Major Insult Research Articles

Plantar somatosensory restoration enhances gait, speed perception, and motor adaptation.

Lower limb loss is a major insult to the body's nervous and musculoskeletal systems. Despite technological advances in prosthesis design, artificial limbs are not yet integrated into the body's physiological systems. Therefore, lower limb amputees (LLAs) experience lower balance confidence, higher fear of falls, and impaired gait compared with their able-bodied peers (ABs). Previous studies have demonstrated that restored sensations perceived as originating directly from the missing limb via neural interfaces improve balance and performance in certain ambulatory tasks; however, the effects of such evoked sensations on neural circuitries involved in the locomotor activity are not well understood. In this work, we investigated the effects of plantar sensation elicited by peripheral nerve stimulation delivered by multicontact nerve cuff electrodes on gait symmetry and stability, speed perception, and motor adaptation. We found that restored plantar sensation increased stance time and propulsive force on the prosthetic side, improved gait symmetry, and yielded an enhanced perception of prosthetic limb movement. Our results show that the locomotor adaptation among LLAs with plantar sensation became similar to that of ABs. These findings suggest that our peripheral nerve-based approach to elicit plantar sensation directly affects central nervous pathways involved in locomotion and motor adaptation during walking. Our neuroprosthesis provided a unique model to investigate the role of somatosensation in the lower limb during walking and its effects on perceptual recalibration after a locomotor adaptation task. Furthermore, we demonstrated how plantar sensation in LLAs could effectively increase mobility, improve walking dynamics, and possibly reduce fall risks.

Inflammation and hypertension: Underlying mechanisms and emerging understandings.

Hypertension remains a major contributor to cardiovascular disease (CVD), a leading cause of global death. One of the major insults that drive increased blood pressure is inflammation. While it is the body's defensive response against some homeostatic imbalances, inflammation, when dysregulated, can be very deleterious. In this review, we highlight and discuss the causative relationship between inflammation and hypertension. We critically discuss how the interplay between inflammation and reactive oxygen species evokes endothelial damage and dysfunction, ultimately leading to narrowing and stiffness of blood vessels. This, along with phenotypic switching of the vascular smooth muscle cells and the abnormal increase in extracellular matrix deposition further exacerbates arterial stiffness and noncompliance. We also discuss how hyperhomocysteinemia and microRNA act as links between inflammation and hypertension. The premises we discuss suggest that the blue-sky scenarios for targeting the underlying mechanisms of hypertension necessitate further research.

Effect of preconditioning on propofol-induced neurotoxicity during the developmental period.

At therapeutic concentrations, propofol (PPF), an anesthetic agent, significantly elevates intracellular calcium concentration ([Ca2 +]i) and induces neural death during the developmental period. Preconditioning enables specialized tissues to tolerate major insults better compared with tissues that have already been exposed to sublethal insults. Here, we investigated whether the neurotoxicity induced by clinical concentrations of PPF could be alleviated by prior exposure to sublethal amounts of PPF. Cortical neurons from embryonic day (E) 17 Wistar rat fetuses were cultured in vitro, and on day in vitro (DIV) 2, the cells were preconditioned by exposure to PPF (PPF-PC) at either 100 nM or 1 μM for 24 h. For morphological observations, cells were exposed to clinical concentrations of PPF (10 μM or 100 μM) for 24 h and the survival ratio (SR) was calculated. Calcium imaging revealed significant PPF-induced [Ca2+]i elevation in cells on DIV 4 regardless of PPF-PC. Additionally, PPF-PC did not alleviate neural cell death induced by PPF under any condition. Our findings indicate that PPF-PC does not alleviate PPF-induced neurotoxicity during the developmental period.

