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High-density lipoprotein (HDL)-bound apolipoprotein M/sphingosine 1-phosphate (ApoM/S1P) complex in cardiovascular diseases serves as a bridge between HDL and endothelial cells, maintaining a healthy endothelial barrier. To date, S1P and ApoM in patients with untreated heterozygous familial hypercholesterolemia (HeFH) have not been extensively studied. Eighty-one untreated patients with HeFH and 32 healthy control subjects were included in this study. Serum S1P, ApoM, sCD40L, sICAM-1, sVCAM-1, oxLDL, and TNFα concentrations were determined by ELISA. PON1 activities were measured spectrophotometrically. Lipoprotein subfractions were detected by Lipoprint. We diagnosed FH using the Dutch Lipid Clinic Network criteria. Significantly higher serum S1P and ApoM levels were found in HeFH patients compared to controls. S1P negatively correlated with large HDL and positively with small HDL subfractions in HeFH patients and the whole study population. S1P showed significant positive correlations with sCD40L and MMP-9 levels and PON1 arylesterase activity, while we found significant negative correlation between sVCAM-1 and S1P in HeFH patients. A backward stepwise multiple regression analysis showed that the best predictors of serum S1P were large HDL subfraction and arylesterase activity. Higher S1P and ApoM levels and their correlations with HDL subfractions and inflammatory markers in HeFH patients implied their possible role in endothelial protection.

Pigment epithelium-derived factor (PEDF) is a serin protease inhibitor and a potent inhibitor of angiogenesis. Its serum level has significant associations with metabolic parameters. However, little is known about the association between PEDF levels and lipid parameters in renal transplanted (TX) patients. Therefore, our aim was to investigate the relationship between PEDF level and lipid parameters in TX patients.Seventy TX patients (47 males, 23 females, mean age 51.7 ± 12.4 years) and 34 healthy controls were enrolled. We examined the serum creatinine, C-reactive protein, fasting glucose and lipid parameters right before, then 1 and 6 months after TX. High-density lipoprotein (HDL)-associated paraoxonase-1 (PON1) activities were measured spectrophotometrically. Lipoprotein subfractions were determined by Lipoprint. PEDF and oxidized low-density liporotein (oxLDL) levels were measured by ELISA.Before transplantation, patients had had a significantly higher PEDF level compared to control subjects (PEDF may play an important role in the increased oxidative stress and enhanced atherogenesis in renal transplant patients.

Cardiovascular (CV) morbidity, mortality and metabolic syndrome are associated with rheumatoid arthritis (RA). A recent trial has suggested increased risk of major CV events (MACE) upon the Janus kinase (JAK) inhibitor tofacitinib compared with anti-tumor necrosis factor α (TNF-α) therapy. In our study, we evaluated lipids and other metabolic markers in relation to vascular function and clinical markers in RA patients undergoing one-year tofacitinib therapy.Thirty RA patients treated with either 5 mg or 10 mg bid tofacitinib were included in a 12-month follow-up study. Various lipids, paraoxonase (PON1), myeloperoxidase (MPO), thrombospondin-1 (TSP-1) and adipokine levels, such as adiponectin, leptin, resistin, adipsin and chemerin were determined. In order to assess flow-mediated vasodilation (FMD), common carotid intima-media thickness (IMT) and arterial pulse-wave velocity (PWV) ultrasonography were performed. Assessments were carried out at baseline, and 6 and 12 months after initiating treatment.One-year tofacitinib therapy significantly increased TC, HDL, LDL, APOA, APOB, leptin, adipsin and TSP-1, while significantly decreasing Lp(a), chemerin, PON1 and MPO levels. TG, lipid indices (TC/HDL and LDL/HDL), adiponectin and resistin showed no significant changes. Numerous associations were found between lipids, adipokines, clinical markers and IMT, FMD and PWV (JAK inhibition by tofacitinib exerts balanced effects on lipids and other metabolic markers in RA. Various correlations may exist between metabolic, clinical parameters and vascular pathophysiology during tofacitinib treatment. Complex assessment of lipids, metabolic factors together with clinical parameters and vascular pathophysiology may be utilized in clinical practice to determine and monitor the CV status of patients in relation with clinical response to JAK inhibition.

Familial hypercholesterolemia (FH) is the most common monogenic metabolic disorder characterized by considerably elevated low-density lipoprotein cholesterol (LDL-C) levels leading to enhanced atherogenesis, early cardiovascular disease (CVD), and premature death. However, the wide phenotypic heterogeneity in FH makes the cardiovascular risk prediction challenging in clinical practice to determine optimal therapeutic strategy. Beyond the lifetime LDL-C vascular accumulation, other genetic and non-genetic risk factors might exacerbate CVD development. Besides the most frequent variants of three genes (

The prevalence of hypertriglyceridemia has been increasing worldwide. Attention is drawn to the fact that the frequency of a special hypertriglyceridemia entity, named chylomicronemia syndrome, is variable among its different forms. The monogenic form, termed familial chylomicronemia syndrome, is rare, occuring in 1 in every 1 million persons. On the other hand, the prevalence of the polygenic form of chylomicronemia syndrome is around 1:600. On the basis of the genetical alterations, other factors, such as obesity, alcohol consumption, uncontrolled diabetes mellitus and certain drugs may significantly contribute to the development of the multifactorial form. In this review, we aimed to highlight the recent findings about the clinical and laboratory features, differential diagnosis, as well as the epidemiology of the monogenic and polygenic forms of chylomicronemias. Regarding the therapy, differentiation between the two types of the chylomicronemia syndrome is essential, as well. Thus, proper treatment options of chylomicronemia and hypertriglyceridemia will be also summarized, emphasizing the newest therapeutic approaches, as novel agents may offer solution for the effective treatment of these conditions.

Background: Cardiovascular (CV) morbidity, mortality, and metabolic syndrome are associated with rheumatoid arthritis (RA) and ankylosing spondylitis (AS). Here, lipids and other metabolic markers in relation to vascular function and clinical markers were evaluated in RA and AS patients undergoing one-year anti-TNF therapy. Patients and methods: Fifty-three patients including 36 RA patients treated with either etanercept (ETN) or certolizumab pegol (CZP) and 17 AS patients treated with ETN were included in a 12-month follow-up study. Various lipids, paraoxonase (PON) and arylesterase (ARE) activities, myeloperoxidase (MPO) and adipokine levels were determined overtime. Ultrasonography was performed to determine flow-mediated vasodilation (FMD), common carotid intima-media thickness (ccIMT), and arterial pulse-wave velocity (PWV) in all patients. All assessments were performed at baseline and 6 and 12 months after treatment initiation. Results: Anti-TNF therapy decreased ARE activity, MPO, adiponectin, and chemerin levels after 12 months (p &lt, 0.05). Lipids, PON activity, and leptin remained unchanged. Regression analyses suggested variable associations of IMT, PWV, and FMD with ARE, MPO, leptin, and lipids (p &lt, 0.05). On the other hand, these metabolic parameters were significantly associated with disease duration, CV history, CRP, obesity, PWV, and IMT (p &lt, 0.05). One-year anti-TNF treatment together with baseline leptin (p = 0.039) or CRP (p = 0.016) levels determined 12 months of lipid changes overtime. TNF inhibition together with baseline disease activity determined ARE activity changes (p = 0.046). Anti-TNF therapy and baseline chemerin levels determined IMT changes overtime (p = 0.003). Conclusions: Assessment of various metabolic parameters together with disease activity, CRP, and ultrasound-based techniques may exert additional value in determining CV burden and in monitoring the effects of biologics on preclinical vascular pathophysiology.

Inflammation is a marker of arterial disease stemming from cholesterol-dependent to -independent molecular mechanisms. In recent years, the role of inflammation in atherogenesis has been underpinned by pharmacological approaches targeting systemic inflammation that have led to a significant reduction in cardiovascular disease (CVD) risk. Although the use of nutraceuticals to prevent CVD has largely focused on lipid-lowering (e.g, red-yeast rice and omega-3 fatty acids), there is growing interest and need, especially now in the time of coronavirus pandemic, in the use of nutraceuticals to reduce inflammatory markers, and potentially the inflammatory CVD burden, however, there is still not enough evidence to confirm this. Indeed, diet is an important lifestyle determinant of health and can influence both systemic and vascular inflammation, to varying extents, according to the individual nutraceutical constituents. Thus, the aim of this Position Paper is to provide the first attempt at recommendations on the use of nutraceuticals with effective anti-inflammatory properties.

