Biomedical subjects
Publications and source records attributed to S K Huang.
Both early and late thromboembolic events are known complications of radiofrequency catheter ablation. This review of 758 patients undergoing 830 radiofrequency ablation procedures finds that embolic complications after radiofrequency ablation in patients without other risk factors for thromboembolism are rare (<0.2%).
Previous studies have reported only short-term (6 to 10 months) follow-up after ablation of atrioventricular (AV) nodal reentrant tachycardia by using the anterior approach. The objective of this study was to determine the long-term efficacy and safety of radiofrequency catheter ablation of AV nodal reentrant tachycardia with the anterior-approach method. In 56 patients (16 men and 40 women; mean [+/-SD] age, 44 +/- 19 years) with symptomatic AV nodal reentrant tachycardia. In 53 patients, ablation was performed initially by using a standard 7F, 2 mm-tipped tripolar His bundle catheter when the large-tip electrode was not as available, and in the remaining 3 patients, ablation was performed with a 7F, 4 mm-tipped catheter. Ablation was successful in the short term in 53 (95%) patients after a median of 7 radiofrequency applications. Three (5%) patients developed complete AV block immediately after ablation. Six (11 %) patients had recurrence of tachycardia within 3 months (n = 5) and 13 months (n = 1) after ablation. Repeated ablation resulted in successful outcome in 4 patients and in complete AV block in 1 patient; the other patient refused a repeated ablation attempt. A total of 51 patients was monitored for 36 +/- 12 months (range, 25 to 72 months), and none had tachycardia recurrence or delayed AV block. In conclusion, our results show that the anterior approach to radiofrequency catheter ablation can be used successfully to treat patients with AV nodal reentrant tachycardia with a good long-term efficacy and safety.
The efficacy of an "allergen-gene immunization" protocol in altering allergic response was examined. Intramuscular injection of rats with a plasmid DNA encoding a house dust mite allergen into the muscle results in its long-term expression and the induction of specific immune responses. Significantly, this approach prevents the induction of immunoglobulin E synthesis, histamine release in bronchoalveolar fluids, and airway hyperresponsiveness in rats challenged with aerosolized allergen. Furthermore, this suppression is persistent and can be transferred into naive rats by CD8+ T cells from gene-immunized rats. These findings suggest that allergen-gene immunization is effective in modulating allergic responses, and may provide a novel therapeutic approach for allergic diseases.
Allergic asthma is characterized by airway hyperresponsiveness and pulmonary eosinophilia, and may be mediated by T helper (Th) lymphocytes expressing a Th2 cytokine pattern. Interleukin (IL) 12 suppresses the expression of Th2 cytokines and their associated responses, including eosinophilia, serum immunoglobulin E, and mucosal mastocytosis. We have previously shown in a murine model that antigen-induced increases in airway hyperresponsiveness and pulmonary eosinophilia are CD4+ T cell dependent. We used this model to determine the ability of IL-12 to prevent antigen-induced increases in airway hyperresponsiveness, bronchoalveolar lavage (BAL) eosinophils, and lung Th2 cytokine expression. Sensitized A/J mice developed airway hyperresponsiveness and increased numbers of BAL eosinophils and other inflammatory cells after single or repeated intratracheal challenges with sheep red blood cell antigen. Pulmonary mRNA and protein levels of the Th2 cytokines IL-4 and IL-5 were increased after antigen challenge. Administration of IL-12 (1 microgram/d x 5 d) at the time of a single antigen challenge abolished the airway hyperresponsiveness and pulmonary eosinophilia and promoted an increase in interferon (IFN) gamma and decreases in IL-4 and IL-5 expression. The effects of IL-12 were partially dependent on IFN-gamma, because concurrent treatment with IL-12 and anti-IFN-gamma monoclonal antibody partially reversed the inhibition of airway hyperresponsiveness and eosinophilia by IL-12. Treatment of mice with IL-12 at the time of a second antigen challenge also prevented airway hyperresponsiveness and significantly reduced numbers of BAL inflammatory cells, reflecting the ability of IL-12 to inhibit responses associated with ongoing antigen-induced pulmonary inflammation. These data show that antigen-induced airway hyperresponsiveness and inflammation can be blocked by IL-12, which suppresses Th2 cytokine expression. Local administration of IL-12 may provide a novel immunotherapy for the treatment of pulmonary allergic disorders such as atopic asthma.
