Evaluation of the quality of life of older people with diabetes.

INTRODUCTION AND OBJECTIVE: Diabetes is commonly classified as a chronic disease of affluence due to the frequency of its incidence and the rate of its spreading. The aim of the study was to evaluate the quality of life of geriatric patients with type 2 diabetes. MATERIAL AND METHODS: 294 seniors diagnosed with type 2 diabetes living in the Lower Silesian Province in south-western Poland took part in the study. The study used a self-developed questionnaire collecting clinical and socio-demographic data, the WHOQOL-Bref questionnaire, Acceptance of Illness Scale (AIS), Self-Care of Diabetes Inventory (SCODI) and the Geriatric Depression Scale (GDS). RESULTS: Significant relationships of QoL with BMI, level of education and place of residence, were observed. BMI was significantly negatively correlated with the psychological domain of functioning and the environmental functioning, the level of education was correlated with physical health, psychological and environmental functioning, while the place of residence was correlated with the perception of the QoL and environmental functioning. Acceptance of illness was positively correlated with the perception of QoL and one's physical health. The results of regression analyses in predicting QoL in all domains showed that all models were a good fit for the data (p < 0.001), and the single predictor was maintenance of self-care. The level of depression was negatively correlated to a statistically significant degree with the perception of QoL and one's health condition. CONCLUSIONS: BMI, level of education and place of residence had the highest impact on the quality of life of the participants. The quality of life of the participants improved with the increase in the acceptance of their illness. The higher the level of depression exhibited by the participants, the poorer they evaluated their quality of life.

A comprehensive review and meta-analysis of suPAR as a predictor of acute kidney injury.

INTRODUCTION AND OBJECTIVE: The global impact of acute kidney injury (AKI) has not been thoroughly investigated. With the development of new techniques, soluble urokinase plasminogen activator receptor (suPAR) has become increasingly important in the diagnosis of AKI. Therefore, a systematic review and meta-analysis was carried out to evaluate the predictive value of suPAR for AKI. MATERIAL AND METHODS: The review and meta-analysis investigated the relationship between suPAR levels and acute kidney injury. Pubmed, Scopus, Cochrane Controlled Register of Trials, and Embase were searched for relevant studies from inception to 10 January 2023. Stata (Ver. 16 StataCorp, College Station, TX, USA) was used for all statistical analyses. A random effects model using the Mantel-Haenszel approach was employed, and odds ratios (OR) and standard mean differences (SMD) with 95% confidence intervals (CI) were calculated for binary and continuous outcomes, respectively. RESULTS: Nine studies reported suPAR levels among patients with and without AKI. Pooled analysis showed that suPAR levels in patients with and without AKI varied and amounted to 5.23 ± 4.07 vs. 3.23 ±0.67 ng/mL (SMD = 3.19; 95%CI: 2.73 to 3.65; p<0.001). The results from the sensitivity analysis did not alter the direction. CONCLUSIONS: This results show that increasing suPAR levels are associated with the occurrence of AKI. SuPAR might act as a novel biomarker for CI-AKI in clinical practice.

Employment of the Evolution RL sheath as a first-choice device shortens transvenous lead extraction time without affecting procedural safety and efficacy compared to its auxiliary use: Insights from the prospective multicenter EVO registry.

BACKGROUND: Transvenous lead extraction (TLE) is recommended in cases of local and systemic infections related to cardiac implantable electronic devices (CIEDs). Additionally, TLE is indicated in the event of lead damage or CIED malfunction. The extraction procedure is associated with a risk of life-threatening complications. OBJECTIVES: The aim of the EVO registry was to assess the safety and efficacy of birotational Evolution tool usage. MATERIAL AND METHODS: This registry study was prospectively conducted in 8 high-volume implantation centers in Poland. The study included 133 patients aged 63.5 ±15.1 years, and 76.69% were male. Indications for the procedure were: local or systemic infection (33.1%) and lead dysfunction (66.9%). The number of leads extracted varied from 1 (39.84%) to 3 (9.77%). RESULTS: Clinical procedural success was achieved in 99.1% of cases. A total of 226 leads were extracted, and 206 used the Evolution system. Two procedural strategies were identified while using the Evolution system: (1) usage of locking stylet, propylene sheaths and the Evolution system (118 leads, 52%) - group A; (2) usage of locking stylet and Evolution (88 leads, 39%) - group B. There were no differences in the number of complications between these 2 groups. The extraction time was significantly shorter (p = 0.02) in group B than in group A. Major complications occurred in 5.2% of cases with 2 intraprocedural deaths. Minor complications occurred in 1.5% of patients. CONCLUSIONS: The registry confirmed the efficacy and relative safety of the birotational Evolution sheath. Using the rotational sheath as a first attempt significantly reduces extraction time without compromising its safety.

