Search results for: therapeutic jurisprudence

Authors: Sunil Kumar, Rajesh Sharma

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Toxic epidermal necrolysis, pruritis, rashes, lichen planus like eruption, hyper pigmentation of skin are rare toxic effects of choloroquine used over a long time. Skin and mucus membrane hyper pigmentation is generally of a bluish black or grayish color and irreversible after discontinuation of the drug. According to Ayurveda, Dushivisha is the name given to any poisonous substance which is not fully endowed with the qualities of poison by nature (i.e. it acts as an impoverished or weak poison) and because of its mild potency, it remains in the body for many years causing various symptoms, one among them being discoloration of skin.The objective of this case report is to investigate the effect of Ayurvedic management of chloroquine induced hyper-pigmentation on the line of treatment of Dushivisha. Case Report: A 26-year-old female was suffering from hyper-pigmentation of the skin over the neck, forehead, temporo-mandibular joints, upper back and posterior aspect of both the arms since 8 years had history of taking Chloroquine came to Out Patient Department of National Institute of Ayurveda, Jaipur, India in Jan. 2015. The routine investigations (CBC, ESR, Eosinophil count) were within normal limits. Punch biopsy skin studied for histopathology under hematoxylin and eosin staining showed epidermis with hyper-pigmentation of the basal layer. In the papillary dermis as well as deep dermis there were scattered melanophages along with infiltration by mononuclear cells. There was no deposition of amyloid-like substances. These histopathological findings were suggestive of Chloroquine induced hyper-pigmentation. The case was treated on the line of treatment of Dushivisha and was given Vamana and Virechana (therapeutic emesis and purgation) every six months followed by Snehana karma (oleation therapy) with Panchatikta Ghrit and Swedana (sudation). Arogyavardhini Vati -1 g, Dushivishari Vati 500 mg, Mahamanjisthadi Quath 20 ml were given twelve hourly and Aragwadhadi Quath 25 ml at bed time orally. The patient started showing lightening of the pigments after six months and almost complete remission after 12 months of the treatment. Conclusion: This patient presented with the Dushivisha effect of Chloroquineandwas administered two relevant procedures from Panchakarma viz. Vamana and Virechana. Both Vamana and Virechanakarma here referred to Shodhana karma (purification procedures) eliminates accumulated toxins from the body. In this process, oleation dislodge the toxins from the tissues and sudation helps to bring them to the alimentary tract. The line of treatment did not target direct hypo pigmentary effects; rather aimed to eliminate the Dushivisha. This gave promising results in this condition.

Keywords: Ayurveda, chloroquine, Dushivisha, hyper-pigmentation

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Authors: Maha J. Balgoon, Gehan A. Raouf, Safaa Y. Qusti, Soad S. Ali

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The main cause of Alzheimer disease (AD) was believed to be mainly due to the accumulation of free radicals owing to oxidative stress (OS) in brain tissue. The mechanism of the neurotoxicity of Aluminum chloride (AlCl3) induced AD in hippocampus Albino wister rat brain tissue, the curative & the protective effects of Lipidium sativum group (LS) water extract were assessed after 8 weeks by attenuated total reflection spectroscopy ATR-IR and histologically by light microscope. ATR-IR results revealed that the membrane phospholipid undergo free radical attacks, mediated by AlCl3, primary affects the polyunsaturated fatty acids indicated by the increased of the olefinic -C=CH sub-band area around 3012 cm-1 from the curve fitting analysis. The narrowing in the half band width(HBW) of the sνCH2 sub-band around 2852 cm-1 due to Al intoxication indicates the presence of trans form fatty acids rather than gauch rotomer. The degradation of hydrocarbon chain to shorter chain length, increasing in membrane fluidity, disorder and decreasing in lipid polarity in AlCl3 group were indicated by the detected changes in certain calculated area ratios compared to the control. Administration of LS was greatly improved these parameters compared to the AlCl3 group. Al influences the Aβ aggregation and plaque formation, which in turn interferes to and disrupts the membrane structure. The results also showed a marked increase in the β-parallel and antiparallel structure, that characterize the Aβ formation in Al-induced AD hippocampal brain tissue, indicated by the detected increase in both amide I sub-bands around 1674, 1692 cm-1. This drastic increase in Aβ formation was greatly reduced in the curative and protective groups compared to the AlCl3 group and approaches nearly the control values. These results were supported too by the light microscope. AlCl3 group showed significant marked degenerative changes in hippocampal neurons. Most cells appeared small, shrieked and deformed. Interestingly, the administration of LS in curative and protective groups markedly decreases the amount of degenerated cells compared to the non-treated group. Also the intensity of congo red stained cells was decreased. Hippocampal neurons looked more/or less similar to those of control. This study showed a promising therapeutic effect of Lipidium sativum group (LS) on AD rat model that seriously overcome the signs of oxidative stress on membrane lipid and restore the protein misfolding.

Keywords: aluminum chloride, alzheimer disease, ATR-IR, Lipidium sativum

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Authors: Yang Yang, Luciana Magalhães Rebelo Alencar, Martha Sahylí Ortega Pijeira, Beatriz da Silva Batista, Alefe Roger Silva França, Erick Rafael Dias Rates, Ruana Cardoso Lima, Sara Gemini-Piperni, Ralph Santos-Oliveira

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Radium-²²³ dichloride ([²²³Rₐ]RₐCl₂) is an alpha particle-emitting radiopharmaceutical currently approved for the treatment of patients with castration-resistant prostate cancer, symptomatic bone metastases, and no known visceral metastatic disease. [²²³Rₐ]RₐCl₂ is bone-seeking calcium mimetic that bonds into the newly formed bone stroma, especially osteoblastic or sclerotic metastases, killing the tumor cells by inducing DNA breaks in a potent and localized manner. Nonetheless, the successful therapy of osteosarcoma as primary bone tumors is still a challenge. Nanomicelles are colloidal nanosystems widely used in drug development to improve blood circulation time, bioavailability, and specificity of therapeutic agents, among other applications. In addition, the enhanced permeability and retention effect of the nanosystems, and the renal excretion of the nanomicelles reported in most cases so far, are very attractive to achieve selective and increased accumulation in tumor site as well as to increase the safety of [²²³Rₐ]RₐCl₂ in the clinical routine. In the present work, [²²³Rₐ]RₐCl₂ nanomicelles were produced, characterized, in vitro evaluated, and compared with pure [²²³Rₐ]RₐCl2 solution using SAOS2 osteosarcoma cells. The [²²³Rₐ]RₐCl₂ nanomicelles were prepared using the amphiphilic copolymer Pluronic F127. The dynamic light scattering analysis of freshly produced [²²³Rₐ]RₐCl₂ nanomicelles demonstrated a mean size of 129.4 nm with a polydispersity index (PDI) of 0.303. After one week stored in the refrigerator, the mean size of the [²²³Rₐ]RₐCl₂ nanomicelles increased to 169.4 with a PDI of 0.381. Atomic force microscopy analysis of [223Rₐ]RₐCl₂ nanomicelles exhibited spherical structures whose heights reach 1 µm, suggesting the filling of 127-Pluronic nanomicelles with [²²³Rₐ]RₐCl₂. The viability assay with [²²³Rₐ]RₐCl₂ nanomicelles displayed a dose-dependent response as it was observed using pure [²²³Rₐ]RₐCl2. However, at the same dose, [²²³Rₐ]RₐCl₂ nanomicelles were 20% higher efficient in killing SAOS2 cells when compared with pure [²²³Rₐ]RₐCl₂. These findings demonstrated the effectiveness of the nanosystem validating the application of nanotechnology in targeted alpha therapy with [²²³Ra]RₐCl₂. In addition, the [²²³Rₐ]RaCl₂nanomicelles may be decorated and incorporated with a great variety of agents and compounds (e.g., monoclonal antibodies, aptamers, peptides) to overcome the limited use of [²²³Ra]RₐCl₂.

Keywords: nanomicelles, osteosarcoma, radium dichloride, targeted alpha therapy

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Authors: Leigh G. Hayden, Susan E. Shepley, Cristina Passarelli, William Tingo

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Introduction: Sensory interventions are popular therapeutic and recreational approaches for people living with all stages of dementia. However, it is unknown which sensory interventions are used to achieve which outcomes across all subtypes of dementia. Methods: To address this gap, we conducted a scoping review of sensory interventions for people living with dementia. We conducted a search of the literature for any article published in English from 1 January 1990 to 1 June 2019, on any sensory or multisensory intervention targeted to people living with any kind of dementia, which reported on patient health outcomes. We did not include complex interventions where only a small aspect was related to sensory stimulation. We searched the databases Medline, CINHAL, and Psych Articles using our institutional discovery layer. We conducted all screening in duplicate to reduce Type 1 and Type 2 errors. The data from all included papers were extracted by one team member, and audited by another, to ensure consistency of extraction and completeness of data. Results: Our initial search captured 7654 articles, and the removal of duplicates (n=5329), those that didn’t pass title and abstract screening (n=1840) and those that didn’t pass full-text screening (n=281) resulted in 174 articles included. The countries with the highest publication in this area were the United States (n=59), the United Kingdom (n=26) and Australia (n=15). The most common type of interventions were music therapy (n=36), multisensory rooms (n=27) and multisensory therapies (n=25). Seven articles were published in the 1990’s, 55 in the 2000’s, and the remainder since 2010 (n=112). Discussion: Multisensory rooms have been present in the literature since the early 1990’s. However, more recently, nature/garden therapy, art therapy, and light therapy have emerged since 2008 in the literature, an indication of the increasingly diverse scholarship in the area. The least popular type of intervention is a traditional food intervention. Taste as a sensory intervention is generally avoided for safety reasons, however it shows potential for increasing quality of life. Agitation, behavior, and mood are common outcomes for all sensory interventions. However, light therapy commonly targets sleep. The majority (n=110) of studies have very small sample sizes (n=20 or less), an indicator of the lack of robust data in the field. Additional small-scale studies of the known sensory interventions will likely do little to advance the field. However, there is a need for multi-armed studies which directly compare sensory interventions, and more studies which investigate the use of layering sensory interventions (for example, adding an aromatherapy component to a lighting intervention). In addition, large scale studies which enroll people at early stages of dementia will help us better understand the potential of sensory and multisensory interventions to slow the progression of the disease.

