Impact of GRIK4 gene polymorphisms on cognitive dysfunction in patients with major depression.

An increasing body of research has focused on the functions of the glutamate receptor ionotropic kainate 4 (GRIK4) gene in treatment for depression, memory, as well as neurodegenerative diseases. It is widely recognized that major depressive disorder (MDD) patients often display cognitive dysfunctions, which do not strictly correlate with the severity of depressive symptoms, and in some individuals persist after clinical remission. However, little is known regarding the particular role of GRIK4 in cognitive functions of patients suffering from a MDD. The current study therefore sought to examine the impact of GRIK4 polymorphism on cognitive functions in MDD patients. A total of 217 MDD patients participated in this study. Their depressive severity was determined with the 17-item Hamilton Depression Rating Scale, and cognitive functions were evaluated using the Stroop Neuropsychological Screening Test, tests of visual reproduction and immediate logical memory, and the verbal fluency test (VFT). All patients were genotyped to determine GRIK4 polymorphisms. Results of VFT revealed statistical differences among all single-nucleotide polymorphism (SNP) genotypes. In the Stroop-color-word test, only rs6589847 was discovered to be statistically different. No significant difference was found in the Stroop-color task scores, the visual reproduction test, or the immediate logical memory test. GRIK4 polymorphism exerted a significant effect on long-term memory retrieval and selective attention, but did not affect immediate memory.

[Screening of microRNAs targeting Notch signaling pathway implicated in inner ear development and the role of microRNA-384-5p].

Objective: To screen the key microRNAs targeting Notch signaling pathway in inner ear and investigate its potential regulating function. Methods: The interaction network and the Core-Notch network, involved with key genes in Notch signal pathway and differential-expressed microRNAs in inner ear, were constructed by bioinformatics methods. The important microRNAs in regulating Notch signaling pathway were screened via topological and GO analysis, followed by in vivo and in vitro investigation. Results: MiRNA-384-5p was identified as a key regulator specifically expressed in mouse brain and inner ear, which could down-regulate Notch1. The Notch1 expression was found significantly down-regulated in miRNA-384-5p-mimic-transfected HeLa cells. The dual-luciferase reporter gene assay further confirmed the effect of miRNA-384-5p on the down-regulation of Notch1 and Dll4 in Notch signaling pathway. Conclusions: The Core-Notch network is constructed to screen microRNAs implicated in inner ear development, and miRNA-384-5p is screened and verified to be target-regulating the Notch signaling pathway, which could be the potential target in the regeneration of impaired hair cells.

Forward error correction supported 150 Gbit/s error-free wavelength conversion based on cross phase modulation in silicon.

We build a forward error correction (FEC) module and implement it in an optical signal processing experiment. The experiment consists of two cascaded nonlinear optical signal processes, 160 Gbit/s all optical wavelength conversion based on the cross phase modulation (XPM) in a silicon nanowire and subsequent 160 Gbit/s-to-10 Gbit/s demultiplexing in a highly nonlinear fiber (HNLF). The XPM based all optical wavelength conversion in silicon is achieved by off-center filtering the red shifted sideband on the CW probe. We thoroughly demonstrate and verify that the FEC code operates correctly after the optical signal processing, yielding truly error-free 150 Gbit/s (excl. overhead) optically signal processed data after the two cascaded nonlinear processes.

Tamoxifen metabolite concentrations, CYP2D6 genotype, and breast cancer outcomes.

We explored whether breast cancer outcomes are associated with endoxifen and other metabolites of tamoxifen and examined potential correlates of endoxifen concentration levels in serum including cytochrome P450 2D6 (CYP2D6) metabolizer phenotype and body mass index (BMI). Concentration levels of tamoxifen, endoxifen, 4-hydroxytamoxifen (4OH-tamoxifen), and N-desmethyltamoxifen (ND-tamoxifen) were measured from samples taken from 1,370 patients with estrogen receptor (ER)-positive breast cancer who were participating in the Women's Healthy Eating and Living (WHEL) Study. We tested these concentration levels for possible associations with breast cancer outcomes and found that breast cancer outcomes were not associated with the concentration levels of tamoxifen, 4-hydroxytamoxifen, and ND-tamoxifen. For endoxifen, a threshold was identified, with women in the upper four quintiles of endoxifen concentration appearing to have a 26% lower recurrence rate than women in the bottom quintile (hazard ratio (HR) = 0.74; 95% confidence interval (CI), (0.55-1.00)). The predictors of this higher-risk bottom quintile were poor/intermediate metabolizer genotype, higher BMI, and lower tamoxifen concentrations as compared with the mean for the cohort as a whole. This study suggests that there is a minimal concentration threshold above which endoxifen is effective against the recurrence of breast cancer and that ~80% of tamoxifen takers attain this threshold.

