Molecular Dynamics Simulation of Complex Reactivity with the Rapid Approach for Proton Transport and Other Reactions (RAPTOR) Software Package.

Simulating chemically reactive phenomena such as proton transport on nanosecond to microsecond and beyond time scales is a challenging task. Ab initio methods are unable to currently access these time scales routinely, and traditional molecular dynamics methods feature fixed bonding arrangements that cannot account for changes in the system's bonding topology. The Multiscale Reactive Molecular Dynamics (MS-RMD) method, as implemented in the Rapid Approach for Proton Transport and Other Reactions (RAPTOR) software package for the LAMMPS molecular dynamics code, offers a method to routinely sample longer time scale reactive simulation data with statistical precision. RAPTOR may also be interfaced with enhanced sampling methods to drive simulations toward the analysis of reactive rare events, and a number of collective variables (CVs) have been developed to facilitate this. Key advances to this methodology, including GPU acceleration efforts and novel CVs to model water wire formation are reviewed, along with recent applications of the method which demonstrate its versatility and robustness.

Handgrip Strength Is Related to Hippocampal and Lobar Brain Volumes in a Cohort of Cognitively Impaired Older Adults with Confirmed Amyloid Burden.

BACKGROUND: Strength and mobility are essential for activities of daily living. With aging, weaker handgrip strength, mobility, and asymmetry predict poorer cognition. We therefore sought to quantify the relationship between handgrip metrics and volumes quantified on brain magnetic resonance imaging (MRI). OBJECTIVE: To model the relationships between handgrip strength, mobility, and MRI volumetry. METHODS: We selected 38 participants with Alzheimer's disease dementia: biomarker evidence of amyloidosis and impaired cognition. Handgrip strength on dominant and non-dominant hands was measured with a hand dynamometer. Handgrip asymmetry was calculated. Two-minute walk test (2MWT) mobility evaluation was combined with handgrip strength to identify non-frail versus frail persons. Brain MRI volumes were quantified with Neuroreader. Multiple regression adjusting for age, sex, education, handedness, body mass index, and head size modeled handgrip strength, asymmetry and 2MWT with brain volumes. We modeled non-frail versus frail status relationships with brain structures by analysis of covariance. RESULTS: Higher non-dominant handgrip strength was associated with larger volumes in the hippocampus (p = 0.02). Dominant handgrip strength was related to higher frontal lobe volumes (p = 0.02). Higher 2MWT scores were associated with larger hippocampal (p = 0.04), frontal (p = 0.01), temporal (p = 0.03), parietal (p = 0.009), and occipital lobe (p = 0.005) volumes. Frailty was associated with reduced frontal, temporal, and parietal lobe volumes. CONCLUSION: Greater handgrip strength and mobility were related to larger hippocampal and lobar brain volumes. Interventions focused on improving handgrip strength and mobility may seek to include quantified brain volumes on MR imaging as endpoints.

Facile nanoplastics formation from macro and microplastics in aqueous media.

The immense production of plastic polymers combined with their discordancy with nature has led to vast plastic waste contamination across the geosphere, from the oceans to freshwater reservoirs, wetlands, remote snowpacks, sediments, air and multiple other environments. These environmental pollutants include microplastics (MP), typically defined as small and fragmented plastics less than 5 mm in size, and nanoplastics (NP), particles smaller than a micrometer. The formation of micro and nanoplastics in aqueous media to date has been largely attributed to fragmentation of plastics by natural (i.e., abrasion, photolysis, biotic) or industrial processes. We present a novel method to create small microplastics (≲ 5 µm) and nanoplastics in water from a wide variety of plastic materials using a small volume of a solubilizer liquid, such as n-dodecane, in combination with vigorous mixing. When the suspensions or solutions are subjected to ultrasonic mixing, the particle sizes decrease. Small micro- and nanoparticles were made from commercial, real world and waste (aged) polyethylene, polystyrene, polycarbonate and polyethylene terephthalate, in addition to other plastic materials and were analyzed using dark field microscopy, Raman spectroscopy and particle size measurements. The presented method provides a new and simple way to create specific size distributions of micro- and nanoparticles, which will enable expanded research on these plastic particles in water, especially those made from real world and aged plastics. The ease of NP and small MP formation upon initial mixing simulates real world environments, thereby providing further insight into the behavior of plastics in natural settings.

