Large Brain Infarcts Research Articles

Association between left atrial volume index and infarct volume in patients with ischemic stroke.

Left atrial volume index (LAVI) is one marker of atrial myopathy, which is increasingly being recognized as a cause of cardioembolic stroke even in the absence of atrial fibrillation. Cardiac embolism is associated with larger strokes than other stroke mechanisms. The purpose of this study was to examine the association between LAVI and total brain infarct volume in patients with ischemic stroke. This was a retrospective study of 545 patients prospectively enrolled in the Cornell ActuE Stroke Academic Registry (CAESAR), which includes all acute ischemic stroke patients admitted to our hospital since 2011. LAVI measurements were obtained from our echocardiography image store system (Xclera, Philips Healthcare). Brain infarcts on diffusion-weighted images (DWI) were manually segmented and infarct volume was obtained on 3D Slicer. We used multiple linear regression models adjusted for age, sex, race, and vascular comorbidities including atrial fibrillation. Among 2,945 CAESAR patients, 545 patients had both total infarct volume and LAVI measured. We found an association between LAVI and log-transformed total brain infarct volume in both unadjusted (β = 0.018; p = 0.002) and adjusted (β = 0.024; p = 0.001) models. We found that larger left atrial volume was associated with larger brain infarcts. This association was independent of known cardioembolic risk factors such as atrial fibrillation and heart failure. These findings support the concept that atrial myopathy may be a source of cardiac embolism even in the absence of traditionally recognized mechanisms such as atrial fibrillation.

Long non-coding RNAs H19 and NKILA are associated with the risk of death and lacunar stroke in the elderly population

IntroductionDifferential expression of long non-coding RNAs (lncRNAs) is a hallmark of cardiovascular aging, cerebrovascular diseases, and neurodegenerative disorders. This research article investigates the association between a panel of lncRNAs and the risk of death and ischemic stroke in a cohort of non-institutionalized elderly subjects. MethodA total of 361 healthy individuals aged 75 years old, prospectively recruited in the Vienna Transdanube Aging (VITA) cohort, were included. Expression of lncRNAs at baseline was assessed using quantitative polymerase chain reaction PCR with pre-amplification reaction, using 18S for normalization. The primary endpoint was all-cause mortality; the secondary endpoint was the incidence of new ischemic brain lesions. Death was assessed over a 14-year follow-up, and ischemic brain lesions were evaluated by magnetic resonance imaging (MRI) over a 90-month follow-up. Ischemic brain lesions were divided into large brain infarcts (Ø≥ 1.5 cm) or lacunes (Ø< 1.5 cm) ResultsThe primary endpoint occurred in 53.5 % of the study population. The incidence of the secondary endpoint was 16 %, with a 3.3 % being large brain infarcts, and a 12.7 % lacunes.After adjustment for potential confounders, the lncRNA H19 predicted the incidence of the primary endpoint (HR 1.194, 95 % C.I. 1.012–1.409, p = 0.036), whereas the lncRNA NKILA was associated with lacunar stroke (HR 0.571, 95 % C.I. 0.375–0.868, p = 0.006). ConclusionIn a prospective cohort of non-institutionalized elderly subjects, high levels of lncRNA H19 are associated with a higher risk of death, while low levels of lncRNA NKILA predict an increased risk of lacunar stroke.