Obesity is an independent predictor of poor survival in metastatic breast cancer: retrospective analysis of a patient cohort whose treatment included high-dose chemotherapy and autologous stem cell support.

The purpose of the study was to identify predictors of long-term survival in metastatic breast cancer (MBC). A cohort of 96 patients, who received high-dose chemotherapy with autologous stem cell support (HD-ASCT) as part of their treatment, was analyzed. Percent long-term survival at 10 years was 24.5% (CI 17.2-34.9%) when metastasis was diagnosed and 14.4% (CI 8.7-23.9%) when MBC was diagnosed. Survival was impacted significantly by body mass index (BMI). Median overall survival from initial diagnosis or from time of metastasis for patients with BMIs ≤30 and >30 (obese) was 7.1 (CI 4.4-8.7) and 3.2 years (2.41-6.75), respectively, or 3.2 or 2.3 years (all P = 0.02). Also, obesity was the only independent patient-related predictor of time to metastasis and of survival. While obesity is linked with poor outcomes in earlier stages of breast cancer, this has not been previously reported for MBC.

Nonlinear properties of and nonlinear processing in hydrogenated amorphous silicon waveguides.

We propose hydrogenated amorphous silicon nanowires as a platform for nonlinear optics in the telecommunication wavelength range. Extraction of the nonlinear parameter of these photonic nanowires reveals a figure of merit larger than 2. It is observed that the nonlinear optical properties of these waveguides degrade with time, but that this degradation can be reversed by annealing the samples. A four wave mixing conversion efficiency of + 12 dB is demonstrated in a 320 Gbit/s serial optical waveform data sampling experiment in a 4 mm long photonic nanowire.

Dosage dependence of the effect of Ginkgo biloba on the rat retinal ganglion cell survival after optic nerve crush.

PURPOSE: To investigate the dosage dependence of the Ginkgo biloba effect on retinal ganglion cell survival in the rat optic nerve crush model. METHODS: The study included 56 Sprague-Dawley rats, the right optic nerve of which was crushed in a standardized manner. Two hours after the crush and once daily during the follow-up, the animals received intragastral applications of saline (saline group; n=13), or of a G. biloba extract of 0.25% concentration (n=14; low-dosage group), 1% concentration (n=15; medium-dosage group), or 4% concentration (n=14; high-dosage group). At 23 days after the optic nerve crush, the retinal ganglion cells were retrogradely labelled by injecting 3% fluorogold into the superior colliculi of the brain. At 4 weeks after baseline, the animals were killed. Retinal flat mount photographs were assessed for number and density of the retinal ganglion cells. RESULTS: The mean survival rate defined as the ratio of retinal ganglion cell density in the right eye with optic nerve crash divided by the retinal ganglion cell density in left eye without optic nerve intervention increased significantly (P<0.001) from 58.4+/-9.0% in the saline group to 68.5+/-5.7% in the low-dosage group, to 73.7+/-6.4% in the medium-dosage group, and to 74.2+/-6.8% in the high-dosage group. CONCLUSIONS: Intragastral applications of a G. biloba extract applied after an experimental and standardized optic nerve crush in rats were associated with a higher survival rate of retinal ganglion cells in a dosage-dependent manner.

Metabolic syndrome, its preeminent clusters, incident coronary heart disease and all-cause mortality--results of prospective analysis for the Atherosclerosis Risk in Communities study.

