Biomedical subjects

Keith Brown

Publications and source records attributed to Keith Brown.

9 recordsLinked to original sources

PubMed2007

Predicting treatment outcome on three measures for post-traumatic stress disorder.

The aim of the present study was to investigate predictors of treatment outcome for Posttraumatic Stress Disorder (PTSD) after treatment completion and at 15-months follow-up (n = 48), in a trial of Eye Movement Desensitisation and Reprocessing (EMDR) versus Imaginal Exposure and Cognitive Restructuring (E+CR). Factors associated with treatment outcome were investigated using regression analyses with the mean change scores in three assessor and self-rated PTSD symptomatology measures, including the Clinician-Administered PTSD Scale (CAPS), the Impact of Events Scale (IES) and the PTSD Symptom Checklist (PCL) from pre- to post-treatment and pre-treatment to follow-up as the dependent variables and demographics, trauma, clinical and personality measures as independent variables. Irrespective to outcome measures and assessment points it was found that four variables were able to predict significantly treatment outcome. These included baseline PTSD symptomatology, number of sessions, gender and therapy type. Overall, our results showed that it is difficult to use pre-treatment variables as a powerful and reliable tool for predicting treatment outcome, as significant predictors were found to be sample-specific and outcome measure-specific. Clinical relevance of the present results and directions for future research are discussed.

Adolescent↗

PubMed2005

Control of lymphocyte development by nuclear factor-kappaB.

The evolutionarily conserved nuclear factor-kappaB family of transcription factors is known to have a crucial role in rapid responses to stress and pathogens, inducing transcription of many genes that are essential for host defence. Now, studies of mice that are deficient in nuclear factor-kappaB-family members (or deficient in the activation of these factors) reveal that nuclear factor-kappaB is extensively involved in the development of T cells and B cells. And, as we review here, although these factors have several roles, their primary cell-autonomous function is to ensure lymphocyte survival at various developmental stages. This function is subverted in numerous diseases and can lead, for example, to survival of self-reactive lymphocytes or tumour cells.

Animals↗

PubMed2004

BCL-3 and NF-kappaB p50 attenuate lipopolysaccharide-induced inflammatory responses in macrophages.

Lipopolysaccharide (LPS) induces expression of tumor necrosis factor alpha (TNFalpha) and other pro-inflammatory cytokines in macrophages. Following its induction, TNFalpha gene transcription is rapidly attenuated, in part due to the accumulation of NF-kappaB p50 homodimers that bind to three kappaB sites in the TNFalpha promoter. Here we have investigated the inhibitory role of BCL-3, an IkappaB-like protein that interacts exclusively with p50 and p52 homodimers. BCL-3 was induced by LPS with delayed kinetics and was associated with p50 in the nucleus. Forced expression of BCL-3 suppressed LPS-induced transcription from the TNFalpha promoter and inhibited two artificial promoters composed of TNFalphakappaB sites that preferentially bind p50 dimers. BCL-3-mediated repression was reversed by trichostatin A and was enhanced by overexpression of HDAC-1, indicating that transcriptional attenuation involves recruitment of histone deacetylase. Analysis of macrophages from p50 and BCL-3 knock-out mice revealed that both transcription factors negatively regulate TNFalpha expression and that BCL-3 inhibits IL-1alpha and IL-1beta. In contrast, induction of the anti-inflammatory cytokine IL-10 was reduced in BCL-3 null macrophages. BCL-3 was not required for the production of p50 homodimers but BCL-3 expression was severely diminished in p50-deficient cells. Together, these findings indicate that p50 and BCL-3 function as anti-inflammatory regulators in macrophages by attenuating transcription of pro-inflammatory cytokines and activating IL-10 expression.

Animals↗

PubMed2004

A prospective randomized comparison of train-of-four monitoring and clinical assessment during continuous ICU cisatracurium paralysis.

STUDY PURPOSE: Train-of-four (TOF) monitoring is often recommended during the continuous use of neuromuscular blockade (NMB) [paralysis] in the ICU. Prior study results are conflicting regarding the benefits of TOF monitoring. DESIGN: Thirty patients in the medical ICU were randomized to TOF monitoring (n = 16) or to clinical assessment (n = 14) during continuous cisatracurium infusion. TOF monitoring was done at least every 4 h, with the goal being maintenance of one to two twitches. Statistical analysis was performed by two-tailed, unpaired t test (with Bonferroni correction for multiple comparisons), chi(2), and Fisher exact test, with p < 0.05 considered significant. Given a power of 80%, and the variance seen in the two groups, we estimate that the sample size used is sufficient to detect a change of > or = 60 min between groups for recovery time. RESULTS: The mean recovery time after cessation of paralytics was no different between TOF and clinical assessment (45 +/- 7 min vs 38 +/- 10 min, respectively [mean +/- SEM]). No differences were noted for mean APACHE (acute physiology and chronic health evaluation) II entry scores, glomerular filtration rates, or use of corticosteroids. No significant differences were noted between TOF monitoring and clinical assessment in mean total paralysis time (4,118 +/- 1,012 min vs 3,188 +/- 705 min, respectively), mean total cisatracurium dose (920 +/- 325 mg vs 715 +/- 167 mg), or dosage (2.3 +/- 0.2 microg/kg/min vs 2.9 +/- 0.2 microg/kg/min). CONCLUSIONS: TOF monitoring does not lead to improved recovery time or lower cisatracurium dosing compared with monitoring by clinical assessment. We conclude that TOF monitoring is unnecessary, and careful titration of the neuromuscular blocking agent by clinical assessment alone is sufficient in patients undergoing continuous cisatracurium NMB.

