Importance of sodium for recovery of calcium control in reoxygenated cardiomyocytes

1994 ◽  
Vol 267 (2) ◽  
pp. H506-H513 ◽  
Author(s):  
B. Siegmund ◽  
Y. V. Ladilov ◽  
H. M. Piper
Keyword(s):  
Phase I ◽  
Phase Ii ◽  
Phase Iii ◽  
Fura 2 ◽  
Adult Rat ◽  
Na Pump ◽  
Initial Drop ◽  
Na Depletion ◽  
Phase I And Ii

The role of Na+ in the recovery from severe anoxic Ca2+ overload was investigated in isolated quiescent ventricular cardiomyocytes from adult rat. Changes of cytosolic Ca2+ and Na+ concentrations were followed by the fura 2 and Na(+)-binding benzofuran isophthalate techniques, respectively. When the fura 2 ratio (340/380 nm) reached saturation in anoxic cells, indicating a severe cytosolic Ca2+ overload, the cells were reoxygenated. This caused a rapid initial drop of cytosolic Ca2+ to a lower but still elevated level (phase I), followed by oscillatory Ca2+ transients at this level (phase II) and, within 10 min, the reestablishment of a stable cytosolic Ca2+ concentration at the normal resting level (phase III). As previously shown [B. Siegmund, R. Zude, and H. M. Piper. Am. J. Physiol. 263 (Heart Circ. Physiol. 32): H1262–H1269, 1992], Ca2+ shifts in phase I and II are mainly due to uptake and release of Ca2+ by the sarcoplasmic reticulum. Phase I was unchanged, and phase II was much prolonged (> 60 min) in cells reoxygenated under Na+ pump inhibition (0.2 mM ouabain) or Na+ depletion. Phase III could only be reestablished (< 10 min) when ouabain was eluted or external Na+ replenished, respectively. The results show that full recovery of cytosolic Ca2+ control (phase III) requires an active sarcolemmal Na+ pump and the availability of external Na+. This indicates that phase III is determined by the transsarcolemmal extrusion of Ca2+ by a tandem mechanism consisting of 1) the Na+ pump, generating an extracellular-to-intracellular Na+ gradient, and 2) the sarcolemmal Na+/Ca2+ exchange, driven by that gradient to extrude Ca2+.

scholarly journals Understanding the Los Angeles County Coronavirus Epidemic: The Critical Role of Intrahousehold Transmission

2020 ◽  
Author(s):  
Jeffrey E. Harris
Keyword(s):  
Los Angeles ◽  
Phase I ◽  
Phase Ii ◽  
Los Angeles County ◽  
Critical Role ◽  
Phase Iii ◽  
Strongly Correlated ◽  
The Individual ◽  
County Public Health

AbstractWe tracked the course of the COVID-19 epidemic among the approximately 300 communities comprising Los Angeles County. The epidemic, we found, had three distinct phases. During Phase I, from early March through about April 4, initial seeding of infection in relatively affluent areas was followed by radial geographic extension to adjoining communities. During Phase II, lasting until about July 11, COVID-19 cases continued to rise at a slower rate, and became increasingly concentrated in four geographic foci of infection across the county. Those communities with larger reductions in social mobility during April - as measured by the proportion of smartphones staying at home and number of smartphones visiting a gym - reported fewer COVID-19 cases in May. During Phase III, COVID-19 incidence only gradually declined, remaining as high as the incidence seen at the end of Phase I. Across communities, the prevalence of households at high risk for intergenerational transmission was strongly correlated with the persistence of continued COVID-19 propagation. This association was even stronger in those communities with a higher rate of gym attendance in Phase II. The map of the prevalence of at-risk households in Los Angeles County coincided strikingly with the map of cumulative COVID-19 incidence. These findings, taken together, support the critical role of household structure in the persistent propagation of COVID-19 infections in Los Angeles County. Public health policy needs to be reoriented from a focus on protecting the individual to a focus on protecting the household.

