A much needed metric: Defining reliable and statistically meaningful change of the oral version Symbol Digit Modalities Test (SDMT).

BACKGROUND: The Symbol Digit Modalities Test (SDMT) has been recommended for use in clinical trials and outcome studies to monitor cognitive change. However, defining what is a meaningful change has been elusive for several years. OBJECTIVE: The present investigation aimed to develop methods for assessing individual-level statistically significant change on the SDMT - reliable change indices (RCIs) and standardized regression-based (SRB) equations. METHODS: A total of 219 healthy individuals completed the oral version SDMT at baseline, 6-month and 1-year follow-up. RESULTS: The SDMT demonstrated high reliability across all time points (r's = 0.83 to 0.86). Reliable change scores of 7, 8, and 10 points for the 6-month intervals represented statistically meaningful change at the 0.70, 0.80, and 0.90 confidence intervals, respectively. Over 1-year, a difference of 8, 10, and 12 was statistically meaningful at the 0.70, 0.80, and 0.90 confidence intervals, respectively. SRB equations are also provided taking into account additional factors found to be predictive of SDMT scores over time. CONCLUSION: Clinicians frequently denote a decline of 4 points on the SDMT as meaningful. Results in this large normative sample show that higher cut-points are needed to demonstrate statistically significant decline at the individual level. RCIs are provided for 6 month and one year assessment, which is typical in clinical practice and trials. SRB equations are also provided for use when applicable and may provide a more precise assessment of meaningful change.

Tired of not knowing what that fatigue score means? Normative data of the Modified Fatigue Impact Scale (MFIS).

BACKGROUND: The Modified Fatigue Impact Scale (MFIS) is one of the most common self-report measures used to assess fatigue in multiple sclerosis (MS). Despite its widespread use, there are no existing normative data for the MFIS. OBJECTIVE: The present investigation aimed to develop normative data for the MFIS in a large community sample, stratified by age, gender, and education and to compare the derived new cutoffs to an existing cutoff. METHODS: A total of 675 healthy individuals, stratified by age, gender, and education completed the MFIS. After the removal of 19 outliers, the final sample consisted of 656 individuals. Archival data of 540 individuals with MS who completed the MFIS were also included to analyze the utility of the new cutoffs. RESULTS: There were no main effects on the MFIS for gender. However, there were main effects for age and education. Specifically, younger cohorts (25-34 and 35-44) reported less physical fatigue compared to the two oldest cohorts (55-64 and 65-74). Similar effects were found for total MFIS fatigue with individuals aged 55-64 reporting greater overall fatigue than 35-44 year olds. Finally, 18-24 year olds reported significantly higher levels of cognitive fatigue compared to 35-44 and 65-74 aged cohorts. No other effects were observed for age. Individuals with higher education consistently reported less fatigue. Subsequent analyses also revealed an interaction effect for age x gender. When examining the age x gender interaction, women age 18-24 reported significantly greater levels of physical, cognitive, psychosocial, and total fatigue than their male counterparts. In contrast, men aged 65-74 reported greater physical, cognitive, and total fatigue than women their age. Comparisons of the existing cutoff of the MFIS to the new age, gender, and education specific cutoffs found either comparable or slightly higher rates of fatigue with the latter. CONCLUSION: Based on these findings, updated normative data and age, gender, and education specific cutoffs are provided. Utilization of these updated norms will result in a more accurate assessment of fatigue and will be valuable for those conducting research and/or clinical practice with individual with MS.

Conventional and surrogate light chains differentially regulate Ig mu and Dmu heavy chain maturation and surface expression.

Positive selection of precursor (pre-) B cells by Ig membrane mu H chains (mum HC) and counterselection mediated by the truncated HC Dmu depend on the ability of each HC to form a pre-B cell receptor (pre-BCR) signaling complex with the surrogate L chain (SLC) components lambda5 and Vpre-B. To better understand how pre-BCR signaling output is determined by its Ig components and the SLC, we investigated the regulation of pre-BCR surface expression and HC secretory maturation in a new nonlymphoid system. We took this approach as a means to distinguish B-lineage-specific effects from pre-BCR-intrinsic properties that may influence these aspects of pre-BCR homeostasis necessary for signaling. As in pre-B cells, the SLC in nonlymphoid cells supported only a limited degree of mum HC maturation and low pre-BCR surface expression levels compared with conventional LCs, indicating that this was due to an intrinsic property of the SLC. We identified the non-Ig region of lambda5 as harboring the restrictive activity responsible for this phenotype. This property of lambda5 was also evident with Dmu, but the overall SLC- and L chain-dependent requirements for Dmu maturation and surface expression were markedly different from those for mum. Surprisingly, Dmu was modified in an unusual manner that was only dependent on Vpre-B. These results establish a novel function of lambda5 in limiting surface pre-BCR levels and reveal biochemical properties of Ig molecules that may underlie the diverse consequences of pre-BCR signaling in vivo by different HCs.

