Trnka Vaclav - Central European Anatomist and Medical Polymath of the Eighteenth Century.

Vaclav Trnka from Krovice (1739-1791, in Latin: Wenzel Trnka Krzowitz) was a remarkable physician whose life serves as an example in the history of medicine by connecting major capital cities of Central Europe. In view of current geographical layout, he was born and brought up in the Czech Republic, graduated from University of Vienna in Austria, and was appointed Professor of the Anatomy at the newly established Faculty of Medicine of University of Nagyszombat, presently Trnava in Slovak Republic. When the University moved to Buda and later to Pest (today Budapest, Hungary), he was the first educator to introduce anatomy as a medical subject to be taught in a Hungarian medical school. He also was elected the Dean of Faculty of Medicine three times and in 1786-1787 he acted as Rector of then the Royal University of Pest. During his life, he published twenty-seven monographs dealing with different areas of clinical medicine, such as malaria (intermittent fever), diabetes, and rickets. Based on these monographs we can proclaim that Václav Trnka was a co-founder of modern infectology, diabetology and ophthalmology in Central Europe. Nowadays, artificial intelligence and bioinformatics are inseparable parts of modern health care system which help the transformation of big data into valuable knowledge. In the 18th century, Professor Trnka owned more than 3,000 scientific books and had natural, innate intelligence and wisdom which made him a real "medical polymath". As a musician, Trnka also composed sixty-one canons, two of them long wrongly considered as Mozart's work. Despite the fact that Trnka is considered to be the founder of Hungarian anatomy education and a major medical figure of the eighteenth century Central Europe, no internationally acclaimed biographical record of his life or work has so far been published in English. Therefore, we would like to reintroduce Václav Trnka both as an anatomist and medical polymath, and to give an overview of the early days of anatomy teaching in present-day Slovakia and Hungary (Fig. 1, Ref. 27). Keywords: Trnka from Krovice, anatomist, medical polymath, history of medicine.

Radiofrequency ablation of focal atrial tachycardia: Benefit of electroanatomical mapping over conventional mapping.

BACKGROUND: Catheter ablation is a proven therapy of focal atrial tachycardia. However limited information is available about the additional value of electroanatomical over conventional mapping methods for this specific arrhythmia. METHODS: Consecutive catheter ablation procedures of FAT were analyzed in two cardiology centres. Only conventional mapping was used in 30 of the 60 procedures whereas additionally CARTO mapping was performed in another 30 procedures. Acute, six-month success rate, and procedural data were analyzed. RESULTS: Localization of ectopic foci is congruent with previously published data. There was no statistically significant difference between procedure time and fluoroscopy time using additionally CARTO mapping, compared to conventional mapping only. Acute success rate was higher in procedures guided by CARTO mapping than in procedures based on conventional mapping (27/30 vs. 18/30, p = 0.0081). During the 6-month follow-up period there was a better outcome (p = 0.045) in case of CARTO guided procedures (success: 11 cases, partial success: 12 cases, failure: 4 cases) compared to conventional mapping (success: 4 cases, partial success: 18 cases, failure: 7 cases). CONCLUSIONS: Catheter ablation of focal atrial tachycardias using the CARTO electroanatomical mapping system seems to provide higher acute and 6-month success rate compared to ablation using conventional mapping methods only.

Receptors of peptides as therapeutic targets in epilepsy research.

