Patient-Specific Characteristics Associated with Favorable Response to Vagus Nerve Stimulation.

OBJECTIVE: The expansion in treatments for medically refractory epilepsy heightens the importance of identifying patients who are likely to benefit from vagus nerve stimulation (VNS). Here, we identify predictors with a positive VNS response. METHODS: We present a retrospective analysis of 158 patients with medically refractory epilepsy. Patients were categorized as VNS responders or nonresponders. Baseline characteristics and time to VNS response were recorded. Univariate and multivariate Cox regression were used to identify predictors of response. Recursive partitioning analysis was used to identify likely VNS responders. RESULTS: Eighty-nine (56.3%) patients achieved ≥50% seizure frequency reduction. Left-hand dominance (hazard ratio [HR] 1.703, P = 0.038), age at epilepsy onset ≥15 years (HR 2.029, P = 0.005), duration of epilepsy ≥8 years (HR 1.968, P = 0.007) and age at implantation ≥35 years (HR 1.809, P = 0.020), and baseline seizure frequency <5/month (HR 1.569, P = 0.044) were significant univariate predictors of VNS response. Following multivariate Cox regression, left-hand dominance, age at epilepsy onset ≥15 years, and duration of epilepsy ≥8 years remained significant. With recursive partitioning analysis, patients with either age at epilepsy onset ≥15 years, left-hand dominance, or baseline seizure frequency <5/month were stratified into Group A and had a 73.9% responder rate; the remaining patients stratified into Group B had a 43.8% responder rate. CONCLUSIONS: Patients with age at epilepsy onset ≥15 years, left-hand dominance, or baseline seizure frequency <5/month are ideal candidates for VNS.

The Yin and Yang of pain: variability in formalin test nociception and morphine analgesia produced by the Yin Yang 1 transcription factor gene.

We recently observed a reliable phenotypic difference in the inflammatory pain sensitivity of a congenic mouse strain compared to its background strain. By constructing and testing subcongenic strains combined with gene-expression assays, we provide evidence for the candidacy of the Yy1 gene - encoding the ubiquitously expressed and multifunctional Yin Yang 1 transcription factor - as responsible. To confirm this hypothesis, we used a Cre/lox strategy to produce mutant mice in which Yy1 expression was ablated in Nav 1.8-positive neurons of the dorsal root ganglion. These mutants also displayed reduced inflammatory pain sensitivity on the formalin test. Further testing of pain-related phenotypes in these mutants revealed robustly increased sensitivity to systemic and spinal (but not supraspinal) morphine analgesia, and greatly increased endogenous (swim stress-induced) opioid analgesia. None of the known biological roles of Yin Yang 1 were suggestive of such a phenotype, and thus a novel player in pain modulatory systems has been identified.

ADAMTS-5 deficient mice do not develop mechanical allodynia associated with osteoarthritis following medial meniscal destabilization.

OBJECTIVE: To characterize pain-related behavior during the course of knee osteoarthritis (OA) induced by destabilization of the medial meniscus (DMM) in wild type (WT) and in ADAMTS-5 null mice. METHODS: DMM surgery was performed in the right knee of CD-1 mice. At regular intervals up to 8 weeks after surgery, mice were assessed for the following parameters: mechanical allodynia (via withdrawal thresholds to von Frey filaments applied to the plantar surface of both hind paws or to the tail), thermal hyperalgesia, locomotor activity and gait analysis. In addition, mechanical allodynia was tested in C57BL/6 WT or ADAMTS-5 null mice following DMM surgery. RESULTS: In CD-1 mice, a robust and progressive decrease in withdrawal threshold was observed in both hind paws after DMM but not sham surgery. Allodynia was apparent as early as 14 days postoperatively. Both sexes developed OA changes after surgery with concurrent mechanical allodynia. No other pain-related behavioral changes were detected up to 8 weeks post-surgery. In C57BL/6 mice, a genetic background in which only males develop OA changes after DMM, males but not females developed allodynia in the ipsilateral hind paw. In contrast, C57BL/6 ADAMTS-5 null mice did not develop OA changes or mechanical allodynia up to 8 weeks post-surgery. CONCLUSION: Joint pathology following DMM surgery in mice is associated with progressive mechanical allodynia. ADAMTS-5 null mice are resistant to DMM-induced OA-like lesions and to the associated mechanical allodynia.

