Publications by authors named "Zoltan Szabo"

268 Publications

Clinical, surgical, and pathological findings in client-owned rabbits with histologically confirmed appendicitis: 19 cases (2015-2019).

J Am Vet Med Assoc 2022 Jan 1:1-12. Epub 2022 Jan 1.

AbLab Veterinary Diagnostic Laboratory, Sarzana, Italy.

Objective: To report clinical, surgical, and pathological findings in client-owned rabbits with histologically confirmed appendicitis.

Animals: 19 rabbits.

Procedures: Medical records for client-owned rabbits that had a histologic diagnosis of appendicitis were reviewed.

Results: Median age of the rabbits at presentation was 24.0 months (range, 4 to 84 months). Seventeen cases occurred during the summer and fall seasons. Decreased appetite (17/19 rabbits), abnormal rectal temperature (hyperthermia, 9/16 rabbits; hypothermia, 4/16 rabbits), hypocalcemia (8/11 rabbits), and hypoglycemia (7/15 rabbits) were common signs. Abdominal ultrasonography and CT findings were suggestive of appendicitis in 6 of 8 rabbits and in 1 of 2 rabbits, respectively. Of the 6 rabbits that received medical treatment, 3 died at 48 hours, 1 died at 24 hours after hospitalization, and 1 died at 10 days after presentation; 1 rabbit was alive at 1,030 days after presentation. Of the 8 rabbits that underwent appendectomy, 3 died before discharge from the hospital and 1 died 113 days after surgery; 4 rabbits were alive at 315, 334, 1,433, and 1,473 days after presentation. The remaining 5 rabbits either died or were euthanized before treatment could be instituted. In each of the 19 rabbits, the appendix had evidence of severe inflammation with mucosal ulceration, heterophilic inflammation, and necrotic debris.

Clinical Relevance: For rabbits with decreased appetite and an apparently painful abdomen, hyperthermia, hypocalcemia, or hypoglycemia, appendicitis should be considered as a differential diagnosis. Further comparisons of medical and surgical treatments are required to establish treatment recommendations for rabbits with appendicitis.
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http://dx.doi.org/10.2460/javma.20.08.0446DOI Listing
January 2022

Screening of (sections and ) germplasm for reactions to the tomato brown rugose fruit virus (ToBRFV).

J Plant Dis Prot (2006) 2021 Oct 9:1-7. Epub 2021 Oct 9.

Applied Plant Genomics Group, Institute of Genetics and Biotechnology, Hungarian University of Agriculture and Life Sciences, Gödöllő, 2100 Hungary.

The reaction of 636 (sections and ) accessions were evaluated under greenhouse conditions after mechanical inoculation with a Jordanian isolate of the new tobamovirus tomato brown rugose fruit virus (ToBRFV). Local and systemic infections were assayed by symptoms evaluation and virus detection via biotests and RT-PCR. All cultivated tomatoes () and the great majority of wild tomato accessions proved susceptible to ToBRFV. They showed a wide range of symptoms (mosaic, leaf deformations, mottling, shoestring, and stunting). Twenty-six accessions representing var. cerasiforme, , and were tolerant. High levels of resistance have been demonstrated in three accessions of , a close relative to wild tomatoes (member of the sect. ) not only to ToBRFV but also to the tobamoviruses, tobacco mosaic virus (TMV) and tomato mosaic virus (ToMV). After mechanical inoculation, the three tobamoviruses could be detected only in inoculated leaves in the accessions LA2160, LA2162, and LA 2166, which remained symptomless. However, two other accessions PI 473,498 and PI 230,519 reacted unusually. They were demonstrated highly resistant to TMV and ToMV, but proved transiently susceptible to ToBRFV showing mild systemic mosaic followed by total recovery from symptoms and the virus.

Supplementary Information: The online version contains supplementary material available at 10.1007/s41348-021-00535-x.
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http://dx.doi.org/10.1007/s41348-021-00535-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8501354PMC
October 2021

Low Levels of Serum Fetuin-A and Retinol-Binding Protein 4 Correlate with Lipoprotein Subfractions in Morbid Obese and Lean Non-Diabetic Subjects.

Life (Basel) 2021 Aug 27;11(9). Epub 2021 Aug 27.

Department of Internal Medicine, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary.

Background: Fetuin-A and retinol-binding protein 4 (RBP4) are secreted as both hepatokine and adipokine. These are involved in insulin resistance, obesity-related dyslipidemia, and atherosclerosis. To date, correlations of circulating fetuin-A and RBP4 with lipoprotein subfractions as well as high-density lipoprotein (HDL)-linked proteins have not been entirely investigated in morbid obese and lean non-diabetic subjects.

Methods: One-hundred obese non-diabetic patients (body mass index, BMI: 42.5 ± 8.1 kg/m) along with 32 gender and age-matched normal weight controls (BMI: 24.5 ± 2.5 kg/m) were enrolled in our study. Serum fetuin-A and RBP4 were measured by ELISA. Lipoprotein subfractions were distributed by Lipoprint gelelectrophoresis.

Results: Serum fetuin-A and RBP4 were unexpectedly lower in obese patients ( < 0.01 and < 0.01, respectively) compared to controls and correlated with each other (r = 0.37; < 0.001). Fetuin-A had positive correlations with HDL-C (r = 0.22; = 0.02), apolipoprotein AI (apoAI) (r = 0.33; < 0.001), very-low density lipoprotein (VLDL) subfraction (r = 0.18; = 0.05), and large HDL subfraction levels (r = 0.3; = 0.001) but did not show correlation with carbohydrate parameters in all subjects. RBP4 correlated positively with HDL-C (r = 0.2; = 0.025), apoAI (r = 0.23; = 0.01), VLDL subfraction (r = 0.37; < 0.001), intermediate HDL subfraction (r = 0.23; = 0.01), and small HDL subfraction (r = 0.21; = 0.02) concentrations, as well as C-peptide levels in overall participants. Backward stepwise multiple regression analysis showed that serum fetuin-A concentration is best predicted by RBP4 and large HDL subfraction. In model 2, VLDL subfraction was the independent predictor of serum RBP4 level.

Conclusions: Our data may indicate a potential role of fetuin-A and RBP4 in impaired lipoprotein metabolism associated with obesity.
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http://dx.doi.org/10.3390/life11090881DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8471801PMC
August 2021

Total Sleep Deprivation Followed by Bright Light Therapy as Rapid Relief for Depression: A Pragmatic Randomized Controlled Trial.

Front Psychiatry 2021 30;12:705090. Epub 2021 Aug 30.

University of Gothenburg, Sahlgrenska Academy, Institute of Neuroscience and Physiology, Gothenburg, Sweden.

