Evaluating Viscosity and Tear Breakup Time of Contemporary Commercial Ocular Lubricants on an In Vitro Eye Model.

Purpose: To evaluate the link between the viscosity of ophthalmic formulation and tear film stability using a novel in vitro eye model. Methods: The viscosities and noninvasive tear breakup time (NIKBUT) of 13 commercial ocular lubricants were measured to evaluate the correlation between viscosity and NIKBUT. The complex viscosity of each lubricant was measured three times for each angular frequency (ranging from 0.1 to 100 rad/s) using the Discovery HR-2 hybrid rheometer. The NIKBUT measurements were performed eight times for each lubricant using an advanced eye model mounted on the OCULUS Keratograph 5M. A contact lens (CL; ACUVUE OASYS [etafilcon A]) or a collagen shield (CS) was used as the simulated corneal surface. Phosphate-buffered saline was used as a simulated fluid. Results: The results showed a positive correlation between viscosity and NIKBUT at high shear rates (at 10 rad/s, r = 0.67) but not at low shear. This correlation was even better for viscosities between 0 and 100 mPa*s (r = 0.85). Most of the lubricants tested in this study also had shear-thinning properties. OPTASE INTENSE, I-DROP PUR GEL, I DROP MGD, OASIS TEARS PLUS, and I-DROP PUR had higher viscosity in comparison to other lubricants (P < 0.05). All of the formulations had a higher NIKBUT than the control (2.7 ± 1.2 seconds for CS and 5.4 ± 0.9 seconds for CL) without any lubricant (P < 0.05). I-DROP PUR GEL, OASIS TEARS PLUS, I-DROP MGD, REFRESH OPTIVE ADVANCED, and OPTASE INTENSE had the highest NIKBUT using this eye model. Conclusions: The results show that the viscosity is correlated with NIKBUT, but further work is necessary to determine the underlying mechanisms. Translational Relevance: The viscosity of ocular lubricants can affect NIKBUT and tear film stability, so it is an important property to consider when formulating ocular lubricants.

Mucoadhesive thermogel platform for treating anterior ocular conditions.

A platform mucoadhesive and thermogelling eyedrop was developed for application to the inferior fornix for the treatment of various anterior segment ocular conditions. The poly(n-isopropylacrylamide) polymers (pNIPAAm), containing a disulfide bridging monomer, were crosslinked with chitosan to yield a modifiable, mucoadhesive, and natively degradable thermogelling system. Three different conjugates were studied including a small molecule for treating dry eye, an adhesion peptide for modeling delivery of peptides/proteins to the anterior eye, and a material property modifier to create gels with different rheologic characteristics. Based on the conjugate used, different material properties such as solution viscosity and lower critical solution temperature (LCST) were produced. In addition to releasing the conjugates through disulfide bridging with ocular mucin, the thermogels were shown to deliver atropine, with 70%-90% being released over 24-h, depending on the formulation studied. The results illustrate that these materials can deliver multiple therapeutic payloads at one time and release them through various mechanisms. Finally, the safety and tolerability of the thermogels was demonstrated both in vitro and in vivo. The gels were instilled into the inferior fornix of rabbits and were shown to not produce any adverse effects over 4 days. These materials were demonstrated to be highly tunable, creating a platform that could be easily modified to deliver various therapeutic agents to treat a multitude of ocular diseases and have the potential to be an alternative to conventional eyedrops.

Thermo-responsive and mucoadhesive gels for the treatment of cystinosis.

Mucoadhesive thermogels were developed by crosslinking poly(n-isopropylacrylamide) based polymers with chitosan and incorporating disulfide bridges, capable of releasing cysteamine upon interaction with mucin, for the treatment of cystinosis. Through crosslinking with chitosan and incorporating varying concentrations of the disulfide monomer into the polymer backbone, the extent of how mucoadhesive the developed thermogels were could be controlled. Through disulfide bridging with mucin, the thermogels released 6 to 10 µg of the conjugate model 2-mercaptopyridine over five days. Utilizing chitosan as the crosslinker, the developed thermogels were shown to degrade to a statistically higher extent following incubation with lysozyme, the highest concentration tear enzyme, by gravimetric and rheologic analysis. The developed thermogels were extensively tested in vivo utilizing a rat model in which materials were applied directly to the corneal surface and a rabbit model in which thermogels were applied to the inferior fornix. With the developed models, there was no adverse reactions or visual discomfort incurred following application of the thermogels. It has been demonstrated that the thermogels produced can be applied to the inferior fornix and release the stable conjugated payload over several days. The developed thermogel was designed to improve upon the current clinical treatment options for ocular cystinosis which are acidic topical formulations that require reapplication multiple times a day.

