Identification of a biological signature for schizophrenia in serum.

Biomarkers are now used in many areas of medicine but are still lacking for psychiatric conditions such as schizophrenia (SCZ). We have used a multiplex molecular profiling approach to measure serum concentrations of 181 proteins and small molecules in 250 first and recent onset SCZ, 35 major depressive disorder (MDD), 32 euthymic bipolar disorder (BPD), 45 Asperger syndrome and 280 control subjects. Preliminary analysis resulted in identification of a signature comprised of 34 analytes in a cohort of closely matched SCZ (n=71) and control (n=59) subjects. Partial least squares discriminant analysis using this signature gave a separation of 60-75% of SCZ subjects from controls across five independent cohorts. The same analysis also gave a separation of ~50% of MDD patients and 10-20% of BPD and Asperger syndrome subjects from controls. These results demonstrate for the first time that a biological signature for SCZ can be identified in blood serum. This study lays the groundwork for development of a diagnostic test that can be used as an aid for distinguishing SCZ subjects from healthy controls and from those affected by related psychiatric illnesses with overlapping symptoms.

Sex-specific serum biomarker patterns in adults with Asperger's syndrome.

Autism spectrum conditions have been hypothesized to be an exaggeration of normal male low-empathizing and high-systemizing behaviors. We tested this hypothesis at the molecular level by performing comprehensive multi-analyte profiling of blood serum from adult subjects with Asperger's syndrome (AS) compared with controls. This led to identification of distinct sex-specific biomarker fingerprints for male and female subjects. Males with AS showed altered levels of 24 biomarkers including increased levels of cytokines and other inflammatory molecules. Multivariate statistical classification of males using this panel of 24 biomarkers revealed a marked separation between AS and controls with a sensitivity of 0.86 and specificity of 0.88. Testing this same panel in females did not result in a separation between the AS and control groups. In contrast, AS females showed altered levels of 17 biomarkers including growth factors and hormones such as androgens, growth hormone and insulin-related molecules. Classification of females using this biomarker panel resulted in a separation between AS and controls with sensitivities and specificities of 0.96 and 0.83, respectively, and testing this same panel in the male group did not result in a separation between the AS and control groups. The finding of elevated testosterone in AS females confirmed predictions from the 'extreme male brain' and androgen theories of autism spectrum conditions. We conclude that to understand the etiology and development of autism spectrum conditions, stratification by sex is essential.

Observer variability in the quantitation of Doppler color flow jet areas for mitral and aortic regurgitation.

Early studies using Doppler color flow imaging have suggested that measurement of the regurgitant jet area provides information regarding the severity of valvular insufficiency. This study was performed to assess the observer variability of mitral and aortic regurgitant jet area measurements using the Doppler color technique. Color Doppler recordings from 45 patients were reviewed: 23 patients had aortic regurgitation and 22 had mitral regurgitation. To assess interobserver variability, the largest definable mitral regurgitant jets from three cardiac cycles were independently chosen and measured by planimetry by two observers who were unaware of other patient information. Measurements were repeated by both observers at a separate time to obtain intraobserver data. Videotapes from 23 patients with aortic regurgitation were similarly analyzed. Each observer measured the isovolumic aortic jet (before mitral valve opening) and the maximal aortic regurgitant jet (at any time during diastole) using computer-assisted planimetry. Both intraobserver and interobserver correlations were excellent for mitral regurgitant jet areas (r = 0.97 and r = 0.93, respectively). The intraobserver correlation for isovolumic aortic regurgitant jet was r = 0.73; the interobserver correlation for this measurement was only fair (r = 0.57). For the maximal aortic regurgitant jet area, intraobserver correlation was good (r = 0.86) and interobserver correlation was fair (r = 0.72). These findings suggest that intraobserver and interobserver reproducibility are acceptable for the measurement of mitral regurgitant jet area.(ABSTRACT TRUNCATED AT 250 WORDS)

Quantitative assessment of mitral regurgitation by Doppler color flow imaging: angiographic and hemodynamic correlations.

