Continuous-wave second-harmonic generation in the far-UVC pumped by a blue laser diode.

Far-UVC light in the wavelength range of 200-230 nm has attracted renewed interest because of its safety for human exposure and effectiveness in inactivating pathogens. Here we present a compact solid-state far-UVC laser source based on second-harmonic generation (SHG) using a low-cost commercially-available blue laser diode pump. Leveraging the high intensity of light in a nanophotonic waveguide and heterogeneous integration, our approach achieves Cherenkov phase-matching across a bonded interface consisting of a silicon nitride (SiN) waveguide and a beta barium borate (BBO) nonlinear crystal. Through systematic investigations of waveguide dimensions and pump power, we analyze the dependencies of Cherenkov emission angle, conversion efficiency, and output power. Experimental results confirm the feasibility of generating far-UVC, paving the way for mass production in a compact form factor. This solid-state far-UVC laser source shows significant potential for applications in human-safe disinfection, non-line-of-sight free-space communication, and deep-UV Raman spectroscopy.

High resolution, high channel count mid-infrared arrayed waveguide gratings in silicon.

Arrayed waveguide gratings (AWGs) working in the 4.7 µm wavelength range are reported on silicon-on-insulator waveguides with 1500 nm thick silicon and 2 µm thick buried oxide layers. For eight channel devices, three different channel spacings (200 GHz, 100 GHz, and 50 GHz) with cross talk levels of -32.31dB, -31.87dB, and -27.28dB and insertion loss levels of -1.43dB, -4.2dB, and -2.3dB, respectively, are demonstrated. Fourteen channel AWGs with 170 GHz channel spacing and 16 channel AWGs with 87 GHz channel spacing are shown to have a cross talk value of -21.67dB and -24.30dB and insertion loss value of -4.2dB and -3.8dB, respectively. Two AWGs with 10 nm difference in channel peak are designed, and the measurements show a 9.3 nm difference. The transmission spectrum shift as a function of temperature is found to be 0.22 nm/°C.

Efficient second harmonic generation in nanophotonic GaAs-on-insulator waveguides.

Nonlinear frequency conversion plays a crucial role in advancing the functionality of next-generation optical systems. Portable metrology references and quantum networks will demand highly efficient second-order nonlinear devices, and the intense nonlinear interactions of nanophotonic waveguides can be leveraged to meet these requirements. Here we demonstrate second harmonic generation (SHG) in GaAs-on-insulator waveguides with unprecedented efficiency of 40 W-1 for a single-pass device. This result is achieved by minimizing the propagation loss and optimizing phase-matching. We investigate surface-state absorption and design the waveguide geometry for modal phase-matching with tolerance to fabrication variation. A 2.0 µm pump is converted to a 1.0 µm signal in a length of 2.9 mm with a wide signal bandwidth of 148 GHz. Tunable and efficient operation is demonstrated over a temperature range of 45 °C with a slope of 0.24 nm/°C. Wafer-bonding between GaAs and SiO2 is optimized to minimize waveguide loss, and the devices are fabricated on 76 mm wafers with high uniformity. We expect this device to enable fully integrated self-referenced frequency combs and high-rate entangled photon pair generation.

The plasma peptides of breast versus ovarian cancer.