Effectiveness of the Functional Movement Screen for assessment of injury risk occurrence in football players.

The aim of the study was to determine whether the Functional Movement Screen (FMS) test carried out among young boys practising football training identifies previous injuries. Sixty-five boys aged 12-13 years, who had regularly practised football in an academy for at least 3 years, were recruited and divided into two groups: an injured group (IG), consisting of players who had experienced at least one injury in the past (n + 25, age 12.32 ± 0.48) and a non-injured group (non-IG), a control group, made up of athletes with no injuries to the musculoskeletal system (n = 40, age 12.25 ± 0.49). Seven FMS tests were used to rate the functional fitness level as a part of the FMS tool. Significant differences between the total scores of the FMS tests (p < 0.001, r = 0.54) were documented. Higher scores in the FMS test were observed in the control group (M = 16.58, SD = 2.04) than in the study group (M = 14.20, ± SD = 1.96). The FMS test is an effective diagnostic tool to identify previous injuries among young football players.

The influence of acute coronary syndrome on levels of clopidogrel active metabolite and platelet inhibition in patients with and without CYP2C19*2(681 G>A), *3(636 G>A) and ABCB1(C3435C> T) gene polymorphisms.

INTRODUCTION: Although ticagrelor and prasugrel remain the standard antiplatelet treatments in acute coronary syndrome (ACS), numerous patients still present with indications for clopidogrel use. AIM: We aimed to assess the levels of clopidogrel active metabolite and to evaluate the effect of the drug on platelet inhibition in patients with ACS as compared with those with stable coronary disease. Patients were assessed for the presence of the most common genetic polymorphisms that reduce the absorption (ABCB1) and activation (CYP2C19*2 and CYP2C19*3) of clopidogrel to exclude the effect of genetic variability on drug concentrations and activity. MATERIAL AND METHODS: This single-center, open-label, prospective study included 199 patients hospitalized due to ST-segment elevation myocardial infarction (STEMI) or non-STEMI (NSTEMI) in Killip class I-III, who underwent percutaneous coronary intervention. The control group included 22 patients with stable coronary artery disease. RESULTS: The mean (SD) levels of active clopidogrel were 17.1 (12.3) ng/ml in controls and 16.4 (12.0) ng/ml in the whole study group (p < 0.68). No differences were noted in clopidogrel levels between patients with STEMI and NSTEMI (mean (SD), 17.6 (2.3) ng/ml and 15.1 (11.5) ng/ml; p < 0.45) or between STEMI and NSTEMI groups and controls (p < 0.38 and p < 0.61, respectively). No effect of ABCB1 or CYP2C19 polymorphism was observed in the study subgroups. CONCLUSIONS: We concluded that ACS does not affect the levels of clopidogrel active metabolite or platelet inhibition in patients in Killip class I-III with or without CYP2C19 or ABCB1 gene polymorphisms.

Original and generic clopidogrel: A comparison of antiplatelet effects and active metabolite concentrations in patients without polymorphisms in the ABCB1 gene and the allele variants CYPC19*2 and *3.

