Albumin Administration in Acute Ischemic Stroke: Safety Analysis of the ALIAS Part 2 Multicenter Trial

Background

Albumin treatment of ischemic stroke was associated with cardiopulmonary adverse events in previous studies and a low incidence of intracranial hemorrhage. We sought to describe the neurological and cardiopulmonary adverse events in the ALIAS Part 2 Multicenter Trial.

Methods

Ischemic stroke patients, aged 18–83 and a baseline NIHSS ≥ 6, were randomized to treatment with ALB or saline control within 5 hours of stroke onset. Neurological adverse events included symptomatic intracranial hemorrhage, hemicraniectomy, neurological deterioration and neurological death. Cardiopulmonary adverse events included pulmonary edema/congestive heart failure, acute coronary syndromes, atrial fibrillation, pneumonia and pulmonary thromboembolism.

Results

Among 830 patients, neurological and cardiopulmonary adverse events were not differentially associated with poor outcome between ALB and saline control subjects. The rate of symptomatic intracranial hemorrhage in the first 24h was low overall (2.9%, 24/830) but more common in the ALB treated subjects (RR = 2.4, CI₉₅ 1.01–5.8). The rate of pulmonary edema/CHF in the first 48h was 7.9% (59/830) and was more common among ALB treated subjects (RR = 10.7, CI₉₅ 4.3–26.6); this complication was expected and was satisfactorily managed with mandated diuretic administration and intravenous fluid guidelines. Troponin elevations in the first 48h were common, occurring without ECG change or cardiac symptoms in 52 subjects (12.5%).

Conclusions

ALB therapy was associated with an increase in symptomatic ICH and pulmonary edema/congestive heart failure but this did not affect final outcomes. Troponin elevation occurs routinely in the first 48 hours after acute ischemic stroke.

Trial Registration

ClincalTrials.gov NCT00235495     

Epidemiology of training injuries in amateur taekwondo athletes: a retrospective cohort study

The objectives of this study were to estimate the incidence and describe the pattern and severity of training injuries in taekwondo, and to compare pattern and severity of training injuries with competition injuries. One hundred and fifty-two active Australian amateur taekwondo athletes, aged 12 years or over, completed an online survey comprising questions on training exposure and injury history over the preceding 12 months. The main outcome measures were: overall injury incidence rate per athlete-year; training injury incidence rate per athlete-year, per 1000 athlete-training-sessions, and per 1000 athlete-hours of training; injury severity; and injury proportions by anatomical region and by type of injury. Injury incidence rates were calculated with 95% confidence intervals using standard methods, while injury proportions were compared using Fisher''s exact test. The vast majority (81.5%) of taekwondo injuries in an average athlete-year occurred during training. The training injury incidence rate was estimated to be 1.6 (95% CI: 1.4, 1.9) per athlete-year, 11.8 (95% CI: 10.4, 13.4) per 1000 athlete-training-sessions, and 7.0 (95% CI: 6.1, 7.9) per 1000 athlete-hours of training. Among athletes with five or fewer injuries, the severity and injury pattern of training injuries were, by and large, the same as for competition injuries. Approximately sixty percent (60.3%) of training injuries required treatment by a health professional. Considering the burden of training injuries exceeds that of competition injuries, taekwondo governing bodies and stakeholders are encouraged to devote more efforts towards the identification of risk factors for, and prevention of, training injuries in the sport of taekwondo.     

25 hydroxy-vitamin D(3)-1alpha hydroxylase expression and activity in cultured human osteoblasts and their modulation by parathyroid hormone, estrogenic compounds and dihydrotestosterone

Human osteoblasts (hOB) produce and respond to 1,25(OH)(2)D(3) (1,25D), suggesting an autocrine/paracrine system. We therefore examined hormonal modulation of the expression and activity of 25 hydroxy-vitamin D(3)-1alpha hydroxylase (1-Ohase) in hOB. Cells from pre- and post-menopausal women or men, were treated with estrogenic compounds and 1-OHase expression and activity were measured. 1-OHase mRNA expression was highest in pre-menopausal women hOB and was increased by all hormones tested. In post-menopausal hOB all hormones except biochainin A (BA) and genistein (G) increased 1-OHase mRNA expressions to less extent. In male-derived hOB only dihydrotestosterone (DHT) and carboxy BA (cBA) increased 1-OHase mRNA expression. 1,25D production from 25(OH)D(3) had a K(m) of approximately 769-400 ng/ml (1.92-1.07 microM) and V(max) of 31.3-17.4 ng/ml (0.078-0.044 microM/60 min/5 x 10(6)cells) respectively, and was increased by all hormones except raloxifene (Ral) with higher stimulation in pre- than in post-menopausal cells. Only BA was almost five times more potent in pre- rather than post-menopausal hOBs. In male hOB only DHT and cBA increased 1,25D production whereas estradiol-17beta (E(2)) had no effect and BA decreased it. These results provide evidence for the expression of 1-OHase mRNA and production of 1,25D in hOBs, which are age and sex dependent and are hormonally modulated. The role of this local autocrine/paracrine 1,25D system in bone physiology deserves further investigation.     

