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BackgroundTakotsubo cardiomyopathy (TTC) is an important complication of subarachnoid hemorrhage (SAH), that may delay surgical or endovascular treatment and may influence patient outcome. This prospective follow-up study intended to collect data on the prevalence, severity, influencing factors and long-term outcome of TTC in patients suffering from non-traumatic SAH.MethodsConsecutive patients admitted with the diagnosis of non-traumatic SAH were included. Intitial assessment consisted of cranial CT, Hunt-Hess, Fisher and WFNS scoring, 12-lead ECG, transthoracic echocardiography (TTE), transcranial duplex sonography and collecting laboratory parameters (CK, CK-MB, cardiac troponin T, NT-proBNP and urine metanephrine and normetanephrine). Diagnosis of TTC was based on modified Mayo criteria. TTC patients were dichotomized to mild and severe forms. Follow-up of TTE, Glasgow Outcome Scale assessment, Barthel's and Karnofsky scoring occurred on days 30 and 180.ResultsOne hundred thirty six patients were included. The incidence of TTC in the entire cohort was 28.7%; of them, 20.6% and 8.1% were mild and severe, respectively. TTC was more frequent in females (30/39; 77%) than in males (9/39; 23%) and was more severe. The occurrence of TTC was related to mFisher scores and WFNS scores. Although the severity of TTC was related to mFisher score, Hunt-Hess score, WFNS score and GCS, multivariate analysis showed the strongest relationship with mFisher scores. Ejection fraction differences between groups were present on day 30, but disappeared by day 180, whereas wall motion score index was still higher in the severe TTC group at day 180. By the end of the follow-up period (180 days), 70 (74.5%) patients survived in the non-TTC, 22 (81.5%) in the mild TTC and 3 (27%) in the severe TTC group (n = 11) (p = 0.002). At day 180, GOS, Barthel, and Karnofsky outcome scores were higher in patients in the control (non-TTC) and the mild TTC groups than in the severe TTC group.ConclusionsTakotsubo cardiomyopathy is a frequent finding in patients with SAH, and severe TTC may be present in 8% of SAH cases. The severity of TTC may be an independent predictor of mortality and outcome at 6 months after disease onset. Therefore, a regular follow-up of ECG and TTE abnormalities is warranted in patients with subrachnoid hemorrhage for early detection of TTC.Trial registrationThe study was registered at the Clinical Trials Register under the registration number of NCT02659878 (date of registration: January 21, 2016).

The importance of researching public support for preventive policies have been amplified by the COVID-19 pandemic. Using a representative sample of the Hungarian population, we investigated the support for commonly used preventive measures (social distancing, hand hygiene and wearing masks) comparing two different policy tools (nudges and regulations). Because of the high risk and unfamiliarity of the pandemic, the respondents' risk perception and experience with the disease was also assessed. All preventive measures were generally supported and, contrary to the findings of previous nudge research, there was no clear pattern whether regulations or nudges are preferred. People with higher level of risk perception supported both types of policies more but slightly favoured the regulations. Those who had contact with the disease (either themselves or a close friend or family member contracting COVID-19) reported a higher level of risk perception. When the person themselves was afflicted, this higher levels of risk perception did not translate to a higher level of support, moreover, it even decreased support for the regulations according to regression analysis. In case of a loved one contracting the disease, there was an increased support for both types of measures, but that is explained by the higher risk perception.

BACKGROUND:The incidence and prevalence of ulcerative colitis (UC) varies geographically. The risk of colorectal cancer (CRC) and possibly some other malignancies is increased among patients with UC. It is still debated if patients with UC are at a greater risk of dying compared with the general population. Our aim was to describe the epidemiology and mortality of the Hungarian UC population from 2010 to 2016 and to analyze the associated malignancies with a special focus on CRC. METHODS:This is an observational, descriptive, epidemiological study based on the National Health Insurance Fund social security databases from 2010 to 2016. All adult patients who had at least two events in outpatient care or at least two medication prescriptions, or at least one inpatient event with UC diagnosis were analyzed. Malignancies and CRC were defined using ICD-10 codes. We also evaluated the survival of patients suffering from UC compared with the general population using a 3 to 1 matched random sample (age, gender, geography) from the full population of Hungary. RESULTS:We found the annual prevalence of UC 0.24-0.34%. The incidence in 2015 was 21.7/100 000 inhabitants. Annual mortality rate was 0.019-0.023%. In this subpopulation, CRC was the most common cancer, followed by non-melanotic skin and prostate cancer. 8.5% of the UC incident subpopulation was diagnosed with CRC. 470 (33%) of the CRC patients died during the course of the study (25% of all deaths were due to CRC), the median survival was 9.6 years. UC patients had significantly worse survival than their matched controls (HR = 1.65, 95% CI: 1.56-1.75). SUMMARY:This is the first population-based study from Eastern Europe to estimate the different malignancies and mortality data amongst Hungarian ulcerative colitis patients. Our results revealed a significantly worse survival of patients suffering from UC compared to the general population.

