Deleterious Systemic Effects Research Articles

Mindful Self-Compassion as an Antidote to Burnout for Mental Health Practitioners.

The objective of this correlational study was to explore the relationship between levels of self-compassion and burnout for currently practicing mental health practitioners (MHPs) in the United States. All professionals are vulnerable to burnout based on various types of organizational stressors, but burnout is of particular concern for health care service providers who may need to adopt a stance of detachment, or emotional distance, as relief from intense workloads, with clients. The data were collected through an online survey. Regression analysis found that scores from Neff's Self-Compassion Scale were a significant negative predictor of levels of MHP burnout, as assessed by Schaufeli et al.'s Burnout Assessment Tool, p < 0.001. The implication of this finding is that cultivating self-compassion appears to be a pragmatic self-care strategy for MHPs to mitigate the negative effects of burnout. More educational and occupational training in self-compassion practices as self-care should be provided to help protect the physical and emotional well-being of MHPs. The deleterious systemic effects of burnout make MHP self-care an ethical issue, along with the need to identify protective factors, prevention, and treatment of burnout.

Off Pump CABG Improves Postoperative Incidence of Coagulopathy Compared with CABG on Pump

Abstract Background Coronary artery bypass grafting remains the standard treatment for patients with extensive coronary artery disease. Coronary surgery without use of cardiopulmonary bypass avoids the deleterious systemic inflammatory effects of the extracorporeal circuit. However there is an ongoing debate surrounding the clinical outcomes after on-pump versus off-pump coronary artery bypass (ONCAB versus OPCAB) grafting surgery. Aim of the Work To compare the incidence of postoperative coagulopathy transfusion of blood product therapy, (Packed RBCs, FFP and platelet concentrate) bleeding (amount of blood in chest tube drains) and reexploration, that occur in adults off pump CABG surgery in comparison to on pump CABG. Patients and Methods We enrolled sixty consecutive adult patients scheduled for isolated CABG surgery (with a median sternotomy) with or without cardiopulmonary bypass pump. The patients are allocated in two groups where thirty patients in each group (group A – On pump – ONCAB- conventional surgery) and (group B – Off pump – OPCAB – beating heart) after obtaining their written informed consent. Results The clinical outcome measure was the incidence of bleeding in group B less than group A. In our study there was highly significant increase in the amount of blood in drains, transfusion requirements and need for re-exploration within twenty four hours after surgery in group A than group B. Conclusion We concluded that off pump cardiac surgery is better than on pump procedure in decreasing risk of bleeding, post-operative transfusion requirements and risk of re-exploration.

Hyaluronic Acid-Mediated Phenolic Compound Nanodelivery for Cancer Therapy.

Phenolic compounds are bioactive phytochemicals showing a wide range of pharmacological activities, including anti-inflammatory, antioxidant, immunomodulatory, and anticancer effects. Moreover, they are associated with fewer side effects compared to most currently used antitumor drugs. Combinations of phenolic compounds with commonly used drugs have been largely studied as an approach aimed at enhancing the efficacy of anticancer drugs and reducing their deleterious systemic effects. In addition, some of these compounds are reported to reduce tumor cell drug resistance by modulating different signaling pathways. However, often, their application is limited due to their chemical instability, low water solubility, or scarce bioavailability. Nanoformulations, including polyphenols in combination or not with anticancer drugs, represent a suitable strategy to enhance their stability and bioavailability and, thus, improve their therapeutic activity. In recent years, the development of hyaluronic acid-based systems for specific drug delivery to cancer cells has represented a pursued therapeutic strategy. This is related to the fact that this natural polysaccharide binds to the CD44 receptor that is overexpressed in most solid cancers, thus allowing its efficient internalization in tumor cells. Moreover, it is characterized by high biodegradability, biocompatibility, and low toxicity. Here, we will focus on and critically analyze the results obtained in recent studies regarding the use of hyaluronic acid for the targeted delivery of bioactive phenolic compounds to cancer cells of different origins, alone or in combination with drugs.

