Biomedical subjects
Publications and source records attributed to J J Barry.
Electroconvulsive therapy (ECT) is sometimes indicated during pregnancy and may offer advantages over pharmacotherapy for the patient and the fetus (1,2). However, very little data is available on the impact of epileptic or ECT-induced seizures on the fetus. We report a case of brief fetal heart rate decelerations in a fetus associated with maternal ECT-induced convulsions.
Psychogenic nonepileptic seizures (NES) can be classified into five categories. This review focuses on NES associated with emotional conflict, by far the most common and important group. Etiology is speculative, but the background histories of these patients are often similar. The presence of a trauma history, depression, post-traumatic stress symptoms, and the use of dissociation plus cognitive dysfunction possibly point to an organic etiology. The presentation of NES in children and adults is discussed, along with the differential diagnosis. The diagnostic differential is lengthy, with epileptic seizures of frontal lobe origin presenting a unique challenge. Diagnostic procedures are reviewed with an emphasis on the utility of hypnosis with seizure induction. Presenting the diagnosis to the patient, the role of the neurologist, and the role of the mental health consultant are reviewed. Issues in the doctor-patient relationship are also addressed, as well as the overall prognosis.
Since before the time of Charcot, nonepileptic seizures (NES) have intrigued and perplexed physicians. With the advent of the electroencephalogram, particularly with the addition of continuous video monitoring, the diagnosis of NES has received increasing evaluation. Characteristic historical features and clinical signs of NES, coupled with new diagnostic techniques, have progressively refined our understanding of the disorder. The treatment of patients who have NES has received much less attention and the prognosis of these patients illustrates the need for a more comprehensive, systematic, and validated intervention. These issues are discussed with an emphasis on the need for future research.
PURPOSE: To determine if local application of L-arginine, r-hirudin, or molsidomine significantly reduces restenosis after balloon angioplasty in stenotic rabbit iliac arteries. MATERIALS AND METHODS: Thirty-one male cholesterol-fed New Zealand white rabbits underwent balloon dilation of both common iliac arteries to induce arterial stenosis. Four weeks later, one stenotic iliac artery was simultaneously dilated and received local application of L-arginine (210 mg/mL, n = 7), r-hirudin (0.5 mg/mL, n = 8), or molsidomine (0.2 mg/mL, n = 8) with a channeled balloon catheter. On the contralateral side, 0.9% saline was injected as a control. In eight sham animals, saline was applied to one iliac artery and balloon dilation to only the contralateral artery. Six weeks after local treatment, vessels were harvested, and computerized morphometric and immunohistologic analyses were performed. RESULTS: Application of drugs resulted in a significant reduction of neointimal area as follows: 53% with L-arginine (1.01 mm(2) vs. 2.17 mm(2), P <.05), 43% with molsidomine (1.04 mm(2) vs. 1.89 mm(2), P <.05), and 20% with r-hirudin (1.79 mm(2) vs. 2.24 mm(2), P <.05). Infusion of saline led to a significant increase (50%, 1.21 mm(2) vs. 1.93 mm(2), P <.05) in neointimal area compared with balloon dilation alone. Immunohistologic findings showed a significant reduction of macrophages (5.0% vs. 10.2%, P <.05) and proliferating cells (6.2% vs. 10.6%, P <.05) in the neointima after local application of L-arginine. CONCLUSION: Reduction of neointimal area was significant for L-arginine and molsidomine but not for r-hirudin. Saline infusion caused significant arterial trauma, resulting in additional neointimal proliferation.
Escherichia coli K1 is an important neonatal pathogen that is usually transferred from maternal to infant gastrointestinal tract at the time of parturition. Approximately 20% of neonates are colonized, and a proportion of colonized infants goes on to have systemic infection. Entry into the bloodstream from the gastrointestinal tract is hypothesized to occur via epithelial cell invasion. Invasion of multiple epithelial cell lines was studied using gentamicin protection assays and transcytosis of polarized monolayers. Electron microscopy was used to confirm cellular invasion. Cell lines used include two human gastrointestinal lines, Caco-2 and T84; a human respiratory cell line, A549; a human laryngeal cell line, HEp-2; and a canine kidney cell line, MDCK. A virulent E. coli K1 strain, RS218, readily invaded HEp-2, A549, and T84 cell lines in gentamicin protection assays, but was less invasive into MDCK and Caco-2 cells. RS218 also demonstrated transcytosis of both T84 and Caco-2 cells. Four clinical isolates of E. coli K1 demonstrated levels of transcytosis of T84 cells similar to RS218. Caco-2 invasiveness correlated with length of time in tissue culture with maximum invasiveness demonstrated at 11 d in culture, when cells were polarized and differentiated.
