The purpose of this study was to test whether a microcatheter can safely be advanced across the right atrial appendage to access the pericardium and then withdrawn despite subsequent high-intensity anticoagulation. We also tested whether transatrial pericardial insufflation of carbon dioxide (CO2) would enhance the safety of subxiphoid needle access to the empty pericardium by separating the heart from the anterior pericardium.
Subxiphoid needle access to the empty pericardium, required for left atrial suture ligation and epicardial ablation for rhythm disorders, risks myocardial or coronary laceration.
A catheter from the femoral vein engaged the right atrial appendage for angiographic confirmation of position. Through that catheter, the back end of a 0.014- or 0.018-inch guidewire crossed the right atrial wall to enter the pericardium and delivered a 2.4-F microcatheter. CO2 1 to 2 ml/kg was insufflated into the pericardium immediately before subxiphoid needle access under lateral projection fluoroscopy. Thirteen patients undergoing subxiphoid suture ligation of the left atrial appendage consented to participate in this research protocol.
Right atrial exit succeeded in 11 subjects (85%) and failed uneventfully in 2 subjects. CO2 insufflation of 96 ± 22 ml achieved 12 ± 4 mm separation of the anterior pericardium from the myocardial wall, allowed rapid and successful subxiphoid anterior needle and guidewire entry in all 11 subjects, and did not have any evident hemodynamic effects. The immediate pericardial aspirate was serous in all but 1 subject.
We report the first human intentional transatrial exit procedure. Transatrial microcatheter access to the pericardium can be achieved safely. Pericardial insufflation with CO2 makes subxiphoid access to the empty pericardium rapid and safe. Although our clinical experience to date remains small, with further experience, this approach may prevent the life-threatening complications of “dry” subxiphoid pericardial access.
epicardial ablation; left atrial appendage ligation; pericardial access; structural heart disease; transatrial exit
The SYMPLICITY HTN-3 randomized, blinded, sham-controlled trial confirmed the safety of renal denervation (RDN), but did not meet its primary efficacy endpoint. Prior RDN studies have demonstrated significant and durable reductions in blood pressure. This analysis investigated factors that may help explain these disparate results.
Methods and results
Patients with resistant hypertension were randomized 2 : 1 to RDN (n = 364) or sham (n = 171). The primary endpoint was the difference in office systolic blood pressure (SBP) change at 6 months. A multivariable analysis identified predictors of SBP change. Additional analyses examined the influence of medication changes, results in selected subgroups and procedural factors. Between randomization and the 6-month endpoint, 39% of patients underwent medication changes. Predictors of office SBP reduction at 6 months were baseline office SBP ≥180 mmHg, aldosterone antagonist use, and non-use of vasodilators; number of ablations was a predictor in the RDN group. Non-African-American patients receiving RDN had a significantly greater change in office SBP than those receiving sham; –15.2 ± 23.5 vs. –8.6 ± 24.8 mmHg, respectively (P = 0.012). Greater reductions in office and ambulatory SBP, and heart rate were observed with a higher number of ablations and energy delivery in a four-quadrant pattern.
Post hoc analyses, although derived from limited patient cohorts, reveal several potential confounding factors that may partially explain the unexpected blood pressure responses in both the sham control and RDN groups. These hypothesis-generating data further inform the design of subsequent research to evaluate the potential role of RDN in the treatment of resistant hypertension.
Renal denervation; Resistant hypertension; SYMPLICITY
An electromagnetic transmitter typically consists of individual components such as a waveguide, antenna, power supply, and an oscillator. In this communication we circumvent complications associated with connecting these individual components and instead combine them into a non-traditional, photonic enabled, compact transmitter device for tunable, ultrawide band (UWB) radiation. This device is a centimeter scale, continuous, thin film superconducting ring supporting a persistent super-current. An ultrafast laser pulse (required) illuminates the ring (either at a point or uniformly around the ring) and perturbs the super-current by the de-pairing and recombination of Cooper pairs. This generates a microwave pulse where both ring and laser pulse geometry dictates the radiated spectrum’s shape. The transmitting device is self contained and completely isolated from conductive components that are observed to interfere with the generated signal. A rich spectrum is observed that extends beyond 30 GHz (equipment limited) and illustrates the complex super-current dynamics bridging optical, THz, and microwave wavelengths.