Atopic asthma is characterized by inflammatory responses of the airway and is associated with up-regulation of Th2 cytokines, notably IL-4 and IL-5. A recently described human cytokine, IL-13, is a potent in vitro modulator of various cell types, including monocytes, B cells, and endothelial cells. Similar to IL-4, it is also involved in the induction of IgE synthesis. However, the in vivo expression and function of IL-13 and its relation to disease remain to be defined. Using a segmental allergen challenge model, we have examined the in vivo expression of IL-13 in the bronchoalveolar lavage (BAL) cells of atopic patients. We found a significant enhancement of both IL-13 transcripts and secreted proteins in the allergen-challenged BAL compared with the saline-challenged control sites of asthmatic and rhinitic patients. In contrast, the expression of IL-13 transcripts was not detected in the BAL of two normal subjects challenged with the same dose of ragweed allergen. The cellular source of IL-13 mRNA was identified in the mononuclear cell fraction of the allergen-challenged BAL. The allergen-induced quantitative differences in the level of transcripts were confirmed by competitive PCR assays. These results suggest that the significant increase in IL-13 in the allergen-challenged BAL is primarily from the mononuclear cells and is involved in the regulation of allergen-induced late phase inflammatory responses.
HLA-DR alpha, beta 1 *1501 (and the closely related DR alpha, beta 1 *1502) heterodimers are the primary class II MHC restriction elements controlling T cell responses to a ragweed pollen allergen, Amb a 5 (M(r) = 5000). Using a novel, quantitative, competitive PCR (QC-PCR) assay and a TCR beta-gene internal standard (IS), we have examined the TCR beta-gene use in Amb a 5-specific T cells. Multiple TCR V beta (and V alpha) genes were found in polyclonal T cell lines from two unrelated subjects, and 30% of the cells were stained positive for V beta 5.2/5.3 as judged by a flow cytometry analysis. An Amb a 5-specific Th2 clone (AP1.2) was found to express V beta 5.2 (and V alpha 8) and to have a unique V-D-J junctional region sequence. To determine the relative frequency of clone AP1.2 beta-gene expression in the polyclonal T cell lines and in the PBMC using a QC-PCR assay, we first created a TCR IS by duplicating the J beta 1.5 gene segment of the AP1.2 beta-gene. A QC-PCR assay was performed using the modified AP1.2 beta-gene as a competitor and a V beta 5.2 or a D beta-specific primer, each paired with a C beta primer. Results showed the presence of 30% of AP1.2 beta transcripts in the polyclonal T cell lines, but no detectable amplified products were found in the total RNAs (200 ng) of autologous PBMC. These findings were confirmed by sequencing independent clones of PCR-amplified V beta 5.2-C beta fragments (from two unrelated subjects) from each cell line, which suggested that the frequency of the clone AP1.2 beta sequence is quite low in the PBMC but is dominant in polyclonal Amb a 5-specific cell lines.
Radiofrequency energy has emerged as the current energy source of first choice for ablation procedures. We review the development of radiofrequency energy for ablation procedures and its advantages and disadvantages. We also review how radiofrequency energy can be applied to treat various arrhythmias. We also discuss some of the insights that catheter ablation has in turn provided in our understanding of arrhythmias.
