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Przemysław Karol Wolak,1,2 Agnieszka Strzelecka,1 Aneta Piotrowska - Gall,1,2 Piotr Przemysław Wolak,3 Ilona Piotrowska,4 Katarzyna Dąbrowska,5 Joanna Wróbel,1 Grażyna Nowak-Starz1 1Collegium Medicum, Jan Kochanowski University of Kielce, Kielce, Poland; 2Department of Pediatric Surgery, Urology and Traumatology, Regional Hospital in Kielce, Kielce, Poland; 3City Hospital of Zabrze, Zabrze, Poland; 4Regional Hospital in Kielce, Kielce, Poland; 5Department of Neonatology and Neonatal Intensive Care, Polish Mother’s Memorial Hospital Research Institute, Łódź, PolandCorrespondence: Przemysław Karol Wolak, Tel +48 501 525 549, Email przemyslaw.wolak@ujk.edu.plIntroduction: The laparoscopic inguinal hernia repair in children using the PIRS technique is a well-established method. However, there are still opinions that this method does not bring more benefits than open surgery.Purpose: The study aims to demonstrate the benefits of laparoscopic technique over conventional, open techniques.Patients and Methods: We conducted a retrospective study that included children aged 0– 18 treated using the PIRS technique in 2008– 2016. The control group consisted of patients treated with the traditional, open method of inguinal hernia repair. A total of 276 children were qualified for laparoscopic surgery, and there were 274 patients in the control group. A full laparoscopic procedure was performed on 247 patients. Assessment of the pathology of the internal inguinal ring was done in all patients during the laparoscopic procedure. Intraoperatively 79 children had bilateral inguinal hernia diagnosed, 133 right-sided inguinal herniae, and 57 left-sided inguinal herniae. The occurrence of hernia was not confirmed in 7 children, whereas 53 patients had open contralateral patent processus vaginalis. In a case of contralateral patent processus vaginalis, the repair was performed using the PIRS method.Results: The recurrence of the inguinal hernia was observed in 10 children in the laparoscopic group and in 5 cases in control group. The duration of the procedure was noted and compared to open inguinal hernia repair. There was a statistically shorter duration of the laparoscopic method. In the control group, there were 16 patients with a metachronous contralateral inguinal hernia.Conclusion: The laparoscopic inguinal hernia repair was associated with a better assessment of hernia pathology, shorter operative time, and lower risk of contralateral hernia repair.Keywords: inguinal hernia, PIRS, children, laparoscopy

The study aims to develop a model for evaluating the technological advancement of teachers engaged in distance education, with variations explained by their individual attributes. These attributes encompass organization skills, adaptation, communication abilities, independence, proficiency, efficiency, and attitude towards distance education. The study involved surveys conducted on 130 geography teachers in Poland during the initial months of the pandemic. The authors hypothesized that the variability in technological advancement could be attributed to the functional capabilities of maps used in geography lessons and the identified personal characteristics. To test these assumptions, 25 original indicators were devised, forming the Technological Advancement Index (TAI). Through statistical analysis, a disparate technological advancement among teachers was observed, with TAI scores ranging from +6.0 to −10.60. At the lower proficiency levels, variability was primarily linked to independence, followed by proficiency and efficiency. As advancement levels increased, so did the functional diversity of maps used, particularly in problem-solving and the creation of new digital maps. This exploration into technological advancement yielded novel conceptual and empirical insights, allowing validation of the Substitution, Augmentation, Modification, Redefinition (SAMR) model used in traditional education. Additionally, it led to development of the Recommendation, Imitation, Gamification, Mobilization, Action (RIGMA) model tailored for distance education. The proposed model holds applicability in enhancing geographic education during distance learning initiatives.

This study analyzed the rearing indicators of Siberian sturgeon (Acipenser baerii) juveniles reared in tanks of different shapes and at various stocking densities. Rearing was conducted in autonomous hatching and rearing modules. Fish of an average body weight of 47.3±1.0 g were divided into four experimental groups: CL, RL, CH, and RH, which differed in stocking density (20 specimens and 50 specimens) and tank shape (C – circular, R – rectangular). The experiment ran for 28 days. Two-factor analysis indicated that lower stocking density significantly affected the final body weight of juvenile Siberian sturgeon, while tank shape had no effect on growth. The results of the current study on rearing Siberian sturgeon juveniles indicated that tanks of different shapes can be applied, but faster growth was obtained at a lower stocking density.

Scientific research and student education aimed at preparing students to practice their profession under the conditions of civilization and technological changes play a special role in geography teaching. It is important to be aware of the impact of key competences which are necessary for every person to function in the modern world and are needed for self-fulfilment, personal development, social integration, flexible adaptation to any changes and which determine the success in adult life. Proper development of such skills contributes to the correct interpretation of natural and socio-economic phenomena and processes. The aim of the article is to present and discuss research work and teaching activities pursued by the Department of Geography Didactics and Ecological Education at the Faculty of Geographical and Geological Sciences of the Adam Mickiewicz University in Poznań, aimed at the use by students of various educational concepts and the resulting key competences necessary for their future work. Students also have the opportunity to develop soft competences, such as communication, courage of expression, self-esteem or responsibility for the group, to which employers have paid special attention in recent years. Therefore, comprehensive preparation of the student requires the implementation of specific educational concepts. The most important ones include bilingual education; CLIL, inquiry based science education (IBSE), project method, fieldwork, geographical educational trails, participation, as well as the use of geoinformation technologies, GIS and ICT.