Transcaval access to the aorta allows transcatheter aortic valve replacement in patients without other good access options. The resulting aortocaval fistula is closed with a nitinol cardiac occluder device. There is no experience traversing a synthetic aortic graft to perform transcaval access and closure. We describe a patient who underwent successful traversal of a polyester aortic graft using radiofrequency energy applied from the tip of a guidewire, to allow retrograde transcatheter aortic valve replacement from a femoral vein, along with details of our technique. The patient did well and was discharged home after 3 days. There was residual aortocaval fistulous flow immediately after implantation of a polyester-seeded nitinol muscular ventricular septal defect occluder device, but this fistula spontaneously occluded within one month.
structural heart disease; transcatheter aortic valve implantation; caval-aortic fenestrated graft; vascular access and closure; extra-anatomic procedures
Transcatheter valve replacement; Extra-anatomic procedures; Vascular access and closure; Medical devices; Cardiac catheterization
We describe the first use of caval-aortic access and closure to enable transcatheter aortic valve replacement (TAVR) in patients who lacked other access options. Caval-aortic access refers to percutaneous entry into the abdominal aorta from the femoral vein through the adjoining inferior vena cava.
TAVR is attractive in high risk or inoperable patients with severe aortic stenosis. Available transcatheter valves require large introducer sheaths, which risk major vascular complications or preclude TAVR altogether. Caval-aortic access has been successful in animals.
We performed a single center retrospective review of procedural and 30-day outcomes of prohibitive-risk patients undergoing TAVR via caval-aortic access.
Between July 2013 and January 2014, 19 patients underwent TAVR via caval-aortic access. 79% were women. Caval-aortic access and tract closure was successful in all 19; TAVR was successful in 17. Six patients suffered modified VARC-2 major vascular complications, two (11%) of whom required intervention. Most (79%) required blood transfusion. There were no deaths attributable to caval-aortic access. Through 111 (39–229) days of follow up, there were no post-discharge complications related to tract creation or closure. All patients had persistent aorto-caval flow immediately post procedure. Of 16 who underwent repeat imaging after the first week, 15 (94%) had complete closure of the residual aorto-caval tract.
Percutaneous transcaval venous access to the aorta allows TAVR in otherwise ineligible patients, and may offer a new access strategy for other applications requiring large transcatheter implants.
Caval-aortic; transcaval; transcatheter aortic valve replacement; extra-anatomic procedures
Estimation of stochastic process models from data is a common application of time series analysis methods. Such system identification processes are often cast as hypothesis testing exercises whose intent is to estimate model parameters and test them for statistical significance. Ordinary least squares (OLS) regression and the Levenberg-Marquardt algorithm (LMA) have proven invaluable computational tools for models being described by non-homogeneous, linear, stationary, ordinary differential equations.
In this paper we extend stochastic model identification to linear, stationary, partial differential equations in two independent variables (2D) and show that OLS and LMA apply equally well to these systems. The method employs an original nonparametric statistic as a test for the significance of estimated parameters.
We show gray scale and color images are special cases of 2D systems satisfying a particular autoregressive partial difference equation which estimates an analogous partial differential equation. Several applications to medical image modeling and classification illustrate the method by correctly classifying demented and normal OLS models of axial magnetic resonance brain scans according to subject Mini Mental State Exam (MMSE) scores. Comparison with 13 image classifiers from the literature indicates our classifier is at least 14 times faster than any of them and has a classification accuracy better than all but one.
Our modeling method applies to any linear, stationary, partial differential equation and the method is readily extended to 3D whole-organ systems. Further, in addition to being a robust image classifier, estimated image models offer insights into which parameters carry the most diagnostic image information and thereby suggest finer divisions could be made within a class. Image models can be estimated in milliseconds which translate to whole-organ models in seconds; such runtimes could make real-time medicine and surgery modeling possible.
