Showing papers by "Università Campus Bio-Medico published in 2000"

Early cervical carcinoma: the natural history of lymph node involvement redefined on the basis of thorough parametrectomy and giant section study.

Abstract: BACKGROUND Although parametrectomy is the most difficult step in the surgical treatment of cervical carcinoma and is the main cause of postoperative complications, little attention has been given to the patterns of parametrial spread. METHODS Sixty-nine patients with previously untreated cervical carcinoma (Federation Internationale de Gynecologie et d'Obstetrique [FIGO] Stage IB1, 49 patients [71%]; Stage IB2, 8 patients [12%]; and Stage IIA, 12 patients [17%]; squamous, 59 patients [86%]; and adenocarcinoma, 10 patients [14%]) underwent radical hysterectomy and pelvic ± aortic lymphadenectomy. Hysterectomy specimens were processed with the giant section technique. To obtain a thorough three-dimensional assessment of the paracervical tissue, both the superficial and deep layers of the cervicovesical ligament (anterior parametrium) and the uterosacral ligament (posterior parametrium) were separated from the uterus and submitted for pathologic evaluation. After resection of the lateral parametrium with hemoclips, the lympho-fatty tissue remaining around the pudendal vessels was removed carefully and referred to as “the distal part of the lateral parametrium.” RESULTS When analyzing all the parametria, lymph nodes were present in 64 patients (93%). Clinically undetected parametrial involvement was found by pathologic examination in 15 Stage IB1 patients (31%), 5 Stage IB2 patients (63%), and 7 Stage IIA patients (58%). Metastases were found in the cardinal, cervicovesical, and sacrouterine ligaments and principally were comprised of lymph node and vascular space invasion. Twenty-five patients (36%) had pelvic lymph node metastases whereas concomitant parametrial involvement was observed in all patients. The overall 5-year survival was 91%, being higher for parametria and lymph node negative patients (100%) than for those with lymph node and/or parametrial metastases (78%). CONCLUSIONS A three-dimensional pathologic assessment showed that subclinical parametrial spreading of the so-called “early” tumors (Stage IB-IIA) occurred in approximately 30–60% of these patients, and metastasis to the pelvic lymph nodes always was associated with parametrial disease. A better understanding of the patterns of parametrial diffusion will improve knowledge of the natural history of cervical carcinoma and in the future may influence the treatment of these patients. Furthermore, pathologic assessment of cervical carcinoma should be modified to evaluate correctly the parametrial status of each patient. The current routine pathologic evaluation of the parametria makes it very difficult to detect lymph node metastases and tumor emboli. Cancer 2000;88:2267–74. © 2000 American Cancer Society.

Lack of association between serotonin transporter gene promoter variants and autistic disorder in two ethnically distinct samples.

Abstract: Family-based studies performed to date provide conflicting evidence of linkage/association between autistic disorder and either the “short” [Cook et al., 1997: Mol Psychiatry 2:247–250] or the “long” [Klauck et al., 1997: Hum Mol Genet 6:2233–2238] allele of a polymorphic repeat located in the serotonin transporter (5-HTT) gene promoter region, affecting 5-HTT gene expression [Lesch et al., 1996: Science 274:1527–1531]. The present study was designed to assess linkage and linkage disequilibrium in two new ethnically distinct samples of families with primary autistic probands. The 5-HTT promoter repeat was genotyped in 54 singleton families collected in Italy and in 32 singleton and 5 multiplex families collected in the U.S.A., yielding a total sample of 98 trios. Linkage/association between 5-HTT gene promoter alleles and autistic disorder was assessed using the transmission/disequilibrium test (TDT) and the haplotype-based haplotype relative risk (HHRR). Both the Italian and the American samples, either singly or combined, displayed no evidence of linkage/association between 5-HTT gene promoter alleles and autistic disorder. Our findings do not support prominent contributions of 5-HTT gene variants to the pathogenesis of idiopathic infantile autism. Heterogeneity in pathogenetic mechanisms underlying the disease may require that linkage/association studies be targeted toward patient subgroups isolated on the basis of specific biochemical markers, such as serotonin (5-HT) blood levels. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:123–127, 2000. © 2000 Wiley-Liss, Inc.

