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The restoration and maintenance of sinus rhythm is a desirable strategy for many patients with atrial fibrillation (AF) since it has been associated with improvement in symptoms and a better quality of life. Sinus rhythm can be achieved by pharmacological or electrical cardioversion or after catheter ablation of AF. Despite high rates of successful cardioversion, AF recurrence remains a major challenge. Anti-arrhythmic drug therapy currently plays a significant role in maintaining sinus rhythm after cardioversion. Amiodarone is the most commonly prescribed anti-arrhythmic drug for patients with AF. This is due to its particular electrophysiological properties and superior anti-arrhythmic effects in comparison with other anti-arrhythmic drugs. Understanding the cardiac electrophysiology and arrhythmogenesis mechanisms may result in identification of new targets for anti-arrhythmic therapy. The aim of this article was to review amiodarone’s clinical pharmacology and evaluate evidence supporting amiodarone for treatment and prevention of AF recurrence after cardioversion.

Viral B and C hepatitis are a major current health issue, both diseases having a chronic damaging effect on the liver and its functions. Chronic liver disease can lead to even more severe and life-threatening conditions, such as liver cirrhosis and hepatocellular carcinoma. Recent years have uncovered an important interplay between the liver and the gut microbiome: the gut-liver axis. Hepatitis B and C infections often cause alterations in the gut microbiota by lowering the levels of 'protective' gut microorganisms and, by doing so, hinder the microbiota ability to boost the immune response. Treatments aimed at restoring the gut microbiota balance may provide a valuable addition to current practice therapies and may help limit the chronic changes observed in the liver of hepatitis B and C patients. This review aims to summarize the current knowledge on the anato-functional axis between the gut and liver and to highlight the influence that hepatitis B and C viruses have on the microbiota balance, as well as the influence of treatments aimed at restoring the gut microbiota on infected livers and disease progression.

Alexandra Dadarlat-Pop,1 Dana Pop,1,2 Lucia Procopciuc,3 Adela Sitar-Taut,4 Dumitru Zdrenghea,1,2 Gyorgy Bodizs,2 Raluca Tomoaia,1 Diana Gurzau,1 Florina Fringu,1 Silvana Susca-Hojda,1 Anca D Buzoianu5 1Department of Cardiology, “Iuliu Hatieganu” University of Medicine and Pharmacy, Cluj-Napoca, Romania; 2Department of Cardiology, Clinical Rehabilitation Hospital, Cluj-Napoca, 400347, Romania; 3Department of Medical Biochemistry, “Iuliu Hatieganu” University of Medicine and Pharmacy, Cluj-Napoca, Romania; 4 4th Medical Clinic, Department of Internal Medicine, “Iuliu HaÅ£ieganu” University of Medicine and Pharmacy, Cluj-Napoca, Romania; 5Department of Pharmacology, Toxicology and Clinical Pharmacology, “Iuliu Hatieganu” University of Medicine and Pharmacy, Cluj-Napoca, RomaniaCorrespondence: Dana PopDepartment of Cardiology, Clinical Rehabilitation Hospital, 46-50 Viilor Street, Cluj-Napoca, 400347, RomaniaTel +40 744 159 933Fax +40 364 818 027Email pop67dana@gmail.comBackground and Aims: Leptin, one of the best-known adipocytes, together with the renin-angiotensin-aldosterone system and galectin-3 are important players in inflammation, arterial hypertension and heart failure pathophysiology. Moreover, uninucleotide A1166C polymorphism is associated with hypertension and poor prognosis in heart failure. The aim of the study was to investigate a possible relationship between leptin serum values, specific heart failure biomarkers and the presence of AT1 receptor A1166C polymorphism in overweight and obese heart failure patients.Methods: The study included 88 consecutive overweight and obese patients admitted for decompensated heart failure. NT-proBNP, MR-proANP, galectin-3 and leptin levels were determined on the arrival day. Genotyping of the A1166C allele – AT1 receptor gene was performed in all patients in order to find variants.Results: We found a strong positive correlation (r = 0.347, p = 0.001) between leptin serum concentrations and BMI. Leptin levels were not correlated with heart failure biomarkers (NT-proBNP, MR-proANP and galectin-3). All homozygote CC variants were hypertensive, but we registered no significant difference in genetic AC and AA variants distribution between hypertensive and normotensive. Leptin was not significantly modified by the presence of potentially pathogenic A1166C–AT 1 receptor genotypes (AC + CC). But, galectin-3 was found in higher concentrations in patients with heterozygous and homozygous A1166C mutations.Conclusion: Overweight and obese patients with heart failure display high leptin serum levels. Leptin does not offer incremental prognostic value in heart failure overweight and obese patients. But, galectin-3 was found in higher concentrations in patients with heterozygous and homozygous A1166C mutations, suggesting a worse prognosis probably due to more advanced cardiac fibrosis.Keywords: leptin, galectin-3, heart failure, obesity, arterial hypertension, AT1 receptor mutation

This prospective meta-analysis summarizes results from the CAPTAIN trial series, evaluating the effects of Cerebrolysin for moderate-severe traumatic brain injury, as an add-on to usual care. The study included two phase IIIb/IV prospective, randomized, double-blind, placebo-controlled clinical trials. Eligible patients with a Glasgow Coma Score (GCS) between 6 and 12 received study medication (50 mL of Cerebrolysin or physiological saline solution per day for ten days, followed by two additional treatment cycles with 10 mL per day for 10 days) in addition to usual care. The meta-analysis comprises the primary ensembles of efficacy criteria for 90, 30, and 10 days after TBI with a priori ordered hypotheses based on multivariate, directional tests. A total 185 patients underwent meta-analysis (mean admission GCS = 10.3, mean age = 45.3, and mean Baseline Prognostic Risk Score = 2.8). The primary endpoint, a multidimensional ensemble of functional and neuropsychological outcome scales indicated a “small-to-medium” sized effect in favor of Cerebrolysin, statistically significant at Day 30 and at Day 90 (Day 30: MWcombined = 0.60, 95%CI 0.52 to 0.66, p = 0.0156; SMD = 0.31; OR = 1.69; Day 90: MWcombined = 0.60, 95%CI 0.52 to 0.68, p = 0.0146; SMD = 0.34, OR = 1.77). Treatment groups showed comparable safety and tolerability profiles. The meta-analysis of the CAPTAIN trials confirms the safety and efficacy of Cerebrolysin after moderate-severe TBI, opening a new horizon for neurorecovery in this field. Integration of Cerebrolysin into existing guidelines should be considered after careful review of internationally applicable criteria.

Background and purpose In Romania, robust data about the prevalence of obesity and heart failure are lacking, especially in the elderly; therefore, this study aims to analyze the profile of overweight and obese patients aged >65 years admitted to a Romanian hospital for worsening heart failure, and also their risk in the presence of comorbidities. Patients and methods This cross-sectional study was conducted in 126 consecutive elderly patients with overweight and obesity admitted to a Romanian hospital for worsening heart failure. They were divided into three groups: with reduced ( 65 years) to 30 (extensive comorbidity). Results NT-proBNP values are negatively correlated with BMI only in patients with HFpEF. Creatinine clearance (p=0.0166), the presence of atrial fibrillation (p=0.0095) and NYHA functional class were independent predictors of increased NT-proBNP values. CCI score is negatively correlated with NT-proBNP values in patients with HFmrEF (r= -0.448, p=0.009) and HFpEF (r= -0.273, p=0.043). The CCI risk was not significantly different between the three groups. Conclusion Elderly heart failure patients with overweight or obesity have particular characteristics in terms of NT-proBNP values and presence of comorbidities. In the studied population, NT-proBNP levels were strongly influenced by renal function, NYHA functional class, the presence of atrial fibrillation and left ventricular ejection fraction.

Chronic heart failure and obesity are two conditions which despite all the advances made in the recent years, still represent two of the leading causes of morbidity and mortality worldwide. Moreover, a well-known fact is that the risk of sudden cardiac death, mostly related to malignant arrhythmias is higher in apparently healthy obese individuals in comparison with lean subjects. On the other hand, obese heart failure patients bring unique challenges in the diagnosis of heart failure, having a better prognosis than their normal or underweight counterparts. Taking into account the above-mentioned existing data, there are questions regarding whether cardiac arrhythmias such as atrial fibrillation or ventricular arrhythmias in this population have certain evolutive particularities. This paper describes various mechanisms of cardiac arrhythmias found in obese heart failure patients, such as myocardial architectural changes, neurohormonal and paracrine modifications.

