Surgical Controls Research Articles

Rapid development of strong, persistent, spatiotemporally extensive cortical synchrony and underlying oscillations following acute MCA focal ischemia

Stroke is a leading cause of death and the leading cause of long-term disability, but its electrophysiological basis is poorly understood. Characterizing acute ischemic neuronal activity dynamics is important for understanding the temporal and spatial development of ischemic pathophysiology and determining neuronal activity signatures of ischemia. Using a 32-microelectrode array spanning the depth of cortex, electrophysiological recordings generated for the first time a continuous spatiotemporal profile of local field potentials (LFP) and multi-unit activity (MUA) before (baseline) and directly after (0–5 h) distal, permanent MCA occlusion (pMCAo) in a rat model. Although evoked activity persisted for hours after pMCAo with minor differences from baseline, spatiotemporal analyses of spontaneous activity revealed that LFP became spatially and temporally synchronized regardless of cortical depth within minutes after pMCAo and extended over large parts of cortex. Such enhanced post-ischemic synchrony was found to be driven by increased bursts of low multi-frequency oscillations and continued throughout the acute ischemic period whereas synchrony measures minimally changed over the same recording period in surgical sham controls. EEG recordings of a similar frequency range have been applied to successfully predict stroke damage and recovery, suggesting clear clinical relevance for our rat model.

Abstract P221: Tregs Do Not Expand In Pregnancy After Recovery From Ischemia Reperfusion Injury

Recent studies in our laboratory report that pregnancy after renal ischemia reperfusion (IR) injury results in adverse maternal and fetal outcomes, including decreased fetal growth, increased fetal demise, and maternal renal insufficiency. In the current study, we examined the effect of IR injury on the immune system during pregnancy. Pregnancy is a unique state of immunosuppression, where regulatory T cells (Tregs) increase to combat the immune response to the allogenic fetus. Tregs are also known to play a critical role in recovery after IR, and may serve as a link between IR and poor pregnancy outcomes. We hypothesized that Tregs would be decreased during pregnancy after recovery from IR. Briefly, female Sprague Dawley rats (12 wks of age, n=4) were randomized to receive either 45 minutes of warm, bilateral renal IR injury or sham surgery. Rats were then allowed 30 days to recover, and renal recovery was confirmed by plasma creatinine and urinary protein excretion. Rats were then randomized to either be mated or serve as an age-matched virgin control. Pregnancy was confirmed by vaginal cytology, with presence of sperm on the slide indicative of day 1 of pregnancy. Pregnancies were terminated on pregnancy day 20, and blood and kidneys were collected for flow cytometric analysis of T cells. Interestingly, Tregs only increased during pregnancy in control rats in the kidney (4.7±0.7 to 12.6±0.3 FoxP3 + T cells as % CD3 + CD4 + , 2-Way ANOVA interaction p<0.01) and blood (5.7±0.3 to 13.4±1.2 % FoxP3 + T cells as % CD3 + CD4 + , 2-Way ANVOA interaction p<0.01) Tregs did not increase during pregnancy in the IR rats in the kidney (5.0±0.3 to 5.2±0.7 FoxP3 + T cells as %CD3 + CD4 + ) or in the blood (6.6±0.4 to 6.8±0.5 % FoxP3 + T cells as %CD3 + CD4 + in the blood). Tregs in IR dams and virgin IR were similar to the virgin surgical sham controls. These data suggest that Tregs fail to expand during pregnancy after IR, potentially contributing to the increased rate of fetal demise and poor pregnancy outcomes observed in this model.