Neuropeptides are signaling molecules participating in the modulation of synaptic transmission. Neuropeptides are stored in dense core synaptic vesicles, the release of which requires profound excitation. Only in the extracellular space, neuropeptides act on G-protein coupled receptors to exert a relatively slow action both pre- and postsynaptically. Consequently, neuropeptide modulators are ideal candidates to influence epileptic tissue overexcited during seizures. Indeed, a number of neuropeptides have receptors implicated in epilepsy and many of them are considered to participate in endogenous neuroprotective actions. Neuropeptide receptors, present in the hippocampus, the most frequent focus of seizures in temporal lobe epilepsy, received the largest attention as potential anti-epileptic targets. Receptors of hippocampal neuropeptides, somatostatin, neuropeptide Y, galanin, dynorphin, enkephalin, substance P, cholecystokinin, vasoactive intestinal polypeptide, and receptors of some neuropeptides, which are also hormones such as ghrelin, angiotensins, corticotropin- releasing hormone, adrenocorticotropin, thyrotropin-releasing hormone, oxytocin and vasopressin involved in epilepsy are discussed in the review article. Activation and inhibition of receptors by oral application of peptides as drugs is typically not efficient because of low bioavailability: rapid degradation and insufficient penetration of peptides through the blood-brain barrier. Recent progress in the development of non-peptide agonists and antagonists of neuropeptide receptors as well as gene therapeutic approaches leading to the local production of agonists and antagonists within the central nervous system will also be discussed.

Microvascular regulatory role and increased expression of vascular endothelial growth factor receptor type 2 in experimental gingivitis.

OBJECTIVE: The aim of the present study was to investigate the possible microvascular regulatory role of vascular endothelial growth factor receptor type 2 (VEGFR2) in experimental gingivitis in rats. BACKGROUND: Our previous results demonstrated that functionally active VEGFR2s are located in the venules of rat gingiva. While there is no remarkable endogenous gingival VEGF production under normal circumstances, exogenous VEGF, via VEGFR2, shows venodilatory effects. We assumed that VEGF plays an important role in vasoregulatory processes (vasodilation, increased permeability, angiogenesis) of gingival inflammation. METHODS: Gingivitis was induced by placing ligatures and composite material around and between the lower incisors of anesthetized Wistar rats next to the gingival margin. Seven days later, VEGFR2 antagonist (ZM323881), was dripped upon the labial gingiva next to the lower incisors. Diameter changes of the selected gingival venules were measured by vital microscopy. Animals with healthy gingiva served as controls. Venule diameter changes were compared to the baseline and to control groups (no ligature). Immunohistochemical and Western blot analysis for VEGFR2 were utilized. RESULTS: After 15, 30 and 60 min of local application of ZM323881, there was a significant venoconstriction in the inflamed gingiva compared to the baseline, while no change was recorded in controls. Endothelium, smooth muscle cells and pericytes of the gingivitis group showed increased VEGFR2 expression. CONCLUSION: Our findings suggest that there is an increased VEGF production in gingivitis, which may play an important role in vasodilation of rat gingival venules.

Comparison of transpulmonary thermodilution, transthoracic echocardiography and conventional hemodynamic monitoring in neonates and infants after open heart surgery: a preliminary study.

BACKGROUND: Transpulmonary thermodilution (TPTD) is an increasingly popular method used to monitor the complex hemodynamic changes in critically ill children. The purpose of our study was to examine the relationship between transthoracic echocardiographic (TTE) parameters and global hemodynamic variables derived from TPTD and those derived from conventional measurements in infants and neonates undergoing corrective cardiac surgery. METHODS: After approval from the Ethics Committee of Gottsegen György Hungarian Institute of Cardiology and individual parental consent were obtained, patients were prospectively enrolled. In parallel with continuous postoperative conventional monitoring, TPTD was measured four times daily, and TTE was performed once per day. Conventional hemodynamic, TPTD and TTE parameters were compared with weighted linear regression statistics and a Pearson correlation. RESULTS: One hundred forty-five TPTD measurements and 35 TTE examinations of thirteen enrolled patients were analyzed. Global end-diastolic volume index (GEDVI) was correlated with the fractional shortening (SF, r=0.67, P=0.001) measured by TTE. Among the preload parameters, the percentage change of GEDVI between two consecutive time points showed a pertinent correlation with changes of cardiac index (r=0.67, P=0.001) and changes of stroke volume index (r=0.57, P=0.008). Percentage changes in SF demonstrated a strong negative correlation with changes of left ventricular end-systolic diameter (r=-0.86, P<0.001). There was no significant relationship between alterations in arterial or central venous pressure values with TTE or TPTD parameters. CONCLUSION: Both TPTD and TTE may be used in the estimating volumetric preload parameters. The time course of TPTD-derived parameters may have clinical relevance in pediatric critical care practice.