Bewegungstherapie und körperliche Aktivität bei Patienten mit Herzinsuffizienz

Praxis ◽  
2018 ◽  
Vol 107 (17-18) ◽  
pp. 951-958 ◽  
Author(s):  
Matthias Wilhelm
Keyword(s):  
Phase I ◽  
Phase Ii ◽  
Körperliche Aktivität ◽  
Phase Iii

Zusammenfassung. Herzinsuffizienz ist ein klinisches Syndrom mit unterschiedlichen Ätiologien und Phänotypen. Die überwachte Bewegungstherapie und individuelle körperliche Aktivität ist bei allen Formen eine Klasse-IA-Empfehlung in aktuellen Leitlinien. Eine Bewegungstherapie kann unmittelbar nach Stabilisierung einer akuten Herzinsuffizienz im Spital begonnen werden (Phase I). Sie kann nach Entlassung in einem stationären oder ambulanten Präventions- und Rehabilitationsprogramm fortgesetzt werden (Phase II). Typische Elemente sind Ausdauer-, Kraft- und Atemtraining. Die Kosten werden von der Krankenversicherung für drei bis sechs Monate übernommen. In erfahrenen Zentren können auch Patienten mit implantierten Defibrillatoren oder linksventrikulären Unterstützungssystemen trainieren. Wichtiges Ziel der Phase II ist neben muskulärer Rekonditionierung auch die Steigerung der Gesundheitskompetenz, um die Langzeit-Adhärenz bezüglich körperlicher Aktivität zu verbessern. In Phase III bieten Herzgruppen Unterstützung.

scholarly journals AB0332 IMMUNOSUPPRESSIVE AND IMMONOMODULATING AGENTS IN RHEUMATOID ARTHRITIS: A SYSTEMATIC REVIEW OF CLINICAL TRIALS AND THEIR CURRENT DEVELOPMENT STAGE

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 1464.1-1465
Author(s):  
J. Blaess ◽  
J. Walther ◽  
J. E. Gottenberg ◽  
J. Sibilia ◽  
L. Arnaud ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Systematic Review ◽  
B Cells ◽  
Phase I ◽  
Phase Ii ◽  
Clinical Development ◽  
Phase Iii ◽  
Jak Inhibitors ◽  
Exclusion Criteria ◽  
Immunomodulating Drugs

