Molecular characterization and in silico evaluation of surfactins produced by endophytic bacteria from Phanera splendens.

The Phanera splendens (Kunth) Vaz. is a medicinal plant that is used in traditional medicine for the treatment of various diseases, such as malaria. This plant presents highly efficient endophytic bacterial isolates with biocontrol properties. Bacillus sp. is responsible for the production of a variety of non-ribosomal synthesized cyclic lipopeptides which highlight the surfactins. Surfactins have a wide range of antimicrobial activity, including antiplasmodial activity. There is scientific evidence that surfactin structure 2d-01 can be a potent inhibitor against a Plasmodium falciparum sirtuin (Sir2) by acting on the Sir2A protein as the target. The Pf genome encodes two known sirtuins, PfSir2A and PfSir2B, where PfSir2A is a regulator of asexual growth and var gene expression. Herein, we have identified six surfactins produced by endophytic bacteria and performed in silico analysis to elucidate the binding mode of surfactins at the active site of the PfSir2A enzyme. Among the characterized surfactins, 1d-02 showed the highest affinity for the PfSir2A enzyme, with binding energy values equal to -45.08 ± 6.0 and -11.95 ± 0.8 kcal/mol, using MM/GBSA and SIE methods, respectively. We hope that the information about the surfactin structures obtained in this work, as well as the potential binding affinity with an important enzyme from P. falciparum, could contribute to the design of new compounds with antimalarial activity.

Constituents of Chamaecrista diphylla (L.) Greene Leaves with Potent Antioxidant Capacity: A Feature-Based Molecular Network Dereplication Approach.

Chamaecrista diphylla (L.) Greene (Fabaceae/Caesalpiniaceae) is a herbaceous plant that is widely distributed throughout the Americas. Plants from this genus have been used in traditional medicine as a laxative, to heal wounds, and to treat ulcers, snake and scorpion bites. In the present study, we investigated the chemical composition of Chamaecrista diphylla leaves through a mass spectrometry molecular network approach. The oxygen radical absorbance capacity (ORAC) for the ethanolic extract, enriched fractions and isolated compounds was assessed. Overall, thirty-five compounds were annotated for the first time in C. diphylla. Thirty-two of them were reported for the first time in the genus. The isolated compounds 9, 12, 24 and 33 showed an excellent antioxidant capacity, superior to the extract and enriched fractions. Bond dissociation energy calculations were performed to explain and sustain the antioxidant capacity found. According to our results, the leaves of C. diphylla represent a promising source of potent antioxidant compounds.

Eplingiella fruticosa leaf essential oil complexed with ß-cyclodextrin produces a superior neuroprotective and behavioral profile in a mice model of Parkinson's disease.

Evidence indicates that oxidative stress has an important role in the onset and progression of Parkinson's disease (PD). Antioxidant agents from natural products have shown neuroprotective effects in animal models of PD. Eplingiella fruticosa is an aromatic and medicinal plant of the Lamiaceae family that include culinary herbs. The essential oil (EPL) has anti-inflammatory and antioxidant activities. Cyclodextrins are used to enhances pharmacological profile of essential oil. We obtained the EPL from leaves and complexed with ß-cyclodextrin (EPL-ßCD). Phytochemical analysis showed as main constituents: ß-caryophyllene, bicyclogermacrene and 1,8-cineole. We evaluated the effects of EPL and EPL-ßCD (5 mg/kg, p.o. for 40 days) on male mice submitted to the progressive reserpine PD model. Behavioral evaluations, lipid peroxidation quantification and immunohistochemistry for tyrosine hydroxylase were conducted. EPL delayed the onset of catalepsy and decreased membrane lipid peroxides levels in the striatum. EPL-ßCD also delayed the onset of catalepsy, reduced the frequency of oral diskynesia, restored memory deficit, produced anxiolytic activity and protected against dopaminergic depletion in the striatum and SNpc. These findings showed that EPL has a potential neuroprotective effect in a progressive PD animal model. Further, EPL-ßCD enhanced this protective effects, suggesting a novel therapeutic approach to ameliorate the symptoms of PD.

[Strategies for malaria elimination: an Afro-Colombian perspective]. / Estrategias para la eliminación de malaria: una perspectiva afro-colombiana.

