Midregional pro-A-type natriuretic peptide for diagnosis and prognosis in patients with suspected acute myocardial infarction

We hypothesized that midregional pro-A-type natriuretic peptide (MR-proANP), the stable midregional epitope of proANP, might be useful in the early diagnosis and risk stratification of patients with suspected acute myocardial infarction (AMI). In this multicenter study we measured MR-proANP, cardiac troponin T (cTnT), and high-sensitive cTnT (hs-cTnT) at presentation in 675 consecutive patients presenting to the emergency department with suspected AMI. The final diagnosis was adjudicated by 2 independent cardiologists. Patients were followed 360 days for mortality and AMI. AMI was the final diagnosis in 119 patients (18%). Median MR-proANP levels at presentation were significantly higher in patients with AMI (189 pmol/L, interquartile range 97 to 341) versus patients with another final diagnosis (83 pmol/L, 49 to 144, p <0.001). However, neither the combination of MR-proANP with cTnT nor its combination with hs-cTnT significantly improved diagnostic accuracy as quantified by area under the receiver operating characteristic curve (0.91 vs 0.89 for cTnT alone, p = 0.086; 0.95 vs 0.96 for hs-cTnT, respectively, p = 0.02). Cumulative 360-day mortality/AMI rates were 2.4% in the first, 3.6% in the second, 9.5% in the third, and 18.8% in the fourth quartiles of MR-proANP (p <0.001). MR-proANP (area under the curve 0.76) predicted mortality/AMI independently of and more accurately than cTnT (area under the curve 0.62), hs-cTnT (area under the curve 0.71), and Thrombolysis In Myocardial Infarction risk score (area under the curve 0.72). Net reclassification improvements offered by the additional use of MR-proANP were 0.388 (p <0.001), 0.425 (p <0.001), and 0.217 (p = 0.007), respectively. In conclusion, MR-proANP improves risk prediction for 360-day mortality/AMI but does not seem to help in the early diagnosis of AMI.     

Is Use of BMP-2 Associated with Tumor Growth and Osteoblastic Differentiation in Murine Models of Osteosarcoma?

