Prolonged Loss Research Articles

Ocular Surface Changes After Sulfur Mustard Exposure in Rabbits, Monitored by Impression Cytology.

Ocular injuries after exposure to sulfur mustard (SM) are characterized by acute corneal erosion and inflammation of the anterior segment that may be followed by delayed corneal neovascularization and epithelial defects, associated with limbal stem cell deficiency in part of the exposed eyes. This study aimed to further clarify the mechanism of the late injury by monitoring SM-induced cytological alterations in the ocular surface, in relation to the clinical symptoms, using impression cytology (IC). Rabbit eyes were exposed to SM vapor (n = 20) and were clinically observed up to 4 weeks. Samples for IC were collected simultaneously from the upper bulbar conjunctiva, limbus, and cornea and then fixed and stained with periodic acid-Schiff and hematoxylin. At 1 month, animals were killed and eyes dissected and processed for histology. Concomitant with clinical symptoms of SM ocular toxicity, IC showed significant long-term loss of conjunctival goblet cells shortly after exposure, followed by abnormal differentiation toward squamous metaplasia. Simultaneously with corneal erosion, apoptotic bodies and cellular debris were seen in the corneal epithelium, followed by regeneration at 1 week. Migration of conjunctival goblet cells toward the cornea was noted in neovascularized eyes, as early as 1 week, indicating limbal stem cell deficiency. The IC findings were supported by histological evaluation. Continuous monitoring of the ocular surface after SM exposure by IC enables earlier detection of pathology and therapeutic intervention, therefore, is recommended for routine follow-up of casualties. Prolonged loss of goblet cells may point toward the role of mucin in the pathogenesis.

Establishing a Short Bowel Model in Mice as a Tool for Studying Genetic Risk Factors of Intestinal Failure

Introduction: Short bowel syndrome (SBS) is a severe condition in which the patient is unable to acquire enough energy due to insufficient bowel length. Failed surgery is the main reason for SBS. Therapy consists in total parenteral nutrition or bowel transplantation. Since the patient population with SBS is heterogenous and it is therefore difficult to perform studies, we established an experimental model to study adaptation in surgery induced short bowel in mice. Herein we report the results after the first 104 animals. Methods: Male C57B6/J mice (Jackson Laboratories) weighing approximately 30 g were switched to liquid diet ad libitum 48h before surgery. They were anaesthetized using ketamine/xylazine intraperitoneally. Mice were intubated and ventilated throughout surgery. Using the operation microscope, a median laparotomy was performed, the cecum exteriorized and 11 cm of small bowel proximal to the cecum exposed. The mesentery of this small bowel including the very proximal part of the ascending colon was clipped using micro clips, the bowel then resected. The bowel was anastomosed using 10–0 nylon suture performing 11–13 full thickness stitches. The bowel was then replaced into the abdominal cavity, irrigated with saline and the abdomen closed. The animals were kept on liquid diet for at least 1 week. Animal condition was measured daily using the wellness score. Sham operation with transection 11 cm proximal to the cecum was used as control. The study was approved by the local animal welfare committee. Results: Animals that died on the day of surgery or day one postoperatively were excluded from analysis because anesthesiologic reasons were observed. The mean length of resected bowel was 11.3 cm. Median body weight loss was 16% in the resected group compared to 8% in the sham group. Unlike Sham controls, resected mice developed diarrhea and prolonged weight loss. Overall survival was 69% in the resected group and 95% in the sham group. Causes of death or surgical complications of all 104 resected mice were ileus (12%), anastomotic insufficiency (6%), anastomotic stenosis (3%), others such as GI bleeding, lung edema etc.) and unknown (21%). The surgical procedure was adapted in course of training including using thinner suture material and different feeding postoperatively. Conclusion: We established a clinical relevant mouse model to study mechanisms of intestinal adaptation and the influence of genetic risk factors (NOD2 mutation or others) on the course of SBS.

Late Therapeutic Intervention with Antibiotics and Fluid Resuscitation Allows for a Prolonged Disease Course with High Survival in a Severe Murine Model of Sepsis.