BACKGROUND: There is a need to demonstrate a proof of principle that proteomics has the capacity to analyze plasma from breast cancer versus other diseases and controls in a multisite clinical trial design. The peptides or proteins that show a high observation frequency, and/or precursor intensity, specific to breast cancer plasma might be discovered by comparison to other diseases and matched controls. The endogenous tryptic peptides of breast cancer plasma were compared to ovarian cancer, female normal, sepsis, heart attack, Alzheimer's and multiple sclerosis along with the institution-matched normal and control samples collected directly onto ice. METHODS: Endogenous tryptic peptides were extracted from individual breast cancer and control EDTA plasma samples in a step gradient of acetonitrile, and collected over preparative C18 for LC-ESI-MS/MS with a set of LTQ XL linear quadrupole ion traps working together in parallel to randomly and independently sample clinical populations. The MS/MS spectra were fit to fully tryptic peptides or phosphopeptides within proteins using the X!TANDEM algorithm. The protein observation frequency was counted using the SEQUEST algorithm after selecting the single best charge state and peptide sequence for each MS/MS spectra. The observation frequency was subsequently tested by Chi Square analysis. The log10 precursor intensity was compared by ANOVA in the R statistical system. RESULTS: Peptides and/or phosphopeptides of common plasma proteins such as APOE, C4A, C4B, C3, APOA1, APOC2, APOC4, ITIH3 and ITIH4 showed increased observation frequency and/or precursor intensity in breast cancer. Many cellular proteins also showed large changes in frequency by Chi Square (χ2 > 100, p < 0.0001) in the breast cancer samples such as CPEB1, LTBP4, HIF-1A, IGHE, RAB44, NEFM, C19orf82, SLC35B1, 1D12A, C8orf34, HIF1A, OCLN, EYA1, HLA-DRB1, LARS, PTPDC1, WWC1, ZNF562, PTMA, MGAT1, NDUFA1, NOGOC, OR1E1, OR1E2, CFI, HSA12, GCSH, ELTD1, TBX15, NR2C2, FLJ00045, PDLIM1, GALNT9, ASH2L, PPFIBP1, LRRC4B, SLCO3A1, BHMT2, CS, FAM188B2, LGALS7, SAT2, SFRS8, SLC22A12, WNT9B, SLC2A4, ZNF101, WT1, CCDC47, ERLIN1, SPFH1, EID2, THOC1, DDX47, MREG, PTPRE, EMILIN1, DKFZp779G1236 and MAP3K8 among others. The protein gene symbols with large Chi Square values were significantly enriched in proteins that showed a complex set of previously established functional and structural relationships by STRING analysis. An increase in mean precursor intensity of peptides was observed for QSER1 as well as SLC35B1, IQCJ-SCHIP1, MREG, BHMT2, LGALS7, THOC1, ANXA4, DHDDS, SAT2, PTMA and FYCO1 among others. In contrast, the QSER1 peptide QPKVKAEPPPK was apparently specific to ovarian cancer. CONCLUSION: There was striking agreement between the breast cancer plasma peptides and proteins discovered by LC-ESI-MS/MS with previous biomarkers from tumors, cells lines or body fluids by genetic or biochemical methods. The results indicate that variation in plasma peptides from breast cancer versus ovarian cancer may be directly discovered by LC-ESI-MS/MS that will be a powerful tool for clinical research. It may be possible to use a battery of sensitive and robust linear quadrupole ion traps for random and independent sampling of plasma from a multisite clinical trial.

The plasma peptidome.