The aim of the study was to determine the impact of different feed rations (0.5, 0.8, 1.1% fish biomass) on the rearing parameters of pikeperch, Sander lucioperca (L.), reared in a recirculating aquaculture system. The study comprised two experiments. In the first, the material used had been sorted by a mean body weight of 35.5 g, while in the second the pikeperch were divided into three size classes: smallest individuals (class S) with a mean body weight of 59.5 g, medium-sized individuals (class M) with a mean weight of 69.3 g, and largest individuals (class L) with a mean body weight of 84.8 g. The experiments ran for 42 days. At the conclusion of the experiments, the highest body weight and length, daily growth rate, and specific growth rate were attained by the group of fish fed the ration of 1.1% of the fish biomass in both experiments I and II. The feed conversion ratio was also the lowest in this feed ration group, and it differed significantly statistically among the experimental groups (P < 0.05). The feed ration of 0.5% of the fish biomass was only sufficient to maintain vital functions, but it contributed only slightly to growth. The different feed rations did not have a significant impact on the final value of the body weight coefficient of variation of the pikeperch reared in the two experiments. The results of the experiment also indicated that pikeperch is a species with weak stock hierarchy and domination structure.

In the emission spectrum of six 12C16O, 13C16O, 12C18O, 14C16O, 13C18O and 14C18O isotopologues of the carbon monoxide molecule, new recordings and analyses or new reanalyses of the selected and strongest bands belonging to the Ångström (B1Σ+ − A1Π) system were carried out. Under high resolution, emission spectra of the 0–1 and 1–1 bands were recorded and reanalysed, representing both the 0 − v″ and 1 − v″ progressions of this system. Unobserved so far, new spectral lines were identified, and for the 12C16O, 13C16O, 12C18O, 14C16O and 14C18O molecules new parameters of the rovibronic structure B0, B1, D0 and D1 of the v = 0 and v = 1 levels of the B1Σ+ state and band origins ν0 of the 0–1 and 1–1 bands of the B − A transition were determined. A detailed analysis included the predissociation regions of the spectra observed in all analysed bands and isotopologues. The values of rotational quantum numbers and rovibronic terms of the highest nonpredissociated Jh as well as the first, already predissociated Jf levels were determined. On that basis, a new and more precise value of dissociation energy of the CO molecule was determined: cm−1. Also, atomic states of the dissociation products of this molecule, which correspond to this energy, were identified as C(3P0) + O(3P2) i.e. as both triplet ground atomic sublevels. [ABSTRACT FROM AUTHOR]

The aim of the study was to determine the optimum timing of the first feeding of live and formulated feeds and its impact on the survival and growth of larval Atlantic sturgeon, Acipenser oxyrinchus Mitchill, reared in recirculating systems. The first experiment compared the rearing effects on larvae that were provided live feed (Artemia sp.) at first feeding on 6, 9, and 12 days post hatch (DPH). The timing of the first feeding with live feed had an impact on the specific growth rate, the final body weight, and the coefficient of body weight variation. The most advantageous rearing parameter values were noted in the group given their first feeding 9 DPH (P < 0.05). The second experiment compared the results of rearing larvae that were first given formulated feed on days 20, 25, and 30 post hatch. The highest specific growth rate and final body weight were obtained by the group of fish given their first feeding of formulated feed on day 20 post hatch (P < 0.05). The timing of the first feeding did not impact fish survival, which was above 76% (P > 0.05) in all groups. The results of the experiment indicate that the optimum timing of Atlantic sturgeon first feeding on live feed was nine DPH, and on formulated feed it was 20 DPH.

Young people, regardless of their social environment, place of residence or work, are looking for values and key competencies that enable achieving goals in life. Therefore, an appropriate education system is important, which in the conditions of changing reality will meet these requirements effectively. The contemporary employer is interested in four groups of key competencies, such as intellectual, professional, personal and interpersonal. Geography is a field with great potential for the development of various competencies. In this context, questions about adjusting geographical education to the expectations of employers are justified. Therefore, the aim of the study is to assess the strengths and weaknesses of the current development of competencies and qualifications at the geography speciality of the Faculty of Geographical and Geological Sciences, Adam Mickiewicz University in Poznań, Poland. The reference points included a report on research carried out among 200 employers in 2012, as well as surveys among students graduating from master‘s studies on the assessment of the level of their competencies and qualifications. It was determined that the strength of the current geographical education at the faculty is to prepare mainly specialists with broad general and professional knowledge, and high self-esteem in terms of cooperation in the group and communication. The area of development for the geographical education are intellectual competencies, above all independent thinking and prioritising. The last year geography students fall out the most in terms of personal competencies. The authors suggest building students‘ awareness because, as the above results show, they are not fully aware of what expectations they may face in the labour market. It is worth modifying the study program so as to put more emphasis on soft competencies and support the development of various forms of extra activities of students. Attention was also paid to the importance of didactic competencies, which on the one hand raise the self-esteem of students, and on the other, increase the chance of finding a good job. An interesting aspect of the research is the wide spectrum of professions in which students work. This reflects their diverse skills, including spatial thinking. Combined with increasing attention paid to the issues related to the natural environment and sustainable development, graduates of geography have a strong position to enter the current labour market. The advantage of geographers is the use of modern technologies. Unfortunately, however, the results of the research presented above, both among Polish students and internationally, indicate insufficient skills in the use of modern technologies by students of geography.

