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The Thirty Meter Telescope (TMT) first light instrument IRIS (Infrared Imaging Spectrograph) will complete its preliminary design phase in 2016. The IRIS instrument design includes a near-infrared (0.85-2.4 micron) integral field spectrograph (IFS) and imager that are able to conduct simultaneous diffraction-limited observations behind the advanced adaptive optics system NFIRAOS. The IRIS science cases have continued to be developed and new science studies have been investigated to aid in technical performance and design requirements. In this development phase, the IRIS science team has paid particular attention to the selection of filters, gratings, sensitivities of the entire system, and science cases that will benefit from the parallel mode of the IFS and imaging camera. We present new science cases for IRIS using the latest end-To-end data simulator on the following topics: Solar System bodies, the Galactic center, active galactic nuclei (AGN), and distant gravitationally-lensed galaxies. We then briefly discuss the necessity of an advanced data management system and data reduction pipeline.

OBJECTIVE: This study was undertaken to determine whether obesity is associated with obstetric complications and cesarean delivery. METHODS: A large prospective multicenter database was studied. Subjects were divided into 3 groups: body mass index (BMI) less than 30 (control), 30 to 34.9 (obese), and 35 or greater (morbidly obese). Groups were compared by using univariate and multivariable logistic regression analyses. RESULTS: The study included 16,102 patients: 3,752 control, 1,473 obese, and 877 morbidly obese patients. Obesity and morbid obesity had a statistically significant association with gestational hypertension (odds ratios [ORs] 2.5 and 3.2), preeclampsia (ORs 1.6 and 3.3), gestational diabetes (ORs 2.6 and 4.0), and fetal birth weight greater than 4000 g (ORs 1.7 and 1.9) and greater than 4500 g (ORs 2.0 and 2.4). For nulliparous patients, the cesarean delivery rate was 20.7% for the control group, 33.8% for obese, and 47.4% for morbidly obese patients. CONCLUSION: Obesity is an independent risk factor for adverse obstetric outcome and is significantly associated with an increased cesarean delivery rate. [ABSTRACT FROM AUTHOR]

After analyzing the clinical research, the authors present a practical approach to the challenge of caring for pregnant women who weigh 250 lb or more. Guidelines for these patients--who tend to have more C/S, larger babies, and longer hospital stays--aim to minimize morbidity and mortality, thus improving perinatal outcome. [ABSTRACT FROM AUTHOR]

Transfer RNAs have been extensively explored as the molecules that translate the genetic code into proteins. At this interface of genetics and biochemistry, tRNAs direct the efficiency of every major step of translation by interacting with a multitude of binding partners. However, due to the variability of tRNA sequences and the abundance of diverse post-transcriptional modifications, a guidebook linking tRNA sequences to specific translational outcomes has yet to be elucidated. Here, we review substantial efforts that have collectively uncovered tRNA engineering principles that can be used as a guide for the tuning of translation fidelity. These principles have allowed for the development of basic research, expansion of the genetic code with non-canonical amino acids, and tRNA therapeutics., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Weiss, Decker, Bolano and Krahn.)

Background: Interdisciplinary therapies for the management of people with multiple sclerosis (MS) are underappreciated. There is an urgent need to introduce music therapy (MT), either alone or in combination with physical therapy (PT), into clinical practice to achieve synergy with disease-modifying therapies. A holistic approach to rehabilitation for people with MS may mitigate symptoms and reduce polypharmacy, potentially lowering health care costs., Results: As MS progresses, patients experience a range of worsening symptoms, and many develop psychosocial comorbidities. As disease-modifying therapies delay disability progression, nonpharmacologic treatments become increasingly important. The main aim of PT is to improve or maintain patients' functional mobility, strength, and flexibility. Because it targets multiple functions, MT can help improve functional and psychosocial domains and may be a valuable intervention to help patients achieve the physical, cognitive, and emotional goals of PT. Exploratory studies showed that MT, alone or in combination with PT, can lead to functional improvements in mobility, balance, gait, and fatigue. Similar to PT, MT also has benefits in improving fine motor skills, cognition, learning, and memory and in providing emotional support., Conclusions: Both MT and PT have the potential to improve overall well-being and health-related quality of life in physically active patients with MS, and MT can provide added emotional support for those who are less able to engage in physical activity. However, MT is not typically a part of standard of care, and PT visits are limited. Nevertheless, interdisciplinary therapies should be incorporated into clinical practice., Competing Interests: FINANCIAL DISCLOSURES: Dr Weiss was an employee of Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA, during the development of this article. Dr Su is an employee of Novartis. Ms Fleming has received consultancy fees from Novartis (independent of the submitted work). Messrs Leong and Sweitzer declare no conflicts of interest., (© 2023 The Consortium of Multiple Sclerosis Centers.)

Neurodegenerative diseases are among the main causes of death in the United States, leading to irreversible disintegration of neurons. Despite intense international research efforts, cellular mechanisms that initiate neurodegeneration remain elusive, thus inhibiting the development of effective preventative and early onset medical treatment. To identify underlying cellular mechanisms that initiate neuron degeneration, it is critical to identify histological and cellular hallmarks that can be linked to underlying biochemical processes. Due to the poor tissue preservation of degenerating mammalian brain tissue, our knowledge regarding histopathological hallmarks of early to late degenerative stages is only fragmentary. Here, we introduce a novel model organism to study histological hallmarks of neurodegeneration, the spider Cupiennius salei. We utilized toluidine blue-stained 0.9-μm serial semithin and 50-nm ultrathin sections of young and old spider nervous tissue. Our findings suggest that the initial stages of neurodegeneration in spiders may be triggered by (1) dissociation of neuron- and glia-derived microtubules, and (2) the weakening of microtubule-associated desmosomal junctions that lead to the unraveling of neuron-insulating macroglia, compromising the structural integrity of affected neurons. The involvement of macroglia in the disposal of neuronal debris described here-although different in the proposed transport mechanisms-shows resemblance to the mammalian glymphatic system. We propose that this model system is highly suitable to investigate invertebrate neurodegenerative processes from early onset to scar formation and that this knowledge may be useful for the study of neurodegeneration in mammalian tissue., (© 2023 Wiley Periodicals LLC.)

Introduction: The mechanisms of action of disease-modifying therapies (DMTs) for multiple sclerosis (MS) are complex and involve an interplay of immune system components. People with MS (PwMS) may lack a clear understanding of the immunological pathways involved in MS and its treatment; effective communication between healthcare professionals (HCPs) and PwMS is needed to facilitate shared decision-making when discussing the disease and selecting DMTs and is particularly important in the coronavirus disease 2019 (COVID-19) era., Methods: In this patient-authored two-part review, we performed a targeted literature search to assess the need for better communication between HCPs and PwMS regarding treatment selection, and also conducted a qualitative survey of four patient and care-partner authors to obtain insights regarding their understanding of and preferences for the treatment and management of MS., Results: Following a search of the Embase and MEDLINE databases using Ovid in June 2020, an analysis of 40 journal articles and conference abstracts relating to patient empowerment and decision-making in DMT selection for MS showed a preference for safety and efficacy of treatments, followed by autonomy and convenience of administration. A need for better communication between HCPs and PwMS during treatment selection to improve patient satisfaction was also identified. The open survey responses from the patient authors revealed a need for greater involvement in decision-making processes and desire for improved communication and information tools., Conclusions: This targeted literature search and phenomenological review confirms PwMS preferences for empowered decision-making in disease management and treatment selection, to optimize independence, safety, and efficacy. It also identifies an unmet need for improved communication and information tools that convey MS information in a relatable manner. Furthermore, this review seeks to address this unmet need by providing plain language figures and descriptions of MS immune mechanisms that can be used to facilitate discussions between HCPs and PwMS., (© 2022. The Author(s).)

