Rationale Use of Neutrophil-to-lymphocyte ratio for early diagnosis and stratification of COVID-19.

Coronavirus disease is caused by a virus that is the cause of a potentially fatal disease worldwide. Coronavirus is a pathogen that primarily affects the human respiratory system. Coronavirus 2019 (COVID-19) has been named WHO since February 11, 2020. The first cases of COVID-19 were reported in December 2019. In January 2020, COVID-19 infection was identified in hospitalized patients in Wuhan, China. We analyze the role of neutrophil-lymphocyte ratio (NLR) in viral infection with special emphasize on novel corona virus disease-COVID-19. NLR may be used for early detection and may reflect progression to the more severe illness leading to SARS-CoV-2. In the mini review we investigate the use of NLR as a surrogate marker for diagnosis and stratification of COVID-19.Clinical symptoms such as pneumonia, acute respiratory distress syndrome, acute heart damage have led to death. In some cases, multiple inflammations have been observed. Treatment with interferon inhalation showed no clinical effect and the condition worsened instead (Tab. 5, Fig. 1, Ref. 18). Keywords: neutrophil-to-lymphocyte ratio, corona virus SARS-CoV-2, COVID-19.

Few Insights on the problem of COVID-19.

The recent Coronavirus 2019 outbreak took the world by surprise and called for global drastic measures. At this early point in the timeline of the pandemic, several questions remain open until the results of large scale studies become available. This article offers few insights on scattered issues; including the clinical characteristics, pathology and diagnosis, as well as treatment perspectives and public health approach. Focusing healthcare resources on necessary treatment and prevention and combining efforts for developing feasible solutions will be decisive for time needed to achieve worldwide containment (Tab. 1, Ref. 23). Keywords: COVID-19, Coronavirus 2019, pandemic, public health.

Adipose derived mesenchymal stem cells harvesting.

BACKGROUND: The lipografting is increasingly used in the field of plastic surgery. Widely used harvesting technique of fatderived stem-cells is lipoaspiration. There exist two big streams of fat harvesting for lipografting: mechanical liposuction and manual liposuction. METHODS: Two harvested specimens were compared in this prospective blind study in the means of stem-cells viability and their ability to grow in cell-cultures. Techniques to compare were: manual lipoaspiration with 50 ml syringe and WAL (water-jet assisted liposuction). RESULTS: Twenty specimens from ten patients were investigated in the tissue bank. There were no differences in the amount of live stem-cells between two groups. Also no differences were found between both harvesting techniques in the mean of cell ability to grow in cell-cultures. CONCLUSION: It can be concluded that there are no statistically significant differences in the number, vitality and viability of stem cells when comparing two ways of mesenchymal stem cell collection, both manual and machine sampling (WAL). When cultured in vitro, both samples collected from each patient also appeared to be able to multiply with no statistical differences (Tab. 2, Fig. 2, Ref. 18).

The effect of GnRH agonists on angiogenesis and its implications for the myocardium in patients with cardiac risk.

Gonadotropin-releasing hormone agonists were described as anti-angiogenic factors in tumors. Simultaneously they were associated with increased cardiovascular risk in patients treated for prostate cancer, especially in those with preexisting cardiac disease. Studies aiming to elucidate the mechanisms by which androgen deprivation therapy causes cardiovascular effects are rare. We believe that gonadotropin-releasing hormone agonists can impair myocardial angiogenesis. That, in patients with myocardial disease can deepen hypoxia, significantly worsen the condition of the myocardium, and therefore increase the risk of cardiac failure. Careful assessment of the myocardial status and consequent timing and typing of therapy can minimalize the adverse effects. Ideally through close cooperation between cardiologists and oncologists (Fig. 1, Ref. 25). Keywords: angiogenesis, cardiovascular risk, follicle stimulating hormone, GnRH agonist, testosterone.

Artificial intelligence in service of medicine.

The race to make the dream of artificial intelligence a reality comes parallel with the increasing struggle of health care systems to cope with information overload and translational pressure. It is clear that a shift in the way data is generated requires a shift in the way they are processed. This is where AI comes with great promises to solve the problem of volume versus applicability of information in science. In medicine, AI is showing exponential progress in the fields of predictive analysis and image recognition. These promises however, come with an intricate package of ethico-social, scientific and economic implications, towards which a reductionist approach leads to distorted and dramatic predictions. All this, in a time when the growing pressure on healthcare systems towards defensive medicine begs the question of the true need for AI for good medical practice.This article examines the concept and achievements of AI and attempts to offer a complex view on the realistic expectations from it in medicine, in the context of current practice (Ref. 38). Keywords: algorithms, artificial intelligence, image recognition, neural networks, predictive analysis.

