82 research outputs found
Advanced Modalizing Problems
I present an internal problem for David Lewis’s genuine modal realism. My aim is to show that his analysis of modality is inconsistent with his metaphysics. I consider several ways of modifying the Lewisian analysis of modality, but argue that none are successful. I argue that the problem also affects theories related to genuine modal realism, including the stage theory of persistence and modal fictionalism
Front-line Bevacizumab in combination with Oxaliplatin, Leucovorin and 5-Fluorouracil (FOLFOX) in patients with metastatic colorectal cancer: a multicenter phase II study
<p>Abstract</p> <p>Purpose</p> <p>To evaluate the efficacy and the toxicity of front line FOLFOX4 combined with bevacizumab in patients with metastatsic CRC (mCRC).</p> <p>Patients and Methods</p> <p>Chemotherapy-naïve patients with mCRC, received bevacizumab (5 mg/kg every 2 weeks d<sub>1</sub>), oxaliplatin (85 mg/m<sup>2 </sup>on d<sub>1</sub>), leucovorin (200 mg/m<sup>2</sup>) on days 1 and 2 and 5-Fluorouracil (400 mg/m<sup>2 </sup>as i.v. bolus and 600 mg/m<sup>2 </sup>as 22 h i.v. continuous infusion on days 1 and 2) every 2 weeks.</p> <p>Results</p> <p>Fifty three patients (46 with a PS 0–1) were enrolled. Complete and partial response was achieved in eight (15.1%) and 28 (52.8%) patients, respectively (ORR: 67.9%; 95% C.I.: 53.8%–92%); 11 (20.7%) patients had stable disease and six (11.3%) progressive disease. With a median follow up period of 13.5 months, time to tumor progression was 11 months while the median survival has not yet been reached; the probability of 1-, 2- and 3- year survival was 79.8%, 63.8% and 58.3%, respectively; Two patients relapsed during the follow up period. Eight (15%) patients underwent metastasectomy with R0 resections. Grade 3–4 neutropenia occurred in 15.1% of patients and one (1.9%) of them presented febrile neutropenia. Non-hematologic toxicity included grade 3 diarrhea (7.6%) and grade 2 and 3 neurotoxicity in 16.9 and 15.1% of patients, respectively. One (1.9%) patient presented pulmonary embolism and one (1.9%) cardiac ischaemia. There was one (1.9%) sudden death after the first cycle.</p> <p>Conclusion</p> <p>The combination of FOLFOX4/bevacizumab appears to be highly effective, well tolerated and merits further evaluation in patients with mCRC.</p
Contemporary management of heart failure patients with reduced ejection fraction: the role of implantable devices and catheter ablation
Heart failure (HF) is a complex clinical syndrome characterised by significant morbidity and mortality worldwide. Evidence-based therapies for the management of HF include several well-established neurohormonal antagonists and antiarrhythmic drug therapy to mitigate the onset of cardiac arrhythmia. However, the degree of rate and rhythm control achieved is often suboptimal and mortality rates continue to remain high. Implantable cardioverter-defibrillators (ICDs), cardiac resynchronization (CRT), and combined (CRT-D) therapies have emerged as integral and rapidly expanding technologies in the management of select patients with heart failure with reduced ejection fraction (HFrEF). ICDs treat ventricular arrhythmia and are used as primary prophylaxis for sudden cardiac death, while CRT resynchronizes ventricular contraction to improve left ventricular systolic function. Left ventricular assist device therapy has also been shown to provide clinically meaningful survival benefits in patients with advanced HF, and His-bundle pacing has more recently emerged as a safe, viable, and promising pacing modality for patients with CRT indication. Catheter ablation is another important and well-established strategy for managing cardiac arrhythmia in HF, demonstrating superior efficacy when compared with antiarrhythmic drug therapy alone. In this article, we provide a comprehensive and in-depth evaluation of the role of implantable devices and catheter ablation in patients with HFrEF, outlining current applications, recent advances, and future directions in practice
Nitrosative and Oxidative Stresses Contribute to Post-Ischemic Liver Injury Following Severe Hemorrhagic Shock: The Role of Hypoxemic Resuscitation
Purpose: Hemorrhagic shock and resuscitation is frequently associated with liver ischemia-reperfusion injury. The aim of the study was to investigate whether hypoxemic resuscitation attenuates liver injury. Methods: Anesthetized, mechanically ventilated New Zealand white rabbits were exsanguinated to a mean arterial pressure of 30 mmHg for 60 minutes. Resuscitation under normoxemia (Normox-Res group, n = 16, PaO2 = 95–105 mmHg) or hypoxemia (Hypox-Res group, n = 15, PaO 2 = 35–40 mmHg) followed, modifying the FiO 2. Animals not subjected to shock constituted the sham group (n = 11, PaO 2 = 95–105 mmHg). Indices of the inflammatory, oxidative and nitrosative response were measured and histopathological and immunohistochemical studies of the liver were performed. Results: Normox-Res group animals exhibited increased serum alanine aminotransferase, tumor necrosis factor- alpha, interleukin (IL)-1b and IL-6 levels compared with Hypox-Res and sham groups. Reactive oxygen species generation, malondialdehyde formation and myeloperoxidase activity were all elevated in Normox-Res rabbits compared with Hypox-Res and sham groups. Similarly, endothelial NO synthase and inducible NO synthase mRNA expression was up-regulated and nitrotyrosine immunostaining increased in animals resuscitated normoxemically, indicating a more intense nitrosative stress. Hypox-Res animals demonstrated a less prominent histopathologic injury which was similar to sham animals. Conclusions: Hypoxemic resuscitation prevents liver reperfusion injury through attenuation of the inflammatory respons