OR22-06 Bone Outcomes Following Sleeve Gastrectomy in Adolescents and Young Adults with Obesity Versus Non-Surgical Controls

Background: Sleeve gastrectomy is the most commonly performed weight loss surgery in adolescents with moderate-to-severe obesity. While studies in adults have reported on the deleterious effects of gastric bypass surgery on bone structure and strength estimates, data are lacking for the impact of sleeve gastrectomy on these measures in adolescents. Objective: To evaluate the impact of sleeve gastrectomy on bone outcomes in adolescents and young adults over 12 months using dual energy x-ray absorptiometry (DXA) and high resolution peripheral quantitative computed tomography (HRpQCT). Participants and Methods: We enrolled 33 youth 14-22 years old with moderate to severe obesity; 17 underwent sleeve gastrectomy and 16 were followed without surgery. DXA was used to assess areal bone mineral density (aBMD). HRpQCT was used to assess bone geometry, microarchitecture and volumetric BMD (vBMD) and finite element analysis to assess strength estimates (stiffness and failure load) at the distal tibia and distal radius at baseline and 12 months. 25(OH) vitamin D (25OHD) levels were obtained at baseline and follow-up. Results: The surgical group lost 28.2% of total body weight compared to 1.4% in the non-surgical group. The groups did not differ for changes in 25OHD levels (P=0.181). After controlling for age and sex, compared to the non-surgical group, the surgical group had reductions in aBMD Z-scores at the femoral neck and total hip (p≤ 0.0005). At the distal tibia, there were reductions in cortical thickness and trabecular number, and increases in trabecular separation and cortical vBMD, without changes in strength estimates in the surgical group vs. controls (p≤0.043). Changes were less marked at the distal radius. While sleeve gastrectomy resulted in deleterious effects on most bone parameters, there was an increase in cortical vBMD at both sites, possibly from a decrease in cortical porosity. Most differences were attenuated after adjusting for changes in BMI over 12 months. Conclusions: Over 12 months, weight loss associated with sleeve gastrectomy in adolescents had deleterious effects on areal BMD, bone geometry and trabecular microarchitecture at weight-bearing sites. However, strength estimates did not decrease, possibly because of a simultaneous increase in cortical volumetric BMD. Additional research is necessary to determine the relative contribution(s) of weight loss and the metabolic effects of surgery, and whether the observed effects on bone stabilize or progress over time.

Balloon Catheter Dilation in Pediatric Chronic Rhinosinusitis: A Meta-analysis.

Paranasal sinus balloon catheter dilation (BCD) represents a tool that has been shown to be safe in the management of pediatric chronic rhinosinusitis (pCRS); however, its efficacy compared to standard treatment regimens has not been well established. The purpose of this meta-analysis was to evaluate the clinical utility of BCD in pCRS. Articles reporting BCD for pCRS in patients under 18 years of age were identified via the following search terms: sinusitis OR rhinosinusitis AND balloon dilatation OR balloon dilation OR balloon sinuplasty OR sinuplasty AND adolescent OR children OR infant OR pediatric OR toddler. The primary outcome analyzed includes quality of life improvement as measured via Sinus and Nasal Quality of Life Survey (SN-5) or Sino-nasal Outcome Test (SNOT-22) scores. Eighty studies were abstracted; 10 studies were included for final qualitative analysis after dual investigator screening. Three studies described BCD with surgical controls, including adenoidectomy, saline irrigation, or maxillary antrostomy. Noninferiority was not demonstrated (ie, BCD is inferior) in 2 of 3 studies. Pooled analysis utilizing a random effects model revealed a decreased effect size yet no statistically significant difference between BCD and standard operative techniques as measured by quality of life measures (g = -0.04, I2 = 41%). This work highlights a lack of published evidence regarding the role of BCD in pCRS. Two of the 3 included studies demonstrated the inferiority of BCD when compared to other standard surgical interventions, whereas meta-analysis was unable to detect any statistically significant difference between standard treatment regimens. Future scientific investigations are necessary to assess the comparative effectiveness of BCD in pCRS.

Is Hysterectomy a Risk Factor for Urinary Retention? A Retrospective Matched Case Control Study

