ITree: a user-driven tool for interactive decision-making with classification trees.

MOTIVATION: ITree is an intuitive web tool for the manual, semi-automatic, and automatic induction of decision trees. It enables interactive modifications of tree structures and incorporates Relative Expression Analysis for detecting complex patterns in high-throughput molecular data. This makes ITree a versatile tool for both research and education in biomedical data analysis. RESULTS: The tool allows users to instantly see the effects of modifications on decision trees, with updates to predictions and statistics displayed in real time, facilitating a deeper understanding of data classification processes. AVAILABILITY AND IMPLEMENTATION: Available online at https://itree.wi.pb.edu.pl. Source code and documentation are hosted on GitHub at https://github.com/hsokolowski/iTree and in supplement.

When modern diagnostics is challenged by a historical disease: A case report.

RATIONALE: Syphilis is a bacterial, systemic infectious disease caused by Treponema pallidum spirochetes, which spread rapidly through the body affecting various organs. The term neurosyphilis (NS) refers to a CNS infection that can occur at any stage of the disease. The lack of a gold standard for the diagnosis of NS greatly hinders diagnosis, which must be based mainly on clinical assessment. PATIENT CONCERNS: A 58-year-old man reported dizziness and headache for a week and right-sided hearing impairment, with suspected transient cerebral ischemic attack. A month later he experience transient speech disturbance and suspected cerebral ischemic stroke. DIAGNOSIS: MRI showed fresh ischemic lesions with a diameter up to 10 mm in the deep brain structures on the left side and foci of subacute ischemia also in the deep structures and the brain stem. Cerebrospinal fluid examination showed positive Pandy's reaction, doubtful Noone-Apelt reaction, increased protein level and decreased glucose level. The reactive result of the USR test performed (VDRL) finally allowed the diagnosis of symptomatic CNS syphilis. INTERVENTIONS: Empiric treatment for bacterial meningitis was administered. The patient was transferred to the Department of Infectious Diseases for further treatment. OUTCOMES: The diagnosis has been confirmed at the Department of Infectious Diseases after repeating CSF analysis including VDRL and FTA-ABS. LESSON: Symptoms of NS are nonspecific, hence the diagnostic process is not straightforward. Despite the availability of modern diagnostic techniques, establishing a final diagnosis was challenging, but the patient ultimately received appropriate treatment. It is important to remember that syphilis is not only a disease known from history lessons but is still present in modern times and its incidence is increasing.

Evolution of Hypodensity on Non-Contrast CT in Correlation with Collaterals in Anterior Circulation Stroke with Successful Endovascular Reperfusion.

INTRODUCTION: The aim of the study was to assess the impact of collaterals on the evolution of hypodensity on non-contrast CT (NCCT) in anterior circulation stroke with reperfusion by mechanical thrombectomy (MT). METHODS: We retrospectively included stroke patients with middle cerebral artery occlusion who were reperfused by MT in early and late time window. Artificial intelligence (AI)-based software was used to calculate of hypodensity volumes at baseline NCCT (V1) and at follow-up NCCT 24 h after MT (V2), along with the difference between the two volumes (V2-V1) and the follow-up (V2)/baseline (V1) volume ratio (V2/V1). The same software was used to classify collateral status by using a 4-point scale where the score of zero indicated no collaterals and the score of three represented contrast filling of all collaterals. The volumetric values were correlated with the collateral scores. RESULTS: Collateral scores had significant negative correlation with V1 (p = 0.035), V2, V2- V1 and V2/V1 (p < 0.001). In cases with collateral score = 3, V2 was significantly smaller or absent compared to V1; in those with collateral score 2, V2 was slightly larger than V1, and in those with scores 1 and 0 V2 was significantly larger than V1. These relationships were observed in both early and late time windows. CONCLUSIONS: The collateral status determined the evolution of the baseline hypodensity on NCCT in patients with anterior circulation stroke who had MT reperfusion. Damage can be stable or reversible in patients with good collaterals while in those with poor collaterals tissues that initially appear normal will frequently appear as necrotic after 24 h. With good collaterals, it is stable or can be reversible while with poor collaterals, normal looking tissue frequently appears as necrotic in follow-up exam. Hence, acute hypodensity represents different states of the ischemic brain parenchyma.

