Cause Of Poor Outcome Research Articles

PO-472 Chemotherapy resistance-associated epithelial to endothelial transition in gastric cancer

Introduction Gastric cancer (GC) is the fifth most common cancer worldwide and the third leading cause of cancer-related deaths. To date, gastrectomy and chemotherapy are the only therapeutic options, but drug resistance is the main cause for treatment failure. Vasculogenic mimicry (VM) is a new model of neovascularization in aggressive tumours and has been correlated with poor prognosis in GC patients. Our group has developed chemotherapy-resistant GC cells using the Caucasian adenocarcinoma cell line AGS and three drugs among the most used in clinic (5-fluorouracil, cisplatin and paclitaxel) henceforward denominated 5FUr, CISr, TAXr. Our study has highlighted phenotypical differences among chemo-sensitive and chemo-resistant cell lines such as acquisition of stem-like phenotype and increased capacity to form vessels. Material and methods Establishment of AGS resistant cell lines exposing cells to increasing dilution of drugs for over 9 months up to dilutions higher than IC50 values initially verified on AGS cells through MTT analysis. Quantitative RT-PCR, flow cytometry and western blot analysis for stemness and VM markers. Vasculogenic mimicryassay Results and discussions AGS cells acquired chemoresistance as indicated by the increase of IC50 values in drug-treated cells with respect to AGS. Furthermore, MTT assay highlighted that there is not cross-resistance among 5FUr, CISr and TAXr. Supportive data is that cells are MDR1 negative. Resistant cells showed an upregulation of Yamanaka factors either in qPCR and flow cytometer analysis, and particularly interesting is ALDH overexpression in 5FUr. TWIST upregulation suggested the investigation of VM which resulted particularly enhanced in 5FUr cells which demonstrated their ability to form and sustain vessels up to 96 hours in the tube formation assay. Markers of VM such Laminin γ2 and Ephrin A2 showed an increase in resistant cells and especially in 5FUr. Conclusion One of the most interesting result is that 5FUr cells acquire stemness properties and are positive to the tube formation assay suggesting that VM might be one mechanisms adopted by cells to avoid drugs exposure. These findings suggest that acquisition of chemoresistance could cause a relapse of disease in which tumour cells take advantage of their capability to perform VM in order to self-sustain their growth and that may be cause of poor outcomes.

Bexarotene attenuates early brain injury via inhibiting micoglia activation through PPARγ after experimental subarachnoid hemorrhage

Objectives Early brain injury (EBI) is considered to be one of the main causes of poor outcome in subarachnoid hemorrhage (SAH) patients. Bexarotene is an agonist of retinoid X receptor and plays a protective role in central nervous system diseases. However, the exact role of bexarotene in SAH has not been reported. Therefore, the present study was to determine whether bexarotene administration attenuate EBI after SAH in mice and to explore the underlying mechanism.Methods SAH was induced in C57BL/6 mice by endovascular perforation. Bexarotene was administrated intraperitoneally. Neurological score, cell death, microglia activation, and pro-inflammatory cytokines were detected at 24 h after SAH. The expression of PPARγ was measured by Western blot.Results Results showed that bexarotene significantly improved neurological score after SAH. In addition, the number of cell death and activated microglia were significantly reduced by bexarotene administration. Compared with vehicle-treated mice, bexarotene-treated mice showed reduced pro-inflammatory cytokines after SAH. The expression of PPARγ was significantly increased with bexarotene treatment compared with vehicle-treated controls.Discussion The present study demonstrats that bexarotene administration protects against EBI after SAH, inhibiting cell death, attenuating microglia activation, and alleviating neuroinflammation. The underlying mechanism may partially involve the activation of PPARγ.

Rolipram Attenuates Early Brain Injury Following Experimental Subarachnoid Hemorrhage in Rats: Possibly via Regulating the SIRT1/NF-κB Pathway.