Compare the rates of urinary retention in patients undergoing endoscopic hysterectomy with those of patients undergoing nonhysterectomy endoscopic gynecologic surgery. Retrospective case control study matched by operative time. Academic medical center. All patients undergoing endoscopic gynecologic surgeries between January 2013 and December 2018. Outpatient endoscopic gynecologic surgery. A total of 200 endoscopic hysterectomy cases were matched to endoscopic nonhysterectomy gynecologic surgery controls in a 1:1 ratio. The differences in baseline and operative characteristics between the 2 groups included age (48.6 years vs 45.7 years, p = .04), perioperative opioid administration (morphine milligram equivalents, 11.6 mg vs 7.6 mg, p = .01), and estimated blood loss (64.1 mL vs 31.8 mL, p = .001). The rate of urinary retention in the hysterectomy group was double that in the nonhysterectomy group (26.5% vs 13%, p = .01). In the hysterectomy group, age, perioperative opioids, operative time, and estimated blood loss did not differ between those who failed and those who passed the void trial. In the nonhysterectomy group, only operative time was significantly longer in those who failed the void trial (108 minutes vs 94.3 minutes, p = .04). After adjusting for perioperative opioid use and operative time, the relative risk of urinary retention in the hysterectomy group was 2.3 (p = .002, 95% confidence interval, 1.38-3.98). Hysterectomy appears to be an independent and major factor contributing to postoperative urinary retention. When compared with nonhysterectomy gynecologic surgical controls with similar operative times, the rate of urinary retention in patients who underwent hysterectomy was doubled.

Evidence first, practice second in arthroscopic surgery: use of placebo surgery in randomised controlled trial

The application of evidence-based medicine helps clinicians avoid unnecessary procedures and decreases unnecessary harm for future patients while sparing economic burdens. Randomised controlled trials (RCTs) most accurately produce best research...

CD3+CD4–CD8– Double-negative αβ T cells attenuate lung ischemia-reperfusion injury

ObjectiveLung ischemia-reperfusion injury (IRI) is a common complication after lung transplantation, and immune cells have been implicated in modulating outcomes. We hypothesized that a newly described subset of αβ T-cell receptor positive cells; that is, CD4–CD8– (double negative [DN]) T cells, are found in lungs and can protect against lung IRI. MethodsIschemia was induced in C57BL/6 mice by left pulmonary artery and vein occlusion for 30 minutes followed by 180 minutes of reperfusion. These mice were paired with sham hilar dissected surgical controls. In mice undergoing IRI, adoptive transfer of DN T cells or conventional T cells was performed 12 hours before occlusion. Flow cytometry was used to quantify T cells and inflammatory cytokines, and apoptotic signaling pathways were evaluated with immunoblotting. Lung injury was assessed with Evans blue dye extravasation. ResultsDN T cells were significantly higher (5.29% ± 1% vs 2.21% ± 3%; P < .01) in IRI lungs and secreted higher levels of interleukin-10 (30% ± 5% vs 6% ± 1%; P < .01) compared with surgical sham controls. Immunoblotting, hematoxylin and eosin staining and Evans blue dye demonstrated that adoptive transfer of DN T cells significantly decreased interstitial edema (P < .01) and attenuated apoptosis/cleaved caspase-3 expression in the lungs following lung IRI (P < .01). ConclusionsDN T cells traffic into lungs during IRI, and have tissue protective functions regulating inflammation and apoptosis. We propose a potential novel immunoregulatory function of DN T cells during lung IRI.

Evidence-Based Evaluation of the Ethics of Sham Surgery for Parkinson's Disease.

The stated purpose of sham or placebo surgery is to enable the implementation of surgical placebo-controlled trials (SPTs) for evaluating the safety and efficacy of surgical interventions. Exposing the participants to the burdens and harms of sham surgery has been justified on the grounds of the absolute necessity for controlling large placebo effects and observer bias, assumed to be associated with surgical procedures. In the present review, we argue that evidence obtained from SPTs of cellular therapies for the treatment of Parkinson’s disease (PD) has failed to demonstrate either large and consistent placebo effects or decisive methodological advantages for relying on sham surgical controls. We outline several alternative assessment strategies and designs available to establish the efficacy of cellular therapies. It is concluded that the evidence evaluated in the present analysis indicated that use of sham surgery in the context of developing novel surgical procedures for PD is not necessary, and therefore, unethical under a utilitarian model.

Association between anti-α-1,4-D-polygalacturonic acid antibodies and Henoch-Schönlein purpura in children.