Objectives Progranulin (PGRN) is a secreted growth factor that helps to regulate neuronal survival by blocking tumor necrosis factor-alpha (TNFα) receptors. The antioxidant alpha-lipoic acid (ALA) is used in diabetic neuropathy to improve nerve conduction and relieve neuropathic pain, but its effects on PGRN levels have not yet been elucidated. Methods In this prospective study, 54 patients with type 2 diabetes and peripheral neuropathy received 600 mg of ALA daily for 6 months. Twenty-four patients with diabetes without neuropathy were also included in the study. Serum PGRN and TNFα levels were determined using enzyme-linked immunosorbent assays. In addition, current perception threshold (CPT) testing was used to assess sensory neuropathy. Results After ALA treatment, serum PGRN levels were significantly increased and CPT values were significantly improved. Furthermore, there were significant positive correlations among TNFα, ICAM-1, and PGRN levels both before and after ALA treatment. A significant negative correlation was observed between the improvements in CPT and the PGRN levels. Furthermore, ICAM-1 levels were an independent predictor of PGRN levels. Conclusions Changes in serum PGRN levels indicate that ALA treatment may have beneficial effects on endothelial function and neuronal inflammation.

This study was designed to characterize the spatial distribution of metformin medication used as first-line monotherapy for prevention of T2DM in relationship with the socioeconomic status (level of deprivation) and T2DM mortality at district level in a nationwide cross-sectional ecological study for the first time in a European country, Hungary. Risk analysis was used to estimate the relationships between socioeconomic status, characterized by tertiles of deprivation index, and mortality caused by diabetes, and metformin medication (both prescription and redemption) for the years of 2018 and 2019 at the district level. The spatial distribution of districts with a higher relative frequency of metformin prescriptions and redemptions showed a positive correlation with socio-economic deprivation. Significant association between the relatively high T2DM mortality and the highest level of deprivation could also be detected, but less-deprived regions with high T2DM mortality and low metformin utilization could also be identified. Although the statistical associations detected in this ecological study do not indicate a causal relationship, it is reasonable to suppose that the underuse of metformin medication may contribute to the unfavourable T2DM mortality in certain regions. Our findings underline the need for more effective preventive services including metformin medication to decrease T2DM morbidity and mortality burden.

Background The European Atherosclerosis Society Familial Hypercholesterolaemia Studies Collaboration (FHSC) global registry provides a platform for the global surveillance of familial hypercholesterolaemia through harmonisation and pooling of multinational data. In this study, we aimed to characterise the adult population with heterozygous familial hypercholesterolaemia and described how it is detected and managed globally. Methods Using FHSC global registry data, we did a cross-sectional assessment of adults (aged 18 years or older) with a clinical or genetic diagnosis of probable or definite heterozygous familial hypercholesterolaemia at the time they were entered into the registries. Data were assessed overall and by WHO regions, sex, and index versus non-index cases. Findings Of the 61 612 individuals in the registry, 42 167 adults (21 999 [53.6%] women) from 56 countries were included in the study. Of these, 31 798 (75.4%) were diagnosed with the Dutch Lipid Clinic Network criteria, and 35 490 (84.2%) were from the WHO region of Europe. Median age of participants at entry in the registry was 46.2 years (IQR 34.3-58.0); median age at diagnosis of familial hypercholesterolaemia was 44.4 years (32.5-56.5), with 40.2% of participants younger than 40 years when diagnosed. Prevalence of cardiovascular risk factors increased progressively with age and varied by WHO region. Prevalence of coronary disease was 17.4% (2.1% for stroke and 5.2% for peripheral artery disease), increasing with concentrations of untreated LDL cholesterol, and was about two times lower in women than in men. Among patients receiving lipid-lowering medications, 16 803 (81.1%) were receiving statins and 3691 (21.2%) were on combination therapy, with greater use of more potent lipid-lowering medication in men than in women. Median LDL cholesterol was 5.43 mmol/L (IQR 4.32-6.72) among patients not taking lipid-lowering medications and 4.23 mmol/L (3.20-5.66) among those taking them. Among patients taking lipid-lowering medications, 2.7% had LDL cholesterol lower than 1.8 mmol/L; the use of combination therapy, particularly with three drugs and with proprotein convertase subtilisin-kexin type 9 inhibitors, was associated with a higher proportion and greater odds of having LDL cholesterol lower than 1.8 mmol/L. Compared with index cases, patients who were non-index cases were younger, with lower LDL cholesterol and lower prevalence of cardiovascular risk factors and cardiovascular diseases (all p, Pfizer Independent Grant for Learning Change [16157823]; Amgen; Merck Sharp Dohme; Sanofi-Aventis; Daiichi Sankyo; Regeneron; National Institute for Health Research (NIHR) Imperial Biomedical Research Centre, UK; NIHR; Czech Ministry of Health [NU20-02-00261]; Canadian Institutes of Health Research; Austrian Heart Foundation; Tyrolean Regional Government; Gulf Heart Association, The EAS FHSC is an academic initiative that has received funding from a Pfizer Independent Grant for Learning & Change 2014 (16157823) and from investigator-initiated research grants to the European Atherosclerosis Society-Imperial College London from Amgen, Merck Sharp & Dohme, Sanofi-Aventis, Daiichi Sankyo, and Regeneron. KKR acknowledges support from the National Institute for Health Research (NIHR) Imperial Biomedical Research Centre, UK. KID acknowledges support from a PhD Studentship from NIHR under the Applied Health Research programme for Northwest London, UK (the views expressed in this publication are those of the authors and not necessarily those of the National Health Service, the NIHR, or the Department of Health). TF was supported by a grant from the Czech Ministry of Health (NU20-02-00261). JG receives support from the Canadian Institutes of Health Research. The Austrian Familial Hypercholesterolaemia registry has been supported by funds from the Austrian Heart Foundation and the Tyrolean Regional Government. The Gulf Familial Hypercholesterolaemia registry was done under the auspices of the Gulf Heart Association.

The high incidence of skin cancers in the Caucasian population is primarily due to the accumulation of DNA damage in epidermal cells induced by chronic ultraviolet B (UVB) exposure. UVB-induced DNA photolesions, including cyclobutane–pyrimidine dimers (CPDs), promote mutations in skin cancer driver genes. In humans, CPDs are repaired by nucleotide excision repair (NER). Several commonly used and investigational medications negatively influence NER in experimental systems. Despite these molecules’ ability to decrease NER activity in vitro, the role of these drugs in enhancing skin cancer risk is unclear. In this study, we investigated four molecules (veliparib, resveratrol, spironolactone, and arsenic trioxide) with well-known NER-inhibitory potential in vitro, using UVB-irradiated CHO epithelial and HaCaT immortalized keratinocyte cell lines. Relative CPD levels, hypoxanthine phosphoribosyltransferase gene mutation frequency, cell viability, cell cycle progression, and protein expression were assessed. All four molecules significantly elevated CPD levels in the genome 24 h after UVB irradiation. However, veliparib, spironolactone, and arsenic trioxide reduced the mutagenic potential of UVB, while resveratrol did not alter UVB-induced mutation formation. UVB-induced apoptosis was enhanced by spironolactone and arsenic-trioxide treatment, while veliparib caused significantly prolonged cell cycle arrest and increased autophagy. Spironolactone also enhanced the phosphorylation level of mammalian target of rapamycin (mTOR), while arsenic trioxide modified UVB-driven mitochondrial fission. Resveratrol induced only mild changes in the cellular UVB response. Our results show that chemically inhibited NER does not result in increased mutagenic effects. Furthermore, the UVB-induced mutagenic potential can be paradoxically mitigated by NER-inhibitor molecules. We identified molecular changes in the cellular UVB response after NER-inhibitor treatment, which may compensate for the mitigated DNA repair. Our findings show that metabolic cellular response pathways are essential to consider in evaluating the skin cancer risk–modifying effects of pharmacological compounds.

Ultraviolet B radiation (UVB) is an environmental complete carcinogen, which induces and promotes keratinocyte carcinomas, the most common human malignancies. UVB induces the formation of cyclobutane pyrimidine dimers (CPDs). Repairing CPDs through nucleotide excision repair is slow and error-prone in placental mammals. In addition to the mutagenic and malignancy-inducing effects, UVB also elicits poorly understood complex metabolic changes in keratinocytes, possibly through CPDs. To determine the effects of CPDs, CPD-photolyase was overexpressed in keratinocytes using an N1-methyl pseudouridine-containing in vitro-transcribed mRNA. CPD-photolyase, which is normally not present in placental mammals, can efficiently and rapidly repair CPDs to block signaling pathways elicited by CPDs. Keratinocytes surviving UVB irradiation turn hypermetabolic. We show that CPD-evoked mitochondrial reactive oxygen species production, followed by the activation of several energy sensor enzymes, including sirtuins, AMPK, mTORC1, mTORC2, p53, and ATM, is responsible for the compensatory metabolic adaptations in keratinocytes surviving UVB irradiation. Compensatory metabolic changes consist of enhanced glycolytic flux, Szent-Györgyi-Krebs cycle, and terminal oxidation. Furthermore, mitochondrial fusion, mitochondrial biogenesis, and lipophagy characterize compensatory hypermetabolism in UVB-exposed keratinocytes. These properties not only support the survival of keratinocytes, but also contribute to UVB-induced differentiation of keratinocytes. Our results indicate that CPD-dependent signaling acutely maintains skin integrity by supporting cellular energy metabolism., Graphical abstract Image 1

