Synthesis and evaluation of selected benzimidazole derivatives as potential antimicrobial agents

© 2015 The Authors. Published by MDPI. This is an open access article available under a Creative Commons licence. The published version can be accessed at the following link on the publisher’s website: https://doi.org/10.3390/molecules200815206© 2015 by the authors. A library of 53 benzimidazole derivatives, with substituents at positions 1, 2 and 5, were synthesized and screened against a series of reference strains of bacteria and fungi of medical relevance. The SAR analyses of the most promising results showed that the antimicrobial activity of the compounds depended on the substituents attached to the bicyclic heterocycle. In particular, some compounds displayed antibacterial activity against two methicillin-resistant Staphylococcus aureus (MRSA) strains with minimum inhibitory concentrations (MICs) comparable to the widely-used drug ciprofloxacin. The compounds have some common features; three possess 5-halo substituents; two are derivatives of (S)-2-ethanaminebenzimidazole; and the others are derivatives of one 2-(chloromethyl)-1Hbenzo[ d]imidazole and (1H-benzo[d]imidazol-2-yl)methanethiol. The results from the antifungal screening were also very interesting: 23 compounds exhibited potent fungicidal activity against the selected fungal strains. They displayed equivalent or greater potency in their MIC values than amphotericin B. The 5-halobenzimidazole derivatives could be considered promising broad-spectrum antimicrobial candidates that deserve further study for potential therapeutic applications.Published versio

Efficacy and safety of 90Y-DOTATATE therapy in neuroendocrine tumours

Wstęp: Celem pracy była ocena skuteczności oraz toksyczności celowanej terapii receptorowej (PRRT) guzów neuroendokrynnych z wykorzystaniem analogu somatostatyny Tyr3-octreotate znakowanego 90Y (90Y-DOTATATE). Materiał i metody: Do badania włączono 46 pacjentów z rozsianym lub nieoperacyjnym guzem NET. 90Y-DOTATATE podawano w 3–5 kursach w odstępach 4–9-tygodniowych. Każdorazowo wyznaczano aktywność terapeutyczną, uwzględniając taką całkowitą powierzchnię ciała, by nie przekroczyć sumarycznej wartości 7,4 GBq/m2. Przed terapią i po niej wykonano oznaczenia parametrów morfotycznych, nerkowych oraz wątrobowych, a także stężenia chromograniny A. Wyniki: Spośród 46 leczonych pacjentów jeden chory zmarł przed zakończeniem pełnego cyklu terapeutycznego, a 16 po zakończeniu terapii, w tym jeden z powodu zawału serca. W 12. miesiącu obserwacji stwierdzono 47% stabilizacji, 31% częściowych odpowiedzi oraz 9% progresji wśród 45 pacjentów, którzy ukończyli leczenie. Pięciu chorych zmarło przed 12. miesiącem obserwacji. W jednym przypadku utracono możliwość uzyskania informacji o chorym po 12 miesiącach. Okres czasu bez progresji choroby wyniósł 37,4 miesiąca. W ciągu pierwszego roku od zakończenia terapii zaobserwowano jedynie przejściowe obniżenie wartości morfotycznych krwi oraz przejściowy wzrost stężenia kreatyniny i spadek wartości przesączania kłębuszkowego (GFR). Wnioski: Celowana terapia receptorowa z użyciem 90Y-DOTATATE może być skuteczną oraz stosunkowo bezpieczną metodą leczenia prowadzącą do częściowej odpowiedzi lub stabilizacji choroby u większości pacjentów. (Endokrynol Pol 2011; 62 (5): 392–400)Background: The aim of this study was to assess the efficacy and toxicity of peptide receptor radionuclide therapy (PRRT) with the use of the high affinity somatostatin receptor subtype 2 analogue, 90Y labelled Tyr3-octreotate, (90Y-DOTATATE) in neuroendocrine tumours (NETs). Material and methods: 46 patients with disseminated or non-operable NET were enrolled in this study. The 90Y-DOTATATE therapeutic activity was calculated per total body surface area up to a total of 7.4 GBq/m2 administered in three to five cycles, repeated every four to nine weeks. Before and after the therapy, blood tests for haematology, kidney and liver function, and chromogranin A were performed. Results: Out of 46 90Y-DOTATATE treated patients, one died before completing the therapy and 16 died after completing the therapy, among them one due to myocardial infarction. After 12 month follow-up, stabilisation of disease was observed in 47%, partial remission in 31%, and progression in 9% of the 45 patients who completed the therapy. Five patients died before completion of 12 months of follow-up. One of the patients died due to myocardial infarction. In one case, the information after 12 months is incomplete. The progression free survival was 37.4 months. During 12 months follow-up, transient decrease of PLT, WBC and haemoglobin values was observed. A transient increase of creatinine level (within normal ranges) and decrease of GFR values were found. Conclusions: NETs 90Y-DOTATATE therapy results in symptomatic relief and tumour mass reduction. The mild critical organ toxicity does not limit the PRRT of NETs. (Pol J Endocrinol 2011; 62 (5): 392–400