OBJECTIVE: To describe strategies for malaria elimination based on the perception of Afro-Colombian residents in Guapi, in the context of the Integrated Management Strategy for the Promotion, Prevention and Control of Vector-Borne Diseases in Colombia (EGI-ETV). MATERIALS AND METHODS: Qualitative study based on focus group discourse analysis. Eight participants from the urban area of Guapi were divided into two groups. The first group included three female nursing assistants, and was called "women with more experience"; they were workers in the current health system and former Malaria Eradication Service officers. The second group was made up of female nursing assistants, and was called "women with limited experience"; they were workers in the current health system and were not directly trained in the malaria program. An inductive and interpretative analysis was performed. RESULTS: Eight subcategories emerged, framed in the EGI-EVT, making emphasis on promotion and prevention aimed at reducing malaria, especially in rural areas. This problem must be addressed comprehensively, including other health issues and social determinants that affect them, such as: basic sanitation, access to health services, lack of education, use of popular treatments, and lack of infrastructure, among others. CONCLUSION: Participants consider that malaria in Guapi can be reduced but not eliminated. This problem needs to be addressed from an institutional and community perspective, taking into account cultural differences, based on strategies that include community empowerment and administrative and institutional strengthening of the program.

OBJETIVO: Describir las estrategias para la eliminación de la malaria a partir de la percepción de pobladores afro-colombianos residentes en Guapi en el contexto de la Estrategia de Gestión Integrada para la promoción, prevención y control de las Enfermedades Transmitidas por Vectores en Colombia (EGI). MÉTODOS: Estudio de tipo cualitativo basado en el análisis de discurso de grupos focales. Ocho participantes residentes en zona urbana de Guapi, divididas en dos grupos: el primero correspondió a tres mujeres auxiliares de enfermería, denominadas "mujeres con mayor experiencia", trabajadoras en el actual sistema de salud y funcionarias del antiguo Servicio de Erradicación de la Malaria. El segundo correspondió a cinco mujeres auxiliares de enfermería, denominadas "mujeres con limitada experiencia", trabajadoras en el actual sistema de salud y no tuvieron formación directa con el programa de malaria. Análisis inductivo e interpretativo. RESULTADOS: Emergieron ocho subcategorias enmarcadas en la EGI, con énfasis en la promoción y prevención orientadas a disminuir la malaria, especialmente en el área rural. El abordaje del problema debe hacerse de forma integral incluyendo otras problemáticas en salud y determinantes sociales que los afectan como: saneamiento básico, acceso al servicio de salud, falta de educación, uso de tratamientos populares, fragilidad de infraestructura, entre otros. CONCLUSIÓN: Las participantes consideran que la malaria en Guapi se puede reducir pero no eliminar. Se requiere abordar este problema desde una perspectiva institucional y comunitaria, teniendo en cuenta las diferencias culturales, a partir de estrategias que incluyan el empoderamiento comunitario y fortalecimiento administrativo e institucional del programa.

A randomised study of tailored toxicity-based dosage of fluorouracil-epirubicin-cyclophosphamide chemotherapy for early breast cancer (SBG 2000-1).

STUDY AIM: Retrospective studies have demonstrated a worse outcome in breast cancer patients not developing leukopenia during adjuvant chemotherapy. The SBG 2000-1 is the first randomised trial designed to compare individually dosed chemotherapy without G-CSF support based on grade of toxicity to standard-dosed chemotherapy based on body surface area (BSA). METHODS: Patients with early breast cancer were included and received the first cycle of standard FEC (fluorouracil 600 mg/m2, epirubicin 60 mg/m2, cyclophosphamide 600 mg/m2). Patients with nadir leukopenia grade 0-2 after first cycle were randomised between either 6 additional courses of tailored FEC with increased doses (E 75-90 mg/m2, C 900-1200 mg/m2) or fixed treatment with 6 standard FEC. Patients with grade 3-4 leukopenia were registered and treated with 6 standard FEC. Primary end-point was distant disease-free survival (DDFS). RESULTS: The study enrolled 1535 patients, of which 1052 patients were randomised to tailored FEC (N = 524) or standard FEC (N = 528), whereas 401 patients with leukopenia grade 3-4 continued standard FEC and formed the registered cohort. Dose escalation did not statistically significantly improve 10-year DDFS (79% and 77%, HR 0.87, CI 0.67-1.14, P = 0.32) or OS (82% and 78%, respectively, HR 0.89, CI 0.57-1.16, P = 0.38). Corresponding estimates for the registered group of patients were DDFS 79% and OS 82%, respectively. CONCLUSIONS: The SBG 2000-1 study failed to show a statistically significant improvement of escalated and tailored-dosed chemotherapy compared with standard BSA-based chemotherapy in patients with low haematological toxicity, although all efficacy parameters showed a numerical advantage for tailored treatment.