Keywords: sensory interventions, dementia, scoping review

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Authors: Tiffany Hollis

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Childhood trauma is well documented in mental health research, yet has received little attention in urban schools. Child trauma affects brain development and impacts cognitive, emotional, and behavioral functioning. When educators understand that some of the behaviors that appear to be aggressive in nature might be the result of a hidden diagnosis of trauma, learning can take place, and the child can thrive in the classroom setting. Traumatized children, however, do not fit neatly into any single ‘box.’ Although many children enter school each day carrying with them the experience of exposure to violence in the home, the symptoms of their trauma can be multifaceted and complex, requiring individualized therapeutic attention. The purpose of this study was to examine how prepared educators are to address the unique challenges facing children who experience trauma. Given the vast number of traumatized children in our society, it is evident that our education system must investigate ways to create an optimal learning environment that accounts for trauma, addresses its impact on cognitive and behavioral development, and facilitates mental and emotional health and well-being. The researcher describes the knowledge, attitudes, dispositions, and skills relating to trauma-informed knowledge of induction level teachers in a diverse middle school. The data for this study were collected through interviews with teachers, who are in the induction phase (the first three years of their teaching career). The study findings paint a clear picture of how ill-prepared educators are to address the needs of students who have experienced trauma and the implications for the development of a professional development workshop or series of workshops that train teachers how to recognize and address and respond to the needs of students. The study shows how teachers often lack skills to meet the needs of students who have experienced trauma. Traumatized children regularly carry a heavy weight on their shoulders. Children who have experienced trauma may feel that the world is filled with unresponsive, threatening adults, and peers. Despite this, supportive interventions can provide traumatized children with places to go that are safe, stimulating, and even fun. Schools offer an environment that potentially meets these requirements by creating safe spaces where students can feel at ease and have fun while also learning via stimulating educational activities. This study highlights the lack of preparedness of educators to address the academic, behavioral, and cognitive needs of students who have experienced trauma. These findings provide implications for the creation of a professional development workshop that addresses how to recognize and address the needs of students who have experienced some type of trauma. They also provide implications for future research with a focus on specific interventions that enable the creation of optimal learning environments where students who have experienced trauma and all students can succeed, regardless of their life experiences.

Keywords: educator preparation, induction educators, professional development, trauma-informed

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Authors: Hager Elsheikh

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Context: Pancreatitis is a condition characterized by inflammation in the pancreas, which can lead to serious complications if untreated. Both acute and chronic pancreatitis are associated with immune reactions and fibrosis, which further damage the pancreas. The type 2 immune response, primarily driven by alternative activated macrophages (AAMs), plays a significant role in the development of fibrosis. The IL-4/STAT6 pathway is a crucial signaling pathway for the activation of M2 macrophages. Pancreatic fibrosis is induced by dysregulated inflammatory responses and can result in the autodigestion and necrosis of pancreatic acinar cells. Research Aim: The aim of this study is to investigate the impact of STAT6, a crucial molecule in the IL-4/STAT6 pathway, on the severity and development of fibrosis during acute and chronic pancreatitis. The research also aims to understand the influence of the JAK/STAT6 signaling pathway on the balance between fibrosis and regeneration in the presence of different macrophage populations. Methodology: The research utilizes murine models of acute and chronic pancreatitis induced by cerulean injection. Animal models will be employed to study the effect of STAT6 knockout on disease severity and fibrosis. Isolation of acinar cells and cell culture techniques will be used to assess the impact of different macrophage populations on wound healing and regeneration. Various techniques such as PCR, histology, immunofluorescence, and transcriptomics will be employed to analyze the tissues and cells. Findings: The research aims to provide insights into the mechanisms underlying tissue fibrosis and wound healing during acute and chronic pancreatitis. By investigating the influence of the JAK/STAT6 signaling pathway and different macrophage populations, the study aims to understand their impact on tissue fibrosis, disease severity, and pancreatic regeneration. Theoretical Importance: This research contributes to our understanding of the role of specific signaling pathways, macrophage polarization, and the type 2 immune response in pancreatitis. It provides insights into the molecular mechanisms underlying tissue fibrosis and the potential for targeted therapies. Data Collection and Analysis Procedures: Data will be collected through the use of murine models, isolation and culture of acinar cells, and various experimental techniques such as PCR, histology, immunofluorescence, and transcriptomics. Data will be analyzed using appropriate statistical methods and techniques, and the findings will be interpreted in the context of the research objectives. Conclusion: By investigating the mechanisms of tissue fibrosis and wound healing during acute and chronic pancreatitis, this research aims to enhance our understanding of the disease progression and potential therapeutic targets. The findings have theoretical importance in expanding our knowledge of pancreatic fibrosis and the role of macrophage polarization in the context of the type 2 immune response.

Keywords: immunity in chronic diseases, pancreatitis, macrophages, immune response

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Authors: Ipsita Biswas, Arnab Sarkar, Ashikur Rahaman, Gopeswar Mukherjee, Subhrangsu Chatterjee, Shamee Bhattacharjee, Deba Prasad Mandal

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One of the major reasons for the high mortality rate of lung cancer is the substantial delays in disease detection at late metastatic stages. It is of utmost importance to understand the detailed molecular signaling and detect the molecular markers that can be used for the early diagnosis of cancer. Several studies explored the emerging roles of long noncoding RNAs (lncRNAs) in various cancers as well as lung cancer. A long non-coding RNA LINC00273 was recently discovered to promote cancer cell migration and invasion, and its positive correlation with the pathological stages of metastasis may prove it to be a potential target for inhibiting cancer cell metastasis. Comparing real-time expression of LINC00273 in various human clinical cancer tissue samples with normal tissue samples revealed significantly higher expression in cancer tissues. This long intergenic noncoding RNA was found to be highly expressed in human liver tumor-initiating cells, human gastric adenocarcinoma AGS cell line, as well as human non-small cell lung cancer A549 cell line. SiRNA and shRNA-induced knockdown of LINC00273 in both in vitro and in vivo nude mice significantly subsided AGS and A549 cancer cell migration and invasion. LINC00273 knockdown also reduced TGF-β induced SNAIL, SLUG, VIMENTIN, ZEB1 expression, and metastasis in A549 cells. Plenty of reports have suggested the role of microRNAs of the miR200 family in reversing epithelial to mesenchymal transition (EMT) by inhibiting ZEB transcription factors. In this study, hsa-miR-200a-3p was predicted via IntaRNA-Freiburg RNA tools to be a potential target of LINC00273 with a negative free binding energy of −8.793 kcal/mol, and this interaction was verified as a confirmed target of LINC00273 by RNA pulldown, real-time PCR and luciferase assay. Mechanistically, LINC00273 accelerated TGF-β induced EMT by sponging hsa-miR-200a-3p which in turn liberated ZEB1 and promoted prometastatic functions in A549 cells in vitro as verified by real-time PCR and western blotting. The similar expression patterns of these EMT regulatory pathway molecules, viz. LINC00273, hsa-miR-200a-3p, ZEB1 and TGF-β, were also detected in various clinical samples like breast cancer tissues, oral cancer tissues, lung cancer tissues, etc. Overall, this LINC00273 mediated EMT regulatory signaling can serve as a potential therapeutic target for the prevention of lung cancer metastasis.

Keywords: epithelial to mesenchymal transition, long noncoding RNA, microRNA, non-small-cell lung carcinoma

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Authors: Tal Braverman Uriel, Tal Litvak Hirsch

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Background and Objectives: Little or only partial emphasis has been placed on exploring the complexity of consensual non-monogamous relationships. The term "polyamory" refers to consensual non-monogamy, and it is defined as having emotional and/or sexual relations simultaneously with two or more people, the consent and knowledge of all the partners concerned. Managing multiple romantic relationships with different people evokes more emotions, leads to more emotional conflicts arising from different interests, and demands practical strategies. An individual's transition from a monogamous lifestyle to a consensual non-monogamous lifestyle yields new challenges, accompanied by stress, uncertainty, and question marks, as do other life-changing events, such as divorce or transition to parenthood. The study examines both the process of transition and adaptation to a consensually non-monogamous relationship, as well as the coping mechanism involved in the daily conduct of this lifestyle. The research focuses on understanding the consequences, challenges, and coping methods from a personal, marital, and familial point of view and focuses on 40 middle-aged individuals (20 men and 20 women ages 40-60). The research sheds light on a way of life that has not been previously studied in Israel and is still considered unacceptable. Theories of crisis (e.g., as Folkman and Lazarus) were applied, and as a result, a deeper understanding of the subject was reached, all while focusing on multiple aspects of dealing with stress. The basic research question examines the consequences of entering a polyamorous life from a personal point of view as an individual, partner, and parent and the ways of coping with these consequences. Method: The research is conducted with a narrative qualitative approach in the interpretive paradigm, including semi-structured in-depth interviews. The method of analysis is thematic. Results: The findings indicate that in most cases, an individual's motivation to open the relationship is mainly a longing for better sexuality and for an added layer of excitement to their lives. Most of the interviewees were assisted by their spouses in the process, as well as by social networks and podcasts on the subject. Some of them therapeutic professionals from the field are helpful. It also clearly emerged that among those who experienced acute emotional crises with the primary partner or painful separations from secondary partners, all believed polyamory to be the adequate way of life for them. Finally, a key resource for managing tension and stress is the ability to share and communicate with the primary partner. Conclusions: The study points to the challenges and benefits of a non-monogamous lifestyle as well as the use of coping mechanisms and resources that are consistent with the existing theory and research in the field in the context of life changes. The study indicates the need to expand the research canvas in the future in the context of parenting and the consequences for children.