Background:Rheumatoid arthritis (RA) is the most frequent chronic inflammatory diseases with an incidence of 0.5% to 1%. Therapeutic arsenal of RA has continuously expanded in recent years with the recent therapeutic progress with the arrival of conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs), biological (bDMARDs) and targeted synthetic (tsDMARDs), JAK inhibitors. However, there are still some unmet needs for patients who do not achieve remission and who continue to worsen despite treatments. Of note, only approximately 40% of patients are ACR70 responders, in most randomized controlled trials. For these patients, finding new therapeutic avenues is challenging.Objectives:The objective of our study was to analyze the whole pipeline of immunosuppressive and immunomodulating drugs evaluated in RA and describe their mechanisms of action and stage of clinical development.Methods:We conducted a systematic review of all drug therapies in clinical development in RA in 17 databases of international clinical trials. Inclusion criterion: study from one of the databases using the keywords “Rheumatoid arthritis” (search date: June 1, 2019). Exclusion criteria: non-drug trials, trials not related to RA or duplicates. We also excluded dietary regimen or supplementations, cellular therapies, NSAIDs, glucorticoids or their derivatives and non-immunosuppressive or non-immunomodulating drugs. For each csDMARD, bDMARD and tsDMARD, we considered the study at the most advanced stage. For bDMARDs, we did not take into account biosimilars.Results:The research identified 4652 trials, of which 242 for 243 molecules met the inclusion and exclusion criteria. The developed molecules belong to csDMARDs (n=21), bDMARDs (n=117), tsDMARDs (n=105).Among the 21 csDMARDs molecules: 8 (38%) has been withdrawn, 4 (19%) are already labelled in RA (hydroxychloroquine, leflunomide, methotrexate and sulfasalazine) and 9 (43%) are in development: 1 (11%) is in phase I/II, 5 (56%) in phase II, 3 (33%) in phase IV.Among the 117 bDMARDs molecules: 69 (59%) has been withdrawn, 9 (8%) are labeled in RA (abatacept, adalimumab, anakinra, certolizumab, etanercept, golimumab, infliximab, rituximab, sarilumab, tocilizumab) and 39 (33%) are in development: 9 (23%) in phase I, 3 (8%) in phase I/II, 21 (54%) in phase II, 5 (12%) are in phase III, 1 (3%) in phase IV. bDMARDs currently under development target B cells (n=4), T cells (n=2), T/B cells costimulation (n=2),TNF alpha (n=2), Interleukine 1 or his receptor (n=3), Interleukine 6 or his receptor (n=7), Interleukine 17 (n=4), Interleukine 23 (n=1), GM-CSF (n=1), other cytokines or chemokines (n=5), integrins or adhesion proteins (n=3), interferon receptor (n=1) and various other targets (n=4).Among the 105 tsDMARDs molecules: 64 (61%) has been withdrawn, 6 (6%) JAK inhibitors, have just been or will probably soon be labelled (baricitinib, filgotinib, peficitinib, tofacitinib and upadacitinib), 35 (33%) are in development: 8 (24%) in phase I, 26 (74%) in phase II, 1 (3%) in phase III and. tsDMARDs currently under development target tyrosine kinase (n=12), janus kinase (JAK) (n=3), sphingosine phostate (n=3), PI3K pathway (n=1), phosphodiesterase-4 (n=3) B cells signaling pathways (n=3) and various other targets (n=10).Conclusion:A total of 242 therapeutic trials involving 243 molecules have been or are being evaluated in RA. This development does not always lead to new treatments since 141 (58%) have already been withdrawn. Hopefully, some of the currently evaluated drugs will contribute to improve the therapeutic management of RA patients, requiring a greater personalization of therapeutic strategies, both in the choice of molecules and their place in therapeutic sequences.Disclosure of Interests:Julien Blaess: None declared, Julia Walther: None declared, Jacques-Eric Gottenberg Grant/research support from: BMS, Pfizer, Consultant of: BMS, Sanofi-Genzyme, UCB, Speakers bureau: Abbvie, Eli Lilly and Co., Roche, Sanofi-Genzyme, UCB, Jean Sibilia: None declared, Laurent Arnaud: None declared, Renaud FELTEN: None declared

scholarly journals Unconventional Anticancer Agents: A Systematic Review of Clinical Trials

2006 ◽  
Vol 24 (1) ◽  
pp. 136-140 ◽  
Author(s):  
Andrew J. Vickers ◽  
Joyce Kuo ◽  
Barrie R. Cassileth
Keyword(s):  
Clinical Trials ◽  
Phase I ◽  
Cancer Patients ◽  
Phase Ii ◽  
Dose Finding ◽  
Phase Iii ◽  
High Dose ◽  
Free Text ◽  
Phase Ii Trials ◽  
Off Label

