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Context: The present work encompasses the theoretical investigation of 14 benzimidazole-based (seven vinyl fused monomeric benzimidazole (VFMBI) and seven vinyl fused oligomeric benzimidazole (VFOBI)) derivatives using density functional theory (DFT) and time-dependent density functional theory (TD-DFT) techniques. The effects of electron donor and acceptor groups on the electronic structure such as HOMO (highest occupied molecular orbital) and LUMO (lowest unoccupied molecular orbital) energies, HOMO-LUMO energy gap, ionization potentials (IPs), electron affinities (EAs), internal reorganization energies of holes and electrons (λ h/e ), and excited state properties have been explored in the present work. In addition, natural bond orbital (NBO) analysis of these compounds has been investigated to reveal the typical stabilization interactions in these molecules. Hence, the aim of the present work is to explore the electronic structures and optoelectronic properties of the title molecules on the basis of the DFT quantum chemical calculations and to make an idea on the parameters influencing the optoelectronic efficiency toward a better understanding of the structure-property relationships. Moreover, the calculated results reveal the suitable optoelectronic properties of benzimidazole oligomer derivatives using theoretical techniques. Of the investigated molecules, 4_MABIMCY and 4_MABIOCY show potential optoelectronic properties and can be used as a potential charge transport material due to their narrow band gap, high hyperpolarizability, low ionization potential, and high electron affinity. The larger λ ab and λ em values favor the system to be used as a potential optoelectronic material with better optical properties., Methods: All quantum chemical calculations were carried out using Gaussian09 theoretical chemistry code. Ground state calculations were made using the B3LYP/6-31+G(d,p) method. All excited state calculations had been computed using TDB3P86/6-311++(d,p). The initial structure for excited state calculations was optimized using the AM1 semi-empirical method., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

This study reveals the ovary micromorphology and the course of oogenesis in the leech Batracobdella algira (Glossiphoniidae). Using light, fluorescence, and electron microscopies, the paired ovaries were analyzed. At the beginning of the breeding season, the ovaries were small, but as oogenesis progressed, they increased in size significantly, broadened, and elongated. A single convoluted ovary cord was located inside each ovary. The ovary cord was composed of numerous germ cells gathered into syncytial groups, which are called germ-line cysts. During oogenesis, the clustering germ cells differentiated into two functional categories, i.e., nurse cells and oocytes, and therefore, this oogenesis was recognized as being meroistic. As a rule, each clustering germ cell had one connection in the form of a broad cytoplasmic channel (intercellular bridge) that connected it to the cytophore. There was a synchrony in the development of the clustering germ cells in the whole ovary cord. In the immature leeches, the ovary cords contained undifferentiated germ cells exclusively, from which, previtellogenic oocytes and nurse cells differentiated as the breeding season progressed. Only the oocytes grew considerably, gathered nutritive material, and protruded at the ovary cord surface. The vitellogenic oocytes subsequently detached from the cord and filled tightly the ovary sac, while the nurse cells and the cytophore degenerated. Ripe eggs were finally deposited into the cocoons. A comparison of the ovary structure and oogenesis revealed that almost all of the features that are described in the studied species were similar to those that are known from other representatives of Glossiphoniidae, which indicates their evolutionary conservatism within this family.

Spermatogenesis and spermatozoa ultrastructure of the amphibian leech Batracobdella algira Moquin-Tandon, 1846 (Hirudinida: Glossiphoniidae) have been investigated by means of electron and fluorescent microscopy. In B. algira, there are seven pairs of testisacs (testes) that are located latero-ventrally throughout the body. Each testis contains numerous cysts with developing germ cells. The germ cells in a given cyst are in the same developmental stage (i.e., there are spermatogonial, spermatocytic, and spermatid cysts); however, there is no developmental synchrony between the cysts, and therefore, all of the developmental stages occur simultaneously in the same testis. In the cysts, each germ cell is connected to acentral cytoplasmic mass, the cytophore, by one intercellular bridge. The spermatozoa of the studied species conform to the general organization plan that is known for Hirudinida: they are filiform cells that are formed in sequence by an elongated and twisted acrosome that consists of an anterior and posterior acrosome, a fully condensed and helicoid nucleus, a midpiece composed of a single and twisted mitochondrion that is characteristically surrounded by an electron-dense sheath, and a flagellum with the conventional 9 × 2 + 2 axonemal pattern. Using a comprehensive approach, we compared our findings with the ultrastructural data that had been obtained from the spermatozoa of the other hirudinids that have been studied to date. Only minor differences in the length and shape of the studied organelles were found which seems to be connected with the different ways of insemination, specific properties of female reproductive tracts, and physiology of fertilization. Additionally, we studied the organization of the microtubular cytoskeleton in male germline cysts at consecutive stages of spermatogenesis using fluorescent and electron microscopy. By comparing the present data with those from Oligochaeta, Branchiobdellida, and Acanthobdellida, we found that only the presence of an anterior acrosome characterizes the true leeches and that, at present, should be regarded as an autapomorphic character of Hirudinida. Our results showed that the arrangement of the microtubules changed dynamically during spermatogenesis.

