Browsing by Subject "INFUSION"

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  • Petaja, Liisa; Vaara, Suvi; Liuhanen, Sasu; Suojaranta-Ylinen, Raili; Mildh, Leena; Nisula, Sara; Korhonen, Anna-Maija; Kaukonen, Kirsi-Maija; Salmenpera, Markku; Pettila, Ville (2017)
    Objectives: Acute kidney injury (AKI) occurs frequently after cardiac surgery and is associated with increased mortality. The Kidney Disease: Improving Global Outcomes (KDIGO) criteria for diagnosing AKI include creatinine and urine output values. However, the value of the latter is debated. The authors aimed to evaluate the incidence of AKI after cardiac surgery and the independent association of KDIGO criteria, especially the urine output criterion, and 2.5-year mortality. Design: Prospective, observational, cohort study. Setting: Single-center study in a university hospital. Participants: The study comprised 638 cardiac surgical patients from September 1, 2011, to June 20, 2012. Interventions: None. Measurements and Main Results: Hourly urine output, daily plasma creatinine, risk factors for AKI, and variables for EuroSCORE II were recorded. AKI occurred in 183 (28.7%) patients. Patients with AKI diagnosed using only urine output had higher 2.5-year mortality than did patients without AKI (9/53 [17.0%] v 23/455 [5.1%], p = 0.001). AKI was associated with mortality (hazard ratios [95% confidence intervals]: 3.3 [1.8-6.1] for KDIGO I; 5.8 [2.7-12.1] for KDIGO 2; and 7.9 [3.5-17.6]) for KDIGO 3. KDIGO stages and AKI diagnosed using urine output were associated with mortality even after adjusting for mortality risk assessed using EuroSCORE II and risk factors for AKI. Conclusions: AKI diagnosed using only the urine output criterion without fulfilling the creatinine criterion and all stages of AKI were associated with long-term mortality. Preoperatively assessed mortality risk using EuroSCORE II did not predict this AKI-associated mortality. (C) 2017 Elsevier Inc. All rights reserved.
  • Iljukov, Sergei; Kauppi, Jukka-Pekka; Uusitalo, Arja L. T.; Peltonen, Juha E.; Schumacher, Yorck O. (2020)
    The purpose of this research was to evaluate the performances of female middle- and long-distance runners before and after the implementation of a new antidoping strategy (the Athlete Biological Passport [ABP]) in a country accused of systematic doping. A retrospective analysis of the results of Russian National Championships from 2008 to 2017 was performed. The 8 best female performances for the 800-m, 1500-m, 3000-m steeplechase, 5000-m, and 10,000-m events from the semifinals and finals were analyzed. The yearly number of athletes fulfilling standard qualifications for international competitions was also evaluated. Overall, numbers of athletes banned for doping in 2008-2017 were calculated. As a result, 4 events (800, 1500, 5000 [all P
  • Turconi, Giorgio; Kopra, Jaakko; Võikar, Vootele; Kulesskaya, Natalia; Vilenius, Carolina; Piepponen, T. Petteri; Andressoo, Jaan-Olle (2020)
    Glial cell line-derived neurotrophic factor (GDNF) supports function and survival of dopamine neurons that degenerate in Parkinson's disease (PD). Ectopic delivery of GDNF in clinical trials to treat PD is safe but lacks significant therapeutic effect. In pre-clinical models, ectopic GDNF is effective but causes adverse effects, including downregulation of tyrosine hydroxylase, only a transient boost in dopamine metabolism, aberrant neuronal sprouting, and hyperactivity. Hindering development of GDNF mimetic increased signaling via GDNF receptor RET by activating mutations results in cancer. Safe and effective mode of action must be defined first in animal models to develop successful GDNF-based therapies. Previously we showed that about a 2-fold increase in endogenous GDNF expression is safe and results in increased motor and dopaminergic function and protection in a PD model in young animals. Recently, similar results were reported using a novel Gdnf mRNA-targeting strategy. Next, it is important to establish the safety of a long-term increase in endogenous GDNF expression. We report behavioral, dopamine system, and cancer analysis of five cohorts of aged mice with a 2-fold increase in endogenous GDNF. We found a sustained increase in dopamine levels, improvement in motor learning, and no side effects or cancer. These results support the rationale for further development of endogenous GDNF-based treatments and GDNF mimetic.