OBJECTIVE: To investigate the prospective association between Metabolic Syndrome (MetS) and coronary heart disease (CHD) and all-cause mortality. SUBJECTS AND DESIGN: A bi-racial cohort of 14 699 middle-aged Americans from the Atherosclerosis Risk in Communities study were followed for the development of new CHD and death over a period of 9 years. MetS, using the original ATP-III criteria, was defined as having at least three of the following components: elevated blood pressure (BP), elevated plasma glucose, elevated blood triglyceride (TG), increased waist circumference, and low HDL cholesterol (HDL-c). Incident CHD cases included hospitalized myocardial infarction (MI), fatal CHD, revascularization procedures, and silent MI as detected by EKG. RESULTS: The prevalence of the MetS at baseline was 29%, 30%, 40% and 26% among CHD-free white women, white men, black women, and black men, respectively. There were 1018 incident CHD cases and 1039 deaths. The relative risk (RR) and 95% confidence interval (CI) of incident CHD associated with MetS was 2.46 (1.99, 3.03) for women and 1.86 (1.59, 2.18) for men. Clear dose-response relationship between the number of MetS components and incidence of CHD was found (P for linear trend <0.001). The following three clusters of MetS components posed the highest risk for CHD: (i) the elevated BP and glucose and low HDL-c group [RR = 5.68 (3.44, 9.37)]; (ii) the elevated BP and glucose and TG group [RR = 5.08 (2.96, 8.70)]; and (iii) the elevated BP and TG and low HDL-c group [RR = 3.98 (2.75, 5.77)]. When all five components co-existed, the risk was the highest [RR = 6.24 (4.65, 8.36)]. Similar results with attenuated RR were found for all-cause mortality. CONCLUSIONS: Individuals, especially women, with the MetS have significantly higher risk of developing CHD. The riskiest combination is high-BP and glucose clustered with low HDL-c or high TG. These data highlight the importance of targeting MetS in the prevention of CHD and premature death.

Development of a two-site ELISA assay for the dimeric form of human TFF1.

TFF1 is one of three human trefoil proteins expressed principally in the gastrointestinal tract in normal tissues. TFF1 protects the gastric mucosa against damage as a result of its ability to facilitate reconstitution of damaged gastric mucosa and its involvement in the secretion and structure of gastric mucus. The most biologically active molecular form in cell culture and animal models tested is a dimer formed by a disulfide bond between two cysteine residues close to the C terminus of the protein. We have therefore developed an assay for this form of TFF1 which should facilitate its measurement in biological samples.

Synergistic effects of systemic trefoil factor family 1 (TFF1) peptide and epidermal growth factor in a rat model of colitis.

Novel therapies for the treatment of colitis are required. We therefore examined the potential value of the trefoil factor family 1 (TFF1) peptide and epidermal growth factor (EGF) alone and in combination. Effects of TFF1- Cys58 +/- EGF on an in vitro HT29 cell wounding model of restitution showed synergistic activity when used in combination. In addition, animals had colitis induced by adding 4% dextran sulphate sodium (DSS) to the drinking water for 7 days and they also received twice daily subcutaneous injections of test peptides. Treatment with TFF1-Cys58 alone (100 microg/kg) reduced histological colitis score by 22%, but the TFF1-Ser58 variant was ineffective. In a second study, TFF1-Cys58 reduced histological colitis score by 15%, EGF (600 microg/kg) by 26%, and an additive response (42% reduction) was demonstrated when used together (P < 0.01 versus either peptide given alone). Similar results were found using tissue myeloperoxidase (MPO) activity as a marker of inflammation. Where clinical risk/benefit seems justified, these initial studies suggest that combination therapy of systemic EGF and TFF peptides may prove useful for treatment of colitis in patients with disease extending beyond the reach of topical (enema) therapy.

Calculation of mitral regurgitant orifice area with use of a simplified proximal convergence method: initial clinical application.

To validate a previously proposed simplified proximal flow convergence method for calculating mitral regurgitant orifice area (ROA), a prospective study was conducted in ambulatory patients and in patients undergoing open heart surgery. Assuming a pressure difference between the left ventricle and left atrium of approximately 100 mm Hg (jet velocity [v(p)] 500 cm/s) and setting the color aliasing velocity (v(a)) to 40 cm/s, we simplified the conventional proximal convergence method formula (ROA = 2pi(r2)v(a)/v(p)) to r2/2, where r is the radius of the proximal convergence isovelocity hemisphere. For 57 ambulatory patients with a wide range of mitral regurgitant severity (1 to 4+), ROA was calculated by the conventional (x) and simplified (y) methods, demonstrating excellent accuracy (r = 0.92; P <.001; DeltaROA [y - x] = 0.004 +/- 0.08 cm2). For 24 intraoperative patients, ROA calculated by the simplified formula (y) correlated well with the pulsed Doppler-thermodilution method (x) (r = 0.84; P <.01; DeltaROA [y - x] = -0.002 +/- 0.08cm2). This simplified proximal convergence formula yields an accurate assessment of ROA for a wide range of regurgitant severity, while the time required for this measurement is shortened by half (1.5 +/- 0.5 minutes versus 3.2 +/- 0.7 minutes). This may increase the frequency of calculating ROA in the clinical laboratory.

