Clinical value of GRACE score combined with DFR in predicting short-term prognosis of patients undergoing early PCI after thrombolysis for acute myocardial infarction.

OBJECTIVE: The aim of the study was to investigate the clinical value of the Global Registry of Arterial Events in Acute Coronary Syndromes (GRACE) score combined with the D-dimer/fibrinogen ratio (DFR) in predicting the short-term prognosis of patients undergoing percutaneous coronary intervention (PCI) early after thrombolysis for acute myocardial infarction (AMI). PATIENTS AND METHODS: A total of 102 patients who underwent PCI early after thrombolysis for AMI during April 2020 to January 2022 in our hospital were picked as study subjects. These subjects were assigned as the good prognosis group (without adverse cardiovascular events) and poor prognosis group (with adverse cardiovascular events) according to whether adverse cardiovascular events occurred during hospitalization and follow-up. Changes in GRACE scores and DFR levels in patients with different prognoses were analyzed. The GRACE score and DFR level of patients with different prognosis were analyzed. The clinic pathological characteristics were collected, and the risk factors for poor prognosis of AMI patients were analyzed by logistic risk regression; ROC curve was used to analyze the prognostic value of GRACE score combined with DFR in early PCI patients after AMI thrombolysis. RESULTS: Compared with the good prognosis group, the GRACE score and DFR level in the poor prognosis group were much higher (p<0.001). Significant differences existed in blood pressure, ejection fraction, number of diseased branches, and Killip grading between the patients with good prognosis and those with poor prognosis (p<0.05). There existed no significant difference in clinical medication between the patients with good prognosis and those with poor prognosis (p>0.05). Logistic multivariate analysis indicated that GRACE score, DFR, ejection fraction, number of lesion branches, and Killip grade were all risk factors influencing the prognosis of patients undergoing early PCI after thrombolysis in AMI (p<0.05). The ROC curve was established and the area under the curve (AUC) of GRACE score, DFR, and combined detection were 0.815, 0.783, and 0.894, respectively, and the sensitivity and specificity were 80.24%, 60.42%, 83.71%, 66.78%, 91.42% and 77.83%, respectively. The AUC, sensitivity, and specificity of combined detection were higher than those of the two alone and had a higher predictive value for the short-term prognosis of patients. CONCLUSIONS: The GRACE score combined with DFR was of great value in diagnosing the short-term prognosis of patients undergoing PCI early after thrombolysis for AMI. Furthermore, the GRACE score, DFR, ejection fraction, number of lesion branches, and Killip classification were all important factors influencing the short-term prognosis of patients, which were of great significance in determining the prognosis of patients.

Aging of bone marrow mesenchymal stromal/stem cells: Implications on autologous regenerative medicine.

With their proliferation, differentiation into specific cell types, and secretion properties, mesenchymal stromal/stem cells (MSC) are very interesting tools to be used in regenerative medicine. Bone marrow (BM) was the first MSC source characterized. In the frame of autologous MSC therapy, it is important to detect donor's parameters affecting MSC potency. Age of the donors appears as one parameter that could greatly affect MSC properties. Moreover, in vitro cell expansion is needed to obtain the number of cells necessary for clinical developments. It will lead to in vitro cell aging that could modify cell properties. This review recapitulates several studies evaluating the effect of in vitro and in vivo MSC aging on cell properties.

Organ reconstruction: Dream or reality for the future.