BACKGROUND: Ticagrelor and prasugrel are widely used as antiplatelet therapy after coronary angioplasty. However, there is a group of patients with indications for clopidogrel treatment. This population includes patients with chronic or acute coronary syndrome who are treated invasively and have contraindications to the use of novel antiplatelet drugs due to antithrombotic treatment (particularly with non-vitamin K antagonist oral anticoagulants). A wide range of generic forms of clopidogrel are available on the market. However, it is unclear whether they are as effective as the originator drug. OBJECTIVES: In the current study, we aimed to assess the concentrations of the active metabolite of clopidogrel and its effect on platelet aggregation inhibition in patients receiving the originator drug in comparison with those receiving generic clopidogrel. MATERIAL AND METHODS: We enrolled 22 healthy individuals without polymorphisms in the ABCB1 gene and the allele variants CYPC19*2 and CYPC19*3. All participants received a loading dose of clopidogrel (600 mg), followed by a maintenance dose of 75 mg for the next 3 days. On day 3, blood samples were obtained 1 h after drug administration to assess active metabolite concentrations using liquid chromatography with tandem mass spectrometry. In each participant, platelet aggregation was assessed with light transmission aggregometry after 5-µmol/L and 10-µmol/L adenosine diphosphate (ADP) stimulation. Assays were performed for the originator clopidogrel and 2 different generic groups. RESULTS: The mean ± standard deviation (SD) concentrations of active clopidogrel did not differ between the originator drug and 2 generic products with clopidogrel (12.7±5 pg/µL compared to 13.0 ±4 pg/µL compared to 14.4 ±4 pg/µL). Platelet aggregation inhibition after stimulation with 5 µmol/L and 10 µmol/L ADP was similar for all preparations. CONCLUSIONS: In comparison with original clopidogrel, the use of its generic form does not affect the blood concentrations of the active metabolite or its antiplatelet effect.

Determinants of primary healthcare patients' dissatisfaction with the quality of provided medical services.

INTRODUCTION: The quality of medical services and health care are complex problems with a number of various definitions, conceptual approaches, measurement tools and techniques. The most important influence on quality in primary health care has the (immaterial) human factor, the relationship between patient and doctor, medical personnel and the primary health care institution, and the skill to use new technologies to improve quality in health care. OBJECTIVE: The aim of the study is to discover the determinants of primary health care patients' dissatisfaction with the quality of medical services. MATERIAL AND METHODS: Patients with medical appointments on the day of the survey and gave their consent to participate were included in the study. A total of 901 patients of primary health care institutions [591 (65.59%) women and 310 (34.41%) men] in the Swietokrzyskie Province took part. The diagnostic poll method based on a questionnaire examining the patients' satisfaction with the quality of health services was used. Logistic regression identified the determinants of dissatisfaction of the patients. RESULTS: The determinants that mostly affected the patients' dissatisfaction with medical services were: rudeness of the doctor (p=0.0001), rudeness of the rest of medical staff (p=0.0001), non-comprehensibility of information about health by the patient (p=0.004), no clear identification of the patient in the health care system (p=0.01), and difficult access to information regarding the health condition (medical documentation) (p=0.018). CONCLUSIONS: Primary health care patients who participated in the study pointed to the attitude of the doctor towards a patient during a visit, and the attitude of the remaining medical personnel among the determinants of dissatisfaction with medical services.

A subjective sense of the quality of life in adolescents from the Swietokrzyskie Voivodship.

OBJECTIVES: The measurement of the health-related quality of life (HRQOL) is one of the most important methods for self-assessment of health, which makes it possible to identify irregularities in the physical, mental and social functioning. The aim of the research was to determine HRQOL using the Health Related Quality of Life Questionnaire for Children and Young People (the KIDSCREEN-52 questionnaire) - the instrument recommended by the World Health Organization - which makes it possible to distinguish groups of adolescents with a diversified subjective sense of the quality of life. MATERIAL AND METHODS: The study involved a group of 871 adolescents, 411 boys and 460 girls, aged 13-16 years, residing in the Swietokrzyskie Voivodship. The method of a diagnostic survey was used in the research. The KIDSCREEN-52 questionnaire, which is an instrument for examining the HRQOL of adolescents, was employed in the study. The k-means clustering method was applied, which made it possible to establish 3 groups of adolescents with a different subjective sense of the quality of life. RESULTS: Three groups of adolescents with a diversified subjective sense of the quality of life (high, average, low) were identified using the KIDSCREEN-52 questionnaire. The subjective quality of life in the majority of the respondents was high, in particular in those living in rural areas. The surveyed boys with a high subjective quality of life showed a significantly higher self-esteem, acceptance and peer support than the surveyed girls. CONCLUSIONS: The KIDSCREEN-52 questionnaire is an accurate and sensitive tool for assessing HRQOL. It allows identifying 3 groups of adolescents with a diversified subjective sense of the quality of life. It can form the basis for further diagnosis of the bio-psycho-social functioning of adolescents. Int J Occup Med Environ Health. 2021;34(3):415-25.

Cerebral Thrombolysis in Rural Residents Aged ≥ 80.