Early brain injury (EBI) is the primary cause of poor outcome in subarachnoid hemorrhage (SAH) patients. Rolipram, a specific phosphodiesterase-4 inhibitor which is traditionally used as an anti-depressant drug, has been recently proven to exert neuroprotective effects in several central nervous system insults. However, the role of rolipram in SAH remains uncertain. The current study was aimed to investigate the role of rolipram in EBI after SAH and explore the potential mechanism. Adult male Sprague-Dawley rats were subjected to an endovascular perforation process to produce an SAH model. Rolipram was injected intraperitoneally at 2h after SAH with a dose of 10mg/kg. We found that rolipram significantly ameliorated brain edema and alleviated neurological dysfunction after SAH. Rolipram treatment remarkably promoted the expression of Sirtuin 1 (SIRT1) while inhibited NF-κB activation. Moreover, rolipram significantly inhibited the activation of microglia as well as down-regulated the expression of pro-inflammatory cytokines TNF-α, IL-1ß, and IL-6. In addition, rolipram increased the expression of protective cytokine IL-10. Furthermore, rolipram significantly alleviated neuronal death after SAH. In conclusion, these data suggested that rolipram exerts neuroprotective effects against EBI after SAH via suppressing neuroinflammation and reducing neuronal loss. The neuroprotective effects of rolipram were associated with regulating the SIRT1/NF-κB pathway. Rolipram could be a novel and promising therapeutic agent for SAH treatment.

A prospective observational study of morbidity and mortality profile of neonates admitted to neonatal intensive care unit in a tribal area of central India

Introduction: Globally, 2.6 (2.5–2.8) million newborns died in 2016 or 7000 every day. High neonatal mortality rate reflects the presence of unfavorable social, economic, and environmental conditions. Objectives: To find morbidities and causes of poor outcome in a tertiary care neonatal unit of eastern part of Maharashtra. Materials and Methods: The present prospective observational study was conducted in the neonatal intensive care unit of a tertiary care center, Gondia, in Central India which is situated in remote, tribal place during. Data were collected by interview method using a predesigned, semi-structured questionnaire. Neonatal variables used were total number of admissions, gender, birth weight, and gestational age, diagnosis at admission, final outcome, and duration of stay. Results: There were a total of 2017 admissions during the study period and out of them, 62.96% were inborn neonates and 37.04% were outborn. Males (56.67%) had slightly higher admission rate than females (43.33%). Pre-term admissions were 40.06%. The majority of admissions were due to low birth weight (LBW) (60.19%). Preterm and related complications (49.43%) were ranked highest followed by jaundice (16.46%). Out of the total 2017 neonates, 218 died following admission. Prematurity (45.41%) followed by sepsis (22.48%) were reasons for mortality among neonates. Conclusion: We have tried to present neonatal morbidity pattern and outcome parameters from a tertiary care neonatal center in a developing country. Prematurity, sepsis, and birth asphyxia were accounting for morbidities and mortalities. The preterm and LBW babies had significantly higher mortality even with standard intensive care.

Recurrent lumbar disc herniation: Is there a correlation with the surgical technique? A multivariate analysis.

Purpose:The recurrence of a lumbar disc herniation (LDH) is a common cause of poor outcome following lumbar discectomy. The aim of this study was to assess a potential relationship between the incidence of recurrent LDH and the surgical technique used. Furthermore, we tried to define the best surgical technique for the treatment of recurrent LDH to limit subsequent recurrences.Materials and Methods:A retrospective study was conducted on 979 consecutive patients treated for LDH. A multivariate analysis tried to identify a possible correlation between (1) the surgical technique used to treat the primary LDH and its recurrence; (2) technique used to treat the recurrence of LDH and the second recurrence; and (3) incidence of recurrence and clinical outcome. Data were analyzed with the Pearson's Chi-square test for its significance.Results:In 582 cases (59.4%), a discectomy was performed, while in 381 (40.6%), a herniectomy was undertaken. In 16 cases, a procedure marked as “other” was performed. Among all patients, 110 (11.2%) had a recurrence. Recurrent LDH was observed in 55 patients following discectomy (9.45%), in 45 following herniectomy (11.8%), and in 10 (62.5%) following other surgery. Our data showed that 90.5% of discectomies and 88.2% of the herniectomies had a good clinical outcome, whereas other surgeries presented a recurrence rate of 62.5% (Pearson's χ2< 0.001). No statistical differences were observed between discectomy or herniectomy, for the treatment of the recurrence, and the incidence for the second recurrences (P > 0.05). A significant statistical correlation emerged between the use of other techniques and the incidence for the second recurrences (P < 0.05).Conclusions:The recurrence of an LDH is one of the most feared complications following surgery. Although the standard discectomy has been considered more protective toward the recurrence compared to herniectomy, our data suggest that there is no significant correlation between the surgical technique and the risk of LDH recurrence.

