Tissue-factor antigen and activity in human coronary atherosclerotic plaques

BACKGROUND: Coronary atherosclerotic-plaque thrombosis is a key event in the pathogenesis of unstable angina and myocardial infarction. Although plaque rupture or fissuring frequently occurs in atherosclerosis, only a small proportion of ruptured plaques develop thromboses. METHODS: Tissue-factor antigen and activity were measured in atherectomy samples from 50 consecutive patients with coronary artery disease (stable angina n = 19, unstable angina n = 24, and myocardial infarction n = 7). FINDINGS: Median tissue-factor antigen and activity concentrations were significantly higher in plaques from patients with unstable angina and myocardial infarction than in those from patients with stable angina (antigen: 66.1 pg/mg [interquartile range 43.8-82.5] vs 32.4 pg/mg [9.8-43.4], p = 0.0001; activity: 0.22 mU/mg [0.17-0.41] vs 0.13 mU/mg [0.05-0.16], p = 0.0004). INTERPRETATION: Tissue-factor, an initiator of the coagulation cascade, may account for the different thrombotic responses to the rupture of human coronary atherosclerotic plaques.     

Renal pyelectasis in fetuses and neonates: diagnostic value of renal pelvis diameter in pre- and postnatal sonographic screening

OBJECTIVE: Pre- and postnatal pyelectasis detected by sonographic screening is of questionable pathologic importance. Therefore, we defined the natural course and diagnostic value of renal pelvis diameter (RPD) during fetal life and the neonatal period as such dilatation was revealed on routine sonography. MATERIALS AND METHODS: Routine sonography in pregnant women was obtained between gestational weeks 22 and 30. Sonograms were obtained for 1021 fetuses, of which 15 could not be followed up as neonates. The remaining 1006 fetuses also underwent neonatal sonography. All neonates with an RPD larger than 5 mm were followed up sonographically. Neonates with an RPD larger than 9 mm or persistent widening (> 5-9 mm) were examined by voiding cystourethrogram, radionuclide renogram, or both. RESULTS: Thirty fetuses (3%) had an RPD larger than 5 mm. Nine of these fetuses also had an RPD larger than 5 mm as neonates. Of these nine neonates, one had bilateral grade II vesicoureteric reflux (VUR) and two had urinary tract obstructions (one posterior urethral valve and one ureteropelvic junction obstruction). Forty-nine neonates whose results on fetal sonograms had been normal showed an RPD larger than 5 mm on neonatal sonograms. Grade III VUR was found in one boy, and ureteropelvic junction obstruction was found in two boys. The kidneys of 54 neonates who showed an RPD larger than 5 mm without urinary tract obstruction were followed up until an RPD of 0-5 mm was evident. RPD normalized within 1 year of birth, whether VUR was present or not. Symptomatic urinary tract infection was diagnosed in 17 infants who had no renal pelvis dilatation seen on pre-or postnatal screening during the observation period. Seven of the 17 neonates had VUR. Conversely, none of the infants with pre- postnatal dilatation presented with symptomatic urinary tract infection. However, in one neonate an asymptomatic urinary tract infection without VUR was diagnosed by routine urinalysis. CONCLUSION: In our study, we linked renal pelvis dilatation on pre- and postnatal sonograms to obstructive uropathies rather than to vesicoureteric reflux. Prenatal sonography proved less sensitive than postnatal sonography in revealing obstructive uropathies. An RPD smaller than 10 mm on neonatal sonography was of no pathologic significance because renal collecting systems normalized spontaneously in all infants within 1 year of birth. These neonates and infants had no significant risk for urinary tract infection and did not need further evaluation.     