Image regression models; dementia classification; MRI classification information; parameter classification information
To determine the impact of suture-mediated vascular closure devices on net adverse clinical events (NACE) after balloon aortic valvuloplasty (BAV).
Ischemic and bleeding complications are common following transfemoral BAV however; previous studies have been single center and limited by varying definitions of major bleeding.
The Effect of Bivalirudin on Aortic Valve Intervention Outcomes (BRAVO) study was a retrospective observational study conducted at two high-volume academic centers over a 6-year period designed to compare the effect of bivalirudin versus unfractionated heparin. This is a sub-analysis of 428 consecutive patients who underwent BAV (with 10-13 French sheaths) to compare the effect of hemostasis with vascular closure devices versus manual compression utilizing standardized definitions. NACE was defined as the composite of major bleeding and major adverse clinical events (MACE). All events were adjudicated by an independent clinical events committee who were blinded to antithrombin use.
Pre-closure was performed in 269 (62.8%) of patients. While bivalirudin was used more frequently in those with pre-closure (60.6% vs. 37.7%, p<0.001), a history of prior BAV (11.1% vs. 3.6%, p=0.04) and peripheral vascular disease (30.7% vs. 19.7%, p=0.01) was more common in those not undergoing pre-closure (n=159, 37%). Other clinical and demographic features were well balanced between groups. Vascular closure was associated with a significant reduction in NACE (24.5% vs 10.0% p<0.001). Results remained significant after adjusting for baseline differences and bivalirudin use (OR 0.38, 95% CI: 0.21 - 0.68; p=0.001).
Our study suggests that suture-mediated vascular closure is associated with a substantial reduction in NACE after transfemoral BAV. Large randomized clinical trials should be conducted to confirm our results.
Balloon Aortic Valvuloplasty; Aortic Stenosis; Bleeding; Closure devices
To evaluate the periprocedural characteristics and outcomes of patients supported with Impella 2.5 prior to percutaneous coronary intervention (pre-PCI) versus those who received it after PCI (post-PCI) in the setting of cardiogenic shock (CS) complicating an acute myocardial infarction (AMI).
Early mechanical circulatory support may improve outcome in the setting of CS complicating an AMI. However, the optimal timing to initiate hemodynamic support has not been well characterized.
Data from 154 consecutive patients who underwent PCI and Impella 2.5 support from 38 US hospitals participating in the USpella Registry were included in our study. The primary end-point was survival to discharge. Secondary end-points included assessment of patients’ hemodynamics and in-hospital complications. A multivariate regression model was used to identify independent predictors for mortality.
Both groups were comparable except for diabetes (P = 0.02), peripheral vascular disease (P = 0.008), chronic obstructive pulmonary disease (P = 0.05), and prior stroke (P = 0.04), all of which were more prevalent in the pre-PCI group. Patients in the pre-PCI group had more lesions (P = 0.006) and vessels (P = 0.01) treated. These patients had also significantly better survival to discharge compared to patients in the post-PCI group (65.1% vs.40.7%, P = 0.003). Survival remained favorable for the pre-PCI group after adjusting for potential confounding variables. Initiation of support prior to PCI with Impella 2.5 was an independent predictor of in-hospital survival (Odds ratio 0.37, 95% confidence interval: 0.17–0.79, P = 0.01) in multivariate analysis. The incidence of in-hospital complications included in the secondary end-point was similar between the 2 groups.
The results of our study suggest that early initiation of hemodynamic support prior to PCI with Impella 2.5 is associated with more complete revascularization and improved survival in the setting of refractory CS complicating an AMI.
Linear measures of auditory receptive fields do not always fully account for a neuron's response to spectrotemporally-complex signals such as frequency-modulated sweeps (FM) and communication sounds. A possible source of this discrepancy is cross-frequency interactions, common response properties which may be missed by linear receptive fields but captured using two-tone masking. Using a patterned tonal sequence that included a balanced set of all possible tone-to-tone transitions, we have here combined the spectrotemporal receptive field with two-tone masking to measure spectrotemporal response maps (STRM). Recording from single units in the mustached bat inferior colliculus, we found significant non-linear interactions between sequential tones in all sampled units. In particular, tone-pair STRMs revealed three common features not visible in linear single-tone STRMs: 1) two-tone facilitative interactions, 2) frequency-specific suppression, and 3) post-stimulatory suppression in the absence of spiking. We also found a correlative relationship between these nonlinear receptive field features and sensitivity for different rates and directions of FM sweeps, dynamic features found in many vocalizations, including speech. The overwhelming prevalence of cross-frequency interactions revealed by this technique provides further evidence of the central auditory system's role as a pattern-detector, and underscores the need to include nonlinearity in measures of the receptive field.
