Biomedical subjects
Publications and source records attributed to Richard J Powell.
The case of a previously healthy HIV seronegative woman with disseminated Mycobacterium tuberculosis infection and markedly reduced interferon gamma production is reported here. Complete healing of her disseminated lesions was seen only after addition of subcutaneous interferon gamma to her tuberculosis treatment.
Recent studies of cyclooxygenase-2 (COX-2) inhibitors suggest that the balance between thromboxane and prostacyclin is a critical factor in cardiovascular homeostasis. Disruption of prostacyclin signaling by genetic deletion of the receptor or by pharmacological inhibition of COX-2 is associated with increased atherosclerosis and restenosis after injury in animal models and adverse cardiovascular events in clinical trials (Vioxx). Human vascular smooth muscle cells (VSMC) in culture exhibit a dedifferentiated, migratory, proliferative phenotype, similar to what occurs after arterial injury. We report that the prostacyclin analog iloprost induces differentiation of VSMC from this synthetic, proliferative phenotype to a quiescent, contractile phenotype. Iloprost induced expression of smooth muscle (SM)-specific differentiation markers, including SM-myosin heavy chain, calponin, h-caldesmon, and SM alpha-actin, as determined by Western blotting and RT-PCR analysis. Iloprost activated cAMP/protein kinase A (PKA) signaling in human VSMC, and the cell-permeable cAMP analog 8-bromo-cAMP mimicked the iloprost-induced differentiation. Both myristoylated PKA inhibitor amide-(14-22) (PKI, specific PKA inhibitor), as well as ablation of the catalytic subunits of PKA by small interfering RNA, opposed the upregulation of contractile markers induced by iloprost. These data suggest that iloprost modulates VSMC phenotype via G(s) activation of the cAMP/PKA pathway. These studies reveal regulation of VSMC differentiation as a potential mechanism for the cardiovascular protective effects of prostacyclin. This provides important mechanistic insights into the induction of cardiovascular events with the use of selective COX-2 inhibitors.
OBJECTIVE: To investigate the effect of mutations in the tumor necrosis factor receptor superfamily 1A (TNFRSF1A) gene on the conformation and behavior of the TNFRSF1A protein. Mutations in TNFRSF1A cause the autosomal-dominant, autoinflammatory TNFR-associated periodic syndrome (TRAPS). METHODS: The expression of recombinant TNFRSF1A was compared in SK-HEp-1 endothelial cells and HEK 293 epithelial cells stably transfected with full-length R347A or Deltasig constructs of wild-type or TRAPS-associated mutant TNFRSF1A. TNF binding was assessed in HEK 293 cell lines expressing R347A wild-type or mutant TNFRSF1A. Homology modeling of the 3-dimensional structure of the ectodomains of wild-type and mutant TNFRSF1A was performed. RESULTS: TRAPS-associated mutant and wild-type TNFRSF1A behaved differently and had different localization properties within the cell, as a direct result of mutations in the ectodomains of TNFRSF1A. From a structural perspective, mutants with a predicted structure similar to that of the wild-type protein (e.g., R92Q) behaved similarly to wild-type TNFRSF1A, whereas forms of TNFRSF1A with mutations predicted to drastically destabilize the protein structure (e.g., cysteine mutations) showed defects in cell surface expression and TNF binding. CONCLUSION: The results obtained from the in vitro experiments, in combination with the modeled structures, indicate that the phenotype and clinical differences between different TRAPS-associated mutants of TNFRSF1A result from different conformations of the TNFRSF1A ectodomains.