This study was performed to test the hypothesis that measurements of jet area by Doppler color flow imaging can predict the angiographic severity and hemodynamic consequences of mitral regurgitation. Doppler color flow imaging was performed in 47 patients undergoing cardiac catheterization and left ventriculography. The jet area was measured as the largest clearly definable flow disturbance in the parasternal and apical views, and expressed as the maximal jet area, the mean of the largest jet area (average jet area) in two views or as the ratio of these measures to left atrial area. Correlation of all Doppler color flow measurements with angiographic grades of mitral regurgitation were comparable, maximal jet area being closest at r = 0.76. A maximal jet area greater than 8 cm2 predicted severe mitral regurgitation with a sensitivity of 82% and specificity of 94%, whereas a maximal jet area less than 4 cm2 predicted mild mitral regurgitation with a sensitivity and specificity of 85% and 75%, respectively. All patients with an average jet area greater than 8 cm2 manifested severe mitral regurgitation. However, jet area measurements showed limited correlation with regurgitant volume and fraction (r = 0.55 and 0.62, respectively) for maximal jet area, and were not predictive of hemodynamic abnormalities, including those of pulmonary wedge pressure, stroke volume or ventricular volumes. Thus, in patients with mitral regurgitation, maximal jet area from Doppler color flow imaging provides a simple measurement that predicts angiographic grade, but manifests a weak correlation with regurgitant volume and does not predict hemodynamic dysfunction.

A prospective, randomized evaluation of prophylactic intraaortic balloon counterpulsation in high risk patients with acute myocardial infarction treated with primary angioplasty. Second Primary Angioplasty in Myocardial Infarction (PAMI-II) Trial Investigators.

OBJECTIVES: A large, international, multicenter, prospective, randomized trial was performed to determine the role of prophylactic intraaortic balloon pump (IABP) counterpulsation after primary percutaneous transluminal coronary angioplasty (PTCA) in acute myocardial infarction (AMI). BACKGROUND: Previous studies have suggested that routine IABP use after primary PTCA reduces infarct-related artery reocclusion, augments myocardial recovery and improves clinical outcomes. METHODS: Cardiac catheterization was performed in 1,100 patients within 12 h of onset of AMI at 34 clinical centers. Clinical and angiographic variables were used to stratify patients undergoing primary PTCA into high and low risk groups. High risk patients were then randomized to 36 to 48 h of IABP (n = 211) or traditional care (n = 226). The study had 80% power to detect a reduction in the primary end point from 30% to 20%. RESULTS: There was no significant difference in the predefined primary combined end point of death, reinfarction, infarct-related artery reocclusion, stroke or new-onset heart failure or sustained hypotension in patients treated with an IABP versus those treated conservatively (28.9% vs. 29.2%, p = 0.95). The IABP strategy conferred modest benefits in reduction of recurrent ischemia (13.3% vs. 19.6%, p = 0.08) and subsequent unscheduled repeat catheterization (7.6% vs. 13.3%, p = 0.05) but did not reduce the rate of infarct-related artery reocclusion (6.7% vs. 5.5%, p = 0.64), reinfarction (6.2% vs. 8.0%, p = 0.46) or mortality (4.3% vs. 3.1%) and was associated with a higher incidence of stroke (2.4% vs. 0%, p = 0.03). IABP use did not result in enhanced myocardial recovery as assessed by paired admission to predischarge and 6-week rest and exercise left ventricular ejection fraction. CONCLUSIONS: In contrast to previous studies, a prophylactic IABP strategy after primary PTCA in hemodynamically stable high risk patients with AMI does not decrease the rates of infarct-related artery reocclusion or reinfarction, promote myocardial recovery or improve overall clinical outcome.

Safety and cost-effectiveness of early discharge after primary angioplasty in low risk patients with acute myocardial infarction. PAMI-II Investigators. Primary Angioplasty in Myocardial Infarction.