Genetic factors of reaction time performance: DRD4 7-repeat allele associated with slower responses.

Twin studies indicate substantial inherited components in cognitive abilities. One of the most extensively studied candidate genes of cognitive functioning is the dopamine D4 receptor gene (DRD4), which has been suggested to be related to attentional disorders. Based on reaction time data of 245 Caucasians participating in different cognitive tasks, slower responses characterized the group with the 7-repeat allele. This effect was present in both sexes and was not because of fatigue. To our knowledge, this is the first report on significant association (P = 0.0001) between the DRD4 variable number of tandem repeat (VNTR) polymorphism and response latencies in a non-clinical adult sample. Other studied dopaminergic polymorphisms did not show an association with reaction time. These results illustrate that speed-of-performance measures derived from multiple reaction time tasks using standardization procedures could be promising tools to detect unique genetic effects in the background of cognitive abilities.

Gallstone Ileus, Bouveret's Syndrome and Choledocholithiasis in a Patient with Billroth II Gastrectomy - A Case Report of Combined Endoscopic and Surgical Therapy.

Intestinal obstruction due to gallstone is a rare, but quite severe gastrointestinal disorder, which always requires a rapid and correct diagnosis to achieve optimal therapy. Digestive endoscopy is an important method to determine the level of the bowel obstruction and to plan an optimal therapeutic strategy. Our present case demonstrates that in a high-risk patient, a combined endoscopic and surgical therapy is the best choice to solve the obstruction of the colon, of the stomach and of the common bile duct caused by multiple gallstones.

Strong relationship between NT-proXNP levels and cardiac output following cardiac surgery in neonates and infants.

BACKGROUND: NT-proXNP, a new natriuretic peptide analyte, incorporates information about the concentrations of both N-terminal pro-atrial and pro-brain natriuretic peptides (NT-proANP, NT-proBNP). We aimed to investigate whether NT-proXNP is a reliable indicator of the cardiac index (CI) and the hemodynamic state in neonates and infants undergoing an open heart surgery. METHODS: We enrolled 26 children under the age of 1 year into this prospective study. All patients underwent an elective cardiac operation with cardiopulmonary bypass (CPB) to achieve complete biventricular repair. Peri-operative hemodynamic parameters were assessed by transpulmonary thermodilution and natriuretic peptide levels were recorded. RESULTS: The NT-proXNP level correlated significantly with the simultaneously measured NT-proANP level (r=0.60, P<0.001), but more strongly with the NT-proBNP level (r=0.89, P<0.001) and the arithmetic sum of both (r=0.88, P<0.001). NT-proXNP had a strong correlation with CI (r=-0.85, P<0.001), the stroke volume index (r=-0.80, P<0.001) and the global ejection fraction (r=-0.67, P<0.009) throughout the post-operative period. Conventionally measured parameters such as heart rate, mean arterial pressure and pulse-pressure product exhibited weaker correlations with CI than NT-proXNP. Among laboratory values, creatinine levels correlated significantly with CI (r=-0.77, P<0.001) and NT-proXNP (r=0.76, P<0.001) during the post-operative period. A post-operative NT-proXNP level of 3079 pmol/l was diagnostic for CI <3 l/min/m(2) with 89% sensitivity and 90% specificity (area under the curve: 0.91 +/- 0.05). CONCLUSION: NT-proXNP is a good marker of cardiac output following pediatric cardiac surgery and might be a useful tool in the recognition of a low output state.

Molecular and behavioral analysis of the intron 2 repeat polymorphism in the canine dopamine D4 receptor gene.