  • Runeberg-Roos, Pia; Piccinini, Elisa; Penttinen, Anna-Maija; Matlik, Kert; Heikkinen, Hanna; Kuure, Satu; Bespalov, Maxim M.; Peranen, Johan; Garea-Rodriguez, Enrique; Fuchs, Eberhard; Airavaara, Mikko; Kalkkinen, Nisse; Penn, Richard; Saarma, Mart (2016)
    In Parkinson's disease midbrain dopaminergic neurons degenerate and die. Oral medications and deep brain stimulation can relieve the initial symptoms, but the disease continues to progress. Growth factors that might support the survival, enhance the activity, or even regenerate degenerating dopamine neurons have been tried with mixed results in patients. As growth factors do not pass the blood-brain barrier, they have to be delivered intracranially. Therefore their efficient diffusion in brain tissue is of crucial importance. To improve the diffusion of the growth factor neurturin (NRTN), we modified its capacity to attach to heparan sulfates in the extracellular matrix. We present four new, biologically fully active variants with reduced heparin binding. Two of these variants are more stable than WT NRTN in vitro and diffuse better in rat brains. We also show that one of the NRTN variants diffuses better than its close homolog GDNF in monkey brains. The variant with the highest stability and widest diffusion regenerates dopamine fibers and improves the conditions of rats in a 6-hydroxydopamine model of Parkinson's disease more potently than GDNF, which previously showed modest efficacy in clinical trials. The new NRTN variants may help solve the major problem of inadequate distribution of NRTN in human brain tissue. (C) 2016 Elsevier Inc. All rights reserved.
  • Pajarinen, Jukka; Lin, Tzu-hua; Sato, Taishi; Loi, Florence; Yao, Zhenyu; Konttinen, Yrjo T.; Goodman, Stuart B. (2015)
    Macrophages play a key role in tissue homeostasis as well as in a range of pathological conditions including atherosclerosis, cancer, and autoimmunity. Many aspects of their in vivo behavior are, however, poorly understood. Bioluminescence imaging (BLI) with green fluorescent protein (GFP) and firefly luciferase (FLUC) labelled autologous reporter macrophages could potentially offer a powerful tool to study macrophage biology, but this approach has been hindered by the relative difficulty of efficient gene transfer into primary macrophages. Here we describe a straightforward method for producing large numbers of GFP/FLUC expressing mouse primary macrophages utilizing lentivirus vector, cyclosporine, and a double infection strategy. Using this method we achieved up to 60% of macrophages to express GFP with correspondingly high FLUC signal. When injected into the circulation using a mouse model of local biomaterial induced inflammation and osteolysis, macrophages were initially detectable within the lungs, followed by systemic homing to the local area of chronic inflammation in the distal femur. In addition, transduced macrophages maintained their ability to assume M1 and M2 phenotypes although the GFP/FLUC expression was altered by the polarizing signals. These reporter macrophages could prove to be valuable tools to study the role of macrophages in health and disease.
  • Mahato, Arun Kumar; Kopra, Jaakko; Renko, Juho-Matti; Visnapuu, Tanel; Korhonen, Ilari; Pulkkinen, Nita; Bespalov, Maxim M.; Domanskyi, Andrii; Ronken, Eric; Piepponen, T. Petteri; Voutilainen, Merja H.; Tuominen, Raimo K.; Karelson, Mati; Sidorova, Yulia A.; Saarma, Mart (2020)
    Background Motor symptoms of Parkinson's disease (PD) are caused by degeneration and progressive loss of nigrostriatal dopamine neurons. Currently, no cure for this disease is available. Existing drugs alleviate PD symptoms but fail to halt neurodegeneration. Glial cell line-derived neurotrophic factor (GDNF) is able to protect and repair dopamine neurons in vitro and in animal models of PD, but the clinical use of GDNF is complicated by its pharmacokinetic properties. The present study aimed to evaluate the neuronal effects of a blood-brain-barrier penetrating small molecule GDNF receptor Rearranged in Transfection agonist, BT13, in the dopamine system. Methods We characterized the ability of BT13 to activate RET in immortalized cells, to support the survival of cultured dopamine neurons, to protect cultured dopamine neurons against neurotoxin-induced cell death, to activate intracellular signaling pathways both in vitro and in vivo, and to regulate dopamine release in the mouse striatum as well as BT13's distribution in the brain. Results BT13 potently activates RET and downstream signaling cascades such as Extracellular Signal Regulated Kinase and AKT in immortalized cells. It supports the survival of cultured dopamine neurons from wild-type but not from RET-knockout mice. BT13 protects cultured dopamine neurons from 6-Hydroxydopamine (6-OHDA) and 1-methyl-4-phenylpyridinium (MPP+)-induced cell death only if they express RET. In addition, BT13 is absorbed in the brain, activates intracellular signaling cascades in dopamine neurons both in vitro and in vivo, and also stimulates the release of dopamine in the mouse striatum. Conclusion The GDNF receptor RET agonist BT13 demonstrates the potential for further development of novel disease-modifying treatments against PD. (c) 2019 International Parkinson and Movement Disorder Society
  • Runeberg-Roos, Pia; Penn, Richard D. (2020)
    The last decade has been a frustrating time for investigators who had envisioned major advances in the treatment of Parkinson's disease using neurotrophic factors. The first trials of glial cell line-derived neurotrophic factor for treating Parkinson's disease were very promising. Later blinded control trials were disappointing, not reaching the predetermined outcomes for improvement in motor function. Consideration of the problems in the studies as well as the biology of the neurotrophins used can potentially lead to more effective therapies. Parkinson's disease presents a multitude of opportunities for the cell biologist wanting to understand its pathology and to find possible new avenues for treatment.
