Radiation-Detoxified Form of Endotoxin Effectively Activates Th1 Responses and Attenuates Ragweed-Induced Th2-Type Airway Inflammation in Mice.

Urbanization with reduced microbial exposure is associated with an increased burden of asthma and atopic symptoms. Conversely, environmental exposure to endotoxins in childhood can protect against the development of allergies. Our study aimed to investigate whether the renaturation of the indoor environment with aerosolized radiation-detoxified lipopolysaccharide (RD-LPS) has a preventative effect against the development of ragweed-induced Th2-type airway inflammation. To explore this, cages of six-week-old BALB/c mice were treated daily with aerosolized native LPS (N-LPS) or RD-LPS. After a 10-week treatment period, mice were sensitized and challenged with ragweed pollen extract, and inflammatory cell infiltration into the airways was observed. As dendritic cells (DCs) play a crucial role in the polarization of T-cell responses, in our in vitro experiments, the effects of N-LPS and RD-LPS were compared on human monocyte-derived DCs (moDCs). Mice in RD-LPS-rich milieu developed significantly less allergic airway inflammation than mice in N-LPS-rich or common environments. The results of our in vitro experiments demonstrate that RD-LPS-exposed moDCs have a higher Th1-polarizing capacity than moDCs exposed to N-LPS. Consequently, we suppose that the aerosolized, non-toxic RD-LPS applied in early life for the renaturation of urban indoors may be suitable for the prevention of Th2-mediated allergies in childhood.

Enalapril Is Superior to Lisinopril in Improving Endothelial Function without a Difference in Blood-Pressure-Lowering Effects in Newly Diagnosed Hypertensives.

Angiotensin-converting enzyme (ACE) inhibitors are the primarily chosen drugs to treat various cardiovascular diseases, such as hypertension. Although the most recent guidelines do not differentiate among the various ACE inhibitory drugs, there are substantial pharmacological differences. GOAL: Here, we tested if lipophilicity affects the efficacy of ACE inhibitory drugs when used as the first therapy in newly identified hypertensives in a prospective study. METHODS: We tested the differences in the cardiovascular efficacy of the hydrophilic lisinopril (8.3 ± 3.0 mg/day) and the lipophilic enalapril (5.5 ± 2.3 mg/day) (n = 59 patients). The cardiovascular parameters were determined using sonography (flow-mediated dilation (FMD) in the brachial artery, intima-media thickness of the carotid artery), 24 h ambulatory blood pressure monitoring (peripheral arterial blood pressure), and arteriography (aortic blood pressure, augmentation index, and pulse wave velocity) before and after the initiation of ACE inhibitor therapy. RESULTS: Both enalapril and lisinopril decreased blood pressure. However, lisinopril failed to improve arterial endothelial function (lack of effects on FMD) when compared to enalapril. Enalapril-mediated improved arterial endothelial function (FMD) positively correlated with its blood-pressure-lowering effect. In contrast, there was no correlation between the decrease in systolic blood pressure and FMD in the case of lisinopril treatment. CONCLUSION: The blood-pressure-lowering effects of ACE inhibitor drugs are independent of their lipophilicity. In contrast, the effects of ACE inhibition on arterial endothelial function are associated with lipophilicity: the hydrophilic lisinopril was unable to improve, while the lipophilic enalapril significantly improved endothelial function. Moreover, the effects on blood pressure and endothelial function did not correlate in lisinopril-treated patients, suggesting divergent mechanisms in the regulation of blood pressure and endothelial function upon ACE inhibitory treatment.

The majority of severe COVID-19 patients develop anti-cardiac autoantibodies.