First Hundred Off-Pump Coronary Artery Bypass Grafting Using Only Acrobat-SUV Stabilizer: How to Do It

Off-pump coronary artery bypass grafting (OPCAB) avoids the deleterious systemic inflammatory effects of the extracorporeal circuit. When a patient must pay all treatment expenses, cost cutting becomes very important to the treating surgeon. Considering both factors, an Acrobat-SUV heart stabiliser was used in the first 110 OPCAB patients to keep the expenditure minimal; the results were analysed at the end of 5 years.

Nanoparticle-assisted targeting of the tumour microenvironment

Cancer collectively represents a major, debilitating source of global disease burden. While we are just beginning to unravel the mysteries behind the multifarious pathways and mechanisms underpinning the complex process of tumourigenesis, advances in tumour biology have led to our current appreciation of the tumour microenvironment (TME). The TME is a dynamic, bidirectional crosstalk between malignant cells and the surrounding microenvironment comprising acellular components such as the extracellular matrix and cellular components which include immune cells and endothelium. Mounting evidence suggests that the TME is instrumental in reprogramming crucial oncogenic processes such as tumour initiation, growth, cellular energetics, invasion and metastasis. Given the significance of the TME, cancer research revolving around a targeted, TME-centric approach to treatment has been gaining traction. Nanoparticle (NP) technology offers a platform for the design of tissue-specific carrier system owing to its versatile and modifiable properties. The prospect of NPs targeting specific cellular or acellular components of the TME offers technical advantages such as high precision of tissue-specific drug delivery and therefore minimizing deleterious systemic toxicity and side effects. This review spotlights the updated image of the TME and its role in tumourigenesis, with emphasis on the hypoxic niche, immune microenvironment, acidic niche and extracellular matrix, before a discussion of NP-based treatment strategies to target the various pillars of the TME.

Pain and Pain Management in Sea Turtle and Herpetological Medicine: State of the Art

Simple SummaryRescue and rehabilitative medicine of sea turtles must deal with several circumstances that would be certainly considered painful in other species (trauma, situations that require surgery); thus, it would be natural to consider the use of analgesic drugs to manage the pain and avoid its deleterious systemic effects to guarantee a rapid recovery and release. However, in these animals (as well as in reptiles in general), many obstacles stand in the way of the application of safe and effective therapeutic protocols. It has been demonstrated that, anatomically and physiologically, turtles and reptiles in general must be considered able to experience pain in its definition of an “unpleasant sensory and emotional experience”. Unfortunately, specific studies concerning sea turtles and reptiles on pain assessment, safety, and clinical efficacy of analgesic drugs currently in use (mostly opioids and non-steroidal anti-inflammatory drugs—NSAIDs) are scarce and fragmentary and suffer from some basic gaps or methodological bias that prevent a correct interpretation of the results. At present, the general understanding of the physiology of reptiles’ pain and the possibility of its reasonable treatment is still in its infancy, considering the enormous amount of information still needed, and the use of analgesic drugs is still anecdotal or dangerously inferred from other species.In sea turtle rescue and rehabilitative medicine, many of the casualties suffer from occurrences that would be considered painful in other species; therefore, the use of analgesic drugs should be ethically mandatory to manage the pain and avoid its deleterious systemic effects to guarantee a rapid recovery and release. Nonetheless, pain assessment and management are particularly challenging in reptilians and chelonians. The available scientific literature demonstrates that, anatomically, biochemically, and physiologically, the central nervous system of reptiles and chelonians is to be considered functionally comparable to that of mammals albeit less sophisticated; therefore, reptiles can experience not only nociception but also “pain” in its definition of an unpleasant sensory and emotional experience. Hence, despite the necessity of appropriate pain management plans, the available literature on pain assessment and clinical efficacy of analgesic drugs currently in use (prevalently opioids and NSAIDs) is fragmented and suffers from some basic gaps or methodological bias that prevent a correct interpretation of the results. At present, the general understanding of the physiology of reptiles’ pain and the possibility of its reasonable treatment is still in its infancy, considering the enormous amount of information still needed, and the use of analgesic drugs is still anecdotal or dangerously inferred from other species.