Complementation of V(D)J recombination deficiency in RAG-1(-/-) B cells reveals a requirement for novel elements in the N-terminus of RAG-1.

RAG-1 is an essential component of the site-specific V(D)J recombinase. A new assay system has revealed a significant contribution of the catalytically dispensible N-terminal region of RAG-1 to recombination activity. The foundation for this system is an Abelson virus-transformed cell line derived from RAG-1(-/-) mice that is dependent on the introduction of exogenous RAG-1 for rearrangement of either plasmid substrates or the endogenous immunoglobulin loci. Use of this line demonstrates that conserved and novel cysteine-containing elements in the N-terminal region are required for full RAG-1 activity when recombination activity is in a RAG-1 dose-responsive range. Our data suggest that the RAG-1 N-terminus enhances the formation of an active recombination complex that facilitates the rearrangement process.

Determinants of nonthoracotomy biphasic defibrillation.

The clinical variables affecting DFT for ICD systems are not completely determined, especially with regard to biphasic shocking devices. To distinguish which factors correlate with DFT, we examined data from patients who were enrolled in the Ventak P2/Endotak protocol. A total of 284 patients were enrolled in the study. Two patients had a DFT > 25 J and did not receive the device; 154 did not undergo stepdown to failure DFT testing. The remaining 128 patients had formal DFT testing and were suitable for analysis. Variables available for analysis included age, body surface area (BSA), LVEF, gender, lead configuration, primary arrhythmia, primary cardiac disease, and use of cardioactive medication. Data were evaluated using regression analysis, fitting DFT (range, 1-25 J, mean 11 +/- 5 J) as a function of each variable. As a univariate predictor. BSA was found to be significant in predicting DFT, but accounted for only 9% of the total variation on the DFT (P < 0.01, r = 0.3). This study suggests that DFT using a biphasic shocking waveform is modestly in fluenced by the BSA of the patient. Other specific factors, including LVEF, do not predict DFT.

Selective radiofrequency ablation of the "slow" atrioventricular nodal pathway for control of the ventricular response to atrial fibrillation.

In summary, this study reports 2 important findings: (1) AV nodal modification using the conservative protocol we describe reduces long-term success for ventricular rate control during atrial fibrillation but eliminates the incidence of permanent AV block; (2) directed lesions that eliminate clinical AV nodal reentry slow ventricular response to acute atrial fibrillation but are not sufficient to control ventricular response of chronic atrial fibrillation. Further refinement of these techniques may allow an optimal balance between rate control and avoidance of permanent pacing.

Genetic evidence that the RAG1 protein directly participates in V(D)J recombination through substrate recognition.

RAG1 protein is essential for the activation of V(D)J recombination in developing lymphocytes (V, variable; D, diversity; J, joining). However, it has not been determined whether its role involves substrate recognition and catalysis. A single amino acid substitution mutation in the RAG1 gene has now been identified that renders its activity sensitive to the sequence of the coding region abutting the heptamer site in the recombination signal sequence. These results strongly imply that RAG1 interacts directly with DNA.

Diagnosis of ICD lead failure using continuous event marker recording.

Stored electrograms enhance the ability to evaluate therapy episodes in the third-generation implantable cardioverter defibrillator. These electrograms are recorded from either the shocking or rate sensing leads, but not both. As a result, differentiation of certain types of sensing abnormalities may be difficult prior to surgical exploration. We present a case of rate sensing lead failure due to an insulation break. Several minutes of recording of the event marker in the laboratory failed to document any abnormal sensing; the diagnosis was made by recording the event marker on a 24-hour continuous (Holter) monitor. The Holter monitor/event marker combination was of substantial diagnostic value and allowed for a more focused surgical evaluation and treatment.

Functional immunoglobulin transgenes guide ordered B-cell differentiation in Rag-1-deficient mice.

