Growth and congenital heart disease

PURPOSE: To assess the efficacy of heparin in preventing the abrupt closure after coronary angioplasty in low risk patients for this phenomenon. METHODS: In the last 4 years, 525 patients successfully dilated were randomized to receive intravenous heparin (n = 264) or not (n = 261) after the angioplasty. The excluding criteria were contraindications for heparin and risk for abrupt closure (refractory unstable angina, primary coronary angioplasty in acute myocardial infarction, evidence of intracoronary thrombus, intimal tear after the procedure and cases of chronic total occlusions). Both heparin and non heparin groups were similar in respect to female sex (15% x 17%; p = NS), age over 70 years old (7% x 9%; p = NS), previous myocardial infarction (26% x 24%; p = NS), multi-vessel procedures (4% x 7%; p = NS, stable angina (40% x 46%; p = NS), unstable angina (52% x 48%; p = NS) and angioplasty after thrombolytic therapy (8% x 6%; p = NS). RESULTS: The overall incidence of abrupt closure was 2/525 (0.4%), with one case (0.4%) in each group. The in-hospital mortality was 1/525 (0.2%), which occurred in a non-heparin patient, due to a anterior myocardial infarction. Major complications occurred similarly in heparin and non-heparin groups (0.4%). Bleeding complications were observed more frequently in the heparin group (7% x 2%; p = 0.002). All of them were in the catheterization site and none required blood transfusion. Severe systemic bleeding were not observed. CONCLUSION: In patients regarded as low risk for abrupt closure, the incidence of this complication was really low (0.4%) and heparin probably do not prevent it.     

Inhibitory effects of formoterol on platelet-activating factor induced eosinophil chemotaxis and degranulation

A new long-acting beta 2-agonist, formoterol, has been reported to have a greater efficacy and duration of action in asthmatic patients as compared to conventional beta 2-agonists. We recently demonstrated that formoterol inhibited antigen-induced late asthmatic response (LAR) and accompanying airway eosinophilia in guinea pigs. In this study, we investigated the direct effect of formoterol in vitro on human eosinophil function, focusing on platelet-activating factor (PAF)-induced eosinophil chemotaxis and eosinophil cationic protein (ECP) release. Purified normodense eosinophils were separated by discontinuous gradient from 12 mild asthmatic patients. Formoterol in concentrations of 1-100 microM significantly inhibited PAF-induced eosinophil chemotaxis in a dose-dependent manner with a concentration of drug required to produce 50% inhibition (IC50) of 10.16 microM; % inhibition: 22.9 +/- 13.0% (1 microM), 51.6 +/- 12.7% (10 microM), 75.0 +/- 11.3% (100 microM). When formyl-methionyl-leucyl-phenylamine (FMLP) was used as a chemoattractant, a similar inhibition of eosinophil chemotaxis by formoterol was observed; % inhibition: 13.1 +/- 5.0% (1 microM). 47.7 +/- 7.6% (10 microM), 65.5 +/- 16.5% (100 microM). A conventional beta 2-agonist, salbutamol, at doses to 100 microM did not show any inhibitory effects on PAF-induced eosinophil chemotaxis. Formoterol in concentrations of 1-100 microM also significantly inhibited PAF-induced ECP release from eosinophils; % inhibition: 21.7 +/- 9.0% (1 microM), 39.3 +/- 7.4% (10 microM), 39.6 +/- 8.4% (100 microM). In the presence of phosphodiesterase inhibitors, theophylline or isobutylmethyl xanthine (IBMX), the inhibition by formoterol on PAF-induced ECP release was enhanced.(ABSTRACT TRUNCATED AT 250 WORDS)     

Neonatal lensectomy and intraocular lens implantation: effects in rhesus monkeys

PURPOSE: To compare the effects of a lensectomy with and without intraocular lens (IOL) implantation on a neonatal rhesus monkey eye. METHODS: A lensectomy and anterior vitrectomy was performed on 75 monkeys during the first 16 days of life; 21 of these monkeys also had an IOL implanted into the posterior chamber. The eyes were examined at regular intervals using biomicroscopy, applanation tonometry, and ophthalmoscopy. RESULTS: The pseudophakic monkeys were studied until they were 92.5 +/- 5.8 weeks of age and the aphakic monkeys until they were 80.4 +/- 5.7 weeks of age. Pupillary membranes (100% versus 55.5%; P < 0.01) and lens regeneration into the pupillary aperture (28.6% versus 5.6%; P = 0.02) occurred more often in the pseudophakic than the aphakic eyes. As a result, the pseudophakic eyes required more reoperations than the aphakic eyes to keep the visual axis clear (P < 0.01). There was not a significant difference in the incidence of ocular hypertension between the pseudophakic and aphakic eyes (9.5% versus 12.7%; P = 0.34). Pupillary capture of the IOL optic occurred in 52% and haptic breakage in 33% of the pseudophakic eyes. All of the eyes with broken haptics had a prominent Soemmerring's ring varying in maximum thickness from 0.6 to 2 mm. Nine of the haptics from the seven eyes with broken IOLs had eroded into the iris, two into the ciliary body, and one into the anterior chamber. CONCLUSIONS: Implanting an IOL into a neonatal monkey eye after a lensectomy and anterior vitrectomy increases the likelihood of a reoperation being necessary. Haptics frequently erode into the iris and ciliary body and may break because of stress placed on the optic-haptic junction by forward movement of the IOL.     