BACKGROUND:How dental education influences students' dental and dentofacial esthetic perception has been studied for some time, given the importance of esthetics in dentistry. However, no study before has studied this question in a large sample of students from all grades of dental school. This study sought to fill that gap. The aim was to assess if students' dentofacial esthetic autoperception and heteroperception are associated with their actual stage of studies (grade) and if autoperception has any effect on heteroperception. METHODS:Between October 2018 and August 2019, a questionnaire was distributed to 919 dental students of all 5 grades of dental school at all four dental schools in Hungary. The questionnaire consisted of the following parts (see also the supplementary material): 1. Demographic data (3 items), Self-Esthetics I (11 multiple- choice items regarding the respondents' perception of their own dentofacial esthetics), Self-Esthetics II (6 Likert-type items regarding the respondents' perception of their own dentofacial esthetics), and Image rating (10 items, 5 images each, of which the respondents have to choose the one they find the most attractive). Both the self-esthetics and the photo rating items were aimed at the assessment of mini- and microesthetic features. RESULTS:The response rate was 93.7% (861 students). The self-perception of the respondents was highly favorable, regardless of grade or gender. Grade and heteroperception were significantly associated regarding maxillary midline shift (p < 0.01) and the relative visibility of the arches behind the lips (p < 0.01). Detailed analysis showed a characteristic pattern of preference changes across grades for both esthetic aspects. The third year of studies appeared to be a dividing line in both cases, after which a real preference order was established. Association between autoperception and heteroperception could not be verified for statistical reasons. CONCLUSION:Our findings corroborate the results of most previous studies regarding the effect of dental education on the dentofacial esthetic perception of students. We have shown that the effect can be demonstrated on the grade level, which we attribute to the specific curricular contents. We found no gender effect, which, in the light of the literature, suggests that the gender effect in dentofacial esthetic perception is highly culture dependent. The results allow no conclusion regarding the relation between autoperception and heteroperception.

Inflammatory bowel diseases (IBD) [Crohn's disease (CD) and ulcerative colitis (UC)], are chronic relapsing disorders of unknown etiology. The aim of this study was to determine demographic features, disease phenotypes, medical and surgical therapies in our IBD patients and to identify which parameters are in association with the need of surgery and/or biologic therapy. Data on demographic and clinical characteristics of the patients were analyzed from the IBD registry of the 1st Department of Medicine, University of Szeged. The study period was between January 2007 and March 2015. Data of 911 IBD patients (428 CD, 483 UC) were analyzed. The median lag time between onset of symptoms and diagnosis proved to be significantly longer in UC than in CD (4.6 years vs. 2.1 years, p = 0.01). 40% of the patients received biological therapy, 301 patients underwent surgery required more frequently for CD than UC. Surgery was more common in CD patients with ileal location and penetrating behaviour. In UC, more severe disease onset predicted to unfavourable disease course. Higher proportion of surgery was shown in patient aged above 40 years in both CD and UC. Diagnostic delay of more than 1 year and appendectomy predicted to unfavourable disease outcome of both CD and UC. This analysis revealed that more than 1 year of diagnostic delay, disease activity at diagnosis in UC, CD, ileal location and penetrating behaviour are factors that may influence disease outcome. Use of thiopurines seemed to be protective in UC.

Beige adipocytes are special cells situated in the white adipose tissue. Beige adipocytes, lacking thermogenic cues, morphologically look quite similar to regular white adipocytes, but with a markedly different response to adrenalin. White adipocytes respond to adrenergic stimuli by enhancing lipolysis, while in beige adipocytes adrenalin induces mitochondrial biogenesis too. A key step in the differentiation and function of beige adipocytes is the deacetylation of peroxisome proliferator-activated receptor (PPARγ) by SIRT1 and the consequent mitochondrial biogenesis. AMP-activated protein kinase (AMPK) is an upstream activator of SIRT1, therefore we set out to investigate the role of AMPK in beige adipocyte differentiation using human adipose-derived mesenchymal stem cells (hADMSCs) from pericardial adipose tissue. hADMSCs were differentiated to white and beige adipocytes and the differentiation medium of the white adipocytes was supplemented with 100 μM [(2R,3S,4R,5R)-5-(4-Carbamoyl-5-aminoimidazol-1-yl)-3,4-dihydroxyoxolan-2-yl]methyl dihydrogen phosphate (AICAR), a known activator of AMPK. The activation of AMPK with AICAR led to the appearance of beige-like morphological properties in differentiated white adipocytes. Namely, smaller lipid droplets appeared in AICAR-treated white adipocytes in a similar fashion as in beige cells. Moreover, in AICAR-treated white adipocytes the mitochondrial network was more fused than in white adipocytes; a fused mitochondrial system was characteristic to beige adipocytes. Despite the morphological similarities between AICAR-treated white adipocytes and beige cells, functionally AICAR-treated white adipocytes were similar to white adipocytes. We were unable to detect increases in basal or cAMP-induced oxygen consumption rate (a marker of mitochondrial biogenesis) when comparing control and AICAR-treated white adipocytes. Similarly, markers of beige adipocytes such as TBX1, UCP1, CIDEA, PRDM16 and TMEM26 remained the same when comparing control and AICAR-treated white adipocytes. Our data point out that in human pericardial hADMSCs the role of AMPK activation in controlling beige differentiation is restricted to morphological features, but not to actual metabolic changes.

