Prevalence, Cardiometabolic Comorbidities and Reporting of Chronic Kidney Disease; A Hungarian Cohort Analysis

Objectives: Chronic kidney disease (CKD) implies increased comorbidity burden, disability, and mortality, becoming a significant public health problem worldwide, however, prevalence data are lacking in Hungary.Methods: We determined CKD prevalence, stage distribution, comorbidities using estimated glomerular filtration rate (eGFR), albuminuria, and international disease codes in a cohort of healthcare utilizing residents within the catchment area of the University of Pécs, in the County Baranya, Hungary, between 2011 and 2019 by database analysis. The number of laboratory-confirmed and diagnosis-coded CKD patients were compared.Results: Of the total 296,781 subjects of the region, 31.3% had eGFR tests and 6.4% had albuminuria measurements, of whom we identified 13,596 CKD patients (14.0%) based on laboratory thresholds. Distribution by eGFR was presented (G3a: 70%, G3b: 22%, G4: 6%, G5: 2%). Amongst all CKD patients 70.2% had hypertension, 41.5% diabetes, 20.5% heart failure, 9.4% myocardial infarction, 10.5% stroke. Only 28.6% of laboratory-confirmed cases were diagnosis-coded for CKD in 2011–2019.Conclusion: CKD prevalence was 14.0% in a Hungarian subpopulation of healthcare-utilizing subjects in 2011–2019, and substantial under-reporting of CKD was also found

Baseline clinical characteristics of heart failure patients with reduced ejection fraction enrolled in the BUDAPEST-CRT Upgrade trial

The BUDAPEST-CRT Upgrade study is the first prospective, randomized, multicentre clinical trial investigating the outcomes after cardiac resynchronization therapy (CRT) upgrade in heart failure (HF) patients with intermittent or permanent right ventricular pacing (RVP) with wide paced QRS. This report describes the baseline clinical characteristics of the enrolled patients and compares them to cohorts from previous milestone CRT studies.This international multicentre randomized controlled trial investigates 360 patients having a pacemaker (PM) or implantable cardioverter defibrillator (ICD) device for at least six months prior to enrollment, reduced left ventricular ejection fraction (LVEF≤35%), HF symptoms (New York Heart Association functional class II-IVa), wide paced QRS (>150 ms), and ≥20% of RVP burden without having a native left bundle branch block. At enrollment, the mean age of the patients was 73±8 years; 89% were male, 97% of the patients were in NYHA II/III functional class, and 56% had atrial fibrillation. Enrolled patients predominantly had conventional PM devices, with a mean RVP burden of 86%. Thus, this is a patient cohort with advanced HF, low baseline LVEF (25%±7%), high N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels [2231 pg/mL (25th - 75th percentile 1254/4309 pg/mL)], and frequent HF hospitalizations during the preceding 12 months (50%).When compared with prior CRT trial cohorts, the BUDAPEST-CRT Upgrade study includes older patients with a strong male predominance and a high burden of atrial fibrillation and other comorbidities. Moreover, this cohort represents an advanced HF population with low LVEFs, high NT-proBNPs, and frequent previous HF events

Stimulatory effect of pituitary adenylate-cyclase activating polypeptide 6-38, M65 and vasoactive intestinal polypeptide 6-28 on trigeminal sensory neurons

Pituitary adenylate-cyclase activating polypeptide (PACAP) acts at G protein-coupled receptors: the specific PAC1 and VPAC1/VPAC2 receptors. PACAP6-38 was described as a potent PAC1/VPAC2 antagonist in several models, but recent studies reported on its agonistic behaviors proposing novel receptorial mechanisms. Since PACAP in migraine is an important research tool, we investigated the effect of PACAP and its peptide fragments on trigeminal primary sensory neurons. Effect of the peptides was studied with ratiometric Ca-imaging technique using the fluorescent indicator fura-2-AM on primary cultures of rat and mouse trigeminal ganglia (TRGs) neurons. Specificity testing was performed on PAC1, VPAC1 and VPAC2 receptor-expressing cell lines with both fluorescent and radioactive Ca-uptake methods. Slowly increasing intracellular free calcium concentration [Ca2+]i was detected after PACAP1-38, PACAP1-27, vasoactive intestinal polypeptide (VIP) and the selective PAC1 receptor agonist maxadilan administration on TRG neurons, but interestingly, PACAP6-38, VIP6-28 and the PAC1 receptor antagonist M65 also caused similar activation. The VPAC2 receptor agonist BAY 55-9837 induced similar activation, while the VPAC1 receptor agonist Ala11,22,28VIP had no significant effect on [Ca2+]i. It was proven that the Ca2+-influx originated from intracellular stores using radioactive calcium-45 uptake experiment and Ca-free solution. On the specific receptor-expressing cell lines the antagonists inhibited the stimulating actions of the respective agonists, but had no effects by themselves. PACAP6-38, M65 and VIP6-28, which were described as antagonists in numerous studies in several model systems, act as agonists on TRG primary sensory neurons. Presently unknown receptors or splice variants linked to distinct signal transduction pathways might explain these differences

