BACKGROUND: In patients with septic shock, the presence of an elevated heart rate (HR) after fluid resuscitation marks a subgroup of patients with a particularly poor prognosis. Several studies have shown that HR control in this population is safe and can potentially improve outcomes. However, all were conducted in a single-center setting. The aim of this multicenter study is to demonstrate that administration of the highly beta1-selective and ultrashort-acting beta blocker landiolol in patients with septic shock and persistent tachycardia (HR ≥ 95 beats per minute [bpm]) is effective in reducing and maintaining HR without increasing vasopressor requirements. METHODS: A phase IV, multicenter, prospective, randomized, open-label, controlled study is being conducted. The study will enroll a total of 200 patients with septic shock as defined by The Third International Consensus Definitions for Sepsis and Septic Shock criteria and tachycardia (HR ≥ 95 bpm) despite a hemodynamic optimization period of 24-36 h. Patients are randomized (1:1) to receive either standard treatment (according to the Surviving Sepsis Campaign Guidelines 2016) and continuous landiolol infusion to reach a target HR of 80-94 bpm or standard treatment alone. The primary endpoint is HR response (HR 80-94 bpm), the maintenance thereof, and the absence of increased vasopressor requirements during the first 24 h after initiating treatment. DISCUSSION: Despite recent studies, the role of beta blockers in the treatment of patients with septic shock remains unclear. This study will investigate whether HR control using landiolol is safe, feasible, and effective, and further enhance the understanding of beta blockade in patients with septic shock. TRIAL REGISTRATION: EU Clinical Trials Register; EudraCT, 2017-002138-22 . Registered on 8 August 2017.

• Klíčová slova
• Beta-blocker, Landiolol, Randomized controlled trial, Sepsis, Septic shock, Tachycardia,
• MeSH
• antiarytmika škodlivé účinky   terapeutické užití   MeSH
• beta blokátory škodlivé účinky   terapeutické užití   MeSH
• časové faktory MeSH
• jednotky intenzivní péče * MeSH
• klinické zkoušky, fáze IV jako téma MeSH
• krevní tlak účinky léků   MeSH
• lidé MeSH
• močovina škodlivé účinky   analogy a deriváty   terapeutické užití   MeSH
• morfoliny škodlivé účinky   terapeutické užití   MeSH
• multicentrické studie jako téma MeSH
• prospektivní studie MeSH
• randomizované kontrolované studie jako téma MeSH
• septický šok diagnóza   farmakoterapie   patofyziologie   MeSH
• srdeční frekvence účinky léků   MeSH
• vazokonstriktory terapeutické užití   MeSH
• výsledek terapie MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• protokol klinické studie MeSH
• Geografické názvy
• Evropa MeSH
• Názvy látek
• antiarytmika MeSH
• beta blokátory MeSH
• landiolol MeSH Prohlížeč
• močovina MeSH
• morfoliny MeSH
• vazokonstriktory MeSH

There is a link between metabolism and reproduction as metabolic hormones affect hypothalamus-pituitary-testis (HPT) hormonal functions and vice versa. The aim of the present study was to investigate the effects of negative energy balance on the reproductive system in male goldfish exposed to testosterone (T) and 17β-estradiol (E2). Following 7 days of food deprivation (FD), ANOVA models showed significant FD × sex steroid interactions on sperm quality and circulating sex steroid levels. When FD effects were investigated, 11-ketotestosterone (11-KT) level and sperm motility and velocity decreased in food-deprived goldfish in the control group. In E2-exposed goldfish, FD decreased sperm production in addition to sperm motility and velocity that coincided with an elevation of circulating E2 level. However, FD did not significantly impact sex steroids and sperm quality in T-exposed goldfish. ANOVA models showed non-significant FD × sex steroid interactions for HSI, GSI, circulating luteinizing hormone (Lh) level, and metabolic (preproghrelin, goat and nucb2) and reproductive (kiss1, gpr54 and gnrh3) mRNAs. Furthermore, results showed that FD decreased HSI, and increased Lh levels and testicular preproghrelin and goat mRNAs, while sex steroids increased mid-brain nucb2, kiss1 and gpr54 mRNAs. Together, our results suggest that FD-induced inhibition of androgenesis resulted in diminished sperm quality associated with activation of the testicular ghrelinergic system, and negative feedback of 11-KT increased Lh level. The FD-induced testicular metabolic and hormonal system was impacted in goldfish exposed to sex steroids. However, the negative effects of FD on sperm quality were accelerated in E2-exposed goldfish due to estrogenic activity. This study provides novel information to better understand metabolic-associated reproductive disorders in fish.