Keywords: a-monogamy, consent, family, stress, tension

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Authors: Sayed Maeen Badshah, Kuen-Song Lin, Abrar Hussain, Jamshid Hussain

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Liver cancer is a significant global health issue, ranking fifth in incidence and second in mortality. Effective therapeutic strategies are urgently needed to combat this disease, particularly in regions with high prevalence. This study focuses on developing and characterizing fluorescent organometallic frameworks as distinct drug delivery carriers with potential applications in both the treatment and biological imaging of liver cancer. This work introduces two distinct organometallic frameworks: the cake-shaped GQD@NH₂-MIL-125 and the cross-shaped M8U6/FM8U6. The GQD@NH₂-MIL-125 framework is particularly noteworthy for its high fluorescence, making it an effective tool for biological imaging. X-ray diffraction (XRD) analysis revealed specific diffraction peaks at 6.81ᵒ (011), 9.76ᵒ (002), and 11.69ᵒ (121), with an additional significant peak at 26ᵒ (2θ), corresponding to the carbon material. Morphological analysis using Field Emission Scanning Electron Microscopy (FE-SEM), and Transmission Electron Microscopy (TEM) demonstrated that the framework has a front particle size of 680 nm and a side particle size of 55±5 nm. High-resolution TEM (HR-TEM) images confirmed the successful attachment of graphene quantum dots (GQDs) onto the NH2-MIL-125 framework. Fourier-Transform Infrared (FT-IR) spectroscopy identified crucial functional groups within the GQD@NH₂-MIL-125 structure, including O-Ti-O metal bonds within the 500 to 700 cm⁻¹ range, and N-H and C-N bonds at 1,646 cm⁻¹ and 1,164 cm⁻¹, respectively. BET isotherm analysis further revealed a specific surface area of 338.1 m²/g and an average pore size of 46.86 nm. This framework also demonstrated UV-active properties, as identified by UV-visible light spectra, and its photoluminescence (PL) spectra showed an emission peak around 430 nm when excited at 350 nm, indicating its potential as a fluorescent drug delivery carrier. In parallel, the cross-shaped M8U6/FM8U6 frameworks were synthesized and characterized using X-ray diffraction, which identified distinct peaks at 2θ = 7.4 (111), 8.5 (200), 9.2 (002), 10.8 (002), 12.1 (220), 16.7 (103), and 17.1 (400). FE-SEM, HR-TEM, and TEM analyses revealed particle sizes of 350±50 nm for M8U6 and 200±50 nm for FM8U6. These frameworks, synthesized from terephthalic acid (H₂BDC), displayed notable vibrational bonds, such as C=O at 1,650 cm⁻¹, Fe-O in MIL-88 at 520 cm⁻¹, and Zr-O in UIO-66 at 482 cm⁻¹. BET analysis showed specific surface areas of 740.1 m²/g with a pore size of 22.92 nm for M8U6 and 493.9 m²/g with a pore size of 35.44 nm for FM8U6. Extended X-ray Absorption Fine Structure (EXAFS) spectra confirmed the stability of Ti-O bonds in the frameworks, with bond lengths of 2.026 Å for MIL-125, 1.962 Å for NH₂-MIL-125, and 1.817 Å for GQD@NH₂-MIL-125. These findings highlight the potential of these organometallic frameworks for enhanced liver cancer therapy through precise drug delivery and imaging, representing a significant advancement in nanomaterial applications in biomedical science.

Keywords: liver cancer cells, metal organic frameworks, Doxorubicin (DOX), drug release.

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Authors: Paul Feyi Waboso

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This case report presents a 57-year-old female patient with a history of colon cancer, colostomy, and immunocompromise, who presented with an unusual bilateral vulval abscess, more prominent on the left side. Due to the atypical presentation, an MRI was performed, revealing a pelvic collection and a fistulous connection between the pelvis and vulva. This finding prompted an urgent surgical intervention. This case highlights the diagnostic and therapeutic challenges of managing complex abscesses and fistulas in immunocompromised patients. Introduction: Vulval abscesses in immunocompromised individuals can present with atypical features and may be associated with complex pathologies. Patients with a history of cancer, colostomy, and immunocompromise are particularly prone to infections and may present with unusual manifestations. This report discusses a case of a large bilateral vulval abscess with an underlying pelvic fistula, emphasizing the importance of advanced imaging in cases with atypical presentations. Case Presentation: A 57-year-old female with a known history of colon cancer, treated with colostomy, presented with severe pain and swelling in the vulval area. Physical examination revealed bilateral vulval swelling, with the abscess on the left side appearing larger and more pronounced than on the right. Given her immunocompromised status and the unusual nature of the presentation, we requested an MRI of the pelvis, suspecting an underlying pathology beyond a typical abscess. Investigations: MRI imaging revealed a significant pelvic collection and identified a fistulous tract between the pelvis and the vulva. This confirmed that the vulval abscess was connected to a deeper pelvic infection, necessitating urgent intervention. Management: After consultation with the multidisciplinary team (MDT), it was agreed that the patient required surgical intervention, having had 48 hours of antibiotics. The patient underwent evacuation of the left-sided vulval abscess under spinal anesthesia. During surgery, the pelvic collection was drained of 200 ml of pus. Outcome and Follow-Up: Postoperative recovery was closely monitored due to the patient’s immunocompromised state. Follow-up imaging and clinical evaluation showed improvement in symptoms, with gradual resolution of infection. The patient was scheduled for regular follow-up visits to monitor for recurrence or further complications. Discussion: Bilateral vulval abscesses are uncommon and, in an immunocompromised patient, warrant thorough investigation to rule out deeper infectious or fistulous connections. This case underscores the utility of MRI in identifying complex fistulous tracts and highlights the importance of a multidisciplinary approach in managing such high-risk patients. Conclusion: This case illustrates a rare presentation of bilateral vulval abscess with an associated pelvic fistula.

Keywords: vulval abscess, MDT team, colon cancer with pelvic fistula, vulval skin condition

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Authors: Seema Dhariwal, Kiran Maan, Ruchi Baghel, Apoorva Sharma, Poonam Rana

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Introduction: Traumatic brain injury (TBI) is defined as the temporary or permanent alteration in brain function and pathology caused by an external mechanical force. It represents the leading cause of mortality and morbidity among children and youth individuals. Various models of TBI in rodents have been developed in the laboratory to mimic the scenario of injury. Blast overpressure injury is common among civilians and military personnel, followed by accidents or explosive devices. In addition to this, the lateral Controlled cortical impact (CCI) model mimics the blunt, penetrating injury. Method: In the present study, we have developed two different mild TBI models using blast and CCI injury. In the blast model, helium gas was used to create an overpressure of 130 kPa (±5) via a shock tube, and CCI injury was induced with an impact depth of 1.5mm to create diffusive and focal injury, respectively. C57BL/6J male mice (10-12 weeks) were divided into three groups: (1) control, (2) Blast treated, (3) CCI treated, and were exposed to different injury models. Serum was collected on Day1 and day7, followed by biphasic extraction using MTBE/Methanol/Water. Prepared samples were separated on Charged Surface Hybrid (CSH) C18 column and acquired on UHPLC-Q-TOF-MS using ESI probe with inhouse optimized parameters and method. MS peak list was generated using Markerview TM. Data were normalized, Pareto-scaled, and log-transformed, followed by multivariate and univariate analysis in metaboanalyst. Result and discussion: Untargeted profiling of lipids generated extensive data features, which were annotated through LIPID MAPS® based on their m/z and were further confirmed based on their fragment pattern by LipidBlast. There is the final annotation of 269 features in the positive and 182 features in the negative mode of ionization. PCA and PLS-DA score plots showed clear segregation of injury groups to controls. Among various lipids in mild blast and CCI, five lipids (Glycerophospholipids {PC 30:2, PE O-33:3, PG 28:3;O3 and PS 36:1 } and fatty acyl { FA 21:3;O2}) were significantly altered in both injury groups at Day 1 and Day 7, and also had VIP score >1. Pathway analysis by Biopan has also shown hampered synthesis of Glycerolipids and Glycerophospholipiods, which coincides with earlier reports. It could be a direct result of alteration in the Acetylcholine signaling pathway in response to TBI. Understanding the role of a specific class of lipid metabolism, regulation and transport could be beneficial to TBI research since it could provide new targets and determine the best therapeutic intervention. This study demonstrates the potential lipid biomarkers which can be used for injury severity diagnosis and identification irrespective of injury type (diffusive or focal).

