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Biomedical subjects

A Rothman

Publications and source records attributed to A Rothman.

At least 55 records · Page 3Linked to original sources
PubMed1996

Adenovirus-mediated increase of exogenous and inhibition of endogenous fosB gene expression in cultured pulmonary arterial smooth muscle cells.

Modification of gene expression in pulmonary arterial smooth muscle cells (PASMCs) could be a valuable tool for investigating the role of specific gene products in normal and pathological PASMC growth, and a novel potential therapy for pulmonary vascular diseases. To examine the direct role of fosB protein in PASMC growth, adenovirus (Ad) vectors were used to transfer sense or antisense full-length fosB cDNAs to cultured PASMCs to modify fosB expression, and investigate the effects of this modification on PASMC growth. The full-length fosB cDNA under the control of the cytomegalovirus (CMV) early gene promoter was constructed into an E1 region-deleted, replication-deficient human type 5 Ad vector in either sense or antisense orientation. Forty-eight hours after infection with the sense construct (Ad.S. fosB) at 3 plaque-forming units per cell (pfu/cell). PASMCs expressed abundant fosB mRNA and fosB protein. FosB protein was detected by immunohistochemistry in approximately 95% of the infected cells. PASMCs infected with Ad.S.fosB at ratios of 0.1, 0.2, 0.5, 1.3, and 10 pfu/cell showed a dose-dependent increase in fosB mRNA expression, with half-maximal and maximal expression at 1 and 10 pfu/cell, respectively. The increase in fosB mRNA expression was detected as early as 8 h and persisted for 25 days after infection. Forty-eight hours after infection with the antisense construct (Ad.A.fosB) at 3 pfu/cell, very low levels of fosB mRNA were detected by Northern blotting, in which the double-stranded fosB cDNA was labeled and used as a hybridization probe. FosB protein was undetectable by Western blotting or immunocytochemical analyses in the Ad.A.fosB infected cells. Cytopathical effects were observed when PASMCs were infected with either Ad.S.fosB or Ad.A.fosB at ratios of 10 pfu/cell or higher. Infection of serum-deprived PASMCs with Ad.S.fosB or Ad.A.fosB alone at 3 pfu/cell did not affect cellular growth. These results show that adenoviral vectors containing sense or antisense fosB cDNA expression units can be used to effectively modify fosB gene expression. Although changes in fos-B gene expression did not affect cellular growth, this model system offers a very effective method for elucidating the biological roles of other gene products and studying the pathways of PASMC gene regulation and signal transduction.

Actins↗
PubMed1996

Transvenous procurement of pulmonary artery smooth muscle and endothelial cells using a novel endoarterial biopsy catheter in a canine model.

OBJECTIVES: The aim of this study was to evaluate the performance of a new arterial biopsy catheter in obtaining pulmonary endovascular samples in a canine model. BACKGROUND: Percutaneous endomyocardial biopsy is a widely used and valuable procedure in the management of posttransplant rejection and selected cardiomyopathies. A similar method of obtaining endoarterial biopsy samples would aid in the study, diagnosis and management of arterial diseases. METHODS: Catheterization was performed in 19 dogs, each weighing 20 to 30 kg, through an 8F sheath in the external jugular vein to obtain pulmonary endoarterial samples. The catheter consists of two sliding tubes: an inner one with a beveled opening that accommodates endoarterial tissue by means of a vacuum and an outer tube with a sharp distal edge that cuts the tissue when activated. RESULTS: Overall, a total of 266 separate biopsy attempts were performed, and 161 tissue samples were obtained (success rate 61%). With modifications in technique in the last nine dogs, 54 (93%) of 58 attempts were successful. There were no deaths, extravasation of contrast material on angiography or thrombi. Of 20 vessels with prebiopsy and postbiopsy angiograms, 1 developed transient spasm (5%). On microscopic examination of cross sections of 50 separate pulmonary endoarterial biopsy samples, all had smooth muscle cells and 30 contained endothelial cells (60%). The arteries of origin showed small intimal and medial tears and mild perivascular hemorrhage. Angiographic and pathologic examination of previously biopsied arterial segments 2 weeks (two dogs) and 8 weeks (two dogs) after the procedure showed patent vessels and no thrombi. Histologically, the biopsy sites revealed mild neointimal and medial proliferation. CONCLUSIONS: This new endoarterial biopsy catheter is safe and effective in obtaining pulmonary artery samples in normotensive dogs.