Total sleep deprivation (TSD) combined with bright light therapy (BLT) has been suggested as a valuable add-on to standard treatment for rapid relief of depression. However, there is a lack of randomized controlled trials in real-life clinical settings. The aim of this pragmatic randomized clinical trial was to investigate the effectiveness, acceptance, and feasibility of TSD combined with BLT as add-on to standard treatment for depression in a real-life clinical setting. Thirty-three inpatients were randomly assigned to either: a) an intervention group receiving a single-night TSD followed by 6 days BLT (10.000 lux, 30 min/day) as add-on to standard treatment; or b) a control group receiving a short sleep-hygiene consultation in addition to standard treatment. The follow-up period was 1 week. No statistical differences were found in response rates, reduction of depressive and insomnia symptoms, length of stay, readmission rate, and clinical improvement. Both groups reported positive experiences toward the received treatment with low drop-out rates. One-night TSD followed by BLT was not effective as a rapid relief for depression at 1-week follow-up; however, the treatment was feasible and well-tolerated.
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http://dx.doi.org/10.3389/fpsyt.2021.705090DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8435586PMC
August 2021

The Effect of Core Replacement on S64315, a Selective MCL-1 Inhibitor, and Its Analogues.

ACS Omega 2021 Aug 18;6(34):22073-22102. Epub 2021 Aug 18.

Servier Research Institute of Medicinal Chemistry, Záhony u. 7., H-1031 Budapest, Hungary.

Following the identification of thieno[2,3-]pyrimidine-based selective and potent inhibitors of MCL-1, we explored the effect of core swapping at different levels of advancement. During hit-to-lead optimization, X-ray-guided S-N replacement in the core provided a new vector, whose exploration led to the opening of the so-called deep-S2 pocket of MCL-1. Unfortunately, the occupation of this region led to a plateau in affinity and had to be abandoned. As the project approached selection of a clinical candidate, a series of core swap analogues were also prepared. The affinity and cellular activity of these compounds showed a significant dependence on the core structure. In certain cases, we also observed an increased and accelerated epimerization of the atropoisomers. The most potent core replacement analogues showed considerable PD response. One compound was progressed into efficacy studies and inhibited tumor growth.
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http://dx.doi.org/10.1021/acsomega.1c02595DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8412899PMC
August 2021

Possible Biochemical Processes Underlying the Positive Health Effects of Plant-Based Diets-A Narrative Review.

Nutrients 2021 Jul 28;13(8). Epub 2021 Jul 28.

Institute of Nutritional Sciences and Dietetics, Faculty of Health Sciences, University of Pecs, 7621 Pecs, Hungary.

Plant-based diets are becoming more popular for many reasons, and epidemiological as well as clinical data also suggest that a well-balanced vegan diet can be adopted for the prevention, and in some cases, in the treatment of many diseases. In this narrative review, we provide an overview of the relationships between these diets and various conditions and their potential biochemical background. As whole plant foods are very rich in food-derived antioxidants and other phytochemicals, they have many positive physiological effects on different aspects of health. In the background of the beneficial health effects, several biochemical processes could stand, including the reduced formation of trimethylamine oxide (TMAO) or decreased serum insulin-like growth factor 1 (IGF-1) levels and altered signaling pathways such as mechanistic target of rapamycin (mTOR). In addition, the composition of plant-based diets may play a role in preventing lipotoxicity, avoiding N-glycolylneuraminic acid (Neu5Gc), and reducing foodborne endotoxin intake. In this article, we attempt to draw attention to the growing knowledge about these diets and provide starting points for further research.
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http://dx.doi.org/10.3390/nu13082593DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8398942PMC
July 2021

First report of sweet potato chlorotic stunt virus infecting sweet potatoes in Hungary.

Plant Dis 2021 Aug 25. Epub 2021 Aug 25.

Hungarian University of Agriculture and Life Sciences, 72402, Institute of Genetics and Biotechnology, Applied Plant Genomics Group, Godollo, Pest, Hungary;

Sweet potato chlorotic stunt virus (SPCSV), a crinivirus in the family Closteroviridae, is a quarantine pest in Europe and one of the most economically important viruses of sweet potato (Ipomoea batatas (L.) Lam) crops globally. It forms synergies with other viruses in sweet potato, leading to yield loss of 30-100% (Qin et al., 2014). In summer 2020, 62 symptomatic and 38 symptomless sweet potato vines were randomly collected in farmers' fields in the south (Ásotthalom, Szeged) and central (Galgahévíz) parts of Hungary and transplanted in an insect-proof greenhouse. Six of the plants expressed SPCSV-like symptoms, including stunting, vein clearing and leaf purpling (Suppl1). To check for common viruses of sweet potato (Suppl2), total RNA and DNA were extracted from leaves of each of the 100 plants using Trizolate reagent (UD-GenoMed, Debrecen, Hungary) and Zenogene kit (Zenon Bio, Szeged, Hungary), respectively. Primer pair Ch2N (Suppl2) was designed using Primer3 (v. 0.4.0) to amplify a 194 bp fragment of SPCSV RNA1. Presence of the RNA viruses was checked by qPCR using qPCRBIO SyGreen 1-step qPCR kit (PCR Biosystems, London, UK), while DNA viruses were checked by PCR using DreamTaq DNA Polymerase (Thermo Scientific, Vilnius, Lithuania), followed by 1% agarose gel electrophoresis. Four samples (labelled A5.1, A6.1, A6V9-1, A6V9-2) out of the 100 tested positive for SPCSV. Two of them (A6V9-1 and A6V9-2) were co-infected with SPCSV, a badnavirus sweet potato pakakuy virus (SPPV) and a potyvirus sweet potato virus 2 (SPV2), while the other two (A5.1 and A6.1) lacked SPV2. Plants infected with SPCSV, SPV2 and SPPV displayed more severe symptoms. To confirm the results, cDNA synthesized from the four SPCSV positive samples using RevertAid first strand cDNA synthesis kit (Thermo Scientific, Vilnius, Lithuania) underwent PCR (94oC 4 min, 94oC 1 min, 53oC 30 s, 72oC 70 s and 72oC 10 min for a total of 30 cycles) using primers CL43U and CL43L for the viral heat shock protein 70 gene (Maliogka et al., 2020). An expected band size of 486 bp was obtained in all cases. The amplicon from sample A6.1 was sequenced and found to be identical to SPCSV Guatemalan isolate GT:B3:08 (acc. JF699628). RNA1 and RNA2 complete sequences from sample A6.1 were obtained via PCR amplifications of cDNA using primers (Suppl2) designed (from acc. KC888966 for RNA1 and acc. KC888963 for RNA2) to amplify overlapping fragments of West African strain of SPCSV. QIAquick gel extraction kit (QIAGEN, Hilden, Germany) was used to purify the PCR fragments, which were then cloned into pGEM-T Easy Vector (Promega, Madison, USA) and sequenced using Sanger sequencing technique (Biomi, Gödöllő, Hungary). BLASTn search revealed that RNA1 of our isolate Hun_01 (acc. MW892835) had 99.63% sequence identity to SPCSV isolate su-17-10 (acc. MK802073), while RNA2 of Hun_01 (acc. MW892836) was 99.68% similar to SPCSV isolate min-17-1 (acc. MK802078) and isolate 24-1 (acc. MK802080). Phylogenetic analysis using MegAlign (v. 7.1.0, 44.1) showed a close relationship between our isolate and those isolated in China, suggesting that they may have a common origin (Suppl1). Severe stunting and leaf yellowing symptoms developed in I. setosa indicator plants grafted with SPCSV infected sweet potato scions. qPCR test for the virus confirmed its presence in the I. setosa leaves. To the best of our knowledge, this is the first report on the occurrence of SPCSV in Hungary and the third in Europe (Valverde et al. 2004; EPPO 2021).
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http://dx.doi.org/10.1094/PDIS-05-21-0944-PDNDOI Listing
August 2021