Összefoglaló. A székletmikrobiota-transzplantáció (faecalismikrobiota-transzplantáció - FMT) a Clostridioides difficile fertőzés (CDI) kezelésében nemzetközileg széles körben elfogadott, megfelelő szakmai háttér mellett végezve biztonságos, potenciálisan életmentő, költséghatékony, valamint a hospitalizációs idő és az orvos-beteg találkozások jelentős redukálására képes eljárás. Az FMT elvégzésére egyes országokban magas szintű minőségirányítási háttérrel működő, célfeladatra szerveződött donor- és székletbankok rendezkedtek be. Máshol, így például hazánkban, az eljáráshoz az egyértelmű jogi szabályozási környezet, a standardizált technológiai háttér és a finanszírozás hiánya miatt nem egységes a hozzáférés. Régóta időszerű továbbá, hogy a heterogén, nemegyszer háztartási eszközökkel előkészített beavatkozások helyett a nemzetközi és legújabban már a hazai ajánlásokban is megfogalmazott, a betegbiztonságot legjobban garantáló elvárások mellett történjen a széklettranszplantáció. Az új koronavírus (SARS-CoV-2) okozta pandémia megjelenése erőteljes szakmai érv országos szinten az FMT minőségirányítási környezetének és technológiai hátterének újragondolására, mert a SARS-CoV-2 egyszerre jelent kockázatot a CDI miatt kórházban kezelt sérülékeny betegpopulációnak, és egyben veszélyezteti az FMT biztonságosságát mind a recipiens, mind pedig az eljárást végző egészségügyi személyzet tekintetében. Ezekre a szakmai és társadalmi kihívásokra reagálva, a széles körű beteghozzáférés és a legmagasabb szintű betegbiztonság garantálására, a Debreceni Egyetemen új eljárásrendet dolgoztunk ki az FMT végzésére. Ezen eljárásrendnek a COVID-19-pandémia miatt módosított, a fagyasztottgraftbank üzemeltetése és a rendszerszemlélet tekintetében releváns elemeit ismertetjük. Javasolt, hogy országos szinten hasonló, megfelelő minőségirányítási és technológiai környezettel, a SARS-CoV-2-fertőzés kizárását is integráló donorszűrési rendszerrel, továbbá fagyasztottgraft-banki háttérrel működő laboratóriumok vegyenek részt a széklettranszplantációk végzésében. Felmerül továbbá, hogy az eljárást a számos analógia és a donor-recipiens koncepció alapján a sejt- és szövettranszplantációkra vonatkozó szabályozórendszer keretei közé ajánlott beágyazni. Orv Hetil. 2020; 161(44): 1858-1871. Summary. Stool transplantation (faecal microbiota transplantation - FMT) is a widely accepted, potentially life-saving, cost-effective medical intervention for the treatment of Clostridioides difficile infection (CDI), which has an acceptable safety profile if performed with an appropriate professional background. FMT can significantly reduce hospitalization time and the number of patient visits. National donor and stool banks with high-standard quality management systems were established in certain countries for supporting the procedures. In other regions, including Hungary, patient access is not uniform due to the lack of clear legal regulations, standardized technology or financial reimbursement. It has been expected for a long time to replace the heterogenous techniques, occasionally utilizing household equipment with a technology providing improved patient safety and fulfilling international and recently published local FMT guidelines. The emergence of the novel coronavirus (SARS-CoV-2) pandemic is a very powerful argument in favour of urgently reconsidering the quality management and technological background of FMT procedures. SARS-CoV-2 is a major threat to the vulnerable patients suffering from CDI and also impose risks for the recipient and healthcare personnel involved in carrying out the transplantation. New FMT guidelines were implemented at the University of Debrecen to address these professional and public challenges, to provide wide patient access and to guarantee the highest achievable patient safety. Relevant elements of this new protocol are presented, focusing on a systemic quality management approach, on the operation of a frozen stool bank and on a modified donor screening algorithm taking the risks of COVID-19 into consideration. We suggest that laboratories with proper quality assurance and technological conditions, implementing SARS-CoV-2 donor screening and operating a frozen graft bank should participate in faecal microbiota transplantations. It is also recommended that, based on the analogies and the similar donor-recipient concept, FMT should be embedded under the organ tissue and cell transplantation polices in Hungary. Orv Hetil. 2020; 161(44): 1858-1871.

Data mainly from one-off surveys clearly show that the health of Roma, the largest ethnic minority of Europe, is much worse than that of the general population. However, results from comprehensive exploratory studies are missing. The aim of our study was to create a complex database for comparative and association studies to better understand the background of the very unfavourable health of Roma, especially the high burden of cardiometabolic diseases. A three-pillar (questionnaire-based, physical and laboratory examinations) health survey was carried out on randomly selected samples of the Hungarian general (HG, n = 417) and Roma (HR, n = 415) populations, and a database consisting of more than half a million datapoints was created. Using selected data, the prevalence rates of metabolic syndrome (MetS) and of its components were determined, and to estimate the risk of insulin resistance (IR), surrogate measures (the homeostasis model assessment of insulin resistance index, quantitative insulin sensitivity check index, McAuley and TyG indices and the TG/HDL-C ratio) were calculated. Receiver operating characteristic curve analysis and Youden’s method were used to define the optimal cut-off values of each IR index. The prevalence of MetS was very high in both study populations (HG: 39.8%, HR: 44.0%) with no statistically significant difference between the two groups in females or males. The prevalence of MetS showed a very marked increase in the HR 35–49 years age group. Among surrogate measures, the TyG index showed the greatest power for predicting IR/MetS at a cut-off value of 4.69 (77% sensitivity, 84% specificity) and indicated a 42.3% (HG) and 40.5% (HR) prevalence of IR. The prevalence of MetS and IR is almost equally very unfavourable in both groups; thus, the factors underlying the high premature mortality burden of Roma should be further clarified by investigating the full spectrum of risk factors available in the database, with a special focus on the access of Roma people to preventive and curative health services.

The prevalence of diabetes mellitus is significantly increasing worldwide. Distal sensorimotor neuropathy (DSPN) is the most common and the earliest detectable microvascular complication. Due to its diverse clinical appearance and atypical symptoms, DSPN is often recognized in an advanced stage.In our study, the data of 431 patients who were examined using the Neurometer® between 2011 and 2018 at the Diabetic Neuropathy Center of the University of Debrecen were processed and the correlations between cardiovascular and microvascular complications, laboratory parameters and the severity of DSPN were investigated.The average age of patients was 63.4 years, 62% of them were women, and 92% had type 2 diabetes mellitus. The average duration of diabetes was 13.7 years. Cardiovascular disease (CVD) was diagnosed in 42% of the patients. The incidence of retinopathy was 12%, persistent microalbuminuria was 16%. Despite DSNP complaints, neuronal damage could not be detected in 19%; in the examined patients 49% had mild, 19% moderate and 13% severe neuropathy. Diabetes-related neurological damage was more serious in the presence of both diabetic retinopathy (p0.001) and microalbuminuria (p0.001). The incidence of these microvascular complications and the severity of DSPN showed a significant positive correlation (p0.001). There was no correlation between the severity of peripheral neuropathy and the development of CVD, and we did not find any correlations between the severity of DSPN and CVD.Based on our investigation, correlation between the progression of diabetic neuropathy and cardiovascular complications was not found, although the progression of diabetic neuropathy indicated the development of other microvascular diseases. Peripheral neurological examination using the Neurometer® is appropriate for controlling the DSPN status and the establishment of the severity of neuropathy determines the quality of life in diabetic patients. Among these patients, the risk of CVD can be assessed by Ewing's test for autonomic nervous system function. Orv Hetil. 2020; 161(30): 1243-1251.

Intraventricular hemorrhage (IVH) is a frequent complication of prematurity that is associated with high neonatal mortality and morbidity. IVH is accompanied by red blood cell (RBC) lysis, hemoglobin (Hb) oxidation, and sterile inflammation. Here we investigated whether extracellular Hb, metHb, ferrylHb, and heme contribute to the inflammatory response after IVH. We collected cerebrospinal fluid (CSF) (n = 20) from premature infants with grade III IVH at different time points after the onset of IVH. Levels of Hb, metHb, total heme, and free heme were the highest in CSF samples obtained between days 0 and 20 after the onset of IVH and were mostly non-detectable in CSF collected between days 41 and 60 of post-IVH. Besides Hb monomers, we detected cross-linked Hb dimers and tetramers in post-IVH CSF samples obtained in days 0–20 and 21–40, but only Hb tetramers were present in CSF samples obtained after 41–60 days. Vascular cell adhesion molecule-1 (VCAM-1) and interleukin-8 (IL-8) levels were higher in CSF samples obtained between days 0 and 20 than in CSF collected between days 41 and 60 of post-IVH. Concentrations of VCAM-1, intercellular adhesion molecule-1 (ICAM-1), and IL-8 strongly correlated with total heme levels in CSF. Applying the identified heme sources on human brain microvascular endothelial cells revealed that Hb oxidation products and free heme contribute to the inflammatory response. We concluded that RBC lysis, Hb oxidation, and heme release are important components of the inflammatory response in IVH. Pharmacological interventions targeting cell-free Hb, Hb oxidation products, and free heme could have potential to limit the neuroinflammatory response following IVH.