Gnao1 (G alphaO protein) is a likely genetic contributor to variation in physical dependence on opioids in mice.

Chronic exposure to opioids leads to physical dependence, which manifests as the symptoms of drug withdrawal. Interindividual differences in withdrawal symptom severity are well known, and at least partially due to genetic variation. To identify genes contributing to variation in withdrawal severity, we chronically treated 30 strains of the AcB/BcA recombinant congenic mouse strain set, including their A/J and C57BL/6J (B6) progenitors, with morphine for seven days and compared jumping frequencies--a sensitive and widely used index of withdrawal magnitude--during naloxone-precipitated withdrawal (NPW). Jumping frequencies of B6 mice were more than threefold greater than values obtained in A/J mice. Visual inspection of the genomic distribution of parental haplotypes in the AcB/BcA strains identified a putative quantitative trait locus (QTL) localized to chromosome 8 (90-117 Mb), and this QTL was confirmed in a B6AF2 intercross. The most salient candidate gene within this QTL, Gnao1 (guanine nucleotide binding protein, alpha(o); G alpha(o); 96.3 Mb), was tested for functional relevance using quantitative PCR and an antisense oligodeoxynucleotide strategy. The expression of Gnao1 in the locus coeruleus was found to be upregulated in morphine-dependent B6 but not A/J mice. Antisense knockdown of Gnao1 reduced NPW jumping in B6, but not A/J, mice rendered dependent on either morphine or heroin, largely rescuing the original strain difference. These data strongly implicate the G alpha(o) protein in the locus coeruleus as contributing to interindividual variability in physical dependence on opioids in mice.

Impact of nitric oxide on blood pressure in hemodialysis patients.

Nitric oxide (NO) is a powerful vasoactive agent that contributes to the regulation of blood pressure (BP). However, the role of NO in uremic patients and during the course of hemodialysis is still debated. Blood L-arginine concentrations and exhaled NO concentrations were measured in 22 healthy controls and in 22 hemodialysis patients before and after dialysis. On the basis of their BP response during hemodialysis, the patients were divided into three groups: 6 of the 22 patients presented with a decrease in BP during dialysis (group 1), eight presented with a stable BP (group 2), and eight with an increase in BP (group 3). The exhaled NO concentration was higher in dialysis patients than in healthy controls (22.7 +/- 2.6 ppb in dialysis patients v 16.7 +/- 0.9 ppb in controls, mean +/- SEM, P = 0.044). The predialysis and postdialysis exhaled NO concentrations were inversely correlated with the change in BP during hemodialysis (r = -0.47, P = 0.013). Patients with a decrease in BP (group 1) had the highest NO concentrations; patients with an increase in BP (group 3) had the lowest values; and patients with a stable BP during the course of dialysis (group 2) had intermediary values (trend test, P = 0.0291). In addition, both the exhaled NO concentration and the blood L-arginine concentration decreased during dialysis in all patients (P = 0.005 and P = 0.001, respectively). These results provide several novel insights into NO metabolism and BP regulation during hemodialysis: (1) maintenance hemodialysis is associated with a chronic increase in NO concentrations; (2) changes in BP during hemodialysis are inversely correlated with exhaled NO concentrations, higher NO levels being associated with a decrease in BP and lower NO levels with an increase in BP during dialysis; (3) blood L-arginine levels decrease during hemodialysis, and this reduction may in turn influence NO production.

Option-4 algorithm for automated disc probe: reduction in the variance of site-specific relative attachment level measurements.

