A paracetamolterápia és az idült májbetegség tragikus következményei

Az őszi és téli meghűléses időszakban sokan vásárolnak különböző, vény nélkül kapható, megfázás elleni készítmé- nyeket, ezen belül is nagy számban paracetamol- (más néven acetaminofén-) tartalmú szereket. A paracetamol külön- böző típusú fájdalmak (fejfájás, migrén, meghűlés-láz okozta fájdalom, fogfájás, menstruációs fájdalom stb.) enyhíté- sére szolgáló, igen népszerű, a nemopioid típusú analgetikumok közé sorolható hatóanyag, amely többek között tabletta, kúp és oldat formájában is elérhető a gyógyszertárakban. Magyarországon 2020-ban 86, törzskönyvezett paracetamoltartalmú készítmény van forgalomban. A paracetamol alkalmazása biztonságos és hatékony, amennyiben az előírásnak megfelelően használják. Közleményünkben három olyan esetet mutatunk be, amelyben a beteg halála összefüggésbe hozható a paracetamol alkalmazásával. Mindhárom, krónikus alkoholizmusban szenvedő beteg (34, 42 és 51 évesek) rövid idővel a kórházba kerülés után elhunyt. Vizsgálataink során három betegből származó, össze- sen kilenc szérumminta került feldolgozásra. A paracetamolnak és metabolitjainak együttes meghatározása enzimati- kus módszerrel (Roche assay) történt, míg a paracetamol specifikus mérésére tandem-tömegspektrométerrel kapcsolt szuperkritikus folyadékkromatográfot (SFC–MS/MS) alkalmaztunk. Enzimatikus meghatározással mindegyik min- tában terápiás koncentrációt mutattunk ki. SFC–MS/MS módszerrel történt meghatározás esetén egy betegtől szár- mazó négy mintában a terápiás tartománynál alacsonyabb paracetamolkoncentrációkat mértünk. A paracetamol- terápia alkalmazása krónikus alkoholizmusban szenvedő betegek esetén fokozott kockázatot jelent. A klinikai toxikológiai gyakorlatban a paracetamol meghatározására használt enzimatikus módszer eredményét a máj- és vese- funkciós paraméterekkel együttesen szükséges értékelni, mert krónikus alkoholizmusban szenvedő betegek esetén az enzimatikus módszerrel kapott terápiás tartományba eső koncentráció nem zárja ki a paracetamoltoxicitást

O-GlcNAcylation in early stages of chronic lymphocytic leukemia; protocol development for flow cytometry

Recent studies proved that metabolic changes in malignant disorders have an impact on protein glycosylation, however, only a few attempts have been made so far to use O-GlcNAc analysis as a prognostic tool. Glucose metabolism is reported to be altered in hematological malignancies thus, we hypothesized that monitoring intracellular O-GlcNAc levels in Rai stage 0-I (Binet A) CLL patients could give deeper insights regarding subtle metabolic changes of progression which are not completely detected by the routine follow-up procedures.In this proof of concept study we established a flow cytometric detection method for the assessment of O-GlcNAcylation as a possible prognostic marker in CLL malignancy which was supported by fluorescence microscopy.Healthy volunteers and CLL patients were recruited for this study. Lymphocytes were isolated, fixed and permeabilised by various methods to find the optimal experimental condition for O-GlcNAc detection by flow cytometry. O-GlcNAc levels were measured and compared to lymphocyte count and various blood parameters including plasma glucose level.The protocol we developed includes red blood cell lysis, formalin fixation, 0.1% Tween 20 permeabilisation and employs standardized cell number per sample and unstained controls. We have found significant correlation between O-GlcNAc levels and WBC (R2= 0.8535, p< 0.0029) and lymphocyte count (R2= 0.9225, p< 0.0006) in CLL patients. Interestingly, there was no such correlation in healthy individuals (R2= 0.05664 for O-GlcNAc vs WBC and R2= 0.04379 for O-GlcNAc vs lymphocytes).Analyzing O-GlcNAc changes in malignant disorders, specifically in malignant hematologic diseases such as CLL, could be a useful tool to monitor the progression of the disease