Current animal models of sepsis often incorporate antibiotics to be consistent with clinical standards for treatment of patients in the intensive care unit. However, such experimental intervention is commonly initiated very early after infectious insult, which likely blunts the progression of systemic inflammation and downstream pathology. The objective of this study was to establish an animal model of sepsis with delayed therapeutic intervention, allowing a longer disease course and downstream pathology, but still resulting in a high survival rate. Severe lethal abdominal infection was initiated in young adult (17-18-week-old) C57BL/6 mice by cecal slurry (CS) injection. When initiated early (1- or 6-h post-CS injection), antibiotic treatment (imipenem, 1.5 mg/mouse i.p., twice/day for 5 days) rescued the majority of mice; however, few of these mice showed evidence of bacteremia, cytokinemia, or organ injury. When antibiotic treatment was delayed until late time-points (12- or 24-h post-CS injection) the majority of animals did not survive beyond 48 h. When fluid resuscitation (physiological saline, s.c.) was performed in combination with antibiotic treatment (twice daily) beginning at these late time-points, the majority of mice survived (75%) and showed bacteremia, cytokinemia, organ dysfunction, and prolonged body weight loss (<90% for 4 weeks). We recommend that this new repeated combination treatment with antibiotics and fluids resuscitation be initiated at a late time point after bacteremia becomes evident because this model more closely mimics the downstream pathological characteristics of severe clinical sepsis yet maintains a high survival rate. This model would be advantageous for studies on severe sepsis and postintensive care illness.

Sleep Loss Promotes Astrocytic Phagocytosis and Microglial Activation in Mouse Cerebral Cortex.

We previously found that Mertk and its ligand Gas6, astrocytic genes involved in phagocytosis, are upregulated after acute sleep deprivation. These results suggested that astrocytes may engage in phagocytic activity during extended wake, but direct evidence was lacking. Studies in humans and rodents also found that sleep loss increases peripheral markers of inflammation, but whether these changes are associated with neuroinflammation and/or activation of microglia, the brain's resident innate immune cells, was unknown. Here we used serial block-face scanning electron microscopy to obtain 3D volume measurements of synapses and surrounding astrocytic processes in mouse frontal cortex after 6-8 h of sleep, spontaneous wake, or sleep deprivation (SD) and after chronic (∼5 d) sleep restriction (CSR). Astrocytic phagocytosis, mainly of presynaptic components of large synapses, increased after both acute and chronic sleep loss relative to sleep and wake. MERTK expression and lipid peroxidation in synaptoneurosomes also increased to a similar extent after short and long sleep loss, suggesting that astrocytic phagocytosis may represent the brain's response to the increase in synaptic activity associated with prolonged wake, clearing worn components of heavily used synapses. Using confocal microscopy, we then found that CSR but not SD mice show morphological signs of microglial activation and enhanced microglial phagocytosis of synaptic elements, without obvious signs of neuroinflammation in the CSF. Because low-level sustained microglia activation can lead to abnormal responses to a secondary insult, these results suggest that chronic sleep loss, through microglia priming, may predispose the brain to further damage.SIGNIFICANCE STATEMENT We find that astrocytic phagocytosis of synaptic elements, mostly of presynaptic origin and in large synapses, is upregulated already after a few hours of sleep deprivation and shows a further significant increase after prolonged and severe sleep loss, suggesting that it may promote the housekeeping of heavily used and strong synapses in response to the increased neuronal activity of extended wake. By contrast, chronic sleep restriction but not acute sleep loss activates microglia, promotes their phagocytic activity, and does so in the absence of overt signs of neuroinflammation, suggesting that like many other stressors, extended sleep disruption may lead to a state of sustained microglia activation, perhaps increasing the brain's susceptibility to other forms of damage.