auditory midbrain; mustached bat; frequency modulation; receptive fields; de Bruijn sequence; sideband inhibition; post-excitatory suppression; combination sensitivity; facilitation
Frequency modulations (FMs) are prevalent in human speech, and are
important acoustic cues for the categorical discrimination of phonetic
contrasts. For bats, FM sweeps are also important for communication and are
often the only component in echolocation calls. Auditory neurons tuned to the
direction and rate of FM might underlie the encoding of rapid frequency
transitions. In the mustached bat, we have discovered a population of such FM
selective cells in an area interposed between the central nucleus of the
inferior colliculus (ICC) and the nuclei of the lateral lemniscus (NLL). We
believe this area to be the ventral extent of the external nucleus of the
inferior colliculus (ICXv). To describe FM selectivity of neurons in the ICXv
and to compare it to other midbrain nuclei, up- and down-sweeping linear FM
stimuli were presented at different modulation rates. Extracellular recordings
were made from 171 single units in the ICC, ICXv, and NLL of 10 mustached bats.
In the ICXv, there was a much higher degree of FM selectivity than in ICC or NLL
and a consistent preference for upward over downward FM sweeps. Anterograde and
retrograde transport was examined following focal injections of wheatgerm
agglutinin-horseradish peroxidase (WGA-HRP) into ICXv. The main targets of
anterograde transport were the deep layers of the superior colliculus and the
suprageniculate division of the medial geniculate body. The primary site of
retrograde transport was the nucleus of the central acoustic tract in the
brainstem. Thus, the ICXv appears to be a part of the central acoustic tract, an
extralemniscal pathway linking the auditory brainstem directly to a multimodal
nucleus of the thalamus.
central acoustic tract; external nucleus of the inferior colliculus; suprageniculate nucleus; superior colliculus; lateral inhibition; temporal processing
Mustached bats emit echolocation and communication calls containing both constant frequency (CF) and frequency-modulated (FM) components. Previously we found that 86% of neurons in the ventral division of the external nucleus of the inferior colliculus (ICXv) were directionally selective for linear FM sweeps and that selectivity was dependent on sweep rate. The ICXv projects to the suprageniculate nucleus (Sg) of the medial geniculate body. In this study, we isolated 37 single units in the Sg and measured their responses to best excitatory frequency (BEF) tones and linear 12-kHz upward and downward FM sweeps centered on the BEF. Sweeps were presented at durations of 30, 12, and 4 ms, yielding modulation rates of 400, 1,000, and 3,000 kHz/s. Spike count versus level functions were obtained at each modulation rate and compared with BEF controls. Sg units responded well to both tones and FM sweeps. BEFs clustered at 58 kHz, corresponding to the dominant CF component of the sonar signal. Spike count functions for both tones and sweeps were predominantly non-monotonic. FM directional selectivity was significant in 53–78% of the units, depending on modulation rate and level. Units were classified as up-selective (52%), down-selective (24%), or bi-directional (non-selective, 16%); a few units (8%) showed preferences that were either rate- or level-dependent. Most units showed consistent directional preferences at all SPLs and modulation rates tested, but typically showed stronger selectivity at lower sweep rates. Directional preferences were attributable to suppression of activity by sweeps in the non-preferred direction (~80% of units) and/or facilitation by sweeps in the preferred direction (~20–30%). Latencies for BEF tones ranged from 4.9 to 25.7 ms. Latencies for FM sweeps typically varied linearly with sweep duration. Most FM latency-duration functions had slopes ranging from 0.4 to 0.6, suggesting that the responses were triggered by the BEF. Latencies for BEF tones and FM sweeps were significantly correlated in most Sg units, i.e., the response to FM was temporally related to the occurrence of the BEF in the FM sweep. FM latency declined relative to BEF latency as modulation rate increased, suggesting that at higher rates response is triggered by frequencies in the sweep preceding the BEF. We conclude that Sg and ICXv units have similar, though not identical, response properties. Sg units are predominantly upsweep selective and could respond to either or both the CF and FM components in biosonar signals in a number of echolocation scenarios, as well as to a variety of communication sounds.