BackgroundThe putative benefit of rhBMP-2 is in the setting of limb reconstruction using structural allografts, whether it be allograft-prosthetic composites, osteoarticular allografts, or intercalary segmental grafts. There are also potential advantages in augmenting osseointegration of uncemented endoprosthetics and in reducing infection. Recombinant human BMP-2 might mitigate nonunion in structural allograft augmented osteosarcoma limb salvage surgery; however, its use is limited because of concerns about the prooncogenic effects of the agent.Questions/purposes(1) To assess if BMP-2 signaling influences osteosarcoma cell line growth. (2) To characterize degree of osteosarcoma cell line osteoblastic differentiation in response to BMP-2. (3) To assess if BMP-2 signaling has a consistent effect on local or systemic tumor burden in various orthotopic murine models of osteosarcoma.MethodsIn this study, 143b, SaOS-2 and DLM8-M1 osteosarcoma cell lines were transfected with BMP-2 cDNA controlled by a constitutive promoter (experimental) or an empty vector (control) using a PiggyBac transposon system. Cellular proliferation was assessed using a quantitative MTT colorimetric assay. Osteoblastic differentiation was compared between control and experimental cell lines using quantitative real-time polymerase chain reaction of the osteoblastic markers connective tissue growth factor, Runx-2, Osterix, alkaline phosphatase and osteocalcin. Experimental and control cell lines were injected into the proximal tibia of either NOD-SCID (143b and SaOS-2 xenograft model), or C3H (DLM8-M1 syngeneic model) mice. Local tumor burden was quantitatively assessed using tumor volume caliper measurements and bioluminescence, and qualitatively assessed using post-mortem ex vivo microCT. Lung metastasis was qualitatively assessed by the presence of bioluminescence, and incidence was confirmed using histology. rhBMP-2 soaked absorbable collagen sponges (experimental) and sterile-H₂O soaked absorbable collagen sponges (control) were implanted adjacent to 143b proximal tibial cell line injections to compare the effects of exogenous BMP-2 application with endogenous upregulation.ResultsConstitutive expression of BMP-2 increased the in vitro proliferation of 143b cells (absorbance values 1.2 ± 0.1 versus 0.89 ± 0.1, mean difference 0.36 [95% CI 0.12 to 0.6]; p = 0.01), but had no effect on SaOS-2 and DLM8-M1 cell proliferation. In response to constitutive BMP-2 expression, 143b cells had no differences in osteoblastic differentiation, while DLM8-M1 cells downregulated the early marker connective tissue growth factor (mean ΔCt 0.2 ± 0.1 versus 0.6 ± 0.1; p = 0.002) and upregulated the early-mid range marker Runx-2 (mean ΔCt -0.8 ± 0.1 versus -1.1 ± 0.1; p = 0.002), and SaOS-2 cells upregulated the mid-range marker Osterix (mean ΔCt -2.1 ± 0.6 versus -3.9 ± 0.6; p = 0.002). Constitutive expression of BMP-2 resulted in greater 143b and DLM8-M1 local tumor volume (143b: 307.2 ± 106.8 mm³ versus 1316 ± 387.4 mm³, mean difference 1009 mm³ [95% CI 674.5 to 1343]; p < 0.001, DLM8-M1 week four: 0 mm³ versus 326.1 ± 72.8 mm³, mean difference 326.1 mm³ [95% CI 121.2 to 531]; p = 0.009), but modestly reduced local tumor growth in SaOS-2 (9.5 x 10⁸ ± 8.3x10⁸ photons/s versus 9.3 x 10⁷ ± 1.5 x 10⁸ photons/s, mean difference 8.6 x 10⁸ photons/s [95% CI 5.1 x 10⁸ to 1.2 x 10⁹]; p < 0.001). Application of exogenous rhBMP-2 also increased 143b local tumor volume (495 ± 91.9 mm³ versus 1335 ± 102.7 mm³, mean difference 840.3 mm³ [95% CI 671.7 to 1009]; p < 0.001). Incidence of lung metastases was not different between experimental or control groups for all experimental conditions.ConclusionsAs demonstrated by others, ectopic BMP-2 signaling has unpredictable effects on local tumor proliferation in murine models of osteosarcoma and does not consistently result in osteosarcoma cell line differentiation. Further investigations into other methods of safe bone and soft tissue healing augmentation and the use of differentiation therapies is warranted.Clinical RelevanceOur results indicate that BMP-2 has the potential to stimulate the growth of osteosarcoma cells that are poorly responsive to BMP-2 mediated osteoblastic differentiation. As this differentiation potential is unpredictable in the clinical setting, BMP-2 may promote the growth of microscopic residual tumor burden after resection. Our study provides further support for the recommendation to avoid the use of BMP-2 after limb-salvage surgery in patients with osteosarcoma.     

In vitro susceptibility of clinical isolates of Brucella melitensis to fucidic acid

Brucella species are facultative intracellular bacteria, and therefore a limited number of antibiotics are effective against these organisms. The side effects of drug combination schemes, and the incidences of relapses and therapeutic failures, have led to investigations of new drugs to treat brucellosis. The purpose of this study was to test the in vitro susceptibility of 50 Brucella melitensis isolates to fucidic acid, which has not previously been used for the treatment of brucellosis. The minimum inhibitory concentrations (MICs) of fucidic acid to 50 B. melitensis isolates that were obtained from blood and bone marrow cultures of patients with brucellosis were studied by the broth microdilution method. The MIC₅₀ and MIC₉₀ values for the 50 B. melitensis strains susceptibility to fucidic acid were determined to be 0.5 and 2µg/ml, respectively, and the MIC range was 0.125–2.0µg/ml. Further experiments are needed to reassess the activity of fucidic acid against intracellular Brucella spp.     

Intraluminal filling defects on coronary angiography: more than meets the eye

Intraluminal filling defects are occasionally encountered on coronary angiography and often related with coronary thrombi. However, other conditions affecting the coronary arteries may present with similar angiographic findings causing diagnostic uncertainty. Accurate characterization of the angiographic filling defect is critical, particularly in patients planned for a percutaneous coronary intervention (PCI), as diagnosis of a coronary thrombus not only increases the risk of post procedural adverse events but also requires a specific therapeutic approach. In this paper, we report three patients in whom coronary angiography revealed intraluminal filling defects mimicking coronary thrombi. When further investigated with intravascular ultrasound (IVUS) as a part of the planned PCI, the thrombus was excluded and alternate etiology of the filling defect was confirmed in all patients. The angiographic "pseudothrombi" were produced by coronary dissection in one and by heavy calcification within the atherosclerotic plaque in two patients. The use of IVUS allowed accurate characterization of the angiographic filling defect and provided important information to guide management and optimize therapeutic approach.     