Atracurium↗

PubMed2003

Familial Parkinson's disease-associated L166P mutation disrupts DJ-1 protein folding and function.

Mutations in DJ-1, a protein of unknown function, were recently identified as the cause for an autosomal recessive, early onset form of familial Parkinson's disease. Here we report that DJ-1 is a dimeric protein that exhibits protease activity but no chaperone activity. The protease activity was abolished by mutation of Cys-106 to Ala, suggesting that DJ-1 functions as a cysteine protease. Our studies revealed that the Parkinson's disease-linked L166P mutation impaired the intrinsic folding propensity of DJ-1 protein, resulting in a spontaneously unfolded structure that was incapable of forming a homodimer with itself or a heterodimer with wild-type DJ-1. Correlating with the disruption of DJ-1 structure, the L166P mutation abolished the catalytic function of DJ-1. Furthermore, as a result of protein misfolding, the L166P mutant DJ-1 was selectively polyubiquitinated and rapidly degraded by the proteasome. Together these findings provide insights into the molecular mechanism by which loss-of-function mutations in DJ-1 lead to Parkinson's disease.

Amino Acid Sequence↗

PubMed2003

Short-time fractional Fourier methods for the time-frequency representation of chirp signals.

The fractional Fourier transform (FrFT) provides a valuable tool for the analysis of linear chirp signals. This paper develops two short-time FrFT variants which are suited to the analysis of multicomponent and nonlinear chirp signals. Outputs have similar properties to the short-time Fourier transform (STFT) but show improved time-frequency resolution. The FrFT is a parameterized transform with parameter, a, related to chirp rate. The two short-time implementations differ in how the value of a is chosen. In the first, a global optimization procedure selects one value of a with reference to the entire signal. In the second, a values are selected independently for each windowed section. Comparative variance measures based on the Gaussian function are given and are shown to be consistent with the uncertainty principle in fractional domains. For appropriately chosen FrFT orders, the derived fractional domain uncertainty relationship is minimized for Gaussian windowed linear chirp signals. The two short-time FrFT algorithms have complementary strengths demonstrated by time-frequency representations for a multicomponent bat chirp, a highly nonlinear quadratic chirp, and an output pulse from a finite-difference sonar model with dispersive change. These representations illustrate the improvements obtained in using FrFT based algorithms compared to the STFT.

Journal Article↗

PubMed2002

BAFF-induced NEMO-independent processing of NF-kappa B2 in maturing B cells.

NF-kappa B is usually activated by signal-induced, ubiquitin-mediated degradation of its inhibitor, I kappa B. This process is initiated by phosphorylation of I kappa B by the I kappa B kinase (IKK) complex, predominantly by the IKK beta catalytic subunit, and requires the regulatory subunit IKK gamma (NEMO). Another activation pathway, with no known physiological inducers, involves ubiquitin-mediated processing of the NF-kappa B2 inhibitory protein p100 and is dependent on phosphorylation of p100 by IKK alpha. We show here that B cell-activating factor (BAFF) activates this second pathway and that this requires the BAFF receptor (BAFF-R), the NF-kappa B-inducing kinase (NIK) and protein synthesis, but not NEMO. This NEMO-independent cascade is physiologically relevant for the survival and, hence, progression of maturing splenic B cells.

Animals↗

PubMed2002

Association of the adaptor TANK with the I kappa B kinase (IKK) regulator NEMO connects IKK complexes with IKK epsilon and TBK1 kinases.

Canonical activation of NF-kappa B is mediated via phosphorylation of the inhibitory I kappa B proteins by the I kappa B kinase complex (IKK). IKK is composed of a heterodimer of the catalytic IKK alpha and IKK beta subunits and a presumed regulatory protein termed NEMO (NF-kappa B essential modulator) or IKK gamma. NEMO/IKK gamma is indispensable for activation of the IKKs in response to many signals, but its mechanism of action remains unclear. Here we identify TANK (TRAF family member-associated NF-kappa B activator) as a NEMO/IKK gamma-interacting protein via yeast two-hybrid analyses. This interaction is confirmed in mammalian cells, and the domains required are mapped. TANK was previously shown to assist NF-kappa B activation in a complex with TANK-binding kinase 1 (TBK1) or IKK epsilon, two kinases distantly related to IKK alpha/beta, but the underlying mechanisms remained unknown. Here we show that TBK1 and IKK epsilon synergize with TANK to promote interaction with the IKKs. The TANK binding domain within NEMO/IKK gamma is required for proper functioning of this IKK subunit. These results indicate that TANK can synergize with IKK epsilon or TBK1 to link them to IKK complexes, where the two kinases may modulate aspects of NF-kappa B activation.

Adaptor Proteins, Signal Transducing↗

PubMed2002

Inappropriate implantable cardioverter defibrillator discharge from sensing of external alternating current leak.

Implantable cardioverter defibrillators (ICDs) are now an accepted and effective therapy for treatment of survivors of sudden cardiac death (SCD) and prevention of SCD in high-risk patients. Normal ICD function and delivery of therapy depends on appropriate sensing and detection of myocardial electrical potentials. Electromagnetic interference resulting in ICD malfunction is a well-documented phenomenon, however, there are less well-known external sources of interference, which may cause life threatening ICD malfunction. We report a unique case of repeated inappropriate ICD shocks in a ten-year old boy caused by the ICD sensing alternating current from an unexpected external source.

Child↗