Search

Implantable medical devices, such as pacemakers, have significantly improved the quality of life for patients with cardiac conditions, allowing them to maintain active lifestyles. Nonetheless, these devices can present unique challenges when interacting with the wearers physical activities, potentially leading to unforeseen complications. Here, we present a case of an 81-year-old male golfer, with a history of atrial fibrillation, congestive heart failure, and sick sinus syndrome, who experienced atrial lead noise from his pacemaker, exclusively triggered by his golf swing. This incident, which led to multiple interventions including lead extraction, reimplantation, and eventually a switch to a unipolar lead configuration, represents the first documented case of its kind. It underscores the intricate relationship between the biomechanical forces of certain sports and the functionality of implanted cardiac devices. Through detailed electrophysiology testing, this case demonstrates how specific movements inherent to the patients golf swing could induce micro-damage to the pacemaker leads, causing noise and malfunction. The findings from this case emphasize the need for healthcare providers to perform sport-specific biomechanical evaluations and create tailored rehabilitation strategies that consider the unique physical demands placed on patients with implanted devices. This approach is important not only for diagnosing and managing similar cases but also for advancing our understanding of how to best support the active lifestyles of patients with implanted cardiac devices, ensuring their safety and longevity.

Aim: Mechanical ventilation (MV) results in diminished diaphragm size and strength, termed ventilator-induced diaphragm dysfunction (VIDD). VID increases dependence, prolongs weaning, and increases discharge mortality rates. The Janus kinase (JAK)/Signal Transducer and Activator of Transcription (STAT) pathway is implicated in VIDD, upregulated following MV. JAK/STAT inhibition alleviates chronic muscle wasting conditions. This study aimed to explore the therapeutic potential of Ruxolitinib, an FDA approved JAK1/2 inhibitor (JI) for the treatment of VIDD. Methods: Rats were subjected to 5 days controlled MV (CMV) with and without daily Ruxolitinib gavage. Muscle fiber size and function were assessed. RNAseq, mitochondrial morphology, respirometry, and mass spectrometry were determined. Results: CMV significantly reduced diaphragm size and specific force by 45% (p < 0.01), associated with a two-fold P-STAT3 upregulation (p < 0.001). CMV disrupted mitochondrial content and reduced the oxygen consumption rate (p < 0.01). Expression of the motor protein myosin was unaffected, however CMV alters myosin function via post-translational modifications (PTMs). Daily administration of JI increased animal survival (40% vs. 87%; p < 0.05), restricted P-STAT3 (p < 0.001), and preserved diaphragm size and specific force. JI was associated with preserved mitochondrial content and respiratory function (p < 0.01), and the reversal or augmentation of myosin deamidation PTMs of the rod and head region. Conclusion: JI preserved diaphragm function, leading to increased survival in an experimental model of VIDD. Functional enhancement was associated with maintenance of mitochondrial content and respiration and the reversal of ventilator-induced PTMs of myosin. These results demonstrate the potential of repurposing Ruxolitinib for treatment of VIDD.

Aim: Mechanical ventilation (MV) results in diminished diaphragm size and strength, termed ventilator-induced diaphragm dysfunction (VIDD). VID increases dependence, prolongs weaning, and increases discharge mortality rates. The Janus kinase (JAK)/Signal Transducer and Activator of Transcription (STAT) pathway is implicated in VIDD, upregulated following MV. JAK/STAT inhibition alleviates chronic muscle wasting conditions. This study aimed to explore the therapeutic potential of Ruxolitinib, an FDA approved JAK1/2 inhibitor (JI) for the treatment of VIDD. Methods: Rats were subjected to 5 days controlled MV (CMV) with and without daily Ruxolitinib gavage. Muscle fiber size and function were assessed. RNAseq, mitochondrial morphology, respirometry, and mass spectrometry were determined. Results: CMV significantly reduced diaphragm size and specific force by 45% (p < 0.01), associated with a two-fold P-STAT3 upregulation (p < 0.001). CMV disrupted mitochondrial content and reduced the oxygen consumption rate (p < 0.01). Expression of the motor protein myosin was unaffected, however CMV alters myosin function via post-translational modifications (PTMs). Daily administration of JI increased animal survival (40% vs. 87%; p < 0.05), restricted P-STAT3 (p < 0.001), and preserved diaphragm size and specific force. JI was associated with preserved mitochondrial content and respiratory function (p < 0.01), and the reversal or augmentation of myosin deamidation PTMs of the rod and head region. Conclusion: JI preserved diaphragm function, leading to increased survival in an experimental model of VIDD. Functional enhancement was associated with maintenance of mitochondrial content and respiration and the reversal of ventilator-induced PTMs of myosin. These results demonstrate the potential of repurposing Ruxolitinib for treatment of VIDD.

Aim: Mechanical ventilation (MV) results in diminished diaphragm size and strength, termed ventilator-induced diaphragm dysfunction (VIDD). VID increases dependence, prolongs weaning, and increases discharge mortality rates. The Janus kinase (JAK)/Signal Transducer and Activator of Transcription (STAT) pathway is implicated in VIDD, upregulated following MV. JAK/STAT inhibition alleviates chronic muscle wasting conditions. This study aimed to explore the therapeutic potential of Ruxolitinib, an FDA approved JAK1/2 inhibitor (JI) for the treatment of VIDD. Methods: Rats were subjected to 5 days controlled MV (CMV) with and without daily Ruxolitinib gavage. Muscle fiber size and function were assessed. RNAseq, mitochondrial morphology, respirometry, and mass spectrometry were determined. Results: CMV significantly reduced diaphragm size and specific force by 45% (p < 0.01), associated with a two-fold P-STAT3 upregulation (p < 0.001). CMV disrupted mitochondrial content and reduced the oxygen consumption rate (p < 0.01). Expression of the motor protein myosin was unaffected, however CMV alters myosin function via post-translational modifications (PTMs). Daily administration of JI increased animal survival (40% vs. 87%; p < 0.05), restricted P-STAT3 (p < 0.001), and preserved diaphragm size and specific force. JI was associated with preserved mitochondrial content and respiratory function (p < 0.01), and the reversal or augmentation of myosin deamidation PTMs of the rod and head region. Conclusion: JI preserved diaphragm function, leading to increased survival in an experimental model of VIDD. Functional enhancement was associated with maintenance of mitochondrial content and respiration and the reversal of ventilator-induced PTMs of myosin. These results demonstrate the potential of repurposing Ruxolitinib for treatment of VIDD.

Aim: Mechanical ventilation (MV) results in diminished diaphragm size and strength, termed ventilator-induced diaphragm dysfunction (VIDD). VID increases dependence, prolongs weaning, and increases discharge mortality rates. The Janus kinase (JAK)/Signal Transducer and Activator of Transcription (STAT) pathway is implicated in VIDD, upregulated following MV. JAK/STAT inhibition alleviates chronic muscle wasting conditions. This study aimed to explore the therapeutic potential of Ruxolitinib, an FDA approved JAK1/2 inhibitor (JI) for the treatment of VIDD. Methods: Rats were subjected to 5 days controlled MV (CMV) with and without daily Ruxolitinib gavage. Muscle fiber size and function were assessed. RNAseq, mitochondrial morphology, respirometry, and mass spectrometry were determined. Results: CMV significantly reduced diaphragm size and specific force by 45% (p < 0.01), associated with a two-fold P-STAT3 upregulation (p < 0.001). CMV disrupted mitochondrial content and reduced the oxygen consumption rate (p < 0.01). Expression of the motor protein myosin was unaffected, however CMV alters myosin function via post-translational modifications (PTMs). Daily administration of JI increased animal survival (40% vs. 87%; p < 0.05), restricted P-STAT3 (p < 0.001), and preserved diaphragm size and specific force. JI was associated with preserved mitochondrial content and respiratory function (p < 0.01), and the reversal or augmentation of myosin deamidation PTMs of the rod and head region. Conclusion: JI preserved diaphragm function, leading to increased survival in an experimental model of VIDD. Functional enhancement was associated with maintenance of mitochondrial content and respiration and the reversal of ventilator-induced PTMs of myosin. These results demonstrate the potential of repurposing Ruxolitinib for treatment of VIDD.

