternotomy Using New Assistive VR-Enhanced Robotic Exoskeleton-Study Protocol for a Randomised Controlled Trial.

(1) Background and objective: Cardiac rehabilitation (CR) means delivering health education by structured exercises with the means of risk reduction, in a cost-effective manner. Well-conducted CR improves functional capacity, decreases re-hospitalization, and reduces mortality up to 25%. We bring to attention the protocol of a randomised control trial with the aim of validating the prototype of an assistive upper-body robotic exoskeleton system enhanced with a non-immersive virtual reality exergame (CardioVR-ReTone) in patients who undergone cardiac surgery. (2) Methods: Description of the CardioVR-ReTone system and the technical specification, followed by the group selection, randomization and evaluated variables. (3) Expected results: The primary outcome measurement is the modification of life quality at the end of the CR exercise training program. Secondary outcomes will encompass measurements of sternal stability, muscular activity, cardiac response to exercise, pain level and compliance/adherence to CR. (4) Conclusions: Implementing these novel features of the CardioVR-ReTone system, addressability, and efficacy of CR, so problematic in certain situations and especially in cardiac surgery, will be greatly facilitated, being independent of the skills and availability of the rehabilitation therapist.

CYP4F2 and VKORC1 Polymorphisms Amplify the Risk of Carotid Plaque Formation.

INTRODUCTION: Atherosclerosis represents the process by which fibrous plaques are formed in the arterial wall, increasing its rigidity with a subsequent decrease in blood flow which can lead to several cardiovascular events. Seeing as vitamin K antagonists are involved in the pathogenesis of atherosclerosis, we decided to investigate whether polymorphisms in genes that influence vitamin K metabolism might have an impact in modulating the risk of plaque formation. PATIENTS AND METHODS: In the current study we included adult patients admitted in the Clinical Municipal Hospital of Cluj-Napoca without any carotid or femoral plaques clinically visible at the initial investigation, and a five year follow-up was subsequently performed. We recorded the following patient characteristics: age at inclusion, gender, area of living, smoking, presence of carotid and/or femoral plaques at five years, ischemic heart disease, arterial hypertension, atrial fibrillation, heart failure, diabetes mellitus, obesity, dyslipidemia, drug (oral anticoagulants, antihypertensives, hypolipidemic, anti-diabetic) use and status for the following gene polymorphisms: VKORC1 1639 G>A, CYP4F2 1347 G>T and GGCX 12970 C>G. RESULTS: We observed that the major predictor of both carotid and femoral plaque formation is represented by ischemic cardiac disease. VKORC1 and CYP4F2 polymorphisms did not predict plaque formation, except for VKORC1 homozygous mutants. Nonetheless, both VKORC1 and CYP4F2 interacted with ischemic cardiac disease, increasing the risk of developing a carotid plaque, while only CYP4F2, but not VKORC1, interacted with ischemic cardiac disease to increase the risk of femoral plaque formation. CONCLUSIONS: We documented that CYP4F2 and VKORC1 polymorphisms boost the proinflammatory plaque environment (observed indirectly through the presence of ischemic heart disease), increasing the risk of plaque development.

Systemic and Local Factors' Influence on the Topological Differences in Deep Vein Thrombosis.

Background and Objectives: Deep vein thrombosis (DVT) is a common cause of intra-hospital morbidity and mortality, and its most severe complication is pulmonary thromboembolism. The risk factors that influence the apparition of DVT are generally derived from Virchow's triad. Since the most severe complications of DVT occur in proximal rather than distal deep vein thrombosis, the aim of this study was to identify the factors influencing the apparition of proximal DVT. Materials and Methods: This was a transversal, cohort study. The study included 167 consecutive patients with lower limb DVT over a two-year period. The following data were recorded or determined: general data, conditions that are known to influence DVT, medical history and coagulation or thrombophilia-related genetic variations. Results: In the univariate analysis, male gender, neoplasia, previous DVT and mutated factor V Leiden were all associated with proximal DVT, while bed rest was associated with distal DVT. In the multivariate analysis, male gender, previous DVT and factor V Leiden mutation were independently correlated with proximal DVT, while bed rest was independently associated with distal deep vein thrombosis. Conclusion: Our observations point out that the factors indicating a systemic involvement of coagulation were correlated with proximal DVT, while local factors were associated with distal DVT.

Role of C5b-9 and RGC-32 in Cancer.

The complement system represents an effective arsenal of innate immunity as well as an interface between innate and adaptive immunity. Activation of the complement system culminates with the assembly of the C5b-9 terminal complement complex on cell membranes, inducing target cell lysis. Translation of this sequence of events into a malignant setting has traditionally afforded C5b-9 a strict antitumoral role, in synergy with antibody-dependent tumor cytolysis. However, in recent decades, a plethora of evidence has revised this view, highlighting the tumor-promoting properties of C5b-9. Sublytic C5b-9 induces cell cycle progression by activating signal transduction pathways (e.g., Gi protein/ phosphatidylinositol 3-kinase (PI3K)/Akt kinase and Ras/Raf1/ERK1) and modulating the activation of cancer-related transcription factors, while shielding malignant cells from apoptosis. C5b-9 also induces Response Gene to Complement (RGC)-32, a gene that contributes to cell cycle regulation by activating the Akt and CDC2 kinases. RGC-32 is expressed by tumor cells and plays a dual role in cancer, functioning as either a tumor promoter by endorsing malignancy initiation, progression, invasion, metastasis, and angiogenesis, or as a tumor suppressor. In this review, we present recent data describing the versatile, multifaceted roles of C5b-9 and its effector, RGC-32, in cancer.