PURPOSE: The proportion of older people in Poland is higher in rural areas than in urban areas. Thus, we aimed to evaluate treatment rate and factors associated with outcome and safety of intravenous thrombolysis (IVT) in rural residents aged ≥80 years admitted to primary stroke centers. PATIENTS AND METHODS: This study was a retrospective, observational cohort study of 873 patients treated with recombinant tissue plasminogen activator (rt-PA) in primary stroke centers between February 1, 2009 and December 31, 2017. Among them were 527 rural residents and 231 (26.5%) were ≥80 years of age. The analyses between rural and urban patients aged ≥80 and between rural patients aged <80 and aged ≥80 were performed. RESULTS: The proportion of patients aged ≥80 treated with rt-PA was comparable in rural and urban residents (27.9% vs 24.3% p = 0.24). Rural patients aged ≥80 were also characterized by lower incidence of cardiovascular risk factors and better patients' conditions on admission to hospital. Symptomatic intracerebral hemorrhage rate among ≥80-year-old stroke patients was lower in those living in rural areas than in those living in urban areas (5.4% vs 14.3%, p = 0.02); there were no differences regarding mortality and 3-month functional outcome between both populations. The older group of rural patients was characterized by a higher 3-month mortality (28.5% vs 12.6%, p < 0.001) and lower functional independence rate (34.0% vs 50.5%, p < 0.001) than rural younger patients. Antiplatelet (OR 2.43, 95% CI 1.04-5.66, p = 0.04) and anticoagulant therapy before stroke (OR 3.64, 95% CI 1.21-10.99, p = 0.022), early ischemic changes in baseline computerized tomograprpahy (OR 2.65, 95% CI 1.03-6.82, p = 0.043) were associated with unfavorable outcome; and higher National Institute of Health Stroke Scale score on admission (OR 1.01, 95% CI 1.01-1.20, p = 0.039), higher baseline count of white blood cells (OR 1.33, 95% CI 1.10-0.62, p = 0.003) were associated with mortality in rural patients over 80. CONCLUSION: We suggest that rural patients aged ≥80 may be safely treated with IVT in routine practice. However, lower efficacy and a higher mortality must be considered in former use of Vitamin K antagonist and antiplatelet or high white blood cells count.

Using affinity analysis in diagnosing the needs of patients as regards e-Health.

INTRODUCTION: E-Health tools allow a medical facility to set a given patient's data in order using ICT techniques, and the patient to use those techniques when contacting a given organisation. MATERIAL AND METHODS: Secondary statistical data was used in the research. The study was carried out among primary health care patients. Mining for affinity rules was done in the R programme. The apriori and inspect functions from the arules package were used. Moreover, any redundant rules were removed from thoseobtained using the afero-mentioned method. Applying the general description of the affinity analysis method onto the survey described herein, it should be stressed that the aim of using affinity analysis was to discover the rules which contain the sub-transaction B={V_6=1} as a consequent. This was determined by the intention to discover associations regarding the knowledge about a uniform information system that the patients under study might have. RESULTS: In the discovered rules, the antecedent most often contained an indication of the need for introducing a uniform solution as regards telemedicine. Moreover, according to the opinions of 'conscious'patients, a uniform IT system should improve the work at primary health care institutions, introducing an on-line booking system for visits should improve the productivity and comfort of doctors, and an IT system should provide unambiguous identification of a patient. CONCLUSIONS: There is potential in using affinity analysis within e-Health. The example of affinity analysis described in his study led to the discovery of interesting and important (from the point of view of a medical facility) regularities regarding the knowledge and expectations of patients as regards e-Health.

Distribution of polymorphisms in the CYP2C19 and ABCB1 genes among patients with acute coronary syndrome in Lower Silesian population.

BACKGROUND: Dual antiplatelet therapy (DAPT) with aspirin and clopidogrel administered to treat patients with acute coronary syndrome (ACS) is still being used. However, despite the proven efficacy of this treatment regimen, thromboembolic complications have been observed in some individuals. The reason for this phenomenon is linked to the so-called increased responsiveness of platelets despite high platelet resistance (HPR). A significant role in HPR is attributed to genetically determined differences in the absorption and activation of clopidogrel. OBJECTIVES: The aim of the study was to assess the incidence of polymorphisms of the ABCB1 and CYPC19 genes that encode proteins involved in the absorption and metabolism of clopidogrel. MATERIAL AND METHODS: The analysis was performed in 199 consecutive patients from Lower Silesian voivodeship (Poland) who underwent coronary angioplasty with stenting for ACS. The single nucleotide polymorphism of the CYP2C19 and ABCB1 genes was performed using a mini sequencing or restriction fragment length polymorphism method. RESULTS: The results of this study revealed the high incidence of patients who may be unresponsive to antiplatelet treatment due to genetic causes. The CYPC19*2 allele in the form of homozygote or mutation heterozygote appeared in 26.1% of the study population. ABCB1 (C3435C> T) polymorphism was associated with 84% of patients. The total incidence of allelic disorders of low drug absorption and metabolism reached 14.6%. CONCLUSIONS: The data obtained should prompt clinicians to use more recent antiplatelet agents (ticagrelor or prasugrel) first, instead of clopidogrel.

