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Biomedical subjects

Peter Williamson

Publications and source records attributed to Peter Williamson.

At least 19 recordsLinked to original sources
PubMed2007

Interaction between allelic variation in IL12B and CCR5 affects the development of AIDS: IL12B/CCR5 interaction and HIV/AIDS.

OBJECTIVE: IL-12 is involved in immune surveillance and response that links the innate and adaptive arms of the immune system. Among its many effects, IL-12 increases the cell surface expression of the CCR5 co-receptor for R5 strains of HIV-1, which are predominantly involved in HIV-1 transmission and spread. In the present study we investigated the effect of epistasis between allelic variants of CCR5 and IL12B on the susceptibility to HIV-1 infection and HIV-1 disease progression. METHODS: HIV-1-positive patients were genotyped for IL12Bpro from two groups of HIV-1 seroincident patients from Western Australia (n = 101 and 200), longitudinal clinical data were available for one of the Western Australian cohorts for a period of over 12 years and a group of seroprevalent individuals from Sydney (n = 112). A group of ethnically matched healthy volunteers (n = 200) was also genotyped as controls. Comparison of allele frequencies between HIV-1 patients and controls was performed to determine the influence on susceptibility to HIV-1 infection, and regression analysis was used to determine the influence on disease progression. RESULTS: Individuals positive for CCR5Delta32 and who carry the IL12Bpro1.1 genotype were underrepresented across all three independent HIV-1-positive cohorts [odds ratio 0.5; 95% confidence interval (CI) 0.28-0.97; P = 0.038]. CCR5wt/wt and IL12Bpro2.2 individuals progressed to AIDS at a significantly faster rate than other CCR5 and IL12Bpro groups (hazards ratio 3.24; 95% CI 1.9-15.1; P = 0.002). CONCLUSION: Epistatic interaction between allelic variants of CCR5 and IL12Bpro exert a significant influence on the clinical outcome of HIV-1 infection.

Acquired Immunodeficiency Syndrome↗
PubMed2006

Marked differences in the structures and protein associations of lymphocyte and monocyte CD4: resolution of a novel CD4 isoform.

The structures, molecular interactions and functions of CD4 in a subset of T lymphocytes have been well characterized. The CD4 receptors of other cell types have, however, been poorly documented. We have previously shown that lymphocytes and monocytes/macrophages differ in their expression of CD4 monomers and dimers. In the present study, we have shown further significant differences. Variability in the blocking of CD4 mAb binding by sulfated polyanions indicated differences in exofacial CD4 structures. In contrast to the well-documented 55 kDa monomers in lymphocytic cells, monocytic cells were found to coexpress two monomer isoforms: the 55 kDa form and a novel 59 kDa species. Experimental uncoupling of CD4 disulfides indicated that the oxidized 55 kDa monomer could be converted to the 59 kDa form. This was achieved by chemical reduction of purified native or recombinant CD4, or in cell transfection experiments by mutation of cysteine to alanine in domain 1 (D1) (Cys16 or Cys84) and in domain 4 (D4) (Cys303 or Cys345). All of these modifications promote CD4 distension on SDS-PAGE analysis and indicate that, when CD4 inter-beta-sheet disulfides in the D1 and D4 Ig folds are disrupted, there is an unravelling of the oxidized form to an extended 59 kDa unfolded state. We hypothesize that this may be a transition-state, structural-intermediate in the formation of disulfide-linked homodimers. Also identified were CD4-tyrosine kinase dissimilarities in which lymphocyte CD4 associated with Lck, but monocyte CD4 associated with HcK. These findings show that there is complex heterogeneity in structures and interactions in the CD4 of T lymphocytes and monocytes.

Amino Acid Substitution↗
PubMed2005

Doubling the cloak of (in)competence in client/therapist interactions.

Cultural competence is used (often implicitly) to make decisions in human service settings. When therapists make decisions about whether or not a particular service will be offered, they place themselves in a position where their own competence can be judged. Using narrative data on independence and the elderly, we apply Edgerton's idea of the cloak of competence to demonstrate this doubling effect.

Adaptation, Psychological↗
PubMed2004

A 4.0-T fMRI study of brain connectivity during word fluency in first-episode schizophrenia.