Angiography↗
PubMed1996

High incidence of cranial ultrasound abnormalities in full-term infants with congenital heart disease.

The objective of this retrospective study was to determine the incidence and types of cranial ultrasound abnormalities in full-term infants with congenital heart disease (CHD). We reviewed the cranial ultrasound scans of 49 full-term infants with CHD and compared them to 42 healthy full-term control infants. The relationship of each abnormality with the type of CHD, the presence of cyanosis, and cardiac catheterization and cardiac surgery were examined. We found that infants with CHD had a higher incidence of cranial ultrasound abnormalities than control infants (59% versus 14%; p < 0.001). Cerebral atrophy and linear echodensities in the basal ganglia and thalamus were the most common sonographic findings in infants with CHD, particularly in those with coarctation of the aorta or ventricular septal defect. Intraventricular hemorrhage occurred more often in infants with acryanotic CHD than in those with cyanotic CHD. Cardiac catheterization and cardiac surgery had no significant effects on cranial ultrasound findings. We conclude that cranial ultrasound abnormalities are very frequent in full-term infants with CHD. These findings emphasize the importance of cranial ultrasonography and long-term neurodevelopmental follow-up of infants with CHD.

Aortic Coarctation↗
PubMed1996

Who should rate candidates in an objective structured clinical examination?

PURPOSE: To determine who is the better rater of history taking in an objective structured clinical examination (OSCE): a physician or a standardized patient (SP). METHOD: During the 1991 pilot administration of an OSCE for the Medical Council of Canada's qualifying examination, five history-taking stations were videotaped. Candidates at these stations were scored by three raters: a physician (MD), an SP observer (SPO), and an SP rating from recall (SPR). To determine the validity of each rater's scores, these scores were compared with a "gold standard", which was the average of videotape ratings by three physicians, each scoring independently. Analysis included both correlations with the standard and a repeated-measures analysis of variance (ANOVA) comparing raters' mean scores on each station with mean scores of the gold standard. RESULTS: Ninety-one videotapes were scored by the "gold-standard" physicians. Correlations with the standard showed no clear preference for MD, SPO, or SPR raters. ANOVAs revealed significant differences from the standard on three stations for the SPR, two stations for the SPO, and one stations for the MD. CONCLUSIONS: An MD rater is less likely to differ from a standard established by a consensus of MD ratings than are SP raters rating from recall. If an MD cannot be used, an SP observer is preferable to an SP rating from recall.

Analysis of Variance↗
PubMed1996

Inhibitory effect of ethanol on the Na(+)-ATPase activity of rat kidney proximal tubular cell plasma membranes.

The inhibitory effect of 2% ethanol (400 mM) in the incubation medium on several characteristics of the Na(+)-ATPase of basolateral plasma membranes from rat kidney proximal tubular cells was investigated. Ethanol did not change the Km of the enzyme for Mg2+, ATP or Na+; it did not change either the optimal pH or temperature values of the incubation medium for the enzyme to act and finally, it did not affect the apparent energy of activation of the enzyme. It was also found that 2% ethanol produced stronger inhibition of the ATPase when it is in an activated or stimulated state, than when it is working at its lower basal level. The presented results can be explained by assuming that 2% ethanol in the incubation medium inhibits Na(+)-ATPase activity by affecting the enzyme structure as well as its activating mechanism.

Adenosine Triphosphatases↗
PubMed1995

Atrioventricular situs concordance with atrioventricular alignment discordance: fetal and neonatal echocardiographic findings.

Fetal echocardiography can reliably assess visceroatrial situs, ventricular morphology, and atrioventricular and ventriculoarterial alignments. The echocardiographic findings of this case were consistent with visceroatrial situs solitus, atrioventricular alignment discordance, and ventriculoarterial alignment concordance. This arrangement is almost always associated with ventricular inversion, or L-looped ventricles, and has therefore been widely referred to as isolated ventricular inversion. Rarely, as in this report, the arrangement may be associated with D-looped ventricles. Fetal and neonatal echocardiography may distinguish situs concordance with atrioventricular alignment discordance from isolated ventricular inversion in situs solitus by the presence, in the former, of superior-inferior ventricles, an anterior right ventricle, and a tricuspid valve that is anterior and to the right of the pulmonary valve, consistent with D-looped ventricles.