Taking the next step in 2005, the year of the diabetic foot

OBJECTIVES: To determine the age-standardized rate of lower limb amputations among Type 2 diabetics admitted to the Port of Spain General Hospital (POSGH), San Fernando General Hospital (SFGH) and Sangre Grande County Hospital (SGCH) for the period 2000-2004. To determine in-hospital mortality following amputation, for the same period. To determine the risk factors that contributed to diabetic foot complications. DESIGN AND METHODS: All patients who had a lower limb amputation at the three major public health institutions in Trinidad during the study period were enrolled. In addition patients attending the surgical out-patient clinic and currently admitted to the ward with a diabetic septic foot was selected for the administration of a questionnaire to determine the major contributing factors. Data on the type of amputation, age, sex, ethnicity, from which an age-standardized mortality rate, was determined for the age group 30-60. RESULTS: Of 822 patient files examined, 515 (80%) of these major amputations were performed on Type 2 diabetics, of which 352 (68%) were AKA and 163 (32%) were BKA. The AKA:BKA ratio for the period 2000-2004 was 2.2:1. There was a significant difference between the mean ages at which females had a major amputation to males (p=0.001). The overall ratio of Africans to South East Asians was 1.5:1 amongst the Type 2 diabetic amputees. For major amputations the average length of stay was found to be 22.5 (0-192) days. The age-standardized rate for the age group 30-60 was 13.85 per 100,000 for 2004. Of 66 deaths, 31 (47%) were septicemia cases and 14 (21%) cardio-respiratory failure cases. Finally, of 97 persons interviewed, the major causative agent for diabetic foot complications and amputations was foot trauma (51%). CONCLUSION: Type 2 diabetic amputation status of Trinidad would seem to have improved as shown by this study. However, steps must be taken to improve patient awareness about prevention and care of the diabetic foot. Doctors must also seek to increase their vigilance when screening diabetic patient in the primary care setting in order to prevent the late detection and treatment of the septic lower limb.     

Paradoxically developed optochiasmatic tuberculoma and tuberculous lymphadenitis: a case report with 18-month follow up by MRI

We report the first case ofextracranial tuberculous lymphadenitis which paradoxically developed during treatment of intracranial tuberculoma. Our patient, a 15-year-old girl who initially presented with meningitis and intracranial tuberculomas, developed extracranial tuberculomas during treatment for central nervous system tuberculosis. She was followed clinically with cerebrospinal fluid (CSF) studies and magnetic resonance imaging (MRI) at three monthly intervals. Within 18 months of specific antituberculous treatment, the patient had fully recovered. The course and response to therapy are discussed in light of the current literature.     

Mid-regional pro-adrenomedullin in the early evaluation of acute chest pain patients

Background

The purpose of this study was to investigate the utility of mid-regional pro-adrenomedullin (MR-proADM) in the early diagnosis and risk stratification of patients with acute chest pain in comparison with established and novel biomarkers and risk scores.

Methods

In this prospective, observational, international, multi-center trial (APACE), MR-proADM was determined in 1179 unselected patients with acute chest pain. Patients were followed for 24 months.

Results

MR-proADM concentrations at presentation were higher in patients with AMI (median: 0.78 nmol/l, IQR 0.60–1.13) than in patients with other diagnoses (0.64 nmol/l, IQR 0.49–0.86 nmol/l; p < 0.001). The diagnostic accuracy of MR-proADM for AMI as quantified by the area under the receiver operating characteristic curve (AUC) was 0.66. Adding MR-proADM to hs-cTnT could not improve its diagnostic accuracy for AMI (p = 0.431). Seventy-six percent of all deaths occurred in the fourth quartile of MR-proADM (> 0.90 nmol/l). Adding MR-proADM to the TIMI-score (AUC 0.87) predicted 1-year mortality more accurately than the TIMI-score alone (AUC 0.82; p < 0.001). Net reclassification improvement (TIMI vs. additionally MR-proADM) amounted to 0.137 (p = 0.012). MR-proADM had higher prognostic accuracy as compared to hs-cTnT in patients with AMI (p = 0.015) and in those without AMI (p = 0.003). MR-proADM at presentation was tantamount to GRACE score and BNP as to its prognostic accuracy for mortality. The AUC for the prediction of cardiovascular events amounted to 0.63.