Interactions were studied among juvenile narrow-claw crayfish, Astacus leptodactylus (Eschscholtz), and common water frog, Rana esculenta (L.), tadpoles and common blue damselfly, Enallagma cyathigerum (Charpentier), larvae during rearing under controlled conditions. Interactions among the species studied had a positive impact on the survival of the crayfish, but the differences were not statistically significant (P ≥ 0.5). The juvenile crayfish attacked and consumed the frog tadpoles and damselflies, but the juvenile crayfish very rarely fell prey to them. Only in the initial stage of life and during molting did larval damselflies prey upon juvenile crayfish. After 30 days of the experiment the interaction between crayfish-tadpoles and crayfish-larval damselflies was not noted to have had a statistically significant (P ≥ 0.05) impact on crayfish growth. Juvenile crayfish aggression toward tadpoles and larval damselflies was often offset by the loss of even both chelipeds. In the crayfish-larval damselfly interaction the loss of both chelipeds was three-fold more common than it was in the crayfish-tadpole interaction; however, these differences were not statistically significant (P ≥ 0.5). The effect of intraspecific interaction (crayfish-crayfish) was more a threat in terms of mortality from cannibalism than were interspecific interactions (crayfish-tadpole and crayfish-larval damselfly).

The experiment examined the possibility of rearing juvenile pikeperch, Sander lucioperca (L.) in polyculture with sterlet Acipenser ruthenus L. in a recirculating system. Three variants of pikeperch rearing were tested: monoculture (group S), with the addition of sterlet at 10% (group S10) and 20% (group S20) of the initial pikeperch biomass. After 56 days of rearing, no differences in the growth rates or survival of the pikeperch were noted. The value of the feed conversion ratio in the monoculture group was 1.19 and was significantly statistically higher than in the polyculture groups, the values of which were 0.84 (S10) and 0.74 (S20). The mean oxygen consumption and ammonia excretion values did not differ significantly statistically among the studied groups. Including the sterlet stock with the pikeperch permitted obtaining the additional value of the sterlet biomass using the same quantity of feed. Additionally, the inclusion of sterlet decreased the labor intensity of pikeperch rearing since the tanks did not need cleaning as frequently.

Vendace, Coregonus albula L., was reared to commercial size in a recirculating system. Three different feed rations were applied during the ten-month-long experiment. The feed rations impacted fish growth rates, and fish in the different groups achieved body weights of 26.6 g to 57.5 g. The final survival in all groups was similar from 44.3% among the fish fed the smallest feed ration to 53.2% in the group receiving the largest feed ration. No differences were noted in the share of viscera, peritoneal fat, or in the hepatosomatic indexes, but there were differences in the gonadosomatic indexes. After thermal stimulation, only males achieved sexual maturity. The number of mature fish was similar in all groups and ranged from 17.8 to 21.3% of all fish. The results of the present study indicated that vendace can achieve commercial size in an intensive rearing period of ten months in RAS.

B a c k g r o u n d: Cardiovascular diseases are the first cause of death globally. Hypercholester- olemia is the most important factor responsible for atherosclerotic plaque formation and increasing cardiovascular risk. Reduction of LDL-C level is the most relevant goal for reduction of cardiovascular risk. A i m s: Real life adherence to guidelines concerning statin therapy in one center study population. M e t h o d s: We analyzed data collected in the Department of Internal Diseases from September 2019 to February 2020, obtained from 238 patients hospitalized in this time period. We assessed application of the new 2019 ESC/EAS Guidelines for the Management of Dyslipidaemias in daily clinical practice and compared effectiveness of LLT according to 2016 and 2019 guidelines. R e s u l t s: Only 1 in 5 patients with dyslipideamia achieve the 2019 ESC/EAS guideline-recommended levels of LDL-C with relation to their TCVR. We noticed that 20 of patients who did not achieve proper 2019 LDL level, meet new therapy targets established in year 2016. We observed that higher patient TCVR resulted in better compliance with guidelines and ordination of proper LLT. Most patients were on monotherapy with statins. C o n c l u s i o n s: It could be beneficial to start treatment with double or even triple therapy especially in group with the highest LDL-C levels.

In this study, we compared the operative time for unilateral inguinal hernia repair in children performed with either an open approach (OA) or the Percutaneous Internal Ring Suturing (PIRS) method. It was a retrospective chart review of all patients ages 0 to 18 who underwent unilateral inguinal hernia repair in the Department of Pediatric Surgery, Urology and Traumatology of the Regional Hospital in Kielce between January 2011 and December 2018. Patients with bilateral hernias or additional problems were excluded. Of 878 patients qualified for the study, 701 were in the OA group and 177 in the PIRS group. Overall, the time needed to complete the procedure was significantly longer for the OA method. The operative time was longer if the hernia was left-sided ( p = 0.024). Analysis by gender showed that operative time was generally longer in males. For both genders, surgery was shorter if the PIRS method was used. For males in the PIRS group the operative time was affected by the location of the hernia, and it was longer for a left-sided hernia. The take-home message is that the PIRS procedure is faster than the OA for inguinal hernia repair in children and it might be considered as a preferred method, especially in females.