MP27: Costs of emergency syncope care in Canada

Introduction: Syncope is a common emergency department (ED) presentation and constitutes 1% of all ED visits, approximately 160,000 visits annually across Canada. Lack of standardized syncope care has economic and cost implications. Currently, emergency medical services (EMS) is over utilized, variations in ED management exist and a substantial proportion (46.5%) are hospitalized for cardiac monitoring. Our previous studies have proposed ways to reduce health care utilization through development of EMS clinical decision tool, ED risk scores and remote cardiac monitoring. We sought to: 1) Estimate costs associated with syncope care in the pre-hospital, ED and inpatient settings; and 2) Determine potential cost savings if the proposed alternate strategies were adopted. Methods: A prospective cohort study was conducted in five Canadian EDs from 2010-2014. We enrolled adult (≥16 years) syncope patients and excluded those with prolonged loss of consciousness, mental status changes, seizure, significant trauma, or alcohol/illicit drug abuse. Demographics, medical history, mode of arrival, EMS time points, reasons for hospitalization, ED and inpatient length of stay, final ED diagnosis and any serious adverse event within 30 days of index visit were collected. Descriptive and inferential statistics were used. Results: Out of 4,064 patients enrolled, 67.3% were transported to the ED by EMS and the average cost per event was $262.78 (range at study sites: $156.43-$553.03). The average cost per ED visit was $267.98 (range: $174.66-$374.95). 12.9% of the patients were admitted and the average of cost per admission was $9,886.15 (range: $9,715.23-$10,277.98). Syncope is associated with an estimated total annual cost of $257 million. In Canada, we estimate that diverting low-risk patients will save $5 million in the pre-hospital setting and $15 million in the ED annually, and implementing a remote cardiac monitoring strategy will save $50 million annually. Conclusion: It is estimated that the proposed strategies will save $70 million annually. This is likely an underestimation as cost savings due to reduction in investigations related to diversion of ED patients, reduction in ED length of stay and hospitalization are unaccounted. Adoption of similar strategies will likely lead to significantly higher cost savings in countries with higher resource utilization for syncope management.

Up/Rooting: Breaching Landscape Architecture in the Jewish-Arab City

This article portrays and theorizes a new utterance of landscape architecture within Israeli Jewish-Arab urbanity, which aims to represent the prolonged and multifaceted Palestinian urban loss since 1948 in the design of a major city park. The analysis of design discourses at Jaffa Slope Park examines differing Israeli and Palestinian landscape sign systems. Dominant and breaching landscape architecture utterances in the constructed landscape of the park will be interpreted and theorized in the context of the discursive landscape sign systems, together with the local post-1948 history of urban institutional ruination and planning. The park's design involves both the intensive use and destabilization of a traditional Zionist/Israeli landscape mold that aims at greening’Ereẓ Yisra'eland at concealing ruined pre-1948 Palestinian locales under green shields. Through a close reading of the park's landscape, the paper explores ethical, political, and allegorical utterances of landscape architecture, immersed in both Israeli and Palestinian landscape semiotics, yet undermining these sign systems at the same time.

Prolonged Sensory Loss Results in Altered Cortico‐cortical Connectivity Patterns

Congenital sensory deprivation results in significant functional and anatomical brain changes. I will discuss how both auditory and visual deprivation specifically lead to significant changes in corticocortical connectivity patterns between the deafferented primary sensory area and the rest of the brain. Using covariance analyses of cortical morphology in human individuals, I will show that early auditory deprivation significantly alters connectivity patterns between auditory and multisensory areas. In contrast, a somewhat different pattern emerges in the blind, where early visual deprivation results in a significant reduction of connectivity between primary visual cortex and areas of the dorsal visual stream responsible for oculomotor control. Furthermore, the strength of the connectivity between visual and multimodal parietal areas in the blind is predictive of auditory perceptual abilities. These findings constitute the first evidence linking altered anatomical covariance to early sensory deprivation.

Hyper Homocysteinemia Related Cerebral Venous Sinus Thrombosis –Presenting as Generalised Tonic-Clonic Seizure –A Case Report

Cerebral venous sinus thrombosis (CVST) is a neuromuscular disorder with protean manifestation requiring a high index of suspicion. Early diagnosis is sometimes lifesaving. It is particularly challenging is to establish an accurate etiology as it guides the clinician for long term thrombo-prophylaxis. We report a young female with no conventional risk factors for CVST, who presented with headache, generalised seizures and prolonged loss of consciousness. Her work-up revealed an elevated serum homocysteine level which might be a possible causative association in the etiopathogenesis of this neuromuscular condition.