Methods and Experiments for Sensing Variations in Solar Activity and Defining Their Impact on Heart Variability.

Sensors (Basel) 2021 Jul 14;21(14). Epub 2021 Jul 14.

Department of Theoretical and Experimental Electrical Engineering, Brno University of Technology, 616 00 Brno, Czech Republic.

This paper evaluates variations in solar activity and their impact on the human nervous system, including the manner in which human behavior and decision-making reflect such effects in the context of (symmetrical) social interactions. The relevant research showed that solar activity, manifesting itself through the exposure of the Earth to charged particles from the Sun, affects heart variability. The evaluation methods focused on examining the relationships between selected psychophysiological data and solar activity, which generally causes major alterations in the low-level electromagnetic field. The investigation within this paper revealed that low-level EMF changes are among the factors affecting heart rate variability and, thus, also variations at the spectral level of the rate, in the VLF, (f = 0.01-0.04 Hz), LF (f = 0.04-0.15 Hz), and HF (f = 0.15 až 0.40 Hz) bands. The results of the presented experiments can also be interpreted as an indirect explanation of sudden deaths and heart failures.
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http://dx.doi.org/10.3390/s21144817DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8309774PMC
July 2021

Cardiopulmonary Resuscitation With Mechanical Chest Compression Device During Percutaneous Coronary Intervention. A Case Report.

Front Cardiovasc Med 2021 10;8:614493. Epub 2021 Jun 10.

Department of Emergency Medicine, Faculty of Medicine, University of Debrecen, Debrecen, Hungary.

Sudden cardiac death is a leading cause of death worldwide, whereby myocardial infarction is considered the most frequent underlying condition. Percutaneous coronary intervention (PCI) is an important component of post-resuscitation care, while uninterrupted high-quality chest compressions are key determinants in cardiopulmonary resuscitation (CPR). In our paper, we evaluate a case of a female patient who suffered aborted cardiac arrest due to myocardial infarction. The ambulance crew providing prehospital care for sudden cardiac arrest used a mechanical chest compression device during advanced CPR, which enabled them to deliver ongoing resuscitation during transfer to the PCI laboratory located 20 km away from the scene. Mechanical chest compressions were continued during the primary coronary intervention. The resuscitation, carried out for 2 h and 35 min, and the coronary intervention were successful, as evidenced by the return of spontaneous circulation and by the fact that, after a short rehabilitation, the patient was discharged home with a favorable neurological outcome. Our case can serve as an example for the effective and safe use of a mechanical compression device during primary coronary intervention.
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http://dx.doi.org/10.3389/fcvm.2021.614493DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8222585PMC
June 2021

Enantioseparation of solriamfetol and its major impurity phenylalaninol by capillary electrophoresis using sulfated gamma cyclodextrin.

Electrophoresis 2021 09 27;42(17-18):1818-1825. Epub 2021 Jun 27.

Department of Pharmacognosy, Semmelweis University, Budapest, Hungary.

R-solriamfetol is a recently approved drug used for the treatment of excessive sleepiness associated with narcolepsy and sleep apnea. Herein, a capillary electrophoretic method was developed, enabling the simultaneous analysis of the API and its S-enantiomer in addition to the enantiomers of its major impurity phenylalaninol. Twenty-nine different cyclodextrins (CDs), including native, neutral, and charged ones were screened as potential chiral selectors, and the best results were obtained with sulfated CDs. Randomly sulfated-β-CD exhibited outstanding enantioresolution, the peaks of phenylalaninol enantiomers inserted between the two peaks of solriamfetol enantiomers, while sulfated-γ-CD (S-γ-CD) showed remarkable resolution values in a much shorter analysis time with the optimal enantiomer migration order. Among the single isomer sulfated CD derivatives, substituent dependent enantiomer migration order reversal could also be observed in the case of heptakis(6-O-sulfo)-β-CD (HS-β-CD) or heptakis(2,3-O-dimethyl-6-O-sulfo)-β-CD (HDMS-β-CD) with R-,S-solriamfetol, and heptakis(2,3-O-diacetyl-6-O-sulfo)-β-CD (HDAS-β-CD) resulting S-,R-solriamfetol migration order. The sulfated-γ-CD system was chosen for method optimization applying orthogonal experimental design. The optimized method (45 mM Tris-acetate buffer, pH 4.5, 4 mM S-γ-CD, 21°C, +19.5 kV) was capable for the baseline separation of solriamfetol and phenylalaninol enantiomers within 7 min. The optimized method was validated according to the ICH guidelines and successfully applied for the analysis of pharmaceutical preparation (Sunosi 75 mg tablet), thus it may serve as a routine procedure for the laboratories of regulatory authorities as well as in Pharmacopoeias.
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http://dx.doi.org/10.1002/elps.202100076DOI Listing
September 2021

Temporal Patterns and Inter-Correlations among Physical and Antioxidant Attributes and Enzyme Activities of Apricot Fruit Inoculated with under Salicylic Acid and Methyl Jasmonate Treatments under Shelf-Life Conditions.

J Fungi (Basel) 2021 Apr 28;7(5). Epub 2021 Apr 28.