Intrauterine deaths — an unsolved problem in Polish perinatology

Objectives: The Polish criteria for “intrauterine death” include fetal demise after 22 weeks of gestation, weighing > 500 g and body length at least 25 cm, when the gestational age is unknown. The rate of fetal death in Poland in 2015 is 3:10,000. In 2020, 1,231 stillbirths were registered. Material and methods: An analysis using 142,662 births in the period between 2015–2020 in 11 living in Poland. The first subgroup was admitted as patients > 22 to the beginning of the 30th week of pregnancy (n = 229), and the second from the 30th week of pregnancy inclusively (n = 179). In the case of women from both subgroups, there was a risk of preterm delivery close to hospitalization. Results: It was found that stillbirth in 41% of women in the first pregnancy. For the patient, stillbirth was also the first in his life. The average stillbirth weight was 1487 g, the average body length was 40 cm. Among fetuses up to 30 weeks, male fetuses are born more often, in subgroup II, the sex of the child was usually female. Most fetal deaths occur in mothers < 15 and > 45 years of age. Conclusions: According to the Polish results of the origin of full-term fetuses > 30 weeks of gestation for death in the concomitant antenatal, such as placental-umbilical and fetal hypoxia, acute intrapartum effects rarely, and moreover < 30 Hbd fetal growth restriction (FGR), occurring placental-umbilical, acute intrapartum often

Proposal of CRM system implementation in a non-profit organization

This bachelor thesis is focused on implementation of CRM system in selected organization. The work itself is divided into three main parts. The first part deals with the problem of CRM, its strategy, the main elements and comparison of existing systems. On the basis of literary research, a framework is defined which is important for the fulfillment of the purposes of the work. Objectives and methods of their fulfillment are described in the methodological part, and consist of the following goals:• Explore the theoretical aspects of CRM;• Discard CRM system types (domestic / foreign);• Perform internal and external business analyzes;• Establish criteria for selecting a suitable CRM system by comparing company requirements and analysis results;• Recommend a suitable CRM for implementation in a given nonprofit organization.Using the interviews with the management of the Museum of Photography and modern video media, the in-house analysis of the environment and the company's needs is the most suitable CRM system for this organization. More detailed analyzes and their results are found in the practical part of the thesis. On the basis of the analyzes and synthesis of the scientific literature, the aims of the baccalaureate work are fulfilled.Tato bakalářská práce je zaměřena na implementaci CRM systému ve vybrané organizaci. Samotná práce je rozdělena do tří hlavních částí. První část se zabírá problematikou CRM, její strategií, hlavními prvky a porovnáním existujících systémů. Na základě literární rešerše je stanoven rámec, důležitý pro naplnění účelů práce. Cíle a metody jejich naplnění jsou popsané v metodologické části, a spočívají v náplní dících cílů:•Prozkoumat teoretické aspekty CRM;•Rozebrat typy systému CRM (tuzemské/zahraniční);•Provést interní a externí analýzy podniku;•Stanovit kritéria pro výběr vhodného systému CRM na základě porovnání požadavků společnosti a výsledů provedení analýz;•Doporučit vhodný systém CRM pro implementaci v dané neziskové organizaci.Pomocí rozhovorů s vedením Muzea fotografie a moderních obrazových médií interní analýzy prostředí a potřeb firmy je zvolen nejvhodnější systém CRM pro tuto organizaci. Detailnější analýzy a jejich výsledky se nacházejí v praktické části práce. Na základě provedených analýz a syntéze odborné literatury jsou naplněni cíle bakalářské práce