RGC-32 and diseases: the first 20 years.

The response gene to complement (RGC)-32 acts as a cell cycle regulator and mediator of TGF-ß effects. However, recent studies have revealed other functions for RGC-32 in diverse processes such as cellular migration, differentiation, and fibrosis. In addition to its induction by complement activation and the C5b-9 terminal complement complex, RGC-32 expression is also stimulated by growth factors, hormones, and cytokines. RGC-32 is induced by TGF-ß through Smad3 and RhoA signaling and plays an important role in cell differentiation. In particular, RGC-32 is essential for the differentiation of Th17 cells. RGC-32-/- mice display an attenuated experimental autoimmune encephalomyelitis phenotype that is accompanied by decreased central nervous system inflammation and reductions in IL-17- and GM-CSF-producing CD4+ T cells. Accumulating evidence has drawn attention to the deregulated expression of RGC-32 in human cancers, atherogenesis, metabolic disorders, and autoimmune disease. Furthermore, RGC-32 is a potential therapeutic target in multiple sclerosis and other Th17-mediated autoimmune diseases. A better understanding of the mechanism(s) by which RGC-32 contributes to the pathogenesis of all these diseases will provide new insights into its therapeutic potential.

RGC-32 is a novel regulator of the T-lymphocyte cell cycle.

We have previously shown that RGC-32 is involved in cell cycle regulation in vitro. To define the in vivo role of RGC-32, we generated RGC-32 knockout mice. These mice developed normally and did not spontaneously develop overt tumors. To assess the effect of RGC-32 deficiency on cell cycle activation in T cells, we determined the proliferative rates of CD4(+) and CD8(+) T cells from the spleens of RGC-32(-/-) mice, as compared to wild-type (WT, RGC-32(+/+)) control mice. After stimulation with anti-CD3/anti-CD28, CD4(+) T cells from RGC-32(-/-) mice displayed a significant increase in [(3)H]-thymidine incorporation when compared to WT mice. In addition, both CD4(+) and CD8(+) T cells from RGC-32(-/-) mice displayed a significant increase in the proportion of proliferating Ki67(+) cells, indicating that in T cells, RGC-32 has an inhibitory effect on cell cycle activation induced by T-cell receptor/CD28 engagement. Furthermore, Akt and FOXO1 phosphorylation induced in stimulated CD4(+) T-cells from RGC-32(-/-) mice were significantly higher, indicating that RGC-32 inhibits cell cycle activation by suppressing FOXO1 activation. We also found that IL-2 mRNA and protein expression were significantly increased in RGC-32(-/-) CD4(+) T cells when compared to RGC-32(+/+) CD4(+) T cells. In addition, the effect of RGC-32 on the cell cycle and IL-2 expression was inhibited by pretreatment of the samples with LY294002, indicating a role for phosphatidylinositol 3-kinase (PI3K). Thus, RGC-32 is involved in controlling the cell cycle of T cells in vivo, and this effect is mediated by IL-2 in a PI3K-dependent fashion.

Role of C5b-9 complement complex and response gene to complement-32 (RGC-32) in cancer.

Complement system activation plays an important role in both innate and acquired immunity, with the activation of complement and the subsequent formation of C5b-9 terminal complement complex on cell membranes inducing target cell death. Recognition of this role for C5b-9 leads to the assumption that C5b-9 might play an antitumor role. However, sublytic C5b-9 induces cell cycle progression by activating signal transduction pathways and transcription factors in cancer cells, indicating a role in tumor promotion for this complement complex. The induction of the cell cycle by C5b-9 is dependent upon the activation of the phosphatidylinositol 3-kinase (PI3K)/Akt/FOXO1 and ERK1 pathways in a Gi protein-dependent manner. C5b-9 also induces response gene to complement (RGC)-32, a gene that plays a role in cell cycle promotion through activation of Akt and the CDC2 kinase. RGC-32 is expressed by tumor cells and plays a dual role in cancers, in that it has both a tumor suppressor role and tumor-promoting activity. Thus, through the activation of tumor cells, the C5b-9-mediated induction of the cell cycle plays an important role in tumor proliferation and oncogenesis.

Epigenetic modifications induced by RGC-32 in colon cancer.