Autophagy: A Potential Therapeutic Target for Reversing Sepsis-Induced Immunosuppression.

Sepsis remains the leading cause of mortality in intensive care units and an intractable condition due to uncontrolled inflammation together with immune suppression. Dysfunction of immune cells is considered as a major cause for poor outcome of septic patients but with little specific treatments. Currently, autophagy that is recognized as an important self-protective mechanism for cellular survival exhibits great potential for maintaining immune homeostasis and alleviating multiple organ failure, which further improves survival of septic animals. The protective effect of autophagy on immune cells covers both innate and adaptive immune responses and refers to various cellular receptors and intracellular signaling. Multiple drugs and measures are reportedly beneficial for septic challenge by inducing autophagy process. Therefore, autophagy might be an effective target for reversing immunosuppression compromised by sepsis.

Does an intervention designed to improve self-management, social support and awareness of palliative-care address needs of persons with heart failure, family caregivers and clinicians?

To conduct a formative evaluation of the iPad-Enhanced Shared Care Intervention for Partners (iSCIP) among persons with heart failure (HF), family caregivers and clinicians. Together, persons with HF and family caregivers are referred to as partners. There is growing awareness of the caregiver's contributions to HF self-management, social support and reciprocal benefits of interventions that involve both partners. The iSCIP engages both partners in a six-session psychosocial intervention toaddress three preventable causes of poor outcomes in a HF population: poor self-management skills, inadequate social support and underutilisation of palliative care. An iPad app is used to organise the intervention. The goals of the iSCIP are to engage partners in HF self-management, communication about the HF patient's care values and preferences, and future planning. A qualitative focus group design was used. Seven clinicians and eight partners participated in focus groups to explore their experiences, needs and reaction to the iSCIP content and technologies employed. Open-ended questions and closed-ended surveys were used to collect data. Deductive content analysis was used to analyse the qualitative data. NVivo software was used for qualitative data analysis. Bayesian statistical models were used to analyse numeric data. The iSCIP met partners' and clinicians' needs to improve self-management, communicate about care values and preferences and plan for the future. Quantitative analysis of numeric data supported our qualitative findings, in that both groups rated the intervention components useful to very useful. These findings add to the growing evidence of the feasibility and acceptability of programs that address care values and preferences, and care planning. The iSCIP can be used as a guide for developing interventions and software applications, which involve both partners in care and palliative-care discussions.

Risk Stratification Models to Predict Hypertensive Disorders of Pregnancy: Additive Value of Standard Electrocardiography

Hypertension disorders complicate up to 10%-11% of all pregnancies and remain leading causes of poor outcome, including placental abruption, organ failure, cerebrovascular accident and disseminated intravascular coagulation. These disorders are also associated with increased risk of perinatal death, fetal intrauterine growth restriction, and prematurity/preterm delivery.