Immunoglobulin VH gene mutational analysis suggests that primary effusion lymphomas derive from different stages of B cell maturation

Primary effusion lymphoma (PEL) is a recently described distinct subtype of non-Hodgkin's lymphoma associated with infection by the Kaposi's sarcoma-associated herpesvirus, also called human herpesvirus-8. Most cases of PEL are also associated with the Epstein-Barr virus (EBV). In order to better characterize the cellular origin of PEL, we investigated the immunoglobulin (Ig) heavy chain variable region (VH,) genes expressed by tumor cells of the BC-1 and BC-3 cell lines derived from PELs and five original PEL specimens. In the six EBV-positive PELs examined, including the BC-1 cell line, the expressed VH gene sequences showed numerous point mutations relative to the putative germline VH gene sequences. In addition, the VH, segment of one of these cases showed intraclonal sequence heterogeneity, indicating ongoing somatic mutation. In five cases, the distribution and type of mutations indicated that tumor cells had been selected by antigen. Because somatically mutated Ig genes are expressed by B cells that have reached a germinal center/post-germinal center stage of development, these findings suggest that the PEL cell of origin is a germinal center or post-germinal center B cell in most cases. In contrast, the VH gene segment expressed by tumor cells of the BC-3 cell line, which was originated from an EBV-negative PEL obtained from an HIV-negative patient, was unmutated, suggesting a pre-germinal center B cell origin for tumor cells of this particular PEL cell line. Taken together, these findings suggest that development of PELs may not be restricted to one stage of B cell differentiation and may represent transformation of B cells at different stages of ontogeny.     

Tidal expired airflow patterns in adults with airway obstruction

Earlier studies have shown that time and flow indices derived from tidal expiratory flow patterns can be used to distinguish the severity of airway obstruction. This study was designed to address two aspects of tidal expiratory flow patterns: 1) how do expiratory flow patterns differ between subjects with normal and obstructed airways; and 2) can a sensitive index of airway obstruction be derived from these pattern differences? Tidal expiratory flow patterns from 66 adult subjects with varying degrees of airway obstructive disease with a forced expiratory volume in one second (FEV1) of 20-121% predicted were examined. In each subject, the expired flow pattern from each consecutive breath was scaled and then averaged together to create a single expired pattern. A detailed examination of the scaled flow patterns in 12 subjects (six with normal airways and six with airway obstruction) showed that the shape of the post-peak expiratory flow portion was different in the subjects with airway obstruction. A slope index, S, was derived from the scaled patterns and found to be sensitive to the severity of airway obstruction, correlating with FEV1 (% pred) with r2=0.74 (p<0.05, n=57). The S index also correlated (r2=0.36, p<0.05, n=47) with the functional residual capacity (FRC) (% pred) which was >100% in subjects with severe airway obstruction and lung overinflation. In subjects with normal airways, three further airflow patterns could be distinguished, which were different from the patterns seen in subjects with the severest airway obstruction. Scaled flow patterns from tidal expiration collected from uncoached subjects, can be used to derive an index of airway obstruction.     

Tumor growth modulation by sense and antisense vascular endothelial growth factor gene expression: effects on angiogenesis, vascular permeability, blood volume, blood flow, fluorodeoxyglucose uptake, and proliferation of human melanoma intracerebral xenografts

Vascular endothelial growth factor (VEGF), also known as vascular permeability factor, has been investigated as a potent mediator of brain tumor angiogenesis and tumor growth. We evaluated the effect of VEGF expression on the pathophysiology of tumor growth in the brain. Human SK-MEL-2 melanoma cells, with minimal VEGF expression, were stably transfected with either sense or antisense mouse VEGF cDNA and used to produce intracerebral xenografts. Vascular permeability, blood volume, blood flow, and tumor fluorodeoxyglucose metabolism were assessed using tissue sampling and quantitative autoradiography. Tumor proliferation was assessed by measuring bromodeoxyuridine labeling indices. Tumor vascular density and morphological status of the blood-brain barrier were evaluated by immunohistochemistry. SK-MEL-2 cells transfected with sense VEGF (V+) expressed large amounts of mouse and human VEGF protein; V+ cells formed well-vascularized, rapidly growing tumors with minimal tumor necrosis. V+ tumors had substantial and significant increases in blood volume, blood flow, vascular permeability, and fluorodeoxyglucose metabolism compared to wild-type and/or V- (antisense VEGF) tumors. VEGF antisense transfected V- expressed no detectable VEGF protein and formed minimally vascularized tumors. V- tumors had a very low initial growth rate with central necrosis; blood volume, blood flow, vascular permeability, and glucose metabolism levels were low compared to wild-type and V+ tumors. A substantial inhibition of intracerebral tumor growth, as well as a decrease in tumor vascularity, blood flow, and vascular permeability may be achieved by down-regulation of endogenous VEGF expression in tumor tissue. VEGF-targeted antiangiogenic gene therapy could be an effective component of a combined strategy to treat VEGF-producing brain tumors.     

X-ray crystal structure of C3d: a C3 fragment and ligand for complement receptor 2

Activation and covalent attachment of complement component C3 to pathogens is the key step in complement-mediated host defense. Additionally, the antigen-bound C3d fragment interacts with complement receptor 2 (CR2; also known as CD21) on B cells and thereby contributes to the initiation of an acquired humoral response. The x-ray crystal structure of human C3d solved at 2.0 angstroms resolution reveals an alpha-alpha barrel with the residues responsible for thioester formation and covalent attachment at one end and an acidic pocket at the other. The structure supports a model whereby the transition of native C3 to its functionally active state involves the disruption of a complementary domain interface and provides insight into the basis for the interaction between C3d and CR2.