Effect of cytokine-induced alterations in extracellular matrix composition on diabetic retinopathy-relevant endothelial cell behaviors

Retinal vascular basement membrane (BM) thickening is an early structural abnormality of diabetic retinopathy (DR). Recent studies suggest that BM thickening contributes to the DR pathological cascade; however, much remains to be elucidated about the exact mechanisms by which BM thickening develops and subsequently drives other pathogenic events in DR. Therefore, we undertook a systematic analysis to understand how human retinal microvascular endothelial cells (hRMEC) and human retinal pericytes (hRP) change their expression of key extracellular matrix (ECM) constituents when treated with diabetes-relevant stimuli designed to model the three major insults of the diabetic environment: hyperglycemia, dyslipidemia, and inflammation. TNFα and IL-1β caused the most potent and consistent changes in ECM expression in both hRMEC and hRP. We also demonstrate that conditioned media from IL-1β-treated human Müller cells caused dose-dependent, significant increases in collagen IV and agrin expression in hRMEC. After narrowing our focus to inflammation-induced changes, we sought to understand how ECM deposited by hRMEC and hRP under inflammatory conditions affects the behavior of naïve hRMEC. Our data demonstrated that diabetes-relevant alterations in ECM composition alone cause both increased adhesion molecule expression by and increased peripheral blood mononuclear cell (PBMC) adhesion to naïve hRMEC. Taken together, these data demonstrate novel roles for inflammation and pericytes in driving BM pathology and suggest that inflammation-induced ECM alterations may advance other pathogenic behaviors in DR, including leukostasis.

Time-Dependent Alterations in Liver Oxidative Stress due to Ethanol and Acetaldehyde

Binge drinking is a major public health issue and ethanol-related liver insult may play a major role in the pathology of alcoholic liver disease. However, the degree of oxidative stress, cell death and contribution of acetaldehyde to liver damage over a 24-h period has yet to be determined. Herein, we aimed to investigate the effect of acute alcohol and elevated acetaldehyde levels on hepatic oxidative damage, apoptosis, and antioxidant enzyme activity over a 24-h period. Male Wistar rats were divided into four groups and animals were pre-injected (intraperitonially [i.p.]) with either saline (0.15 mol/L) or cyanamide (5-mmol/kg body weight), followed by either saline (0.15 mol/L) or ethanol (75-mmol/kg bodyweight). After 2.5, 6 and 24 h, hepatic cytosolic and mitochondrial fractions were analysed for indices of oxidative stress. At 2.5 h, cytosolic glutathione and malondialdehyde levels were significantly reduced and increased, respectively, with alcohol treatment. Caspase-3 activity and cytochrome c levels were increased with alcohol treatment at 24 h. The combination of cyanamide and alcohol treatment at 24 h led to a significant increase in serum alanine aminotransferase levels, and reduced albumin and total protein levels. Furthermore, glutathione peroxidase activity and glutathione reductase activity were significantly decreased and increased, respectively. Finally, superoxide dismutase activity was decreased in cytosol and increased in the mitochondria after cyanamide and ethanol treatment, respectively. This study indicates a complex differential effect of alcohol and acetaldehyde, whereby alcohol toxicity in the mitochondria takes place throughout the 24-h period, but raised acetaldehyde has a further detrimental effect on liver function.

The Role of Exercise Training in Preconditioning the Liver Against Ischemia/Reperfusion Injury in an Orthotopic Liver Murine Transplant Model

Introduction: Liver transplantation (LT) remains the most effective treatment for end stage liver disease. During transplantation the liver undergoes several major insults including cold storage and subsequent reperfusion, which together reduce immediate function and precipitate innate inflammatory changes known to aggravate adaptive immune rejection. Translational applications to target the host response to ischemia and reperfusion injury (IRI) have been slow to emerge. We have shown that exercise training (ExT) confers protections against IRI in a murine model by altering the liver damaging innate inflammatory events. Methods: 8-week-old C57BL6 mice were exercised (ExT) (60-minutes/d; 4-weeks) or kept sedentary (Sed). After 4-weeks, livers from both ExT and Sed mice were perfused with University of Wisconsin (UW) solution and subjected to 1-hour cold storage (4 °C) prior to orthotopic transplantation into syngeneic C57BL6 mice. 6h following transplantation, liver damage and immune infiltration were assessed. Results: ExT pre-conditioning conferred sustainable graft protection against IRI evident by reduced liver damage, 6-hours following revascularization. Liver from ExT mice showed decreased necrosis compared to Sed and decreased liver infiltration and activation of neutrophils. In addition, ExT increased the infiltration of anti-inflammatory M2-subtype macrophages rather than pro-inflammatory M1 within the graft. Following cold storage, ExT liver grafts showed significantly lower levels of apoptosis and increasesd levels of mitochondrial biogenesis. Conclusion: These findings suggest that livers from ExT mice may be resistant to damage during cold storage and warm I/R and that ExT leads to alteration in inflammatory cells within the liver upon reperfusion.