Specific patterns of DNA mutations in normal skin show history of UV exposure and association with cancer risk., In ultraviolet (UV) radiation–exposed skin, mutations fuel clonal cell growth. The relationship between UV exposure and the accumulation of clonal mutations (CMs) and the correlation between CMs and skin cancer risk are largely unexplored. We characterized 450 individual-matched sun-exposed (SE) and non-SE (NE) normal human skin samples. The number and relative contribution of CMs were significantly different between SE and NE areas. Furthermore, we identified hotspots in TP53, NOTCH1, and GRM3 where mutations were significantly associated with UV exposure. In the normal skin from patients with cutaneous squamous cell carcinoma, we found that the cancer burden was associated with the UV-induced mutations, with the difference mostly conferred by the low-frequency CMs. These findings provide previously unknown information on UV’s carcinogenic effect and pave the road for future development of quantitative assessment of subclinical UV damage and skin cancer risk.

Hemolytic diseases are characterized by an accelerated breakdown of red blood cells (RBCs) and the release of hemoglobin (Hb). Following, RBC lysis Hb oxidation occurs with the formation of different redox states of Hb (metHb and ferrylHb) and the release of heme. ferrylHb is unstable and decomposes to metHb with the concomitant formation of globin radicals and eventually covalently crosslinked Hb multimers. The goal of the present study was to determine the concentrations of the different redox states of Hb in biological samples during hemolytic conditions. We used plasma and urine samples of mice with intravascular hemolysis and human cerebrospinal fluid (CSF) samples following intraventricular hemorrhage. Because ferrylHb is highly unstable, we also addressed the fate of this species. metHb and free heme time-dependently accumulate in plasma and CSF samples following intravascular hemolysis and intraventricular hemorrhage, respectively. ferrylHb is hardly detectable in the biological samples during hemolytic conditions. Under in vitro conditions, ferrylHb decomposes quickly to metHb, which process is associated with the formation of covalently crosslinked Hb multimers. We detected these covalently crosslinked Hb multimers in plasma, urine, and CSF samples during hemolytic conditions. Because globin modification is specific for these Hb forms, we propose to call this heterogeneous form of Hb produced during ferrylHb decomposition as globin-modified oxidized Hb (gmoxHb). Understanding the formation and the contribution of gmoxHb species to the pathogenesis of hemolytic conditions could have therapeutic implications in the treatment of hemolytic diseases.

Acute and chronic physical exercises may enhance the development of statin-related myopathy. In this context, the recent (2019) guidelines of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS) for the management of dyslipidemias recommend that, although individuals with dyslipidemia should be advised to engage in regular moderate physical exercise (for at least 30 min daily), physicians should be alerted with regard to myopathy and creatine kinase (CK) elevation in statin-treated sport athletes. However it is worth emphasizing that abovementioned guidelines, previous and recent ESC/EAS consensus papers on adverse effects of statin therapy as well as other previous attempts on this issue, including the ones from the International Lipid Expert Panel (ILEP), give only general recommendations on how to manage patients requiring statin therapy on regular exercises. Therefore, these guidelines in the form of the Position Paper are the first such an attempt to summary existing, often scarce knowledge, and to present this important issue in the form of step-by-step practical recommendations. It is critically important as we might observe more and more individuals on regular exercises/athletes requiring statin therapy due to their cardiovascular risk.

Background The role of sun exposure in the development of melanoma and nonmelanoma skin cancers is known; however, there are limited data on the contribution of pretransplantation total sun burden (TSB) to the increased skin cancer risk in organ transplant recipients (OTRs). The importance of patient education about sun-safe behaviors is understood, but educations are often unsuccessful in OTRs. Methods A questionnaire-based cross-sectional study was performed with kidney transplant patients at a single academic center to assess the pre- and post-transplant sun exposure, sun protection habits, and skin cancers. Results Two hundred and twenty-one patients participated in the study. 13.1% developed at least one skin cancer. High total sun burden before transplantation was reported by 58.4%, and 65.2% reported education about increased skin cancer risk at the time of transplantation. However, that education did not lead to less sun exposure or better sun protection methods after transplantation. Overall, OTR related but not sun protection-guided lifestyle changes affecting OTRs after transplantation led to reduction in sun exposure. Conclusion Our findings highlight the need for more tailored, population-specific education programmes, even for patients who expect to receive a transplant in the future, and suggest the importance of pretransplantation TSB in determining the post-transplant skin cancer risk.

Background Obestatin is a ghrelin-associated peptide, derived from preproghrelin. Although many of its effects are unclear, accumulating evidence supports positive actions on both metabolism and cardiovascular function. To date, level of obestatin and its correlations to the lipid subfractions in non-diabetic obese (NDO) patients have not been investigated. Methods Fifty NDO patients (BMI: 41.96 ± 8.6 kg/m2) and thirty-two normal-weight, age- and gender-matched healthy controls (BMI: 24.16 ± 3.3 kg/m2) were enrolled into our study. Obestatin level was measured by ELISA. Low-density lipoprotein (LDL) and high-density lipoprotein (HDL) subfractions, intermediate density lipoprotein (IDL) and very low-density lipoprotein (VLDL) levels and mean LDL size were detected by nongradient polyacrylamide gel electrophoresis (Lipoprint). Results Serum level of obestatin was significantly lower in NDO patients compared to controls (3.01 ± 0.5 vs. 3.29 ± 0.6 μg/ml, p

Background: Advances in single-cell sequencing provide unprecedented opportunities for clinical examination of circulating tumor cells, cancer stem cells, and other rare cells responsible for disease progression and drug resistance. On the genomic level, single-cell whole exome sequencing (scWES) started to gain popularity with its unique potentials in characterizing mutational landscapes at a single-cell level. Currently, there is little known about the performance of different exome capture kits in scWES. Nextera rapid capture (NXT; Illumina, Inc.) has been the only exome capture kit recommended for scWES by Fluidigm C1, a widely accessed system in single-cell preparation. Results: In this study, we compared the performance of NXT following Fluidigm’s protocol with Agilent SureSelectXT Target Enrichment System (AGL), another exome capture kit widely used for bulk sequencing. We created DNA libraries of 192 single cells isolated from spheres grown from a melanoma specimen using Fluidigm C1. Twelve high-yield cells were selected to perform dual-exome capture and sequencing using AGL and NXT in parallel. After mapping and coverage analysis, AGL outperformed NXT in coverage uniformity, mapping rates of reads, exome capture rates, and low PCR duplicate rates. For germline variant calling, AGL achieved better performance in overlap with known variants in dbSNP and transition-transversion ratios. Using calls from high coverage bulk sequencing from blood DNA as the golden standard, AGL-based scWES demonstrated high positive predictive values, and medium to high sensitivity. Lastly, we evaluated somatic mutation calling by comparing single-cell data with the matched blood sequence as control. On average, 300 mutations were identified in each cell. In 10 of 12 cells, higher numbers of mutations were identified using AGL than NXT, probably caused by coverage depth. When mutations are adequately covered in both AGL and NXT data, the two methods showed very high concordance (93–100% per cell). Conclusions: Our results suggest that AGL can also be used for scWES when there is sufficient DNA, and it yields better data quality than the current Fluidigm’s protocol using NXT.

Opposite lineage-specific regulation of tumor progression by the same transcription factor is an understudied phenomenon. Here, we report that levels of a carcinoma oncogenic transcription factor FOXQ1 are decreased during melanoma progression. Moreover, in melanoma cells, FOXQ1 suppresses the same processes it activates in carcinoma cells: epithelial-to-mesenchymal transition, invasion, and metastasis. We identify that lineage-specific tumor suppressor or oncogenic functions of FOXQ1 in large part depend on its ability to repress or activate expression of the same gene (N-cadherin, (CDH2)) in melanoma or carcinoma cells, respectively. Mechanistically, we demonstrate that FOXQ1 interacts with nuclear β-catenin and TLE proteins, and that repression of CDH2 by FOXQ1 occurs in the presence of TLE and absence of nuclear β-catenin, levels of which are lower in human melanomas than carcinomas. Accordingly, FOXQ1-dependent phenotypes can be manipulated by altering nuclear β-catenin or TLE proteins levels. Our data identify a novel melanoma suppressor and establish a unique mechanism underlying inverse lineage-specific transcriptional regulation of transformed phenotypes.