Aim: Mechanical ventilation (MV) results in diminished diaphragm size and strength, termed ventilator-induced diaphragm dysfunction (VIDD). VID increases dependence, prolongs weaning, and increases discharge mortality rates. The Janus kinase (JAK)/Signal Transducer and Activator of Transcription (STAT) pathway is implicated in VIDD, upregulated following MV. JAK/STAT inhibition alleviates chronic muscle wasting conditions. This study aimed to explore the therapeutic potential of Ruxolitinib, an FDA approved JAK1/2 inhibitor (JI) for the treatment of VIDD. Methods: Rats were subjected to 5 days controlled MV (CMV) with and without daily Ruxolitinib gavage. Muscle fiber size and function were assessed. RNAseq, mitochondrial morphology, respirometry, and mass spectrometry were determined. Results: CMV significantly reduced diaphragm size and specific force by 45% (p < 0.01), associated with a two-fold P-STAT3 upregulation (p < 0.001). CMV disrupted mitochondrial content and reduced the oxygen consumption rate (p < 0.01). Expression of the motor protein myosin was unaffected, however CMV alters myosin function via post-translational modifications (PTMs). Daily administration of JI increased animal survival (40% vs. 87%; p < 0.05), restricted P-STAT3 (p < 0.001), and preserved diaphragm size and specific force. JI was associated with preserved mitochondrial content and respiratory function (p < 0.01), and the reversal or augmentation of myosin deamidation PTMs of the rod and head region. Conclusion: JI preserved diaphragm function, leading to increased survival in an experimental model of VIDD. Functional enhancement was associated with maintenance of mitochondrial content and respiration and the reversal of ventilator-induced PTMs of myosin. These results demonstrate the potential of repurposing Ruxolitinib for treatment of VIDD.

Amebic liver abscesses should be considered in adult males with a liver abscess and a history of travel to endemic areas. Effective treatment includes metronidazole, followed by paromomycin.

Utvecklingen och intresset för små modulära kärnkraftverk (SMR) har ökat det senaste årtiondet i flera länder i samband med målet att minska växthusgaser. Tack vare nya möjligheter att driva kärnkraftverk närmare konsumenten på grund av SMRs flexibla egenskaper blir det mer relevant att undersöka möjligheten att driva ett SMR som ett kärnkraftvärmeverk (KKVV) och koppla det till fjärrvärmenätet. Syftet med denna rapport är att undersöka om det är ekonomiskt lönsamt att driva ett SMR som KKVV gentemot som kärnkraftverk (KKV). De ekonomiska mätvärdena som undersöks i denna studie är nettonuvärde (NPV) och levelized cost of electricity (LCOE). En förenklad ångcykelmodell används för att kunna ta fram verkningsgraden på ett KKVV som följer Stockholms värmelast. Resultaten i denna rapport ger gynnsamma värden på LCOE och NPV för KKVVet vilket indikerar att det är mer lönsamt att driva ett SMR som KKVV än som KKV. Det ska dock tas hänsyn till att den elektriska verkningsgraden som fås från ångcykelmodellen är något lägre än i traditionella kärnkraftverk, samt att de uppskattade kostnaderna kan ha varit högre än i andra kraftverk., The development and interest in small modular nuclear reactors (SMRs) have increased in several countries over the past decade, in connection with the goal of reducing greenhouse gases. Thanks to new possibilities to operate nuclear power plants closer to consumers due to the flexible nature of SMRs, it becomes more relevant to explore the possibility of operating an SMR as a nuclear cogeneration plant (NCP) and connecting it to the district heating network. The purpose of this report is to investigate whether it is economically viable to operate an SMR as an NCP versus as a nuclear power plant (NPP). The financial metrics examined in this study are net present value (NPV) and levelized cost of electricity (LCOE). In the methodology, a simplified steam cycle was created to determine the power plant's efficiency, and a model of Stockholm's annual heat demand was developed. The results in this report present favorable values for LCOE and NPV for the NCP, indicating that it is more profitable to operate an SMR as an NCP than as an NPP. However, it should be taken into account that the electrical efficiency obtained from the steam cycle model is somewhat lower than those of traditional nuclear power plants, and that the estimated costs may have been higher than in other power plants.

Utvecklingen och intresset för små modulära kärnkraftverk (SMR) har ökat det senaste årtiondet i flera länder i samband med målet att minska växthusgaser. Tack vare nya möjligheter att driva kärnkraftverk närmare konsumenten på grund av SMRs flexibla egenskaper blir det mer relevant att undersöka möjligheten att driva ett SMR som ett kärnkraftvärmeverk (KKVV) och koppla det till fjärrvärmenätet. Syftet med denna rapport är att undersöka om det är ekonomiskt lönsamt att driva ett SMR som KKVV gentemot som kärnkraftverk (KKV). De ekonomiska mätvärdena som undersöks i denna studie är nettonuvärde (NPV) och levelized cost of electricity (LCOE). En förenklad ångcykelmodell används för att kunna ta fram verkningsgraden på ett KKVV som följer Stockholms värmelast. Resultaten i denna rapport ger gynnsamma värden på LCOE och NPV för KKVVet vilket indikerar att det är mer lönsamt att driva ett SMR som KKVV än som KKV. Det ska dock tas hänsyn till att den elektriska verkningsgraden som fås från ångcykelmodellen är något lägre än i traditionella kärnkraftverk, samt att de uppskattade kostnaderna kan ha varit högre än i andra kraftverk., The development and interest in small modular nuclear reactors (SMRs) have increased in several countries over the past decade, in connection with the goal of reducing greenhouse gases. Thanks to new possibilities to operate nuclear power plants closer to consumers due to the flexible nature of SMRs, it becomes more relevant to explore the possibility of operating an SMR as a nuclear cogeneration plant (NCP) and connecting it to the district heating network. The purpose of this report is to investigate whether it is economically viable to operate an SMR as an NCP versus as a nuclear power plant (NPP). The financial metrics examined in this study are net present value (NPV) and levelized cost of electricity (LCOE). In the methodology, a simplified steam cycle was created to determine the power plant's efficiency, and a model of Stockholm's annual heat demand was developed. The results in this report present favorable values for LCOE and NPV for the NCP, indicating that it is more profitable to operate an SMR as an NCP than as an NPP. However, it should be taken into account that the electrical efficiency obtained from the steam cycle model is somewhat lower than those of traditional nuclear power plants, and that the estimated costs may have been higher than in other power plants.

Referring to a story told by Cosmas Vestitor in his Life of St. John Chrysostom, Robert Browning, as well as a number of authors before him, inferred the existence of diglossia in the fourth century. We examine the story, and its predecessors to see what exactly they say.

