Response profile of the face-sensitive N170 component: a rapid adaptation study.

To study the response profile of the face-selective N170 component, an adaptation procedure was employed where adaptor and test stimuli were presented in rapid succession. Test stimuli came from 4 different face categories (upright, inverted, and eyeless faces and eyes-only images). The same face stimuli, as well as upright and inverted houses, served as adaptors. Strong N170 amplitude reductions indicative of adaptation were found for all types of face test stimuli preceded by face adaptors relative to house adaptors, demonstrating that at a generic level, the N170 reflects the activation of face-selective neurons by full faces and by face parts. The highly specific pattern of N170 adaptation effects for different combinations of adaptor and test stimulus categories suggests additional distinct contributions of eye-selective neurons and of face-sensitive neurons that are tuned to deviations from canonical stimulus orientations to the N170 component. Results demonstrate that the N170 is generated by multiple neural sources at both early and later stages of configural face processing and that rapid adaptation techniques provide a powerful tool to dissociate these sources.

Distinctive ERK and p38 signaling in remote and infarcted myocardium during post-MI remodeling in the mouse.

Global activation of MAP kinases has been reported in both human and experimental heart failure. Chronic remodeling of the surviving ventricular wall after myocardial infarction (MI) involves both myocyte loss and fibrosis; we hypothesized that this cardiomyopathy involves differential shifts in pro- and anti-apoptotic MAP kinase signaling in cardiac myocyte (CM) and non-myocyte. Cardiomyopathy after coronary artery ligation in mice was characterized by echocardiography, ex vivo Langendorff preparation, histologic analysis and measurements of apoptosis. Phosphorylation (activation) of signaling molecules was analyzed by Western blot, ELISA and immunohistochemistry. Post-MI remodeling involved dramatic changes in the phosphorylation of both stress-activated MAP (SAP) kinase p38 as well as ERK, a known mediator of cell survival, but not of SAP kinase JNK or the anti-apoptotic mediator of PI3K, Akt. Phosphorylation of p38 rose early after MI in the infarct, whereas a more gradual rise in the remote myocardium accompanied a rise in apoptosis in that region. In both areas, ERK phosphorylation was lowest early after MI and rose steadily thereafter, though infarct phosphorylation was consistently higher. Immunostaining of p-ERK localized to fibrotic areas populated primarily by non-myocytes, whereas staining of p38 phosphorylation was stronger in areas of progressive CM apoptosis. Relative segregation of CMs and non-myocytes in different regions of the post-MI myocardium revealed signaling patterns that imply cell type-specific changes in pro- and anti-apoptotic MAP kinase signaling. Prevention of myocyte loss and of LV remodeling after MI may therefore require cell type-specific manipulation of p38 and ERK activation.

Burnt-out diabetes: impact of chronic kidney disease progression on the natural course of diabetes mellitus.

Many individuals with diabetic nephropathy, the leading cause of chronic kidney disease (CKD) in the United States, progress to stage 5 of CKD and undergo maintenance dialysis treatment. Recent data indicate that in up to one third of diabetic dialysis patients with a presumptive diagnosis of diabetic nephropathy, glycemic control improves spontaneously with the progression of CKD, loss of residual renal function, and the initiation of dialysis therapy, leading to normal-to-low hemoglobin A1c (<6%) and glucose levels, requiring cessation of insulin or other anti-diabetic medications. Potential contributors to this so-called "burnt-out diabetes" include decreased renal and hepatic insulin clearance, a decline in renal gluconeogenesis, deficient catecholamine release, diminished food intake (because of anorexia or diabetic gastroparesis), protein-energy wasting (with resultant loss of weight and body fat), and the hypoglycemic effects of dialysis treatment. Although the concept of "burnt-out diabetes" appears in sharp contradistinction to the natural history of diabetes mellitus, studying this condition and its potential causes and consequences, including the role of genetic factors, may lead to a better understanding of the pathophysiology of metabolic syndrome and diabetes mellitus in the CKD population and in many other individuals with chronic disease states associated with wasting syndrome that can confound the natural history of diabetes.

Efficacy and safety of sildenafil in men with serotonergic antidepressant-associated erectile dysfunction: results from a randomized, double-blind, placebo-controlled trial.