BACKGROUND: It may be possible to discover new diagnostic or therapeutic peptides or proteins from blood plasma using LC-ESI-MS/MS to identify, with a linear quadrupole ion trap to identify, quantify and compare the statistical distributions of peptides cleaved ex vivo from plasma samples from different clinical populations. METHODS: A systematic method for the organic fractionation of plasma peptides was applied to identify and quantify the endogenous tryptic peptides from human plasma from multiple institutions by C18 HPLC followed nano electrospray ionization and tandem mass spectrometry (LC-ESI-MS/MS) with a linear quadrupole ion trap. The endogenous tryptic peptides, or tryptic phospho peptides (i.e. without exogenous digestion), were extracted in a mixture of organic solvent and water, dried and collected by preparative C18. The tryptic peptides from 6 institutions with 12 different disease and normal EDTA plasma populations, alongside ice cold controls for pre-analytical variation, were characterized by mass spectrometry. Each patient plasma was precipitated in 90% acetonitrile and the endogenous tryptic peptides extracted by a stepwise gradient of increasing water and then formic acid resulting in 10 sub-fractions. The fractionated peptides were manually collected over preparative C18 and injected for 1508 LC-ESI-MS/MS experiments analyzed in SQL Server R. RESULTS: Peptides that were cleaved in human plasma by a tryptic activity ex vivo provided convenient and sensitive access to most human proteins in plasma that show differences in the frequency or intensity of proteins observed across populations that may have clinical significance. Combination of step wise organic extraction of 200 µL of plasma with nano electrospray resulted in the confident identification and quantification ~ 14,000 gene symbols by X!TANDEM that is the largest number of blood proteins identified to date and shows that you can monitor the ex vivo proteolysis of most human proteins, including interleukins, from blood. A total of 15,968,550 MS/MS spectra ≥ E4 intensity counts were correlated by the SEQUEST and X!TANDEM algorithms to a federated library of 157,478 protein sequences that were filtered for best charge state (2+ or 3+) and peptide sequence in SQL Server resulting in 1,916,672 distinct best-fit peptide correlations for analysis with the R statistical system. SEQUEST identified some 140,054 protein accessions, or some ~ 26,000 gene symbols, proteins or loci, with at least 5 independent correlations. The X!TANDEM algorithm made at least 5 best fit correlations to more than 14,000 protein gene symbols with p-values and FDR corrected q-values of ~ 0.001 or less. Log10 peptide intensity values showed a Gaussian distribution from E8 to E4 arbitrary counts by quantile plot, and significant variation in average precursor intensity across the disease and controls treatments by ANOVA with means compared by the Tukey-Kramer test. STRING analysis of the top 2000 gene symbols showed a tight association of cellular proteins that were apparently present in the plasma as protein complexes with related cellular components, molecular functions and biological processes. CONCLUSIONS: The random and independent sampling of pre-fractionated blood peptides by LC-ESI-MS/MS with SQL Server-R analysis revealed the largest plasma proteome to date and was a practical method to quantify and compare the frequency or log10 intensity of individual proteins cleaved ex vivo across populations of plasma samples from multiple clinical locations to discover treatment-specific variation using classical statistics suitable for clinical science. It was possible to identify and quantify nearly all human proteins from EDTA plasma and compare the results of thousands of LC-ESI-MS/MS experiments from multiple clinical populations using standard database methods in SQL Server and classical statistical strategies in the R data analysis system.

Silicon arrayed waveguide gratings at 2.0-µm wavelength characterized with an on-chip resonator.

Low-loss arrayed waveguide gratings (AWGs) are demonstrated at a 2.0-µm wavelength. These devices promote rapidly developing photonic applications, supported by the recent development of mid-infrared lasers integrated on silicon (Si). Multi-spectral photonic integrated circuits at 2.0-µm are envisioned since the AWGs are fabricated with the 500-nm-thick Si-on-insulator platform compatible with recently demonstrated lasers and semiconductor optical amplifiers on Si. Characterization with the AWG-ring method improves the on-chip transmission uncertainty to ∼6% compared to the conventional method with an uncertainty of ∼53%. Channel losses of ∼2.4 dB are found, with -31 dB crosstalk per channel. Fully integrated multi-spectral sources at 2.0 µm with pump lasers, low-loss multiplexers, and an output amplifier are now feasible.

The plasma peptides of ovarian cancer.