  • Udd, Marianne; Lyytinen, Jukka; Eerola-Rautio, Johanna; Kenttämies, Anu; Lindström, Outi; Kylänpää, Leena; Pekkonen, Eero (2017)
    Background: Continuous levodopa-carbidopa intestinal gel (LCIG) diminishes daily off time and dyskinesia in patients with advanced Parkinsons disease (PD). Complications are common with percutaneous endoscopic gastrostomy with a jejunal extension tube (PEG-J). Aim of the Study: To report the clinical outcome of LCIG in patients with advanced PD in the years 2006-2014 at Helsinki University Hospital. Patients and Methods: Levodopa-carbidopa intestinal gel treatment started following PEG-J placement in patients with advanced PD after successful in-hospital LCIG trial with a nasojejunal tube. Demographics, PEG-J procedures, discontinuation of LCIG, complications and mortality were retrospectively analyzed. Results [mean (SD)]: Sixty patients with advanced PD [age 68(7) years; duration of PD: 11(4) years] had LCIG treatment for 26(23) months. The majority of patients with advanced PD were satisfied with the LCIG treatment. For 51 patients (85%), the pump was on for 16hr a day, and for nine patients (15%) it was on for 24hr a day. After 6months, the levodopa-equivalent daily dose (LEDD) had increased by 30% compared to pre-LCIG LEDD. Sixty patients underwent a total of 156 PEG-J procedures, and 48 patients (80%) had a total of 143 complications. Forty-six patients (77%) had 119 PEG-J or peristomal complications, and 22 patients (37%) had a total of 25 other complications. The most common complications were accidental removal of the J-tube in 23 patients (38%) and 5% weight loss in 18 patients (30%). Fifteen patients discontinued the LCIG after 21 (21) months. At the end of the follow-up period of 33(27) months, 38 patients were still on LCIG and nine (15%) had died. Conclusion: Most patients were satisfied with LCIG treatment. A few patients lost weight whereas the majority had complications with PEG-J. When LCIG treatment is carried out, neurological and endoscopic units must be prepared for multiple endoscopic procedures.
  • Adam, Rene; Yi, Bin; Innominato, Pasquale F.; Barroso, Eduardo; Laurent, Christophe; Giuliante, Felice; Capussotti, Lorenzo; Lapointe, Real; Regimbeau, Jean-Marc; Lopez-Ben, Santiago; Isoniemi, Helena; Hubert, Catherine; Lin, Jen-Kou; Gruenberger, Thomas; Elias, Dominique; Skipenko, Oleg G.; Guglielmi, Alfredo; LiverMetSurvey Int Contributing (2017)
    Purpose: Patient outcome after resection of colorectal liver metastases (CLM) following second-line preoperative chemotherapy (PCT) performed for insufficient response or toxicity of the first-line, is little known and has here been compared to the outcome following first-line. Patients and methods: From January 2005 to June 2013, 5624 and 791 consecutive patients of a prospective international cohort received 1 and 2 PCT lines before CLM resection (group 1 and 2, respectively). Survival and prognostic factors were analysed. Results: After a mean follow-up of 30.1 months, there was no difference in survival from CLM diagnosis (median, 3-, and 5-year overall survival [OS]: 58.6 months, 76% and 49% in group 2 versus 58.9 months, 71% and 49% in group 1, respectively, P = 0.32). After hepatectomy, disease-free survival (DFS) was however shorter in group 2: 17.2 months, 27% and 15% versus 19.4 months, 32% and 23%, respectively (P = 0.001). Among the initially unresectable patients of group 1 and 2, no statistical difference in OS or DFS was observed. Independent predictors of worse OS in group 2 were positive primary lymph nodes, extrahepatic disease, tumour progression on second line, R2 resection and number of hepatectomies/year Conclusion: CLM resection following second-line PCT, after oncosurgically favourable selection, could bring similar OS compared to what observed after first-line. For initially unresectable patients, OS or DFS is comparable between first-and second-line PCT. Surgery should not be denied after the failure of first-line chemotherapy. (C) 2017 Elsevier Ltd. All rights reserved.