Physical periodontal measurement is plagued by many confounders which result in aberrant values. Replicate measurements can reduce the number of aberrant values, the measurement error, and the variance of site-specific measurements. This study aimed to reduce the variance of site-specific measurements by using a new clinical algorithm (the Option-4 algorithm) for an automated disk probe. A single clinician recorded full-mouth relative attachment levels (RAL) at one visit in 32 patients (mean age 45.5 years) with moderately advanced chronic adult periodontitis. RAL was recorded over two passes at six sites per tooth (4,675 sites). The algorithm accepted the first and second pass RALs (RAL1 and RAL2) if their difference was < or = 1 mm, otherwise a maximum of two further RALs (RAL3 and RAL4) were recorded until the difference between any two RALs was < or = 1 mm (SAL1 and SAL2): 4,048 sites (86.6%) required two recordings, 580 sites (12.4%) required three recordings and 47 sites (1%) required four recordings. Correlation coefficients for RAL1 and RAL2 and SAL1 and SAL2 (4,675 sites) were both > or = 0.91 (P = 0.00). Site-specific variances were calculated for RAL1 and RAL2 and SAL1 and SAL2. The mean of the RAL1/RAL2 site-specific variances (A) was 0.45 mm2 (range 0.00 mm2 to 35.28 mm2) whilst the mean of the SAL1/SAL2 variances (B) was 0.09 mm2 (range 0.00 mm2 to 0.5 mm2): the respective medians were 0.08 mm2 and 0.02 mm2. The study demonstrated high intra-examiner RAL reproducibility. The Option-4 algorithm produced an 80% reduction in the mean site-specific variance of RAL1/RAL2 (Y) and a 75% reduction in the median site-specific variance of RAL1/RAL2 (y = [(A - B)/A] x 100).

Important differences in clinical data from third, second, and first generation periodontal probes.

This study compared relative attachment levels (RAL) and probable crevice depths (PCD) from 6 periodontal probes (1 third, 4 second, and 1 first generation). A single clinician recorded RAL and PCD in 6 patients with chronic adult periodontitis (mean age 48.2 years) during two visits (interval: 1 week) using a Latin square examination order. Replicate measurements were recorded at the 4 interproximal sites of the Ramford index teeth to examine intra-probe differences. Additional single measurements were recorded at similar sites of units 11, 26, 31 and 46 to investigate interprobe differences. Intra-probe RAL and PCD reproducibility was < or = 1 mm at > 94% of the sites. All intra-probe Pearson correlation coefficients were > 0.85 (P = 0.00). Inter-probe RAL and PCD agreement was < or = 1 mm at > 49% of the sites for RAL and > 61% of the sites for PCD. All inter-probe Pearson correlation coefficients were > 0.42 (P = 0.00) for RAL and > 0.49 (P = 0.00) for PCD. Analyses of variance showed significant differences in RAL and PCD between the first generation probe and the second generation probes (P < 0.005); in RAL between the third generation probe and the first and second generation probes (P = 0.0354); and in PCD between the third generation probe and the first and second generation probes (P = 0.0475). Inter-probe differences were clinically significant in the recorded percentages of pockets > or = 4 mm and > or = 6 mm. Significant inter-probe differences were found in RAL and PCD which have clinical importance in data interpretation and comparison.

Health outcome improvements in patients with systemic lupus erythematosus using two telephone counseling interventions.

OBJECTIVE: To examine the effectiveness of two telephone intervention strategies for improving the health outcomes of patients with systemic lupus erythematosus (SLE). METHODS: Fifty-eight SLE patients were randomly assigned to receive a 6-month telephone counseling intervention using either a treatment counseling (TC) or symptom monitoring (SM) strategy. Health outcomes were assessed using the Fatigue Severity Scale (FSS) and the Arthritis Impact Measurement Scales 2 (AIMS2). RESULTS: At the 6-month followup, the mean AIMS2 Physical Function scale and AIMS2 Social Support scale scores were significantly improved (P < 0.05) for the TC group compared to the SM groups. The mean FSS score, AIMS2 Affect score, and AIMS2 Pain score were significantly improved (P < 0.05) for both groups. CONCLUSIONS: Telephone interventions, especially using the TC approach, can be effective for improving the functional status of persons with SLE.

The effect of person-centered counseling on the psychological status of persons with systemic lupus erythematosus or rheumatoid arthritis: a randomized, controlled trial.

OBJECTIVE: We tested the effectiveness of a 6-month person-centered (PC), nondirective, telephone-based counseling intervention for improving the psychological status of persons with systemic lupus erythematosus (SLE) or rheumatoid arthritis (RA). METHODS: The design was a parallel-group, randomized, controlled study comparing a PC counseling intervention (8 SLE, 28 RA patients) with usual care (7 SLE, 30 RA patients). The Arthritis Impact Measurement Scales was used to measure psychological dysfunction, physical dysfunction, and pain at baseline and at followup. RESULTS: The main finding was that the PC counseling intervention significantly improved the psychological status of the SLE patients (P < 0.05, effect size = 1.13, responsiveness = 0.77) in comparison to usual care. There was no evidence of a benefit for persons with RA or of improvements in physical function or pain for persons with either disease. CONCLUSIONS: PC counseling may be an effective intervention for improving the psychological status of persons with SLE, but may not be for those with RA.