Gelatinase (MMP-2 and -9) expression in gastrointestinal malignancy

The aim of the study was to investigate expression of the active and inactive gelatinases (MMP-2 and -9) in colorectal neoplasia and gastric cancer compared with normal mucosa. A total of 53 colorectal cancers and corresponding normal mucosa were studied using gelatin zymography as well as 15 colorectal adenomas and 13 gastric cancers with corresponding normal mucosa. Overexpression of all the gelatinases occurs in both colorectal and gastric cancer, with activation of MMP-2 appearing to be a feature of the malignant phenotype. Overexpression of MMP-9 occurs in colorectal adenomas. The gelatinases are overexpressed in gastrointestinal neoplasia, suggesting that these enzymes may have an important role in tumour invasion and metastasis.     

Agonistic activity of a CD40-specific single-chain Fv constructed from the variable regions of mAb G28-5

A single-chain Fv (sFv) was expressed from the variable regions of the CD40-specific mAb G28-5. The molecule bound CD40 with a high affinity (2.2 nM) and was a monomer in solution. Surprisingly, G28-5 sFv was a potent CD40 agonist that rapidly crosslinked CD40 on the cell surface but did not crosslink CD40-Ig in solution. G28-5 sFv was a more potent agonist than G28-5 IgG and was able to stimulate CD40 responses by B cells and monocytes. G28-5 IgG partially blocked, whereas G28-5 sFv augmented CD40 responses during stimulation with natural ligand (gp39-CD8 fusion protein). These results indicate that the functional activity of ligands built from the binding site of G28-5 is highly dependent upon the size and physical properties of the molecule both in solution and on the cell surfaces.     

Cost-effectiveness of thrombolytic therapy for acute myocardial infarction

OBJECTIVE: To estimate the cost-effectiveness of thrombolytic therapy versus no thrombolytic therapy for patients following acute myocardial infarction, focusing on the impact of time to treatment on outcome. METHODS: A decision model was developed to assess the benefits, risks, and costs associated with thrombolytic therapy for treatment of acute myocardial infarction compared with standard nonthrombolytic therapy. The model used pooled data from a recent study of nine large randomized, controlled clinical trials and 12-month outcome data from a recently published meta-analysis of thrombolytic therapy trial data. Outcomes were expressed in terms of survival to hospital discharge and survival to 1 year after discharge. The risks of treatment that led to death, morbidity, or added costs were estimated. The model determined excess and marginal costs per death averted to hospital discharge and at 1 year. Results were also estimated in terms of cost per year of life saved. Sensitivity analyses included variations in time to treatment and drug cost. RESULTS: The marginal cost of thrombolytic therapy per death averted at 1 year was $222,344, or $14,438 per year of life saved. For patients treated within 6 hours of acute myocardial infarction, the marginal cost per death averted was $181,536 at 1 year, or $11,788 per year of life saved. CONCLUSIONS: Thrombolytic therapy is significantly more cost-effective than many other cardiovascular interventions and compares favorably with other forms of medical therapy. Results suggest that shortening the time to treatment has a critical impact on the cost-effectiveness of thrombolytic therapy.     

Molecular cytogenetics of prostate cancer

Prostate cancer is the most common malignancy among men in many developed countries. One-fourth of prostate cancers are diagnosed at metastatic stage but there is no curative treatment for such disease and palliative androgen withdrawal therapy remains the most used one. Thus, understanding the molecular events that underlie the development and progression of prostate cancer could help to answer many clinical questions on its treatment. In this review article, I want to illustrate some of the most interesting findings (by fluorescence in situ hybridization and comparative genomic hybridization) in the molecular cytogenetics of prostate cancer.     

Impact of diagnostic laparoscopy in the management of the unilateral impalpable testis

OBJECTIVE: To evaluate the impact of laparoscopy on the management of children with a unilateral impalpable testis. PATIENTS AND METHODS: The study population consisted of 27 children who underwent a primary inguinal exploration for a unilateral impalpable testis. RESULTS: Twelve of 27 (44%) children had inguinal or 'peeping' testes and 10 of 27 (37%) had blind-ending vasa and vessels in the inguinal canal; four of these 10 had atrophic tubular tissue in the excised remant. Four of 27 (15%) had blind-ending vasa and vessels proximal to the internal ring. Only one child had a testis proximal to the internal ring. Only the four children (15%) with blind-ending vasa and vessels proximal to the internal ring would have benefited from a laparoscopy by avoiding an inguinal exploration. CONCLUSIONS: Because of the time, expense and limited usefulness of laparoscopy in altering the management of children with a unilateral unpalpable testis, we reserve laparoscopy for cases where inguinal exploration has failed.     