No breast cancer subgroup can be spared postoperative radiotherapy after breast-conserving surgery. Fifteen-year results from the Swedish Breast Cancer Group randomised trial, SweBCG 91 RT.

BACKGROUND: Breast-conserving surgery (BCS) followed by radiotherapy (RT) is an established treatment for women with T1-2N0 breast cancers. Since subgroups of patients have low ipsilateral breast tumour recurrence (IBTR) rates, it is important to study whether RT is necessary for all patients. PATIENTS AND METHODS: A total of 1187 women with primary T1-2N0M0 breast cancer were randomised, after standardised sector resection, to postoperative whole breast RT or no local treatment. Adjuvant systemic therapy was offered to patients with stage II cancers. Patients were followed with clinical examinations and annual mammography for 10 years and thereafter referred to the Swedish mammography screening program. RESULTS: After 15 years of follow-up, a higher cumulative incidence of IBTR was observed in control patients, 23.9%, versus irradiated patients, 11.5%, P<0.001. Recurrence-free survival was inferior, 51.7% versus 60.4%, P=0.0013. The main effect of RT was seen during the first 5 years. However, overall survival was not significantly lower 68.4% versus 71.1%, P=0.68, nor was breast cancer-specific mortality significantly higher. CONCLUSIONS: RT after BCS significantly reduced the incidence of IBTR at 15 years of follow-up. We were unable to identify subgroups which could be spared RT. Breast cancer mortality was not significantly reduced after RT. Good predictive markers for radiation sensitivity and improved adjuvant systemic therapy are needed to omit RT after BCS.

High leucovorin doses during high-dose methotrexate treatment may reduce the cure rate in childhood acute lymphoblastic leukemia.

We explored the relationship between time to relapse and different exposure variables (serum methotrexate (S-MTX) 23, 36 and 42 h after start of administration, MTX elimination time and leucovorin (LV) dose) during high-dose MTX (HDM) treatment of 445 children with acute lymphoblastic leukemia. MTX was infused at 5 g/m2 (non-high risk) or 8 g/m2 (high risk) over 24 h, 2-9 times per patient. LV rescue dose was adjusted according to the S-MTX concentration. Time from end of the last HDM to relapse was analyzed by Cox regression analysis with the logarithms of S-MTX and LV dose as exposures. The combined results from all risk groups suggest that high LV dose is related to higher risk for relapse. Doubling of the LV dose increased the relapse risk by 22% (95% confidence interval 1-49%, P = 0.037). High LV doses correlated with high MTX levels at 23, 36 and 42 h and longer elimination time. The results suggest that high doses of LV increase the risk for relapse despite the fact that they were correlated with high MTX levels and longer MTX elimination time. The choice of MTX and LV doses may be regarded as an intricate balance between effect and counter-effect.

Changes in aspects of children's oral-health-related quality of life following dental treatment under general anaesthesia.

OBJECTIVES: This study was intended to examine the treatment-associated change in aspects of oral-health-related quality of life (QoL) among children (and their families) undergoing dental rehabilitation under general anaesthesia (GA). METHODS: The parents or caregivers of a consecutive clinical sample of children receiving comprehensive dental treatment under GA at the University of Otago School of Dentistry, Dunedin, and the Christchurch Oral Health Centre, Christchurch, New Zealand, were interviewed by telephone before and after the treatment. Questions were asked relating to the impact of the condition on the child and the family. The post-treatment questionnaire also sought information related to parental satisfaction with the care provided under GA. RESULTS: The parents or caregivers of 95 children participated in the study: 49 had treatment completed at the University of Otago School of Dentistry; and 46 were treated at the Christchurch Oral Health Centre. The child sample comprised 55.8% males and 44.2% females with a mean age of 5.1 years. Their mean dmft was 8.2. A consistent pattern of improvement was found with each indicator used. Complaints of pain, problems with eating and sleeping, and behaviour concerns showed significant improvements, with 100% improvement for children for whom frequent pre-GA problems associated with eating, sleeping and behaviour were reported. Sixty-six parents had to arrange time away from employment on the day of the GA and almost half of those incurred a loss of income. The majority of parents reported a high degree of satisfaction with the care received. CONCLUSIONS: Treating young children with high disease experience in a single session under GA results in immediate improvement in oral health and aspects of their QoL for both the children and their families.