Are GnRH and FSH potentially damaging factors in the cardiovascular system?

In the physiological view the human cardiomyocytes express receptors of gonadotropin-releasing hormone and follicle-stimulating hormone. The local effects of these hormones in the heart are related also to some interstitial cells, such as endothelial cells with follicle-stimulating hormone receptors and immune cells with gonadotropin-releasing hormone receptors. The administration of androgen deprivation therapy in patients with prostate cancer is associated with increased incidence of cardiovascular complications. It is suggested that negative action of this therapy on cardiovascular system is due to the loss of testosterone but also levels of gonadotropin-releasing hormone and follicle-stimulating hormone are changed by therapy. In this article we review the literature to date with an emphasis on recent investigation focused on potential role of abnormal gonadotropin-releasing hormone and follicle-stimulating hormone levels induced by gonadotropin-releasing hormone agonists on the cardiovascular risk. These facts exacerbate the complexity of specific hormone and cell relationships within heart and vessels. Androgen deprivation therapy reveals the physiological relationships between hormones and specific tissues that are not part of the endocrine system.

Androgen deprivation therapy and cardiovascular complications.

Cardiovascular complications associated with the use of antiandrogens have already been known for some time. Based on the results of the latest meta-analyses and clinical studies published in the last few years, the attention of the scientific community is focused on the deleterious cardiovascular effects of gonadotropine-releasing hormon agonists in context of the androgen deprivating therapy. The cardiac toxicity is a problem especially in patients with preexisting cardiovascular comorbidities. Increased arterial wall thickening along with endothelial dysfunction has been observed in patients with descreased androgens levels in the peripheral blood. The treatment with gonadotropine-releasing hormon agonists may disrupt the intracellular concentration of calcium ions and the contractile process and potentially result in pathological remodelling of heart. Here, we give several possible mechanisms of action of gonadotropine-releasing hormon agonists on the cardiovascular system that may be a potential explanation of the clinical observations (Ref. 44).

Prevalence of cleft lip and palate in western Slovakia in the years 2001-2007.

OBJECTIVES: The aim of this study was to investigate the prevalence of orofacial clefts (OC) in live newborns from 2001 to 2007 in Western Slovakia and correlate their occurrence with a number of relevant seasonal and geographical factors and epidemiological trend of this condition. In this study we used retrospective active survey collecting clinical data of 220 children with OC registered and operated at the cleft centre in Bratislava. Our study group included 67 patients from Bratislava region and 151 patients from the remaining Western Slovakia (Nitra, Trnava, Trencín regions). Data of live births was obtained from Health Statistics of the Slovak Republic. RESULTS: Total incidence (TI) of 1.49/1000 live births (LB) in the region of Western Slovakia in 2001-2007 marked a decrease of prevalence compared to 1.64/1000 LB in the years 1985-2000. Bratislava region dominated in total prevalence of 1.82/1000 LB compared to the rest of Western Slovakia regions with 1.37/1000 LB. Most observed cleft type was the CP with 38.6 % frequency, followed by CLP with 35.5 % and CL with a frequency of 24.1 %. The frequency of AM with 1.82 % was the lowest. CONCLUSION: The results showed that the frequency risk rate of a birth of a child with OC was 1 to 671 LB in Western Slovakia. The data proved a higher prevalence of OC in Bratislava region with 1 child with this type of congenital anomaly to 549 LB compared with 1 child with OC to 730 LB in the rest of the Western Slovakia regions (Tab. 7, Ref. 16).

Timing of primary lip repair in cleft patients according to surgical treatment protocol.

OBJECTIVES: The goal of this article is to focus on the results of meeting the primary lip repair timing in compliance with the surgical treatment protocol used at the Cleft Center, Bratislava. METHODS: Retrospective analysis of 45 initial lip repairs among all cleft operations in a period of 3 years (2006-2008). The object of the analysis was the "day of surgery after birth". The defined time period was that of 90th-180th day (3-6 months) for the initial lip surgery according to surgical protocol. Histories of patients who underwent surgery before the 90th or after the 180th day were examined. RESULTS: 40 patients (89%) underwent primary lip surgery in the defined time period of 3-6 months following the surgical treatment protocol. 5 patients (11%) underwent primary lip surgery at a later age than 6 months only because of pediatric reasons: recurrent bronchopneumonia (3 patients), recurrent respiratory infections plus prematurity (1 patient) and sideropenic anaemia (1 patient). There were no operative and postoperative surgical or anesthesiological complications. There were only serious pediatric reasons for surgery delays. CONCLUSION: The determined timing of primary lip closure in 3-6 months is considered adequate according to the achieved results. In most of the cases this timing offers reliable conditions to perform early surgery in baby patients. The successfull realisation of the primary lip repair in the defined time period of 3-6 months is very important for proper timing of subsequent surgeries as well as for that of consecutive completion of treatment (Tab. 1, Fig. 1, Ref. 8).