Background: Therapeutic monoclonal antibodies against the calcitonin gene-related peptide (CGRP) receptor or its ligand have changed the landscape of treatment options for migraine. Erenumab is the first and only fully human monoclonal antibody designed to target and block the CGRP receptor. It is approved by the Food and Drug Administration for preventive treatment of migraine in adults. The recommended dose of erenumab is 70 mg monthly, with guidance that some patients may benefit from the 140 mg monthly dose. There is a need for information to guide clinical practice on the comparative efficacy and safety of these two dosing options., Objective: To evaluate therapeutic and tolerability differences between erenumab 70 and 140 mg based on evidence from published literature., Methods: This narrative review evaluates therapeutic and tolerability differences between erenumab 70 and 140 mg based on a literature search using PubMed interface, Embase and Ovid MEDLINE(R) databases. The key search terms included migraine, AMG 334, AMG334, erenumab, erenumab-aooe, and Aimovig. The search was limited to English language articles or conference abstracts published up to May 2021., Results: From the literature search, we retrieved 23 relevant articles/conference abstracts (19 articles [5 randomized, double-blind studies] and 4 conference abstracts) for inclusion in this narrative review. Although the recommended starting dosage of erenumab is 70 mg, this narrative review of the literature indicates that some patients may benefit from a dosage of 140 mg erenumab once monthly-especially those with difficult-to-treat disease and prior treatment failures. The evidence indicates that erenumab at 140 mg has a numerically better efficacy than 70 mg across a broad spectrum of migraine outcomes, including preventing progression to chronic migraine., Conclusion: Cumulative data from the literature support a therapeutic gain with an increase from erenumab 70 to 140 mg and a rationale for initiating 140 mg in selected patients., (© 2022 American Headache Society.)

Introduction: Acute ischemic stroke (AIS) in the young age (≤50 years) is a major cause of disability. The underlying mechanism of AIS in this age group is usually different from elderly. Transthoracic echocardiography (TTE) is used to detect the potential cardiac sources of embolism in AIS patients. Transthoracic echocardiogram (TEE) is superior to detect specific underlying cardio-aortic source of embolism when compared to TTE. We aim to evaluate the diagnostic yield and therapeutic impact of TEE in AIS of young adults., Methods: We retrospectively reviewed the consecutive patients with AIS in our comprehensive center in a 5-year period from our prospectively collected registry. We selected patients with age ≤50 years who had acute infarcts on brain magnetic resonance imaging or head computed tomography and underwent TEE as part of their diagnostic workup. Demographic details including, age, gender, body mass index, cardiovascular risk factors profile, and TEE findings were collected., Results: Among a total 7,930 patients, 876 (11.04%) were found to be ≤50 years old. Among those, TEE was done in 113 patients (12.8%) in addition to TTE. Those who underwent TEE had a mean age of 40.4 ± 7.9 years, 60 were male (53%), 7 (6.2%) had a history of coronary artery disease, 38 (33%) had a history of diabetes, and 45 (40%) had a history of smoking. TEE showed new abnormal findings in a total of 15 patients (13.2%) that were not reported in their TTEs. Out of these, left atrial appendage thrombus was found in 5, infective endocarditis in 4, atrial septal aneurysms associated with patent foramen ovale (PFO) in 3, and spontaneous mobile echo density in three patients. Overall, new findings from TEE resulted in change in the secondary stroke prevention strategy in 14 patients of those who underwent TEE (12.3%). TEE also confirmed the presence of PFO, which was present on TTE with bubble study in 20 (17.6%) patients., Conclusion: TEE may provide additional information in the evaluation of the AIS in young adults, which could lead to change of the secondary stroke prevention strategy., Competing Interests: There are no conflicts of interest., (Copyright: © 2021 Brain Circulation.)

Background: Injectable disease-modifying therapies (iDMTs) are often used as first-line treatments for relapsing multiple sclerosis. Fingolimod is frequently used following treatment with iDMTs. Whether prior iDMT treatment impacts the effectiveness of subsequent fingolimod therapy is unclear. Here, we assessed switching from iDMTs to fingolimod, and the impact of treatment history on fingolimod escalation using data from the 12-month 'Prospective, Randomized, active-controlled, open-label study to Evaluate patient retention on Fingolimod versus approved first-line disease-modifying thErapies in adults with Relapsing-remitting Multiple Sclerosis' (PREFERMS). The study design and results at the end of randomized treatment (EoRT) in PREFERMS have been published., Methods: Both treatment-naïve patients and those who had previously received an iDMT were eligible for enrolment in PREFERMS, and one treatment switch was permitted on study. Pre-specified exploratory analyses compared outcomes in those randomized to fingolimod or to an iDMT at end of study (EoS), which included time spent on randomized and on switch treatment. Post hoc exploratory analyses (unadjusted for multiplicity owing to the large number of comparisons) among patients randomized to an iDMT who switched to fingolimod, compared outcomes longitudinally before (EoRT) and after (EoS) switching, and compared outcomes at EoRT and EoS among subgroups stratified by iDMT-treatment history. Outcomes included brain volume, various measures of gadolinium-enhancing [Gd+] lesion counts, annualized relapse rate (ARR), Symbol Digit Modalities Test (SDMT) score, patient-reported treatment satisfaction using the Medication Satisfaction Questionnaire (MSQ) and adverse event (AE) rates., Results: At EoS, 255 of 439 patients randomized to an iDMT had switched to fingolimod and 27 of 436 patients randomized to fingolimod had switched to an iDMT. By EoS, 44.2% of total treatment exposure in the iDMT group was to fingolimod and the mean time spent on fingolimod in this group was 220 days (approximately 7 months). Outcomes in the fingolimod group at EoS (brain volume, changes in Gd+ lesion counts, ARR, oral SDMT score and MSQ score) were similar to those seen at EoRT, but in the iDMT group these outcomes were more favorable at EoS than at EoRT and were similar to rates seen in the fingolimod group. Among patients who switched from iDMT to fingolimod, there were longitudinal improvements in ARR (EoRT, 0.3 [95% confidence interval (CI), 0.2-0.4]; EoS, 0.2 [0.1-0.3]; odds ratio, 0.5 [0.3-0.9]) and in treatment satisfaction (proportion of patients with MSQ > 5; EoRT, 67.4%; EoS, 90.4%; odds ratio, 5.7 [95% CI, 3.4-9.4]) after fingolimod treatment, and changes in brain volume, Gd+ lesion count, and AEs or AEs causing discontinuation were also more favorable at EoS than at EoRT. In all patient groups stratified by iDMT-treatment history, differences in outcomes narrowed or disappeared after fingolimod treatment., Conclusion: These analyses indicate that patients in PREFERMS had improved outcomes within months of switching to fingolimod from an iDMT and that improvements occurred irrespective of the number of iDMTs previously administered. These data provide a unique opportunity to explore clinical, radiological and safety outcomes associated with a range of clinically relevant treatment pathways., Competing Interests: Declaration of Competing Interest SFH has received consulting fees and/or research support from and/or served on speakers’ bureaux for Acorda Therapeutics, Avanir, Bayer HealthCare Pharmaceuticals, Novartis, Osmotica, Roche/Genentech, Sanofi Genzyme and Teva Neuroscience. FPT has served as a speaker and/or consultant for Acorda Therapeutics, Biogen, Genzyme, Novartis and Teva Neuroscience, and has received research support from Biogen and Teva Neuroscience. MC has received research support and/or consulting fees from Acorda Therapeutics, Bayer HealthCare, Biogen Idec, EMD Serono, Genzyme, Genentech, Novartis, Roche and Sanofi Aventis. IMW is an employee of Oxford PharmaGenesis Ltd. XM, LS, JLW and NT are employees of Novartis Pharmaceuticals Corporation. BACC has received personal compensation for consulting from AbbVie, Akili, Alexion, Biogen, EMD Serono, Novartis and TG Therapeutics., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)