383 Fever and Leukocytosis as a Predictor of DCI After SAH

Abstract INTRODUCTION Aneurysmal subarachnoid hemorrhage (SAH) is associated with significant morbidity and mortality. Delayed cerebral ischemia (DCI) is a major cause for poor outcome after SAH. Cerebral vasospasm is the primary driver of DCI, and the largest independent contributor to poor outcome after SAH. Prior studies have reported an association between fever and leukocytosis, and cerebral vasospasm. In this study, we assessed the utility of fever and/or leukocytosis to predict DCI after SAH. METHODS We performed a retrospective analysis of 187 SAH patients. Univariate and multivariate logistic regression was performed to identify potential risk factors for three different endpoints - (a) Mild, Moderate, or Severe Angiographic Vasospasm, (b) Moderate or Severe Angiographic Vasospasm, and (c) Symptomatic DCI. Multiple independent variables including age, Hunt-Hess grade, modified Fisher grade, fever (T&gt;/= 38.0 °C), WBC &gt;/= 10, WBC &gt;/= 15, fever and WBC &gt;/= 10, fever and WBC &gt;/= 15 were examined over the course of each hospital stay. RESULTS &gt;Presence of fever and/or leukocytosis were both significant predictors of symptomatic DCI. In addition, number of days with fever following aneurysm rupture was strongly associated with angiographic vasospasm, while number of days with WBC&gt;/= 15 was strongly associated with symptomatic DCI. When these variables were combined, number of days with concurrent fever and WBC&gt;/= 10 was an independent predictor of angiographic vasospasm, and number of days with concurrent fever and WBC&gt;/= 15 was an independent predictor of both angiographic vasospasm and symptomatic DCI. Time intervals of Day 0–3 and Day 3–7 after aneurysm rupture had the highest odds ratios for angiographic vasospasm. CONCLUSION Patients with aneurysmal SAH who had higher number of days with fever and/or leukocytosis after aneurysm rupture were more likely to have angiographic vasospasm and symptomatic DCI. Presence of fever and/or leukocytosis may have utility in assessing the risk of DCI following SAH.

Consequences of traumatic spinal cord injury during pregnancy in Pakistan.

Traumatic spinal cord injury (SCI) is one of the major causes for poor outcomes of pregnancy. Injury during pregnancy is uncommon; therefore, outcome data are scarce. This case series presents outcomes of pregnancy in five women who sustained SCI during their pregnancies. Five women who sustained SCIs during pregnancy (age range: 24-38 years) were identified and included in this case series. The causes of SCI in this population were fall from heights (cases 1 and 2), road traffic accidents (cases 3 and 4) and firearm injury (case 5). Two of the females were managed conservatively (cases 1 and 5) and the rest underwent surgical procedures for fixing their spine. Out of these patients, four patients delivered normal healthy babies, while the baby of one patient died within 1 hour after delivery. Limited data about the outcomes of pregnancy in women who sustained SCIs during pregnancy are available in the literature. The outcomes of pregnancy in women who sustained SCIs during the first trimester are not satisfactory, and special attention may be needed to improve the expected outcomes. Data from our study show similar findings to developed countries.

RESULTS OF STAGED SURGICAL TREATMENT OF PATIENTS WITH TANDEM STENOSIS OF THE CERVICAL AND LUMBOSACRAL SPINE

Objective. To conduct a retrospective analysis of staged surgery in patients with tandem stenosis of the cervical and lumbosacral spine, to identify causes of poor outcomes. Material and Methods . The study included 190 patients with tandem stenosis of the cervical and lumbosacral spine. Out of them 72 had symptomatic cervical and asymptomatic lumbosacral tandem stenosis (Group 1), 67 - symptomatic lumbar and asymptomatic cervical tandem stenosis (Group 2), and 51 - compression with neurological manifestations in both spine departments (Group 3). Patient’s anthropometric data, initial clinical symptoms, and duration of disease were analyzed. The intraoperative characteristics of surgical interventions and features of the postoperative period, clinical parameters and the existence of complications were evaluated. Results . Excellent and good postoperative outcomes were achieved in patients of Groups 1 and 2 with monosymptomatic tandem stenosis, in patients of Group 3 with symptomatic tandem stenosis, and in patients of all groups who underwent laminectomy and bilateral foraminotomy for bilateral symptomatic foraminal stenosis, and minimally invasive bilateral foraminotomy through unilateral approach in case of radiographic evidence of foraminal stenosis without symptoms. Conclusion . Symptomatic tandem stenosis of the cervical and lumbosacral spine is a severe nosological entity requiring meticulous removal of pathological substrate primarily in the cervical spine. The early implementation of the second stage of surgery significantly reduces neurological symptoms, relieves pain and improves quality of life in patients.