Delivery of Cells to the Cornea Using Synthetic Biomaterials.

ABSTRACT: The cornea is subject to a myriad of ocular conditions often attributed to cell loss or cell dysfunction. Owing to the superficial positioning of tissues composing the anterior segment of the eye, particularly the cornea, regenerative medicine in this region is aided by accessibility as compared with the invasive delivery methods required to reach deep ocular tissues. As such, cell therapies employing the use of carrier substrates have been widely explored. This review covers recent advances made in the delivery of stem cells, corneal epithelial cells, and corneal endothelial cells. Particular focus is placed on the most popular forms of synthetic scaffolds currently being examined: contact lenses, electrospun substrates, polymeric films, and hydrogels.

Thermo-sensitivity and erosion of chitosan crosslinked poly[N-isopropylacrylamide-co-(acrylic acid)-co-(methyl methacrylate)] hydrogels for application to the inferior fornix.

Thermo-gels based on chitosan crosslinked poly(N-isopropylacrylamide) were developed as alternatives to conventional eye drops for the sustained release of ketotifen fumarate in the treatment of allergic conjunctivitis. The thermo-gelling properties of the base polymer were altered prior to crosslinking with chitosan by incorporation of the hydrophilic and hydrophobic comonomers acrylic acid and methyl methacrylate respectively. Varying amounts of chitosan were incorporated by ionic interaction to produce polyelectrolyte complexes or by carbodiimide chemistry to produce covalently crosslinked networks. The lower critical solution temperature of all the chitosan crosslinked thermo-gels produced was below the surface temperature of the eye. All the chitosan crosslinked thermo-gels were found to have greater than 80% equilibrium water contents following gelation. The method and amount of chitosan incorporation allowed for tailor-ability of material rheologic properties, with full degradation occurring over a one-to-four-day period, and tailorable rates of release of 40-60% of the loaded allergy medication ketotifen fumarate. The chitosan crosslinked thermo-gels were demonstrated to be nontoxic both in vitro and in vivo. It was demonstrated that the synthesized materials could be applied to the inferior fornix of eye, sustaining a multiple day release of ketotifen fumarate, as an alternative to conventional eyedrops. STATEMENT OF SIGNIFICANCE: Topical eyedrops are the main treatment modality for anterior ocular conditions. However, due to the natural clearance mechanisms of the eye, topical eyedrops are well established to be largely ineffective as a method of drug delivery. Herein, we investigate a method of altering thermo-gel properties of an n-isopropylacrylamide based polymer to enable the incorporation of greater amounts of chitosan by different methods of crosslinking. By controlling the synthesis parameters, final material properties can be tailored to impart ideal spreading, retention on the eye, and the rate of degradation and drug release over several days. This work also focuses on studying the rheological properties of the chitosan crosslinked thermo-gels which has not been investigated previously.

Corneal bioprinting utilizing collagen-based bioinks and primary human keratocytes.

Corneal transplantation is the treatment of choice for patients with advanced corneal diseases. However, the outcome may be affected by graft rejection, high associated costs, surgical expertise, and most importantly the worldwide donor shortage. In recent years, bioprinting has emerged as an alternative method for fabricating tissue equivalents using autologous cells with architecture resembling the native tissue. In this study, we propose a freeform and cell-friendly drop-on-demand bioprinting strategy for creating corneal stromal 3D models as suitable implants. Corneal stromal keratocytes (CSK) were bioprinted in collagen-based bioinks as 3D biomimetic models and the geometrical outcome as well as the functionality of the bioprinted specimens were evaluated after in vitro culture. We showed that our bioprinting method is feasible to fabricate translucent corneal stromal equivalents with optical properties similar to native corneal stromal tissue, as proved by optical coherence tomography. Moreover, the bioprinted CSK were viable after the bioprinting process and maintained their native keratocyte phenotypes after 7 days in in vitro culture, as shown by immunocytochemistry. The proposed bioprinted human 3D corneal models can potentially be used clinically for patients with corneal stromal diseases.