First described as a cell cycle activator, RGC-32 is both an activator and a substrate for CDC2. Deregulation of RGC-32 expression has been detected in a wide variety of human cancers. We have now shown that RGC-32 is expressed in precancerous states, and its expression is significantly higher in adenomas than in normal colon tissue. The expression of RGC-32 was higher in advanced stages of colon cancer than in precancerous states or the initial stages of colon cancer. In order to identify the genes that are regulated by RGC-32, we used gene array analysis to investigate the effect of RGC-32 knockdown on gene expression in the SW480 colon cancer cell line. Of the 230 genes that were differentially regulated after RGC-32 knockdown, a group of genes involved in chromatin assembly were the most significantly regulated in these cells: RGC-32 knockdown induced an increase in acetylation of histones H2B lysine 5 (H2BK5), H2BK15, H3K9, H3K18, and H4K8. RGC-32 silencing was also associated with decreased expression of SIRT1 and decreased trimethylation of histone H3K27 (H3K27me3). In addition, RGC-32 knockdown caused a significantly higher percentage of SW480 cells to enter S phase and subsequently G2/M. These data suggest that RGC-32 may contribute to the development of colon cancer by regulating chromatin assembly.

Response gene to complement 32 is required for C5b-9 induced cell cycle activation in endothelial cells.

Proliferation of vascular endothelial cells (EC) and smooth muscle cells (SMC) is a critical event in angiogenesis and atherosclerosis. We previously showed that the C5b-9 assembly during complement activation induces cell cycle in human aortic EC (AEC) and SMC. C5b-9 can induce the expression of Response Gene to Complement (RGC)-32 and over expression of this gene leads to cell cycle activation. Therefore, the present study was carried out to test the requirement of endogenous RGC-32 for the cell cycle activation induced by C5b-9 by knocking-down its expression using siRNA. We identified two RGC-32 siRNAs that can markedly reduce the expression of RGC-32 mRNA in AEC. RGC-32 silencing in these cells abolished DNA synthesis induced by C5b-9 and serum growth factors, indicating the requirement of RGC-32 activity for S-phase entry. RGC-32 siRNA knockdown also significantly reduced the C5b-9 induced CDC2 activation and Akt phosphorylation. CDC2 does not play a role in G1/S transition in HeLa cells stably overexpressing RGC-32. RGC-32 was found to physically associate with Akt and was phosphorylated by Akt in vitro. Mutation of RGC-32 protein at Ser 45 and Ser 47 prevented Akt mediated phosphorylation. In addition, RGC-32 was found to regulate the release of growth factors from AEC. All these data together suggest that cell cycle induction by C5b-9 in AEC is RGC-32 dependent and this is in part through regulation of Akt and growth factor release.

Role of response gene to complement 32 in diseases.

The role of response gene to complement (RGC)-32 as a cell cycle regulator has been attributed to its ability to activate cdc2 kinases and to induce S-phase entry and mitosis. However, recent studies revealed novel functions for RGC-32 in diverse processes such as cellular differentiation, inflammation, and fibrosis. Besides responding to C5b-9 stimulation, RGC-32 expression is also induced by growth factors, hormones, and cytokines. Transforming growth factor beta activates RGC-32 through Smad and RhoA signaling, thus initiating smooth muscle cell differentiation. Accumulating evidence has drawn attention to the deregulated expression of RGC-32 in human malignancies, hyper-immunoglobulin E syndrome, and fibrosis. RCG-32 expression is up-regulated in cutaneous T cell lymphoma and colon, ovarian, and breast cancer, but down-regulated in invasive prostate cancer, multiple myeloma, and drug-resistant glioblastoma. A better understanding of the mechanism by which RGC-32 contributes to the pathogenesis of these diseases will provide new insights into its therapeutic potential. In this review we provide an overview of this field and discuss the most recent research on RGC-32.

Trends of mortality rates from gastric cancer and colorectal cancer in Romania, 1955-2003.

BACKGROUND: Steady and persisting falls in gastric cancer (GC) mortality rates have been observed worldwide in the last 50 years, and in Romania too. Colorectal cancer (CRC) is presently the most frequent digestive neoplasia in the Western countries. An increase of CRC incidence and mortality rates has been reported recently in Eastern European countries, including Romania. METHODS: Mortality data from GC and CRC, derived from population based mortality statistics, have been available on a national scale for 1955-2003. The data were identified from the statistics of the Ministry of Health (Bucharest, Romania) and of IARC/OMS (Lyon, France). GC and CRC mortality rates global and/or per gender were registered by time intervals. After 1995, only data on general mortality rates were available. RESULTS: Between 1955-59 and 1990-92, GC mortality rates/100,000 decreased from 33.14 to 17.70 in males and from 18.77 to 7.00 in females. Between 1995 and 2003, general mortality rates/100,000 from GC remained stable (17.54 and 17.74, respectively). Between 1955-59 and 1990-92, CRC mortality rates/100,000/gender increased from 4.65 to 10.10 in males and from 4.57 to 7.40 in females. Between 1995 and 2003, CRC general mortality rates/100 000 increased from 14.90 to 19.20. CONCLUSIONS: Our study reports opposite trends in GC and CRC mortality rates in the period under study, with GC declining and CRC increasing. A male predominance was registered in both neoplasms under study, more obvious in GC (male/female ratio: 2-3/1) than in CRC (male/female ratio: 1.5/1).