Aim: Spermidine/spermine N 1 -acetyltransferase (SSAT-1) regulates cell growth, proliferation and death. Amantadine is converted by SSAT-1 to acetylamantadine (AA). In our earlier studies, although SSAT-1 was activated in patients with cancer, a number of ostensibly healthy adult volunteers had higher than expected AA concentration. This study was therefore undertaken to examine the outlier group., Materials & Methods: A follow up of urine analysis for AA by liquid chromatography-tandem mass spectrometry as well as clinical assessments and additional blood analyses were conducted., Results: In some of the outlier controls, higher than expected AA concentration was linked to increased serum carcinoembryonic antigen. Clinical and radiographic assessments revealed underlying abnormalities in other cases that could represent premalignant conditions. Hematology tests revealed elevations in white blood cells and platelets, which are markers of inflammation., Conclusion: High urine concentration of AA could be used as a simple and useful test for screening of cancer in high-risk populations., Competing Interests: Financial & competing interests disclosure RB Ahmed is the President and CEO and B Cheng is the acting CTO of BioMark Diagnostics Inc. A Maksymiuk, DS Sitar, H Bach, PS Tappia and B Ramjiawan are minor shareholders of BioMark Diagnostics Inc. This study was supported, in part, by BioMark Diagnostics Inc. (BC, Canada) and the Maunders-McNeil Foundation (AB, Canada). LC–MS/MS analysis was conducted by Biopharmaceutical Research Inc. (BC, Canada). Infrastructural support was provided by the St Boniface Hospital Foundation and the University of Manitoba. Part of this work was published in abstract form in the 2019 ASCO meeting proceedings (online): https://meetinglibrary.asco.org/record/177214/abstract The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.

Aim: Spermidine/spermine N 1 -acetyltransferase (SSAT-1) plays a critical role in cell growth, proliferation and death, and is known to be activated in human cancer cells. Amantadine, a US FDA-approved antiviral drug, is a substrate for SSAT-1 and can be used to indirectly measure SSAT-1 activity because of its conversion to acetylamantadine (AA). This study was undertaken to further validate SSAT-1 activity in breast and lung cancer patients., Results: An increase in the urinary concentration of AA in lung and breast cancer patients was observed. The 0-2 h collection time point was determined to be optimal in revealing significant differences in urinary AA concentration between healthy controls and cancer patients., Conclusion: The high urine concentration of AA could be used as a simple and useful test for the detection of breast and lung cancer., Competing Interests: Financial & competing interests disclosure This study was supported, in part, by Biomark Diagnostics, Inc. (Richmond, BC, Canada) and the Maunders-McNeil Foundation (Edmonton, AB, Canada). The study was also funded by the University of Manitoba and Biomark Diagnostics, Inc. None of the authors has conflict of interest to disclose. However, RB Ahmed is the President and CEO and B Cheng is the acting CTO of BioMark Diagnostics, Inc. A Maksymiuk, DS Sitar, H Bach, PS Tappia and B Ramjiawan are minor shareholders of BioMark Diagnostics, Inc. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.