A38 EVALUATING GLYCOCAGED DEXAMETHASONE IN SHIP-DEFICIENT MICE

Abstract Background Corticosteroids systemically reduce immune system activity thereby limiting inflammation in the GI tract. Corticosteroid use is limited by deleterious systemic effects including immunosuppression and adverse effects on growth and development (Giles et al., 2018). The metabolism of dietary polysaccharides, such as plant cell wall xyloglucan, by gut symbionts has been demonstrated to be mediated by niche members of the human gut microbiota (Larsbrink et al., 2014). By caging corticosteroids like dexamethasone (DEX) with xyloglucans to be released by microbiota at the site of disease, there is potential to increase efficacy and limit adverse effects. Mice deficient in Src homology 2 domain-containing inositol polyphosphate 5’-phosphatase (SHIP-/-) develop spontaneous CD-like ileal inflammation (Ngoh et al., 2016). We have used SHIP-/- mice to compare the efficacy of DEX versus caged DEX to reduce intestinal inflammation. Aims Caged DEX will reduce CD-like ileal inflammation in SHIP-/- mice at a lower dose than uncaged DEX because it is released and acts at the site of inflammation. To assess this hypothesis we propose 3 aims: Measure decaging activity along the GI tract of SHIP-/- mice ex vivo Determine the minimum effective dose of DEX required to reduce ileal inflammation in SHIP-/- mice Determine if equimolar and lower concentrations of caged DEX can reduce ileal inflammation in SHIP-/- mice Methods Intestinal contents and feces were harvested from SHIP-/- mice. Decaging activity was measured ex vivo, using caged resorufin (a fluorescent reporter). SHIP-/- mice were orally gavaged with dexamethasone (or vehicle), or the molar equivalent of caged dexamethasone from 6–8 weeks of age. At 8 weeks of age, gross and histopathology were assessed and IL-1β concentrations were measured in full-thickness tissue homogenates. Results SHIP-/- mice demonstrated decaging activity in the cecal, colon, and fecal contents assayed. DEX treatment (3 or 1 mg/kg) of SHIP-/- mice eliminated CD-like gross pathology and histopathology, and reduced IL-1β concentrations in full-thickness ileal tissue homogenates from SHIP-/- mice compared to untreated or vehicle-treated mice. DEX did not have any harmful effects on the intestines of SHIP+/+ mice. 1 or 0.3 mg/kg molar equivalent of caged DEX (3-fold lower concentrations) eliminated CD-like gross pathology in SHIP-/- mice compared to treatment with vehicle control. Additionally, the mean IL-1β concentration in tissue homogenates of mice treated with the molar equivalent of 1 mg/kg caged DEX was reduced Conclusions SHIP-/- mice express decaging activity are effectively treated by DEX, and caged DEX shows similar efficacy at reducing SHIP-/- ileal pathology at lower concentrations than uncaged DEX. In future experiments, we will examine caged DEX at a lower concentration, and in 2nd mouse model of intestinal inflammation. Funding Agencies GlycoNet

Effect of repeated oral administration of butachlor and lead alone and in combination on oxidative stress and histopathology in Wistar rats

The experiment was carried out to evaluate the rising concern over the additive effect of one chemical with another chemical, which has raised a lot of health concerns in the general population. In the experiment, adult wistar rats of either sex were divided into 4 groups and the study was conducted for a period of 28 days. Group I served as control and was provided with water only for drinking purposes. Animals of group II were administered butachlor@262mg/kg B.W/P.O. Group III received administered lead acetate@265ppm orally, while animals of group IV received a combination of butachlor@262mg/kg and lead acetate@265ppm. Oxidative stress was revealed by significantly increasing lipid peroxidation and decreased blood glutathione, glutathione peroxidase and transferase, catalase and superoxide dismutase in blood and tissues. Histopathologically, the liver and and kidney exhibited structural alterations as compared to control. The study concluded butachlor and lead produced a more deleterious systemic effect in combination than alone (additive toxic effect).