Introduction: Emergency medicine is a developing specialty in low-to-middle income countries. The specialty was in its infancy in Syria when the war started a decade ago. Syria has since experienced civil war, unrest, famine, and financial collapse that has strained its healthcare system. There is limited research and information regarding Emergency Medicine residencies and training in Syria. Therefore, this article describes the growing and current state of Emergency Medicine and its training in Syria.Methods: A mixed methods approach using a systematic review and semi-structure interviews was utilized. MEDLINE, EMBASE and PsychINFO were searched from inception until March 9, 2022. Eligible studies were specific to emergency medicine and discussed the training of emergency medicine physicians in Syria. Semi-structured key informant interviews and a review of the Ministry of Health website were utilized to supplement information regarding the structure of emergency medicine residency in Syria.Results: Out of 252 unique citations identified, none described emergency medicine training in Syria. The most common articles identified were case reports (40), studies of mental health (34) and nicotine use (33). Public information from the Ministry of Health website was used to gather further information regarding the current state of healthcare in Syria; however, it provided little data specific to emergency medicine. Semi-structured interviews provided additional information regarding emergency medicine training in Syria. This revealed that prior to the 2011 onset of war, Syrian EM had begun to develop and included residency training, Arab Board certification and the establishment of a national specialist society. However, it also revealed, that in Syria, emergency medicine deteriorated much faster than other sectors of health care.Conclusion: As of now, Emergency Medicine remains in a very early phase of development as a field and medical specialty. It requires renewed co

Mechanical ventilation (MV), however brief results in the loss of diaphragm muscle mass and strength, termed ventilator induced diaphragm dysfunction (VIDD). VIDD increases dependence, complicates and prolongs weaning and significantly increases discharge mortality rate and health care costs worldwide. The Janus kinase (JAK)/Signal Transducer and Activator of Transcription (STAT) pathway was recently identified as an important signalling pathway implicated in VIDD, upregulated in the diaphragm following MV and limb muslces during critical care. Regulation of STAT3 is imperritve to skeletal muscle mass and function, as STAT3 is required in proper muscle growth and regeneration, while chronic activation of STAT3 is implicated in muscle dysfunction. As JAK/STAT pathway inhibition can restrict the development of chronic muscle wasting conditons, this study aimed to explore the therapeutic potential of Ruxolitinib, an approved JAK1/2 inhibitor for myelofibrosis, for treatment of CIM. We hypothesised Ruxolitinib would reduce loss of muscle mass and function associated with VIDD. Here, rats were subjected to five days controlled MV (CMV) with and without daily Ruxolitinib gavage. Five-days CMV significantly reduced diaphragm muscle size and impaired specific force, which was associated with 2-fold upregulation of P-STAT3, disrupted mitochondrial structure and respiratory function. Expression of the motor protein myosin was not affected, however CMV may alter myosin function through deamidation post translational modification. Ruxolitinib increases five-day survival rate, restored P-STAT3 expression and preserved diaphragm muscle size and specific force. These functional improvements were associated with improved mitochondrial structure, augmented mitochondrial respiratory function and reversal or augmentation of myosin deamidations. These results provide evidence of the preclinical potential of repurposing Ruxolitinib for the treatment of VIDD.

Questions about the nature of emotions and the role of emotional expressions have been addressed frequently in the study of the history of emotions. However, the extent to which emotional suffering is present in the cultures and societies of the past is seldom queried. Our first goal is to identify criteria that historians of emotions can use to evaluate the emotional suffering of the people they study. We locate these criteria not in the theory of emotions, whether Norbert Elias’s psychoanalytic theory or William M. Reddy’s theory of emotives, but in the theory of basic, universal human needs proposed by Richard M. Ryan and Edward L. Deci. Although we agree with most contemporary historians of emotions that emotions themselves can be understood only within the context of a particular culture, we propose that additional inquiry into basic needs and their satisfaction could help historians of emotions cast more light on the inner lives of the members of the societies they investigate. Our second goal is to apply these insights to the case of acedia, a peculiar psychological state experienced by the Desert Fathers. We examine what acedia was for the Desert Fathers by analyzing Evagrius’s writings. Our goal here is to capture what historians of emotions regularly do; that is, we aim to reconstruct how monks of the fourth century felt, expressed, and thought about emotions from within their own monastic culture. In addition, we analyze acedia from the perspective of the theory of needs. In this way, we hope to show how the theory of needs can help historians in their endeavors to understand the past.

Para que puedan participar en el mundo académico y se les tenga en cuenta como académicos por derecho propio, y no solo en su calidad de académicos desplazados, es necesario que reciban apoyo a varios niveles.

Our ability to explore the cosmos by direct contact has been limited to a small number of lunar and interplanetary missions. However, the NASA Starlight program points a path forward to send small, relativistic spacecraft far outside our solar system via standoff directed-energy propulsion. These miniaturized spacecraft are capable of robotic exploration but can also transport seeds and organisms, marking a profound change in our ability to both characterize and expand the reach of known life. Here we explore the biological and technological challenges of interstellar space biology, focusing on radiation-tolerant microorganisms capable of cryptobiosis. Additionally, we discuss planetary protection concerns and other ethical considerations of sending life to the stars., Comment: 17 pages, 3 figures

A logo is a vital part of any company’s visual identity. The following report exploreshow logo design got affected by the recent age of digitalization. The report helpsoutline essential parts of successful logo design for current and future mediums. Sincecompanies want to hire designers or agencies who work based on research andsuccessful methods, this study helps create a generalization of good logo design that iseasy to implement. Our research confirms the notion that design is a science and not an art, since logosare strong when they fulfill their intended purpose and follow specific guidelines.With the help of gathering both quantitative and qualitative data, we found out that theprimary change of logo design through digitalization was done because of the mediumof which the logos lived. The specific elements that changed were that logos nowfocus more on logo marks and have solid and memorable colours. Further, we sawthat logos had to be distinct and unique to work in the overly saturated digital market.At the same time, logos had to be responsive and have the ability to be showcased in asimple way for it to be ready for any medium it could be thrown against. By analyzing some of the most successful logos of all time such as Apple, Adidas,and Nike this report gets an understanding of the part their logo had in making theirbrands successful. Which is also complemented by insightful interviews with industryprofessional designers who helped develop logos and brands for companies such asBurger King, Netflix, and Audi. All this together helped outline a valid understandingof what makes a good logo for the digital age.

A logo is a vital part of any company’s visual identity. The following report exploreshow logo design got affected by the recent age of digitalization. The report helpsoutline essential parts of successful logo design for current and future mediums. Sincecompanies want to hire designers or agencies who work based on research andsuccessful methods, this study helps create a generalization of good logo design that iseasy to implement. Our research confirms the notion that design is a science and not an art, since logosare strong when they fulfill their intended purpose and follow specific guidelines.With the help of gathering both quantitative and qualitative data, we found out that theprimary change of logo design through digitalization was done because of the mediumof which the logos lived. The specific elements that changed were that logos nowfocus more on logo marks and have solid and memorable colours. Further, we sawthat logos had to be distinct and unique to work in the overly saturated digital market.At the same time, logos had to be responsive and have the ability to be showcased in asimple way for it to be ready for any medium it could be thrown against. By analyzing some of the most successful logos of all time such as Apple, Adidas,and Nike this report gets an understanding of the part their logo had in making theirbrands successful. Which is also complemented by insightful interviews with industryprofessional designers who helped develop logos and brands for companies such asBurger King, Netflix, and Audi. All this together helped outline a valid understandingof what makes a good logo for the digital age.

Our ability to explore the cosmos by direct contact has been limited to a small number of lunar and interplanetary missions. However, the NASA Starlight program points a path forward to send small, relativistic spacecraft far outside our solar system via standoff directed-energy propulsion. These miniaturized spacecraft are capable of robotic exploration but can also transport seeds and organisms, marking a profound change in our ability to both characterize and expand the reach of known life. Here we explore the biological and technological challenges of interstellar space biology, focusing on radiation-tolerant microorganisms capable of cryptobiosis. Additionally, we discuss planetary protection concerns and other ethical considerations of sending life to the stars., Comment: 17 pages, 3 figures

© Wang et al. Learning reduces variability but variability can facilitate learning. This paradoxical relationship has made it challenging to tease apart sources of variability that degrade performance from those that improve it. We tackled this question in a context-dependent timing task requiring humans and monkeys to flexibly produce different time intervals with different effectors. We identified two opposing factors contributing to timing variability: Slow memory fluctuation that degrades performance and reward-dependent exploratory behavior that improves performance. Signatures of these opposing factors were evident across populations of neurons in the dorsomedial frontal cortex (DMFC), DMFC-projecting neurons in the ventrolateral thalamus, and putative target of DMFC in the caudate. However, only in the thalamus were the performanceoptimizing regulation of variability aligned to the slow performance-degrading memory fluctuations. These findings reveal how variability caused by exploratory behavior might help to mitigate other undesirable sources of variability and highlight a potential role for thalamocortical projections in this process.

