Emergency off-pump coronary artery surgery

Background Off-pump coronary artery bypass grafting is fast-becoming a procedure of choice for elective revascularization in high-risk patients with multi-vessel coronary artery disease. However, the role of off-pump coronary artery bypass grafting for patients with acute coronary syndromes requiring emergency revascularization still requires validation. We present our experience to show the feasibility of off-pump coronary artery surgery as an emergency revascularization technique. Methods From April 2001 to September 2003, emergency (operation within 24 hours after hospitalization) coronary artery bypass grafting without cardiopulmonary bypass (CPB) was performed in 66 patients with a mean age of (66.9±5.4) years (range 49-72 years). They presented acute coronary syndromes with 38 patients on platelet glycoprotein Ⅱb/Ⅲa receptor antagonists. All patients underwent off-pump coronary artery bypass surgery via sternotomy with the intention of complete coronary revascularization.Results An average of 2.9 grafts per patient were performed and the posterior descending artery and marginal branches of the circumflex artery were grafted in 83.3% of the patients. There were 4 events of intraoperative cardiac instability, precipitated by occlusion of right coronary artery or positioning of a cardiomegaly heart, leading to immediate conversion to CPB. The mortality rate was 3% (2/66). Two patients suffered postoperative stroke while three needed hemofiltration for acute renal failure. Post surgery elective coronary angiography (n=46) showed no significant stenosis.Conclusion Emergency off-pump coronary artery surgery with complete revascularization is feasible in patients with acute coronary syndrome with low morbidity and mortality and excellent early results.     

Quantification of tumour response to radiotherapy

In 1979, the World Health Organization (WHO) established criteria based on tumour volume change for classifying response to therapy as (i) progressive disease (PD), (ii) partial recovery (PR), and (iii) no change (NC). Typically, the tumour volume is reported from diameter measurements, using the calliper method. Alternatively, the Cavalieri method provides unbiased volume estimates of any structure without assumptions about its shape. In this study, we applied the Cavalieri method in combination with point counting to investigate the changes in tumour volume in four patients with high grade glioma, using 3D MRI. In particular, the volume of tumour within the enhancement boundary, the enhancing abnormality (EA), was estimated from T(1) weighted images, and the volume of the non-enhancing abnormality, (NEA) enhancing abnormality, was estimated from T(2) relaxation time and magnetic transfer ratio tissue characterization maps. We compared changes in tumour volume estimated by the Cavalieri method with those obtained using the calliper method. Absolute tumour volume differed significantly between the two methods. Analysis of relative change in tumour volume, based on the WHO criteria, provided a different classification using the calliper and Cavalieri methods. The benefit of the Cavalieri method over the calliper method in the estimation of tumour volume is justified by the following factors. First, Cavalieri volume estimates are mathematically unbiased. Second, the Cavalieri method is highly efficient under an appropriate sampling density (i.e. EA volume estimates can be obtained with a coefficient of error no higher than 5% in 2-3 min). Third, the source of variation of the volume estimates due to disagreements between observers, and within observer, is much greater in the positioning of the calliper diameters than in the identification of the tumour boundaries when applying the Cavalieri method. Additionally, the error prediction formula, available to estimate the coefficient of error of Cavalieri volume estimates from the data, allows us to establish more precise classification criteria against which to identify potentially clinical significant changes in tumour volume.     

Successful orthotopic liver transplantation after trimethoprim-sulfamethoxazole associated fulminant liver failure

Trimethoprim-sulfamethoxazole (TMP-SMZ) is one of the most commonly used antibiotics. Although many of its adverse effects are well recognized, TMP-SMZ related hepatotoxicity is considered rare and is usually characterized by cholestasis or mixed hepatocellular-holestatic reactions. In this study, we describe the case of a previously healthy young man with acute fulminant liver failure caused by TMP-SMZ. The patient presented with complaints of 'flu-like' symptoms with myalgia and fever after taking TMP-SMZ for 7 d for otitis externa. The patient subsequently developed fever, worsening jaundice, and a rash on his neck and chest. Liver enzymes peaked on day 3 with alanine aminotransferase (ALT) 11,549, aspartate aminotransferase (AST) 23,289, alkaline phosphatase 245, and total bilirubin 10.3 mg/dL, with a conjugated bilirubin of 8.3 mg/dL, prothrombin time (PT) 60.5 s, partial normalized ratio (PTT) 49 s, and international normalized ratio (INR) 7.5. Of note, acetaminophen level on admission was undetectable. Serology for hepatitis A, B, C, cytomegalovirus, HIV, toxoplasmosis, and blood cultures were all negative. The patient developed hepatic encephalopathy with hallucination on day 4. Laboratory tests revealed a serum ammonia level of 190 U, serum creatinine kinase (CK) 10,466 (42 on admission), serum creatinine 8.2 mg/dL (1.2 on admission), and significant metabolic acidosis. Renal ultrasound was unremarkable. The patient was started on hemodialysis for acute renal failure. Meanwhile, liver transplantation assessment was also initiated. On day 8 post-admission (15 d after taking TMP-SMZ), the patient received a successful orthotopic liver transplant.     