• Klíčová slova
• Preproghrelin mRNA, nucleobindin2 mRNA, Hypothalamus-pituitary-testis, Sperm motility, Sperm production, Sperm velocity,
• MeSH
• estradiol * krev   farmakologie   MeSH
• karas zlatý * fyziologie   MeSH
• motilita spermií účinky léků   MeSH
• pohlavní steroidní hormony krev   metabolismus   MeSH
• potravinová deprivace * fyziologie   MeSH
• rozmnožování účinky léků   MeSH
• spermie účinky léků   fyziologie   MeSH
• testis účinky léků   metabolismus   MeSH
• testosteron * analogy a deriváty   krev   farmakologie   MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• 11-ketotestosterone MeSH Prohlížeč
• estradiol * MeSH
• pohlavní steroidní hormony MeSH
• testosteron * MeSH

The abnormal production of matrix metalloproteinases (MMPs), especially MMP-9 and MMP-2, plays a pivotal role in hypertensive disorders of pregnancy, and as such, can influence the development of preeclampsia. These alterations may result from functional genetic polymorphisms in the promoter region of MMP-9 and MMP-2 genes, which modify MMP-9 and MMP-2 expression. We investigated the association of MMP-9 polymorphism rs3918242 (-1562 C>T) and MMP-2 polymorphism rs2285053 (-735 C>T) with the risk of preeclampsia. This case-control study was conducted on 345 women with preeclampsia and 281 age-matched women with normal pregnancies from Tunisian hospitals. Genomic DNA was extracted from whole blood collected at delivery. Genotypes for -1562 C>T and -735 C>T polymorphisms were performed using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). An increased frequency of heterozygous MMP-9 -1562 C/T genotype carriers was observed in women with preeclampsia compared to healthy controls (p = 0.03). In contrast, the MMP-2 -735 C>T polymorphism was not significantly different regarding frequency distribution of the allele and genotype between healthy pregnant women and women with preeclampsia. Our study suggests that the MMP-9 -1562 C/T variant, associated with high MMP-9 production, could be a genetic risk factor for preeclampsia in Tunisian women.

• Klíčová slova
• MMP-2, MMP-9, SNPs, genotyping, preeclampsia,
• Publikační typ
• časopisecké články MeSH

Exceptionally fast temperature-responsive, mechanically strong, tough and extensible monolithic non-porous hydrogels were synthesized. They are based on divinyl-crosslinked poly(N-isopropyl-acrylamide) (PNIPAm) intercalated by hydroxypropyl methylcellulose (HPMC). HPMC was largely extracted after polymerization, thus yielding a 'template-modified' PNIPAm network intercalated with a modest residue of HPMC. High contents of divinyl crosslinker and of HPMC caused a varying degree of micro-phase-separation in some products, but without detriment to mechanical or tensile properties. After extraction of non-fixed HPMC, the micro-phase-separated products combine superior mechanical properties with ultra-fast T-response (in 30 s). Their PNIPAm network was highly regular and extensible (intercalation effect), toughened by hydrogen bonds to HPMC, and interpenetrated by a network of nano-channels (left behind by extracted HPMC), which ensured the water transport rates needed for ultra-fast deswelling. Moreover, the T-response rate could be widely tuned by the degree of heterogeneity during synthesis. The fastest-responsive among our hydrogels could be of practical interest as soft actuators with very good mechanical properties (soft robotics), while the slower ones offer applications in drug delivery systems (as tested on the example of Theophylline), or in related biomedical engineering applications.