Introduction: Cardiac autonomic neuropathy (CAN) causes substantial morbidity and increased mortality in patients with diabetes mellitus (DM). Besides heart rate variability (HRV), heart rate turbulence (HRT) is an important method of assessment of cardiac autonomic regulation. The aim of the study was to assess the correlation between HRT and diabetic control., Material and Methods: Fifty-nine patients met the inclusion criteria - 38 males and 21 females, age 64.4 ±7.6. The patients included had inadequately controlled DM type 2 defined as glycated haemoglobin (HbA1c) > 9% (mean 11.8 ±2.7%). In all patients, intensive insulin treatment had been applied for 6 months. After 6 months, HbA1c was measured. ECG Holter monitoring was performed before and after insulin treatment to evaluate the time domain HRV and HRT parameters (turbulence onset (TO) and turbulence slope (TS))., Results: After 6 months of intensive insulin treatment, HbA1c concentrations ranged from 6.3% (45 mmol/mol) to 11.2% (99 mmol/mol) - mean 8.5 ±3.8% (69 ±18 mmol/mol). Significant improvement of TO, TS and SDNN was observed. The TO and TS significantly correlated with HbA1c (r = 0.35, p = 0.006 and r = -0.31, p = 0.02 respectively). Among analyzed HRV time domain parameters such as SDNN, rMSSD and pNN50, only SDNN correlated with HbA1c (r = -0.41, p = 0.001). It was further concluded that intensive insulin therapy led to better glycemic control, resulting in improvement of HRT., Conclusions: Heart rate turbulence may be useful in monitoring changes of the autonomic nervous system functions in patients with DM, similarly to HRV parameters.

Objectives: The aims were to evaluate whether any changes in blood flow in fetal inferior vena cava (IVC) are observed during Atosiban tocolysis within the first 48 hours of therapy., Methods: Detailed Doppler evaluation of blood flow in fetal IVC was performed prior to Atosiban administration and after 24 and 48 hours respectively. Maternal and fetal heart rate was assessed. IVC Doppler indices, such as, S/D (systole/diastole), PVIV (peak velocity index for the vein) and PLI (preload index) were calculated. To determine changes over time in all study variables, analysis of variance (ANOVA) for repeated measurements was used and followed by Tukey-Kramer's post hoc test. The effects of additional clinical covariates were checked., Results: Maternal heart rate was not altered significantly during Atosiban administration. No significant changes in FHR (fetal heart rate) as well as following IVC Doppler parameters (S/D, PVIV) were recorded after 24/48 hours of tocolytic treatment. The fetal IVC PLI values were significantly reduced after 24 hours and 48 hours of treatment. The changes in PLI values when comparing 24 and 48 hours results were not statistically significant., Conclusions: As the questions about drug safety appeared after the animal study had been published about possible myocyte injury, detailed Doppler evaluation of IVC blood flow was performed. It revealed the changes in preload conditions which could be a reflection of successful Atosiban tocolytic treatment. No hemodynamic changes in IVC were noted, suggesting the presence of fetal acidemia due to possible heart damage was observed.

Objective: to investigate whether any changes in the preload index (PLI) occur within the first 48 hours of fenoterol intravenous tocolysis., Material and Methods: Doppler evaluation of placental and fetal circulation was performed in 36 pregnant women prior to fenoterol administration and after 24/48 hours. Measurements were obtained from a longitudinal section of the inferior vena cava (IVC) and preload index was calculated. To determine changes over time, an all study variable analysis of variance (ANOVA) for repeated measurements, followed by Tukey-Kramer's multiple comparison test was used. The effects of additional clinical covariates were checked., Results: The maternal heart rate values were significantly increased after 24 hours and 48 hours in comparison to pre-treatment values. No significant changes in fetal heart rate were observed during treatment. The fetal IVC PLI values were significantly reduced after 24 hours and 48 hours of treatment. The increase in PLI values when comparing 24 and 48 hours results were not statistically significant. These observations were consistent with ANOVA post-hoc analysis., Conclusions: 48 hours intravenous administration of fenoterol appears not to alter inferior vena cava blood flow by itself. The reduction in PLI values may reflect lower fetal preload conditions during the course of successful tocolytic treatment. Therefore, Doppler IVC PLI measurement should be considered as a possible additional assessment method of effectiveness of treatment. However, other Doppler venous blood flow parameters should be assessed to confirm the results and clarify whether maternal corticosteroids administration may be interfering with the results.