Whole genome sequence association analysis of Brain MRI measures

AbstractBackgroundGenome‐wide association studies (GWAS) of brain volumes have identified common genetic variants with modest effect sizes that lie mainly in non‐coding regions. We sought to identify low frequency and rare variants influencing brain volumes by performing association analyses using whole‐genome sequence data from the Trans‐Omics for Precision Medicine (TOPMed) Program.MethodWe analyzed up to 7,607 participants (57% women; 62% European ancestry, 21% African‐Americans, 15% Hispanic/Latino, 2% Chinese‐American), mean age of 60.5 (16.2), from eight TOPMed population‐ or family‐based studies (FHS, GENESTAR, CHS, GENOA, ARIC, CARDIA, MESA, and SAFS). We excluded participants with dementia, stroke, presence of large brain infarcts, tumor or low‐quality scans. We tested the association of hippocampal (HV), total brain (TBV), lateral ventricular (LVV) and intracranial (ICV) volumes to individual genetic variants with minor allele counts ≥ 15 using mixed‐effect linear regression models adjusted for age, age2, sex, study and the first 10 principal components. Models for HV, TBV and log(LVV) were adjusted for ICV. We accounted for relatedness using an empirical kinship matrix and trait variance variability by using a random effect for study.ResultWe detected one novel region with low frequency variants associated with HV (13q14, P = 5.8×10−9). The top 13q14 variant for HV (rs115674829) minor allele frequency (MAF) was 2% in our pooled sample but was more common in the pan‐African 1000 Genomes population (MAF = 14%). This variant lies in LINC00598 at 237kb from FOXO1, a member of the forkhead family of transcription factors that has been linked to Alzheimer’s Disease. Additionally, we detected new suggestive associations (P≤10−7) for TBV (16p11) and LVV (1q25, 2q22, 3q13, 5q14, and 10q23), including common variants. Finally, we confirmed the association of common variants in GWAS loci for all traits.ConclusionOur whole genome sequence analyses revealed intriguing new loci of low‐frequency and common variants, and replicated loci previously associated with brain volumes. Future work will include ancestry‐specific and conditional analyses, as well as gene‐based and scan tests.Supported by: AG058589, AG052409, AG054076, NO1‐HC‐25195, HHSN268201500001I and 75N92019D00031, R01HL131136, P30 AG066546, and K99AG066849.

Recurring cervical internal carotid artery vasospasm elicited by head rotation: illustrative case.

Idiopathic extracranial internal carotid artery vasospasm (IEICAV) is a rare cerebrovascular disorder causing transient or permanent cerebral ischemia. The pathophysiology underlying this disorder is not well understood. Although various medical treatments have been tried, complete remission of vasospasm is difficult to achieve. The first case of bilateral IEICAV induced by head rotation, which was successfully treated by carotid artery stenting (CAS), was presented. A 40-year-old woman with bilateral IEICAV had been conservatively treated for 13 years. However, transient ischemic attacks (TIAs) were not suppressed. She eventually presented with a large brain infarction in the left hemisphere and was referred to our department. Digital subtraction angiography clearly demonstrated the triggering of internal carotid artery (ICA) vasospasm by head rotation. After CAS treatment, the TIAs disappeared completely. Clinicians should recognize that ordinary mechanical stimulation to the ICA by head rotation can induce vasospasm, and CAS should be performed for refractory IEICAV at the appropriate time to avoid cerebral infarction causing severe neurological deficits.

Chronic high-fat diet consumption exacerbates pyroptosis- and necroptosis-mediated HMGB1 signaling in the brain after ischemia and reperfusion injury.

Obesity is categorized as a common comorbidity found in people who experience an ischemic stroke. However, the mechanisms to explain this correlation have still not been elucidated fully. Pyroptosis and necroptosis are novel forms of programmed cell death that occur upon intracellular danger signals. The major feature of pyroptosis and necroptosis is damage to the lipid membrane, which consequently results in lytic cell death and allows the release of high mobility group box protein 1 (HMGB1) into the extracellular space. We aimed to investigate the influences of high-fat diet (HFD) consumption on cerebral ischemia and reperfusion (I/R) injury and hypothesized that HFD consumption exacerbated the activation of pyroptosis, necroptosis, and HMGB1 signaling pathways. All rats received normal diet (ND) or HFD for 16weeks. Subsequently, both groups were divided into either a sham- or an I/R-operated group. Twenty-four hours after the surgery, all rats were evaluated for neurological deficits and then sacrificed. After I/R injury, there were more severe functional deficits and larger brain infarcts in the HFD compared with the ND group. The histological observation revealed an increase in tissue abnormalities in the HFD group, consistent with the massive reduction of intact neurons along the peri-infarct region. Furthermore, cerebral I/R injury dramatically activated the pyroptotic, necroptotic, and HMGB1 signaling pathways in HFD-fed rats compared with ND-fed rats. These findings suggest that chronic HFD consumption worsens ischemic brain pathology and leads to poor post-stroke outcomes by exacerbating pyroptotic and necroptotic cell death.