OBJECTIVES: The second Primary Angioplasty in Myocardial Infarction (PAMI-II) study evaluated the hypothesis that primary percutaneous transluminal coronary angioplasty (PTCA), with subsequent discharge from the hospital 3 days later, is safe and cost-effective in low risk patients. BACKGROUND: In low risk patients with myocardial infarction (MI), few data exist regarding the need for intensive care and noninvasive testing or the appropriate length of hospital stay. METHODS: Patients with acute MI underwent emergency catheterization with primary PTCA when appropriate. Low risk patients (age <70 years, left ventricular ejection fraction >45%, one- or two-vessel disease, successful PTCA, no persistent arrhythmias) were randomized to receive accelerated care (admission to a nonintensive care unit and day 3 hospital discharge without noninvasive testing [n = 237] or traditional care [n = 234]). RESULTS: Patients who received accelerated care had similar in-hospital outcomes but were discharged 3 days earlier (4.2+/-2.3 vs. 7.1+/-4.7 days, p = 0.0001) and had lower hospital costs ($9,658+/-5,287 vs. $11,604+/-6,125 p = 0.002) than the patients who received traditional care. At 6 months, accelerated and traditional care groups had a similar rate of mortality (0.8% vs. 0.4%, p = 1.00), unstable ischemia (10.1% vs. 12.0%, p = 0.52), reinfarction (0.8% vs. 0.4%, p = 1.00), stroke (0.4% vs. 2.6%, p = 0.07), congestive heart failure (4.6% vs. 4.3%, p = 0.85) or their combined occurrence (15.2% vs. 17.5%, p = 0.49). The study was designed to detect a 10% difference in event rates; at 6 months, only a 2.3% difference was measured between groups, indicating an actual power of 0.19. CONCLUSIONS: Early identification of low risk patients with MI allowed safe omission of the intensive care phase and noninvasive testing, and a day 3 hospital discharge strategy, resulting in substantial cost savings.

Effect of isometric exercise on mitral and aortic regurgitation as assessed by color Doppler flow imaging.

Isometric exercise produces well-defined hemodynamic changes in normal and diseased states. However, the effect of isometrics on the degree of valvular regurgitation recorded by color Doppler flow imaging (CDFI) has not been reported. CDFI was therefore used to evaluate changes in valvular regurgitation in 34 patients, mean age 53 +/- 16 years. Data were collected for 43 regurgitant lesions including 20 cases of aortic regurgitation and 23 cases of mitral regurgitation. Isometrics produced a significant increase in heart rate (71 to 83 beats/min) and blood pressure (132/64 to 153/70 mm Hg) in all patients (p less than 0.0001). Regurgitant jet area by CDFI increased significantly in both aortic regurgitation (4.5 to 6.2 cm2, p less than 0.0001) and mitral regurgitation (6.2 to 8.2 cm2, p less than 0.001). Patients taking concurrent vasodilator or angiotensin-converting enzyme inhibitor therapy had similar responses to those not receiving long-term therapy. Thus, CDFI detects an increase in aortic and mitral regurgitant jet area induced by isometric exertion. The change in CDFI jet area with handgrip demonstrates the influence of loading conditions on the size of a regurgitant jet area, and suggests that isometric exertion may increase the magnitude of mitral and aortic regurgitation.

Sensitive high-performance liquid chromatographic method for the determination of etodolac in serum.

A sensitive high-performance liquid chromatographic method for the determination of etodolac in serum was developed. The limit of detection was 0.2 microgram/ml. The specificity of the method was demonstrated by the lack of response obtained with a variety of control sera, sera spiked with etodolac congeners, and sera obtained from rats treated with a variety of other drugs.

Confirmation of 11-nor-delta 9-tetrahydrocannabinol in urine as its t-butyldimethylsilyl derivative using GC/MS.

A procedure for the detection and quantitation of 11-nor-delta 9-tetrahydrocannabinol-9-carboxylic acid, the major metabolite of delta 9-tetrahydrocannabinol, in urine is presented. Because a significant portion of the metabolite is present as a conjugated form, the urine was hydrolyzed by the addition of strong base. The solution was then acidified and the metabolite extracted into an organic solvent. It was subsequently converted to the t-butyldimethylsilyl ether and t-butyldimethylsilyl ester, and analyzed by GC/MS utilizing electron ionization (EI). Confirmation of the product was carried out by using selected ion monitoring (SIM) for three ions which represent logical demonstrable fragmentation pathways for the molecule and by comparing their relative abundances to a reference standard. A deuterated analog was carried through the entire process as an internal standard. The method provides excellent linearity and the derivatives are stable for more than 10 days at room temperature.

Dehydrohalogenation of atmospheric contaminants in the space cabin.

A total of nine chlorinated ethanes and ethenes were circulated over lithium hydroxide in a laboratory scale closed system simulator. System volume and lithium hydroxide temperature were varied from that intended to maximize possible reactions to conditions approximating those of a space cabin environment. Of the nine compounds tested, seven were found to be dehydrohalogenated (viz., loss of hydrogen chloride) in the course of one or more experimental treatments. Of particular significance was the conversion of 1,2-dichloroethane to chloroethene, a known carcinogen, and of trichloroethene to dichloroethyne, a highly toxic substance. It is therefore concluded that a potentially hazardous situation exists for the inhabitants of closed ecological systems such as spacecraft, one for which precautions must continue to be taken.