Local delivery devices have been used for adenovirus-mediated gene transfer to the arterial wall for the potential treatment of vascular proliferative diseases. However, low levels of adenoviral gene expression in vascular smooth muscle cells may pose a serious limitation to the success of these procedures in the clinic. In this study, we examined the mechanisms controlling adenoviral transport to the vessel wall, using both hydrogel-coated and infusion-based local delivery catheters, with the goal of enhancing in vivo gene transfer under clinically relevant delivery conditions. The following delivery parameters were tested in vivo: applied transmural pressure, viral solution volume and concentration, and delivery time. We found that viral particles are transported into the vessel wall in a manner consistent with diffusion rather than pressure-driven convection. Consistent with diffusion, viral concentration was shown to be the key variable for viral transport in the vessel wall and thus gene expression in vascular smooth muscle cells. A transduction level of 17.8+/-3.2% was achieved by delivering a low volume of concentrated adenoviral beta-galactosidase solution through an infusion balloon catheter at low pressure without an adverse effect on medial cellularity. Under these conditions, effective gene transfer was accomplished within a clinically relevant time frame of 2 min, indicating that longer delivery times may not be necessary to achieve efficient gene transfer.
PURPOSE: To assess the feasibility of intravascular delivery of nadroparin, a low-molecular-weight heparin, via hydrogel-coated angioplasty balloons, and the effects of nadroparin delivered in this manner on platelet deposition and smooth muscle cell (SMC) proliferation. MATERIALS AND METHODS: Tritiated nadroparin was used to determine the nadroparin-carrying capacity of the hydrogel-coating, kinetics of release from the balloons, and, in four pigs, delivery of the nadroparin to the iliac arterial wall. Platelet deposition in nadroparin-treated iliac arteries versus contralateral iliac arteries dilated with saline-loaded, hydrogel-coated balloons was quantified in seven pigs using 111Indium-labeled platelets. Smooth muscle cell proliferation in nadroparin and saline-treated iliac arteries in 10 pigs was evaluated 7 days after angioplasty with use of proliferating cell nuclear antigen. RESULTS: Approximately 98 international units of nadroparin were delivered by the hydrogel-coated balloon, the majority to the angioplasty site and distal vessel. There was a trend toward decreased platelet deposition in nadroparin-treated arteries, but statistical significance was not achieved (P = .1563). Medial SMC proliferation was decreased in the nadroparin-treated arteries in nine of 10 pigs (P = .0137). CONCLUSIONS: Hydrogel-coated balloons may be used to deliver nadroparin to the arterial wall, with measurable levels of the drug delivered to the site of angioplasty, and with resultant decrease in SMC proliferation.
PURPOSE: To determine the validity of the Hypnotic Induction Profile (HIP) followed by seizure induction during continuous video-electroencephalographic (EEG) monitoring to discriminate between epileptic (EE) and nonepileptic events (NEE). METHODS: Eighty-two patients admitted to the Stanford Comprehensive Epilepsy Center for differential diagnosis of seizure-like events were evaluated. Exclusion criteria included inability or refusal to complete the HIP, lack of a "typical" event, an IQ <70, present evidence of psychosis, or a physiological cause for NEE. Sixty-nine patients met these criteria. While undergoing continuous video-EEG monitoring, the patient completed an HIP, an inventory designed to measure the degree of hypnotizability. An attempt was then made to induce the patient's typical events under hypnosis by using a split-screen technique. An event without an EEG correlate was thought to represent an NEE. A diagnosis of NEE was made independently by the neurology team and was compared with results obtained with the hypnotic evaluation. RESULTS: Results for patients with EE were compared with those with NEE and a group consisting of both EE/NEE. All patients with NEE were then contrasted with the EE group. HIP scores for the EE patients indicated lower hypnotizability than the NEE group and were statistically significant when NEE patients and those with NEE/EE were combined. The sensitivity of seizure induction in the diagnosis of NEE was 77%, with a specificity of 95%. CONCLUSIONS: The HIP coupled with seizure induction is a useful technique to aid in the diagnosis of patients with NEE. It is sensitive and specific, and it may provide the patient with a useful behavioral tool to control NEEs. It may also furnish a conduit for long-term treatment.