Aspirated Almond Masquerading as an Obstructing Endobronchial Mass Suspicious for Lung Cancer.

Foreign body aspiration is relatively rare in adults compared to children. In adults with delayed presentation, a history of choking is often absent, resulting in delayed diagnosis and significant morbidity. Common presenting features in adults include nonresolving cough with or without fever, hemoptysis, or wheezing and may mimic infectious, inflammatory, or neoplastic disorders. We present a case of a 64-year-old man with 80-pack-year smoking history who had a nonresolving left lower lobe infiltrate on chest radiograph after treatment for community-acquired pneumonia. His insidious-onset symptoms included cough, decreased exercise tolerance, and localized wheezing. Computed tomography of the chest showed a left lower lobe consolidation, with narrowing of the bronchus. Flexible bronchoscopy revealed a fleshy endobronchial mass, prompting endobronchial needle aspiration and biopsies, all of which revealed acute inflammation on rapid onsite evaluation. After multiple biopsies, a white pearly object with a detached brown cover was revealed; the object was found to be an aspirated almond. The almond and its peel were retrieved. The patient acknowledged that he had frequently eaten almonds in the supine position while recovering from a previous injury. His symptoms completely resolved at 3-month follow up, and he has ceased smoking and no longer consumes food while supine.

Incidental extensive adenocarcinoma in lungs explanted from a transplant recipient with an idiopathic pulmonary fibrosis flare-up: A clinical dilemma.

Patients under consideration for lung transplantation as treatment for end-stage lung diseases such as idiopathic pulmonary fibrosis (IPF) often have risk factors such as a history of smoking or concomitant emphysema, both of which can predispose the patient to lung cancer. In fact, IPF itself increases the risk of lung cancer development by 6.8% to 20%. Solid organ malignancy (non-skin) is an established contraindication for lung transplantation. We encountered a clinical dilemma in a patient who presented with an IPF flare-up and underwent urgent evaluation for lung transplantation. After transplant, the patient's explanted lungs showed extensive adenocarcinoma in situ, with the foci of invasion and metastatic adenocarcinoma in N1-level lymph nodes, as well as usual interstitial pneumonia. Retrospectively, we saw no evidence to suggest malignancy in addition to the IPF flare-up. Clinical diagnostic dilemmas such as this emphasize the need for new noninvasive testing that would facilitate malignancy diagnosis in patients too sick to undergo invasive tissue biopsy for diagnosis. Careful pathological examination of explanted lungs in patients with IPF is critical, as it can majorly influence immunosuppressive regimens, surveillance imaging, and overall prognosis after lung transplant.

Coexistent Non-Small Cell Carcinoma and Small Cell Carcinoma in a Patient Presenting with Hyponatremia.

Despite recent advances in screening methods, lung cancer remains the leading cause of cancer-related deaths worldwide. By the time lung cancer becomes symptomatic and patients seek treatment, it is often too advanced for curative measures. Low-dose computed tomography (CT) screening has been shown to reduce mortality in patients at high risk of lung cancer. We present a 66-year-old man with a 50-pack-year smoking history who had a right upper lobe (RUL) pulmonary nodule and left lower lobe (LLL) consolidation on a screening CT. He reported a weight loss of 45 pounds over 3 months, had recently been hospitalized for hyponatremia, and was notably cachectic. A CT of the chest showed a stable LLL mass-like consolidation and a 9 × 21 mm subsolid lesion in the RUL. Navigational bronchoscopy biopsy of the RUL lesion revealed squamous non-small cell lung cancer (NSCLC). Endobronchial ultrasound-guided transbronchial needle aspiration of the LLL lesion revealed small cell lung cancer (SCLC). The final diagnosis was a right-sided Stage I NSCLC (squamous) and a left-sided limited SCLC. The RUL NSCLC was treated with stereotactic radiation; the LLL SCLC was treated with concurrent chemotherapy and radiation. In patients with multiple lung nodules, a diagnosis of synchronous multiple primary lung cancers (MPLCs) is crucial, as inadvertent upstaging of patients with MPLC (to T3 and/or T4 tumors) can lead to erroneous staging, inaccurate prognosis, and improper treatment. Recent advances in the diagnosis of small pulmonary nodules via navigational bronchoscopy and management of these lesions dramatically affect a patient's overall prognosis.