5-Fluorouracil-induced angina.

5-Fluorouracil-induced cardiac ischemia is rare and poorly understood. We present the second known case of catheterization data and provide new information regarding possible mechanisms.

Ethanol production from Eucalyptus plantation thinnings.

Conditions for optimal pretreatment of eucalypt (Eucalyptus dunnii) and spotted gum (Corymbia citriodora) forestry thinning residues for bioethanol production were empirically determined using a 3(3) factorial design. Up to 161mg/g xylose (93% theoretical) was achieved at moderate combined severity factors (CSF) of 1.0-1.6. At CSF>2.0, xylose levels declined, owing to degradation. Moreover at high CSF, depolymerisation of cellulose was evident and corresponded to glucose (155mg/g, ∼33% cellulose) recovery in prehydrolysate. Likewise, efficient saccharification with Cellic® CTec 2 cellulase correlated well with increasing process severity. The best condition yielded 74% of the theoretical conversion and was attained at the height of severity (CSF of 2.48). Saccharomyces cerevisiae efficiently fermented crude E. dunnii hydrolysate within 30h, yielding 18g/L ethanol, representing a glucose to ethanol conversion rate of 0.475g/g (92%). Based on our findings, eucalyptus forest thinnings represent a potential feedstock option for the emerging Australian biofuel industry.

Bilirubin interference with determination of uric acid, cholesterol, and triglycerides in commercial peroxidase-coupled assays, and the effect of ferrocyanide.

We examined the effect of bilirubin on measurement of serum uric acid, cholesterol, and triglyceride in the BMD-8700, Hitachi 705, Multistat III, CentrifiChem, Cobas-Bio, Ektachem 400, aca II, and RA-1000 analyzers. In general, bilirubin interferes more in peroxidase-coupled assays than in either direct methods or those coupled to NAD(P)+. The degree of interference, which can be spectral or chemical, varies and depends on the chromogen and wavelength used. We present data to show the origin and extent of the interference by bilirubin in these systems and demonstrate how ferrocyanide can provide a satisfactory resolution in some cases.

Composition of serum very-low-density and high-density lipoproteins in diabetes.

We examined the cholesterol/protein ratio and the apoprotein composition of serum lipoproteins in a randomly selected population of maturity-onset diabetics and in a group of nondiabetics of similar age. We found no differences in cholesterol distribution between the groups as a whole, but diabetics with above-normal low-density lipoproteins (LDL) had decreased concentrations of high-density lipoprotein (HDL) cholesterol. In the diabetics as a whole, there was an increase in the cholesterol/protein ratio in HDL, a negative correlation between the amounts of LDL cholesterol and HDL cholesterol, an increase in the proportion of apolipoprotein C in very-low-density lipoprotein (VLDL), and a decrease in the proportion of the apolipoprotein AI component of HDL. In diabetic subjects with increased VLDL, there was an increase in the relative amount of apolipoprotein CIII, and a consequent decrease in the ratio of apolipoprotein CII/apolipoprotein CIII in the VLDL. In both diabetic and control subjects, apolipoprotein E and cholesterol content of VLDL were linearly related.

Multiple effects of serum low-density lipoprotein on cultured human fibroblasts.

The effects of serum low-density lipoproteins (LDL) were studied in cultures of human skin fibroblasts grown in medium supplemented with human serum deficient in lipoproteins and in platelet factor. The LDL led to a temporary increase in the rate of cell replication, to increases in the cell content of protein and cholesterol, to an increase in average cell size, and to an increased secretion of glycosaminoglycans. The increases in cholesterol and protein were proportional to the increase in cell size, suggesting that the additional protein and cholesterol were of a structural, rather than a storage, nature. The increase in cell protein during the first few days of exposure to LDL was due to a decrease in the rate of protein degradation. Ultrafiltration of the serum to remove substances of molecular weight less than 30,000 did not reduce the basal rate of cell proliferation but did prevent the stimulation of proliferation by LDL; it did not alter the effect of LDL on cell protein and cholesterol, indicating that the latter responses are independent of the mitogenic action. The response of cells from diabetic donors did not differ from that of normal cells.