Two-tone stimuli have traditionally been used to reveal regions of inhibition in auditory spectral receptive fields, particularly for neurons with low spontaneous rates. These techniques reveal how different frequencies excite or suppress the response to an excitatory frequency of a cell, but have often been assessed at a fixed masker–probe time interval. We used a variation of this methodology determine whether two-tone spectrotemporal interactions can account for rate-dependent directional selectivity for frequency modulations (FM) in the mustached bat inferior colliculus (IC). First, we quantified the response to upward and downward sweeping, linear, fixed-bandwidth FM tones centered at a unit’s characteristic frequency (CF) at 6 sweep durations ranging from 2 to 64 ms. Then, to examine how responses to instantaneous frequencies contained within the sweeps might interact in time, we varied the frequency and relative onset of a brief (4 ms) “conditioner” tone paired with a fixed 4-ms CF probe tone. We constructed “conditioned response areas” (CRA) depicting regions of suppression and facilitation of the probe tone caused by the conditioning tone. We classified the CRAs as predominantly excitatory (40.9%), inhibitory (22.7%), or mixed (36.4%). To generate FM response predictions, the CRAs were multiplied with spectrograms of the same sweeps used to assess response to FM. The predictions of FM rate and directionality were accurate by our criteria in approximately 20% of units. Conversely, the CRAs from the remaining units failed to predict FM responses as accurately, suggesting that most IC units respond differently to FM sweeps than they do to tone-pairs matched to the instantaneous frequencies contained in those sweeps. The implications of these results for models of FM directionality are discussed.
Auditory midbrain; Frequency modulation; Spectrotemporal receptive field; Mustached bat; Neural delay lines; FM models; Temporal processing
Exposure to traumatic stressors typically causes lasting changes in emotionality and behavior. However, coping strategies have been shown to prevent and alleviate many stress consequences and the biological mechanisms that underlie coping are of great interest. Whereas the laboratory stressor inescapable tail-shock induces anxiety-like behaviors, here we demonstrate that permitting a rat to chew on a wooden dowel during administration of tail-shock prevented the development of anxiety like behaviors in the open field and juvenile social exploration tests. Uncontrollable stressors increase corticosterone and decrease thyroid hormone, and we hypothesized that coping would blunt these changes. While tail-shock did produce these effects, active coping did not alter hormone levels. The dissociation between behavioral resilience and circulating hormones is discussed with regard to the utility of these molecules as biomarkers for psychiatric disease.
Chewing; Coping; Corticosterone; Thyroxine; Open-field test; Social Exploration; Rat
The economic burden of heart disease is heavy and growing. As advanced technologies for treating heart disease become available, decision makers need to be able to assess the relative value of such options against existing standards of care.
To compare the clinical and economic benefits of a percutaneous ventricular assist device (pVAD) versus an intra-aortic balloon pump (IABP) observed during the 90-day duration of the PROTECT II clinical trial, and to supplement these findings with a simulation of the longer-term value of this technology through the use of a Markov model to estimate the incremental cost-effectiveness of a pVAD relative to an IABP, in terms of quality-adjusted life-years (QALYs).
Hospital bills were collected for patients enrolled in the PROTECT II trial who received hemodynamic support for high-risk percutaneous coronary intervention (PCI) provided by a pVAD (Impella 2.5) versus a conventional IABP during a 90-day episode of care (EOC). Length of stay, charges, and costs were analyzed for the index admissions, intensive care unit confinements, readmissions, and overall EOC. In addition, a probabilistic Markov model was used to project these parameters and their impact on a patient's quality of life for up to 10 years in relation to a pVAD versus an IABP.