The potential use of serum HBV RNA to guide the functional cure of chronic hepatitis B

Hepatitis B virus (HBV) covalently closed circular DNA (cccDNA) in infected hepatocytes is the main cause of off-therapy viral rebound. The half-life of cccDNA is only 33-50 days, so the conversion of newly synthesized rcDNA to cccDNA in the nucleus is essential for the maintenance of cccDNA pool in infected hepatocytes. Though not directly targeting the existing cccDNA, current nucleos(t)ide analogues (NAs) may exhaust the cccDNA reservoir by blocking the rcDNA formation. Indeed, a prolonged consolidation therapy post loss of serum HBV DNA can achieve sustained remission and thus safe drug discontinuation in a small proportion of chronic hepatitis B (CHB) patients. In recent studies, we and others have demonstrated that it is the serum HBV RNA that reflects the cccDNA activity in infected hepatocytes, particularly among the patients on NAs. Here we suggest that instead of measuring serum HBV DNA only, simultaneous measurement of both viral DNA and RNA would improve the accuracy to reflect the cccDNA activity; therefore, the virological response should be redefined as consistent loss (less than the lower limit of detection) of both serum HBV DNA and RNA, which indicates the safety of drug discontinuation. Accumulating evidence has suggested that for the CHB patients with lower serum HBsAg, switch-to or add-on pegylated interferon (Peg-IFN) treatment would result in loss of serum HBsAg in a relatively large proportion of CHB patients. Since serum HBV RNA is an ideal biomarker to reflect the intrahepatic cccDNA activity, for the patients with a serum HBsAg level lower than 1 500 IU/ml after long-term NAs treatment, the serum HBV RNA should be measured. If serum HBV RNA is detected, peg-IFN should be added on; if serum HBV RNA is not detected, NAs treatment should be switched to peg-IFN treatment. We believe the therapy based on serum HBV RNA would make the functional cure of CHB (serum HBsAg loss or even conversion to anti-HBs) more efficient.

Opposing FlnA and FlnB interactions regulate RhoA activation in guiding dynamic actin stress fiber formation and cell spreading

Filamins are a family of actin-binding proteins responsible for diverse biological functions in the context of regulating actin dynamics and vesicle trafficking. Disruption of these proteins has been implicated in multiple human developmental disorders. To investigate the roles of different filamin isoforms, we focused on FlnA and FlnB interactions in the cartilage growth plate, since mutations in both molecules cause chondrodysplasias. Current studies show that FlnA and FlnB share a common function in stabilizing the actin cytoskeleton, they physically interact in the cytoplasm of chondrocytes, and loss of FlnA enhances FlnB expression of chondrocytes in the growth plate (and vice versa), suggesting compensation. Prolonged FlnB loss, however, promotes actin-stress fiber formation following plating onto an integrin activating substrate whereas FlnA inhibition leads to decreased actin formation. FlnA more strongly binds RhoA, although both filamins overlap with RhoA expression in the cell cytoplasm. FlnA promotes RhoA activation whereas FlnB indirectly inhibits this pathway. Moreover, FlnA loss leads to diminished expression of β1-integrin, whereas FlnB loss promotes integrin expression. Finally, fibronectin mediated integrin activation has been shown to activate RhoA and activated RhoA leads to stress fiber formation and cell spreading. Fibronectin stimulation in null FlnA cells impairs enhanced spreading whereas FlnB inhibited cells show enhanced spreading. While filamins serve a primary static function in stabilization of the actin cytoskeleton, these studies are the first to demonstrate a dynamic and antagonistic relationship between different filamin isoforms in the dynamic regulation of integrin expression, RhoGTPase activity and actin stress fiber remodeling.

Traumatic subdural hematoma: Is there a weekend effect?

