Study protocol of the Hungarian Longitudinal Study of Healthy Brain Aging (HuBA).

Background and purpose:

Neuro­cog­nitive aging and the associated brain diseases impose a major social and economic burden. Therefore, substantial efforts have been put into revealing the lifestyle, the neurobiological and the genetic underpinnings of healthy neurocognitive aging. However, these studies take place almost exclusively in a limited number of highly-developed countries. Thus, it is an important open question to what extent their findings may generalize to neurocognitive aging in other, not yet investigated regions. The purpose of the Hungarian Longitudinal Study of Healthy Brain Aging (HuBA) is to collect multi-modal longitudinal data on healthy neurocognitive aging to address the data gap in this field in Central and Eastern Europe.

We adapted the Australian Ima­ging, Biomarkers and Lifestyle (AIBL) study of aging study protocol to local circumstances and collected demographic, lifestyle, men­tal and physical health, medication and medical history related information as well as re­cor­ded a series of magnetic resonance imaging (MRI) data. In addition, participants were al­so offered to participate in the collection of blood samples to assess circulating in­flam­matory biomarkers as well as a sleep study aimed at evaluating the general sleep quality based on multi-day collection of subjective sleep questionnaires and whole-night elec­troencephalographic (EEG) data.

Baseline data collection has al­ready been accomplished for more than a hundred participants and data collection in the se­cond
session is on the way. The collected data might reveal specific local trends or could also indicate the generalizability of previous findings. Moreover, as the HuBA protocol al­so offers a sleep study designed for tho­rough characterization of participants’ sleep quality and related factors, our extended multi-modal dataset might provide a base for incorporating these measures into healthy and clinical aging research. 

Besides its straightforward na­tional benefits in terms of health ex­pen­di­ture, we hope that this Hungarian initiative could provide results valid for the whole Cent­ral and Eastern European region and could also promote aging and Alzheimer’s disease research in these countries.

Comparative features and outcomes of major neurological complications of COVID-19.

BACKGROUND AND PURPOSE: The aim of this study was to assess the neurological complications of SARS-CoV-2 infection and compare phenotypes and outcomes in infected patients with and without selected neurological manifestations. METHODS: The data source was a registry established by the European Academy of Neurology during the first wave of the COVID-19 pandemic. Neurologists collected data on patients with COVID-19 seen as in- and outpatients and in emergency rooms in 23 European and seven non-European countries. Prospective and retrospective data included patient demographics, lifestyle habits, comorbidities, main COVID-19 complications, hospital and intensive care unit admissions, diagnostic tests, and outcome. Acute/subacute selected neurological manifestations in patients with COVID-19 were analysed, comparing individuals with and without each condition for several risk factors. RESULTS: By July 31, 2021, 1523 patients (758 men, 756 women, and nine intersex/unknown, aged 16-101 years) were registered. Neurological manifestations were diagnosed in 1213 infected patients (79.6%). At study entry, 978 patients (64.2%) had one or more chronic general or neurological comorbidities. Predominant acute/subacute neurological manifestations were cognitive dysfunction (N = 449, 29.5%), stroke (N = 392, 25.7%), sleep-wake disturbances (N = 250, 16.4%), dysautonomia (N = 224, 14.7%), peripheral neuropathy (N = 145, 9.5%), movement disorders (N = 142, 9.3%), ataxia (N = 134, 8.8%), and seizures (N = 126, 8.3%). These manifestations tended to differ with regard to age, general and neurological comorbidities, infection severity and non-neurological manifestations, extent of association with other acute/subacute neurological manifestations, and outcome. CONCLUSIONS: Patients with COVID-19 and neurological manifestations present with distinct phenotypes. Differences in age, general and neurological comorbidities, and infection severity characterize the various neurological manifestations of COVID-19.

Relationship between arterial stiffness, left ventricular diastolic function, and renal function in chronic kidney disease.