Keywords: LipidBlast, lipidomic biomarker, LIPID MAPS®, TBI

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Authors: S. Jayasinghe, W. G. D. Wickramasingha, V. Karunaratne, D. N. Karunaratne, A. Ekanayake

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Multi-drug resistant microbial pathogens are a serious global health problem, and hence, there is an urgent necessity for discovering new drug therapeutics. However, finding alternatives is a one of the biggest challenges faced by the global drug industry due to the spiraling high cost and serious side effects associated with modern medicine. On the other hand, plants and their secondary metabolites can be considered as good sources of scaffolds to provide structurally diverse bioactive compounds as potential therapeutic agents. 6β-hydroxy betunolic acid is a triterpenoid isolated from bark of Schumacheria castaneifolia which is an endemic plant to Sri Lanka which has shown antibacterial activity against both Staphylococcus aureus (ATCC 29213) and methicillin-resistant S. aureus with Minimum Inhibition Concentration (MIC) of 16 µg/ml. The objective of this study was to determine the anti-bacterial activity for the derivatives of 6β- hydroxy betunolic acid against standard strains of Staphylococcus aureus (ATCC 29213 and ATCC 25923), Enterococcus faecalis (ATCC 29212), Escherichia coli (ATCC 35218 and ATCC 25922), Pseudomonas aeruginosa (ATCC 27853), carbepenemas produce Kebsiella pneumonia (ATCC BAA 1705) and carbepenemas non produce Kebsiella pneumonia (ATCC BAA 1706) and four stains of clinically isolated methicillin resistance S. aureus and Acinetobacter. Structural analogues of 6β-hydroxy betunolic acid were synthesized by modifying the carbonyl group at C-3 to obtain olefin and oxime, the hydroxyl group at C-6 position to a ketone, the carboxylic acid at C-17 to obtain amide and halo ester and the olefin group at C-20 position to obtain epoxide. Chemical structures of the synthesized analogues were confirmed with spectroscopic data and antibacterial activity was determined through broth micro dilution assay. Results revealed that 6β- hydroxy betunolic acid shows significant antibacterial activity only against the Gram positive strains and it was inactive against all the tested Gram negative strains for the tested concentration range. However, structural modifications into oxime and olefin at C-3, ketone at C-6 and epoxide at C-20 decreased its antibacterial activity against the gram positive organisms and it was totally lost with the both modifications at C-17 into amide and ester. These results concluded that the antibacterial activity of 6β- hydroxy betunolic acid and derivatives is predominantly depending on the cell wall difference of the bacteria and the presence of carboxylic acid at C-17 is highly important for the antibacterial activity against Gram positive organisms.

Keywords: antibacterial activity, 6β- hydroxy betunolic acid, broth micro dilution assay, structure activity relationship

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Authors: Joanna Gerszon, Aleksandra Rodacka

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In the pathogenesis of neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease, protein and peptide aggregation processes play a vital role in contributing to the formation of intracellular and extracellular protein deposits. One of the major components of these deposits is the oxidatively modified glyceraldehyde-3-phosphate dehydrogenase (GAPDH). Therefore, the purpose of this research was to answer the question whether piceatannol, a stilbene derivative, counteracts and/or slows down oxidative stress-induced GAPDH aggregation. The study also aimed to determine if this natural occurring compound prevents unfavorable nuclear translocation of GAPDH in hippocampal cells. The isothermal titration calorimetry (ITC) analysis indicated that one molecule of GAPDH can bind up to 8 molecules of piceatannol (7.3 ± 0.9). As a consequence of piceatannol binding to the enzyme, the loss of activity was observed. Parallel with GAPDH inactivation the changes in zeta potential, and loss of free thiol groups were noted. Nevertheless, the ligand-protein binding does not influence the secondary structure of the GAPDH. Precise molecular docking analysis of the interactions inside the active center allowed to presume that these effects are due to piceatannol ability to assemble a covalent binding with nucleophilic cysteine residue (Cys149) which is directly involved in the catalytic reaction. Molecular docking also showed that simultaneously 11 molecules of ligand can be bound to dehydrogenase. Taking into consideration obtained data, the influence of piceatannol on level of GAPDH aggregation induced by excessive oxidative stress was examined. The applied methods (thioflavin-T binding-dependent fluorescence as well as microscopy methods - transmission electron microscopy, Congo Red staining) revealed that piceatannol significantly diminishes level of GAPDH aggregation. Finally, studies involving cellular model (Western blot analyses of nuclear and cytosolic fractions and confocal microscopy) indicated that piceatannol-GAPDH binding prevents GAPDH from nuclear translocation induced by excessive oxidative stress in hippocampal cells. In consequence, it counteracts cell apoptosis. These studies demonstrate that by binding with GAPDH, piceatannol blocks cysteine residue and counteracts its oxidative modifications, that induce oligomerization and GAPDH aggregation as well as it prevents hippocampal cells from apoptosis by retaining GAPDH in the cytoplasm. All these findings provide a new insight into the role of piceatannol interaction with GAPDH and present a potential therapeutic strategy for some neurological disorders related to GAPDH aggregation. This work was supported by the by National Science Centre, Poland (grant number 2017/25/N/NZ1/02849).

Keywords: glyceraldehyde-3-phosphate dehydrogenase, neurodegenerative disease, neuroprotection, piceatannol, protein aggregation

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Authors: João Pedro Zanella, Michel J. O. Fagundes

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Introduction: Drug use has been practised by humans universally for millennia, not excluding any population from these habits, however, the rampant drug use is a global concern due to the harm that affects the health of the world population. In this sense, it is observed the reduction of lasting and effective public policies for the resolution, increasing the demand for treatment services. With this comes ibogaine, an alkaloid derived from the root of an African bush (Tabernanthe Iboga), found mostly in Gabon and used widely by the native Bwiti population in rituals, and also other social groups, which demonstrates efficacy against chemical dependence, psychic and emotional disorders, opioid withdrawal was first confirmed by a study in rats done by Michailo Dzoljic and associates in 1988 and again in 1994. Methods: A brief description of the plant, its neurohumoral potential and the effects caused by ingested doses, in a simplified and objective way, will be discussed in the course of this abstract. Results: Ibogaine is not registered or passed by Anvisa, regarding safety and efficacy, and cannot be sold in Brazil. Its illegal trade reaches R$ 5 thousand for a session with the proceeds of the root, and its effect can last up to 72 hours, attributing Iboga's psychoactive effects to the alkaloid called ibogaine. The shrub where Ibogaine is located has pink and yellow flowers, and its fruit produced does not have psychoactive substances, but its root bark contains 6 to 7% indolic alkaloids. Besides extraction from the iboga plant, ibogaine hydrochloride can be semisynthesized from voacangine, another plant alkaloid that acts as a precursor. Its potential has the ability to perform multiple interactions with the neurotransmitter system, which are closely associated with addiction, including nicotinic, opioid and serotoninergic systems. Studies carried out by Edwards found that the doses administered of Iboga should be determined by a health professional when its purpose is to treat individuals for dependence on other drugs. Its use in small doses may cause an increase in sensibility, impaired vision and motor alterations; in moderate quantities, hallucinations, motor and neurological alterations and impaired vision; in high quantities it may cause hallucinations with personal events at a deeper level lasting up to 24 hours or more, followed by motor and visual alterations. Conclusion: The product extracted from the Iboga plant is of great importance in controlling addiction, reducing the need for the use of narcotics by patients, thus gaining a space of extreme importance in the treatment of users of psychoactive substances. It is remarkable the progress of the latest’s research about the usefulness of Ibogaine, and its benefits for certain treatments, even with the restriction of its sale in Brazil. Besides this, Ibogaine has an additional benefit of helping the patient to gain self-control over their destructive behaviours.

Keywords: alkaloids, dependence, Gabon, ibogaine

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Authors: Antonio Martín-Pardo

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With regard to the context in which this paper is inserted, it is noteworthy that the current criminal policy model in which we find immersed, denominated by some doctrine sector as the citizen security model, is characterized by a marked tendency towards the discredit of expert knowledge. This type of technic knowledge has been displaced by the common sense and by the daily experience of the people at the time of legislative drafting, as well as by excessive attention to the short-term political effects of the law. Despite this criminal-political adverse scene, we still find valuable efforts in the side of experts to bring some rationality to the legislative development. This is the case of the proposal for a new cannabis regulation model in Spain carried out by the Cannabis Policy Studies Group (hereinafter referred as ‘GEPCA’). The GEPCA is a multidisciplinary group composed by authors with multiple/different orientations, trajectories and interests, but with a common minimum objective: the conviction that the current situation regarding cannabis is unsustainable and, that a rational legislative solution must be given to the growing social pressure for the regulation of their consumption and production. This paper details the main lines through which this technical proposal is developed with the purpose of its dissemination and discussion in the Congress. The basic methodology of the proposal is inductive-expository. In that way, firstly, we will offer a brief, but solid contextualization of the situation of cannabis in Spain. This contextualization will touch on issues such as the national regulatory situation and its relationship with the international context; the criminal, judicial and penitentiary impact of the offer and consumption of cannabis, or the therapeutic use of the substance, among others. In second place, we will get down to the business properly by detailing the minutia of the three main cannabis access channels that are proposed. Namely: the regulated market, the associations of cannabis users and personal self-cultivation. In each of these options, especially in the first two, special attention will be paid to both, the production and processing of the substance and the necessary administrative control of the activity. Finally, in a third block, some notes will be given on a series of subjects that surround the different access options just mentioned above and that give fullness and coherence to the proposal outlined. Among those related issues we find some such as consumption and tenure of the substance; the issue of advertising and promotion of cannabis; consumption in areas of special risk (work or driving v. g.); the tax regime; the need to articulate evaluation instruments for the entire process; etc. The main conclusion drawn from the analysis of the proposal is the unsustainability of the current repressive system, clearly unsuccessful, and the need to develop new access routes to cannabis that guarantee both public health and the rights of people who have freely chosen to consume it.