A systems-biology clinical trial of a personalized multimodal lifestyle intervention for early Alzheimer's disease.

INTRODUCTION: There is an urgent need to develop effective interventional treatments for people with Alzheimer's disease (AD). AD results from a complex multi-decade interplay of multiple interacting dysfunctional biological systems that have not yet been fully elucidated. Epidemiological studies have linked several modifiable lifestyle factors with increased incidence for AD. Because monotherapies have failed to prevent or ameliorate AD, interventional studies should deploy multiple, targeted interventions that address the dysfunctional systems that give rise to AD. METHODS: This randomized controlled trial (RCT) will examine the efficacy of a 12-month personalized, multimodal, lifestyle intervention in 60 mild cognitive impairment (MCI) and early stage AD patients (aged 50+, amyloid positivity). Both groups receive data-driven, lifestyle recommendations designed to target multiple systemic pathways implicated in AD. One group receives these personalized recommendations without coaching. The other group receives personalized recommendations with health coaching, dietary counseling, exercise training, cognitive stimulation, and nutritional supplements. We collect clinical, proteomic, metabolomic, neuroimaging, and genetic data to fuel systems-biology analyses. We will examine effects on cognition and hippocampal volume. The overarching goal of the study is to longitudinally track biological systems implicated in AD to reveal the dynamics between these systems during the intervention to understand differences in treatment response. RESULTS: We have developed and implemented a protocol for a personalized, multimodal intervention program for early AD patients. We began enrollment in September 2019; we have enrolled a third of our target (20 of 60) with a 95% retention and 86% compliance rate. DISCUSSION: This study presents a paradigm shift in designing multimodal, lifestyle interventions to reduce cognitive decline, and how to elucidate the biological systems being targeted. Analytical efforts to explain mechanistic or causal underpinnings of individual trajectories and the interplay between multi-omic variables will inform the design of future hypotheses and development of effective precision medicine trials.

Ponseti Idiopathic and Nonidiopathic Clubfoot Correction With Secondary Surgeries.

The Ponseti method has revolutionized clubfoot treatment for not only idiopathic clubfoot but also non-idiopathic clubfoot. This study aimed to validate the existing literature with respect to the Ponseti method serving as first line treatment for clubfoot. The purpose of this study was to compare clubfoot type and recurrence with secondary surgical procedures following Ponseti method. Kaiser Permanente Northern California database was queried to identify clubfoot children under 3 years old with a consecutive 3-year membership. Associated comorbidities and operative procedure codes were identified. Chart review was performed on all surgical clubfoot patients who completed Ponseti method. Patients' average age at time of surgery, frequency of surgeries, and types of procedures performed were recorded. A logistic regression analysis assessed the adjusted association between surgery status and clubfoot type. Clubfoot incidence was about 1 in 1000 live births. Of the 375 clubfoot children, 334 (89%) were idiopathic and 41 (11%) were non-idiopathic. In the total study population, 82% (n = 309) patients maintained Ponseti correction without a secondary surgery; 66 patients (18%) underwent subsequent secondary surgeries. The non-idiopathic clubfoot underwent surgery more frequently compared to idiopathic clubfoot patients (41.5% vs 14.7%, respectively, p = .0001). Non-idiopathic clubfoot children underwent surgery at a younger age. This study validates the Ponseti method is the first line treatment for clubfoot correction despite etiology. However, patients with recurrent clubfoot may require secondary surgery following Ponseti method. Clubfoot recurrence surveillance is key for identifying early symptomatic recurrence in order to minimize foot rigidity and the need for osseous procedures.

Simultaneous Aerobic Exercise and Memory Training Program in Older Adults with Subjective Memory Impairments.