Low-Dose Metformin as a Monotherapy Does Not Reduce Non-Small-Cell Lung Cancer Tumor Burden in Mice.

Non-small-cell lung cancer (NSCLC) makes up 80–85% of lung cancer diagnoses. Lung cancer patients undergo surgical procedures, chemotherapy, and/or radiation. Chemotherapy and radiation can induce deleterious systemic side effects, particularly within skeletal muscle. To determine whether metformin reduces NSCLC tumor burden while maintaining skeletal muscle health, C57BL/6J mice were injected with Lewis lung cancer (LL/2), containing a bioluminescent reporter for in vivo tracking, into the left lung. Control and metformin (250 mg/kg) groups received treatments twice weekly. Skeletal muscle was analyzed for changes in genes and proteins related to inflammation, muscle mass, and metabolism. The LL/2 model effectively mimics lung cancer growth and tumor burden. The in vivo data indicate that metformin as administered was not associated with significant improvement in tumor burden in this immunocompetent NSCLC model. Additionally, metformin was not associated with significant changes in key tumor cell division and inflammation markers, or improved skeletal muscle health. Metformin treatment, while exhibiting anti-neoplastic characteristics in many cancers, appears not to be an appropriate monotherapy for NSCLC tumor growth in vivo. Future studies should pursue co-treatment modalities, with metformin as a potentially supportive drug rather than a monotherapy to mitigate cancer progression.

AR-negative prostate cancer is vulnerable to loss of JMJD1C demethylase

Prostate cancer is a leading cause of cancer-related mortality in men. The widespread use of androgen receptor (AR) inhibitors has generated an increased incidence of AR-negative prostate cancer, triggering the need for effective therapies for such patients. Here, analysis of public genome-wide CRISPR screens in human prostate cancer cell lines identified histone demethylase JMJD1C (KDM3C) as an AR-negative context-specific vulnerability. Secondary validation studies in multiple cell lines and organoids, including isogenic models, confirmed that small hairpin RNA (shRNA)-mediated depletion of JMJD1C potently inhibited growth specifically in AR-negative prostate cancer cells. To explore the cooperative interactions of AR and JMJD1C, we performed comparative transcriptomics of 1) isogenic AR-positive versus AR-negative prostate cancer cells, 2) AR-positive versus AR-negative prostate cancer tumors, and 3) isogenic JMJD1C-expressing versus JMJD1C-depleted AR-negative prostate cancer cells. Loss of AR or JMJD1C generates a modest tumor necrosis factor alpha (TNFα) signature, whereas combined loss of AR and JMJD1C strongly up-regulates the TNFα signature in human prostate cancer, suggesting TNFα signaling as a point of convergence for the combined actions of AR and JMJD1C. Correspondingly, AR-negative prostate cancer cells showed exquisite sensitivity to TNFα treatment and, conversely, TNFα pathway inhibition via inhibition of its downstream effector MAP4K4 partially reversed the growth defect of JMJD1C-depleted AR-negative prostate cancer cells. Given the deleterious systemic side effects of TNFα therapy in humans and the viability of JMJD1C-knockout mice, the identification of JMJD1C inhibition as a specific vulnerability in AR-negative prostate cancer may provide an alternative drug target for prostate cancer patients progressing on AR inhibitor therapy.

The psychobiological links between chronic stress-related diseases, periodontal/peri-implant diseases, and wound healing.