ObjectiveTo investigate the relationship between anti-α-1,4-D-polygalacturonic acid (PGA) antibodies, particularly immunoglobulin (Ig)A, and Henoch-Schönlein purpura (HSP) in children.MethodsThis observational case–control study investigated PGA-IgA, PGA-IgG, and PGA/PGA-IgA circulating immune complex (PGA/PGA-IgA CIC) in paediatric patients with HSP versus controls. Children with HSP were also evaluated for food specific IgG and food intolerance. Between-group differences in anti-PGA antibodies were analysed.ResultsSerum PGA-IgA and PGA-IgG levels were significantly increased in patients with acute HSP (n = 251) versus those with urticaria (n = 48), acute respiratory infections (n = 95), surgical controls (n = 53) and neonates (n = 92). PGA/PGA-IgA CIC levels were also significantly higher in the acute HSP group versus surgical control and neonate groups. Levels of PGA/PGA-IgA CIC and PGA-IgA were significantly correlated (r = 0.997), and PGA-IgA showed high diagnostic specificity for HSP. No statistically significant differences were observed in PGA-IgA and PGA-IgG between various degrees of food intolerance in children with HSP.ConclusionIncreased anti-PGA antibodies, particularly PGA-IgA and PGA/PGA-IgA CIC, were significantly associated with acute HSP in children. Food intolerance was not found to be associated with increased anti-PGA antibodies in children with HSP.

Use of Acellular Dermal Matrix Following Fasciectomy for the Treatment of Dupuytren's Disease.

Background:Recurrence rates following surgical intervention for Dupuytren's disease (DD) remains high. In this study, we investigate the use of acellular dermal matrix (ADM) to reduce recurrence and improve long-term clinical outcome.Methods:We examined 132 patients undergoing open fasciectomy for DD from 2007 to 2017. The experimental group had a sheet of ADM (FlexHD) sutured into the surgical bed controls were not closed with ADM. Patient characteristics, range of motion, and complications were examined.Results:Twenty-eight (21.2%) patients were treated with acellular dermal matrix, whereas 104 (78.8%) patients were not. The median age was 67.0 years (range 34–91 years). with no differences between group regarding age, comorbidities, and laterality. The mean preoperative interphalangeal joint flexion contracture in the ADM group of 66.5 ± 29.9 degrees was corrected to 9.7 ± 12.4 degrees, whereas the mean metacarpophalangeal joint preoperative flexion contracture of 51.4 ± 23.9 degrees was corrected to 7.8 ± 14.1 degrees at postoperative examination (P < 0.05). The median follow-up was 18.7 months, during which the recurrence of contracture was observed in 1 of 28 patients in the group receiving ADM compared with 9 of 104 in the control group (P = 0.37). There were no differences in the incidence of minor wound complications observed.Conclusion:The adjunct placement of acellular dermal matrix into the wound bed following fasciectomy for DD may be an important surgical strategy to reduce recurrence rates as well as augment coverage of exposed vital structures in cases of severe flexion contracture.

Cancer and cancer survival modulates brain and behavior in a time-of-day-dependent manner in mice

Improvements in breast cancer therapy/diagnosis have substantially increased the cancer survivor population, although many survivors report persistent mental health issues including fatigue, mood and anxiety disorders, and cognitive impairments. These behavioral symptoms impair quality-of-life and are often associated with increased inflammation. Nocturnal rodent models of cancer are critical to the identification of the neurobiological mechanisms underlying these behavioral changes. Although both behavior and immunity display distinct diurnal patterns, most rodent research in this field is performed during the rodents’ inactive (light) period, which could potentially undermine the conclusions and clinical relevance. Therefore, here we tested the extent to which mammary tumors or tumor resection (“survivors”) in mice affects behavior and neuroinflammation in a nyctohemeral (day versus night)-dependent manner. Indeed, only the dark (active) phase unmasked fatigue-like behavior and altered novel object investigation for both tumor-bearing and -resected mice relative to surgical controls. Several inflammatory markers were expressed in a time-of-day-dependent manner (lower in the dark phase) in the blood and brains of surgical control mice, whereas this temporal pattern was absent (IL-1β, CXCL1, Myd88, Cd4) or reversed (C3) in the respective tissues of tumor-bearing and -resected mice. Taken together, these data indicate that the time of day of assessment significantly modulates various persistent and transient tumor-induced behavioral and immune changes.