Objectives: The aims were to investigate whether any changes in placental and fetal circulation were observed during fenoterol tocolysis within the first 48 hours of therapy., Material and Methods: Doppler evaluation of placental and fetal circulation was performed prior to fenoterol administration and then after 24 and 48 hours. Maternal heart rate and pulsatility index (PI) in uterine arteries were assessed. FHR, RI and PI of umbilical artery and middle cerebral artery were measured. E/A ratio for A-V valves, the myocardial performance index (MPI) and shortening fraction (SF) were calculated for both ventricles independently. The blood flow pattern in DV was assessed using PI, S/a ratio and peak velocity index for the vein. To determine changes over time in all study variable analysis of variance (ANOVA) for repeated measurements followed by Tukey-Kramer's multiple comparison test was used. The effects of additional clinical covariates were checked., Results: Uterine and fetal arterial blood flow patterns were not altered significantly during 48 hours of tocolysis. No significant changes were observed in fetal cardiac function parameters as well. The evaluation of Doppler parameters in the DV revealed a significant increase in PVIV after 48 hours. Additionally after 48 hours of successful tocolysis S/a ratio values were significantly lower., Conclusions: Short term intravenous administration of fenoterol seems not to alter uterine and fetal arterial blood flow pattern. Direct fetal cardiac function remained unaffected. However significant changes of selected Doppler parameters in DV may suggest further studies should be performed to assess more precisely fetal venous blood flow.

Objectives: The aims were to assess the placental and fetal circulation during nifedipine tocolysis within the first 48 hours of therapy., Methods: Placental and fetal circulation was assessed in Doppler ultrasound examination prior to nifedipine administration and then after 24 and 48 hours. Maternal heart rate and PI in uterine arteries were evaluated as well as FHR, RI and PI of UA and MCA. E/A-wave ratio for A-V valves, MPI and SF were calculated for both ventricles independently. To determine changes over time in all study variable analysis of variance (ANOVA) for repeated measurements followed by Tukey-Kramer's multiple comparison test was used. The effects of additional clinical covariates were checked., Results: Uterine and umbilical blood flow patterns were not altered significantly during administration of nifedypine tocolysis. While MCA Doppler indicies such as RI and PI were unchanged, the evaluation of MCA PSV revealed a transient significant decrease after 24 hours. A resolution of this distraction was observed within the following 24 hours. No significant changes were observed in direct fetal cardiac function parameters calculated separately for both ventricles., Conclusions: The decrease of MCA PSV after 24 hours of treatment was isolated and transient hemodynamic distraction observed during treatment. Neither fetal cardiac parameters nor other Doppler indices were changed. Therefore oral administration of nifedipine seems not to alter uterine nor fetal arterial blood flow pattern seriously. As significant changes were observed by different authors, further studies should be performed to verify the optimal total dose of nifedipine and its influence on hemodynamic conditions.

Introduction: Fundamental research identified new therapy targets implicated in tumor proliferation and angiogenesis which lead to the development of several targeted therapies. Currently, three drugs are used in the treatment of advanced colorectal cancer, cetuximab and panitumumab, two anti epidermal growth factor receptor, and bevacizumab, an anti vascular endothelial growth factor., Patients and Methods: We evaluated a treatment with oxaliplatin-based chemotherapy (Folfox7 regimen) and bevacizumab in patients with locally advanced and/or metastatic colorectal cancer. Objectives of the study are the evaluation of the efficacy, toxicity, progression free survival, overall survival and tumor cell expression of the vascular endothelial growth factor by immunochemistry., Results: 47 patients are included in the study during the period between April 2005 and June 2007; 28 men and 19 women. After six cycles of treatment, we achieved 67.3% of objectives responses and 76% of tumor control. The median progression free survival evaluated was 12 months (9.3-14.6 months) and median overall survival 18 months (9-26.9 months). The immunochemistry study of 46 tumours of the study achieved the following results: 13% (0), 17.4% (1+), 23.9% (2+) and 45.7% (3+). A correlation between the vascular endothelial growth factor expression, therapeutic responses and survival has been demonstrated but the difference was not significant in term of survival. Both chemotherapy toxicity and bevacizumab related toxicity are acceptable in our study., Conclusion: The fact that vascular endothelial growth factor expression is common in more than 80% of colorectal cancers, lead to recommend the systematic use of bevacizumab with chemotherapy in the treatment of advanced colorectal cancer.