The characteristics and prognostic role of acute abdominal on-admission pain in acute pancreatitis: A prospective cohort analysis of 1432 cases

Introduction Pain is the most common symptom in acute pancreatitis (AP) and is among the diagnostic criteria. Therefore, we aimed to characterize acute abdominal pain in AP. Methods The Hungarian Pancreatic Study Group prospectively collected multicentre clinical data on 1435 adult AP patients between 2012 and 2017. Pain was characterized by its intensity (mild or intense), duration prior to admission (hours), localization (nine regions of the abdomen) and type (sharp, dull or cramping). Results 97.3% of patients (n = 1394) had pain on admission. Of the initial population with acute abdominal pain, 727 patients answered questions about pain intensity, 1148 about pain type, 1134 about pain localization and 1202 about pain duration. Pain was mostly intense (70%, n = 511/727), characterized by cramping (61%, n = 705/1148), mostly starting less than 24 h prior to admission (56.7%, n = 682/1202). Interestingly, 50.9% of the patients (n = 577/1134) had atypical pain, which means pain other than epigastric or belt-like upper abdominal pain. We observed a higher proportion of peripancreatic fluid collection (19.5% vs. 11.0%; p = 0.009) and oedematous pancreas (8.4% vs. 3.1%; p = 0.016) with intense pain. Sharp pain was associated with AP severity (OR = 2.481 95% CI: 1.550-3.969) and increased mortality (OR = 2.263, 95% CI: 1.199-4.059) compared to other types. Longstanding pain (>72 h) on admission was not associated with outcomes. Pain characteristics showed little association with the patient's baseline characteristics. Conclusion A comprehensive patient interview should include questions about pain characteristics, including pain type. Patients with sharp and intense pain might need special monitoring and tailored pain management. Significance Acute abdominal pain is the leading presenting symptom in acute pancreatitis; however, we currently lack specific guidelines for pain assessment and management. In our cohort analysis, intense and sharp pain on admission was associated with higher odds for severe AP and several systemic and local complications. Therefore, a comprehensive patient interview should include questions about pain characteristics and patients with intense and sharp pain might need closer monitoring

A SARS-CoV-2-pandémia hatása a vérkészítmény-felhasználásra a Pécsi Tudományegyetemen

Összefoglaló. Bevezetés: A COVID-19-világjárvány betegellátásra gyakorolt hatása hazánkban is jelentős. A vérellátást nehezítette a járványügyi intézkedések következményeként a véradási események elmaradása, a csökkent véradási hajlandóság, továbbá a nehezen megítélhető vérkészítményigény . A "Patient Blood Management" irányelveinek az orvosi gyakorlatban történő egyre szélesebb körű alkalmazása elősegíti az optimális vérkészítmény-felhasználást a transzfúziók lehetőség szerinti elkerülésével. Célkitűzés és módszer: Vizsgálatunk célja a Pécsi Tudományegyetem Klinikai Központjának Janus Pannonius Klinikai Tömbjében a vérkészítmény-felhasználás változásainak felmérése volt a 2020. év első öt hónapjában. Eredmények: A járványügyi intézkedéseket követő időszakban szignifikánsan csökkent a hospitalizált betegeknek (34,08%), a transzfúziót igénylő betegeknek (39,69%) és a felhasznált vörösvérsejt-készítményeknek (46,41%) a száma, valamint az egy betegre jutó felhasznált vörösvérsejt-koncentrátum átlaga (2,61-ről 1,97-re) is. Közel 30%-os arányban csökkent a felhasznált friss fagyasztott plazma egységeinek és a thrombocytakoncentrátumoknak a száma is. Következtetés: A szigorú korlátozások életbe léptetését követően a nehézségek ellenére sikerült elegendő mennyiségű vérkészítményt biztosítani a betegeknek. Az Országos Vérellátó Szolgálat Pécsi Regionális Vérellátó Központja munkatársainak és a klinikusok erőfeszítéseinek köszönhetően a vérkészítményigény és -kínálat között új egyensúly alakult ki, mely megfelelő ellátást biztosított a feltétlenül szükséges transzfúziók kivitelezéséhez. Orv Hetil. 2021; 162(43): 1717-1723.The impact of COVID-19 pandemic on patient care is pronounced also in Hungary. Blood supply was hindered by the reduction of public blood donation events, the reduced willingness to donate, and the difficult predictability of blood product demand as a result of the epidemiological regulations. The wider application of Patient Blood Management guidelines in the medical practice will promote optimal blood product utilization by avoiding transfusions where possible.The aim of our study was to assess the changes in the usage of blood products in the first five months of 2020 at the Clinical Center of the University of Pécs, Janus Pannonius Clinical Building.In the period following the epidemiological measures, we found reduction in the number of hospitalized patients (34.08%), in the number of patients requiring transfusion (39.69%) and in the number of red blood cell products used (46.41%). The number of transfused red blood cell concentrates per patient was also significantly reduced (from 2.61 to 1.97) in this period. The number of transfused fresh frozen plasma units and platelet concentrates also decreased by approximately 30%.After the implementation of the strict restrictions, despite the difficulties, it was possible to provide patients with sufficient blood products. Due to the efforts of both the Regional Blood Transfusion Center of Pécs of the Hungarian National Blood Transfusion Service and of the clinicians, a new balance was established between the demand and the supply of blood products, which provided adequate care for the necessary transfusions. Orv Hetil. 2021; 162(43): 1717-1723