Genetic polymorphisms in the human dopamine D4 receptor (DRD4) gene, especially the exon 3 variable number of tandem repeats (VNTR), have been related to several psychiatric disorders and personality traits. A homologous exon 3 VNTR has been described in dogs, and we previously showed an association between the DRD4 exon 3 polymorphism and activity/impulsivity trait in German shepherds. In this study, we present a detailed analysis of the intron 2 VNTR of the DRD4 gene. A short and a long form of the intronic variation were identified in 678 unrelated dogs from five breeds and in 22 wolves. For molecular analysis, the intron 2 region was cloned into a promoterless luciferase reporter vector that led to an elevation in transcriptional activity. Moreover, an allelic difference in promoter activity was detected, and a repressive effect of the long allele was observed. Behavioral analysis of 96 unrelated German shepherds showed a significant association between the social impulsivity endophenotype of the Greeting Test and both the exonic (P = 0.002) and the intronic (P = 0.003) VNTRs of the DRD4 gene. Moreover, an additive effect of the two polymorphisms was also shown (Spearman's rho = 0.356, P = 0.0004). In conclusion, these results give further support to our previous findings that the DRD4 gene is associated with dog behavior. We also present molecular evidence for the functional role of the intron 2 VNTR in the canine DRD4 gene.

Antiinflammatory effect of BPC 157 on experimental periodontitis in rats.

The pentadecapeptide BPC 157 has been shown to have anti-inflammatory and wound healing effects on multiple target tissues and organs. The purpose of the present study was to investigate the effect of BPC 157 on inflammation and bone resorption in experimental periodontitis in rats. First the acute effect of BPC was tested on gingival blood flow by laser doppler flowmetry. Then periodontitis was produced by a silk ligature placed around the lower left first molar. Rats were treated with BPC 157 (once daily for 12 days) or vehicle. At day 13, the gingivomucosal tissues encircling the molars were removed on both sides. Inflammation was assessed by Evans blue plasma extravasation technique and by histology. Alveolar bone loss was analyzed by microCT. BPC 157 had no effect on gingivomucosal blood flow. Twelve day ligature caused a significantly increased Evans blue extravasation in the gingivomucosal tissue, histological signs of inflammation, and alveolar bone destruction. BPC 157 treatment significantly reduced both plasma extravasation, histological alterations and alveolar bone resorption. In conclusion, systemic application of BPC 157 does not alter blood circulation in healthy gingiva. Chronic application of the peptide has potent antiinflammatory effects on periodontal tissues in ligature induced periodontitis in rats. Taken together, this proof of concept study suggests that BPC 157 may represent a new peptide candidate in the treatment of periodontal disease.

Suicide methods in Europe: a gender-specific analysis of countries participating in the "European Alliance Against Depression".

OBJECTIVE: To identify the most frequent gender-specific suicide methods in Europe. DESIGN: Proportions of seven predominant suicide methods utilised in 16 countries participating in the European Alliance Against Depression (EAAD) were reported in total and cross-nationally. Relative risk (RR) relating to suicide methods and gender was calculated. To group countries by pattern of suicide methods, hierarchical clustering was applied. SETTING AND PARTICIPANTS: Data on suicide methods for 119,122 male and 41,338 female cases in 2000-4/5 from 16 EAAD countries, covering 52% of European population were obtained. RESULTS: Hanging was the most prevalent suicide method among both males (54.3%) and females (35.6%). For males, hanging was followed by firearms (9.7%) and poisoning by drugs (8.6%); for females, by poisoning by drugs (24.7%) and jumping from a high place (14.5%). Only in Switzerland did hanging rank as second for males after firearms. Hanging ranked first among females in eight countries, poisoning by drugs in five and jumping from a high place in three. In all countries, males had a higher risk than females of using firearms and hanging and a lower risk of poisoning by drugs, drowning and jumping. Grouping showed that countries might be divided into five main groups among males; for females, grouping did not yield clear results. CONCLUSIONS: Research on suicide methods could lead to the development of gender-specific intervention strategies. Nevertheless, other approaches, such as better identification and treatment of mental disorders and the improvement of toxicological aid should be put in place.

