Short latency activation of cortex by clinically effective thalamic brain stimulation for tremor.

Deep brain stimulation (DBS) relieves disabling symptoms of neurologic and psychiatric diseases when medical treatments fail, yet its therapeutic mechanism is unknown. We hypothesized that ventral intermediate (VIM) nucleus stimulation for essential tremor activates the cortex at short latencies, and that this potential is related to the suppression of tremor in the contralateral arm. We measured cortical activity with electroencephalography in 5 subjects (seven brain hemispheres) across a range of stimulator settings, and reversal of the anode and cathode electrode contacts minimized the stimulus artifact, allowing visualization of brain activity. Regression quantified the relationship between stimulation parameters and both the peak of the short latency potential and tremor suppression. Stimulation generated a polyphasic event-related potential in the ipsilateral sensorimotor cortex, with peaks at discrete latencies beginning less than 1 ms after stimulus onset (mean latencies 0.9 ± 0.2, 5.6 ± 0.7, and 13.9 ± 1.4 ms, denoted R1, R2, and R3, respectively). R1 showed more fixed timing than the subsequent peaks in the response (P < 0.0001, Levene's test), and R1 amplitude and frequency were both closely associated with tremor suppression (P < 0.0001, respectively). These findings demonstrate that effective VIM thalamic stimulation for essential tremor activates the cerebral cortex at approximately 1 ms after the stimulus pulse. The association between this short latency potential and tremor suppression suggests that DBS may improve tremor by synchronizing the precise timing of discharges in nearby axons and, by extension, the distributed motor network to the stimulation frequency or one of its subharmonics.

Epitope-specific immunotherapy of rheumatoid arthritis: clinical responsiveness occurs with immune deviation and relies on the expression of a cluster of molecules associated with T cell tolerance in a double-blind, placebo-controlled, pilot phase II trial.

OBJECTIVE: Induction of immune tolerance to maintain clinical control with a minimal drug regimen is a current research focus in rheumatoid arthritis (RA). Accordingly, we are developing a tolerization approach to dnaJP1, a peptide part of a pathogenic mechanism that contributes to autoimmune inflammation in RA. We undertook this study to test 2 hypotheses: 1) that mucosal induction of immune tolerance to dnaJP1 would lead to a qualitative change from a proinflammatory phenotype to a more tolerogenic functional phenotype, and 2) that immune deviation of responses to an inflammatory epitope might translate into clinical improvement. METHODS: One hundred sixty patients with active RA and with immunologic reactivity to dnaJP1 were enrolled in a pilot phase II trial. They received oral doses of 25 mg of dnaJP1 or placebo daily for 6 months. RESULTS: The dnaJP1 peptide was safe and well-tolerated. In response to treatment with dnaJP1, there was a significant reduction in the percentage of T cells producing tumor necrosis factor alpha and a corresponding trend toward an increased percentage of T cells producing interleukin-10. Coexpression of a cluster of molecules (programmed death 1 and its ligands) associated with T cell regulation was also found to be a prerequisite for successful tolerization in clinical responders. Analysis of the primary efficacy end point (meeting the American College of Rheumatology 20% improvement criteria at least once on day 112, 140, or 168) showed a difference between treatment groups that became significant in post hoc analysis using generalized estimating equations. Differences in clinical responses were also found between treatment groups on day 140 and at followup. Post hoc analysis showed that the combination of dnaJP1 and hydroxychloroquine (HCQ) was superior to the combination of HCQ and placebo. CONCLUSION: Tolerization to dnaJP1 leads to immune deviation and a trend toward clinical efficacy. Susceptibility to treatment relies on the coexpression of molecules that can down-regulate adaptive immunity.

Canine hemangiosarcoma originates from hematopoietic precursors with potential for endothelial differentiation.

OBJECTIVE: Two competing hypotheses can be formulated regarding the origin of canine hemangiosarcoma (HSA). One states HSA originates from differentiated vascular endothelial cells that undergo mutations which endow them with malignant potential. The other states HSA originates from transformed hemangioblastic stem cells. This study was designed to begin to distinguish between these possibilities, as well as to test if flow cytometry was sufficiently sensitive to detect malignant cells in blood samples from dogs with HSA. METHODS: We used multiparameter flow cytometry to examine expression of cell-surface determinants associated with hematopoietic precursors (c-kit, CD34, CD133, CD45) or with lineage-committed cells (CD3, CD11b, CD14, CD21, CD105, CD146, alphavbeta3-integrin) in HSA cell lines and in blood samples from healthy dogs or dogs with HSA. RESULTS: The data show that HSA cells coexpress surface markers associated with hematopoietic precursors and with commitment to endothelial lineage, providing a means to identify their presence in circulation and distinguish them from normal or malignant white blood cells. The percentage of cells that coexpressed these markers ranged from 0.5 to 1.25% for HSA dogs, and was less than 0.3% for unaffected dogs or dogs with HSA that had the tumors removed within 48 hours prior to obtaining samples. CONCLUSIONS: The results place the ontogeny of HSA with multipotential bone marrow-derived stem cells whose progeny arrest differentiation at the hemangioblast or angioblast stage. In addition, these expression patterns may assist to confirm an HSA diagnosis, monitor minimal residual disease, and detect the disease in early stages.

Distinct B-cell and T-cell lymphoproliferative disease prevalence among dog breeds indicates heritable risk.

Immunophenotypes in lymphoproliferative diseases (LPD) are prognostically significant, yet causative factors for these conditions, and specifically those associated with heritable risk, remain elusive. The full spectrum of LPD seen in humans occurs in dogs, but the incidence and lifetime risk of naturally occurring LPD differs among dog breeds. Taking advantage of the limited genetic heterogeneity that exists within dog breeds, we tested the hypothesis that the prevalence of LPD immunophenotypes would differ among different breeds. The sample population included 1,263 dogs representing 87 breeds. Immunophenotype was determined by the presence of clonal rearrangements of immunoglobulin heavy chain or T-cell receptor gamma chain. The probability of observing the number of B-cell or T-cell tumors in a particular breed or breed group was compared with three reference populations. Significance was computed using chi2 test, and logistic regression was used to confirm binomial predictions. The data show that, among 87 breeds tested, 15 showed significant differences from the prevalence of LPD immunophenotypes seen across the dog population as a whole. More significantly, elevated risk for T-cell LPD seems to have arisen ancestrally and is retained in related breed groups, whereas increased risk for B-cell disease may stem from different risk factors, or combinations of risk factors, arising during the process of breed derivation and selection. The data show that domestic dogs provide a unique and valuable resource to define factors that mediate risk as well as genes involved in the initiation of B-cell and T-cell LPD.