OBJECTIVE: To use functional magnetic resonance imaging (fMRI) to investigate functional connectivity, and hence, underlying neural networks, in never-treated, first-episode patients with schizophrenia using a word fluency paradigm known to activate prefrontal, anterior cingulate, and thalamic regions. Abnormal connectivity between the prefrontal cortex (PFC) and other brain regions has been demonstrated in chronic, medicated patients in previous positron emission tomography (PET) studies, but has not to our knowledge, previously been demonstrated using both first-episode, drug-naïve patients and fMRI technology. METHODS: A 4.0-Tesla (T) fMRI was used to examine activation and functional connectivity [psychophysiological interactions (PPIs)] during a word fluency task compared to silent reading in 10 never-treated, first-episode patients with schizophrenia and 10 healthy volunteers of comparable age, sex, handedness, and parental education. RESULTS: Compared to healthy volunteers, the schizophrenia patient group exhibited less activation during the word fluency task, mostly in the right anterior cingulate and prefrontal regions. Psychophysiological interactions between right anterior cingulate and other parts of the brain revealed a localized interaction with the left temporal lobe in healthy volunteers during the task and a widespread unfocussed interaction in patients. CONCLUSION: These findings suggest anterior cingulate involvement in the neuronal circuitry underlying schizophrenia.

Adult↗
PubMed2004

E2F1 promotes cytokine mediated cell survival via a mechanism that is separable from its cell cycle regulatory effects.

Cytokines are important regulators of lymphocyte proliferation and survival during immune responses. The retinoblastoma pathway constitutes an important intracellular network that forms the basis of cell cycle regulation and cellular proliferation in all mammalian cells. Transcription factors of the E2F family form a central component of this pathway, and represent important targets for activation by mitogenic cytokines such as interleukin-2 (IL-2). We have previously described a model for study of the E2F1 transcription factor by stable overexpression in the cytokine-dependent lymphoid progenitor cell line BaF-B03. In this model of IL-2 receptor signalling, E2F1 overexpressing BaF-B03 cells exhibit cytokine-independent cellular proliferation and survival, thereby supporting the concept that E2F activation is a critical step in the genesis of clonal expansion of antigen-primed lymphocytes. Here, we provide evidence linking E2FI to a serum-dependent cell survival pathway that is separable from its cell cycle regulatory effects. Our data show that the serum glycerophospholipid lysophosphatidic acid is capable of mediating this survival effect via a mechanism that is sensitive to chemical inhibition of phosphatidylinositol 3-kinase. IL-2 mediated cell survival, but not cell cycle progression, is dependent upon this serum-dependent cell survival pathway. The findings presented here provide an insight into how mitogenic cytokines such as IL-2 regulate the apparently separate processes of lymphocyte proliferation and survival via recruitment of the retinoblastoma pathway.

Animals↗
PubMed2004

HIV type 1 Nef increases the association of T cell receptor (TCR)-signaling molecules with T cell rafts and promotes activation-induced raft fusion.

HIV-1 Nef (Nef) is a myristoylated protein that contributes to HIV disease pathogenesis. Nef has a modulatory effect on T cell receptor (TCR) signaling, resulting in up-regulation of interleukin-2 (IL-2) production in stimulated T cells. Recent studies have shown that efficient TCR signaling requires enhanced association of TCR-signaling molecules with plasma membrane microdomains (lipid rafts) and fusion of rafts into larger structures. We utilized Jurkat T cell lines expressing wild-type Nef (Nef(wt)) and a myristoylation-deficient form of Nef (Nef(G)2(A)), from an inducible promoter, to determine the effects of Nef on the association of TCR-signaling molecules with rafts in nonstimulated T cells. In addition, the effect of Nef on raft size, before and after TCR activation by CD3 cross-linking, was also examined. Following induction, Nef(wt) was associated with both rafts and nonrafts, while Nef(G)2(A) was almost exclusively cytosolic. Induction of Nef(wt), but not Nef(G)2(A), coincided with an increased association of the src family tyrosine kinase, Lck, and TCRzeta with rafts, but not with nonrafts. Further, rafts were found to be significantly larger in CD3-activated T cells in the presence of Nef(wt) when compared to nonexpressing cells. We propose that myristoylated, raft-localized Nef primes resting T cells for activation by increasing the levels of signaling molecules within rafts, and that TCR activation is enhanced by the capacity of Nef to promote raft fusion.

Gene Products, nef↗
PubMed2003

Chemokine receptor genotype and response to interleukin-2 therapy in HIV-1-infected individuals.

Interleukin-2 therapy is an immune-based treatment for HIV-1-infected individuals with declining CD4(+) T cell counts. Intravenous IL-2 produces an elevation of circulating CD4(+) T cells, but with a varying degree of effectiveness in individual patients. IL-2 is also known to increase the expression of chemokine receptors, coreceptors for HIV-1. Allelic variation in chemokine receptor genes can markedly affect the course of HIV disease; consequently, we analyzed CCR5 and CCR2B genotypes among a cohort of HIV-1-infected individuals that received IL-2 therapy. DNA was extracted from treated individuals and genotyping was performed using PCR followed by allele-specific detection or cleavage of the amplified product. Samples from 47 trial participants (25 CIV-IL-2 group; 22 placebo group) were analyzed for CCR5 and CCR2B genotype. We report that CCR5 Delta 32 heterozygous individuals had a greater CD4(+) T cell response to continuous intravenous IL-2 (CIV-IL-2) treatment than those homozygous for the wild-type allele (median = 427 vs 237 cells/mm(3); P = 0.03). This study highlights the importance of interactions between IL-2 and CCR5; at the clinical level, it argues for assessment of chemokine receptor genotype in IL-2 and perhaps other immune-based therapy trials.