Faculty of Agronomy, University of Debrecen, Böszörményi út 138, 4032 Debrecen, Hungary.

causes serious postharvest damage on apricot fruits under shelf-life storage conditions. Plant elicitors of methyl jasmonate (MeJA) and salicylic acid (SA) can reduce this damage, and their research can explain the background of the plant defense physiological processes in -infected fruits. The aims of this study were: (i) to evaluate the effect of various concentrations of MeJA and SA on brown rot incidence (BRI) and lesion diameter (LD) of apricot fruits; (ii) to measure the temporal patterns for the effect of 0.4 mmol L MeJA and 2 mmol L SA treatments on BRI, LD and seven fruit measures (fruit firmness (FF), lignin content (LC), total soluble phenol content (TSPC), total antioxidant capacity (TAC) and enzyme activities of PAL, POD and SOD) in treatments of -inoculated versus (vs.) non-inoculated fruits over an eight-day shelf-life storage period; and (iii) to determine inter-correlations among the seven fruit measures for MeJA and SA treatments. Both MeJA and SA significantly reduced BRI and LD. LC, FF, TAC, TSPC, as well as SOD and PAL activities in the MeJA and SA treatments were higher than the water-treated control in most assessment days and both inoculation treatments. In both inoculation treatments, the activity of POD in the SA-treated fruits was higher than MeJA-treated and control fruits at all dates. In MeJA vs. SA and inoculated vs. non-inoculated treatments, six variable pairs (FF vs. TSPC, FF vs. TAC, TAC vs. PAL, PAL vs. POD, PAL vs. SOD, and POD vs. SOD) showed significant inter-correlation values. Principal component analyses explained 96% and 93% of the total variance for inoculated and non-inoculated treatments, respectively. In inoculated treatments, both PC1 and PC2 explained 41% of the total variance and correlated with FF, TSPC and TAC and with PAL, SOD and POD, respectively. In non-inoculated treatments, PC1 and PC2 explained 49% and 44% of the total variance and correlated with LC, PAL, POD and SOD and with FF, TSPC and TAC, respectively. It can be concluded that MeJA and SA are useful in the practice to enhance the plant defense system against brown rot by reducing fungal growth and by improving physical and antioxidant attributes (FF, LC, TAC and TSPC) and the activity of defense-related enzymes (PAL, POD and SOD) in apricot fruits during shelf-life storage conditions.
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http://dx.doi.org/10.3390/jof7050341DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8145973PMC
April 2021

Meta-studtite stability in aqueous solutions. Impact of HCO, HO and ionizing radiation on dissolution and speciation.

Dalton Trans 2021 May;50(19):6568-6577

Department of Chemistry, School of Engineering Sciences in Chemistry, Biotechnology and Health, KTH Royal institute of Technology, SE-10044 Stockholm, Sweden.

Two uranyl peroxides meta-studtite and studtite exist in nature and can form as alteration phases on the surface of spent nuclear fuel upon water intrusion in a geological repository. Meta-studtite and studtite have very low solubility and could therefore reduce the reactivity of spent nuclear fuel toward radiolytic oxidants. This would inhibit the dissolution of the fuel matrix and thereby also the spreading of radionuclides. It is therefore important to investigate the stability of meta-studtite and studtite under conditions that may influence their stability. In the present work, we have studied the dissolution kinetics of meta-studtite in aqueous solution containing 10 mM HCO3-. In addition, the influence of the added H2O2 and the impact of γ-irradiation on the dissolution kinetics of meta-studtite were studied. The results are compared to previously published data for studtite studied under the same conditions. 13C NMR experiments were performed to identify the species present in aqueous solution (i.e., carbonate containing complexes). The speciation studies are compared to calculations based on published equilibrium constants. In addition to the dissolution experiments, experiments focussing on the stability of H2O2 in aqueous solutions containing UO22+ and HCO3- were conducted. The rationale for this is that H2O2 was consumed relatively fast in some of the dissolution experiments.
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http://dx.doi.org/10.1039/d1dt00436kDOI Listing
May 2021

Preventive Metformin Monotherapy Medication Prescription, Redemption and Socioeconomic Status in Hungary in 2018-2019: A Cross-Sectional Study.

Int J Environ Res Public Health 2021 02 24;18(5). Epub 2021 Feb 24.

MTA-DE-Public Health Research Group, University of Debrecen, 4028 Debrecen, Hungary.

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.
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http://dx.doi.org/10.3390/ijerph18052206DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7956358PMC
February 2021

Two Targets, One Hit: new Anticancer Therapeutics to Prevent Tumorigenesis Without Cardiotoxicity.

Front Pharmacol 2020 10;11:569955. Epub 2021 Feb 10.

MTA-DE Momentum Genome Architecture and Recombination Research Group, Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Debrecen, Doctoral School of Molecular Cell and Immune Biology, Debrecen, Hungary.

A serious adverse effect of cancer therapies is cardiovascular toxicity, which significantly limits the widespread use of antineoplastic agents. The promising new field of cardio-oncology offers the identification of potent anti-cancer therapeutics that effectively inhibit cancer cell proliferation without causing cardiotoxicity. Future introduction of recently identified cardio-safe compounds into clinical practice (including ERK dimerization inhibitors or BAX allosteric inhibitors) is expected to help oncologists avoid unwanted cardiological complications associated with therapeutic interventions.
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http://dx.doi.org/10.3389/fphar.2020.569955DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7902874PMC
February 2021

Antibacterial effect of local anaesthetics

Orv Hetil 2021 01 31;162(5):171-176. Epub 2021 Jan 31.

