[Myocardial bridge: morphological factors which influence symptoms]. / Myocardialis izomhíd: a tüneteket befolyásoló morfológiai faktorok vizsgálata.

INTRODUCTION: Myocardial bridge is a frequently detected congenital coronary anomaly which is kept benign. It is unique because it can cause a dynamic compression during systole. OBJECTIVE: In this article, we focus on the detection and evaluation of morphological parameters that can determine the symptomatic bridges. METHOD: We summarize the invasive and noninvasive modalities regarding this topic. We also present our retrospective research when we studied the morphological features of the left anterior descendent bridges with coronarography which led to angina pectoris. We compared the prognosis of patients where only myocardial bridge was found to those where atherosclerosis also had been presented. RESULTS: Intravascular ultrasound can be adapted for the visualization of myocardial bridge and for measuring the severity of compression. Intracoronary Doppler- and fractional flow reserve allow the appreciation of functional significance. Stress echocardiography is the most used non-invasive imaging modality in this field. According to our results, the group where only myocardial bridge was presented has more severe morphological features. The shortening of the tunneled segment was more expressed. The mortality during long term (appr. 10 years) follow-up was low. Meanwhile, our results have demonstrated that none of the morphological parameters influence mortality. CONCLUSION: There is an essential discrepancy between the phenomenon's high prevalence, the good prognosis, and the numerous case reports where the authors report about severe complications. Today we possess those invasive and non-invasive techniques which can help us to design prospective trials clarify the morphological features' functional significance. Orv Hetil. 2023; 164(14): 563-570.

Diagnosis of neuroborreliosis in the context of local seroprevalence: A chart review study and a methodological overview.

Background & objectives: In neuroborreliosis (NB) serology might objectively differentiate ongoing from past infection when the intrathecal space is involved. The hierarchy of the parallel serum-CSF (cerebrospinal fluid) methods is seldom discussed and remains elusive in daily practice. We compared the efficacy of certain methods and assessed the prevalence of anti-Borrelia antibodies in the local population. Methods: We summarized standard two-tier test results in all ELISA-reactive samples of patients with suspected NB (n=152) since 2017 and tested 122 unrelated sera for anti-Borrelia antibodies from central Hungary. Results: The most common central nervous system symptom was a cranial nerve palsy (27.6% of all subjects). CSF was available in 25 cases. A serum-CSF IgG-matched line immunoassay (LIA) detected intrathecal antibody production correctly in 6 of 8 samples when compared to the ELISA-based antibody-index (AI). Among the 122 random sera the prevalence of specific anti-Borrelia IgG antibodies (on LIA, not including anti-p41) were 6.8% above 30 and 10% above 60 years. Our results enable us to assume the predictive values of serological results according to the pretest probability of neuroborreliosis. Interpretation & conclusion: Our results suggest that recombinant antigen-based two-tier serology from solely the sera might have sufficient positive predictive value to verify NB in young individuals with characteristic anamnestic data in our region. When parallel serum-CSF testing is warranted, AI should have priority. IgG and albumin concentrations in the both serum and the CSF, the potential time of exposure and the nature and duration of symptoms form the bare minimal set of data for conclusive testing.

Long-Term SARS-CoV-2-Specific Humoral and T Cell Responses after the BNT162b2 or BBIBP-CorV Booster and the Incidence of Breakthrough Infections among Healthcare Workers.

The effectiveness of COVID-19 vaccines developed against the original virus strain deteriorated noticeably in efficacy against the Omicron variant (B.1.1.529). Moreover, the immunity developed after vaccination or due to natural infection rapidly waned. In the present study, covering this period, we summarize the incidence of breakthrough infections among healthcare workers (HCWs) with respect to administration of the three vaccine doses. Additionally, we evaluate the long-term SARS-CoV-2-specific humoral and T cell responses at two different time points: six and twelve months after receipt of the third (booster) dose. The spike-protein-specific antibody levels and the quantity of structural-protein-specific T cells were evaluated at these time points and compared with the values measured earlier, 14 days after the booster vaccination. The study participants were categorized into two cohorts: Members of the first cohort received a two-dose BNT162b2 mRNA-based vaccine regimen, followed by an additional BNT162b2 booster six months later. Individuals in the second cohort received an inactivated-virus-based BBIBP-CorV booster six months after the initial two-dose BNT162b2 vaccination. Overall, 64.3% of participants were infected with SARS-CoV-2 confirmed by PCR or antigen test; however, additional subjects from the first cohort (23%) who did not know about their previous infection but had an anti-nucleocapsid T cell response were also considered virus-experienced. According to our results, no statistically significant difference was found between the two cohorts regarding the SARS-CoV-2-specific T cell response, neutralizing anti-RBD IgG, and anti-S IgA serum antibody levels either six or twelve months after receiving the booster, despite the overall higher median values of the first cohort. The only significant difference was the higher anti-S1/S2 IgG antibody level in the first cohort one year after the BNT162b2 booster (p = 0.039). In summary, the BNT162b2 and BBIBP-CorV boosters maintain durable humoral and T cell-mediated immune memory even one year after application. Although the booster provided limited protection against Omicron breakthrough infections, as 73.6% of these infections occurred after the booster vaccination, which means 53.5% cumulative incidence, it still offered excellent protection against severe disease and hospitalization in both cohorts.