Abstract. Background: In hyperlipidaemic state, increased levels of myeloperoxidase (MPO) and decreased paraoxonase-1 (PON1) activity have been reported; however, their relationships with other atherosclerotic biomarkers have not been completely clarified. Patients and methods: Serum concentrations of lipid and inflammatory parameters, MPO levels, and PON1 activities were investigated in 167 untreated hyperlipidaemic patients with and without vascular complications and in 32 healthy controls. Additionally, levels of CD40 ligand (sCD40L) and asymmetric dimethyl arginine (ADMA), soluble intercellular adhesion molecule-1 (sICAM-1), soluble vascular cell adhesion molecule-1, and oxidized LDL were determined. Results: We found elevated C-reactive protein (CRP), ADMA, sCD40L, sICAM-1 concentrations, and higher MPO levels in patients with vascular complications compared to those without. The PON1 arylesterase activity correlated negatively with sCD40L, ADMA, and sICAM-1 levels, respectively. In contrast, MPO concentrations showed positive correlations with sCD40L, ADMA, and sICAM-1 levels, respectively. Conclusions: It can therefore be stated that PON1 activity and MPO level correlate strongly with the vascular biomarkers, highlighting the importance of the HDL-associated pro- and antioxidant enzymes in the development of endothelial dysfunction and atherogenesis.

Uvod: I přes velký pokrok v nedavne době je familiarni hypercholesterolemie (FH) stale jestě celosvětově podceňovane, nedostatecně diagnostikovane, a tedy i nedostatecně lecene onemocněni. O přesne prevalenci pacientů postižených familiarni hypercholesterolemii v regionu středni, východni a jižni Evropy (CESE) mame jen velmi malo informaci. Cilem studie bylo popsat na zakladě dostupných udajů epidemiologickou situaci v regionu CESE. Metody: Vsichni vedouci představitele projektu ScreenPro FH v jednotlivých oblastech byli požadani o poskytnuti lokalnich udajů, ktere se týkaji (a) expertniho odhadu prevalence FH, (b) již fungujicich zdravotnických zařizeni, (c) použitých diagnostických kriterii, (d) poctu pacientů již zavedených v mistni databazi a konecně (e) dostupnosti možnosti lecby (zejmena plazmaferezy). Výsledky: Vzhledem k odhadovane prevalenci FH přibližně 1 : 500 odhadujeme, že celkova populace FH heterozygotů v regionu CESE zahrnuje 588 363 osob. V mistnich databazich se vsak zobrazilo pouze 14 108 osob (2,4 %), přicemž mira zobrazeni se lisila v rozmezi od 0,1 % až 31,6 %. Pouze 4 země oznamily dostupnost LDL aferezy. Zavěr: Nase udaje svědci o velke populaci pacientů postižených heterozygotni formou FH v regionu CESE a zaroveň o nizkých podilech jejich zobrazeni. V ramci projektu ScreenPro FH jsou vsak nyni vytvařeny potřebne struktury a můžeme tak doufat v dosaženi přiznivějsich výsledků.

To evaluate the ability of two-step irradiance to maintain pain control during red light 5-aminolevulinic acid (ALA) photodynamic therapy (PDT) for actinic keratoses (AK) and assess factors influencing pain.PDT provides excellent clinical and cosmetic results in the treatment AK and early basal cell carcinomas (BCC). Widespread use of PDT is limited, in part, by pain. A two-step irradiance method for PDT has previously been shown to significantly reduce PDT-associated pain during the treatment of BCC, but the ability of this method to limit pain during the treatment of AKs has not been reported.We performed a retrospective chart review to assess the level of pain during AK treatment by red light PDT (n = 99). Natural density filter was used to reduce the irradiance of the light source and initially 10 J/cmPain was low to moderate in most patients (mean ± standard error of the mean pain score: 2.35 ± 0.19). Higher pain was seen midprocedure versus at the beginning (p 0.0001) and at the end (p = 0.003) of PDT. There was no significant difference in pain perception between genders and different treatment areas.Our results provide evidence that red light ALA PDT of AKs is very well tolerated with the two-step irradiance protocol.

Visual examination plays a central role in the diagnosis of skin diseases. Many dermatologists use magnification, or dermoscopy, to improve diagnostic certainty when assessing the skin under visible light. In addition to magnification, other technological advances have been made over the last century to improve our visual assessment of the skin. Examination of skin under ultraviolet (UV) radiation, with Wood's light, gained traction for its utility in assessing superficial cutaneous infections and pigmentary changes. During Wood's light examination, UV light is directed at the skin and fluorescence is detected by our eyes. The variable fluorescent characteristics of endogenous and exogenous cutaneous chromophores help us better diagnose skin disease. UV fluorescent photography is based on the same concept as the Wood's light, but also allows image analysis and documentation of the captured image. In addition to UV-induced fluorescence, the differential reflection and absorption of UV light captured in the UV spectral range can also provide a new contrast for diagnosing skin diseases during UV reflectance photography. This review discusses the most widely used UV imaging techniques and provides an overview of the role of UV imaging in dermatology.

Purpose of Review Familial hypercholesterolemia (FH) is often perceived and described as underdiagnosed and undertreated, though effective treatment of FH is available. Owing to the mentioned facts, it is ever more imperative to screen and treat FH patients. Subsequent to the identification of patients, the project focuses on the improvement of their prognoses. The ScreenPro FH project was established as a functional international network for the diagnosis, screening, and treatment of FH. Individual countries were assigned goals, e.g., to define the actual situation and available treatment. With “central support,” more centers and countries participated in the project. Subsequently, individual countries reported the results at the beginning and end of the project. Collected data were statistically evaluated. Recent Findings The increasing number of patients in databases, from 7500 in 2014 to 25,347 in 2018, demonstrates the improvement in overall effectiveness, as well as an increase in the number of centers from 70 to 252. Before all, LDL-C decreased by 41.5% and total cholesterol by 32.3%. As data from all countries and patients were not available at the time of the analysis, only those results from 10 countries and 5585 patients at the beginning of the project and at the time of writing are included. Summary Our data are quite positive. However, our results have only limited validity. Our patients are far from the target levels of LDL-C. The situation can be improved with the introduction of new therapy, PCSK9-i, evolocumab, and alirocumab. International cooperation improved the screening of FH and finally led to an improvement in cardiovascular risk.

Progranulin is a recently recognized multifunctional glycopeptide shown to be related to obesity and diabetes mellitus. Progranulin is an endogenous antagonist of tumor necrosis factor-α by competitively binding to its receptor, therefore, it exerts anti-inflammatory activity. Paradoxically, previous studies have shown that serum levels of progranulin were elevated in patients with diabetes and associated to its complications including micro- and macroangiopathies, macroalbuminuria or reduced renal function. Moreover, hyperprogranulinemia may be involved in the pathogenesis of obesity-associated insulin resistance. The review summarizes the currently available data on progranulin as a novel marker of the carbohydrate metabolism and inflammation. Orv Hetil. 2019; 160(25): 973-979.Absztrakt: A progranulin egy újonnan felfedezett multifunkcionális glikoprotein, amely összefüggésben van az elhízás és a cukorbetegség kialakulásával. A progranulin a tumornekrózisfaktor-α endogén antagonistája, kompetitíven kötődik annak receptorához, így antiinflammatoricus aktivitással rendelkezik. Érdekes módon korábbi tanulmányok kimutatták, hogy a progranulin szérumszintje emelkedett a cukorbetegekben, és összefüggésbe hozták a cukorbetegség bizonyos komplikációival, beleértve a micro- és macroangiopathiát, a macroalbuminuriát és a csökkent vesefunkciót. Továbbá a hyperprogranulinaemia közrejátszhat az elhízáshoz társuló inzulinrezisztencia patogenezisében. A cikkben összefoglaljuk a jelenleg elérhető adatokat a progranulinnak – mint új markernek – a szénhidrát-metabolizmusban és a gyulladásban betöltött szerepére vonatkozóan. Orv Hetil. 2019; 160(25): 973–979.

Objective- Vascular calcification is associated with high risk of cardiovascular events and mortality. Osteochondrogenic differentiation of vascular smooth muscle cells (VSMCs) is the major cellular mechanism underlying vascular calcification. Because tissue hypoxia is a common denominator in vascular calcification, we investigated whether hypoxia per se triggers osteochondrogenic differentiation of VSMCs. Approach and Results- We studied osteochondrogenic differentiation of human aorta VSMCs cultured under normoxic (21% O

The application of natural plant extracts in UV-protection is popular and intensively studied. Silymarin (from Silibum marianum), a naturally occurring polyphenol, has recently received attention due to its antioxidant, anti-inflammatory and anti-apoptotic effects. However, its role in the UV-mediated keratinocyte cell response is still controversial. In this study, we investigated the effects of Silibum marianum extracts with different origins and formulations on UVA-exposed HaCaT keratinocytes in vitro. Our results show, that silymarin treatment caused an inverse dose-dependent photosensitivity relationship (at higher doses, a decrease in cell viability and ROS production) after UVA exposure. The attenuation of the UVA-induced ROS generation after silymarin treatment was also observed. Moreover, silymarin pre-treatment increased the cyclobutane pyrimidine dimer photolesions in keratinocytes after UVA exposure. These results indicated the dual role of silymarin in UVA-exposed keratinocytes. It scavenges ROS but still induces phototoxicity. Based on our results dermatological applications of silymarin and related compounds should be considered very carefully.