AIM: In chronic kidney disease, IgA nephropathy, and left ventricular diastolic dysfunction have prognostic significance as well. However, the relationship between diastolic dysfunction, arterial stiffness, and renal function has not been fully elucidated. METHODS: 79 IgA nephropathy patients (aged 46 ± 11 years) and 50 controls were investigated. Tissue Doppler imaging was used to measure early (Ea) and late (Aa) diastolic velocities. Arterial stiffness was measured by a photoplethysmographic (stiffness index (SI)) and an oscillometric method (aortic pulse wave velocity (PWVao)). RESULTS: We compared the IgAN patients to a similar cardiovascular risk group with a preserved eGFR. A strong correlation was found between Ea/Aa and SI (p < 0.001), also with PWVao (p < 0.001), just in IgAN, and with eGFR (p < 0.001) in both groups. IgAN patients were divided into groups CKD1-2 vs. CKD3-5. In the CKD 3-5 group, the incidence of diastolic dysfunction increased significantly: 39% vs. 72% (p = 0.003). Left ventricle rigidity (LVR) was calculated, which showed a close correlation with SI (p = 0.009) and eGFR (p = 0.038). By linear regression analysis, the independent predictors of SI were age, E/A, and E/Ea; SI was the predictor of LVR; and E/A and hypertension were the predictors of eGFR. CONCLUSION: In chronic kidney disease, increased cardiac rigidity and vascular stiffness coexist with decreased renal function, which is directly connected to diastolic dysfunction and vascular stiffness. On the basis of comparing the CKD group to the control group, vascular alterations in very early CKD can be identified.

The Small-Molecule Enhancers of Autophagy AUTEN-67 and -99 Delay Ageing in Drosophila Striated Muscle Cells.

Autophagy (cellular self-degradation) plays a major role in maintaining the functional integrity (homeostasis) of essentially all eukaryotic cells. During the process, superfluous and damaged cellular constituents are delivered into the lysosomal compartment for enzymatic degradation. In humans, age-related defects in autophagy have been linked to the incidence of various age-associated degenerative pathologies (e.g., cancer, neurodegenerative diseases, diabetes, tissue atrophy and fibrosis, and immune deficiency) and accelerated ageing. Muscle mass decreases at detectable levels already in middle-aged patients, and this change can increase up to 30-50% at age 80. AUTEN-67 and -99, two small-molecule enhancers of autophagy with cytoprotective and anti-ageing effects have been previously identified and initially characterized. These compounds can increase the life span in wild-type and neurodegenerative model strains of the fruit fly Drosophila melanogaster. Adult flies were treated with these AUTEN molecules via feeding. Fluorescence and electron microscopy and Western blotting were used to assess the level of autophagy and cellular senescence. Flying tests were used to measure the locomotor ability of the treated animals at different ages. In the current study, the effects of AUTEN-67 and -99 were observed on striated muscle cells using the Drosophila indirect flight muscle (IFM) as a model. The two molecules were capable of inducing autophagy in IFM cells, thereby lowering the accumulation of protein aggregates and damaged mitochondria, both characterizing muscle ageing. Furthermore, the two molecules significantly improved the flying ability of treated animals. AUTEN-67 and -99 decrease the rate at which striated muscle cells age. These results may have a significant medical relevance that could be further examined in mammalian models.

The Role of Two Heart Biomarkers in IgA Nephropathy.