Chronic stress is a relevant disease to periodontal practice, encompassing 25%-28% of the US population (American Psychological Association 2015). While it is well established that chronic psychologic stress can have significant deleterious systemic effects, only in recent decades have we begun to explore the biochemical, microbial, and physiologic impacts of chronic stress diseases on oral tissues. Currently, chronic stress is classified as a "risk indicator" for periodontal disease. However, as the evidence in this field matures with additional clinically controlled trials, more homogeneous data collection methods, and a better grasp of the biologic underpinnings of stress-mediated dysbiosis, emerging evidence suggests that chronic stress and related diseases (depression, anxiety) may be significant contributing factors in periodontal/peri-implant disease progression and inconsistent wound healing following periodontal-related therapeutics. Ideal solutions for these patients include classification of the disease process and de-escalation of chronic stress conditions through coping strategies. This paper also summarizes periodontal/implant-related therapeutic approaches to ensure predictable results for this specific patient subpopulation.

Plasma pharmacokinetics and distribution of ruxolitinib into skin following oral and topical administration in minipigs.

This preclinical study compared plasma concentrations and distribution of ruxolitinib in the skin of Göttingen minipigs following twice a day oral (40mg/kg) versus topical administration (1.5% w/w cream applied to 10% of body surface area). Following oral administration, the plasma area-under-the-curve was approximately 31-fold and maximum drug concentration was 38-fold higher than those observed following topical application. Following ruxolitinib cream application, the average plasma concentration at steady-state was 2.7±1.8nM, a concentration that is not pharmacologically relevant. The average total dermis concentration of ruxolitinib at steady-state after topical administration was 507-fold higher versus that following oral dosing, while the ratio for the total epidermal concentration following topical vs oral dosing was 1989-fold. The concentration of unbound ruxolitinib in the dermis after topical application was predicted to result in sustained and near-complete inhibition of Janus kinase/signal transducer and activator of transcription proteins (JAK/STAT) signaling in this tissue. In contrast, only partial inhibition of downstream signaling was predicted to occur after oral dosing. In conclusion, ruxolitinib cream affords an attractive disposition profile in minipigs, wherein dermis concentrations of ruxolitinib are fully effective whereas corresponding plasma concentrations are negligible. Consequently, this distribution profile should maximize the efficacy of ruxolitinib cream in the skin while minimizing the potential for deleterious systemic effects.

Production of IL-18 Binding Protein by Radiosensitive and Radioresistant Cells in CpG-Induced Macrophage Activation Syndrome

IL-18 binding protein (IL-18BP) acts as a naturally occurring IL-18 decoy receptor. If the balance between IL-18 and IL-18BP is dysregulated, abnormal levels of free bioactive IL-18 are detected, such as in the sera of Il-18bp knockout (KO) mice with CpG-induced macrophage activation syndrome. To determine the cellular sources of Il-18bp in vivo, we selectively depleted Il-18bp expression in either radiosensitive or radioresistant cells using bone marrow transfer between wild-type (WT) and Il-18bp KO mice. Following repeated CpG injections, Il-18bp KO (donor)→ Il-18bp KO (recipient) chimeric mice exhibited more severe disease, with an enhanced Ifn-γ signature and circulating free Il-18 levels, in comparison with WT→WT chimeras. Interestingly, the phenotype of KO→WT and WT→KO mice did not differ from that of WT→WT mice. Consistent with this finding, serum Il-18bp levels were similar in these three groups of mice. The contribution of radioresistant and radiosensitive cells to Il-18bp production varied markedly according to the organ examined, with a major contribution of radiosensitive cells in the spleen as opposed to a major contribution of radioresistant cells in the lung. Finally, Ifn-γ blockade abrogated the CpG-induced but not the constitutive Il-18bp production. Our results demonstrate that circulating Il-18bp is induced in response to Ifn-γ during CpG-induced macrophage activation syndrome and is present at high levels in the circulation to prevent the deleterious systemic effects of Il-18.