BACKGROUND: Several modifiable lifestyle factors have been shown to have potential beneficial effects in slowing cognitive decline. Two such factors that may affect cognitive performance and slow the progression of memory loss into dementia in older adults are cognitive training and physical activity. There are currently no effective treatments for dementia; therefore, preventative strategies to delay or prevent the onset of dementia are of critical importance. OBJECTIVE: The aim of this study was to determine the relative effectiveness of simultaneous performance of memory training and aerobic exercise to a sequential performance intervention on memory functioning in older adults. METHODS: 55 older adults (aged 60- 75) with subjective memory impairments (non-demented and non-MCI) completed the intervention that consisted of 90-minute small group classes held twice weekly. Participants were randomized to either 4-weeks of supervised strategy-based memory training done simultaneously while stationary cycling (SIM) or sequentially after the stationary cycling (SEQ). Standardized neurocognitive measures of memory, executive functioning, speed of processing, attention, and cognitive flexibility were assessed at baseline and post-intervention. RESULTS: The SIM group, but not the SEQ group, had a significant improvement on composite memory following the intervention (t(51) = 2.7, p = 0.01, effect size (ES) = 0.42) and transfer to non-trained reasoning abilities (t(51) = 6.0, ES = 0.49) and complex attention (t(51) = 3.1, p = 0.003, ES = 0.70). Conversely, the SEQ group, but not the SIM, showed significant improvement in executive functioning (t(51) = 5.0, p = 0.0001, ES = 0.96). CONCLUSION: These findings indicate that a 4-week simultaneous memory training and aerobic exercise program is sufficient to improve memory, attention, and reasoning abilities in older adults.

Alzheimer's "Prevention" vs. "Risk Reduction": Transcending Semantics for Clinical Practice.

The terms "prevention" and "risk reduction" are often used interchangeably in medicine. There is considerable debate, however, over the use of these terms in describing interventions that aim to preserve cognitive health and/or delay disease progression of Alzheimer's disease (AD) for patients seeking clinical care. Furthermore, it is important to distinguish between Alzheimer's disease prevention and Alzheimer's dementia prevention when using these terms. While prior studies have codified research-based criteria for the progressive stages of AD, there are no clear clinical consensus criteria to guide the use of these terms for physicians in practice. A clear understanding of the implications of each term will help guide clinical practice and clinical research. The authors explore the semantics and appropriate use of the terms "prevention" and "risk reduction" as they relate to AD in clinical practice.

Ischiofemoral Impingement in Children: Imaging With Clinical Correlation.

OBJECTIVE: The purpose of this study is to correlate the MRI finding of quadratus femoris edema in children with established measures of ischiofemoral impingement in adults and to determine their clinical significance. MATERIALS AND METHODS: A case-control retrospective review was performed of MR images of 12 hips of nine children (mean age, 10 years) that showed abnormal signal intensity in the quadratus femoris muscle. The findings were compared with those for 13 hips in 13 control subjects (mean age, 9.8 years). Two musculoskeletal radiologists independently measured the ischiofemoral space, quadratus femoris space, inclination angle, and hamstring tendon area. Quadratus femoris muscle edema, tears, or fatty replacement were assessed visually. Statistical analysis determined inter- and intraobserver variability and statistical differences between the two subject groups. RESULTS: Subjects with abnormal signal in the quadratus femoris muscle had a statistically significantly narrower ischiofemoral space (mean, 11.5 vs 20.7 mm; p < 0.05) and quadratus femoris space (mean, 7.2 vs 14.3 mm, p < 0.05) compared with control subjects. Inclination angles were statistically significantly larger in affected subjects (145.5° vs 138.7°; p < 0.05). No statistically significant difference was found in hamstring tendon area. Four of 12 patient hips had no symptoms or symptoms unrelated to the abnormality. Inter- and intraobserver variability scores were strong for all continuous variables. CONCLUSION: Ischiofemoral impingement is a cause of hip pain in children and should be considered with the combination of quadratus femoris muscle edema and narrowing of ischiofemoral space and quadratus femoris space. Coxa valga may contribute to narrowing of these parameters and predispose to ischiofemoral impingement. The MRI features of ischiofemoral impingement, however, are nonspecific and may be seen in patients with pain localized to that hip or in patients with symptoms unrelated to the abnormality.

Internal Fixation of Posterior Pelvic Ring Injuries Using Iliosacral Screws in the Dysmorphic Upper Sacrum.

