Serum uri acid: neuroprotection in thrombolysis. The Bergen NORSTROKE study

<p>Abstract</p> <p>Background</p> <p>A possible synergic role of serum uric acid (SUA) with thrombolytic therapies is controversial and needs further investigations. We therefore evaluated association of admission SUA with clinical improvement and clinical outcome in patients receiving rt-PA, early admitted patients not receiving rt-PA, and patients admitted after time window for rt-PA.</p> <p>Methods</p> <p>SUA levels were obtained at admission and categorized as low, middle and high, based on 33° and 66° percentile values. Patients were categorized as patients admitted within 3 hours of symptom onset receiving rt-PA (rt-PA group), patients admitted within 3 hours of symptom onset not receiving rt-PA (non-rt-PA group), and patients admitted after time window for rt-PA (late group). Short-term clinical improvement was defined as the difference between NIHSS on admission minus NIHSS day 7. Favorable outcome was defined as mRS 0 - 3 and unfavorable outcome as mRS 4 - 6.</p> <p>Results</p> <p>SUA measurements were available in 1136 patients. Clinical improvement was significantly higher in patients with high SUA levels at admission. After adjustment for possible confounders, SUA level showed a positive correlation with clinical improvement (r = 0.012, 95% CI 0.002-0.022, p = 0.02) and was an independent predictor for favorable stroke outcome (OR 1.004; 95% CI 1.0002-1.009; p = 0.04) only in the rt-PA group.</p> <p>Conclusions</p> <p>SUA may not be neuroprotective alone, but may provide a beneficial effect in patients receiving thrombolysis.</p

Gender Differences in Patients with Brugada Syndrome and Arrhythmic Events: Data from a Survey on Arrhythmic Events in 678 Patients.

BACKGROUND: There is limited information on gender differences in patients with Brugada syndrome (BrS) who experienced arrhythmic events (AEs). OBJECTIVES: To compare clinical, electrocardiographic (ECG), electrophysiologic (EP) and genetic characteristics between males and females in BrS-patients with their first AE. METHODS: The multicenter Survey on AE in BrS (SABRUS) collected data on first AE in 678 BrS-patients including 619 (91.3%) males and 59 (8.7%) females aged 0.27 to 84 (mean 42.5±14.1) years at the time of AE. RESULTS: After excluding pediatric patients, females were older than males (49.5±14.4 vs. 43±12.7 years, respectively, P=0.001). Higher proportions of females were observed in the pediatric and elderly populations. In Asians, male/female ratio of AE was ≈9-fold higher compared to Caucasians. Spontaneous type 1 BrS-ECG was associated with earlier onset of AE in pediatric females. A similar prevalence (≈65%) of spontaneous type 1 BrS-ECG was present in males and females above age of 60 years. Females less frequently showed a spontaneous type-1 BrS-ECG (31% vs. 59%, P<0.001) or arrhythmia-inducibility at EP study (34% vs. 64%, P<0.001). An SCN5A mutation was more frequently found in females (47.6% vs. 27.8% in males, P=0.007). CONCLUSIONS: This study confirms that female BrS-patients are much rarer, display less type 1 Brugada-ECG and exhibit lower inducibility rates than males. It shows for the first time that BrS females with AE have higher SCN5A mutation rates as well as the relationship between gender vs. age at onset of AE and ethnicity

Age of First Arrhythmic Event in Brugada Syndrome: Data From the SABRUS (Survey on Arrhythmic Events in Brugada Syndrome) in 678 Patients.

BACKGROUND: Data on the age at first arrhythmic event (AE) in Brugada syndrome are from limited patient cohorts. The aim of this study is 2-fold: (1) to define the age at first AE in a large cohort of patients with Brugada syndrome, and (2) to assess the influence of the mode of AE documentation, sex, and ethnicity on the age at first AE. METHODS AND RESULTS: A survey of 23 centers from 10 Western and 4 Asian countries gathered data from 678 patients with Brugada syndrome (91.3% men) with first AE documented at time of aborted cardiac arrest (group A, n=426) or after prophylactic implantable cardioverter-defibrillator implantation (group B, n=252). The vast majority (94.2%) of the patients were 16 to 70 years old at the time of AE, whereas pediatric (70 years) comprised 4.3% and 1.5%, respectively. Peak AE rate occurred between 38 and 48 years (mean, 41.9±14.8; range, 0.27-84 years). Group A patients were younger than in Group B by a mean of 6.7 years (46.1±13.2 versus 39.4±15.0 years; P<0.001). In adult patients (≥16 years), women experienced AE 6.5 years later than men (P=0.003). Whites and Asians exhibited their AE at the same median age (43 years). CONCLUSIONS: SABRUS (Survey on Arrhythmic Events in Brugada Syndrome) presents the first analysis on the age distribution of AE in Brugada syndrome, suggesting 2 age cutoffs (16 and 70 years) that might be important for decision-making. It also allows gaining insights on the influence of mode of arrhythmia documentation, patient sex, and ethnic origin on the age at AE

Profile of Brugada Syndrome Patients Presenting with Their First Documented Arrhythmic Event. Data from the Survey on Arrhythmic Events in BRUgada Syndrome (SABRUS).