Atrial fibrillation (AF) recurrence after radiofrequency catheter ablation (RFCA) remains a challenging issue. This study aims to explore the left atrial appendage function by transesophageal echocardiography (TEE) and assess its value in predicting AF recurrence following RFCA in paroxysmal AF patients. Eighty-one patients with paroxysmal AF that underwent RFCA were recruited. TEE was performed before ablation with the assessment of left atrial appendage emptying flow velocity (LAAeV). AF recurrence occurred in 24 patients (29.6%) within 12 months after RFCA. The left atrium diameter (LAD) and left atrium volume index (LAVI) were both significantly higher in the recurrence group compared to the non-recurrence group, while the LAAeV was significantly lower in the recurrence group. LAD, LAVi and LAAeV were univariately significant risk factors for AF recurrence after ablation. Based on receiver operating curve (ROC), LAAeV < 40.5 cm/s, LAVi > 40.5 mL and LAD > 41 mm were identified as cut-off values for predicting AF recurrence. In multivariate regression analysis LAAeV < 40.5 cm/s (HR 8.194, 95% CI 2.980–22.530, p < 0.001) was identified as the only statistically significant independent predictor of AF recurrence, as the statistical significance threshold was not achieved for LAVI > 40.5 mL and LAD > 41 mm (p = 0.319; p = 0.507, respectively). A low LAAeV was the only important independent predictor of AF recurrence within 1 year after first RFCA.

Obesity and Overweight have the highest rate of incidence and prevalence in the past 3 decades, as global pathologies. The purpose of this study was to evaluate cardiovascular, classic and modern risk factors in overweight and obese patients by studying lipid metabolism (total cholesterol, HDL-cholesterol, non-HDL-cholesterol, LDL-cholesterol, serum triglycerides), glucose metabolism, insulin resistance and insulin sensitivity, the prevalence of hypertension (HBP) and the prevalence of metabolic syndrome (MS). This analytical study was performed on 111 subjects divided as follows: Group I consisting of 27 normal weight subjects - NW; Group II consisting of 84 overweight and obese subjects - OW + O: 36 overweight patients - OW; 33 patients with grade I obesity - O-I; 13 patients with grade II obesity - O-II; 2 patients with grade III obesity - O-III. The overweight and obese, although unknown with heart disease, have significant metabolic changes, such as atherogenic dyslipidemia, dysglycemia, high insulin resistance and low insulin sensitivity, metabolic syndrome, these being the first steps towards endothelial dysfunction and early atherosclerosis.

Asthma is defined by The Initiative for Asthma (GINA 2018) as a heterogeneous disease, which include chronic airway inflammation and a history of respiratory symptoms. In the last decades asthma had a rise in prevalence, becoming one of the most frequent diagnosed diseases in the world. The main goals of asthma management are to achieve good symptom control, minimize the risks of exacerbations, decrease rescue medication intake, improve the quality of life by decreasing respiratory system inflammation and ameliorating the patient’s lung function. Beside effective medications, asthma continues to impair quality of life for most patients. Due to the difficulty of controlling symptoms and exacerbations, the need of developing complementary options of treatment is increasing in order to achieve an optimum control and a lower risk of acute episodes or fatal events. Pulmonary rehabilitation is suggested for asthma patients when adequate medical therapy poorly control the symptoms and mental, physical or social consequences of illness persist during the daily life. The following non-drug therapy components are included in the rehabilitation program: physical training, comprehensive smoking cessation program, comprehensive patient education, respiratory physiotherapy, psychosocial support and comprehensive nutritional counseling. These complementary therapies have been proven to improve muscle strength, exercise capacity and symptomatology. Also, it has been associated to fewer exacerbations and a lower use of rescue medication, leading to a better quality of life. Key words: asthma, quality of life, symptomatology, rehabilitation, physiotherapy

Heart failure continues to be a major worldwide medical issue, associated with high morbidity and mortality. The need for ideal biomarkers to aid the diagnosis and prognosis in certain situations, such as obesity or atrial fibrillation is still ongoing. Obese patients are commonly hyperleptinemic. The aim of the study is to assess the role of several biomarkers in overweight and obese patients diagnosed with heart failure, depending on the presence or absence of atrial fibrillation and also their relationship with leptin. The study included 88 overweight and obese patients, with a body mass index (BMI) ≥25 kg/m2, admitted for worsening heart failure. Of these, 52.2% had atrial fibrillation. Dosage of NT-proBNP was performed using the chemiluminescence method. MR-proANP, galectin-3 and leptin were dosed using the ELISA method. A value of P [0.05 was defined as statistically significant. The values of natriuretic peptides NT-proBNP and MR-proANP were significantly increased. Only NT-proBNP was significantly influenced by renal function. No statistically significant correlation was found between heart failure-specific biomarkers and leptin secretion. There were no significant differences in the biomarkers levels between the 2 groups of patients. No statistically significant correlation was found between heart failure-specific biomarkers and leptin secretion. Obese patients with heart failure had significantly increased values of all the studied parameters, but the presence of atrial fibrillation did not influence their levels. High leptin levels were not directly correlated with the levels of heart failure-specific biomarkers.

The ability of Berberis vulgaris bark extract (BVE) to improve the lipid profile was evaluated in an experimental model of dyslipidemia, along with its effects on liver and kidney functions. Fifty rats divided into five groups of ten animals each were fed with normal or lard-based diet and orally treated with 0.9% saline solution, atorvastatin (2.5 mg/kg per body weight) or extract of BVE (300 and 500 mg/kg/day) for eight weeks. Lipid profile, liver and renal functions were assessed in normal and diet-induced hypercholesterolemic rats. The results were compared between the groups treated with Berberis extract and the group without treatment, respectively that one treated with the standard drug (atorvastatin). Administration of BVE or atorvastatin significantly decreases the elevated serum lipid profile (p [0.05). The extract also protects against dyslipidemia-induced non-alcoholic fatty liver disease (NAFLD). The activities of the plant extract are dose dependent and it compares favorably with the standard drug atorvastatin. Variations in aspartate aminotransferase (AST), alanine aminotransferase (ALT), and urea level measurements were neither different between the two determinations nor between groups, but creatinine values decreased in rats in the BVE or atorvastatin-treated groups. The findings of the current study have suggested that BVE intake suppresses the accumulation of hepatic lipids and lipid parameters and reduce the risk of NAFLD. So, BVE can be useful in hypercholesterolemia.

The overlap syndrome (OS) is defined as a synergic relation between obstructive sleep apnea (OSA) and chronic obstructive pulmonary disease (COPD). Patients with overlap syndrome present the clinical features of each disorder to a greater or a lesser extend depending on the predominant disease. We assessed the main differences between patients with OS and patients with OSA and we highlight the importance of nocturnal hypoxemia on clinical status and management of the patients with overlap syndrome, in order to simplify OSA screening tests in patients with COPD. The study population included 62 selected patients divided in two groups: the first group � subjects diagnosed with OS and the second group - subjects with OSA, without the diagnostic of COPD. The majority of the patients were male, with a mean age of 55�9.84 years in the OSA group and 65.5�10.32 years in the OS group. The nocturnal hypoxemia was more important in the OS grup, with 276.83 minutes spent at a SpO2 below 90% versus 132.98 minutes in the OSA group. The mean AHI was 57.7�29.244 events/hour of sleep in the OS group and 50.7�26.01 events/hour of sleep in the OSA group. At the diagnosis, the mean daytime SpO2 was 90.9�3.59% in the OS group and 95.9�1.57 % in the OSA group. There were statistically significant differences between the two groups concerning age, AHI, Epworth Slepiness Scale, nocturnal desaturation, medium and minimum SpO2 during sleep, daytime SpO2 at the diagnosis and at 1-year follow-up, the presence of cardiovascular comorbidities such as pulmonary hypertension and heart failure. Our study showed that patients with COPD have OSA predictors that differ from those usually recognise in the general population. In OS patients, the most important parameter is the nocturnal hypoxemia. So, it is very useful that the clinicians be trained to include in the management of selected obese COPD patients, comprehensive sleep history, sleep hygiene and OSA screening because, in clinical practice, OSA is quite often underdiagnosed in these patients.