Severe cases of COVID-19 are characterized by an inflammatory burst, which is accompanied by multiorgan failure. The elderly population has higher risk for severe or fatal outcome for COVID-19. Inflammatory mediators facilitate the immune system to combat viral infection by producing antibodies against viral antigens. Several studies reported that the pro-inflammatory state and tissue damage in COVID-19 also promotes autoimmunity by autoantibody generation. We hypothesized that a subset of these autoantibodies targets cardiac antigens. Here we aimed to detect anti-cardiac autoantibodies in severe COVID-19 patients during hospitalization. For this purpose, 104 COVID-19 patients were recruited, while 40 heart failure patients with dilated cardiomyopathy and 20 patients with severe aortic stenosis served as controls. Patients were tested for anti-cardiac autoantibodies, using human heart homogenate as a bait. Follow-up samples were available in 29 COVID-19 patients. Anti-cardiac autoantibodies were detected in 68% (71 out of 104) of severe COVID-19 patients. Overall, 39% of COVID-19 patients had anti-cardiac IgG autoantibodies, while 51% had anti-cardiac autoantibodies of IgM isotype. Both IgG and IgM anti-cardiac autoantibodies were observed in 22% of cases, and multiple cardiac antigens were targeted in 38% of COVID-19 patients. These anti-cardiac autoantibodies targeted a diverse set of myocardial proteins, without apparent selectivity. As controls, heart failure patients (with dilated cardiomyopathy) had similar occurrence of IgG (45%, p = 0.57) autoantibodies, while significantly lower occurrence of IgM autoantibodies (30%, p = 0.03). Patients with advanced aortic stenosis had significantly lower number of both IgG (11%, p = 0.03) and IgM (10%, p < 0.01) type anti-cardiac autoantibodies than that in COVID-19 patients. Furthermore, we detected changes in the anti-cardiac autoantibody profile in 7 COVID-19 patients during hospital treatment. Surprisingly, the presence of these anti-cardiac autoantibodies did not affect the clinical outcome and the prevalence of the autoantibodies did not differ between the elderly (over 65 years) and the patients younger than 65 years of age. Our results demonstrate that the majority of hospitalized COVID-19 patients produce novel anti-cardiac IgM autoantibodies. COVID-19 also reactivates resident IgG autoantibodies. These autoantibodies may promote autoimmune reactions, which can complicate post-COVID recuperation, contributing to post-acute sequelae of COVID-19 (long COVID).

The role of protein kinase C isoenzymes in the pathogenesis of human autoimmune diseases.

The physiological role of protein kinase C (PKC) enzymes in the immune system is presented briefly. From earlier publications of others data were collected how the defects of one/two isoenzymes of PKC system suggested their involvement in the pathogenesis of human autoimmune diseases. Our observations on the defects of seven PKC isoenzymes in the peripheral blood mononuclear cells (PBMC) demonstrate that these molecular impairments are not prerequisits of the pathogenesis of systemic lupus erythematosus (SLE), mixed connective tissue disease and Sjögren's syndrome. However, these defects can modulate the disease activity and symptoms especially in SLE by several pathways. The role of PKC system in other forms of autoimmune diseases is also very small. It was of note that we detected decreased expression of PKC isoenzymes in PBMC of a European white family with an X-linked genetic background showing seasonal undulations in the lupus patient and also in her healthy mother.

Standardized data on the incidence and mortality of female and male breast cancers in Hungary between 2000 and 2016. / A noi és a férfiemlorák standardizált incidencia- és mortalitásadatai Magyarországon 2000 és 2016 között.

Összefoglaló. Bevezetés: A rákbetegségek incidencia- (gyakorisági) értékei világszerte, így Magyarországon is folyamatosan növekednek. Az emlorákok elofordulása és kórlefolyása a két nemben azonban sajátosan különbözik. Célkituzés: Célul tuztük ki, hogy megvizsgáljuk és értékeljük a noi és a férfiemlorák incidencia- és mortalitási (halálozási) adatait Magyarországon 2000 és 2016 között. Módszer: A Központi Statisztikai Hivatalból és a Nemzeti Rákregiszterbol származó adatok standardizált, 100 000 fore számított feldolgozása. Eredmények: Magyarországon a vizsgált idoszakban az emlorákok gyakoriságának növekedése megközelítoleg ugyanolyan mértéku (39%) volt, mint az összes ráké (34%). Az emelkedés jelentos: a 2016-ban 8,7% részarányú noi emlorák esetében 39%, a 0,22%-os részarányú férfiráknál 60%. Ezzel szemben a halálozási adatok jelentos mértéku csökkenéseket mutatnak mind az összes daganat, mind a noi emlorák vonatkozásában, míg a férfiemlorák esetében a csökkenés nagyobb mértéku. A rosszindulatú daganatok incidenciája és a 2-es típusú diabetes mellitus (2DM) prevalenciája egyaránt magasan szignifikáns korrelációt mutatott az egy fore jutó bruttó nemzeti össztermék (GDP) értékének növekedésével. Új megfigyelés, hogy a 2DM-növekedés idoben megelozte a daganatok incidenciájának növekedését. Következtetés: A vizsgált idoszakban a noi és a férfiemlorákok magyarországi gyakorisági és halálozási adatai a nemzetköziekhez hasonló tendenciákat mutatnak. A férfiemlorákok sokkal ritkábbak, de kezelésük kevésbé hatékony. Új szempont, hogy a rosszindulatú daganatok gyakoribb megjelenésében a klinikailag kedvezotlenebb 2DM százalékos arányának (prevalenciájának) emelkedése is jelentos tényezo lehet az elhízáshoz kapcsolódva. A GDP növekedése kedvezoen hathatott a halálozások csökkenésében a kedvezobb gyógyítási és megelozési feltételek megteremtésével. Ugyanakkor ennek a növekedésnek szerepe lehet az elhízással összefüggo 2DM prevalenciájának emelkedésében is. Orv Hetil. 2022; 163(5): 181-186. INTRODUCTION: The incidence of malignant cancers is continuously growing. In breast cancers, the incidence and clinical course are greatly different in the two genders. OBJECTIVE: We aimed to investigate the incidence and mortality of breast cancers in females and males in Hungary between 2000 and 2016. METHODS: The data derived from the Hungarian Central Statistical Office and the National Cancer Registry were evaluated and standardized for 100 000 inhabitants. RESULTS: In Hungary, the elevation of breast cancer incidence (39%) showed a similar extent as that of total tumours (34%). In female breast cancers representing a much greater percent (8.7% in 2016) than that in males (0.22%), the increase was significant (39%) as in males (60 %). On the other hand, mortality was significantly lower for both of them regarding total malignant and female breast tumours, whereas the decrease was greater in the male breast cancers. The increase of GDP per capita showed highly significant correlation with the incidence of malignant tumours and prevalence of diabetes mellitus type 2 (2DM). It was a new finding that the increase in the prevalence of 2DM precedes the elevation of the incidence of cancer. CONCLUSION: In Hungary, the data of incidence and mortality of female and male breast cancers showed similar tendencies as the international ones. The breast cancers of males were rarer but their treatment was less effective. However, it was a new aspect that in the increased incidence of malignant tumours also the greater prevalence of 2DM could be an important factor related to obesity. Orv Hetil. 2022; 163(5): 181-186.