Cancer cells are characterized by metabolic alterations, namely, depressed mitochondrial oxidation, enhanced glycolysis and pentose phosphate shunt flux to support rapid cell growth, which is called the Warburg effect. In our study we assessed the metabolic consequences of a joint treatment of MCF-7 breast cancer cells with AICAR, an inducer of AMP-activated kinase (AMPK) jointly with methotrexate (MTX), a folate-analog antimetabolite that blunts de novo nucleotide synthesis. MCF7 cells, a model of breast cancer cells, were resistant to the individual application of AICAR or MTX, however combined treatment of AICAR and MTX reduced cell proliferation. Prolonged joint application of AICAR and MTX induced AMPK and consequently enhanced mitochondrial oxidation and reduced the rate of glycolysis. These metabolic changes suggest an anti-Warburg rearrangement of metabolism that led to the block of the G1/S and the G2/M transition slowing down cell cycle. The slowdown of cell proliferation was abolished when mitotropic transcription factors, PGC-1α, PGC-1β or FOXO1 were silenced. In human breast cancers higher expression of AMPKα and FOXO1 extended survival. AICAR and MTX exerts similar additive antiproliferative effect on other breast cancer cell lines, such as SKBR and 4T1 cells, too. Our data not only underline the importance of Warburg metabolism in breast cancer cells but nominate the AICAR+MTX combination as a potential cytostatic regime blunting Warburg metabolism. Furthermore, we suggest the targeting of AMPK and FOXO1 to combat breast cancer.

Glycogen phosphorylase (GP) catalyzes the breakdown of glycogen and largely contributes to hepatic glucose production making GP inhibition an attractive target to modulate glucose levels in diabetes. Hereby we present the metabolic effects of a novel, potent, glucose-based GP inhibitor (KB228) tested in vitro and in vivo under normoglycemic and diabetic conditions. KB228 administration enhanced glucose sensitivity in chow-fed and obese, diabetic mice that was a result of higher hepatic glucose uptake. Besides improved glucose sensitivity, we have observed further unexpected metabolic rearrangements. KB228 administration increased oxygen consumption that was probably due to the overexpression of uncoupling protein-2 (UCP2) that was observed in animal and cellular models. Furthermore, KB228 treatment induced mammalian target of rapamycin complex 2 (mTORC2) in mice. Our data demonstrate that glucose based GP inhibitors are capable of reducing glucose levels in mice under normo and hyperglycemic conditions. Moreover, these GP inhibitors induce accommodation in addition to GP inhibition--such as enhanced mitochondrial oxidation and mTORC2 signaling--to cope with the glucose influx and increased glycogen deposition in the cells, however the molecular mechanism of accommodation is unexplored.

Biomedical experimental work often focuses on altering the functions of selected proteins. These changes can hit signaling pathways, and can therefore unexpectedly and non-specifically affect cellular processes. We propose PathwayLinker, an online tool that can provide a first estimate of the possible signaling effects of such changes, e.g., drug or microRNA treatments. PathwayLinker minimizes the users' efforts by integrating protein-protein interaction and signaling pathway data from several sources with statistical significance tests and clear visualization. We demonstrate through three case studies that the developed tool can point out unexpected signaling bias in normal laboratory experiments and identify likely novel signaling proteins among the interactors of known drug targets. In our first case study we show that knockdown of the Caenorhabditis elegans gene cdc-25.1 (meant to avoid progeny) may globally affect the signaling system and unexpectedly bias experiments. In the second case study we evaluate the loss-of-function phenotypes of a less known C. elegans gene to predict its function. In the third case study we analyze GJA1, an anti-cancer drug target protein in human, and predict for this protein novel signaling pathway memberships, which may be sources of side effects. Compared to similar services, a major advantage of PathwayLinker is that it drastically reduces the necessary amount of manual literature searches and can be used without a computational background. PathwayLinker is available at http://PathwayLinker.org. Detailed documentation and source code are available at the website.