210Pb-dating of a lake sediment core from Lough Carra (Co. Mayo, western Ireland): use of paleolimnological data for chronology validation below the 210Pb dating horizon.

The chronologies and sediment accumulation rates for a lake sediment sequence from Lough Carra (Co. Mayo, western Ireland) were established by applying the constant initial concentration (CIC) and constant rate of supply (CRS) hypotheses to the measured (210)Pb(excess) profile. The resulting chronologies were validated using the artificial fallout radionuclides (137)Cs and (241)Am, which provide independent chronostratigraphic markers for the second half of the 20th century. The validity of extrapolating the derived CIC and CRS dates below the (210)Pb dating horizon using average sedimentation rates was investigated using supplementary paleolimnological information and historical data. Our data confirm that such an extrapolation is well justified at sites characterised by relatively stable sedimentation conditions.

Taking digital imaging to the next level: challenges and opportunities.

New medical imaging technology, such as multi-detector computed tomography (CT) scanners and positron emission tomography (PET) scanners, are creating new possibilities for non-invasive diagnosis that are leading providers to invest heavily in these new technologies. The volume of data produced by such technology is so large that it cannot be "read" using traditional film-based methods, and once in digital form, it creates a massive data integration and archiving challenge. Despite the benefits of digital imaging and archiving, there are several key challenges that healthcare organizations should consider in planning, selecting, and implementing the information technology (IT) infrastructure to support digital imaging. Decisions about storage and image distribution are essentially questions of "where" and "how fast." When planning the digital archiving infrastructure, organizations should think about where they want to store and distribute their images. This is similar to decisions that organizations have to make in regard to physical film storage and distribution, except the portability of images is even greater in a digital environment. The principle of "network effects" seems like a simple concept, yet the effect is not always considered when implementing a technology plan. To fully realize the benefits of digital imaging, the radiology department must integrate the archiving solutions throughout the department and, ultimately, with applications across other departments and enterprises. Medical institutions can derive a number of benefits from implementing digital imaging and archiving solutions like PACS. Hospitals and imaging centers can use the transition from film-based imaging as a foundational opportunity to reduce costs, increase competitive advantage, attract talent, and improve service to patients. The key factors in achieving these goals include attention to the means of data storage, distribution and protection.

Repetitive 4-week periods of atrial electrical remodeling promote stability of atrial fibrillation: time course of a second factor involved in the self-perpetuation of atrial fibrillation.

BACKGROUND: Episodes of atrial fibrillation (AF) are known to cause both a rapid reduction in atrial refractoriness (atrial electrical remodeling) and a more delayed increase in AF stability thought to be due to a so-called "second factor." The aim of this study was to quantify the effects and time course of such a factor on AF stability in the chronic goat model. METHODS AND RESULTS: AF was maintained in 6 goats by burst atrial pacing for 3 consecutive 4-week periods separated a mean of 6+/-2.1 days of sinus rhythm. Six days of sinus rhythm was just sufficient for refractoriness changes to reverse fully in all goats. Atrial effective refractory period, AF inducibility, and duration of individual episodes of AF were assessed at regular intervals. There was a progressive reduction from month 1 to 2 to 3 in the mean duration of burst pacing required to induce individual episodes of AF of 60 seconds (178+/-251, 110+/-102, and 21+/-30 hours), 1 hour (229+/-224, 136+/-104, and 68+/-51 hours), and 24 hours (277+/-218, 192+/-190, and 102+/-75 hours; P<0.03). The frequency with which AF was induced during extrastimulus pacing increased progressively from 16.7% in month 1 to 31.7% in month 2 and 46.9% in month 3 (P<0.001). CONCLUSIONS: Sequential 4-week periods of atrial fibrillation result in a progressive increase in AF stability independent of baseline atrial refractory period. This finding suggests the presence of a second factor in the self-perpetuation of AF with a time course comparable to that of AF-induced ultrastructural changes in the atria.

Effect of amiodarone on dispersion of atrial refractoriness and cycle length in patients with atrial fibrillation.