Association of polymorphisms in the dopamine D4 receptor gene and the activity-impulsivity endophenotype in dogs.

A variable number of tandem repeats (VNTR) polymorphism in exon 3 of the human dopamine D4 receptor gene (DRD4) has been associated with attention deficit hyperactivity disorder (ADHD). Rodents possess no analogous repeat sequence, whereas a similar tandem repeat polymorphism of the DRD4 gene was identified in dogs, horses and chimpanzees. Here, we present a genetic association study of the DRD4 VNTR and the activity-impulsivity dimension of the recently validated dog-ADHD Rating Scale. To avoid false positives arising from population stratification, a single breed of dogs (German shepherd) was studied. Two DRD4 alleles (referred to as 2 and 3a) were detected in this breed, and genotype frequencies were in Hardy-Weinberg equilibrium. For modelling distinct environmental conditions, 'pet' and 'police' German shepherds were characterized. Police German shepherds possessing at least one 3a allele showed significantly higher scores in the activity-impulsivity dimension of the dog-ADHD Rating Scale than dogs without this allele (P = 0.0180). This difference was not significant in pet German shepherds. To the best of our knowledge, this is the first report of an association between a candidate gene and a behaviour trait in dogs, and it reinforces the functional role of DRD4 exon 3 polymorphism.

A novel A/G SNP in the -615th position of the dopamine D4 receptor promoter region as a source of misgenotyping of the -616 C/G SNP.

The polymorphic 5' upstream region of the dopamine D4 receptor (DRD4) gene containing several single nucleotide polymorphisms (SNPs) has recently become a focus of association studies in psychiatric genetics. Most SNP genotyping methods are based on the two-step procedure of restriction fragment length polymorphism (RFLP). An alternative technique is a single-step method of allele-specific amplification (ASA), previously introduced for genotyping the -521 C/T SNP of the DRD4 promoter region and applied here for the -616 C/G SNP. Parallel genotyping of individuals with the novel ASA method and the conventionally used Ava II RFLP showed a potential underestimation of the -616 GG genotype frequency by the conventional method. Sequencing the dubious samples clearly demonstrated a novel A/G SNP at the -615th position influencing the Ava II digestion and thus resulting in misgenotyping. To avoid this problem, we introduced the Sau96 I RFLP for the -616 C/G genotyping as this restriction enzyme is not sensitive for the -615 A/G sequence variation. Allele (-616 G = 0.48; -616 C = 0.52) and genotype (-616 GG = 0.25; -616 GC = 0.46; -616 CC = 0.29) frequencies were determined by both the novel ASA and the Sau96 I methods. The obtained genotype frequencies corresponded to the Hardy-Weinberg equilibrium in our healthy Caucasian sample (N = 534, P = 0.168). Using these methods, no association was found between the -616 C/G SNP and personality factors of Cloninger's temperament and character inventory (N = 153) in our population.

Human personality dimensions of persistence and harm avoidance associated with DRD4 and 5-HTTLPR polymorphisms.

The associations of human personality traits as measured by the Temperament and Character Inventory (TCI) with two genetic polymorphisms, the dopamine D4 receptor (DRD4) gene exon III repeat polymorphism (VNTR) and the serotonin transporter-linked functional polymorphism (5-HTTLPR) are presented in a population of 157 ethnically homogeneous Caucasians. No association was found between Novelty Seeking and the DRD4 VNTR, but male individuals with a 7-repeat allele exhibited significantly lower Persistence scores. The 5-HTTLPR polymorphism itself had no significant effect on any of the temperament dimensions, but a significant DRD4 VNTR x 5-HTTLPR interaction was observed for Harm Avoidance, the subgroup with a s/s 5-HTTLPR, 7-repeat DRD4 genotype showed a higher mean Harm Avoidance score than the other groups. These results are discussed in relation to the recent findings on infant temperament. Association between the DRD4 7-repeat allele and Persistence can be theoretically linked to the 7-repeat allele as a risk factor for attention deficit hyperactivity disorder.