Cardiotoxicity is a well-recognised side effect of cancer-related therapies with a great impact on outcomes and quality of life in the cancer survivor population. The pathogenesis of chemotherapy-induced cardiotoxicity in patients with gastrointestinal cancers involves various molecular mechanisms, and the combined use of various chemotherapies augments the risk of each drug used alone. In terms of cardiotoxicity diagnosis, novel biomarkers, such as troponins, brain natriuretic peptide (BNP), myeloperoxidases and miRNAs have been recently assessed. Echocardiography is a noninvasive imaging method of choice for the primary assessment of chemotherapy-treated patients to generally evaluate the cardiovascular impact of these drugs. Novel echocardiography techniques, like three-dimensional and stress echocardiography, will improve diagnosis efficacy. Cardiac magnetic resonance (CMR) can evaluate cardiac morphology, function and wall structure. Corroborated data have shown the importance of CMR in the early evaluation of patients with gastrointestinal cancers, treated with anticancer drugs, but further studies are required to improve risk stratification in these patients. In this article, we review some important aspects concerning the cardiotoxicity of antineoplastic drugs used in gastrointestinal cancers. We also discuss the mechanism of cardiotoxicity, the role of biomarkers and the imaging methods used in its detection.

The study’s aim was to characterize the composition of Nigella sativa seed (NSO) and grape seed (GSO) oils, and to evaluate their cardioprotective and anti-inflammatory effect on isoproterenol (ISO)-induced ischemia in rats. Materials and Methods: NSO and GSO supplements were physicochemically characterized. Liquid chromatography–mass spectrometry (HPLC-MS), Fourier-transform infrared spectroscopy (FTIR), and gas chromatography–mass spectrometry (GC-MS) analyses were used to determine the phytochemical composition in the oils. Total polyphenol content (TPC) and in vitro antioxidant activity were also determined. Pretreatment with 4 mL/kg/day NSO or GSO was administered to rats for 14 days. The experimental ischemia was induced by a single administration of ISO 45 mg/kg after 14 days. An electrocardiogram (ECG) was performed initially and 24 h after ISO. Biological evaluation was done at the end of experiment. Results: The HPLC-MS, GC-MS, and FTIR analyses showed that both NSO and GSO are important sources of bioactive compounds, especially catechin and phenolic acids in GSO, while NSO was enriched in flavonoids and thymol derivatives. Pretreatment with GSO and NSO significantly reduced ventricular conduction, prevented the cardiotoxic effect of ISO in ventricular myocardium, and reduced the level of proinflammatory cytokines and CK-Mb. Conclusion: Both NSO and GSO were shown to have an anti-inflammatory and cardioprotective effect in ISO-induced ischemia.

Background: Health policies in transitioning health systems are rarely informed by the economic burden of disease due to scanty access to data. This study aimed to estimate direct and indirect costs for first-ever acute ischemic stroke (AIS) during the first year for patients residing in Cluj, Romania, and hospitalized in 2019 at the County Emergency Hospital (CEH). Methods: The study was conducted using a mixed, retrospective costing methodology from a societal perspective to measure the cost of first-ever AIS in the first year after onset. Patient pathways for AIS were reconstructed to aid in mapping inpatient and outpatient cost items. We used anonymized administrative and clinical data at the hospital level and publicly available databases. Results: The average cost per patient in the first year after stroke onset was RON 25,297.83 (EUR 5226.82), out of which 80.87% were direct costs. The total cost in Cluj, Romania in 2019 was RON 17,455,502.7 (EUR 3,606,505.8). Conclusions: Our costing exercise uncovered shortcomings of stroke management in Romania, particularly related to acute care and neurorehabilitation service provision. Romania spends significantly less on healthcare than other countries (5.5% of GDP vs. 9.8% European Union average), exposing stroke survivors to a disproportionately high risk for preventable and treatable post-stroke disability.

Heart failure is still the leading cause of hospitalization in patients over 65 years of age and is defined as a multifactorial pathology which involves environmental factors and also genetic predispositions. The aim of the present study was to evaluate a possible correlation between single nucleotide polymorphisms (SNPs) of angiotensin converting enzyme 2 (ACE2) and monocyte chemoattractant protein-1 (MCP-1) genes and cardiac remodeling in Caucasian patients diagnosed with heart failure. Our comparative translational research study included 116 patients diagnosed with heart failure and was carried out in Cluj-Napoca, Romania between September 2017 and March 2019. Three SNPs, namely rs4646156, rs4646174 and rs1024611, were genotyped using a Taqman real-time PCR technique. Our results showed that carriers of the AA genotype for ACE2 rs4646156 had a significant dilatation of the left ventricle (LV) with signs of LV hypertrophy (LVH), while TT carriers had a significant left atrial dilatation. For ACE2 rs4646174, homozygotes for the C allele presented a dilated LV with signs of LVH with statistical significance and had a tendency towards a lower ejection fraction. MCP-1 rs1024611 AA variant carriers had a significant LVH in the dominant model. In conclusion, our study showed a strong association between echocardiographic parameters of cardiac remodeling and SNPs rs4646156, rs4646174 of ACE2 and rs1024611 of MCP-1.

N-Pep-12 is a dietary supplement with neuroprotective and pro-cognitive effects, as shown in experimental models and clinical studies on patients after ischemic stroke. We tested the hypothesis that N-Pep-12 influences quantitative electroencephalography (QEEG) parameters in patients with subacute to chronic supratentorial ischemic lesions. We performed secondary data analysis on an exploratory clinical trial (ISRCTN10702895), assessing the efficacy and safety of 90 days of once-daily treatment with 90 mg N-Pep-12 on neurocognitive function and neurorecovery outcome in patients with post-stroke cognitive impairment against a control group. All participants performed two 32-channel QEEG in resting and active states at baseline (30–120 days after stroke) and 90 days later. Power spectral density on the alpha, beta, theta, delta frequency bands, delta/alpha power ratio (DAR), and (delta+theta)/(alpha+beta) ratio (DTABR) were computed and compared across study groups using means comparison and descriptive methods. Secondarily, associations between QEEG parameters and available neuropsychological tests were explored. Our analysis showed a statistically significant main effect of EEG segments (p

Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease worldwide. The aim of this study was to evaluate the possible association between paraoxonase-1 (PON1), periostin (POSTN), tumor necrosis factor (TNF)-α, interleukin (IL)-6, IL-10 serum concentration with non-invasive liver fibrosis scores, in a cohort of patients with NAFLD. We studied a cohort of 52 patients diagnosed with NAFLD. The NAFLD fibrosis score (NFS), Fibrosis-4 Index (FIB-4), AST to platelet ratio index (APRI) and BARD scores were calculated for each patient. We determined the PON1, POSTN, TNF-α, IL-6, and IL-10 serum values using ELISA kits. There was no correlation between PON1 or POSTN serum levels and non-invasive liver fibrosis. The TNF-α serum values were independently associated with the liver fibrosis scores (P=0.02 for NFS and P=0.002 for FIB-4). Age and metabolic syndrome were also independently linked to the fibrosis scores. In conclusion, serum levels of TNF-α, age and metabolic syndrome were associated with the non-invasive liver fibrosis scores.

Military personnel are the most susceptible to concussive head injury (CHI) caused by explosion, blast or missile or blunt head trauma. Mild to moderate CHI could induce lifetime functional and cognitive disturbances causing significant decrease in quality of life. Severe CHI leads to instant death and lifetime paralysis. Thus, further exploration of novel therapeutic agents or new features of known pharmacological agents are needed to enhance quality of life of CHI victims. Previous reports from our laboratory showed that mild CHI induced by weight drop technique causing an impact of 0.224N results in profound progressive functional deficit, memory impairment and brain pathology from 5h after trauma that continued over several weeks of injury. In this investigation we report that TiO2 nanowired delivery of oxiracetam (50mg/kg, i.p.) daily for 5 days after CHI resulted in significant improvement of functional deficit on the 8th day. This was observed using Rota Rod treadmill, memory improvement assessed by the time spent in finding hidden platform under water. The motor function improvement is seen in oxiracetam treated CHI group by placing forepaw on an inclined mesh walking and foot print analysis for stride length and distance between hind feet. TiO2-nanowired oxiracetam also induced marked improvements in the cerebral blood flow, reduction in the BBB breakdown and edema formation as well as neuroprotection of neuronal, glial and myelin damages caused by CHI at light and electron microscopy on the 7th day after 5 days TiO2 oxiracetam treatment. Adverse biochemical events such as upregulation of CSF nitrite and nitrate, IL-6, TNF-a and p-Tau are also reduced significantly in oxiracetam treated CHI group. On the other hand post treatment of 100mg/kg dose of normal oxiracetam in identical conditions after CHI is needed to show slight but significant neuroprotection together with mild recovery of memory function and functional deficits on the 8th day. These observations are the first to point out that nanowired delivery of oxiracetam has superior neuroprotective ability in CHI. These results indicate a promising clinical future of TiO2 oxiracetam in treating CHI patients for better quality of life and neurorehabilitation, not reported earlier.