Adenosine deaminase alleles and autistic disorder: Case-control and family-based association studies

Abstract: Adenosine deaminase (ADA) plays a relevant role in purine metabolism, immune responses, and peptidase activity, which may be altered in some autistic patients. Codominant ADA1 and ADA2 alleles code for ADA1 and ADA2 allozymes, the most frequent protein isoforms in the general population. Individuals carrying one copy of the ADA2 allele display 15 to 20% lower catalytic activity compared to ADA1 homozygotes. Recent preliminary data suggest that ADA2 alleles may be more frequent among autistic patients than healthy controls. The present study was undertaken to replicate these findings in a new case-control study, to test for linkage/association using a family-based design, and to characterize ADA2-carrying patients by serotonin blood levels, peptiduria, and head circumference. ADA2 alleles were significantly more frequent in 91 Caucasian autistic patients of Italian descent than in 152 unaffected controls (17.6% vs. 7.9%, P = 0.018), as well as among their fathers. Family-based tests involving these 91 singleton families, as well as 44 additional Caucasian-American trios, did not support significant linkage/association. However, the observed preferential maternal transmission of ADA2 alleles, if replicated, may point toward linkage disequilibrium between the ADA2 polymorphism and an imprinted gene variant located in its vicinity. Racial and ethnic differences in ADA allelic distributions, together with the low frequency of the ADA2 allele, may pose methodological problems to future linkage/association studies. Direct assessments of ADA catalytic activity in autistic individuals and unaffected siblings carrying ADA1/ADA1 vs ADA1/ADA2 genotypes may provide stronger evidence of ADA2 contributions to autistic disorder. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:784–790, 2000. © 2000 Wiley-Liss, Inc.

Serotonin Depletion and Barrel Cortex Development: Impact of Growth Impairment vs. Serotonin Effects on Thalamocortical Endings

Abstract: Converging evidence supports a role of serotonin (5-hydroxytryptamine; 5-HT) in barrel cortex development. Systemic administration of 5-HT-depleting drugs reduces cross-sectional whisker barrel areas in the somatosensory cortex (SSC) of neonatal rats. Here we assess the relative impact on barrel pattern formation of (i) 5-HT depletion and (ii) decreased brain growth, which is often associated with pharmacological 5-HT depletion, by comparing the effects of 5-HT-depleting drugs with those of reduced protein intake. Left hemisphere 5-HT levels in the SSC and right hemisphere whisker barrel areas were assessed at postnatal day 6 (P6) in the same animal following injection of p-chloroamphetamine (PCA) or p-chlorophenylalanine (PCPA) at P0. Both drugs significantly reduced cortical 5-HT content and mean barrel areas at P6, but also body and brain growth. Differences in brain weight accounted for 84.4% of the variance in barrel size, with negligible contributions by cortical 5-HT content. PCPA-treated animals sacrificed at P14 yielded similar trends, albeit less pronounced. Finally, reduced protein intake resulted in lower body weight and cortical 5-HT levels at P6, but yielded no change in brain weight or mean barrel area. Barrel formation therefore appears markedly less sensitive to 5-HT depletion per se than to drug-induced growth impairment.

Frameshift mutations at coding mononucleotide repeat microsatellites in endometrial carcinoma with microsatellite instability.

Abstract: BACKGROUND Microsatellite instability (MI) is a frequent occurrence in endometrioid carcinoma of the endometrium (EC). Several genes known to contain mononucleotide short tracts in their coding sequences (TGF-β RII, IGFIIR, BAX, hMSH6, and hMSH3) are likely targets for mutations in these tumors. METHODS DNA from 24 patients with EC and MI was extracted from blood and from fresh-frozen and paraffin embedded tumor tissue. Seven of these patients were found to have metastatic spread to paraaortic lymph nodes. DNA also was studied from 10 patients with EC without MI. RESULTS Frameshift mutations at coding mononucleotide repeats were detected by single strand conformation polymorphism analysis and DNA sequencing. Frameshift mutations were detected more frequently in BAX (11 of 24 MI positive (+) tumors; 45.8%) than in TGF-β RII (0 of 24 tumors; 0%), IGFIIR (3 of 24 tumors; 12.5%), hMSH3 (6 of 24 tumors; 25%), or hMSH6 (0 of 24 tumors; 0%). The mutations frequently were distributed heterogeneously throughout the tumors. Overall, frameshift mutations at 1 or more of these mononucleotide repeat microsatellites were found in 17 of 24 MI+ tumors (70.8%) but in none of the 10 MI negative neoplasms. In the seven EC patients with lymph node metastases, mutations in IGFRII were found more commonly in those with metastatic (three of seven patients) rather than primary (one of seven) tumors. CONCLUSIONS The results of the current study confirm that BAX is an important target gene in ECs with MI. The frequent detection of IGFRII frameshift mutations in lymph node metastases suggest that IGFRII may play a role in tumor progression in these patients. Cancer 2000;88:2290–7. © 2000 American Cancer Society.

