[CONTROVERSIAL EFFECTS OF NITRIC OXIDE: INTEGRITY AND TOXICITY]
KISS Róbert Gábor1, BÉRES Bernát János2
JULY 14, 2007
Lege Artis Medicinae - 2007;17(06-07)
KISS Róbert Gábor1, BÉRES Bernát János2
JULY 14, 2007
Lege Artis Medicinae - 2007;17(06-07)
[Nitric oxide is a key molecule of the human body. Since its discovery, a library of books and papers have been published on its physiological and pathophysiological role. It is involved in almost all pathological processes. In healthy individuals nitric oxide plays a crucial role in the vascular regulation by protecting against atherosclerosis, myocardial infarction and stroke. In the central nervous system, nitric oxide in its function as a neurotransmitter is responsible for synaptic plasticity, long-term potentiation, memory and a number of neuroendocrine control mechanisms. Furthermore, during inflammation and host defense, macrophages and neutrophils produce nitric oxide that has antibacterial, antiviral, and tumour cell killing activity. In pathologic conditions, however, nitric oxide reacts with superoxide anion to form peroxynitrite that damages the enzymes of the mitochondrial respiratory chain, superoxide-dismutase, reduced glutathion and activates or inactivates signalling molecules. During ischaemia- reperfusion, nitric oxide and peroxynitrite contribute to nitrative/nitrosative stress, DNAfragmentation and consequent polyADP-ribosepolymerase- 1 enzyme activation both in coronary thrombosis and ischaemic stroke.]
Lege Artis Medicinae
Lege Artis Medicinae
[The beneficial effects of treatment with betablockers in patients with chronic heart failure have been demonstrated in several large, prospective, randomised, placebo-controlled clinical trials. In large trials with mortality as the endpoint, the long-term use of bisoprolol, carvedilol, nevibolol and metoprolol succinate have been associated with a reduction in total mortality, cardiovascular mortality, sudden cardiac death and death due to progression of heart failure in patients of functional classes II-IV. These favorable clinical experiences warrant a recommendation that beta-blockers should be used in all haemodynamically stable heart failure patients with reduced left ventricular systolic function who are on standard treatment, unless contraindicated. In this review, the most important data of clinical trials and practical considerations of therapy with beta-blockers in heart failure are summarized.]
Lege Artis Medicinae
[For the optimal treatment of heart failure patients with systolic dysfunction, supplementation of the standard diuretics plus neurohormonal antagonists treatment with the direct vasodilator combination dihydralazine+nitrate, as well as with digitalis may be necessary. Addition of hydralazine/dihydralazine+nitrate to the treatment of chronic heart failure is recommended if ACE-inhibitors or angiotensin-receptor blockers cannot be administered. Beta blockers should also be used in these cases. If symptoms persist or worsen, addition of this combination to the standard therapy is reasonable. Supplementation with digitalis, mostly digoxin should be considered in similar conditions. It can be especially beneficial for patients with high-ventricular-rate atrial fibrillation. To achieve maximal survival benefit, the dose of digoxin must not exceed 0.125 mg/day. Low body weight or muscle mass, significantly reduced renal function may make further dose reduction necessary. If renal function is severely limited, digitoxin instead of digoxin may be used.]
Lege Artis Medicinae
Lege Artis Medicinae
[Acute heart failure may develop in previously healthy hearts. Nevertheless, structural abnormalities can facilitate its development and also, chronic heart failure can progress into acute stage. Considering the total cost of care in the patient's life, this is the most expensive heart disease. The clinical signs and physical abnormalities are usually of diagnostic power, however, instrumental investigations are necessary to recognize complications and to guide therapy. Patients should be monitored in well equipped coronary care units. Therapy consists of medications, coronary revascularization and use of mechanical assist devices.]
Clinical Neuroscience
Evidence suggests that pathogen-associated pattern recognition receptors (Toll-like receptors, TLRs) are implicated in the pathophysiology of schizophrenia. TLRs are important in both peripheral immune responses and neuronal plasticity. However, the relationship between peripheral TLR expression and regional brain volumes is unknown in schizophrenia. We therefore assessed 30 drug-naïve, first-episode patients with schizophrenia. TLR4+/TLR1+ monocytes were measured using flow-cytometry. High resolution magnetic resonance images (T1 MRI) were obtained and analyzed with FreeSurfer. Results revealed significant negative correlations between the percentage of TLR4+ monocytes, mean fluorescent intensities, and brain volumes in frontal and anterior cingulate regions. The measures of TLR1+ monocytes did not show significant relationships with regional brain volumes. These results raise the possibility that abnormal TLR-activation is associated with decreased brain volumes in schizophrenia.