Primary Nocardia Infection Causing a Fluorodeoxyglucose-Avid Right Renal Mass in a Redo Lung Transplant Recipient.

Immunosuppression after lung transplantation may increase susceptibility to opportunistic infection and is associated with early and delayed deaths in lung transplant recipients. Factors that may predispose lung transplant recipients to opportunistic bacterial and fungal infections include prolonged corticosteroid use, renal impairment, treatment of acute rejection, and post-transplant diabetes mellitus. We present a unique case of a 63-year-old woman with diabetes mellitus who underwent redo lung transplantation. Three years after her right-sided single redo lung transplant, she presented with right-sided abdominal pain, nausea, and vomiting. Upon examination, computed tomography showed a 4.5 × 3.3 cm heterogeneous, enhancing right renal mass with a patent renal vein. Magnetic resonance imaging confirmed a T1/T2 hypointense, diffusion-restricting, right mid-renal mass that was fluorodeoxyglucose-avid on positron emission tomography. We initially suspected primary renal cell carcinoma. However, after a right nephrectomy, no evidence of neoplasia was observed; instead, a renal abscess containing filamentous bacteria was noted, raising suspicion for infection of the Nocardia species. Special stains confirmed a diagnosis of Nocardia renal abscess. Computed tomography of the chest and brain revealed no lesions consistent with infection. We initiated a long-term therapeutic regimen of anti-Nocardia therapy with imipenem and trimethoprim-sulfamethoxazole.

Nerve growth factor inhibitor with novel-binding domain demonstrates nanomolar efficacy in both cell-based and cell-free assay systems.

Nerve growth factor (NGF), a member of the neurotrophin family, is known to regulate the development and survival of a select population of neurons through the binding and activation of the TrkA receptor. Elevated levels of NGF have been associated with painful pathologies such as diabetic neuropathy and fibromyalgia. However, completely inhibiting the NGF signal could hold significant side effects, such as those observed in a genetic condition called congenital insensitivity to pain and anhidrosis (CIPA). Previous methods of screening for NGF-inhibitors used labeling techniques which have the potential to alter molecular interactions. SPR spectroscopy and NGF-dependent cellular assays were utilized to identify a novel NGF-inhibitor, BVNP-0197 (IC50  = 90 nmol/L), the first NGF-inhibitor described with a high nanomolar NGF inhibition efficiency. The present study utilizes molecular modeling flexible docking to identify a novel binding domain in the loop II/IV cleft of NGF.

Live cell imaging of cytoplasmic dynein movement in transfected embryonic rat neurons.

Live cell imaging of the movement of various membrane-bounded organelle cargos has enhanced our understanding of their function. Eukaryotic cells utilize microtubules and two classes of microtubule-based motor proteins, cytoplasmic dynein and members of the kinesin family, to deliver a variety of membrane-bounded organelles and other cargos to their appropriate locations. In order to better understand the functions and regulation of cytoplasmic dynein, we developed a method to study its location and motility in living cells. The technique takes advantage of the long thin axons of cultured hippocampal neurons. We use calcium phosphate to transfect fluorescent-tagged dynein intermediate chain (IC) subunits (DYNC1I) into cultured neurons. When the ICs are expressed at low levels, they are effective probes for the location of the cytoplasmic dynein complex in axons when living cells are imaged with fluorescence microscopy. The fluorescent subunit probes can be used to identify specific cargos of dynein complexes with different IC isoforms as well as the kinetic properties of cytoplasmic dynein.

An algorithm for noise correction of dual-energy computed tomography material density images.