The SnRK2.10 kinase mitigates the adverse effects of salinity by protecting photosynthetic machinery.

SNF1-Related protein kinases Type 2 (SnRK2) are plant-specific enzymes widely distributed across the plant kingdom. They are key players controlling abscisic acid (ABA)-dependent and ABA-independent signaling pathways in the plant response to osmotic stress. Here we established that SnRK2.4 and SnRK2.10, ABA-nonactivated kinases, are activated in Arabidopsis thaliana rosettes during the early response to salt stress and contribute to leaf growth retardation under prolonged salinity but act by maintaining different salt-triggered mechanisms. Under salinity, snrk2.10 insertion mutants were impaired in the reconstruction and rearrangement of damaged core and antenna protein complexes in photosystem II (PSII), which led to stronger non-photochemical quenching, lower maximal quantum yield of PSII, and lower adaptation of the photosynthetic apparatus to high light intensity. The observed effects were likely caused by disturbed accumulation and phosphorylation status of the main PSII core and antenna proteins. Finally, we found a higher accumulation of reactive oxygen species (ROS) in the snrk2.10 mutant leaves under a few-day-long exposure to salinity which also could contribute to the stronger damage of the photosynthetic apparatus and cause other deleterious effects affecting plant growth. We found that the snrk2.4 mutant plants did not display substantial changes in photosynthesis. Overall, our results indicate that SnRK2.10 is activated in leaves shortly after plant exposure to salinity and contributes to salt stress tolerance by maintaining efficient photosynthesis and preventing oxidative damage.

Alterations in Circulating MicroRNAs and the Relation of MicroRNAs to Maximal Oxygen Consumption and Intima-Media Thickness in Ultra-Marathon Runners.

The impact of long-term training on cardiovascular disease (CVD) is not clear. Carotid intima-media thickness (CIMT) test is recommended as a useful measure to diagnose the early stages of atherosclerosis. MicroRNAs (miRNAs) are altered due to endurance exercise and can be promising biomarkers of pathophysiological changes. We aimed to evaluate the association of circulating miRNAs with physical fitness and markers of atherosclerosis in ultra-marathon runners. Ultra-marathon runners had 28-fold upregulation of miR-125a-5p expressions compared to control individuals (p = 0.002), whereas let-7e and miR-126 did not differ statistically between ultra-marathon runners and controls. In the ultra-marathon runners' group, negative correlations were observed between VO2max/kg and relative expression of miR-125a-5p and miR-126 (r = -0.402, p = 0.028; r = -0.438, p = 0.032, respectively). Positive correlations were observed between CIMT and miR-125a-5p and miR-126 (r = 0.388, p = 0.050; r = 0.504, p = 0.023, respectively) in ultra-marathon runners. Individuals with the highest quartile of VO2max/kg had 23-fold lower miR-126 expression in comparison to subgroups with lower VO2max/kg (p = 0.017). Our results may indicate that both miRNAs may serve as a biomarker for early pathological changes leading to atherosclerosis burden in athletes. Furthermore, the association between miRNAs and traditional risk factors for CVD indicate a possible use of these molecules as early biomarkers of future cardiovascular health.

Epicardial Adipose Tissue and Cardiovascular Risk Assessment in Ultra-Marathon Runners: A Pilot Study.