Laparoscopic Repair of Near Complete Traumatic Duodenal Transaction in an Eight Years Old Child: A Case Report

Background: Traumatic duodenal perforation is a serious injury and is a result of major trauma and insult to the body. The management is difficult due to associated injuries and these children often need major resuscitation. The standard surgical treatment of traumatic duodenal perforation is laparotomy and repair of duodenal perforation. In children, laparoscopic repair of duodenal perforation is reported in only a few cases. Case: A repair of a near-complete duodenal transaction is not reported in the pediatric population. Herein, we report a case of an eight years old child who had a road traffic accident, and sustained multiple injuries and duodenal perforation, as confirmed by radiological evaluation including CT abdomen. The child was resuscitated, and later laparoscopy was performed, which showed gross bruising of the abdominal wall and a nearcomplete transaction at the level of 3rd part of the duodenum. Conclusion: Laparoscopic repair of the duodenum was performed using interrupted polyglycolic sutures. The child had a smooth post-op recovery and was discharged home in stable condition. At one-year follow-up, the child remained well and symptom-free. This case highlights the role of the safety of laparoscopic surgery in abdominal trauma and duodenal perforations.

Comparison of propofol and sevoflurane on cerebral oxygenation using juglar venous oximetery (SjVo2) in patients undergoing surgery for traumatic brain injury

Background:Traumatic brain injury (TBI) induces major insult to the normal cerebral physiology. The anesthetic agents may infrequently produce deleterious effects and further aggravate damage to the injured brain. This study was conducted to evaluate the effects of propofol and sevoflurane on cerebral oxygenation, brain relaxation, systemic hemodynamic parameters and levels of interleukin-6 (IL-6) in patients with severe TBI undergoing decompressive craniectomy.Methods:A prospective randomized comparative study was conducted on 42 patients undergoing surgery for severe TBI. Patients were randomized into two groups, Group P received propofol and Group S received sevoflurane for maintenance of anesthesia. All patients were induced with fentanyl, propofol, and vecuronium. The effect of these agents on cerebral oxygenation was assessed by jugular venous oxygen saturation (SjVO2). Hemodynamic changes and quality of intraoperative brain relaxation were also assessed. The serum levels of IL-6 were quantitated using enzyme-linked immunosorbent assay technique.Results:SjVO2 values were comparable and mean arterial pressure (MAP) was found to be significantly lower in Group P as compared to those in Group S (P < 0.05). Brain relaxation scores were comparable between the groups. The level of IL-6 decreased significantly at the end of surgery compared to baseline in patients receiving sevoflurane (P = 0.040).Conclusions:Cerebral oxygenation measured by SjVO2 was comparable when anesthesia was maintained with propofol or sevoflurane. However, significant reduction in MAP by propofol needs attention in patients with severe TBI. The decrease in IL-6 level reflects anti-inflammatory effect and probable neuroprotective potential of propofol and sevoflurane.

Dim light at night exacerbates stroke outcome.

Circadian rhythms are endogenous biological cycles that synchronize physiology and behaviour to promote optimal function. These ~24-hr internal rhythms are set to precisely 24hr daily by exposure to the sun. However, the prevalence of night-time lighting has the potential to dysregulate these biological functions. Hospital patients may be particularly vulnerable to the consequences of light at night because of their compromised physiological state. A mouse model of stroke (middle cerebral artery occlusion; MCAO) was used to test the hypothesis that exposure to dim light at night impairs responses to a major insult. Stroke lesion size was substantially larger among animals housed in dLAN after reperfusion than animals maintained in dark nights. Mice housed in dLAN for three days after the stroke displayed increased post-stroke anxiety-like behaviour. Overall, dLAN amplified pro-inflammatory pathways in the CNS, which may have exacerbated neuronal damage. Our results suggest that exposure to LAN is detrimental to stroke recovery.