Mesenchymal stromal cell-derived small extracellular vesicles promote neurological recovery and brain remodeling after distal middle cerebral artery occlusion in aged rats

Small extracellular vesicles (sEVs) obtained from mesenchymal stromal cells (MSCs) promote neurological recovery after middle cerebral artery occlusion (MCAO) in young rodents. Ischemic stroke mainly affects aged humans. MSC-sEV effects on stroke recovery in aged rodents had not been assessed. In a head-to-head comparison, we exposed young (4–5 months) and aged (19–20 months) male Sprague–Dawley rats to permanent distal MCAO. At 24 h, 3 and 7 days post-stroke, vehicle or MSC-sEVs (2 × 106 or 2 × 107 MSC equivalents/kg) were intravenously administered. Neurological deficits, ischemic injury, brain inflammatory responses, post-ischemic angiogenesis, and endogenous neurogenesis were evaluated over 28 days. Post-MCAO, aged vehicle-treated rats exhibited more severe motor-coordination deficits evaluated by rotating pole and cylinder tests and larger brain infarcts than young vehicle-treated rats. Although infarct volume was not influenced by MSC-sEVs, sEVs at both doses effectively reduced motor-coordination deficits in young and aged rats. Brain macrophage infiltrates in periinfarct tissue, which were evaluated as marker of a recovery-aversive inflammatory environment, were significantly stronger in aged than young vehicle-treated rats. sEVs reduced brain macrophage infiltrates in aged, but not young rats. The tolerogenic shift in immune balance paved the way for structural brain tissue remodeling. Hence, sEVs at both doses increased periinfarct angiogenesis evaluated by CD31/BrdU immunohistochemistry in young and aged rats, and low-dose sEVs increased neurogenesis in the subventricular zone examined by DCX/BrdU immunohistochemistry. Our study provides robust evidence that MSC-sEVs promote functional neurological recovery and brain tissue remodeling in aged rats post-stroke. This study encourages further proof-of-concept studies in clinic-relevant stroke settings.

White matter hyperintensities associate with cognitive slowing in patients with systemic lupus erythematosus and neuropsychiatric symptoms

ObjectiveTo compare cognitive function between patients with different phenotypes of neuropsychiatric systemic lupus erythematosus (NPSLE) and assess its association with brain and white matter hyperintensity (WMH) volumes.MethodsPatients attending the Leiden...

Effect of High Frequency Transcranial Magnetic Stimulation on Recovery of Chronic Post-Stroke Aphasia

BackgroundBoth hemispheres have role in post-stroke aphasia recovery but better recovery is expected with the restoration of function by the left hemisphere. Transcranial stimulation has been used to favor recruitment of left-hemispheric language networks and increase activity of the left hemisphere, thus helps aphasia recovery . ObjectiveThe aim of this study is to evaluate the effect of excitatory repetitive transcranial magnetic stimulation (rTMS) on recovery of post stroke aphasic patients . Materials and methodsTwenty patients with post stroke chronic aphasia were enrolled in the study. Aphasia severity was assessed using Aphasia Severity Rating Scale (ASRS). Linguistic deficits were assessed using Kasr Al-Aini Arabic Aphasia test (KAAT). Real rTMS was applied three for 10 sessions of 10-Hz stimulation, positioned over the left Broca's area of the affected hemisphere. All patients were evaluated before, after the end of treatment sessions and one month later . ResultsThere was a significant improvement in the mean total score and mean scores of components of KAAT scale before, immediately after and after one month of rTMS (P< 0.05). Moreover, there was a significant improvement in mean scores of ASRS before, immediately after and after one month of rTMS (P= 0.000). There was a significant difference in mean scores of ASRS and KAAT before, immediately after the last session and after one month between small, medium and large brain infarcts. (P< 0.05). ConclusionExcitatory rTMS is a beneficial adjuvant therapy that improves language skills in patients with chronic post-stroke non-fluent aphasia in short and long term.The protocol of this observational study was registered in clinical trial registration: www.ClinicalTrials.gov, identifier: NCT04708197