ObjectiveTraumatic subdural hematoma (TSDH) is a surgical emergency. The effect of weekend admission on surgery and in-hospital outcomes in TSDH is not known. MethodsWe queried the Nationwide Inpatient Sample from 2002 to 2011 and used ICD-9-CM codes to identify all non-elective admissions with a primary diagnosis of TSDH. We did a subgroup analysis of patients who underwent surgical evacuation. Predictor variables included several patient and hospital characteristics. Outcome variables included length of stay, total hospitalization cost, in-hospital complications, adverse discharge disposition, and in-hospital mortality. We used multivariable analysis to determine if weekend admission was independently associated with increased likelihood of poor outcomes. ResultsOut of a total of 404,212 TSDH admissions, 24.8% received surgical intervention. Patients admitted on weekends were less likely to undergo surgical intervention (odds ratio [OR]: 0.85). In the surgical cohort, weekend admissions consisted of more patients with prolonged loss of consciousness (24+h) without return to baseline (7.0% vs. 4.8%). In all TSDH patients and in sub-group of surgical cohort, weekend admission was associated with an increased likelihood of in-hospital complication (OR: 1.06 and 1.12), prolonged length of stay (OR: 1.08 and 1.17), increased total hospital costs (OR: 1.04 and 1.11), adverse discharge (OR: 1.08 and 1.18), and in-hospital mortality (OR: 1.04 and 1.11). All p-values were less than 0.01. ConclusionOur study demonstrates that patients admitted on weekends had similar mortality despite higher severity with no clinically significant weekend effect for tSDH.

The Use of Indigenous Cultural Practices by the Ashantis for the Conservation of Forests in Ghana

Indigenous cultural practices play a significant role in the conservation of forests. Most of the forests within traditional communities in the Ashanti region of Ghana were preserved centuries ago through traditional beliefs and practices. Yet, less attention has been given to them in modern forest management. In most communities, these traditional practices are gradually “dying out.” This work identified cultural practices that have been used to successfully conserve forests by four communities purposively selected from the Ashanti region of Ghana (i.e., Semanhyiakrom, Akegyesu, Kubease, and Jachie), their benefits, and the perceived reasons for their neglect in the management of public forests. Qualitative data were collected through semistructured interviews using stratified random sampling technique to select respondents. The study found that beliefs, taboos, myths, proverbs, and songs were vital traditional systems used by the Ashantis to effectively conserve their forests. The Ashantis believe that the neglect of cultural practices in the management of public forests has resulted in increasing rate of deforestation, destruction of water bodies, and disasters inflicted by the gods such as prolonged drought and loss of soil fertility. To avoid forest degradation, it is important for forest managers, decision makers, and governments to recognize various cultural practices and traditional beliefs as very useful tools and integrate them into current national and international forestry plans and programs.

Kikuchi-Fujimoto disease with multisystem involvement: A case report

Kikuchi-Fujimoto disease (KFD) is a self-limited, usually benign condition of unknown etiology characterized by fever and cervical lymphadenitis. Multisystem involvement is not very common. We report a case of a 14-year-old Chinese boy who presented with prolonged fever, rashes, cervical lymphadenitis, oral ulcers, and weight loss eventually diagnosed with Kikuchi’s disease. This case is interesting as the child subsequently developed multisystem involvement secondary to Kikuchi disease. The child recovered and remains well on follow-up clinic visits. KFD may have to be differentiated from many other infective, inflammatory, and malignant disorders. Diagnosis is confirmed by characteristic histopathological findings on excision lymph node biopsy. Long-term careful monitoring of these patients for signs and symptoms of evolving systemic lupus erythematosus or other autoimmune disorders is required.