Cardiovascular mortality is a leading cause of death in chronic kidney disease (CKD), as is IgA nephropathy (IgAN). The purpose of this study is to find different biomarkers to estimate the outcome of the disease, which is significantly influenced by the changes in vessels (characterized by arterial stiffness) and the heart. In our cross-sectional study, 90 patients with IgAN were examined. The N-terminal prohormone of brain natriuretic peptide (NT-proBNP) was measured as a heart failure biomarker by an automated immonoassay method, while the carboxy-terminal telopeptide of collagen type I (CITP) as a fibrosis marker was determined using ELISA kits. Arterial stiffness was determined by measuring carotid-femoral pulse wave velocity (cfPWV). Renal function and routine echocardiography examinations were performed as well. Based on eGFR, patients were separated into two categories, CKD 1-2 and CKD 3-5. There were significantly higher NT-proBNP (p = 0.035), cfPWV (p = 0.004), and central aortic systolic pressure (p = 0.037), but not CITP, in the CKD 3-5 group. Both biomarker positivities were significantly higher in the CKD 3-5 group (p = 0.035) compared to the CKD 1-2 group. The central aortic systolic pressure was significantly higher in the diastolic dysfunction group (p = 0.034), while the systolic blood pressure was not. eGFR and hemoglobin levels showed a strong negative correlation, while left ventricular mass index (LVMI), aortic pulse pressure, central aortic systolic pressure, and cfPWV showed a positive correlation with NT-proBNP. cfPWV, aortic pulse pressure, and LVMI showed a strong positive correlation with CITP. Only eGFR was an independent predictor of NT-proBNP by linear regression analysis. NT-proBNP and CITP biomarkers may help to identify IgAN patients at high risk for subclinical heart failure and further atherosclerotic disease.

Isolation and NMR Scaling Factors for the Structure Determination of Lobatolide H, a Flexible Sesquiterpene from Neurolaena lobata.

A new flexible germacranolide (1, lobatolide H) was isolated from the aerial parts of Neurolaena lobata. The structure elucidation was performed by classical NMR experiments and DFT NMR calculations. Altogether, 80 theoretical level combinations with existing 13C NMR scaling factors were tested, and the best performing ones were applied on 1. 1H and 13C NMR scaling factors were also developed for two combinations utilizing known exomethylene containing derivatives, and the results were complemented by homonuclear coupling constant (JHH) and TDDFT-ECD calculations to elucidate the stereochemistry of 1. Lobatolide H possessed remarkable antiproliferative activity against human cervical tumor cell lines with different HPV status (SiHa and C33A), induced cell cycle disturbance and exhibited a substantial antimigratory effect in SiHa cells.

N6-Methyladenine Progressively Accumulates in Mitochondrial DNA during Aging.

N6-methyladenine (6mA) in the DNA is a conserved epigenetic mark with various cellular, physiological and developmental functions. Although the presence of 6mA was discovered a few years ago in the nuclear genome of distantly related animal taxa and just recently in mammalian mitochondrial DNA (mtDNA), accumulating evidence at present seriously questions the presence of N6-adenine methylation in these genetic systems, attributing it to methodological errors. In this paper, we present a reliable, PCR-based method to determine accurately the relative 6mA levels in the mtDNA of Caenorhabditis elegans, Drosophila melanogaster and dogs, and show that these levels gradually increase with age. Furthermore, daf-2(-)-mutant worms, which are defective for insulin/IGF-1 (insulin-like growth factor) signaling and live twice as long as the wild type, display a half rate at which 6mA progressively accumulates in the mtDNA as compared to normal values. Together, these results suggest a fundamental role for mtDNA N6-adenine methylation in aging and reveal an efficient diagnostic technique to determine age using DNA.

Short- and long-term outcome and predictors in an international cohort of patients with neuro-COVID-19.