BACKGROUND: It may be possible to discover new diagnostic or therapeutic peptides or proteins from blood plasma by using liquid chromatography and tandem mass spectrometry to identify, quantify and compare the peptides cleaved ex vivo from different clinical populations. The endogenous tryptic peptides of ovarian cancer plasma were compared to breast cancer and female cancer normal controls, other diseases with their matched or normal controls, plus ice cold plasma to control for pre-analytical variation. METHODS: The endogenous tryptic peptides or tryptic phospho peptides (i.e. without exogenous digestion) were analyzed from 200 µl of EDTA plasma. The plasma peptides were extracted by a step gradient of organic/water with differential centrifugation, dried, and collected over C18 for analytical HPLC nano electrospray ionization and tandem mass spectrometry (LC-ESI-MS/MS) with a linear quadrupole ion trap. The endogenous peptides of ovarian cancer were compared to multiple disease and normal samples from different institutions alongside ice cold controls. Peptides were randomly and independently sampled by LC-ESI-MS/MS. Precursor ions from peptides > E4 counts were identified by the SEQUEST and X!TANDEM algorithms, filtered in SQL Server, before testing of frequency counts by Chi Square (χ2), for analysis with the STRING algorithm, and comparison of precursor intensity by ANOVA in the R statistical system with the Tukey-Kramer Honestly Significant Difference (HSD) test. RESULTS: Peptides and/or phosphopeptides of common plasma proteins such as HPR, HP, HPX, and SERPINA1 showed increased observation frequency and/or precursor intensity in ovarian cancer. Many cellular proteins showed large changes in frequency by Chi Square (χ2 > 60, p < 0.0001) in the ovarian cancer samples such as ZNF91, ZNF254, F13A1, LOC102723511, ZNF253, QSER1, P4HA1, GPC6, LMNB2, PYGB, NBR1, CCNI2, LOC101930455, TRPM5, IGSF1, ITGB1, CHD6, SIRT1, NEFM, SKOR2, SUPT20HL1, PLCE1, CCDC148, CPSF3, MORN3, NMI, XTP11, LOC101927572, SMC5, SEMA6B, LOXL3, SEZ6L2, and DHCR24. The protein gene symbols with large Chi Square values were significantly enriched in proteins that showed a complex set of previously established functional and structural relationships by STRING analysis. Analysis of the frequently observed proteins by ANOVA confirmed increases in mean precursor intensity in ZFN91, TRPM5, SIRT1, CHD6, RIMS1, LOC101930455 (XP_005275896), CCDC37 and GIMAP4 between ovarian cancer versus normal female and other diseases or controls by the Tukey-Kramer HSD test. CONCLUSION: Here we show that separation of endogenous peptides with a step gradient of organic/water and differential centrifugation followed by random and independent sampling by LC-ESI-MS/MS with analysis of peptide frequency and intensity by SQL Server and R revealed significant difference in the ex vivo cleavage of peptides between ovarian cancer and other clinical treatments. There was striking agreement between the proteins discovered from cancer plasma versus previous biomarkers discovered in tumors by genetic or biochemical methods. The results indicate that variation in plasma proteins from ovarian cancer may be directly discovered by LC-ESI-MS/MS that will be a powerful tool for clinical research.

Low-loss demonstration and refined characterization of silicon arrayed waveguide gratings in the near-infrared.

A resonator is characterized with two cascaded arrayed waveguide gratings (AWGs) in a ring formation. From this structure, the on-chip transmittance of a single AWG is extracted, independent of coupling efficiency. It provides improved measurement accuracy, which is essential for developing AWGs with extremely low loss. Previous methods normalize the off-chip AWG transmittance to that of a reference waveguide with identical coupling, leading to an uncertainty of ∼14 % on the extracted on-chip AWG transmittance. It is shown here that the proposed "AWG-ring" method reduces this value to ∼3 %. A low-loss silicon AWG and an AWG-ring are fabricated. Channel losses with <2 dB are found, with a crosstalk per channel approaching -30 dB. Such an efficient wavelength multiplexing device is beneficial for the integration of spectroscopic sensors, multi-spectral lasers, and further progress in optical communication systems.

Heterogeneous integration of lithium niobate and silicon nitride waveguides for wafer-scale photonic integrated circuits on silicon.

An ideal photonic integrated circuit for nonlinear photonic applications requires high optical nonlinearities and low loss. This work demonstrates a heterogeneous platform by bonding lithium niobate (LN) thin films onto a silicon nitride (Si3N4) waveguide layer on silicon. It not only provides large second- and third-order nonlinear coefficients, but also shows low propagation loss in both the Si3N4 and the LN-Si3N4 waveguides. The tapers enable low-loss-mode transitions between these two waveguides. This platform is essential for various on-chip applications, e.g., modulators, frequency conversions, and quantum communications.

Multi-octave spectral beam combiner on ultra-broadband photonic integrated circuit platform.

We present the design of a novel platform that is able to combine optical frequency bands spanning 4.2 octaves from ultraviolet to mid-wave infrared into a single, low M2 output waveguide. We present the design and realization of a key component in this platform that combines the wavelength bands of 350 nm - 1500 nm and 1500 nm - 6500 nm with demonstrated efficiency greater than 90% in near-infrared and mid-wave infrared. The multi-octave spectral beam combiner concept is realized using an integrated platform with silicon nitride waveguides and silicon waveguides. Simulated bandwidth is shown to be over four octaves, and measured bandwidth is shown over two octaves, limited by the availability of sources.