We assessed the usefulness of routine follow-up electrophysiologic studies after successful catheter ablation for supraventricular tachycardia and the role of event monitoring as an alternative modality in 310 patients at 11 centers using an investigational catheter ablation system with closed-loop temperature control. A routine follow-up electrophysiologic study between 1 and 3 months after ablation was required as part of the study protocol, and patients developing palpitations after ablation were encouraged to use event monitors. Recurrence of the initially targeted arrhythmia developed in 23 patients (7.4%) at a mean of 1.5 +/- 1.5 months after ablation. However, only 2 of these 23 recurrences were discovered by routine follow-up electrophysiologic study in asymptomatic patients (both with concealed accessory pathways); in the remaining 21 patients a positive follow-up electrophysiologic study was heralded by either recurrent symptoms, documented recurrent supraventricular tachycardia, and/or preexcitation on the electrocardiogram. Eighteen patients complained of palpitations after ablation and received an event monitor, which correctly diagnosed another cause of palpitations and ruled out recurrence of the ablated arrhythmia in 8 patients. Thus, the combination of clinical follow-up and event monitoring appears to be an effective alternative to routine follow-up electrophysiologic studies after catheter ablation of supraventricular tachycardia.
CABG is associated with many perioperative complications, including supraventricular and ventricular arrhythmias and conduction disturbances. Atrial fibrillation occurs in < or = 40% of patients after CABG and is especially common in older patients. Although it is often benign and self-limited, it can lead to complications such as stroke. Treatment consists primarily of control of the ventricular response rate; in some cases, antiarrhythmic drugs or electrical cardioversion are needed. Anticoagulation should be considered in appropriate cases of persistent (48 to 72 hours) atrial fibrillation after initial treatment. Prophylaxis, especially with beta-blocking agents, seems to be effective and should be considered in appropriate cases. Simple ventricular arrhythmias are common after CABG and do not affect the patient's prognosis; however, sustained VT/VF occur infrequently (< 2% of patients) and carry a high mortality rate. Treatment is aimed at correcting precipitating factors (e.g., myocardial ischemia). Electrophysiologically guided drug therapy and implantation of an ICD should be considered in appropriate cases for patients who survive the initial events. Transient minor conduction disturbances are common after CABG; in some patients persistent AV block and sinus node dysfunction develop and may require treatment with permanent pacemaker.
PURPOSE: To formulate thermosensitive sterically stabilized liposomes and to study the effects of plasma and serum components in vitro. METHODS: The rate of release of encapsulated doxorubicin (Dox) from liposomes of various compositions was followed by fluorometric assay at 37 degrees, 42 degrees and 45 degrees C, in buffer and also in both calf serum and human plasma up to 50% by volume. RESULTS: The optimal composition for the maximal differential release of doxorubicin between 37 degrees C and 42 degrees C in human plasma was a mixture of dipalmitoylphosphatidylcholine/hydrogenated soy phosphatidylcholine/cholesterol and distearoylphosphatidylethanolamine derivatized with polyethylene glycol at a molar ratio of 100:50:30:6. In experiments designed to study the mechanism causing increased permeability of liposomes in bovine serum, we found two different distinct release patterns: a slow linear rise of rate of Dox release for fluid liposomes and fast exponential rise reaching plateau within 5 minutes for solid phase (rigid) liposomes. This release of Dox from rigid but not fluid liposomes was inhibited by pre-heating serum at 55 degrees C for 30 minutes or by addition of EDTA (but not EGTA) or antiserum to the C3 component of complement. CONCLUSIONS: A formulation of sterically stabilized liposomes with the proper thermal sensitivity in human plasma has been obtained. In addition, the results suggest that complement may play an important role in the interaction of rigid but not fluid liposomes with bovine serum. Human plasma did not show this effect.
A fragment of fractured retention wire of an atrial J lead (Accufix) was found in the pulmonary artery in an asymptomatic patient by routine chest X ray, fluoroscopy, and pulmonary angiography. The lead itself looked normal in these imaging studies. Results after successful surgical removal was reported.