Nomos Georgikos is an invaluable resource for the study of the Greek language in one of the periods in which its colloquial registers are less well documented. It deals with the areas of everyday life which are rarely touched upon by the more literary composition. Moreover, there are numerous rare forms and usages, rarely, or even never, found in other works. Some have descendants in the Modern Greek, and even those which do not, can be reasonably assumed to have been a part of the more colloquial registers.

Aim Critical illness myopathy (CIM) represents a common consequence of modern intensive care, negatively impacting patient health and significantly increasing health care costs; however, there is no treatment available apart from symptomatic and supportive interventions. The chaperone co-inducer BGP-15 has previously been shown to have a positive effect on the diaphragm in rats exposed to the intensive care unit (ICU) condition. In this study, we aim to explore the effects of BGP-15 on a limb muscle (soleus muscle) in response to the ICU condition. Methods Sprague-Dawley rats were subjected to the ICU condition for 5, 8 and 10 days and compared with untreated sham-operated controls. Results BGP-15 significantly improved soleus muscle fibre force after 5 days exposure to the ICU condition. This improvement was associated with the protection of myosin from post-translational myosin modifications, improved mitochondrial structure/biogenesis and reduced the expression of MuRF1 and Fbxo31 E3 ligases. At longer durations (8 and 10 days), BGP-15 had no protective effect when the hallmark of CIM had become manifest, that is, preferential loss of myosin. Unrelated to the effects on skeletal muscle, BGP-15 had a strong positive effect on survival compared with untreated animals. Conclusions BGP-15 treatment improved soleus muscle fibre and motor protein function after 5 days exposure to the ICU condition, but not at longer durations (8 and 10 days) when the preferential loss of myosin was manifest. Thus, long-term CIM interventions targeting limb muscle fibre/myosin force generation capacity need to consider both the post-translational modifications and the loss of myosin.

Aim Critical illness myopathy (CIM) represents a common consequence of modern intensive care, negatively impacting patient health and significantly increasing health care costs; however, there is no treatment available apart from symptomatic and supportive interventions. The chaperone co-inducer BGP-15 has previously been shown to have a positive effect on the diaphragm in rats exposed to the intensive care unit (ICU) condition. In this study, we aim to explore the effects of BGP-15 on a limb muscle (soleus muscle) in response to the ICU condition. Methods Sprague-Dawley rats were subjected to the ICU condition for 5, 8 and 10 days and compared with untreated sham-operated controls. Results BGP-15 significantly improved soleus muscle fibre force after 5 days exposure to the ICU condition. This improvement was associated with the protection of myosin from post-translational myosin modifications, improved mitochondrial structure/biogenesis and reduced the expression of MuRF1 and Fbxo31 E3 ligases. At longer durations (8 and 10 days), BGP-15 had no protective effect when the hallmark of CIM had become manifest, that is, preferential loss of myosin. Unrelated to the effects on skeletal muscle, BGP-15 had a strong positive effect on survival compared with untreated animals. Conclusions BGP-15 treatment improved soleus muscle fibre and motor protein function after 5 days exposure to the ICU condition, but not at longer durations (8 and 10 days) when the preferential loss of myosin was manifest. Thus, long-term CIM interventions targeting limb muscle fibre/myosin force generation capacity need to consider both the post-translational modifications and the loss of myosin.

Aim Critical illness myopathy (CIM) represents a common consequence of modern intensive care, negatively impacting patient health and significantly increasing health care costs; however, there is no treatment available apart from symptomatic and supportive interventions. The chaperone co-inducer BGP-15 has previously been shown to have a positive effect on the diaphragm in rats exposed to the intensive care unit (ICU) condition. In this study, we aim to explore the effects of BGP-15 on a limb muscle (soleus muscle) in response to the ICU condition. Methods Sprague-Dawley rats were subjected to the ICU condition for 5, 8 and 10 days and compared with untreated sham-operated controls. Results BGP-15 significantly improved soleus muscle fibre force after 5 days exposure to the ICU condition. This improvement was associated with the protection of myosin from post-translational myosin modifications, improved mitochondrial structure/biogenesis and reduced the expression of MuRF1 and Fbxo31 E3 ligases. At longer durations (8 and 10 days), BGP-15 had no protective effect when the hallmark of CIM had become manifest, that is, preferential loss of myosin. Unrelated to the effects on skeletal muscle, BGP-15 had a strong positive effect on survival compared with untreated animals. Conclusions BGP-15 treatment improved soleus muscle fibre and motor protein function after 5 days exposure to the ICU condition, but not at longer durations (8 and 10 days) when the preferential loss of myosin was manifest. Thus, long-term CIM interventions targeting limb muscle fibre/myosin force generation capacity need to consider both the post-translational modifications and the loss of myosin.

Supplemental Digital Content is available in the text.

A growing body of evidence suggests that the regular use of non-steroidal anti-inflammatory drugs (NSAIDs), especially aspirin, is associated with a reduced risk of many types of cancer including colorectal, breast, and prostate malignancies. It has also been shown that they might be beneficial in reducing metastasis and lengthening remission periods. However, the prolonged exposure to this class of drugs does not come without a cost as it carries with it the risk of augmenting the serious side effects of NSAIDs. These include haemorrhages, increased bleeding time, peptic ulcers, and hypersensitivity, to name a few. This work aimed at employing the principles of nanotherapy to maximise the benefits of NSAIDs and minimise the risks of their harmful side effects. By exploiting the enhanced permeability and retention effect (EPR) unique to inflammatory tissues, NSAID-loaded nanocarriers could deliver high concentrations of the drugs to cancer tissue, compared to conventional therapy, while reducing the systemic exposure to their effects.

Aim Critical illness myopathy (CIM) represents a common consequence of modern intensive care, negatively impacting patient health and significantly increasing health care costs; however, there is no treatment available apart from symptomatic and supportive interventions. The chaperone co-inducer BGP-15 has previously been shown to have a positive effect on the diaphragm in rats exposed to the intensive care unit (ICU) condition. In this study, we aim to explore the effects of BGP-15 on a limb muscle (soleus muscle) in response to the ICU condition. Methods Sprague-Dawley rats were subjected to the ICU condition for 5, 8 and 10 days and compared with untreated sham-operated controls. Results BGP-15 significantly improved soleus muscle fibre force after 5 days exposure to the ICU condition. This improvement was associated with the protection of myosin from post-translational myosin modifications, improved mitochondrial structure/biogenesis and reduced the expression of MuRF1 and Fbxo31 E3 ligases. At longer durations (8 and 10 days), BGP-15 had no protective effect when the hallmark of CIM had become manifest, that is, preferential loss of myosin. Unrelated to the effects on skeletal muscle, BGP-15 had a strong positive effect on survival compared with untreated animals. Conclusions BGP-15 treatment improved soleus muscle fibre and motor protein function after 5 days exposure to the ICU condition, but not at longer durations (8 and 10 days) when the preferential loss of myosin was manifest. Thus, long-term CIM interventions targeting limb muscle fibre/myosin force generation capacity need to consider both the post-translational modifications and the loss of myosin.