Perspectives and complexity of an experimental cancer study. the secrets of tumorigenesis. (To the Gupta's, Chaffer's and Weinberg's "perspectives" and to the nurse's "horizons").

We would like to add to the "mysteriousness", our observations from the application of "identical" BP6 cells either intraperitoneally or subcutaneously. In connection with the concept that tumor development is not only a portrayal of cells proliferation, we could presume that different "environment" will result in structurally different tumors. Morphological differences observed are not significant, but they are present (Fig. 2, Ref. 12). Full Text (Free, PDF) www.bmj.sk.

Diastolic blood pressure as a major determinant of tissue perfusion: potential clinical consequences.

Blood pressure measuring represents a routine investigation in general medicine. In the last decades large studies have determined average blood pressure values all around the world. Large clinical trials have shown that blood pressure reduction irrespective of the used type of therapeutic intervention reduces mortality. Based on the outcomes of these trials current guidelines for hypertension encourage more "aggressive" hypertension treatment compared to recommendations from the past. In clinical practice blood pressure is sometimes reduced even below normotensive values (at least in comparison with pre-treatment levels). However there is evidence that achieving too low levels of diastolic blood pressure during antihypertensive treatment has undesirable effects. Especially in the elderly a diastolic blood pressure reduction below 70 mm Hg should be avoided, because it is associated with increased mortality. A possible explanation of this phenomenon could be that antihypertensive treatment disequilibriates the balance between sufficient perfusion pressure and arteriolar vasodilation, both of which are required for adequate tissue perfusion. Impaired microcirculation, especially in the coronary bed may account for the increased mortality in hypertensive patients with low diastolic blood pressure levels. Thus we support the idea of cautious blood pressure reduction in the elderly. Furthermore, we suggest, that monitoring the level of tissue perfusion in treated hypertensive patients might help to provide individually tailored therapy (Fig. 1, Ref. 9). Full Text (Free, PDF) www.bmj.sk.

Does incorporation of gene for green fluorescent protein in BP6 fibrosarcoma tumor cells depress their intraperitoneal growth in rats? (In honour of Nobel Prize laureates 2008--Osamu Shimomura, Martin Chalfie, Roger Y. Tsien).

This manuscript was in honour of Nobel Prize in chemistry "for the discovery and development of the green fluorescent protein, GFP" to Osamu Shimomura, Martin Chalfie, and Roger Y. Tsien, simultaneously a brief information about experience with GFP in experimental tumorigenesis used this study is also presented. The experimental data have showed that BP6 cells incorporated with GFP gene have had smaller ability to induce both experimental intraperitoneal and subcutaneous tumor process. It was anticipated that incorporation of GFP gene might change physiological properties of cytoskeleton and worsen adhesive characteristics of tumor cells. It was also supposed that aftertime GFP will enable to monitor proliferation of cells not only within experimental work, but also in human medicine. GFP could help (supposedly) as reporter of proliferation, but also can serve as "target" for guide of tumorigenesis inhibiting substances. These ideas which are consequences of our experiments we append as congratulation to Nobel Prize in chemistry of the 2008 (Fig. 2, Ref. 44). Full Text (Free, PDF) www.bmj.sk.

Dangerous versus useful hypertension (a holistic view of hypertension).

The authors aim to offer a holistic view on hypertension and its treatment. Their approach is fairly confrontational, particularly by suggesting that hypertension may play a role in optimizing the blood flow and enhancing oxygen delivery. An increase in blood pressure brings about a threat of catastrophes. Therefore hypertension might be considered as either a subsequent complication, or an inevitable adaptation. When changes of many complicated and complex mechanisms result in retention of sodium and water, then the treatment of this condition is so far the most logical conclusion, and possibly beneficial to the patient. This can be done by influencing the peripheral resistance or the load of vascular bed. However, in some cases a moderate overfilling of the system with no increase in heart rate could be interpreted as an optimal solution for organism that does not necessarily need to be medically treated. This may apply especially to young hypertensive patients, and in cases when no catastrophe is assumed to take place. Lowering the blood pressure to average population levels in each case, especially by means of aggressive therapy may not necessarily lead to improved tissue perfusion. A decrease in blood pressure reduces the risk of catastrophes. However, on the other hand, it can deteriorate the tissue perfusion and cause unfavorable long-term consequences.