&amp;lt;i&amp;gt;MTHFRC677T&amp;lt;/i&amp;gt; Polymorphism and Hyperhomocysteinemia in Ischemic Stroke Patients

Background: Homocysteine is an intermediate sulfur amino acid of methionine metabolism. Hyperhomocysteinemia, characterized by increased level of homocysteine, is an independent and modifiable vascular risk factor which metabolic pathway involves vitamins B6, folate and vitamin B12. Objective: We compared the prevalence of MTHFRC677T polymorphism, homocysteine folate and vitamin B12 in ischemic stroke patient’s subgroups. Methods: We conducted a cross-sectional analytical study. The study included 128 consecutive ischemic stroke patients associated with hyperhomocysteinemia. The MTHFRC677T polymorphism was investigated by TaqMan probes (thermos Fisher Scientific) combined with polymerase chain reaction (PCR). We compared the prevalence of MTHFRC677T polymorphism and homocysteine level in ischemic stroke patient’s subgroups. We adjusted the variable homocysteine level to the covariates, MTHFR polymorphism, folate and vitamin B12 with ANCOVA. Results: The sex ratio (men/women) was 1.5 with an average age of 60 years. The prevalence of MTHFRC677T polymorphism was 19.5% with 18% CT and 1.5% TT. Homocysteine level was 29.89 µmol/l in wildtype patients, 26.54 µmol/l in patients with CT genotype, and 56.17 µmol/l in patients with TT genotype (t=2.04, p=0.033, CI 95% [0.017; 0.407]). The MTHFR polymorphism prevalence, homocysteine, folate and vitamin B12 level did not differ between large brain infarction and multiple small brain infarction patients respectively (chi square: Qobs=0.05, p=0.94, 95% CI; ttest: t=0.716, df=126, p=0.475, 95% CI). Conclusion: The MTHFRT677T genotype increases homocysteine level. MTHFR polymorphism and homocysteine did not influence the subtypes of brain ischemic stroke.

Whole genome sequence association analyses of brain volumes in the TOPMed program

AbstractBackgroundGenome‐wide association studies (GWAS) of brain volumes have identified common genetic variants with modest effect sizes that lie mainly in non‐coding regions. We sought to identify low frequency and rare variants influencing brain volumes by performing whole genome association analyses using sequence data from the Trans‐Omics for Precision Medicine (TOPMed) Program.MethodsWe analyzed up to 3,975 participants (58% women; 78% Europeans, 22% African‐Americans), mean age of 62.5 (13.9), from four TOPMed population‐ or family‐based studies (FHS, GENESTAR, CHS, and GENOA). We excluded participants with dementia, stroke, presence of large brain infarcts, tumor or any other finding affecting the scan. We tested the association of hippocampal (HV), total brain (TBV), lateral ventricular (LVV) and intracranial (ICV) volumes with individual genetic variants using mixed‐effect linear regression models adjusted for age, age2, sex, study and principal components. Models including HV, TBV and LVV were adjusted for ICV. We accounted for relatedness using a kinship matrix and trait variance variability using a random effects model. We retained variants with a minor allele count greater than 40.ResultsWe detected new genome‐wide significant (P &lt; 5 × 10−8) low frequency or rare variants in five regions associated with HV (5q31, P = 10−9) and TBV (2p22, P = 10−8; 17q25, P = 4 × 10−9; Xp11, P = 2 × 10−10; Xq21, P = 4 × 10−8). We also confirmed previously observed common variants in GWAS loci for HV (12q14 &amp; 12q24), LVV (3q28, 12q23 &amp; 16q24) and ICV (6q21, 6q22 &amp; 17q21). The top 5q31 hit for HV (rs246587) lies at 19kb from the PCDHAC2 gene, encoding neural cadherin‐like cell adhesion proteins that most likely play a critical role in the establishment and maintenance of specific neuronal connections in the brain.ConclusionsOur whole genome analysis revealed intriguing new loci associated with brain volumes. Future work will include ancestry‐specific and conditional analyses, gene‐based and burden tests as well as the inclusion of additional TOPMed cohorts. Supported by: U01s AG058589, AG052409, R01s AG054076, AG033040 AG049607, HL112064, NS062059, FHS contracts HHSN268201500001I and 75N92019D00031, R01HL131136 (Analysis Commons).