BACKGROUND: Specific immunotherapy is widely used to treat allergic rhinitis, but few large-scale clinical trials have been performed. OBJECTIVE: We sought to assess the efficacy and safety of specific immunotherapy with 2 doses of Alutard grass pollen in patients with moderately severe seasonal allergic rhinitis inadequately controlled with standard drug therapy. METHODS: We performed a double-blind, randomized, placebo-controlled study of 410 subjects (203 randomized to 100,000 standardized quality units [SQ-U] maintenance, 104 to 10,000 SQ-U, and 103 to placebo). Three hundred forty-seven (85%) completed treatment. Groups were well matched for demographics and symptoms. RESULTS: Across the whole pollen season, mean symptom and medication scores were 29% and 32% lower, respectively, in the 100,000-SQ-U group compared with those in the placebo group (both P < .001). Over the peak pollen season, mean symptom and medication scores were 32% and 41% lower, respectively, than those in the placebo group. The 10,000-SQ-U group had 22% less symptoms than the placebo group over the whole season (P < .01), but medication scores reduced by only 16% (P = .16). Quality-of-life measures confirmed the superiority of both doses to placebo. Local and delayed side effects were common but generally mild. Clinically significant early and delayed systemic side effects were confined to the 100,000-SQ-U group, but no life-threatening reactions occurred. CONCLUSIONS: One season of immunotherapy with Alutard grass pollen reduced symptoms and medication use and improved the quality of life of subjects with moderately severe hay fever. The 100,000-SQ-U regimen was more effective, but the 10,000-SQ-U regimen caused fewer side effects.
Extensive use of stent-grafts in the iliac arteries is an increasingly common endovascular alternative to an aortobifemoral bypass procedure. The treatment of diffuse bilateral disease is frequently performed by using the technique of paired stent-grafts in the proximal common iliac arteries to effectively re-create the aortic-bifurcation. We present three patients treated with this technique who returned with recurrent occlusive disease. During subsequent treatment, the stent-grafts were noted to be in different positions from where they were initially deployed. A discussion of the possible explanations for the shifting positions follows.
This Clinical Update summarizes the results of larger case series, industry-sponsored registries, and randomized trials of carotid artery stenting (CAS). In >20 case series that studied >24,000 patients undergoing CAS, 51% of patients were symptomatic, most procedures (97%) resulted in successful stent deployment, and 30-day stroke rates varied from 1% to 8%, with a trend toward lower rates as experience and embolic protection device (EPD) use increased. In 12 industry-sponsored registries (none were published in peer-reviewed journals), 30-day stroke rates varied from 2% to 7%, and 30-day combined adverse events, including stroke, death, and myocardial infarction, were 3% to 9%. More than 12 randomized trials comparing CAS and carotid endarterectomy (CEA) have been initiated since 1998. Results have varied over time, depending on the population studied and the technology used. However, the largest and most recent results of the completed SAPPHIRE trial in high-risk patients undergoing CAS with the use of EPDs demonstrated that CAS is at least not inferior to CEA, with a 1-year combined adverse event rate of 12% for CAS and 20% for CEA (P = .05). Other ongoing trials will address not only whether CAS could be superior to CEA in high-risk patients but also, more importantly, whether CAS is beneficial in other subgroups, such as low-risk and asymptomatic patients.
BACKGROUND: Embolic protection devices (EPDs) consisting of an internal carotid artery (ICA) filter or balloon occlusion are typically used during carotid artery stenting (CAS). This study compares the technical difficulties encountered using these two types of EPD. METHODS: A retrospective review was conducted of patients undergoing CAS using a balloon occlusion EPD (balloon group: PercuSurge GuardWire) or filter EPD (filter group: Accunet, AngioGuard, or FilterWire). Complications were defined as minor stroke, National Institutes of Health (NIH) stroke scale <3; major stroke, NIH stroke scale > or =3; transient ischemic attack (TIA), reversible focal neurologic impairment; technical, reversible neurologic compromise during EPD deployment, inability to cross lesion, ICA spasm requiring treatment, EPD-related factors that prolonged CAS. RESULTS: CAS (n = 141) was performed in 133 patients (82% men) with a mean age of 72 of years. Comorbidities included diabetes, 35%; coronary artery disease, 75%; hypertension, 82%; and renal insufficiency, 15%. Indication was previous cerebrovascular accident in 10%, TIA in 29%, and asymptomatic >80% stenosis in 61%. Primary lesions were treated in 83% vs restenosis in 17%. The 30-day event rate was 1.4% major stroke, 2.1% minor stoke, 1.4% myocardial infarction, and 0.7% death. The overall combined 30-day stroke, death, and myocardial infarction rate was 5.6%. The 30-day stroke and death rate was 4.0% in the balloon group (n = 99) and 4.6% in the filter group (n = 42, P = .51). EPD-related technical difficulties occurred in 15% of the balloon group and 31% of the filter group (P < .05). Technical difficulties included a 10% incidence of reversible neurologic compromise during balloon deployment compared with 0% in the filter group (P = .002) and 12% incidence of inability to cross the lesion before predilation in the filter group compared with 0% in the balloon group (P = .001). CONCLUSIONS: During CAS, both balloon occlusion and filter devices provide acceptable results and appear complimentary. Filters can be used preferentially to avoid a 10% incidence of reversible neurologic compromise associated with balloon occlusion, except in critically narrowed or tortuous lesions when balloon occlusion may be preferred because of a 12% need for unprotected predilatation with filters.