Background: The calcific aortic valve disease (CAVD) is a common heart pathology that involves inflammation, fibrosis, and calcification of aortic valve leaflets. All these processes could be affected by changes in the extracellular purinergic signaling that depend on the activity of ectonucleotidases, mainly ectonucleoside triphosphate diphosphohydrolase 1 (CD39, eNTPD1) and ecto-5'nucleotidase (CD73, e5NT)., Objective and Methods: We investigated the localization of CD39 and CD73 proteins in human noncalcified and calcified aortic valves using immunohistochemistry together with analysis of NTPDases and e5NT activities in aortic valve homogenates by analysis of substrate into product conversion by high-performance liquid chromatography. We also measured the rates of extracellular nucleotide catabolism on the surface of isolated cultured aortic valve endothelial (hAVECs) and interstitial cells (hAVICs) as well as characterized cellular CD39 and CD73 distribution., Results: In noncalcified valves, CD39 and CD73 were expressed in both endothelial and interstitial cells, while in calcified valves, the expressions of CD39 and CD73 were significantly down-regulated with the exception of calcified regions where the expression of CD73 was maintained. This correlated with activities in valve homogenates. NTPDase was reduced by 35% and e5NT activity by 50% in calcified vs. noncalcified valve. CD39 and CD73 were present mainly in the cell membrane of hAVECs, but in hAVICs, these proteins were also present intracellularly. The rates of extracellular adenosine triphosphate and adenosine monophosphate hydrolysis in isolated hAVECs and hAVICs were comparable., Conclusion: The presence of ectonucleotidases in valves and especially in aortic valve interstitial cells highlights important local role of purinergic signaling and metabolism. Changes in the local expression and hence the activity of CD39 and CD73 in calcified valves suggest their potential role in CAVD., (Copyright © 2018. Published by Elsevier Inc.)

Purpose: Anthracyclines cause chronic irreversible cardiac failure, but the mechanism remains poorly understood. Emerging data indicate that cardiac damage begins early, suggesting protective modalities delivered in the acute stage may confer prolonged benefit. Ischaemic preconditioning (IPC) activates the pro-survival reperfusion injury salvage kinase (RISK) pathway which involves PI3-kinase and MAPK/ERK1/2., Methods: We investigated whether simulated IPC (sIPC), in the form of a sublethal exposure to a hypoxic buffer simulating ischaemic conditions followed by reoxygenation, protects primary adult rat cardiomyocytes against anthracycline-induced injury. PI3-kinase and MAPK/ERK1/2 were inhibited using LY294002, and PD98059. The role of reactive oxygen species (ROS), mitochondrial membrane potential (Δψ m ) and mitochondrial permeability transition pore (mPTP) were also investigated in doxorubicin-treated cells. We further examined whether sIPC protected HeLa cancer cells from doxorubicin-induced death., Results: sIPC protected cardiomyocytes against doxorubicin-induced death (35.4 ± 1.7% doxorubicin vs 14.7 ± 1.5% doxorubicin + sIPC; p < 0.01). This protection was abrogated by the PI3-kinase inhibitor, LY294002, but not the MAPK/ERK1/2 inhibitor, PD98059. A ROS scavenger failed to rescue cardiomyocytes from doxorubicin toxicity, and no significant influence on Δψ m or mPTP opening was identified after subjecting cells to a doxorubicin insult. Importantly, sIPC did not protect HeLa cancer cells from doxorubicin-induced death., Conclusion: sIPC is able to protect cardiomyocytes against anthracycline injury via a pathway involving PI3-kinase. This mechanism appears to be independent of ROS, changes to Δψ m, and mPTP. Further investigation of the mechanism of sIPC-induced protection against anthracycline-injury is warranted.

The World Marrow Donor Organization recommends original granulocyte-colony stimulating factor (G-CSF) for the mobilization of stem cells in healthy unrelated hematopoietic stem cell donors. We report the comparison of a biosimilar G-CSF (Zarzio) with two original G-CSFs (filgrastim and lenograstim) in mobilization in unrelated donors. We included data of 313 consecutive donors who were mobilized during the period from October 2014 to March 2016 at the Medical University of Warsaw. The primary endpoints of this study were the efficiency of CD34+ cell mobilization to the circulation and results of the first apheresis. The mean daily dose of G-CSF was 9.1 μg/kg for lenograstim, 9.8 μg/kg for biosimilar filgrastim, and 9.3 μg/kg for filgrastim (p < 0.001). The mean CD34+ cell number per microliter in the blood before the first apheresis was 111 for lenograstim, 119 for biosimilar filgrastim, and 124 for filgrastim (p = 0.354); the mean difference was even less significant when comparing CD34+ number per dose of G-CSF per kilogram (p = 0.787). Target doses of CD34+ cells were reached with one apheresis in 87% donors mobilized with lenograstim and in 93% donors mobilized with original and biosimilar filgrastim (p = 0.005). The mobilized apheresis outcomes (mean number of CD34+ cells/kg of donor collected during the first apheresis) was similar with lenograstim, biosimilar filgrastim, and filgrastim: 6.2 × 10 6 , 7.6 × 10 6 , and 7.3 × 10 6 , respectively, p = 0.06. There was no mobilization failure in any of the donors. Biosimilar G-CSF is as effective in the mobilization of hematopoietic stem cells in unrelated donors as original G-CSFs. Small and clinically irrelevant differences seen in the study can be attributed to differences in G-CSF dose and collection-related factors. Active safety surveillance concurrent to clinical use and reporting to donor outcome registry (e.g., EBMT donor outcome registry or WMDA SEAR/SPEAR) might help to evaluate the possible short- and long-term complications of biosimilar G-CSF.