2 Pécsi Tudományegyetem, Általános Orvostudományi Kar, Klinikai Központ, Orvosi Mikrobiológiai Intézet, Pécs.

Összefoglaló. Gyógyszereink egy részének jelentős, az eredeti alkalmazástól eltérő hatása is van. Ezek felismerése fontos, hogy elkerüljük a nem várt mellékhatásokat, vagy kihasználjuk ezeket a kedvező adottságokat. A helyi érzéstelenítők antibakteriális hatása 1909 óta ismert, de ennek több évtizeden keresztül nem tulajdonítottak jelentőséget. Az 1960-as években figyeltek fel először az álnegatív mikrobiológiai eredmények lehetőségére, helyi érzéstelenítőket használva a mintavételhez. Tanulmányok igazolták, hogy a bronchoszkópiás, seb-, bőr- vagy fül-, orr-, gégészeti bakteriológiai eredmények is érintve lehetnek. A ma is használt gyógyszerek közül a 0,5%-os bupivakainnak és a 2%-os lidokainnak van jelentős antibakteriális hatása Gram-pozitív és Gram-negatív baktériumokkal szemben, ami kifejezettebb 37 °C-on, mint szobahőmérsékleten. A legerősebb antibakteriális hatást a 0,5%-os bupivakain mutatta. A napi gyakorlatban alkalmazott koncentrációjuk magasabb, mint a különböző klinikai izolátumokkal szemben meghatározott minimális gátló koncentráció. Fenti tulajdonságaik alapján felmerült szerepük a kórházi sebfertőzések csökkentésében is. A hatásmechanizmus több pontja ismert, károsítják a sejthártya integritását, és több bakteriális enzim működését gátolják. Orv Hetil. 2021; 162(5): 171-176. Summary. Medications may have important impacts other than the original effect. It is important to know about these to avoid side effects or use these beneficial capabilities. The antibacterial effect of local anaesthetics has been known since 1909. For decades, no attention has been payed to this fact. In the 1960s, the high number of negative microbiological results when local anaesthetics were used before sampling drew attention to the possible antibacterial effect. Studies suggested that cultures from bronchoscopy, wound, skin or nasal samples may be affected. Bupivacaine 0,5% and lidocaine 2% have the most noticeable effect against both Gram-positive and Gram-negative bacteria. This impact is more pronounced at 37 °C than at room temperature. Bupivacaine 0,5% has the most pronounced effect. The concentration of local anaesthetics in daily routine is higher than the minimal inhibitory concentration against various clinical isolates. In the view of these results, they may contribute to reduce surgical site infections. There are known details regarding the mechanism of action. Local anaesthetics have target sites on cellular membrane and inhibit bacterial enzymes. Orv Hetil. 2021; 162(5): 171-176.
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http://dx.doi.org/10.1556/650.2021.32002DOI Listing
January 2021

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

Front Cell Dev Biol 2020 19;8:607080. Epub 2020 Nov 19.

Institute of Pharmacology and Toxicology, Paracelsus Medical University, Salzburg, Austria.

-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 -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 -GlcNAcylated. Here, we show that experimentally increased -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 -GlcNAcylation augmented the current magnitude. In parallel, increases or decreases in -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 -GlcNAc variations, and the ICln interaction with α-integrin insensitive to -GlcNAcylation. In addition, exposure of cells to a hypotonic solution reduced the -GlcNAcylation of cellular proteins. Together, these findings show that -GlcNAcylation affects RVD by influencing IClswell and further indicate that hypotonicity may activate IClswell by reducing the -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 -GlcNAcylation, including diabetic nephropathy.
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http://dx.doi.org/10.3389/fcell.2020.607080DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7717961PMC
November 2020

The timed up & go test sit-to-stand transition: Which signals measured by inertial sensors are a viable route for continuous analysis?

Gait Posture 2021 02 12;84:8-10. Epub 2020 Nov 12.

Department of Neurology and Centre of Clinical Neuroscience, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic. Electronic address:

Background: The Timed Up and Go test is a well-known clinical test for assessing of mobility and fall risk. It has been shown that the IMU which use an accelerometer and gyroscope are capable of analysing the quantitative parameters of the sit-to-stand transition.

Research Question: Which signals obtained by the inertial sensors are suitable for continuous Timed Up & Go test sit-to-stand transition analysis?

Methods: In the study we included 29 older adult volunteers and 31 de-novo Parkinson disease (PD) patients. All subjects performed an instrumented extended TUG wearing a gyro-accelerometer. The sit-to-stand transition was detected from an angular velocity signal. The sit-to-stand signal pattern within the subject group was analyzed via an intra-class correlation between curves. Inter-subjects' variability was visualized using prediction bands.

Results: The angular velocity about the pitch axis exhibited the best signal match across subjects in both groups (0.50 < ICC < 0.75). When analysing acceleration, the acceleration along the antero-posterior axis showed moderate inter-subjects signal pattern match (0.50 < ICC < 0.75) in the reference group. The analysis of other signals revealed a poor signal pattern in both subject groups.

Significance: For optimal interpretation of the analysis of continuous curves, the signal pattern must be considered. Also, the inter-subject variability along this pattern can be informative and useful.
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http://dx.doi.org/10.1016/j.gaitpost.2020.11.006DOI Listing
February 2021

Discovery of S64315, a Potent and Selective Mcl-1 Inhibitor.

J Med Chem 2020 11 4;63(22):13762-13795. Epub 2020 Nov 4.

Servier Research Institute of Medicinal Chemistry, Záhony u. 7, H-1031 Budapest, Hungary.

Myeloid cell leukemia 1 (Mcl-1) has emerged as an attractive target for cancer therapy. It is an antiapoptotic member of the Bcl-2 family of proteins, whose upregulation in human cancers is associated with high tumor grade, poor survival, and resistance to chemotherapy. Here we report the discovery of our clinical candidate S64315, a selective small molecule inhibitor of Mcl-1. Starting from a fragment derived lead compound, we have conducted structure guided optimization that has led to a significant (3 log) improvement of target affinity as well as cellular potency. The presence of hindered rotation along a biaryl axis has conferred high selectivity to the compounds against other members of the Bcl-2 family. During optimization, we have also established predictive PD markers of Mcl-1 inhibition and achieved both efficient in vitro cell killing and tumor regression in Mcl-1 dependent cancer models. The preclinical candidate has drug-like properties that have enabled its development and entry into clinical trials.
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http://dx.doi.org/10.1021/acs.jmedchem.0c01234DOI Listing
November 2020

Sleep deprivation as treatment for depression: Systematic review and meta-analysis.

Acta Psychiatr Scand 2021 01 27;143(1):22-35. Epub 2020 Dec 27.

Region Västra Götaland, Psykiatri Affektiva, Department of Psychiatry, Sahlgrenska University Hospital, Gothenburg, Sweden.

Objective: To systematically review evidence on the efficacy and safety of sleep deprivation (SD) as a treatment option for patients with unipolar or bipolar depression.

Methods: A systematic review according to PRISMA guidelines was conducted. The certainty of evidence was assessed using the GRADE approach. Controlled trials were included in efficacy analysis, case series for evaluating complications and qualitative studies for patients' experiences.

Results: Eight controlled studies (368 patients), one qualitative study and seven case series (825 patients) were included. One week after treatment start, SD combined with standard treatment did not reduce depressive symptoms compared with standard treatment (standardized mean difference, SMD = -0.29, [95% confidence interval, CI: -0.84 to 0.25], p = 0.29). When excluding a study in elderly patients in a post hoc analysis, the difference was statistically significant (SMD = -0.54 ([95% CI: -0.86 to -0.22], p < 0.001)) but it diminished two weeks after treatment start. No superiority of SD was found compared with antidepressants, but SD may be superior to exercise in certain settings. It is uncertain whether SD affects quality of sleep, quality of life, everyday functioning or length of stay. Apart from switch to mania (ranging between 2.7% and 10.7%), no other serious complications were reported.