Serum IGF-binding protein 2 (IGFBP-2) concentrations change early after gastric bypass bariatric surgery revealing a possible marker of leptin sensitivity in obese subjects.

Expression of IGFBP-2 in mice is regulated by leptin. Over-expression of IGFBP-2 is associated with reduced caloric intake and resistance to weight gain. Hormonal variations contributing to weight loss occur very early after bariatric surgery but have not been fully elucidated. We evaluated IGFBP-2 serum changes after bariatric surgery and their relationship with leptin variations to test the hypothesis that an increase of leptin sensitivity may explain some of the effects of gastric bypass. This is a historical prospective study. Fifty-one obese patients (41 women e 10 men), 9 non-obese surgical controls and 41 lean matched controls were studied. Serum IGFBP-2 and leptin were measured after bariatric bypass surgery at various time points up to 18 months, after non-bariatric laparoscopic surgery in a control group, and in lean matched controls. Compared to lean controls, serum IGFBP-2 levels were lower in obese patients. After gastric bypass, IGFBP-2 significantly increased at 3 days and became normal before the occurrence of relevant changes in body weight, remaining stable up to 18 months after surgery. IGFBP-2/leptin ratio increased early after surgery and became normal after one year. After gastric bypass, serum IGFBP-2 increases in a window of time when variations of hormones mediating the effects of bariatric surgery occur. Our results suggest that IGFBP-2, a leptin-regulated protein, may be an in-vivo marker of leptin action. If this is the case, an early improvement of leptin sensitivity might contribute to the anorectic effect of gastric bypass.

Kappa Opioid Receptors Drive a Tonic Aversive Component of Chronic Pain.

Pain is a multidimensional experience and negative affect, or how much the pain is "bothersome", significantly impacts the sufferers' quality of life. It is well established that the κ opioid system contributes to depressive and dysphoric states, but whether this system contributes to the negative affect precipitated by the occurrence of chronic pain remains tenuous. Using a model of persistent pain, we show by quantitative real-time-PCR, florescence in situ hybridization, Western blotting and GTPgS autoradiography an upregulation of expression and the function of κ opioid receptors (KORs) and its endogenous ligand dynorphin in the mesolimbic circuitry in animals with chronic pain compared with surgical controls. Using in vivo microdialysis and microinjection of drugs into the mesolimbic dopamine system, we demonstrate that inhibiting KORs reinstates evoked dopamine release and reward-related behaviors in chronic pain animals. Chronic pain enhanced KOR agonist-induced place aversion in a sex-dependent manner. Using various place preference paradigms, we show that activation of KORs drives pain aversive states in male but not female mice. However, KOR antagonist treatment was effective in alleviating anxiogenic and depressive affective-like behaviors in both sexes. Finally, ablation of KORs from dopamine neurons using AAV-TH-cre in KORloxP mice prevented pain-induced aversive states as measured by place aversion assays. Our results strongly support the use of KOR antagonists as therapeutic adjuvants to alleviate the emotional, tonic-aversive component of chronic pain, which is argued to be the most significant component of the pain experience that impacts patients' quality of life.SIGNIFICANCE STATEMENT We show that KORs are sufficient to drive the tonic-aversive component of chronic pain; the emotional component of pain that is argued to significantly impact a patient's quality of life. The impact of our study is broadly relevant to affective disorders associated with disruption of reward circuitry and thus likely contributes to many of the devastating sequelae of chronic pain, including the poor response to treatment of many patients, debilitating affective disorders (other disorders including anxiety and depression that demonstrate high comorbidity with chronic pain) and substance abuse. Indeed, coexisting psychopathology increases pain intensity, pain-related disability and effectiveness of treatments (Jamison and Edwards, 2013).