BACKGROUND: Detailed information on the profile of Brugada syndrome (BrS) patients presenting their first arrhythmic event (AE) after prophylactic implantation of a cardioverter defibrillator (ICD) is limited. OBJECTIVES: 1) To compare clinical, electrocardiographic, electrophysiologic and genetic profiles of patients who exhibited their first documented AE as aborted cardiac arrest (CA) (group A) with those in whom the AE was documented after prophylactic ICD implantation (group B); 2) To characterize group B patients' profile using the Class II indications for ICD implantation established by HRS/EHRA/APHRS Expert Consensus Statement in 2013. METHODS: A survey of 23 centers from 10 Western and 4 Asian countries enabled data collection of 678 BrS patients with AE (group A, n=426; group B, n=252). RESULTS: First AE occurred in group B patients 6.7 years later than in group A (46.1+ 13.3 vs. 39.4+15.1, P<0.001). Group B patients had a higher incidence of family history of sudden cardiac death (SCD) and SCN5A mutations. Of the 252 group B patients, 189 (75%) complied with the HRS/EHRA/APHRS indications whereas the remaining 63 (25%) did not. CONCLUSION: BrS patients with first AE documented after prophylactic ICD implantation exhibited their AE at a later age with a higher incidence of positive family history of SCD and SCN5A mutations compared to those presenting with an aborted CA. Only 75% of patients who suffered an AE after receiving a prophylactic ICD complied with the 2013 Class II indications, suggesting efforts are still required for improving risk stratification

Fever-related arrhythmic events in the multicenter Survey on Arrhythmic Events in Brugada Syndrome

BACKGROUND: The literature on fever related arrhythmic events (AE) in Brugada syndrome (BrS) is currently limited to few case reports and small series. OBJECTIVE: The current study aims to describe the characteristics of fever-related AE in a large cohort of BrS patients. METHODS: SABRUS is a multicenter study on 678 BrS patients with first AE documented at time of aborted cardiac arrest (ACA) (n=426) or after prophylactic ICD implantation (n=252). RESULTS: In 35(6%) of the 588 patients with available information, the AE occurred during a febrile illness. Most of the 35 patients were male (80%), Caucasian (83%) and proband (70%). Age at time of AE was 29±24 (range 0.3-76) years. Most patients (80%) presented with ACA and 6 (17%) with arrhythmic storm. Family history of sudden death, history of syncope and spontaneous type 1 Brugada-ECG were noted in 17%, 40% and 66% of patients, respectively. VF was induced at EPS in 9/19(47%) patients. An SCN5A mutation was found in 14/28(50%) patients. The highest proportion of fever-related AE was observed in the pediatric population (age <16), with disproportionally higher event rate in the very young (0-5 years old) (65%). Males were involved in all age groups and females only in the pediatric and elderly groups. Fever-related AE affected 17 Caucasians aged<24 years, but no Asians aged <24 years. CONCLUSIONS: The risk of fever-related AE in BrS markedly varies according to age group, gender and ethnicity. Taking these factors into account could help the clinical management of BrS patients with fever

Time-to-first appropriate shock in patients implanted prophylactically with an implantable cardioverter-defibrillator: data from the Survey on Arrhythmic Events in BRUgada Syndrome (SABRUS).

Aims: Data on predictors of time-to-first appropriate implantable cardioverter-defibrillator (ICD) therapy in patients with Brugada Syndrome (BrS) and prophylactically implanted ICD's are scarce. Methods and results: SABRUS (Survey on Arrhythmic Events in BRUgada Syndrome) is an international survey on 678 BrS patients who experienced arrhythmic event (AE) including 252 patients in whom AE occurred after prophylactic ICD implantation. Analysis was performed on time-to-first appropriate ICD discharge regarding patients' characteristics. Multivariate logistic regression models were utilized to identify which parameters predicted time to arrhythmia ≤5 years. The median time-to-first appropriate ICD therapy was 24.8 ± 2.8 months. A shorter time was observed in patients from Asian ethnicity (P < 0.05), those with syncope (P = 0.001), and those with Class IIa indication for ICD (P = 0.001). A longer time was associated with a positive family history of sudden cardiac death (P < 0.05). Multivariate Cox regression revealed shorter time-to-ICD therapy in patients with syncope [odds ratio (OR) 1.65, P = 0.001]. In 193 patients (76.6%), therapy was delivered during the first 5 years. Factors associated with this time were syncope (OR 0.36, P = 0.001), spontaneous Type 1 Brugada electrocardiogram (ECG) (OR 0.5, P < 0.05), and Class IIa indication (OR 0.38, P < 0.01) as opposed to Class IIb (OR 2.41, P < 0.01). A near-significant trend for female gender was also noted (OR 0.13, P = 0.052). Two score models for prediction of <5 years to shock were built. Conclusion: First appropriate therapy in BrS patients with prophylactic ICD's occurred during the first 5 years in 76.6% of patients. Syncope and spontaneous Type 1 Brugada ECG correlated with a shorter time to ICD therapy