Heterogeneously integrated 2.0 µm CW hybrid silicon lasers at room temperature.

Here we experimentally demonstrate room temperature, continuous-wave (CW), 2.0 µm wavelength lasers heterogeneously integrated on silicon. Molecular wafer bonding of InP to Si is employed. These hybrid silicon lasers operate CW up to 35°C and emit up to 4.2 mW of single-facet CW power at room temperature. III-V tapers transfer light from a hybrid III-V/silicon optical mode into a Si waveguide mode. These lasers enable the realization of a number of sensing and detection applications in compact silicon photonic systems.

A direct comparison of the natriuretic peptides and their relationship to survival in chronic heart failure of a presumed non-ischaemic origin.

The natriuretic peptides have been validated as sensitive and specific markers of left ventricular dysfunction; brain natriuretic peptide (BNP), N-terminal atrial natriuretic peptide (NT-proANP) and N-terminal brain natriuretic peptide (NT-proBNP) elevations have been associated with New York Heart Association (NYHA) Class I-IV heart failure. We directly compared the association of each of these markers with 1-year survival in 173 patients with chronic heart failure of a presumed nonischaemic origin entering the PRAISE-2 Trial, a clinical study which assessed the therapeutic effect of Amlodipine in patients with NYHA Class III and IV heart failure and a left ventricular ejection fraction (LVEF) <30%. BNP, NT-proBNP, and NT-proANP levels were all correlated with 1-year mortality by univariate Cox proportional hazards analyses. With respect to multivariate Cox proportional hazards regression models containing variables deemed significant in univariate analyses, NT-proANP alone was identified as an independent predictor of 1-year mortality when log-transformed continuous covariates were utilized in the analysis. When the analysis was repeated using dichotomous covariates, NT-proANP remained the most significant predictor of 1-year mortality, followed by NT-proBNP, NYHA classification and BNP. We conclude that all three natriuretic peptides are significant predictors of short-term mortality in subjects with chronic congestive heart failure (CHF) of a presumed nonischaemic origin. Larger prospective studies are required to validate the clinical utility of NT-proANP as a discriminating marker of short-term survival, and to validate proposed cutoffs of approximately 2300 pmol/l for NT-proANP, 1500 pg/ml for NT-proBNP, and 50 pmol/l for BNP as prognostic indicators of adverse short-term outcome.

Cardiac troponin I, a possible predictor of survival in patients with stable congestive heart failure.

BACKGROUND: Cardiac troponin I (cTnI) has been validated as a sensitive and specific marker of myocyte damage, and is elevated in some patients with congestive heart failure. OBJECTIVE: To assess the relationship between elevated levels of cTnI and survival in stable patients with congestive heart failure. PATIENTS AND METHODS: It was assessed whether detectable serial levels of cTnI were associated with mortality in 211 patients with stable, severe heart failure at entry and one month into the Prospective Randomized Flosequinan Longevity Evaluation (PROFILE) study. Of these patients, 66 also had measurements taken at 12 months. RESULTS: Patients were New York Heart Association (NYHA) class III (n=197) or IV (n=14), with a baseline left ventricular ejection fraction of 22+/-7% (range 8% to 35%). Patients with a detectable level of cTnI at one month had an increased mortality (OR 2.608 [95% CI 1.061 to 6.409]; P=0.037). The association between mortality and detectable cTnI levels at baseline or 12 months did not reach statistical significance. Patients with a cTnI level that rose or remained elevated between baseline and one month had a higher mortality rate (50%) than those in whom the cTnI level fell (9%) between baseline and one month (P=0.025). In a multivariate model of survival that included sex, treatment, age, left ventricular ejection fraction, NYHA class and creatinine, only detectable levels of cTnI at one month were associated with survival (P=0.037). CONCLUSIONS: cTnI is released in stable, chronic heart failure and is associated with a poor prognosis, independent of other important risk factors. The risk is particularly elevated when detectable cTnI levels rise or remain elevated over time.

Troponin is more useful than creatine kinase in predicting one-year mortality among acute coronary syndrome patients.

