'Rescue' after failed thrombolysis for acute myocardial infarction

Prompt restoration of coronary artery patency in acute myocardial infarction is associated with substantial improvements in morbidity and mortality. The pivotal role of thrombolysis and aspirin in achieving these goals is well established. However, despite the success of thrombolytic therapy in large trials, clinical assessment in individual patients often suggests that reperfusion has not occurred after initial therapy. This review considers the validity of such bedside predictions and discusses whether such patients should be managed differently.     

Long-term followup and selection criteria for penile revascularization in erectile failure

PURPOSE: We report the long-term results of penile revascularization surgery for erectile failure and suggest possible selection criteria for this controversial surgical procedure. MATERIALS AND METHODS: In 7 years 62 impotent men who did not respond to pharmacotherapy underwent microsurgical penile revascularization and completed long-term followup evaluation in 41 months (range 18 to greater than 62) consisting of a detailed questionnaire, duplex sonography and optional pharmacotherapy or angiography. The Virag procedure was chosen for the first 7 patients, the original Hauri technique for the next 13 and the modified Mannheim triple anastomosis for 42. RESULTS: Of all patients 34% achieved spontaneous and another 20% pharmacologically induced erections. Success in diabetics and older patients was lower (43% for diabetics, 39% for those older than 50 years at surgery), while it was high in men with less than 2 risk factors (58%) as well as in younger patients (69% for those up to 50 years old). Shunt patency was 92%. Complications such as glans hyperemia developed in 13% of patients, shunt thrombosis in 8% and inguinal hernias in 6.5%. CONCLUSIONS: Patient selection is vital for the successful outcome of penile revascularization surgery. We adhere to strict selection criteria, such as patient age maximum of 50 years, less than 2 risk factors, no recent diabetes and termination of nicotine abuse. Penile revascularization surgery is highly indicated in this group of patients, especially since it is the only causal therapy for erectile failure.     

bcl-2 expression in the spectrum of preinvasive breast lesions

This study was designed to define more precisely the relationship between specific angiotensin receptors and the growth of vascular smooth muscle cells in response to angiotensin II. These experiments employed quiescent A10 cells which were characterized as smooth muscle by the expression of specific contractlle proteins. Cell growth was monitored by measuring the incorporation of metabolic precursors into RNA or DNA. The treatment of A10 cells with angiotensin II (1 microM) stimulated a hypertrophic response as indicated by an increase in RNA synthesis and protooncogene expression in the absence of DNA synthesis. This increase in RNA synthesis could be blocked by PD123319, an AT2 antagonist, but not by losartan, an AT1 antagonist. RT-PCR analysis demonstrated that quiescent A10 cells express only the AT2 receptor while proliferating A10 cells express the AT1a and AT1b receptors in addition to the AT2 receptor. In addition, induction of AT2 receptor-mediated RNA synthesis was prevented by indomethacin, a cyclooxygenase inhibitor. These studies therefore support a direct connection between the AT2 receptor and smooth muscle growth that is mediated, in part, by prostaglandin synthesis.     

Conduct of phase I trials in children with cancer

PURPOSE AND METHODS: Future progress in the care of children with cancer requires appropriate evaluations of promising new agents for pediatric indications, beginning with well-conducted phase I trials. This report summarizes current guidelines for the conduct of pediatric phase I trials and represents a consensus between American and European investigators. The primary objective of pediatric phase I trials is to define safe and appropriate doses and schedules of new agents that can subsequently be used in phase II trials to test for activity against specific childhood malignancies. Prioritization of agents for evaluation in children is critical, since many more investigational agents are evaluated in adult patients than can be systematically evaluated in children. Considerations used in prioritizing agents include activity in xenograft models, novel mechanism of action, favorable drug-resistance profile, and activity observed in adult trials of the agent. RESULTS AND CONCLUSION: Distinctive characteristics of pediatric phase I trials, in comparison to adult phase I trials, include the necessity for multiinstitutional participation and their higher starting dose (typically 80% of the adult maximum-tolerated dose [MTD]), both of which reflect the relative unavailability of appropriate patients. The application of uniform eligibility criteria and standard definitions for MTD and dose-limiting toxicity (DLT) help to assure that pediatric phase I trials are safely conducted and reliably identify appropriate doses and schedules of agents for phase II evaluation. Where possible, pediatric phase I trials also define the pharmacokinetic behavior of new agents in children.     

Bioactive and nuclease-resistant L-DNA ligand of vasopressin

In vitro selection experiments have produced nucleic acid ligands (aptamers) that bind tightly and specifically to a great variety of target biomolecules. The utility of aptamers is often limited by their vulnerability to nucleases present in biological materials. One way to circumvent this problem is to select an aptamer that binds the enantiomer of the target, then synthesize the enantiomer of the aptamer as a nuclease-insensitive ligand of the normal target. We have so identified a mirror-image single-stranded DNA that binds the peptide hormone vasopressin and have demonstrated its stability to nucleases and its bioactivity as a vasopressin antagonist in cell culture.     

