Thrombolytic removal of intraventricular haemorrhage in treatment of severe stroke: results of the randomised, multicentre, multiregion, placebo-controlled CLEAR III trial

Background: Intraventricular haemorrhage is a subtype of intracerebral haemorrhage, with 50% mortality and serious disability for survivors. We aimed to test whether attempting to remove intraventricular haemorrhage with alteplase versus saline irrigation improved functional outcome. Methods: In this randomised, double-blinded, placebo-controlled, multiregional trial (CLEAR III), participants with a routinely placed extraventricular drain, in the intensive care unit with stable, non-traumatic intracerebral haemorrhage volume less than 30 mL, intraventricular haemorrhage obstructing the 3rd or 4th ventricles, and no underlying pathology were adaptively randomly assigned (1:1), via a web-based system to receive up to 12 doses, 8 h apart of 1 mg of alteplase or 0·9% saline via the extraventricular drain. The treating physician, clinical research staff, and participants were masked to treatment assignment. CT scans were obtained every 24 h throughout dosing. The primary efficacy outcome was good functional outcome, defined as a modified Rankin Scale score (mRS) of 3 or less at 180 days per central adjudication by blinded evaluators. This study is registered with ClinicalTrials.gov, NCT00784134. Findings: Between Sept 18, 2009, and Jan 13, 2015, 500 patients were randomised: 249 to the alteplase group and 251 to the saline group. 180-day follow-up data were available for analysis from 246 of 249 participants in the alteplase group and 245 of 251 participants in the placebo group. The primary efficacy outcome was similar in each group (good outcome in alteplase group 48% vs saline 45%; risk ratio [RR] 1·06 [95% CI 0·88–1·28; p=0·554]). A difference of 3·5% (RR 1·08 [95% CI 0·90–1·29], p=0·420) was found after adjustment for intraventricular haemorrhage size and thalamic intracerebral haemorrhage. At 180 days, the treatment group had lower case fatality (46 [18%] vs saline 73 [29%], hazard ratio 0·60 [95% CI 0·41–0·86], p=0·006), but a greater proportion with mRS 5 (42 [17%] vs 21 [9%]; RR 1·99 [95% CI 1·22–3·26], p=0·007). Ventriculitis (17 [7%] alteplase vs 31 [12%] saline; RR 0·55 [95% CI 0·31–0·97], p=0·048) and serious adverse events (114 [46%] alteplase vs 151 [60%] saline; RR 0·76 [95% CI 0·64–0·90], p=0·002) were less frequent with alteplase treatment. Symptomatic bleeding (six [2%] in the alteplase group vs five [2%] in the saline group; RR 1·21 [95% CI 0·37–3·91], p=0·771) was similar. Interpretation: In patients with intraventricular haemorrhage and a routine extraventricular drain, irrigation with alteplase did not substantially improve functional outcomes at the mRS 3 cutoff compared with irrigation with saline. Protocol-based use of alteplase with extraventricular drain seems safe. Future investigation is needed to determine whether a greater frequency of complete intraventricular haemorrhage removal via alteplase produces gains in functional status

A Novel Role for Mc1r in the Parallel Evolution of Depigmentation in Independent Populations of the Cavefish Astyanax mexicanus

The evolution of degenerate characteristics remains a poorly understood phenomenon. Only recently has the identification of mutations underlying regressive phenotypes become accessible through the use of genetic analyses. Focusing on the Mexican cave tetra Astyanax mexicanus, we describe, here, an analysis of the brown mutation, which was first described in the literature nearly 40 years ago. This phenotype causes reduced melanin content, decreased melanophore number, and brownish eyes in convergent cave forms of A. mexicanus. Crosses demonstrate non-complementation of the brown phenotype in F2 individuals derived from two independent cave populations: Pachón and the linked Yerbaniz and Japonés caves, indicating the same locus is responsible for reduced pigmentation in these fish. While the brown mutant phenotype arose prior to the fixation of albinism in Pachón cave individuals, it is unclear whether the brown mutation arose before or after the fixation of albinism in the linked Yerbaniz/Japonés caves. Using a QTL approach combined with sequence and functional analyses, we have discovered that two distinct genetic alterations in the coding sequence of the gene Mc1r cause reduced pigmentation associated with the brown mutant phenotype in these caves. Our analysis identifies a novel role for Mc1r in the evolution of degenerative phenotypes in blind Mexican cavefish. Further, the brown phenotype has arisen independently in geographically separate caves, mediated through different mutations of the same gene. This example of parallelism indicates that certain genes are frequent targets of mutation in the repeated evolution of regressive phenotypes in cave-adapted species

Recollective homeostasis and the immune consequences of peritransplant depletional induction therapy

Close view of the ruins on the west side; Situated in the Rhone valley, the ancient theatre of Orange, with its 103-m-long facade, is one of the best preserved of all the great Roman theatres, built early in the 1st Century CE. It is owned by the municipality of Orange and is the home of the summer opera festival, the Chorégies d'Orange. It is one of the best preserved of all the Roman theatres in the Roman colony of Arausio (or, more specifically, Colonia Julia Firma Secundanorum Arausio: "the Julian colony of Arausio established by the soldiers of the second legion") which was founded in 40 BCE. In 1981 UNESCO declared the theatre to be a World Heritage site. Source: Wikipedia; http://en.wikipedia.org/wiki/Main_Page (accessed 7/16/2008

T-Cell Adhesion in Healthy and Inflamed Skin.