Abstract 2262: Low-dose targeted radionuclide therapy has favorable local and systemic effects on immune populations in a murine prostate cancer model

Abstract Introduction: Prostate cancer remains the second leading cause of cancer-related death in American men because of its metastatic, incurable form. Prostate cancer responds poorly to checkpoint blockade likely due to its immunosuppressive microenvironment with relatively few infiltrating CD8+ T cells, limited mutational burden, and activity of myeloid-derived suppressor cells (MDSCs). External beam radiotherapy (EBRT) has been shown to help overcome this suppressive state, but EBRT is infeasible for patients with widely metastatic disease. Our group has developed a compound called NM600 that can be used to deliver radiation to all sites of disease simultaneously in an approach called Targeted radionuclide therapy (TRT). However, the effects of TRT on immune populations within prostate tumors are not yet well described. In this study, we examined the effects of TRT in the form of 90Y-NM600 on mice bearing Myc-CaP prostate tumors. Methods: 6-week old male FVB mice were implanted subcutaneously with Myc-CaP cells, then given a single intravenous injection of either 50 (“low-dose”) or 250 (“high-dose”) μCi of 90Y-NM600, estimated to deliver 3.1 Gy or 15.5 Gy to 300 mm3 tumors, respectively. Groups of mice (n=3) were then euthanized at several timepoints following TRT administration. Their tumors and spleens were collected for analysis by flow cytometry and Luminex cytokine analysis. A separate group (n=5) were followed for survival to 2000 mm3. Results: Flow cytometry of splenocytes revealed that high-dose, but not low-dose TRT caused a 6-fold increase in numbers of MDSCs (p = 0.002) at Day 21 compared to baseline. Additionally, low-dose TRT caused a 2-fold (p = 0.005) increase in CD8+ T cells at Day 21 compared to baseline, unlike in the high-dose condition. These CD8+ T cells in the low-dose TRT condition were predominantly proliferating naïve T cells. Flow cytometry of tumor infiltrating lymphocytes showed a 13% increase in CD8+ T cells in both dose conditions at Day 14 (p = 0.03). Returning CD8+ T cells displayed high expression of PD-1, CTLA-4, and LAG-3. Within the tumor, there was an 8-fold increase in chemokines including CXCL1, Rantes, and MIP2 at Day 21, suggesting that there may be further recruitment of tumor infiltrating cells even three weeks following treatment. Mice treated with high-dose TRT (median survival 37 days, p = .029) had significantly improved median survival compared to control (median survival 23 days), unlike low-dose treated mice (median survival 29 days, p =.250). Conclusions: These data suggest that low-dose TRT is superior for immunomodulation because, although it has little effect on tumor growth, it increases intratumoral CD8+ T cell infiltration while avoiding deleterious systemic immune effects. We hypothesize that immunomodulatory TRT combined with checkpoint blockade will improve anti-tumor efficacy compared to high-dose TRT. Citation Format: Hemanth Kumar Potluri, Reinier Hernandez, Christopher D. Zahm, Joseph Grudzinski, Christopher Massey, Jamey Weichert, Douglas G. McNeel. Low-dose targeted radionuclide therapy has favorable local and systemic effects on immune populations in a murine prostate cancer model [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2262.

Indirect, Non-Thermal Atmospheric Plasma Promotes Bacterial Killing in vitro and Wound Disinfection in vivo Using Monogenic and Polygenic Models of Type 2 Diabetes (Without Adverse Metabolic Complications).

A novel atmospheric plasma device that uses indirect, non-thermal plasma generated from room air is being studied for its effects on wound disinfection in animal wounds of monogenic and polygenic murine models of type 2 diabetes. As a proof-of-concept report, the goal of this study was to demonstrate the efficacy and safety of the indirect non-thermal plasma (INTP) device in disinfecting polycarbonate filters established with Pseudomonas aeruginosa (PAO1) biofilms as well as wound disinfection in diabetic murine wounds. Dorsal excisional wounds in BALB/c, polygenic TALLYHO, and monogenic db/db mice established with PAO1 infection all demonstrated a 3-log colony-forming unit (CFU) reduction when subjected to a course of 20-min INTP treatments. Importantly, blood glucose and body weights in these animals were not significantly impacted by plasma treatment over the study period. Plasma safety was also analyzed via complete blood count and comprehensive metabolic panels, showing no deleterious systemic effects after 3 consecutive days of 20-min plasma applications. Therefore, the results obtained demonstrated the Pseudomonas aeruginosa isolates were highly sensitive to INTP in vitro, CFU reduction of infectious Pseudomonas in wounds of diabetic mice after INTP treatment is far superior to that of non-treated infected wounds, and the application of INTP shows no indication of toxic effects. Our results are consistent with indirect non-thermal atmospheric plasma as a promising adjunct to disinfecting wounds.