An audit of postoperative pain management was conducted before and after the introduction of an Acute Pain Service (APS) run entirely by medical staff. The ability of patients to complete two pain-scoring systems, a verbal rating score (VRS) and a numerical rating score (NRS, where 0 = no pain, 10 = worst pain) was compared. We surveyed 605 adults 24 hours postoperatively. For major operations, the incidence of "severe" or "unbearable" pain at rest (VRS) over the first 24 hours decreased from 18.1% before to 3.5% after the APS (P = 0.0002) and severe/unbearable pain with movement decreased from 50% to 31% (P = 0.0037). The average NRS pain scores fell from 4.65 to 3.37 at rest (P < 0.0001) and from 6.77 to 6.19 with movement (P = 0.046). The incidence of severe/unbearable pain at rest with patient-controlled analgesia (PCA) decreased from 19.7% to 3.2% after the APS (P = 0.0012) and with movement from 51.3% to 35.1% (P = 0.049). For epidural analgesia, severe/unbearable pain at rest was 18.8% prior to the APS and 4.4% after (P = 0.14), and with movement was 43.8% before and 19.1% after (P = 0.079). The NRS pain-scoring system was unsuitable for Aboriginal or Torres Strait Islander patients. Patient satisfaction was high both before and after the introduction of the APS, and was an unreliable indicator of effective pain relief. We conclude that an APS can improve postoperative pain control with PCA and epidural analgesia.
To determine the potential utility of local treatment of enoxaparin on restenosis, four groups of rabbits underwent balloon injury of bilateral iliac arteries with the Channeled Balloon (balloon/artery = 1.1), followed by assigned treatment (5 controls received local saline, 7 local-treatment rabbits received a one-time local delivery of 10 mg/kg of enoxaparin, 5 systemic-treatment rabbits received 10 mg/kg of enoxaparin subcutaneously once daily for 1 wk, and 5 combined-treatment rabbits received both local and systemic enoxaparin). The percentage of nuclei positive for proliferating cell nuclear antigen/microns2 of media 1 wk later was 1.97 +/- 2.01 for the control group, 2.68 +/- 2.52 for the local group, 0.22 +/- 0.32 for the systemic group, and 0.07 +/- 0.09 for the combined group (P < 0.0001 by Kruskal-Wallis test, with P < 0.05 for combined treatment group vs. controls or local treatment group and systemic vs. local groups). Feasibility study with 3H-enoxaparin showed intramural retention of 0.1-0.2% of locally delivered amount for 24 h. We conclude that one-time local delivery of enoxaparin following angioplasty is ineffective in inhibiting medial smooth muscle cell proliferation, most likely due to low efficiency. Only sustained treatment resulted in significant reduction.