Immunomodulatory activity of products from the helminth parasite Fasciola hepatica

THESIS 9855Helminths have evolved strategies to evade host immune responses and these have been shown to be associated with simultaneous subversion of immune responses towards bystander antigens. This phenomenon forms the basis of the hygiene hypothesis and partially explains the lower incidence of allergy and autoimmune disease observed in areas of developing countries where helminth infections are endemic. Moreover, evidence from human clinical trials has demonstrated that helminth infections can attenuate disease symptoms in patients with allergy, inflammatory bowel disease and multiple sclerosis (MS). Therefore a greater understanding of how helminth parasites modulate the immune response could give invaluable insight into the host regulatory mechanisms that control allergy and autoimmunity. Furthermore, the immunomodulatory molecules secreted by helminth parasites, or their synthetic analogues, could provide novel therapeutics against immune-mediated diseases such as MS

Affiliation between vascular pericytes and renin producing cells in the human foetal kidney

Pericytes, progenitor cells embedded in the microvascular wall, are crucial for vascular homeostasis. Renin is the rate-limiting enzyme that regulates blood pressure and fluid/electrolyte balance. Previous work suggested the relationship between renin-expressing/ producing cells and pericytes, however human kidney pericytes have not been characterized in depth and the molecular switch controlling renin cell plasticity is not understood. Here, I describe a method of isolation of CD146+CD34-CD45-CD56- pericytes, putative progenitors for renin-producing cells, from the human foetal kidney and demonstrate their potential in vitro to express and produce renin. Co-staining of pericyte markers (CD146 and NG2) and renin showed coincidence in the juxtaglomerular region and along renal arterioles in the human foetal kidney. I have obtained primary cultures of renal pericytes from the developing human kidney that were purified via fluorescence-activated cell sorting. Primary cultures of renal pericytes exhibited tri-lineage mesodermal differentiation potential. Renin expression was triggered by cAMP induction (10μM forskolin and 100μM 3-isobutyl-1- methylxanthine [IBMX] and resulted in 64.3 fold increase of renin mRNA (p <0.01) and 41.5 fold increase in enzymatic activity of renin (p <0.05) over controls. Pericytes derived from non-renal tissues (placenta and foetal adrenal glands) also expressed renin in an inducible fashion. Renin positive cells following induction were confirmed to be CD146+/NG2+. Interestingly, alpha-smooth muscle actin expression was not always correlated with renin immunostaining. Wnt/β-catenin signalling plays a crucial role during kidney development and in disease, specifically; in pericyte modulation of the Wnt pathway has been shown to regulate cell differentiation. CHIR 99021, a specific inhibitor of glycogen synthase kinase 3, mimicking Wnt signalling, and C59, a potent Porcupine acyltransferase inhibitor that is required for Wnt biological activity, were tested in renin induction experiments. Preliminary data showed that renin expression was blocked by Wnt activation, whereas Wnt suppression increased renin mRNA levels above the level of stimulation achieved with cAMP inducers. These findings provide evidence that renin expression is an intrinsic feature of pericytes and can be regulated through the Wnt pathway

A-FABP Concentration Is More Strongly Associated with Cardiometabolic Risk Factors and the Occurrence of Metabolic Syndrome in Premenopausal Than in Postmenopausal Middle-Aged Women