Hospital costs for the index admission were lower for the IABP compared with the pVAD ($33,684 vs $47,667; P <.001), whereas readmission length of stay and costs were lower for the pVAD versus the IABP (5 days vs 7 days; and $11,007 vs $21,834, respectively; P <.001). The total 90-day hospital charges were similar for the pVAD and the IABP ($172,564 vs $172,758, respectively; P = .785); however, the total 90-day EOC cost was lower for the IABP than for the pVAD ($44,032 vs $53,171, respectively; P <.001). The median hospital days for the entire EOC were 7 days for the pVAD versus 9 days for the IABP (P = .008). Critical care stays were considerably shorter for a pVAD than for an IABP on readmissions (3.88 days vs 7.00 days; P = .145). Reduction in major adverse cardiovascular and cerebrovascular events resulted in a projected gain of 0.26 QALYs over 10 years, yielding an incremental cost-effectiveness ratio of $39,389/QALY.
For high-risk patients with advanced heart failure undergoing PCI, the new pVAD reduced major adverse events, critical care and readmission length of stay, and readmission cost over the 90-day EOC, and was determined to be cost-effective over the long-term. These findings can assist decision makers in forming value-based judgments with regard to new hemodynamic support strategies.
In patients with hypertrophic obstructive cardiomyopathy, hemodynamically significant ventricular septal defect after septal myectomy is a rare sequela that warrants closure. Percutaneous closure provides a safer alternative to repeated sternotomy, which is associated with significant morbidity and mortality rates. We report a possibly unique case of successful retrograde percutaneous closure, with an AMPLATZER Muscular VSD Occluder, of an iatrogenic ventricular septal defect consequent to surgical therapy for hypertrophic obstructive cardiomyopathy.
Cardiac catheterization/methods; cardiomyopathy, hypertrophic/therapy; heart septal defects, ventricular/therapy; iatrogenic disease; myectomy; postoperative complications; prosthesis implantation/methods; septal occluder device; ventricular septal defect
Transcatheter aortic valve replacement is an increasingly common treatment of critical aortic stenosis. Many aortic stenosis patients have concomitant left ventricular dysfunction, which can instigate the formation of thrombus resistant to anticoagulation. Recent trials evaluating transcatheter aortic valve replacement have excluded patients with left ventricular thrombus. We present a case in which an 86-year-old man with known left ventricular thrombus underwent successful transcatheter aortic valve replacement under cerebral protection.
Aortic valve stenosis/therapy; cerebral infarction/etiology; embolic protection devices; heart valve prosthesis implantation; intracranial embolism/prevention & control; stroke/etiology; thrombus, left ventricular
At our institutions, increasing numbers of aortic stenosis patients were not candidates for surgical aortic valve replacement. Accordingly, we initiated the Cali Colombian Transcatheter Aortic Valve Implantation (TAVI) program. From March 2008 through January 2011, 53 consecutive patients (mean age, 79 ± 6 yr; men, 58%) underwent TAVI with the Medtronic CoreValve System, and data were prospectively collected. Our study's endpoints conformed with Valve Academic Research Consortium recommendations. We report our clinical results.
Predicted mortality rates were 25% (interquartile range, 17%–34%) according to logistic EuroSCORE and 6% (interquartile range, 3%–8%) according to the Society of Thoracic Surgeons score. The 30-day mortality rate was 9% (3 intraprocedural deaths, 5 total). The combined 30-day safety endpoint was 30% (major vascular sequelae, 23%; life-threatening bleeding, 12%; myocardial infarction, 4%; major stroke, 4%; and acute kidney injury [stage 3], 2%). Eight patients (15%) required post-implantation balloon dilation and 2 (4%) required valve-in-valve implantation, for a technical device success rate of 77%. Mean peak transvalvular gradient decreased from 74 ± 29 to 17 ± 8 mmHg and mean transvalvular gradient from 40 ± 17 to 8 ± 4 mmHg (both P=0.001). Moderate or severe aortic regurgitation decreased from 32% to 18% (P=0.12) and mitral regurgitation from 32% to 13% (P=0.002). The 1-year survival rate was 81%.