Keywords: cannabis regulation proposal, cannabis policies studies group, criminal policy, expertise participation

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Authors: Jonathon Smith, Alba Agostino

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Autism, also referred to as autism spectrum disorder (ASD), is commonly associated with difficulties in social and communication skills. Other characteristics common to autistic individuals include repetitive behaviours, difficulties adhering to routine, as well as paying attention. Recent findings indicate that autism is the fastest-growing neurodevelopmental disorder in North America, yet programming aimed at improving the quality of autistic individual’s real-world social interactions is limited. Although there are social skills programs for autistic youth, participation appears to improve social knowledge, but that knowledge does not improve social competence or transfer to the participant’s daily social interactions. Peers are less likely to interact with autistic people based thin slice judgements, meaning that even when an autistic youth has successfully completed a social skills program, they most likely will still be rejected by peers and not have a social group to participate in. Recently, many researchers are exploring therapeutic interventions using Dungeon and Dragons (D&D) for conditions such as social anxiety, loneliness, and identity exploration. D&D is a table-top role-playing game (TTRPG) based on social play experience where the players must communicate, plan, negotiate, and compromise with other players to achieve a shared goal. The game encourages players to assume the role of their character and act out their play within the rules of the game with the guidance of the games dungeon master. The popularity Dungeons and Dragons has increased at a rapid rate, and many suggest that there social-emotional benefits of joining and participating in these types of gaming experiences, however this is an under researched topic and studies examining the benefits of such games is lacking in the field. The main purpose of this exploratory study is to examine the autistic youth’s experiences of participating in a D&D club. Participants of this study were four high functioning autistic youth between the ages of 14-18 (average age – 16) enrolled in a D&D Club that was specifically designed for neurodiverse youth. The youth participation with the club ranged from 4 months to 8 months. All participants completed a 30–40-minute semi-structured interview where they were able to express their perceptions as participants of the D&D club. Preliminary findings suggest that the game provided a place for the youth to engage in authentic social interactions. Additionally, preliminary results suggest that the youth report being in a positive space with other neurodivergent youth created an atmosphere where they felt confident and could connect with others. The findings from this study will aid clinicians, researchers, and educators in developing programming aimed at improving social interactions and connections for autistic youth.

Keywords: autism, social connection, dungeons and dragons, neurodivergent affirming space

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Authors: Caroline Lavratti, Pedro Dal Lago, Gustavo Reinaldo, Gilson Dorneles, Andreia Bard, Laira Fuhr, Daniela Pochmann, Alessandra Peres, Luciane Wagner, Viviane Elsner

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Approximately 1% of the world's population is affected by schizophrenia (SZ), a chronic and debilitating neurodevelopmental disorder. Among possible factors, reduced levels of Brain-derived neurotrophic factor (BDNF) has been recognized in physiopathogenesis and course of SZ. In this context, peripheral BDNF levels have been used as a biomarker in several clinical studies, since this neurotrophin is able to cross the blood-brain barrier in a bi-directional manner and seems to present a strong correlation with the central nervous system fluid levels. The patients with SZ usually adopts a sedentary lifestyle, which has been partly associated with the increase in obesity incidence rates, metabolic syndrome, type 2 diabetes and coronary heart disease. On the other hand, exercise, a non-invasive and low cost intervention, has been considered an important additional therapeutic option for this population, promoting benefits to physical and mental health. To our knowledge, few studies have been pointed out that the positive effects of exercise in SZ patients are mediated, at least in part, to enhanced levels of BDNF after training. However, these studies are focused on evaluating the effect of single bouts of exercise of chronic interventions, data concerning the short- and long-term exercise outcomes on BDNF are scarce. Therefore, this study aimed to evaluate the effect of a concurrent exercise protocol (CEP) on plasma BDNF levels of SZ patients in different time-points. Material and Methods: This study was approved by the Research Ethics Committee of the Centro Universitário Metodista do IPA (no 1.243.680/2015). The participants (n=15) were subbmited to the CEP during 90 days, 3 times a week for 60 minutes each session. In order to evaluate the short and long-term effects of exercise, blood samples were collected pre, 30, 60 and 90 days after the intervention began. Plasma BDNF levels were determined with the ELISA method, from Sigma-Aldrich commercial kit (catalog number RAB0026) according to manufacturer's instructions. Results: A remarkable increase on plasma BDNF levels at 90 days after training compared to baseline (p=0.006) and 30 days (p=0.007) values were observed. Conclusion: Our data are in agreement with several studies that show significant enhancement on BDNF levels in response to different exercise protocols in SZ individuals. We might suggest that BDNF upregulation after training in SZ patients acts in a dose-dependent manner, being more pronounced in response to chronic exposure. Acknowledgments: This work was supported by Fundação de Amparo à Pesquisa do Estado do Rio Grande do Sul (FAPERGS)/Brazil.

Keywords: exercise, BDNF, schizophrenia, time-points

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Authors: Adi Sharabi, Dafna Marom-Golan

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Parents’ involvement in the care of their children with Autism Spectrum Disorder (ASD) and its beneficial effect on the children’s developmental and educational outcomes is well documented. At the same time, parents of children with ASD tend to experience greater psychological distress than parents of children with other developmental disabilities or with typical development. Positive social support is an important resource used by parents to reduce their psychological distress. The goal of the current research was to examine the contribution of formal and informal social support in explaining mothers’ and fathers’ involvement with their young children with ASD. The sample consisted of 107 parents who live in Israel (61 mothers and 46 fathers) of children aged between 2 and 7, all diagnosed with ASD and attending special kindergartens or special day care for children with ASD. Parental involvement and social support perception were assessed. Initial analysis focused on the relations between involvement, support, and demographic variables. In addition, analysis of variance (ANOVA) was conducted to test differences between mothers and fathers. Two hierarchical multiple regression analyses were performed to examine the predicted factors in the involvement model while controlling for group (mothers/fathers). Results indicate that mothers reported significantly higher levels of parenting involvement than fathers. Mothers reported higher levels of general involvement and all sub-types of involvement. For example, mothers reported that they were more interested in and have higher levels of attendance in their child’s educational program. They were also more collaborative in their child’s educational therapeutic program, and socialized with other parents of children from their child’s kindergarten than fathers. Mothers’ involvement was found to be related to their informal support (non-formal relatives). Findings also reveal significant differences between mothers and fathers on the formal support subscale measure of specializes services. Fathers, more than mothers, reported more specializes services support such as social workers or professional therapists. Separate hierarchical multiple regression analyses revealed a unique gender difference in the factors that explained parental involvement. Specifically, informal support only had a unique positive contribution in explaining mothers’, but not fathers’ involvement. This study highlights the central role of mothers in maintaining constant contact with the educational system and the professionals who help care for their child with ASD. At the same time, this research emphasizes the crucial role of both mothers and fathers in their child's development and well-being at every development stage, particularly in early development. Further, different kinds of social support seem to relate to the different kinds of parental involvement. It is in the best interest of educators and family therapists who work with families with children with ASD to support the cohesiveness of the family and the collaboration of the parents by understanding and respecting the way each member addresses the responsibilities of parenting a child with ASD, and her or his need for different types of social support.

Keywords: parental differences, parental involvement, social support, specialized support services

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Authors: Ammar Asma, Bouafia Nabiha, Ben Cheikh Asma, Ezzi Olfa, Mahjoub Mohamed, Sma Nesrine, Chouchène Imed, Boussarsar Hamadi, Njah Mansour

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Background: Ventilator-associated pneumonia (VAP) is currently recognized as one of the most relevant causes of morbidity and mortality among intensive care unit (ICU) patients worldwide. Identifying modifiable risk factors for VAP could be helpful for future controlled interventional studies aiming at improving prevention of VAP. The purposes of this study were to determine the incidence and risk factors for VAP in in a Tunisian medical ICU. Materials / Methods: A retrospective case-control study design based on the prospective database collected over a 14-month period from September 15th, 2015 through November 15th, 2016 in an 8-bed medical ICU. Patients under ventilation for over 48 h were included. The number of cases was estimated by Epi-info Software with the power of statistical test equal to 90 %. Each case patient was successfully matched to two controls according to the length of mechanical ventilation (MV) before VAP for cases and the total length of MV in controls. VAP in the ICU was defined according to American Thoracic Society; Infectious Diseases Society of America guidelines. Early onset or late-onset VAP were defined whether the infectious process occurred within or after 96 h of ICU admission. Patients’ risk factors, causes of admission, comorbidities and respiratory specimens collected were reviewed. Univariate and multivariate analyses were performed to determine variables associated with VAP with a p-value < 0.05. Results: During the period study, a total of 169 patients under mechanical ventilation were considered, 34 patients (20.11%) developed at least one episode of VAP in the ICU. The incidence rate for VAP was 14.88/1000 ventilation days. Among these cases, 9 (26.5 %) were early-onset VAP and 25 (73.5 %) were late-onset VAP. It was a certain diagnosis in 66.7% of cases. Tracheal aspiration was positive in 80% of cases. Multi-drug resistant Acinerobacter baumanii was the most common species detected in cases; 67.64% (n=23). The rate of mortality out of cases was 88.23% (n= 30). In univariate analysis, the patients with VAP were statistically more likely to suffer from cardiovascular diseases (p=0.035) and prolonged duration of sedation (p=0.009) and tracheostomy (p=0.001), they also had a higher number of re-intubation (p=0.017) and a longer total time of intubation (p=0.012). Multivariate analysis showed that cardiovascular diseases (OR= 4.44; 95% IC= [1.3 - 14]; p=0.016), tracheostomy (OR= 4.2; 95% IC= [1.16 -15.12]; p= 0.028) and prolonged duration of sedation (OR=1.21; 95% IC= [1.07, 1.36]; p=0.002) were independent risk factors for the development of VAP. Conclusion: VAP constitutes a therapeutic challenge in an ICU setting, therefore; strategies that effectively prevent VAP are needed. An infection control-training program intended to all professional heath care in this unit insisting on bundles and elaboration of procedures are planned to reduce effectively incidence rate of VAP.