Adult↗
PubMed1995

Partial and transient relief of conduit obstruction by low-pressure balloon dilation in patients with congenital heart disease.

Seven patients underwent attempted low pressure balloon dilation of stenotic conduits or homografts from right ventricle to pulmonary artery (n = 5), in the aortic valve position (n = 1), or from right atrium to left pulmonary artery (n = 1). In the right ventricle to pulmonary artery group, mean gradient reduction was only 17%. At follow-up, two patients underwent surgical conduit replacement, one had a stent implanted at cardiac catheterization, the other two are awaiting surgical intervention. The patient with a homograft in the aortic valve position had a good initial result but restenosed within 1 year and underwent a pulmonary autograft operation. The patient with the Fontan homograft stenosis had transient obstruction relief but subsequently required stent implantation. Low-pressure balloon dilation of conduits or homografts is only partially and transiently successful. Whether stent implantation will offer better long-term results remains to be determined.

Adolescent↗
PubMed1995

Intravascular ultrasound imaging of coarctation of the aorta: animal and human studies.

Although the use of balloon dilation for treatment of native and recurrent coarctation of the aorta (coA) has become widespread, the optimal balloon size and postdilation vessel wall changes remain undetermined. Intravascular ultrasound (IVUS) imaging has emerged as a an important adjunct in the treatment and follow-up of patients with coronary artery and peripheral vascular lesions, and has been used for evaluation in a limited number of patients with CoA. We used a combination of balloon dilation/ultrasound imaging catheter in animals with experimentally-induced CoA. We used a combination balloon dilation/ultrasound imaging catheter in animals with experimentally-induced CoA . This technique provided real-time data regarding aortic wall morphology and luminal diameter during balloon angioplasty of the CoA. In humans, we used IVUS to study CoA before and after both transcatheter and surgical therapy. IVUS was more sensitive than angiography in the detection of intimal tears post-balloon dilation and in the evaluation of vessel wall changes and remodelling observed at follow-up after relief of CoA. IVUS may provide valuable information regarding vascular wall changes that predict aneurysm format ion, restenosis, or a successful result after balloon dilation.

Animals↗
PubMed1994

Agonist-selective regulation of polyphosphoinositide metabolism in pulmonary artery smooth muscle cells.

Using a rat pulmonary artery smooth muscle cell line (PAC1), detailed analysis of polyphosphoinositide (PPI) metabolism reveals receptor type-selective patterns in the formation of inositol phosphates and 3-hydroxyphosphorylated PPIs. Responses to several agonists that stimulate hypertrophy or proliferation were examined, and distinct categories of response profile were observed. Thrombin and angiotensin II stimulated the hydrolysis of phosphatidylinositol (PI) 4,5-bisphosphate and the formation of several cytosolic species of inositol phosphates without the activation of PI 3-hydroxykinase. The response to thrombin was distinctive because a very large production of inositol 1,4-bisphosphate was accompanied by hydrolysis of PI 4-phosphate. The response to platelet-derived growth factor (PDGF) was distinguished by the production of the PI 3-hydroxykinase product, PI 3,4,5-trisphosphate, and the appearance of PI 3-hydroxykinase activity in immunoprecipitates. PDGF treatment of PAC1 cultures did not produce accumulation of detectable amounts of inositol 1,4,5-trisphosphate, although a small sustained elevation in the level of inositol monophosphate and a gradual accumulation of inositol 1,3,4-trisphosphate were observed. Characterization of these distinctive responses permitted us to correlate agonist-regulated PPI metabolism with induction of immediate-early genes and stimulation of hypertrophy or proliferation of PAC1 cultures (Rothman, A., Wolner, B., Button, D., and Taylor, P. (1994) J. Biol. Chem. 269, 6399-6404). Thrombin-stimulated PPI turnover and the production of a high level of inositol bisphosphate may be early signals linked to the induction of fosB and PAC1 cell hypertrophy, whereas the activation of PI 3-hydroxykinase and the accumulation of PI 3,4,5-trisphosphate in response to PDGF appear to be associated with mitogenesis.

Angiotensin II↗
PubMed1994

Immediate-early gene expression in response to hypertrophic and proliferative stimuli in pulmonary arterial smooth muscle cells.