High-throughput screening with immobilized metal ion affinity-based fluorescence polarization detection, a homogeneous assay for protein kinases

Protein kinases are one of the most important target classes in high-throughput screening today. The use of generic assay technologies facilitates assay development for new targets and decreases the time needed for implementation of assays in robotic screening. For tyrosine kinases, several generic assay technology platforms are available. These technologies make use of high-affinity antibodies that discriminate between phosphorylated tyrosines and non-phosphorylated tyrosines. Similar generic antibodies specific for phosphoserine or phosphothreonine are lacking. Recently, a non-antibody-based fluorescence polarization assay for protein kinases has become available, called IMAP (Molecular Devices, Sunnyvale, CA). In this assay, a fluorescently labeled peptide substrate that is phosphorylated by kinase is captured on metal-derivatized nanoparticles. We have evaluated IMAP in high-throughput screening, and compared this technology with a competition fluorescence polarization immunoassay based on an antibody specific for a phosphorylated peptide substrate. A random collection of >250000 compounds was screened with the two assays. Fluorescent library compounds were identified by calculation of fluorescence intensity values from the screening data, and by assaying in the absence of fluorescent reagents. Fluorescence polarization artifacts were filtered out further by testing in an ELISA-based kinase assay. Our data show that IMAP is a robust technology for high-throughput screening of kinase targets, and suggest that it is less susceptible to fluorescence polarization artifacts than the competition fluorescence polarization immunoassay.     

Effect of dietary n-3 and n-6 oils with and without food restriction on activity of antioxidant enzymes and lipid peroxidation in livers of cyclophosphamide treated autoimmune-prone NZB/W female mice

OBJECTIVE: Cyclophosphamide (CTX), an alkylating agent, is extensively used in the treatment of lupus nephritis, but its administration has been associated with free radical mediated oxidative stress. The present study was designed to investigate the effect of dietary corn oil (CO), fish oil (FO) and food restriction (FR) on the activities of hepatic antioxidant enzymes, fatty acid composition and lipid peroxidation following CTX administration in autoimmune-prone NZB/W female mice. METHODS: Autoimmune-prone NZB/W female mice were fed either ad libitum (AL) or food restricted (60% of AL intake), semipurified diets containing 5% CO or 5% FO supplemented with equal levels of antioxidants and injected with either phosphate buffered saline (PBS), or CTX (50 mg/kg body weight) every 10 days. Proteinuria was measured biweekly. The treatment was stopped at 10 months and diets were continued until the mice were killed at 12 months. Fatty acid composition, activity of antioxidant enzymes and lipid peroxidation were analyzed in liver homogenates, and anti-DNA antibodies were analyzed in the serum. RESULTS: Mice in the FO/AL dietary group exhibited significantly higher liver catalase (CAT), superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activities compared to the CO/AL dietary group. CTX significantly decreased SOD and GSH-Px activity in the FO/AL group and CAT and GSH-Px in the CO/AL group. In AL fed mice given CTX, activities of CAT, GSH-Px and GST were significantly higher in mice fed FO diets than in mice fed CO diets. FR increased the activity of enzymes in both the CO and FO diet groups. In FR mice, CTX decreased CAT and GSH-Px activity in both the CO and FO dietary groups, but glutathione S-transferase (GST) only in the CO group. The decrease in SOD activity was not significant in either of the restricted groups. CTX significantly increased generation of thiobarbituric acid reactive substances (TBARS) in both AL groups. FR significantly decreased lipid peroxidation in both the CO and FO groups, with or without CTX. CTX decreased serum anti-DNA antibody levels in both the CO and FO dietary groups. FR also decreased antibody titer in both the CO and FO dietary groups, and it was decreased further with CTX treatment. FO fed animals had higher levels of n-3 fatty acids, whereas CO fed animals had high levels of n-6 fatty acids. CTX significantly increased 20:4 and decreased 18:1 in CO/AL fed animals, whereas it increased 18:1 and decreased 22:6 in FO/AL fed animals. CONCLUSIONS: Results obtained in the present study suggests that FO and, more significantly, FO combined with FR can have a beneficial effect in hepatic tissues subjected to CTX induced oxidative stress by regulating the activity of antioxidant enzymes. In addition, the study also indicates that n-3 and n-6 dietary lipids are susceptible to lipid peroxidation, particularly in the presence of a prooxidant like CTX, and that FR is beneficial in decreasing lipid peroxidation. The study also suggests that FO and CTX can have additive effects in preventing kidney disease in NZB/W mice.     

Systematic review: peginterferon vs. standard interferon in the treatment of chronic hepatitis C

BACKGROUND: Randomized controlled trials over the last decade have demonstrated incremental improvement in the treatment efficacy of chronic hepatitis C with combination interferon and ribavirin therapy when compared with interferon monotherapy. AIM: To perform a systematic review of clinical trials directly comparing interferon formulations to test the hypothesis that a true difference in terms of efficacy exists between standard interferon (with and without ribavirin) and peginterferon (with and without ribavirin). METHODS: A search of the on-line bibliographic databases MEDLINE and PUBMED was performed independently by two authors to identify all relevant articles. In addition, the reference sections of all relevant articles were manually searched to identify any missed articles. Quality was assessed using the Jadad scale, which is an accepted scale specific for randomized controlled trials. A priori, it was decided to include only articles with a Jadad score of three or higher in the final analysis. Data were abstracted on to pre-determined abstraction sheets. The inclusion of articles, the data abstracted and the methodological score differences were adjudicated by consensus with agreement of the authors performing the search. RESULTS: Seven citations of randomized controlled trials, comparing at least two different interferon formulations and evaluating the sustained virological response as a primary end-point, were identified. These relevant articles were abstracted, and five of the seven were found to have a Jadad score of three or higher and comprised the final set of citations reviewed. The studies consistently demonstrated that peginterferon monotherapy was superior to standard interferon, even in patients with advanced fibrosis. With regard to combination interferon therapy, only two high-quality articles compared peginterferon plus ribavirin with standard interferon plus ribavirin. Both studies demonstrated that the overall sustained virological response was statistically better with peginterferon plus ribavirin. CONCLUSIONS: On the basis of this systematic review, peginterferon-based regimens are superior to standard interferon-based regimens for the treatment of chronic hepatitis C.