Challenges and experiences of the SARS-CoV-2 pandemic in molecular diagnostics / A SARS-CoV-2-járvány kihívásai és tapasztalatai a molekuláris diagnosztikában

Összefoglaló. Bár a SARS-CoV-2-pandémia próbára tette a diagnosztikus kapacitásokat, számos hasznos tapasztalattal is szolgált, melyek alacsonyabb mintaszám mellett nem lettek volna levonhatók. Míg korábban a PCR-vizsgálatok jellemzoen diagnosztikus, illetve kvantitatív követési célokat szolgáltak, a járvány során többségbe kerültek a szuro- és (kezdetben) a felszabadító vizsgálatok. Jól követheto volt, hogy a tesztek piacra juttatásának eroltetett üteme sokszor nem tette lehetové a teljesen kiforrott koncepciók létrehozását. Tekintettel arra, hogy a molekuláris diagnosztika során nem teljes vírusgenomokat, hanem célszakaszokat mutatunk ki, amelyek aránya a fertozés egyes szakaszaiban nem feltétlenül állandó, egyre valószínubb, hogy nem azonos célgének a legmegfelelobbek diagnosztikus, szuro- és felszabadító vizsgálatokhoz. A nagy mennyiségu, aspecifikusan végzett vizsgálat még kiváló fajlagosság mellett is a pozitív prediktív érték csökkenéséhez vezethet, amennyiben a fertozés tényleges prevalenciája a vizsgálati csoportban alacsony. Munkánkban megkíséreljük irodalmi és saját adatok felhasználásával összefoglalni az elmúlt két év fontosabb diagnosztikus tapasztalatait a teljesség igénye nélkül. Orv Hetil. 2021; 162(52): 2071-2078. Summary. Although the SARS-CoV-2 pandemic has been a great challenge for the diagnostic capacities, it also proved to be a unique source of experience. While previously PCR tests had overwhelmingly been used for targeted diagnostic and quantitative follow-up testing, screening and (initially) release tests became far more prevalent during the pandemic. It was well to be seen that the forced pace of bringing tests to market often gave way to not fully mature concepts. The PCR method is based on the detection of sequences, the proportions of which are likely to alter throughout the course of the disease. It is becoming increasingly clear that different target genes might be the best suitable for diagnostic, screening and release testing. Even with specific assays, an unprecedentedly high number of tests might result in the inflation of the positive predictive value, when the true prevalence of the infection remains very low among the tested individuals. Here we try to summarize some of the potentially most relevant diagnostic conclusions of the pandemic so far according to our own data and the literature. Orv Hetil. 2021; 162(52): 2071-2078.

Immunologic complications of infections: the relevance of the grey zone / Fertozésekhez kapcsolódó immunológiai jelenségek: a szürkezóna jelentosége.