INTRODUCTION: The correct usage of preoperative and intraoperative imaging allows fixation of posterior pelvic ring injuries with safely positioned iliosacral screws in the setting of sacral dysmorphism. STEP 1 PREOPERATIVE PLANNING: Obtain CT reformats along the longitudinal axis of the sacrum to determine the orientation and diameter of the osseous corridor for selection of the ideal screw size, length, and trajectory. STEP 2 PATIENT POSITIONING: Proper positioning enables reduction and accurate iliosacral screw placement. STEP 3 FRACTURE REDUCTION: Reduction of the posterior pelvic ring confers stability; if closed reduction is unsuccessful, proceed with open reduction. STEP 4 IDENTIFICATION OF THE ENTRY POINT: The entry point for an iliosacral screw into the upper sacral segment of a dysmorphic pelvis lies more posterior and caudal on the outer table of the posterior ilium than does a transsacral screw; adjust the entry point on the basis of inlet and outlet fluoroscopic views. STEP 5 DRILLING TECHNIQUE: Insert a stout cannulated drill bit of 4.5 to 5 mm (depending on the core diameter of the intended iliosacral screw) over the Kirschner wire and drill it into the sacral body under fluoroscopic guidance, in accordance with the preoperative plan. STEP 6 SCREW INSERTION: With the guidewire in the ideal position, measure the screw length off the inserted guidewire and advance a tap into the pathway; insert the screw and verify its position on the inlet, outlet, and lateral sacral views. RESULTS: Understanding the three-dimensional anatomy of the posterior pelvic ring is essential to successful reduction and fixation of unstable pelvic injuries with use of percutaneous iliosacral screws.IndicationsContraindicationsPitfalls & Challenges.

Anatomic Determinants of Sacral Dysmorphism and Implications for Safe Iliosacral Screw Placement.

BACKGROUND: Upper sacral segment dysplasia increases the risk of cortical perforation during iliosacral screw insertion. Dysmorphic sacra have narrow and angled upper osseous corridors. However, there is no validated definition of this anatomic variation. We hypothesized that pelves could be quantitatively grouped by anatomic measurements. METHODS: One hundred and four computed tomography (CT) scans and virtual outlet views of uninjured pelves were analyzed for the presence of the five qualitative characteristics of upper sacral segment dysplasia. CT scans were reformatted to measure the cross-sectional area, angulation, and length of the osseous corridor. Principal components analysis was used to identify multivariable explanations of anatomic variability, and discriminant analysis was used to assess how well such combinations can classify dysmorphic pelves. RESULTS: The prevalences of the five radiographic qualitative characteristics of upper sacral segment dysplasia, as determined by two reviewers, ranged from 28% to 53% in the cohort. The rates of agreement between the two reviewers ranged from 70% to 81%, and kappa coefficients ranged from 0.26 to 0.59. Cluster analysis revealed three pelvic phenotypes based on the maximal length of the osseous corridor in the upper two sacral segments. Forty-one percent of the pelves fell into the dysmorphic cluster. The five radiographic qualitative characteristics of dysmorphism were significantly more frequent (p < 0.007) in this cluster. A combination of upper sacral coronal and axial angulation effectively explained the variance in the data, and an inverse linear relationship between these angles and a long upper sacral segment corridor was identified. A sacral dysmorphism score was derived with the equation: (first sacral coronal angle) + 2(first sacral axial angle). An increase in the sacral dysmorphism score correlated with a lower likelihood of a safe transsacral first sacral corridor. No subjects with a sacral dysmorphism score >70 had a safe transsacral first sacral corridor. CONCLUSIONS: Sacral dysmorphism was found in 41% of the pelves. The major determinants of sacral dysmorphism are upper sacral segment coronal and axial angulation. The sacral dysmorphism score quantifies dysmorphism and can be used in preoperative planning of iliosacral screw placement.

An observational cohort study of the adoption of elastic stable intramedullary nailing for the treatment of pediatric femur fractures in Kumasi, Ghana.