BACKGROUND AND PURPOSE: Despite the increasing number of reports on the spectrum of neurological manifestations of COVID-19 (neuro-COVID), few studies have assessed short- and long-term outcome of the disease. METHODS: This is a cohort study enrolling adult patients with neuro-COVID seen in neurological consultation. Data were collected prospectively or retrospectively in the European Academy of Neurology NEuro-covid ReGistrY ((ENERGY). The outcome at discharge was measured using the modified Rankin Scale and defined as 'stable/improved' if the modified Rankin Scale score was equal to or lower than the pre-morbid score, 'worse' if the score was higher than the pre-morbid score. Status at 6 months was also recorded. Demographic and clinical variables were assessed as predictors of outcome at discharge and 6 months. RESULTS: From July 2020 to March 2021, 971 patients from 19 countries were included. 810 (83.4%) were hospitalized. 432 (53.3%) were discharged with worse functional status. Older age, stupor/coma, stroke and intensive care unit (ICU) admission were predictors of worse outcome at discharge. 132 (16.3%) died in hospital. Older age, cancer, cardiovascular complications, refractory shock, stupor/coma and ICU admission were associated with death. 262 were followed for 6 months. Acute stroke or ataxia, ICU admission and degree of functional impairment at discharge were predictors of worse outcome. 65/221 hospitalized patients (29.4%) and 10/32 non-hospitalized patients (24.4%) experienced persisting neurological symptoms/signs. 10/262 patients (3.8%) developed new neurological complaints during the 6 months of follow-up. CONCLUSIONS: Neuro-COVID is a severe disease associated with worse functional status at discharge, particularly in older subjects and those with comorbidities and acute complications of infection.

Genetic landscape of early-onset dementia in Hungary.

INTRODUCTION: Early-onset dementias (EOD) are predominantly genetically determined, but the underlying disease-causing alterations are often unknown. The most frequent forms of EODs are early-onset Alzheimer's disease (EOAD) and frontotemporal dementia (FTD). PATIENTS: This study included 120 Hungarian patients with EOD (48 familial and 72 sporadic) which had a diagnosis of EOAD (n = 49), FTD (n = 49), or atypical dementia (n = 22). RESULTS: Monogenic dementia was detected in 15.8% of the patients. A pathogenic hexanucleotide repeat expansion in the C9ORF72 gene was present in 6.7% of cases and disease-causing variants were detected in other known AD or FTD genes in 6.7% of cases (APP, PSEN1, PSEN2, GRN). A compound heterozygous alteration of the TREM2 gene was identified in one patient and heterozygous damaging variants in the CSF1R and PRNP genes were detected in two other cases. In two patients, the coexistence of several heterozygous damaging rare variants associated with neurodegeneration was detected (1.7%). The APOE genotype had a high odds ratio for both the APOE ɛ4/3 and the ɛ4/4 genotype (OR = 2.7 (95%CI = 1.3-5.9) and OR = 6.5 (95%CI = 1.4-29.2), respectively). In TREM2, SORL1, and ABCA7 genes, 5 different rare damaging variants were detected as genetic risk factors. These alterations were not present in the control group. CONCLUSION: Based on our observations, a comprehensive, targeted panel of next-generation sequencing (NGS) testing investigating several neurodegeneration-associated genes may accelerate the path to achieve the proper genetic diagnosis since phenotypes are present on a spectrum. This can also reveal hidden correlations and overlaps in neurodegenerative diseases that would remain concealed in separated genetic testing.

Left ventricular myocardial mass index associated with cardiovascular and renal prognosis in IgA nephropathy.

INTRODUCTION: In chronic kidney disease (CKD), like in IgA nephropathy (IgAN), cardiovascular (CV) mortality and morbidity are many times higher than in the general population, and left ventricular hypertrophy (LVH) is an independent risk factor for CV disease. This follow-up study investigated the association between left ventricular mass index (LVMI) and renal or cardiovascular outcomes. METHODS: We examined 118 IgAN patients prospectively. LVMI and LV geometry was investigated using echocardiography. The primary combined endpoints were total mortality, major CV events, and end-stage renal disease. Secondary endpoints, i.e.-cardiovascular or renal endpoints,-were also examined separately. RESULTS: Sixty seven percent were males, mean age 53.5 ± 13.5. Mean follow-up time: 184 months. LVMI inversely correlated with eGFR (corr. coefficient: -0.365; p < 0.01). We divided the patients into two groups based on the LVMI cut-off suggested by the literature. The presence of LVH caused a worse prognosis in primary (p < 0.001), renal endpoints (p = 0.01), and also in CV endpoints (p = 0.001). The higher LVMI in men significantly worsened the prognosis in all endpoints. Concentric hypertrophy meant a worse prognosis. Independent predictors of LVMI were gender and eGFR in uni- and multivariate regression and hemoglobin levels only in logistic regression. Independent predictors of the primary endpoint were LVMI, eGFR, gender, obesity, HT, DM, and metabolic syndrome in Cox regression analysis. CONCLUSION: Increased LVMI may predict the progression to end-stage renal disease and CV events in IgAN. Determining LVMI may be a useful parameter not only in CV risk but also in the stratification of renal risk in CKD.