Összefoglaló. A fertozésekhez kapcsolódó immunológiai kórképekre különösen jellemzo, hogy mind etiológiai tényezoikben, mind klinikai képükben rendkívül heterogének. Az átfedo és inkomplett megjelenési formák nem ritkák, ami a diagnosztika standardizálását nehezíti. Egyes, a fertozésekhez opcionálisan kapcsolódó tünetek megfigyelése már több mint egy évszázaddal ezelott elvezetett a gócelmélet megszületéséhez, amely eredeti formájában leginkább elnagyolt és naiv feltételezéseken alapult. Folyamatosan bovülo ismereteink ugyanakkor egyre több esetben támasztják alá, hogy az átvészelt, esetleg krónikus vagy perzisztáló fertozések, illetve a mikrobiom összetétele számos ponton lehet befolyással immunológiai, metabolikus és endokrin homeosztázisunkra. A jelen munkában az ismert összefüggéseket, illetve a meghaladott feltételezéseket is röviden érintve megkíséreljük a rendelkezésre álló ismereteken keresztül áttekinteni a fertozésekhez kapcsolódó immunológiai jelenségek szürkezónáját, azon kórtani folyamatokat és tüneteket, amelyek létezése igazolható, de terápiás következményeik az egyén szintjén egyelore bizonytalanok. Orv Hetil. 2021; 162(38): 1526-1532. Summary. Immunologic phenomena related to infections are well known to be truly heterogeneous, both regarding their etiology and the clinical picture. Overlapping symptoms and incomplete presentations are not seldom, which often constitute diagnostic challenge. Certain, optional complications of infectious diseases led to the creation of the focal infection theory more than a century ago, although only on the basis of assumptions derived from elusive and naive theories. However, an expanding body of evidence ever since did underline the impact of previous and persistent infections on the immunologic, metabolic and endocrine homeostasis. Besides briefly touching the well-defined diseases, as well as the outdated theories of this field, we aim to provide an overview of the grey zone of infection-related immunologic phenomena, the existence of which is biologically well established, however, their true significance on an individual basis remains uncertain. Orv Hetil. 2021; 162(38): 1526-1532.

The potential impact of Helicobacter pylori seropositivity on recombinant antigen-based Lyme serology.

We assessed the impact of Helicobacter pylori seropositivity on recombinant antigen-based Lyme serology. We compared the IgG ELISA+LIA (line immunoassay) reactivity of anti-Helicobacter IgG positive and negative samples. The ELISA S/Co values and LIA band numbers were identical. Our results suggest that Helicobacter seropositivity lacks an apparent effect on Lyme disease test reactivity.

Reduced GLP-1 response to a meal is associated with the CTLA4 rs3087243 G/G genotype.

Although insulitis is the characteristic main feature of type 1 diabetes mellitus (T1DM), many aspects of ß cell loss still remain elusive. Immune dysregulation and alterations in the dipeptidyl-peptidase-4-incretin system might have a role in disease development, but their connection is poorly understood. We assessed the associations of a few selected, immunologically relevant single nucleotide gene variants with the DPP-4-incretin system in individuals with T1DM and in healthy controls. Prandial plasma (total, active) GLP-1 levels, serum DPP-4 activity, CD25 and CTLA-4 expression of T cells and DPP4 rs6741949, CTLA4 rs3087243, CD25 rs61839660 and PTPN2 rs2476601 SNPs were assessed in 33 T1DM patients and 34 age-, gender-, BMI-matched non-diabetic controls without a family history of T1DM. CTLA-4 expression was lower in the Foxp3+CD25+ regulatory T cells from individuals homozygous for the CTLA4 rs3087243-G variant compared to those who carry an A allele. Prandial plasma total GLP-1 levels 45 min after a standardized meal were reduced in individuals homozygous for the CTLA4 rs3087243 G major allele compared to A allele carriers both in the entire study population (with statistical power over 90%) and within the T1DM group. Here we report for the first time a reduced total prandial GLP-1 plasma concentration in individuals with the CTLA4 rs3087243 G/G genotype. One may speculate that immune response-related L cell damage might possibly explain this novel association.

[A brief of gestational diabetes mellitus, risk factors and current criteria of diagnosis]. / A terhességi cukorbetegség rövid története, kockázati tényezoi és diagnosztikája napjainkban.

Diabetes is one of the most common metabolic disorders that may cause pathological pregnancy. Treating diabetes recognized during pregnancy results in lowering maternal and fetal complications. These patients present higher risk for excessive weight gain, preeclampsia, delivery with cesarean sections, high risk of developing type 2 diabetes and cardiovascular disease in the future. Fetuses of mothers with gestational diabetes are at higher risk for macrosomia and birth trauma, after delivery they present higher risk of developing neonatal hypoglycemia, hyperbilirubinemia, and respiratory distress syndrome. There is still no consensus in the recommendations for the diagnosis of gestational diabetes mellitus by expert committees. Orv. Hetil., 2017, 158(8), 283-290.

Increased Proportion of Hematopoietic Stem and Progenitor Cell Population in Cord Blood of Neonates Born to Mothers with Gestational Diabetes Mellitus.