Synthesis of novel 13α-18-norandrostane–ferrocene conjugates via homogeneous catalytic methods and their investigation on TRPV1 receptor activation

13α-Steroid–ferrocene derivatives were synthesized via two reaction pathways starting from an unnatural 16-keto-18-nor-13α-steroid. The unnatural steroid was converted to ferrocene derivatives via copper- catalyzed azide–alkyne cycloaddition or palladium-catalyzed aminocarbonylation. 16-Azido- and 16-N-(prop-2-ynyl)-carboxamido-steroids were synthesized as starting materials for azide–alkyne cycloaddition with the appropriate ferrocene derivatives. Based on our earlier work, aminocarbonylation of 16-iodo-16-ene and 16-iodo-15-ene derivatives was studied with ferrocenylmethylamine. The new products were obtained in moderate to good yields and were characterized by 1H and 13C NMR, IR and MS. The solid state structure of the starting material 13α-18-norandrostan-16-one and two carboxamide products were determined by X-ray crystallography. Evidences were provided that the N-propargylcarboxamide compound as well as its ferrocenylmethyltriazole derivative are able to decrease the activation of TRPV1 receptor on TRG neurons

Efficacy of repetitive transcranial magnetic stimulation (rTMS) adjunctive therapy for major depressive disorder (MDD) after two antidepressant treatment failures: meta-analysis of randomized sham-controlled trials

Abstract Background Several meta-analyses demonstrated the efficacy of unilateral High-Frequency Left-sided (HFL) repetitive Transcranial Magnetic Stimulation (rTMS) for individuals with Major Depressive Disorder (MDD); however, results are contradictory due to heterogeneity of the included studies. Methods A systematic literature review (SLR) of English language articles published since 2000 was performed in March 2022 on PubMed and Scopus databases. Empirical evidence on the relative efficacy of rTMS treatment compared with standard pharmacotherapy in Treatment-Resistant Depression (TRD) were extracted. Random effects models were used to assess the effects of rTMS on response and remission rates. Results 19 randomized double-blinded sham-controlled studies were included for quantitative analysis for response (n = 854 patients) and 9 studies for remission (n = 551 patients). The risk ratio (RR) for response and remission are 2.25 and 2.78, respectively for patients after two treatment failures using rTMS as add-on treatment compared to standard pharmacotherapy. Cochrane’s Q test showed no significant heterogeneity. No publication bias was detected. Conclusions rTMS is significantly more effective than sham rTMS in TRD in response and remission outcomes and may be beneficial as an adjunctive treatment in patients with MDD after two treatment failures. This finding is consistent with previous meta-analyses; however, the effect size was smaller than in the formerly published literature

CCDC 1054250: Experimental Crystal Structure Determination

An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures

CCDC 1054252: Experimental Crystal Structure Determination

An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures

Carboxamido steroids inhibit the opening properties of Transient Receptor Potential ion channels by lipid raft modulation

Transient Receptor Potential (TRP) cation channels, like the TRP Vanilloid 1 and TRP Ankyrin 1 (TRPV1 and TRPA1) are expressed on primary sensory neurons. These thermosensor channels play role in pain processing. We provided evidence that lipid raft disruption influenced the TRP channel activation and a carboxamido-steroid compound (C1) inhibited TRPV1 activation. Therefore, our aim was to investigate whether this compound exerts its effect through lipid raft disruption and the steroid backbone (C3) or altered position of the carboxamido group (C2) influence the inhibitory action by measuring Ca2+-transients on isolated neurons and calcium-uptake on receptor-expressing CHO cells. Membrane cholesterol content was measured by filipin staining and membrane polarisation by fluorescence spectroscopy. Both the percentage of responsive cells and the magnitude of the intracellular Ca2+-enhancement evoked by the TRPV1 agonist capsaicin were significantly inhibited after C1 and C2 incubation, but not after C3 administration. C1 was able to reduce other TRP channel activation as well. The compounds induced cholesterol depletion in CHO cells, but only C1 induced changes in membrane polarisation. The inhibitory action of the compounds on TRP channel activation develops by lipid raft disruption, and the presence and the position of the carboxamido group is essential