We found that TAVI with the CoreValve prosthesis was safe and feasible, with sustained long-term results, for treating aortic stenosis in patients at excessive surgical risk; nonetheless, serious adverse events occurred in 30% of the patients.
Aortic valve stenosis/complications/mortality/surgery; comorbidity; heart valve prosthesis implantation/methods; postoperative complications/etiology/prevention & control; registries; risk factors; treatment outcome
The vascular disease in-stent restenosis (ISR) is characterized by formation of neointima and adverse inward remodeling of the artery after injury by coronary stent implantation. We hypothesized that the analysis of gene expression in peripheral blood mononuclear cells (PBMCs) would demonstrate differences in transcript expression between individuals who develop ISR and those who do not.
Methods and Results
We determined and investigated PBMC gene expression of 358 patients undergoing an index procedure to treat in de novo coronary artery lesions with bare metallic stents, using a novel time-varying intercept model to optimally assess the time course of gene expression across a time course of blood samples. Validation analyses were conducted in an independent sample of 97 patients with similar time-course blood sampling and gene expression data. We identified 47 probesets with differential expression, of which 36 were validated upon independent replication testing. The genes identified have varied functions, including some related to cellular growth and metabolism, such as the NAB2 and LAMP genes.
In a study of patients undergoing bare metallic stent implantation, we have identified and replicated differential gene expression in peripheral blood mononuclear cells, studied across a time series of blood samples. The genes identified suggest alterations in cellular growth and metabolism pathways, and these results provide the basis for further specific functional hypothesis generation and testing of the mechanisms of ISR.
Over the past decade, electrical detection of chemical and biological species using novel nanostructure-based devices has attracted significant attention for chemical, genomics, biomedical diagnostics, and drug discovery applications. The use of nanostructured devices in chemical/biological sensors in place of conventional sensing technologies has advantages of high sensitivity, low decreased energy consumption and potentially highly miniaturized integration. Owing to their particular structure, excellent electrical properties and high chemical stability, carbon nanotube and graphene based electrical devices have been widely developed for high performance label-free chemical/biological sensors. Here, we review the latest developments of carbon nanostructure-based transistor sensors in ultrasensitive detection of chemical/biological entities, such as poisonous gases, nucleic acids, proteins and cells.
chemical and biological sensors; carbon nanotubes; grapheme
Auditory brainstem-evoked response (ABR) thresholds were obtained in a longitudinal study of C57BL/6J mice between 10 and 53 weeks old, with repeated testing every 2 weeks. On alternate weeks, acoustic startle reflex (ASR) amplitudes were measured, elicited by tone pips with stimulus frequencies of 3, 6, 12, and 24 kHz, and intensities from subthreshold up to 110 dB sound pressure level. The increase in ABR thresholds for 3 and 6 kHz test stimuli followed a linear time course with increasing age from 10 to 53 weeks, with a slope of about 0.7 dB/week, and for 48 kHz a second linear time course, but beginning at 10 weeks with a slope of about 2.3 dB/week. ABR thresholds for 12, 24, and 32 kHz increased after one linear segment with a 0.7 dB slope, then after a variable delay related to the test frequency, shifted to a second segment having slopes of 3–5 dB/week. Hearing loss initially reduced the ASR for all eliciting stimuli, but at about 6 months of age, the response elicited by intense 3 and 6 kHz stimuli began to increase to reach values about three times above normal, and previously subthreshold stimuli came to elicit vigorous responses seen at first only for the intense stimuli. This hyperacusis-like effect appeared in all mice but was especially pronounced in mice with more serious hearing loss. These ABR data, together with a review of histopathological data in the C57BL/6 literature, suggest that the non-frequency-specific slow time course of hearing loss results from pathology in the lateral wall of the cochlea, whereas the stimulus-specific hearing loss with a rapid time course results from hair cell loss. Delayed exaggeration of the ASR with hearing loss reveals a deficit in centrifugal inhibitory control over the afferent reflex pathways after central neural reorganization, suggesting that this mouse may provide a useful model of age-related tinnitus and associated hyperacusis.