Long-term remote organ consequences following acute kidney injury.

Acute kidney injury (AKI) has been a global health epidemic problem with soaring incidence, increased long-term risks for multiple comorbidities and mortality, as well as elevated medical costs. Despite the improvement of patient outcomes following the advancements in preventive and therapeutic strategies, the mortality rates among critically ill patients with AKI remain as high as 40–60 %. The distant organ injury, a direct consequence of deleterious systemic effects, following AKI is an important explanation for this phenomenon. To date, most evidence of remote organ injury in AKI is obtained from animal models. Whereas the observations in humans are from a limited number of participants in a relatively short follow-up period, or just focusing on the cytokine levels rather than clinical solid outcomes. The remote organ injury is caused with four underlying mechanisms: (1) “classical” pattern of acute uremic state; (2) inflammatory nature of the injured kidneys; (3) modulating effect of AKI of the underlying disease process; and (4) healthcare dilemma. While cytokines/chemokines, leukocyte extravasation, oxidative stress, and certain channel dysregulation are the pathways involving in the remote organ damage. In the current review, we summarized the data from experimental studies to clinical outcome studies in the field of organ crosstalk following AKI. Further, the long-term consequences of distant organ-system, including liver, heart, brain, lung, gut, bone, immune system, and malignancy following AKI with temporary dialysis were reviewed and discussed.

Rationale and Approaches to Phosphate and Fibroblast Growth Factor 23 Reduction in CKD.

Patients with CKD often progress to ESRD and develop cardiovascular disease (CVD), yet available therapies only modestly improve clinical outcomes. Observational studies report independent associations between elevated serum phosphate and fibroblast growth factor 23 (FGF23) levels and risks of ESRD, CVD, and death. Phosphate excess induces arterial calcification, and although elevated FGF23 helps maintain serum phosphate levels in the normal range in CKD, it may contribute mechanistically to left ventricular hypertrophy (LVH). Consistent epidemiologic and experimental findings suggest the need to test therapeutic approaches that lower phosphate and FGF23 in CKD. Dietary phosphate absorption is one modifiable determinant of serum phosphate and FGF23 levels. Limited data from pilot studies in patients with CKD stages 3-4 suggest that phosphate binders, low phosphate diets, or vitamin B3 derivatives, such as niacin or nicotinamide, may reduce dietary phosphate absorption and serum phosphate and FGF23 levels. This review summarizes current knowledge regarding the deleterious systemic effects of phosphate and FGF23 excess, identifies questions that must be addressed before advancing to a full-scale clinical outcomes trial, and presents a novel therapeutic approach to lower serum phosphate and FGF23 levels that will be tested in the COMBINE Study: The CKD Optimal Management With BInders and NicotinamidE study.

Systemic Responses following Brain Injuries and Inflammatory Process Activation Induced by a Neurotoxin of Androctonus Scorpion Venom