T-cell Subset Profile in Kidney Recipients of Extended or Standard Donors.

INTRODUCTION: The usage of extended-criteria donors (ECD) became a routinely accepted manner in the last decade. ECD is a potential risk factor for antibody-mediated rejection. Analysis of lymphocyte subsets might be a complementary diagnostic toolkit because there is limited knowledge about this term. METHOD: Between May 12, 2016, and September 4, 2019, a total of 130 patients who had undergone kidney transplant were investigated. Patients were divided in ECD and standard criteria donor (SCD) groups. Blood samples were collected before the operation, then in the first week and after 30, 60, 180, and 365 days. Besides routine laboratory tests, multicolor flow cytometry was performed for lymphocyte subsets. RESULTS: ECD grafts were transplanted to older recipients. The number of CD4+ cells increased in the SCDs from the first week to until the end of first month, and then decreased. The number of CD4+ cells decreased from the beginning of the study until the end of first year to 66% of its original value in ECDs. At the first month, the number of CD19+ cells was higher in SCD compared with ECD cases; the number then decreased in both groups. T-regulatory cells had a drop at the first week that lasted until the first month. A bigger increase in SCD and a moderate increase in ECD group were then observed. The kinetics of CD19+ and CD19+ naive cells are similar in the ECD and SCD groups. In the SCD group, cell count decreased in both CD19+ (13%) and CD19+ naive (12%) between third and sixth month. The count of CD19+ cells decreased by 9%, but the count of CD19+ naive cells increased by 11% between the sixth month and first year. DISCUSSION: The prolonged postoperative uremic state caused by the poorer initial function, together with an aging immune system, explains the weaker immune response in ECD patients, which may be the cause of the decreased number of memory and regulatory T cells. Older patients with an ECD graft need a tailored, personalized, and less aggressive immunosuppressive treatment.

Level of the SARS-CoV-2 receptor ACE2 activity is highly elevated in old-aged patients with aortic stenosis: implications for ACE2 as a biomarker for the severity of COVID-19.