Introduction: Ultraviolet light induced DNA damage, combined with immunosuppression and inflammation are involved in the pathogenesis of actinic keratosis. Photodynamic therapy not only destroys dysplastic cells via tissue destruction and vascular shutdown, but also induces an acute local inflammatory response and activates both the innate and adaptive immune system. In our current work we aimed to compare immunohistochemistry features of inflammatory infiltrate of actinic keratoses after 5-aminolevulinic acid photodynamic therapy with or without Er:YAG laser resurfacing. Methods: Eleven patients with multiple actinic keratosis on the scalp, face, hands or forearms were treated by conventional and Er:YAG laser assisted 5-aminolevulinic acid PDT in split-site manner. Biopsies of AKs were taken before, 48 h and 3 months after the treatment. CD3, CD4, CD8, CD1a, Ki67 and p53 expressions were analyzed by immunohistochemical methods. Results: The number of p53 and Ki67 positive cells decreased significantly 3 months after treatment, but the abnormal cells were not eliminated totally. The number of CD1a+ Langerhans cells significantly decreased 48 h after both treatments, while CD8+ T cell count was significantly lower 3 months after Er:YAG laser assisted photodynamic therapy. However, the number of CD3+ and CD4+ T cells were not changed significantly 48 h and 3 months later. Conclusions: One session of 5-aminolevulinic acid photodynamic therapy even with Er:YAG laser pretreatment could not terminate actinic damage totally. Photodynamic therapy induced immunological changes. However further investigations are needed to answer how the composition of actinic keratosis’ immune infiltrate influence the effect of photodynamic therapy.

Although antioxidants promote melanoma metastasis, the role of reactive oxygen species (ROS) in other stages of melanoma progression is controversial. Moreover, genes regulating ROS have not been functionally characterized throughout the entire tumor progression in mouse models of cancer. To address this question, we crossed mice-bearing knock-out of Klf9, an ubiquitous transcriptional regulator of oxidative stress, with two conditional melanocytic mouse models: Braf(CA) mice, where Braf(V600E) causes premalignant melanocytic hyperplasia, and Braf(CA)/Pten(−/−) mice, where Braf(V600E) and loss of Pten induce primary melanomas and metastases. Klf9 deficiency inhibited premalignant melanocytic hyperplasia in Braf(CA) mice but did not affect formation and growth of Braf(CA)/Pten(−/−) primary melanomas. It also, as expected, promoted Braf(CA)/Pten(−/−) metastasis. Treatment with antioxidant N-acetyl cysteine phenocopied loss of Klf9 including suppression of melanocytic hyperplasia. We were interested in a different role of Klf9 in regulation of cell proliferation in Braf(CA) and Braf(CA)/Pten(−/−) melanocytic cells. Mechanistically, we demonstrated that BRAF(V600E) signaling transcriptionally upregulated KLF9 and that KLF9-dependent ROS were required for full-scale activation of ERK1/2 and induction of cell proliferation by BRAF(V600E). PTEN depletion in BRAF(V600E)-melanocytes did not further activate ERK1/2 and cell proliferation, but rendered these phenotypes insensitive to KLF9 and ROS. Our data identified an essential role of KLF9-dependent ROS in BRAF(V600E) signaling in premalignant melanocytes, offered an explanation to variable role of ROS in premalignant and transformed melanocytic cells and suggested a novel mechanism for suppression of premalignant growth by topical antioxidants.

Opioids are routinely prescribed for postoperative home pain management for most patients in the United States, with limited evidence of the amount needed to be dispensed. Opioid-based treatment often adversely affects recovery. Prescribed opioids increase the risk of chronic opioid use, abuse, and diversion and contribute to the current opioid epidemic.To evaluate whether after hospital discharge, postsurgical acute pain can be effectively managed with a markedly reduced number of opioid doses.In this case-control cohort study, an ultrarestrictive opioid prescription protocol (UROPP) was designed and implemented from June 26, 2017, through June 30, 2018, at a single tertiary-care comprehensive cancer center. All patients undergoing gynecologic oncology surgery were included. Patients undergoing ambulatory or minimally invasive surgery (laparoscopic or robotic approach) were not prescribed opioids at discharge unless they required more than 5 doses of oral or intravenous opioids while in the hospital. Patients who underwent a laparotomy were provided a 3-day opioid pain medication supply at discharge.Total number of opioid pain medications prescribed in the 60-day perioperative period, requests for opioid prescription refills, and postoperative pain scores and complications were evaluated. Factors associated with increased postoperative pain, preoperative and postoperative pain scores, inpatient status, prior opioid use, and all opioid prescriptions within the 60-day perioperative window were monitored among the case patients and compared with those from consecutive control patients treated at the center in the 12 months before the UROPP was implemented.Patient demographics and procedure characteristics were not statistically different between the 2 cohorts of women (605 cases: mean [SD] age, 56.3 [14.5] years; 626 controls: mean [SD] age, 55.5 [13.9] years). The mean (SD) number of opioid tablets given at discharge after a laparotomy was 43.6 (17.0) before implementation of the UROPP and 12.1 (8.9) after implementation (P .001). For patients who underwent laparoscopic or robotic surgery, the mean (SD) number of opioid tablets given at discharge was 38.4 (17.4) before implementation of the UROPP and 1.3 (3.7) after implementation (P .001). After ambulatory surgery, the mean (SD) number of opioid tablets given at discharge was 13.9 (16.6) before implementation of the UROPP and 0.2 (2.1) after implementation (P .001). The mean (SD) perioperative oral morphine equivalent dose was reduced to 64.3 (207.2) mg from 339.4 (674.4) mg the year prior for all opioid-naive patients (P .001). The significant reduction in the number of dispensed opioids was not associated with an increase the number of refill requests (104 patients [16.6%] in the pre-UROPP group vs 100 patients [16.5%] in the post-UROPP group; P = .99), the mean (SD) postoperative visit pain scores (1.1 [2.2] for the post-UROPP group vs 1.4 [2.3] for pre-UROPP group; P = .06), or the number of complications (29 cases [4.8%] in the post-UROPP group vs 42 cases [6.7%] in the pre-UROPP group; P = .15).Implementation of a UROPP was associated with a significant decrease in the overall amount of opioids prescribed to patients after gynecologic and abdominal surgery at the time of discharge for all patients, and for the entire perioperative time for opioid-naive patients without changes in pain scores, complications, or medication refill requests.

1. Preamble : Hypercholesterolemia is a major risk factor for atherosclerotic cardiovascular disease (ASCVD) [1]. Increased levels of low density lipoprotein cholesterol (LDL-C) are associated with an increased risk of coronary heart disease (CHD) and many clinical trials have shown that reducing LDL-C levels significantly reduced the CHD and CVD risk [[2], [3], [4], [5]]. Thus LDL-C-lowering is the main approach for the management of cardiovascular disease. Current guidelines suggest LDL-C levels targets based on the individual CV risk; such targets can be achieved by several means, which include both lifestyle changes and pharmacological approaches [6], with statins being the cornerstone of cardiovascular prevention. [...]

Oxidative stress and chronic low-grade inflammation are major characteristics of obesity-related disorders. The dominance of pro-oxidant and pro-inflammatory mechanisms triggers insulin resistance and enhances the progression of atherosclerosis. Discovered first as an esterase that hydrolyze organophosphates, human paraoxonase-1 is bound to high-density lipoprotein and inhibits the oxidation of lipoproteins and reduces the degree of inflammation, hence it is considered to act against atherosclerosis. In contrast, the majority of the adipokines secreted from the enlarged white adipose tissue promote the atherosclerotic process; and altered adipokine secretion is now regarded as one of the major contributors of increased cardiovascular morbidity and mortality in obesity. In this review, we detail the correlations between paraoxonase-1 and some selected adipokines, namely leptin, adiponectin and chemerin. Adipokine imbalance leads to decreased paraoxonase-1 activity that results in enhanced atherosclerosis; therefore, altered adipokine secretion may be predictive of cardiovascular complications in obesity. As an active organ secreting biological active substances, white adipose tissue may also act as a "fine-tuner" of immune and endocrine actions attenuating or enhancing reactions triggered by pathogens, inflammation and metabolic stimuli; and obesity, as a chronic noxious state may perturb the proper functioning of this fine-tuning process. Further investigations are of major importance to elucidate the associations between adipokines and paraoxonase-1 and to establish accurate interventions against obesity-related disorders.