Following publication of the original article [1], the authors reported a mistake regarding the year found in the paragraph of the Background section.

Background: Fingolimod (Gilenya®) is approved for relapsing forms of multiple sclerosis in the USA. Owing to transient heart-rate effects when initiating fingolimod, eligible patients undergo precautionary baseline assessment and first-dose observation (FDO) for ≥6 h. Prior to 2014, FDO was undertaken only in clinics. As the FDO period is short, and fingolimod has accumulated evidence of a positive benefit:risk ratio, an in-home treatment-initiation program, Gilenya@Home, was developed to offer a convenient alternative., Methods: Cardiac parameters and adverse events (AEs) were recorded by healthcare professionals performing fingolimod FDOs in the US Gilenya@Home program or in US Gilenya Assessment Network clinics. Anonymized data were collated retrospectively from the first 34 months in the home setting and from 78 months in clinics; data are reported descriptively. Satisfaction with Gilenya@Home was rated by patients using a 7-item questionnaire that considered aspects such as ease of scheduling, courtesy, and competency., Results: Data were captured as part of standard care from 5573 patients initiating fingolimod in-home (October 2014 to July 2017) and from 15,025 patients initiating in-clinic (July 2010 to December 2016). In the Gilenya@Home questionnaire, 91.7% of 1848 respondents rated their overall satisfaction as "very good," and 7.6% rated their satisfaction as "good." AEs were reported for 30.7 and 32.6% of in-home and in-clinic patients, respectively. In total, 557 in-home (10.0%) and 398 in-clinic (2.6%) patients were monitored for > 6 h; 15 (0.3%) in-home and 129 (0.9%) in-clinic patients were transferred to an emergency room for overnight monitoring. The mean (standard deviation) heart rate (HR; bpm) pre-FDO was 74.8 (12.2) in-home and 74.2 (11.3) in-clinic; reduction in HR at 6 h postdose was 10.6 (12.0) and 6.3 (9.6), respectively. New-onset first-degree atrioventricular block was experienced by 132 (2.4%) in-home and 74 (0.5%) in-clinic patients, and Wenckebach (Mobitz type I) second-degree atrioventricular block by four (0.07%) and nine (0.1%) patients, with no cases of third-degree atrioventricular block., Conclusions: A substantial number of patients have initiated fingolimod at home, reporting very high levels of satisfaction. Gilenya@Home was as rigorous as the clinic setting in detecting cardiovascular events. Overall, FDO safety outcomes were similar with Gilenya@Home and in-clinic.

Purpose: To screen for subclinical keratoconus by analyzing corneal, epithelial, and stromal thickness map patterns with Fourier-domain optical coherence tomography (OCT)., Setting: Four centers in the United States., Design: Cross-sectional observational study., Methods: Eyes of normal subjects, subclinical keratoconus eyes, and the topographically normal eye of a unilateral keratoconus patient were studied. Corneas were scanned using a 26,000 Hz Fourier-domain OCT system (RTVue). Normal subjects were divided into training and evaluation groups. Corneal, epithelial, and stromal thickness maps and derived diagnostic indices, including pattern standard deviation (PSD) variables and pachymetric map-based keratoconus risk scores, were calculated from the OCT data. Area under the receiver operating characteristic curve (AUC) analysis was used to evaluate the diagnostic accuracy of the indices., Results: The study comprised 150 eyes of 83 normal subjects, 50 subclinical keratoconus eyes of 32 patients, and 1 topographically normal eye of a unilateral keratoconus patient. Subclinical keratoconus was characterized by inferotemporal thinning of the cornea, epithelium, and stroma. The PSD values for corneal (P < .001), epithelial (P < .001), and stromal (P = .049) thickness maps were all significantly higher in subclinical keratoconic eyes than in the normal group. The diagnostic accuracy was significantly higher for PSD variables (pachymetric PSD, AUC = 0.941; epithelial PSD, AUC = 0.985; stromal PSD, AUC = 0.924) than for the pachymetric map-based keratoconus risk score (AUC = 0.735)., Conclusions: High-resolution Fourier-domain OCT could map corneal, epithelial, and stromal thicknesses. Corneal and sublayer thickness changes in subclinical keratoconus could be detected with high accuracy using PSD variables. These new diagnostic variables might be useful in the detection of early keratoconus., Financial Disclosures: Oregon Health and Science University (OHSU) and Drs. Li, Tan, and Huang have a significant financial interest in Optovue, Inc. These potential conflicts have been reviewed and managed by OHSU. Dr. Brass receives research grants from Optovue, Inc. Drs. Chamberlain and Weiss have no financial or proprietary interest in any material or method mentioned., (Copyright © 2016 ASCRS and ESCRS. Published by Elsevier Inc. All rights reserved.)

Background: This study investigated the trend of phone calls in the Banner Good Samaritan Medical Center (BGSMC) Heart Failure Transitional Care Program (HFTCP). The primary goal of the HFTCP is to reduce 30-Day readmissions for heart failure patients by using a multi-pronged approach., Methods: This study included 104 patients in the HFTCP discharged over a 51-week period who had around-the-clock telephone access to the Transitionalist. Cellular phone records were reviewed. This study evaluated the length and timing of calls., Results: A total of 4398 telephone calls were recorded of which 39% were inbound and 61% were outbound. This averaged to 86 calls per week. During the "Weekday Daytime" period, Eighty-five percent of the totals calls were made. There were 229 calls during the "Weekday Nights" period with 1.5 inbound calls per week. The "Total Weekend" calls were 10.2% of the total calls which equated to a weekly average of 8.8., Conclusions: Our experience is that direct, physician-patient telephone contact is feasible with a panel of around 100 HF patients for one provider. If the proper financial reimbursements are provided, physicians may be apt to participate in similar transitional care programs. Likewise, third party payers will benefit from the reduction in unnecessary emergency room visits and hospitalizations.