Assessment of accuracy of the Doppler pressure half-time method in the estimation of the mitral valve area immediately after balloon mitral valvuloplasty

AIM: The reliability of Doppler echocardiography in determining the mitral valve area after balloon mitral valvuloplasty has been questioned, as discrepancies were noted between measurements obtained by the pressure half-time method and those derived haemodynamically, immediately following completion of the procedure. Recent investigations, however, have indicated that these discrepancies may be attributable to the over-estimation of the mitral valve area by haemodynamic measurements, caused by the presence of the iatrogenic atrial septal defect complicating transseptal catheterization. The aim of the present study was to further test this hypothesis. METHODS AND RESULTS: Measurements of the mitral valve area by the Doppler pressure half-time method and the Gorlin formula were obtained and compared in 238 consecutive patients before and immediately after retrograde non-transseptal balloon mitral valvuloplasty, which does not involve puncture and/or dilatation of the inter-atrial septum. No significant difference was found between Doppler- and Gorlin-derived measurements, neither before (1.04 +/- 0.23 vs 1.03 +/- 0.23 cm2, P = ns) nor immediately after (2.14 +/- 0.47 vs 2.12 +/- 0.49 cm2, P = ns) valvuloplasty. Linear regression analysis demonstrated a high degree of correlation between Doppler and Gorlin measurements before (r = 0.778) and after (r = 0.886) the procedure. Good agreement was confirmed by the Bland-Altman method. CONCLUSION: Doppler echocardiography yields accurate measurements of the mitral valve area immediately after retrograde non-transseptal balloon mitral valvuloplasty. This finding supports the hypothesis that the creation of an iatrogenic atrial septal defect during transseptal catheterization may contribute to the poor agreement between Doppler and Gorlin data after balloon mitral valvuloplasty.     

Two separable T cell receptor signals reconstitute positive selection of CD4 lineage T cells in vivo

Positive selection is an obligatory step during intrathymic T cell differentiation. It is associated with rescue of short-lived, self major histocompatibility complex (MHC)-restricted thymocytes from programmed cell death, CD4/CD8 T cell lineage commitment, and induction of lineage-specific differentiation programs. T cell receptor (TCR) signaling during positive selection can be closely mimicked by targeting TCR on immature thymocytes to cortical epithelial cells in situ via hybrid antibodies. We show that selection of CD4 T cell lineage cells in mice deficient for MHC class I and MHC class II expression can be reconstituted in vivo by two separable T cell receptor signaling steps, whereas a single TCR signal leads only to induction of short-lived CD4+CD8lo intermediates. These intermediates remain susceptible to a second TCR signal for 12-48 h providing an estimate for the duration of positive selection in situ. While both TCR signals induce differentiation steps, only the second one confers long-term survival on immature thymocytes. In further support of the two-step model of positive selection we provide evidence that CD4 T cell lineage cells rescued by a single hybrid antibody pulse in MHC class II-deficient mice are pre-selected by MHC class I.     

Improving the processes of care and outcomes in obstetrics/gynecology

BACKGROUND: The obstetrics/gynecology department of York Hospital (York Health System, York, Pennsylvania) initiated a program to improve the processes of care and control costs for common women's and newborns' health care services. Twelve clinical policies were established between June 1993 and February 1995. CONDUCTING THE QUALITY IMPROVEMENT (QI) PROJECTS: Using the plan-do-check-act (PDCA) improvement cycle method, the QI group established clinical pathways for high-volume conditions or procedures known to have low rates of complications and clinical guidelines for those conditions or procedures not requiring coordinated efforts of a group of health care professionals. EXAMPLE--PYELONEPHRITIS IN PREGNANCY: The literature had indicated that the prevalence of pyelonephritis can be decreased by identifying and treating asymptomatic bacteriuria early in prenatal care. After the validity of the clinical policy was demonstrated in the resident service, the policy was extended to all private obstetric practices. Dissemination of the finding that most of the admissions for pyelonephritis were for referred patients (for whom we had no control over prenatal care) or for patients referred by private physicians who were not yet following the guidelines quickly led to complete compliance by our obstetricians and other health care providers referring patients to the York Health System. RESULTS: The 12 clinical policies resulted in the elimination of 113 admissions and 5,595 inpatient days and in the reduction of the cost of patient care by $1,306,214 for the years 1994-1995 and 1995-1996 combined, without apparent adverse effects on patient health. CONCLUSION: A voluntary clinical policies program can change the culture of a department and lead to cost-effectiveness and better quality of patient care.     

Dogs infected with a human granulocytotropic Ehrlichia spp. (Rickettsiales: Ehrlichieae)

In contrast to the anticipation that in sepsis granulocyte colony-stimulating factor (G-CSF) would overactivate the nonspecific immune system by recruiting and priming leukocytes with consequent aggravation of inflammatory tissue lesions, recombinant (r) G-CSF pretreatment was protective in various experimental non-neutropenic models of inflammation. The mechanisms of protection, however, are not fully understood. Using intravital fluorescence microscopy, we show that rG-CSF enhances leukocyte endothelial cell interaction within the microvasculature of normal rat livers, whereas rG-CSF pretreatment of animals exposed to lipopolysaccharide (LPS) attenuates the LPS-induced leukocytic response, including stasis in sinusoids as well as rolling and adherence in postsinusoidal venules with subsequent tissue infiltration. Moreover, rG-CSF, which did not affect Kupffer cell activity in normal rat livers, reduced the immediate activation of Kupffer cells on LPS exposure, as indicated in vivo by the delayed adherence/phagocytosis of intra-arterially administered latex particles associated with attenuation of proinflammatory cytokine release (tumor necrosis factor alpha and interleukin-6). Finally, rG-CSF reduced LPS-induced nutritive perfusion failure and hepatocellular excretory dysfunction. This study provides evidence for a distinct, possibly tumor necrosis factor alpha-dependent modulation of LPS-induced cellular response within the liver by rG-CSF, thereby achieving protection against microcirculatory perfusion failure and hepatic dysfunction.