Remodeling of the pulmonary vascular tree in pulmonary hypertension is associated with hypertrophy and proliferation of smooth muscle cells. Since the stimuli and signaling pathways for these processes are not well understood, we used a rat pulmonary arterial smooth muscle cell line (PAC1) to examine the effects of thrombin and platelet-derived growth factor (PDGF) on cellular growth and immediate-early gene expression. Over 72 h, thrombin (1 unit/ml) caused hypertrophy as reflected by a 102 +/- 12% increase in protein synthesis and a 49 +/- 11% increase in protein content per cell, but no change in cell number. PDGF (2.5 ng/ml) stimulated proliferation as evidenced by an increase in cell number (doubling in 5 days), but no significant change in protein content per cell. Immediate-early gene expression was examined by Northern blotting: both thrombin and PDGF induced egr-1, c-fos, c-jun, junB, and fra-1 mRNAs within 15 min; the response was maximal at 30-60 min (increases ranging from 2.9- to 9.3-fold over control serum-deprived cells) and returned to base-line levels within 2-4 h. Neither agent affected junD mRNA levels. However, thrombin but not PDGF, caused an increase in fosB mRNA levels (7.7 +/- 4.0-fold higher than control, n = 12, p < 0.0005). The immediate-early gene response to both agonists was generally dependent on extracellular Ca2+, Na2+/H+ exchange, and protein kinase C activation, but not on cAMP. The exception was c-jun mRNA, the levels of which were not affected by inhibition of protein kinase C, but decreased significantly by prevention of cAMP formation. Thapsigargin-sensitive intracellular Ca2+ stores were necessary for the response to thrombin, but not to PDGF. These results demonstrate that thrombin is a hypertrophic agent and that PDGF is a proliferative agent in PAC1 cells. These two agonists stimulate increases in a variety of immediate-early gene mRNAs, but only thrombin induces fosB mRNA.

Animals↗
PubMed1994

Percutaneous closure of the small patent ductus arteriosus using occluding spring coils.

OBJECTIVES: This report summarizes our experience with the use of occluding spring coils to close the small patent ductus arteriosus. BACKGROUND: Several patent ductus arteriosus occluders (most notably the Rashkind device) have been developed and studied. Occluding spring coils have been used to close abnormal vessels and vascular connections. We previously reported the use of occluding spring coils to close the small patent ductus arteriosus in a small group of patients. This report describes our series of patients having patent ductus arteriosus closure with occluding spring coils. METHODS: Between June 1990 and June 1993, 30 patients underwent cardiac catheterization to have patent ductus arteriosus closure by occluding spring coils. Selection criteria were age > 6 months and narrowest patent ductus arteriosus internal dimension < or = 3.0 mm by color flow imaging. Definitive selection was based on review of aortograms performed at catheterization. A 5.2F coronary catheter was used to deliver one or two standard occluding spring coils. A loop was delivered in the main pulmonary artery, and the remainder of the coil was delivered across the patent ductus arteriosus and into the aortic diverticulum. Patent ductus arteriosus closure was confirmed by aortography or color flow imaging, or both. Follow-up after coil placement occurred at 6 weeks and 6 months and included two-view chest radiography, echocardiography and color flow imaging. RESULTS: Of the 30 patients, 29 had successful implantation by one (27 patients) or two (2 patients) occluding spring coils. Of these 29 patients, 19 had a clinically apparent and 10 had a silent patent ductus arteriosus. Average ductus minimal internal dimension was 1.7 mm (range 1.0 to 3.0). Complete closure of the ductus was confirmed in 27 patients by aortography or color flow imaging or both (in 24 within 4 h, in 2 after 6 weeks and in 1 after 6 months). Six weeks after implantation, two patients had a tiny residual patent ductus arteriosus noted on color flow imaging. One patient did not have successful implantation. This patient had a 3.2-mm ductus, and two coils migrated to the distal left pulmonary artery and could not be retrieved. There were no deaths or any significant complications noted during early or late follow-up in these patients. CONCLUSIONS: Occluding spring coils may have additional application in closing the small patent ductus arteriosus.

Aortography↗
PubMed1994

A high resolution physical map of 2.5 Mbp of the Down syndrome region on chromosome 21.