EffectS of non-nutritive sWeetened beverages on appetITe during aCtive weigHt loss (SWITCH): Protocol for a randomized, controlled trial assessing the effects of non-nutritive sweetened beverages compared to water during a 12-week weight loss period and a follow up weight maintenance period

BackgroundAcute and medium-term intervention studies suggest that non-nutritive sweeteners (NNS) are beneficial for weight loss, however there is limited human data on the long-term effects of consuming NNS on weight loss, maintenance, and appetite. Further research is therefore required to elucidate the prolonged impact of NNS consumption on these outcome measures. Methods/designA randomized parallel groups design will be used to assess whether regular NNS beverage intake is equivalent to a water control in promoting weight loss over 12-weeks (weekly weight loss sessions; Phase I), then supporting weight maintenance over 40-weeks (monthly sessions; Phase II) and subsequently independent weight maintenance over 52-weeks (Phase III) in 432 participants. A subset of these participants (n=116) will complete laboratory-based appetite probe days (15 sessions; 3 sessions each at baseline, at the start of phase I and the end of each phase). A separate subset (n=50) will complete body composition scans (DXA) at baseline and at the end of each phase. All participants will regularly be weighed and will complete questionnaires and cognitive tasks to assess changes in body weight and appetitive behaviours. Measures of physical activity and biochemical markers will also be taken. DiscussionThe trial will assess the efficacy of NNS beverages compared to water during a behavioural weight loss and maintenance programme. We aim to understand whether the impact of NNS on weight, dietary adherence and well-being are beneficial or transient and effects on prolonged successful weight loss and weight maintenance through sustained changes in appetite and eating behaviour.Trial registration: Clinical Trials: NCT02591134; registered: 23.10.2015

Effects of the Use of the Provider Resilience Mobile Application in Reducing Compassion Fatigue in Oncology Nursing.

Oncology nurses have increased exposure to the prolonged illness, tragedy, loss, and premature death of patients. As a result, they are at higher risk for developing compassion fatigue. The aim of this study was to examine if use of the Provider Resilience mobile application (PRMA) will improve oncology nurses' professional quality of life. The quasiexperimental design was comprised of a longitudinal approach to evaluate the effect of an intervention program, PRMA, on professional quality of life between two nonrandomized groups (intervention and control) using pre- and post-tests in a sample of oncology RNs. The findings of this study demonstrated no significant relationships between the intervention and control groups on secondary traumatic stress, compassion satisfaction, and burnout among oncology nurses.

Mechanisms underpinning protection against eccentric exercise-induced muscle damage by ischemic preconditioning

Eccentric exercise training is effective for increasing muscle mass and strength, and improving insulin sensitivity and blood lipid profiles. However, potential muscle damage symptoms such as prolonged loss of muscle function and delayed onset of muscle soreness may restrict the use of eccentric exercise, especially in clinical populations. Therefore, strategies to reduce eccentric exercise-induced muscle damage (EIMD) are necessary, and an extensive number of scientific studies have tried to identify potential intervention modalities to perform eccentric exercises without adverse effects. The present paper is based on a narrative review of current literature, and provides a novel hypothesis by which an ischemic preconditioning (IPC) of the extremities may reduce EIMD. IPC consists of an intermittent application of short-time non-lethal ischemia to an extremity (e.g. using a tourniquet) followed by reperfusion and was discovered in clinical settings in an attempt to minimize inflammatory responses induced by ischemia and ischemia-reperfusion-injury (I/R-Injury) during surgery. The present hypothesis is based on morphological and biochemical similarities in the pathophysiology of skeletal muscle damage during clinical surgery and EIMD. Even though the primary origin of stress differs between I/R-Injury and EIMD, subsequent cellular alterations characterized by an intracellular accumulation of Ca2+, an increased production of reactive oxygen species or increased apoptotic signaling are essential elements for both. Moreover, the incipient immune response appears to be similar in I/R-Injury and EIMD, which is indicated by an infiltration of leukocytes into the damaged soft-tissue. Thus far, IPC is considered as a potential intervention strategy in the area of cardiovascular or orthopedic surgery and provides significant impact on soft-tissue protection and downregulation of undesired excessive inflammation induced by I/R-Injury. Based on the known major impact of IPC on skeletal muscle physiology and immunology, the present paper aims to illustrate the potential protective effects of IPC on EIMD by discussing possible underlying mechanisms.