Coronavirus disease 2019 (COVID-19) has a high mortality in elderly patients with pre-existing cardiovascular diseases. The cellular receptor of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the angiotensin-converting enzyme 2 (ACE2), thereby implicating a link between cardiovascular diseases and SARS-CoV-2 susceptibility. Aortic stenosis (AS) represents a chronic inflammatory state with severe cardiovascular complications in the elderly, a prime condition for COVID-19 mortality. The circulating ACE2 levels were measured in 111 patients with severe AS and compared to patients with hypertension and healthy individuals. About 4 times higher circulating ACE2 activity was found in patients with severe AS than in hypertensives or healthy individuals (88.3 ± 61.6., n = 111, 20.6 ± 13.4, n = 540, and 16.1 ± 7.4 mU/L, n = 46, respectively). Patients with severe AS were older than patients with hypertension (80 ± 6 years vs. 60 ± 15 years, P < 0.05). Serum ACE2 activity correlated negatively with the left ventricular ejection fraction, aortic root area, TAPSE, and positively with the right ventricular systolic pressure, cardiac diameters in patients with AS. In contrast, circulating ACE2 activity was independent of the blood pressure, peak flow velocity at the aortic root, kidney function (GFR), and inflammatory state (CRP). We found no effect of RAAS inhibitory drugs on the serum ACE2 activity in this group of patients. Our results illustrate circulating ACE2 as a potential interface between chronic inflammation, cardiovascular disease, and COVID-19 susceptibility. Elderly patients with AS have markedly elevated ACE2 levels together with altered left and right ventricular functions, which may pose higher risks during COVID-19. Our clinical data do not support a role for RAAS inhibitors in regulating circulating ACE2 levels.

Age-dependent possible role of contact-activated blood coagulation factor XII as a potential contributor to the "bradykinin storm" in COVID-19 patients / A felületaktivált XII-es véralvadási faktor életkortól függo lehetséges szerepe a "bradikininvihar" kialakításában COVID-19-betegekben.

Összefoglaló. Bevezetés: Egy új, számítógép által segített betegminta-asszociációs analízis eredménye szerint a COVID-19 tüneteinek kialakításában kiemelt tényezoként jelenik meg a bradikinin. Eszerint a bradikinin lebontása lelassul az angiotenzinkonvertáló enzim aktivitásának csökkenése miatt, ami jelentosen megemelkedo bradikininszinthez vezet a tüdoben. Nem merült fel azonban a véralvadási faktorok lehetséges szerepe a "bradikininviharban", annak ellenére, hogy az idosebb cardiovascularis betegekben aktiválódó XII-es faktor és a C1-észteráz-inhibitor (C1INH) alacsony szintje nagy mennyiségu bradikinin képzodéséhez vezethet. Módszer: Átfogó irodalmi áttekintés. Eredmények: 1) A vírus által fertozött, sérült endotheliumsejtek felülete az a hely, amellyel érintkezve elindulhat a XII-es véralvadási faktor aktivációja - ez serkenti a prekallikrein/kallikrein/kinin rendszert, és bradikininképzodést okoz. Ez a folyamat megtörténik a súlyos vese- és tüdokárosodást okozó hantavírus-fertozésekben. 2) Idos betegekben az atherosclerosis miatt többszörösen sérült, merev, "stiff" erek endotheliumfelszínein jóval magasabb lehet a XII-es faktor kontakt úton történo aktivációja, mint a fiatal egyének ereiben. Ez a tény egyik oka lehet az idos, cardiovascularis betegek körében tapasztalt magasabb halálozásnak. Következtetés: Az aktivált XII-es véralvadási faktor célzott gátlása újabb gyógyítási lehetoség lehet a SARS-CoV-2-fertozött idos betegekben. Jelenleg már hatásosnak bizonyult a bradikininképzést gátló C1INH-nak, továbbá a bradikininreceptor-gátlóknak az adása is. Orv Hetil. 2020; 161(50): 2099-2103. INTRODUCTION: Bradykinin was implicated in a new complex model of pathomechanism leading to the symptoms of COVID-19 created by a computer-assisted association analysis. According to this model, the decrease in angiotensin-converting enzyme expression leads to impaired bradykinin elimination and subsequent enrichment in the lungs. However, there is no mentioning of the importance of blood coagulation factor XII in increased bradykinin production, in spite of its age-dependent activation and the lower level of C1-esterase inhibitor (C1INH). Activated factor XII may be an important contributor to the "bradykinin storm" in elder cardiovascular patients. METHOD: Literature review. RESULTS: 1) Activation of the coagulation factor XII on the surface of SARS-CoV-2 infected endothelial cells may trigger the prekallikrein/kallikrein/kinin system producing bradykinin. Such process is taking place in hantavirus infections causing severe lung and kidney damages. 2) The endothelial system is dysregulated in elderly patients, resulting in potentially higher factor XII activities on the surface of damaged endothelial cells in the stiffened arteries. This can contribute to the higher mortality rates in the elderly. CONCLUSION: The targeted inhibition of activated blood coagulation factor XII may represent a new therapeutic target for COVID-19, especially for elder patients. Recently, beneficial results have already been observed by the clinical applications of recombinant C1INH and bradykinin receptor antagonists. Orv Hetil. 2020; 161(50): 2099-2103.