The relevance of research on reconstructed organs is justified by the lack of organs available for transplant and the growing needs for the ageing population. The development of a reconstructed organ involves two parallel complementary steps: de-cellularization of the organ with the need to maintain the structural integrity of the extracellular matrix and vascular network and re-cellularization of the scaffold with stem cells or resident cells.Whole organ engineering for liver, heart, lung or kidneys, is particularly difficult because of the structural complexity of organs and heterogeneity of cells. Rodent, porcine and rhesus monkey organs have been de-cellularized to obtain a scaffold with preserved extracellular matrix and vascular network. As concern the cells for re-cellularization, embryonic, foetal, adult, progenitor stem cells and also iPS have been proposed.Heart construction could be an alternative option for the treatment of cardiac insufficiency. It is based on the use of an extra-cellular matrix coming from an animal's heart and seeded with cells likely to reconstruct a normal cardiac function. Though de-cellularization techniques now seem controlled, the issues posed by the selection of cells capable of generating the various components of cardiac tissue are not settled yet. In addition, the recolonisation of the matrix does not only depend on the phenotype of cells that are used, but it is also impacted by the nature of biochemical signals emitted.Recent researches have shown that it is possible to use decellularized whole liver treated by detergents as scaffold, which keeps the entire network of blood vessels and the integrated extracellular matrix (ECM). Beside of decellularized whole organ scaffold seeding cells selected to repopulate a decellularized liver scaffold are critical for the function of the bioengineered liver. At present, potential cell sources are hepatocyte, and mesenchymal stem cells.Pulmonary regeneration using engineering approaches is complex. In fact, several types of local progenitor cells that contribute to cell repair have been described at different levels of the respiratory tract. Moving towards the alveoles, one finds bronchioalveolar stem cells as well as epithelial cells and pneumocytes. A promising option to increase the donor organ pool is to use allogeneic or xenogeneic decellularized lungs as a scaffold to engineer functional lung tissue ex vivo.The kidney is certainly one of the most difficult organs to reconstruct due to its complex nature and the heterogeneous nature of the cells. There is relatively little research on auto-construction, and experiments have been performed on rats, pigs and monkeys.Nevertheless, before these therapeutic approaches can be applied in clinical practice, many researches are necessary to understand and in particular the behaviour of cells on the decellularized organs as well as the mechanisms of their interaction with the microenvironment. Current knowledges allow optimism for the future but definitive answers can only be given after long term animal studies and controlled clinical studies.

Stem cells and vascular regenerative medicine: A mini review.

Most human tissues do not regenerate spontaneously, which is why "cell therapy" are promising alternative treatments. The Principe is simple: patients' or donors' cells are collected and introduced into the injured tissues or organs directly or in a porous 3D material, with or without modification of their properties. This concept of regenerative medicine is an emerging field which can be defined as "the way to improve health and quality of life by restoring, maintaining, or enhancing tissue and organ functions".There is an extraordinarily wide range of opportunities for clinical applications: artheropathies, diabetes, cartilage defects, bone repair, burns, livers or bladder regeneration, organs reconstruction (lung, heart, liver ...) neurodegenerative disorders, sepsis ...  Different stem cells (SC) with different potential can be used and characterised (totipotent, mesenchymal of different origins, especially those present in tissues...). Today it is undeniable that cells like bone marrow, adipose tissue or Wharton Jelly stem cells, are of potential interest for clinical applications because they are easily separated and prepared and no ethical problems are involved in their use.In this paper some potential clinical applications in the vascular field are considered: peripheral arteriopathy in diabetic patients, cardiac insufficiency, traitment of erectile dysfunction, or organ regeneration with liver as example. But the regeneration of tissue or organ is and will remain a challenge for the future development of cell therapy. Many problems remain to be solved that could lead to the development of innovative strategies to facilitate cell differentiation, increase the yield of cells and ensure a standardised product, overcome the risks of teratogenic effects and/or immune reactions, enable grafting via direct cell or biotissue transplantation and avoid legal issues involved in national regulations.

Selenium deficiency contributes to the chronic myocarditis in coxsackievirus-infected mice.

