To determine whether pulmonary venous flow and mitral inflow measured by transesophageal pulsed Doppler echocardiography can be used to estimate mean left atrial pressure (LAP), we prospectively studied 47 consecutive patients undergoing cardiovascular surgery. We correlated Doppler variables of pulmonary venous flow and mitral inflow with simultaneously obtained mean LAP and changes in pressure measured by left atrial or pulmonary artery catheters. Among the pulmonary venous flow variables, the systolic fraction (i.e., the systolic velocity-time integral expressed as a fraction of the sum of systolic and early diastolic velocity-time integrals) correlated most strongly with mean LAP (r= -0.88). Of the mitral inflow variables, the ratio of peak early diastolic to peak late diastolic mitral flow velocity correlated most strongly with mean LAP (r=0.43), but this correlation was not as strong as that with the systolic fraction of pulmonary venous flow. Similarly, changes in the systolic fraction correlated more strongly with changes in mean LAP (r= -0.78) than did changes in the ratio of peak early diastolic to peak late diastolic mitral inflow velocity (r= 0.68). We conclude that in the surgical setting observed, pulmonary venous flow from transesophageal pulsed Doppler echocardiography can be used to estimate mean LAP. This technique may provide a rapid, simple, and relatively noninvasive means of gauging this variable in patients undergoing intraoperative transesophageal echocardiography. (Circulation 1990;82:1127-1139 In patients with heart disease, left ventricular diastolic performance is often clinically evaluated by using a flow-directed balloon-tipped catheter to measure pulmonary capillary wedge pressure (PCWP)

To determine the feasibility of noninvasive determination of right ventricular systolic pressure (RVSP) during a graded-exercise protocol, saline contrast-enhanced Doppler echocardiography of tricuspid insufficiency was performed in 36 patients with chronic lung disease and 12 normal controls. In the patients with chronic pulmonary disease, symptom-limited, incremental supine bicycle exercise and pulse oximetry were performed on and off high-flow oxygen. Technically adequate Doppler studies were initially obtained in 20 patients (56%) at rest and 14 (39%) on exercise; these numbers increased to 33 (92%) and 32 (89%), respectively, after enhancement with agitated saline (both p less than 0.001). In 10 patients with chronic lung disease who had simultaneous hemodynamic monitoring during exercise, the correlation between Doppler and catheter measurements of pulmonary artery systolic pressure was close (r = 0.98). Among controls, RVSP increased from 22 +/- 4 at rest (mean +/- SD) to 31 +/- 7 mm Hg at peak exercise. In patients with chronic lung disease, RVSP increased from 46 +/- 20 to 83 +/- 30 mm Hg (both p less than 0.001 vs. controls). Despite normal resting values for RVSP in 28% of study patients, nearly all showed abnormal increases in RVSP during supine bicycle exercise. Increases in RVSP during exercise were greatest in patients who showed oxyhemoglobin desaturation. The short-term administration of oxygen significantly blunted the increase in RVSP during exercise. Saline contrast-enhanced Doppler evaluation of tricuspid insufficiency seems a potentially valuable noninvasive method of determining the exercise response of RVSP in patients with chronic pulmonary disease.

Acitretin does not appear to cause significant long-term side effects at low doses; the implications for thousands of patients are that use of this medication can be continued for long periods of time with routine monitoring.

The calcium-sensing receptor (CaSR) drives essential calcium ion (Ca 2þ ) and E-cadherin-mediated processes in the epidermis, including differentiation, cell-to-cell adhesion, and epidermal barrier homeostasis in cells and in young adult mice. We now report that decreased CaSR expression leads to impaired Ca 2þ signal propagation in aged mouse (aged >22 months) epidermis and human (aged >79 years, donor age) keratinocytes. Baseline cytosolic Ca 2þ concentrations were higher, and capacitive Ca 2þ entry was lower in aged than in young keratinocytes. As in Casr-knockout mice ( Epid CaSR e/e ), decreased CaSR expression led to decreased E-cadherin and phospholipase C-g expression and to a compensatory upregulation of STIM1. Pretreatment with the CaSR agonist N-(3-[2-chlorophenyl]propyl)-(R)-alpha-methyl-3-methoxybenzylamine normalized Ca 2þ propagation and E-cadherin organization after experimental wounding. These results suggest that age-related defects in CaSR expression dysregulate normal keratinocyte and epidermal Ca 2þ signaling, leading to impaired E-cadherin expression, organization, and function. These findings show an innovative mechanism whereby Ca 2þ -and Ecadherin-dependent functions are impaired in aging epidermis and suggest a new therapeutic approach by restoring CaSR function.

Background Ceramide kinase-like protein (CERKL) was originally described in retinal tissue. CERKL has been shown to protect cells from oxidative stress, and mutations in CERKL underlie the inherited disease retinitis pigmentosa. CERKL expression maintains cellular sphingolipids via an unknown mechanism. Objectives To determine whether CERKL is expressed in epidermis and cutaneous squamous cell carcinoma (cSCC) and whether CERKL expression affects cSCC sphingolipid metabolism and susceptibility to oxidative stress. Methods CERKL expression was determined by RNA-Seq, quantitative polymerase chain reaction and immunohistochemistry. CERKL was knocked down in cSCC cells using small interfering RNA. Sphingolipid content was analysed by liquid chromatography-mass spectrometry. Oxidative stress was induced by treatment with H 2 O 2 , and apoptosis was measured using flow cytometry to determine annexin V binding. Results CERKL mRNA and protein are highly expressed in actinic keratosis and cSCC in comparison with normal epidermis. CERKL is also expressed in metabolically active epithelial cells in normal hair bulbs and sebaceous glands. CERKL knockdown in cultured cSCC cells reduces cellular sphingolipid content and enhances susceptibility to oxidative stress. Conclusions These findings suggest that CERKL may be important in cSCC progression and could lead to novel strategies for prevention and treatment of cSCC.What is already known about this topic?• Ceramide kinase-like protein (CERKL) is thought to protect cells from oxidative stress, and mutations in CERKL underlie the inherited disease retinitis pigmentosa.What does this study add?• We found that CERKL is upregulated in cutaneous squamous cell carcinoma (cSCC) compared with normal epidermis.• CERKL protects cSCC cells from oxidative stress and maintains cellular sphingolipids.