Background: Despite a variety of national efforts to improve transitions of care for patients at risk for rehospitalization, 30-day rehospitalization rates for patients with heart failure have remained largely unchanged., Methods: This is a retrospective review of 73 patients enrolled in our hospital-based, physican-directed Heart Failure Transitional Care Program (HFTCP). This study evaluated the 30- and 90- day readmission rates before and after enrollment in the program. The Transitionalist's services focused on bedside consultation prior to hospital discharge, follow-up home visits within 72 hours of discharge, frequent follow-up phone calls, disease-specific education, outpatient intravenous diuretic therapy, and around-the-clock telephone access to the Transitionalist., Results: The pre-enrollment 30-day readmission rates for acute decompensated heart failure (ADHF) and all-cause readmission was 26.0% and 28.8%, respectively, while the post-enrollment rates for ADHF and all-cause readmission were 4.1% (P < 0.001) and 8.2% (P = 0.002), respectively. The pre-enrollment 90-day all-cause and ADHF readmission rates were 69.8%, and 58.9% respectively, while the post-enrollment rates for all-cause and ADHF were 27.3% (P < 0.001) and 16.4% (P < 0.001) respectively., Conclusions: Our physician-implemented HFTCP reduced rehospitalization risk for patients enrolled in the program. This program may serve as a model to assist other hospital systems to reduce readmission rates of patients with HF.

Objective: To map the corneal epithelial thickness with Fourier-domain optical coherence tomography (OCT) and to develop epithelial thickness-based variables for keratoconus detection., Design: Cross-sectional observational study., Participants: One hundred forty-five eyes from 76 normal subjects and 35 keratoconic eyes from 22 patients., Methods: A 26,000-Hz Fourier-domain OCT system with 5-μm axial resolution was used. The cornea was imaged with a Pachymetry + Cpwr scan pattern (6-mm scan diameter, 8 radials, 1024 axial-scans each, repeated 5 times) centered on the pupil. Three scans were obtained at a single visit in a prospective study. A computer algorithm was developed to map the corneal epithelial thickness automatically. Zonal epithelial thicknesses and 5 diagnostic variables, including minimum, superior-inferior (S-I), minimum-maximum (MIN-MAX), map standard deviation (MSD), and pattern standard deviation (PSD), were calculated. Repeatability of the measurements was assessed by the pooled standard deviation. The area under the receiver operating characteristic curve (AUC) was used to evaluate diagnostic accuracy., Main Outcome Measures: Descriptive statistics, repeatability, and AUC of the zonal epithelial thickness and diagnostic variables., Results: The central, superior, and inferior epithelial thickness averages were 52.3 ± 3.6 μm, 49.6 ± 3.5 μm, and 51.2 ± 3.4 μm in normal eyes and 51.9 ± 5.3 μm, 51.2 ± 4.2 μm, and 49.1 ± 4.3 μm in keratoconic eyes. Compared with normal eyes, keratoconic eyes had significantly lower inferior (P = 0.03) and minimum (P<0.0001) corneal epithelial thickness, greater S-I (P = 0.013), more negative MIN-MAX (P<0.0001), greater MSD (P<0.0001), and larger PSD (P<0.0001). The repeatability of the zonal average, minimum, S-I, and MIN-MAX epithelial thickness variables were between 0.7 and 1.9 μm. The repeatability of MSD was better than 0.4 μm. The repeatability of PSD was 0.02 or better. Among all epithelial thickness-based variables investigated, PSD provided the best diagnostic power (AUC = 1.00). Using an PSD cutoff value of 0.057 alone gave 100% specificity and 100% sensitivity., Conclusions: High-resolution Fourier-domain OCT mapped corneal epithelial thickness with good repeatability in both normal and keratoconic eyes. Keratoconus was characterized by apical epithelial thinning. The resulting deviation from the normal epithelial pattern could be detected with very high accuracy using the PSD variable., Financial Disclosure(s): Proprietary or commercial disclosure may be found after the references., (Copyright © 2012 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Calcium (Ca(2+)) is a crucial intracellular messenger in physiological aspects of cell signaling. Adrenal chromaffin cells are the secretory cells from the adrenal gland medulla that secrete catecholamines, which include epinephrine and norepinephrine important in the 'fight or flight' response. Bovine adrenal chromaffin cells have long been used as an important model for secretion -(exocytosis) not only due to their importance in the short-term stress response, but also as a neuroendocrine model of neurotransmtter release, as they have all the same exocytotic proteins as neurons but are easier to prepare, culture and use in functional assays. The components of the Ca(2+) signal transduction cascade and it role in secretion has been extensively characterized in bovine adrenal chromaffin cells. The Ca(2+) sources, signaling molecules and how this relates to the short-term stress response are reviewed in this book chapter in an endeavor to generally -overview these mechanisms in a concise and uncomplicated manner.

Objective: Conventional CT requires generation of separate images utilizing different convolution kernels to optimize lesion detection. Our goal was to develop and test a hybrid CT algorithm to simultaneously optimize bone and soft-tissue characterization, potentially halving the number of images that need to be stored, transmitted, and reviewed., Materials and Methods: CT images generated with separate high-pass (bone) and low-pass (soft tissue) kernels were retrospectively combined so that low-pass algorithm pixels less than -150 HU or greater than 150 HU are substituted with corresponding high-pass kernel reconstructed pixels. A total of 38 CT examinations were reviewed using the hybrid technique, including 20 head, eight spine, and 10 head and neck scans. Three neuroradiologists independently reviewed all 38 hybrid cases, comparing them to both standard low-pass and high-pass kernel convolved images for characterization of anatomy and pathologic abnormalities. The conspicuity of bone, soft tissue, and related anatomy were compared for each CT reconstruction technique., Results: For the depiction of bone, in all 38 cases, the three neuroradiologists scored the hybrid images as being equivalent to high-pass kernel reconstructions but superior to the low-pass kernel. For depiction of extracranial soft tissues and brain, the hybrid kernel was rated equivalent to the low-pass kernel but superior to that of the high-pass kernel., Conclusion: The hybrid convolution kernel is a promising technique affording optimized bone and soft tissue evaluation while potentially halving the number of images needed to be transmitted, stored, and reviewed.