In vitro study of the effect of anti-hypertensive medication with anti-oxidant side effect on the chemiluminescence of peripheral blood phagocytes in patients with hypertension and healthy individuals / Egyes, antioxidáns mellékhatású "vérnyomás"gyógyszerek hatása magas vérnyomásban szenvedo és egészséges személyek vérsejtjeinek fagocitakemilumineszcenciájára in vitro.

Összefoglaló. Bevezetés: Az atorvasztatin (koleszterincsökkento), nifedipin (Ca2+-antagonista), kaptopril (angiotenzinkonvertáz-gátló) vegyületek a magas vérnyomás komplex kezelésének "alap"gyógyszerei. Mindhárom antioxidáns is. Célkituzés: A tanulmány célja annak megválaszolása volt, hogy e molekulák gátolhatják-e a vérsejtek fagocitamuködését. Betegek és módszer: Magas vérnyomásos betegek: 15 fo, 39-80 éves, no: 6, férfi: 9. Egészséges kontroll: 7 fo, 30-75 éves, no: 3, férfi: 4. A vizsgálat a téli hónapokban zajlott. A zimozán- (Saccharomyces cerevisiae) részecskék fagocitózisa során képzodo kemilumineszcencia mérése perifériás vérben a gyógyszerek jelenlétében történt luminométerrel. A gátlást a stimulációs index értékének csökkenésével jellemeztük. Eredmények: Mindhárom vegyület gátolta a kemilumineszcenciát (oxigénszabadgyök-képzést) a 65 év feletti, magas vérnyomásos betegek többségében: 11/13 fonél. Foleg magasabb életkorban és cukorbetegségben, de más társbetegségekben nott a gátlás. Következtetés: Az idos, magas vérnyomásos betegek fokozott orvosi figyelmet igényelnek a téli idoszakokban, mivel antioxidáns hatással is rendelkezo "alap"gyógyszereiknek, egyéntol függoen, lehetnek gátló hatásaik a fagociták mikrobaölo, oxigénszabadgyök-termelo képességére. Orv Hetil. 2020; 161(45): 1908-1913. INTRODUCTION: Atorvastatin (cholesterol synthesis blocker), nifedipine (Ca2+ antagonist), captopril (angiotensin-convertase inhibitor) are basic drugs in the therapy of hypertension. They are also antioxidants. OBJECTIVE: To investigate whether these molecules can inhibit the phagocytic activity of peripheral blood cells. PATIENTS AND METHOD: Hypertension group: 15 patients with ages between 39-80 years (6 women and 9 men). Healthy control group: 7 individuals with ages between 30-75 years (3 women and 4 men). The study was carried out in wintertime. The measurement of phagocytic activity was carried out by luminometry in peripheral blood samples. Chemiluminescence intensities were determined by the engulfment of zymosan (Saccharomyces cerevisiae) particles in the presence of drugs. The inhibitory effects were characterized by the decreased values of the stimulation index. RESULTS: All three substances decreased the chemiluminescence (reactive oxygen species production) in the majority of samples from hypertensive patients over 65 years: in 11 of 13 patients. Stronger inhibition was detected in older, diabetic patients with other co-morbidities, too. CONCLUSION: Older patients with hypertension require a special attention in wintertime. Antihypertensive drugs with antioxidant capabilities may have individually different inhibitory effects on the production of reactive oxygen species by phagocytes, which decreases their antimicrobial potency. Orv Hetil. 2020; 161(45): 1908-1913.

Analysis of Low Cancer Mortality Rates in the Wine Regions of Tokaj and Balaton in Hungary.

The age-adjusted death rates (AADRs) due to cancers were investigated in two historical regions of white wines (Tokaj and Balaton) and in Hódmezovásárhely (HMV) as a control territory in Hungary between 2000 and 2010 evaluating 111,910 persons. The results of AADRs due to the eight most frequent types/gastrointestinal cancers were as follows: Tokaj 2120/664, Balaton: 2417/824, HMV: 2770/821, nationwide: 2773/887. The values found in Tokaj and Balaton regions were significantly less than those of HMV and nationwide. However, the least values were found in Tokaj. This Tokaj-related strong difference was not found among the regions in the case of young populations with hematological diseases but only in the older people who have been consuming their wines for decades. Supposedly, this wine-specific anti-cancer phenomenon could be related to the chemical differences existing in the two types of white wines, namely, to the pro-oxidant molecules of Tokaj wines derived from Botrytis cinerea. The roles of red meat consumption, hardness of drinking water, mineral content of soil, and socioeconomic status were negligible. It should be stressed that these data are valid only for these populations, for this period. Noteworthily, the different types of wines may have different effects on mortality rates during long-lasting consumptions.