PURPOSE: Dual-energy computed tomography (DECT) images can undergo a two-material decomposition process which results in two images containing material density information. Material density images obtained by that process result in images with increased pixel noise. Noise reduction in those images is desirable in order to improve image quality. METHODS: A noise reduction algorithm for material density images was developed and tested. A three-level wavelet approach combined with the application of an anisotropic diffusion filter was used. During each level, the resulting noise maps are further processed, until the original resolution is reached and the final noise maps obtained. Our method works in image space and, therefore, can be applied to any type of material density images obtained from any DECT vendor. A quantitative evaluation of the noise-reduced images using the signal-to-noise ratio (SNR), contrast-to-noise ratio (CNR) and 2D noise power spectrum was done to quantify the improvements. RESULTS: The noise reduction algorithm was applied to a set of images resulting in images with higher SNR and CNR than the raw density images obtained by the decomposition process. The average improvement in terms of SNR gain was about 49 % while CNR gain was about 52 %. The difference between the raw and filtered regions of interest mean values was far from reaching statistical significance (minimum [Formula: see text], average [Formula: see text]). CONCLUSION: We have demonstrated through a series of quantitative analyses that our novel noise reduction algorithm improves the image quality of DECT material density images.

Live cell imaging reveals differential modifications to cytoplasmic dynein properties by phospho- and dephosphomimic mutations of the intermediate chain 2C S84.

Cytoplasmic dynein is a multisubunit motor protein responsible for intracellular cargo transport toward microtubule minus ends. There are multiple isoforms of the dynein intermediate chain (DYNC1I, IC), which is encoded by two genes. One way to regulate cytoplasmic dynein is by IC phosphorylation. The IC-2C isoform is expressed in all cells, and the functional significance of phosphorylation on IC-2C serine 84 was investigated by using live cell imaging of fluorescent protein-tagged IC-2C wild type (WT) and phospho- and dephosphomimic mutant isoforms in axonal transport model systems. Both mutations modulated dynein functional properties. The dephosphomimic mutant IC-2C S84A had greater colocalization with mitochondria than the IC-2C WT or the phosphomimic mutant IC-2C S84D. The dephosphomimic mutant IC-2C S84A was also more likely to be motile than the phosphomimic mutant IC-2C S84D or the IC-2C WT. In contrast, the phosphomimic mutant IC-2C S84D mutant was more likely to move in the retrograde direction than was the IC-2C S84A mutant. The phosphomimic IC-2C S84D was also as likely as the IC-2C WT to colocalize with mitochondria. Both the S84D phospho- and the S84A dephosphomimic mutants were found to be capable of microtubule minus-end-directed (retrograde) movement in axons. They were also observed to be passively transported in the anterograde direction. These data suggest that the IC-2C S84 has a role in modulating dynein properties.

Vitamin D and long-term memory in multiple sclerosis.

BACKGROUND AND OBJECTIVE: Memory disturbance is a frequent cognitive complaint by patients with multiple sclerosis (MS). Recent dementia research suggests a beneficial role for vitamin D in long-term memory functioning. While data suggest ameliorative effects of vitamin D for the physical impairments of MS, it is unknown whether vitamin D can benefit the cognitive sequelae. We examined the relationship between serum levels of vitamin D and performance on verbal and nonverbal tests of long-term memory in patients with MS. METHODS: A sample of 35 adults with relapsing-remitting MS completed cognitive testing and a vitamin D serum (25[OH]D) assay. Memory assessment used clinically established neuropsychological tests with multiple testing formats to determine whether vitamin D level was associated with memory during conditions of varying retrieval demands. Intellectual functioning and mood were also assessed to control for potential confounds. RESULTS: Vitamin D level was positively associated with performance on immediate and delayed recall trials of the Rey Complex Figure Test, effects that held after controlling for intelligence and disease duration. Vitamin D level was not associated with mood, intelligence, or verbal memory performance on the California Verbal Learning Test, Second Edition. CONCLUSIONS: Higher vitamin D level was associated with better nonverbal long-term memory performance in MS, particularly in conditions when no aid was given to help retrieval. These results supplement the literature on the neuroprotective effects of vitamin D and suggest that vitamin D is a worthwhile adjunct treatment for MS.

Trk activation of the ERK1/2 kinase pathway stimulates intermediate chain phosphorylation and recruits cytoplasmic dynein to signaling endosomes for retrograde axonal transport.