Both coxsackievirus B3 (CVB3) infection and selenium (Se) deficiency play a pivotal role in Keshan disease of the heart. The Se deficiency was known to contribute to the CVB3-induced myocarditis in acute and subacute phase of infection. However, its effect on the myocarditis in chronic phase of infection has not been examined yet. To address this question, we kept mice on a Se-replete or Se-deficient diet for 28 days, infected them intraperitoneally with CVB3 and maintaining previous diets, we examined them for next 90 days for several parameters indicative of the infection or disease. We found out that the mice on the Se-deficient diet exhibited a higher mortality, lower serum glutathione peroxidase (GPx) activity, evident histopathological changes indicative of myocarditis, and a higher level of viral RNA in the heart. Summing up, these data suggest that the Se-deficiency creates a chronic myocarditis-prone condition by fostering the active virus replication.

The main functions and structural modifications of tripeptide N-formyl-methionyl-leucyl-phenylalanine (fMLP) as a chemotactic factor.

Gram negative bacteria-derived and synthetic N-formyl peptides play a key role in host defense as chemotactic factors for phagocytic leukocytes. The first compound to be identified was N-formylmethionyl-leucyl-phenylalanine (fMLP) which contains highly potent leukocyte chemoattractant. Natural fMLP was subsequently purified and identified in supernatants of gram negative bacteria. Recently, much more attention has been focused on the human formyl peptide receptor (FPR) and its variant formyl peptide receptor-like 1 (FPRL1) and formyl peptide receptor-like 2 (FPRL2). Chemotactic factors such as fMLP interact with their specific cell surface receptors, which results in multiple biological responses through a G protein-coupled signal pathway. In this review, the functions and structural modifications of fMLP are discussed in view of future drug development.

Gene delivery for lung cancer using nonviral gene vectors.

Multiple options for the treatment of lung cancer have often been described in the past, including surgery, chemotherapy and radiation, but the therapeutic effect is typically transient and mostly absent with advanced disease. New approaches to the treatment of lung cancer are urgently needed. Gene therapy has been widely proposed as a novel strategy to improve therapy. Although progress has been made using viral vectors, rapid advances in transfection technologies employing nonviral vectors, together with their relatively low toxicity, suggest that nonviral vectors may have significant potential for clinical applications. This paper briefly reviews general principles of gene delivery with emphasis on recent developments in the arena of lung cancer using nonviral vectors (naked DNA, polycationic polymers, cationic liposomes). Employing gene transfer techniques to achieve therapeutically useful levels of expression of therapeutic genes in the lung could provide a new strategy for treatment of lung cancer.

An integrated treatment delivery system for CSRS and CSRT and clinical applications.

An integrated treatment delivery system for conformal stereotactic radiosurgery (CSRS) and radiotherapy (CSRT) has been developed through a collaboration involving Siemens Medical Systems, Inc., Tyco/Radionics, Inc., and The University of Texas M. D. Anderson Cancer Center. The system consists of a 6-MV linear accelerator (LINAC) equipped with a Tyco/Radionics miniature multileaf collimator (mMLC). For the conventional SRS treatment, the circular collimator housing can be attached to the opening window of the mMLC. The treatment delivery system is integrated with a radiotherapy treatment planning system and a record-and-verify system. The purpose of this study is to report the characteristics, performance, benefits, and the clinical applications of this delivery system. The technical specifications of the LINAC and mMLC were tested, and all the specifications were met. The 80% to 20% penumbral width for each mMLC leaf is approximately 3 mm and is nearly independent of the off-axis positions of a leaf. The maximum interleaf leakage is 1.4% (1.1% on average) and the maximum intra-leaf leakage is 1.0% (0.9% on average). The leaf position precision is better than 0.5 mm for all the leaves. The integration of the SRS/SRT treatment planning system, mMLC, and LINAC has been evaluated successfully for transferring the patient treatment data file through radiotherapy treatment planning system to the patient information and treatment record-and-verify server and the mMLC controller. Subsequently, the auto-sequential treatment delivery for SRS, CSRS/CSRT, and the step-and-shoot intensity-modulated radiotherapy has also been tested successfully. The accuracy of dose delivery was evaluated for a 2-cm spherical target in a Radiological Physics Center SRS head phantom with GAFChromic films and TLD. Five non-coplanar arcs, using a 2-cm diameter circular collimator, were used for this simulation treatment. The accuracy to aim the center of the spherical target was within 0.5 mm and the deviation of dose delivery to the isocenter of the target was within 2% of the calculated dose. For the irregularly shaped tumor, a tissue-equivalent head phantom was used to evaluate the accuracy of dose delivery for using either geometric conformal treatment or IMRT. The accuracy of dose delivery to the isocenter was within 2% and 3% of the calculated dose, respectively. From October 26, 1999 to September 30, 2002, we treated over 400 SRS patients and 70 SRT patients. Four representative cases are presented to illustrate the capabilities of this dedicated unit in performing conventional SRS, CSRS, and CSRT. For all the cases, the geometric conformal-plan dose distributions showed a high degree of conformity to the target shape. The degree of conformity can be evaluated using the target-volume-ratio (TVR). Our preferred TVR values for highly conformed dose distributions range from 1.6 to 2.0. The patient setup reproducibility for the Gill-Thomas-Cosman (GTC) noninvasive head frame ranges from 0.5 to 1 mm, and the head and neck noninvasive frame is within 2 mm. The integrated treatment delivery system offers excellent conformation for complicated planning target volumes with the stereotactic setup approach, ensuring that dose delivery can be achieved within the specified accuracy. In addition, the treatment time is comparable with that of single isocenter multiple-arc treatments.