Altered intestinal transport of amino acids in cirrhotic rats: the effect of insulin-like growth factor-I

Abstract: The intestine is an important target organ for insulin-like growth factor-I (IGF-I), an anabolic hormone synthesized in the liver upon growth hormone (GH) stimulation. Levels of IGF-I are reduced in cirrhosis, and altered GH/IGF-I axis may contribute to malnutrition in cirrhotic patients. Our aim was to study Na(+)-dependent jejunal transport of amino acids (L-leucine, L-proline, L-glutamic acid, and L-cysteine) in cirrhotic rats and to analyze the effect of IGF-I on this function. IGF-I or saline was administered for 2 wk to rats with CCl(4)-induced cirrhosis and saline was administered to healthy control rats. Transport of amino acids was assessed in brush-border membrane vesicles (BBMV) using (14)C- or (35)S-labeled amino acids, and the kinetic constants V(max) and K(t) were determined. Na(+)-independent uptake of L-leucine, L-proline, L-glutamic acid, and L-cysteine by BBMV was similar in all groups. Na(+)-dependent uptake of all four amino acids was significantly diminished in cirrhotic rats compared with both controls and IGF-I-treated cirrhotic rats. The latter two groups exhibited similar V(max) and K(t), whereas untreated cirrhotic rats had reduced V(max) and increased K(t) compared with normal controls and IGF-I-treated cirrhotic animals. In conclusion, the transport of all four tested amino acids by BBMV is impaired in cirrhotic rats, and low doses of IGF-I can correct this defect.

Deafferentation-induced apoptosis of neurons in thalamic somatosensory nuclei of the newborn rat: critical period and rescue from cell death by peripherally applied neurotrophins.

Abstract: This study shows that unilateral transection of the infraorbital nerve (ION) in newborn (P0) rats induces apoptosis in the contralateral ventrobasal thalamic (VB) complex, as evidenced by terminal transferase-mediated deoxyuridine triphosphate-biotin nick end labelling (TUNEL) and electron miscroscopy. Double-labelling experiments using retrograde transport of labelled microspheres injected into the barrel cortex, followed by TUNEL staining, show that TUNEL-positive cells are thalamocortical neurons. The number of TUNEL-positive cells had begun to increase by 24 h postlesion, increased further 48 h after nerve section, and decreased to control levels after 120 h. Lesion-induced apoptosis in the VB complex is less pronounced if ION section is performed at P4, and disappears if the lesion is performed at P7. This time course closely matches the critical period of lesion-induced plasticity in the barrel cortex. Nerve growth factor (NGF) or brain-derived neurotrophic factor (BDNF), applied on the ION stump alone or in combination, are able to partially rescue thalamic neurons from apoptosis. Total cell counts in the VB complex of P7 animals that underwent ION section at P0 confirm the rescuing effect of BDNF and NGF. Blockade of axonal transport in the ION mimics the effect of ION section. These data suggest that survival-promoting signals from the periphery, maybe neurotrophins, are required for the survival of higher-order neurons in the somatosensory system during the period of fine-tuning of neuronal connections. We also propose that anterograde transneuronal degeneration in the neonatal rat trigeminal system may represent a new animal model for studying the pathways of programmed cell death in vivo.

Early and long-term results of stenting of diffuse coronary artery disease.