Primary culture of rat growth plate chondrocytes: an in vitro model of growth plate histotype, matrix vesicle biogenesis and mineralization.

During endochondral ossification (EO), cartilage is replaced by bone. Chondrocytes of growth plate undergo proliferation, maturation, hypertrophy, matrix vesicle (MV) biogenesis and programmed cell death (PCD, apoptosis). The in vitro system presented here provides a potential experimental model for studying in vitro differentiation and MV biogenesis in chondrocyte cultures. Chondrocytes were obtained from collagenase-digested tibial and femoral growth plate cartilage of 7-week-old rachitic rats. The isolated chondrocytes were plated as monolayers at a density of 0.5 x 10(6) cells per 35-mm plate and grown for 17 days in BGJ(b) medium supplemented with 10% fetal bovine serum, 50 microg/ml ascorbic acid. Light microscopy revealed Sirius red-positive, apparent bone matrix in layers at the surfaces of cartilaginous nodules that developed in the cultures. The central matrix was largely alcian blue staining thus resembling cartilage matrix. Electron microscopy revealed superficial areas of bone like matrix with large banded collagen fibrils, consistent with type I collagen. Most of the central matrix was cartilaginous, with small fibrils, randomly arranged consistent with type II collagen. The presence of peripheral type I and central type II and type X collagen was confirmed by immunohistochemical staining. Immunohistochemistry with anti-Bone morphogenetic proteins 2, 4 and 6 showed that BMP expression is associated with maturing hypertrophic central chondrocytes, many of which were TUNEL positive and undergoing cell death with plasma membrane breaks, hydropic swelling and cell fragmentation. During early mineralization, small radial clusters of hydroxyapatite-like mineral were associated with matrix vesicles. Collagenase digestion-released MVs from the cultures showed a high specific activity for alkaline phosphatase and demonstrated a pattern of AMP-stimulated nonradioactive (40)Calcium deposition comparable to that observed with native MVs. These studies confirm that primary cultures of rat growth plate chondrocytes are a reasonable in vitro model of growth plate histotype, MV biogenesis and programmed cell death.

Extracranial internal carotid artery aneurysm presenting as symptomatic hypoglossal and glossopharyngeal nerve paralysis.

Aneurysms of the extracranial portion of the internal carotid artery are rare, particularly in young patients. They usually develop following trauma, or secondary to infection involving the parapharyngeal space that extends to the vessel wall. This is a case of an internal carotid artery aneurysm presenting acutely following chiropractic neck manipulation with hypoglossal and glossopharyngeal nerve palsy. The imaging findings and subsequent operative management are described.

Effects of air pollution on general practitioner consultations for upper respiratory diseases in London.

OBJECTIVES: Few published studies have examined the effect of air pollution on upper respiratory conditions. Furthermore, most epidemiological studies on air pollution focus on mortality or hospital admissions as the main health outcomes, but very rarely consider the effect in primary care. If pollution effects do exist then the public health impact could be considerable because of the many patient contacts involved. We investigated the relation between air pollution and upper respiratory disease as reflected in number of consultations made at family practices in London. METHODS: The study used non-parametric methods of analysis of time series data, adjusting for seasonal factors, day of the week, holiday effects, influenza, weather, pollen concentrations, and serial correlation. RESULTS: It was estimated that a 10-90th percentile change (13-31 microg/m(3)) in sulphur dioxide (SO(2)) measures resulted in a small increase in numbers of childhood consultation: 3.5% (95% confidence interval (95% CI 1.4% to 5.8%). Stronger associations were found in the case of a 10-90th percentile change (16-47 microg/m(3)) in fine particles (PM(10)) in adults aged 15-64 5.7% (2.9% to 8.6%), and in adults aged 65 and over: 10.2% (5.3% to 15.3%). In general, associations were strongest in elderly people, weakest in the children, and were largely found in the winter months for these two age groups, and in the summer months for adults aged 15-64. An apparent decrease in consultations was associated with ozone concentrations but this was most pronounced in colder months when ozone concentrations were at their lowest. CONCLUSIONS: The results suggest an adverse effect of air pollution on consultations for upper respiratory symptoms, in particular in the case of PM(10) and SO(2). The effects are relatively small; however, due to the many consultations made in primary care, the impact on demand for services could be considerable.