OBJECTIVE: To evaluate the efficacy of short-term treatment with sildenafil citrate in men with serotonin reuptake inhibitor (SRI)-associated erectile dysfunction (ED). METHOD: Men (aged>or=18 years) with major depressive disorder (MDD; DSM-IV criteria) in remission and taking SRIs who experienced SRI-associated ED were enrolled in this multicenter, 6-week, randomized, flexible-dose, double-blind, placebo-controlled trial. The primary study measures were questions 3 (Q3: frequency of penetration) and 4 (Q4: frequency of maintained erections after penetration) of the International Index of Erectile Function (IIEF) questionnaire. Secondary study measures were all other questions and domains of the IIEF, the Erectile Dysfunction Index of Treatment Satisfaction (EDITS), a global efficacy questionnaire (GEQ), and a patient-maintained event log of sexual activity. RESULTS: Patients receiving sildenafil (N=71) versus placebo (N=71) reported significantly higher mean+/-SE scores on Q3 (3.9+/-0.2 vs. 3.1+/-0.2, p=.003) and Q4 (3.7+/-0.2 vs. 2.8+/-0.2, p<.001) of the IIEF and significantly higher scores on all domains of the IIEF. Patients receiving sildenafil also reported significantly improved scores on all questions of the EDITS questionnaire (p<.02) and the GEQ (p<.0001) and an increased number of successful sexual intercourse attempts per week (p<.0001) compared with patients receiving placebo. All patients remained in MDD remission (score

An innovative phase I clinical study demonstrates inhibition of FLT3 phosphorylation by SU11248 in acute myeloid leukemia patients.

PURPOSE: Obtaining direct and rapid proof of molecular activity in early clinical trials is critical for optimal clinical development of novel targeted therapies. SU11248 is an oral multitargeted kinase inhibitor with selectivity for fms-related tyrosine kinase 3/Flk2 (FLT3), platelet-derived growth factor receptor alpha/beta, vascular endothelial growth factor receptor 1/2, and KIT receptor tyrosine kinases. FLT3 is a promising candidate for targeted therapy in acute myeloid leukemia (AML), because activating mutations occur in up to 30% of patients. We conducted an innovative single-dose clinical study with a primary objective to demonstrate inhibition of FLT3 phosphorylation by SU11248 in AML. EXPERIMENTAL DESIGN: Twenty-nine AML patients each received a single dose of SU11248, escalated from 50 to 350 mg, in increments of 50 mg and cohorts of three to six patients. FLT3 phosphorylation and plasma pharmacokinetics were evaluated at seven time points over 48 h after SU11248 administration, and FLT3 genotype was determined. Study drug-related adverse events occurred in 31% of patients, mainly grade 1 or 2 diarrhea and nausea, at higher dose levels. RESULTS: Inhibition of FLT3 phosphorylation was apparent in 50% of FLT3-wild-type (WT) patients and in 100% of FLT3-mutant patients. FLT3 internal tandem duplication (ITD) mutants showed increased sensitivity relative to FLT3-WT, consistent with preclinical predictions. The primary end point, strong inhibition of FLT3 phosphorylation in >50% patients, was reached in 200 mg and higher dose cohorts. Downstream signaling pathways were also inhibited; signal transducer and activator of transcription 5 (STAT5) was reduced primarily in internal tandem duplication patients and at late time points in FLT3-WT patients, whereas extracellular signal-regulated kinase (ERK) activity was reduced in the majority of patients, independent of FLT3 inhibition. CONCLUSIONS: This novel translational study bridges preclinical models to the patient setting and provides the first evidence of anti-FLT3 activity in patients. Proof of target inhibition accomplishes a crucial milestone in the development of novel oncology therapeutics.

Expression profiling of blood samples from an SU5416 Phase III metastatic colorectal cancer clinical trial: a novel strategy for biomarker identification.