Military personnel are often exposed to high environmental heat associated with industrial or ambient abundance of nanoparticles (NPs) affecting brain function. We have shown that engineered metal NPs Ag and Cu exacerbate hyperthermia induced brain pathology. Thus, exploration of novel drug therapy is needed for effective neuroprotection in heat stroke intoxicated with NPs. In this investigation neuroprotective effects of cerebrolysin, a balanced composition of several neurotrophic factors and active peptides fragments exhibiting powerful antioxidant and anti-ischemic effects was examined in heat stroke after NPs intoxication. In addition, its efficacy is compared to currently used drugs in post-stroke therapies in clinics. Thus, levertiracetam, pregabalin, topiramat and valproate were compared in standard doses with cerebrolysin in heat stroke intoxicated with Cu or Ag NPs (50-60nm, 50mg/kg, i.p./day for 7 days). Rats were subjected to 4h heat stress (HS) in a biological oxygen demand incubator at 38°C (Relative Humidity 45-47%; Wind velocity 22.4-25.6cm/s) that resulted in profound increase in oxidants Luminol, Lucigenin, Malondialdehyde and Myeloperoxidase, and a marked decrease in antioxidant Glutathione. At this time severe reductions in the cerebral blood flow (CBF) was seen together with increased blood-brain barrier (BBB) breakdown and brain edema formation. These pathophysiological responses were exacerbated in NPs treated heat-stressed animals. Pretreatment with cerebrolysin (2.5mL/kg, i.v.) once daily for 3 days significantly attenuated the oxidative stress, BBB breakdown and brain edema and improved CBF in the heat stressed group. The other drugs were least effective on brain pathology following heat stroke. However, in NPs treated heat stressed animals 5mL/kg conventional cerebrolysin and 2.5mL/kg nanowired cerebrolysin is needed to attenuate oxidative stress, BBB breakdown, brain edema and to improve CBF. Interestingly, the other drugs even in higher doses used are unable to alter brain pathologies in NPs and heat stress. These observations are the first to demonstrate that cerebrolysin is the most superior antioxidant and anti-ischemic drug in NPs exposed heat stroke, not reported earlier.

Spinal cord injury (SCI) is one of the leading causes of disability in Military personnel for which no suitable therapeutic strategies are available till today. Thus, exploration of novel therapeutic measures is highly needed to enhance the quality of life of SCI victims. Previously, topical application of BDNF and GDNF in combination over the injured spinal cord after 90 min induced marked neuroprotection. In present investigation, we added CNTF in combination with BDNF and/or GDNF treatment to examine weather the triple combination applied over the traumatic cord after 90 or 120 min could thwart cord pathology. Since neurotrophins attenuate nitric oxide (NO) production in SCI, the role of carbon monoxide (CO) production that is similar to NO in inducing cell injury was explored using immunohistochemistry of the constitutive isoform of enzyme hemeoxygenase-2 (HO-2). SCI inflicted over the right dorsal horn of the T10–11 segments by making an incision of 2 mm deep and 5 mm long upregulated the HO-2 immunostaining in the T9 and T12 segments after 5 h injury. These perifocal segments are associated with breakdown of the blood-spinal cord barrier (BSCB), edema development and cell injuries. Topical application of CNTF with BDNF and GDNF in combination (10 ng each) after 90 and 120 min over the injured spinal cord significantly attenuated the BSCB breakdown, edema formation, cell injury and overexpression of HO-2. These observations are the first to show that CNTF with BDNF and GDNF induced superior neuroprotection in SCI probably by downregulation of CO production, not reported earlier.

Military personnel often exposed to high summer heat are vulnerable to heat stroke (HS) resulting in abnormal brain function and mental anomalies. There are reasons to believe that leakage of the blood-brain barrier (BBB) due to hyperthermia and development of brain edema could result in brain pathology. Thus, exploration of suitable therapeutic strategies is needed to induce neuroprotection in HS. Extracts of Gingko Biloba (EGb-761) is traditionally used in a variety of mental disorders in Chinese traditional medicine since ages. In this chapter, effects of TiO2 nanowired EGb-761 and BN-52021 delivery to treat brain pathologies in HS is discussed based on our own investigations. We observed that TiO2 nanowired delivery of EGb-761 or TiO2 BN-52021 is able to attenuate more that 80% reduction in the brain pathology in HS as compared to conventional drug delivery. The functional outcome after HS is also significantly improved by nanowired delivery of EGb-761 and BN-52021. These observations are the first to suggest that nanowired delivery of EGb-761 and BN-52021 has superior therapeutic effects in HS not reported earlier. The clinical significance in relation to the military medicine is discussed.

Military personnel are vulnerable to environmental or industrial exposure of engineered nanoparticles (NPs) from metals. Long-term exposure of NPs from various sources affect sensory-motor or cognitive brain functions. Thus, a possibility exists that chronic exposure of NPs affect blood-brain barrier (BBB) breakdown and brain pathology by inducing oxidative stress and/or nitric oxide production. This hypothesis was examined in the rat intoxicated with Ag, Cu or Al (50-60nm) nanoparticles (50mg/kg, i.p. once daily) for 7 days. In these NPs treated rats the BBB permeability, brain edema, neuronal nitric oxide synthase (nNOS) immunoreactivity and brain oxidants levels, e.g., myeloperoxidase (MP), malondialdehyde (MD) and glutathione (GT) was examined on the 8th day. Cu and Ag but not Al nanoparticles increased the MP and MD levels by twofold in the brain although, GT showed 50% decline. At this time increase in brain water content and BBB breakdown to protein tracers were seen in areas exhibiting nNOS positive neurons and cell injuries. Pretreatment with insulin like growth factor-1 (IGF-1) in high doses (1μg/kg, i.v. but not 0.5μg/kg daily for 7 days) together with NPs significantly reduced the oxidative stress, nNOS upregulation, BBB breakdown, edema formation and cell injuries. These novel observations demonstrate that (i) NPs depending on their metal constituent (Cu, Ag but not Al) induce oxidative stress and nNOS expression leading to BBB disruption, brain edema and cell damage, and (ii) IGF-1 depending on doses exerts powerful neuroprotection against nanoneurotoxicity, not reported earlier.

Military personnel are prone to traumatic brain injury (TBI) that is one of the risk factors in developing Alzheimer's disease (AD) at a later stage. TBI induces breakdown of the blood-brain barrier (BBB) to serum proteins into the brain and leads to extravasation of plasma amyloid beta peptide (ΑβP) into the brain fluid compartments causing AD brain pathology. Thus, there is a need to expand our knowledge on the role of TBI in AD. In addition, exploration of the novel roles of nanomedicine in AD and TBI for neuroprotection is the need of the hour. Since stem cells and neurotrophic factors play important roles in TBI and in AD, it is likely that nanodelivery of these agents exert superior neuroprotection in TBI induced exacerbation of AD brain pathology. In this review, these aspects are examined in details based on our own investigations in the light of current scientific literature in the field. Our observations show that TBI exacerbates AD brain pathology and TiO2 nanowired delivery of mesenchymal stem cells together with cerebrolysin-a balanced composition of several neurotrophic factors and active peptide fragments, and monoclonal antibodies to amyloid beta protein thwarted the development of neuropathology following TBI in AD, not reported earlier.

Military personnel are often exposed to high altitude (HA, ca. 4500–5000 m) for combat operations associated with neurological dysfunctions. HA is a severe stressful situation and people frequently use methamphetamine (METH) or other psychostimulants to cope stress. Since military personnel are prone to different kinds of traumatic brain injury (TBI), in this review we discuss possible effects of METH on concussive head injury (CHI) at HA based on our own observations. METH exposure at HA exacerbates pathophysiology of CHI as compared to normobaric laboratory environment comparable to sea level. Increased blood-brain barrier (BBB) breakdown, edema formation and reductions in the cerebral blood flow (CBF) following CHI were exacerbated by METH intoxication at HA. Damage to cerebral microvasculature and expression of beta catenin was also exacerbated following CHI in METH treated group at HA. TiO2-nanowired delivery of H-290/51 (150 mg/kg, i.p.), a potent chain-breaking antioxidant significantly enhanced CBF and reduced BBB breakdown, edema formation, beta catenin expression and brain pathology in METH exposed rats after CHI at HA. These observations are the first to point out that METH exposure in CHI exacerbated brain pathology at HA and this appears to be related with greater production of oxidative stress induced brain pathology, not reported earlier.