Multidisciplinary blended learning to build a breast cancer specialist career: survey on the perspective of the first 2 cohorts of the ESO-ULM Certificate of Competence in Breast cancer (CCB).

BACKGROUND: Breast Cancer (BC) specialists need to acquire comprehensive knowledge, covering their own specialty and principles of related disciplines. Blended learning, the integration of online and face-to-face learning, is becoming more and more important in academic education and has added value during pandemics which limit face-to-face learning and residential training. In this context, the ESO-ULM Certificate of Competence in Breast Cancer (CCB) provides postgraduate multidisciplinary education and delivers an academic postgraduate title. The aim of this work is to investigate the degree of satisfaction of 42 participants to the first two editions of the programme and to assess if attending the programme entailed any professional gain. METHODS: An ad-hoc questionnaire was developed exploring 4 areas: participants' characteristics, administrative aspects, CCB Program syllabus and design, professional impact. RESULTS: The program was attractive for specialists of different disciplines from all over the world: > 90% of responders appreciated the curriculum set up and the quality of the teaching. Despite 64% of responders changed their clinical practice, only 33% could implement institutional changes. One third of the participants activated a collaboration with other colleagues and 64% used the CCB as a trigger to take part in other educational activities. Only 12% of the participants had the opportunity, after CCB, to visit other BC Units or to be involved in international research projects. More than half of the attendees profited from attending CCB in terms of promotions (16.7%), change of working institution (9.5%) or development of a more structured educational program at their home institutions (28.6%). CONCLUSIONS: Results provide interesting and stimulating considerations on the expectations and needs of training physicians and on what modern educational tools and formats can achieve. This paper can provide useful information to navigate through what the post-graduate training market is currently offering to develop a specific curriculum in modern multidisciplinary BC care but might not be applicable to other fields of multidisciplinary oncology.

Synthesis and Vibrational Circular Dichroism Analysis of N-Heterocyclic Carbene Precursors Containing Remote Chirality Centers.

VCD analysis of 16 diastereomeric pairs of NHC precursors containing two isolated chirality centers and different substitution patterns identified VCD transitions characteristic of the chirality center in the imidazolium ring or in the side chain, which, in contrast to ECD and OR, could be utilized to assign the two chirality centers separately by simple comparison, regardless of the type and position of achiral aromatic substituents. While the ECD and OR data showed great dependence on the position of an achiral substituent such as a methoxy group, characteristic experimental VCD transitions remained consistent and they could be used to determine the absolute configuration of all the regio- and stereoisomers and substituted analogues. VCD, ECD and OR approaches were evaluated, and several carbene precursors were found, for which only the VCD method could distinguish the four stereoisomers. With t-butyl, phenyl or 2-naphthyl substituents at the C-1' chirality center, the ECD spectra of the C-1' epimers were near-identical, and hence it was only the VCD approach that showed distinct differences suitable for the configurational assignment. The chiroptical characterization of our diastereomeric pairs of NHC precursors enables the future application of related derivatives having different substitution patterns in stereoselective transformations.

Breast conservation and axillary management after primary systemic therapy in patients with early-stage breast cancer: the Lucerne toolbox.