Epicardial adipose tissue (EAT) volume is associated with cardiovascular disease (CVD). Data regarding the influence of extremely intensive training on CVD are scarce. We compared EAT volume among ultra-marathon runners and in the sedentary control group, and assessed the correlations between EAT and risk factors of coronary artery disease (CAD). EAT volume around three main coronary vessels and right ventricle (RV) was measured in 30 healthy amateur ultrarunners and 9 sex- and age-matched sedentary controls using cardiac magnetic resonance. In addition, body composition, lipid profile, interleukin-6 (IL-6) plasma concentration, and intima-media thickness (IMT) were measured as well. The EAT volume was lower in all measured locations in the ultrarunners' group compared to control group (p < 0.001 for all). Ultrarunners had lower BMI and fat percentage (FAT%) and more favorable lipid profile compared to the control group (p < 0.05 for all). Ultrarunners had lower rate of pathologically high levels of plasma IL-6 (>1 pg/mL) compared to the control group (17% vs. 56%, p < 0.05). IMT was similar in both groups. In the ultrarunners' group, there was a positive correlation between EAT surrounding left anterior descending artery, circumflex artery, and RV and FAT%, and between EAT around circumflex artery and LDL and non-HDL cholesterol (p < 0.05 for all). In summary, extremely intensive training may decrease the risk of cardiovascular events in adult population of amateur athletes by reducing the amount and pro-inflammatory activity of EAT. However, more research is needed to draw firm conclusions regarding the anti- and pro-inflammatory effects of intensive training.

The Effect of the Ultra-Marathon Run at a Distance of 100 Kilometers on the Concentration of Selected Adipokines in Adult Men.

Pro-inflammatory adipokines have a multifunctional role in adipogenesis, angiogenesis, glucose homeostasis, and inflammation. The aim of the present study is to evaluate the effect of running a 100 km ultra-marathon on serum levels of two adipokines: resistin and chemerin. Fifteen male participants complete a medical questionnaire and their body composition is assessed. Serum resistin, chemerin, high sensitivity C-reactive protein (hs-CRP), glucose, and lactate levels are measured at baseline and post-race. During-race data on fluid and food consumption and energy expenditure are calculated. There is a higher (p < 0.001) post-race concentration of resistin and hs-CRP compared with resting values, with no change in chemerin levels. There is an inverse correlation of the change in resistin levels with post-run glucose values (r = 0.742, p < 0.001) and a positive correlation between changes in hs-CRP and energy expenditure (r = 0.782, p < 0.001). The present results show the impact of running an ultra-marathon on serum levels of pro-inflammatory markers released by adipose tissue. It is difficult to establish whether these results may be due to the stress of exercise, high energy expenditure or caloric deficit. However, we suggest that an addition of resistin to traditional pro-inflammatory markers (including CRP) may improve the assessment of inflammation in conditions of high-energy expenditure.

Acute Effects of a Static Vs. a Dynamic Stretching Warm-up on Repeated-Sprint Performance in Female Handball Players.

This randomized cross-over study examined the effects of typical static and dynamic stretching warm-up protocols on repeated-sprint performance. Thirteen young female handball players performed a 5 min aerobic warm-up followed by one of three stretching protocols for the lower limbs: (1) static stretching, (2) dynamic-ballistic stretching, and (3) no stretching before performing five all-out sprints on a cycle ergometer. Each protocol was performed on a different occasion, separated by 2-3 days. Range of movement (ROM) was also measured before and after the warm-up protocols with a sit-and-reach test. Fixed and random effects of each stretching protocol on repeated sprint performance were estimated with mixed linear modeling and data were evaluated via standardization and magnitude-based inferences. In comparison to no stretching, there were small increases in ROM after dynamic stretching (12.7%, ±0.7%; mean, ±90% confidence limits) and static stretching (19.2%, ±0.9%). There were small increases in the average power across all sprints with dynamic stretching relative to static stretching (3.3%, ±2.4%) and no stretching (3.0%, ±2.4%) and trivial to small increases in the average power in the 1st and 5th trials with dynamic stretching compared to static stretching (3.9%, ±2.6%; 2.6%, ±2.6%, respectively) and no stretching (2.0%, ±2.7%; 4.1%, ±2.8%, respectively). There were also trivial and small decreases in power across all sprints with static relative to dynamic stretching (-1.3%, ±2.8%) and no stretching (-3.5%, ±2.9%). Dynamic stretching improved repeated-sprint performance to a greater extent than static stretching and no stretching.