Abstract: Diffuse coronary artery disease (CAD) is considered unfavorable for interventional procedures; however, the results of stenting of diffuse CAD have not been completely characterized. We performed stenting in 100 consecutive patients with diffuse CAD, defined as significant stenosis >20 mm (n = 59 patients), multiple significant stenoses in the same artery (n = 23 patients), or significant narrowing involving the whole length of the coronary artery (n = 18 patients). Angiographic success was achieved in 103 arteries (100%) and clinical success was obtained in all 100 patients. There were no deaths; no patient had stent closure, acute myocardial infarction, or required emergency coronary artery bypass surgery. All 100 patients had >6 months follow-up (mean 18 ± 7 months, range 7 to 31); 77 (77%) remained asymptomatic, and 5 (5%) had acute myocardial infarction, of whom 2 died (2%). In-stent restenosis was observed in 12 patients (12%) and repeat angioplasty was performed in 10. Including those patients who underwent repeat angioplasty, 89 (89%) maintained clinical improvement and 95 (95%) were alive and free of bypass surgery during follow-up. Life-table analysis showed 86% freedom from death, myocardial infarction, and target lesion revascularization at 28 months. Thus, selected patients with diffuse CAD may be treated with satisfactory acute and long-term results by stent implantation.

Treatment of severe hypercholesterolemia in apolipoprotein E-deficient mice by intramuscular injection of plasmid DNA.

Abstract: We report on systemic delivery and long-term biological effects of apolipoprotein E (apoE) obtained by intramuscular (i.m.) plasmid DNA injection. ApoE plays an important role in lipoprotein catabolism and apoE knock-out mice develop severe hypercholesterolemia and diffuse atherosclerosis. We have injected apoE-deficient mice with 80 microg of a plasmid vector (pCMV-E3) encoding the human apoE3 cDNA under the control of the CMV promoter-enhancer in both posterior legs. Local expression of the transgene was demonstrated throughout 16 weeks. Human apoE3 recombinant protein reached 0.6 ng/ml serum level. After i.m. injection of pCMV-E3 expression vector the mean serum cholesterol concentrations decreased from 439 +/- 57 mg/dl to 253 +/- 99 mg/dl (P < 0.05) 2 weeks after injection and persisted at a significantly reduced level throughout the 16 weeks observation period (P < 0.005). Serum cholesterol was unaffected and reached an absolute level of 636 +/- 67 mg/dl in control groups. Finally, injection of pCMV-E3 into apoE-deficient mice resulted in a redistribution of cholesterol content between lipoprotein fractions, with a marked decrease in VLDL, IDL and LDL cholesterol content and an increase in HDL cholesterol. These results demonstrate that severe hypercholesterolemia in apoE-deficient mice can be effectively reversed by i.m. DNA injection, and indicate that this approach could represent a useful tool to correct several hyperlipidemic conditions resulting in atherosclerosis.

Intestinal Microvascular Patterns During Hemorrhagic Shock

Abstract: While injuries due to a hypoxic state commonly appear later in both intestinal crypts and basal portion of the villi than in the apical portion, a nonhomogeneous distribution of blood flow in the intestinal mucosa may be supposed. The presence of two different microvascular plexuses inside the mucosa, corresponding to the cryptal plexus and the villous plexus, supports the above hypothesis. This work studies the intestinal microvasculature in shocked versus normal rats. Forty-five rats were divided into four groups to study the histological damage and the microvascular bed by ink injection, fluorescent microsphere infusion, and resin injection for scanning electron microscopy (SEM) of vascular corrosion cast (VCC) observations. An infusion pressure of 100 +/- 5 mm Hg was used in control animals, while 30 +/- 5 mm Hg infusion pressure was adopted for controls as well as for shocked animals to simulate physiological or shock conditions. Hemorrhagic shock was induced by removing blood and maintaining a mean arterial pressure of 30 +/- 5 mm Hg for 45-120 mins. A close connection among the patterns of microvasculature obtained with VCC and ink injection technique can be appreciated. In normal rats the whole microvasculature was visualized, but in both normal and shocked animals injected at low pressure different patterns could be found, generally showing a highly incomplete visualization of the vascular network. A significant decrease of visualization of both the entire microvasculature and the villous plexus is present in shocked animals when compared to unshocked controls, while no difference in the cryptal plexus visualization was observed. These observations suggest that the cryptal plexus is perfused preferentially during hemorrhagic shock, as a consequence of its peculiar microvascular organization. This may explain the relative resistance of the crypts, compared to villi, to hypoxic injuries in order to sustain endocrine function and the regenerative capability of the mucosa after prolonged hypoperfusion conditions that can lead to villous damage and temporary loss of the intestinal barrier function.

Apoptosis in recent myocardial infarction.