Concussive head injury (CHI) often associated with military personnel, soccer players and related sports personnel leads to serious clinical situation causing lifetime disabilities. About 3-4k head injury per 100k populations are recorded in the United States since 2000-2014. The annual incidence of concussion has now reached to 1.2% of population in recent years. Thus, CHI inflicts a huge financial burden on the society for rehabilitation. Thus, new efforts are needed to explore novel therapeutic strategies to treat CHI cases to enhance quality of life of the victims. CHI is well known to alter endogenous balance of excitatory and inhibitory amino acid neurotransmitters in the central nervous system (CNS) leading to brain pathology. Thus, a possibility exists that restoring the balance of amino acids in the CNS following CHI using therapeutic measures may benefit the victims in improving their quality of life. In this investigation, we used a multimodal drug Cerebrolysin (Ever NeuroPharma, Austria) that is a well-balanced composition of several neurotrophic factors and active peptide fragments in exploring its effects on CHI induced alterations in key excitatory (Glutamate, Aspartate) and inhibitory (GABA, Glycine) amino acids in the CNS in relation brain pathology in dose and time-dependent manner. CHI was produced in anesthetized rats by dropping a weight of 114.6g over the right exposed parietal skull from a distance of 20cm height (0.224N impact) and blood-brain barrier (BBB), brain edema, neuronal injuries and behavioral dysfunctions were measured 8, 24, 48 and 72h after injury. Cerebrolysin (CBL) was administered (2.5, 5 or 10mL/kg, i.v.) after 4-72h following injury. Our observations show that repeated CBL induced a dose-dependent neuroprotection in CHI (5-10mL/kg) and also improved behavioral functions. Interestingly when CBL is delivered through TiO2 nanowires superior neuroprotective effects were observed in CHI even at a lower doses (2.5-5mL/kg). These observations are the first to demonstrate that CBL is effectively capable to attenuate CHI induced brain pathology and behavioral disturbances in a dose dependent manner, not reported earlier.

In inflammatory bowel disease (IBD), experimental models have proven to be important tools for evaluating potential therapeutic agents and for investigating the mechanisms of pathogenesis. Oxidative stress and the immune response have been associated with acetic acid (AA)-induced ulcerative colitis (UC). Our study aimed to evaluate, for the first time, the ability of a spore-based probiotic and an amino acid and immunoglobulin supplement in reducing tissue damage and inflammatory responses in an experimental animal model of UC. Forty-two Wistar rats were divided into six groups, receiving 1% carboxymethylcellulose, 4% AA, MegaSporeBiotic&trade, (MSB, 1 &times, 109 colony forming units/day) and MegaMucosa&trade, (MM, 70 mg/100 g/day). Pretreatment with MSB or MM alone and in combination significantly lowered inflammation and reduced damage to the colonic mucosa. Pretreatment with these agents resulted in levels of proinflammatory cytokines, vascular tight junction proteins, and measures of oxidative stress similar to those reported for methylprednisolone, one of the first-line therapies for moderate to severe activity of UC. The protection was further confirmed by histologic analysis of the colon tissue. In conclusion, pretreatment with probiotic spore-forming Bacillus strains and a supplement of amino acids in combination with immunoglobulins exhibited anti-inflammatory and antioxidant effects in an AA-induced rat model of UC.

(1) Background: The approach of bleeding complications in patients treated with non-vitamin K oral anticoagulants (NOACs) represents an important issue in clinical practice. Both dabigatran and apixaban are substrates for P-glycoprotein and, therefore, ABCB1 gene variations may be useful in individualizing NOACs treatment, especially in high-risk patients. (2) Methods: ABCB1 rs1045642 and rs4148738 were determined in 218 atrial fibrillation patients treated with dabigatran or apixaban (70.94 &plusmn, 9.04 years, 51.83% men). (3) Results: Non-major bleeding appeared in 7.34% NOACs&ndash, treated patients. The logistic tested models based on the four genetic models revealed no significant association between the variant genotype of two ABCB1 SNPs and the risk of bleeding (p &gt, 0.05). Among the four two-locus haplotypes, TA and CA haplotypes had the highest frequency in NOACs-treated patients with bleeding, involving a possible positive association with the susceptibility of bleeding complications (OR = 1.04 and OR = 1.91, respectively). The logistic model found no significant association of estimated haplotypes with bleeding (p &gt, 0.05) except for the TG haplotype which had a trend toward statistical significance (p = 0.092). Among the risk factors for bleeding, only age &gt, 70 years and stroke/TIA showed a tendency toward statistical significance. (4) Conclusions: We found no significant associations between the studied ABCB1 variant genotypes with non-major bleeding risk in NOACs-treated patients. A trend of association between TG haplotype with bleeding risk was observed, implying a protective role of this haplotype against bleeding in patients treated with dabigatran or apixaban.

(1) Aim: The aim of this study was to assess the preferences of oral anticoagulants (OA) in patients diagnosed with deep vein thrombosis (DVT) of lower limbs or non-valvular atrial fibrillation (AF) requiring anticoagulation for medium/long term. (2) Materials and methods: the study included consecutive patients admitted with a diagnosis of either acute DVT of lower limbs (without signs of pulmonary embolism) or non-valvular AF who required oral anticoagulation, in a time frame of 18 months from January 2017 until June 2018. The following data were recorded: demographic variables, comorbidities (ischemic heart disease, arterial hypertension, heart failure, stroke, peripheral artery disease, diabetes mellitus, obesity), type and dose of OA (acenocoumarol, dabigatran, apixaban, rivaroxaban), complications due to the use of OA. (3) Results: AF patients were older and had considerably more cardiovascular comorbidities than DVT patients. Vitamin K antagonists (VKA) were more likely to be administered in patients with AF, as they had indication for indefinite anticoagulation. VKA were more frequently prescribed in patients with ischemic heart disease, heart failure, and diabetes compared with DVT patients. Moreover, complications related to OA use were more frequent in the VKA group. Almost half of patients with acute DVT (48.5%) were treated with direct OA (DOAC) rather than VKA, and only a quarter of AF patients (24.8%) were treated with DOACs.

Introduction: Atherosclerosis represents the process by which fibrous plaques are formed in the arterial wall, increasing its rigidity with a subsequent decrease in blood flow which can lead to several cardiovascular events. Seeing as vitamin K antagonists are involved in the pathogenesis of atherosclerosis, we decided to investigate whether polymorphisms in genes that influence vitamin K metabolism might have an impact in modulating the risk of plaque formation. Patients and Methods: In the current study we included adult patients admitted in the Clinical Municipal Hospital of Cluj-Napoca without any carotid or femoral plaques clinically visible at the initial investigation, and a five year follow-up was subsequently performed. We recorded the following patient characteristics: age at inclusion, gender, area of living, smoking, presence of carotid and/or femoral plaques at five years, ischemic heart disease, arterial hypertension, atrial fibrillation, heart failure, diabetes mellitus, obesity, dyslipidemia, drug (oral anticoagulants, antihypertensives, hypolipidemic, anti-diabetic) use and status for the following gene polymorphisms: VKORC1 1639 G&gt, A, CYP4F2 1347 G&gt, T and GGCX 12970 C&gt, G. Results: We observed that the major predictor of both carotid and femoral plaque formation is represented by ischemic cardiac disease. VKORC1 and CYP4F2 polymorphisms did not predict plaque formation, except for VKORC1 homozygous mutants. Nonetheless, both VKORC1 and CYP4F2 interacted with ischemic cardiac disease, increasing the risk of developing a carotid plaque, while only CYP4F2, but not VKORC1, interacted with ischemic cardiac disease to increase the risk of femoral plaque formation. Conclusions: We documented that CYP4F2 and VKORC1 polymorphisms boost the proinflammatory plaque environment (observed indirectly through the presence of ischemic heart disease), increasing the risk of plaque development.