BACKGROUND: In high- and middle-income countries, elastic stable intramedullary nailing (ESIN) is the commonest treatment of femur fractures in children 5-11 years of age. At Komfo Anokye Teaching hospital (KATH) in Kumasi, Ghana, prior to this study all pediatric femur fractures were treated with skin traction to union. This study was designed to report the early results and costs of the adoption of ESIN at KATH to provide data to other low- and middle-income sites considering adoption of this surgical technique. METHODS: An observational cohort study that included 84 pediatric patients ages 3-14 years presenting with closed femur fractures and treated with either skin traction or ESIN. Multivariate logistic regression was used to compare the rate of treatment success between treatment groups. RESULTS: Treatment success (coronal and sagittal angulation less than 10 ° and shortening less than 15 mm at osseous union) was achieved in 92 % of the ESIN group versus 67 % of the skin traction group (odds ratio for ESIN group 9.28 (1.6-54.7); p = 0.0138). Average length of stay was significantly lower in the ESIN group (p = 0.001), but charges to patients were higher in the ESIN group (p < 0.001) because of the high cost of implants. CONCLUSIONS: The initial experience of operative treatment of femoral shaft fractures in children using ESIN was positive, with improved rates of treatment success and no surgical complications. Because of the high cost of implants, direct costs of treatment remained higher with ESIN despite reductions in length of hospital stay.

Orthopedic surgery in the developing world: workforce and operative volumes in Ghana compared to those in the United States.

BACKGROUND: Musculoskeletal disease is a growing burden in low- and middle-income countries (LMICs), yet little research exists to describe the problem. The purposes of this study were to characterize orthopedic surgery in an LMIC and compare the findings to those from a developed country. METHODS: The study location was the Komfo Anokye Teaching Hospital (KATH) in Kumasi, Ghana. Orthopedic surgeon, resident, and postgraduate training program numbers were compared to analogous data from a developed nation, the United States. Annual surgical volumes were compared to those at a level I trauma center in the United States, the San Francisco General Hospital (SFGH). RESULTS: There were 24 surgeons in Ghana compared to 23,956 in the United States. There were 7 orthopedic residents and 1 residency program in Ghana versus 3,371 residents and 155 residencies in the United States. Annual case volume was 2,161 at KATH and 2,132 at SFGH. Trauma accounted for 95 % of operations at KATH compared to 65 % at SFGH. The proportion of surgeries devoted to severe fractures was 29 % at KATH compared to 12 % at SFGH. Infections comprised 15 % of procedures at KATH and 5 % at SFGH. CONCLUSIONS: Annual case volume at a referral hospital in an LMIC is equivalent to that of a level I trauma center in an industrialized country. Total case volume is similar, but the LMIC institution manages a disproportionately large number of trauma cases, severe fractures, and infections. There is a large burden of orthopedic disease in the developing nation, and there are too few providers and training programs to address these conditions.

High-risk pediatric orthopedic pitfalls.

Pediatric patients often present to the emergency department with orthopedic pathology that can challenge the emergency department physician. This article focuses on key diagnoses that are frequently mismanaged. These diagnoses require specific knowledge to execute appropriate treatment. Pediatric fractures, compartmental syndrome, bone and joint infection, limp and non-accidental trauma are reviewed. Approach to the workup of these patients and treatment algorithms are discussed.

Atrial fibrillation propagates through gaps in ablation lines: implications for ablative treatment of atrial fibrillation.

BACKGROUND: It has been hypothesized that atrial lesions must be transmural to successfully cure atrial fibrillation (AF). However, ablation lines often do not extend completely across the atrial wall. OBJECTIVE: The purpose of this study was to determine the effect of residual gaps on conduction properties of atrial tissue. METHODS: Canine right atria (n = 13) were isolated, perfused, and mounted on a 250-lead electrode plaque. The atria were divided with a bipolar radiofrequency ablation clamp, leaving a gap that was progressively narrowed. Conduction velocities at varying pacing rates and AF frequencies were measured before and after ablations. AF was induced with an extra stimulus and acetylcholine. RESULTS: Gap widths from 11.2 to 1.1 mm were examined. Conduction velocities through gaps were dependent cycle length (P = .002) and gap size (P <.001). Overall, 253 (97%) of a total of 260 gaps allowed paced propagation; 51 (91%) of 56 gaps 1-3 mm in width permitted paced propagation, as did 202 (99%) of 204 gaps >or=3.0 mm. Similarly, 253 (97%) of a total of 260 gaps allowed propagation of AF. For AF, 51 (93%) of 55 gaps 1-3 mm allowed AF to pass through, as did 202 (99%) of 205 gaps >or=3.0 mm. Gaps as small as 1.1 mm conducted paced and AF impulses. CONCLUSIONS: Conduction velocities were slowed through residual gaps. However, propagation of wave fronts during pacing and AF occurred through the majority of residual gaps, down to sizes as small as 1.1 mm. Leaving viable tissue in ablation lines for the treatment of AF could account for failures.