Adolescent↗
PubMed2003

Detergent-resistant membrane fractions contribute to the total 1H NMR-visible lipid signal in cells.

Leukocytes and other cells show an enhanced intensity of mobile lipid in their 1H NMR spectra under a variety of conditions. Such conditions include stimulation, which has recently been shown to involve detergent-resistant, plasma membrane domains (DRMs) often called lipid rafts. As there is much speculation surrounding the origin of cellular NMR-visible lipid, we analysed subcellular fractions, including DRMs, by NMR spectroscopy. We demonstrated that DRMs isolated by density gradient centrifugation from lymphoid (CEM-T4, stimulated Jurkat cells), and monocytoid (THP-1) cells produced NMR-visible, lipid signals. Large scale subfractionation of THP-1 cells determined that while cytoplasmic lipid droplets constituted much of the total NMR-visible lipid, the contribution of DRMs was significant. Qualitative and quantitative lipid analyses revealed that DRMs and lipid droplets differed in their lipid composition. DRMs were enriched in cholesterol and ganglioside GM1, and contained relatively unsaturated fatty acids compared with the lipid droplets. Both lipid droplets and DRMs contained neutral lipids (triacylgycerols, cholesterol ester, fatty acids in THP-1 cells) that could, in addition to phospholipids, contribute to the NMR-visible lipid. The lipid droplets also exhibited different protein profiles and contained 500-fold less protein than DRMs, confirming that DRMs and droplets were fractionated as separate entities. The NMR-visible lipid in DRMs is therefore unlikely to be a contaminant from lipid droplets. We propose a micropartitioning of the NMR-visible mobile lipid of whole cells between intracellular lipid droplets, where most of this lipid resides, and detergent-resistant plasma membrane domains.

Cell Fractionation↗
PubMed2003

Expression of an active p110 catalytic subunit of phosphatidylinositol 3-kinase alters the proliferative capacity of interleukin-2 receptor signals.

Activation of phosphatidylinositol 3-kinase (PI3K) is an early and essential step in interleukin-2 receptor (IL-2R) signalling, and plays an important role in regulating both cell survival and cellular proliferation. In the present study, we utilized Baf-B03 cells expressing mutated IL-2R to examine the contribution of PI3K to proliferative capacity. In this model IL-2-mediated induction of the downstream PI3K-dependent signalling molecule p70 S6 kinase was detected, but there was no proliferative response. Increasing the level of PI3K activity by transfection of an active form of the catalytic subunit, p110*, enabled the proliferative capacity of the mutated receptor. Whereas, in cells without p110*, IL-2 lacked the capacity to induce c-myc and to overcome an S-phase checkpoint, S-phase transition was restored by transfection of p110*, and this was accompanied by an increase in the c-myc response. Despite the presence of p110*, activity cells still required IL-2R-derived signals for proliferation, and IL-2Rbeta truncated at amino acid 350 were sufficient to provide this signalling activity. The data support a model in which the level of available PI3K can determine the cellular response to IL-2.

Animals↗
PubMed2003

Practice parameter: temporal lobe and localized neocortical resections for epilepsy.

PURPOSE: To examine evidence for effectiveness of anteromesial temporal lobe and localized neocortical resections for disabling complex partial seizures. METHODS: Systemic review and analysis of the literature since 1990. RESULTS: One intention-to-treat Class I randomized controlled trial of surgery for mesial temporal lobe epilepsy found that 58% of patients randomized to be evaluated for surgical therapy (64% of those who received surgery) were free of disabling seizures and 10 to 15% were unimproved at the end of 1 year, compared with 8% free of disabling seizures in the group randomized to continued medical therapy. There was a significant improvement in quantitative quality-of-life scores and a trend toward better social function at the end of 1 year for patients in the surgical group, no surgical mortality, and infrequent morbidity. Twenty-four Class IV series of temporal lobe resections yielded essentially identical results. There are similar Class IV results for localized neocortical resections; no Class I or II studies are available. CONCLUSIONS: A single Class I study and 24 Class IV studies indicate that the benefits of anteromesial temporal lobe resection for disabling complex partial seizures is greater than continued treatment with antiepileptic drugs, and the risks are at least comparable. For patients who are compromised by such seizures, referral to an epilepsy surgery center should be strongly considered. Further studies are needed to determine if neocortical seizures benefit from surgery, and whether early surgical intervention should be the treatment of choice for certain surgically remediable epileptic syndromes.