Cardio-oncology is a discipline based on early screening, monitoring, and treating chemotherapy-induced cardiotoxicity. There are many chemotherapeutics known for their cardiac toxic effects, including fluoropyrimidines. Fluoropyrimidine represents the cornerstone of many types of cancer and each year almost two million cancer patients undergo this treatment. Fluoropyrimidine-induced cardiotoxicity can be manifested in several forms, from angina pectoris to sudden death. This paper is a review of how the cardiotoxicity of fluoropyrimidines is presented, the mechanisms of its occurrence, its diagnosis, and management.

Background: Atrial fibrillation is a major health problem due to the stroke risk associated with it. To reduce stroke risk, oral anticoagulants (OAC) are prescribed using the CHA2DS2-VASc (Congestive heart failure, Hypertension, Age &ge, 75 years, Diabetes Mellitus, Stroke, Vascular disease, Age 65&ndash, 74 years, Sex category) risk score, a clinical probability assessment that includes a combination of risk factors predicting the probability of a stroke. Not all patients with high risk are receiving this treatment. The aim of this study was to assess physician adherence to clinical guidelines concerning the OAC treatment and to identify the factors that were associated with the decision to prescribe it. Methods: Registry data from 784 patients with non-valvular atrial fibrillation were evaluated in this retrospective cross-sectional study. Demographic data, subtype of AF, comorbidities associated with higher stroke and bleeding risk, and antithrombotic treatment received were recorded. We compared stroke and bleeding risk in patients with and without OAC treatment to determine if the clinicians followed guidelines: prescribed when necessary and abstained when not needed. Results: OAC treatment was administered in 617 (78.7%) patients. Of the 167 patients who did not receive OAC, 161 (96.4%) were undertreated according to their risk score, as opposed to those who received OAC in which the percentage of overtreated was 3.2%. Most undertreated patients (60.5%, p &lt, 0.001) were with paroxysmal atrial fibrillation subtype. Conclusions: The decision to use anticoagulants for stroke prevention was based on the type of atrial fibrillation, rather than on the risk of stroke as quantified by CHA2DS2-VASc as per the recommended guidelines.

Recurrent wheezing (RW) in infancy is one of the most frequent reasons for parents to consult health care providers and creates a significant global burden. Clinical course of RW is difficult to predict, also which infants will progress to asthma, since no valid biomarkers have been established. Identification of those infants with RW who are at risk of further recurrences and/or severe acute respiratory tract infection (ARTI) could help pediatricians to improve their therapeutic decisions. Increasing research interest is focused on the extra-skeletal actions of vitamin D (VD) and the clinical impact of VD insufficiency/deficiency. As VD deficiency could be a risk factor for causing RW in children, measurement of their serum level of 25-hydroxycholecalciferol [25(OH)D] is recommended. In the case of deficiency, VD administration is recommended in age-appropriate doses for at least 6 weeks, until achievement of normal blood 25(OH)D level, followed by supplementation as long as exposure to sun is inadequate. Higher doses of VD given in an attempt to prevent asthma development appear to be of no additional benefit. In children with severe ARTI, VD level is recommended to be assess.

Background and Objectives: The evolution of allergic rhinitis to asthma is a part of &ldquo, atopic march&rdquo, The aim of this study was to analyze possible predictive markers for asthma occurrence in patients with allergic rhinitis to house dust mites (HDM). Materials and Methods: Fifty-eight patients with persistent allergic rhinitis (PAR) were included. The clinical, biological evaluation and fractionated exhaled nitric oxide (FeNO) measurement were performed at enrolment. The patients were clinically evaluated after one year to determine asthma occurrence. Results: The severity of rhinitis symptoms, levels of total immunoglobulin E (IgE), ICAM-1, VCAM-1, E-selectin and IL-6, but not IL-8 and TNF-&alpha, were higher in patients with allergic rhinitis who developed asthma compared to non-asthmatics, but the differences were not significant to considered them as predictive factors for asthma occurrence. The risk of asthma was independently influenced by patients aged over 30 years ((OR-3.74, CI95% 0.86&ndash, 16.31, p = 0.07), a duration of allergic rhinitis over 12 months ((OR-4.20, CI95% 0.88&ndash, 20, p = 0.07) and a basal FeNO over 28 parts per billion (pbb) ((OR-18.68, CI95% 3.79&ndash, 92.05, p &lt, 0.001). Conclusion: Clinical and biological parameters may predict asthma occurrence in patients with persistent allergic rhinitis to HDM. Adult patients with a longer duration of rhinitis symptoms and a high level of FeNO have a greater risk to develop asthma.

Fluoropyrimidines, after more than 50 years of their discovery, are still the treatment of many types of cancer, and annually is estimated that two million patients use fluoropyrimidine treatment. The toxicity associated with fluoropyrimidines affects 30-40% of patients and some adverse effects can be lethal. Dihydroypyrimidine dehydrogenase is the main enzyme in the catabolism of 5-FU and DPD activity deficiency can cause important toxicity. There is an important reason for determinate DPD activity in order to improve patient safety and to limit potential life-threating toxicity. Now, are available multiple phenotypic and genotypic methods to determinate DPD activity, some of this methods have proven their usefulness in practice, but yet there are not routinely recommended in clinical practice. This review is another statement of the importance of determination DPD status, the phenotypic and genotypic methods that are available and can be used.

Sleep deprivation (SD) is common in military personnel engaged in combat operations leading to brain dysfunction. Military personnel during acute or chronic SD often prone to traumatic brain injury (TBI) indicating the possibility of further exacerbating brain pathology. Several lines of evidence suggest that in both TBI and SD alpha-melanocyte-stimulating hormone (α-MSH) and brain-derived neurotrophic factor (BDNF) levels decreases in plasma and brain. Thus, a possibility exists that exogenous supplement of α-MSH and/or BDNF induces neuroprotection in SD compounded with TBI. In addition, mesenchymal stem cells (MSCs) are very portent in inducing neuroprotection in TBI. We examined the effects of concussive head injury (CHI) in SD on brain pathology. Furthermore, possible neuroprotective effects of α-MSH, MSCs and neurotrophic factors treatment were explored in a rat model of SD and CHI. Rats subjected to 48 h SD with CHI exhibited higher leakage of BBB to Evans blue and radioiodine compared to identical SD or CHI alone. Brain pathology was also exacerbated in SD with CHI group as compared to SD or CHI alone together with a significant reduction in α-MSH and BDNF levels in plasma and brain and enhanced level of tumor necrosis factor-alpha (TNF-α). Exogenous administration of α-MSH (250 μg/kg) together with MSCs (1 × 106) and cerebrolysin (a balanced composition of several neurotrophic factors and active peptide fragments) (5 mL/kg) significantly induced neuroprotection in SD with CHI. Interestingly, TiO2 nanowired delivery of α-MSH (100 μg), MSCs, and cerebrolysin (2.5 mL/kg) induced enhanced neuroprotection with higher levels of α-MSH and BDNF and decreased the TNF-α in SD with CHI. These observations are the first to show that TiO2 nanowired administration of α-MSH, MSCs and cerebrolysin induces superior neuroprotection following SD in CHI, not reported earlier. The clinical significance of our findings in light of the current literature is discussed.

Glioblastoma Multiforme (GBM) is one the most common intracranial tumors discovered by Burns (1800) and Abernethy (1804) based on gross morphology of the autopsied material and referred to as "medullary sarcoma" and later "fungus medullare" (Abernethy, 1804; Burns, 1800). Virchow in 1863 was the first German pathologist using histomorphological techniques discovered that GBM is a tumor of glial origin. Virchow (1863/65) also then used the term Glioma for the first time and classified as low-grade glioma and high-grade glioma very similar to that of today according to World health organization (WHO) classification (Jellinger, 1978; Virchow, 1863/65). After almost >50 years of this discovery, Baily and Cushing (1926) based on modern neuropathological tools provide the classification of gliomas that is still valid today (Baily & Cushing, 1926). Although, our knowledge about development of gliomas has advanced through development of modern cellular and molecular biological tools (Gately, McLachlan, Dowling, & Philip, 2017; Omuro & DeAngelis, 2013), therapeutic advancement of GBM still requires lot of efforts for the benefit of patients. This review summarizes new developments on pathophysiological aspects of GBM and novel therapeutic strategies to enhance quality of life of patients. These novel therapeutic approaches rely on enhanced penetration of drug therapy into the tumor tissues by use of nanomedicine for both the diagnostic and therapeutic purposes, referred to as "theranostic nanomedicine" (Alphandery, 2020; Zhao, van Straten, Broekman, Preat, & Schiffelers, 2020). Although, the blood-brain barrier (BBB) is fenestrated around the periphery of the tumor tissues, the BBB is still tight within the deeper tissues of the tumor. Thus, drug delivery is a challenge for gliomas and requires new therapeutic advances (Zhao et al., 2020). Associated edema development around tumor tissues is another factor hindering therapeutic effects (Liu, Mei, & Lin, 2013). These factors are discussed in details using novel therapeutic advances in gliomas.

