A classical cellular response to hypoxia is a cessation of growth. Hypoxia-induced growth arrest differs in different cell types but is likely an essential aspect of the response to wounding and injury. An important component of the hypoxic response is the activation of the hypoxia-inducible factor 1 (HIF-1) transcription factor. Although this transcription factor is essential for adaptation to low oxygen levels, the mechanisms through which it influences cell cycle arrest, including the degree to which it cooperates with the tumor suppressor protein p53, remain poorly understood. To determine broadly relevant aspects of HIF-1 function in primary cell growth arrest, we examined two different primary differentiated cell types which contained a deletable allele of the oxygen-sensitive component of HIF-1, the HIF-1␣ gene product. The two cell types were murine embryonic fibroblasts and splenic B lymphocytes; to determine how the function of HIF-1␣ influenced p53, we also created double-knockout (HIF-1␣ null, p53 null) strains and cells. In both cell types, loss of HIF-1␣ abolished hypoxia-induced growth arrest and did this in a p53-independent fashion. Surprisingly, in all cases, cells lacking both p53 and HIF-1␣ genes have completely lost the ability to alter the cell cycle in response to hypoxia. In addition, we have found that the loss of HIF-1␣ causes an increased progression into S phase during hypoxia, rather than a growth arrest. We show that hypoxia causes a HIF-1␣-dependent increase in the expression of the cyclin-dependent kinase inhibitors p21 and p27; we also find that hypophosphorylation of retinoblastoma protein in hypoxia is HIF-1␣ dependent. These data demonstrate that the transcription factor HIF-1 is a major regulator of cell cycle arrest in primary cells during hypoxia.Mammalian cells have evolved to utilize molecular oxygen for energy production. Cells can respond differently to wide ranges of oxygen through alterations in both their metabolic states and growth rates. In recent years, several lines of evidence have indicated that hypoxia can alter cell proliferation in two distinct ways: via programmed cell death and through growth arrest. In transformed cells, hypoxia can provoke apoptosis via the p53 pathway; ultimately, this can represent a potent mechanism for the selection of p53 mutants in tumor cell populations (30,34). Nontransformed hypoxic cells, on the other hand, can undergo cell cycle arrest at the G 1 /S interface without any alteration in their long-term viability (10).It has been proposed that hypoxically induced cell cycle arrest is caused by inactivation of enzymes responsible for nucleotide synthesis, ultimately inhibiting DNA replication (19, 39). However, inhibition of nucleotide synthesis occurs only under severe hypoxia (0.01% oxygen) or anoxia, but not under moderate hypoxia (0.1 to ϳ1% oxygen) (10).In the moderately hypoxic microenvironment, various biological reactions show significant changes relative to normoxia. Numerous studies on moderate hypoxia have indicated tha...

EA at the TP has an inhibitory effect on the C-fiber afferents. The analgesic benefit observed is most likely A-delta afferent mediated. Further correlation studies in functional imaging may provide defining data for the observed analgesic mechanism.

A 59-year-old man with exertional dyspnea was referred for pre-operative evaluation before nephrectomy for a renal mass. Transthoracic echocardiography demonstrated Ebstein's anomaly and marked left ventricular (LV) trabeculation (A and B, Online Videos 1, 2, and 3). Cardiac magnetic resonance imaging confirmed LV dilation with moderately to severely depressed global systolic function. There was extensive LV trabeculation, especially in the mid-ventricle and apex, and a mildly stenotic bicuspid aortic valve (BAV) (C to E, Online Videos 4 and 5). The maximal ratio of noncompacted to compacted myocardium was 2.8, consistent with the diagnosis of LV noncompaction. The displacement of the septal tricuspid leaflet from the mitral valve annulus was 1.9 cm (0.92 cm/m 2 ).The present case illustrates an unusual combination of left-sided abnormalities in a patient with Ebstein's anomaly, including LV noncompaction, LV systolic dysfunction, and BAV. To our knowledge, this is the first reported case with this constellation of findings. LA ϭ left atrial; RA ϭ right atrial; RV ϭ right ventricular.

Patients with persistent LSVC have a significantly higher CS-CSA than those with elevated RA pressure. When dilated CS is present, a CS-EI <0.8 is 100% sensitive and specific for persistent LSVC. Thus, the CS-EI can be used in cases of dilated CS to diagnose the presence of persistent LSVC with a very high degree of certainty, and can help differentiate this congenital anomaly from RAPO.

Background: Oxidation of lipoproteins generates multiple bioactive oxidized lipids that affect atherothrombosis and endothelial dysfunction, but direct evidence of their role during therapeutic procedures is lacking. Liberated oxidized lipids may result in no-reflow phenomenon, myocardial infarction and stroke. To assess whether oxidized vasoactive lipids are released downstream from atherosclerotic plaques following percutaneous coronary and peripheral interventions we undertook a lipidomic analysis of material recovered from distal embolic protection devices from different vascular beds. Methods: The presence of specific oxidized lipids was assessed in embolized material captured by distal embolic protection devices during saphenous vein graft, carotid, renal, and superficial femoral artery interventions. Following lipid extraction, specific oxidized phospholipids (OxPL) and cholesterol esters (OxCE) were quantified in 12 filters using liquid chromatography, tandem mass spectrometry. Results: Phosphatidylcholine (PC) containing OxPL, including 1-palmitoyl-2-(5-oxovaleroyl)-sn-glycero-3-phosphocholine (POVPC), C9 aldehyde PC, E2 and F2 isoprostane PC, and hydroperoxy PC were identified in the extracted lipid portion. The major oxidized PC by mass was the C9 aldehyde PC, representing 38% of all oxidized PL. Several species of OxCE, such as aldehyde, hydroperoxide, oxide and epoxy cholesterol ester derivatives from cholesteryl linoleate and cholesteryl arachidonate, were also present. The pattern of OxPL and OxCE within filters correlated well with molecules found in various forms of oxidized LDL and did not differ significantly in different vascular beds. The presence of OxPL was also confirmed using ELISA and immunohistochemistry. Conclusions: This is the first documentation of the presence and direct release of oxidized lipids from atherosclerotic plaques during percutaneous interventions from multiple vascular beds in humans. The release of such oxidized lipids into the microcirculation may mediate some of the adverse clinical outcomes that result during these intravascular interventions.Background: An intra-coronary device becoming ЉstuckЉ is a very uncommon complication that may lead to tragic consequences such as occlusion of the artery and systemic embolism. Methods: Of 14,198 lesions in 13,188 patients who underwent PCI between 1999 and 2011, 40 Љdevice stuckЉ (0.28%) incidents occurred during PCI procedures. The incidence, outcomes and management of these Љdevice stuckЉ occurrences were evaluated. Results: The overall procedural success rate was 97.8% (13,884/14,198). The stuck devices included stents (nϭ20; 50%), wires (nϭ14; 35%), balloons (nϭ4; 10%), intra-vascular ultrasound (nϭ1; 2.5%), and rotablator burrs (nϭ1; 2.5%), respectively. Management of the complication and acute/long-term outcomes are shown in the table. Of 54 instances of Љdevice stuck,Љ 15 (37.5%) were retrieved successfully, and 7 (18%) resulted in rupture and were left in the coronary artery. Thirty-seven patients recovered in the ...