Soft tissue-based surgical techniques for treatment of posterior shoulder instability.

Posterior shoulder instability is a rare clinical condition that encompasses different degrees of severity including various possible pathologies involving the labrum, capsule, bony lesions, and even locked posterior dislocation. When focusing on soft tissue involvement, the diagnosis of posterior instability may be difficult to make because frequently patients report vague symptoms not associated with a clear history of traumatic shoulder dislocation. Pathological soft tissue conditions associated with posterior instability in most cases are related to posterior labral tear and/or posterior capsular detensioning/tear. The diagnosis can be facilitated by physical examination using specific clinical tests (i. e., jerk test, Kim test, and reinterpreted O’Brien test) together with appropriate imaging studies (i. e., magnetic resonance arthrography). Arthroscopy may help in a complete evaluation of the joint and allows for the treatment of soft tissue lesions in posterior instability. Caution is warranted in the case of concomitant posterior glenoid chondral defect as a potential cause of poor outcome after soft tissue repair in posterior instability.

Effect of delayed onset prostacyclin on markers of endothelial function and damage after subarachnoid hemorrhage.

Subarachnoid hemorrhage (SAH) is a neurological emergency. Delayed ischemic neurological deficit is one of the main causes of poor outcome after SAH and is probably caused, at least in part, by cerebral vasospasm. The pathophysiology of this is multifaceted, but endothelial damage and activation as well as glycocalyx damage have been implicated. Prostacyclin has been shown to protect damaged and activated endothelium and to facilitate glycocalyx repair. We investigated biomarkers of endothelial activation and damage in patients with SAH randomized to 5days prostacyclin infusion or placebo. Patients with aneurysmal SAH managed by coiling or surgery, and a World Federation of Neurological Surgeons score between 1 and 4, and Fisher grade 3 or 4, were treated with a continuous low-dose intravenous prostacyclin infusion or placebo initiated on day 5 and discontinued on day 10 after SAH. Blood samples were drawn from the patients before, during and after prostacyclin/placebo infusion. Soluble biomarkers of endothelial cell activation (sE-selectin, sVE-cadherin) and damage (sTM), glycocalyx damage (syndecan-1) and sympathoadrenal activation (adrenaline, noradrenaline), were measured by ELISA. Ninety patients were randomized. Prostacyclin infusion influenced neither biomarkers of sympathoadrenal activation, endothelial activation and damage nor biomarkers of endothelial glycocalyx breakdown. We did not find any effects on markers of sympathoadrenal activation, endothelial damage and activation, or glycocalyx degradation of delayed onset prostacyclin infusion compared to placebo. Further trials investigating early onset endothelial repair using prostacyclin are warranted.

Factors that influence recurrent lumbar disc herniation.

The most common cause of poor outcome following lumbar disc surgery is recurrent herniation. Recurrence has been noted in 5% to 15% of patients with surgically treated primary lumbar disc herniation. There have been many studies designed to determine the risk factors for recurrent lumbar disc herniation. In this study, we retrospectively analysed the influence of disc degeneration, endplate changes, surgical technique, and patient's clinical characteristics on recurrent lumbar disc herniation. Patients who underwent primary single-level L4-L5 lumbar discectomy and who were reoperated on for recurrent L4-L5 disc herniation were retrospectively reviewed. All these operations were performed between August 2004 and September 2009 at the Neurosurgery Department of Ataturk Education and Research Hospital in Ankara, Turkey. During the study period, 126 patients were reviewed, with 101 patients underwent primary single-level L4-L5 lumbar discectomy and 25 patients were reoperated on for recurrent L4-L5 disc herniation. Preoperative higher intervertebral disc height (P<0.001) and higher body mass index (P=0.042) might be risk factors for recurrence. Modic endplate changes were statistically significantly greater in the recurrent group than in the non-recurrent group (P=0.032). Our study suggests that patients who had recurrent lumbar disc herniation had preoperative higher disc height and higher body mass index. Modic endplate changes had a higher tendency for recurrence of lumbar disc herniation. Well-planned and well-conducted large-scale prospective cohort studies are needed to confirm this and enable convenient treatment modalities to prevent recurrent disc pathology.