The retrograde transport of Trk-containing endosomes from the axon to the cell body by cytoplasmic dynein is necessary for axonal and neuronal survival. We investigated the recruitment of dynein to signaling endosomes in rat embryonic neurons and PC12 cells. We identified a novel phosphoserine on the dynein intermediate chains (ICs), and we observed a time-dependent neurotrophin-stimulated increase in intermediate chain phosphorylation on this site in both cell types. Pharmacological studies, overexpression of constitutively active MAP kinase kinase, and an in vitro assay with recombinant proteins demonstrated that the intermediate chains are phosphorylated by the MAP kinase ERK1/2, extracellular signal-regulated kinase, a major downstream effector of Trk. Live cell imaging with fluorescently tagged IC mutants demonstrated that the dephosphomimic mutants had significantly reduced colocalization with Trk and Rab7, but not a mitochondrial marker. The phosphorylated intermediate chains were enriched on immunoaffinity-purified Trk-containing organelles. Inhibition of ERK reduced the amount of phospho-IC and the total amount of dynein that copurified with the signaling endosomes. In addition, inhibition of ERK1/2 reduced the motility of Rab7- and TrkB-containing endosomes and the extent of their colocalization with dynein in axons. NGF-dependent survival of sympathetic neurons was significantly reduced by the overexpression of the dephosphomimic mutant IC-1B-S80A, but not WT IC-1B, further demonstrating the functional significance of phosphorylation on this site. These results demonstrate that neurotrophin binding to Trk initiates the recruitment of cytoplasmic dynein to signaling endosomes through ERK1/2 phosphorylation of intermediate chains for their subsequent retrograde transport in axons.

Is elevated creatinine a reliable marker for methanol toxicity in nitromethane-containing model fuel ingestions in children?

CONTEXT: In the absence of a rapid serum methanol level estimation, it is difficult to assess the risk from unintentional childhood ingestion of model fuels containing methanol and nitromethane (MFNM). Previous reports have documented false elevations of serum creatinine from the nitromethane in these fuels, suggesting its utility as a readily available marker of significant methanol ingestion. METHOD: We performed a 2-year retrospective chart review of cases of ingestion of MFNM in children, with both a methanol level and measured creatinine level. RESULTS: Seven children, ages 19 months to 3 years, ingested MFNM. All seven children were seen in a hospital and had measured methanol and creatinine levels. All blood samples for methanol and creatinine were drawn within 3 hours of ingestion with methanol estimation delayed up to 24 hours. Creatinine ranged from 0.39 (0.034 mmol/l) to 10.7 mg/dl (0.95 mmol/l). All methanol levels were <10 mg/dl (0.31 mmol/l) or reported as negative. Fomepizole was initiated empirically in two patients due to delay in obtaining methanol analysis results. DISCUSSION: Transient elevations of creatinine occurred in five of the seven children. Blood urea nitrogen was within normal limits, and there was no history of renal impairment in these children, suggesting the elevated creatinine was mostly related to nitromethane ingestion. No child had a significantly elevated methanol level. CONCLUSION: Elevated creatinine level, as measured by Jaffe colorimetric method, is not a reliable marker for elevated methanol levels after unintentional ingestion of MFNM.

Bivalirudin for anticoagulation in children.

BACKGROUND: Thromboembolism in children is typically treated with unfractionated heparin (UH) or low molecular weight heparin (LMWH). Both rely on antithrombin (AT) for their action. In addition, heparin-induced thrombocytopenia (HIT) is a potentially serious complication of heparin use in children. Bivalirudin or other direct thrombin inhibitors may be a useful alternative to heparins in treating thrombosis in children. PROCEDURE: We report a retrospective review to assess the efficacy and safety of bivalirudin in pediatric patients with thrombosis. RESULTS: Sixteen children received bivalirudin for thrombosis or prevention of thrombosis at the Children's Hospital of Illinois from January 2005 to January 2007. Patients received a bolus dose of 0.25 mg/kg followed by a continuous infusion (0.16 +/- 0.07 mg kg(-1) hr(-1)) titrated to 1.5-2.5 times the baseline activated partial thromboplastin time (aPTT). Positive correlation between the bivalirudin average infusion rate and aPTT was observed in twelve patients. Ultrasonographic evidence of thrombus regression was noted at 72 hr in 10 of 10 patients. One patient experienced hematuria after catheterization of the urethra. CONCLUSION: Bivalirudin was effective and well-tolerated in these patients. Further studies should be conducted to better define safety and efficacy of bivalirudin in pediatric patients.