Primary systemic therapy is increasingly used in the treatment of patients with early-stage breast cancer, but few guidelines specifically address optimal locoregional therapies. Therefore, we established an international consortium to discuss clinical evidence and to provide expert advice on technical management of patients with early-stage breast cancer. The steering committee prepared six working packages to address all major clinical questions from diagnosis to surgery. During a consensus meeting that included members from European scientific oncology societies, clinical trial groups, and patient advocates, statements were discussed and voted on. A consensus was reached in 42% of statements, a majority in 38%, and no decision in 21%. Based on these findings, the panel developed clinical guidance recommendations and a toolbox to overcome many clinical and technical requirements associated with the diagnosis, response assessment, surgical planning, and surgery of patients with early-stage breast cancer. This guidance could convince clinicians and patients of the major clinical advancements purported by primary systemic therapy, the use of less extensive and more targeted surgery to improve the lives of patients with breast cancer.

Real-time ex vivo perfusion of human lymph nodes invaded by cancer (REPLICANT): a feasibility study.

Understanding how breast cancer (BC) grows in axillary lymph nodes (ALNs), and refining how therapies might halt that process, is clinically important. However, modelling the complex ALN microenvironment is difficult, and no human models exist at present. We harvested ALNs from ten BC patients, and perfused them at 37 °C ex vivo for up to 24 h. Controlled autologous testing showed that ALNs remain viable after 24 h of ex vivo perfusion: haematoxylin and eosin-stained histological appearance and proliferation (by Ki67 immunohistochemistry) did not change significantly over time for any perfused ALN compared with a control from time-point zero. Furthermore, targeted gene expression analysis (NanoString PanCancer IO360 panel) showed that only 21/750 genes were differentially expressed between control and perfused ALNs (|log2 FC| > 1 and q < 0.1): none were involved in apoptosis and metabolism, but rather all 21 genes were involved in immune function and angiogenesis. During perfusion, tissue acid-base balance remained stable. Interestingly, the flow rate increased (p < 0.001) in cancer-replaced (i.e. metastasis occupied more than 90% of the surface area on multiple levels) compared to cancer-free nodes (i.e. nodes with no metastasis on multiple sections). CXCL11 transcripts were significantly more abundant in cancer-replaced nodes, while CXCL12 transcripts were significantly more abundant in cancer-free nodes. These cytokines were also detected in the circulating perfusate. Monoclonal antibodies (nivolumab and trastuzumab) were administered into a further three ALNs to confirm perfusion efficacy. These drugs saturated the nodes; nivolumab even induced cancer cell death. Normothermic ALN perfusion is not only feasible but sustains the tumour microenvironment ex vivo for scientific investigation. This model could facilitate the identification of actionable immuno-oncology targets. © 2019 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

An optically active isochroman-2H-chromene conjugate potently suppresses neuronal oxidative injuries associated with the PI3K/Akt and MAPK signaling pathways.

Increasing evidence suggests that the use of potent neuroprotective agents featured with novel pharmacological mechanism would offer a promising strategy to delay or prevent the progression of neurodegeneration. Here, we provide the first demonstration that the chiral nonracemic isochroman-2H-chromene conjugate JE-133, a novel synthetic 1,3-disubstituted isochroman derivative, possesses superior neuroprotective effect against oxidative injuries. Pretreatment with JE-133 (1-10 µM) concentration-dependently prevented H2O2-induced cell death in SH-SY5Y neuroblastoma cells and rat primary cortical neurons. Pretreatment with JE-133 significantly alleviated H2O2-induced apoptotic changes. These protective effects could not be simply attributed to the direct free radical scavenging as JE-133 had moderate activity in reducing DPPH free radical. Further study revealed that pretreatment with JE-133 (10 µM) significantly decreased the phosphorylation of MAPK pathway proteins, especially ERK and P38, in the neuronal cells. In addition, blocking PI3K/Akt pathway using LY294002 partially counteracted the cell viability-enhancing effect of JE-133. We conclude that JE-133 exerts neuroprotection associated with dual regulative mechanisms and consequently activating cell survival and inhibiting apoptotic changes, which may provide important clues for the development of effective neuroprotective drug lead/candidate.