AIMS: To compare the long-term prognostic value of troponins (Tn) vs. conventional cardiac biomarker creatine kinase (CK) and CK-MB across the spectrum of acute coronary syndromes (ACS). METHODS AND RESULTS: In the prospective, observational Canadian ACS Registry, 4627 patients with ACS were enrolled from 51 centres. The CK, CK-MB, Tn samples were analysed in each hospital clinical laboratory and the results related to the reference levels of the individual laboratories. The study cohort comprised 3138 (67.8%) patients who had both CK (or CK-MB) and Tn measurements during the first 24 h of hospitalisation. Vital status at one-year was determined by standardized telephone interview. 61.2% and 59.0% of patients had abnormal Tn and CK (or CK-MB) levels, respectively. Vital status at one-year was ascertained for 2950 patients (6% lost to follow-up). Among patients with normal CK (or CK-MB) levels, elevated Tn was associated with increased one-year mortality (odds ratio [OR] 2.06; 95% CI 1.37-3.11; P=0.001). Similarly, among patients with abnormal CK (or CK-MB) levels, abnormal Tn predicted higher one-year mortality (OR 1.83; 95% CI 1.14-2.93; P=0.01). In contrast, abnormal CK (or CK-MB) was not predictive of mortality after stratification by Tn status. In multivariable analysis controlling for other known prognosticators including creatinine, abnormal Tn (adjusted OR 1.78; 95% CI 1.30-2.44; P<0.001) but not CK/CK-MB was independently associated with increased one-year mortality. CONCLUSIONS: Elevated Tn was independently associated with worse outcome at one-year, while CK or CK-MB status did not provide incremental prognostic information. Our findings support the use of Tn in the risk stratification of unselected ACS patients.

Human serum proteins preseparated by electrophoresis or chromatography followed by tandem mass spectrometry.

Electrophoretic and chromatographic sample preparations were compared and together detected the presence of some 600 types of protein products in human serum. Proteins from crude serum preseparated by ionic electrophoresis, chromatography, or a combination of both were analyzed. Proteins were digested with trypsin or chymotrypsin. Naturally occurring peptides were also collected by reversed-phase chromatography. The resulting peptides were identified by tandem mass spectrometry. The peptides were either desorbed by a laser from a metal chip into a quadrupole-time-of-flight mass spectrometer or ionized as an electro-spray from reversed-phase chromatography via a metal needle under voltage into an ion-trap mass spectrometer. All of the commonly known proteins associated with serum were detected, and the two mass spectrometers agreed on the identity of abundant serum proteins. Preseparation of serum proteins prior to digestion markedly enhanced the capacity to detect un-common proteins from blood. Electrophoretic- and chromatography-based experiments were found to be complementary. Many novel cellular proteins not previously associated with serum were recorded.

Can troponin I measurement predict short-term serious cardiac outcomes in patients presenting to the emergency department with possible acute coronary syndrome?

OBJECTIVE: To determine the ability of troponin I (TnI) measurement to predict the likelihood of a serious cardiac outcome over the subsequent 72 hours in patients presenting to the emergency department (ED) with symptoms suggestive of an acute coronary syndrome. METHODS: This prospective observational study enrolled consecutive patients presenting to 2 urban tertiary care hospital EDs over a 5-week period. Eligible patients included those for whom a TnI test was ordered within 24 hours of arrival and in whom no serious cardiac outcome occurred before the test result was available. Patients were followed for 72 hours and serious cardiac outcomes documented; these included cardiovascular death, myocardial infarction, congestive heart failure, serious arrhythmia and refractory pain. We calculated likelihood ratios (LRs) to describe the association of the TnI result with serious cardiac outcomes. RESULTS: Of the 352 enrolled patients, 20 had a serious cardiac outcome within 72 hours of ED presentation. The derived LRs (and 95% confidence interval [CI]) were 0.5 (0.3-0.9) for TnI values <0.5 microg/L, 1.6 (0.4-6.5) for TnI values from 0.5 to 2.0 microg/L, 5.8 (1.7-19.5) for TnI values from >2.0 to 10.0 microg/L and 14.4 (4.8-42.9) for TnI values >10.0 microg/L. CONCLUSIONS: TnI values >2.0 microg/L are associated with an increased probability of serious cardiac outcomes within 72 hours. TnI values between 0.5 and 2.0 microg/L are weakly positive predictors. TnI values <0.5 microg/L have LRs in the range of 0.5 and thus are weakly negative predictors, not substantially decreasing the likelihood of serious cardiac outcomes, particularly in patients with a moderate or high pretest probability.