17 - Early readmission, delayed discharge, and reoperation after lumbar discectomy discectomy: an analysis from a multicenter, prospective, randomized study

BACKGROUND CONTEXT: Readmissions and reoperations within the first few months of surgery are major factors driving negative clinical and financial outcomes. Providers are increasingly being asked to bear the financial burden of hospital admissions that occur within 90 days of index surgery. Same-level reherniation and progressive degeneration are the main causes of poor outcome after lumbar discectomy and often require early readmission and reoperation.

Causes of poor outcome in patients admitted with good-grade subarachnoid haemorrhage

Surgical risk in patients with unruptured aneurysms is well known. The relative impact of surgery and natural history of subarachnoid haemorrhage (SAH) on patients in good clinical condition (World Federation of Neurological Surgeons [WFNS] grades 1 and 2) is less well quantified. The aim of this study was to determine causes of poor outcome in patients admitted in good grade SAH. A retrospective study of prospectively collected data among WFNS-1 and -2 patients: demographics, SAH and aneurysm-related data, surgical complications and outcome as assesed by the Glasgow Outcome Scale (GOS). Causes of poor outcome (GOS 1-3) were determined. During a 7-year period (2009-15), 56 patients with SAH WFNS-1 (39 patients) or WFNS-2 (17 patients) were treated surgically (21 men, 35 women; mean age, 52.4years). According to the Fisher scale, 19 patients were grade 1 or 2; 37 patients were grade 3 or 4. Most aneurysms were located at anterior communicating (26) or middle cerebral (15) artery. Altogether, 11 patients (19.6%) achieved GOS 1-3. This was attributed to SAH-related complications in six patients (rebleeding, vasospasm), surgery in four patients (postoperative ischaemia in two, haematoma and ventriculitis in one patient each), grand-mal seizure with aspiration in one patient. Age over 60years (p = 0.017) and presence of hydrocephalus (p < 0.001) were statistically significant predictors of poor GOS; other variables (e.g. sex, Fisher grade, aneurysm size or location, use of temporary clips, intraoperative rupture, vasospasm) were not significant. Patients admitted in good-grade SAH achieve favourable outcome following surgical aneurysm repair in the majority of cases. Negative factors include age over 60years and presence of hydrocephalus. Aneurysm surgery following good-grade SAH still carries a small but significant risk similar to that shown in large multi-institutional trials.

Asymptomatic Mild Hyperperfusion for the Prediction of Clinical Outcome in Postoperative Patients After Subarachnoid Hemorrhage.

BackgroundDelayed cerebral ischemia (DCI) is one of the main causes of poor outcomes after subarachnoid hemorrhage (SAH). The early identification of DCI by noninvasive imaging modalities would provide valuable information of therapeutic intervention for improving the patient outcomes. We aimed to describe the clinical features of cerebral blood flow (CBF) data obtained from the single-photon emission computed tomography (SPECT) during the risk period for DCI after SAH.Material/MethodsClinical data from 94 SAH patients who underwent surgical clipping of anterior circulation aneurysms were reviewed retrospectively. 99mTc-HMPAO SPECT images were visually and semiquantitatively analyzed on days 7 and 14 after SAH.ResultsIn all cases, the areas of hypoperfusion were found in the middle cerebral artery territories. By contrast, the areas of mild hyperperfusion were always detected on the surgical side, the prevalence which increased from days 7 (n=28; 30%) to 14 (n=48; 51%) without neurological defects. Univariate analysis revealed that the hyperperfusion on day 14 had a significant relationship with functional outcome at 3 months (P=0.04). Multivariate analysis including age, clinical SAH grade, DCI, and hyperperfusion on day 14 showed that DCI (P=0.004; odds ratio [OR], 0.10; 95% confidence interval [CI], 0.02–0.48) and hyperperfusion on day 14 (P=0.002; OR, 2.44; 95% CI, 1.40–4.29) were independently associated with functional outcome at 3 months.ConclusionsDelayed mild hyperperfusion around the surgical site can predict good prognosis after SAH, although it may hinder the CBF diagnosis of focal ischemia attributable to DCI.