Calcium (Ca(2+)) is an important intracellular messenger underlying cell physiology. Ca(2+) channels are the main entry route for Ca(2+) into excitable cells, and regulate processes such as neurotransmitter release and neuronal outgrowth. Neuronal Calcium Sensor-1 (NCS-1) is a member of the Calmodulin superfamily of EF-hand Ca(2+) sensing proteins residing in the subfamily of NCS proteins. NCS-1 was originally discovered in Drosophila as an overexpression mutant (Frequenin), having an increased frequency of Ca(2+)-evoked neurotransmission. NCS-1 is N-terminally myristoylated, can bind intracellular membranes, and has a Ca(2+) affinity of 0.3 μM. Over 10 years ago it was discovered that NCS-1 overexpression enhances Ca(2+)-evoked secretion in bovine adrenal chromaffin cells. The mechanism was unclear, but there was no apparent direct effect on the exocytotic machinery. It was revealed, again in chromaffin cells, that NCS-1 regulates voltage-gated Ca(2+) channels (Cavs) in G-Protein Coupled Receptor (GPCR) signaling pathways. This work in chromaffin cells highlighted NCS-1 as an important modulator of neurotransmission. NCS-1 has since been shown to regulate and/or directly interact with many proteins including Cavs (P/Q, N, and L), TRPC1/5 channels, GPCRs, IP3R, and PI4 kinase type IIIβ. NCS-1 also affects neuronal outgrowth having roles in learning and memory affecting both short- and long-term synaptic plasticity. It is not known if NCS-1 affects neurotransmission and synaptic plasticity via its effect on PIP2 levels, and/or via a direct interaction with Ca(2+) channels or their signaling complexes. This review gives a historical account of NCS-1 function, examining contributions from chromaffin cells, PC12 cells and other models, to describe how NCS-1's regulation of Ca(2+) channels allows it to exert its physiological effects.

Objective: Vertebral column variation is a common, often overlooked finding on traditional spine MRI. Standard localizers do not image the entire neuroaxis, masking variation. The purpose of this study was to use a subminute automated spine survey iterative scan technique (ASSIST) to evaluate 207 patients undergoing thoracic spine MRI., Conclusion: We found variation in 7.7%, with 69% of these cases going unreported. To enhance patient care and decrease medicolegal implications, we recommend ASSIST be performed on all thoracic and lumbar examinations, with variations documented.

We developed and tested an automated sub-minute 3D dual-echo MR imaging technique producing fat-water color-encoded labeled images of the entire spine. Twenty-one subjects were scanned with the 2-point Dixon technique utilizing 2 contiguous 21-22 second breath-hold sagittal acquisitions. Fourteen alternating subject scan sessions were achieved in 58 minutes. In all cases, fat-water separation was homogenous over the 70 cm FOV; in 2 lower stations fat/water assignments were reversed. Rapid automated fat-water decomposition spine screening is a promising technique.

MR imaging automated spine survey iterative scan technique (ASSIST) provides an automated subminute, submillimeter, in-plane resolution survey of the entire spine in 2 contiguous sagittal fast gradient-echo breath-hold series with computer labeling of vertebrae and disks. The technique was prospectively tested in 13 school-aged children for a wide range of clinical indications. In all cases, imaging was successful without requiring repeated sequencing. In all but 1 patient manifesting prominent scoliosis, automated labeling was concordant with neuroradiologist assignments.

There are two major forms of long-term depression (LTD) of synaptic transmission in the central nervous system that require activation of either N-methyl-D-aspartate receptors (NMDARs) or metabotropic glutamate receptors (mGluRs). In synapses in the perirhinal cortex, we have directly compared the Ca(2+) signaling mechanisms involved in NMDAR-LTD and mGluR-LTD. While both forms of LTD involve Ca(2+) release from intracellular stores, the Ca(2+) sensors involved are different; NMDAR-LTD involves calmodulin, while mGluR-LTD involves the neuronal Ca(2+) sensor (NCS) protein NCS-1. In addition, there is a specific requirement for IP3 and PKC, as well as protein interacting with C kinase (PICK-1) in mGluR-LTD. NCS-1 binds directly to PICK1 via its BAR domain in a Ca(2+)-dependent manner. Furthermore, the NCS-1-PICK1 association is stimulated by activation of mGluRs, but not NMDARs, and introduction of a PICK1 BAR domain fusion protein specifically blocks mGluR-LTD. Thus, NCS-1 plays a distinct role in mGluR-LTD.

P/Q-type (Ca(V)2.1) and N-type (Ca(V)2.2) Ca2+ channels are critical to stimulus-secretion coupling in the nervous system; feedback regulation of these channels by Ca2+ is therefore predicted to profoundly influence neurotransmission. Here we report divergent regulation of Ca2+-dependent inactivation (CDI) of native N- and P/Q-type Ca2+ channels by calmodulin (CaM) in adult chromaffin cells. Robust CDI of N-type channels was observed in response to prolonged step depolarizations, as well as repetitive stimulation with either brief step depolarizations or action potential-like voltage stimuli. Adenoviral expression of Ca2+-insensitive calmodulin mutants eliminated CDI of N-type channels. This is the first demonstration of CaM-dependent CDI of a native N-type channel. CDI of P/Q-type channels was by comparison modest and insensitive to expression of CaM mutants. Cloning of the C terminus of the Ca(V)2.1 alpha1 subunit from chromaffin cells revealed multiple splice variants lacking structural motifs required for CaM-dependent CDI. The physiological relevance of CDI on stimulus-coupled exocytosis was revealed by combining perforated-patch voltage-clamp recordings of pharmacologically isolated Ca2+ currents with membrane capacitance measurements of exocytosis. Increasing stimulus intensity to invoke CDI resulted in a significant decrease in the exocytotic efficiency of N-type channels compared with P/Q-type channels. Our results reveal unexpected diversity in CaM regulation of native Ca(V)2 channels and suggest that the ability of individual Ca2+ channel subtypes to undergo CDI may be tailored by alternative splicing to meet the specific requirements of a particular cellular function.

The calcium- and sodium-permeable transient receptor potential channel TRPC5 has an inhibitory role in neuronal outgrowth but the mechanisms governing its activity are poorly understood. Here we propose a mechanism involving the neuronal calcium sensor-1 (NCS-1) protein. Inhibitory mutants of TRPC5 and NCS-1 enhance neurite outgrowth similarly. Mutant NCS-1 does not inhibit surface-expression of TRPC5 but generally suppresses channel activity, irrespective of whether it is evoked by carbachol, store depletion, lanthanides or elevated intracellular calcium. NCS-1 and TRPC5 are in the same protein complex in rat brain and NCS-1 directly binds to the TRPC5 C-terminus. The data suggest protein-protein interaction between NCS-1 and TRPC5, and involvement of this protein complex in retardation of neurite outgrowth.