Validity and Reliability of Neurological Scores in Mice Exposed to Middle Cerebral Artery Occlusion.

Background and Purpose- The selection of appropriate neurological scores and tests is crucial for the evaluation of stroke consequences. The validity and reliability of neurological deficit scores and tests has repeatedly been questioned in ischemic stroke models in the past. Methods- In 198 male mice exposed to transient intraluminal middle cerebral artery occlusion, we examined the validity and reliability of 11 neurological scores (Bederson score 0-3, Bederson score 0-4, Bederson score 0-5, modified neurological severity [0-14], subjective overall impression [0-10], or simple neurological tests: grip test, latency to move body length test, pole test, wire hanging test, negative geotaxis test, and elevated body swing test) in the acute stroke phase, that is, after 24 hours. Combinations of neurological scores or tests for predicting infarct volume were statistically analyzed. Results- Infarct volume was left skewed (median [Q1-Q3], 78.4 [54.8-101.3] mm3). Among all tests, the Bederson (0-5; r=0.63, P<0.001), modified neurological severity (r=0.80, P<0.001), and subjective overall impression (r=-0.63, P<0.001) scores had the highest test validities, using infarct volume as external reference. Subjective overall impression had the best agreement between 5 raters (Kendall W=0.11, P<0.001). The Bederson (0-5) score discriminated infarct volume in mice with small (≤50 mm3; r=0.33, P=0.027) and large (>50 mm3; r=0.48, P<0.001) brain infarcts, all other tests only in mice with large infarcts. Combining subjective overall impression with Bederson (0-5) score explained 47.6% of the variance of infarct volume. Conclusions- Despite their simplicity, the Bederson (0-5) score, modified neurological severity score, and subjective overall impression have reasonable validity and reliability in the acute stroke phase. The Bederson (0-5) score equally distinguishes infarct volume in small and large infarcts. Visual Overview- An online visual overview is available for this article.

Ischemic Stroke In infant With Tetralogy of Fallot

Objectives: Although stroke is often viewed as occurring primarily in the elderly, it also strikes infants, children, young adults. Stroke in children are rare but increasingly important conditions due to the severity of their complications and diverse diagnostic differentials. It is not yet clearly understood and with multifactorial etiologies. When it comes to stroke, children are not just little adults. Stroke risk factors, symptoms, prevention efforts, and treatment are often different in children than in adults. Up to 80 % of children with ischemic stroke have cardiovascular disease. Case report: RS, An infant, aged two and half years old was admitted to DR. M. Djamil hospital Padang, with right hemiplegy and developed aphasia after activity. One year ago, he had history of cyanotic skin but neglected by his parents and never sought medical treatment. Physical findings on this patient are cyanosis and clubbing fingers. Cardiac auscultation revealed a pansystolic murmur grade III-IV best heard at the upper left sternal border. Chest radiograph showed a characteristic “bootshaped” heart, which is a reflection of Right Ventricular (RV) hypertrophy. The ECG showed right axis deviation. Brain CT Scan revealed a large hypodense lesion on the left cerebral hemisphere suggested as large brain infarction. Echocardiogram revealed tetralogy of fallot with a larged malaligned ventricular septal defect (VSD) with 60 % aortic override. Patient was managed conservatively. After two weeks of admission, patient was discharged with improvement.Conclusion : Ischemic stroke in this infant with tetralogy of fallot occurred via paradoxical embolism mechanism.