INTRODUCTION: Amiodarone is effective in preventing the recurrence of atrial fibrillation (AF) after cardioversion (CV). Dispersion of atrial refractoriness may be relevant to the generation of AF. We designed a study to determine the electrophysiologic effects of amiodarone in patients with previous early recurrence of AF after CV. METHODS AND RESULTS: Fifteen patients with previous AF recurrence (without antiarrhythmic drugs) after CV (CV1) were selected for amiodarone therapy and repeat CV (CVamio). Prior to CV1, mean AF cycle length (AFCL) had been recorded at four atrial sites (right atrial appendage [RAA], distal coronary sinus [DCS], right atrial lateral wall [LAT], and interatrial septum [IAS]) and dispersion of AFCL had been calculated. These patients were treated with amiodarone and, prior to CVamio, AFCL was recorded at the four atrial sites as for CV1. Between CV1 and CVamio, AFCL increased at all atrial sites: 153 +/- 13 msec to 179 +/- 14 msec at RAA, 144 +/- 12 msec to 174 +/- 18 msec at DCS, 158 +/- 13 msec to 182 +/- 16 msec at LAT, and 161 +/- 18 msec to 181 +/- 17 msec at IAS. Dispersion of AFCL decreased from 24 +/- 10 msec at CV1 to 15 +/- 11 msec at CVamio (P = 0.01). The median time in sinus rhythm increased from 3.12 hours post CV1 to 28 days post CVamio, (P < 0.02). CONCLUSION: Amiodarone causes a reduction in the dispersion of AFCL. This action may be relevant to the beneficial effects of amiodarone in patients with AF.

Clinical evaluation of a policy of early repeated internal cardioversion for recurrence of atrial fibrillation.

INTRODUCTION: The clinical value of cardioversion (CV) of persistent atrial fibrillation (AF) is limited by the high rate of early AF recurrence, which may be related to the persistence of atrial electrical remodeling. We examined the hypothesis that the likelihood of maintaining sinus rhythm after CV of persistent AF is significantly enhanced by a policy of early repeated CV. METHODS AND RESULTS: Fifty-nine patients with persistent AF underwent internal CV (CV 1). Those patients cardioverted were monitored with daily transtelephonic ECG. In the event of AF recurrence, these patients were admitted rapidly for repeat CV (CV 2) and, if further recurrence occurred, a third CV (CV 3) was performed. Daily ECG monitoring was continued until 1 month of sinus rhythm was maintained or a total of three CVs were performed. Of the 59 patients undergoing CV 1, 43 were discharged in sinus rhythm and 29 subsequently had AF recurrence during monitoring. Twenty-three of these underwent CV 2 and 11 of these underwent CV 3. Of those having repeated CVs, only 4 patients maintained sinus rhythm for 1 month (3 after CV 2 and 1 after CV 3). The remaining patients had repeated AF recurrence during the monitoring period. Mean time from AF recurrence to CV 2 was 20+/-13 hours and from AF recurrence to CV 3 was 13+/-7.2 hours. Atrial effective refractory periods increased from 189+/-16 msec at CV 1 to 215+/-18 msec at CV 3 (P < 0.05), indicating reversal of atrial electrical remodeling during this period. CONCLUSION: A policy of early repeated CVs for AF recurrence has very limited clinical value despite evidence of reversal of atrial electrical remodeling. The time between AF recurrence and repeat CV may need to be reduced further if such a policy is to succeed.

Role of dispersion of atrial refractoriness in the recurrence of clinical atrial fibrillation; a manifestation of atrial electrical remodelling in humans?

AIMS: The mechanism of atrial fibrillation recurrence following cardioversion is unknown, although experimental studies have indicated that changes in dispersion of atrial refractoriness may play a role. The aims of this study were to assess (1) if dispersion of atrial refractoriness is relevant to atrial fibrillation recurrence and (2) if dispersion of refractoriness is part of the atrial electrical remodelling process in humans. METHODS AND RESULTS: Thirty-seven consecutive patients underwent internal cardioversion (CV1) of persistent atrial fibrillation. Patients were monitored by daily transtelephonic recordings following discharge and if there was spontaneous atrial fibrillation recurrence they were rapidly admitted for repeat cardioversion (CV2). We used the 5th percentile of 100 consecutive atrial fibrillation cycle lengths (AFCL(P5)) and the atrial effective refractory period (AERP) as measures of atrial refractoriness at four different atrial sites. Dispersion of AFCL(P5)at CV1 was significantly higher in those who had subsequent recurrence of atrial fibrillation than in those who remained in sinus rhythm for at least 1 month after cardioversion (35+/-17 ms vs 9+/-13 ms;P<0.02). Dispersion of AFCL(P5)measured at CV2 was significantly lower than that measured in the same patients at CV1 (19+/-8 ms vs 35+/-11 ms;P=0.02). i.e. dispersion of AFCL(P5)had reduced following a period of sinus rhythm. In contrast, there was no difference in dispersion of AERP between the recurrers and non-recurrers. Dispersion of AERP between CV1 and CV2 did not change following a period of sinus rhythm. CONCLUSION: Dispersion of AFCL is relevant to atrial fibrillation recurrence and may represent a manifestation of atrial electrical remodelling in humans. Treatment directed at AFCL dispersion may be useful in the suppression of atrial fibrillation recurrence following cardioversion.