Factors Related to Cardiac Troponin T Increase after Participation in a 100 Km Ultra-Marathon.

BACKGROUND: Intensive and prolonged exercise leads to a rise of troponin concentration in blood. The mechanism responsible for troponin release during exercise remains ill-defined. The study aim was to search for risk factors of troponin increase after a prolonged endurance competition. METHODS: The study included a group of 18 amateurs, healthy volunteers (median age 41.5 years, interquartile range - IQR 36-53 years, 83% male) who participated in a 100 km running ultra-marathon. Information on demographic characteristics, pre- and post-race heart rate, blood pressure, body composition and glucose, lactate (L), troponin T (hs-TnT) and C reactive protein (hs-CRP) concentration were obtained. Additionally, data on L and glucose levels every 9.2 km and fluid/food intakes during the race were collected. RESULTS: There was a significant hs-TnT increase after the race exceeding upper reference values in 66% of runners (from 5 IQR 3-7 ng/L to 14 IQR 12-26 ng/L, p < 0.0001). None of the baseline parameters predicted a post-race hs-TnT increase. The only factors, correlating with changes of hs-TnT were mean L concentration during the race (rho = 0.52, p = 0.03) and change of hs-CRP concentration (rho = 0.59, p = 0.01). CONCLUSIONS: Participation in a 100 km ultra-marathon leads to a modest, but significant hs-TnT increase in the majority of runners. Among analysed parameters only mean lactate concentration during the race and change in hs-CRP correlated with troponin change.

Cerebral amyloid angiopathy-related inflammation (CAARI): case report.

Cerebral amyloid angiopathy-related inflammation is a new disease entity whose proper diagnosis may be difficult due to the fact that the early phase and radiological image resemble other conditions such as intracerebral haemorrhage or proliferative disorder. Also, the brain biopsy, which is an important part of the evaluation to confirm the diagnosis and rule out mimics, cannot be performed in each patient. In this paper we present the case of a 58yearold man who was correctly diagnosed with cerebral amyloid angiopathy-related inflammation (CAARI) based on the results of the histopathological examination of the brain tissue, which was possible mainly owing to the inclusion of the expansive process as the underlying cause in the initial differentiation. Further progression of the disease, despite applying treatment of increasing intensity in response to progressive deterioration of the patient's condition, revealed the multiplicity of clinical courses that a new and not easily pinpointed entity can take.

Cardiovascular magnetic resonance with parametric mapping in long-term ultra-marathon runners.

PURPOSE: There is a direct reverse dose-effect relationship between the amount of physical activity and cardiovascular risk. It is unknown whether this is true for extreme, persistent endurance training. The aim of the study was to assess structural changes of the heart in long-time ultra-marathon runners with special focus on myocardial fibrosis using parametric mapping. METHOD: We studied a group of 30 healthy, male ultra-marathon runners (mean age 40.9 ±â€¯6.6 yrs, median 9 yrs of running with frequent competitions) and 10 matched controls not engaged in any regular activities. All of them underwent cardiovascular magnetic resonance (CMR) with 3 T scanner including T1-mapping, late gadolinium enhancement (LGE) and extracellular volume (ECV) quantification. RESULTS: Athletes demonstrated significantly larger heart chambers and left ventricular (LV) mass. LV systolic function was unchanged. 73.3% of athletes fulfilled volumetric criteria for dilated cardiomyopathy or arrhythmogenic right ventricular cardiomyopathy. Non-ischemic, small volume LGE was found in 8 athletes and in 1 control (27% vs. 10%, p = 0.40). It was localised at insertion points (5 athletes, 1 control) or in the septum or infero-lateral wall (3 athletes). Athletes with insertion point LGE had higher right ventricular end-diastolic volume index in comparison to athletes without LGE (p = 0.04), which suggests its relation to volume overload. There were no differences between athletes and non-athletes in terms of ECV values (26.1% vs. 25%, p = 0.29). CONCLUSIONS: Ultra-marathon runner's hearts demonstrate a high degree of structural remodelling, but there is no significant increase in focal or diffuse myocardial fibrosis.