Explore the source record for details and available documents.
OBJECTIVE: Renal artery percutaneous transluminal angioplasty (RPTA) and stenting (RAS) are accepted therapies for selected patients with renovascular hypertension and chronic renal insufficiency. We evaluated the outcomes and complications of RAS performed by vascular surgeons at our institution with modern low-profile systems. METHOD: We retrospectively analyzed all RPTA and RAS procedures attempted with the use of low-profile systems from June 2000 to September 2003. Eighty-two patients (96 arteries) with atherosclerotic renal artery stenosis were treated. Indication for treatment was hypertension in 44 (54%) and chronic renal insufficiency in 38 (46%). Technical success, complication rates, clinical success for control of hypertension or renal insufficiency, restenosis, and survival were reviewed with a mean follow-up of 1 year. RESULTS: Ninety-three arteries were treated with stents, three with RPTA only. Primary technical success was 95%, with 98% overall technical success. Major complications occurred in 6.1% and minor complications in 1.2%. Hypertension was improved in 81% at 1 year. Renal function was improved in 23%, stable in 53%, and worse in 24% at 1 year. Restenosis was seen by routine duplex surveillance in 25% at 1 year. Restenosis associated with clinical deterioration and confirmed by angiogram was seen in 10%. The overall 3-year survival was 83%. CONCLUSION: RPTA/RAS can be performed with low-profile systems with excellent technical success, low complication rates, and clinical outcomes that compare favorably with prior reports.
OBJECTIVE: Interactions between endothelial cells (ECs) and smooth muscle cells (SMCs) are fundamental in diverse cardiovascular processes such as arteriogenesis, atherosclerosis, and restenosis. We aimed to determine the intracellular signaling mechanisms by which ECs promote a differentiated SMC phenotype. METHODS: Bovine thoracic aorta ECs and SMCs were isolated and cultured. For co-culture studies, ECs were grown to confluence on one side of a semi-permeable Cyclopore membrane. SMCs were then plated on the opposite side of the membrane and cultured for 24 to 48 hours. For adenovirus experiments, SMCs were infected prior to plating opposite ECs. For conditioned media studies, SMCs cultured alone on plastic were treated with media harvested from EC/SMC in co-culture. SMC phenotype was assayed by microscopy and measurement of two-dimensional area, or by western blotting for contractile protein markers of differentiation. Akt activation was measured by western blotting for phospho-Serine 473. RESULTS: Although SMCs cultured alone exhibit a dedifferentiated synthetic phenotype, we report that bilayer co-culture with ECs induced a differentiated SMC phenotype as measured by morphology and cell area and expression of protein markers of differentiation, including contractile proteins and the cyclin-dependent kinase inhibitor p27 kip . The EC/SMC bilayer co-culture resulted in activation of the SMC protein kinase Akt, with no effect on total Akt expression. Similarly, conditioned media from co-cultured EC/SMC promoted rapid Akt phosphorylation and subsequent expression of differentiation protein markers in SMCs cultured alone. Adenoviral overexpression of constitutively active Akt in SMCs cultured alone mimicked the ability of ECs to induce SMC differentiation. Notably, inhibition of phosphoinositide 3 (PI 3)-kinase activity with wortmannin or adenoviral overexpression of a dominant-negative Akt prevented the EC-mediated effect on SMC morphology and differentiation protein marker expression. CONCLUSIONS: ECs direct SMCs towards a differentiated phenotype through activation of the SMC PI 3-kinase/Akt pathway. CLINICAL RELEVANCE: Interactions between endothelial cells (ECs) and smooth muscle cells (SMCs) are fundamental in diverse cardiovascular processes such as arteriogenesis, collateral blood vessel development, atherosclerosis, and restenosis. Alterations in SMC phenotype occur in each of these processes. Endothelial denudation has been suggested to contribute to the SMC proliferative response to vessel injury by angioplasty or other catheterization procedures. We have employed a co-culture approach to dissect the molecular signals that are dependent on the spatial relationship between ECs and SMCs, and have identified the importance of the PI3K/Akt pathway in EC-induced SMC differentiation. This pathway may suggest targets for therapeutic interventions for intimal hyperplasia and restenosis.