Purpose A substantial number of cancer patients turn to treatments other than those recommended by mainstream oncologists in an effort to sustain tumor remission or halt the spread of cancer. These unconventional approaches include botanicals, high-dose nutritional supplementation, off-label pharmaceuticals, and animal products. The objective of this study was to review systematically the methodologies applied in clinical trials of unconventional treatments specifically for cancer. Methods MEDLINE 1966 to 2005 was searched using approximately 200 different medical subject heading terms (eg, alternative medicine) and free text words (eg, laetrile). We sought prospective clinical trials of unconventional treatments in cancer patients, excluding studies with only symptom control or nonclinical (eg, immune) end points. Trial data were extracted by two reviewers using a standardized protocol. Results We identified 14,735 articles, of which 214, describing 198 different clinical trials, were included. Twenty trials were phase I, three were phase I and II, 70 were phase II, and 105 were phase III. Approximately half of the trials investigated fungal products, 20% investigated other botanicals, 10% investigated vitamins and supplements, and 10% investigated off-label pharmaceuticals. Only eight of the phase I trials were dose-finding trials, and a mere 20% of phase II trials reported a statistical design. Of the 27 different agents tested in phase III, only one agent had a prior dose-finding trial, and only for three agents was the definitive study initiated after the publication of phase II data. Conclusion Unconventional cancer treatments have not been subject to appropriate early-phase trial development. Future research on unconventional therapies should involve dose-finding and phase II studies to determine the suitability of definitive trials.

Hydrogeological Characterization Based on Long Term Groundwater Pressure Monitoring

2010 ◽  
Author(s):  
Shuji Daimaru ◽  
Ryuji Takeuchi ◽  
Masaki Takeda ◽  
Masayuki Ishibashi
Keyword(s):  
Phase I ◽  
Phase Ii ◽  
Large Scale ◽  
Pumping Test ◽  
Phase Iii ◽  
Pressure Monitoring ◽  
Energy Agency ◽  
Hydrogeological Characteristics ◽  
Under Construction

The Mizunami Underground Research Laboratory (MIU) is now under construction by the Japan Atomic Energy Agency in the Tono area of central Japan. The MIU project is being implemented in three overlapping Phases: Surface-based Investigation (Phase I), Construction (Phase II) and Operation (Phase III). The changes of groundwater pressure due to shaft excavation can be considered analogous to a large-scale pumping test. Therefore, there is the possibility that the site scale groundwater field (several km square) can be approximated by the long-term groundwater pressure monitoring data from Phase II. Based on the monitoring observations, hydrogeological characteristics were estimated using the s-log(t/r2) plot based on the Cooper-Jacob straight line method. Results of the s-log(t/r2) plots are as follows. The groundwater flow field around the MIU construction site is separated into domains by an impermeable fault. In other words, the fault is a hydraulic barrier. Hydraulic conductivity calculated from s-log(t/r2) plots are in the order of 1.0E−7(m/s). The above results from the long term monitoring during Phase II are a verification of the hydrogeological characteristics determined in the Phase I investigations.

Phase I Trial of Escalating-Dose Irinotecan Given Weekly With Cisplatin and Concurrent Radiotherapy in Locally Advanced Esophageal Cancer

2003 ◽  
Vol 21 (15) ◽  
pp. 2926-2932 ◽  
Author(s):  
David H. Ilson ◽  
Manjit Bains ◽  
David P. Kelsen ◽  
Eileen O’Reilly ◽  
Martin Karpeh ◽  
...  
Keyword(s):  
Esophageal Cancer ◽  
Phase I ◽  
Induction Chemotherapy ◽  
Phase Ii ◽  
Phase I Trial ◽  
Locally Advanced ◽  
Phase Iii ◽  
Concurrent Radiotherapy ◽  
Minimal Toxicity ◽  
Grade 3