Aortic valve replacement in octogenarians: risk factors for early and late mortality.

BACKGROUND: Excellent outcomes after aortic valve replacement (AVR) in elderly patients can be achieved, yet some practitioners are reticent to refer elderly patients for surgery. This study analyzed risk factors for mortality in patients aged 80 years and older undergoing AVR with or without concomitant coronary artery bypass grafting (CABG). METHODS: A retrospective review was performed of 245 patients (129 women) with a mean age of 83.6 +/- 2.9 years who had AVR with (n = 140) or without CABG (n = 105) at a single institution from 1993 to 2005. Data were analyzed with a multivariate logistic regression for predictors of operative mortality, Kaplan-Meier estimates of survival, and a Cox multivariate proportional analysis of factors influencing long-term survival. RESULTS: Mean preoperative New York Heart Association (NYHA) classification was 3.1 +/- 0.9, and 78% (192/245) of patients were classified as NYHA class III or IV. Operative (30-day) mortality was 9% (22/245). Independent risk factors for operative mortality included postoperative renal failure (odds ratio [OR], 20.9; 95% confidence interval [CI], 6.5 to 67.6; p < 0.001), postoperative permanent stroke (OR, 11.3; 95% CI, 1.7 to 75.1; p = 0.019), or intraoperative/postoperative intraaortic balloon pump (IABP) placement (OR, 14.9; 95% CI 2.9 to 75.8; p = 0.002). Survival after surgery was 82% (n = 183) at 1 year and 56% (n = 88) at 5 years. Prognostic factors for decreased long-term survival were regurgitant valve pathology (hazard ratio [HR], 6.0; 95% CI, 2.5 to 14.2; p = 0.002), intraoperative/postoperative IABP (HR, 2.9; 95% CI, 1.4 to 6.0; p = 0.010), postoperative renal failure (HR, 3.5, 95% CI, 2.2 to 5.7; p < 0.001), and postoperative stroke (HR, 7.0, 95% CI, 3.2 to 15.9; p < 0.001). Performing concomitant CABG was protective in terms of operative mortality (OR, 0.3; 95% CI, 0.09 to 0.83; p = 0.017) and improved long-term survival (HR, 0.7, 95% CI, 0.47 to 0.96; p = 0.020). Preoperative NYHA classification did not affect operative or long-term survival. CONCLUSIONS: Patients aged 80 years and older who undergo AVR have acceptable short-term and long-term survival regardless of NYHA status. Concomitant CABG improved operative and long-term survival in this population. Despite their increased age, aggressive surgical treatment is warranted for most patients.

Long-term outcomes in valve replacement surgery for infective endocarditis.

BACKGROUND: Infective endocarditis is associated with a high rate of long-term mortality. Patients with a history of intravenous drug use (IVDU) are at increased risk for infective endocarditis. However, few studies have reported results of surgical treatment on this population. We present 19.5 years of experience with surgically treated patients with infective endocarditis. METHODS: A retrospective study of all cardiac surgeries with a diagnosis of infective endocarditis at a single institution from 1986 to 2005 was performed. Logistic stepwise regression with an end point of operative mortality was done. Variables were age, gender, race, history of drug use, previous valve surgery, and previous valve replacement. Perioperative and outcome variables were compared between IVDU and non-IVDU populations. RESULTS: The IVDU population required surgery at a younger age (39 +/- 9 years versus 54 +/- 15 years; p < 0.001). Overall operative mortality was 12% (41/346). The perioperative complication rate was similar for both groups. When adjusted for age, the two groups had similar long-term survival (p = 0.78). Kaplan-Meier estimator showed that survival at 10 and 15 years was 66% and 54% for IVDU and 56% and 42% for non-IVDU (number at risk, 19, 11, and 61, 28, respectively; p = 0.137). Reoperation for recurrent infective endocarditis was necessary in 9 (17%) of 52 of the IVDU group versus 14 (5%) of 270 of the non-IVDU group (p = 0.03). CONCLUSIONS: Patients with a history of IVDU required reoperation for recurrent infective endocarditis at a significantly higher rate than the non-IVDU patients. Long-term survival was similar between the younger IVDU population and the older non-IVDU population. Anticipated life span is one of many factors when considering prosthetic valve choice in this population.