[The complexity of interactions of the tumour growth process]. / Komplexita interakcií nádorového procesu.

It was believed for rather a long time that the only components of tumour tissue are transformed cells characterised by hyper-proliferation, invasivity and immortalisation. Therapeutic strategies thus focused on autonomous proliferation and tumour cell survival. These result from oncogene activation and inactivation of tumour-suppressor genes. Research studies showed that tumour growth itself is a complex process. In addition, studies confirmed involvement of heterotypical multicellular interactions in tumour tissue. Complexity as a characteristic is one of the processes that do not demonstrate attributes of linear systems. The process of tumour growth involves certain patterns that cannot be classified according to duration and sequence. Consequently, tumour growth can be viewed as a process with features typical for complexity. From this perspective, tumour environment consists of a range of cells, such as endothelial cells and their progenitor cells, pericytes, fibroblasts, tumour-associated fibroblasts, myofibroblasts, smooth muscle cells, mast cells, T- and B-lymphocytes, neutrophils, eosinophils, basophils, NK-cells and several different forms of macrophages. At present, well-founded assumptions exist that in-depth study of intra-tumour environment might lead to formulation of new principles in tumour biology as well as introduction of new therapeutic strategies. Research into details oftumour microenvironment is needed to expand scientific knowledge as well as to, subsequently, define tumour biomarkers. Monitoring of these biomarkers will facilitate molecular diagnostics. Biomarkers will be widely used to monitor tumour growth as well as to monitor the process of treatment. Monitoring of combinations of biomarkers will enable more detailed characterisation of tumour microenvironment. These might include, apart from receptors, signal molecules, growth factors and molecules accelerating apoptosis, specific molecules as well as their combinations or neoangiogenesis or tumour innervation parameters. Tumour complexity involves not just intracellular environment but also intracellular relationships and associations between cells and extracellular tumour components. Detection of circulating tumour cells represents another parameter to be monitored. Low-molecular weight fluorescent dyes will very likely be used for their detection. It can be assumed that circulating tumour cells will be used as markers of prognosis as well as indicators of malignity progression and treatment. Scientific advances in this area will facilitate individualised therapy of patients suffering from cancers. The aim of the present review study was to analyze scientific knowledge from the perspective of acceptance of complexity and heterogeneity of each tumour. We perceived processing of the vast amounts of literature as meaningful with respect to recognition of new knowledge and theoretical preparation for expected changes in diagnostics and treatment of tumours. We believe that the presented findings are a useful step towards achievement of comprehensive insight into tumour microenvironment.

Regression of left ventricular hypertrophy and aortic remodelling in NO-deficient hypertensive rats: effect of L-arginine and spironolactone.

AIM: We investigated, whether the substrate for nitric oxide (NO) formation -L-arginine - and the aldosterone receptor antagonist - spironolactone - are able to reverse alterations of the left ventricle (LV) and aorta in N(omega)-nitro-L-arginine methyl ester (L-NAME)-induced hypertension. METHODS: Six groups of male adult Wistar rats were investigated: controls after 4 and 7 weeks of experiment, rats treated with L-NAME for 4 weeks and three recovery groups: spontaneous-reversion (4 weeks L-NAME + 3 weeks placebo), spironolactone-induced reversion (4 weeks L-NAME + 3 weeks spironolactone) and L-arginine-induced reversion (4 weeks L-NAME+ 3 weeks L-arginine). Blood pressure was measured by tail-cuff plethysmography. Relative weight of the LV, myocardial fibrosis (based upon histomorphometry and hydroxyproline determination) and conjugated dienes in the LV and aortic cross-sectional area, inner diameter and wall thickness were determined. NO-synthase activity was investigated in the LV and aorta. RESULTS: L-NAME administration induced hypertension, left ventricular hypertrophy (LVH), LV fibrosis, aortic thickening and diminution of NO-synthase activity in the LV and aorta. Reduction in blood pressure and regression of LVH were observed in all recovery groups, yet reduction in LV fibrosis and aortic thickening were not. NO-synthase activity was restored only in the L-arginine and spironolactone group. CONCLUSION: In our study, the reversion of hypertension and LVH was not dependent on the restoration of NO-synthase activity. Moreover, LV fibrosis and aortic remodelling seem to be more resistant to conditions resulting in regression of LVH. Preserved level of fibrosis in the initial period of LVH regression might result in loss of structural homogeneity and possible functional alterations of the LV.

[Essential hypertension--syndrome, or compensatory mechanism]. / Esenciálna hypertenzia ako syndróm alebo kompenzacný mechanizmus?