Cancer Research UK procedures in manufacture and toxicology of radiotracers intended for pre-phase I positron emission tomography studies in cancer patients.

Radiolabelled compounds formulated for injection (radiopharmaceuticals), are increasingly being employed in drug development studies. These can be used in tracer amounts for either pharmacokinetic or pharmacodynamic studies. Such radiotracer studies can also be carried out early in man, even prior to conventional Phase I clinical testing. The aim of this document is to describe procedures for production and safety testing of oncology radiotracers developed for imaging by positron emission tomography in cancer patients. We propose strategies for overcoming the inability to produce compounds in sufficient quantities via the radiosynthetic routes for full chemical characterisation and toxicology testing including (i) independent confirmation as far as possible that the stable compound associated with the radiopharmaceutical is identical to the non-labelled compound, (ii) animal toxicity studies with > or = 10 times (typically 100 times) the intended tracer dose in humans scaled by body surface area, and (iii) patient monitoring during the radiotracer positron emission tomography clinical trial.

Impact evaluation of a folate education campaign with and without the use of a health claim.

OBJECTIVE: To measure the impact of a Kellogg/Northcott Society multimedia folate education campaign, run nationally from July 1998 to June 1999, with and without the use of health claims. METHOD: Three national telephone surveys of more than 500 Australian women aged 18-44 in July and November 1998 and May 1999. RESULTS: Awareness of the role of folate in the prevention of birth defects rose from 21% at baseline to 29% in November 1998 and 44% in May 1999. Awareness of the recommendation to take folate before pregnancy rose by 8% in the first six months of the campaign (without health claims) and by 22% in the second half (when health claims were incorporated). At the end of the campaign, the foods most commonly cited as sources of folate were leafy green vegetables (72%), breakfast cereals (70%), fruit (41%) and bread (40%). CONCLUSION: Inclusion of a specific health claim explaining the role of folate in preventing birth defects appeared to increase the impact of the folate education campaign. IMPLICATIONS: Changing food regulations to permit health claims may increase the impact of health promotion campaigns involving industry partnerships. Future folate programs should target young women (aged 18-24), those in rural areas and those on lower incomes.

Risk assessment of first-degree relatives of women with breast cancer: a feasibility study.

PURPOSE/OBJECTIVES: To measure psychological distress and test the feasibility of a psychological intervention to reduce distress in patients undergoing risk assessment. DESIGN: Descriptive. SETTING: A comprehensive cancer center located in the southeastern United States. SAMPLE: 20 first-degree relatives of women diagnosed with breast cancer (X age = 42; range = 21-70) completed the risk assessment process. Three were lost to follow-up at three months, leaving a total of 17 evaluable patients. METHODS: Data collection was by means of family/medical history forms and questionnaires administered at baseline and one and three months. Participants were randomized to either a control group consisting of standard education about risk for breast cancer or to an intervention group consisting of standard education plus a psychological intervention designed to teach stress-management skills. MAIN RESEARCH VARIABLES: Psychological distress, depressive symptoms, intrusive thoughts about breast cancer, and perceived risk for developing breast cancer. FINDINGS: Delivery of a psychological intervention proved feasible. Although no statistically significant differences existed between the intervention and control groups on distress and depressive symptoms, the intervention group reported fewer intrusive thoughts about breast cancer at follow-up. Risk did not predict anxiety levels. A large majority (73%) of the women overestimated the risk of breast cancer at baseline. CONCLUSIONS: This study demonstrated the feasibility of a multidisciplinary team approach to breast cancer risk assessment and counseling and management of psychological distress in first-degree relatives of women with breast cancer. The data suggest that a psychological intervention may reduce cancer-specific psychological distress in women at increased risk for breast cancer. IMPLICATIONS FOR NURSING PRACTICE: Oncology nurses can play an important role in the delivery of interventions to educate and reduce distress in women undergoing breast cancer risk assessment.

Use of imported folk remedies and medications in the Wisconsin Hmong community.