Epicardial microwave ablation on the beating heart for atrial fibrillation: the dependency of lesion depth on cardiac output.

BACKGROUND: Microwave energy is commonly used on the beating heart to create lesions for the surgical treatment of atrial fibrillation. However, lesion transmurality is likely to depend on several factors including tissue thickness and blood flow. This study was designed to determine the effect of cavitary blood flow on transmurality of acute atrial lesions with the FLEX 10 (Guidant Corporation, Santa Clara, Calif) microwave device. METHODS: Six pigs underwent median sternotomy and were placed on cardiopulmonary bypass. Microwave lesions on the atrium were performed for 60 seconds at 65 Watts at 4 different levels of cardiac output by varying cardiopulmonary bypass flow rates. Cardiac output was measured with a pulmonary artery flow probe. Four additional lesions on 2 animals were done for 120 seconds at 65 Watts with 0.0 to 0.5 L/min cardiac output. The animals were sacrificed, and tissue was stained with 2,3,5-triphenyltetrazolium chloride and sectioned at 5-mm intervals. Lesion depth and width were determined from photomicrographs. RESULTS: Sixty-second lesions were transmural in 90%, 65%, 54%, and 46% of atrial sections at cardiac output of 0.0 to 0.5 L/min, 0.6 to 1.9 L/min, 2.0 to 3.9 L/min, and 4.0 L/min or greater, respectively (P < .001). When ablations were performed for 120 seconds with a cardiac output of 0.0 to 0.5 L/min, 100% of lesions were transmural. Lesion width was also related to cardiac output, with the widest lesions produced when cardiac output was 0.0 to 0.5 L/min. CONCLUSIONS: Acute microwave ablation lesion depth and width are strongly dependent on the magnitude of cardiac output. Transmural lesions can be reliably produced on the porcine heart only while on cardiopulmonary bypass.

Gene expression profiles with activation of the estrogen receptor alpha-selective estrogen receptor modulator complex in breast cancer cells expressing wild-type estrogen receptor.

Selective Estrogen Receptor Modulators (SERMs) are a new class of drugsthat bind to estrogen receptor (ER) and elicit agonistic or antagonistic responses, depending on the target tissue. We have developed an in vitro system in which some SERMs (4-hydroxytamoxifen and resveratrol) demonstrate estrogenic response through wild-type (wt) ER, whereas others (raloxifene and GW7604) remain antiestrogenic. This system mimics the tamoxifen-resistant phenotype in clinic, when resistant tumors contain wtER. We used Atlas cDNA arrays to study gene expression profiles after ER activation by different SERMs in MDA-MB-231 human breast cancer cells stably transfected with wtER. Cells were treated with estradiol, four different SERMs, and the pure antiestrogen ICI 182,780. The obtained expression data were analyzed using GeneSpring software. Real-time reverse transcription-PCR was used to verify the array data. Our results showed that treatment with various compounds altered the expression of a diverse group of genes, revealing sets of overlapping genes that may represent a complex network of genes of interrelated signal transduction pathways. Sets of "agonistic" and "antagonistic" genes were identified on the basis of the known response to different SERMs. Further analysis of selected sets of genes revealed functionally related group of genes in each set, encoding proteins that were related to cell proliferation, survival, and apoptosis. Flow cytometry data indicated an antiapoptotic activity in cells treated with agonists versus apoptotic activity in cells treated with antagonists. A model for estradiol-like (survival) and antiestrogen-like (apoptosis) activities of SERMs on the basis of their gene expression profiles is suggested.