Comparison of quantitative and semiquantitative methods for assessing mitral regurgitation by transesophageal echocardiography.

Semiquantitative grading of mitral regurgitation (MR) by transesophageal echocardiography (TEE) is widely used for clinical decision making. However, the relation between semiquantitative grading by biplane or multiplane TEE and quantitative measures remains undetermined. Biplane or multiplane TEE was performed in 113 patients in the operating room. MR severity was graded from 1 to 4+ by Doppler color flow mapping. MR was quantified using the thermodilution-Doppler method as mitral regurgitant stroke volume (RSV) derived from the difference between total mitral inflow measured by pulsed Doppler and forward flow measured by thermodilution. Mitral regurgitant orifice area (ROA) was calculated by RSV divided by mitral regurgitant velocity. RSV and ROA were also calculated using the proximal isovelocity surface area method. RSV and ROA significantly correlated with the semiquantitative grading either by TEE or angiogram in a nonlinear fashion, with the best fit being given by an exponential model with correlation coefficients from 0.73 to 0.87 (p <0.001). Substantially increased RSV and ROA were observed in MR grades of > or =3+. In the same grades of 3+ or 4+ MR, the largest RSV was 4 times larger than the smallest (190 to 220 vs 44 to 45 ml), and the largest ROA (1.82 to 2.0 vs 0.26 to 0.27 cm2) was sixfold larger than the smallest. Patients with 2 to 3+ MR had significantly variable RSV and ROA (range 21 to 91 ml and 0.12 to 0.65 cm2, respectively). Color flow mapping by biplane or multiplane TEE or angiography is able to categorize precisely mild (< or =2+) and severe (> or =3+) MR, but cannot accurately determine actual hemodynamic load of MR in more severe degrees of MR.

Degradation of stimulus selectivity of visual cortical cells in senescent rhesus monkeys.

Human visual function declines with age. Much of this decline is probably mediated by changes in the central visual pathways. We compared the stimulus selectivity of cells in primary visual cortex (striate cortex or V1) in young adult and very old macaque monkeys using single-neuron in vivo electrophysiology. Our results provide evidence for a significant degradation of orientation and direction selectivity in senescent animals. The decreased selectivity of cells in old animals was accompanied by increased responsiveness to all orientations and directions as well as an increase in spontaneous activity. The decreased selectivities and increased excitability of cells in old animals are consistent with an age-related degeneration of intracortical inhibition. The neural changes described here could underlie declines in visual function during senescence.

Theta ganglion cell type of cat retina.

We define a new bistratified ganglion cell type of cat retina using intracellular staining in vitro. The theta cell has a small soma, slender axon, and delicate, highly branched dendritic arbor. Dendritic fields are intermediate in size among cat ganglion cells, with diameters typically two to three times those of beta cells. Fields increase in size with distance from the area centralis, ranging in diameter from 70 to 150 microns centrally to a maximum of 700 microns in the periphery. Theta cells have markedly smaller dendritic fields within the nasal visual streak than above or below it and smaller fields nasally than temporally. Dendritic arbors are narrowly bistratified. The outer arbor lies in the lower part of sublamina a (OFF sublayer) of the inner plexiform layer where it costratifies with the dendrites of OFF alpha cells. The inner arbor occupies the upper part of sublamina b (ON sublayer), where it costratifies with ON alpha dendrites. The outer and inner arbors are composed of many relatively short segments and are densely interconnected by branches that traverse the a/b sublaminar border. Experiments combining retrograde labeling with intracellular staining indicate that theta cells project to the superior colliculus and to two components of the dorsal lateral geniculate nucleus (the C laminae and medial interlaminar nucleus). Theta cells project contralaterally from the nasal retina and ipsilaterally from the temporal retina. They apparently correspond to a sluggish transient or phasic W-cell with an ON-OFF receptive field center.

Physiological response properties of cat retinal ganglion cells projecting to suprachiasmatic nucleus.

The aim of this experiment was to characterize the physiological properties of cat retinal ganglion cells that project to the suprachiasmatic nucleus (SCN). Retrogradely labeled SCN-projecting ganglion cells were recorded extracellularly in vitro. For the first time, this study provides crucial information on visual response properties of ganglion cells in the entrainment circuitry. All recorded cells gave sustained responses (n = 9). Although most of the cells (n = 8) had an "on" center receptive field, one cell showed "on-off" center receptive field properties. The range of receptive field sizes was 2 to 5 deg. For most of the cells tested, the spectral wavelength that evoked peak responses was 500 nm (3 out of 5 cells). All recorded cells (n = 9) preferred still or extremely slow-moving stimuli (3.3 deg/s). These results indicate that cat SCN-projecting cells receive inputs from conventional photoreceptors. The hypothesis that both conventional and cryptochromic photoreceptors are involved in transferring photic signals is discussed.