We aimed at the evaluation of the relationship between adipocyte fatty acid binding protein (A-FABP) and cardiometabolic risk factors in premenopausal and postmenopausal women. Additionally, we compared A-FABP with adipokines related to metabolic syndrome (MetS) such as leptin and adiponectin. 94 premenopausal and 90 early postmenopausal middle-aged Caucasian women were subject to examinations. Postmenopausal women had higher A-FABP than premenopausal; this difference became insignificant after controlling for age. We found significantly higher correlation coefficients between A-FABP and TC/HDL-C ratio and number of MetS components in premenopausal women, compared to postmenopausal. Each 1 ng/dL increase in A-FABP concentration significantly increased the probability of occurrence of atherogenic lipid profile in premenopausal women, even after multivariate adjustment. All odds ratios became insignificant after controlling for BMI in postmenopausal women. A-FABP was more strongly associated with MetS than leptin and adiponectin in premenopausal women. Adiponectin concentration was a better biomarker for MetS after menopause. Our results suggest that the A-FABP is more strongly associated with some cardiometabolic risk factors in premenopausal than in postmenopausal women. Higher values of A-FABP after menopause are mainly explained by the fact that postmenopausal women are older. Because of the limitation of study, these results should be interpreted with caution

The Kynurenine Pathway in Obese Middle-Aged Women with Normoglycemia and Type 2 Diabetes

We examined the relationships of tryptophan (Trp) and the metabolites of the kynurenine pathway (KP) to the occurrence of type 2 diabetes (T2D) and metabolic risk factors in obese middle-aged women. The study included 128 obese women divided into two subgroups: a normoglycemic group (NG, n = 65) and a T2D group (n = 63). The concentrations of serum tryptophan (Trp), kynurenine (Kyn), 3-hydroxykynurenine (3HKyn), quinolinic acid (QA), and kynurenic acid (Kyna) were analyzed using ultra-high-performance liquid chromatography coupled with electrospray ionization/triple quadrupole mass spectrometry. Blood biochemical parameters and anthropometric parameters were measured. The women with T2D had significantly higher Trp, Kyna, Kyna/QA ratio, and Kyna/3HKyn ratio values than the NG women. Logistic regression analysis showed that the concentrations of Trp and Kyna and the values of the Kyna/3HKyn ratio were most strongly associated with T2D occurrence, even after controlling for confounding factors. The model with Trp level and Kyna/3HKyn ratio accounted for 20% of the variation in the presence of T2D. We also showed a different pattern of correlations between kynurenines and metabolic factors in the NG and T2D women, which was mostly reflected in the stronger relationship between BMI and KP metabolites in the NG obese women. An increase in Trp and Kyna levels with an accompanying increase in Kyna/3HKyn ratio value is associated with the occurrence of T2D in obese middle-aged women

Efficacy of multimodal anticancer therapy in the course of pancreatic neuroendocrine carcinoma

Not required for Clinical Vignette

Association between Fasting and Postprandial Levels of Liver Enzymes with Metabolic Syndrome and Suspected Prediabetes in Prepubertal Children

Elevated liver enzyme activity may be associated with metabolic syndrome (MetS); however, it is not included in the MetS definition for children. Postprandial changes in the levels of biochemistry tests are related to manifestations of metabolic abnormalities. We assessed the association between fasting and postprandial liver enzymes levels with MetS and elevated hemoglobin A1c (HbA1c) in children aged 9–11. The study included 51 girls and 48 boys, all presumably healthy. In all participants’ anthropometric indices, fasting glucose, insulin, lipid profile and HbA1c were measured. Enzymes, including alanine aminotransferase (ALT) and gamma-glutamyl transferase (GGT), were assayed in fasting and postprandial states. Individuals were divided into subgroups: with (MetS(+): n = 26); without MetS (MetS(−): n = 73); with HbA1c levels ≤ 5.3% (n = 39); and ≥5.7% (n = 11). Elevated fasting GGT levels were found in 23% of MetS(+) children and rarely in MetS(−) children; increased postprandial GGT was noted in 35% of MetS(+) individuals. Postprandial GGT changes tend to predict MetS (OR = 1.16; p = 0.092). Increased fasting ALT was found rarely in MetS(+) children, but did not occur in MetS(−) children. HbA1c ≥ 5.7% occurred rarely and neither fasting ALT nor GGT were related to elevated HbA1c. However, postprandial change of ALT was a good positive predictor of increased HbA1c (OR = 1.33; p = 0.021). Postprandial GGT performs better as an indicator of metabolic syndrome occurrence, and instead postprandial ALT may predict prediabetes in prepubertal children