Acute hypoxia elevates nitric oxide generation in rat carotid body in vitro.

In acute hypoxia, the release of nitric oxide (NO) produced in rat carotid body is unclear. The concentration of NO was measured electrochemically with a Pt/Nafion/Pd-IrOx/POAP-modified electrode placed on the surface of isolated carotid bodies superfused with bicarbonate-buffer saline at 35 degrees C. In hypoxia, the concentration of NO in the carotid body was increased by 17+/-2 nM. The amount of NO release during hypoxia was augmented by increasing the number of carotid bodies surrounding the electrode and also in the presence of L-arginine. In addition, the hypoxia-induced elevation of NO was abolished by pretreatment with a nitric oxide synthase (NOS) inhibitor, L-N(G)-nitroarginine methylester (L-NAME). The results suggest that endogenous NO production in the carotid body increases during hypoxia. Electrophysiological measurement of single fiber activity in the sinus nerve revealed that L-NAME treatment enhances the afferent discharge in response to hypoxia. This confirms that the hypoxia-induced elevation of NO suppresses the carotid chemoreceptor response to hypoxia. Taken together, it is concluded that acute hypoxia increases NO generation in the rat carotid body, and that the elevated levels of NO suppress carotid chemoreceptor activity during hypoxia. Hence, NO may play an active inhibitory role in the control of carotid chemoreceptor activity during hypoxia.

Oxidative modification of neurogranin by nitric oxide: an amperometric study.

Neurogranin (Ng) is a neuron-specific protein kinase C (PKC) substrate, which contains four cysteine (Cys) residues. Recently, it has been shown that Ng is a redox-sensitive protein and is a likely target of nitric oxide (NO) and other oxidants [F.-S. Sheu, C.W. Mahoney, K. Seki, K.-P. Huang, Nitric oxide modification of rat brain neurogranin affects its phosphorylation by protein kinase C and affinity for calmodulin, J. Biol. Chem. 271 (1996) 22407-22413: J. Li, J.H. Pak, F.L. Huang, K.-P. Huang, N-methyl-D-aspartate induces neurogranin/RC3 oxidation in rat brain slices, J. Biol. Chem. 274 (1999) 1294-1300]. In this study, we directly examine the redox reactions between dissolved NO and Cys as well as between NO and bacterial expressed Ng in its reduced form, at concentrations approximate to the physiological levels in phosphate buffer solution (PBS) under aerobic conditions. The reaction kinetics are measured directly by our newly developed electrochemical sensor. Our sensor is based on the chemical modification of electrode with immobilized nanoparticles of transition metal palladium (Pd) which serves as catalytic centers for the electrochemical oxidation of thiol and NO selectively and quantitatively at different potentials. It detects Cys and Ng in a linear range from nano to micromolar concentration at + 450 mV, vs. a saturated calomel reference electrode (SCE), while the detection of NO at the sensor can be optimally achieved at + 700 mV (vs. SCE) with a linear current-to-concentration range of nM to microM. It thus provides a selective control to monitor two reactants independently. With this sensor as a detector, we found that (1) the oxidation of either Cys or Ng by NO is a fast reaction which reaches a near completion within 1-2 min at its physiological concentration; and (2) after the completion of reaction, NO is mostly, if not all, regenerated, an observation consistent with the reaction mechanism involving the formation of S-nitrosothiol as an intermediate. The reaction kinetics of both NO to Cys and NO to Ng implies that NO can achieve local action on cellular proteins in addition to its effect on targets located in neighboring cells via concentration-gradient-dependent diffusion.