Freezing temperatures strongly influence vegetation in the hottest desert of North America, in part determining both its overall boundary and distributions of plant species within. To evaluate recent variability of freezing temperatures in this context, minimum temperature data from weather stations in the Sonoran Desert are examined. Data show widespread warming trends in winter and spring, decreased frequency of freezing temperatures, lengthening of the freeze-free season, and increased minimum temperatures per winter year. Local land use and multidecadal modes of the global climate system such as the Pacific decadal oscillation and the Atlantic multidecadal oscillation do not appear to be principal drivers of this warming. Minimum temperature variability in the Sonoran Desert does, however, correspond to global temperature variability attributed to human-dominated global warming. With warming expected to continue at faster rates throughout the 21st century, potential ecological responses may include contraction of the overall boundary of the Sonoran Desert in the south-east and expansion northward, eastward, and upward in elevation, as well as changes to distributions of plant species within and other characteristics of Sonoran Desert ecosystems. Potential trajectories of vegetation change in the Sonoran Desert region may be affected or made more difficult to predict by uncertain changes in warm season precipitation variability and fire. Opportunities now exist to investigate ecosystem response to regional climate disturbance, as well as to anticipate and plan for continued warming in the Sonoran Desert region.

Objective: Several studies suggest that cardiac troponin-I (cTn-I) is a more sensitive indicator of cardiac injury compared with other biochemical markers of injury, but the strategy with the highest diagnostic yield (true positive and true negative) for perioperative surveillance is unknown. The authors undertook a prospective evaluation of the perioperative incidence of myocardial infarction (MI) and evaluated surveillance strategies for the diagnosis of MI., Design: Prospective, cohort study., Setting: Two university hospitals., Participants: Four hundred sixty-seven high-risk patients requiring noncardiac surgery., Interventions: None., Measurements and Main Results: The diagnosis of myocardial injury was determined by cardiac protein markers combined with either postoperative changes on 12-lead electrocardiography or 1 of 3 clinical symptoms consistent with MI (chest pain, dyspnea, requirement for hemodynamic support). A receiver operating characteristic curve evaluating troponin in the diagnosis of MI revealed a value of 2.6 ng/mL as having the highest sensitivity and specificity. The sensitivity and specificity of cTn-I value > or =2.6 ng/mL, troponin > or =1.5 ng/mL, total creatine kinase (CK) > or =170 IU/L with MB > or =5%, and CK-MB > or =8 ng/mL were compared. Surveillance strategies were determined on a subset of patients (n = 257). The incidence of MI was 9.0% by cTn-I > or =2.6 ng/mL criteria, 19% by cTn-I > or =1.5 ng/mL, 13% by CK-MB mass, and 2.8% by CK-MB%. The specificity of cTn-I > or =2.6 ng/mL as an indicator of MI was 98%, and its positive predictive value (PPV) was 85%. Cardiac troponin-I > or =2.6 ng/mL had equal specificity but greater PPV than the cTn-I > or =1.5 ng/mL (specificity 98% and PPV 79%). If surveillance of cTn-I > or =2.6 ng/mL was used to detect MI, then the strategy with the highest diagnostic yield was surveillance on postoperative days 1, 2, and 3., Conclusions: Perioperative cardiac injury continues to occur frequently after noncardiac surgery, as detected by cTn-I. Serial monitoring of cardiac troponin-I on postoperative days 1, 2, and 3 provides the strategy with the highest diagnostic yield for surveillance of MI.

We report the protein isolation, cloning and characterization of members of an unusual protein family, which comprise the most abundant proteins present in the squid eye. The proteins in this family have a range of molecular weights from 32 to 36 kDa. Electron microscopy and detergent solubilization demonstrate that these proteins are tightly associated with membrane structures where they may form tetramers. Despite this, these proteins have no stretches of hydrophobic residues that could form typical transmembrane domains. They share an unusual protein sequence rich in methionine, and contain multiple repeating motifs. We have therefore named these proteins Methionine-Rich Repeat Proteins (MRRPs). The use of structure prediction algorithms suggest very little recognized secondary structure elements. At the time of cloning no sequence or structural homologues have been found in any database. We have isolated three closely related cDNA clones from the MRRP family. Coupled in vitro transcription/translation of the MRRP clones shows that they encode proteins with molecular masses similar to components of native MRRPs. Immunoblot analysis of these proteins reveals that they are also present in squid brain, optic lobe, and heart, and also indicate that MRRP-like protein motifs may also exist in mammalian tissues. We propose that MRRPs define a family of important proteins that have an unusual mode of attachment or insertion into cell membranes and are found in evolutionarily diverse organisms.

Objective: The purpose of this study was to determine whether patients with first-trimester threatened abortion are at increased risk for poor pregnancy outcome., Study Design: A large prospective multicenter database was studied. Subjects were divided into three groups: (1) no bleeding, (2) light bleeding, and (3) heavy bleeding. Univariate and multivariable logistic regression analyses were used., Results: The study comprised 16,506 patients: 14,160 patients without bleeding, 2094 patients with light bleeding, and 252 patients with heavy bleeding. Patients with vaginal bleeding, light or heavy, were more likely to experience a spontaneous loss before 24 weeks of gestation (odds ratio, 2.5 and 4.2, respectively) and cesarean delivery (odds ratio, 1.1 and 1.4, respectively). Light bleeding subjects were more likely to have preeclampsia (odds ratio, 1.5), preterm delivery (odds ratio, 1.3), and placental abruption (odds ratio, 1.6). Heavy vaginal bleeding subjects were more likely to have intrauterine growth restriction (odds ratio, 2.6), preterm delivery (odds ratio, 3.0), preterm premature rupture of membranes (odds ratio, 3.2), and placental abruption (odds ratio, 3.6)., Conclusion: First-trimester vaginal bleeding is an independent risk factor for adverse obstetric outcome that is directly proportional to the amount of bleeding.

Multicystic encephalomalacia occurs in approximately 20% of surviving cotwins after second- and third-trimester intrauterine fetal death of one twin in monochorionic pregnancies. We report a case of multicystic encephalomalacia after the demise of a cotwin in the first trimester diagnosed by magnetic resonance imaging and confirmed pathologically.

Background and Purpose: Head CT prescriptions are currently plagued by intra- and intersubject image variance and do not match standardized MR imaging planes. We developed and tested a simple method to improve CT precision and approximate the Talairach reference standard advocated for MR imaging., Methods: We retrospectively reviewed midline sagittal T2-weighted brain MR images of 126 consecutive patients to determine the mean angle subtended by the Talairach anterior commissure-posterior commissure (AC-PC) line and the hard palate. On the basis of this data set, a new head CT protocol was instituted with pitch similarly prescribed relative to the hard palate as identified on the lateral CT scout film. We then compared the precision of the new protocol, our former method (nominally parallel to the orbito-meatal line) and fixed-gantry angulation. Two head CT studies from 50 consecutive patients imaged with our old protocol and 50 consecutive patients imaged with our new protocol were reviewed for a total of 200 CT examinations., Results: The Talairach AC-PC line was rotated 12.0 degrees +/- 6.1 degrees from the hard palate line and 15.6 degrees +/- 10.1 degrees from the axial plane of the magnet. The new CT protocol approximated the Talairach-referenced MR images obtained at our institution and improved intrapatient CT scan precision compared with fixed-gantry selection (P <.004) and compared with our previous prescription technique (P <.064; P <.025, controlling for excessive head extension)., Conclusion: By prescribing CT images angled +12 degrees from the hard palate, a structure readily identified by technologists, interscan precision can be improved and Talairach-referenced MR imaging studies can be approximated. Along with AC-PC-referenced MR imaging studies, we advocate this CT protocol as a new clinical standard.