BACKGROUND: Gold coating improves stent visibility under fluoroscopy. This is particularly valuable for precise stent placement during renal artery stenting (RAS). There is conflicting evidence regarding restenosis with gold-coated stents. To evaluate the effect of gold coating on restenosis after renal stenting, we reviewed the results of all patients undergoing RAS in our practice. METHODS: A retrospective cohort study of all patients undergoing RAS between June 2000 and September 2003 was performed. During this time, both gold-coated and stainless steel stents were used. Restenosis (>60% diameter) was determined by serial follow-up duplex exams (peak systolic velocity >180 cm/s and renal-aortic ratio >3.5). Restenosis rates were determined by using the Kaplan-Meier life-table method. Variables potentially affecting restenosis were evaluated with the log-rank test and Cox proportional hazards modeling. RESULTS: RAS was performed in 97 arteries (78 patients). Gold-coated (NIRoyal) stents were placed in 59 arteries (48 patients). Stainless steel stents (Corinthian, Genesis, and Herculink) were placed in 38 arteries (34 patients). Patient demographics, indication for treatment, technical success, and complications did not differ between gold and stainless steel stent groups. Mean follow-up was 15 months for gold-coated stents and 18 months for stainless steel stents (NS). By life-table method, 1-year and 2-year freedom from restenosis rates were 84% and 78% in arteries treated with stainless steel stents versus 69% and 39% in those treated with gold-coated stents (P = .012, log-rank test). By multivariate analysis, only the use of gold-coated stents (P = .018; hazard ratio [HR], 3.3; 95% confidence interval [CI], 1.2 to 8.7) and bilateral disease (P = .046; HR, 2.3; 95% CI, 1.02 to 5.2) predicted restenosis. Stent diameter, patient demographics, and indication for RAS had no effect on restenosis by univariate analysis. According to American Heart Association criteria, 87% of patients in the stainless steel group had improved blood pressure at 1 year, compared with 77% in the gold-coated stent group (Kaplan-Meier; P = .042, log-rank test). There were no significant differences in the effect of RAS on serum creatinine levels between the two groups. CONCLUSION: Gold-coated renal stents had a substantially higher rate of restenosis than stainless steel stents in our series. These findings have led us to abandon the use of gold-coated stents for RAS. Patients who have received gold-coated stents for the treatment of atherosclerotic renal artery stenosis should be followed closely for evidence of restenosis.