Quantification of Immune Dysregulation by Next-generation Polymerase Chain Reaction to Improve Sepsis Diagnosis in Surgical Patients

To quantify immunological dysfunction in surgical patients with presence/absence of sepsis using a droplet digital polymerase chain reaction (ddPCR) transcriptomic analysis. The study also aims to evaluate this approach for improving identification of sepsis in these patients. Immune dysregulation is a central event in sepsis. Quantification of the expression of immunological genes participating in the pathogenesis of sepsis could represent a new avenue to improve its diagnosis. Expression of 6 neutrophil protease genes (MMP8, OLFM4, LCN2/NGAL, LTF, PRTN3, MPO) and also of 5 genes involved in the immunological synapse (HLA-DRA, CD40LG, CD3E, CD28, ICOS) was quantified in blood from 101 surgical patients with sepsis, 53 uninfected surgical patients, and 16 blood donors by using ddPCR. Areas under receiver operating characteristic curves (AUROC) and multivariate regression analysis were employed to test individual genes and gene ratios to identify sepsis, in comparison with procalcitonin. Sepsis-induced overexpression of neutrophil protease genes and depressed expression of immunological synapse genes. MMP8/HLA-DRA, LCN2/HLA-DRA outperformed procalcitonin in differentiating between patients with sepsis and surgical controls in the AUROC analysis: LCN2/HLA-DRA: 0.90 (0.85-0.96), MMP8/HLA-DRA: 0.89 (0.84-0.95), procalcitonin: 0.80 (0.73-0.88) (AUROC, confidence interval 95%), and also in the multivariate analysis: LCN2/HLA-DRA: 8.57 (2.25-32.62); MMP8/HLA-DRA: 8.03 (2.10-30.76), procalcitonin: 4.20 (1.15-15.43) [odds ratio (confidence interval 95%)]. Gene expression levels of HLA-DRA were an independent marker of hospital mortality. Quantifying the transcriptomic ratios MMP8/HLA-DRA, LCN2/HLA-DRA by ddPCR is a promising approach to improve sepsis diagnosis in surgical patients.

Alterations in the invasive properties of peripheral blood monocytes from patients with endometriosis

Purpose of this Investigation: The primary aim of this pilot study was to determine if the increase in monocyte/macrophage number in the peritoneal cavity of women with endometriosis is due to differences in peritoneal fluid signaling content (e.g. cytokine levels) or inherent differences in monocyte migration in response to those signals. Materials and Methods: Peripheral blood and peritoneal fluid samples were collected from endometriosis and surgical control patients at the time of surgery. Peripheral blood was also collected from a group of healthy ‘non-surgical control’ patients in an internal medicine clinic. Monocytes were isolated from blood and invasion was assessed using peritoneal fluid from endometriosis patients and controls as a chemoattractant. Results: Regardless of peritoneal fluid source a &gt; 10-fold change was seen in monocyte invasion with endometriotic monocytes. Conclusion: Peripheral blood monocytes from women with endometriosis are more invasive than those from other women. This is true when compared to both surgical and nonsurgical controls.

Abstract 23: Circulating Peripheral Factors Induce Age-Related Epigenetic Changes in Microglia Which Induces a Primed Phenotype

Background: Microglia populate the neuroepithelium during embryonic development and reside the CNS as innate immune cells for the lifetime of the individual. However, microglia acquire a dysregulated phenotype with age and are primed to respond to neurological injury such as stroke in an exaggerated, detrimental fashion. We have previously shown that pro-inflammatory microglia are regulated epigenetically and have elevated histone H3 lysine 27 trimethylation (H3K27me3). Hypothesis: We hypothesized that aged microglia are epigenetically dysregulated by peripheral factors to induce a pro-inflammatory, primed phenotype. Methods: We used naïve 3 to 24 month-old C57Bl/6 male mice (Charles River, NIA). We also performed heterochronic parabiosis where young (2-3 month) and aged (18-20 month) male mice were surgically attached for 8 weeks and came to share a common blood supply. Isochronic young (Y ISO) and aged (A ISO) pairs served as surgical controls. A cohort of parabionts was stimulated with i.p. lipopolysaccharide (LPS) for 24hr. Brains were collected for Western blot, real-time PCR (RT-PCR), and multiplex cytokine analysis. Results: We found the brains of aged mice have increased levels of H3K27me3 (p&lt;0.05). Aging increased 18 pro-inflammatory cytokines in the brain, notably IFNγ (3mo 20.5pg/mg vs. 24mo 28.7pg/mg, n=5-8, p&lt;0.05) and GM-CSF (3mo 15.7pg/mg vs. 24mo 25.3pg/mg, p&lt;0.005) which are both implicated in microglia priming phenotype. In brains of aged heterochronics (A HET) mice, we found a reduction in H3K27me3 and decrease in IFNγ (p&lt;0.05) and GM-CSF (p&lt;0.05) compared to A ISO controls. In parabionts stimulated with LPS, A HET mice had significantly less pro-inflammatory cytokines in the CNS suggesting faster neuroinflammatory recovery. Conclusion: We conclude that circulating peripheral factors are responsible for the epigenetic dysregulation and primed phenotype of aged microglia which may be rejuvenated by manipulation of peripheral factors.

