Hypertensive extracorporeal limb perfusion (HELP): A new technique for managing critical lower limb ischemia

ObjectiveThe concept of repeatedly connecting an extracorporeal blood pump to produce pancycle suprasystolic inflow pressures to ischemic limbs is introduced. Balloon catheters allow for limb isolation from the systemic circulation. In the acute phase, it is assumed that pressure is proportion to flow (Poiseuille's Law) and in the chronic phase that collateral growth is related to endothelial shear stress and wall tension. The primary objective was to establish that increased flow could be achieved through collateral circulation in animals and in man with extracorporeal limb hyperperfusion. The second objective was to develop and test an arterial access system capable of intermittent regional hyperperfusion similar in concept to intermittent hemodialysis. Finally, to demonstrate the translocation of these concepts into humans facing major limb amputation where all standard treatment options had been exhausted.MethodsTwelve sheep (6 hyperperfusion and 6 controls) were attached to a cardiac vortex pump and perfused at 200 mm Hg pancycle with the superficial femoral artery doubly ligated and isolated from the systemic circulation with a balloon catheter. Pressure transducers measured carotid and distal femoral pressures and the carotid-femoral index was calculated. To allow hyperperfusion to be repeated transcutaneously, a peripheral access system (PAS [Allvascular, St Leonards, New South Wales, Australia]) was constructed. This device was implanted in the common carotid artery in 8 sheep and opened approximately 3 days a week for continuous arterial access up to 37 days for 67 openings. To demonstrate these principles in humans, 3 patients with critically ischemic limbs were hyperperfused intermittently. Digital thermography compared the other limb as controls and provided objective evidence of the vascular changes.ResultsThe mean carotid-femoral index was 0.6 ± 0.01 for controls compared with 1.1 ± 0.28 for the hyperperfusion group (P < .001). The collateral flow was superior to normal flow (ie, with the superficial femoral not occluded). Continuous access to the carotid arterial tree via the access device was 25.3 ± 8.8 days with 5 of 8 devices open for the entire observational period (maximum 37 days). The human ischemic limbs were hyperperfused at 2-4 times the mean arterial pressure producing 3-6 times an increase in pump flow measurements intermittently for 53 ± 16 hours. The clinical findings of rest pain, paresthesia, capillary return, and movement showed dramatic improvement as did thermographic emissions. Major amputation was avoided in the cases presented.ConclusionBlood flow through collaterals can be very significantly augmented by connection to an extracorporeal pump with isolation from the systemic circulation. The pancycle hyperperfusion can be safely repeated by implantation of an arterial access device. In the longer term, there is evidence of collateral development. When amputation is the only alternative, hypertensive extracorporeal limb perfusion should be considered

The Antarctic Submillimeter Telescope and Remote Observatory (AST/RO)

AST/RO, a 1.7 m diameter telescope for astronomy and aeronomy studies at wavelengths between 200 and 2000 microns, was installed at the South Pole during the 1994-1995 Austral summer. The telescope operates continuously through the Austral winter, and is being used primarily for spectroscopic studies of neutral atomic carbon and carbon monoxide in the interstellar medium of the Milky Way and the Magellanic Clouds. The South Pole environment is unique among observatory sites for unusually low wind speeds, low absolute humidity, and the consistent clarity of the submillimeter sky. Four heterodyne receivers, an array receiver, three acousto-optical spectrometers, and an array spectrometer are installed. A Fabry-Perot spectrometer using a bolometric array and a Terahertz receiver are in development. Telescope pointing, focus, and calibration methods as well as the unique working environment and logistical requirements of the South Pole are described.Comment: 57 pages, 15 figures. Submitted to PAS

Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition)1.

In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monitoring autophagy in different organisms. Despite numerous reviews, there continues to be confusion regarding acceptable methods to evaluate autophagy, especially in multicellular eukaryotes. Here, we present a set of guidelines for investigators to select and interpret methods to examine autophagy and related processes, and for reviewers to provide realistic and reasonable critiques of reports that are focused on these processes. These guidelines are not meant to be a dogmatic set of rules, because the appropriateness of any assay largely depends on the question being asked and the system being used. Moreover, no individual assay is perfect for every situation, calling for the use of multiple techniques to properly monitor autophagy in each experimental setting. Finally, several core components of the autophagy machinery have been implicated in distinct autophagic processes (canonical and noncanonical autophagy), implying that genetic approaches to block autophagy should rely on targeting two or more autophagy-related genes that ideally participate in distinct steps of the pathway. Along similar lines, because multiple proteins involved in autophagy also regulate other cellular pathways including apoptosis, not all of them can be used as a specific marker for bona fide autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field

The genetic architecture of the human cerebral cortex

The cerebral cortex underlies our complex cognitive capabilities, yet little is known about the specific genetic loci that influence human cortical structure. To identify genetic variants that affect cortical structure, we conducted a genome-wide association meta-analysis of brain magnetic resonance imaging data from 51,665 individuals. We analyzed the surface area and average thickness of the whole cortex and 34 regions with known functional specializations. We identified 199 significant loci and found significant enrichment for loci influencing total surface area within regulatory elements that are active during prenatal cortical development, supporting the radial unit hypothesis. Loci that affect regional surface area cluster near genes in Wnt signaling pathways, which influence progenitor expansion and areal identity. Variation in cortical structure is genetically correlated with cognitive function, Parkinson's disease, insomnia, depression, neuroticism, and attention deficit hyperactivity disorder

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Incompetent venous valves: Ultrasound imaging and exo-stent repair

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Popliteal vein compression syndrome pathophysiology and correlation with popliteal compartment pressures

Objective: The link between obesity and popliteal vein compression syndrome (PVCS) has been documented, but the pathophysiological mechanism is unclear. The aim of this study is to understand the pathogenesis of PVCS by assessing popliteal compartment pressures (PCP). Methods: Twenty-three limbs (15 patients) were included. Eleven limbs were ultrasonically diagnosed with PVCS and underwent popliteal vein decompression. The control group consisted of 12 limbs with functional popliteal artery entrapment. Perioperatively, PCP measurements were obtained. The body mass index (BMI) was calculated and the clinical symptoms were documented (CEAP). Results: The median BMI for the PVCS group was 32 (range, 26-45.8) compared with 28 (range, 19-31) for the control group (P = .05). In PVCS, the popliteal vein internal diameter was 9.4 mm (range, 8.0-20.0 mm) upon knee flexion, compared with 0 mm (range, 0.0-0.1 mm) upon knee extension. Upon knee flexion, there was no difference in pressure (PVCS 10.0 [range, 4-20] vs control 11.5 [range, 3-22]; P = .95). Upon knee extension, the median PCP in the PVCS group was 53 cm H₂O (range, 38-76 cm H₂O) compared with 26 cm H2O (range, 17-43 cm H₂O) in the control group (P < .001). Conclusions: PVCS is associated with high popliteal compartment pressures compared with controls. The pathophysiology of popliteal obstruction, in the absence of anatomical abnormalities, is related to an increase in popliteal compartment pressure while standing due an increase of the popliteal fat pad, related to high BMI.6 page(s