Analysis of COVID-19-Related RT-qPCR Test Results in Hungary : Epidemiology, Diagnostics, and Clinical Outcome

Background: Effective testing is an essential tool for controlling COVID-19. We aimed to analyse the data from first-wave PCR test results in Hungary's Southern Transdanubian region to improve testing strategies. Methods: We performed a retrospective analysis of all suspected COVID-19 cases between 17 March and 8 May 2020, collecting epidemiological, demographic, clinical and outcome data (ICU admission and mortality) with RT-qPCR test results. Descriptive and comparative statistical analyses were conducted. Results: Eighty-six infections were confirmed among 3,657 tested patients. There was no difference between the positive and negative cases in age and sex distribution; however, ICU admission (8.1 vs. 3.1%, p = 0.006) and in-hospital mortality (4.7 vs. 1.6%, p = 0.062) were more frequent among positive cases. Importantly, none of the initially asymptomatic patients (n = 20) required ICU admission, and all survived. In almost all cases, if the first test was negative, second and third tests were performed with a 48-h delay for careful monitoring of disease development. However, the positive hit rate decreased dramatically with the second and third tests compared to the first (0.3 vs. 2.1%, OR = 0.155 [0.053-0.350]). Higher E-gene copy numbers were associated with a longer period of PCR positivity. Conclusion: In our immunologically naïve suspected COVID-19 population, coronavirus infection increased the need for intensive care and mortality by 3-4 times. In the event of the exponential phase of the pandemic involving a bottleneck in testing capacity, a second or third test should be reconsidered to diagnose more coronavirus infections

Novel coronavirus epidemic in the Hungarian population, a cross-sectional nationwide survey to support the exit policy in Hungary

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Loss-of-Function Variants in a Hungarian Cohort Reveal Structural Insights on TSH Receptor Maturation and Signaling

Context Congenital hypothyroidism (CH) is one of the most common inborn endocrine disorders with genetic background. Despite the well-established newborn CH screening program in Hungary, no systematic examination of the underlying genetic alterations has been performed yet. Objective We aimed to explore thyrotropin receptor (TSHR) mutations in a cohort of Hungarian patients with CH. Patients 85 unrelated patients with permanent primary CH, all diagnosed at newborn screening, were selected. Main outcome measures Coding exons of the TSHR gene were sequenced and evaluated together with the thyroid-specific clinical parameters. Functional features of the novel mutations were experimentally examined, and their comparative molecular models were built. Results In 4 patients (one heterozygous and three compound heterozygous) 7 TSHR mutations were identified. Among these N4321.50D and P4492.39L are novel missense alterations. Importantly, the N4321.50 residue is highly conserved among G protein-coupled receptors (GPCR-s), and its function has not been examined yet in human glycoprotein hormone receptors (GPHR-s). Our results indicate that the N4321.50D mutation disrupts important, architecture-stabilizing intramolecular interactions, and ultimately lead to the complete intracellular retention of the receptor. On the other hand P4492.39 is located in the intracellular part of the receptor which is important in G protein coupling. The P4492.39L mutation results in signaling impairment, with a more profound effect on the Gq/11 pathway. Conclusion TSHR mutations are common among Hungarian patients with CH. The novel genetic alterations revealed important structural role of the N4321.50 and the P4492.39 residues in receptor expression and signaling, respectively