BACKGROUND: Mesenteric stenting has not been widely adopted for the treatment of chronic mesenteric ischemia (CMI). The recent availability of embolic protection and low-profile devices with the theoretical ability to decrease perioperative bowel necrosis, led us to begin using mesenteric stenting for patients with CMI. We review our initial experience to examine short-term outcomes. METHODS: We performed a retrospective analysis of all patients who were treated by vascular surgeons with mesenteric stenting for CMI. Patients with acute mesenteric ischemia were excluded. We evaluated perioperative morbidity and mortality, restenosis, recurrent symptoms, and reintervention. Kaplan-Meier methods were used to assess events during follow-up. We also compared these outcomes with a historical control group of patients treated with open surgical revascularization. RESULTS: Fourteen patients underwent mesenteric stenting over the past 3 years. Mean age was 73, and 64% were women. There was no perioperative or 30-day mortality or major morbidity. Early restenosis and recurrent symptoms occurred in 10% and 9% of patients at 6 months. At a mean follow-up of 13 months, 53% of patients underwent reintervention. However, 93% were symptom-free at their last follow-up. Compared with open surgery, stent patients had lower perioperative major morbidity (30% vs 0%, P < .01) and shorter hospital and intensive care unit length of stay (median 10 days vs 2 days, and 3 days vs 0 days, respectively, P < .01 for both). However, stent patients were seven times as likely to develop restenosis (P < .01), four times more likely to develop recurrent symptoms (P < .01), and 15 times more likely to undergo reintervention (P < .01). There was one death 13 months after stenting due to mesenteric infarction in a patient lost to follow-up. One patient was successfully converted to open surgery after a second restenosis. He had regained 20 pounds and was determined to be a better operative candidate than at his initial presentation. There was no perioperative or 30-day mortality or major morbidity with reintervention after mesenteric stenting. CONCLUSION: Mesenteric stenting for CMI can be performed with low perioperative risk. However, stenting is associated with early restenosis and recurrent symptoms requiring secondary procedures. Patients with severe nutritional depletion or high surgical risk may benefit from mesenteric stenting for CMI, but close follow-up is required. Later open surgery can be performed for restenosis if nutritional status and surgical risk are improved, or repeat angioplasty and stenting can be effectively performed if operative risk remains high.
Explore the source record for details and available documents.
CONCLUSIONS: A subgroup of patients with idiopathic sensorineural hearing loss (SNHL) will have steroid-dependent symptoms which can be confirmed using pure-tone audiometry. Long-term treatment with high-dose corticosteroids exposes patients to potentially serious adverse effects. Immunosuppression with ciclosporin can be an effective and well-tolerated treatment for steroid-responsive sudden SNHL. OBJECTIVE: To highlight ciclosporin as a therapeutic option in the treatment of steroid-responsive sudden SNHL. MATERIAL AND METHODS: A 39-year-old male with idiopathic sudden SNHL that was responsive to corticosteroids was treated with ciclosporin for 18 months. RESULTS: Steroid-dependent SNHL was confirmed on audiological evaluation. Ciclosporin was administered, allowing corticosteroid therapy to be discontinued. Ciclosporin was effective at controlling all symptoms of SNHL. Remission was confirmed objectively with pure-tone audiometry.
Hyperoxia is cytotoxic and depresses many cellular metabolic functions including protein synthesis. Translational control is exerted primarily during initiation by two mechanisms: 1) through inhibition of translation initiation complex formation via sequestration of the cap-binding protein, eukaryotic initiation factor (eIF) 4E, with inhibitory 4E-binding proteins (4E-BP); and 2) by prevention of eIF2-GTP-tRNA(i)(Met) formation and eIF2B activity by phosphorylated eIF2alpha. In this report, exposure of human lung fibroblasts to 95% O2 decreased the incorporation of thymidine into DNA at 6 h and the incorporation of leucine into protein beginning at 12 h. The reductions in DNA and protein synthesis were accompanied by increased phosphorylation of eIF4E protein and reduced phosphorylation of 4E-BP1. At 24 h, hyperoxia shifted 4E-BP1 phosphorylation to lesser-phosphorylated isoforms, increased eIF4E expression, and increased the association of eIF4E with 4E-BP1. Although hyperoxia did not change eIF2alpha expression, it increased its phosphorylation at Ser51, but not until 48 h. In addition, the activation of eIF2alpha was not accompanied by the formation of stress granules. These findings suggest that hyperoxia diminishes protein synthesis by increasing eIF4E phosphorylation and enhancing the affinity of 4E-BP1 for eIF4E.