The prognostic role of heart rate recovery after exercise and metabolic syndrome in IgA nephropathy.

BACKGROUND: Cardiovascular (CV) morbidity and mortality are higher in chronic kidney disease (CKD) than in the general population. Reduced heart rate recovery (HRR) is an independent risk factor for CV disease. The aim of the study was to determine the prognostic role of HRR in a homogenous group of CKD patients. METHODS: One hundred and twenty-five IgA nephropathy patients (82 male, 43 female, age 54.7 ± 13 years) with CKD stage 1-4 were investigated and followed for average 70 months. We performed a graded exercise treadmill stress test. HRR was derived from the difference of the peak heart rate and the heart rate at 1 min after exercise. Patients were divided into two groups by the mean HRR value (22.9 beats/min). The composite (CV and renal) endpoints included all-cause mortality and any CV event such as stroke, myocardial infarction, revascularisation (CV) and end-stage renal disease, renal replacement therapy (renal). RESULTS: Patients with reduced HRR (< 23 bpm) had significantly more end point events (22/62 patients vs. 9/53 patients, p = 0.013) compared to the higher HRR (≥23 bpm). Of the secondary the endpoints (CV or renal separately) rate of the renal endpoint was significantly higher in the lower HRR group (p = 0.029), while there was no significant difference in the CV endpoint between the two HRR groups (p = 0.285). Independent predictors of survival were eGFR and diabetes mellitus by using Cox regression analysis. Kaplan-Meier curves showed significant differences in metabolic syndrome and non-metabolic syndrome when examined at the combined endpoints (cardiovascular and renal) or at each endpoint separately. The primary endpoint rate was increased significantly with the increased number of metabolic syndrome component (Met.sy. comp. 0 vs. Met. sy. comp. 2+, primary endpoints, p = 0.012). CONCLUSION: Our results showed that reduced HRR measured by treadmill exercise test has a predictive value for the prognosis of IgA nephropathy. The presence of metabolic syndrome may worsen the prognosis of IgA nephropathy.

May Measurement Month 2019: an analysis of blood pressure screening results from Hungary.

Cardiovascular diseases are not only the leading causes of mortality in Hungary but also the mortality rate is twice as high as the European Union average, so screening programmes identifying subjects with elevated blood pressure (BP) are of utmost importance. May Measurement Month (MMM) is an annual global initiative that began in 2017 aimed at raising awareness of high BP. Hungary joined the 3rd campaign of MMM in 2019 and an overview of the results are presented in this paper. An opportunistic cross-sectional survey of participants aged ≥18 years was carried out in May 2019. Hypertension was defined as systolic BP ≥140 mmHg and diastolic BP ≥90 mmHg or treatment for hypertension, statistical analysis followed the standard MMM protocol. In Hungary, 55 sites were set up in primary and secondary care facilities, in pharmacies, and in malls across all regions, in both cities and villages. Out of 2766 individuals screened, 1286 participants (46.5%) had hypertension. Out of 1869 participants not on antihypertensive medication, 389 (20.8%) had elevated BP. In the case of treated individuals (n = 897), 420 (46.8%) had uncontrolled hypertension. Almost every 2nd subject of the screened cohort had hypertension (treated and controlled, treated and uncontrolled, or untreated). In the untreated cohort, every 5th subject had elevated BP, whilst among patients on antihypertensive medication, every second had uncontrolled BP. By identifying almost one-third of the whole screened cohort with the possibility of newly diagnosed or uncontrolled hypertension, our results confirm the importance of BP screening campaigns.

Cholinesterase inhibitors and memantine for the treatment of Alzheimer and non-Alzheimer dementias.