Strength Abilities in Men 50+ as an Effect of Long-Distance Run Training.

The aim of this study was to evaluate the effect of long-term running training on muscle strength of men aged 50 and above. The study involved two groups of men aged 50 and above: physically active (E, n = 34) and inactive (NE, n = 20). Body composition was assessed with the electrical bioimpedance method. The isometric maximum voluntary contraction (MVC) was the main measurement. The value of muscle torque achieved by a group of synergists (operating in the given joint) during a short isometric contraction was evaluated. Ten groups of flexor and extensor muscles of the elbow, shoulder, hip, knee, and torso joints were measured. In addition, a 3 s measurement of grip strength of the right (Fr) and left (Fl) hand was taken using a hand dynamometer. The obtained values enabled to calculate the symmetry index (SI). Men who had been running regularly were characterized by a significantly lower strength level (p < .05). Results in the NE group were determined to a great extent by significantly different body weights (p < .001) and a significantly higher body fat mass (FAT) content (p < .001). SI was statistically higher in the reference group (p < .05). Long-distance run training reduces FAT while maintaining a high level of muscle strength. These studies indirectly confirm the effect of strengthening slow-twitch motor units in men aged 50 (Doherty & Brown 1993; Kanda & Hashizume 1989). In addition, stimulating the body through physical effort helps it also to maintain a high level of strength symmetry, which is a preventive factor in reducing the number of injuries.

Accuracy of Impedance Cardiography for Hemodynamic Assessment During Rest and Exercise in Wheelchair Rugby Players.

Purpose: The aim of the study was to analyze the accuracy of impedance cardiography (ICG) for hemodynamic assessment in wheelchair rugby players during rest and exercise. Method: The study included 21 players (mean age 33.0 ± 5.4, 86% male) with posttraumatic tetraplegia. ECG, echocardiography, and gas exchange analysis during rest and exercise were used to obtain heart rate (HR), stroke volume (SV), and cardiac output (CO) for comparison with PhysioFlow®. Results: There was a good correlation between reference methods and ICG for HR, SV, CO at rest and CO at peak exercise (r = 0.69-0.77, p < .001) and a very good correlation for peak HR (r = 0.91, p < .0001). ICG overestimated SV at rest, CO at rest, and peak CO, which resulted in low intraclass correlation coefficients (ICC = 0.250 and 0.570). Conclusions: ICG can serve as a good estimate of basic hemodynamic parameters during rest and exercise in wheelchair rugby players but overestimates stroke volume and cardiac output.

Left ventricular hypertrophy in middle-aged endurance athletes: is it blood pressure related?

Both regular physical activity and hypertension may be related to increased myocardial thickness, but the interplay between these two factors in causing cardiac remodeling in athletes is still a matter of debate. The aim of this study was to analyze the relation between resting and peak exercise blood pressure (BP) and myocardial hypertrophy in healthy middle-aged amateur endurance athletes. The study included 30 male, long-term athletes (mean age 40.9±6.6 years) who underwent resting BP assessment, cardiopulmonary exercise testing with peak exercise BP measurement, and cardiac magnetic resonance. We found that interventricular septal diameter is increased in athletes with high-normal resting BP (n=11, 37%) - median 13 mm (interquartile range: 12-13.75 mm), but not in those with optimal or normal BP (n=19) - median 10 mm (10-11.75 mm), P=0.001. This finding is accompanied by significantly higher left and right ventricular mass index and larger left atrial area in the first group. These differences are even more pronounced in athletes in whom high-normal BP is accompanied by exaggerated blood pressure response (EBPR) to exercise, whereas isolated EBPR to exercise does not lead to hypertrophy or further left atrial enlargement. Prehypertension, isolated or combined with EBPR to exercise, affects cardiac remodeling in athletes. Identification of increased myocardial thickness in pure endurance middle-aged athletes should merit further investigation on masked hypertension.