Supplementation with folic acid during methotrexate therapy for rheumatoid arthritis. A double-blind, placebo-controlled trial.

OBJECTIVE: To determine the effect of two different weekly doses of folic acid on the toxicity and efficacy of low-dose methotrexate therapy for rheumatoid arthritis. DESIGN: Randomized, double-blind, placebo-controlled study. PATIENTS: 79 persons between 19 and 78 years of age who fulfilled the American Rheumatism Association's criteria for rheumatoid arthritis. INTERVENTION: Participants were randomly assigned to visually identical placebo or to 5 mg or 27.5 mg of folic acid each week. MEASUREMENTS: Duration, intensity, and clinical severity of toxic events; efficacy (indices of joint tenderness and swelling and grip strength); plasma and erythrocyte folate levels; and other laboratory variables. RESULTS: Folic acid supplementation at either dose did not affect the efficacy of methotrexate therapy as judged by joint indices and patient and physician assessments of disease. Patients given folic acid supplements had lower toxicity scores than did participants given placebo (P < or = 0.001). Low blood folate levels and increased mean corpuscular volumes were associated with substantial methotrexate toxicity, whereas daily dietary intakes of more than 900 nmol (400 micrograms) of folic acid were associated with little methotrexate toxicity. CONCLUSIONS: Folic acid, an inexpensive vitamin, is safe in a broad range of doses and protects patients with rheumatoid arthritis who are taking methotrexate from toxicity while preserving the efficacy of methotrexate.

College-bound students: are we meeting their needs?

This research investigated the relationship of educational level and marital status of parents, number of children in the family, and family stability to the social, emotional, and academic development of college-bound students. Subjects were 52 tenth-grade college-preparatory students from a southern public high school. Data were collected using the Measures of Psychosocial Development (MPD), the School Environment Preference Survey (SEPS), and the Study Attitudes and Methods Survey (SAMS). Results of a multivariate analysis of variance indicated significant differences in autonomy, initiative, ego integrity, guilt, isolation, academic interest, study methods, manipulation, and alientation toward authority. Implications for school personnel are noted.

A comparison of the full and short versions of the Arthritis Impact Measurement Scales.

This study examined the validity and reliability of full and short versions of the Arthritis Impact Measurement Scales (AIMS). One hundred fifty-five patients with Rheumatoid Arthritis followed at a University Hospital Rheumatology Clinic completed the full AIMS at baseline, 6 months, 12 months, and 18 months. After reducing the 45-item AIMS to 22, alpha reliabilities and test-retest correlations showed that, with the exception of test-retest correlations for mobility at 6 months and for pain at 12 and 18 months, the full and short scales were comparably reliable. Convergent validity correlations with theoretically related scales were also comparable. However, some of the short scales did not detect the same differences over time that the full scales did. Specifically, the short mobility, pain, anxiety, and depression scales were not as sensitive to change as the full scales. Except for these four scales, the short version appears to be a viable alternative for use by health professionals and researchers.

Rheumatoid arthritis patients and clinical drug trials. A case-control study.

In order to understand better why patients do or do not participate in clinical drug trials, we sent questionnaires to 100 patients with rheumatoid arthritis (RA) who participated in clinical drug trials at our center and to 100 RA patients with similar disease durations who did not participate in clinical drug trials at our center. We compared demographic, socioeconomic, and clinical characteristics of respondents. Those who participated and those who did not participate in clinical drug trials selected similar rank-order preferences of potential reasons for doing so. The most frequent reasons cited by participants and nonparticipants were physician recommendation (50% and 56%) and benefit to society (25% and 17%). Participants and nonparticipants were similar in reference to their age, sex, educational level, reported income per household, employment status, distance from the medical center, disease duration, number of tender joints, American Rheumatism Association functional class, and mean erythrocyte sedimentation rate variables. There were two differences between the groups: participants included a lower percentage of blacks and had a greater number of swollen joints. Even with those exceptions, we concluded that participants in clinical trials appear to be comparable to the general population of RA patients followed at our outpatient department.