Aim Critical illness myopathy (CIM) represents a common consequence of modern intensive care, negatively impacting patient health and significantly increasing health care costs; however, there is no treatment available apart from symptomatic and supportive interventions. The chaperone co-inducer BGP-15 has previously been shown to have a positive effect on the diaphragm in rats exposed to the intensive care unit (ICU) condition. In this study, we aim to explore the effects of BGP-15 on a limb muscle (soleus muscle) in response to the ICU condition. Methods Sprague-Dawley rats were subjected to the ICU condition for 5, 8 and 10 days and compared with untreated sham-operated controls. Results BGP-15 significantly improved soleus muscle fibre force after 5 days exposure to the ICU condition. This improvement was associated with the protection of myosin from post-translational myosin modifications, improved mitochondrial structure/biogenesis and reduced the expression of MuRF1 and Fbxo31 E3 ligases. At longer durations (8 and 10 days), BGP-15 had no protective effect when the hallmark of CIM had become manifest, that is, preferential loss of myosin. Unrelated to the effects on skeletal muscle, BGP-15 had a strong positive effect on survival compared with untreated animals. Conclusions BGP-15 treatment improved soleus muscle fibre and motor protein function after 5 days exposure to the ICU condition, but not at longer durations (8 and 10 days) when the preferential loss of myosin was manifest. Thus, long-term CIM interventions targeting limb muscle fibre/myosin force generation capacity need to consider both the post-translational modifications and the loss of myosin.

Aim Critical illness myopathy (CIM) represents a common consequence of modern intensive care, negatively impacting patient health and significantly increasing health care costs; however, there is no treatment available apart from symptomatic and supportive interventions. The chaperone co-inducer BGP-15 has previously been shown to have a positive effect on the diaphragm in rats exposed to the intensive care unit (ICU) condition. In this study, we aim to explore the effects of BGP-15 on a limb muscle (soleus muscle) in response to the ICU condition. Methods Sprague-Dawley rats were subjected to the ICU condition for 5, 8 and 10 days and compared with untreated sham-operated controls. Results BGP-15 significantly improved soleus muscle fibre force after 5 days exposure to the ICU condition. This improvement was associated with the protection of myosin from post-translational myosin modifications, improved mitochondrial structure/biogenesis and reduced the expression of MuRF1 and Fbxo31 E3 ligases. At longer durations (8 and 10 days), BGP-15 had no protective effect when the hallmark of CIM had become manifest, that is, preferential loss of myosin. Unrelated to the effects on skeletal muscle, BGP-15 had a strong positive effect on survival compared with untreated animals. Conclusions BGP-15 treatment improved soleus muscle fibre and motor protein function after 5 days exposure to the ICU condition, but not at longer durations (8 and 10 days) when the preferential loss of myosin was manifest. Thus, long-term CIM interventions targeting limb muscle fibre/myosin force generation capacity need to consider both the post-translational modifications and the loss of myosin.

Background: Sleep is considered to be very important for cognitive function and also cognitive deficits and sleep disorders are influenced by one another. Currently, growing evidence suggests that sleep disturbances is common in vascular dementia (VaD). Study Objectives: The goal of the current study was to assess the disturbance in sleep pattern in patients with vascular dementia(VaD) and compare it to healthy normally cognitive elderly individuals. The study further investigated whether meaningful differences in the Subjective sleep assessment (ESS and PSQI) and sleep measurements (PSG) in VaD patients. Study Design/Method: Overnight PSG recordings and self-reported sleep measures were obtained from 20 healthy elderly subjects and 20 VaD patients at the sleep laboratory. Results: This study showed abnormal subjective sleep quality in all patients and revealed that the most common sleep complaintsamong VaD patients were excessive daytime sleepiness (EDS), sleep disordered breathing (SDB), insomnia and RLS and PLMS and REM behavioral disordered, respectively. Moreover, patients spent more time in stage I sleep, but less time in SWS and REM sleep compared to control populations, with delayed REML and less 1st REML. In addition, increased sleep fragmentation (WASO and SFI) and increased AI and PLMS index were detected in VaD patients. Finally, VaD patients had significantly (p < 0.05) high apnea, hypopnea and RDI score with high average SpO2 desaturation. Conclusions: It is conclude that sleep is significantly (p < 0.05) impaired in patients with VaD at both the objective and subjective levels which may be used as a diagnostic marker of VaD. SBD is a common feature of VaD leading to fragmented sleep, increased nocturnal confusion and excessive daytime sleepiness. Subjective sleep assessment questionnaire by (ESS and PSQI) can be used in VaD patients when objective sleep assessment by PSG recordings is difficult to be done. The PSG study of sleep continuity, sleep arch

Background: Sleep is considered to be very important for cognitive function and also cognitive deficits and sleep disorders are influenced by one another. Currently, growing evidence suggests that sleep disturbances is common in vascular dementia (VaD). Study Objectives: The goal of the current study was to assess the disturbance in sleep pattern in patients with vascular dementia(VaD) and compare it to healthy normally cognitive elderly individuals. The study further investigated whether meaningful differences in the Subjective sleep assessment (ESS and PSQI) and sleep measurements (PSG) in VaD patients. Study Design/Method: Overnight PSG recordings and self-reported sleep measures were obtained from 20 healthy elderly subjects and 20 VaD patients at the sleep laboratory. Results: This study showed abnormal subjective sleep quality in all patients and revealed that the most common sleep complaintsamong VaD patients were excessive daytime sleepiness (EDS), sleep disordered breathing (SDB), insomnia and RLS and PLMS and REM behavioral disordered, respectively. Moreover, patients spent more time in stage I sleep, but less time in SWS and REM sleep compared to control populations, with delayed REML and less 1st REML. In addition, increased sleep fragmentation (WASO and SFI) and increased AI and PLMS index were detected in VaD patients. Finally, VaD patients had significantly (p < 0.05) high apnea, hypopnea and RDI score with high average SpO2 desaturation. Conclusions: It is conclude that sleep is significantly (p < 0.05) impaired in patients with VaD at both the objective and subjective levels which may be used as a diagnostic marker of VaD. SBD is a common feature of VaD leading to fragmented sleep, increased nocturnal confusion and excessive daytime sleepiness. Subjective sleep assessment questionnaire by (ESS and PSQI) can be used in VaD patients when objective sleep assessment by PSG recordings is difficult to be done. The PSG study of sleep continuity, sleep arch

Background: Sleep is considered to be very important for cognitive function and also cognitive deficits and sleep disorders are influenced by one another. Currently, growing evidence suggests that sleep disturbances is common in vascular dementia (VaD). Study Objectives: The goal of the current study was to assess the disturbance in sleep pattern in patients with vascular dementia(VaD) and compare it to healthy normally cognitive elderly individuals. The study further investigated whether meaningful differences in the Subjective sleep assessment (ESS and PSQI) and sleep measurements (PSG) in VaD patients. Study Design/Method: Overnight PSG recordings and self-reported sleep measures were obtained from 20 healthy elderly subjects and 20 VaD patients at the sleep laboratory. Results: This study showed abnormal subjective sleep quality in all patients and revealed that the most common sleep complaintsamong VaD patients were excessive daytime sleepiness (EDS), sleep disordered breathing (SDB), insomnia and RLS and PLMS and REM behavioral disordered, respectively. Moreover, patients spent more time in stage I sleep, but less time in SWS and REM sleep compared to control populations, with delayed REML and less 1st REML. In addition, increased sleep fragmentation (WASO and SFI) and increased AI and PLMS index were detected in VaD patients. Finally, VaD patients had significantly (p < 0.05) high apnea, hypopnea and RDI score with high average SpO2 desaturation. Conclusions: It is conclude that sleep is significantly (p < 0.05) impaired in patients with VaD at both the objective and subjective levels which may be used as a diagnostic marker of VaD. SBD is a common feature of VaD leading to fragmented sleep, increased nocturnal confusion and excessive daytime sleepiness. Subjective sleep assessment questionnaire by (ESS and PSQI) can be used in VaD patients when objective sleep assessment by PSG recordings is difficult to be done. The PSG study of sleep continuity, sleep arch