The ability of single paced ventricular beats during tachycardia to penetrate the tachycardia circuit and reset the subsequent atrial depolarization (atrial preexcitation), enabling calculation of the "preexcitation index," can be helpful in analyzing supraventricular tachycardias. However, the ventricular refractory period often prevents ventricular capture of beats with the necessary prematurity to demonstrate atrial preexcitation, particularly in atrioventricular nodal reentrant tachycardia (AVNRT). We hypothesized that the use of double premature stimuli could overcome this limitation. In 25 consecutive patients with either AVNRT or atrioventricular reciprocating tachycardia (AVRT) we attempted to demonstrate atrial preexcitation with single and double ventricular extrastimuli. Whereas atrial preexcitation with a single extrastimulus could only be achieved in 3 of 11 patients with AVNRT, all but 1 patient demonstrated atrial preexcitation with the use of double ventricular extrastimuli. On the other hand, in all but 1 patient with AVRT, atrial preexcitation could be achieved with single and double extrastimuli. A formula was derived for obtaining a preexcitation index with double extrastimuli and shown to correspond closely with the preexcitation index obtained with a single extrastimulus in the 16 patients in whom atrial preexcitation could be achieved with single and double extrastimuli. Thus, this technique significantly enhances the ability to achieve atrial preexcitation and to calculate the preexcitation index in patients with AVNRT, and thus may be useful in deciphering tachycardia mechanism in some patients, as well as being a useful technique in studying the electrophysiological properties of the antegrade and retrograde limbs of AVNRT.
Although radiofrequency catheter ablation has undergone explosive growth as the treatment for a variety of arrhythmias, a limiting factor with the existing catheter delivery system has been the relatively small size of the lesions, which appears to be in part due to coagulum formation around the catheter tip, producing a rise in impedance and limiting energy delivery. In order to test the hypothesis that infusion of saline during radiofrequency current application can increase the lesion size and decrease the incidence of impedance rise, ten dogs were each given two radiofrequency ablation lesions to the left ventricular endocardium. One of these lesions was delivered with a standard 7 French quadripolar catheter with a 2-mm tip, and the second was done with a 7 French luminal electrode catheter (also with a 2-mm tip) for the infusion of normal saline during the delivery of radiofrequency energy. Energy was delivered for 60 seconds at either 10 or 20 watts at two distinct sites in the left ventricle for each animal. Four to 7 days following ablation, the animals were sacrificed for pathological examination. The lesions created with the saline infusion catheter were significantly bigger than those produced with a standard catheter (7.3 x 7.0 x 5.1 vs 5.2 x 4.9 x 3.5 mm, respectively, P < 0.001). At the lower energy level (10 W), none of the animals with the saline infusion catheter experienced an impedance rise versus 3 of 5 of the animals in whom the standard catheter was used.(ABSTRACT TRUNCATED AT 250 WORDS)
Cyclic nucleotide phosphodiesterase (PDE) enzymes may participate in regulation of the inflammatory response through their effects on second messengers. In the present study, we have investigated the role of nonselective and isozyme selective PDE inhibitors in altering the antigen-driven cytokine gene expression of peripheral blood mononuclear cells (PBMCs) from atopic individuals. Ragweed and tetanus toxoid were used as model antigens. The nonselective PDE inhibitor, 3-isobutyl-1-methylxanthine (IBMX), and the selective PDE4 inhibitor, rolipram, markedly suppressed interleukin-5 (IL-5) and interferon gamma (IFN gamma) gene expression in both antigen-driven systems. Gene expression for IL-4 was unaffected by these agents in the ragweed-driven system. Message for IL-4 could not be detected in the tetanus toxoid-driven system, despite the use of a quantitative, competitive reverse transcription-polymerase chain reaction (RT-PCR) assay sensitive to less than 10 fg of target template. The PDE3 inhibitor, siguazodan, was ineffective in downregulating gene expression for the proinflammatory cytokines assayed; when used in combination with the PDE4 inhibitor, the PDE3 inhibitor provided no increase in efficacy over that seen with the PDE4 inhibitor alone. Gene expression for the A and B isoforms of the PDE4 in PBMCs was unaffected by antigen stimulation or treatment with the PDE4 inhibitor; however, differences in expression of these two isoforms were apparent when a variety of immune cell lines were studied. These data support the hypothesis that the primary anti-inflammatory target for PDE inhibition in PBMCs is the PDE4. Furthermore, the expression of various isoforms of this enzyme may differ between immune cell types. Finally, PDE4 isoform expression in PBMCs is independent of treatment with an isozyme selective inhibitor.