Efficient activation of viral genomes by levels of herpes simplex virus ICP0 insufficient to affect cellular gene expression or cell survival.

Herpes simplex virus (HSV) ICP0 can effectively activate gene expression from otherwise silent promoters contained on persisting viral genomes. However, the expression of high levels of ICP0, as from ICP4(-) HSV type 1 (HSV-1) vectors, results in marked toxicity. We have analyzed the results of ICP0 expressed from an E1(-) E4(-) adenovirus vector (AdS.11E4ICP0) in which ICP0 expression is controlled from the endogenous adenoviral E4 promoter. In this system, the expression level of ICP0 was reduced more than 1,000-fold relative to the level of expression from HSV-1 vectors. This low level of ICP0 did not affect cellular division or greatly perturb cellular metabolism as assessed by gene expression array analysis comparing the effects of HSV and adenovirus vector strains. However, this amount of ICP0 was sufficient to quantitatively destroy ND10 structures as measured by promyelocytic leukemia immunofluorescence. The levels of adenovirus-expressed ICP0 were sufficient to activate quiescent viral genomes in trans and promote persistent transgene expression in cis. Moreover, infection of complementing cells with AdS.11E4ICP0 promoted viral growth and resulted in a 20-fold increase in the plaquing efficiency of d109, a virus defective for all five immediate-early genes. Thus, the low level expression of ICP0 from the E1(-) E4(-) adenovirus vector may increase the utility of adenovirus vectors and also provides a means to efficiently quantify and possibly propagate HSV vectors defective in ICP0. Importantly, the results demonstrate that the activation function of ICP0 may not result from changes in cellular gene expression, but possibly as a direct consequence of an enzymatic function inherent to the protein that may involve its action at ND10 resulting in the preferential activation of viral genomes.

Evaluation and management of shoulder instability in the elite overhead thrower.

The elite throwing athlete places significant forces on the soft-tissue stabilizers of the shoulder with every pitch. Anterior translation forces can be as high as 40% of body weight and distraction forces as high as 80% body weight during the act of throwing. Injury to the static and dynamic stabilizers can lead to significant pain and loss of function in these athletes. To successfully treat the injured thrower, it is important to accurately diagnose the pathologic process. This article reviews the biomechanics of throwing and pathologic processes seen in the elite thrower. We cover the essentials of the history and physical in this population and conclude with a discussion of the various treatment regimens.

Minocycline inhibits caspase-1 and caspase-3 expression and delays mortality in a transgenic mouse model of Huntington disease.

Huntington disease is an autosomal dominant neurodegenerative disease with no effective treatment. Minocycline is a tetracycline derivative with proven safety. After ischemia, minocycline inhibits caspase-1 and inducible nitric oxide synthetase upregulation, and reduces infarction. As caspase-1 and nitric oxide seem to play a role in Huntington disease, we evaluated the therapeutic efficacy of minocycline in the R6/2 mouse model of Huntington disease. We report that minocycline delays disease progression, inhibits caspase-1 and caspase-3 mRNA upregulation, and decreases inducible nitric oxide synthetase activity. In addition, effective pharmacotherapy in R6/2 mice requires caspase-1 and caspase-3 inhibition. This is the first demonstration of caspase-1 and caspase-3 transcriptional regulation in a Huntington disease model.

Prevalence and significance of focal sources of atrial arrhythmia in patients undergoing cardioversion of persistent atrial fibrillation.

INTRODUCTION: Recent reports have high-lighted the importance of focal atrial arrhythmias as a curable cause for a group of patients with frequently recurrent paroxysmal atrial fibrillation (AF). The importance of this arrhythmia mechanism in the general population of patients with persistent AF is unknown. METHODS AND RESULTS: After successful internal cardioversion of 50 consecutive patients with persistent AF (mean age 60 years, mean duration of AF 26 months), endocardial activity in the immediate postcardioversion period was analyzed for the presence of focal atrial activity. Postcardioversion atrial arrhythmias were considered to be focal if there was evidence of a localized source of repetitive early atrial activation, either in the form of (1) self-terminating monomorphic atrial tachycardia (at least five beats) or (2) recurrences of AF with an initial atrial activation sequence (first five beats) that was both monomorphic and reproducible with repeated recurrences. Evidence for a focal atrial arrhythmia was present in 20 of the total group of 50 patients (40%). Multivariate analysis of clinical characteristics revealed the diagnosis of lone AF as the only independent predictor of a focal source of AF (P = 0.028). Thirty-nine patients were discharged from hospital in sinus rhythm. At 1-month follow-up, 25 (64%) of these 39 patients had suffered AF recurrence. The only significant predictor of AF recurrence was evidence of a focal source of atrial arrhythmia immediately after cardioversion, with a relative risk of 1.73 (range 1.1 to 2.7; P = 0.015). CONCLUSION: Focal atrial arrhythmias are common in patients presenting with "idiopathic" persistent AF, suggesting a possible causative role in the generation of this common arrhythmia.