• Klíčová slova
• cellulose, drug release, hydrogels, poly(N-isopropylacrylamide), semi-interpenetrating networks, smart materials,
• Publikační typ
• časopisecké články MeSH

The Eocene Baltic amber fossil flies of the genus Acartophthalmites Hennig, 1965 (Diptera: Acalyptratae) are revised. Seven species are recognized and described or redescribed. Five species, A. crassipes sp. nov., A. luridus sp. nov., A. rugosus sp. nov., A. tertiaria Hennig, 1965 (type species) and A. willii Pérez-de la Fuente, Hoffeins et Roháček, 2018 are retained in Acartophthalmites while Clusiomites gen. nov. is described for two other species, C. clusioides (Roháček, 2016) comb. nov. (type species) and C. ornatus sp. nov. Relationships of these fossil taxa are discussed and, because they cannot be confidently placed in any known family of Diptera, a new family, Clusiomitidae, is established for them. Clusiomitidae is recognized as a family of Opomyzoidea, probably most closely allied to Clusiidae. These results again confirmed that the diversity of acalyptrate flies was very high in the Mid-late Eocene amber forest.

• Klíčová slova
• Paleogene, amber forest, ancient diversity, extinct acalyptrate flies,
• Publikační typ
• časopisecké články MeSH

Previously, we proposed the hypothesis that similarities in the inflammatory response observed in acne vulgaris and degenerative disc disease (DDD), especially the central role of interleukin (IL)-1β, may be further evidence of the role of the anaerobic bacterium Cutibacterium (previously Propionibacterium) acnes in the underlying aetiology of disc degeneration. To investigate this, we examined the upregulation of IL-1β, and other known IL-1β-induced inflammatory markers and neurotrophic factors, from nucleus-pulposus-derived disc cells infected in vitro with C. acnes for up to 48 h. Upon infection, significant upregulation of IL-1β, alongside IL-6, IL-8, chemokine (C-C motif) ligand 3 (CCL3), chemokine (C-C motif) ligand 4 (CCL4), nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF), was observed with cells isolated from the degenerative discs of eight patients versus non-infected controls. Expression levels did, however, depend on gene target, multiplicity and period of infection and, notably, donor response. Pre-treatment of cells with clindamycin prior to infection significantly reduced the production of pro-inflammatory mediators. This study confirms that C. acnes can stimulate the expression of IL-1β and other host molecules previously associated with pathological changes in disc tissue, including neo-innervation. While still controversial, the role of C. acnes in DDD remains biologically credible, and its ability to cause disease likely reflects a combination of factors, particularly individualised response to infection.

• Klíčová slova
• Cutibacterium acnes, co-culture, disc cells, gene expression, inflammation, intracellular, neurotrophic factors,
• MeSH
• degenerace meziobratlové ploténky genetika   mikrobiologie   MeSH
• dospělí MeSH
• interakce hostitele a patogenu MeSH
• interleukin-1beta genetika   MeSH
• kultivované buňky MeSH
• lidé středního věku MeSH
• lidé MeSH
• meziobratlová ploténka metabolismus   mikrobiologie   MeSH
• neurotrofní faktory genetika   MeSH
• Propionibacterium acnes fyziologie   MeSH
• upregulace MeSH
• zánět genetika   mikrobiologie   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• interleukin-1beta MeSH
• neurotrofní faktory MeSH

The dabrafenib plus trametinib (dab + tram) combination has demonstrated durable long-term efficacy in patients with BRAF V600-mutant metastatic melanoma. However, real-world data characterizing patients with long-term benefit are limited. DESCRIBE III was a global, observational, retrospective, chart review study in patients with unresectable or metastatic melanoma treated with dab monotherapy and/or dab + tram combination therapy as part of the Named Patient Program or Individual Patient Program. Overall, 509 patients were enrolled. Patients were categorized into three groups based on their observed treatment duration: long-term (on therapy ≥12 months), intermediate (on therapy ≥6 months and <12 months), and short-term (on therapy <6 months) duration of benefit. More patients in the short-term duration of benefit group had baseline characteristics associated with poor prognosis compared with the other two groups. Median lactate dehydrogenase (LDH) levels (368 U/L) at baseline were also higher in the short-term duration of benefit group. No new safety signals were identified. DESCRIBE III identified baseline characteristics associated with long-term benefit of dab + tram. Lower LDH level and <3 metastatic sites at baseline were associated with a longer duration of benefit, confirming that the findings from COMBI-d and COMBI-v are relevant to patients treated in a real-world setting.

