EORTC (30885) randomised phase III study with recombinant interferon alpha and recombinant interferon alpha and gamma in patients with advanced renal cell carcinoma. The EORTC Genitourinary Group.

In the treatment of renal cell carcinoma both complete (CRs) and partial remissions (PRs) have been obtained using recombinant (r) interferon alpha (IFN-alpha), with response rates ranging from 0 to 31% (mean 16%). rIFN-gamma is a potent immunostimulating agent, but the clinical experience of its use is limited and results are conflicting. In a phase II study with the combination of rIFN-alpha 2c (Boehringer Ingelheim) and rIFN-gamma (Genentech, supplied by Boehringer Ingelheim) in 31 eligible patients, a response rate of 25% was recorded. Based on this observation a randomised phase III study was initiated to investigate the possible advantage of the addition rIFN-gamma to rIFN-alpha 2c treatment. Treatment consisted of rIFN-alpha 2c 30 micrograms m-2 = 10 x 10(6) IU m-2 s.c. twice weekly in arm A and the same dose of rIFN-alpha combined with rIFN-gamma 100 micrograms m-2 = 2 x 10(6) IU m-2 in arm B. Eligibility criteria included documented progression of disease; patients with bone lesions only and overt central nervous system metastases were excluded. Between November 1988 and September 1990, 102 patients were entered into the study. An interim analysis showed a response in 7/53 (13%) patients (two CRs and five PRs) in the rIFN-alpha 2c monotherapy arm and in 2/45 (4%) (one CR and one PR) patients in the combination arm. This difference was not statistically significant (P = 0.17). The probability of missing an eventual 10% advantage for the combination is 0.001. The numbers are insufficient to rule out a negative effect of the addition of rIFN-gamma. The dose intensity of IFN-alpha 2c for the two treatment arms was the same. The addition of rIFN-gamma does not improve the response rate of rIFN-alpha 2c monotherapy. A possible detrimental effect cannot be excluded

Transcriptome analysis reveals the contribution of oligodendrocyte and radial glia-derived cues for maintenance of microglia identity

Microglia are increasingly being recognized as druggable targets in neurodegenerative disorders, and good in vitro models are crucial to address cell biological questions. Major challenges are to recapitulate the complex microglial morphology and their in vivo transcriptome. We have therefore exposed primary microglia from adult rhesus macaques to a variety of different culture conditions including exposure to soluble factors as M-CSF, IL-34, and TGF-β as well as serum replacement approaches, and compared their morphologies and transcriptomes to those of mature, homeostatic in vivo microglia. This enabled us to develop a new, partially serum-free, monoculture protocol, that yields high numbers of ramified cells. We also demonstrate that exposure of adult microglia to M-CSF or IL-34 induces similar transcriptomes, and that exposure to TGF-β has much less pronounced effects than it does on rodent microglia. However, regardless of culture conditions, the transcriptomes of in vitro and in vivo microglia remained substantially different. Analysis of differentially expressed genes inspired us to perform 3D-spherical coculture experiments of microglia with oligodendrocytes and radial glia. In such spheres, microglia signature genes were strongly induced, even in the absence of neurons and astrocytes. These data reveal a novel role for oligodendrocyte and radial glia-derived cues in the maintenance of microglial identity, providing new anchor points to study microglia in health and disease

A database of whole-body action videos for the study of action, emotion, and untrustworthiness

We present a database of high-definition (HD) videos for the study of traits inferred from whole-body actions. Twenty-nine actors (19 female) were filmed performing different actions—walking, picking up a box, putting down a box, jumping, sitting down, and standing and acting—while conveying different traits, including four emotions (anger, fear, happiness, sadness), untrustworthiness, and neutral, where no specific trait was conveyed. For the actions conveying the four emotions and untrustworthiness, the actions were filmed multiple times, with the actor conveying the traits with different levels of intensity. In total, we made 2,783 action videos (in both two-dimensional and three-dimensional format), each lasting 7 s with a frame rate of 50 fps. All videos were filmed in a green-screen studio in order to isolate the action information from all contextual detail and to provide a flexible stimulus set for future use. In order to validate the traits conveyed by each action, we asked participants to rate each of the actions corresponding to the trait that the actor portrayed in the two-dimensional videos. To provide a useful database of stimuli of multiple actions conveying multiple traits, each video name contains information on the gender of the actor, the action executed, the trait conveyed, and the rating of its perceived intensity. All videos can be downloaded free at the following address: http://www-users.york.ac.uk/~neb506/databases.html. We discuss potential uses for the database in the analysis of the perception of whole-body actions

Right ventricular peak systolic longitudinal strain is a sensitive marker for right ventricular deterioration in adult patients with tetralogy of Fallot