Lipophilicity profiling of anthracycline antibiotics by microemulsion electrokinetic chromatography-effects on cardiotoxicity and endotheliotoxicity.

Accurate profiling of the lipophilicity of amphoteric compounds might be complex and laborious. In the present work the lipophilicity of 12 anthracycline antibiotics-four parent drugs: doxorubicin, daunorubicin, epidoxorubicin, and epidaunorubicin and eight novel formamidyne derivatives with attached morpholine, hexamethylenoimine or piperidine rings-was determined based on novel approach using MEEKC. In the second stage, lipophilicity was correlated with anthracycline toxicity towards two cell lines. In rat cardiomyoblast cell line (h9c2) a significant correlation between the logP and toxicity was found. The anthracycline lipophilicity was not correlated with toxicity towards the endothelial hybrid cell line (EAhy.926). In conclusion, the lipophilicity of anthracyclines seems to determine their toxicity towards cardiomyoblasts but not on endothelial cells, suggesting a different mechanism of anthracyclines intercellular transport or extrusion in cardiomyoblast and endothelial cells.

Impact of cell cycle dynamics on pathology recognition: Raman imaging study.

Confocal Raman imaging combined with fluorescence-activated cell sorting was used for in vitro studies of cell cultures to look at biochemical differences between the cells in different cell phases. To answer the question what is the impact of the cell cycle phase on discrimination of pathological cells, the combination of several factors was checked: a confluency of cell culture, the cell cycle dynamics and development of pathology. Confluency of 70% and 100% results in significant phenotypic cell changes that can be also diverse for different batches. In 100% confluency cultures, cells from various phases become phenotypically very similar and their recognition based on Raman spectra is not possible. For lower confluency, spectroscopic differences can be found between cell cycle phases (G0 /G1 , S and G2 /M) for control cells and cells incubated with tumor necrosis factor alpha (TNF-α), but when the mycotoxin cytochalasin B is used the Raman signatures of cell phases are not separable. Generally, this work shows that heterogeneity between control and inflamed cells can be bigger than heterogeneity between cell cycle phases, but it is related to several factors, and not always can be treated as a rule.

Dual antiplatelet therapy with clopidogrel and aspirin increases mortality in 4T1 metastatic breast cancer-bearing mice by inducing vascular mimicry in primary tumour.

Platelet inhibition has been considered an effective strategy for combating cancer metastasis and compromising disease malignancy although recent clinical data provided evidence that long-term platelet inhibition might increase incidence of cancer deaths in initially cancer-free patients. In the present study we demonstrated that dual anti-platelet therapy based on aspirin and clopidogrel (ASA+Cl), a routine regiment in cardiovascular patients, when given to cancer-bearing mice injected orthotopically with 4T1 breast cancer cells, promoted progression of the disease and reduced mice survival in association with induction of vascular mimicry (VM) in primary tumour. In contrast, treatment with ASA+Cl or platelet depletion did reduce pulmonary metastasis in mice, if 4T1 cells were injected intravenously. In conclusion, distinct platelet-dependent mechanisms inhibited by ASA+Cl treatment promoted cancer malignancy and VM in the presence of primary tumour and afforded protection against pulmonary metastasis in the absence of primary tumour. In view of our data, long-term inhibition of platelet function by dual anti-platelet therapy (ASA+Cl) might pose a hazard when applied to a patient with undiagnosed and untreated malignant cancer prone to undergo VM.

FT-IR Spectroscopic Imaging of Endothelial Cells Response to Tumor Necrosis Factor-α: To Follow Markers of Inflammation Using Standard and High-Magnification Resolution.