Processing of serum proteins underlies the mass spectral fingerprinting of myocardial infarction.

The MALDI-TOF spectra of peptides from the sera of normal and myocardial infarction patients produced patterns that provided an accurate diagnostic of MI. In myocardial infarction, the spectral pattern originated from the cleavage of complement C3 alpha chain to release the C3f peptide and cleavage of fibrinogen to release peptide A. The fibrinogen peptide A and complement C3f peptide were in turn progressively truncated by aminopeptidases to produce two families of fragments that formed the characteristic spectral pattern of MI. Time course and inhibitor studies demonstrated that the peptide patterns in the serum reflect the balance of disease-specific-protease and aminopeptidase activity ex vivo.

Relation of circulating cardiac myosin light chain 1 isoform in stable severe congestive heart failure to survival and treatment with flosequinan.

The myocardial contractile protein myosin light chain 1 isoform (MLC-1) is released into the circulation during myocyte necrosis and could thus be a marker of low-grade myocardial damage and of poor prognosis in patients with heart failure. Two hundred eighteen patients with stable heart failure (ejection fraction [EF] <35%) and in New York Heart Association (NYHA) class III to IV had MLC-1 measured at baseline and 1 month after being randomized to the direct vasodilator flosequinan or placebo. Patients were followed a mean of 302 +/- 142 days. The prognostic value of an increase in MLC-1 above the 98th percentile of normal controls was compared with that of conventional prognostic variables in heart failure. MLC-1 was increased in over half of patients at baseline and 1 month, and this was associated with increased age, NYHA class IV, and renal insufficiency. By Kaplan-Meier survival analysis, patients with a baseline increase in MLC-1 had a greater mortality (26%) than those without an increase (15%) (p = 0.043). A significant interaction among MLC-1, survival, and treatment was found (p = 0.043). In the placebo group, MLC-1 was associated with increased mortality (29% vs 12%, p = 0.025), whereas there was no significant difference among patients receiving flosequinan. In a multivariate logistic regression model including age, treatment, and left ventricular (LV) ejection fraction, the MLC-1 chain was most predictive of mortality (p = 0.049). Thus, circulating MLC-1 is elevated in over half of patients with stable severe heart failure, and this increase is associated with a poor prognosis. Flosequinan treatment eliminates this association, highlighting the complexity of the relation between cardiac myocyte damage, drug treatment, and mortality.

Elevated cardiac troponin levels in patients with submassive pulmonary embolism.

BACKGROUND: Cardiac troponins are reliable markers of myocardial injury that are being used increasingly in patients presenting with undifferentiated chest pain or dyspnea to diagnose an acute coronary syndrome. If elevated cardiac troponin levels also occur in patients with pulmonary embolism because of right ventricular dilation and myocardial injury, such patients could be misdiagnosed. We performed a prospective cohort study to determine the prevalence of elevated cardiac troponin I (cTnI) levels in patients with submassive pulmonary embolism. METHODS: Consecutive patients with objectively confirmed submassive pulmonary embolism and no previous history of ischemic heart disease, other cardiac disease, or renal insufficiency were included. Creatine kinase and cTnI levels were measured within 24 hours of clinical presentation on 2 occasions 8 to 12 hours apart. RESULTS: Of 24 patients with submassive pulmonary embolism, 5 (20.8%) had elevated cTnI levels of 0.4 microg/L or higher (95% confidence interval, 7.1-42.2%). One of these patients had a cTnI level higher than 2.3 microg/L that was suggestive of myocardial infarction. CONCLUSION: Pulmonary embolism should be considered in the differential diagnosis of patients presenting with undifferentiated chest pain or dyspnea and an elevated cardiac troponin level.