Objectives: Bone marrow harvesting is one of the essential sources of stem cells for hematopoietic stem cell transplantation. We describe here the current "up-to-date" standard of the bone marrow harvest in unrelated stem cell donors., Methods: We analyzed medical data of 187 unrelated hematopoietic stem cell donors who underwent bone marrow harvest without previous peripheral blood stem collection at the center between 2011 and 2015. The methodology of marrow collection includes multiple cells aimed at safety of the procedure, for example, educational movie, modified skin disinfection protocol, cell enumeration during the procedure, reduction of the contamination surfaces, and ongoing monitoring of the quality of work of the doctors., Results: The total nucleated cell count over 2×10 8 per kg of recipient has been reached in 93.6% of harvests. All of the donors harvested more than 1×10 8 per kg of the recipient. There were no donors who required transfusions or had serious adverse events during and after the harvest., Conclusion: We describe here the current up-to-date standard of bone marrow harvest, which leads to excellent results in majority of donors without causing significant complications during the donation., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Doxorubicin is a potent chemotherapeutic agent that is widely-used to treat a variety of cancers but causes acute and chronic cardiac injury, severely limiting its use. Clinically, the acute side effects of doxorubicin are mostly manageable, whereas the delayed consequences can lead to life-threatening heart failure, even decades after cancer treatment. The cardiotoxicity of doxorubicin is subject to a critical cumulative dose and so dosage limitation is considered to be the best way to reduce these effects. Hence, a number of studies have defined a "safe dose" of the drug, both in animal models and clinical settings, with the aim of avoiding long-term cardiac effects. Here we show that a dose generally considered as safe in a mouse model can induce harmful changes in the myocardium, as early as 2 weeks after infusion. The adverse changes include the development of fibrotic lesions, disarray of cardiomyocytes and a major transcription dysregulation. Importantly, low-dose doxorubicin caused specific changes in the transcriptional profile of several histone deacetylases (HDACs) which are epigenetic regulators of cardiac remodelling. This suggests that cardioprotective therapies, aimed at modulating HDACs during doxorubicin treatment, deserve further exploration.

Anthracycline chemotherapy maintains a prominent role in treating many forms of cancer. Cardiotoxic side effects limit their dosing and improved cancer outcomes expose the cancer survivor to increased cardiovascular morbidity and mortality. The basic mechanisms of cardiotoxicity may involve direct pathways for reactive oxygen species generation and topoisomerase 2 as well as other indirect pathways. Cardioprotective treatments are few and those that have been examined include renin angiotensin system blockade, beta blockers, or the iron chelator dexrazoxane. New treatments exploiting the ErbB or other novel pro-survival pathways, such as conditioning, are on the cardioprotection horizon. Even in the forthcoming era of targeted cancer therapies, the substantial proportion of today's anthracycline-treated cancer patients may become tomorrow's cardiac patient.

Skeletal muscle remodelling and contractile dysfunction occur through both acute and chronic disease processes. These include the accumulation of insoluble aggregates of misfolded amyloid proteins that is a pathological feature of Huntington's disease (HD). While HD has been described primarily as a neurological disease, HD patients' exhibit pronounced skeletal muscle atrophy. Given that huntingtin is a ubiquitously expressed protein, skeletal muscle fibres may be at risk of a cell autonomous HD-related dysfunction. However the mechanism leading to skeletal muscle abnormalities in the clinical and pre-clinical HD settings remains unknown. To unravel this mechanism, we employed the R6/2 transgenic and HdhQ150 knock-in mouse models of HD. We found that symptomatic animals developed a progressive impairment of the contractile characteristics of the hind limb muscles tibialis anterior (TA) and extensor digitorum longus (EDL), accompanied by a significant loss of motor units in the EDL. In symptomatic animals, these pronounced functional changes were accompanied by an aberrant deregulation of contractile protein transcripts and their up-stream transcriptional regulators. In addition, HD mouse models develop a significant reduction in muscle force, possibly as a result of a deterioration in energy metabolism and decreased oxidation that is accompanied by the re-expression of the HDAC4-DACH2-myogenin axis. These results show that muscle dysfunction is a key pathological feature of HD.