Background: Sleep is considered to be very important for cognitive function and also cognitive deficits and sleep disorders are influenced by one another. Currently, growing evidence suggests that sleep disturbances is common in vascular dementia (VaD). Study Objectives: The goal of the current study was to assess the disturbance in sleep pattern in patients with vascular dementia(VaD) and compare it to healthy normally cognitive elderly individuals. The study further investigated whether meaningful differences in the Subjective sleep assessment (ESS and PSQI) and sleep measurements (PSG) in VaD patients. Study Design/Method: Overnight PSG recordings and self-reported sleep measures were obtained from 20 healthy elderly subjects and 20 VaD patients at the sleep laboratory. Results: This study showed abnormal subjective sleep quality in all patients and revealed that the most common sleep complaintsamong VaD patients were excessive daytime sleepiness (EDS), sleep disordered breathing (SDB), insomnia and RLS and PLMS and REM behavioral disordered, respectively. Moreover, patients spent more time in stage I sleep, but less time in SWS and REM sleep compared to control populations, with delayed REML and less 1st REML. In addition, increased sleep fragmentation (WASO and SFI) and increased AI and PLMS index were detected in VaD patients. Finally, VaD patients had significantly (p < 0.05) high apnea, hypopnea and RDI score with high average SpO2 desaturation. Conclusions: It is conclude that sleep is significantly (p < 0.05) impaired in patients with VaD at both the objective and subjective levels which may be used as a diagnostic marker of VaD. SBD is a common feature of VaD leading to fragmented sleep, increased nocturnal confusion and excessive daytime sleepiness. Subjective sleep assessment questionnaire by (ESS and PSQI) can be used in VaD patients when objective sleep assessment by PSG recordings is difficult to be done. The PSG study of sleep continuity, sleep arch

Background: Sleep is considered to be very important for cognitive function and also cognitive deficits and sleep disorders are influenced by one another. Currently, growing evidence suggests that sleep disturbances is common in vascular dementia (VaD). Study Objectives: The goal of the current study was to assess the disturbance in sleep pattern in patients with vascular dementia(VaD) and compare it to healthy normally cognitive elderly individuals. The study further investigated whether meaningful differences in the Subjective sleep assessment (ESS and PSQI) and sleep measurements (PSG) in VaD patients. Study Design/Method: Overnight PSG recordings and self-reported sleep measures were obtained from 20 healthy elderly subjects and 20 VaD patients at the sleep laboratory. Results: This study showed abnormal subjective sleep quality in all patients and revealed that the most common sleep complaintsamong VaD patients were excessive daytime sleepiness (EDS), sleep disordered breathing (SDB), insomnia and RLS and PLMS and REM behavioral disordered, respectively. Moreover, patients spent more time in stage I sleep, but less time in SWS and REM sleep compared to control populations, with delayed REML and less 1st REML. In addition, increased sleep fragmentation (WASO and SFI) and increased AI and PLMS index were detected in VaD patients. Finally, VaD patients had significantly (p < 0.05) high apnea, hypopnea and RDI score with high average SpO2 desaturation. Conclusions: It is conclude that sleep is significantly (p < 0.05) impaired in patients with VaD at both the objective and subjective levels which may be used as a diagnostic marker of VaD. SBD is a common feature of VaD leading to fragmented sleep, increased nocturnal confusion and excessive daytime sleepiness. Subjective sleep assessment questionnaire by (ESS and PSQI) can be used in VaD patients when objective sleep assessment by PSG recordings is difficult to be done. The PSG study of sleep continuity, sleep arch

Background: Sleep is considered to be very important for cognitive function and also cognitive deficits and sleep disorders are influenced by one another. Currently, growing evidence suggests that sleep disturbances is common in vascular dementia (VaD). Study Objectives: The goal of the current study was to assess the disturbance in sleep pattern in patients with vascular dementia(VaD) and compare it to healthy normally cognitive elderly individuals. The study further investigated whether meaningful differences in the Subjective sleep assessment (ESS and PSQI) and sleep measurements (PSG) in VaD patients. Study Design/Method: Overnight PSG recordings and self-reported sleep measures were obtained from 20 healthy elderly subjects and 20 VaD patients at the sleep laboratory. Results: This study showed abnormal subjective sleep quality in all patients and revealed that the most common sleep complaintsamong VaD patients were excessive daytime sleepiness (EDS), sleep disordered breathing (SDB), insomnia and RLS and PLMS and REM behavioral disordered, respectively. Moreover, patients spent more time in stage I sleep, but less time in SWS and REM sleep compared to control populations, with delayed REML and less 1st REML. In addition, increased sleep fragmentation (WASO and SFI) and increased AI and PLMS index were detected in VaD patients. Finally, VaD patients had significantly (p < 0.05) high apnea, hypopnea and RDI score with high average SpO2 desaturation. Conclusions: It is conclude that sleep is significantly (p < 0.05) impaired in patients with VaD at both the objective and subjective levels which may be used as a diagnostic marker of VaD. SBD is a common feature of VaD leading to fragmented sleep, increased nocturnal confusion and excessive daytime sleepiness. Subjective sleep assessment questionnaire by (ESS and PSQI) can be used in VaD patients when objective sleep assessment by PSG recordings is difficult to be done. The PSG study of sleep continuity, sleep arch

The human body typically contains over 600 skeletal muscles that make up about 40% of total body weight. These muscles work together to perform functions such as locomotion, breathing, mastication, heat regulation and speech. Skeletal muscles can change their size and protein content in response to endogenous or exogenous signals, including physical, neural or chemical ones. Critically ill patients, usually treated intensively, are prone to developing a condition of muscle wasting and paralysis, called critical illness myopathy (CIM), where limb and truck muscles suffer severe atrophy and loss of force production capacity coupled with a preferential myosin loss, but craniofacial muscles remain less affected. Triggers of CIM are thought to be the exposure to the intensive care unit (ICU) interventions per se, such as unloading, mechanical ventilation (MV) and high doses of certain drugs such as muscle relaxants and glucocorticoids (GCs). The rapidly compromised diaphragm function due to the impact of the ventilator has been given a specific name, ventilator induced diaphragm dysfunction (VIDD). CIM and VIDD have dire consequences and research into their underlying mechanisms is urgently needed. This research is inherently difficult in patients and thus suitable animal models mimicking the ICU condition must be implemented. In this thesis, we used a pig and a rat ICU models with extended periods of immobilization, deep sedation and MV, in which we used different analyses to understand the muscle specific mechanistic differences of the masticatory, limb and the diaphragm muscles. In addition, we explored the effects of two new drugs on skeletal muscles: BGP-15, a chaperone co-inducer and vamorolone, a first-in-class dissociative GC. In paper I, we report that a 5-day GC treatment in the pig ICU model induces numerous transcriptional changes that affect myofiber function in a limb muscle. In paper II, we conclude that the masseter, the main masticatory muscle, is partia

The human body typically contains over 600 skeletal muscles that make up about 40% of total body weight. These muscles work together to perform functions such as locomotion, breathing, mastication, heat regulation and speech. Skeletal muscles can change their size and protein content in response to endogenous or exogenous signals, including physical, neural or chemical ones. Critically ill patients, usually treated intensively, are prone to developing a condition of muscle wasting and paralysis, called critical illness myopathy (CIM), where limb and truck muscles suffer severe atrophy and loss of force production capacity coupled with a preferential myosin loss, but craniofacial muscles remain less affected. Triggers of CIM are thought to be the exposure to the intensive care unit (ICU) interventions per se, such as unloading, mechanical ventilation (MV) and high doses of certain drugs such as muscle relaxants and glucocorticoids (GCs). The rapidly compromised diaphragm function due to the impact of the ventilator has been given a specific name, ventilator induced diaphragm dysfunction (VIDD). CIM and VIDD have dire consequences and research into their underlying mechanisms is urgently needed. This research is inherently difficult in patients and thus suitable animal models mimicking the ICU condition must be implemented. In this thesis, we used a pig and a rat ICU models with extended periods of immobilization, deep sedation and MV, in which we used different analyses to understand the muscle specific mechanistic differences of the masticatory, limb and the diaphragm muscles. In addition, we explored the effects of two new drugs on skeletal muscles: BGP-15, a chaperone co-inducer and vamorolone, a first-in-class dissociative GC. In paper I, we report that a 5-day GC treatment in the pig ICU model induces numerous transcriptional changes that affect myofiber function in a limb muscle. In paper II, we conclude that the masseter, the main masticatory muscle, is partia