Diagnosis of essential hypertension is created per exclusionem--with exclusion of all, so called secondary hypertensions (nephrogenic, endocrine conditioned etc). Idea and the name-essential hypertension are unclear. We have a lot of hypotheses about mechanisms of hypertension but no one is explaining satisfactorily the "fixation" of hypertension. From this point of view essential hypertension looks more like a syndrome than disease sui generis. Authors analyzed all possible pathways of hypertension origin as well as compensatory mechanisms in peripheral circulation in effort to reach relevant tissue perfusion. If these mechanisms lead to salt and water retention the best mode of the treatment would be to influence volume and blood vessels lumen. It is clear that optimization of blood pressure is advantageous for prevention of vascular catastrophes (myocardial and cerebral infarction). Nevertheless inadequate lowering of the peripheral tissue perfusion (kidney, CNS) can lead to degenerative changes in tissues and to disturbances in centrally regulated processes of blood pressure.

Inflammation--a lifelong companion. Attempt at a non-analytical holistic view.

Inflammation is a key component of the immune system. It has important functions in both defense and pathophysiological events maintaining the dynamic homeostasis of a host organism including its tissues, organs and individual cells. On the cellular level it is controlled by more than 400 currently known genes. Their polymorphisms and environmental conditions give rise to different genotypes in human population. Pro-inflammatory genotype, which dominates in the present population, may be advantageous in childhood but not in elderly people because it is characterized by an increased vulnerability to, and intensity of, inflammatory reactions. These reactions may be the possible reasons of chronic inflammatory diseases, especially in old age. Better understanding of complex molecular and cellular inflammatory mechanisms is indispensable for detailed knowledge of pathogenesis of many diseases, their prevention and directed drug therapy. Here we summarize the basic current knowledge on these mechanisms.

Does vagus nerve constitute a self-organization complexity or a "hidden network"?

The vagus nerve provides wide visceromotor and viscerosensory innervation of internal organs. Findings accumulated in last years suggest that vagus nerve participates on regulation of much wider spectrum of functions than described previously. Many different studies provide plausible evidence that vagus nerve importantly participates not only in transmission of information from inflamed tissues, but also in efferent modulation of inflammatory processes. Moreover, there are some findings supporting the hypothesis that vagus nerve might participates in monitoring and modulation of tumorigenesis. Electrical stimulation of the vagus nerve is used as a treatment of epilepsy. Moreover, data also suggest a beneficial effect of electrical stimulation of the vagus nerve in patients with depression, anxiety, migraine and Alzheimer's disease. We suggest, that the vagus nerve might constitute a highly differentiated complex system which modulates various functions. Moreover, we propose that the vagus nerve as a complex system might participate in constitution of a biological compartment of conscious. In this article we discuss findings and ideas supporting these hypotheses (Ref. 73).

Long-term monitoring of the changes in signal-averaged ECG after coronary artery occlusion and intracoronary endothelin-1 injection in dogs.

Myocardium undergoes functional changes in the infarcted region primarily due to ischemia. Following myocyte functional alterations of the noninfarcted myocardium are caused by remodelling and hypertrophy. We have monitored and compared changes in the electrocardiographical (ECG) image after coronary artery occlusion (CAO, n=5) and intracoronary endothelin-1 (ET-1, n=3) administration during a 6-month period. In 3 dogs, the CAO was repeated 6 months after the first occlusion. Signal-averaged ECG (SA ECG) was recorded before the operation and 10 days, 1 month, 3 months and 6 months after myocardial infarction (MI). The modified Wigner distribution was used for spectrotemporal analysis of the SA ECG. Eight-hour Holter monitoring was performed in each dog before and after experimental MI. Spectrotemporal representations of the QRS complex were stabilized after the first 1-month period in the group of dogs after CAO. The same results were also observed after the repeated CAO. No arrhythmias were recorded 9 days after CAO. The spectrotemporal representations of the QRS complex after intracoronary ET-1 administration were not stabilized during the whole observed period. Very few arrhythmic events were recorded by Holter monitoring already 3 days after intracoronary ET-1 injection. Experimental MI induced by CAO caused a changed ECG image, which was stable from 1 month after MI induction till the end of the monitoring. However, the ECG image after ET-1 administration was not stable during the whole observed period. No arrhythmic events were recorded in either group 3 months postoperatively that could be caused by healthy myocardial status before the experimental MI induction. In clinical practice, however, ischemic heart disease usually precedes the MI. Arrhythmogenic substrate could thus be a consequence of combination of healthy status of the myocardium before MI and MI itself.