Purpose: To identify the maximum-tolerated dose and dose-limiting toxicity (DLT) of weekly irinotecan combined with cisplatin and radiation in esophageal cancer. Patients and Methods: Nineteen patients with clinical stage II to III esophageal squamous cell or adenocarcinoma were treated on this phase I trial. Induction chemotherapy with weekly cisplatin 30 mg/m2 and irinotecan 65 mg/m2 was administered for four treatments during weeks 1 to 5. Radiotherapy was delivered weeks 8 to 13 in 1.8-Gy daily fractions to a dose of 50.4 Gy. Cisplatin 30 mg/m2 and escalating-dose irinotecan (40, 50, 65, and 80 mg/m2) were administered on days 1, 8, 22, and 29 of radiotherapy. DLT was defined as a 2-week delay in radiotherapy for grade 3 to 4 toxicity. Results: Minimal toxicity was observed during chemoradiotherapy, with no grade 3 or 4 esophagitis, diarrhea, or stomatitis. DLT caused by myelosuppression was seen in two of six patients treated at the 80-mg/m2 dose level, thus irinotecan 65 mg/m2 was defined as the recommended phase II dose. Dysphagia improved or resolved after induction chemotherapy in 13 (81%) of 16 patients who reported dysphagia before therapy. Only one patient (5%) required a feeding tube. Six complete responses (32%) were observed, including four pathologic complete responses in 15 patients selected to undergo surgery (27%). Conclusion: Cisplatin, irinotecan, and concurrent radiotherapy can be administered on a convenient schedule with relatively minimal toxicity and an acceptable rate of complete response in esophageal cancer. Further phase II evaluation of this regimen is ongoing. A phase III comparison to fluorouracil or taxane-containing chemoradiotherapy should be considered.

scholarly journals CHARACTERISTICS ANALYSIS OF DRAGON FRUIT EXTRACT SKIN BETACYANIN of Hylocereus polyrhizus AND Hylocereus undatus WITH TEST OF STABILITY ORGANOLEPTIC JELLY AS ATLAS MEDIA

2016 ◽  
Vol 2 (1) ◽  
Author(s):  
Tutut Puji Lestari
Keyword(s):  
High School ◽  
Phase I ◽  
Junior High School ◽  
Junior High ◽  
Phase Iii ◽  
Fruit Skin ◽  
Dragon Fruit ◽  
Hylocereus Undatus ◽  
Hylocereus Polyrhizus ◽  
Phase I And Ii

Dragon fruit Hylocereus polyrhizus  and Hylocereus undatus are familiy of cactus, grown in Malang. The high consumption of dragon fruit, have an impact on the fruit skin buildup that simply disposed of as trash. Dragon fruit skin is known to have a source of natural red dye, which is Betacyanin. The purpose of this study was to determine the characteristics of the dragon fruit peel extract Betacyanin Hylocereus polyrhizus and Hylocereus undatus as well as the stability of the organoleptic jelly, which will be developed into a learning materials atlas for class VIII Junior High School. The study was conducted in September-October 2015. The study was conducted in three stages. This type of research phase I and II is True Experimental, and phase III is development. The results of phase I shows that various concentrations of ethanol (70% and 90%) have an effect on the characteristics of the extract Betacyanin skin dragon fruit Hylocereus polyrhizus and Hylocereus undatus, but very significant effect on skin extract dragon fruit Hylocereus undatus the treatment of N2, EI at pH 4,5. Later in the phase II study results showed that different concentrations of extracts of the best Betacyanin significantly affect the organoleptic stability of jelly. The results of phase III is the development of phase I and II studies into Atlas media for 8th grade of  Junior High School.  

scholarly journals Etude par resonance magnetique des mouvements moléculaires dans l'acrylonitrile solide

1973 ◽  
Vol 51 (23) ◽  
pp. 3889-3900 ◽  
Author(s):  
Buu Ban ◽  
C. CHACHATY
Keyword(s):  
Phase Transitions ◽  
Phase I ◽  
Phase Ii ◽  
Phase Iii ◽  
Solid Matrix ◽  
Peroxy Radicals ◽  
Γ Irradiation ◽  
Rotational Oscillation ◽  
Résonance Magnétique ◽  
Oxygen Addition