We assessed the hematopoietic stem and progenitor cell (HSPC) population in the cord blood of neonates born to mothers with gestational diabetes mellitus (GDM) in a hypothesis generating pilot study, due to that, neonatal polycythemia may be the consequence of GDM pregnancy. Forty-five pregnant women with GDM (last trimester mean HbA1C = 33.9 mmol/mol) and 42 (nondiabetic) control pregnant women were enrolled after their routine 75 g oral glucose tolerance test (OGTT) between the 24th and 28th gestational week (with expected differences in their mean routine clinical characteristics: plasma glucose at OGTT: 0' = 5.07 vs. 4.62 mM, 120' = 8.9 vs. 5.76 mM, age = 35.07 vs. 31.66 years, prepregnancy body mass index = 27.9 vs. 23.9 kg/m(2), GDM vs. control, respectively) on a voluntary basis after signing the informed consent. EDTA-treated cord blood samples were analyzed by flow cytometry and the software Kaluza1.2 using CD45 and CD34-specific fluorescent antibodies to identify the HSPC population (CD34(+) cells within the CD45(dim) blast gate). The proportion of CD34(+)CD45(dim) HSPCs among the nucleated cells was significantly (P < 0.05, statistical power = 60.8%) higher in the cord blood samples of neonates born to mothers with GDM (median 0.38%) compared to neonates born to nondiabetic mothers (median 0.32%) and according to treatment types (P < 0.05) median: control 0.32%, GDM-diet only 0.37%, GDM-on insulin 0.45%; control versus GDM on insulin (P < 0.05). The increased proportion of circulating CD34(+)CD45(dim) cells in the cord blood may possibly be related to altered fetal stem cell mobilization in GDM pregnancy, yet these results should be interpreted only as preliminary due to the small sample sizes.

Altered crosstalk in the dipeptidyl peptidase-4-incretin-immune system in type 1 diabetes: A hypothesis generating pilot study.

Both GLP1(7)(-)(36) (via GLP1 receptor) and the dipeptidyl peptidase-4 (DPP4) cleaved form of GLP1 (GLP1(9)(-)(36), independently of GLP1R) may modulate the response of lymphocytes to cytokine stimuli. The incretin axis, CXCR3 (receptor of DPP4 ligand cytokines CXCL9-11) expression on T(reg)s and hematologic parameters were assessed in 34 patients with long standing type 1 diabetes (T1DM) and in 35 healthy controls. Serum DPP4 (sDPP4) activity, plasma total GLP1 and GLP1(7)(-)(36) concentrations were determined. GLP1(9)(-)(36) concentrations were calculated. CXCR3 expression (flow cytometry) was higher on the CD25(-/)(low)Foxp3(+) than on the CD25(+)Foxp3(+) T(reg)s independently from T1DM, suggesting that CD25(-/)(low)Foxp3(+) T(reg)s are possibly waiting for orientational chemotactic stimuli in a "standby mode". The higher sDPP4 activities in T1DM were inversely correlated with GLP1(7)(-)(36) levels and GLP1(9)(-)(36) levels directly with lymphocyte counts in controls. Our results might indicate an altered DPP4-incretin system and altered immunoregulation including a potentially dysfunctional GLP1(9)(-)(36) signaling in T1DM.

Cord serum dipeptidyl-peptidase 4 activity in gestational diabetes.

BACKGROUND: Tissue-specific dipeptidyl-peptidase 4 (DPP4) dysregulation has been described in adults with diabetes mellitus. The DPP4 -incretin system has not been studied in foetal life. In this study, DPP4 activity and glucagon-like peptide-1 (GLP-1) levels were assessed in cord blood of neonates born to women with gestational diabetes mellitus (GDM) and nondiabetic controls. MATERIAL AND METHODS: This study has been conducted in two Hungarian and one Austrian centres. PATIENTS: A total of 568 pregnant women were enrolled in the study after their OGTT between the 24th and 28th gestational week. Cord blood samplings with DPP4 activity and GLP-1 level measurements were possible in 270 (DPP4: 159 control, 111 GDM) and 112 (GLP-1: 72 control, 40 GDM) cases. OGTT (24-28th gestational week) and cord blood sampling at delivery were performed. Cord serum DPP4 activity was determined in a continuous monitoring microplate-based kinetic assay, and cord plasma GLP-1 was measured using a fluorescence ELISA method. RESULTS: Cord serum DPP4 activity was lower in GDM [mean (95% CI): 28.07 U/L (26.32-29.82 U/L)] than in controls [31.61 U/L (29.93-33.29 U/L), MWU P = 0.0015]. Cord plasma active GLP-1 levels were close to the lower detection limit and were not altered in GDM (control: mean = 3.43 pM, 95% CI: 3.04-3.82 pM, GDM: mean = 3.61 pM, 95% CI: 2.96-4.28 pM - MWU test P = 0.6). CONCLUSIONS: Decreased cord serum DPP4 activity in gestational diabetes mellitus might be the result of an adaptive foetal response or an early dysregulation in the entero-insular axis with consequences beyond the incretin system. Cord plasma GLP-1 levels may reflect the missing oral intake with a limited glucose sensing of L cells via the circulation in foetal life.