BACKGROUND: Microarray-based gene expression profiling is a powerful approach for the identification of molecular biomarkers of disease, particularly in human cancers. Utility of this approach to measure responses to therapy is less well established, in part due to challenges in obtaining serial biopsies. Identification of suitable surrogate tissues will help minimize limitations imposed by those challenges. This study describes an approach used to identify gene expression changes that might serve as surrogate biomarkers of drug activity. METHODS: Expression profiling using microarrays was applied to peripheral blood mononuclear cell (PBMC) samples obtained from patients with advanced colorectal cancer participating in a Phase III clinical trial. The PBMC samples were harvested pre-treatment and at the end of the first 6-week cycle from patients receiving standard of care chemotherapy or standard of care plus SU5416, a vascular endothelial growth factor (VEGF) receptor tyrosine kinase (RTK) inhibitor. Results from matched pairs of PBMC samples from 23 patients were queried for expression changes that consistently correlated with SU5416 administration. RESULTS: Thirteen transcripts met this selection criterion; six were further tested by quantitative RT-PCR analysis of 62 additional samples from this trial and a second SU5416 Phase III trial of similar design. This method confirmed four of these transcripts (CD24, lactoferrin, lipocalin 2, and MMP-9) as potential biomarkers of drug treatment. Discriminant analysis showed that expression profiles of these 4 transcripts could be used to classify patients by treatment arm in a predictive fashion. CONCLUSIONS: These results establish a foundation for the further exploration of peripheral blood cells as a surrogate system for biomarker analyses in clinical oncology studies.

What top-down task sets do for us: an ERP study on the benefits of advance preparation in visual search.

When target-defining features are specified in advance, attentional target selection in visual search is controlled by preparatory top-down task sets. We used ERP measures to study voluntary target selection in the absence of such feature-specific task sets, and to compare it to selection that is guided by advance knowledge about target features. Visual search arrays contained two different color singleton digits, and participants had to select one of these as target and report its parity. Target color was either known in advance (fixed color task) or had to be selected anew on each trial (free color-choice task). ERP correlates of spatially selective attentional target selection (N2pc) and working memory processing (SPCN) demonstrated rapid target selection and efficient exclusion of color singleton distractors from focal attention and working memory in the fixed color task. In the free color-choice task, spatially selective processing also emerged rapidly, but selection efficiency was reduced, with nontarget singleton digits capturing attention and gaining access to working memory. Results demonstrate the benefits of top-down task sets: Feature-specific advance preparation accelerates target selection, rapidly resolves attentional competition, and prevents irrelevant events from attracting attention and entering working memory.

The N170 component and its links to configural face processing: a rapid neural adaptation study.

A neural adaptation paradigm where adaptor and test stimuli were presented in rapid succession was employed to investigate links between the face-sensitive N170 component and configural face processing. In Experiment 1, schematic adaptor stimuli preceded naturalistic images of upright faces, inverted faces, or isolated eyes. Relative to a baseline condition with schematic house adaptors, upright and inverted schematic faces adapted the N170 to subsequent naturalistic faces, demonstrating that this component is associated with neural processes involved in the analysis of first-order relational face configuration. In Experiment 2, two-tone Mooney faces adapted the N170 to naturalistic faces relative to a baseline condition with Mooney houses, suggesting links between the N170 and holistic face processing. Results demonstrate that the N170 component does not exclusively reflect the detection and analysis of individual face parts, but also the processing of first-order configural and global gestalt features of faces. They also show that neural adaptation procedures can be used to identify the neural mechanisms that are responsible for category-specific ERP components such as the N170.

Surgical ventricular reconstruction in mice: elucidating potential targets for combined molecular/surgical intervention.

OBJECTIVES: We hypothesize that persistent alterations in molecular signaling may drive recurrent pathologic remodeling even after the reduction of mechanical stress achieved via surgical ventricular reconstruction. We developed a murine model of surgical ventricular reconstruction that would facilitate molecular analysis of the postreconstruction myocardium and allow future exploitation of genetic models. METHODS: C57/B6 mice underwent coronary artery ligation. For surgical ventricular reconstruction at 4 weeks after myocardial infarction, a purse-string suture (7-0 polypropylene) achieved at least partial exclusion of the apical aneurysm. Serial echocardiography was correlated to measurements of apoptosis and to Western blot analysis of key signaling cascades. RESULTS: An immediate 21.7% +/- 2.6% improvement in fractional shortening was seen in the remaining myocardium after surgical ventricular reconstruction. Reduction in left ventricular volume and improved function persisted at 1 week, but recurrent dilatation at 4 weeks (left ventricular end-diastolic volume of 63.5 +/- 2.5 vs 42.1 +/- 5.4 microL immediately after reconstruction; P < .05) was associated with a loss of functional improvement (fractional shortening 41.2% +/- 2% vs 46% +/- 0.9%; P < .01). At 1 week after surgical ventricular reconstruction, there was a transient reduction in myocardial apoptosis. A steady reduction in cardioprotective myocardial Akt activation, however, was not affected by ventricular reconstruction. CONCLUSION: This murine model recapitulates both the immediate benefits of surgical ventricular reconstruction and the longer-term recurrence of dilated cardiomyopathy seen previously in some animal models and human studies. Early analysis has begun to implicate persistent signaling changes in the postinfarction myocardium that may be responsible for recurrent dilatation after surgical ventricular reconstruction and that may become targets for combined surgical and molecular interventions.