Conclusions

While MR-proADM does not have clinical utility in the early diagnosis of AMI or predicting cardiovascular events in patients with acute chest pain, it may provide prognostic value for all-cause mortality.     

Early Diagnosis of Myocardial Infarction Using Absolute and Relative Changes in Cardiac Troponin Concentrations

Background

Absolute changes in high-sensitivity cardiac troponin T (hs-cTnT) seem to have higher diagnostic accuracy in the early diagnosis of acute myocardial infarction compared with relative changes. It is unknown whether the same applies to high-sensitivity cardiac troponin I (hs-cTnI) assays and whether the combination of absolute and relative change might further increase accuracy.

Methods

In a prospective, international multicenter study, high-sensitivity cardiac troponin (hs-cTn) was measured with 3 novel assays (hs-cTnT, Roche Diagnostics Corp, Indianapolis, Ind; hs-cTnI, Beckman Coulter Inc, Brea, Calif; hs-cTnI, Siemens, Munich, Germany) in a blinded fashion at presentation and after 1 and 2 hours in a blinded fashion in 830 unselected patients with suspected acute myocardial infarction. The final diagnosis was adjudicated by 2 independent cardiologists.

Results

The area under the receiver operating characteristic curve for diagnosing acute myocardial infarction was significantly higher for 1- and 2-hour absolute versus relative hs-cTn changes for all 3 assays (P < .001). The area under the receiver operating characteristic curve of the combination of 2-hour absolute and relative change (hs-cTnT 0.98 [95% confidence interval {CI}, 0.97-0.99]; hs-cTnI, Beckman Coulter Inc, 0.97 [95% CI, 0.96-0.99]; hs-cTnI, Siemens, 0.96 [95% CI, 0.93-0.99]) were high and provided some benefit compared with the use of absolute change alone for hs-cTnT, but not for the hs-cTnI assays. Reclassification analysis confirmed the superiority of absolute changes versus relative changes.

Conclusions

Absolute changes seem to be the preferred metrics for both hs-cTnT and hs-cTnI in the early diagnosis of acute myocardial infarction. The combination of absolute and relative changes provides a small added value for hs-cTnT, but not for hs-cTnI.     

Systolic blood pressure at Emergency Department presentation and 1-year mortality in acute chest pain patients

Background

High blood pressure at rest has been an established risk factor for cardiovascular disease. However the relationship between Systolic Blood Pressure (SBP) and 1-year-mortality among acute chest pain patients presenting to Emergency Department (ED); and effects of preexisting renal insufficiency, hemodynamic stress — as quantified by Brain Natriuretic Peptide (BNP) and chest pain duration, on this relationship is unknown.

Methods

Data was used from APACE (Advantageous Predictors of Acute Coronary Syndrome Evaluation), a prospective observational multicenter study of 1240 ED chest pain patients. SBP at presentation was categorized into quartiles: Q1 ≤ 127 mm Hg; Q2 128–142 mm Hg; Q3 143–160 mm Hg; Q4 ≥ 161 mm Hg.

Results

60 deaths occurred during 1-year. One-year-mortality-rate showed lower Hazard Ratios for Q2, Q3 and Q4 vs Q1 (HR [95% CI]; 0.39 (0.19–0.78), 0.34 (0.17–0.70), 0.35 (0.17–0.72); p < 0.01 respectively). Cox model adjusted for various demographic and treatment variables showed that participants in Q3 and Q4 had better prognoses than Q1. Patients showed progressively better prognosis from Q2 through Q4 vs Q1 only in patients who presented to ED with for more than 12 h of chest pain duration. Patients with renal insufficiency had lower SBP at presentation than others (p = 0.001). There was no association between the outcome and interaction variable of SBP quartiles and BNP (p = 0.27).

Conclusion

Acute chest pain patients presenting to ED exhibit an inverse association between SBP at presentation and 1-year-mortality; a relationship which appears stronger in those who present with chest pain of greater than 12 h duration.