Usefulness of anticoagulant therapy in the prevention of embolic complications of atrial fibrillation

The medical records of 254 patients with atrial fibrillation were reviewed to determine the incidence of embolic events in relation to type of cardiovascular disease, duration of atrial fibrillation, and use of anticoagulants. During a total follow-up of 833 patient-years in atrial fibrillation, there were 32 instances of systemic embolism: 21 involved the cerebral circulation and 11 were extracerebral. Thirty of these events occurred during 549 patient-years of follow-up without anticoagulation therapy (5.46 of 100 patient-years), while only two embolic events occurred during 284 patient-years on anticoagulants (0.7 of 100 patient-years). Thus, the incidence of embolism was eight times more frequent during the unanticoagulated period of observation in atrial fibrillation (p less than 0.002). The incidence of embolism during follow-up without anticoagulants was the same regardless of the presence or absence of mitral valve disease and regardless of whether atrial fibrillation was chronic or paroxysmal. The rate of serious hemorrhagic complications on anticoagulants was acceptably low (2.11 of 100 patient-years). We conclude that in this study population anticoagulant therapy reduced the risk of embolic complications of atrial fibrillation. The results also indicate that the use of anticoagulants should not be limited to patients with atrial fibrillation due to mitral valve disease.     

Biopharmaceutical Characterization of Nebulized Antimicrobial Agents in Rats: 2. Colistin

The purpose of this study was to investigate the pharmacokinetic properties of colistin following intrapulmonary administration of colistin sulfate in rats. Colistin was infused or delivered in nebulized form at a dose of 0.35 mg/kg of body weight in rats, and plasma drug concentrations were measured for 4 h after administration. Bronchoalveolar lavages (BAL) were also conducted at 0.5, 2, and 4 h after intravenous (i.v.) administration and administration via nebulized drug to estimate epithelial lining fluid (ELF) drug concentrations. Unbound colistin plasma concentrations at distribution equilibrium (2 h postdosing) were almost identical after i.v. infusion and nebulized drug inhalation. ELF drug concentrations were undetectable in BAL samples after i.v. administration, but they were about 1,800 times higher than unbound plasma drug levels at 2 h and 4 h after administration of the nebulized drug. Simultaneous pharmacokinetic modeling of plasma and ELF drug concentrations was performed with a model characterized by a fixed physiological volume of ELF (V_ELF), a passive diffusion clearance (Q_ELF) between plasma and ELF, and a nonlinear influx transfer from ELF to the central compartment, which was assessed by reducing the nebulized dose of colistin by 10-fold (0.035 mg kg⁻¹). The k_m was estimated to be 133 μg ml⁻¹, and the V_{max, in}-to-K_m ratio was equal to 2.5 × 10⁻³ liter h⁻¹ kg⁻¹, which was 37 times higher than the Q_ELF (6.7 × 10⁻⁵ liter h⁻¹ kg⁻¹). This study showed that with the higher ELF drug concentrations after administration via nebulized aerosol than after intravenous administration, for antibiotics with low permeability such as colistin, nebulization offers a real potential over intravenous administration for the treatment of pulmonary infections.     

Assessment of Oncologic Control Obtained After Open Versus Laparoscopic Nephroureterectomy for Upper Urinary Tract Urothelial Carcinomas (UUT-UCs): Results from a Large French Multicenter Collaborative Study

Background

The purpose of this study was to compare the postsurgical survival of UUT-UC patients treated with ONU and LNU.

Methods

Using a multi-institutional, national, retrospective database, we identified patients with UUT-UC who underwent radical nephroureterectomy by open access (ONU) or by the minimally invasive alternative (LNU). Survival curves were estimated using Kaplan-Meier method. A multivariate Cox model was used to evaluate the association between surgical approach and disease recurrence.

Results

Overall, 609 patients were included (ONU?=?459 and LNU?=?150). The median age was 69.8?years (range 61.9?C76), and the male-to-female ratio was 2:1. Postoperative complications occurred in 80 patients, with no significant difference between ONU and LNU on the whole (P?=?0.64). The median follow-up was 27?months. There was no difference between the 2 procedures in the 5-year CSS or 5-year RFS. Moreover, the 5-year CSS (P?=?0.053) and 5-year RFS (P?=?0.9) for cases with locally advanced disease (pT3/pT4) were similar between ONU and LNU. In the multivariate analysis, the surgical procedure used was not found to be associated with survival. The main limitation of the study is its retrospective design, which is the result of the rarity of the disease.

Conclusions

There is no evidence that oncological outcomes for LNU are inferior to those for open surgery, provided that the appropriate precautionary measures are taken.     