Two endothelial cell lines were selected as models to investigate an effect of incubation with cytokine tumor necrosis factor type α (TNF-α) using Fourier transform infrared (FT-IR) imaging spectroscopy. Both cell lines are often used in laboratories and are typical lung vascular endothelial cells (HMLVEC) derived from the fusion of umbilical vein endothelial cells with lung adenocarcinoma cells (EA.hy926). This study was focused on alteration of spectral changes accompanying inflammation at the cellular level by applying two resolution systems of FT-IR microscopy. The standard approach, with a pixel size of ca. 5.5 µm2, determined the inflammatory state of the whole cell, while a high-magnification resolution (pixel size of ca. 1.1 µm2) provided information at the subcellular level. Importantly, the analysis of IR spectra recorded with different modes produced similar results overall and yielded unambiguous classification of inflamed cells. Generally, the most significant changes in the cells under the influence of TNF-α are related with lipids-their composition and concentration; however, segregation of cells into subcellular compartments provided an additional insight into proteins and nucleic acids related events. The observed spectral alterations are specific for the type of endothelial cell line.

Characterization of Fluorescein-Based Monoboronate Probe and Its Application to the Detection of Peroxynitrite in Endothelial Cells Treated with Doxorubicin.

Boronate probes have emerged recently as a versatile tool for the detection of reactive oxygen and nitrogen species. Here, we present the characterization of a fluorescein-based monoboronate probe, a 4-(pinacol boronate)benzyl derivative of fluorescein methyl ester (FBBE), that proved to be useful to detect peroxynitrite in cell culture experiments. The reactivity of FBBE toward peroxynitrite as well hypochlorite, hydrogen peroxide, and tyrosyl hydroperoxide was determined. Second-order rate constants of the reactions of FBBE with peroxynitrite, HOCl, and H2O2 at pH 7.4 were equal to (2.8 ± 0.2) × 10(5) M(-1) s(-1), (8.6 ± 0.5) × 10(3) M(-1) s(-1), and (0.96 ± 0.03) M(-1) s(-1), respectively. The presence of glutathione completely blocked the oxidation of the probe by HOCl and significantly inhibited its oxidation by H2O2 and tyrosyl hydroperoxide but not by peroxynitrite. The oxidative conversion of the probe was also studied in the systems generating singlet oxygen, superoxide radical anion, and nitric oxide in the presence and absence of glutathione. Spectroscopic characterization of FBBE and its oxidation product has been also performed. The differences in the reactivity pattern were supported by DFT quantum mechanical calculations. Finally, the FBBE probe was used to study the oxidative stress in endothelial cells (Ea.hy926) incubated with doxorubicin, a quinone anthracycline antibiotic. In endothelial cells pretreated with doxorubicin, FBBE was oxidized, and this effect was reversed by PEG-SOD and L-NAME but not by catalase.

In vitro study of histamine and histamine receptor ligands influence on the adhesion of purified human eosinophils to endothelium.

It is a well-known fact that histamine is involved in eosinophil-dependent inflammatory responses including cellular chemotaxis and migration. Nevertheless, the relative role of histamine receptors in the mechanisms of eosinophils adhesion to endothelial cells is not known. Therefore the aim of presented study was to examine the effect of selective histamine receptors ligands on eosinophils adhesion to endothelium. For that purpose the highly purified human eosinophils have been isolated from the peripheral blood. The viability and functional integrity of isolated eosinophils have been validated in several tests. Histamine as well as 4-methylhistamine (selective H4 agonist) in concentration-dependent manner significantly increased number of eosinophils that adhere to endothelium. Among the selective histamine receptors antagonist or H1 inverse agonist only JNJ7777120 (histamine H4 antagonist) and thioperamide (dual histamine H3/H4 antagonist) had direct effect on eosinophils adhesion to endothelial cells. Antagonists of H1 (diphenhydramine, mepyramine) H2 (ranitidine and famotidine) and H3 (pitolisant) histamine receptors were ineffective. To the best of our knowledge, this is the first study to demonstrate that histamine receptor H4 plays a dominant role in histamine-induced eosinophils adhesion to endothelium.

Detrimental effects of chemotherapeutics and other drugs on the endothelium: A call for endothelial toxicity profiling.