The aim of this study was to evaluate the feasibility of right ventricular (RV) longitudinal peak systolic strain (LPSS) assessment for the follow-up of adult patients with corrected tetralogy of Fallot (TOF). Adult patients (n = 18) with corrected TOF underwent echocardiography and CMR twice with a time interval of 4.2 ± 1.7 years. RV performance was derived from CMR, and included RV volumes and ejection fraction (EF). LPSS was calculated globally (GLPSS) and in the RV free wall (LPSS FW), with echocardiographic speckle-tracking strain-analysis. Baseline (G)LPSS values were compared between patients and healthy controls; the relation between (G)LPSS and CMR parameters was evaluated and the changes in (G)LPSS and CMR parameters during follow-up were compared. GLPSS and LPSS FW were significantly reduced in patients as compared to controls (−14.9 ± 0.7% vs. −21.6 ± 0.9% and −15.5 ± 0.9% vs. −22.7 ± 1.5%, P < 0.01). Moderate agreement between LPSS and CMR parameters was observed. RV EF remained unchanged during follow-up, whereas GLPSS and LPSS FW demonstrated a significant reduction. RVEF showed a 1% increase, whereas GLPSS decreased by 14%, and LPSS FW by 27%. RV LPSS is reduced in TOF patients as compared to controls; during follow-up RV EF remained unchanged whereas LPSS decreased suggesting that RV LPSS may be a sensitive marker to detect early deterioration in RV performance

Intravital correlated microscopy reveals differential macrophage and microglial dynamics during resolution of neuroinflammation

Many brain diseases involve activation of resident and peripheral immune cells to clear damaged and dying neurons. Which immune cells respond in what way to cues related to brain disease, however, remains poorly understood. To elucidate these in vivo immunological events in response to brain cell death we used genetically targeted cell ablation in zebrafish. Using intravital microscopy and large-scale electron microscopy, we defined the kinetics and nature of immune responses immediately following injury. Initially, clearance of dead cells occurs by mononuclear phagocytes, including resident microglia and macrophages of peripheral origin, whereas amoeboid microglia are exclusively involved at a later stage. Granulocytes, on the other hand, do not migrate towards the injury. Remarkably, following clearance, phagocyte numbers decrease, partly by phagocyte cell death and subsequent engulfment of phagocyte corpses by microglia. Here, we identify differential temporal involvement of microglia and peripheral macrophages in clearance of dead cells in the brain, revealing the chronological sequence of events in neuroinflammatory resolution. Remarkably, recruited phagocytes undergo cell death and are engulfed by microglia. Because adult zebrafish treated at the larval stage lack signs of pathology, it is likely that this mode of resolving immune responses in brain contributes to full tissue recovery. Therefore, these findings suggest that control of such immune cell behavior could benefit recovery from neuronal damage.</p

Per-operative stent placement in the right pulmonary artery; a hybrid technique for the management of pulmonary artery branch stenosis at the time of pulmonary valve replacement in adult Fallot patients

After having undergone surgical correction at an early age, many patients with tetralogy of Fallot develop long-term complications including progressive pulmonary regurgitation and peripheral pulmonary stenosis. A high percentage of these patients need to undergo a second operation in their adolescence or early adulthood. If simultaneous treatment of both pulmonary regurgitation and peripheral pulmonary stenosis is warranted, a complete surgical approach has several disadvantages. We describe four cases of Fallot patients with severe pulmonary regurgitation and peripheral pulmonary stenosis who were treated using a hybrid approach involving surgical implantation of a pulmonary homograft and peroperative stenting of the pulmonary artery

Passive tracer transport relevant to the TRACE A experiment

This paper explores some of the mechanisms governing the accumulation of passive tracers over the tropical southern Atlantic Ocean during the northern hemisphere fall season. There has been a pioneering observation regarding ozone maxima over the South Atlantic during austral spring. The understanding of the formation of this maxima has been the prime motivation for this study. Using a global model as a frame of reference, we have carried out three kinds of experiments during the period of the Transport and Atmospheric Chemistry Near the Equator-Atlantic (TRACE A) project of 1992. The first of these is a simple advection of total ozone (a passive tracer) in time using the Florida State University global spectral model. Integration over the period of roughly 1 week showed that the model quite closely replicates the behavior of the observed total ozone from the total ozone mapping spectrometer (TOMS). This includes many of the changes in the features of total ozone over the tropical and subtropical region of the southern Atlantic Ocean. These studies suggest a correlation of 0.8 between the observed ozone over this region and ozone modeled from “dynamics alone,” i.e., without recourse to any photochemistry. The second series of experiments invoke sustained sources of a tracer over the biomass burn region of Africa and Brazil. Furthermore, sustained sources were also introduced in the active frontal “descending air” region of the southern hemisphere and over the Asian monsoon's east-west circulation. These experiments strongly suggest that air motions help to accumulate tracer elements over the tropical southern Atlantic Ocean. A third series of experiments address what may be required to improve the deficiencies of the vertical stratification of ozone predicted by the model over the flight region of the tropical southern Atlantic during TRACE A. Here we use the global model to optimally derive plausible accumulation of burn elements over the fire count regions of Brazil and Africa to provide passive tracer advections to closely match what was observed from reconnaissance aircraft-based measurements of ozone over the tropical southern Atlantic Ocean.Engineering and Applied Science