PD42-11 CIGARETTE SMOKE, E-CIGARETTES AND BLADDER CANCER CELL-DERIVED EXTRACELLULAR VESICLES INDUCE BLADDER CARCINOGENESIS

You have accessJournal of UrologyBladder Cancer: Basic Research & Pathophysiology III (PD42)1 Apr 2020PD42-11 CIGARETTE SMOKE, E-CIGARETTES AND BLADDER CANCER CELL-DERIVED EXTRACELLULAR VESICLES INDUCE BLADDER CARCINOGENESIS Chia-Hao Wu*, Wei-Min Chung, Irfan Rahman, and Yi-Fen Lee Chia-Hao Wu*Chia-Hao Wu* More articles by this author , Wei-Min ChungWei-Min Chung More articles by this author , Irfan RahmanIrfan Rahman More articles by this author , and Yi-Fen LeeYi-Fen Lee More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000000922.11AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Cigarette smoke (CS) is the most well-established risk factor for bladder cancer. Although some evidence indicates that E-cigarettes (E-cig) may be a safer alternative to traditional CS, their full safety profile remains largely unproven. Extracellular vesicles (EVs) are recognized as intriguing entities in cancer pathogenesis. We reported that EVs derived from bladder cancer cells drive the malignant transformation of normal urothelial recipient cells. This model allows us to determine the impact of various genotoxic stresses present in the bladder environment including CS, E-cigs, and cancer EVs that drive the malignant transformation of normal urothelial cells and to study the underlying oncogenesis mechanisms. METHODS: E-Cigs, including unflavored and Icy menthol (12mg nicotine/mL, VistaVapors, Inc.) and research cigarettes (3R4F, University of Kentucky) were used. Cigarette smoke extract (CSE) was prepared by flowing CS though phenol red-free DMEM medium. Cell lines, including TCCSUP bladder cancer cells, and non-malignant urothelial SV-HUC cells were used. EVs were purified through serial centrifugation, and the released EV number was determined by nanoparticle tracking analysis. The carcinogenicity of interplays among CSE, E-cigs, and EVs was determined for DNA damage and colony formation assay. To reflect this scenario in a clinical setting, patient-derived bladder organoids were applied and tumorigenicity was further confirmed by a nude mouse xenograft model. RESULTS: We demonstrated that chronic exposure to naïve TCCSUP EVs induced SV-HUC cells’ malignant transformation as shown by increased colony formation and tumor growth in nude mice. CSE and mentholated E-Cigs, but not unflavored E-Cigs, induced double-strand DNA (dsDNA) breaks in normal SV-HUC cells, suggesting menthol is the major insult from E-Cig treatment. More critically, CSE and mentholated E-Cigs induce TCCSUP cells releasing EVs, and those EVs significantly cause more dsDNA breaks than naïve EVs. Thus, the interplays among cancer EVs, CSE and E-cigs form a positive feedback oncogenesis loop. CONCLUSIONS: Investigation of tumorigenesis regulated by cancer EVs in response to CS and E-cigs provides a novel view of field cancerization present in post-TURBT smokers and establishes CS vs. E-cigs’ carcinogenicity in the urinary bladder. The results may lead to new therapeutic strategies and dispel the unsubstantiated claims that E-cigs are safe. Source of Funding: Department of Defense W81XWH-19-0198 © 2020 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 203Issue Supplement 4April 2020Page: e831-e831 Advertisement Copyright & Permissions© 2020 by American Urological Association Education and Research, Inc.MetricsAuthor Information Chia-Hao Wu* More articles by this author Wei-Min Chung More articles by this author Irfan Rahman More articles by this author Yi-Fen Lee More articles by this author Expand All Advertisement PDF downloadLoading ...