Cell-Intrinsic Adaptation Arising from Chronic Ablation of a Key Rho GTPase Regulator

Genome-editing technologies allow systematic inactivation of human genes. Whether knockout phenotypes always reflect gene functions as determined by acute RNAi is an important question. Here we show how the acute knockdown of the Adams-Oliver syndrome (AOS) gene DOCK6, coding for a RAC1/CDC42 guanine nucleotide exchange factor, results in strikingly different phenotypes to those generated by genomic DOCK6 disruption. Cell-intrinsic adaptation compensates for loss of DOCK6 function. Prolonged DOCK6 loss impacts upon the MRTF-A/SRF transcription factor, reducing levels of the ubiquitin-like modifier ISG15. Reduced ISGylation of the IQGAP1 protein increases levels of active CDC42 and RAC1 to compensate for DOCK6 disruption. Similar downregulation of ISG15 in cells from DOCK6 AOS patients indicates that such adaptation can compensate for genetic defects during development. Thus, phenotypes of gene inactivation are critically dependent on the timescale, as acute knockdown reflects a transient state of adjustment to a new equilibrium that is attained following compensation.

Distal airway epithelial progenitor cells are radiosensitive to High-LET radiation.

Exposure to high-linear energy transfer (LET) radiation occurs in a variety of situations, including charged particle radiotherapy, radiological accidents, and space travel. However, the extent of normal tissue injury in the lungs following high-LET radiation exposure is unknown. Here we show that exposure to high-LET radiation led to a prolonged loss of in vitro colony forming ability by airway epithelial progenitor cells. Furthermore, exposure to high-LET radiation induced clonal expansion of a subset of progenitor cells in the distal airway epithelium. Clonal expansion following high-LET radiation exposure was correlated with elevated progenitor cell apoptosis, persistent γ-H2AX foci, and defects in mitotic progression of distal airway progenitors. We discovered that the effects of high-LET radiation exposure on progenitor cells occur in a p53-dependent manner. These data show that high-LET radiation depletes the distal airway progenitor pool by inducing cell death and loss of progenitor function, leading to clonal expansion. Importantly, high-LET radiation induces greater long-term damage to normal lung tissue than the relative equivalent dose of low-LET γ-rays, which has implications in therapeutic development and risk assessment.

P.316 - Potential mechanisms for prolonged loss of ambulation with deflazacort in Duchenne muscular dystrophy – Tolerability profile and effects on growth

P.316 - Potential mechanisms for prolonged loss of ambulation with deflazacort in Duchenne muscular dystrophy – Tolerability profile and effects on growth

Changes to Intestinal Transport Physiology and Carbonate Production at Various CO2 Levels in a Marine Teleost, the Gulf Toadfish (Opsanus beta).

Most marine teleosts defend blood pH during high CO2 exposure by sustaining elevated levels of HCO3(-) in body fluids. In contrast to the gill, where measures are taken to achieve net base retention, elevated CO2 leads to base loss in the intestine of marine teleosts studied to date. This loss is thought to occur through transport pathways previously demonstrated to be involved with routine osmoregulation in marine teleosts. The main objective of this study was to characterize the intestinal transport physiology of the gulf toadfish (Opsanus beta) when exposed to varied levels of CO2: control, 5,000, 10,000, and 20,000 μatm CO2 (0.04, 0.5, 1, and 2 kPa, respectively). Results of this study suggest that intestinal apical anion exchange is highly responsive to hypercarbia, evidenced by a dose-dependent increase in intestinal luminal HCO3(-) (mmol L(-1)) that was mirrored by a reduction in Cl(-) (mmol L(-1)). Despite activation of HCO3(-) transport pathways typically used during osmoregulation, fractional fluid absorption was only significantly lower at the highest level of CO2. Although increased HCO3(-) excretion could provide more substrate for intestinally produced carbonates, carbonate production was not significantly increased during hypercarbia at the levels tested. This study is among the first to thoroughly characterize how compensation for elevated CO2 affects transport physiology and carbonate production in the marine fish intestine. This deeper understanding may be particularly relevant when considering the impacts of future predicted ocean acidification, where prolonged base loss may alter the energetic cost of acid-base balance or osmoregulation in marine fish.