Abstract: Purpose Apoptosis is considered a common pathological feature in acute myocardial infarction (MI) and heart failure; however its role in the later phases post MI has not been characterized. The goal of our study was to investigate by pathological examination human hearts at 20 to 30 days post MI and identify signs of ongoing cell apoptosis. Materials and methods Two hearts were collected at autopsy from patients who died 20 to 30 days from the onset of MI (Cases 1 and 2). Gross anatomy and light microscopy examination of the hearts was performed to define the infarcted area and the infarct-related artery. The in situ end-labeling of DNA fragmentation (TUNEL) was performed to identify apoptotic cells and the apoptotic rate (AR) was calculated. Results There were no signs of acute necrosis in any of the specimens examined. A high number of myocardiocyte were positive at TUNEL examination in specimens obtained at sites of infarction, mean AR = 44%, but not in specimens derived from the same patients at regions remote from the MI, AR = 0. Conclusions High grade apoptosis is present at sites of infarction and not in regions remote from the infarcted area in the later phases post MI. These data support persistent myocardiocyte loss and identify a possible explanation of progressive left ventricular dysfunction in the subacute phases of MI.

Atypical case of metastatic undifferentiated prostate carcinoma in a 36 years old man: Clinical report and literature review

Abstract: Prostate carcinoma occurs infrequently in patient less than 50 years old with an incidence of 0.8% to 1.1%. In literature are described less than 20 cases occurred in younger men (< 40 years old). A 36 year-old man with a two-months history of lower back pain, anorexia and loss of weight, showed at clinical examination a mild enlargement of inguinal lymph nodes and right inferior leg and scrotus edema. CT scan demonstrated marked enlargement and fusion of pelvic, inguinal, sacral and periaortic nodes with a pelvic mass that caused local ureterohydronephrosis and obstruction of the urinary flow. X-rays showed osteoblastic metastases. At total body scintigram were observed fixation areas corresponding to lumbar metamers, pelvis, thigh bones, left humeral head, left acromioclavicular articulation and multiple ribs. Tumor markers resulted negative except prostate specific antigen (PSA: 500 mgr/ml) and prostatic acid phosphatase (PAP: 208 U/l); prostate biopsy showed an undifferentiated carcinoma. The patient was submitted to right percutaneous nephrostomy, chemotherapy (PEB, cisplatinum, etoposide and bleomycin for 6 cycles) and ormonotherapy (LHRH analogues) reporting a clinical partial response. After 6 months the disease progressed and was started a second line chemotherapy. After 18 months from diagnosis patient is still alive with progressing disease. Our patient represents, with respect to many features, an original clinical case of prostate carcinoma occurring in young age, for the atypical association of an undifferentiated carcinoma with high levels of PSA and PAP and with osteoblastic-pattern of bone metastases. Further studies would be useful to identify new risk factors for development of prostate cancer in young men in order to achieve early diagnosis.

Vascular and haemostatic gene polymorphisms associated with non-fatal myocardial infarction: a critical review.

Abstract: The importance of genetics to the pathogenesis of myocardial infarction is suggested by the frequent familial clustering of premature disease. Yet, studies associating myocardial infarction with gene polymorphisms of vascular proteins (angiotensinogen, angiotensin converting enzyme, angiotensin II type 1 receptor, endothelial nitric oxide synthase) and haemostatic factors (fibrinogen, coagulation factors II, V, VII and XIII, plasminogen activator inhibitor-1, tissue-type plasminogen activator, platelet glycoproteins IIb/IIIa, Ia/IIa and Ib-IX-V, or methylenetetrahydrofolate reductase) have revealed conflicting results. This is hardly surprising, given: 1) the multigenic nature of myocardial infarction, whereby single polymorphisms are bound to play at best only a limited role in the global risk of disease; 2) the multiple pathogenetic mechanisms of infarction (e.g., atheromatous obstruction, plaque rupture, thrombosis, vasospasm), each of which is likely influenced by a number of genes and by several environmental factors. The simultaneous investigation of a set of polymorphisms--and of their interactions with environmental factors--in extremely homogeneous sets of patients should offer a better understanding of the contribution of specific genes to the risk of myocardial infarction.

Diagnostic value of cytokine assays in cerebrospinal fluid in culture-negative, polymerase chain reaction-positive bacterial meningitis.