Previously, human genetics-based approaches allowed us to show that mutations in the IL-1 receptor accessory protein-like gene (IL1RAPL) are responsible for a non-specific form of X-linked mental retardation. This gene encodes a predicted protein of 696 amino acids that belongs to a novel class of the IL-1/Toll receptor family. In addition to the extracellular portion consisting of three Ig-like domains and the intracellular TIR domain characteristic of the IL-1/Toll receptor family, IL1RAPL contains a specific 150 amino acid carboxy terminus that has no significant homology with any protein of known function. In order to begin to elucidate the function of this IL-1/Toll receptor-like protein, we have assessed the effect of recombinant IL1RAPL on the binding affinity of type I IL-1R for its ligands IL-1alpha and beta and searched for proteins interacting with the specific carboxy terminus domain of IL1RAPL. Our results show that IL1RAPL is not a protein receptor for IL-1. In addition we present here the identification of Neuronal Calcium Sensor-1 (NCS-1) as an IL1RAPL interactor. Remarkably, although NCS-1 and its non-mammalian homologue, frequenin, are members of a highly conserved EF-hand Ca(2+) binding protein family, our data show that IL1RAPL interacts only with NCS-1 through its specific C-terminal domain. The functional relevance of IL1RAPL activity was further supported by the inhibitory effect on exocytosis in PC12 cells overexpressing IL1RAPL. Taken together, our data suggest that IL1RAPL may regulate calcium-dependent exocytosis and provide insight into the understanding of physiopathological mechanisms underlying cognitive impairment resulting from IL1RAPL dysfunction.

Background and Purpose: Variability in patient head positioning may yield substantial interstudy image variance in the clinical setting. We describe and test three-step technologist and computer-automated algorithms designed to image the brain in a standard reference system and reduce variance., Methods: Triple oblique axial images obtained parallel to the Talairach anterior commissure (AC)-posterior commissure (PC) plane were reviewed in a prospective analysis of 126 consecutive patients. Requisite roll, yaw, and pitch correction, as three authors determined independently and subsequently by consensus, were compared with the technologists' actual graphical prescriptions and those generated by a novel computer automated three-step (CATS) program. Automated pitch determinations generated with Statistical Parametric Mapping '99 (SPM'99) were also compared., Results: Requisite pitch correction (15.2 degrees +/- 10.2 degrees ) far exceeded that for roll (-0.6 degrees +/- 3.7 degrees ) and yaw (-0.9 degrees +/- 4.7 degrees ) in terms of magnitude and variance (P <.001). Technologist and computer-generated prescriptions substantially reduced interpatient image variance with regard to roll (3.4 degrees and 3.9 degrees vs 13.5 degrees ), yaw (0.6 degrees and 2.5 degrees vs 22.3 degrees ), and pitch (28.6 degrees, 18.5 degrees with CATS, and 59.3 degrees with SPM'99 vs 104 degrees ). CATS performed worse than the technologists in yaw prescription, and it was equivalent in roll and pitch prescriptions. Talairach prescriptions better approximated standard CT canthomeatal angulations (9 degrees vs 24 degrees ) and provided more efficient brain coverage than that of routine axial imaging., Conclusion: Brain MR prescriptions corrected for direct roll, yaw, and Talairach AC-PC pitch can be readily achieved by trained technologists or automated computer algorithms. This ability will substantially reduce interpatient variance, allow better approximation of standard CT angulation, and yield more efficient brain coverage than that of routine clinical axial imaging.

Young, urban, African American men are at particularly high risk of hypertension and its cardiovascular complications. Left ventricular hypertrophy and renal dysfunction are manifestations of target organ damage from hypertension that predict adverse cardiovascular events. The subjects of this study were 309 African American men, age 18-54 years, with hypertension, residing in inner-city Baltimore. Echocardiograms, electrocardiograms, serum creatinine, and the urinary albumin-creatinine ratio were obtained to evaluate hypertensive target organ damage. Fifty-three percent of the men reported use of antihypertensive medications, of whom 80% were on monotherapy. Calcium channel blockers were used most frequently. The mean echocardiographic left ventricular mass was 211+/-68 g, with a prevalence of echocardiographic left ventricular hypertrophy of 30%. There were 14 men (5%) with extremely high left ventricular mass, >350 grams. Left ventricular systolic dysfunction was seen in 9% of the men with uncontrolled hypertension, and none of the men with controlled hypertension (p=0.02). Renal dysfunction was found in 12% of the subjects, and microalbuminuria or gross proteinuria in 34%. The authors conclude that there is a high prevalence of cardiac and renal abnormalities in inner-city African American men with hypertension, especially in men on antihypertensive therapy with uncontrolled hypertension. It is imperative that cost-effective medications and culturally acceptable health care delivery programs be developed, tested, and integrated into health systems, with strategies specifically relevant to this high-risk population, to decrease the largely preventable morbidity and mortality associated with hypertension., (Copyright 2003 Le Jacq Communications, Inc.)

Voltage-gated Ca(2+) channels are crucial for neurotransmitter release and other neuronal functions, and their activity-dependent regulation could underlie various aspects of synaptic plasticity. Recent studies have identified Ca(2+)-sensing proteins involved in Ca(2+)-channel modulation. These have complex effects on channel gating, and data suggest that the actions of multiple Ca(2+) sensors are important for the fine-tuning of Ca(2+) channel activity.

The neuronal calcium sensors are a family of EF-hand-containing Ca(2+)-binding proteins expressed predominantly in retinal photoreceptors and neurons. One of the family members is neurocalcin delta, the function of which is unknown. As an approach to elucidating the protein interactions made by neurocalcin delta, we have identified brain cytosolic proteins that bind to neurocalcin delta in a Ca(2+)-dependent manner. We used immobilized recombinant myristoylated neurocalcin delta combined with protein identification using MS. We demonstrate a specific interaction with clathrin heavy chain, alpha- and beta-tubulin, and actin. These interactions were dependent upon myristoylation of neurocalcin delta indicating that the N-terminal myristoyl group may be important for protein-protein interactions in addition to membrane association. Direct binding of neurocalcin delta to clathrin, tubulin and actin was confirmed using an overlay assay. These interactions were also demonstrated for endogenous neurocalcin delta by co-immunoprecipitation from rat brain cytosol. When expressed in HeLa cells, neurocalcin delta was cytosolic at resting Ca(2+) levels but translocated to membranes, including a perinuclear compartment (trans-Golgi network) where it co-localized with clathrin, following Ca(2+) elevation. These data suggest the possibility that neurocalcin delta functions in the control of clathrin-coated vesicle traffic.