The human body typically contains over 600 skeletal muscles that make up about 40% of total body weight. These muscles work together to perform functions such as locomotion, breathing, mastication, heat regulation and speech. Skeletal muscles can change their size and protein content in response to endogenous or exogenous signals, including physical, neural or chemical ones. Critically ill patients, usually treated intensively, are prone to developing a condition of muscle wasting and paralysis, called critical illness myopathy (CIM), where limb and truck muscles suffer severe atrophy and loss of force production capacity coupled with a preferential myosin loss, but craniofacial muscles remain less affected. Triggers of CIM are thought to be the exposure to the intensive care unit (ICU) interventions per se, such as unloading, mechanical ventilation (MV) and high doses of certain drugs such as muscle relaxants and glucocorticoids (GCs). The rapidly compromised diaphragm function due to the impact of the ventilator has been given a specific name, ventilator induced diaphragm dysfunction (VIDD). CIM and VIDD have dire consequences and research into their underlying mechanisms is urgently needed. This research is inherently difficult in patients and thus suitable animal models mimicking the ICU condition must be implemented. In this thesis, we used a pig and a rat ICU models with extended periods of immobilization, deep sedation and MV, in which we used different analyses to understand the muscle specific mechanistic differences of the masticatory, limb and the diaphragm muscles. In addition, we explored the effects of two new drugs on skeletal muscles: BGP-15, a chaperone co-inducer and vamorolone, a first-in-class dissociative GC. In paper I, we report that a 5-day GC treatment in the pig ICU model induces numerous transcriptional changes that affect myofiber function in a limb muscle. In paper II, we conclude that the masseter, the main masticatory muscle, is partia

Докторска дисертација Слово ,,О светим и часним иконама“: Прилог проучавању историјата грчког текста и његових српскословенских превода, заснована је на палеографској, текстолошкој и књижевноисторијској анализи средњегрчких и српскословенских споменика из периода од IX до XVII века. Основни циљ ове студије био је да се изменом застарелих метода у анализи расположивог корпуса направи што прецизнија реконструкција историјата овог иконофилског извора из VIII века, погрешно приписаног Јовану Дамаскину. Ревизијом текстолошких анализа Бориса Михајловича Мелиоранског, тачније, сагледавањем обимне филолошке грађе из књижевноисторијске перспективе, оповргнута је теорија из 1901. године да је аутор беседе, по свој прилици, јерусалимски синђел Јован, прерађивао одломке из извора Поуке старца о светим иконама (Nouthesia Gerontos). Уместо тога, анализом садржаја указано је на беседу као на предање ,,отвореног типа“ које стоји у вези са Синодиком православља и другим црквено-правним документима актуалним у доба политичког зближавања трију оријенталних патријаршија и Свете столице. Процењује се да је ауторски запис О светим и часним иконама (Adversus Constantinum Caballinum), осведочен у преписима Vat. gr. 1652 и Synod. gr. 293, настао око 768. године, док анализе специфичних цитата откривају његову оријенталну провенијенцију. Старије предање (МПТ 522, Synod. gr. 265, Synod. gr. 413, Synod. gr. 293, Auct. T. 3. 12, Marc. gr. Z 575, Paris. gr. 900, Paris. gr. 1115, Mt. Sinai 1699 и Vat. gr. 1652) било је пренето с источних рубова Медитерана у Рим и развијало се нагло у периоду између 768. и 775. године, што се поклапа са кризом око икона и политичким удаљавањем Константина V од франачког краља и папе..., Doctoral dissertation Sermon “On holy and honorable icons": Contribution to the study of the history of the Greek text and its Old Church Slavonic translations, based on palaeographic, textual and history of literature analysis of Middle Greek and Old Church Slavonic transcriptions from the period of the ninth century up to the seventeenth century. The main objective of this study is to make more accurate reconstruction of the textual history of this VIII century iconophile source, wrongly attributed to John of Damascus, by changing the obsolete methods in the analysis of the preserved corpus. Revising the textual history reconstruction made by Boris Mikhailovich Melioranski, namely, reviewing the extensive philological material from historical and literary perspective, we refuted the theory of 1901 that the author of the words, presumably John of Jerusalem, fabricated the excerpts from sources Admonition of the Old Man Concerning the Holy Images (the Nouthesia Gerontos). Instead of this, analizing the content we pointed out that the sermon On holy and honorable icons might be an open type traditon genealogically close to the Synodikon of Orthodoxy and other Church Legal Documents, simultaneous to the three Oriental patriarchs approaching the to the Holy See. It is estimated that Adversus Constantinum Caballinum original, witnessed by the manuscripts Vat. gr. 1652 and the Synod. gr. 293, can be dated back to around 768, while the analysis of specific quotations reveals its oriental provenance. Older tradition (MПТ 522, Synod. gr 265, Synod. gr. 413, Synod. gr. 293, Auct. T. 3. 12 , Marc. gr. Z 575, Paris. gr. 900, Paris. gr. 1115 Mt. Sinai 1699 and Vat. gr. 1652) was transferred from the eastern edge of the Mediterranean to Rome and developed rapidly in the period between 768 and 775 years, which coincides with the crisis around the icon and political removal of Constantine V by the Frankish king and the Pope...

The human body typically contains over 600 skeletal muscles that make up about 40% of total body weight. These muscles work together to perform functions such as locomotion, breathing, mastication, heat regulation and speech. Skeletal muscles can change their size and protein content in response to endogenous or exogenous signals, including physical, neural or chemical ones. Critically ill patients, usually treated intensively, are prone to developing a condition of muscle wasting and paralysis, called critical illness myopathy (CIM), where limb and truck muscles suffer severe atrophy and loss of force production capacity coupled with a preferential myosin loss, but craniofacial muscles remain less affected. Triggers of CIM are thought to be the exposure to the intensive care unit (ICU) interventions per se, such as unloading, mechanical ventilation (MV) and high doses of certain drugs such as muscle relaxants and glucocorticoids (GCs). The rapidly compromised diaphragm function due to the impact of the ventilator has been given a specific name, ventilator induced diaphragm dysfunction (VIDD). CIM and VIDD have dire consequences and research into their underlying mechanisms is urgently needed. This research is inherently difficult in patients and thus suitable animal models mimicking the ICU condition must be implemented. In this thesis, we used a pig and a rat ICU models with extended periods of immobilization, deep sedation and MV, in which we used different analyses to understand the muscle specific mechanistic differences of the masticatory, limb and the diaphragm muscles. In addition, we explored the effects of two new drugs on skeletal muscles: BGP-15, a chaperone co-inducer and vamorolone, a first-in-class dissociative GC. In paper I, we report that a 5-day GC treatment in the pig ICU model induces numerous transcriptional changes that affect myofiber function in a limb muscle. In paper II, we conclude that the masseter, the main masticatory muscle, is partia