Huntington's disease (HD) is a hereditary neurodegenerative disorder caused by the expansion of a polyglutamine stretch within the huntingtin protein (HTT). The neurological symptoms, that involve motor, cognitive and psychiatric disturbances, are caused by neurodegeneration that is particularly widespread in the basal ganglia and cereberal cortex. HTT is ubiquitously expressed and in recent years it has become apparent that HD patients experience a wide array of peripheral organ dysfunction including severe metabolic phenotype, weight loss, HD-related cardiomyopathy and skeletal muscle wasting. Although skeletal muscles pathology became a hallmark of HD, the mechanisms underlying muscular atrophy in this disorder are unknown. Skeletal muscles account for approximately 40% of body mass and are highly adaptive to physiological and pathological conditions that may result in muscle hypertrophy (due to increased mechanical load) or atrophy (inactivity, chronic disease states). The atrophy is caused by degeneration of myofibers and their replacement by fibrotic tissue is the major pathological feature in many genetic muscle disorders. Under normal physiological conditions the muscle function is orchestrated by a network of intrinsic hypertrophic and atrophic signals linked to the functional properties of the motor units that are likely to be imbalanced in HD. In this article, we highlight the emerging field of research with particular focus on the recent studies of the skeletal muscle pathology and the identification of new disease-modifying treatments.

Fetal cardiomyocyte adaptation to low levels of oxygen in utero is incompletely understood, and is of interest as hypoxia tolerance is lost after birth, leading to vulnerability of adult cardiomyocytes. It is known that cardiac mitochondrial morphology, number and function change significantly following birth, although the underlying molecular mechanisms and physiological stimuli are undefined. Here we show that the decrease in cardiomyocyte HIF-signaling in cardiomyocytes immediately after birth acts as a physiological switch driving mitochondrial fusion and increased postnatal mitochondrial biogenesis. We also investigated mechanisms of ATP generation in embryonic cardiac mitochondria. We found that embryonic cardiac cardiomyocytes rely on both glycolysis and the tricarboxylic acid cycle to generate ATP, and that the balance between these two metabolic pathways in the heart is controlled around birth by the reduction in HIF signaling. We therefore propose that the increase in ambient oxygen encountered by the neonate at birth acts as a key physiological stimulus to cardiac mitochondrial adaptation., (Crown Copyright © 2014. Published by Elsevier Ltd. All rights reserved.)

Growth and development in utero is a complex and dynamic process that requires interaction between the mother organism and the fetus. The delivery of macro--and micronutrients, oxygen and endocrine signals has crucial importance for providing a high level of proliferation, growth and differentiation of cells, and a disruption in food intake not only has an influence on the growth of the fetus, but also has negative consequences for the offspring’s health in the future. Diseases that traditionally are linked to inappropriate life style of adults, such as type 2 diabetes, obesity, and arterial hypertension, can be "programmed" in the early stage of life and the disturbed growth of the fetus leads to the symptoms of the metabolic syndrome. The structural changes of some organs, such as the brain, pancreas and kidney, modifications of the signaling and metabolic pathways in skeletal muscles and in fatty tissue, epigenetic mechanisms and mitochondrial dysfunction are the basis of the metabolic disruptions. The programming of the metabolic disturbances is connected with the disruption in the intrauterine environment experienced in the early and late gestation period. It causes the changes in deposition of triglycerides, activation of the hormonal "stress axis" and disturbances in the offspring’s glucose tolerance. The present review summarizes experimental results that led to the identification of the above-mentioned links and it underlines the role of animal models in the studies of this important concept.

Annexins are calcium- and membrane-binding proteins that have been shown to have diverse properties such as actin, integrin and GTP binding, both in animals and plants. Recently, Medicago truncatula annexin 1 (AnnMt1) has been suggested to participate in nodulation (Nod factor signaling) and mycorrhization in legume plants. In this report we demonstrate for the first time that recombinant AnnMt1 (rec-AnnMt1) mediates membrane permeabilization to cations with conductance ranging from 16 pS to 329 pS. In agreement with other structurally determined annexins, homology modeling of AnnMt1 suggests that most of the functional determinants are found on the convex surface of the modeled structure. In conclusion, we propose a potential constitutive role of AnnMt1 in Nod factor signaling as a non-specific ion channel., (Copyright © 2013 Elsevier Masson SAS. All rights reserved.)

Cardiomyocytes are vulnerable to hypoxia in the adult, but adapted to hypoxia in utero. Current understanding of endogenous cardiac oxygen sensing pathways is limited. Myocardial oxygen consumption is determined by regulation of energy metabolism, which shifts from glycolysis to lipid oxidation soon after birth, and is reversed in failing adult hearts, accompanying re-expression of several "fetal" genes whose role in disease phenotypes remains unknown. Here we show that hypoxia-controlled expression of the transcription factor Hand1 determines oxygen consumption by inhibition of lipid metabolism in the fetal and adult cardiomyocyte, leading to downregulation of mitochondrial energy generation. Hand1 is under direct transcriptional control by HIF1α. Transgenic mice prolonging cardiac Hand1 expression die immediately following birth, failing to activate the neonatal lipid metabolising gene expression programme. Deletion of Hand1 in embryonic cardiomyocytes results in premature expression of these genes. Using metabolic flux analysis, we show that Hand1 expression controls cardiomyocyte oxygen consumption by direct transcriptional repression of lipid metabolising genes. This leads, in turn, to increased production of lactate from glucose, decreased lipid oxidation, reduced inner mitochondrial membrane potential, and mitochondrial ATP generation. We found that this pathway is active in adult cardiomyocytes. Up-regulation of Hand1 is protective in a mouse model of myocardial ischaemia. We propose that Hand1 is part of a novel regulatory pathway linking cardiac oxygen levels with oxygen consumption. Understanding hypoxia adaptation in the fetal heart may allow development of strategies to protect cardiomyocytes vulnerable to ischaemia, for example during cardiac ischaemia or surgery., Competing Interests: The authors have declared that no competing interests exist.