The localizations of three members of the neuronal calcium sensor (NCS) family were studied in HeLa cells. Using hippocalcin-EYFP and NCS-1-ECFP, it was found that their localization differed dramatically in resting cells. NCS-1 had a distinct predominantly perinuclear localization (similar to trans-Golgi markers), whereas hippocalcin was present diffusely throughout the cell. Upon the elevation of intracellular Ca(2+), hippocalcin rapidly translocated to the same perinuclear compartment as NCS-1. Another member of the family, neurocalcin delta, also translocated to this region after a rise in Ca(2+) concentration. Permeabilization of transfected cells using digitonin caused loss of hippocalcin and neurocalcin delta in the absence of calcium, but in the presence of 10 microm Ca(2+), both proteins translocated to and were retained in the perinuclear region. NCS-1 localization was unchanged in permeabilized cells regardless of calcium concentration. The localization of NCS-1 was unaffected by mutations in all functional EF hands, indicating that its localization was independent of Ca(2+). A minimal myristoylation motif (hippocalcin-(1-14)) fused to EGFP resulted in similar perinuclear targeting, showing that localization of these proteins is because of the exposure of the myristoyl group. This was confirmed by mutation of the myristoyl motif of NCS-1 and hippocalcin that resulted in both proteins remaining cytosolic, even at elevated Ca(2+) concentration. Dual imaging of hippocalcin-EYFP and cytosolic Ca(2+) concentration in Fura Red-loaded cells demonstrated the kinetics of the Ca(2+)/myristoyl switch in living cells and showed that hippocalcin rapidly translocated with a half-time of approximately 12 s after a short lag period when Ca(2+) was elevated. These results demonstrate that closely related Ca(2+) sensor proteins use their myristoyl groups in distinct ways in vivo in a manner that will determine the time course of Ca(2+) signal transduction.

In common with many neurons, adrenal chromaffin cells possess distinct voltage-dependent and voltage-independent pathways for Ca(2+) channel regulation. In this study, the voltage-independent pathway was revealed by addition of naloxone and suramin to remove tonic blockade of Ca(2+) currents via opioid and purinergic receptors due to autocrine feedback inhibition. This pathway requires the Ca(2+)-binding protein neuronal calcium sensor-1 (NCS-1). The voltage-dependent pathway was pertussis toxin-sensitive, whereas the voltage-independent pathway was largely pertussis toxin-insensitive. Characterization of the voltage-independent inhibition of Ca(2+) currents revealed that it did not involve protein kinase C-dependent signaling pathways but did require the activity of a Src family tyrosine kinase. Two structurally distinct Src kinase inhibitors, 4-amino-5-(4-methylphenyl)7-(t-butyl)pyrazolo[3,4-d] pyrimidine (PP1) and a Src inhibitory peptide, increased the Ca(2+) currents, and no further increase in Ca(2+) currents was elicited by addition of naloxone and suramin. In addition, the Src-like kinase appeared to act in the same pathway as NCS-1. In contrast, addition of PP1 did not prevent a voltage-dependent facilitation elicited by a strong pre-pulse depolarization indicating that this pathway was independent of Src kinase activity. PPI no longer increased Ca(2+) currents after addition of the P/Q-type channel blocker omega-agatoxin TK. The alpha(1A) subunit of P/Q-type Ca(2+) channels was immunoprecipitated from chromaffin cell extracts and found to be phosphorylated in a PP1-sensitive manner by endogenous kinases in the immunoprecipitate. A high molecular mass (around 220 kDa) form of the alpha(1A) subunit was detected by anti-phosphotyrosine, suggesting a possible target for Src family kinase action. These data demonstrate a voltage-independent mechanism for autocrine inhibition of P/Q-type Ca(2+) channel currents in chromaffin cells that requires Src family kinase activity and suggests that this may be a widely distributed pathway for Ca(2+) channel regulation.

Background: Although there have been recent advances in echocardiography, many studies remain suboptimal due to poor image quality and unclear blood-myocardium border. We developed a novel image processing technique, cardiac variability imaging (CVI), based on the variance of pixel intensity values during passage of ultrasound microbubble contrast into the left ventricle chamber, with the aim of enhancing endocardial border delineation and image quality., Methods and Results: CVI analysis was performed on simulated data to test and verify the mechanism of image enhancement. Then CVI analysis was applied to echocardiographic images obtained in two different clinical studies, and still images were interpreted by expert reviewers. In the first study (N = 15), using contrast agent EchoGen, the number of observable wall segments in end-diastolic images, for example, was significantly increased by CVI (4.93) as compared to precontrast (3.28) and contrast images (3.36), P < 0.001 for both comparisons to CVI. In the second study (N = 8), using contrast agent Optison, interobserver variability of manually traced end-diastolic volumes was significantly decreased using CVI (22.3 ml) as compared to precontrast (63.4) and contrast images (49.0), P < 0.01 for both comparisons to CVI., Conclusion: CVI can substantially enhance endocardial border delineation and improve echocardiographic image quality and image interpretation.

Most noninvasive measures of diastolic function are made during left ventricular (LV) filling and are therefore subject to "pseudonormalization," because variation in left atrial (LA) pressure may confound the estimation of relaxation rate. Counterclockwise twist of the LV develops during ejection, but untwisting occurs rapidly during isovolumic relaxation, before mitral opening. We hypothesized that the rate of untwisting might reflect the process of relaxation independent of LA pressure. Recoil rate (RR), the velocity of LV untwisting, was measured by tagged magnetic resonance imaging and regressed against the relaxation time constant (tau), recorded by catheterization, in 10 dogs at baseline and after dobutamine, saline, esmolol, and methoxamine treatment. RR correlated closely (average r = -0.86) with tau and was unaffected by elevated LA pressure. Multiple regression showed that tau, but not LA or aortic pressure, was an independent predictor of RR (P < 0.0001, P = 0.99, and P = 0.18, respectively). The rate of recoil of torsion, determined wholly noninvasively, provides an isovolumic phase, preload-independent assessment of LV relaxation. Use of this novel parameter should allow the detailed study of diastolic function in states known to affect filling rates, such as aging, hypertension, and congestive heart failure.

Background: Oxygen (O(2)) homeostasis is central to myocardial tissue functioning, and increased O(2) demand is thought to be satisfied by a vasodilatory mechanism that results in increased blood and O(2) delivery. We applied blood oxygenation level-dependent (BOLD) MRI in conjunction with vasodilatory stress to index the ability to augment intramyocardial oxygenation in hypertensive hypertrophy, the primary cause of heart failure., Methods and Results: Nine healthy controls and 10 hypertensive subjects with moderate-to-severe hypertrophy underwent imaging on a 1.5 T clinical scanner. The dipyridamole-induced change in the apparent transverse relaxation rate, R2*, which correlates with hemoglobin oxygenation, was -5.4+/-2.2 s(-1) (95% CI, -4.0 to -6.8 s(-1)) in controls compared with -1.7+/-1.4 s(-1) (95% CI, -0.8 to -2.6 s(-1)) in hypertensive patients (P=0.0003)., Conclusions: Patients with hypertensive hypertrophy demonstrate an impaired ability to increase intramyocardial oxygenation during vasodilatory stress, as indexed by BOLD MRI. The capacity to image vascular function with BOLD MRI may advance the understanding of the development of ventricular dysfunction in hypertension.