Εφαρμογή εντοπισμού και πλοήγησης σε εσωτερικό χώρο με τη χρήση τεχνολογίας Bluetooth beacons
Novel therapeutic strategies in the management of arterial hypertension
Essential hypertension is a disease with a major impact on health
worldwide, thus control of blood pressure seems to be a key component of
cardiovascular disease prevention. Despite considerable advances in the
treatment of hypertension, effective management remains poor and new
strategies to control high blood pressure and cardiovascular risk
reduction are required. These seem to be divided into two major
categories: those seeking to advance blood pressure-lowering efficacy of
already existing agents, and others related to novel approaches, both
pharmacological and non-pharmacological. Moreover, numerous clinical
trials have evaluated the use of nutritional supplements in the
prevention of cardiovascular diseases and in achievement of optimal
blood pressure control. Additionally, the advent of interventional
techniques, such as carotid baroreceptor stimulation and renal ablation
of sympathetic nerve activity, seems to be proved effective in cases
where medical management and lifestyle modifications are insufficient.
Genetic technology, which has advanced tremendously over the past few
years, could assist novel treatment options in hypertensive patients,
such as RNA interference targeting hypertension-related genes. However,
continued efforts must progress in these areas and the effects of
therapeutic strategies in hypertensive patients need to be further
explored in larger trials over a longer period of time. (C) 2012
Elsevier Inc. All rights reserved
Favorable Clinical Course of Patients Experiencing Bevacizumab-Induced Proteinuria
Nephrotic-range proteinuria, which denotes structural damage to the glomerular filtration barrier, occurs in 1–2% of bevacizumab-treated patients. The glomerular injury and subsequent proteinuria is probably due to a direct targeting of vascular endothelial growth factor (VEGF). We report a case series of six patients who developed a syndrome characterized by proteinuria and hypertension after starting therapy with bevacizumab and who experienced prolonged progression-free survival. Given that altered glomerular permeability appears to be a direct consequence of VEGF inhibition, we hypothesize that proteinuria may indeed correlate with drug efficacy. Optimizing safe and effective drug dosing is critical to achieve the best therapeutic impact due to limited treatment options for many life-threatening advanced cancers. Clinicians should be aware that the development of proteinuria might serve as a surrogate marker of bevacizumab antitumor efficacy and determine the appropriate criteria for withholding this effective anticancer therapy
Homoarginine in the shadow of asymmetric dimethylarginine: from nitric oxide to cardiovascular disease
It is well known that the endothelium maintains the vascular
homeostasis. Importantly, endothelial dysfunction is regarded as a key
early step in the development of atherosclerosis. Back in the early
1990s, it was found that asymmetric dimethylarginine (ADMA), an arginine
metabolite derived from l-arginine (Arg) residues in proteins by
asymmetric dimethylation on its guanidine group, is an endogenous
inhibitor of nitric oxide (NO) synthase (NOS) isoforms. Inhibition of NO
synthesis from Arg by the endothelial NOS isoform (eNOS) leads to
endothelial dysfunction. Due to this action, ADMA participates in the
pathophysiology of atherosclerosis and potentially contributes to
cardiovascular events. Nowadays, homoarginine (hArg) is considered as a
new key player in atherogenesis. hArg is a non-essential,
non-proteinogenic amino acid which is synthesized from Arg by
arginine:glycine amidinotransferase (AGAT). hArg is structurally related
to Arg; formally, hArg is by one methylene (CH2) group longer than Arg,
and may serve as a substrate for NOS, thus contributing to NO synthesis.
For several decades, the pathophysiological role of hArg has been
entirely unknown. hArg has been in the shadow of ADMA. Clinical studies
have sought to investigate the relationship between circulating hArg
levels and human disease states as well as cardiovascular prognosis.
Recent studies indicate that hArg is actively involved in the vascular
homeostasis, yet the underlying mechanisms are incompletely understood.
In this article, we review the available literature regarding the role
of ADMA and hArg in endothelial dysfunction and in cardiovascular
disease as well as the possible associations between these endogenous
Arg derivatives
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