Exploratory Investigation of Intestinal Function and Bacterial Translocation After Focal Cerebral Ischemia in the Mouse.

Background and Purpose: The gut communicates with the brain bidirectionally via neural, humoral and immune pathways. All these pathways are affected by acute brain lesions, such as stroke. Brain-gut communication may therefore impact on the overall outcome after CNS-injury. Until now, contradictory reports on intestinal function and translocation of gut bacteria after experimental stroke have been published. Accordingly, we aimed to specifically investigate the effects of transient focal cerebral ischemia on intestinal permeability, gut associated lymphoid tissue and bacterial translocation in an exploratory study using a well-characterized murine stroke model.Methods: After 60 min of middle cerebral artery occlusion (MCAO) we assessed intestinal morphology (time points after surgery day 0, 3, 5, 14, 21) and tight junction protein expression (occludin and claudin-1 at day 1 and 3) in 12-week-old male C57Bl/6J mice. Lactulose/mannitol/sucralose test was performed to assess intestinal permeability 24–72 h after surgery. To investigate the influence of cerebral ischemia on the local immune system of the gut, main immune cell populations in Peyer's patches (PP) were quantified by flow cytometry. Finally, we evaluated bacterial translocation to extraintestinal organs 24 and 72 h after MCAO by microbiological culture and fluorescence in situ hybridization targeting bacterial 16S rRNA.Results: Transient MCAO decreased claudin-1 expression in the ileum but not in the colon. Intestinal morphology (assessed by light microscopy) and permeability did not change measurably after MCAO. After MCAO, animals had significantly fewer B cells in PP compared to naïve mice.Conclusions: In a murine model of stroke, which leads to large brain infarctions in the middle cerebral artery territory, we did not find evidence for overt alterations neither in gut morphology, barrier proteins and permeability nor presence of intestinal bacterial translocation.

Patients with large brain infarcts might also benefit from thrombectomy

Patients with large brain infarcts might also benefit from thrombectomy

Chapter 4 - Raised intracranial pressure and brain edema

Acutely increased intracranial pressure (ICP) is a life-threatening neurosurgical emergency. Optimal management strategy is selected according to the causative process. Typical causes are intracranial bleeds like traumatic subdural, epidural, or intracerebral hematoma (ICH); spontaneous ICH, intraventricular hemorrhage, subarachnoid hemorrhage, and hydrocephalus. When occurring without significant brain injury and treated effectively before herniation, a full recovery can be expected. In intraparenchymal injuries a full recovery is unlikely since dead cells in the central nervous system leave an "empty hole," to be replaced by cerebrospinal fluid. The clinical recovery is based on the surviving cells that are able to make new synapses. Surgery may decrease ICP by removing significant mass effect. In all conditions, when notable injury of brain parenchyma occurs, brain edema may gradually increase ICP and further worsen the clinical condition. This is seen typically in large brain infarctions when the formation of brain edema may lead to increased ICP for hours and days. Brain edema is traditionally classified as vasogenic or cytotoxic but according to current knowledge is rather a continuum, starting with cytotoxic cell swelling followed by ionic edema and then vasogenic edema. Here we review the causes of increased ICP, including mechanisms of brain edema, with clinical examples.