Dendritic morphology of cat retinal ganglion cells projecting to suprachiasmatic nucleus.

The morphological properties of cat retinal ganglion cells projecting to the suprachiasmatic nucleus (SCN) of the hypothalamus were studied by using retrograde labeling, in vitro intracellular injection, confocal optical section, and computer three-dimensional reconstruction techniques. A total of 218 stained cells were studied. Neither the dendritic fields nor soma diameters of SCN-projecting cells varied with eccentricity. Approximately 50% of cells were concentrated not in the area centralis, but rather in the visual streak. SCN-projecting cells showed large and symmetrical dendritic fields (596 +/- 159 microm) and medium to small sized somas (17.2 +/- 3.3 microm). The ramification patterns of SCN-projecting cells were similar. Most cells primarily ramify in either sublamina A or B. Evidence from quantitatively analyzed cells (n = 39) suggests that these cells ramified more frequently in sublamina A (n = 17) than in sublamina B (n = 8). A large number of cells, on the other hand, showed diffuse ramification (n = 14) throughout the inner plexiform layer (IPL). The functional roles of these cells and the corresponding retinal neurocircuitry in circadian entrainment remain to be studied.

The value of assessing pulmonary venous flow velocity for predicting severity of mitral regurgitation: A quantitative assessment integrating left ventricular function.

Although alteration in pulmonary venous flow has been reported to relate to mitral regurgitant severity, it is also known to vary with left ventricular (LV) systolic and diastolic dysfunction. There are few data relating pulmonary venous flow to quantitative indexes of mitral regurgitation (MR). The object of this study was to assess quantitatively the accuracy of pulmonary venous flow for predicting MR severity by using transesophageal echocardiographic measurement in patients with variable LV dysfunction. This study consisted of 73 patients undergoing heart surgery with mild to severe MR. Regurgitant orifice area (ROA), regurgitant stroke volume (RSV), and regurgitant fraction (RF) were obtained by quantitative transesophageal echocardiography and proximal isovelocity surface area. Both left and right upper pulmonary venous flow velocities were recorded and their patterns classified by the ratio of systolic to diastolic velocity: normal (>/=1), blunted (<1), and systolic reversal (<0). Twenty-three percent of patients had discordant patterns between the left and right veins. When the most abnormal patterns either in the left or right vein were used for analysis, the ratio of peak systolic to diastolic flow velocity was negatively correlated with ROA (r = -0.74, P <.001), RSV (r = -0.70, P <.001), and RF (r = -0.66, P <.001) calculated by the Doppler thermodilution method; values were r = -0.70, r = -0.67, and r = -0.57, respectively (all P <.001), for indexes calculated by the proximal isovelocity surface area method. The sensitivity, specificity, and predictive values of the reversed pulmonary venous flow pattern for detecting a large ROA (>0.3 cm(2)) were 69%, 98%, and 97%, respectively. The sensitivity, specificity, and predictive values of the normal pulmonary venous flow pattern for detecting a small ROA (<0.3 cm(2)) were 60%, 96%, and 94%, respectively. However, the blunted pattern had low sensitivity (22%), specificity (61%), and predictive values (30%) for detecting ROA of greater than 0.3 cm(2) with significant overlap with the reversed and normal patterns. Among patients with the blunted pattern, the correlation between the systolic to diastolic velocity ratio was worse in those with LV dysfunction (ejection fraction <50%, r = 0.23, P >.05) than in those with normal LV function (r = -0.57, P <.05). Stepwise linear regression analysis showed that the peak systolic to diastolic velocity ratio was independently correlated with RF (P <.001) and effective stroke volume (P <.01), with a multiple correlation coefficient of 0.71 (P <.001). In conclusion, reversed pulmonary venous flow in systole is a highly specific and reliable marker of moderately severe or severe MR with an ROA greater than 0.3 cm(2), whereas the normal pattern accurately predicts mild to moderate MR. Blunted pulmonary venous flow can be seen in all grades of MR with low predictive value for severity of MR, especially in the presence of LV dysfunction. The blunted pulmonary venous flow pattern must therefore be interpreted cautiously in clinical practice as a marker for severity of MR.