The vascular endothelium is a real "maestro of circulation", and endothelial dysfunction leads to atherothrombosis, its cardiovascular complications, as well as to many other diseases. It is surprising that quite a large number of drugs seem to hamper the vasoprotective mechanisms of the endothelium, possibly promoting the development of cardiovascular diseases in patients initially treated for non-cardiological conditions. Toxicity profiling (including cardiac and liver toxicity assessment) is a routine procedure performed during pre-clinical drug development. Unfortunately, endothelium-dependent side effects are not taken into account in standard toxicity profiling protocols, as the "endothelial safety" of drugs is not required in order to enter the clinical phase of drug development. Presumably, this might be one of the reasons why several efficient therapeutics, including rofecoxib (COX-2 inhibitor), torcetrapib (CETP-inhibitor), and bardoxolone (Nrf2 activator), have unexpectedly displayed clinically significant cardiovascular hazard, resulting in their withdrawal from the market or alarming comments, respectively. In this review, we will briefly characterize the endothelial activity profiles of chemotherapeutics, antidepressants and antipsychotics-all drugs prescribed for severe, life-threatening and/or life-long diseases-and will show that at least some of them may display clinically relevant detrimental effects on endothelial function.

Differential involvement of IL-6 in the early and late phase of 1-methylnicotinamide (MNA) release in Concanavalin A-induced hepatitis.

Exogenous 1-methylnicotinamide (MNA) displays anti-inflammatory activity. The aim of this work was to characterize the profile of release of endogenous MNA during the initiation and progression of murine hepatitis induced by Concanavalin A (ConA). In particular we aimed to clarify the role of interleukin-6 (IL-6) as well as the energy state of hepatocytes in MNA release in early and late phases of ConA-induced hepatitis in mice. Hepatitis was induced by ConA in IL-6(+/+) and IL-6(-/-) mice, and various parameters of liver inflammation and injury, as well as the energy state of hepatocytes, were analysed in relation to MNA release. The decrease in ATP/ADP and NADH/NAD ratios, cytokine release (IL-6, IFN-ɤ), acute phase response (e.g. haptoglobin) and liver injury (alanine aminotransaminase, ALT) were all blunted in ConA-induced hepatitis in IL-6(-/-) mice as compared to IL-6(+/+) mice. The release of MNA in response to Con A was also significantly blunted in IL-6(-/-) mice as compared to IL-6(+/+) mice in the early stage of ConA-induced hepatitis. In turn, nicotinamide N-methyltransferase (NNMT) and aldehyde oxidase (AO) activities were blunted in the liver and MNA plasma concentration was elevated to similar degree in the late stage after Concanavalin A in IL-6(+/+) and IL-6(-/-) mice. In conclusion, we demonstrated that in ConA-induced hepatitis, early, but not late MNA release was IL-6-dependent. Our results suggest that in the initiation and early hepatitis, MNA release is linked to the energy deficit/impaired redox status in hepatocytes, while in a later phase, MNA release is rather linked to the systemic inflammation.

Rhodamine 6G conjugated to gold nanoparticles as labels for both SERS and fluorescence
studies on live endothelial cells.

Fluorescence and surface-enhanced Raman scattering (SERS) spectroscopy were employed to investigate the cellular uptake of rhodamine 6G (R6G) alone and of R6G loaded with gold nanoparticles (AuNPs) by endothelial cells. R6G plays the role of a Raman reporter in SERS but also displays strong fluorescence. The presence of bare R6G molecules and R6G-AuNPs in the cytoplasm of the cells is detected via the 2D fluorescence of the dye after a 0.5 h of the incubation with R6G and R6G-AuNPs, and then the concentration of the dye increases within 4 h of exposure. The examination of the cellular uptake of the R6G and R6G-AuNPs species at different temperatures suggests that the internalization of the R6G-AuNPs into endothelial cells occurs mainly via endocytosis. 3D fluorescence imaging of R6G inside cells reveals inhomogeneous distribution of the dye in the cytoplasm. The SERS signal of the Raman reporter inside the cell disappears after 2 h of incubation with R6G-AuNPs and then amino acid residues, purines and pyrimidines become SERS-active via their interactions with the gold. The results highlight the significance of using multiple techniques to cover a spectrum of issues in the application of SERS nanosensors for probing an intracellular environment under comparable and standardized conditions. FigureCellular uptake of bare rhodamine 6G and rhodamine 6G adsorbed onto AuNPs were studied on endothelial cells using fluorescence and surface-enhanced Raman spectroscopy. The internalization of R6G-AuNPs occurs via endocytosis and diffusion resulting in uneven distribution in the cytoplasm.