The Channel balloon is a new local drug-delivery catheter that has the dual capability of high-pressure lesion dilation and low-pressure drug infusion. The purpose of this study was to assess the safety and efficacy of this device in the local delivery of urokinase in the porcine model. Three in vivo protocols were performed in 57 anesthetized swine to assess the safety of Channel balloon use in the coronary vasculature, the pharmacokinetics of local urokinase delivery, and the ability of the catheter to lyse intraluminal thrombus. First, safety studies were performed in 18 coronary vessels in 13 pigs to compare angiographic and histologic changes following use of the Channel balloon with conventional balloon angioplasty. Second, intramural deposition of 123I-labeled urokinase was measured in 24 coronary arteries in 20 pigs to assess the efficiency and technical determinants of urokinase delivery and the time course of intramural drug retention. Finally, an in vivo thrombus model was used in 24 pigs to compare the thrombolytic capacity of local urokinase delivery with the Channel balloon in comparison with conventional urokinase infusion techniques. All balloon inflations and drug infusions with the Channel balloon were well tolerated in all animals without adverse angiographic, hemodynamic, or electrical sequelae. Comparative histologic studies with the Channel balloon demonstrated no additional vessel trauma beyond that seen with conventional balloon angioplasty. Between 0.09 and 0.35% of infused urokinase was intramurally deposited, with intracoronary persistence for at least 5 h. Drug infusion pressure did not significantly affect drug deposition, although larger amounts of urokinase were deposited with larger balloon:artery ratios and higher urokinase concentrations. In comparison to conventional systemic and guiding catheter infusions, local delivery of urokinase with the Channel balloon resulted in higher levels of clot dissolution. These studies have demonstrated safe intracoronary use of the Channel balloon in the porcine model. Local infusion of urokinase with this device results in significant intramural drug deposition that persists for at least 5 h. In comparison with conventional thrombolytic techniques, local urokinase delivery with the Channel balloon may result in enhanced intravascular thrombolysis.
OBJECTIVES: The expression of gax, an anti-proliferative homeobox gene, is rapidly downregulated in vascular smooth muscle cells (VSMCs) following arterial injury. Here we performed percutaneous adenovirus-mediated gene transfer into the iliac arteries of normal rabbits using a channel balloon catheter to assess the effects of gax overexpression on neointima formation, lumen diameter, reendothelialization and functional vasomotion. METHODS: A channel balloon catheter was used to perform both the arterial injury and local gene delivery. In each animal both iliac arteries were randomly assigned to receive either an adenovirus expressing the gax gene (Ad-Gax) or the beta-galactosidase gene (Ad-beta gal). In a second group of animals arteries were randomly assigned to receive either Ad-beta gal or saline. RESULTS: At one month, angiography revealed 36% less luminal narrowing in the Ad-Gax-treated arteries relative to the Ad-beta gal-treated control arteries. Histological analysis revealed that the intimal/medial ratio (I/M) was reduced by 56% in the Ad-Gax group. Endothelium-dependent vasomotion was not affected by the gax gene transfer. In the second group, no statistically significant differences were found between the saline and the Ad-beta gal-treated vessels for any of these parameters. CONCLUSIONS: Percutaneous adenovirus delivery of the gax gene to rabbit iliac arteries following endothelial denudation and vessel wall injury reduces neointimal hyperplasia and luminal stenosis, but does not affect endothelium-dependent vasomotion. This study demonstrates that a VSMC transcription factor can potentially be utilized for the development of a molecular therapy for vascular disorders.
Antibiotic-resistant Burkholderia (Pseudomonas) cepacia is an important etiologic agent of nosocomial and cystic fibrosis infections. The primary resistance mechanism which has been reported is decreased outer membrane permeability. We previously reported the cloning and characterization of a chloramphenicol resistance determinant from an isolate of B. cepacia from a patient with cystic fibrosis that resulted in decreased drug accumulation. In the present studies we subcloned and sequenced the resistance determinant and identified gene products related to decreased drug accumulation. Additional drug resistances encoded by the determinant include resistances to trimethoprim and ciprofloxacin. Sequence analysis of a 3.4-kb subcloned fragment identified one complete and one partial open reading frame which are homologous with two of three components of a potential antibiotic efflux operon from Pseudomonas aeruginosa (mexA-mexB-oprM). On the basis of sequence data, outer membrane protein analysis, protein expression systems, and a lipoprotein labelling assay, the complete open reading frame encodes an outer membrane lipoprotein which is homologous with OprM. The partial open reading frame shows homology at the protein level with the C terminus of the protein product of mexB. DNA hybridization studies demonstrated homology of an internal mexA probe with a larger subcloned fragment from B. cepacia. The finding of multiple antibiotic resistance in B. cepacia as a result of an antibiotic efflux pump is surprising because it has long been believed that resistance in this organism is caused by impermeability to antibiotics.
