PubMed Health⌕ Search

Biomedical subjects

Gareth Williams

Publications and source records attributed to Gareth Williams.

At least 19 recordsLinked to original sources
PubMed2006

Places, people and mental health: a multilevel analysis of economic inactivity.

This paper investigates multilevel associations between the common mental disorders of anxiety, depression and economic inactivity measured at the level of the individual and the UK 2001 census ward. The data set comes from the Caerphilly Health & Social Needs study, in which a representative survey of adults aged 18-74 years was carried out to collect a wide range of information which included mental health status (using the Mental Health Inventory (MHI-5) scale of the Short Form-36 health status questionnaire), and socio-economic status (including employment status, social class, household income, housing tenure and property value). Ward level economic inactivity was measured using non-means tested benefits data from the Department of Work and Pensions (DWP) on long-term Incapacity Benefit and Severe Disablement Allowance. Estimates from multilevel linear regression models of 10,653 individuals nested within 36 census wards showed that individual mental health status was significantly associated with ward-level economic inactivity, after adjusting for individual-level variables, with a moderate effect size of -0.668 (standard error=0.258). There was a significant cross-level interaction between ward-level and individual economic inactivity from permanent sickness or disability, such that the effect of permanent sickness or disability on mental health was significantly greater for people living in wards with high levels of economic inactivity. This supports the hypothesis that living in a deprived neighbourhood has the most negative health effects on poorer individuals and is further evidence for a substantive effect of the place where you live on mental health.

Adolescent↗
PubMed2006

The fibroblast growth factor receptor acid box is essential for interactions with N-cadherin and all of the major isoforms of neural cell adhesion molecule.

Interactions between the neural cell adhesion molecules NCAM and N-cadherin with the fibroblast growth factor receptor (FGFR) are important for a number of developmental events and have also been implicated in tumor progression. The factors regulating these interactions are not known. We have used co-immunoprecipitation and co-clustering paradigms to show that both adhesion molecules can interact with the 3Ig IIIC isoform of the FGFR1 in a number of cell types. Interestingly, whereas the interaction can be seen over most of the cell surface, it is not seen at points of cell-cell contact where the adhesion molecules accumulate at stable junctions. We also demonstrate for the first time that all of the major isoforms of NCAM can interact with the FGFR. Using deletion mutagenesis we have found that the adhesion molecule/FGFR interaction can withstand the removal of most of any one of the FGFR immunoglobulin-like domains (D1-D3). In contrast, the FGFR interaction with N-cadherin and NCAM (but not FGF) is absolutely dependant on the presence of the acid box motif that can be found in the linker region between D1 and D2. As this motif can be spliced out of all four FGFRs, it suggests that this is one mechanism that can regulate the interaction of the receptor with different ligand classes.

Animals↗
PubMed2006

Myostatin inhibition slows muscle atrophy in rodent models of amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disease leading to motor neuron cell death, but recent studies suggest that non-neuronal cells may contribute to the pathological mechanisms involved. Myostatin is a negative regulator of muscle growth whose function can be inhibited using neutralizing antibodies. In this study, we used transgenic mouse and rat models of ALS to test whether treatment with anti-myostatin antibody slows muscle atrophy, motor neuron loss, or disease onset and progression. Significant increases in muscle mass and strength were observed in myostatin-antibody-treated SOD1(G93A) mice and rats prior to disease onset and during early-stage disease. By late stage disease, only diaphragm muscle remained significantly different in treated animals in comparison to untreated controls. Myostatin inhibition did not delay disease onset nor extend survival in either the SOD1(G93A) mouse or rat. Together, these results indicate that inhibition of myostatin does not protect against the onset and progression of motor neuron degenerative disease. However, the preservation of skeletal muscle during early-stage disease and improved diaphragm morphology and function maintained through late stage disease suggest that anti-myostatin therapy may promote some improved muscle function in ALS.

Age of Onset↗
PubMed2006

Novel markers of cell kinetics to evaluate progression from cirrhosis to hepatocellular carcinoma.