Myeloperoxidase (MPO), matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) were shown to contribute to atherogenesis, while human paraoxonase-1 (PON1) protects against oxidative stress. Although several studies investigated these biomarkers, their associations have not been completely clarified yet. We aimed to investigate these parameters in overweight hyperlipidemic, lipid-lowering therapy-naive patients (n=167) with and without vascular complications.MPO, MMP-9 and TIMP-1 levels were measured by ELISA. PON1 activities were detected spectrophotometrically. PON1 phenotype was calculated by using a dual substrate method.Patients with vascular complications (VC) had significantly higher MPO and TIMP-1 levels compared to those without (patients with no vascular complications; NVC) (728 (367.25-1177.90) mg/ml vs. 315.9 (176.05-687.40) mg/ml; p0.001; and 172.7 (157.7-197.7) ng/ml vs. 152.6 (129.3-172.3) ng/ml; p0.0001; respectively). MPO levels showed a significant negative correlation with PON1 arylesterase activity (whole patient group (W): r=0.42, p0.0001; VC: r=0.44, p=0.01; NVC: r=0.39, p0.0001) and positive correlations with MMP-9 (W: r=0.37, p0.0001; VC: r=0.29, p=0.07; NVC: r=0.42, p0.0001) and TIMP-1 (W: r=0.42, p0.0001; VC: r=0.33, p0.05; NVC: r=0.41, p0.0001), respectively. PON1 arylesterase activity was found to be an independent predictor of MPO levels in the whole patient group (β=-0.350, p0.0001) or when studied separately in the subgroups with or without cardiovascular complications (VC: β=-0.57, p0.05; NVC: β=-0.33, p0.0001).Our results suggest that parallel investigation of MPO, MMP-9 and TIMP-1 levels and PON1 arylesterase activity may be a more accurate indicator of atherosclerosis, which may allow earlier treatment and therefore, improvement of treatment efficacy.

After a "silence" period for decades, a great body of new information has become available about the pathogenesis, diagnosis and treatment of gout. New data on purine metabolism and urate transporters have been published. It has become evident that gout is an autoinflammatory disease involving the inflammasome and interleukin-1. With respect to diagnosis, microscopic evaluation of the urate crystal is still the gold standard, however, sensitive imaging techniques (ultrasound, modern computed tomography methods) are able to visualize crystal deposition and tophus formation. Tophus size may also be monitored over time. We see a renaissance of non-pharmacological, lifestyle-related treatment modalities. Pharmacotherapy includes the resolution of attacks and urate-lowering maintenance therapy. In 2016, two recent series of recommendations have been published. Treat-to-target therapy aiming at urate levels ≤360 μmol/l is crucial. Urate-lowering therapy includes xanthine oxidase inhibitors (allopurinol, febuxostat). However, a number of novel compounds (urate transporter inhibitors, recombinant uricase, interleukin-1 inhibitors) are under development or before introduction to gout treatment. Comorbidites should be considered throughout the follow-up of gout patients. Orv Hetil. 2018; 159(40): 1625-1636.Absztrakt: Több évtizedes „szünetet” követően az utóbbi években számos új adat jelent meg a köszvény patogenezise, diagnosztikája és terápiája vonatkozásában. Megismertük a húgysavanyagcsere újabb vonatkozásait, az uráttranszporterekkel kapcsolatos legfrissebb adatokat. Nyilvánvalóvá vált, hogy a köszvény autoinflammatoricus betegség, melynek kialakulásában az inflammasoma és az interleukin-1 kiemelt szerepet játszik. A diagnosztikában ma is a legfontosabb a mononátrium-urát kristály kimutatása, de érzékenyebb képalkotókkal (ultrahang, modern komputertomográfiás technikák) a kristálylerakódás és a tophusképződés is kimutatható, sőt a tophusok mérete is követhető. Újra reneszánszukat élik a különböző életmódbeli, diétás megfontolások, amelyek a gyógyszeres kezelés fontos kiegészítői. A gyógyszeres kezelés alapja a rohamoldás és a fenntartó kezelés, melyekre vonatkozóan 2016-ban két új ajánlás is megjelent. Ezek lényege a célértékre (≤360 μmol/l húgysavszint) való törekvés. A húgysavszintcsökkentés középpontjában ma is a xantin-oxidáz-gátlók (allopurinol, febuxostat) állnak. Ugyanakkor számos új molekula (uráttranszporter-gátlók, rekombináns urikázok, interleukin-1-gátlók) áll fejlesztés alatt, sőt bevezetés előtt. A beteg kezelése és gondozása során kiemelt figyelmet kell fordítanunk a köszvény társbetegségeire is. Orv Hetil. 2018; 159(40): 1625–1636.

Background Chest compression is a decisive element of cardio-pulmonary resuscitation (CPR). By applying a mechanical CPR device, compression interruptions can be minimised. We examined the efficiency of manual and device-assisted resuscitation as well as the effects of cardiovascular risk factors on the outcome of resuscitation. Methods In our retrospective, randomised 3-year study the data of adult patients suffering non-traumatic, out-of-hospital, sudden cardiac death (SCD) were analysed (n = 287). The data were retrieved by processing case reports, Utstein sheets and acute coronary syndrome sheets. We compared the data of patients undergoing manual (n = 232) and device-assisted resuscitation (LUCAS-2, n = 55). The primary endpoint was the on-site restoration of spontaneous circulation (ROSC). Results and conclusion In 37% of the cases ROSC happened. With respect to ROSC an insignificantly more favourable tendency was demonstrated in the case of device-assisted resuscitation (p = 0.072). In the Lucas group, a higher success rate occurred even in the case of prolonged resuscitation. We found a better outcome in the Lucas group in the case of CPR started a longer time after the SCD (p

Afamin is a plasma vitamin E-binding glycoprotein partially associated with ApoA1-containing high-density lipoprotein (HDL) subfractions. In a previous study, the serum vitamin E decreased after low-density lipoprotein (LDL) apheresis, while vitamin E/cholesterol ratio increased. We aimed to study the effect of LDL apheresis on serum afamin level.The serum level of afamin and oxidized LDL were measured by enzyme-linked immunosorbent assay in six severe heterozygous FH patients before and after their first LDL apheresis treatments and in seven healthy controls. We also investigated the changes in total cholesterol, LDL-C, HDL-C, ApoB, ApoA1, HDL subfractions, and α- and γ-tocopherol levels during the treatment. HDL subfractions were detected by an electrophoretic method on polyacrylamide gel (Lipoprint). Serum α- and γ-tocopherol levels were detected by gas chromatography-mass spectrometry.The first treatment sessions decreased serum afamin levels by an average of 9.4%. Total cholesterol, LDL-C, HDL-C and ApoA1 levels decreased by 52.6; 61.8; 10.5; and 14.1%, respectively. We found that α- and γ-tocopherol levels markedly decreased (by 34.1 and 32.9%, respectively), while α- tocopherol/cholesterol and γ-tocopherol/cholesterol ratios significantly increased (by 41.4 and 40.3%, respectively). Oxidized LDL levels significantly decreased. There was a shift toward the larger HDL subfractions.LDL apheresis moderately decreases the circulating levels of afamin parallel to lowering HDL-C and ApoA1 levels. Tocopherol levels decreases markedly compared to afamin levels, however, beneficial changes in vitamin E/cholesterol ratios, oxidized LDL levels and HDL subfraction distribution were detected. These additional effects of LDL apheresis may result in further cardiovascular risk reduction in FH patients.

Purpose Graves’ orbitopathy (GO) is a complication of Graves’ disease (GD), the development of which cannot be predicted at the time of diagnosis of GD. Our aims were (i) to test if orbital 99mTc-labelled diethylenetriamine pentaacetic acid single-photon emission computer tomography (DTPA SPECT) can predict development of GO later during the course of the disease and (ii) to study whether orbital immune activity can be detected in GD patients who do not develop GO during follow-up. Methods Fifty-four orbits of 27 patients with newly diagnosed GD were entered into the case-control study. Individuals showing signs of GO at enrolment were excluded. During the two-year follow-up, eye signs were recorded every 3 months. Orbital DTPA uptakes on SPECT images were measured when entering the study and at the end of the follow-up period, or when clinical signs of GO developed, whichever occurred first. Results During the follow-up, 6 patients (22%) were diagnosed with GO. There was no significant difference between the initial DTPA uptakes of the patients with or without later developing GO (10.45±1.72 MBq/cm3 vs. 9.18±1.18 MBq/cm3 respectively). However, the DTPA uptakes of both GD groups (ie. with and without GO) were higher than that of the control group (7.45±1.36 MBq/cm3, p Conclusions We have shown that GD is accompanied by moderate orbital immune activity in GD patients without GO, irrespective of later development of GO. Why this orbital autoimmunity remains subclinical in the majority of the cases, and progresses into clinically detectable GO in others, remains unclear.

Previous studies showed that plasma levels of high-density lipoprotein (HDL) cholesterol are inversely related to risk of cardiovascular diseases. However, in the last few decades it became obvious that beyond its plasma level, HDL structure and function have a critical role in its anti-atherogenic efficacy. Apolipoprotein M (ApoM) is an HDL-associated plasma protein affecting HDL metabolism and exhibits various anti-atherosclerotic functions, such as protection against oxidation and regulation of cholesterol efflux. Sphingosine 1-phosphate (S1P) is a potent sphingolipid mediator that regulates numerous cellular responses including cell differentiation and migration, apoptosis and vascular inflammation. The majority of S1P is associated to ApoM containing HDL particles. Therefore, ApoM and S1P content of HDL have an impact on the atherosclerotic process. Moreover, HDL-ApoM and S1P content can be altered in several pathologic conditions such as coronary artery disease. This review covers the currently available data on the contribution of ApoM and S1P to HDL function in health and cardiovascular diseases. Orv Hetil. 2018; 159(5): 168-175.