Consistent directions of effect for established type 2 diabetes risk variants across populations: the population architecture using Genomics and Epidemiology (PAGE) Consortium

Common genetic risk variants for type 2 diabetes (T2D) have primarily been identified in populations of European and Asian ancestry. We tested whether the direction of association with 20 T2D risk variants generalizes across six major racial/ethnic groups in the U.S. as part of the Population Architecture using Genomics and Epidemiology Consortium (16,235 diabetes case and 46,122 control subjects of European American, African American, Hispanic, East Asian, American Indian, and Native Hawaiian ancestry). The percentage of positive (odds ratio [OR] >1 for putative risk allele) associations ranged from 69% in American Indians to 100% in European Americans. Of the nine variants where we observed significant heterogeneity of effect by racial/ethnic group (P(heterogeneity) < 0.05), eight were positively associated with risk (OR >1) in at least five groups. The marked directional consistency of association observed for most genetic variants across populations implies a shared functional common variant in each region. Fine-mapping of all loci will be required to reveal markers of risk that are important within and across populations.     

A role for anterior thalamic nuclei in affective cognition: Interaction with environmental conditions

Damage to anterior thalamic nuclei (ATN) is a well‐known cause of diencephalic pathology that produces a range of cognitive deficits reminiscent of a hippocampal syndrome. Anatomical connections of the ATN also extend to cerebral areas that support affective cognition. Enriched environments promote recovery of declarative/relational memory after ATN lesions and are known to downregulate emotional behaviors. Hence, the performance of standard‐housed and enriched ATN rats in a range of behavioral tasks engaging affective cognition was compared. ATN rats exhibited reduced anxiety responses in the elevated plus maze, increased activity and reduced corticosterone responses when exploring an open field, and delayed acquisition of a conditioned contextual fear response. ATN rats also exhibited reduced c‐Fos and phosphorylated cAMP response element‐binding protein (pCREB) immunoreactivity in the hippocampal formation and the amygdala after completion of the contextual fear test. Marked c‐Fos hypoactivity and reduced pCREB levels were also evident in the granular retrosplenial cortex and, to a lesser extent, in the anterior cingulate cortex. Unlike standard‐housed ATN rats, enriched ATN rats expressed virtually no fear of the conditioned context. These results show that the ATN regulate affective cognition and that damage to this region may produce markedly different behavioral effects as a function of environmental housing conditions. © 2013 Wiley Periodicals, Inc.     

Targetable activating mutations are very frequent in GCB and ABC diffuse large B‐cell lymphoma

Diffuse large B cell lymphoma (DLBCL) is an aggressive and heterogeneous malignancy that can be divided in two major subgroups, germinal center B‐cell‐like (GCB) and activated B‐cell‐like (ABC). Activating mutations of genes involved in the BCR and NF‐κB pathways (CD79A, CD79B, MYD88, and CARD11) or in epigenetic regulation (EZH2) have been recently reported, preferentially in one of the two DLBCL subtypes. We analyzed the mutational status of these five recurrently mutated genes in a cohort of 161 untreated de novo DLBCL. Overall, 93 mutations were detected, in 61 (38%) of the patients. The L265P MYD88 mutation was the most frequent MYD88 variant (n = 18), observed exclusively in the ABC subtype. CD79A/CD79B ITAM domains were targeted in ABC DLBCL (12/77; 16%), whereas CARD11 mutations were equally distributed in the two subtypes. The EZH2 Y641 substitution was found almost exclusively in the GCB subgroup (15/62; 24%). Twenty cases (12%) displayed two activating mutations, including the most frequent CD79/MYD88 variants combination (n = 8) which is observed exclusively in the ABC subtype. When considering only ABC DLBCL patients treated by rituximab plus chemotherapy, the presence of an activating NF‐κB mutation was associated with an unfavorable outcome (3‐years OS 26% for mutated cases versus 67% for the cases without mutations, P = 0.0337). Our study demonstrates that activating and targetable mutations are observed at a very high frequency in DLBCL at the time of diagnosis, indicating that sequencing of a limited number of genes could help tailor an optimal treatment strategy in DLBCL. © 2013 Wiley Periodicals, Inc.     

The burden of disease in Spain: results from the global burden of disease study 2010

Background

We herein evaluate the Spanish population’s trends in health burden by comparing results of two Global Burden of Diseases, Injuries, and Risk Factors Studies (the GBD studies) performed 20 years apart.

Methods

Data is part of the GBD study for 1990 and 2010. We present results for mortality, years of life lost (YLLs), years lived with disability, and disability-adjusted life years (DALYs) for the Spanish population. Uncertainty intervals for all measures have been estimated.

Results

Non-communicable diseases accounted for 3,703,400 (95% CI 3,648,270–3,766,720) (91.3%) of 4,057,400 total deaths, in the Spanish population. Cardiovascular and circulatory diseases were the main cause of mortality among non-communicable diseases (34.7% of total deaths), followed by neoplasms (27.1% of total deaths). Neoplasms, cardiovascular and circulatory diseases, and chronic respiratory diseases were the top three leading causes for YLLs. The most important causes of DALYs in 2010 were neoplasms, cardiovascular and circulatory diseases, musculoskeletal disorders, and mental and behavioral disorders.

Conclusions

Mortality and disability in Spain have become even more linked to non-communicable diseases over the last years, following the worldwide trends. Cardiovascular and circulatory diseases, neoplasms, mental and behavioral disorders, and neurological disorders are the leading causes of mortality and disability. Specific focus is needed from health care providers and policy makers to develop health promotion and health education programs directed towards non-communicable disorders.