BACKGROUND: We investigated cell cycle kinetics of nodular lesions in cirrhosis to differentiate hepatocellular carcinoma (HCC) from its precursor lesions. METHODS: Twelve small HCC, 10 regenerative (RN), six large regenerative (LRN), and five dysplastic nodules (DN), identified in explant cirrhotic livers of five consecutive patients transplanted at Royal Free Hospital in 2002. Immunoperoxidase for MCM2, geminin and Ki67 was performed and the percentage of positive cells counted. RESULTS: The proportion of cells expressing MCM2 was more than those expressing Ki67, which in turn was more than those expressing geminin (overall median=16%, 2% and 0.5%, respectively, P<0.001). There was a statistically significant trend of increasing Ki67 expression (P=0.006), from RN to HCC; this trend was not statistically significant for geminin (P=0.18) or MCM2 (P=0.51). The median percentage of cells expressing Ki67 was 1% in RN, 0.5% in LRN, 2.2% in DN and 5.4% in HCC. The combination of these markers identified four different cell kinetics patterns: 'resting' (G0 cells: MCM2 -ve, Ki67 -ve, geminin -ve); 'licensed' (MCM2 +ve, Ki67 -ve, geminin -ve); 'slowly growing' (G1 phase arrest, MCM2 +ve, Ki67 +ve, low (0.4%) geminin) and expanding (MCM2 +ve, Ki67 +ve, geminin +ve) nodules. CONCLUSIONS: The combination of MCM2, geminin and Ki67 could represent a valuable tool in the understanding of HCC progression in cirrhosis.

Adult↗
PubMed2006

Recently published papers: pulmonary care, pandemics, and eugenics in surviving sepsis?

Respiratory failure is one of the leading admission diagnoses on the critical care unit, and the journals have reflected this over the past few months. An understanding of the aetiology of pulmonary sepsis is important but your choice of ventilator gas humidification system is not. There are prophecies of more pandemics, but panic is futile because survival is all down to your genes.

Disease Outbreaks↗
PubMed2006

Recently published papers: pneumonia, hypothermia and the elderly.

Pneumonia (hospital-acquired and community-acquired) is commonly encountered in intensive care. Several papers recently published on this subject have shed more light on different aspects of this important topic. Hypothermia has been shown to improve post-arrest outcome, but how often do we use it? And finally, several papers have recently appeared in the journals related to the admission of the elderly to the critical care area and their outcome.

Aged↗
PubMed2005

Melanocortin-4 receptors, beta-MSH and leptin: key elements in the satiety pathway.

This paper reviews aspects of our research, focusing on the role of the melanocortin system in the central regulation of feeding and energy balance, which was begun in 1997. It describes data from successive physiological studies, concerning the identity of the appetite-regulating melanocortin receptor, melanocortin-4 receptor (MC4R) regulation with altered nutritional status, the role of MC4R in dietary obesity and the identity of the endogenous MC4R ligand.

Animals↗
PubMed2005

Effect of intraperitoneal CCK-8 on food intake and brain orexin-A after 48 h of fasting in the rat.

We investigated the interactions of the peripheral satiety peptide cholecystokinin and the brain orexin-A system in the control of food intake. The effect of an intraperitoneal (i.p.) injection of sulfated cholecystokinin octapeptide (in this article called CCK) (5 microg/kg, 4.4 nmol/kg) or of phosphate-buffered saline (PBS, vehicle control) on 48 h fasting-induced feeding and on orexin-A peptide content was analyzed in diverse brain regions innervated by orexin neurons and involved in the control of food intake. Administration of CCK after a 48 h fast reduced fasting-induced hyperphagia (P<0.05). I.p. CCK increased the orexin-A content in the posterior brainstem of 48 h fasted rats by 35% (P<0.05). Fed animals receiving CCK had 48% higher orexin-A levels in the posterior brainstem than fasted rats (P<0.05). In the lateral hypothalamus, fasting decreased orexin-A levels by 50% as compared to fed rats (P<0.05). In the septal nuclei, the combination of fasting and CCK administration reduced orexin-A contents compared to fed PBS and CCK animals by 13% and 17%, respectively (P<0.05). These results suggest a convergence of pathways activated by peripheral CCK and by fasting on the level of orexin-A released in the posterior brainstem and provide evidence for a novel interaction between peripheral satiety signaling and a brain orexigen in the control of food intake.

Animals↗
PubMed2005

Recently published papers: an ancient debate, novel monitors and post ICU outcome in the elderly.

Tracheostomies have been around for close to 3000 years, so one would hope that the controversies might have been thrashed out by now, but apparently not. Judging by some recent publications it would appear that we still do not know when or how to insert them. Monitoring is fundamental to critical care; two papers describe novel/modified techniques for assessing traumatic brain injury and cardiac output. The intensive care unit imposes a heavy treatment burden, particularly on the elderly. What impact does this have on the lives of the survivors?

Aged↗
PubMed2005

Recently published papers: A clinical conundrum, new from old and advances in ventilation?

'Every day' clinical conundrums are all too infrequently addressed in the mainstream literature, but in the past few months two reports attempted to tackle the thorny problem of the occult cervical spine injury on the intensive care unit. Are we approaching the death knell for prone ventilation, and how much more can we squeeze out of the PROWESS study? Also, we must of course mention noninvasive ventilation.

Cervical Vertebrae↗
PubMed2005

Effect of CCK-8 on insulin-induced hyperphagia and hypothalamic orexigenic neuropeptide expression in the rat.

The influence of cholecystokinin octapeptide (CCK-8) on normal and insulin-induced feeding and expression of orexigenic hypothalamic neuropeptides was investigated in male rats. CCK-8, administered during meals (4 microg/kg) or continuously (32 microg/kg over 60 min), blunted the stimulating effect of insulin (50 IU/kg) on feeding by reducing meal size (-60%; P<0.05 or -86%; P<0.0001, respectively). Rats without access to food and injected with IP insulin (50 IU/kg) showed increased hypothalamic mRNA levels of orexin (+30%; P<0.05) and melanin-concentrating hormone (+52%; P<0.05), as compared with ad libitum-fed and saline-injected control rats. Continuous IP infusion of CCK-8 (32 microg/kg) blunted these increases. Our results suggest that both orexin and melanin-concentrating hormone participate in the response to insulin hypoglycemia without food being present; these neurons may be involved in mechanisms related to insulin-induced hyperphagia. Signals triggered by peripheral CCK-8 act to decrease the expression of orexin and melanin-concentrating hormone. This may be associated with a reduction in hyperphagia.

Animals↗
PubMed2005

Cell proliferation and granule cell dispersion in human hippocampal sclerosis.

Granule cell dispersion (GCD) is observed in approximately 40% of cases of hippocampal sclerosis (HS) in patients with epilepsy. Studies in animal models suggest that GCD may be a consequence of enhanced proliferation of granule cell precursors as a result of seizures. We quantified the number of cells in cycle in subfields of the hippocampus with immunohistochemistry for Mcm2 in 14 HS cases with or without severe GCD compared to 6 epilepsy patients without classical HS or GCD as well as 5 postmortem controls. Higher numbers of Mcm2-positive cells were seen in the region of the granule cell layer in patients with severe GCD, and immunolabeling with Geminin and Ki-67 confirmed a proportion were progressing through cycle. Double labeling with Mcm2 and GFAP confirmed the majority of these cycling cells were GFAP-negative and occasional cells stained colocalized with stem cell marker nestin. These findings support the view that GCD may be a phenomenon related to increased progenitor cell proliferation in patients with hippocampal damage and chronic epilepsy.

Adult↗
PubMed2005

A complementary peptide approach applied to the design of novel semaphorin/neuropilin antagonists.

Semaphorin 3A can inhibit axonal growth and induce neuronal apoptosis following binding to neuropilin-1, with the membrane proximal MAM (meprin, A5, mu) domain in neuropilin-1 playing a key role in the formation of a higher order receptor complex. If functional motifs on semaphorin 3A and/or the MAM domain can be identified, then small-constrained peptides might be developed as antagonists. We have scored peptide pairs for complementary hydropathy and antisense homology to identify a candidate functional motif in the Ig domain of semaphorin 3A, and in the MAM domain of neuropilin-1. Synthetic peptides corresponding to these sequences fully inhibit growth cone collapse induced by semaphorin 3A. A number of smaller peptides derived from the parental sequence also inhibited the response, particularly after they were constrained by a disulfide bond. Finally, we have used an algorithm to design a peptide that is a near-perfect hydropathic complement of the candidate functional site in the MAM domain; this also inhibits the semaphorin 3A response. Thus, an algorithm-driven methodology has led to the identification of three independent semaphorin 3A antagonists. Semaphorin 3F stimulates growth cone collapse following binding to the closest relative to neuropilin-1 in the genome, neuropilin-2. Where tested, the peptides that antagonise semaphorin 3A failed to inhibit the semaphorin 3F response.

Animals↗
PubMed2005

Mental health inequalities in Wales, UK: multi-level investigation of the effect of area deprivation.

BACKGROUND: Geographical variation in the prevalence of common mental disorders has not been explained adequately. AIMS: To investigate whether regional mental health differences in Wales would persist after having taken into account the characteristics of individuals and regional social deprivation. METHOD: Data from the 1998 Welsh Health Survey were used. Common mental disorders were assessed with the mental health index included in the Short-Form 36 health survey (SF-36). The data were analysed using a multi-level linear regression model. RESULTS: Of the total variance in the mental health index, 1.47% occurred at regional level (95% CI 0.56-2.38). Adjustment for individual characteristics did not explain the between-region variation. A higher area deprivation score was associated with a higher score on the mental health index. CONCLUSIONS: Mental health differences in Wales are partly explained by the level of regional social deprivation.

Adolescent↗
PubMed2004

Overcoming the inhibitors of myelin with a novel neurotrophin strategy.

Myelin inhibitors activate a p75(NTR)-dependent signaling cascade in neurons that not only inhibits axonal growth but also prevents neurotrophins (NT) from stimulating growth. Most intriguingly, in addition to Trk receptors, neurotrophins also bind to p75(NTR). We have designed a "mini-neurotrophin" called B(AG) to activate TrkB in the absence of p75(NTR) binding. We find that B(AG) is as effective as the natural TrkB ligands (brain-derived neurotrophic factor (BDNF) and NT-4) at promoting neurite outgrowth from cerebellar neurons. Furthermore, the neurite outgrowth responses stimulated by BDNF and B(AG) are inhibited by a common set of reagents, including the Trk receptor inhibitor K252a, as well as protein kinase A and phosphoinositide 3-kinase inhibitors. However, in contrast to BDNF, B(AG) promotes growth in the presence of a myelin inhibitor or when antibodies directly activate the p75(NTR) inhibitory pathway. On the basis of this observation, we postulated that the binding of BDNF to the p75(NTR) might compromise the ability of BDNF to stimulate neurite outgrowth in an inhibitory environment. To test this, we used NGF, and an NGF-derived peptide, to compete for the BDNF/p75(NTR) interaction; remarkably, in the presence of either agent, BDNF acquired the ability to promote neurite outgrowth in the presence of a myelin inhibitor. The data suggest that in an inhibitory environment, the BDNF/p75(NTR) interaction compromises regeneration. Agents that activate Trk receptors in the absence of p75(NTR) binding, or agents that inhibit neurotrophin/p75(NTR) binding, might therefore be better therapeutic candidates than neurotrophins.

3T3 Cells↗
PubMed2004

Inter-residue distances derived from fold contact propensities correlate with evolutionary substitution costs.

BACKGROUND: The wealth of information on protein structure has led to a variety of statistical analyses of the role played by individual amino acid types in the protein fold. In particular, the contact propensities between the various amino acids can be converted into folding energies that have proved useful in structure prediction. The present study addresses the relationship of protein folding propensities to the evolutionary relationship between residues. RESULTS: The contact preferences of residue types observed in a representative sample of protein structures are converted into a residue similarity matrix or inter-residue distance matrix. Remarkably, these distances correlate excellently with evolutionary substitution costs. Residue vectors are derived from the distance matrix. The residue vectors give a concrete picture of the grouping of residues into families sharing properties crucial for protein folding. CONCLUSIONS: Inter-residue distances have proved useful in showing the explicit relationship between contact preferences and evolutionary substitution rates. It is proposed that the distance matrix derived from structural analysis may be useful in aligning proteins where remote homologs share structural features. Residue vectors derived from the distance matrix illustrate the spatial arrangement of residues and point to ways in which they can be grouped.

Amino Acid Substitution↗