The region surrounding D21S55 in band 21q22 of human chromosome 21 has been implicated in the etiology of Down syndrome (DS). In this paper, we report the construction of a high resolution map of a 2.5 Mb region around the marker D21S55. Characterization of YAC clones by accurate size determination, end isolation and marker assignment was used to build a refined YAC-based map. The YAC clones were then used to isolate 284 cosmid clones, covering 2.3 Mb, from a chromosome 21-specific cosmid library. The cosmid clones were ordered into overlapping groups and a restriction map of each group was determined. The groups of cosmids were then ordered and oriented with respect to the YAC-based map. This high resolution map provides the framework for further analysis of the region by transcribed sequence mapping and sequence determination.

Base Composition↗
PubMed1994

Acute and follow-up intravascular ultrasound findings after balloon dilation of coarctation of the aorta.

BACKGROUND: The study objective was to examine the vascular wall changes caused by balloon dilation of coarctation of the aorta (CoA) acutely and at short-term follow-up using intravascular ultrasound imaging. Intravascular ultrasound has been valuable in assessing the vessel wall changes in coronary and peripheral arteries after balloon dilation, often with more detail than angiography. METHODS AND RESULTS: Intravascular ultrasound imaging, using 4.8F, 20-MHz or 6.2F, 12.5-MHz catheters on either Diasonics or HP scanners, was performed in 17 patients during balloon angioplasty for native (n = 12) and recurrent (n = 5) CoAs. Nine patients were also studied at the time of follow-up cardiac catheterization 28.1 +/- 18.0 months after angioplasty. Immediately after dilation, the mean pressure gradient across the CoA decreased from 42.9 +/- 16.4 to 9.0 +/- 5.4 mm Hg (P < .001) and the mean diameter of the coarcted segment increased from 4.4 +/- 1.9 to 7.9 +/- 2.4 mm (P < .001). An intimal tear or flap was noted by ultrasound in 12 of the 12 native CoAs and 4 of the 5 recoarctations. In contrast, only 6 of the native CoAs and 2 of the recoarctations had an intimal flap or dissection detected by angiography. At follow-up, the residual pressure gradient did not significantly change from that measured immediately after dilation, but the CoA diameter increased from 7.8 +/- 1.5 to 9.9 +/- 2.3 mm (P < .01). No aneurysms were detected. Four of the 9 patients showed ultrasonic and angiographic evidence of healing and remodeling with diminution in size or disappearance of the intimal tears. CONCLUSIONS: There is a high incidence of intimal tears and dissections immediately after balloon angioplasty for native and recurrent CoAs. Intravascular ultrasound is more sensitive than angiography in detecting the vascular wall changes. Even significant intimal tears are not necessarily associated with aneurysm formation, and many decrease in size or disappear at short-term follow-up.

Adolescent↗
PubMed1994

Immunization of monkeys with baculovirus-dengue type-4 recombinants containing envelope and nonstructural proteins: evidence of priming and partial protection.

Groups of rhesus monkeys were immunized with baculovirus-dengue type-4 (DEN-4) recombinant-infected cell extracts. One recombinant contained all of the DEN-4 structural proteins and two nonstructural (NS) proteins (C-M-E-NS1-NS2a), while the other was a fusion protein containing a portion of the respiratory syncytial virus G glycoprotein and DEN-4 envelope glycoprotein (RSVG-E). Both preparations were immunogenic; all monkeys receiving either immunogen responded with the production of antivirion antibodies in enzyme immunoassays. All except one monkey receiving the recombinant b(C-M-E-NS1-NS2a) made antibodies to NS1. One monkey that received b(RSVG-E) showed the production of low levels of neutralizing antibodies. Following challenge with unmodified DEN-4 virus, seven of nine monkeys in the immunized group became infected and were viremic for a mean of 4.1 days. The control, sham-inoculated monkeys were also viremic; the mean number of days of viremia in this group was 4.7 days. The remaining monkeys in the immunized group (n = 7), although not protected, had evidence of priming. Hemagglutination inhibition antibody responses following challenge indicated an anamnestic response in this group of animals. Based on these results, it was concluded that future immunization schedules should be altered to optimize immune responses and that immunization with more potent and purified immunogens would probably result in higher seroconversion rates and antibody levels in monkeys.

Animals↗