Conclusion: Sleep deprivation has been studied in a wide range of settings resulting in divergent results for the short-term efficacy on depressive symptoms. Post hoc analyses indicated that there may be a significant but transient effect in certain populations. Further studies should focus on identifying subgroups of responders as well as examining feasibility in routine clinical care.
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http://dx.doi.org/10.1111/acps.13253DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7839702PMC
January 2021

Inhibition of ABCG2/BCRP-mediated transport-correlation analysis of various expression systems and probe substrates.

Eur J Pharm Sci 2021 Jan 13;156:105593. Epub 2020 Oct 13.

Solvo Biotechnology, a Charles River Company, 52 Közép fasor, Szeged H-6726, Hungary; Solvo Biotechnology, a Charles River Company, 4-20 Irinyi J str, Budapest H-1117, Hungary; Faculty of Information Technology and Bionics, Pázmány Péter Catholic University, Práter str 50/a, Budapest H-1083, Hungary; Semmelweis University, Faculty of Health Sciences, Vas str 17, Budapest H-1088, Hungary. Electronic address:

BCRP / ABCG2 is a key determinant of pharmacokinetics of substrate drugs. Several BCRP substrates and inhibitors are of low passive permeability, and the vesicular transport assay works well in this permeability space. Membranes were prepared from BCRP-HEK293, MCF-7/MX, and baculovirus-infected Sf9 cells with (BCRP-Sf9-HAM), and without (BCRP-Sf9) cholesterol loading. K values for three substrates - estrone-3-sulfate, sulfasalazine, topotecan - correlated well between the four expression systems. In contrast, a 10-20-fold range in V values was observed, with BCRP-HEK293 membranes possessing the largest dynamic range. IC values of the different test systems were similar to each other, with 94.4% of pairwise comparisons being within 3-fold. Substrate dependent inhibition showed somewhat greater variation, as 81.4% of IC values in the BCRP-HEK293 membranes were within 3-fold in pairwise comparisons. Overall, BCRP-HEK293 membranes demonstrated the highest activity. The IC values showed good concordance but substrate dependent inhibition was observed for some drugs.
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http://dx.doi.org/10.1016/j.ejps.2020.105593DOI Listing
January 2021

Antithrombotic Preventive Medication Prescription Redemption and Socioeconomic Status in Hungary in 2016: A Cross-Sectional Study.

Int J Environ Res Public Health 2020 09 19;17(18). Epub 2020 Sep 19.

MTA-DE-Public Health Research Group, Department of Public Health and Epidemiology, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary.

This work was designed to investigate antithrombotic drug utilization and its link with the socioeconomic characteristics of specific population groups in Hungary by a comparative analysis of data for prescriptions by general practitioners and the redeemed prescriptions for antithrombotic drugs. Risk analysis capabilities were applied to estimate the relationships between socioeconomic status, which was characterized by quintiles of a multidimensional composite indicator (deprivation index), and mortality due to thromboembolic diseases as well as antithrombotic medications for the year 2016 at the district level in Hungary. According to our findings, although deprivation is a significant determinant of mortality due to thromboembolic diseases, clusters can be identified that represent exemptions to this rule: an eastern part of Hungary, consisting of two highly deprived counties, had significantly lower mortality than the country average; by contrast, the least-deprived northwestern part of the country, consisting of five counties, had significantly higher mortality than the country average. The fact that low socioeconomic status in general and poor adherence to antithrombotic drugs irrespective of socioeconomic status were associated with increased mortality indicates the importance of more efficient control of preventive medication and access to healthcare in all districts of the country to reduce mortality due to thromboembolic diseases.
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http://dx.doi.org/10.3390/ijerph17186855DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7559548PMC
September 2020

Instrumental analysis of finger tapping reveals a novel early biomarker of parkinsonism in idiopathic rapid eye movement sleep behaviour disorder.

Sleep Med 2020 11 18;75:45-49. Epub 2020 Jul 18.

Department of Neurology and Center of Clinical Neuroscience, First Faculty of Medicine, Charles University and General University Hospital, Czech Republic.

Background: Idiopathic rapid eye movement sleep behaviour (iRBD) is considered as a risk factor for Parkinson's disease (PD) development. Evaluation of repetitive movements with finger tapping, which serves as a principal task to measure the extent of bradykinesia in PD, may undercover potential PD patients. The aim of this study was to explore whether finger tapping abnormalities, evaluated with a 3D motion capture system, are already present in RBD patients.

Methods: Finger tapping data was acquired using a contactless 3D motion capture system from 40 RBD subjects and compared to 25 de-novo PD patients and 25 healthy controls. Objective assessment of amplitude decrement, maximum opening velocity and their combination representing finger tapping decrement was performed in the sequence of the first ten tapping movements. The association between instrumental finger tapping data and semi-quantitative clinical evaluation was analyzed.

Results: While significant differences between PD and controls were found for all investigated finger tapping measures (p < 0.002), RBD differed from controls in finger tapping amplitude (p = 0.004) and velocity (p = 0.007) decrement but not in maximal opening velocity. A significant relationship between the motor score from the Movement Disorders Society - Unified Parkinson's Disease Rating Scale and finger tapping decrement was shown for both patient groups, ie RBD (r = 0.36, p = 0.02) and PD (r = 0.60, p = 0.002).

Conclusions: In our group of RBD patients we demonstrated amplitude decrement of repetitive movements, which may correspond with prodromal bradykinesia. Our findings suggest instrumental analysis of finger tapping abnormalities as a potential novel clinical marker reflecting subclinical motor disturbances in RBD.
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http://dx.doi.org/10.1016/j.sleep.2020.07.019DOI Listing
November 2020

Ecosystem shift of a mountain lake under climate and human pressure: A move out from the safe operating space.

Sci Total Environ 2020 Nov 7;743:140584. Epub 2020 Jul 7.