Compressed representation of a partially defined integer function over multiple arguments

In OLAP (OnLine Analitical Processing) data are analysed in an n-dimensional cube. The cube may be represented as a partially defined function over n arguments. Considering that often the function is not defined everywhere, we ask: is there a known way of representing the function or the points in which it is defined, in a more compact manner than the trivial one

A novel nucleo-cytoplasmic hybrid clone formed via androgenesis in polyploid gibel carp

<p>Abstract</p> <p>Background</p> <p>Unisexual vertebrates have been demonstrated to reproduce by gynogenesis, hybridogenesis, parthenogenesis, or kleptogenesis, however, it is uncertain how the reproduction mode contributes to the clonal diversity. Recently, polyploid gibel carp has been revealed to possess coexisting dual modes of unisexual gynogenesis and sexual reproduction and to have numerous various clones. Using sexual reproduction mating between clone D female and clone A male and subsequent 7 generation multiplying of unisexual gynogenesis, we have created a novel clone strain with more than several hundred millions of individuals. Here, we attempt to identify genetic background of the novel clone and to explore the significant implication for clonal diversity contribution.</p> <p>Methods</p> <p>Several nuclear genome markers and one cytoplasmic marker, the mitochondrial genome sequence, were used to identify the genetic organization of the randomly sampled individuals from different generations of the novel clone.</p> <p>Results</p> <p>Chromosome number, <it>Cot</it>-1 repetitive DNA banded karyotype, microsatellite patterns, AFLP profiles and transferrin alleles uniformly indicated that nuclear genome of the novel clone is identical to that of clone A, and significantly different from that of clone D. However, the cytoplasmic marker, its complete mtDNA genome sequence, is same to that of clone D, and different from that of clone A.</p> <p>Conclusions</p> <p>The present data indicate that the novel clone is a nucleo-cytoplasmic hybrid between the known clones A and D, because it originates from the offspring of gonochoristic sexual reproduction mating between clone D female and clone A male, and contains an entire nuclear genome from the paternal clone A and a mtDNA genome (cytoplasm) from the maternal clone D. It is suggested to arise via androgenesis by a mechanism of ploidy doubling of clone A sperm in clone D ooplasm through inhibiting the first mitotic division. Significantly, the selected nucleo-cytoplasmic hybrid female still maintains its gynogenetic ability. Based on the present and previous findings, we discuss the association of rapid genetic changes and high genetic diversity with various ploidy levels and multiple reproduction modes in several unisexual and sexual complexes of vertebrates and even other invertebrates.</p

The interaction between caveolin-1 and Rho-GTPases promotes metastasis by controlling the expression of alpha5-integrin and the activation of Src, Ras and Erk

Proteins containing a caveolin-binding domain (CBD), such as the Rho-GTPases, can interact with caveolin-1 (Cav1) through its caveolin scaffold domain. Rho-GTPases are important regulators of p130Cas, which is crucial for both normal cell migration and Src kinase-mediated metastasis of cancer cells. However, although Rho-GTPases (particularly RhoC) and Cav1 have been linked to cancer progression and metastasis, the underlying molecular mechanisms are largely unknown. To investigate the function of Cav1–Rho-GTPase interaction in metastasis, we disrupted Cav1–Rho-GTPase binding in melanoma and mammary epithelial tumor cells by overexpressing CBD, and examined the loss-of-function of RhoC in metastatic cancer cells. Cancer cells overexpressing CBD or lacking RhoC had reduced p130Cas phosphorylation and Rac1 activation, resulting in an inhibition of migration and invasion in vitro. The activity of Src and the activation of its downstream targets FAK, Pyk2, Ras and extracellular signal-regulated kinase (Erk)1/2 were also impaired. A reduction in α5-integrin expression, which is required for binding to fibronectin and thus cell migration and survival, was observed in CBD-expressing cells and cells lacking RhoC. As a result of these defects, CBD-expressing melanoma cells had a reduced ability to metastasize in recipient mice, and impaired extravasation and survival in secondary sites in chicken embryos. Our data indicate that interaction between Cav1 and Rho-GTPases (most likely RhoC but not RhoA) promotes metastasis by stimulating α5-integrin expression and regulating the Src-dependent activation of p130Cas/Rac1, FAK/Pyk2 and Ras/Erk1/2 signaling cascades