Keywords: case control study, intensive care unit, risk factors, ventilator associated pneumonia

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Authors: Alinka Molnár-Tóth, Tímea Tánczos, Regina Barna, Katalin Jakab, Péter Klivényi

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Supported by neuroscientific findings, the so-called Hub-and-Spoke model of the human semantic system is based on two subcomponents of semantic cognition, namely the semantic control process and semantic representation. Our semantic knowledge is multimodal in nature, as the knowledge system stored in relation to a conception is extensive and broad, while different aspects of the conception may be relevant depending on the purpose. The motivation of our research is to develop a new diagnostic measurement procedure based on the preservation of semantic representation, which is appropriate to the specificities of the Hungarian language and which can be used to compare the non-verbal semantic knowledge of healthy and aphasic persons. The development of the test will broaden the Hungarian clinical diagnostic toolkit, which will allow for more specific therapy planning. The sample of healthy persons (n=480) was determined by the last census data for the representativeness of the sample. Based on the concept of the Pyramids and Palm Tree Test, and according to the characteristics of the Hungarian language, we have elaborated a test based on different types of semantic information, in which the subjects are presented with three pictures: they have to choose the one that best fits the target word above from the two lower options, based on the semantic relation defined. We have measured 5 types of semantic knowledge representations: associative relations, taxonomy, motional representations, concrete as well as abstract verbs. As the first step in our data analysis, we examined the normal distribution of our results, and since it was not normally distributed (p < 0.05), we used nonparametric statistics further into the analysis. Using descriptive statistics, we could determine the frequency of the correct and incorrect responses, and with this knowledge, we could later adjust and remove the items of questionable reliability. The reliability was tested using Cronbach’s α, and it can be safely said that all the results were in an acceptable range of reliability (α = 0.6-0.8). We then tested for the potential gender differences using the Mann Whitney-U test, however, we found no difference between the two (p < 0.05). Likewise, we didn’t see that the age had any effect on the results using one-way ANOVA (p < 0.05), however, the level of education did influence the results (p > 0.05). The relationships between the subtests were observed by the nonparametric Spearman’s rho correlation matrix, showing statistically significant correlation between the subtests (p > 0.05), signifying a linear relationship between the measured semantic functions. A margin of error of 5% was used in all cases. The research will contribute to the expansion of the clinical diagnostic toolkit and will be relevant for the individualised therapeutic design of treatment procedures. The use of a non-verbal test procedure will allow an early assessment of the most severe language conditions, which is a priority in the differential diagnosis. The measurement of reaction time is expected to advance prodrome research, as the tests can be easily conducted in the subclinical phase.

Keywords: communication disorders, diagnostic toolkit, neurorehabilitation, semantic knowlegde

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Authors: Aoxue Yang, Weili Tian, Haikun Liu

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Brain tumor stem cells (BTSCs) are resistant to therapy and give rise to recurrent tumors. These rare and elusive cells are likely to disseminate during cancer progression, and some may enter dormancy, remaining viable but not increasing. The identification of dormant BTSCs is thus necessary to design effective therapies for glioblastoma (GBM) patients. Glucocorticoids (GCs) are used to treat GBM-associated edema. However, glucocorticoids participate in the physiological response to psychosocial stress, linked to poor cancer prognosis. This raises concern that glucocorticoids affect the tumor and BTSCs. Identifying markers specifically expressed by brain tumor stem cells (BTSCs) may enable specific therapies that spare their regular tissue-resident counterparts. By ribosome profiling analysis, we have identified that glycerol-3-phosphate dehydrogenase 1 (GPD1) is expressed by dormant BTSCs but not by NSCs. Through different stress-induced experiments in vitro, we found that only dexamethasone (DEXA) can significantly increase the expression of GPD1 in NSCs. Adversely, mifepristone (MIFE) which is classified as glucocorticoid receptors antagonists, could decrease GPD1 protein level and weaken the proliferation and stemness in BTSCs. Furthermore, DEXA can induce GPD1 expression in tumor-bearing mice brains and shorten animal survival, whereas MIFE has a distinct adverse effect that prolonged mice lifespan. Knocking out GR in NSC can block the upregulation of GPD1 inducing by DEXA, and we find the specific sequences on GPD1 promotor combined with GR, thus improving the efficiency of GPD1 transcription from CHIP-Seq. Moreover, GR and GPD1 are highly co-stained on GBM sections obtained from patients and mice. All these findings confirmed that GR could regulate GPD1 and loss of GPD1 Impairs Multiple Pathways Important for BTSCs Maintenance GPD1 is also a critical enzyme regulating glycolysis and lipid synthesis. We observed that DEXA and MIFE could change the metabolic profiles of BTSCs by regulating GPD1 to shift the transition of cell dormancy. Our transcriptome and lipidomics analysis demonstrated that cell cycle signaling and phosphoglycerides synthesis pathways contributed a lot to the inhibition of GPD1 caused by MIFE. In conclusion, our findings raise concern that treatment of GBM with GCs may compromise the efficacy of chemotherapy and contribute to BTSC dormancy. Inhibition of GR can dramatically reduce GPD1 and extend the survival duration of GBM-bearing mice. The molecular link between GPD1 and GR may give us an attractive therapeutic target for glioblastoma.

Keywords: cancer stem cell, dormancy, glioblastoma, glycerol-3-phosphate dehydrogenase 1, glucocorticoid receptor, dexamethasone, RNA-sequencing, phosphoglycerides

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Authors: Heather Warfield, Brad Genereux

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Military personnel encounter a number of challenges when separating from military service to include career uncertainty, relational/family dynamics, trauma as a result of military experiences, reconceptualization of identity, and existential issues related to purpose, meaning making and framing of the military experience(s). Embedded within military culture are well-defined rites of passage and a significant sense of belonging. Consequently, transition out of the military can result in the loss of such rites of passage and belongingness. However, a pilgrimage journey can provide the time and space to engage in a new rite of passage, to construct a new pilgrim identity, and a to develop deep social relationships that lead to a sense of belongingness to a particular pilgrim community as well as to the global community of pilgrims across numerous types of pilgrimage journeys. The aims of the current paper are to demonstrate the rationale for why pilgrimage journeys are particularly significant for military veterans, provide an overview of an innovative program that facilitates the Camino de Santiago pilgrimage for military veterans, and discusses the lessons learned from the initial pilot project of a recently established program. Veterans on the Camino (VOC) is an emerging nongovernmental organization in the USA. Founded by a military veteran, after leaving his military career, the primary objective of the organization is to facilitate healing for veterans via the Camino de Santiago pilgrimage journey. As part of the program, participants complete a semi-structured interview at three time points – pre, during, and post journey. The interview items are based on ongoing research by the principal investigator and address such constructs as meaning-making, wellbeing, therapeutic benefits and transformation. In addition, program participants complete The Sources of Meaning and Meaning in Life Questionnaire (SoMe). The pilot program occurred in the spring of 2017. Five participants were selected after an extensive application process and review by a three-person selection board. The selection criteria included demonstrated compatibility with the program objectives (i.e., prior military experience, availability for a 40 day journey, and awareness of the need for a transformational intervention). The participants were connected as a group through a private Facebook site and interacted with one another for several months prior to the pilgrimage. Additionally, the participants were interviewed prior to beginning the pilgrimage, at one point during the pilgrimage and immediately following the conclusion of the pilgrimage journey. The interviews yielded themes related to loss, meaning construction, renewed hope in humanity, and a commitment to future goals. The lessons learned from this pilot project included a confirmation of the need for such a program, a need for greater focus on logistical details, and the recognition that the pilgrimage experience needs to continue in some manner once the veterans return home.

Keywords: pilgrimage, healing, military veterans, Camino de Santiago

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Authors: Nyathi Mpumelelo; Moeng Thabiso Maria

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BACKGROUND AND OBJECTIVES: Radiopharmaceuticals are used for diagnosis, treatment, staging and follow up of various diseases. However, there is concern that the ionizing radiation (gamma rays, α and ß particles) emitted by radiopharmaceuticals may result in exposure of radiographers and nurses with limited knowledge of the principles of radiation protection and safety, raising the risk of cancer induction. This study aimed at investigation radiation safety awareness levels among radiographers and nurses at a small tertiary hospital in South Africa. METHODS: An analytical cross-sectional study. A validated two-part questionnaire was implemented to consenting radiographers and nurses working in a Nuclear Medicine Department. Part 1 gathered demographic information (age, gender, work experience, attendance to/or passing ionizing radiation protection courses). Part 2 covered questions related to knowledge and awareness of radiation protection principles. RESULTS: Six radiographers and five nurses participated (27% males and 73% females). The mean age was 45 years (age range 20-60 years). The study revealed that neither professional development courses nor radiation protection courses are offered at the Nuclear Medicine Department understudy. However, 6/6 (100%) radiographers exhibited a high level of awareness of radiation safety principles on handling and working with radiopharmaceuticals which correlated to their years of experience. As for nurses, 4/5 (80%) showed limited knowledge and awareness of radiation protection principles irrespective of the number of years in the profession. CONCLUSION: Despite their major role of caring for patients undergoing diagnostic and therapeutic treatments, the nurses showed limited knowledge of ionizing radiation and associated side effects. This was not surprising since they never received any formal basic radiation safety course. These findings were not unique to this Centre. A study conducted in a Kuwaiti Radiology Department also established that the vast majority of nurses did not understand the risks of working with ionizing radiation. Similarly, nurses in an Australian hospital exhibited knowledge limitations. However, nursing managers did provide the necessary radiation safety training when requested. In Guatemala and Saudi Arabia, where there was shortage of professional radiographers, nurses underwent radiography training, a course that equipped them with basic radiation safety principles. The radiographers in the Centre understudy unlike others in various parts of the world demonstrated substantial knowledge and awareness on radiation protection. Radiations safety courses attended when an opportunity arose played a critical role in their awareness. The knowledge and awareness levels of these radiographers were comparable to their counterparts in Sudan. However, it was much more above that of their counterparts in Jordan, Nigeria, Nepal and Iran who were found to have limited awareness and inadequate knowledge on radiation dose. Formal radiation safety and awareness courses and workshops can play a crucial role in raising the awareness of nurses and radiographers on radiation safety for their personal benefit and that of their patients.