The diverse populations of tissue-resident and transitory T cells present in the skin share a common functional need to enter, traverse, and interact with their environment. These processes are largely dependent on the regulated expression of adhesion molecules, such as selectins and integrins, which mediate bidirectional interactions between immune cells and skin stroma. Dysregulation and engagement of adhesion pathways contribute to ectopic T-cell activity in tissues, leading to the initiation and/or exacerbation of chronic inflammation. In this paper, we review how the molecular interactions supported by adhesion pathways contribute to T-cell dynamics and function in the skin. A comprehensive understanding of the molecular mechanisms underpinning T-cell adhesion in inflammatory skin disorders will facilitate the development of novel tissue-specific therapeutic strategies

The distribution of cutaneous metastases correlates with local immunologic milieu.

BackgroundMetastases to the skin are found with increased frequency at certain sites, such as the scalp, but the biological factors that influence this distribution are not understood.ObjectiveWe aimed to compare the proportional frequency of metastases at various cutaneous locations with the immunologic microenvironments at those sites.MethodsWe retrospectively identified all biopsy specimens of cutaneous metastases diagnosed at our institution from 1991 to 2014 (n = 1984) and mapped their anatomic distribution while controlling for regional surface area. Using a separate, mapped cohort of normal-appearing skin samples (n = 140), we measured the density of regulatory T cells, CD4(+) effector T cells, and CD8(+) T cells by flow cytometry.ResultsPer unit surface area, cutaneous metastases arise most commonly on the head and neck, followed by the trunk, upper extremities, and lower extremities, respectively. Sites with more frequent metastases tend to contain a greater density of regulatory T cells and a lower proportion of CD8(+) T cells (P < .05).LimitationsImmunologic factors were only assessed in control tissue and were not measured from patients with metastatic disease in this correlative single-center study.ConclusionThe distribution of cutaneous metastases follows the distribution of regulatory and effector T cells in skin. Further studies are required to prove a mechanistic association between local immunologic factors and the development of cutaneous metastases

Hybrid coronary revascularization versus coronary artery bypass surgery with bilateral or single internal mammary artery grafts

Hybrid coronary revascularization (HCR) combines minimally invasive left internal mammary artery (LIMA)-left anterior descending artery (LAD) bypass with percutaneous intervention of non-LAD vessels. The purpose of this study was to compare outcomes of HCR to conventional coronary artery bypass graft (CABG) surgery with single internal mammary artery (SIMA) or bilateral internal mammary artery (BIMA) grafting. Between October 2003 and September 2013, 306 consecutive patients who underwent HCR were compared with 8254 patients who underwent CABG with SIMA (7381; 89.4%) or BIMA (873; 10.6%) at a US academic center. The primary outcome was a composite of 30-day death, myocardial infarction, and stroke (major cerebrovascular and cardiac event [MACCE]). In addition to multiple logistic and linear regression analysis, a propensity score-matched analysis was used to compare HCR with SIMA and with BIMA. The Society of Thoracic Surgeons-predicted risk of mortality was 1.6% for HCR, 2.1% for SIMA, and 1.1% for BIMA (P < .001). Factors associated with HCR use were older age, lower body mass index, history of percutaneous coronary intervention, and 2-vessel disease. In propensity-matched groups, 30-day MACCE rates were comparable (3.3% for HCR vs 1.3% for BIMA [odds ratio (OR), 2.50; P = .12] and vs 3.6% for SIMA [OR, 1.00; P = 1.00]). In-hospital complications were lower after HCR versus SIMA or BIMA (OR, 0.59; P = .033 and OR, 0.55; P = .015, respectively), as was the need for blood transfusion (OR, 0.44; P < .001 and OR, 0.57; P < .001). HCR was associated with shorter hospital stay compared with SIMA (OR, 1.28; P = .038) or BIMA (OR, 1.40; P = .006). No survival difference between matched groups was found at midterm follow-up (HCR vs SIMA: hazard ratio [HR], 0.66; 95% confidence interval [CI], 0.32-1.38; P = .66; HCR vs BIMA: HR, 1.05; 95% CI, 0.48-2.29; P = .91). HCR may represent a safe, less invasive alternative to conventional CABG in carefully selected patients, with similar short-term and midterm outcomes as CABG performed with either SIMA or BIMA graftin