High versus low energy administration in the early phase of acute pancreatitis (GOULASH trial): protocol of a multicentre randomised double-blind clinical trial

INTRODUCTION: Acute pancreatitis (AP) is an inflammatory disease with no specific treatment. Mitochondrial injury followed by ATP depletion in both acinar and ductal cells is a recently discovered early event in its pathogenesis. Importantly, preclinical research has shown that intracellular ATP delivery restores the physiological function of the cells and protects from cell injury, suggesting that restoration of energy levels in the pancreas is therapeutically beneficial. Despite several high quality experimental observations in this area, no randomised trials have been conducted to date to address the requirements for energy intake in the early phase of AP. METHODS/DESIGN: This is a randomised controlled two-arm double-blind multicentre trial. Patients with AP will be randomly assigned to groups A (30 kcal/kg/day energy administration starting within 24 hours of hospital admission) or B (low energy administration during the first 72 hours of hospital admission). Energy will be delivered by nasoenteric tube feeding with additional intravenous glucose supplementation or total parenteral nutrition if necessary. A combination of multiorgan failure for more than 48 hours and mortality is defined as the primary endpoint, whereas several secondary endpoints such as length of hospitalisation or pain will be determined to elucidate more detailed differences between the groups. The general feasibility, safety and quality checks required for high quality evidence will be adhered to. ETHICS AND DISSEMINATION: The study has been approved by the relevant organisation, the Scientific and Research Ethics Committee of the Hungarian Medical Research Council (55961-2/2016/EKU). This study will provide evidence as to whether early high energy nutritional support is beneficial in the clinical management of AP. The results of this trial will be published in an open access way and disseminated among medical doctors. TRIAL REGISTRATION: The trial has been registered at the ISRCTN (ISRTCN 63827758)

O-GlcNAcylation Suppresses the Ion Current IClswell by Preventing the Binding of the Protein ICln to α-Integrin

O-GlcNAcylation is a post-translational modification of proteins that controls a variety of cellular processes, is chronically elevated in diabetes mellitus, and may contribute to the progression of diabetic complications, including diabetic nephropathy. Our previous work showed that increases in the O-GlcNAcylation of cellular proteins impair the homeostatic reaction of the regulatory volume decrease (RVD) after cell swelling by an unknown mechanism. The activation of the swelling-induced chloride current IClswell is a key step in RVD, and ICln, a ubiquitous protein involved in the activation of IClswell, is O-GlcNAcylated. Here, we show that experimentally increased O-GlcNAcylation of cellular proteins inhibited the endogenous as well as the ICln-induced IClswell current and prevented RVD in a human renal cell line, while decreases in O-GlcNAcylation augmented the current magnitude. In parallel, increases or decreases in O-GlcNAcylation, respectively, weakened or stabilized the binding of ICln to the intracellular domain of α-integrin, a process that is essential for the activation of IClswell. Mutation of the putative YinOYang site at Ser67 rendered the ICln-induced IClswell current unresponsive to O-GlcNAc variations, and the ICln interaction with α-integrin insensitive to O-GlcNAcylation. In addition, exposure of cells to a hypotonic solution reduced the O-GlcNAcylation of cellular proteins. Together, these findings show that O-GlcNAcylation affects RVD by influencing IClswell and further indicate that hypotonicity may activate IClswell by reducing the O-GlcNAcylation of ICln at Ser67, therefore permitting its binding to α-integrin. We propose that disturbances in the regulation of cellular volume may contribute to disease in settings of chronically elevated O-GlcNAcylation, including diabetic nephropathy