Spinal cord evoked potentials (SCEP) are good indicators of spinal cord function in health and disease. Disturbances in SCEP amplitudes and latencies during spinal cord monitoring predict spinal cord pathology following trauma. Treatment with neuroprotective agents preserves SCEP and reduces cord pathology after injury. The possibility that cerebrolysin, a balanced composition of neurotrophic factors improves spinal cord conduction, attenuates blood-spinal cord barrier (BSCB) disruption, edema formation, and cord pathology was examined in spinal cord injury (SCI). SCEP is recorded from epidural space over rat spinal cord T9 and T12 segments after peripheral nerves stimulation. SCEP consists of a small positive peak (MPP), followed by a prominent negative peak (MNP) that is stable before SCI. A longitudinal incision (2mm deep and 5mm long) into the right dorsal horn (T10 and T11 segments) resulted in an immediate long-lasting depression of the rostral MNP with an increase in the latencies. Pretreatment with either cerebrolysin (CBL 5mL/kg, i.v. 30min before) alone or TiO2 nanowired delivery of cerebrolysin (NWCBL 2.5mL/kg, i.v.) prevented the loss of MNP amplitude and even enhanced further from the pre-injury level after SCI without affecting latencies. At 5h, SCI induced edema, BSCB breakdown, and cell injuries were significantly reduced by CBL and NWCBL pretreatment. Interestingly this effect on SCEP and cord pathology was still prominent when the NWCBL was delivered 2min after SCI. Moreover, expressions of c-fos and c-jun genes that are prominent at 5h in untreated SCI are also considerably reduced by CBL and NWCBL treatment. These results are the first to show that CBL and NWCBL enhanced SCEP activity and thwarted the development of cord pathology after SCI. Furthermore, NWCBL in low doses has superior neuroprotective effects on SCEP and cord pathology, not reported earlier. The functional significance and future clinical potential of CBL and NWCBL in SCI are discussed.

Mild traumatic brain injury (mTBI) is one of the leading predisposing factors in the development of Parkinson's disease (PD). Mild or moderate TBI induces rapid production of tau protein and alpha synuclein (ASNC) in the cerebrospinal fluid (CSF) and in several brain areas. Enhanced tau-phosphorylation and ASNC alters the molecular machinery of the brain leading to PD pathology. Recent evidences show upregulation of constitutive isoform of hemeoxygenase (HO-2) in PD patients that correlates well with the brain pathology. mTBI alone induces profound upregulation of HO-2 immunoreactivity. Thus, it would be interesting to explore whether mTBI exacerbates PD pathology in relation to tau, ASNC and HO-2 expression. In addition, whether neurotrophic factors and stem cells known to reduce brain pathology in TBI could induce neuroprotection in PD following mTBI. In this review role of mesenchymal stem cells (MSCs) and cerebrolysin (CBL), a well-balanced composition of several neurotrophic factors and active peptide fragments using nanowired delivery in PD following mTBI is discussed based on our own investigation. Our results show that mTBI induces concussion exacerbates PD pathology and nanowired delivery of MSCs and CBL induces superior neuroprotection. This could be due to reduction in tau, ASNC and HO-2 expression in PD following mTBI, not reported earlier. The functional significance of our findings in relation to clinical strategies is discussed.

Blast brain injury (bBI) is a combination of several forces of pressure, rotation, penetration of sharp objects and chemical exposure causing laceration, perforation and tissue losses in the brain. The bBI is quite prevalent in military personnel during combat operations. However, no suitable therapeutic strategies are available so far to minimize bBI pathology. Combat stress induces profound cardiovascular and endocrine dysfunction leading to psychosomatic disorders including diabetes mellitus (DM). This is still unclear whether brain pathology in bBI could exacerbate in DM. In present review influence of DM on pathophysiology of bBI is discussed based on our own investigations. In addition, treatment with cerebrolysin (a multimodal drug comprising neurotrophic factors and active peptide fragments) or H-290/51 (a chain-breaking antioxidant) using nanowired delivery of for superior neuroprotection on brain pathology in bBI in DM is explored. Our observations are the first to show that pathophysiology of bBI is exacerbated in DM and TiO2-nanowired delivery of cerebrolysin induces profound neuroprotection in bBI in DM, not reported earlier. The clinical significance of our findings with regard to military medicine is discussed.

Alina Deniza Ciubean,1,2 Rodica Ana Ungur,2,3 Laszlo Irsay,2,3 Viorela Mihaela Ciortea,2,3 Ileana Monica Borda,2,3 Ioan Onac,2,3 Stefan Cristian Vesa,1 Anca Dana Buzoianu1 1Department of Pharmacology, Toxicology and Clinical Pharmacology, Iuliu Haţieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania; 2Department of Rehabilitation, Clinical Rehabilitation Hospital, Cluj-Napoca, Romania; 3Department of Rehabilitation Medicine, Iuliu Haţieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania Objectives: Osteoporosis is a common skeletal disorder characterized by decreased bone mass and increased susceptibility to fractures, which are associated with pain and decrease in physical function, social function, and well-being, which are all aspects of quality of life (QoL). The purpose of this study was to evaluate the burden of osteoporosis and fragility fractures in Romanian postmenopausal women from Cluj County using the 36-Item Short Form Health Survey (SF-36) and Quality of life questionnaire of the European Foundation for Osteoporosis (QUALEFFO-41) questionnaires.Materials and methods: An analytical cross-sectional study on 364 postmenopausal women was carried out between June 2016 and August 2017 in the Clinical Rehabilitation Hospital in Cluj-Napoca, Cluj County, Romania. Data were collected by interview and from the medical documents: clinical and demographic data, personal medical history, risk factors for osteoporosis, and bone mineral density at the lumbar spine and femur. The patients included in the study were asked to complete the Romanian versions of the SF-36 and QUALEFFO-41 questionnaires.Results: Women with osteoporosis had significantly lower scores in the SF-36 domains (P

Chronic hyperglycemia is an important cause for the development of chronic complications of diabetes, but glycemic variability has emerged in recent years as an independent contributor to diabetes-related complications. Our objective was to evaluate glycemic variability in patients with T2DM treated with insulin compared with other antidiabetic drugs. In this retrospective study, we collected 24-hour continuous glucose monitoring (CGM) recording data from 95 patients with T2DM, of which 27 treated with insulin and 68 with non-insulin treatment. We calculated and compared 16 glucose variability parameters in the insulin-treated and non-insulin treated groups. Insulin treated patients had significantly higher values of parameters describing the amplitude of glucose value fluctuations (standard deviation of glucose values, percentage coefficient of variation [%CV], and mean amplitude of glycemic excursion [MAGE], p

Despite all advanced evidence-based therapeutic opportunities, heart failure remains a major public health burden, with a dramatically increasing in prevalence. Moreover, the diagnosis of chronic heart failure in obese patients brings unique challenges. So, the aim of this study was to identify the cardiovascular risk factors profile in heart failure obese patients, admitted in rehabilitation programs. Material and methods. This study enrolled 80 obese (body mass index ≥30 kg/m2) patients, 56.2% men with average age ranged of 69.75 ± 9.12 years who were hospitalized for decompensated heart failure in the Rehabilitation Hospital, Cardiology-Department, Cluj-Napoca, Romania. Baseline characteristics, clinical presentation, NT-proBNP values, echocardiographic parameters and in-hospital therapies were evaluated. The lot was divided into three groups: obese heart failure patients with reduced (

Our study aimed to identify inorganic elements and bacterial load on the inner surface of the CPAP masks and tubing using scanning electron microscopy (SEM), and energy-dispersive X-ray spectroscopy (EDX) and microbiological surface analysis. By SEM were identified structures similar to Staphylococcus and Candida types. When completed by EDX were identified Cl, K, Ca, O, Ti, Na, Mg, Al, Si, S, Cl. Microbiological analysis identified Staphylococcus epidermidis (5000 CFU/mL), Staphylococcus hominis (8600 CFU/mL), and Staphylococcus haemolyticus (6500 CFU/mL). The presence of microbiological and inorganic structures raises concerns on the risk of their inhalation into the airways.