Acute fibrinolysis shutdown occurs early in septic shock and is associated with increased morbidity and mortality: results of an observational pilot study

BackgroundSeptic coagulopathy represents a very dynamic disease entity, tilting from initial hypercoagulability towards a subsequent hypocoagulable disease state, entitled overt disseminated intravascular coagulation. Acute fibrinolysis shutdown has recently been described to be a crucial component of initial hypercoagulability in critically ill patients, although the underlying pathomechanisms, the specific temporal kinetics and its outcome relevance in patients with sepsis remain to be determined.MethodsIn total, 90 patients (30 with septic shock, 30 surgical controls and 30 healthy volunteers) were enrolled. Blood samples were collected at sepsis onset or prior and immediately after the surgical procedure as well as 3 h, 6 h, 12 h, 24 h, 48 h and 7 d later, whereas blood samples from healthy volunteers were collected once. Besides viscoelastic and aggregometric point-of-care testing (POCT), enzyme-linked immunosorbent and thrombin generation assays and liquid chromatography–mass spectrometry-based measurements were performed.ResultsAs assessed by viscoelastic POCT, fibrinolysis shutdown occurred early in sepsis. Significant increases in tissue plasminogen activator had no effect on thromboelastometrical lysis indices (LIs). Contrariwise, plasminogen activator inhibitor-1 was already significantly increased at sepsis onset, which was paralleled by significantly increased LIs in patients suffering from septic shock in comparison with both control groups. This effect persisted throughout the 7-day observation period and was most pronounced in severely ill as well as non-surviving septic patients. Thromboelastometrical LI, therefore, proved to be suitable for early diagnosis [e.g. LI 45 min: area under the curve (AUC) up to 0.933] as well as prognosis (e.g. LI 60 min: AUC up to 1.000) of septic shock.ConclusionsEarly inhibition of plasminogen activation leads to acute fibrinolysis shutdown with improved clot stability and is associated with increased morbidity and mortality in septic patients.Trial registration This study was approved by the local ethics committee (Ethics Committee of the Medical Faculty of Heidelberg; Trial-Code No. S247-2014/German Clinical Trials Register (DRKS)-ID: DRKS00008090; retrospectively registered: 07.05.2015). All study patients or their legal representatives signed written informed consent.

Is Hemispheric Hypoperfusion a Treatable Cause of Cognitive Impairment?

To review the current literature that supports the notion that cerebral hemodynamic compromise from internal carotid artery stenosis may be a cause of vascular cognitive impairment that is amenable to treatment by revascularization. Converging evidence suggests that successful carotid endarterectomy and carotid artery stenting are associated with reversal of cognitive decline in many patients with severe but asymptomatic carotid artery stenosis. Most of these findings have been derived from cohort studies and comparisons with either normal or surgical controls. Failure to find treatment benefit in a number of studies appears to have been the result of patient heterogeneity or confounding from concomitant conditions independently associated with cognitive decline, such as heart failure and other cardiovascular risk factors, or failure to establish pre-procedure hemodynamic failure. Patients with severe carotid artery stenosis causing cerebral hemodynamic impairment may have a reversible cause of cognitive decline. None of the prior studies, however, were done in the context of a randomized clinical trial with large numbers of participants. The ongoing CREST-2 trial comparing revascularization with medical therapy versus medical therapy alone, and its associated CREST-H study determining whether cognitive decline is reversible among those with hemodynamic compromise may address this question.