The human body typically contains over 600 skeletal muscles that make up about 40% of total body weight. These muscles work together to perform functions such as locomotion, breathing, mastication, heat regulation and speech. Skeletal muscles can change their size and protein content in response to endogenous or exogenous signals, including physical, neural or chemical ones. Critically ill patients, usually treated intensively, are prone to developing a condition of muscle wasting and paralysis, called critical illness myopathy (CIM), where limb and truck muscles suffer severe atrophy and loss of force production capacity coupled with a preferential myosin loss, but craniofacial muscles remain less affected. Triggers of CIM are thought to be the exposure to the intensive care unit (ICU) interventions per se, such as unloading, mechanical ventilation (MV) and high doses of certain drugs such as muscle relaxants and glucocorticoids (GCs). The rapidly compromised diaphragm function due to the impact of the ventilator has been given a specific name, ventilator induced diaphragm dysfunction (VIDD). CIM and VIDD have dire consequences and research into their underlying mechanisms is urgently needed. This research is inherently difficult in patients and thus suitable animal models mimicking the ICU condition must be implemented. In this thesis, we used a pig and a rat ICU models with extended periods of immobilization, deep sedation and MV, in which we used different analyses to understand the muscle specific mechanistic differences of the masticatory, limb and the diaphragm muscles. In addition, we explored the effects of two new drugs on skeletal muscles: BGP-15, a chaperone co-inducer and vamorolone, a first-in-class dissociative GC. In paper I, we report that a 5-day GC treatment in the pig ICU model induces numerous transcriptional changes that affect myofiber function in a limb muscle. In paper II, we conclude that the masseter, the main masticatory muscle, is partia

The human body typically contains over 600 skeletal muscles that make up about 40% of total body weight. These muscles work together to perform functions such as locomotion, breathing, mastication, heat regulation and speech. Skeletal muscles can change their size and protein content in response to endogenous or exogenous signals, including physical, neural or chemical ones. Critically ill patients, usually treated intensively, are prone to developing a condition of muscle wasting and paralysis, called critical illness myopathy (CIM), where limb and truck muscles suffer severe atrophy and loss of force production capacity coupled with a preferential myosin loss, but craniofacial muscles remain less affected. Triggers of CIM are thought to be the exposure to the intensive care unit (ICU) interventions per se, such as unloading, mechanical ventilation (MV) and high doses of certain drugs such as muscle relaxants and glucocorticoids (GCs). The rapidly compromised diaphragm function due to the impact of the ventilator has been given a specific name, ventilator induced diaphragm dysfunction (VIDD). CIM and VIDD have dire consequences and research into their underlying mechanisms is urgently needed. This research is inherently difficult in patients and thus suitable animal models mimicking the ICU condition must be implemented. In this thesis, we used a pig and a rat ICU models with extended periods of immobilization, deep sedation and MV, in which we used different analyses to understand the muscle specific mechanistic differences of the masticatory, limb and the diaphragm muscles. In addition, we explored the effects of two new drugs on skeletal muscles: BGP-15, a chaperone co-inducer and vamorolone, a first-in-class dissociative GC. In paper I, we report that a 5-day GC treatment in the pig ICU model induces numerous transcriptional changes that affect myofiber function in a limb muscle. In paper II, we conclude that the masseter, the main masticatory muscle, is partia

Little is known about how pro-obesity diets regulate tissue stem and progenitor cell function. Here we find that high fat diet (HFD)-induced obesity augments the numbers and function of Lgr5[superscript +] intestinal stem-cells (ISCs) of the mammalian intestine. Mechanistically, HFD induces a robust peroxisome proliferator-activated receptor delta (PPAR-d) signature in intestinal stem and (nonISC) progenitor cells, and pharmacologic activation of PPAR-d recapitulates the effects of a HFD on these cells. Like a HFD, ex vivo treatment of intestinal organoid cultures with fatty acid constituents of the HFD enhances the self-renewal potential of these organoid bodies in a PPAR-d dependent manner. Interestingly, HFD- and agonist-activated PPAR-d signaling endow organoidinitiating capacity to progenitors, and enforced PPAR-d signaling permits these progenitors to form in vivo tumors upon loss of the tumor suppressor Apc. These findings highlight how dietmodulated PPAR-d activation alters not only the function of intestinal stem and progenitor cells, but also their capacity to initiate tumors., Howard Hughes Medical Institute, Ellison Medical Foundation (Aging Grant), United States. Department of Defense (PRCRP Career Development Award CA120198), National Institutes of Health (U.S.) (Grants R01 CA103866, AI47389, K08 CA198002, R00 AG045144, R00 AG041765, and DK043351), National Institutes of Health (U.S.) (Cancer Center Support Core Grant P30-CA14051), Kathy and Curt Marble Cancer Research Fund, American Federation for Aging Research, V Foundation for Cancer Research (Scholar Grant), Massachusetts Institute of Technology. Ludwig Center for Molecular Oncology (Post-doctoral Fellowship), Massachusetts General Hospital (Fellowship T32DK007191), Damon Runyon Cancer Research Foundation (Robert Black Fellowship)

Multiple sclerosis (MS) is a prevalent neurological disease of complex etiology. Here, we describe the characterization of a multi-incident MS family that nominated a rare missense variant (p.G420D) in plasminogen (PLG) as a putative genetic risk factor for MS. Genotyping of PLG p.G420D (rs139071351) in 2160 MS patients, and 886 controls from Canada, identified 10 additional probands, two sporadic patients and one control with the variant. Segregation in families harboring the rs139071351 variant, identified p.G420D in 26 out of 30 family members diagnosed with MS, 14 unaffected parents, and 12 out of 30 family members not diagnosed with disease. Despite considerably reduced penetrance, linkage analysis supports cosegregation of PLG p.G420D and disease. Genotyping of PLG p. G420D in 14446 patients, and 8797 controls from Canada, France, Spain, Germany, Belgium, and Austria failed to identify significant association with disease (P = 0.117), despite an overall higher prevalence in patients (OR = 1.32; 95% CI = 0.931.87). To assess whether additional rare variants have an effect on MS risk, we sequenced PLG in 293 probands, and genotyped all rare variants in cases and controls. This analysis identified nine rare missense variants, and although three of them were exclusively observed in MS patients, segregation does not support pathogenicity. PLG is a plausible biological candidate for MS owing to its involvement in immune system response, blood-brain barrier permeability, and myelin degradation. Moreover, components of its activation cascade have been shown to present increased activity or expression in MS patients compared to controls; further studies are needed to clarify whether PLG is involved in MS susceptibility.

Multiple sclerosis (MS) is a prevalent neurological disease of complex etiology. Here, we describe the characterization of a multi-incident MS family that nominated a rare missense variant (p.G420D) in plasminogen (PLG) as a putative genetic risk factor for MS. Genotyping of PLG p.G420D (rs139071351) in 2160 MS patients, and 886 controls from Canada, identified 10 additional probands, two sporadic patients and one control with the variant. Segregation in families harboring the rs139071351 variant, identified p.G420D in 26 out of 30 family members diagnosed with MS, 14 unaffected parents, and 12 out of 30 family members not diagnosed with disease. Despite considerably reduced penetrance, linkage analysis supports cosegregation of PLG p.G420D and disease. Genotyping of PLG p. G420D in 14446 patients, and 8797 controls from Canada, France, Spain, Germany, Belgium, and Austria failed to identify significant association with disease (P = 0.117), despite an overall higher prevalence in patients (OR = 1.32; 95% CI = 0.931.87). To assess whether additional rare variants have an effect on MS risk, we sequenced PLG in 293 probands, and genotyped all rare variants in cases and controls. This analysis identified nine rare missense variants, and although three of them were exclusively observed in MS patients, segregation does not support pathogenicity. PLG is a plausible biological candidate for MS owing to its involvement in immune system response, blood-brain barrier permeability, and myelin degradation. Moreover, components of its activation cascade have been shown to present increased activity or expression in MS patients compared to controls; further studies are needed to clarify whether PLG is involved in MS susceptibility.

The availability of ICT services can be severely disrupted in the aftermath of disasters. Ad-hoc assemblages of communication technology have the potential to bridge such breakdowns. This article investigates the use of an ad-hoc system for sending SOS signals in a large-scale exercise that simulated a terrorist attack. In this context, we found that the sensitivity that was introduced by the adversarial nature of the situation posed unexpected challenges for our approach, as giving away one's location in the immediate danger of a terrorist attack became an issue both for first responders and the affected people in the area. We show how practices of calling for help and reacting to help calls can be affected by such a system and affect the management of the visibility and validity of SOS calls, implying a need for further negotiation in situations where communication is sensitive and technically restrained.