Beneficial effects of pre-stroke statins use in cardioembolic stroke patients with atrial fibrillation: a hospital-based retrospective analysis.

INTRODUCTION: Statins are widely used in stroke patients. The AHA/ASA guidelines recommend aggressive statin therapy in atherosclerotic stroke patients. Their beneficial effects are due to both their hypolipemic and pleiotropic properties. The aim of this study was to establish potential benefits from statin use in ischemic stroke patients with the diagnosis of atrial fibrillation (AF). MATERIAL AND METHODS: Ischemic stroke patients with AF were enrolled in the study. Group I, the statin group (n = 181), consisted of patients who had been treated with statins before stroke. Group II, the non-statin group (n = 153), consisted of patients who had not received such treatment in the last year. In-hospital mortality and neurological deficit on admission and at discharge were analyzed using the National Institutes of Health Stroke Scale (NIHSS) score. RESULTS: Patients from the non-statin group had greater initial and discharge NIHSS scores (10 vs. 11.9, probability value p < 0.05; 7.6 vs. 9.5, p < 0.05 respectively). The improvement in NIHSS score was greater in the statin group (73.5% vs. 59.5%, p < 0.01). In-hospital mortality was more frequent in the non-statin group (9.9% vs. 18.3%, p < 0.05). CONCLUSIONS: Despite the predominant use of statins in atherothrombotic stroke patients, we demonstrated the beneficial effects of statins in cardioembolic stroke patients. Detailed cardiovascular screening for statin therapy should be carried out in all AF patients with regard to primary and secondary stroke prevention.

A Novel NOTCH3 Gene Mutation in a Polish CADASIL Family.

Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) is a genetically determined disease of the cerebral vessels, characterized by recurrent ischemic strokes, dementia, and degeneration of the cerebral white matter. The condition is caused by a mutation in the NOTCH3 gene, whose product plays a great role in the development and physiology of the cardiovascular system. Magnetic resonance imaging reveals multiple hyperintensive lesions of the white matter in the T2-weighted images also in asymptomatic carriers of CADASIL and can be detected even 10-15 years prior to clinical signs. Diagnosis is confirmed by genetic testing. We present 2 patients (mother and daughter) carrying the same mutation p.Cys212Gly in 1 allele of the NOTCH-3 gene, which has not yet been recorded in the Human Gene Mutation Database for that gene and therefore described as a new one. The clinical manifestation of the disease differs between patients -the 63-year-old mother has been suffering from severe migraine headaches since her early youth and the first vascular event occurred when she was about 50 years old, she is now presenting with impaired cognitive functions, left facial palsy, bilateral pyramidal syndrome more prominent on the left side, and four-wheel support assisted walking. The neurological deficits that her 42-year-old daughter is afflicted with are discreet. Observation to date indicates a definitely less severe clinical course of the disease. This indicates that members of the same family carrying the same mutation may produce different clinical course of the disease.

Effects of Short-Term Plyometric Training on Physical Performance in Male Handball Players.

The aim of this study was to compare the effects of plyometric and jump training on physical performance in young male handball players. Twenty-six young male handball players were divided into two sub-groups to perform a five-week pre-season training programme supplemented with two ground-reactive protocols with an equal number of jumping exercises referred as to ground contacts: plyometric training (PLY; n = 14) and standard jump training (CON; n = 12). Before and after training, repeated sprint ability (RSA), jumping ability (JA), maximal oxygen uptake (VO2max) and aerobic power at the anaerobic threshold (PAT) were measured. A two-factor analysis revealed significant time effects with improvements in fat mass (p = 0.012), maximal power during the incremental cycling test (p = 0.001) and PAT (p < 0.001), power decline (PDEC) and maximal power (Pmax) in the 5th repetition (p < 0.05 and p < 0.01, respectively). The training-induced changes in absolute and relative peak power in the RSA test and absolute VO2max approached significance (p = 0.06, p = 0.053 and p = 0.06). No intervention time × exercise protocol effects were observed for any indices of JA, RSA and aerobic capacity. A five-week pre-season conditioning programme supplemented with only 15 sessions of plyometric exercise did not induce any additional benefits, compared to a matched format of standard jump training, in terms of improving jumping performance and maximal power in the RSA test. Aerobic capacity and the fatigue index in RSA were maintained under these two training conditions.