Since cardiovascular diseases are the main cause of mortality worldwide, the reduction of their risk is a crucial point of present-day medicine. It has been proven unequivocally that the administration of various treatments has a favorable effect on the frequency of cardiovascular events and on the atherosclerosis leading to them. Although systematic and guideline-driven administration of these drugs has led to a decrease in the incidence and mortality of vascular events, the leading position of this group of diseases in mortality and morbidity has not changed. That is why medicine, besides keeping up actual guidelines optimally, is always searching for new modalities to further decrease residual risk. This residual risk can be diverse. The present paper summarizes the possibilities of reducing residual lipid and residual inflammatory risk after treatment according to the guidelines. It has been proven that lowering LDL-cholesterol below 1.8 mmol/l has a further advantage on the occurrence of vascular events. Treating the elevated lipoprotein(a), triglyceride and low HDL-cholesterol levels should decrease the residual lipid risk. Statins and statin-ezetimibe combination, besides lipid modulation, have an anti-inflammatory effect proved by C-reactive protein level reduction. Canakinumab has solely inflammation reducing effect through the inhibition of interleukin-1β. It was administered subcutaneously once in 3 months in a large-scale clinical study and it has shown a 15% reduction in non-fatal myocardial infarction, non-fatal stroke and cardiovascular death, which opens new horizons in the anti-inflammatory treatment of atherosclerosis. Orv Hetil. 2018; 159(4): 124-130.

Ultraviolet (UV) light is absorbed by nucleic acids, proteins or other endogenous chromophores, such as porphyrins, flavins and melanin, triggering biological processes in skin cells. Both UV-induced mutations in melanocytes and changes in the immune microenvironment are understood to play a role in the development of cutaneous melanoma. The degree of UV-induced stress and the protection against this stress are influenced by both intracellular and intercellular molecular interactions. The present review summarizes the known major molecular biological changes induced by UV light in the skin that play a role in melanoma initiation and promotion. Nevertheless, cutaneous melanoma is not a homogenous disease, and the interaction of variable environmental exposure and different genetic susceptibility and other host factors lead to the formation of melanomas with different biological behavior and clinical characteristics. This review highlights the challenges in the understanding of how UV radiation contributes to the formation of cutaneous melanoma, and reviews the new results of photobiology and their link to tumor genetics and tumor immunology with potential implications on melanoma prevention and therapeutic strategies. The information presented here is expected to add clarity to ongoing research efforts in this field to aid the development of novel strategies to prevent and treat melanoma.

Photodynamic therapy (PDT) is an office-based treatment for precancerous and early cancerous skin changes. PDT induces cell death through the production of reactive oxygen species (ROS). Cyclobutane pyrimidine dimers (CPDs) are the most important DNA changes responsible for ultraviolet (UV) carcinogenesis. Recently ROS induced by UVA were shown to generate CPDs via activating melanin. This raised the possibility that PDT induced ROS may also induce CPDs and mutagenesis in melanin containing cells. Previously the effect of PDT on CPDs in melanin containing cells has not been assessed. Our current work aimed to compare the generation of CPDs in melanin containing cells subjected to UVA treatment and porfimer sodium red light PDT. We used ELISA to detect CPDs. After UVA we found a dose dependent increase in CPDs in melanoma cells (B16-F10, MNT-1) with CPD levels peaking hours after discontinuation of UVA treatment. This indicated the generation of UVA induced dark-CPDs in the model. Nevertheless, PDT in biologically relevant doses was unable to induce CPDs. Our work provides evidence for the lack of CPD generation by PDT in melanin containing cells.

Obesity is a growing health problem worldwide. It is associated with an increased cardiovascular risk on the one hand of obesity itself and on the other hand of associated medical conditions (hypertension, diabetes, insulin resistance, and sleep apnoea syndrome). Obesity has an important role in atherosclerosis and coronary artery disease. Obesity leads to structural and functional changes of the heart, which causes heart failure. The altered myocardial structure increases the risk of atrial fibrillation and sudden cardiac death. However, obesity also has a protective effect on the clinical outcome of underlying cardiovascular disease, the phenomenon called obesity paradox. The improved cardiac imaging techniques allow the early detection of altered structure and function of the heart in obese patients. In this review, we attempt to summarize the relationship between obesity and cardiovascular diseases and outline the underlying mechanisms. The demonstrated new techniques of cardiac diagnostic procedures allow for the early detection and treatment of subclinical medical conditions and, therefore, the prevention of cardiovascular events.

Statins are the most common drugs administered for patients with cardiovascular disease. However, due to statin-associated muscle symptoms, adherence to statin therapy is challenging in clinical practice. Certain nutraceuticals, such as red yeast rice, bergamot, berberine, artichoke, soluble fiber, and plant sterols and stanols alone or in combination with each other, as well as with ezetimibe, might be considered as an alternative or add-on therapy to statins, although there is still insufficient evidence available with respect to long-term safety and effectiveness on cardiovascular disease prevention and treatment. These nutraceuticals could exert significant lipid-lowering activity and might present multiple non–lipid-lowering actions, including improvement of endothelial dysfunction and arterial stiffness, as well as anti-inflammatory and antioxidative properties. The aim of this expert opinion paper is to provide the first attempt at recommendation on the management of statin intolerance through the use of nutraceuticals with particular attention on those with effective low-density lipoprotein cholesterol reduction.

Background and aims Familial hypercholesterolemia (FH) is one of the most frequent diseases with monogenic inheritance. Previous data indicated that the heterozygous form occurred in 1:250 people. Based on these reports, around 36,000–40,000 people are estimated to have FH in Hungary, however, there are no exact data about the frequency of the disease in our country. Therefore, we initiated a cooperation with a clinical site partner company that provides modern data mining methods, on the basis of medical and statistical records, and we applied them to two major hospitals in the Northern Great Plain region of Hungary to find patients with a possible diagnosis of FH. Methods Medical records of 1,342,124 patients were included in our study. From the mined data, we calculated Dutch Lipid Clinic Network (DLCN) scores for each patient and grouped them according to the criteria to assess the likelihood of the diagnosis of FH. We also calculated the mean lipid levels before the diagnosis and treatment. Results We identified 225 patients with a DLCN score of 6–8 (mean total cholesterol: 9.38 ± 3.0 mmol/L, mean LDL-C: 7.61 ± 2.4 mmol/L), and 11,706 patients with a DLCN score of 3–5 (mean total cholesterol: 7.34 ± 1.2 mmol/L, mean LDL-C: 5.26 ± 0.8 mmol/L). Conclusions The analysis of more regional and country-wide data and more frequent measurements of total cholesterol and LDL-C levels would increase the number of FH cases discovered. Data mining seems to be ideal for filtering and screening of FH in Hungary.

The incidence of atrial fibrillation is increased during hemodialysis (HD); however, the effects of hemodiafiltration (HDF) on atrial arrhythmias have not been evaluated. The prolongation of the P wave and P dispersion (Pd) can predict atrial arrhythmias. Data from 30 patients receiving HDF over a period of 3 months were collected; the same group of patients was then evaluated during treatment with conventional HD for at least another 3 months. Electrolyte values were obtained, and surface electrocardiograms (ECG), echocardiography, and Holter ECGs were performed. The duration of the P wave and Pd increased significantly during HD. The left atrial diameter decreased significantly only during HDF. During HDF, the left atrial cross diameter measured at the beginning of the session was positively correlated with the incidence of supraventricular premature beats (p = 0.011, r = 0.4556). The decrease in left atrial diameter during HDF was negatively correlated with the incidence of supraventricular premature beats (p = 0.016, r = −0.43). During HDF, the changes in sodium and Pd were significantly positively correlated (p

Background The National Comprehensive Cancer Network guidelines for Merkel cell carcinoma recommend performance of the sentinel lymph node biopsy in all patients with clinically negative nodal disease for staging and treatment. Nevertheless, sentinel lymph node biopsy in the periocular region is debated as tumors are typically smaller and lymphatic variability can make performance procedurally problematic. Case presentation We present a case of a Caucasian patient in their seventies who presented with a 1.0 cm periocular Merkel cell carcinoma, who underwent Mohs surgery with a Tenzel flap repair, that was found to have a positive sentinel lymph node biopsy, but who, despite parotidectomy, selective neck dissection, and radiation, succumbed to the disease. Conclusions Evidence in both the site-specific and non-specific literature demonstrates: (1) Worsening prognosis with extent of lymph node burden, (2) improvements in our abilities to perform lymphoscintigraphy, (3) locoregional and distant metastatic disease in patients with tumor sizes ≤1 cm, and (4) significant rates of sentinel lymph node positivity in patients with tumor sizes ≤1 cm. Our case supports that sentinel lymph node biopsy should be considered in all clinically nodal negative periocular Merkel cell carcinoma, regardless of size, and despite limited site-specific studies on the subject.