MP47-09 VERIFICATION OF FORCE SENSOR APPARATUS DATA USING EXPERT GRADING OF A RADICAL PROSTATECTOMY NERVE SPARING SIMULATION

You have accessJournal of UrologySurgical Technology & Simulation: Training & Skills Assessment II (MP47)1 Apr 2020MP47-09 VERIFICATION OF FORCE SENSOR APPARATUS DATA USING EXPERT GRADING OF A RADICAL PROSTATECTOMY NERVE SPARING SIMULATION Patrick Saba, Rachel Melnyk, Michael Witthaus, Jack Dalton, Shamroz Farooq, Guan Wu, Hani Rashid, Thomas Frye, Jean Joseph, and Ahmed Ghazi* Patrick SabaPatrick Saba More articles by this author , Rachel MelnykRachel Melnyk More articles by this author , Michael WitthausMichael Witthaus More articles by this author , Jack DaltonJack Dalton More articles by this author , Shamroz FarooqShamroz Farooq More articles by this author , Guan WuGuan Wu More articles by this author , Hani RashidHani Rashid More articles by this author , Thomas FryeThomas Frye More articles by this author , Jean JosephJean Joseph More articles by this author , and Ahmed Ghazi*Ahmed Ghazi* More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000000902.09AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: A necessary aspect of radical prostatectomy nerve sparing (NS-RARP) includes minimal traction to the neurovascular bundle (NVB) during dissection to limit postoperative neuropraxia. Current simulation platforms for NS-RARP lack the measurement of various insults during NVB dissection. We sought to verify the accuracy of force sensors incorporated into the NVB of a hydrogel based NS-RARP simulation compared to expert ratings. METHODS: Anatomically correct hydrogel models containing relevant structures were constructed using 3D-printed injection molds. A calibrated force sensor apparatus (FSA) is incorporated into the NVB that outputs the force applied to the NVB during surgery. The FSA uses an algorithm that looks for major insults characterized by minimum peak prominence over 0.1x standard deviation of the overall force. Five experts (>250 caseload) completed the simulation and FSA data and video recording was collected from the nerve sparing (NS). Each (NS) video was graded by an expert urologist for clinically relevant insults, classified as a compression/tension that would lead to damage of the NVB. Insults marked by the expert were overlaid with the insults identified by the FSA. If insults were marked within 5 seconds of each other, a true positive was recorded (Fig 1). The FSA identified insults and the expert grading was compared using an error matrix to determine the sensitivity, precision, and F1 score. RESULTS: Overall, the FSA returned 239 true positives, 101 false positives, and 97 false negatives. These values returned a sensitivity of 67.73%, and precision of 70.29% indicating that FSA was successful at marking that same insults as the expert and did so without over indication. Additionally, the FSA retuned a F1 score of 0.7071 which is a weighted measurement of precision using the negative results to determine the harmonic mean of the precision and sensitivity. The score supports the efficacy of the FSA. CONCLUSIONS: The FSA provides an accurate, time effective and mass producible metric that removes the need for expert review. The addition of the FSA to the hydrogel NS-RARP simulation provides a standardized metric to measure insults during NS; an advantage not seen in other simulation platforms. Overall, this benefit further bolsters the usefulness of the NS-RARP hydrogel model. Source of Funding: None © 2020 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 203Issue Supplement 4April 2020Page: e687-e687 Advertisement Copyright & Permissions© 2020 by American Urological Association Education and Research, Inc.MetricsAuthor Information Patrick Saba More articles by this author Rachel Melnyk More articles by this author Michael Witthaus More articles by this author Jack Dalton More articles by this author Shamroz Farooq More articles by this author Guan Wu More articles by this author Hani Rashid More articles by this author Thomas Frye More articles by this author Jean Joseph More articles by this author Ahmed Ghazi* More articles by this author Expand All Advertisement PDF downloadLoading ...

Nrf2/Keap1/ARE Signaling Mediated an Antioxidative Protection of Human Placental Mesenchymal Stem Cells of Fetal Origin in Alveolar Epithelial Cells.