Identification and collection of quality indicators for perinatal care.

We describe the development of a database of quality indicators and outcomes for perinatal care as part of a multi-institutional collaborative quality improvement project, Neonatal Intensive Care Quality 2002. Important principles of developing such a database are also discussed including eligibility criteria that identify high-risk patients without burdening data collectors, clinically important and well-defined measures, development of systems within each hospital to ensure identification of all eligible patients, use of data collectors with knowledge of perinatal care, appropriate design of paper and electronic data-collection tools, multiple pilot tests, and periodic feedback of data to participating hospitals.

Endoventricular patch plasty for dyskinetic anteroapical left ventricular aneurysm increases systolic circumferential shortening in sheep.

OBJECTIVE: Endoventricular patch plasty (Dor procedure) has gained favor as a surgical treatment for heart failure associated with large anteroapical myocardial infarction. We tested the hypotheses that the Dor procedure increases systolic circumferential shortening and longitudinal shortening in noninfarcted left ventricular regions in sheep. METHODS: In 6 male Dorsett sheep, the left anterior descending coronary artery and its second diagonal branch were ligated 40% of the distance from the apex to the base. Sixteen weeks after myocardial infarction, a Dor procedure was performed with a Dacron patch that was 50% of the infarct neck dimension. Two weeks before and 2 and 6 weeks after the Dor procedure, animals underwent magnetic resonance imaging with tissue tagging in multiple short-axis and long-axis slices. Fully three-dimensional strain analyses were performed. All 6 end-systolic strain components were compared in regions 1 cm, 2 cm, 3 cm, and 4 cm below the valves, as well as in the anterior, posterior, and lateral left ventricular walls and the interventricular septum. RESULTS: Circumferential shortening increased from before the Dor procedure to 6 weeks after repair in nearly every left ventricular region (13/16). The greatest regional change in circumferential shortening was found in the equatorial region or 2 cm below the base and in the posterior wall (from 9.0% to 18.4%; P < .0001). Longitudinal shortening increased 2 weeks after the Dor procedure but then returned near baseline by 6 weeks after the Dor procedure. CONCLUSION: The Dor procedure significantly increases systolic circumferential shortening in nearly all noninfarcted left ventricular regions in sheep.

Left ventricular volume and function after endoventricular patch plasty for dyskinetic anteroapical left ventricular aneurysm in sheep.

OBJECTIVE: Endoventricular patch plasty (the Dor procedure) has gained favor as a surgical treatment for heart failure associated with large anteroapical myocardial infarction. We tested the hypothesis that the Dor procedure reduces left ventricular volume, increases end-systolic elastance, decreases diastolic compliance, and maintains left ventricular function. METHODS: In 6 male Dorsett sheep, the left anterior descending coronary artery and its second diagonal branch were ligated 40% of the distance from apex to base. Sixteen weeks after myocardial infarction, a Dor procedure was performed with a Dacron patch that was 50% of the infarct neck dimension. Absolute left ventricular volume was measured with magnetic resonance imaging, and left ventricular pressure and relative left ventricular volume changes during pharmacologic preload reduction were measured with a volume conductance catheter 2 weeks before and 2 and 6 weeks after the Dor procedure. End-systolic elastance, diastolic compliance, and Starling relationships were calculated from the resultant left ventricular pressure/volume loops. RESULTS: Two weeks after the Dor procedure, the left ventricular volume at end systole and end diastole was significantly reduced, and there was no redilation at 6 weeks. Six weeks after the Dor procedure, the ejection fraction was significantly increased. Although stroke volume increased slightly at 6 weeks, the change was not significant. The slopes of end-systolic elastance, diastolic compliance, and Starling relationships were unchanged at 2 and 6 weeks. CONCLUSIONS: The Dor procedure significantly reduces left ventricular volume. Unlike linear repair, left ventricular volume changes seem stable. The ejection fraction is improved, and left ventricular function (stroke volume and the Starling relationship) is maintained.