Keywords: radiation safety, radiation awareness, training, nuclear medicine

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Authors: Sakshi Piplani, Ajit Kumar

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Valproic acid (VPA) is the first synthetic therapeutic agent used to treat epileptic disorders, which account for affecting nearly 1% world population. Teratogenicity caused by VPA has prompted the search for next generation drug with better efficacy and lower side effects. Recent studies have posed HDAC8 as direct target of VPA that causes the teratogenic effect in foetus. We have employed molecular dynamics (MD) and docking simulations to understand the binding mode of VPA and their analogues onto HDAC8. A total of twenty 3D-structures of human HDAC8 isoforms were selected using BLAST-P search against PDB. Multiple sequence alignment was carried out using ClustalW and PDB-3F07 having least missing and mutated regions was selected for study. The missing residues of loop region were constructed using MODELLER and energy was minimized. A set of 216 structural analogues (>90% identity) of VPA were obtained from Pubchem and ZINC database and their energy was optimized with Chemsketch software using 3-D CHARMM-type force field. Four major neurotransmitters (GABAt, SSADH, α-KGDH, GAD) involved in anticonvulsant activity were docked with VPA and its analogues. Out of 216 analogues, 75 were selected on the basis of lower binding energy and inhibition constant as compared to VPA, thus predicted to have anti-convulsant activity. Selected hHDAC8 structure was then subjected to MD Simulation using licenced version YASARA with AMBER99SB force field. The structure was solvated in rectangular box of TIP3P. The simulation was carried out with periodic boundary conditions and electrostatic interactions and treated with Particle mesh Ewald algorithm. pH of system was set to 7.4, temperature 323K and pressure 1atm respectively. Simulation snapshots were stored every 25ps. The MD simulation was carried out for 20ns and pdb file of HDAC8 structure was saved every 2ns. The structures were analysed using castP and UCSF Chimera and most stabilized structure (20ns) was used for docking study. Molecular docking of 75 selected VPA-analogues with PDB-3F07 was performed using AUTODOCK4.2.6. Lamarckian Genetic Algorithm was used to generate conformations of docked ligand and structure. The docking study revealed that VPA and its analogues have more affinity towards ‘hydrophobic active site channel’, due to its hydrophobic properties and allows VPA and their analogues to take part in van der Waal interactions with TYR24, HIS42, VAL41, TYR20, SER138, TRP137 while TRP137 and SER138 showed hydrogen bonding interaction with VPA-analogues. 14 analogues showed better binding affinity than VPA. ADMET SAR server was used to predict the ADMET properties of selected VPA analogues for predicting their druggability. On the basis of ADMET screening, 09 molecules were selected and are being used for in-vivo evaluation using Danio rerio model.

Keywords: HDAC8, docking, molecular dynamics simulation, valproic acid

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Authors: Vijaya Kumar, Vidayasagar Pagilla, Abraham Joshua, Rakshith Kedambadi, Prasanna Mithra

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Background: Post stroke rehabilitation are aimed to accelerate for optimal sensorimotor recovery, functional gain and to reduce long-term dependency. Intensive physical therapy interventions can enhance this recovery as experience-dependent neural plastic changes either directly act at cortical neural networks or at distal peripheral level (muscular components). Neuromuscular Electrical Stimulation (NMES), a traditional bottom-up approach, mirror therapy (MT), a relatively new top down approach have found to be an effective adjuvant treatment methods for lower extremity motor and functional recovery in stroke rehabilitation. However there is a scarcity of evidence to compare their therapeutic gain in stroke recovery.Aim: To compare the efficacy of neuromuscular electrical stimulation (NMES) and mirror therapy (MT) in very early phase of post stroke rehabilitation addressed to lower extremity motor recovery and balance. Design: observer blinded Randomized Clinical Trial. Setting: Neurorehabilitation Unit, Department of Physical Therapy, Tertiary Care Hospitals. Subjects: 32 acute stroke subjects with first episode of unilateral stroke with hemiparesis, referred for rehabilitation (onset < 3 weeks), Brunnstorm lower extremity recovery stages ≥3 and MMSE score more than 24 were randomized into two group [Group A-NMES and Group B-MT]. Interventions: Both the groups received eclectic approach to remediate lower extremity recovery which includes treatment components of Roods, Bobath and Motor learning approaches for 30 minutes a day for 6 days. Following which Group A (N=16) received 30 minutes of surface NMES training for six major paretic muscle groups (gluteus maximus and medius,quadriceps, hamstrings, tibialis anterior and gastrocnemius). Group B (N=16) was administered with 30 minutes of mirror therapy sessions to facilitate lower extremity motor recovery. Outcome measures: Lower extremity motor recovery, balance and activities of daily life (ADLs) were measured by Fugyl Meyer Assessment (FMA-LE), Berg Balance Scale (BBS), Barthel Index (BI) before and after intervention. Results: Pre Post analysis of either group across the time revealed statistically significant improvement (p < 0.001) for all the outcome variables for the either group. All parameters of NMES had greater change scores compared to MT group as follows: FMA-LE (25.12±3.01 vs. 23.31±2.38), BBS (35.12±4.61 vs. 34.68±5.42) and BI (40.00±10.32 vs. 37.18±7.73). Between the groups comparison of pre post values showed no significance with FMA-LE (p=0.09), BBS (p=0.80) and BI (p=0.39) respectively. Conclusion: Though either groups had significant improvement (pre to post intervention), none of them were superior to other in lower extremity motor recovery and balance among acute stroke subjects. We conclude that eclectic approach is an effective treatment irrespective of NMES or MT as an adjunct.

Keywords: balance, motor recovery, mirror therapy, neuromuscular electrical stimulation, stroke

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Authors: Milu T. Cherian, Sergio C. Chai, Morgan A. Casal, Taosheng Chen

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This study aims to use CINPA1, a recently discovered small-molecule inhibitor of the xenobiotic receptor CAR (constitutive androstane receptor) for understanding the binding modes of CAR and to guide CAR-mediated gene expression profiling studies in human primary hepatocytes. CAR and PXR are xenobiotic sensors that respond to drugs and endobiotics by modulating the expression of metabolic genes that enhance detoxification and elimination. Elevated levels of drug metabolizing enzymes and efflux transporters resulting from CAR activation promote the elimination of chemotherapeutic agents leading to reduced therapeutic effectiveness. Multidrug resistance in tumors after chemotherapy could be associated with errant CAR activity, as shown in the case of neuroblastoma. CAR inhibitors used in combination with existing chemotherapeutics could be utilized to attenuate multidrug resistance and resensitize chemo-resistant cancer cells. CAR and PXR have many overlapping modulating ligands as well as many overlapping target genes which confounded attempts to understand and regulate receptor-specific activity. Through a directed screening approach we previously identified a new CAR inhibitor, CINPA1, which is novel in its ability to inhibit CAR function without activating PXR. The cellular mechanisms by which CINPA1 inhibits CAR function were also extensively examined along with its pharmacokinetic properties. CINPA1 binding was shown to change CAR-coregulator interactions as well as modify CAR recruitment at DNA response elements of regulated genes. CINPA1 was shown to be broken down in the liver to form two, mostly inactive, metabolites. The structure-activity differences of CINPA1 and its metabolites were used to guide computational modeling using the CAR-LBD structure. To rationalize how ligand binding may lead to different CAR pharmacology, an analysis of the docked poses of human CAR bound to CITCO (a CAR activator) vs. CINPA1 or the metabolites was conducted. From our modeling, strong hydrogen bonding of CINPA1 with N165 and H203 in the CAR-LBD was predicted. These residues were validated to be important for CINPA1 binding using single amino-acid CAR mutants in a CAR-mediated functional reporter assay. Also predicted were residues making key hydrophobic interactions with CINPA1 but not the inactive metabolites. Some of these hydrophobic amino acids were also identified and additionally, the differential coregulator interactions of these mutants were determined in mammalian two-hybrid systems. CINPA1 represents an excellent starting point for future optimization into highly relevant probe molecules to study the function of the CAR receptor in normal- and pathophysiology, and possible development of therapeutics (for e.g. use for resensitizing chemoresistant neuroblastoma cells).

Keywords: antagonist, chemoresistance, constitutive androstane receptor (CAR), multi-drug resistance, structure activity relationship (SAR), xenobiotic resistance

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Authors: Eun-Seop Kim, Eun-Ha Jang, Rana R. Kim, Sae-Byul Jang

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Objective: Preterm labor is the most common antecedent of preterm birth(PTB), which is characterized by regular uterine contraction before 37 weeks of pregnancy and cervical change. In acute preterm labor, tocolytics are administered as the first-line medication to suppress uterine contractions but rarely delay pregnancy to 37 weeks of gestation. On the other hand, according to the Korean Traditional Medicine, PTB is caused by the deficiency of Qi and unnecessary energy in the body of the mother. The aim of this study was to demonstrate the benefit of Traditional Korean Medicine as an adjuvant therapy in management of early uterine contractions and the prevention of PTB. Methods: It is a case report of a 38-year-old woman (0-0-6-0) hospitalized for irregular uterine contractions and cervical change at 33+3/7 weeks of gestation. Past history includes chemical pregnancies achieved by Artificial Rroductive Technology(ART), one stillbirth (at 7 weeks) and a laparoscopic surgery for endometriosis. After seven trials of IVF and articificial insemination, she had succeeded in conception via in-vitro fertilization (IVF) with help of Traditional Korean Medicine (TKM) treatments. Due to irregular uterine contractions and cervical changes, 2 TKM were prescribed: Gami-Dangguisan, and Antae-eum, known to nourish blood and clear away heat. 120ml of Gami-Dangguisan was given twice a day monring and evening along with same amount of Antae-eum once a day from 31 August 2013 to 28 November 2013. Tocolytics (Ritodrine) was administered as a first aid for maintenance of pregnancy. Information regarding progress until the delivery was collected during the patient’s visit. Results: On admission, the cervix of 15mm in length and cervical os with 0.5cm-dilated were observed via ultrasonography. 50% cervical effacement was also detected in physical examination. Tocolysis had been temporarily maintained. As a supportive therapy, TKM herbal preparations(gami-dangguisan and Antae-eum) were concomitantly given. As of 34+2/7 weeks of gestation, however intermittent uterine contractions appeared (5-12min) on cardiotocography and vaginal bleeding was also smeared at 34+3/7 weeks. However, enhanced tocolytics and continuous administration of herbal medicine sustained the pregnancy to term. At 37+2/7 weeks, no sign of labor with restored cervical length was confirmed. The woman gave a term birth to a healthy infant via vaginal delivery at 39+3/7 gestational weeks. Conclusions: This is the first successful case report about a preter labor patient administered with conventional tocolytic agents as well as TKM herbal decoctions, delaying delivery to term. This case deserves attention considering it is rare to maintain gestation to term only with tocolytic intervention. Our report implies the potential of herbal medicine as an adjuvant therapy for preterm labor treatment. Further studies are needed to assess the safety and efficacy of TKM herbal medicine as a therapeutic alternative for curing preterm birth.