The oxidative stresses are a major insult in pulmonary injury such as acute lung injury (ALI) and acute respiratory distress syndrome (ARDS), two clinical manifestations of acute respiratory failure with substantially high morbidity and mortality. Mesenchymal stem cells (MSCs) hold a promise in treatments of many human diseases, mainly owing to their capacities of immunoregulation and antioxidative activity. The strong immunoregulatory role of human placental MSCs of fetal origin (hfPMSCs) has been previously demonstrated; their antioxidant activity, however, has yet been interrogated. In this report, we examined the antioxidative activity of hfPMSCs by accessing the ability to scavenge oxidants and radicals and to protect alveolar epithelial cells from antioxidative injury using both a cell coculture model and a conditioned culture medium (CM) of hfPMSCs. Results showed a comparable antioxidative capacity of the CM with 100 μM of vitamin C (VC) in terms of the total antioxidant capacity (T-AOC), scavenging abilities of free radicals DPPH, hydroxyl radical (·OH), and superoxide anion radical (O2 −), as well as activities of antioxidant enzymes of SOD and GSH-PX. Importantly, both of the CM alone and cocultures of hfPMSCs displayed a protection of A549 alveolar epithelial cells from oxidative injury of 600 μM hydrogen peroxide (H2O2) exposure, as determined in monolayer and transwell coculture models, respectively. Mechanistically, hfPMSCs and their CM could significantly reduce the apoptotic cell fraction of alveolar epithelial A549 cells exposed to H2O2, accompanied with an increased expression of antiapoptotic proteins Bcl-2, Mcl-1, Nrf-2, and HO-1 and decreased proapoptotic proteins Bax, caspase 3, and Keap1, in comparison with naïve controls. Furthermore, hfPMSCs-CM (passage 3) collected from cultures exposed an inhibition of the Nrf2/Keap1/ARE signaling pathway which led to a significant reduction in caspase 3 expression in A549 cells, although the addition of Nrf2 inhibitor ML385 had no effect on the antioxidative activity of hfPMSCs-CM. These data clearly suggested that hfPMSCs protected the H2O2-induced cell oxidative injury at least in part by regulating the Nrf2-Keap1-ARE signaling-mediated cell apoptosis. Our study thus provided a new insight into the antioxidative mechanism and novel functions of hfPMSCs as antioxidants in disease treatments, which is warranted for further investigations.

Clinical manifestations following intramuscular exposure of mice to a lethal dose of ricin

Abstract Ricin a plant toxin derived from seeds of Ricinus communis, irreversibly inactivates ribosomes by site-specific depurination, thereby arresting cell protein synthesis, while its clinical manifestations following intramuscular exposure have not yet been investigated in depth. Here we report an extensive pathological study of intramuscular intoxication with a lethal dose of ricin in a murine model. Ricin injection caused neutrophilia, thrombocytopenia and coagulopathy. Although histopathological alternations including hemorrhages, vessel congestion and focal necrosis were observed in various organs, major insults were limited to the spleen, bone marrow (BM) and cardiovascular system. Intensive atrophy, evident in the BM and splenic white pulps, were accompanied be severe depletion of megakaryocytes in both organs. Moreover, splenic T and B lymphocytes, NK cells, macrophages and dendritic cells decreased significantly. The most striking damage was in the heart, where we observed diffuse hemorrhages, myocyte disconnection, loss of striation, interstitial edema, collagen deposition and elevated levels of serum cardiac troponin. Finally, echocardiography revealed marked thickening of the walls, along with sequential decrease in left ventricular volume. These were accompanied by a significant reduction in stroke volume and cardiac output, while the ejection fraction remained unaltered. Measurements of the toxin direct catalytic performance in the spleen, BM and heart of the ricin-intoxicated mice revealed no substantial 28S rRNA depurination. The lack of measurable ricin catalytic activity in conjunction with the striking clinical disorders observed, suggests that ricin affects these organs in an indirect manner.