Changes in Anthropometry and Selected Metabolic Parameters in Young Men During Their First Year of Study at a University of Physical Education.

This study aims to determine main health-related anthropometric and metabolic parameters in young physically active male students in their first year of study. Sixty one male students from a Polish university of physical education were studied twice-at the beginning of their first and second academic years. Body weight, height, waist circumference, and body composition were measured. Plasma levels of thyroid-stimulating hormone (TSH), leptin, cortisol, and insulin, as well as insulin resistance (IR) using the homeostatic model assessment (HOMA) were determined. In 64% of the participants body weight and body mass index (BMI) significantly increased during the study. An average students' weight gain amounted to 1.2 kg. In most of the subjects it resulted from the increase of fat-free mass ( r = .886, p < .001). TSH and leptin levels did not change, but a significant increase of cortisol levels and a tendency toward decreased insulin levels and also HOMA-IR values were observed. However, there were no significant correlations identified between the changes in anthropometric and biochemical parameters. The study revealed that body weight gain seen in male students during their first year at the university of physical education was mainly due to the increase in fat-free mass. Apart from anthropometrics, changes in their insulin and cortisol levels were also detected, but further studies are required to evaluate these findings. The documented insufficient energy and carbohydrates consumption in physically active male students proves the need for nutritional education among them.

Synthesis and antimicrobial activity of chiral quaternary N-spiro ammonium bromides with 3',4'-dihydro-1'H-spiro[isoindoline-2,2'-isoquinoline] skeleton.

A new class of highly functionalized tetrahydroisoquinolines with a quaternary carbon stereocenter was synthesized starting from an easily accessible L-tartaric acid. Nine strains of bacteria (Staphylococcus aureus, Streptococcus pyogenes, Streptococcus mutans, Streptococcus salivarius, Bacillus subtilis, Enterococcus faecalis, Moraxella catarrhalis, Escherichia coli, Campylobacter jejuni) were used for the determination of minimal inhibitory concentration (MIC) and minimal bactericidal concentration (MBC) of synthesized compounds. The influence of analyzed compounds on viability and induction of apoptosis in human skin fibroblasts was determined. A majority of the synthesized compounds showed the strongest antibacterial properties toward some gram-negative bacteria (M. catarrhalis and C. jejuni) with a high level of selectivity. High antibacterial compounds have bactericidal activity ratio MBC/MIC ≤4. Our studies also proved that the novel compounds do not possess cytotoxic and proapoptotic potential in normal cells.

Biological evaluation of octahydropyrazin[2,1-a:5,4-a']diisoquinoline derivatives as potent anticancer agents.

In this study, we evaluated the cytotoxic activity and antiproliferative potency of novel octahydropyrazin[2,1-a:5,4-a']diisoquinoline derivatives (1-7) in MCF-7 and MDA-MB-231 breast cancer cell lines. Annexin V binding assay and disruption of the mitochondrial potential were performed to determine apoptosis. The activity of caspases 3, 8, 9, and 10 was measured after 24 h of incubation with tested compounds to explain detailed molecular mechanism of induction of apoptosis. The results from experiments were compared with effects obtained after incubation in the presence of camptothecin and etoposide. Our study demonstrated that the most active compounds in both analyzed breast cancer cell lines were compounds 3 and 4. We also observed that all compounds induced apoptosis. We demonstrated the higher activity of caspases 3, 8, 9, and 10, which confirmed that induction of apoptosis is associated with external and internal cell death pathway. Our study revealed that the novel compounds in group of diisoquinoline derivatives are promising candidates in anticancer treatment by activation of both extrinsic and intrinsic apoptotic pathways.