Phase transitions and molecular motions in solid acrylonitrile and its deuterated homologue CH2=CDCN, have been studied between 100 and 191 °K (m.p.) by wide line n.m.r. and by T1 relaxation time measurements. Phase I (164 °K < T < 191 °K) is trapped and becomes metastable by quick cooling of acrylonitrile at 77 °K. It changes into the phase II, stable between 113 °K and 164 °K by a long duration annealing at 155–160 °K. The phase II → phase III transition occurs at 113 °K. It may be assumed that phase III, stable below this temperature, is rigid at T < 105 °K. Phase II may be characterized by a rotational oscillation of molecules around an axis defined by the N atom and the middle of the vinyl double bond. In phase I, acrylonitrile molecules undergo a binary reorientation motion around this axis with an activation energy of 4.2 kcal mol−1. The motion of peroxy radicals, trapped in acrylonitrile has been also studied by e.s.r. These radicals were produced by oxygen addition to free radicals previously formed by γ irradiation of acrylonitrile at 77 °K. The g anisotropy variation with temperature, shows no discontinuities at phase transitions, the activation of reorientation of peroxy radicals being 0.65 kcal mol−1. This result suggests that we are dealing in fact with macroradicals, the internal rotation of which is only observable in a solid matrix.

Offline Well Abandonment SIMOPs: An 81 Well Phase I & II Case Study Enabling ABEX Reduction in South East Asia

2021 ◽  
Author(s):  
Steven A. Canny ◽  
Jane Amarin ◽  
Verapich Pinprayong ◽  
Chumpae Sratongroy ◽  
Pancharat Pitchayang ◽  
...  
Keyword(s):  
Phase I ◽  
Phase Ii ◽  
Business Performance ◽  
Net Present Value ◽  
Balance Sheet ◽  
Pressure Control ◽  
Phase Iii ◽  
Well Abandonment ◽  
The Cost

Abstract In the decommissioning phase of oilfield facility lifecycles, focus pivots from positive net present value to executing the care and preservation, then decommissioning in the safest and most environmentally sensitive manor, and at the lowest total cost of ownership. Asset Retirement Obligation (ARO) is a long-term liability carried on the balance sheet, as a provision for the cost to return a wellsite to pre-exploration condition. The reduction of abandonment and decommissioning expenditure (ABEX) in executing compliant operations is a key business performance factor, and critical in executing higher volumes of wells earlier than planned. In doing so maximizing value to company shareholders, residents, industries and government level stakeholders. In the case study, an offline pre-abandonment and Phase I primary reservoir isolation project is presented, which seeks to maximize net project efficiency via offline wellbore intervention, executing the primary reservoir isolation of the wellbore via rigless techniques. This approach contributed to ABEX reductions by up to 40% per well vs the planned approval for expenditure (AFE) provisions taken for the operations. The project execution structure utilized offline intervention and Phase I primary reservoir isolation of 81 wellbores, across 5 wellhead platforms and 47 days continuous operations. Operations were part of a simultaneous operation (SIMOPS) project, as an offline work front located on the wellhead platform (WHP) weather deck. A second work front for Phase II and Phase III well abandonment operations, is executed concurrently, from the jack-up rig cantilever above the WHP. Live well operations are conducted concurrently by both work fronts, through the Christmas Tree (XT) and pressure control equipment in Phase I, and through the drilling riser and blowout preventor for Phase II and Phase III, to maximize productivity when the rig is on location. The scope of operations included wellhead qualification, wellbore access and preparation, well kill, injectivity testing, various wellbore preparation and cement placement techniques, pressure testing and lubrication of the wellbore. The operator's system engineering, design of operations and planning agility are key to its success. Acute focus was given to the batching of operations and delivery of these in a phased approach to increase productivity and maintain high service delivery through repetition of tasks. The project successfully executed Incident Free Operations (IFO) with 100% productive time and facilitated combined project performance, which delivered wells up to 44% ahead of the planned AFE. To enable this, over 4.19 million feet of slickline was run, conveying 428 bottom hole assemblies (BHAs), preparing the wellbores to isolate 804 primary reservoirs, and 2 intermediate reservoirs.

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