aging; hearing loss; startle; plasticity; mixed strial/sensory presbycusis; tinnitus/hyperacusis
Over the past decade, many investigators have used sophisticated time series tools for the analysis of genomic sequences. Specifically, the correlation of the nucleotide chain has been studied by examining the properties of the power spectrum. The main limitation of the power spectrum is that it is restricted to stationary time series. However, it has been observed over the past decade that genomic sequences exhibit non-stationary statistical behavior. Standard statistical tests have been used to verify that the genomic sequences are indeed not stationary. More recent analysis of genomic data has relied on time-varying power spectral methods to capture the statistical characteristics of genomic sequences. Techniques such as the evolutionary spectrum and evolutionary periodogram have been successful in extracting the time-varying correlation structure. The main difficulty in using time-varying spectral methods is that they are extremely unstable. Large deviations in the correlation structure results from very minor perturbations in the genomic data and experimental procedure. A fundamental new approach is needed in order to provide a stable platform for the non-stationary statistical analysis of genomic sequences.
In this paper, we propose to model non-stationary genomic sequences by a time-dependent autoregressive moving average (TD-ARMA) process. The model is based on a classical ARMA process whose coefficients are allowed to vary with time. A series expansion of the time-varying coefficients is used to form a generalized Yule-Walker-type system of equations. A recursive least-squares algorithm is subsequently used to estimate the time-dependent coefficients of the model. The non-stationary parameters estimated are used as a basis for statistical inference and biophysical interpretation of genomic data. In particular, we rely on the TD-ARMA model of genomic sequences to investigate the statistical properties and differentiate between coding and non-coding regions in the nucleotide chain. Specifically, we define a quantitative measure of randomness to assess how far a process deviates from white noise. Our simulation results on various gene sequences show that both the coding and non-coding regions are non-random. However, coding sequences are "whiter" than non-coding sequences as attested by a higher index of randomness.
We demonstrate that the proposed TD-ARMA model can be used to provide a stable time series tool for the analysis of non-stationary genomic sequences. The estimated time-varying coefficients are used to define an index of randomness, in order to assess the statistical correlations in coding and non-coding DNA sequences. It turns out that the statistical differences between coding and non-coding sequences are more subtle than previously thought using stationary analysis tools: Both coding and non-coding sequences exhibit statistical correlations, with the coding regions being "whiter" than the non-coding regions. These results corroborate the evolutionary periodogram analysis of genomic sequences and revoke the stationary analysis' conclusion that coding DNA behaves like random sequences.
Kv3.1b channel protein is widely distributed in the mammalian auditory brainstem, but studies have focused mainly on regions critical for temporal processing, including the medial nucleus of the trapezoid body (MNTB) and anteroventral cochlear nucleus (AVCN). Because temporal processing declines with age, this study was undertaken to determine if the expression of Kv3.1b likewise declines, and if changes are specific to these nuclei. Immunocytochemistry using an anti-Kv3.1b antibody was performed, and the relative optical density of cells and neuropil was determined from CBA/CaJ mice of four age groups. Declines in expression in AVCN, MNTB, and lateral superior olive (35, 26, and 23%) were found, but changes were limited to neuropil. Interestingly, cellular optical density declines were found in superior paraolivary nucleus, ventral nucleus of the trapezoid body, and lateral nucleus of the trapezoid body (24, 29, and 26%), which comprise the medial olivocochlear (MOC) feedback system. All declines occurred by middle age (15 months old). No age-related changes were found in the remaining regions of cochlear nucleus or in the inferior colliculus. Contralateral suppression of distortion-product otoacoustic emission amplitudes of age-matched littermates also declined by middle age, suggesting a correlation between Kv3.1 expression and MOC function. In search of more direct evidence for such a correlation, Kv3.1b knockout mice were examined. Knockouts show poor MOC function as compared to +/+ and +/− genotypes. Thus, Kv3.1b expression declines in MOC neurons by middle age, and these changes appear to correlate with functional declines in efferent activity in both middle-aged CBA mice and Kv3.1b knockout mice.
voltage-gated K+ channels; medial olivocochlear system; auditory processing; presbycusis; aging; otoacoustic emissions