Radiotherapy after chemotherapy for metastatic seminoma--a diminishing role. MRC Testicular Tumour Working Party

In a retrospective study, data from 302 patients with metastatic testicular seminoma treated with chemotherapy between 1978 and 1990 in 10 European centres were analysed to evaluate the role, if any, of postchemotherapy treatment with irradiation. The primary endpoint of this study was the progression-free survival rate after chemotherapy with or without additional radiotherapy. This was related to the type of primary chemotherapy, sites and sizes of pre- and postchemotherapy masses, the extent of surgical resection after chemotherapy and the use of radiotherapy. 174 patients had residual disease at the end of chemotherapy. The most important prognostic factors for progression were the presence of any visceral metastases or raised LDH prechemotherapy, and the presence of residual disease at visceral sites after chemotherapy. Approximately half the patients with residual masses underwent postchemotherapy radiotherapy, with selection based predominantly on institutional practice. In patients receiving platinum-based chemotherapy, no significant difference was detected in progression-free survival whether or not radiotherapy was employed. Patients receiving BEP (bleomycin, etoposide and cisplatin) had a progression-free survival rate of 88% (95% CI, 80-96%) uninfluenced by postchemotherapy radiotherapy. In patients with residual masses confined to the abdomen after platinum-based chemotherapy, the absolute benefit to radiotherapy was estimated to be 2.3%. The potential benefit of postchemotherapy radiotherapy is minimal, and so it is concluded that the use of adjuvant radiotherapy to residual masses after platinum-based chemotherapy for metastatic seminoma is unnecessary.     

Effect of transdermal nitroglycerin or N-acetylcysteine, or both, in the long-term treatment of unstable angina pectoris

OBJECTIVES: This study was designed to evaluate whether the addition of transdermal nitroglycerin or oral N-acetylcysteine, or both, to conventional medical therapy improves the natural history of unstable angina pectoris. BACKGROUND: Transdermal nitroglycerin is widely used to treat angina pectoris, but the development of tolerance is a major problem that may reduce its clinical efficacy. It has been suggested that the addition of N-acetylcysteine to nitroglycerin reverses the development of tolerance, potentiates the hemodynamic response to nitroglycerin and may improve in-hospital prognosis in unstable angina. METHODS: We assessed the efficacy of adding transdermal nitroglycerin or oral N-acetylcysteine, or both, to conventional medical therapy in a randomized, double-blind, placebo-controlled trial involving 200 patients with unstable angina who were followed up for 4 months. RESULTS: Outcome events--death, myocardial infarction or refractory angina requiring revascularization--occurred in 31% of patients receiving nitroglycerin, 42% of those receiving N-acetylcysteine, 13% of those receiving nitroglycerin plus N-acetylcysteine and 39% of those receiving placebo (p = 0.0052). Kaplan-Meier curves showed a higher probability (p < 0.01) of no failure of medical treatment in the group receiving both nitroglycerin and N-acetylcysteine than in those receiving placebo, N-acetylcysteine or nitroglycerin alone. The combination of nitroglycerin and N-acetylcysteine was associated with a high incidence of side effects (35%), mainly intolerable headache, which was almost twice as frequent as in patients receiving nitroglycerin alone. CONCLUSIONS: The combination of nitroglycerin and N-acetylcysteine, associated with conventional medical therapy in the long-term treatment of patients with unstable angina, reduces the occurrence of outcome events. However, the high incidence of side effects limits the clinical applicability of this therapeutic strategy at least at the dosage used in the present study.