CIRCULATING VEGF AND STIE2 AND MRI FINDINGS IN YOUNG AND MIDDLE-AGED ADULTS IN THE FRAMINGHAM HEART STUDY

Vascular Endothelial Growth Factor (VEGF) is an angiogenic factor that promotes vascular development and preservation; VEGF binds to angiopoietin receptor Tie2 to regulate angiogenesis. VEGF dysregulation is associated with poorer hemodynamic function and increased risk of vascular brain injury. However, little is known about how it is associated with brain volumetric measurements, particularly in young and middle aged adults. In the present study, we investigated associations between circulating VEGF and Tie2 concentrations and brain MRI markers of small vessel disease and atrophy in young and middle-aged adults. Participants in the third generation of the Framingham Heart Study without stroke, large cerebral brain infarcts, and other neurological disorders, who had brain MRI and serum VEGF and Tie2 measurements were included (n=1877, age 46±8, 54% women). Mean interval between blood draw and MRI was 1.5±0.77 years. MRI volumetric measurements of gray (GM) and white matter, white matter hyperintensity (WMH), and cerebrospinal fluid were regressed onto total intracranial volumes to account for differences in head sizes, and the residuals of each regression were used as outcomes in separate models. VEGF and Tie2 were log-transformed to normalize the distributions and were analyzed in SDU as predictors. All analyses were adjusted for age, age2, sex, time between blood draw and MRI, waist-to-hip ratio, systolic blood pressure, hypertension treatment, diabetes mellitus, current smoking, and prevalent cardiovascular disease. Higher circulating VEGF levels were associated with lower hippocampal volume (Estimate by standard deviation units ± se= -0.07±0.03, p=0.041). Higher Tie2 levels were associated with lower total brain (-0.07±0.02, p=0.001) and cortical GM (-0.06±0.02, p=0.008) volumes, and with higher WMH volume (0.04±0.01, p=0.001). Our results suggest that increased levels of VEGF and Tie2 are associated with early gray matter loss and white matter disease in young and middle-aged adults, independent of the effects of vascular risk factors and cardiovascular disease. These preliminary findings suggest a role of growth factors in early brain changes that are observed in small vessel disease and Alzheimer's disease. We plan to expand these findings by relating vascular growth factors to cognitive function, and with Mendelian randomization analyses.

Infective endocarditis following tumor necrosis factor-\u03b1 antagonist therapy for management of psoriatic erythroderma: a case report

BackgroundThe introduction of biological agents, such as infliximab, which act against tumor necrosis factor-α was a major advance for the treatment of an increasing number of chronic diseases. Tumor necrosis factor-α antagonists represent a major therapeutic advance for the management of chronic inflammatory diseases, such as psoriasis. Previous studies have reported that the use of tumor necrosis factor-α antagonists increased the risk of opportunistic infections and reactivation of latent bacterial infections. Cardiac involvement, such as infective endocarditis, is very rare in the literature.Case presentationA 77-year-old Asian man with a 10-year history of psoriatic erythroderma was referred due to high fever and general malaise. He was treated with Predonine (prednisolone) and infliximab. After treatment, cardiac echography showed mitral valve vegetation and brain magnetic resonance imaging indicated multiple fresh infarctions. He died from large brain infarction in October 2013. An autopsy showed fresh thrombosis in his left middle cerebral artery, mitral valve vegetations, and septic micro-embolisms in multiple organs.ConclusionsLethal bacterial endocarditis was revealed after administration of tumor necrosis factor-α inhibitor, infliximab, for the treatment of psoriatic erythroderma. An autopsy showed vegetation in his mitral valve and brain infarction with fresh purulent embolism in his left middle cerebral artery and septic micro-embolisms.

Abstract TP98: Genetic Deletion of Kruppel-Like Factor 11 Aggravates Ischemic Brain Injury

Kruppel-like factors (KLFs) are members of the zinc finger family of transcription factors and the function of the KLFs in the central nervous system is largely unexplored. KLF11 is a member of the KLF family and we have previously demonstrated that peroxisome proliferator-activated receptor gamma-mediated cerebral protection during ischemic insults needs recruitment of KLF11 as its critical coactivator. In this study we sought to determine the role of KLF11 itself in cerebrovascular function and the pathogenesis of ischemic stroke. Transient middle cerebral artery occlusion (MCAO) was performed in KLF11 knockout and wild-type control mice, and brain infarction size was analyzed by TTC staining. BBB integrity was assessed by using Evans Blue and TMR-Dextran extravasation assays. KLF11 KO mice exhibited significantly larger brain infarct volume and worse neurological outcomes in response to ischemic insults. Genetic deficiency of KLF11 in mice also significantly aggravated ischemia-induced BBB disruption by increasing cerebrovascular permeability and edema in comparison with wild-type mice. Mechanistically, KLF11 was found to directly regulate several key inflammatory cytokines in the brains of ischemic mice. These findings suggest that KLF11 acts as a novel protective factor in ischemic stroke. Elucidating the functional importance of KLF11 in ischemic process may lead us to discover novel pharmaceutical targets for the development of effective therapies against ischemic stroke.