Keywords: preterm labor, traditional Korean medicine, herbal medicine, integrative treatment, complementary and alternative medicine

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Authors: R. P. Hewawasam, A. F. Dulhunty

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The ryanodine receptor (RyR) is an intracellular ion channel that releases Ca2+ from the sarcoplasmic reticulum and is essential for the excitation-contraction coupling and contraction in striated muscle. Human muscle specific glutathione transferase M2-2 (GSTM2-2) is a highly specific inhibitor of cardiac ryanodine receptor (RyR2) activity. Single channel-lipid bilayer studies and Ca2+ release assays performed using the C-terminal half of the GSTM2-2 and its mutants F157A and Y160A confirmed the ability of the C terminal domain of GSTM2-2 to specifically inhibit the cardiac ryanodine receptor activity. Objective of the present study is to determine the effect of C terminal domain of GSTM2-2 (GSTM2-2C) and the mutants, F157A and Y160A on the Ca2+ transients of neonatal ventricular cardiomyocytes. Primary cardiomyocytes were cultured from neonatal rats. They were treated with GSTM2-2C and the two mutants F157A and Y160A at 15µM and incubated for 2 hours. Then the cells were led with Fluo-4AM, fluorescent Ca2+ indicator, and the field stimulated (1 Hz, 3V and 2ms) cells were excited using the 488 nm argon laser. Contractility of the cells were measured and the Ca2+ transients in the stained cells were imaged using Leica SP5 confocal microscope. Peak amplitude of the Ca2+ transient, rise time and decay time from the peak were measured for each transient. In contrast to GSTM2C which significantly reduced the % shortening (42.8%) in the field stimulated cells, F157A and Y160A failed to reduce the % shortening.Analysis revealed that the average amplitude of the Ca2+ transient was significantly reduced (P<0.001) in cells treated with the wild type GSTM2-2C compared to that of untreated cells. Cells treated with the mutants F157A and Y160A didn’t change the Ca2+ transient significantly compared to the control. A significant increase in the rise time (P< 0.001) and a significant reduction in the decay time (P< 0.001) were observed in cardiomyocytes treated with GSTM2-2C compared to the control but not with F157A and Y160A. These results are consistent with the observation that GSTM2-2C reduced the Ca2+ release from the cardiac SR significantly whereas the mutants, F157A and Y160A didn’t show any effect compared to the control. GSTM2-2C has an isoform-specific effect on the cardiac ryanodine receptor activity and also it inhibits RyR2 channel activity only during diastole. Selective inhibition of RyR2 by GSTM2-2C has significant clinical potential in the treatment of cardiac arrhythmias and heart failure. Since GSTM2-2C-terminal construct has no GST enzyme activity, its introduction to the cardiomyocyte would not exert any unwanted side effects that may alter its enzymatic action. The present study further confirms that GSTM2-2C is capable of decreasing the Ca2+ release from the cardiac SR during diastole. These results raise the future possibility of using GSTM2-2C as a template for therapeutics that can depress RyR2 function when the channel is hyperactive in cardiac arrhythmias and heart failure.

Keywords: arrhythmia, cardiac muscle, cardiac ryanodine receptor, GSTM2-2

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Authors: Caterina Grandi, Lukas Lochner, Marco Padovan, Mirco Rizzi, Paola Sperinde, Fabio Vittadello, Luisa Cavada

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Background: In recent years, the use of Complementary Alternative Medicine (CAM) has achieved worldwide popularity. With the increased public interest in CAMs, attention to it within Health Care Schools and Colleges has also improved. Studies generally assess the knowledge and attitudes regarding CAMs in medical and nursing students. The current study focused on the knowledge, attitudes and practice of CAM in healthcare students. Aim: To assess the knowledge and attitudes regarding complementary and alternative medicine (CAM) in healthcare students in South Tyrol, a region in Northern Italy. Methodology: This cross-sectional study was carried out among 361 students. Self-administered questionnaire was adapted and modified by the researchers from several questionnaires. The instrument consisted of three sections: 1) demographical characteristics (gender, place of residence and year of study); 2) general attitudes towards CAM, evaluated through 11 items using a Likert scale (agree, partly agree, partly disagree, disagree); 3) knowledge and use about any particular CAM practices (acupuncture, aromatherapy, creative therapies, diet/nutritional therapies, phytotherapy/herbal therapies, compresses, massage therapy, Ayurvedic therapy, Tibetan medicine, naturopathy, homeopathy, pet therapy, reflexology, therapeutic touch, chiropractic/osteopathy). Results: The sample consisted of 63 males and 297 females, 58% living in villages. 151 students (42%) were in the first year, 99 (27%) in the second and 106 (30%) in the third. Both men and women agreed with statements about the utility and benefits of CAMs. Women were significantly more likely than men to agree that the CAM practices should be included in the curriculum (p < 0.004), that the health professionals should be able to advice their patients about commonly used CAM methods (p < 0.002) and that the clinical care should integrate CAM practices (p < 0.04). Students in the second year showed the highest mean score for the statement 'CAM includes ideas and methods from which conventional medicine could benefit' (p = 0.049), highlighting a positive attitude, while students in the third year achieved the lowest mean score for the negative statement 'The results of CAM are in most cases due to a placebo effect'. Regarding this statement, participants living in villages disagreed significantly than students living in the city (p < 0.001). Females appeared to be significantly more familiar with homeopathy (p < 0.002), aromatherapy (p < 0.033), creative therapies (p < 0.001) and herbal therapies (p<0.002) than males. Moreover, women were likely to use CAM more frequently than men, particularly to solve psychological problems (p < 0.004). In addition, women perceived the benefit significantly more positive than men (p < 0.001). Students in the second year revealed to use the CAM mostly to improve the quality of life (p < 0.023), while students in the third year used CAMs particularly for chronic diseases (p < 0.001). Conclusions: Results from this study suggested that female students show more positive attitudes on CAM than male students. Moreover, the prevalence of CAM use and its perceived benefits differ between males and females, so that women are more willing to use CAM practices.

Keywords: attitude, CAM, complementary and alternative medicine, healthcare students, knowledge

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Authors: Almudena Espin Perez, Tyler Risom, Carl Pelz, Isabel English, Robert M. Angelo, Rosalie Sears, Andrew J. Gentles

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Pancreatic ductal adenocarcinoma (PDAC) is one of the most deadly malignancies. The role of the tumor microenvironment (TME) is gaining significant attention in cancer research. Despite ongoing efforts, the nature of the interactions between tumors, immune cells, and stromal cells remains poorly understood. The cell-intrinsic properties that govern cell lineage plasticity in PDAC and extrinsic influences of immune populations require technically challenging approaches due to the inherently heterogeneous nature of PDAC. Understanding the cell lineage plasticity of PDAC will improve the development of novel strategies that could be translated to the clinic. Members of the team have demonstrated that the acquisition of ductal to neuroendocrine lineage plasticity in PDAC confers therapeutic resistance and is a biomarker of poor outcomes in patients. Our approach combines computational methods for deconvolving bulk transcriptomic cancer data using CIBERSORTx and high-throughput single-cell imaging using Multiplexed Ion Beam Imaging (MIBI) to study lineage plasticity in PDAC and its relationship to the infiltrating immune system. The CIBERSORTx algorithm uses signature matrices from immune cells and stroma from sorted and single-cell data in order to 1) infer the fractions of different immune cell types and stromal cells in bulked gene expression data and 2) impute a representative transcriptome profile for each cell type. We studied a unique set of 300 genomically well-characterized primary PDAC samples with rich clinical annotation. We deconvolved the PDAC transcriptome profiles using CIBERSORTx, leveraging publicly available single-cell RNA-seq data from normal pancreatic tissue and PDAC to estimate cell type proportions in PDAC, and digitally reconstruct cell-specific transcriptional profiles from our study dataset. We built signature matrices and optimized by simulations and comparison to ground truth data. We identified cell-type-specific transcriptional programs that contribute to cancer cell lineage plasticity, especially in the ductal compartment. We also studied cell differentiation hierarchies using CytoTRACE and predict cell lineage trajectories for acinar and ductal cells that we believe are pinpointing relevant information on PDAC progression. Collaborators (Angelo lab, Stanford University) has led the development of the Multiplexed Ion Beam Imaging (MIBI) platform for spatial proteomics. We will use in the very near future MIBI from tissue microarray of 40 PDAC samples to understand the spatial relationship between cancer cell lineage plasticity and stromal cells focused on infiltrating immune cells, using the relevant markers of PDAC plasticity identified from the RNA-seq analysis.

Keywords: deconvolution, imaging, microenvironment, PDAC

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