Current Understanding of Diabetes Mellitus-Induced Lower Urinary Tract Dysfunction

Diabetes mellitus (DM) is slowly emerging as an epidemic in India, afflicting majority of the population, thus having serious public health consequences. DM usually inflicts major insult to almost all organ systems of the body, including the urinary tract. However, there is a dearth of literature on potential hazardous effects of DM on the urinary tract in a particular population. Considering its negative impact on the quality of life, particularly among the growing elderly population in India, we performed literature search through PubMed and unbound Medline database using the terms “diabetic cystopathy,” “diabetic complication urinary tract,” “diabetic urethropathy,” and “diabetic bladder dysfunction” to study the current understanding on the pathophysiology of diabetes induced on the lower urinary tract dysfunction. All the literature based on DM relevant to lower urinary tract dysfunction were studied, and a comprehensive overview of the current understanding of the pathophysiology of diabetes induced on the lower urinary tract dysfunction is provided. These results will facilitate the future directions for research and clinical care of patients with DM-induced lower urinary tract dysfunction. In conclusion, the long-term hyperglycemic state may result in structural and functional changes in urinary bladder and urethra, contributing to deterioration of lower urinary tract coordinated function.

Perturbed Biochemical Pathways and Associated Oxidative Stress Lead to Vascular Dysfunctions in Diabetic Retinopathy.

Diabetic retinopathy (DR) is a vascular insult that accompanies the hyperglycemic state. Retinal vasculature holds a pivotal role in maintaining the integrity of the retina, and any alteration to retinal vasculature affects retinal functions. The blood retinal barrier, a prerequisite to vision acuity, is most susceptible to damage during the progression of DR. This is a consequence of impaired biochemical pathways such as the polyol, advanced end glycation products (AGE), hexosamine, protein kinase C (PKC), and tissue renin-angiotensin system (RAS) pathways. Moreover, the role of histone modification and altered miRNA expression is also emerging as a major contributor. Epigenetic changes create a link between altered protein function and redox status of retinal cells, creating a state of metabolic memory. Although various biochemical pathways underlie the etiology of DR, the major insult to the retina is due to oxidative stress, a unifying factor of altered biochemical pathways. This review primarily focuses on the critical biochemical pathways altered in DR leading to vascular dysfunctions and discusses antioxidants as plausible treatment strategies.

Multimodal Prehabilitation Programs as a Bundle of Care in Gastrointestinal Cancer Surgery: A Systematic Review.

Prehabilitation reflects a proactive process of preoperative optimization undertaken between cancer diagnosis and definitive surgical treatment, with the intent of improving physiological capacity to withstand the major insult of surgery. Prehabilitation before GI cancer surgery is currently not widely adopted, and most research has focused on unimodal interventions such as exercise therapy, nutritional supplementation, and hematinic optimization. A review of the existing literature was undertaken to investigate the impact of multimodal prehabilitation programs as a "bundle of care." A systematic literature search was performed utilizing Medline, PubMed, Embase, Cinahl, Cochrane, and Google Scholar databases. The quality of studies was assessed by using the Cochrane tool for assessing risk of bias (randomized trials) and the Newcastle-Ottawa Quality Assessment scale (cohort studies). Studies were chosen that involved pre-operative optimization of patients before GI cancer surgery. The primary outcome measured was the impact of prehabilitation programs on preoperative fitness and postoperative outcomes. Of the 544 studies identified, 20 were included in the qualitative analysis. Two trials investigated the impact of multimodal prehabilitation (exercise, nutritional supplementation, anxiety management). Trials exploring prehabilitation with unimodal interventions included impact of exercise therapy (7 trials), impact of preoperative iron replacement (5 trials), nutritional optimization (5 trials), and impact of preoperative smoking cessation (2 trials). Compliance within the identified studies was variable (range: 16%-100%). There is a lack of adequately powered trials that utilize objective risk stratification and uniform end points. As such, a meta-analysis was not performed because of the heterogeneity in study design. Although small studies are supportive of multimodal interventions, there are insufficient data to make a conclusion about the integration of prehabilitation in GI cancer surgery as a bundle of care. Larger, prospective trials, utilizing uniform objective risk stratification and structured interventions, with predefined clinical and health economic end points, are required before definitive value can be assigned to prehabilitation programs.