Objective: Kaliotoxin 2 (KTX₂), a neurotoxin isolated from Androctonus australis hector scorpion venom, presents a high affinity with the voltage-gated potassium channels. The targets of KTX₂ in the brain and its toxic effects on the cerebral cortex have been extensively studied; however, its deleterious systemic effects on other organ systems have not yet been investigated. Inflammatory response induced by KTX₂ is supported by cytokine release which could provoke multiple organ dysfunction and diverse biological disorders in mammals. The possibility that inflammatory response and brain injuries induced by KTX₂ may lead to functional disturbances, e.g. in the pancreas and the liver, were investigated. The contribution of IL-6 and TNF-α to the modulation of pathophysiological effects induced by KTX₂ was also tested. Methods: NMRI mice were injected by the intracerebroventricular route with a sublethal dose of KTX₂ or saline solution. Inflammatory response and oxidative stress were assessed in sera and tissue homogenates. Biomarkers of pancreatic and hepatic functions and the correlation with tissue damage in the brain, liver and pancreas were also analyzed. Results: The obtained results revealed that KTX₂ injection induced an inflammatory process activation and imbalanced redox status. It also induced severe alterations in cerebral cortex, hepatic and pancreatic tissues associated with a significant increase in pancreatic and hepatic pathological biomarkers. Cytokine antagonists injected 30 min prior to KTX₂ led to a significant reduction of all disturbances induced by KTX₂. Conclusion: In addition to its significant toxicity on the central nervous system, KTX₂ can also affect pancreatic and hepatic functions, probably by an indirect mechanism involving activation of the inflammatory response with release of IL-6 and TNF-α.

The Effect of Atorvastatin on Acute Pancreatitis in Rat: Biochemical and Pathological study

Acute pancreatitis (AP) is a common clinical disease caused mainly by gallstone impacting the distal common bile-pancreatic duct and alcohol abuse, but other potential causes as Endoscopic retrograde cholangiopancreatography (ERCP), intra duct papillary mucinous tumor and hypercalcemia are claimed . The incidence of AP has been increasing in recent years . Accordingly, AP is a multifactorial disease associated with tissue edema, acinar necrosis, hemorrhage and the release of digestive enzymes to the pancreatic interstitium and to the systemic circulation with increased cytokine production and release, which can ultimately lead to deleterious local and systemic effects . Previous evidence suggests that the pathogenesis of both AP and chronic pancreatitis can be associated with oxidative stress, regardless of the etiology of pancreatitis and is considered as a major pathogenic factor in AP . In fact, reactive oxygen species (ROS) are the important mediators in the initiation and development of the disease which destroy the cellular membrane, releasing the digestive enzymes and cellular proteins into the pancreatic interstitium .

Mitigation of Lethal Radiation Syndrome in Mice by Intramuscular Injection of 3D Cultured Adherent Human Placental Stromal Cells

Exposure to high lethal dose of ionizing radiation results in acute radiation syndrome with deleterious systemic effects to different organs. A primary target is the highly sensitive bone marrow and the hematopoietic system. In the current study C3H/HeN mice were total body irradiated by 7.7 Gy. Twenty four hrs and 5 days after irradiation 2×106 cells from different preparations of human derived 3D expanded adherent placental stromal cells (PLX) were injected intramuscularly. Treatment with batches consisting of pure maternal cell preparations (PLX-Mat) increased the survival of the irradiated mice from ∼27% to 68% (P<0.001), while cell preparations with a mixture of maternal and fetal derived cells (PLX-RAD) increased the survival to ∼98% (P<0.0001). The dose modifying factor of this treatment for both 50% and 37% survival (DMF50 and DMF37) was∼1.23. Initiation of the more effective treatment with PLX-RAD injection could be delayed for up to 48 hrs after irradiation with similar effect. A delayed treatment by 72 hrs had lower, but still significantly effect (p<0.05). A faster recovery of the BM and improved reconstitution of all blood cell lineages in the PLX-RAD treated mice during the follow-up explains the increased survival of the cells treated irradiated mice. The number of CD45+/SCA1+ hematopoietic progenitor cells within the fast recovering population of nucleated BM cells in the irradiated mice was also elevated in the PLX-RAD treated mice. Our study suggests that IM treatment with PLX-RAD cells may serve as a highly effective “off the shelf” therapy to treat BM failure following total body exposure to high doses of radiation. The results suggest that similar treatments may be beneficial also for clinical conditions associated with severe BM aplasia and pancytopenia.