Abstract: Analysis of bacterial DNA using a polymerase chain reaction performed with broad-range eubacterial 16S rDNA primers may yield a diagnosis of bacterial meningitis in cases where Gram staining of cerebrospinal fluid (CFS), antigen detection techniques or culture fail. Since this PCR technique occasionally gives false-positive results due to contamination of samples or laboratory reagents, a study was performed to establish the diagnostic value of assaying concentrations of tumour necrosis factor-α (TNF-α) and interleukin-10 (IL-10) in 90 CSF samples. A high correlation was found between a positive PCR result and the concentrations of TNF-α and IL-10, indicating that cytokine assays may be used as a confirmatory test. The findings suggested that a combination of the PCR technique, amplicon sequencing and assay of TNF-α and IL-10 concentrations in CSF is a reliable and cost-effective procedure for diagnosis of culture-negative bacterial meningitis.

Fill, fit and conformation : an anatomical and morphometric study of a hip component in total hip arthroplasty (Rippen-Link)

Abstract: Total joint replacement arthroplasties are well-established surgical procedures in the management of arthropathies. All seek to restore function and relieve symptoms. There has been great advancement in the development of materials and in the design of such implants. The composition, surface modification and the use of bone ongrowth enhancing substances has improved the longevity of such implants and therefore clinical outcomes. An important feature however, is the conformation of these implants to the anatomic configuration of the proximal femur and neck into which the prostheses are implanted. Recent literature has indicated that implants should conform to the anatomical configuration of the host bone. We undertook to study such conformation of a newly designed implant (Link Femoral Hip Implant) to the anatomic configuration of the proximal femur and neck. This implant did indeed conform to the bi-curved shape of the femoral canal. It impacted in the trabecular bone proximally. Its outer contour provided sufficient space for tissue ingrowth with the expectation that it preserved blood supply to the inner aspect of the cortex. While the fine detail radiological studies of the cadaveric femora showed a marked variability in cortical size and structure between patients, the pre-selection of implant size and contour addressed this issue providing good interfac e between implant and host bone. This was achieved with limited diameter of reaming, thus minimizing loss of bone integrity along the seat of the entire implants. Thus, at an anatomic al and morphometric level, this study demonstrated that this implant achieved fill, fit and conformation with the host bone in the proximal femur.

[Prevention of acute tubular necrosis caused by the administration of non-ionic radiologic contrast media].

Abstract: Radiographic contrast agents can cause acute renal failure that may be due to acute tubular necrosis (ATN). We prospectively studied 45 patients with risk factors for ATN who were undergoing computed tomography with three nonionic contrast agents (ioversolo, iobitridolo and iodixanolo). Patients were randomly assigned either to receive preventive management (0.45% saline intravenously, before and after administration of the contrast agent; mannitol 20% 250 mL i.v. 60 min before and 60 min after the contrast agent; furosemide 80 mg i.v. 30 min before the contrast agent; dopamine 3 g/Kg/min i.v. after administration of the contrast agent for 24 hours) or to receive placebo. Prophylactic management prevents the reduction in renal function induced by ioversolo, iobitridolo and iodixanolo, three noninonic contrast agents in patients with risk factors for ATN.

[Platelet glycoprotein IIB-IIIA receptor inhibitors in patients with ischemic heart disease].

Abstract: Glycoprotein IIb-IIIa receptor inhibitors are the newest anti-platelets drugs currently used in patients with coronary artery disease. We examined mechanisms of their action and different pharmacokinetic and pharmacodynamic characteristics of the four glycoprotein IIb-IIIa antagonists evaluated in randomized, controlled and multicenter trials. We reviewed results of these trials in the settings of percutaneous revascularizations procedures or unstable coronary syndromes. Platelet glycoprotein IIb-IIIa receptor inhibitors reduced incidence of cardiac death and myocardial infarction during the short- and midterm, and benefit was greater in: a) patients undergoing coronary angioplasty with or without stent implantation, particularly in the presence of unstable angina, diabetes or complex and diffuse coronary artery disease; b) as a direct therapy of unstable coronary syndromes, particularly in patients with refractory angina, diabetes and elevated Troponin; more recently they have been used as adjuvant therapy in acute myocardial infarction. Infusion of these drugs was not associated with higher rates of major bleedings.