Transcatheter device closure of interatrial septal defects in patients with hypoxia.

BACKGROUND: There has been growing interest in transcatheter closure of interatrial septal defects (IASDs) for a variety of indications, but reports are limited in patients with hypoxia from right-to-left shunting. METHODS: Between August 2000 and October 2004, 181 patients were referred to our institution for elective closure of a patent foramen ovale (PFO) or atrial septal defect (ASD). Among these patients, 10 (5.5%) underwent closure for hypoxia due to persistent or intermittent right-to-left shunting. Clinical evaluation, including echocardiography with color Doppler and agitated saline, was performed in all patients to determine the degree of right-to-left shunting. Defects were closed with Amplatzer (n = 4) or Cardioseal (n = 6) devices, under transesophageal (TEE) or intracardiac echocardiography (ICE) guidance. RESULTS: Mean age was 62.7 years (range: 31-88 years) with 70% female. Characteristics for closure included four patients with persistent hypoxia and six with intermittent hypoxia, including two with platypnea-orthodeoxia syndrome. All patients had echocardiography showing moderate (n = 6) or severe (n = 4) shunting. Patients had significant comorbidities, including chronic lung disease requiring supplemental oxygen (n = 5) and congestive heart failure (n = 2). TEE guidance was used in three patients, and ICE was performed in the remainder. Mean closure device diameter was 27 mm. Mean preprocedural arterial oxygen saturation of 86.7% improved to 95.9% immediately after closure, with color Doppler and agitated saline revealing the absence of (n = 5) or mild (n = 5) shunting. In-hospital major complications were limited to one patient with a transient ischemic attack after an initially unsuccessful closure attempt. CONCLUSIONS: Percutaneous closure of IASDs in a heterogeneous group of patients with hypoxia can be safely and effectively performed. The procedure results in immediate arterial saturation improvement and reduced right-to-left shunting.

Angiographic variables predict increased risk for adverse ischemic events after coronary stenting with glycoprotein IIb/IIIa inhibition: results from the TARGET trial.

OBJECTIVES: We sought to assess whether pre-procedural angiographic characteristics are associated with adverse clinical outcomes after coronary stenting with glycoprotein IIb/IIIa inhibition. BACKGROUND: Ischemic complications after balloon angioplasty are associated with pre- and post-procedural angiographic variables. However, in the current era of stenting with IIb/IIIa inhibition, it is unknown whether angiographic features assessed before intervention confer an increased risk of adverse procedural and subsequent clinical outcomes. METHODS: In the Do Tirofiban and ReoPro Give Similar Efficacy Outcomes? Trial (TARGET), 4,809 patients undergoing planned stenting were randomized to tirofiban or abciximab. Baseline demographic, clinical, and angiographic variables were obtained. Clinical end points were recorded at 30 days and six months. The relationship between angiographic variables and adverse clinical outcomes was assessed. RESULTS: Patients with the combination of thrombus, lesion eccentricity, and lesion length >20 mm had a 21.4% composite incidence of death, myocardial infarction, or urgent target vessel revascularization (TVR) at 30 days, compared with 4.2% in those patients without these high-risk features (hazard ratio [HR] 3.24, p < 0.001). After adjustment, the risk was independently associated with thrombus (HR 1.40, p = 0.034), eccentricity (HR 1.67, p < 0.001), and lesion length >20 mm (HR 1.89, p < 0.001). The risk of six-month TVR was independently associated with left anterior descending coronary artery lesions (HR 1.46, p < 0.001), restenotic lesions at baseline (HR 1.58, p = 0.006), and lesion length (HR 1.19, p = 0.03). CONCLUSIONS: Patients with thrombus, eccentric lesions, or lesion length >20 mm are at high risk for ischemic outcomes after coronary stenting, despite IIb/IIIa inhibition. Further research into novel anti-thrombotic therapies or procedural strategies is necessary for these patients.