Purification and characterization of manganese superoxide dismutase from Ganoderma microsporum.

Manganese superoxide dismutase (Mn-SOD) in the mycelium of Ganoderma microsporum was purified to homogeneity by heat treatment at 70 degrees C, ammonium sulfate fractionation, DEAE-52 anion-exchange chromatography, and Sephacryl SH-200 chromatography. The molecular mass of its native form was estimated to be 98 kD by size-exclusion chromatography. This enzyme is tetrameric composed of four subunits of equal size of 25 kD. The pI of this purified Mn-SOD was located at pH 6.34 and 5.06 by isoelectric focusing. Comparisons of 17 amino acids from the N-terminus of Mn-SOD subunit with the derived amino acid sequences from the reported Mn-SOD cDNA clones of other sources indicated a high degree of homology among the Ganoderma genus but the Mn-SOD from G. microsporum showed a high variation when compared with other organisms.

Small-dose Harringtonine induces complete remission in patients with acute promyelocytic leukemia.

Small-dose Harringtonine (1-3 mg infused during 4-5 hr) was used as a single agent to treat 10 patients with acute promyelocytic leukemia. Every patient received one to three courses, each lasting 13-81 days (mean 33 days). The interval between courses (i.e., interruptions) was 5-11 days. During treatment, marrow aplasia occurred in one patient and hypoplasia in three. Pancytopenia occurred in all 10 patients. Complete remission was achieved in seven patients (70%) and cytoreduction in two. In vitro studies showed that, although Harringtonine produced a decrease in leukemic cells in all five series of marrow cultures from five patients, there was only one wherein the decrease was accompanied by a simultaneous absolute increase in differentiated myeloid cells. Considerable discrepancy existed between the culture results and clinical responses. These results seem to suggest that the therapeutic effect of Harringtonine on acute promyelocytic leukemia originates chiefly from cytotoxicity.

Low-dose Ara-C can cause complete remission of acute non-lymphocytic leukemia: differentiation induction?

Fourteen patients with acute nonlymphocytic leukemia were treated with low-dose arabinosylcytosine (LDAC). Thirteen patients received subcutaneous injections at a dose of 10 mg/M2 every 12 h. One patient received 25 mg intramuscularly daily. All cases received one to three courses with each course lasting 10-60 days (median 19). Complete remission was achieved in 6 (or 43%) of the patients. Three patients had only cytoreduction and 5 patients did not respond. During the therapy severe thrombocytopenia occurred in all patients while prominent other cytopenias occurred in 10. Two-thirds of the patients achieving a remission had significant myelosuppression. There was one treatment-related death. During therapy 11 patients demonstrated a decrease in leukemia cells with an associated increase in differentiated granulocytes. This included 3 of the 4 complete remitters, and 3 of the 5 nonresponders. These results seem to suggest that the therapeutic effect of low-dose Ara-C may result from a combination of differentiation induction, cytotoxicity and unusual sensitivity of the leukemic cells to this agent.