The Hardness of Drinking Water Negatively while Socio-Economic Deprivation Positively Correlate with the Age-Adjusted Mortality Rates due to Cardiovascular Diseases in Hungarian Wine Regions.

We compared the age-adjusted death rates (AADR) for cardiovascular diseases (CVD) among 206,159 inhabitants analyzed between 2000 and 2010 in four wine territories of Hungary: Tokaj (white wines), Eger (mostly red wines), Balaton (mostly white wines), Szekszárd-Villány (mostly red wines) and Hódmezovásárhely (HMV) (not a wine region). The mortality rates were also assessed from the aspects of total hardness of drinking water and index of socio-economic deprivation (ID). We found the highest cardiovascular mortality in the Tokaj region and HMV. On the other hand, lower numbers of CVD were observed in Szekszárd-Villány, Balaton and Eger. These findings on cardiovascular mortality correlated negatively and significantly with the values of total hardness of drinking waters, which were low in Tokaj and HMV. They were higher in Szekszárd-Villány, Balaton and Eger. Additionally, and surprisingly, the mortality of CVD correlated positively and significantly with the ID values despite of the small numeric differences. The hardness of drinking water and the level of socio-economic state seem to have a greater impact on the mortality rate of CVD than the consumption of "red" or "white" dominant types of wines at a region. This study shows data on a population larger than 200,000 persons.

[Staphylococcus-induced immunglobulin E-dependent allergic anaphylaxis in Crohn's disease. First description of an association of symptoms]. / Staphylococcus által kiváltott, immunglobulin-E-alapú anafilaxiás reakciók Crohn-betegségben. Egy tünetegyüttes elso leírása.

Immunglobulin E (IgE)-based, irregularly recurring, severe anaphylactic reactions occurred in a 50-year-old European white male patient suffering also from Crohn's disease. On the base of immunologic laboratory tests concerning the mechanism of the phenomenon, the idea arose whether molecules derived for certain microbial derivatives could enter the blood circulation via the damaged bowel walls in the patient with Crohn's disease and they might act as allergens. The microbial analysis diagnosed atypical Staphylococcus in the stool. The serum level of IgE was very high. The concomitant use of targeted antibiotics and anti-allergy and immunosuppressive agents resulted in a complete remission during a couple of months. Not only Crohn's disease has improved, but also the total serum IgE level has decreased significantly, and the unpredictable anaphylactic attacks have been completely eliminated. In Crohn's disease, the anaphylactic complications induced by atypical microbial allergens (e.g., derivatives of Staphylococcus) can be effectively treated after the recognition of this pathological mechanism. This is the first description of such a pathologic state. Orv Hetil. 2019; 160(38): 1514-1518.

T Cell Subset Profile and Appearance of Donor-specific Antibodies in Primary and Retransplanted Kidney Recipients.

INTRODUCTION: Accelerated antibody-mediated rejection is a major challenge after kidney transplantation. While the clinical course, diagnosis, and treatment of cell-mediated acute rejection is agreed upon and has been successfully performed, the antibody-mediated rejection remains a problem. Biopsies cannot be repeated several times, are not always representative, and are refused by many patients. Analysis of T-cell subsets and donor-specific antibodies (DSAs) might be an additive diagnostic tool in the case of kidney transplantation. METHOD: Between 2015 and 2017, 50 kidney transplant patients were enrolled in the study. Patients were divided into 2 clinical groups: primary transplants and regrafted patients. Serum samples were collected right before the operation, then in 1 week; 30, 60, and 180 days; and yearly. Besides routine laboratory, multicolor flow cytometry was performed for T cell subsets, and Luminex Single Antigen Bead assay for the detection on donor-specific anti-HLA antibodies. Medical data were also fixed. RESULTS: The percentage of CD4+ and CD8+ cells (the CD4+/CD8+ rate) did not change much over time in either group. The percentage of CD19+ cells increased until week 1, then decreased back to its original level by day 180. CD56+/3-% was high in both groups and had no characteristic kinetics by the time. The CD4+ naïve absolute cell count increased in first-time transplants and did not decreased back to its original value until the end of year 1. This is in contrast to retransplants, where CD4+ naïve cell count rapidly dropped below its original value and remained low throughout the first year after transplantation. The CD8+ effector memory absolute cell-count was higher in first-time transplants compared to retransplanted patients in all time points. By the end of month 1, the CD19+ naïve absolute cell-count increased in first-time transplants to 170% of its original value; however, it remained or decreased in second transplants. By the end of the first year, the CD19+ naïve absolute cell count diminished to 70% in first-time transplants and 38% in second transplants. DSA was detected in 9 out of the 38 first-time transplants (23.7%) compared to 7 out of 12 (58.3%) in regrafted patients during the observational period (P = .001). It was typical for regrafted patients for DSAs to appear earlier after transplantation, and that more simultaneously different antibodies were detected against more antigens at the first time point compared to first-time transplants. DISCUSSION: The 2 groups were similar in demographics and there were no differences regarding the clinical course, complications, or output data. However, we found statistical differences regarding the dynamics of T cell subsets and DSAs. The parallel measurement of CD subsets and DSAs might be a sensitive and useful additive tool in diagnosing subclinical immunologic changes after transplantation.