CLU (clusterin) is a tumor suppressor gene that we have previously shown to be negatively modulated by the MYCN proto-oncogene, but the mechanism of repression was unclear. Here, we show that MYCN inhibits the expression of CLU by direct interaction with the non-canonical E box sequence CACGCG in the 5'-flanking region. Binding of MYCN to the CLU gene induces bivalent epigenetic marks and recruitment of repressive proteins such as histone deacetylases and Polycomb members. MYCN physically binds in vitro and in vivo to EZH2, a component of the Polycomb repressive complex 2, required to repress CLU. Notably, EZH2 interacts with the Myc box domain 3, a segment of MYC known to be essential for its transforming effects. The expression of CLU can be restored in MYCN-amplified cells by epigenetic drugs with therapeutic results. Importantly, the anticancer effects of the drugs are ablated if CLU expression is blunted by RNA interference. Our study implies that MYC tumorigenesis can be effectively antagonized by epigenetic drugs that interfere with the recruitment of chromatin modifiers at repressive E boxes of tumor suppressor genes such as CLU.

Purpose: Neuroblastoma is a rare childhood cancer whose high risk, metastatic form has a dismal outcome in spite of aggressive therapeutic interventions. The toxicity of drug treatments is a major problem in this pediatric setting. In this study, we investigated whether Polyphenon E, a clinical grade mixture of green tea catechins under evaluation in multiple clinical cancer trials run by the National Cancer Institute (Bethesda, MD), has anticancer activity in mouse models of neuroblastoma., Experimental Design: We used three neuroblastoma models: (i) transgenic TH-MYCN mouse developing spontaneous neuroblastomas; (ii) nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice xenotransplanted with human SHSY5Y cells; and (iii) A/J mice transplanted with syngeneic Neuro 2A cells. Mice were randomized in control and Polyphenon E-drinking groups. Blood from patients with neuroblastoma and normal controls was used to assess the phenotype and function of myeloid cells., Results: Polyphenon E reduced the number of tumor-infiltrating myeloid cells, and inhibited the development of spontaneous neuroblastomas in TH-MYCN transgenic mice. In therapeutic models of neuroblastoma in A/J, but not in immunodeficient NOD/SCID mice, Polyphenon E inhibited tumor growth by acting on myeloid-derived suppressor cells (MDSC) and CD8 T cells. In vitro, Polyphenon E impaired the development and motility of MDSCs and promoted differentiation to more neutrophilic forms through the 67 kDa laminin receptor signaling and induction of granulocyte colony-stimulating factor. The proliferation of T cells infiltrating a patient metastasis was reactivated by Polyphenon E., Conclusions: These findings suggest that the neuroblastoma-promoting activity of MDSCs can be manipulated pharmacologically in vivo and that green tea catechins operate, at least in part, through this mechanism., (©2012 AACR.)

The 25 kDa branched polyethylenimine (PEI) is a highly efficient synthetic polycation used in transfection protocols, but also triggers mitochondrial-mediated apoptotic cell death processes where the mechanistic issues are poorly understood. We now demonstrate that PEI in a concentration- and time-dependent manner can affect functions (membrane potential, swelling and respiration) and ultrastructural integrity of freshly isolated rat liver mitochondria. The threshold concentration for detection of PEI-mediated impairment of rat liver mitochondrial functions is 3 μg/mL, however, lower PEI levels still exert some effects on mitochondrial morphology and respiration, and these may be related to the inherent membrane perturbing properties of this polycation. The PEI-mediated mitochondrial swelling phase is biphasic, with a fast decaying initial period (most prominent from 4 μg/mL PEI) followed by a slower, linear swelling response. The slow phase is presumably the result of a time-dependent transition permeability opening in mitochondria initially resistant to swelling/depolarization, but may further be related to PEI-induced nanoscale structural defects and/or formation of pores in the outer membrane. Respiration assessments further suggested that PEI in the presence of exogenous ADP behaves in a similar fashion to a slow-acting inhibitory compound. PEI further shows an uncoupling property that is detectable at low respiration rates. The relevance of these findings to PEI-mediated initiation of intrinsic apoptotic pathway is discussed., (Copyright © 2011 Elsevier B.V. and Mitochondria Research Society. All rights reserved.)