The Marathon County Health Department and the Wisconsin Division of Public Health evaluated several imported drugs and folk remedies that were being used by 2 Hmong families. These included a powdered blend of folk remedies that had been purchased in California and 5 packets of medication that had been imported from Thailand. The powdered folk remedy contained arsenic sulfide as a principal ingredient. The drug packets contained acetyl aspirin, acetaminophen and chloramphenicol. The purity of these drugs was not assessed, and their dates of manufacture could not be determined. To discourage use of folk remedies and imported drugs, the county health department issued a press release that was published in a Hmong community newsletter. Despite these efforts, many Asian immigrants may continue to use these products.

Cell-based screen for antimitotic agents and identification of analogues of rhizoxin, eleutherobin, and paclitaxel in natural extracts.

We describe a cell-based assay for antimitotic compounds that is suitable for drug discovery and for quantitative determination of antimitotic activity. In the assay, cells arrested in mitosis as a result of exposure to antimitotic agents in pure form or in crude natural extracts are detected by ELISA using the monoclonal antibody TG-3. The assay was used to screen >24,000 extracts of marine microorganisms and invertebrates and terrestrial plants and to guide the purification of active compounds from 5 of 119 positive extracts. A new rhizoxin analogue was found in a Pseudomonas species, six new eleutherobin analogues were identified from the octocoral Erythropodium caribaeorum, and two paclitaxel analogues were found in the stem bark of the tree Ilex macrophylla. The assay was also used for quantitative comparison of the antimitotic activity of different analogues. It revealed the importance of the C-11 to C-13 segment of the diterpene core of eleutherobin for its antimitotic activity. The identification of antimitotic compounds in very low abundance and their high (0.5%) occurrence in natural extracts indicates that drug discovery efforts using this cell-based assay may lead to the identification of structurally novel antimitotic agents.

Nightly home hemodialysis: improvement in nutrition and quality of life.

In September, 1997, we began a Nightly Home Hemodialysis Program modeled after a program in Toronto, Canada. We have assessed nutritional parameters and quality of life indicators before initiation of the program, and at 3, 6, 12, and 18 months. Data suggest that patients have improved overall quality of life as measured by the CHOICE Health Experience Questionnaire. Three-day dietary recalls at 0, 3, 6, 12, and 18 months also show patients are eating healthy and maintaining adequate kilocalorie and protein intakes, as well as maintaining adequate dry weight and protein stores.

A multicenter, randomized study of argatroban versus heparin as adjunct to tissue plasminogen activator (TPA) in acute myocardial infarction: myocardial infarction with novastan and TPA (MINT) study.

OBJECTIVES: This study examined the effect of a small-molecule, direct thrombin inhibitor, argatroban, on reperfusion induced by tissue plasminogen activator (TPA) in patients with acute myocardial infarction (AMI). BACKGROUND: Thrombin plays a crucial role in thrombosis and thrombolysis. In vitro and in vivo studies have shown that argatroban has advantages over heparin for the inhibition of clot-bound thrombin and for the enhancement of thrombolysis with TPA. METHODS: One hundred and twenty-five patients with AMI within 6 h were randomized to heparin, low-dose argatroban or high-dose argatroban in addition to TPA. The primary end point was the rate of thrombolysis in myocardial infarction (TIMI) grade 3 flow at 90 min. RESULTS: TIMI grade 3 flow was achieved in 42.1% of heparin, 56.8% of low-dose argatroban (p = 0.20 vs. heparin) and 58.7% of high-dose argatroban patients (p = 0.13 vs. heparin). In patients presenting after 3 h, TIMI grade 3 flow was significantly more frequent in high-dose argatroban versus heparin patients: 57.1% versus 20.0% (p = 0.03 vs. heparin). Major bleeding was observed in 10.0% of heparin, and in 2.6% and 4.3% of low-dose and high-dose argatroban patients, respectively. The composite of death, recurrent myocardial infarction, cardiogenic shock or congestive heart failure, revascularization and recurrent ischemia at 30 days occurred in 37.5% of heparin, 32.0% of low-dose argatroban and 25.5% of high-dose argatroban patients (p = 0.23). CONCLUSIONS: Argatroban, as compared with heparin, appears to enhance reperfusion with TPA in patients with AMI, particularly in those patients with delayed presentation. The incidences of major bleeding and adverse clinical outcome were lower in the patients receiving argatroban.