The signaling lipid PI(3,5)P2 stabilizes V1–Vo sector interactions and activates the V-ATPase

Vacuolar proton-translocating ATPases (V-ATPases) are highly conserved, ATP-driven proton pumps regulated by reversible dissociation of its cytosolic, peripheral V₁ domain from the integral membrane V_o domain. Multiple stresses induce changes in V₁-V_o assembly, but the signaling mechanisms behind these changes are not understood. Here we show that certain stress-responsive changes in V-ATPase activity and assembly require the signaling lipid phosphatidylinositol 3,5-bisphosphate (PI(3,5)P₂). V-ATPase activation through V₁-V_o assembly in response to salt stress is strongly dependent on PI(3,5)P₂ synthesis. Purified V_o complexes preferentially bind to PI(3,5)P₂ on lipid arrays, suggesting direct binding between the lipid and the membrane sector of the V-ATPase. Increasing PI(3,5)P₂ levels in vivo recruits the N-terminal domain of V_o-sector subunit Vph1p from cytosol to membranes, independent of other subunits. This Vph1p domain is critical for V₁-V_o interaction, suggesting that interaction of Vph1p with PI(3,5)P₂-containing membranes stabilizes V₁-V_o assembly and thus increases V-ATPase activity. These results help explain the previously described vacuolar acidification defect in yeast fab1∆ and vac14∆ mutants and suggest that human disease phenotypes associated with PI(3,5)P₂ loss may arise from compromised V-ATPase stability and regulation.     

Nicotine Promotes Acquisition of Stem Cell and Epithelial-to-Mesenchymal Properties in Head and Neck Squamous Cell Carcinoma

The ability of nicotine to enhance the malignancy of cancer cells is known; however, the possibility that nicotine could regulate a cancer stem cell phenotype remains to be well-established. In this study we sought to determine whether long-term exposure to nicotine could promote cancer stem cell-like properties in two head and neck squamous cell carcinoma cell lines, UMSCC-10B and HN-1. Nicotine treatment induced epithelial-to-mesenchymal transition (EMT) in both cell lines by repressing E-cadherin expression, and led to the induction of stem cell markers Oct-4, Nanog, CD44 and BMI-1, which was reversed upon ectopic re-expression of E-cadherin. Nicotine-treated cells formed spheres at a higher efficiency than non-treated cells, formed larger tumors when injected into mice, and formed tumors with 4-fold greater efficiency compared to control cells when injected at limiting doses. Consistent with previous literature, nicotine-treated cells demonstrated a greater capacity for survival and also a higher tendency to invade. Comparison of microRNA profiles between nicotine and control cells revealed the upregulation of miR-9, a repressor of E-cadherin, and the downregulation of miR-101, a repressor of EZH2. Taken together, these results suggest that nicotine may play a critical role in the development of tobacco-induced cancers by regulating cancer stem cell characteristics, and that these effects are likely mediated through EMT-promoting, microRNA-mediated pathways. Further characterization of such pathways remains a promising avenue for the understanding and treatment of tobacco-related cancers.     