Department of Environmental and Landscape Geography, Eötvös Loránd University, Pázmány Péter str. 1/C, H-1117 Budapest, Hungary; Centre for Ecological Research, GINOP Sustainable Ecosystems Group, Klebelsberg Kuno str. 3, H-8237 Tihany, Hungary; MTA-MTM-ELTE Research group for Paleontology, Pázmány Péter str. 1/C, H-1117 Budapest, Hungary. Electronic address:

A multiproxy approach including chironomid, diatom, pollen and geochemical analyses was applied on short gravitational cores retrieved from an alpine lake (Lacul Bâlea) in the Southern Carpathians (Romania) to unveil how this lake responded to natural and anthropogenic forcing over the past 500 years. On the basis of chironomid and diatom assemblage changes, and supported by sediment chemical data and historical information, we distinguished two main phases in lake evolution. Before 1926 the lake was dominated by chironomids belonging to Micropsectra insignilobus-type and benthic diatoms suggesting well-oxygenated oligotrophic environment with only small-scale disturbance. We considered this state as the lake's safe operational space. After 1926 significant changes occurred: Tanytarsus lugens-type and T. mendax-type chironomids took over dominance and collector filterers increased until 1970 pointing to an increase in available nutrients. The diatom community showed the most pronounced change between 1950 and 1992 when planktonic diatoms increased. The highest trophic level was reconstructed between 1970 and 1992, while the indicator species of increasing nutrient availability, Asterionella formosa spread from 1982 and decreased rapidly at 1992. Statistical analyses evidenced that the main driver of the diatom community change was atmospheric reactive nitrogen (Nr) fertilization that drastically moved the community towards planktonic diatom dominance from 1950. The transformation of the chironomid community was primarily driven by summer mean temperature increase that also changed the dominant feeding guild from collector gatherers to collector filterers. Our results overall suggest that the speed of ecosystem reorganisation showed an unprecedented increase over the last 100 years; biological systems in many cases underwent threshold type changes, while several system components displayed non-hysteretic change between alternating community composition. We conclude that Lake Bâlea is outside of its safe operating space today. The main trigger of changes since 1926 was climate change and human impact acting synergically.
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http://dx.doi.org/10.1016/j.scitotenv.2020.140584DOI Listing
November 2020

Small Extracellular Vesicles Isolated from Serum May Serve as Signal-Enhancers for the Monitoring of CNS Tumors.

Int J Mol Sci 2020 Jul 28;21(15). Epub 2020 Jul 28.

Laboratory of Microscopic Image Analysis and Machine Learning, Institute of Biochemistry, Biological Research Centre, H-6726 Szeged, Hungary.

Liquid biopsy-based methods to test biomarkers (e.g., serum proteins and extracellular vesicles) may help to monitor brain tumors. In this proteomics-based study, we aimed to identify a characteristic protein fingerprint associated with central nervous system (CNS) tumors. Overall, 96 human serum samples were obtained from four patient groups, namely glioblastoma multiforme (GBM), non-small-cell lung cancer brain metastasis (BM), meningioma (M) and lumbar disc hernia patients (CTRL). After the isolation and characterization of small extracellular vesicles (sEVs) by nanoparticle tracking analysis (NTA) and atomic force microscopy (AFM), liquid chromatography -mass spectrometry (LC-MS) was performed on two different sample types (whole serum and serum sEVs). Statistical analyses (ratio, Cohen's d, receiver operating characteristic; ROC) were carried out to compare patient groups. To recognize differences between the two sample types, pairwise comparisons (Welch's test) and ingenuity pathway analysis (IPA) were performed. According to our knowledge, this is the first study that compares the proteome of whole serum and serum-derived sEVs. From the 311 proteins identified, 10 whole serum proteins and 17 sEV proteins showed the highest intergroup differences. Sixty-five proteins were significantly enriched in sEV samples, while 129 proteins were significantly depleted compared to whole serum. Based on principal component analysis (PCA) analyses, sEVs are more suitable to discriminate between the patient groups. Our results support that sEVs have greater potential to monitor CNS tumors, than whole serum.
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http://dx.doi.org/10.3390/ijms21155359DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7432723PMC
July 2020

The Potential Beneficial Effect of EPA and DHA Supplementation Managing Cytokine Storm in Coronavirus Disease.

Front Physiol 2020 19;11:752. Epub 2020 Jun 19.

Faculty of Health Sciences, Institute of Nutritional Sciences and Dietetics, University of Pecs, Pecs, Hungary.

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http://dx.doi.org/10.3389/fphys.2020.00752DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7318894PMC
June 2020

Amiodarone that has antibacterial effect against human pathogens may represent a novel catheter lock.

Acta Microbiol Immunol Hung 2020 Jul 6;67(2):133-137. Epub 2020 Jul 6.

1Department of Medical Microbiology, Medical School, University of Pecs, Pecs, Hungary.

Infection is one of the most feared hospital-acquired complications. Infusion therapy is frequently administered through a central line. Infusions facilitating bacterial growth may be a source of central line-associated bloodstream infections. On the other hand, medications that kill bacteria may protect against this kind of infection and may be used as a catheter lock.In this study, we examined the impact of amiodarone on bacterial growth. Amiodarone is used for controlling cardiac arrhythmias and can be administered as an infusion for weeks. Standard microbiological methods have been used to study the growth of laboratory strains and clinical isolates of Staphylococcus aureus, Staphylococcus epidermidis, Pseudomonas aeruginosa, Escherichia coli, Klebsiella pneumoniae, and multidrug-resistant Acinetobacter baumannii in amiodarone. The minimum inhibitory concentration (MIC) of amiodarone was determined. Bacterial growth from in use amiodarone syringes and giving sets was also investigated.Most examined strains were killed within 1 min in amiodarone. The other strains were killed within 1 h. The MICs of amiodarone were <0.5-32 μg/mL.Amiodarone infusion is unlikely to be responsible for bloodstream infections as contaminating bacteria are killed within 1 h. Amiodarone may also protect against central line infections if used as a catheter lock.
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http://dx.doi.org/10.1556/030.2020.01144DOI Listing
July 2020

A feasibility study of zebrafish embryo irradiation with laser-accelerated protons.

Rev Sci Instrum 2020 Jun;91(6):063303

Department of Medical Physics, Faculty of Physics, Ludwig-Maximilians-Universität München, 85748 Garching bei München, Germany.

The development from single shot basic laser plasma interaction research toward experiments in which repetition rated laser-driven ion sources can be applied requires technological improvements. For example, in the case of radio-biological experiments, irradiation duration and reproducible controlled conditions are important for performing studies with a large number of samples. We present important technological advancements of recent years at the ATLAS 300 laser in Garching near Munich since our last radiation biology experiment. Improvements range from target positioning over proton transport and diagnostics to specimen handling. Exemplarily, we show the current capabilities by performing an application oriented experiment employing the zebrafish embryo model as a living vertebrate organism for laser-driven proton irradiation. The size, intensity, and energy of the laser-driven proton bunches resulted in evaluable partial body changes in the small (<1 mm) embryos, confirming the feasibility of the experimental system. The outcomes of this first study show both the appropriateness of the current capabilities and the required improvements of our laser-driven proton source for in vivo biological experiments, in particular the need for accurate, spatially resolved single bunch dosimetry and image guidance.
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http://dx.doi.org/10.1063/5.0008512DOI Listing
June 2020

Occurrence and Geochemistry of Lead-210 and Polonium-210 Radionuclides in Public-Drinking-Water Supplies from Principal Aquifers of the United States.