Palmitic acid elicits hepatic stellate cell activation through inflammasomes and hedgehog signaling

AimsActivation of hepatic stellate cells (HSCs) plays a pivotal role at the center of the fibrogenic progression in nonalcoholic steatohepatitis (NASH). However, it is poorly understood that how various molecules interact within HSCs during the progression of NASH to fibrosis. The aim of the present study is to delineate how inflammasome molecules, hedgehog signaling and autophagy provoke HSC activation using palmitic acid (PA) as a major insult. Main methodsInflammasome activation, hedgehog signaling activity and autophagy in PA-exposed HSCs were determined to investigate their role in activation of human and rodent HSC lines or primary HSCs. Key findingsPA treatment elicited HSC activation reflected by increased mRNA levels of transforming growth factor-β1, connective tissue growth factor, tissue inhibitor of metalloproteinase-1 and procollagen type I (α1). In addition, expression levels of NOD-like receptor protein 3 (NLRP3) and hedgehog signaling transcription factor Gli-1 were increased in PA-exposed HSCs. It's evident that PA treatment resulted in increased production of light chain 3-II and autophagosomes, as well as enhanced autophagy flux reflected by transduction of an adeno-associated viral vector. Whereas, reduced autophagy, which is often seen in the late stage of NASH, provoked inflammasome activation. Moreover, suppressing the Hh signaling pathway by LDE225 blocked production of light chain 3-II and autophagy flux. SignificanceSaturated fatty acids, such as PA, stimulate HSC activation through inflammasomes and hedgehog signaling. Meanwhile, compromised autophagy may facilitate HSC activation, implicating valuable candidates for pharmacologic intervention against the progression of fibrogenesis in NASH.

Giardia duodenalis Rad52 protein: biochemical characterization and response upon DNA damage.

Giardia duodenalis is a flagellated binucleated protozoan that colonizes the small intestine in mammals, causing giardiasis, acute or chronic diarrhea. DNA double strand break either endogenously or exogenously generated is a major insult to DNA and its repair by homologous recombination (HR) is crucial for genomic stability. During HR, Rad52 plays key roles in the loading of the Rad51 recombinase, and the annealing of the second double-strand break end to the displaced strand of the D-loop structure. Among the functions found in vitro in yeast and human Rad52 protein are: ssDNA or dsDNA binding activity, ability to anneal bare or RPA coated-ssDNA, as well as multimeric ring formation. In this work, we searched for conserved domains in a putative Rad52 protein from G. duodenalis (GdRad52). Its coding sequence was cloned, expressed and purified to study its biochemical properties. rGdRad52 binds to dsDNA and ssDNA, with greater affinity for the latter. Likewise, rGdRad52 promotes annealing of DNA uncoated and coated with GdRPA1. rGdRad52 interacts with GdDMC1B and with GdRPA1 protein as shown in far western blotting assay. Additionally, rGdRad52 formed multimeric rings as observed by electronic microscopy. Finally, GdRad52 is over expressed in response upon DNA damage inflicted on trophozoites.

Nutritional Support in the Setting of Persistent Inflammation, Immunosuppression, and Catabolism Syndrome (PICS)

Purpose of Review The Persistent Inflammation, Immunosuppression, and Catabolism syndrome (PICS) is a new phenotype of survivors of critical illness that occurs after major inflammatory insults such as sepsis, severe postoperative complication, and trauma.

Oxygen--a limiting factor for brain recovery.

Effective brain metabolism is highly dependent on a narrow therapeutic window of oxygen. In major insults to the brain (e.g., intracerebral hemorrhage), a slight decrease in oxygen supply, as occurs in a hypobaric environment at high altitude, has devastating effects on the injured brain tissue. Conversely, increasing brain oxygenation, by the use of hyperbaric oxygen therapy, can improve brain metabolism and its dependent regenerative processes.