The foetal hippocampal tissue (transplant) at 17th day of embryonic age was implanted into the ventral hippocampus of adult rats (host). The catecholaminergic fibre projections in the hippocampal transplants 90 days after operation were studied by immunohistochemical technique. It was observed that in the host hippocampus there was a large population of TH- immunoreactive slender fibres of only 0.5-1 microns in diameter. These fibres were distributed more densely in the hippocampal hilus and CA3 transparent layers than in molecular layers, but sparsely in pyramidal or granular layers. In the molecular and cellular layers of transplanted hippocampus some thicker (> 1 micron) TH-positive fibers were ended in a relatively dense branching. The immunoelectron-microscopic observations showed that many TH-positive boutons made synaptic contacts with immunonegative dendrites and dendritic spines in the hippocampal transplants, the majority of which were asymmetrical synapses with a 30 nm synaptic cleft and conspicuously thickened postsynaptic membranes. It is concluded that catecholaminergic fibres extend from the host brain into the hippocampal transplant to establish synapses with the target neurons.
Cyclic nucleotide phosphodiesterase (PDE) enzymes are felt to play a role in the regulation of inflammatory responses through their effects on cAMP. In this study, we investigated the effects of nonselective and isozyme selective PDE inhibitors on the proliferative responses of peripheral blood mononuclear cells (PBMCs) to ragweed (RW, a Th2 stimulus), tetanus toxoid (TT, a Th1 stimulus), and phytohemagglutinin in ragweed-allergic patients. The nonselective PDE inhibitor 3-isobutyl-1-methylxanthine (IBMX) produced nearly identical concentration-dependent inhibition for PBMCs cultured with either Ag (RW and TT) or mitogen (phytohemagglutinin). Neither the type V inhibitor, zaprinast, nor the type III inhibitor, siguazodan, was effective at inhibiting antigen- or mitogen-driven proliferative responses of human PBMCs. The type IV inhibitor, rolipram, was unique in its ability to inhibit the RW-driven proliferative response and, to a lesser extent, the TT-driven proliferative response. However, rolipram was ineffective at inhibiting the mitogen-driven proliferative response. Only with a combination of type III and type IV inhibitors could the efficacy on the TT response be made to approximate that of the type IV inhibitor alone in the RW-driven system. Although the efficacies of IBMX and rolipram were identical in the RW-driven system, the IC50 value of the latter was 10-fold lower, similar to the difference noted in the TT-driven system between IBMX alone and the combination of rolipram with siguazodan. Dose-response curves generated by using the D- or L-isomers of rolipram were not appreciably different from each other or from the curve generated with racemic rolipram. The addition of supraphysiologic doses of human rIL-2 and rIL-4 was unable to counteract the inhibitory effect of IBMX or rolipram. These data support the hypothesis that modulation of proliferation of PBMCs by selective PDE inhibitors varies in sensitivity with the type of stimulus used, and that the type IV PDE exerts the predominant cAMP-associated regulatory effect on allergen-driven proliferation. Finally, the inhibitory effect induced by rolipram is independent of its stereochemistry and cannot be exclusively attributed to deficits in IL-2 or IL-4.
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Microvascular permeability and interstitial penetration of sterically stabilized liposomes in both normal s.c. tissue and human colon adenocarcinoma LS174T xenograft were quantified by using the dorsal skin-fold chamber implanted in severe combined immunodeficient mice and intravital fluorescence microscopy. Significant extravascular accumulation was the dominant feature of liposome distribution in tumors, whereas only minimal intramural accumulation in postcapillary and collecting venules was observed in normal s.c. tissue. The extravasated liposomes in tumors distributed heterogeneously and formed perivascular clusters that did not move significantly and could be observed for up to 1 week. The effective permeability of tumor vessels to liposomes (2.0 +/- 1.6 x 10(-8) cm/s; n = 23) was six times smaller than that to bovine serum albumin (1.2 +/- 0.5 x 10(-7) cm/s; n = 6). These results provide new insights into the mechanisms of transendothelial pathways of liposomes and improvements in liposome-mediated drug delivery.