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BACKGROUND: Systemic administration of heparin can decrease mortality and morbidity of acute ischemic coronary syndromes such as unstable angina and myocardial infarction. Hemorrhage is the major limiting factor in the clinical use of systemic heparin. The objective of the present study was to determine whether local delivery of heparin could inhibit platelet-dependent thrombosis without altering systemic bleeding parameters. METHODS AND RESULTS: Hydrogel-coated angioplasty balloon catheters were dipped in a heparin solution, dried, and applied to a platelet-rich mural thrombus in a chronic ex vivo porcine arteriovenous shunt. 111In-labeled platelet deposition was quantified by gamma camera imaging. In a separate series of experiments, 3H-heparin was used to estimate the amount of heparin delivered to the thrombus with the coated balloon. Systemic heparin administration produced a dose-dependent decrease in platelet-dependent thrombus formation that was maximal at 200 units/kg. Bleeding times and activated partial thromboplastin times were prolonged at this dose. An equal inhibition of thrombus formation was achieved after the coated balloon was dipped in a heparin solution (10,000 units/mL) and deployed at the mural thrombus. In contrast to systemic heparin administration, there was no alteration in bleeding parameters associated with local heparin delivery. The estimated amount of heparin delivered with the coated balloon was 40 units. CONCLUSIONS: Local delivery of heparin in amounts sufficient to inhibit platelet-dependent thrombosis can be accomplished with a hydrogel-coated coronary angioplasty balloon catheter. Local heparin delivery can inhibit thrombus formation in amounts that are several orders of magnitude lower than the required systemic dose. Local delivery of heparin was not associated with prolongation of bleeding parameters.
A dual-purpose angioplasty catheter with intramural channels and exterior pores for local drug delivery ("channeled balloon") was studied in eight atherosclerotic human necropsy arteries and in 22 rabbits with atherosclerotic peripheral arteries, in which markers (0.005 microns to 15 microns) were infused locally at 2 atmospheres during simultaneous angioplasty at 6 atmospheres. Thirteen of the rabbits were sacrificed at 4 or 24 h after procedure to determine the intramural retention over time. Histology confirmed effective angioplasty and revealed presence of markers in the arterial wall in 29 of 43 treated arteries (67%), whereas all control segments without local delivery had no marker staining. majority of the ineffective local delivery (12/14) occurred when 15 micron particles were infused (12/13 arteries without intramural markers), especially when examined 4 or 24 h later. Thus, in atherosclerotic arteries, the channeled balloon enabled simultaneous local drug delivery at low pressure during effective angioplasty, although particle size may play a role in successful intramural impregnation and retention.
Recombinant adenoviruses are the most efficient vectors with which to perform arterial gene transfer. Previous in vivo studies of adenovirus-mediated arterial transfection, however, have been performed using normal or endothelium-denuded arteries. It is unclear whether these results can be extended to atherosclerotic arteries. Accordingly, this study was designed to (a) assess the feasibility of adenovirus-mediated gene transfer to atherosclerotic lesions, and (b) compare the transfection efficiency, anatomic distribution of transfected cells, and duration of transgene expression achieved in normal versus atherosclerotic arteries. A recombinant adenovirus including a nuclear-targeted beta-galactosidase gene was percutaneously delivered to the iliac artery of normal (n = 25) and atherosclerotic (n = 25) rabbits. Transgene expression, assessed by morphometric as well as chemiluminescent analyses, was documented in all normal and atherosclerotic arteries between 3 and 14 d after gene transfer, but was undetectable at later time points. Transfected cells were identified as smooth muscle cells located in the media of normal arteries, and in the neointima and the vasa-vasora of atherosclerotic arteries. Two percent of medial cells, but only 0.2% of medial and neointimal cells expressed the transgene in normal and atherosclerotic arteries, respectively (P = 0.0001). Similarly, nuclear beta-galactosidase activity was higher in normal than in atherosclerotic arteries (3.2 vs. 0.8 mU/mg protein, P = 0.02). These findings indicate that atherosclerosis reduces the transfection efficiency which can be achieved with adenoviral vectors, and thus constitutes a potential limitation to adenovirus-based, arterial gene therapy.