Reinforcer devaluation by extinction depends on the food restriction protocol

A common feature of reinforcer devaluation studies is that new learning induces the devaluation. The present study used extinction to induce new learning about the conditioned reinforcer in a heterogeneous chain schedule. Rats pressed a lever in a heterogeneous chain schedule to produce a conditioned reinforcer (light) associated with the opportunity to obtain an unconditioned reinforcer (food) by pulling a chain. The density of food reinforcement correlated with the conditioned reinforcer was varied in a comparison of continuous and variable-ratio reinforcement schedules of chain pulling; this had no noticeable effect on conditioned reinforcer devaluation produced by extinction of chain pulling. In contrast, how rats were deprived appeared to matter very much. Restricting meal duration to 1h daily produced more lever pressing during baseline training and a greater reductive effect of devaluation on lever pressing than restricting body weight to 80% of a control rat's weight, which eliminated the devaluation effect. Further analysis suggested that meal-duration restriction may have produced devaluation effects because it was more effective than weight restriction in reducing rats' body weights. Our results exposed an important limitation on the devaluation of conditioned reinforcers: slight differences in food restriction, using two commonly employed food-restriction procedures, can produce completely different interpretations of reinforcer devaluation while leaving reinforcer-based learning intact.     

Serosurveillance for foot-and-mouth disease in Mongolian gazelles (Procapra gutturosa) and livestock on the Eastern Steppe of Mongolia

Foot-and-mouth disease (FMD) is a highly contagious, viral disease that affects most ruminant and porcine species, and periodic outbreaks on Mongolia's Eastern Steppe affect Mongolian gazelles (Procapra gutturosa) and livestock. During 2005-08, we collected sera from 36 and 57 calf and adult gazelles, respectively, and from adult domestic animals sympatric with the gazelles, including 138 sheep (Ovis aries), 140 goats (Capra aegagrus hircus), 139 Bactrian camels (Camelus bactrianus), and 138 cattle (Bos taurus). Our goal was to determine whether the prevalence of the antibody to foot-and-mouth disease virus (FMDV) in gazelles declined relative to previous estimates in the absence of FMD outbreaks. Overall, 2.0% (95% CI 0.7-3.3%, n=555) of the four livestock species were antibody-positive for nonstructural proteins of FMDV (FMDV-NS), whereas 30.3% (95% CI 26.5-34.1%, n=555) had antibodies for structural proteins (i.e., vaccination-derived antibodies). Seven of 57 free-ranging gazelle calves (7.5%, 95%CI 1.6-12.4%) were FMDV-NS positive. None of 36 adult gazelles sampled in 2008 were antibody-positive for exposure to FMDV, indicating a significant decline (χ(2)=18.99; P<0.001; df=1) in antibody prevalence among gazelles from the same area during a livestock outbreak in 2001. The episodic nature of FMD outbreaks on the Eastern Steppe, Mongolia, with evidence of FMDV exposure in gazelles only during or following concurrent outbreaks in livestock, suggests that FMDV may spill over into the gazelle population during livestock outbreaks and that successful control of FMD on the Eastern Steppe requires a focus on control in livestock populations through vaccination.     

Inflammatory bowel disease serologies in ankylosing spondylitis patients: a pilot study

Introduction  

Ankylosing spondylitis (AS) and inflammatory bowel disease (IBD) share similarities and are classified as spondyloarthropathies. In IBD, anti-Saccharomyces cerevisiae antibody (ASCA), anti-I2 (associated with anti-Pseudomonas activity), anti-Escherichia coli outer membrane porin C (anti-OmpC), anti-flagellin (anti-CBir1), and antineutrophil cytoplasmic antibodies (ANCA) possess clinical significance. Because of the overlap between the two conditions, a pilot study was designed to compare the frequency of these antibodies in AS patients compared to normal controls.     

Do leucocytes reflect condition in nestling burrowing parrots Cyanoliseus patagonus in the wild?

The different leucocyte types are an important part of the immune system. Thus, they have been used in ecological studies to assess immune function and physiological stress in wild birds. It is generally assumed that increased stress and decreased condition are associated with an increase in the ratio of heterophils to lymphocytes, the H/L ratio. We studied leucocyte profiles in relation to body condition in nestling Burrowing Parrots (Cyanoliseus patagonus) in North-eastern Patagonia, Argentina. As in other wild parrots, heterophils were the most numerous leucocyte type, suggesting strong investment into innate immunity. Leucocyte profiles did not change with the age, while nestlings in better body condition increased the number of heterophils. Because the number of lymphocytes was independent of body condition, as a result we observed a positive correlation between body condition and the H/L ratio. The total number of leucocytes relative to erythrocytes increased in nestlings in better body condition, indicating a larger overall investment into immune function in well-nourished nestlings. The observed heterophilic profiles of nestling Burrowing Parrots together with the positive relationship between H/L ratio and body condition may indicate a favoured investment in a robust innate immunity that reduces the risk of infection taking hold in these long-lived birds.