Reversal of atrial electrical remodeling after cardioversion of persistent atrial fibrillation in humans.

BACKGROUND: Although atrial electrical remodeling has been studied extensively in animal models, the reversibility of this phenomenon after termination of clinical atrial fibrillation (AF) has not been demonstrated. We aimed to examine this important question of reversibility by using AF cycle length (AFCL) and coupling intervals of atrial premature beats after cardioversion as measures of atrial refractoriness. METHODS AND RESULTS: We measured AFCL at the right atrial appendage and distal coronary sinus before attempting internal cardioversion in 39 patients with persistent AF. Patients were monitored by daily transtelephonic recordings after discharge and admitted rapidly for repeat internal cardioversion if there was spontaneous AF recurrence. Measurements of AFCL were repeated immediately before repeat cardioversions in the 17 patients who had recurrence of AF. There was an increase in AFCL from the initial cardioversion to that measured at the time of first AF recurrence at both the right atrial appendage (161+/-22 vs 167+/-26 ms, P=0.05) and distal coronary sinus (162+/-20 vs 168+/-22 ms, P=0.01) sites. The magnitude of increase in AFCL was positively correlated with duration of sinus rhythm before AF recurrence (r=0.524, P=0.001). Other measures of refractoriness (shortest coupling interval of atrial premature beats and directly measured refractory periods after cardioversion) also increased from initial to subsequent cardioversions. CONCLUSIONS: These findings demonstrate that changes in atrial electrophysiology associated with chronic AF in humans are reversible after cardioversion and that the extent of this reversal is dependent on the duration of sinus rhythm after cardioversion.

Alpha-synuclein immunoreactivity is present in axonal swellings in neuroaxonal dystrophy and acute traumatic brain injury.

The primary neuroaxonal dystrophies (NAD), which include infantile NAD and Hallervorden-Spatz syndrome (HSS), are characterized by dystrophic terminal axons and axonal swellings. Lewy bodies have been found in some cases. In Parkinson disease (PD) and dementia with Lewy bodies (DLB), Lewy bodies and neurites display prominent alpha-synuclein immunoreactivity. We examined 2 cases of HSS and 4 cases of infantile NAD with alpha-synuclein immunohistochemistry to test the hypothesis that these disorders with similar morphological findings might share a biochemical phenotype. Furthermore, we compared them to 8 cases of secondary or physiologic NAD of various causes and 2 cases of recent traumatic head injury. Alpha-synuclein positive neuronal cytoplasmic inclusions, including Lewy bodies, and neurites were numerous in 1 HSS and 1 infantile NAD case. In addition, axonal spheroids were immunostained in all 6 cases of primary NAD, 5 cases of secondary NAD, and 2 cases of recent head injury. Axonal spheroids were faintly stained in the 3 physiologic NAD cases. Alpha-synuclein positive axonal swellings may suggest a mechanism, such as axonal injury, leading to the neuronal cytoplasmic accumulation of alpha-synuclein in NAD and other disorders.

Perturbation of cell cycle progression and cellular gene expression as a function of herpes simplex virus ICP0.

Herpes simplex virus type 1 is capable of inhibiting host cell DNA synthesis following lytic infection. However, the mechanism and nature of potential effects on cell cycle progression have not been described. In this report, we characterize the dysregulation of the cell cycle following infection with the replication-incompetent virus d106, where immediate-early gene expression is restricted to infected-cell polypeptide 0 (ICP0) and the expression of all other viral genes is dramatically reduced or is not observed. Infection with d106 resulted in the accumulation of cells in both the G(1)/S and G(2)/M compartments, consistent with cell cycle arrest at both checkpoints. The isogenic variant d109, which does not express any viral proteins, failed to induce this phenotype, suggesting that the expression of ICP0 is crucial for cell cycle arrest. Analysis of global cellular gene expression patterns following infection with d106 and d109 revealed that a relatively small subset of cellular genes were induced as a consequence of ICP0 expression. A number of these genes induced in the presence of ICP0 are classically considered p53-responsive genes, including p21, gadd45, and mdm-2. However, infection with d106 of cells with both alleles of p53 deleted resulted in the same cell cycle arrest phenotype and similar cellular gene expression patterns, suggesting that the expression of ICP0 results in cell cycle arrest potentially via p53-dependent and p53-independent mechanisms. In addition, it was found that the effects of infection with d106 on viral and cellular gene expression were similar to the effects observed following treatment of cells with the histone deacetylase inhibitor trichostatin A.