Clinical Neuroscience
Background - Lumbar disc herniation (LDH) causes major disabilities worldwide. Several studies in the literature had reported the correlation between radiculopathy and inflammatory markers. Mean platelet volume (MPV), red cell distribution width (RDW) and neutrophil to lymphocyte (N/L) ratio are parameters of hemogram which have been found to be associated with inflammatory conditions. Purpose - Since inflammation has an important role in lumbar disc hernias, and RDW, MPV and N/L ratio are also known to be in correlation with inflammation, we have investigated these parameters of the patients with lumbar disc hernias and compared them with the results of the healthy subjects. Methods - Our study group was composed of patients with lumbar disc hernia, whereas the control group was consisted of healthy volunteers whom visited our outpatient clinics for a routine check-up. Patient characteristics and hemogram parameters of the study cohort were obtained from computerized database system of our institution. SPSS software (SPSS 15.0 for Windows, Chicago, IL, USA) was used for the analysis. Results - There was no significant difference between study and control groups in terms of WBC, neutrophil count, lymphocyte count, neu\lym ratio, Hb, Htc, MCV, and PLT levels (all p>0.05). RDW was significantly increased in study group [15.6 (12.3-22.5)] when compared to control group [14.5(11.9-16.3)] (p=0.004). And MPV in the study group [9.25 (6.38-14.5)] was also significantly increased in comparison to the control subjects [8.8 (6-10.1)] (p=0.013). Discussion - In this retrospective study, we found that, RDW and MPV values in hemograms were increased in patients with lumbar disc herniation when compared to the control group. Conclusions - We suggest that, elevated RDW and MPV may help physicians in decision taking to order radiological imagings in patients with symptoms which can be associated with possible LDH diagnosis. However, for the sake of precision, prospective studies with larger populations are needed.
Clinical Neuroscience
Objective - Benign paroxysmal positional vertigo (BPPV) is the most common cause of recurrent vertigo. Inflammation is a hypothetic etiological factor in BPPV. The aim of this study was to evaluate inflammatory biomarker levels in BPPV patients and compare these with the healthy subjects. Materials and methods - This prospective case-control study was conducted with 114 newly diagnosed BPPV patients and age- and sex- matched 83 healthy subjects. The laboratory investigations included serum hemogram, full biochemistry profiles, vitamin levels, thyroid hormone profiles, high sensitivity C-reactive protein (hsCRP) and erythrocyte sedimentation rate (ESR). Neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and monocyte to HDL-cholesterol ratio (MHR) values were calculated and compared between the patients and healthy subjects. Results - The mean age was 39.1 ± 12.4 years for patients, and 37.0 ± 11.9 for controls. Vitamin B12, hematocrit (Hct), creatinine, urea, and fT4 values, lymphocyte, total bilirubin, direct bilirubin and indirect bilirubin levels were significantly lower in BPPV patients (p ˂ 0.05), while HDL, SGOT, and ESR values were significantly higher. In the BPPV patients the mean NLR, PLR, and mean platelet volume (MPV) values were significantly higher than in the control subjects. Neutrophil, platelet, monocyte, MHR, and CRP values were similar in both groups (p ˃ 0.05). Conclusion - Our result suggests that NLR, PLR, MPV, ESR, and bilirubin levels should be taken into account as potential biomarkers of BPPV. As they are inexpensive parameters and widely available, they can be used in clinical practice for prediction of BPPV. However, further large-scale studies are required to confirm this relationship.
Hypertension and nephrology
[Endothelial nitric oxide synthase enzyme is regulated through the phosphorylation of the Ser(1177) and the Thr(495) sites, which influence the biological availabilaty of nitric oxide. We examined the acute effect of cigarette smoke, which decreases nitric oxide production. Endothelial cells were treated with different concentrations and for different times with cigarette smoke buffer, then with reduced glutathione or different protein kinase inhibitors. We determined the total and the phosphorylated nitric oxide synthase levels with Western blot. Cigarette smoke increased phosphorylation in a concentration- and time dependent manner at the Ser(1177) site and more pronounced at the Thr(495) site. Besides, it also led to the dissociation of the active dimer form of the enzyme. Reduced glutathione inhibited these phosphorylations and prevented the dissociation of endothelial nitric oxide synthase enzyme. The inhibition of protein kinase A or B did not influence the effect of cigarette smoke. However, protein kinase C inhibitors increased the phosphorylation caused by cigarette smoke at Ser(1177), but decreased it at Thr(495) sites. Summarized, cigarette smoke shifts the phosphorylation of the enzyme towards an inhibitory state, further on, it leads to the dissociation of the enzymatically active form. This results in the decreased biological availabilaty of nitric oxide, in which protein kinase C may play an important role.]
Hypertension and nephrology
[Author presents the formation of nitric oxide as a largest vasodilator of human endothelium as well as the endothelial dysfunction a result of formation at adrenergic stimulus. He demonstrates in detail the benefits of selective β-1 blocker and β-3 adrenergic agonist nebivolol in the vascular system. This drug has also receptor independent effects. Complex effects of nebivolol causes vasodilation, inhibits oxidative stress and it is capable to neutralize the effects of free oxygen radicals and as a result the endothelial function will be better. Its clinical effects and the less wellknown beneficial properties are listed. The use of drug is discussed especially in hypertensives with smoking, COPD or PAD. The β-3 agonist effect provides positive reactions not only in the adipocytes and the myocardial tissue. but in the skeletal muscle as well: Increase in energy expenditure - as a compensatory mechanism - is increased in obesity and the glucose uptake + storage on skeletal muscle cells are increased in hyperglycemia. The insulin sensitivity will be better, leptin level is decreased, adiponectin level is increased by nebivolol. It is assumed this drug has antidiabetic and anti-obesity effects.]
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