Level of Granzyme B-positive T-regulatory cells is a strong predictor biomarker of acute Graft-versus-host disease after day +30 after allo-HSCT

Acute Graft-versus-host-disease (aGVHD), the major complication and one of the main causes of poor outcomes of allogeneic hematopoietic stem cell transplantation (allo-HSCT). Nowadays there are no widely accepted cell, plasma or another biomarker that can be used for aGVHD prediction. We hypothesized that a level of Granzyme B-positive T regulatory (GZMB-positive Treg) cells on day+30 after allo-HSCT could be the measure of immune response suppression and could predict aGVHD development after day +30. We applied a widespread and easy-to-perform method of multicolor flow cytometry to measure level of GZMB-positive Treg cells. Levels of GZMB-positive Tregs on day +30 after allo-HSCT were significantly higher in those patients who never developed aGVHD in comparison with the other group of patient with aGVHD after day +30 (p=0.0229). We conclude that the level of GZMB-positive Treg cells is a strong predictor of acute Graft-versus-host disease after day +30 after allo-HSCT.

Toll-like receptor 4 as a possible therapeutic target for delayed brain injuries after aneurysmal subarachnoid hemorrhage.

Neuroinflammation is a well-recognized consequence of subarachnoid hemorrhage (SAH), and Toll-like receptor (TLR) 4 may be an important therapeutic target for post-SAH neuroinflammation. Of the TLR family members, TLR4 is expressed in various cell types in the central nervous system, and is unique in that it can signal through both the myeloid differentiation primary-response protein 88-dependent and the toll receptor associated activator of interferon-dependent cascades to coordinate the maximal inflammatory response. TLR4 can be activated by many endogenous ligands having damage-associated molecular patterns including heme and fibrinogen at the rupture of an intracranial aneurysm, and the resultant inflammatory reaction and thereby tissue damages may furthermore activate TLR4. It is widely accepted that the excreted products of TLR4 signaling alter neuronal functions. Previous studies have focused on the pathway through nuclear factor (NF)-κB signaling among TLR4 signaling pathways as to the development of early brain injury (EBI) such as neuronal apoptosis and blood-brain barrier disruption, and cerebral vasospasm. However, many findings suggest that both pathways via NF-κB and mitogen-activated protein kinases may be involved in EBI and cerebral vasospasm development. To overcome EBI and cerebral vasospasm is important to improve outcomes after SAH, because both EBI and vasopasm are responsible for delayed brain injuries or delayed cerebral ischemia, the most important preventable cause of poor outcomes after SAH. Increasing evidence has shown that TLR4 signaling plays an important role in SAH-induced brain injuries. Better understanding of the roles of TLR4 signaling in SAH will facilitate development of new treatments.

Synthesis of Mannosylated Glycodendrimers and Evaluation against BC2L-A Lectin from Burkholderia Cenocepacia.

Chronic colonization of lungs by opportunist bacteria is the major cause of mortality for cystic fibrosis patients. Among these pathogens, Burkholderia cenocepacia is responsible for cepacia syndrome, a deadly exacerbation of infection that is the main cause of poor outcomes of lung transplantation. This bacterium contains three soluble carbohydrate-binding proteins, including the B. cenocepacia lectin A (BC2L-A), which is proposed to bind to oligomannose-type N-glycan structures to adhere to host tissues. In this work, several mannosylated glycoclusters and glycodendrimers with valencies ranging from four to 24 were prepared and their interactions with BC2L-A were thermodynamically characterized by isothermal titration calorimetry. The results show that a 24-valent structure binds to BC2L-A at nanomolar concentration, which makes this compound the highest affinity monodisperse ligand for this lectin.