The role of atrial electrical remodeling in the progression of focal atrial ectopy to persistent atrial fibrillation.

Although atrial fibrillation- (AF) induced changes in atrial refractoriness (atrial electrical remodeling) have been demonstrated in a number of different animal models, the clinical significance of this process is unknown. We describe a patient in whom there has been documented progression of atrial ectopy to persistent AF accompanied by evidence of atrial electrical remodeling, with reversal of remodeling following successful ablation of the focal source of AF. A second patient with focal AF, but with a "nonfocal" appearance on the ECG, is also described. These cases illustrate: (1) the possibility that a significant proportion of younger patients with idiopathic persistent AF may well have a focal source as the underlying abnormality; and (2) atrial electrical remodeling reverses following ablation of the underlying source.

Influence of aluminum on the regulation of PTH- and 1,25(OH)2D3-dependent pathways in the rat osteosarcoma cell line ROS 17/2.8.

The role of hormonal status in the development of aluminum (Al)-dependent renal osteodystrophy, which is characterized by reduced bone matrix deposition, still remains largely unknown. To address this question, we used the osteoblast-like osteosarcoma cell line ROS 17/2.8 to evaluate the role of Al on parathyroid hormone (PTH)- and 1,25-dihydroxyvitamin D3 (1,25(OH)2D3)-dependent activities in these cells. Al (1 microM) caused an inhibition of basal and 1,25(OH)2D3-induced alkaline phosphatase, but only at low doses (< 1 nM) of the steroid. Al partly inhibited basal osteocalcin (OC) secretion in ROS cells (p < 0.001), and the dose-dependent increase in 1,25(OH)2D3-induced OC release by these cells was also reduced by 1 microM Al at low concentrations of the steroid (< or = 1 nM), whereas high doses of 1,25(OH)2D3 (> or = 5 nM) totally prevented the inhibiting effects of Al. Al also had strong inhibitory actions on PTH-dependent cAMP production by ROS cells over the concentration range tested (0.5-50 nM). This inhibitory action of Al was also observed for PTH-related peptide- (PTHrp, 50 nM) but not for Isoproterenol-dependent (100 nM) cAMP formation. To evaluate more fully the mechanism of this inhibition of cAMP formation, we investigated the effect of Al on toxin-modulated, G protein-dependent regulation of cAMP formation and on the activation of adenylate cyclase by Forskolin. Cholera toxin (CT, 10 micrograms/ml), applied to cells for 4 h prior to PTH challenge, enhanced cAMP production about 2-fold above PTH alone (p < 0.001), a process that was further stimulated by Al. Pertussis toxin (PT, 1 microgram/ml, 4 h) did not modify basal PTH-dependent cAMP formation by ROS cells. However, PT treatment prevented the inhibitory effect of Al on cAMP formation by these cells (p < 0.025). The stimulation of adenylate cyclase by Forskolin (0.1 and 1 microM), which bypasses G protein regulation, was not modified by Al, indicating that Al does not affect adenylate cyclase directly. Northern blot analysis of PTH receptor mRNA levels showed that Al did not modify PTH receptor message in ROS cells. Likewise, Western blot analyses of G protein subunits showed that Al did not significantly alter Gs alpha subunit levels, in accordance with the results obtained for cAMP-dependent formation in response to CT. In contrast, Gi alpha-1 and Gi alpha-2 subunits were decreased by Al treatment, consistent with PT-restricted increases in cAMP formation in Al-treated ROS cells. Taken together, these results suggest that Al has multiple actions in osteoblast-like ROS cells. The effects of Al are modulated by hormonal control of the pathways investigated. Al affects 1,25(OH)2D3-regulated functions only when this steroid is low. Al has large inhibitory effects on PTH- and PTHrp-dependent cAMP formation. This last feature is related to the ability of Al to alter the G protein transducing pathway for PTH/PTHrp-dependent formation of cAMP since it does not affect adenylate cyclase activity directly and does not affect the PTH receptor message level. Thus, Al has stronger deleterious effects in osteoblast-like cells with an already compromised 1,25(OH)2D3 status and can modulate specifically PTH/PTHrp-mediated cAMP formation at the postreceptor level.