Transgenic Mice Overexpressing Human Angiotensin I Receptor Gene Are Susceptible to Stroke Injury.

Hypertension is one of the co-morbid conditions for stroke and profoundly increases its incidence. Angiotensin II (AngII) is shown to be at the center stage in driving the renin angiotensin system via activation of angiotensin 1 receptor (AT1R). This makes the AT1R gene one of the candidates whose differential regulation leads to the predisposition to disorders associated with hypertension. A haplotype block of four SNPs is represented primarily by haplotype-I, or Hap-I (TTAA), and haplotype-II, or Hap-II (AGCG), in the promoter of human AT1R (hAT1R) gene. To better understand the physiological role of these haplotypes, transgenic (TG) mice containing Hap-I and Hap-II of the hAT1R gene in a 166-kb bacterial artificial chromosome (BAC) were generated. Mice received injection of endothelin-1 (1 mg/ml) directly in to the striatum and were evaluated for neurologic deficit scores and sacrificed for analysis of infarct volume and mRNA levels of various proteins. Mice containing Hap-I suffered from significantly higher neurological deficits and larger brain infarcts than Hap II. Similarly, the molecular analysis of oxidant and inflammatory markers in brains of mice showed a significant increase (p < 0.05) in NOX-1 (2.3-fold), CRP (4.3-fold), and IL6 (1.9-fold) and a corresponding reduced expression of antioxidants SOD (60%) and HO1 (55%) in Hap-I mice as compared to Hap-II mice. These results suggest that increased expression of hAT1R rendered Hap-I TG mice susceptible to stroke-related pathology, possibly due to increased level of brain inflammatory and oxidative stress markers and a suppressed antioxidant defense system.

Abstract 482: Transgenic Mice Containing Haplotype-I Of Human Angiotensin Receptor Type-1 Gene Are Susceptible To Stroke

Hypertension is one of the co-morbid conditions for, and profoundly increases the incidence of stroke in humans. Hypertension is polygenic in nature and its familial inheritance is regulated by single nucleotide polymorphisms (SNPs) in the genes associated with renin angiotensin aldosterone system (RAAS). Angiotensin II (AngII) is shown to be at the center stage in driving the RAAS via activation of angiotensin 1 receptor (AT 1 R). This makes AT 1 R gene one of the prime candidates whose differential regulation leads to the predisposition to disorders associated with hypertension. A haplotype block of four SNPs is represented primarily by haplotype-I, or Hap-I (TTAA), and haplotype-II, or Hap-II (AGCG), in the promoter of human AT 1 R (hAT 1 R) gene. To better understand the physiological role of these haplotypes, transgenic (TG) mice containing haplotype-I and II of the hAT 1 R gene in a 166Kb BAC (bacterial artificial chromosome) were generated. Our results show that 8 weeks old male transgenic mice containing Hap-I have increased brain hAT1R expression (6.5 fold) and have increased systolic blood pressure (11mmHg) as compared to the mice with Hap-II. Also, the results post PMCAO (permanent middle cerebral artery occlusion) suggest that the mice containing Hap-I suffered from significantly higher (p&lt;0.05) neurological deficits (30% higher than Hap-II) and larger brain infarcts (26% larger than Hap-II). Similarly the molecular analysis of oxidant/inflammatory markers post PMCAO show a significant increase (p&lt;0.05) in NOX-1 (1.85 fold up), CRP (9 fold up) and IL6 (2.8 fold up) and a corresponding reduced expression of antioxidants SOD (60% down) and HO-1 (55% down) in Hap-I mice as compared to Hap-II mice. These results suggest that increased expression of hAT 1 R leads to the damage associated with endothelial dysfunction and vascular remodeling, eventually rendering Hap-I TG mice susceptible to stroke related pathology.