Season Dependent Changes in the Expression of Protein Kinase C Isoenzymes in a Female Patient with Systemic Lupus Erythematosus.

We aimed to answer the question whether the decreased expression of protein kinase C (PKC) isoenzymes in the peripheral blood mononuclear cells (PBMC) of patients with systemic lupus erythematosus (SLE) is inherited or not. For this reason we examined the expression of PKC isoenzymes in a European white girl with acute SLE and in her healthy mother and father simultaneously in summer and winter during one year using western blotting and densitometry. We found that in the father the expression of PKC isoenzymes did not differ from that of eight healthy controls included women and men. However, in the "SLE-free" mother and in the patient arrived in July with acute symptoms of lupus, the expression of PKC isoenzymes showed a season dependent undulation in parallel. Namely, in summer the expression values were significantly lower, in winter they were significantly higher than those in the controls. Thus, the decreased expression of PKC isoenzymes in the PBMC of SLE patient is not a disease specific marker; it appears also in her lupus free mother. This phenomenon may be due to a season dependent female genetic background. However, the low PKC levels in summer can still decrease further the low production of IL-2 in T cells of lupus patients augmenting the existing AP-1 defects. This is the first report on the season and female dependent inherited changing of PKC expression in a European white patient with SLE and her mother. Further studies are needed to confirm these findings in other populations.

Determination of Reference Values of MDR-ABC Transporter Activities in CD3+ Lymphocytes of Healthy Volunteers Using a Flow Cytometry Based Method.

BACKGROUND: MDR transporters are important biomarkers of drug resistance in cancer and in autoimmune conditions. We determined the MDR1, MRP1 and BCRP activity in CD3+ lymphocytes using a flow cytometry based method from 120 healthy volunteers in order to describe normal reference values of the activity of these transporters. The effects of gender and age were also determined. METHODS: The Solvo MDQ Kit™ was used for measurements. In this assay, fluorescent reporter substrates (Calcein-AM for MDR1 and MRP1 and mitoxantrone for BCRP, respectively) are trapped in the cytoplasm and pumped out by MDR proteins depending on the presence or absence of specific inhibitors (verapamil for MDR1 and MRP1, indomethacin for MRP1 and KO134 for BCRP, respectively), allowing for quantitative, standardized assessment. Cell surface staining was applied to select CD3+ cells. RESULTS: MAF values of MRP1 and BCRP are independent from age. MAFC and MAF of MDR1 show negative correlation with the age of the studied subjects (P = 0.003, r = -0.27 and P = 0.0001, r = -0.34, respectively). No difference was detected in any of the four MAF values between men and women. Gender does not affect the presence or lack of correlation between MAF values and age. CONCLUSIONS: The determination of the functional activity of MDR-ABC transporters is achievable using a flow cytometry based standardized method. Having established the normal range of MAF values on CD3+ lymphocytes of a healthy population, our results allow for the development of novel flow cytometry based diagnostic tools. © 2018 International Clinical Cytometry Society.

[The standardized mortality numbers of patients with gastrointestinal tumors and cardiovascular diseases in four wine regions and in one not-wine region of Hungary between 2000-2010]. / A gastrointestinalis daganatok és szív-ér rendszeri betegségek standardizált halálozási arányszámai Magyarország négy borvidékén és egy nem borvidéken 2000­2010 között.

INTRODUCTION: Eating habits act on mortalities from gastrointestinal tumors and cardiovascular diseases. AIM: To investigate the role of wine drinking on these mortalities in Hungary. METHOD: The standardized mortality data of people from 206,159 subjects died of gastrointestinal tumors and cardiovascular diseases between 2000-2010 were compared in four wine regions: Tokaj (white), Eger (red), Balaton (white), Szekszárd/Villány (red) and in Hódmezovásárhely (not-wine region). RESULTS: The significantly smallest number of tumors (664) occurred in Tokaj, but the cardiovascular mortality here was the highest (5955). On the other hand, the fewest cardiovascular mortality occurred in Szekszárd/Villány (3907), but showing here (831) and in Eger (934) the highest values of tumor death. CONCLUSIONS: The protective effect of red wine on cardiovascular mortality was verified. Surprisingly, the low value of gastrointestinal mortality in "Tokaj" - besides the higher level of selenium in tap water - shows some hidden features of these white wines. Orv Hetil. 2017; 158(25): 992-998.