High-throughput genotyping of repeat polymorphism in the regulatory region of serotonin transporter gene by gel microchip electrophoresis.

Large-scale genotyping of the repeat polymorphism in the regulatory region of the serotonin transporter gene (5-HTTLPR) was attempted by polymerase chain reaction (PCR) amplification followed by gel microchip electrophoresis analysis. The multilane (96) format of the gel microchip system allowed parallel separation of a large number of samples. The separation and visualization of the PCR amplicons from either the 5-HTTLPR short allele (number of repeats are 14) or the 5-HTTLPR long form (16 repeats) was completed in a few minutes. Genotyping of healthy Caucasian individuals showed that the short allele had a somewhat lower frequency (0.42) than the long form (0.58), and the genotype frequencies fulfilled the criteria of the Hardy-Weinberg equilibrium (chi = 0.012, p = 0.994). Based on these results, gel microchip electrophoresis system proved to be a powerful tool for high throughput genotyping of repeat polymorphism.

Evidence for a role of GABA interneurones in the cortical modulation of midbrain 5-hydroxytryptamine neurones.

Recent electrophysiological studies demonstrate that the ventral medial prefrontal cortex has a powerful inhibitory influence on 5-hydroxytryptamine (5-HT) neurones in the dorsal raphe nucleus. Here we utilised a combination of anatomical and electrophysiological methods to characterise the cellular substrate underlying this effect.Anterograde tracing (Phaseolus vulgaris leucoagglutinin) using electron microscopy demonstrated a pathway from the ventral medial prefrontal cortex that makes neuronal contacts throughout the dorsal raphe nucleus. These contacts were predominantly asymmetrical synapses adjoining GABA immunoreactive dendrites and spines. In vivo extracellular recordings were made in the dorsal raphe nucleus of the anaesthetised rat from a subpopulation of non-5-HT neurones. These neurones were fast-firing, irregular and with short spike width, properties strongly reminiscent of immunochemically identified GABA interneurones in other brain regions. Recordings of classical 5-HT neurones were also included. Electrical stimulation of the ventral medial prefrontal cortex elicited a rapid onset (16 ms latency), orthodromic excitation of the non-5-HT neurones (13/25 neurones). This stimulation also caused a pronounced inhibition of most 5-HT neurones tested, with a longer latency (30 ms), and this was partially blocked by locally applied bicuculline. These data provide the first evidence that the ventral medial prefrontal cortex influences the activity of large numbers of raphe 5-HT neurones by targeting a local network of GABA neurones. This circuitry predicts that physiological and pathological changes in the ventral medial prefrontal cortex will impact on significant parts of the forebrain 5-HT system.

Analysis of dopamine D4 receptor gene polymorphism using microchip electrophoresis.

A microfabricated electrophoresis device was used for rapid polymerase chain reaction product analysis in genotyping the dopamine D4 receptor gene (DRD4) 48 base pairs repeat polymorphism. An allelic ladder, prepared from homozygous individuals, was used as internal standard during the microchip electrophoresis based analysis. Comparison of this novel separation method with the conventional slab gel and previously reported ultra-thin-layer techniques confirmed the reliability of this new method. Genotyping of 332 healthy Hungarian individuals gave the following allele frequencies: two-repeat: 0.089; three-repeat: 0.026; four-repeat: 0.674; five-repeat: 0.011; six-repeat: 0.002; seven-repeat: 0.189; eight-repeat: 0.011. The genotype frequencies obtained showed no deviation from the Hardy-Weinberg equilibrium (p>0.903), further underlying the reliability of this new genotyping technique.