Aim of the study Our main purpose was to investigate if the chronic treatment with the disease-modifying drug natalizumab shows quantifiable effect on BDNF levels in multiple sclerosis patients. Materials and Methods BDNF plasma concentration was evaluated using enzyme-linked immunosorbent assay in healthy individuals, not treated multiple sclerosis patients and patients treated with natalizumab. Results Multiple sclerosis patients have a significantly lower amount of peripheral BDNF than healthy individuals. Patients treated with natalizumab have significantly higher BDNF levels than not treated patients. Conclusions Chronic natalizumab treatment is associated with significantly increased plasma BDNF concentration in multiple sclerosis.

Background & Aims: The mutations in the gene that encodes vitamin K epoxide reductase (VKOR) enzyme are responsible for low levels of vitamin K. The purpose of this study was to evaluate whether the presence of the VKORC1 -1639 G> A polymorphism is a risk factor for non-variceal upper gastrointestinal bleeding (UGIB) in patients without concomitant therapy with vitamin K antagonists.Methods: This case-control study comprised 163 consecutive patients diagnosed with UGIB and 178 controls, in whom the diagnosis of UGIB was excluded. The following data were recorded: age, gender, alcohol consumption, smoking, history of UGIB, nonsteroidal anti-inflammatory drugs (NSAIDs) or low-dose aspirin consumption. Genetic analysis included genotyping for the VKORC1 -1639 G>A polymorphism.Results: History of UGIB (OR 3.463, CI95% 1.463-8.198, p=0.005), smoking (OR 2.498, CI95% 1.358-4.597, p=0.003), alcohol consumption (OR 3.283, CI95% 1.796-6.000, p A AA genotype (OR 1.364, CI95% 0.998-1.863, p=0.05) were associated with an increased risk of UGIB. The risk of UGIB was analyzed in patients with genotype AA who used aspirin or NSAIDs. The genotype AA has not kept its status of independent risk factor (p=0.3). In subjects with NSAIDs/aspirin therapy and genotype AA there was a two times higher chance of UGIB compared to those under NSAIDs/aspirin therapy alone (OR 7.6 vs. 3.6, pA AA genotype, as compared to those without UGIB.

NASH consists in lipid accumulation in hepatocytes that trigger oxidative stress, secretion of proinflammatory cytokines leading to steatohepatitis (NASH). The study aimed to investigate the levels of proinflammatory (TNF-αand IL-6) along with anti-inflammatory cytokine IL-10 in patients with NASH and to correlate the cytokines’ level with their polymorphism. Sixty-six patients with NASH and 30 healthy volunteers were included in the study. The plasmatic level of IL-6, IL-10, and TNF-αwere determined by ELISA. IL-10 -1082 G/A, IL-6 -174 G/C, and TNF-α-308 G/A polymorphisms were determined using the PCR-RFLP technique. IL-6, TNF-α, and CRP levels were significantly higher in patients with NASH. There was a positive correlation between proinflammatory cytokines and a negative correlation between IL-10 and proinflammatory markers. The G allele and GG genotype of IL-6 -174 G/C polymorphism were more frequently noticed in NASH patients. Regarding IL-10 -1082 G/A polymorphism, the AA genotype was correlated with NASH and with a low plasmatic level of IL-10. The A allele in position 308 of the TNF-αgene was associated with high level of cytokine. In conclusion, there was an imbalance between pro- and anti-inflammatory cytokines in NASH patients. IL-10 -1082 G/A and TNF-α-308 G/A genotypes were correlated with the plasmatic levels of cytokines.

Background: Non-alcoholic fatty liver disease (NAFLD) is an important cause of chronic liver diseases around the world. Paraoxonase-1 (PON1) is an enzyme produced by the liver with an important antioxidant role. The aim of this study was to evaluate PON1 serum concentration and PON1 gene polymorphisms in patients with NAFLD. Materials and methods: We studied a group of 81 patients with NAFLD with persistently elevated aminotransferases and a control group of 81 patients without liver diseases. We collected clinical information and performed routine blood tests. We also measured the serum concentration of PON1 and evaluated the PON1 gene polymorphisms L55M, Q192R, and C-108T. Results: There was a significant difference (p &lt, 0.001) in serum PON1 concentrations among the two groups. The heterozygous and the mutated homozygous variants (LM + MM) of the L55M polymorphism were more frequent in the NAFLD group (p &lt, 0.001). These genotypes were found in a multivariate binary logistic regression to be independently linked to NAFLD (Odds ratio = 3.4, p = 0.04). In a multivariate linear regression model, the presence of NAFLD was associated with low PON1 concentration (p &lt, 0.001). Conclusions: PON1 serum concentrations were diminished in patients with NAFLD, and the presence of NAFLD was linked with low PON1 concentration. The LM + MM genotypes of the PON1 L55M polymorphism were an independent predictor for NAFLD with persistently elevated aminotransferases.

Cisplatin is one of the most used drugs in the therapy of different types of cancer. However, its use is limited by nephrotoxicity. This study investigated the effects of a commercially available grape pomace extract (GE) from Vitis vinifera on cisplatin-induced kidney toxicity in rats. Sixty-four male Wistar albino rats were randomly divided into eight groups. Groups 1&ndash, 3 were controls, receiving 0.9% saline and doses 1 and 2 of GE respectively. Cisplatin was given to groups 4&ndash, 8. Two groups received pretreatment with GE, while another two groups received pre- and post-treatment with GE. Blood samples were collected and all animals sacrificed. Kidneys were harvested for histopathological analysis. GE significantly increased blood creatinine and urea levels, the severity of kidney histopathological damage, and mortality in all cisplatin groups, except for group 7 which received pre- and post-treatment with a low dose of GE. Renal toxicity was determined by mortality and severe histopathological renal lesions. Additionally, the serum total antioxidant capacity (TAC) was not significantly modified in the treated groups compared to the control. These results indicate that the GE did not have a protective effect on cisplatin-induced nephrotoxicity, on the contrary, GE accentuated the toxic effect of cisplatin.

Background and Objectives: Prior studies have identified a number of predictors for Atrial fibrillation (AF) ablation success, including comorbidities, the type of AF, and left atrial (LA) size. Ectopic foci in the initiation of paroxysmal AF are frequently found in pulmonary veins. Our aim was to assess how pulmonary vein anatomy influences the recurrence of atrial fibrillation after radiofrequency catheter ablation. Materials and Methods: Eighty patients diagnosed with paroxysmal or persistent AF underwent radiofrequency catheter ablation (RFCA) between November 2016 and December 2017. All of these patients underwent computed tomography before AF ablation. PV anatomy was classified according to the presence of common PVs or accessory PVs. Several clinical and imagistic parameters were recorded. After hospital discharge, all patients were scheduled for check-up in an outpatient clinic at 3, 6, 9, and 12 months after RFCA to detect AF recurrence. Results: A total of 80 consecutive patients, aged 53.8 &plusmn, 9.6 years, 54 (67.5%) men and 26 (32.5%) women were enrolled. The majority of patients had paroxysmal AF 53 (66.3%). Regular PV anatomy (2 left PVs, 2 right PVs) was identified in 59 patients (73.7%), a left common trunk (LCT) was detected in 15 patients (18.7%), an accessory right middle pulmonary vein (RMPV) was found in 5 patients (6.25%) and one patient presented both an LCT and an RMPV. The median follow-up duration was 14 (12, 15) months. Sinus rhythm was maintained in 50 (62.5%) patients. Age, gender, antiarrhythmic drugs, and the presence of cardiac comorbidities were not predictive of AF recurrence. The diagnosis of persistent AF before RFCA was more closely associated with an increase in recurrent AF after RFCA than after paroxysmal AF (p = 0.01). Longer procedure times (&gt, 265 minutes) were associated with AF recurrence (p = 0.04). Patients with an LA volume index of over 48.5 (mL/m2) were more likely to present AF recurrence (p = 0.006). Multivariate analysis of recurrence risk showed that only the larger LA volume index and variant PV anatomy were independently associated with AF recurrence. Conclusion: The study demonstrated that an increased volume of the left atrium was the most important predictive factor for the risk of AF recurrence after catheter ablation. Variant anatomy of PV was the only other independent predictive factor associated with a higher rate of AF recurrence.