Nitric oxide controls src kinase activity through a sulfhydryl group modification-mediated Tyr-527-independent and Tyr-416-linked mechanism.

c-Src kinase was activated when either murine NIH3T3 fibroblast cells or immunoprecipitated c-Src proteins were treated with nitric oxide generator, S-nitroso-N-acetyl penicillamine (SNAP) or sodium nitroprusside. Nitric oxide (NO) scavenger hemoglobin and N(2)O(3) scavenger homocysteine abolished the SNAP-mediated c-Src kinase activation. Phosphoamino acid analysis and peptide mapping of in vitro labeled phospho-c-Src proteins revealed that SNAP promoted the autophosphorylation at tyrosine, which preferentially took place at Tyr-416. Peptide mapping of in vivo labeled c-Src kinase excluded the involvement of phospho-Tyr-527 dephosphorylation in the SNAP-mediated activation mechanism. Correspondingly, protein-tyrosine phosphatase inhibitor Na(3)VO(4) did not abolish the SNAP-mediated activation of Src kinase, and the constitutively activated v-Src kinase was also further up-regulated in activity by SNAP. SNAP, however, failed to up-regulate the kinase activity of Phe-416 mutant v-Src. 2-Mercaptoethanol or dithiothreitol, which should disrupt N(2)O(3)-mediated S-nitrosylation and subsequent formation of the S-S bond, abolished the up-regulated catalytic activity, and the activity was regained after re-exposing the enzyme to SNAP. Exposure of Src kinase to SNAP promoted both autophosphorylation and S-S bond-mediated aggregation of the kinase molecules, demonstrating a linkage between the two events. These results suggest that the NO/N(2)O(3)-provoked S-nitrosylation/S-S bond formation destabilizes the Src structure for Tyr-416 autophosphorylation-associated activation bypassing the Tyr-527-linked regulation.

The Eta ganglion cell type of cat retina.

We define a morphologic type of ganglion cell in cat retina by using intracellular staining in vitro. The eta cell has a small soma, slender axon, and delicate, highly branched dendritic arbor. Dendritic fields are intermediate in size among cat ganglion cells, with diameters typically two to three times those of beta cells. Fields increase in size as a function of distance from the area centralis, ranging in diameter from 90 microm to 200 microm centrally to a maximum of 600 microm in the periphery. This increase is unusually radially symmetric. By contrast with other cat ganglion cell types, eta cells do not have markedly smaller dendritic fields within the visual streak than above or below it nor much smaller fields nasally than temporally. Dendrites ramify broadly throughout sublamina a (OFF sublayer) of the inner plexiform layer. They arborize most densely in S2, where they costratify with dendrites of OFF alpha cells. There is apparently no matching ON variety of eta cell. Experiments combining retrograde labeling with intracellular staining indicate that eta cells project to the superior colliculus and to two components of the dorsal lateral geniculate nucleus (the C laminae and medial interlaminar nucleus). Eta cells apparently project contralaterally from the nasal retina and ipsilaterally from the temporal retina. The morphology and projection patterns of the eta cell suggest that its physiologic counterpart is a type of sluggish or W-cell with an OFF center, an ON surround, and possibly a transient light response.

Application of color Doppler flow mapping to calculate orifice area of St Jude mitral valve.

BACKGROUND: The effective orifice area (EOA) of a prosthetic valve is superior to transvalvular gradients as a measure of valve function, but measurement of mitral prosthesis EOA has not been reliable. METHODS AND RESULTS: In vitro flow across St Jude valves was calculated by hemispheric proximal isovelocity surface area (PISA) and segment-of-spheroid (SOS) methods. For steady and pulsatile conditions, PISA and SOS flows correlated with true flow, but SOS and not PISA underestimated flow. These principles were then used intraoperatively to calculate cardiac output and EOA of newly implanted St Jude mitral valves in 36 patients. Cardiac output by PISA agreed closely with thermodilution (r=0.91, Delta=-0.05+/-0.55 L/min), but SOS underestimated it (r=0.82, Delta=-1.33+/-0.73 L/min). Doppler EOAs correlated with Gorlin equation estimates (r=0.75 for PISA and r=0.68 for SOS, P<0.001) but were smaller than corresponding in vitro EOA estimates. CONCLUSIONS: Proximal flow convergence methods can calculate forward flow and estimate EOA of St Jude mitral valves, which may improve noninvasive assessment of prosthetic mitral valve obstruction.