We have examined the regulatory role of the individual components of the immunoglobulin antigen receptor in B-cell development by transgenic complementation of Rag-1 deficient (Rag-1-) mice. Complementation with a membrane mu heavy chain (mu HC) gene allows progression of developmentally arrested Rag-1- pro-B-cells to the small pre-B cell stage, whereas the introduction of independently integrated mu HC and kappa light chain (kappa LC) transgenes promotes the appearance of peripheral lymphocytes which, however, remain unresponsive to external stimuli. Complete reconstitution of the B-cell lineage and the emergence of functionally nature Rag-1- peripheral B cells is achieved by the introduction of cointegrated heavy and light chain transgenes encoding an anti-H-2k antibody. This experimental system demonstrates the competence of the mu HC and kappa LC to direct and regulate the sequential stages of B-cell differentiation, defines the time at which negative selection of self-reactive B cells occurs, and shows that elimination of these cells occurs equally well in the absence of Rag-1 as in its presence. These data also support the hypothesis that Rag-1 directly participates in the V(D)J recombination process.

Treatment of supraventricular tachycardia due to atrioventricular nodal reentry by radiofrequency catheter ablation of slow-pathway conduction.

BACKGROUND: Atrioventricular nodal reentrant tachycardia (AVNRT), the most common form of supraventricular tachycardia, results from conduction through a reentrant circuit comprising fast and slow atrioventricular nodal pathways. Antiarrhythmic-drug therapy is not consistently successful in controlling this rhythm disturbance. Catheter ablation of the fast pathway with radiofrequency current eliminates AVNRT, but it can produce heart block. We hypothesized that catheter ablation of the site of insertion of the slow pathway into the atrium would eliminate AVNRT while leaving normal (fast-pathway) atrioventricular nodal conduction intact. METHODS AND RESULTS: Eighty patients with symptomatic AVNRT were studied. Retrograde slow-pathway conduction (in which the earliest retrograde atrial potential was recorded at the posterior septum, close to the coronary sinus) was present in 33 patients. The retrograde atrial potential was preceded by a potential consistent with activation of the atrial end of the slow pathway (ASP). In 46 of the 47 patients without retrograde slow-pathway conduction, a potential with the same characteristics as the ASP potential was recorded during sinus rhythm. Radiofrequency current delivered through a catheter to the ASP site (in the posteroseptal right atrium or coronary sinus) abolished or modified slow-pathway conduction in 78 patients, eliminating AVNRT without affecting normal atrioventricular nodal conduction. In the single patient without ASP, the application of radiofrequency current to the proximal coronary sinus ablated the fast pathway and AVNRT: Atrioventricular block occurred in one patient (1.3 percent) with left bundle-branch block, after inadvertent ablation of the right bundle branch. AVNRT has not recurred in any patient during a mean (+/- SD) follow-up of 15.5 +/- 11.3 months. Electrophysiologic study 4.3 +/- 3.3 months after ablation in 32 patients demonstrated normal atrioventricular nodal conduction without AVNRT: CONCLUSIONS: Catheter ablation of the atrial end of the slow pathway using radiofrequency current, guided by ASP potentials, can eliminate AVNRT with very little risk of atrioventricular block.

Catheter ablation of accessory atrioventricular pathways (Wolff-Parkinson-White syndrome) by radiofrequency current.

BACKGROUND: Surgical or catheter ablation of accessory pathways by means of high-energy shocks serves as definitive therapy for patients with Wolff-Parkinson-White syndrome but has substantial associated morbidity and mortality. Radiofrequency current, an alternative energy source for ablation, produces smaller lesions without adverse effects remote from the site where current is delivered. We conducted this study to develop catheter techniques for delivering radiofrequency current to reduce morbidity and mortality associated with accessory-pathway ablation. METHODS: Radiofrequency current (mean power, 30.9 +/- 5.3 W) was applied through a catheter electrode positioned against the mitral or tricuspid annulus or a branch of the coronary sinus; when possible, delivery was guided by catheter recordings of accessory-pathway activation. Ablation was attempted in 166 patients with 177 accessory pathways (106 pathways in the left free wall, 13 in the anteroseptal region, 43 in the posteroseptal region, and 15 in the right free wall). RESULTS: Accessory-pathway conduction was eliminated in 164 of 166 patients (99 percent) by a median of three applications of radiofrequency current. During a mean follow-up (+/- SD) of 8.0 +/- 5.4 months, preexcitation or atrioventricular reentrant tachycardia returned in 15 patients (9 percent). All underwent a second, successful ablation. Electrophysiologic study 3.1 +/- 1.9 months after ablation in 75 patients verified the absence of accessory-pathway conduction in all. Complications of radiofrequency-current application occurred in three patients (1.8 percent): atrioventricular block (one patient), pericarditis (one), and cardiac tamponade (one) after radiofrequency current was applied in a small branch of the coronary sinus. CONCLUSIONS: Radiofrequency current is highly effective in ablating accessory pathways, with low morbidity and no mortality.