• Klíčová slova
• BRAF V600, chart review, dabrafenib, melanoma, real-world, trametinib,
• Publikační typ
• časopisecké články MeSH

The liver is a complex organ that governs many types of metabolisms, including energy metabolism and other cellular processes. The liver also plays a crucial role in important functions in immunity, and the activity of liver tissue-associated immunity affects the outcome of many liver pathologies. A thorough characterization of the liver immune microenvironment may contribute to a better understanding of immune signaling, the mechanisms of specific immune responses, and even to improved predictions about therapy outcomes. In this paper, we present an optimized, simple, and rapid protocol to characterize the liver-associated immune cell milieu. We believe that the most suitable technique for obtaining a complex immune cell suspension and for removing contaminating blood cells is to perform mouse liver perfusion, using only phosphate buffer saline. Combining an enzymatic digestion and a mechanical dissociation of liver tissue, followed by cell purification, improves downstream applications. This combination is an essential prerequisite for immune cell determination and characterization. We then demonstrate a flow cytometry-based multiparametric immunophenotyping along with a gating strategy to detect and quantify liver endothelial cells, T cells (helper and cytotoxic), B cells, NK cells, NKT cells, neutrophils, monocytes (subsets included), dendritic cells (subsets included), macrophages and Kupffer cells.

• Klíčová slova
• PBS-based liver perfusion, flow cytometry, immunophenotyping, mouse liver, non-parenchymal cells,
• Publikační typ
• časopisecké články MeSH

BACKGROUND: The COVID-19 lockdown has had a significant impact on mental health. Patients with eating disorders (ED) have been particularly vulnerable. AIMS: (1) To explore changes in eating-related symptoms and general psychopathology during lockdown in patients with an ED from various European and Asian countries; and (2) to assess differences related to diagnostic ED subtypes, age, and geography. METHODS: The sample comprised 829 participants, diagnosed with an ED according to DSM-5 criteria from specialized ED units in Europe and Asia. Participants were assessed using the COVID-19 Isolation Scale (CIES). RESULTS: Patients with binge eating disorder (BED) experienced the highest impact on weight and ED symptoms in comparison with other ED subtypes during lockdown, whereas individuals with other specified feeding and eating disorders (OFSED) had greater deterioration in general psychological functioning than subjects with other ED subtypes. Finally, Asian and younger individuals appeared to be more resilient. CONCLUSIONS: The psychopathological changes in ED patients during the COVID-19 lockdown varied by cultural context and individual variation in age and ED diagnosis. Clinical services may need to target preventive measures and adapt therapeutic approaches for the most vulnerable patients.

• Klíčová slova
• COVID-19 Isolation Eating Scale (CIES), COVID-19 lockdown, eating disorders, eating symptoms, psychological impact,
• MeSH
• COVID-19 prevence a kontrola   psychologie   MeSH
• dítě MeSH
• dospělí MeSH
• internacionalita MeSH
• karanténa psychologie   MeSH
• lidé MeSH
• longitudinální studie MeSH
• mladiství MeSH
• mladý dospělý MeSH
• poruchy příjmu potravy psychologie   MeSH
• SARS-CoV-2 MeSH
• sociální izolace psychologie   MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• multicentrická studie MeSH
• pozorovací studie MeSH
• Geografické názvy
• Asie MeSH
• Evropa MeSH

Trophoblast cell surface antigen 2 (Trop2) is a widely expressed glycoprotein and an epithelial cell adhesion molecule (EpCAM) family member. Although initially identified as a transmembrane protein, other subcellular localizations and processed forms were described. Its congenital mutations cause a gelatinous drop-like corneal dystrophy, a disease characterized by loss of barrier function in corneal epithelial cells. Trop2 is considered a stem cell marker and its expression associates with regenerative capacity in various tissues. Trop2 overexpression was described in tumors of different origins; however, functional studies revealed both oncogenic and tumor suppressor roles. Nevertheless, therapeutic potential of Trop2 was recognized and clinical studies with drug-antibody conjugates have been initiated in various cancer types. One of these agents, sacituzumab govitecan, has been recently granted an accelerated approval for therapy of metastatic triple-negative breast cancer. In this article, we review the current knowledge about the yet controversial function of Trop2 in homeostasis and pathology.

• Klíčová slova
• TACSTD2, Trop2, cancer, epithelial-to-mesenchymal transition, metastases, proliferation, therapy,
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH