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Biomedical subjects

Philip Thomas

Publications and source records attributed to Philip Thomas.

At least 19 recordsLinked to original sources
PubMed2006

A review of genome mutation and Alzheimer's disease.

Alzheimer's disease (AD) is a complex progressive neurodegenerative disorder of the brain and is the commonest form of dementia. The prevalence of this disease is predicted to increase 3-fold over the next 30 years and to date no reliable and conclusive diagnostic test exists that will identify individuals presymptomatically of susceptibility risk. This review examines the molecular, genetic, dietary and environmental evidence underlying the known pathology of AD and proposes a biologically plausible chromosome instability model to explain some of the features of the disease. Genome damage biomarkers such as aneuploidy of chromosome 17 and 21, oxidative damage to DNA and telomere shortening together with abnormal expression of APP, beta amyloid and tau proteins are discussed in terms of their potential value as risk biomarkers. These biomarkers could then be used in diagnosis and the evaluation of potentially effective preventative measures.

Alzheimer Disease↗
PubMed2006

Mutations in the gene encoding GlyT2 (SLC6A5) define a presynaptic component of human startle disease.

Hyperekplexia is a human neurological disorder characterized by an excessive startle response and is typically caused by missense and nonsense mutations in the gene encoding the inhibitory glycine receptor (GlyR) alpha1 subunit (GLRA1). Genetic heterogeneity has been confirmed in rare sporadic cases, with mutations affecting other postsynaptic glycinergic proteins including the GlyR beta subunit (GLRB), gephyrin (GPHN) and RhoGEF collybistin (ARHGEF9). However, many individuals diagnosed with sporadic hyperekplexia do not carry mutations in these genes. Here we show that missense, nonsense and frameshift mutations in SLC6A5 (ref. 8), encoding the presynaptic glycine transporter 2 (GlyT2), also cause hyperekplexia. Individuals with mutations in SLC6A5 present with hypertonia, an exaggerated startle response to tactile or acoustic stimuli, and life-threatening neonatal apnea episodes. SLC6A5 mutations result in defective subcellular GlyT2 localization, decreased glycine uptake or both, with selected mutations affecting predicted glycine and Na+ binding sites.

Amino Acid Sequence↗
PubMed2006

A simple noninvasive test to detect vascular disease in patients with erectile dysfunction: a novel method.

INTRODUCTION: The association between erectile dysfunction (ED) and cardiovascular disease (CVD) is becoming increasingly evident. Both conditions are thought to share a common denominator, which is endothelial dysfunction. Therefore, testing endothelial function in ED patients may serve to detect vascular disease in this cohort of patients. AIMS: To investigate whether measuring the reactive hyperemic response (RHR) of the forearm vessels through a simple noninvasive method could identify vascular disease in patients with ED. PATIENTS AND METHODS: Forty-eight male subjects were recruited into the study, 35 of whom presented to the sexual dysfunction clinic with a complaint of ED, and 13 healthy subjects served as a control group. The ED patients were subdivided into two groups, according to the presence or absence of CVD or its risk factors. The RHR of the forearm vessels was measured noninvasively in all subjects by using a handheld Doppler device. RESULTS: Significant reduction in the peak systolic velocity ration was observed in ED patients with concomitant CVD or risk factors in comparison with the other ED patients with no CVD or risk factors and the control group. Results were highly significant on both occasions (P < 0.001). The 50% recovery time was not significantly different between any of the groups (P > 0.05). CONCLUSION: Our results suggest that those patients with impaired RHR have an abnormality in their vascular system, which is likely to be the cause of their ED and CVD. Using this simple noninvasive method can help to identify vascular disease in ED patients. It can also be used to suggest vascular disease in any patient, where further tests might be indicated.

Adult↗
PubMed2006

Vagus nerve stimulation in chronic treatment-resistant depression: preliminary findings of an open-label study.

We evaluated the efficacy and safety of vagus nerve stimulation therapy in the treatment of 11 patients with chronic treatment-resistant depression. Mood was evaluated at frequent intervals over the year following implantation. All measures of depression, including the Hamilton Rating Scale for Depression reduced significantly. The response and remission rates were 55% and 27% respectively at 1 year. Side-effects were common, and some were severe.

Adult↗
PubMed2005

Folic acid deficiency increases chromosomal instability, chromosome 21 aneuploidy and sensitivity to radiation-induced micronuclei.

Folic acid deficiency can lead to uracil incorporation into DNA, hypomethylation of DNA, inefficient DNA repair and increase chromosome malsegregation and breakage. Because ionising radiation increases demand for efficient DNA repair and also causes chromosome breaks we hypothesised that folic acid deficiency may increase sensitivity to radiation-induced chromosome breakage. We tested this hypothesis by using the cytokinesis-block micronucleus assay in 10 day WIL2-NS cell cultures at four different folic acid concentrations (0.2, 2, 20, and 200 nM) that span the "normal" physiological range in humans. The study showed a significant dose-dependent increase in frequency of binucleated cells with micronuclei and/or nucleoplasmic bridges with decreasing folic acid concentration (P<0.0001, P=0.028, respectively). These biomarkers of chromosomal instability were also increased in cells irradiated (1.5 Gy gamma-rays) on day 9 relative to un-irradiated controls (P<0.05). Folic acid deficiency and gamma-irradiation were shown to have a significant interactive effect on frequency of cells containing micronuclei (two-way ANOVA, interaction P=0.0039) such that the frequency of radiation-induced micronucleated cells (i.e. after subtracting base-line frequency of un-irradiated controls) increased with decreasing folic acid concentration (P-trend<0.0001). Aneuploidy of chromosome 21, apoptosis and necrosis were increased by folic acid deficiency but not by ionising radiation. The results of this study show that folate status has an important impact on chromosomal stability and is an important modifying factor of cellular sensitivity to radiation-induced genome damage.

Aneuploidy↗
PubMed2005

Dynamic mobility of functional GABAA receptors at inhibitory synapses.

Importing functional GABAA receptors into synapses is fundamental for establishing and maintaining inhibitory transmission and for controlling neuronal excitability. By introducing a binding site for an irreversible inhibitor into the GABAA receptor alpha1 subunit channel lining region that can be accessed only when the receptor is activated, we have determined the dynamics of receptor mobility between synaptic and extrasynaptic locations in hippocampal pyramidal neurons. We demonstrate that the cell surface GABAA receptor population shows no fast recovery after irreversible inhibition. In contrast, after selective inhibition, the synaptic receptor population rapidly recovers by the import of new functional entities within minutes. The trafficking pathways that promote rapid importation of synaptic receptors do not involve insertion from intracellular pools, but reflect receptor diffusion within the plane of the membrane. This process offers the synapse a rapid mechanism to replenish functional GABAA receptors at inhibitory synapses and a means to control synaptic efficacy.

Biological Transport↗
PubMed2004

Huntingtin-associated protein 1 regulates inhibitory synaptic transmission by modulating gamma-aminobutyric acid type A receptor membrane trafficking.

Gamma-aminobutyric acid type A receptors (GABA(A)Rs) are the major sites of fast synaptic inhibition in the brain. An essential determinant for the efficacy of synaptic inhibition is the regulation of GABA(A)R cell surface stability. Here, we have examined the regulation of GABA(A)R endocytic sorting, a critical regulator of cell surface receptor number. In neurons, rapid constitutive endocytosis of GABA(A)Rs was evident. Internalized receptors were then either rapidly recycled back to the cell surface, or on a slower time scale, targeted for lysosomal degradation. This sorting decision was regulated by a direct interaction of GABA(A)Rs with Huntingtin-associated protein 1 (HAP1). HAP1 modulated synaptic GABA(A)R number by inhibiting receptor degradation and facilitating receptor recycling. Together these observations have identified a role for HAP1 in regulating GABA(A)R sorting, suggesting an important role for this protein in the construction and maintenance of inhibitory synapses.

Animals↗
PubMed2004

Folate deficiency induces aneuploidy in human lymphocytes in vitro-evidence using cytokinesis-blocked cells and probes specific for chromosomes 17 and 21.

Folate plays a critical role in the prevention of chromosome breakage and hypomethylation of DNA. Deficiency in this vitamin may lead to demethylation of heterochromatin causing structural centromere defects that could induce abnormal distribution of replicated chromosomes during nuclear division. Because aneuploidy of chromosomes 17 and 21 is often observed in breast cancer and leukaemia and increased risk for these cancers is associated with folate deficiency, we hypothesized that folate deficiency may lead to aneuploidy of chromosomes 17 and 21. To test these hypotheses we cultured lymphocytes from eight female volunteers (aged 40-48 years) in RPMI 1640 medium containing 12 or 120nM of folic acid (FA) or 5-methyltetrahydrofolate (MF) for 9 days. Chromosomes 17 and 21 aneuploidies induced by folate deficiency were measured in mononucleated (MONO) and cytokinesis-blocked binucleated (BN) lymphocytes after dual-color fluorescent in situ hybridization (FISH) with a digoxigenin-labeled probe for the alphoid satellite sequence of chromosome 17 and a biotin-labeled probe for the pericentric region of chromosome 21. The results showed that 12nm of MF or FA caused a significant 26-35% increment in frequency of aneuploidy of chromosome 17 (P = 0.0017) and aneupoidy of chromosome 21 (P = 0.0008) relative to 120nM MF or FA. The pattern of aneuploidy in binucleated cells was significantly correlated with that observed in mononucleated cells (R = 0.51-0.75, P < 0.0004) and was consistent with a model based on chromosome loss or partial aneusomy rescue as the cause rather than non-disjunction, although the latter mechanism could not be excluded. MF was not more efficient than FA in preventing aneuploidy in this in vitro system. We conclude that folate deficiency is a risk factor for chromosomes 17 and 21 aneuploidy.

Aneuploidy↗
PubMed2004

Brain-derived neurotrophic factor modulates fast synaptic inhibition by regulating GABA(A) receptor phosphorylation, activity, and cell-surface stability.

The efficacy of GABAergic synaptic inhibition is a principal factor in controlling neuronal activity. We demonstrate here that brain-derived neurotrophic factor modulates the activity of GABA(A) receptors, the main sites of fast synaptic inhibition in the brain, within minutes of application. Temporally, this comprised an early enhancement in the miniature IPSC amplitude, followed by a prolonged depression. This modulation was concurrent with enhanced PKC-mediated phosphorylation, followed by protein phosphatase 2A (PP2A)-mediated dephosphorylation of the GABA(A) receptor. Mechanistically, these events were facilitated by differential recruitment of PKC, receptor for activated C-kinase, and PP2A to GABA(A) receptors, depending on the phosphorylation state of the receptor beta3-subunit. Thus, transient formation of GABA(A) receptor signaling complexes has the potential to provide a basis for acute changes in receptor function underlying GABAergic synaptic plasticity.

Animals↗
PubMed2004

Cystic fibrosis: recent structural insights.

Cystic fibrosis (CF) is a debilitating human disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. The recently solved crystal structures of the murine CFTR nucleotide binding domain (NBD) provide insight into the molecular basis of several CF-causing mutations. In addition, the NBD structures reveal several unexpected findings that may have implications concerning CFTR function. In this mini-review, we discuss the key structural features of ATP Binding Cassette (ABC) transporter NBDs, as well as highlight how structural information has aided our understanding of the ATP-regulated solute transport cycle.

ATP-Binding Cassette Transporters↗
PubMed2004

Methylenetetrahydrofolate reductase C677T polymorphism, folic acid and riboflavin are important determinants of genome stability in cultured human lymphocytes.

We tested the hypothesis that methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism, folic acid deficiency and riboflavin deficiency, independently or interactively, are important determinants of genomic stability, cell death, cell proliferation and homocysteine (Hcy) concentration in 9-d human lymphocyte cultures. Lymphocytes of seven wild-type (CC) and seven mutant (TT) homozygotes were cultured under the four possible combinations of deficiency and sufficiency of riboflavin (0 and 500 nmol/L) and folic acid (20 and 100 nmol/L) at a constant L-methionine concentration of 50 micromol/L. Viable cell growth was 25% greater in TT than in CC cells (P<0.05) and 32% greater at 100 nmol/L folic acid than at 20 nmol/L folic acid (P=0.002). The comprehensive cytokinesis-block micronucleus assay was used to measure micronuclei (MNi; a marker for chromosome breakage and loss), nucleoplasmic bridges (NPB; a marker of chromosome rearrangement) and nuclear buds (NBUD, a marker of gene amplification). The MNi levels were 21% higher in TT cells than in CC cells (P<0.05) and 42% lower in the high folic acid medium than in the low folic acid medium (P<0.0001). The NBUD levels were 27% lower in TT cells than in CC cells (P<0.05) and 45% lower in the high folic acid medium than in the low folic acid medium (P<0.0001). High riboflavin concentration (500 nmol/L) increased NBUD levels by 25% (compared with 0 nmol/L riboflavin) in folate-deficient conditions (20 nmol/L folic acid medium; P<0.05), and there was an interaction between folic acid and riboflavin that affected NBUD levels (P=0.042). This preliminary investigation suggests that MTHFR C677T polymorphism and riboflavin affect genome instability; however, the effect is relatively small compared with that of folic acid.

Adult↗
PubMed2004

Engaging communities.

Explore the source record for details and available documents.

Community Mental Health Services↗
PubMed2003

A conserved GXXXG motif in APH-1 is critical for assembly and activity of the gamma-secretase complex.

The multipass membrane protein APH-1, found in the gamma-secretase complex together with presenilin, nicastrin, and PEN-2, is essential for Notch signaling in Caenorhabditis elegans embryos and is required for intramembrane proteolysis of Notch and beta-amyloid precursor protein in mammalian and Drosophila cells. In C. elegans, a mutation of the conserved transmembrane Gly123 in APH-1 (mutant or28) leads to a notch/glp-1 loss-of-function phenotype. In this study, we show that the corresponding mutation in mammalian APH-1aL (G122D) disrupts the physical interaction of APH-1aL with hypoglycosylated immature nicastrin and the presenilin holoprotein as well as with mature nicastrin, presenilin, and PEN-2. The G122D mutation also reduced gamma-secretase activity in intramembrane proteolysis of membrane-tethered Notch. Moreover, we found that the conserved transmembrane Gly122, Gly126, and Gly130 in the fourth transmembrane region of mammalian APH-1aL are part of the membrane helix-helix interaction GXXXG motif and are essential for the stable association of APH-1aL with presenilin, nicastrin, and PEN-2. These findings suggest that APH-1 plays a GXXXG-dependent scaffolding role in both the initial assembly and subsequent maturation and maintenance of the active gamma-secretase complex.

Amino Acid Motifs↗