Extension of the CD4⁺Foxp3⁺CD25(-/low) regulatory T-cell subpopulation in type 1 diabetes mellitus.

Regulatory T-cells (Treg) have a crucial role in limiting physiologic autoreactivity. Foxp3 is a master regulator transcription factor of Treg differentiation and active Treg cells express high levels of IL-2 receptor α-chain (CD25). The aim of our study was to assess the key markers of Treg cell function in type 1 diabetic (T1DM) and control subjects by flow cytometry. The proportion of CD25(-/low) cells among CD4(+)Foxp3(+) Treg cells was higher in T1DM patients that might suggest a shifted proportion of the incomplete/reserve and the fully active (CD4(+)Foxp3(+)CD25(+)) Treg cell subpopulations in T1DM, similarly to other Th1-mediated autoimmune diseases. In addition to the decreased expression of CD25 and CTLA-4 in T1DM patients, a positive correlation was observed between the CD25 expression on CD4(+) and the CTLA-4 expression in CD8(-) T-lymphocytes both in the T1DM and in the healthy control group. Our results suggest an impaired balance of CD25(+) and CD25(-/low) Treg cells in T1DM which might reflect a decreased late phase peripheral Treg activation even in patients with a mean disease duration of more than a decade.

Altered immune regulation in type 1 diabetes.

Research in genetics and immunology was going on separate strands for a long time. Type 1 diabetes mellitus might not be characterized with a single pathogenetic factor. It develops when a susceptible individual is exposed to potential triggers in a given sequence and timeframe that eventually disarranges the fine-tuned immune mechanisms that keep autoimmunity under control in health. Genomewide association studies have helped to understand the congenital susceptibility, and hand-in-hand with the immunological research novel paths of immune dysregulation were described in central tolerance, apoptotic pathways, or peripheral tolerance mediated by regulatory T-cells. Epigenetic factors are contributing to the immune dysregulation. The interplay between genetic susceptibility and potential triggers is likely to play a role at a very early age and gradually results in the loss of balanced autotolerance and subsequently in the development of the clinical disease. Genetic susceptibility, the impaired elimination of apoptotic ß -cell remnants, altered immune regulatory functions, and environmental factors such as viral infections determine the outcome. Autoreactivity might exist under physiologic conditions and when the integrity of the complex regulatory process is damaged the disease might develop. We summarized the immune regulatory mechanisms that might have a crucial role in disease pathology and development.

[Type 1 diabetes mellitus: most recent advances in its pathogenesis and treatment]. / 1-es típusú diabetes mellitus: a patogenezis és terápia aktuális kérdései.

The incidence and prevalence of diabetes mellitus is globally increasing. The causes of this trend are relatively obvious in the case of type 2 diabetes. In contrast, in case of type 1 diabetes the amount of available data is continuously growing, but the causes are not so well defined. The genetic risk, especially related to the MHC genes is well known, and the increasing amount of data underlines the role of additional risks due to non-MHC genetic polimorphisms. Hopefully, they will provide the basis for future diagnostic and therapeutic approaches. There is increasing knowledge about the pathophysiological aspects including the role of immunological disregulation (balance of autotolerance, role of regulatory T-cells) and environmental triggers (nutrients, viruses). Information on the entero-insular axis and the ß-cell protective role of incretin hormones might offer an opportunity for new therapeutic strategies. In this paper, the authors try to summarize some current aspects of the pathomechanism and related therapeutic approaches.

Ventricular septal rupture caused by myocardial bridge, solved by interventional closure device.

Myocardial bridging is a common coronary anomaly, which is generally described as a benign phenomenon. However, a growing number of studies consider this anomaly a relevant pathophysiological phenomenon with serious pathological consequences. Here we report on the case of an 88-year-old woman suffering from myocardial infarction and ventricular septal rupture, lacking any recognizable coronary disease except for a myocardial bridge causing the systolic compression of the left anterior descending coronary artery. A wide range of diagnostic procedures, including coronarography, echocardiography, and magnetic resonance imaging were used. The septal rupture was finally closed by using a percutaneous closure device. This event indicates that myocardial bridges - at least in some cases - may have notable clinical relevance.