Intravascular platelet aggregation and spontaneous contrast.

The purpose of this study was to determine why spontaneous contrast developed after general anesthesia in dogs. Twenty-seven dogs underwent echocardiography before and after pentobarbital or chloralose-urethane general anesthesia. The results showed that none of the 12 dogs receiving pentobarbital and 10 of 15 dogs receiving chloralose-urethane anesthesia developed contrast, in association with large platelet and platelet-neutrophil aggregates (P < 0.01); this effect could also be reproduced in vitro. The administration of adenosine diphosphate or antiplatelet antibody to nine dogs confirmed that intravascular platelet aggregation can cause ultrasonic contrast. The implications of these findings for patients with spontaneous contrast are discussed.

Temporal variability of color Doppler jet areas in patients with mitral and aortic regurgitation.

The temporal variability of color flow jets during regurgitation has not been systematically examined. We therefore analyzed color Doppler images in 52 patients (29 with mitral regurgitation and 23 with aortic regurgitation) for frame-to-frame variability in the size of the regurgitant color jet. Planimetered jet areas varied markedly throughout the flow period, with the difference between the largest and smallest mitral regurgitant jets ranging from 1.1 to 11.9 cm2 in individual patients. Maximal and minimal aortic regurgitant jets varied from 1.5 to 6.6 cm2 between frames. The point during the cardiac cycle at which the largest regurgitant jet area was recorded also varied markedly for mitral and aortic lesions. Mitral regurgitant jets peaked at 51% of systole, with a range from 9% to 100%. The point during diastole at which the maximal aortic regurgitant jet was recorded varied from 2% to 84%, with a mean of 31.2% of the diastolic period. The persistence of the flow disturbance was examined as the percent of systole or diastole during which the maximal jet area remained at least 50% or 75% of its maximal size. Mitral regurgitant jets remained at least one-half maximal size for a mean of 60.7% (range, 20% to 90%) of systole, but remained at 75% of maximal size for a mean of only 39% of systole. Aortic regurgitant jets persisted at over one-half maximal size for a mean of 63.2% (range, 30% to 90%) of diastole, but sustained 75% of maximal size for a mean of only 44% of diastole.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute myocardial infarction in Oklahoma: are we different?

Data regarding 787 patients admitted to Saint Francis Hospital in Tulsa, Oklahoma, with acute myocardial infarction (MI) were analyzed to determine circadian variation and to assess demographic and anatomic characteristics. The study population consisted of 634 men (81%) and 153 women (19%). This cohort displayed a circadian rhythm that nearly duplicated a previously published national data base. As was seen nationally, our patients had a peak incidence between 6 AM and noon. Of the total population, 448 patients had acute cardiac catheterization allowing definition of the infarct vessel. The majority of myocardial infarctions were from right coronary artery occlusions. Men were more likely than women to have an anterior MI. Both men and women were more likely to have an inferior MI if they were less than 65 years of age, though this was more pronounced for women. As the population aged, they were more likely to have an anterior myocardial infarction.

Standardization of a commercial (Boehringer Mannheim diagnostics) enzymic method for cholesterol.

The Laboratory Standardization Panel of the National Cholesterol Education Program recommends that cholesterol method accuracy ideally be within 3% of the true value determined by the Abell-Kendall Reference Method, a component of the National Reference System for Cholesterol. As one of the Abell-Kendall network laboratories established to facilitate cholesterol standardization, the approach we recommend for determining accuracy involves a comparison analysis on patients' specimens by the method in question and by the Abell-Kendall method. Use of fresh specimens precludes matrix interactions that may influence enzymic measurement. Using this approach, we assessed an enzymic method for cholesterol with two instruments (Boehringer Mannheim/Hitachi 717 and 737), with BMD reagent, controls, and calibrator. Fresh and frozen sera were analyzed with both instruments over three days. The Abell-Kendall method was used at the Northwest Lipid Research Center on frozen aliquots of the same sera. Both instruments demonstrated good agreement with the Reference Method, as determined by linear regression; overall bias averaged less than -2% for the Hitachi 717 and -1% for the Hitachi 737 at 2000 mg/L--i.e., within the accuracy recommendation. We observed a difference in bias for fresh and frozen specimens; with the Hitachi 717, fresh specimens exhibited -3% bias at 2000 mg/L, but there was virtually no bias of determinations of frozen specimens.