OBJECTIVE: To investigate the effect of mutations in tumor necrosis factor receptor superfamily 1A (TNFRSF1A) on the ability of the receptors to be cleaved from the cell surface upon stimulation. The mutations we studied are associated with clinically distinct forms of TNF receptor-associated periodic syndrome (TRAPS). We also investigated different cell types within the same form of TRAPS. METHODS: The shedding of TNFRSF1A in response to stimulation with phorbol myristate acetate was assessed in leukocytes and dermal fibroblasts from patients with C33Y TRAPS, and in HEK 293 cell lines stably transfected with constructs containing wild-type TNFRSF1A and/or TNFRSF1A mutants identified in TRAPS patients. RESULTS: The shedding of TNFRSF1A differed between cell types within the same form of TRAPS. In particular, dermal fibroblasts, but not leukocytes, from C33Y TRAPS patients demonstrated reduced shedding of TNFRSF1A. Shedding of both wild-type and mutant TNFRSF1A from the transfected HEK 293 cells showed minor differences, but was in all cases induced to a substantial extent. CONCLUSION: Differences in TNFRSF1A shedding are not purely a function of the TNFRSF1A structure, but are also influenced by other features of genetic makeup and/or cellular differentiation. It is unlikely that a defect in TNFRSF1A shedding per se can fully explain the clinical features that are common to TRAPS patients with different TNFRSF1A mutations.
Hyperimmunoglobulinemia D (hyper-IgD) and periodic fever syndrome, a hereditary autoinflammatory syndrome, is characterized by lifelong recurrent episodes of fever and inflammation. No effective treatment is known. It is caused by a defect of mevalonate kinase, an enzyme that follows 3'-hydroxy-3'-methylglutaryl-coenzyme A (HMG-CoA) reductase in the isoprenoid pathway. We wanted to test the hypothesis that inhibition of HMG-CoA reductase would ameliorate the inflammatory attacks. Six patients with hyper-IgD syndrome and proven mevalonate kinase deficiency were followed up for 2 treatment periods with either simvastatin, 80 mg/d, or placebo for 24 weeks, separated by a 4-week washout period in a double-blind fashion. Simvastatin resulted in a drop in urinary mevalonic acid concentration in all patients and decreased the number of febrile days in 5 of 6 patients. No side effects were observed. These data offer preliminary evidence for the hypothesis that simvastatin may improve inflammatory attacks in the hyper-IgD syndrome. This highlights the anti-inflammatory properties of HMG-CoA reductase inhibition.
OBJECTIVE: The purpose of this study was to review the initial results of carotid artery angioplasty with stenting (CAS) performed by vascular surgeons to treat bifurcation occlusive disease. Most patients were selected for CAS if they had indications for endarterectomy (CEA) but were considered at high risk for surgery. METHODS: Since December 2000, 74 carotid arteries in 69 patients underwent CAS, with distal balloon embolization protection in 96%. Mean patient age was 72 years; 82% of patients were men. Indications for CAS included asymptomatic disease (62%), transient ischemic attack (TIA; 23%), and cerebrovascular accident (15%). Mean internal carotid artery diameter stenosis was 82%. CAS was chosen over CEA because of cardiac (49%) or pulmonary (4%) comorbid conditions, hostile neck (25%), distal extent of disease (6%), and contralateral cranial nerve injury (1%). CAS was performed in 15% patients who were good surgical candidates, because of patient preference. Pathologic conditions were primary atherosclerosis (81%), recurrent carotid stenosis (18%), and dissection (1%). Procedures were transfemoral in 95% of cases and transcarotid in 5%. In 30% of cases the contralateral carotid artery had 80% or greater stenosis or was completely occluded. RESULTS: Technical success was achieved in 96% of cases. There were no deaths, no major strokes, one minor stroke (National Institutes of Health Stroke Scale, 3), and one TIA (neurologic event rate, 2.6%). The single minor stroke resolved completely by 1 month. One patient (1.3%) had a perioperative myocardial infarction. Transient neurologic changes occurred in 8% of patients during the protection balloon inflation, and all resolved with deflation. Bradyarrhythmia requiring pharmacologic treatment occurred in 14% of patients. At mean follow-up of 6 months there have been two instances of recurrent stenosis greater than 50% as noted at duplex scanning. During the same period, 266 carotid CEAs were performed, with a neurologic event rate of 0.8% (major stroke, 0.4%; no minor strokes; TIA, 0.4%) and a myocardial infarction rate of 3%. Combined stroke and death rate was 1.3% in patients who underwent CAS and 0.5% in patients who underwent CEA. CONCLUSION: CAS with cerebral protection can be performed safely in patients at high surgical risk, with low perioperative morbidity and mortality. The durability of the procedure must be determined with longer follow-up.