Abstract 16669: Left Atrial Function After Closure of Atrial Septal Defect in Adults: Comparison Between Transcatheter Closure and Surgical Closure

Introduction: Transcatheter closure is offered as an alternative to surgery for the majority of patients with secundum atrial septal defect (ASD). However, little is known about the effect of a mechanical device on left atrial (LA) function. Hypothesis: Transcatheter closure of secundum ASD preferably preserves LA function compared with surgical closure in adult patients. Methods: We examined adult patients who underwent transcatheter (n = 58) and surgical ASD closure (n = 17) and controls (n = 20). Patients with greater than mild mitral or tricuspid regurgitation and those with a history of atrial fibrillation were not included. All the devices employed were the Amplatzer TM Septal Occluders. LA volumes were measured by the biplane area-length method using 2-dimensional transthoracic echocardiography at the onset of mitral opening (Vmax), the beginning of LA systole (Va) and the onset of mitral closure (Vmin) before and 15 ± 11 months after ASD closure. LA reservoir, conduit and booster pump functions were assessed by (Vmax-Vmin)/Vmax, (Vmax-Va)/Vmax and (Va-Vmin)/Va, respectively. Left ventricular (LV) ejection fraction was obtained to estimate LV systolic function. For the estimation of LV diastolic function, the ratio of transmitral early to late flow velocity (E/A), deceleration time of early mitral flow velocity (DT) and the ratio of systolic to diastolic pulmonary venous flow velocity (S/D) were obtained by conventional Doppler echocardiography. Results: In transcatheter closure, employed device size indexed to body surface area was 12 ± 3 mm/m 2 . Before ASD closure, there was no significant difference in all the LA parameters between the 2 groups, whereas LV ejection fraction was significantly decreased in the surgical group as compared with the transcatheter group. After ASD closure, Vmax index was significantly increased in the surgical group. LV end-diastolic volume index were significantly increased both after transcatheter and surgical ASD closure. After ASD closure, the surgery group showed significantly decreased LA reservoir and conduit functions as compared with the transcatheter group and controls. Conclusions: The transcatheter group, not surgical group, showed preserved LA function at mid-term follow-up after ASD closure.

Differential Expression of Vascular Endothelial Growth Factor-A165 Isoforms Between Intracranial Atherosclerosis and Moyamoya Disease

BackgroundVascular endothelial growth factor-A165 (VEGF-A165) has been identified as a combination of 2 alternative splice variants: proangiogenic VEGF-A165a and antiangiogenic VEGF-A165b. Intracranial atherosclerotic disease (ICAD) and moyamoya disease (MMD) are 2 main types of intracranial arterial steno-occlusive disorders with distinct capacities for collateral formation. Recent studies indicate that VEGF-A165 regulates collateral growth in ischemia. Therefore, we investigated if there is a distinctive composition of VEGF-A165 isoforms in ICAD and MMD. MethodsSixty-six ICAD patients, 6 MMD patients, and 5 controls were enrolled in this prospective study. ICAD and MMD patients received intensive medical management upon enrollment. Surgery was offered to 9 ICAD patients who had recurrent ischemic events, 6 MMD patients, and 5 surgical controls without ICAD. VEGF-A165a and VEGF-A165b plasma levels were measured at baseline, within 1 week after patients having surgery, and at 1, 3, and 6 months after treatment. ResultsA significantly higher baseline VEGF-A165a/b ratio was observed in MMD compared to ICAD (P = .016). The VEGF-A165a/b ratio increased significantly and rapidly after surgical treatment in ICAD (P = .026) more so than in MMD and surgical controls. In patients with ICAD receiving intensive medical management, there was also an elevation of the VEGF-A165a/b ratio, but at a slower rate, reaching the peak at 3 months after initiation of treatment (baseline versus 3 months VEGF-A165a/b ratio, P = .028). ConclusionsOur study shows an increased VEGF-A165a/b ratio in MMD compared to ICAD, and suggests that both intensive medical management and surgical revascularization elevate the VEGF-A165a/b ratio in ICAD patients.