Entomopathogenic fungi are important natural regulatory factors of insect populations and have potential as biological control agents of insect pests. The cosmopolitan soil fungus Conidiobolus coronatus (Entomopthorales) easily attacks Galleria mellonella (Lepidoptera) larvae. Prompt death of invaded insects is attributed to the action of toxic metabolites released by the invader. Effect of fungal metabolites on hemocytes, insect blood cells involved in innate defense response, remains underexplored to date. C. coronatus isolate 3491 inducing 100% mortality of G. mellonella last instar larvae exposed to sporulating colonies, was cultivated at 20 °C in minimal medium. Post-incubation filtrates were used as a source of fungal metabolites. A two-step HPLC (1 step: Shodex KW-803 column eluted with 50 mM KH(2)PO(4) supplemented with 0.1 M KCl, pH 6.5; 2 step: ProteinPak™ CM 8HR column equilibrated with 5 mM KH(2)PO(4), pH 6.5, proteins eluted with a linear gradient of 0.5 M KCl) allowed the isolation of coronatin-1, an insecticidal 36 kDa protein showing both elastolytic and chitinolytic activities. Addition of coronatin-1 into primary in vitro cultures of G. mellonella hemocytes resulted in rapid disintegration of spherulocytes freely floating in culture medium and shrinkage of plasmatocytes adhering to the bottom of culture well. Coronatin-1 stimulated pseudopodia atrophy and, in consequence, disintegration of nets formed by cultured hemocytes. After incorporation of coronatin-1 into planar lipid membrane (PLM) ion channels selective for K(+) ions in 50/450 mM KCl solutions were observed. Potassium current flows were recorded in nearly 70% of experiments with conductance from 300 pS up to 1 nS. All observed channels were active at both positive and negative membrane potentials. Under experimental conditions incorporated coronatin-1 exhibited a zero current potential (E(rev)) of 47.7 mV, which indicates K(+)-selectivity of this protein. The success of the purification of coronatin-1 will allow further characterization of the mode of action of this molecule, including ability of coronatin-1 to form potassium channels in immunocompetent hemocytes., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Objectives: We studied fibrosis, collagen metabolism, MMPs/TIMPs and cytokine expression in various forms of human heart failure (HF) by quantitative immunofluorescent microscopy, Western blot, zymography, RT-PCR and in situ hybridization. In explanted human hearts with HF due to either dilated (DCM, n=6) or ischemic (ICM-BZ-borderzone, ICM-RZ-remote zone, n=7) or inflammatory (myocarditis, MYO, n=6) cardiomyopathy and 8 controls MMP2, 8, 9, 19, and TIMP1, 2, 3, 4 as well as procollagens I and III (PINP, PIIINP), mature collagen III (IIINTP) and the cross-linked collagen I degradation product (ICTP) were measured., Results: In comparison with controls, MMPs and TIMPs were significantly upregulated ranging (from highest to lowest) from ICM-BZ, DCM, ICM-RZ, MYO for all MMPs with the exception of MMP9 (highest in DCM), and for TIMPs from ICM-BZ, ICM-RZ, DCM and MYO. MMP2 and 9 were activated in all groups. The TIMP/MMP ratio was 1.3 for control, 1.9 in ICM-BZ (TIMP>MMP) and lowered to 1.0 in the other groups. Collagen I/collagen III ratio correlated significantly with the decrease in LVEDP. PINP was higher than ICTP in all groups. PIIINP elevation was present in DCM and ICM-RZ and IIINTP was up to 4-fold augmented in all groups. Fibrosin mRNA was upregulated in ICM-BZ, activin A in MYO but FGF1 and FGF2 remained unchanged. ANP mRNA was increased in all groups., Conclusions: Although different degrees of severity of collagen metabolism, MMP/TIMP imbalance and cytokine expression in diverse forms of HF are present, the end product is collagen deposition. These findings suggest multiple mechanisms acting alone or in concert in fibrosis development in HF., (Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.)

Muscle LIM protein (MLP, also known as cysteine rich protein 3 (CSRP3, CRP3)) is a muscle-specific-expressed LIM-only protein. It consists of 194 amino-acids and has been described initially as a factor involved in myogenesis (Arber et al. Cell 79:221-231, 1994). MLP soon became an important model for experimental cardiology when it was first demonstrated that MLP deficiency leads to myocardial hypertrophy followed by a dilated cardiomyopathy and heart failure phenotype (Arber et al. Cell 88:393-403, 1997). At this time, this was the first genetically altered animal model to develop this devastating disease. Interestingly, MLP was also found to be down-regulated in humans with heart failure (Zolk et al. Circulation 101:2674-2677, 2000) and MLP mutations are able to cause hypertrophic and dilated forms of cardiomyopathy in humans (Bos et al. Mol Genet Metab 88:78-85, 2006; Geier et al. Circulation 107:1390-1395, 2003; Hershberger et al. Clin Transl Sci 1:21-26, 2008; Knöll et al. Cell 111:943-955, 2002; Knöll et al. Circ Res 106:695-704, 2010; Mohapatra et al. Mol Genet Metab 80:207-215, 2003). Although considerable efforts have been undertaken to unravel the underlying molecular mechanisms-how MLP mutations, either in model organisms or in the human setting cause these diseases are still unclear. In contrast, only precise knowledge of the underlying molecular mechanisms will allow the development of novel and innovative therapeutic strategies to combat this otherwise lethal condition. The focus of this review will be on the function of MLP in cardiac mechanosensation and we shall point to possible future directions in MLP research.