  • Kuryk, Lukasz; Vassilev, Lotta; Ranki, Tuuli; Hemminki, Akseli; Karioja-Kallio, Aila; Levälampi, Onerva; Vuolanto, Antti; Cerullo, Vincenzo; Pesonen, Sari (2017)
    The purpose of this work was to carry out preclinical toxicity and bio-distribution studies required for regulatory approval of a clinical trial application for Phase I clinical studies of ONCOS-102 (Ad5/3-D24-GM-CSF) for therapy of advanced cancers (NCT01598129). The study design, route of administration and dosage differs from the clinical protocol and in more detail, investigate bio-distribution and toxicological profile of ONCOS-102 treatment in animal model. The study was carried out in 300 hamsters divided into nine test groups-three bio-distribution groups and six groups for analysis of toxicity. Hamsters received ONCOS-102 by intracardial, intraperitoneal or subcutaneous injections. Additionally, one group was administered twice a week with intraperitoneal injections of Cyclophosphamide. The control animals were administered with NaCl solution without ONCOS-102 in the same volume and the same way. No adverse effects of repeated administration of ONCOS-102 including body weight, food consumption, hematology and clinical chemistry parameters, histopathology and bio-accumulation were observed in the course of 6-month administration and following 3-month recovery period. All obtained findings indicate the treatment clinically safe.
  • Hemila, Harri; Suonsyrja, Timo (2017)
    Background: Atrial fibrillation (AF), a common arrhythmia contributing substantially to cardiac morbidity, is associated with oxidative stress and, being an antioxidant, vitamin C might influence it. Methods: We searched the Cochrane CENTRAL Register, MEDLINE, and Scopus databases for randomised trials on vitamin C that measured AF as an outcome in high risk patients. The two authors independently assessed the trials for inclusion, assessed the risk of bias, and extracted data. We pooled selected trials using the Mantel-Haenszel method for the risk ratio (RR) and the inverse variance weighting for the effects on continuous outcomes. Results: We identified 15 trials about preventing AF in high-risk patients, with 2050 subjects. Fourteen trials examined post-operative AF (POAF) in cardiac surgery patients and one examined the recurrence of AF in cardioversion patients. Five trials were carried out in the USA, five in Iran, three in Greece, one in Slovenia and one in Russia. There was significant heterogeneity in the effect of vitamin C in preventing AF. In 5 trials carried out in the USA, vitamin C did not prevent POAF with RR = 1.04 (95% CI: 0.86-1.27). In nine POAF trials conducted outside of the USA, vitamin C decreased its incidence with RR = 0.56 (95% CI: 0.47-0.67). In the single cardioversion trial carried out in Greece, vitamin C decreased the risk of AF recurrence by RR = 0.13 (95% CI: 0.02-0.92). In the non-US cardiac surgery trials, vitamin C decreased the length of hospital stay by 12.6% (95% CI 8.4-16.8%) and intensive care unit (ICU) stay by 8.0% (95% CI 3.0-13.0%). The US trials found no effect on hospital stay and ICU stay. No adverse effects from vitamin C were reported in the 15 trials. Conclusions: Our meta-analysis indicates that vitamin C may prevent post-operative atrial fibrillation in some countries outside of the USA, and it may also shorten the duration of hospital stay and ICU stay of cardiac surgery patients. Vitamin C is an essential nutrient that is safe and inexpensive. Further research is needed to determine the optimal dosage protocol and to identify the patient groups that benefit the most.