Down-regulation of increased TRAF6 expression in the peripheral mononuclear cells of patients with primary Sjögren's syndrome by an EBV-EBER1-specific synthetic single-stranded complementary DNA molecule.

AIM: We described earlier a simultaneously increased that the increased expression of miRNA-146a/b was accompanied by an increase in the expression of and TRAF6 and a decrease in the expression of IRAK1 genes in the peripheral mononuclear cells (PBMCs) of patients with primary Sjogren's syndrome (pSS) patients. Recently, the expression of EBV encoded. RNA (EBER) was published in the B cells of salivary glands of in pSS. In the present study, we applied an EBV-EBER1 specific synthetic single stranded complementary DNA molecule (EBV-EBER1-cDNA) to test whether any EBER1 related effect exists also in PBMCs of pSS patients. METHODS: In the PBMCs of pSS patients and healthy controls, we investigated in vitro the effects of a synthetic single stranded EBV-EBER1-cDNA molecule, synthetic double-stranded (ds)RNA polyinosinic-polycytidylic acid [poly (I:C)] and polyadenylic acid potassium salt poly-adenylic acid [poly-(A)] on the expression of TRAF6 gene tested by qRTPCR. The release of interferon -α was detected by ELISA. RESULTS: EBV-EBER1-cDNA resulted in a significant reduction in the expression of TRAF6 in the cells of patients, but in the healthy controls not, whereas the treatments with poly (I:C) and poly-(A) could not reduce the TRAF6 over-expression. No release of EBER1 could be observed in the culture supernatants of patients with pSS. Only the treatment with poly (I:C) resulted in a significant increase of interferon -α release, and only in the heathy controls. No release of EBER1 molecules took place during the culturing of cells. EBV-EBER- cDNA acted functionally on the cells of patients only. CONCLUSION: These findings give a further evidence of the linkage between EBV and pSS, furthermore, they show the possible role of EBV-EBER1 in the induction of increased TRAF6 expression in the peripheral B cells of Sjögren's patients.

Meloxicam ameliorates the cartilage and subchondral bone deterioration in monoiodoacetate-induced rat osteoarthritis.

OBJECTIVE: This study aimed to quantify the cartilage- and subchondral bone-related effects of low-dose and high-dose meloxicam treatment in the late phase of mono-iodoacetate-induced osteoarthritis of the stifle. METHODS: Thirty-four male Wistar rats received intra-articular injection of mono-iodoacetate to trigger osteoarthritis; 10 control animals (Grp Co) received saline. The mono-iodoacetate-injected rats were assigned to three groups and treated from week 4 to the end of week 7 with placebo (Grp P, n = 11), low-dose (GrpM Lo, 0.2 mg/kg, n = 12) or high-dose (GrpM Hi, 1 mg/kg, n = 11) meloxicam. After a period of 4 additional weeks (end of week 11) the animals were sacrificed, and the stifle joints were examined histologically and immunohistochemically for cyclooxygenase 2, in conformity with recommendations of the Osteoarthritis Research Society International. Serum cytokines IL-6, TNFα and IL-10 were measured at the end of weeks 3, 7, and 11. RESULTS: Compared with saline-treated controls, animals treated with mono-iodoacetate developed various degrees of osteoarthritis. The cartilage degeneration score and the total cartilage degeneration width were significantly lower in both the low-dose (p = 0.012 and p = 0.014) and high-dose (p = 0.003 and p = 0.006) meloxicam-treated groups than in the placebo group. In the subchondral bone, only high-dose meloxicam exerted a significant protective effect (p = 0.011). Low-grade Cox-2 expression observed in placebo-treated animals was abolished in both meloxicam groups. Increase with borderline significance of TNFα in GrpP from week 3 to week 7 (p = 0.049) and reduction of IL-6 in GrpM Lo from week 3 to week 11 (p = 0.044) were observed. CONCLUSION: In this rat model of osteoarthritis, both low-dose and high-dose meloxicam had a chondroprotective effect, and the high dose also protected against subchondral bone lesions. The results suggest a superior protection of the high-dose meloxicam arresting the low-grade inflammatory pathway accompanied by chronic cartilage deterioration.