Environ Sci Technol 2020 06 5;54(12):7236-7249. Epub 2020 Jun 5.

U.S. Geological Survey, 215 Limekiln Road, New Cumberland, Pennsylvania 17070, United States.

On the basis of lifetime cancer risks, lead-210 (Pb) and polonium-210 (Po) ≥ 1.0 and 0.7 pCi/L (picocuries per liter), respectively, in drinking-water supplies may pose human-health concerns. Pb and Po were detected at concentrations greater than these thresholds at 3.7 and 1.5%, respectively, of filtered untreated groundwater samples from 1263 public-supply wells in 19 principal aquifers across the United States. Nationally, 72% of samples with radon-222 (Rn) concentrations > 4000 pCi/L had Pb ≥ 1.0 pCi/L. Pb is mobilized by alpha recoil associated with the decay of Rn and short-lived progeny. Pb concentrations ≥ 1.0 pCi/L occurred most frequently where acidic groundwaters inhibited Pb readsorption (felsic-crystalline rocks) and where reducing alkaline conditions favored dissolution of iron-manganese- (Fe-Mn-) oxyhydroxides (which adsorb Pb) and formation of lead-carbonate complexes (enhancing lead (Pb) mobility). Po concentrations ≥ 0.7 pCi/L occurred almost exclusively in confined Coastal Plain aquifers where old (low percent-modern carbon-14) groundwaters were reducing, with high pH (>7.5) and high sodium/chloride (Na/Cl) ratios resulting from cation exchange. In high-pH environments, aqueous polonium (Po) is poorly sorbed, occurring as dihydrogen polonate (HPoO(aq)) or, under strongly reducing conditions, as a hydrogen-polonide anion (HPo). Fe-Mn- and sulfate-reduction and cation-exchange processes may mobilize polonium from mineral surfaces. Po occurrence in low-to-neutral-pH waters is attenuated by adsorption.
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http://dx.doi.org/10.1021/acs.est.0c00192DOI Listing
June 2020

Systemic blockade of ACVR2B ligands attenuates muscle wasting in ischemic heart failure without compromising cardiac function.

FASEB J 2020 08 19;34(8):9911-9924. Epub 2020 May 19.

Research Unit of Biomedicine, Department of Pharmacology and Toxicology, University of Oulu, Oulu, Finland.

Signaling through activin receptors regulates skeletal muscle mass and activin receptor 2B (ACVR2B) ligands are also suggested to participate in myocardial infarction (MI) pathology in the heart. In this study, we determined the effect of systemic blockade of ACVR2B ligands on cardiac function in experimental MI, and defined its efficacy to revert muscle wasting in ischemic heart failure (HF). Mice were treated with soluble ACVR2B decoy receptor (ACVR2B-Fc) to study its effect on post-MI cardiac remodeling and on later HF. Cardiac function was determined with echocardiography, and myocardium analyzed with histological and biochemical methods for hypertrophy and fibrosis. Pharmacological blockade of ACVR2B ligands did not rescue the heart from ischemic injury or alleviate post-MI remodeling and ischemic HF. Collectively, ACVR2B-Fc did not affect cardiomyocyte hypertrophy, fibrosis, angiogenesis, nor factors associated with cardiac regeneration except modification of certain genes involved in metabolism or cell growth/survival. ACVR2B-Fc, however, was able to reduce skeletal muscle wasting in chronic ischemic HF, accompanied by reduced LC3II as a marker of autophagy and increased mTOR signaling and Cited4 expression as markers of physiological hypertrophy in quadriceps muscle. Our results ascertain pharmacological blockade of ACVR2B ligands as a possible therapy for skeletal muscle wasting in ischemic HF. Pharmacological blockade of ACVR2B ligands preserved myofiber size in ischemic HF, but did not compromise cardiac function nor exacerbate cardiac remodeling after ischemic injury.
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http://dx.doi.org/10.1096/fj.201903074RRDOI Listing
August 2020

The relation of geogenic contaminants to groundwater age, aquifer hydrologic position, water type, and redox conditions in Atlantic and Gulf Coastal Plain aquifers, eastern and south-central USA.

Sci Total Environ 2020 Jun 16;723:137835. Epub 2020 Mar 16.

U.S. Geological Survey, New Jersey Water Science Center, 3450 Princeton Pike, Suite 110, Lawrenceville, NJ 08648, United States.

Groundwater age distributions developed from carbon-14 (C), tritium (H), and helium-4 (He) concentrations, along with aquifer hydrologic position, water type, and redox conditions, were compared to geogenic contaminants of concern (GCOC) from 252 public-supply wells in six Atlantic and Gulf Coastal Plain unconsolidated-sediment aquifers. Concentrations of one or more GCOCs in 168 (67%) wells exceeded MCLs (maximum contaminant levels), SMCLs (secondary MCLs), or HBSLs (health-based screening levels). Human-health benchmark thresholds (MCLs or HBSLs) were exceeded in 31 (12%) wells, and included 0.8% for fluoride (F), 2.4% for arsenic (As), 4% for lead-210 (Pb), and 6.7% for polonium-210 (Po). Values of pH increase with age and were outside the SMCL in 31% of wells (23% < 6.5 and 7.5% > 8.5, SMCL). Among GCOCs with concentrations that increased significantly with groundwater age, the frequency of sentry threshold exceedances (i.e., one-half of MCL, SMCL, or HBSL) included 40% for dissolved solids (DS), 12% for chloride (Cl), 3.6% for F, 4.4% for As, and 9.5% for Po. Iron (Fe) concentrations did not correlate with groundwater age, but exceeded sentry thresholds in 29% of wells. Groundwater age, water types, redox, pH, and GCOCs varied because of unique hydrogeologic features of the aquifers (recharge locations and geometry). As expected, primarily confined aquifers had young, oxic, low to near-neutral pH water near the outcrop (recharge area), and older, reduced, high pH water deeper and farther along flow paths. However, unique aquifer hydrogeologic conditions, such as multiple-recharge zones produced anomalous patterns of young and old groundwater at varying depths and locations along flow paths. Evidence for this variability is seen in disequilibrium patterns in the progression of the chemical evolution of groundwater with hydrologic position. When hydrogeologic differences are considered, groundwater age combined with hydrologic-position data, can provide a strong basis for inferring potential occurrence of GCOCs.
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http://dx.doi.org/10.1016/j.scitotenv.2020.137835DOI Listing
June 2020
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