In aging societies, the morbidity and mortality of dementia is increasing at a significant rate, thereby imposing burden on healthcare, economy and the society as well. Patients' and caregivers' quality of life and life expectancy are greatly determined by the early diagnosis and the initiation of available symptomatic treatments. Cholinesterase inhibitors and memantine have been the cornerstones of Alzheimer's therapy for approximately two decades and over the years, more and more experience has been gained on their use in non-Alzheimer's dementias too. The aim of our work was to provide a comprehensive summary about the use of cholinesterase inhibitors and memantine for the treatment of Alzheimer's and non-Alzheimers's dementias.

Sex-specific regulation of neuronal functions in Caenorhabditis elegans: the sex-determining protein TRA-1 represses goa-1/Gα(i/o).

Females and males differ substantially in various neuronal functions in divergent, sexually dimorphic animal species, including humans. Despite its developmental, physiological and medical significance, understanding the molecular mechanisms by which sex-specific differences in the anatomy and operation of the nervous system are established remains a fundamental problem in biology. Here, we show that in Caenorhabditis elegans (nematodes), the global sex-determining factor TRA-1 regulates food leaving (mate searching), male mating and adaptation to odorants in a sex-specific manner by repressing the expression of goa-1 gene, which encodes the Gα(i/o) subunit of heterotrimeric G (guanine-nucleotide binding) proteins triggering physiological responses elicited by diverse neurotransmitters and sensory stimuli. Mutations in tra-1 and goa-1 decouple behavioural patterns from the number of X chromosomes. TRA-1 binds to a conserved binding site located in the goa-1 coding region, and downregulates goa-1 expression in hermaphrodites, particularly during embryogenesis when neuronal development largely occurs. These data suggest that the sex-determination machinery is an important modulator of heterotrimeric G protein-mediated signalling and thereby various neuronal functions in this organism and perhaps in other animal phyla.

The nucleoside diphosphate kinase NDK-1/NME1 promotes phagocytosis in concert with DYN-1/Dynamin.

Phagocytosis of various targets, such as apoptotic cells or opsonized pathogens, by macrophages is coordinated by a complex signaling network initiated by distinct phagocytic receptors. Despite the different initial signaling pathways, each pathway ends up regulating the actin cytoskeletal network, phagosome formation and closure, and phagosome maturation leading to degradation of the engulfed particle. Herein, we describe a new phagocytic function for the nucleoside diphosphate kinase 1 (NDK-1), the nematode counterpart of the first identified metastasis inhibitor NM23-H1 (nonmetastatic clone number 23) nonmetastatic clone number 23 or nonmetastatic isoform 1 (NME1). We reveal by coimmunoprecipitation, Duolink proximity ligation assay, and mass spectrometry that NDK-1/NME1 works in a complex with DYN-1/Dynamin (Caenorhabditis elegans/human homolog proteins), which is essential for engulfment and phagosome maturation. Time-lapse microscopy shows that NDK-1 is expressed on phagosomal surfaces during cell corpse clearance in the same time window as DYN-1. Silencing of NM23-M1 in mouse bone marrow-derived macrophages resulted in decreased phagocytosis of apoptotic thymocytes. In human macrophages, NM23-H1 and Dynamin are corecruited at sites of phagosome formation in F-actin-rich cups. In addition, NM23-H1 was required for efficient phagocytosis. Together, our data demonstrate that NDK-1/NME1 is an evolutionarily conserved element of successful phagocytosis.-Farkas, Z., Petric, M., Liu, X., Herit, F., Rajnavölgyi, É., Szondy, Z., Budai, Z., Orbán, T. I., Sándor, S., Mehta, A., Bajtay, Z., Kovács, T., Jung, S. Y., Afaq Shakir, M., Qin, J., Zhou, Z., Niedergang, F., Boissan, M., Takács-Vellai, K. The nucleoside diphosphate kinase NDK-1/NME1 promotes phagocytosis in concert with DYN-1/dynamin.