Anticonvulsants↗
PubMed2003

Neurostimulation for refractory epilepsy.

Neurostimulation is an emerging treatment for refractory epilepsy. To date the precise mechanism of action remains to be elucidated. Better insight in the mechanism of action may identify seizure types or syndromes that respond to such a treatment and may guide the search for optimal stimulation parameters and finally improve clinical efficacy. In the past ten years some progress has been made through neurophysiological, neuroanatomical, neurochemical and cerebral blood flow studies in patients and animals undergoing vagus nerve stimulation (VNS). Interesting results have been found in VNS-treated patients that underwent evoked potential measurements, cerebrospinal fluid investigation, neuropsychological testing and PET, SPECT and fMRI testing. Desynchronisation of abnormal synchronous epileptic activity is one of the hypotheses on the mode of action that might primarily be responsible for an anti-seizure effect. There is however increasing evidence from research and clinical observation that VNS might establish a true and long-term anti-epileptic effect. It has been shown that VNS influences neurotransmission in the brain and provokes long-term changes in cerebral blood flow in areas crucial for epileptogenesis such as the thalamus and medial temporal lobe structures. Deep brain stimulation (DBS) for epilepsy has regained interest. Central nervous system structures known to play a key role in the epileptogenic network such as the thalamus and subthalamic nucleus have been targeted. Another approach is to target the ictal onset zone such as the medial temporal lobe. At Ghent University Hospital 10 patients have been treated with long-term amygdalohippocampal DBS. Several hypotheses have been raised for the mechanism of action of DBS for refractory seizures. Seizure reduction may be due to a microlesion caused by electrode insertion or by provoking a reversible functional lesion due to the effect of electrical current on hyperexcitable tissue. Neurophysiological techniques such as evoked potentials monitoring and intraoperative single unit potential recordings may guide correct electrode placement, individual DBS titration and elucidation of the mechanims of action of DBS for epilepsy.

Animals↗
PubMed2002

T-cell antigen receptor peptides inhibit signal transduction within the membrane bilayer.

Previous studies have shown that a synthetic peptide (core peptide, CP) corresponding to a 9-amino-acid region in the transmembrane domain of the alpha subunit of the T-cell antigen receptor (TCR) can suppress T-cell function in vitro and in vivo. The aim of these experiments was to determine the cellular site and molecular mechanism of CP inhibition in T cells. The cytochrome c-sensitive TCR-expressing hybridoma (2B4) was stimulated with pigeon cytochrome c antigen, anti-CD3 crosslinking, or PMA and ionomycin, in the presence or absence of CP, and the resulting IL-2 produced was measured in a bioassay using an IL-2-dependent cell line (CTLL-2). In the presence of CP, IL-2 production was inhibited following antigen-induced stimulation. By contrast, when stimulated with cross-linking antibodies to the CD3 complex or with PMA and ionomycin, both of which activate T cells downstream of the TCR antigen recognition site, CP had no effect on IL-2 production. These experiments suggest that CP interferes with TCR function by inhibiting T-cell activation at the transmembrane/receptor level. In addition, we show that CP inhibits early TCR signal transduction events such as TCR zeta chain phosphorylation following stimulation with either antigen or anti-CD3-crosslinking antibodies, although this is unlikely to be the mechanism leading to the reduced IL-2 production.

Amino Acid Sequence↗
PubMedDate not supplied

Vagus nerve stimulation for refractory epilepsy: a transatlantic experience.

Vagus nerve stimulation (VNS) is an alternative treatment for medically or surgically refractory epilepsy. The long-term efficacy and safety of VNS were evaluated in a large patient series at Ghent University Hospital and Dartmouth-Hitchcock Medical Center. Between March 1995 and February 2003, seizure frequency and type as well as prescribed antiepileptic drugs and side effects were prospectively assessed in 131 patients treated with VNS in either center. Patients with a minimum follow-up duration of 6 months were included in the efficacy and safety analysis. A total of 118 of 131 implanted patients had a minimum postimplantation follow-up period of 6 months (mean, 33 months). The mean age of these patients was 32 years and the mean duration of refractory epilepsy was 22 years. The mean reduction in monthly seizure frequency in all patients was 55% (range, 0-100; SD = 31.6). Seven percent of patients were free of seizures with impaired consciousness, 50% of patients had a seizure frequency reduction of more than 50%, and 21% of patients were nonresponders. Fifteen patients reported stimulation-related side effects such as hoarseness or gagging. In a large patient series from two geographically distinct epilepsy centers located in two different continents, VNS proved to be efficacious and safe during long-term follow-up.

Adolescent↗